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Skin Diseases Associated With COVID-19: A Narrative Review

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Skin Diseases Associated With COVID-19: A Narrative Review
Author(s)
Konstantinos-Antonios Kostopoulos-Kanitakis, MD
Jean Kanitakis, MD, PhD

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.3 As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.4

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.5 Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,6 an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,7,8 the COVIDSKIN registry of the French Dermatology Society,9 and the Italian registry.10 Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)5 and Japan (0.56%),11 compared with Europe (up to 20%).6 Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.12 They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Morbilliform maculopapular eruption. Histopathology shows mild dermal cell spongiosis and diffuse, predominantly perivascular, dermal-cell infiltration with lymphocytes and numerous eosinophils (hematoxylin-eosin-saffron, original magnification ×100).
FIGURE 1. Morbilliform maculopapular eruption. Histopathology shows mild dermal cell spongiosis and diffuse, predominantly perivascular, dermal-cell infiltration with lymphocytes and numerous eosinophils (hematoxylin-eosin-saffron, original magnification ×100).

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

 

 

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-1913 and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,19 which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.30

Chilblainlike lesions (so-called COVID toes) manifested with red-violaceous macules over the distal toes.
FIGURE 2. Chilblainlike lesions (so-called COVID toes) manifested with red-violaceous macules over the distal toes.

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Histopathology of chilblainlike lesions (so-called COVID toes) shows scattered epidermal keratinocyte necroses, severe edema of the papillary dermis, and dermal lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×100).
FIGURE 3. Histopathology of chilblainlike lesions (so-called COVID toes) shows scattered epidermal keratinocyte necroses, severe edema of the papillary dermis, and dermal lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×100).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Acro-ischemia livedoid lesions from an elderly patient with severe COVID-19 manifested histologically with epidermal necrosis, dermal capillary thromboses and necroses, red blood cell extravasation (purpura), and a moderately dense diffuse lymphocytic
FIGURE 4. Acro-ischemia livedoid lesions from an elderly patient with severe COVID-19 manifested histologically with epidermal necrosis, dermal capillary thromboses and necroses, red blood cell extravasation (purpura), and a moderately dense diffuse lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×200).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

Erythema multiforme–like eruption following COVID-19 infection manifesting histologically with epidermal keratinocyte necroses and dermoepidermal bullae (hematoxylin-eosin-saffron, original magnification ×200).
FIGURE 5. Erythema multiforme–like eruption following COVID-19 infection manifesting histologically with epidermal keratinocyte necroses and dermoepidermal bullae (hematoxylin-eosin-saffron, original magnification ×200).

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.33

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.34

 

 

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).35 Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance36; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.39 It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.40 Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.41 Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.42

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children43 and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).44 Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).45

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.46

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.47 This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,3 a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.48 In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals51; 54.4% of 879 health care professionals in one study reported such events.52 These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

 

 

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).53,54

Follicular papulopustular eruption (so-called maskne) distributed over the facial zones covered by a surgical mask.
FIGURE 6. Follicular papulopustular eruption (so-called maskne) distributed over the facial zones covered by a surgical mask.

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.55 Psoriasis and acrodermatitis continua of Hallopeau,56 which may progress into generalized, pustular, or erythrodermic forms,57 have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.57 Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.58 The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.59 Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,60 possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.61 Lupus erythematosus, which may relapse in the form of Rowell syndrome,62 and livedoid vasculopathy63 also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,4 an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.65 Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.70 Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.70
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.70

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.70

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.70

 

 

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.70

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.71

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.72

• Chilblainlike lesions: several such cases have been reported so far73; they constitute 0.03% of postvaccination reactions.70 Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.76

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).70

• Severe reactions: these include acute generalized exanthematous pustulosis77 and Stevens-Johnson syndrome.78 One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,79,80 leukocytoclastic vasculitis,81,82 lymphocytic83 or urticarial84 vasculitis, Sweet syndrome,85 lupus erythematosus, dermatomyositis,86,87 alopecia,37,88 infection with Trichophyton rubrum,89 Grover disease,90 and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30+], and de novo development of lymphomatoid papulosis).91

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.92 Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

References
  1. Ashraf UM, Abokor AA, Edwards JM, et al. SARS-CoV-2, ACE2 expression, and systemic organ invasion. Physiol Genomics. 2021;53:51-60.
  2. Ganier C, Harun N, Peplow I, et al. Angiotensin-converting enzyme 2 expression is detectable in keratinocytes, cutaneous appendages, and blood vessels by multiplex RNA in situ hybridization. Adv Skin Wound Care. 2022;35:219-223.
  3. Ulloa AC, Buchan SA, Daneman N, et al. Estimates of SARS-CoV-2 omicron variant severity in Ontario, Canada. JAMA. 2022;327:1286-1288.
  4. World Health Organization. Coronavirus (COVID-19) Dashboard. Accessed April 6, 2023. https://covid19.who.int
  5. Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert Group for COVID-19. clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-1720.
  6. Recalcati S. Cutaneous manifestations in COVID-9: a first perspective. J Eur Acad Dermatol Venereol. 2020;34:E212-E213.
  7. Freeman EE, McMahon DE, Lipoff JB, et al. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries. J Am Acad Dermatol. 2020;83:1118-1129.
  8. Freeman EE, Chamberlin GC, McMahon DE, et al. Dermatology COVID-19 registries: updates and future directions. Dermatol Clin. 2021;39:575-585.
  9. Guelimi R, Salle R, Dousset L, et al. Non-acral skin manifestations during the COVID-19 epidemic: COVIDSKIN study by the French Society of Dermatology. J Eur Acad Dermatol Venereol. 2021;35:E539-E541.
  10. Marzano AV, Genovese G, Moltrasio C, et al; Italian Skin COVID-19 Network of the Italian Society of Dermatology and Sexually Transmitted Diseases. The clinical spectrum of COVID-19 associated cutaneous manifestations: an Italian multicenter study of 200 adult patients. J Am Acad Dermatol. 2021;84:1356-1363.
  11. Sugai T, Fujita Y, Inamura E, et al. Prevalence and patterns of cutaneous manifestations in 1245 COVID-19 patients in Japan: a single-centre study. J Eur Acad Dermatol Venereol. 2022;36:E522-E524.
  12. Holmes Z, Courtney A, Lincoln M, et al. Rash morphology as a predictor of COVID‐19 severity: a systematic review of the cutaneous manifestations of COVID‐19. Skin Health Dis. 2022;2:E120. doi:10.1002/ski2.120
  13. Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020;183:71-77.
  14. Garduño‑Soto M, Choreño-Parra JA, Cazarin-Barrientos J. Dermatological aspects of SARS‑CoV‑2 infection: mechanisms and manifestations. Arch Dermatol Res. 2021;313:611-622.
  15. Huynh T, Sanchez-Flores X, Yau J, et al. Cutaneous manifestations of SARS-CoV-2 Infection. Am J Clin Dermatol. 2022;23:277-286.
  16. Kanitakis J, Lesort C, Danset M, et al. Chilblain-like acral lesions during the COVID-19 pandemic (“COVID toes”): histologic, immunofluorescence, and immunohistochemical study of 17 cases. J Am Acad Dermatol. 2020;83:870-875.
  17. Kolivras A, Thompson C, Pastushenko I, et al. A clinicopathological description of COVID-19-induced chilblains (COVID-toes) correlated with a published literature review. J Cutan Pathol. 2022;49:17-28.
  18. Roca-Ginés J, Torres-Navarro I, Sánchez-Arráez J, et al. Assessment of acute acral lesions in a case series of children and adolescents during the COVID-19 pandemic. JAMA Dermatol. 2020;156:992-997.
  19. Le Cleach L, Dousset L, Assier H, et al; French Society of Dermatology. Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing. Br J Dermatol. 2020;183:866-874.
  20. Discepolo V, Catzola A, Pierri L, et al. Bilateral chilblain-like lesions of the toes characterized by microvascular remodeling in adolescents during the COVID-19 pandemic. JAMA Netw Open. 2021;4:E2111369.
  21. Gehlhausen JR, Little AJ, Ko CJ, et al. Lack of association between pandemic chilblains and SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2022;119:e2122090119.
  22. Neri I, Virdi A, Corsini I, et al. Major cluster of paediatric ‘true’ primary chilblains during the COVID-19 pandemic: a consequence of lifestyle changes due to lockdown. J Eur Acad Dermatol Venereol. 2020;34:2630-2635.
  23. De Greef A, Choteau M, Herman A, et al. Chilblains observed during the COVID-19 pandemic cannot be distinguished from the classic, cold-related chilblains. Eur J Dermatol. 2022;32:377-383.
  24. Colmenero I, Santonja C, Alonso-Riaño M, et al. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol. 2020;183:729-737.
  25. Quintero-Bustos G, Aguilar-Leon D, Saeb-Lima M. Histopathological and immunohistochemical characterization of skin biopsies from 41 SARS-CoV-2 (+) patients: experience in a Mexican concentration institute: a case series and literature review. Am J Dermatopathol. 2022;44:327-337.
  26. Arkin LM, Moon JJ, Tran JM, et al; COVID Human Genetic Effort. From your nose to your toes: a review of severe acute respiratory syndrome coronavirus 2 pandemic-associated pernio. J Invest Dermatol. 2021;141:2791-2796.
  27. Frumholtz L, Bouaziz JD, Battistella M, et al; Saint-Louis CORE (COvid REsearch). Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak. Br J Dermatol. 2021;185:1176-1185.
  28. Hubiche T, Cardot-Leccia N, Le Duff F, et al. Clinical, laboratory, and interferon-alpha response characteristics of patients with chilblain-like lesions during the COVID-19 pandemic. JAMA Dermatol. 2021;157:202-206.
  29. Lesort C, Kanitakis J, Villani A, et al. COVID-19 and outbreak of chilblains: are they related? J Eur Acad Dermatol Venereol. 2020;34:E757-E758.
  30. Sanchez A, Sohier P, Benghanem S, et al. Digitate papulosquamous eruption associated with severe acute respiratory syndrome coronavirus 2 infection. JAMA Dermatol. 2020;156:819-820.
  31. Drago F, Broccolo F, Ciccarese G. Pityriasis rosea, pityriasis rosea-like eruptions, and herpes zoster in the setting of COVID-19 and COVID-19 vaccination. Clin Dermatol. 2022;S0738-081X(22)00002-5.
  32. Dursun R, Temiz SA. The clinics of HHV-6 infection in COVID-19 pandemic: pityriasis rosea and Kawasaki disease. Dermatol Ther. 2020;33:E13730.
  33. Nuno-Gonzalez A, Magaletsky K, Feito Rodríguez M, et al. Palmoplantar erythrodysesthesia: a diagnostic sign of COVID-19. J Eur Acad Dermatol Venereol. 2021;35:e247-e249.
  34. Sil A, Panigrahi A, Chandra A, et al. “COVID nose”: a unique post-COVID pigmentary sequelae reminiscing Chik sign: a descriptive case series. J Eur Acad Dermatol Venereol. 2022;36:E419-E421.
  35. Starace M, Iorizzo M, Sechi A, et al. Trichodynia and telogen effluvium in COVID-19 patients: results of an international expert opinion survey on diagnosis and management. JAAD Int. 2021;5:11-18.
  36. Wong-Chew RM, Rodríguez Cabrera EX, Rodríguez Valdez CA, et al. Symptom cluster analysis of long COVID-19 in patients discharged from the Temporary COVID-19 Hospital in Mexico City. Ther Adv Infect Dis. 2022;9:20499361211069264.
  37. Bardazzi F, Guglielmo A, Abbenante D, et al. New insights into alopecia areata during COVID-19 pandemic: when infection or vaccination could play a role. J Cosmet Dermatol. 2022;21:1796-1798.
  38. Christensen RE, Jafferany M. Association between alopecia areata and COVID-19: a systematic review. JAAD Int. 2022;7:57-61.
  39. Wollina U, Kanitakis J, Baran R. Nails and COVID-19: a comprehensive review of clinical findings and treatment. Dermatol Ther. 2021;34:E15100.
  40. Méndez-Flores S, Zaladonis A, Valdes-Rodriguez R. COVID-19 and nail manifestation: be on the lookout for the red half-moon nail sign. Int J Dermatol. 2020;59:1414.
  41. Alobaida S, Lam JM. Beau lines associated with COVID-19. CMAJ. 2020;192:E1040.
  42. Durmaz EÖ, Demirciog˘lu D. Fluorescence in the sclera, nails, and teeth secondary to favipiravir use for COVID-19 infections. J Clin Aesthet Dermatol. 2022;15:35-37.
  43. Brumfiel CM, DiLorenzo AM, Petronic-Rosic VM. Dermatologic manifestations of COVID-19-associated multisystem inflammatory syndrome in children. Clin Dermatol. 2021;39:329-333.
  44. Akçay N, Topkarcı Z, Menentog˘lu ME, et al. New dermatological findings of MIS-C: can mucocutaneous involvement be associated with severe disease course? Australas J Dermatol. 2022;63:228-234. doi:10.1111/ajd.13819
  45. Vogel TP, Top KA, Karatzios C, et al. Multisystem inflammatory syndrome in children and adults (MIS-C/A): case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2021;39:3037-3049.
  46. Conforti C, Dianzani C, Agozzino M, et al. Cutaneous manifestations in confirmed COVID-19 patients: a systematic review. Biology (Basel). 2020;9:449.
  47. Hubiche T, Le Duff F, Fontas E, et al. Relapse of chilblain-like lesions during the second wave of the COVID-19 pandemic: a cohort follow-up. Br J Dermatol. 2021;185:858-859.
  48. Fernandez-Nieto D, Ortega-Quijano D, Suarez-Valle A, et al. Lack of skin manifestations in COVID-19 hospitalized patients during the second epidemic wave in Spain: a possible association with a novel SARS-CoV-2 variant: a cross-sectional study. J Eur Acad Dermatol Venereol. 2021;35:E183-E185.
  49. Martinez-Lopez A, Cuenca-Barrales C, Montero-Vilchez T, et al. Review of adverse cutaneous reactions of pharmacologic interventions for COVID-19: a guide for the dermatologist. J Am Acad Dermatol. 2020;83:1738-1748.
  50. Türsen Ü, Türsen B, Lotti T. Cutaneous side-effects of the potential COVID-19 drugs. Dermatol Ther. 2020;33:E13476.
  51. Mawhirt SL, Frankel D, Diaz AM. Cutaneous manifestations in adult patients with COVID-19 and dermatologic conditions related to the COVID-19 pandemic in health care workers. Curr Allerg Asthma Rep. 2020;20:75.
  52. Nguyen C, Young FG, McElroy D, et al. Personal protective equipment and adverse dermatological reactions among healthcare workers: survey observations from the COVID-19 pandemic. Medicine (Baltimore). 2022;101:E29003.
  53. Rathi SK, Dsouza JM. Maskne: a new acne variant in COVID-19 era. Indian J Dermatol. 2022;67:552-555.
  54. Damiani G, Girono L, Grada A, et al. COVID-19 related masks increase severity of both acne (maskne) and rosacea (mask rosacea): multi-center, real-life, telemedical, and observational prospective study. Dermatol Ther. 2021;34:E14848.
  55. Aram K, Patil A, Goldust M, et al. COVID-19 and exacerbation of dermatological diseases: a review of the available literature. Dermatol Ther. 2021;34:E15113.
  56. Samotij D, Gawron E, Szcze˛ch J, et al. Acrodermatitis continua of Hallopeau evolving into generalized pustular psoriasis following COVID-19: a case report of a successful treatment with infliximab in combination with acitretin. Biologics. 2021;15:107-113.
  57. Demiri J, Abdo M, Tsianakas A. Erythrodermic psoriasis after COVID-19 [in German]. Hautarzt. 2022;73:156-159.
  58. de Wijs LEM, Joustra MM, Olydam JI, et al. COVID-19 in patients with cutaneous immune-mediated diseases in the Netherlands: real-world observational data. J Eur Acad Dermatol Venereol. 2021;35:E173-E176.
  59. Marques NP, Maia CMF, Marques NCT, et al. Continuous increase of herpes zoster cases in Brazil during the COVID-19 pandemic. Oral Surg Oral Med Oral Pathol Oral Radiol. 2022;133:612-614.
  60. Rinaldi F, Trink A, Giuliani G, et al. Italian survey for the evaluation of the effects of coronavirus disease 2019 (COVID-19) pandemic on alopecia areata recurrence. Dermatol Ther (Heidelb). 2021;11:339-345.
  61. Rudnicka L, Rakowska A, Waskiel-Burnat A, et al. Mild-to-moderate COVID-19 is not associated with worsening of alopecia areata: a retrospective analysis of 32 patients. J Am Acad Dermatol. 2021;85:723-725.
  62. Drenovska K, Shahid M, Mateeva V, et al. Case report: Rowell syndrome-like flare of cutaneous lupus erythematosus following COVID-19 infection. Front Med (Lausanne). 2022;9:815743.
  63. Kawabe R, Tonomura K, Kotobuki Y, et al. Exacerbation of livedoid vasculopathy after coronavirus disease 2019. Eur J Dermatol. 2022;32:129-131. doi:10.1684/ejd.2022.4200
  64. McMahon DE, Kovarik CL, Damsky W, et al. Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: a registry-based study. J Am Acad Dermatol. 2022;86:113-121.
  65. Avallone G, Quaglino P, Cavallo F, et al. SARS-CoV-2 vaccine-related cutaneous manifestations: a systematic review. Int J Dermatol. 2022;61:1187-1204. doi:10.1111/ijd.16063
  66. Gambichler T, Boms S, Susok L, et al. Cutaneous findings following COVID-19 vaccination: review of world literature and own experience. J Eur Acad Dermatol Venereol. 2022;36:172-180.
  67. Kroumpouzos G, Paroikaki ME, Yumeen S, et al. Cutaneous complications of mRNA and AZD1222 COVID-19 vaccines: a worldwide review. Microorganisms. 2022;10:624.
  68. Robinson L, Fu X, Hashimoto D, et al. Incidence of cutaneous reactions after messenger RNA COVID-19 vaccines. JAMA Dermatol. 2021;157:1000-1002.
  69. Wollina U, Chiriac A, Kocic H, et al. Cutaneous and hypersensitivity reactions associated with COVID-19 vaccination: a narrative review. Wien Med Wochenschr. 2022;172:63-69.
  70. Wei TS. Cutaneous reactions to COVID-19 vaccines: a review. JAAD Int. 2022;7:178-186.
  71. Katsikas Triantafyllidis K, Giannos P, Mian IT, et al. Varicella zoster virus reactivation following COVID-19 vaccination: a systematic review of case reports. Vaccines (Basel). 2021;9:1013.
  72. Maronese CA, Caproni M, Moltrasio C, et al. Bullous pemphigoid associated with COVID-19 vaccines: an Italian multicentre study. Front Med (Lausanne). 2022;9:841506.
  73. Cavazos A, Deb A, Sharma U, et al. COVID toes following vaccination. Proc (Bayl Univ Med Cent). 2022;35:476-479.
  74. Lesort C, Kanitakis J, Danset M, et al. Chilblain-like lesions after BNT162b2 mRNA COVID-19 vaccine: a case report suggesting that ‘COVID toes’ are due to the immune reaction to SARS-CoV-2. J Eur Acad Dermatol Venereol. 2021;35:E630-E632.
  75. Russo R, Cozzani E, Micalizzi C, et al. Chilblain-like lesions after COVID-19 vaccination: a case series. Acta Derm Venereol. 2022;102:adv00711. doi:10.2340/actadv.v102.2076
  76. Ortigosa LCM, Lenzoni FC, Suárez MV, et al. Hypersensitivity reaction to hyaluronic acid dermal filler after COVID-19 vaccination: a series of cases in São Paulo, Brazil. Int J Infect Dis. 2022;116:268-270.
  77. Agaronov A, Makdesi C, Hall CS. Acute generalized exanthematous pustulosis induced by Moderna COVID-19 messenger RNA vaccine. JAAD Case Rep. 2021;16:96-97.
  78. Dash S, Sirka CS, Mishra S, et al. COVID-19 vaccine-induced Stevens-Johnson syndrome. Clin Exp Dermatol. 2021;46:1615-1617.
  79. Huang Y, Tsai TF. Exacerbation of psoriasis following COVID-19 vaccination: report from a single center. Front Med (Lausanne). 2021;8:812010.
  80. Elamin S, Hinds F, Tolland J. De novo generalized pustular psoriasis following Oxford-AstraZeneca COVID-19 vaccine. Clin Exp Dermatol 2022;47:153-155.
  81. Abdelmaksoud A, Wollina U, Temiz SA, et al. SARS-CoV-2 vaccination-induced cutaneous vasculitis: report of two new cases and literature review. Dermatol Ther. 2022;35:E15458.
  82. Fritzen M, Funchal GDG, Luiz MO, et al. Leukocytoclastic vasculitis after exposure to COVID-19 vaccine. An Bras Dermatol. 2022;97:118-121.
  83. Vassallo C, Boveri E, Brazzelli V, et al. Cutaneous lymphocytic vasculitis after administration of COVID-19 mRNA vaccine. Dermatol Ther. 2021;34:E15076.
  84. Nazzaro G, Maronese CA. Urticarial vasculitis following mRNA anti-COVID-19 vaccine. Dermatol Ther. 2022;35:E15282.
  85. Hoshina D, Orita A. Sweet syndrome after severe acute respiratory syndrome coronavirus 2 mRNA vaccine: a case report and literature review. J Dermatol. 2022;49:E175-E176.
  86. Lemoine C, Padilla C, Krampe N, et al. Systemic lupus erythematous after Pfizer COVID-19 vaccine: a case report. Clin Rheumatol. 2022;41:1597-1601.
  87. Nguyen B, Lalama MJ, Gamret AC, et al. Cutaneous symptoms of connective tissue diseases after COVID-19 vaccination: a systematic review. Int J Dermatol. 2022;61:E238-E241.
  88. Gallo G, Mastorino L, Tonella L, et al. Alopecia areata after COVID-19 vaccination. Clin Exp Vaccine Res. 2022;11:129-132.
  89. Norimatsu Y, Norimatsu Y. A severe case of Trichophyton rubrum-caused dermatomycosis exacerbated after COVID-19 vaccination that had to be differentiated from pustular psoriasis. Med Mycol Case Rep. 2022;36:19-22.
  90. Yang K, Prussick L, Hartman R, et al. Acantholytic dyskeratosis post-COVID vaccination. Am J Dermatopathol. 2022;44:E61-E63.
  91. Koumaki D, Marinos L, Nikolaou V, et al. Lymphomatoid papulosis (LyP) after AZD1222 and BNT162b2 COVID-19 vaccines. Int J Dermatol. 2022;61:900-902.
  92. World Health Organization. Statement on the fourteenth meeting of the International Health Regulations (2005) Emergency Committee regarding the coronavirus disease (COVID-19) pandemic. Published January 30, 2023. Accessed April 12, 2023. https://www.who.int/news/item/30-01-2023-statement-on-the-fourteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic
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The authors report no conflict of interest.

Correspondence: Jean Kanitakis, MD, PhD, Department of Dermatology, Edouard Herriot Hospital, 69437 Lyon cx 03, France (jean.kanitakis@univ-lyon1.fr).

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Jean Kanitakis, MD, PhD
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Dr. Kostopoulos-Kanitakis is from the School of Medicine, European University of Cyprus, Nicosia. Dr. Kanitakis is from the Department of Dermatology, Edouard Herriot Hospital, Lyon, France.

The authors report no conflict of interest.

Correspondence: Jean Kanitakis, MD, PhD, Department of Dermatology, Edouard Herriot Hospital, 69437 Lyon cx 03, France (jean.kanitakis@univ-lyon1.fr).

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The authors report no conflict of interest.

Correspondence: Jean Kanitakis, MD, PhD, Department of Dermatology, Edouard Herriot Hospital, 69437 Lyon cx 03, France (jean.kanitakis@univ-lyon1.fr).

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CT111004019_e.pdf
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COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.3 As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.4

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.5 Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,6 an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,7,8 the COVIDSKIN registry of the French Dermatology Society,9 and the Italian registry.10 Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)5 and Japan (0.56%),11 compared with Europe (up to 20%).6 Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.12 They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Morbilliform maculopapular eruption. Histopathology shows mild dermal cell spongiosis and diffuse, predominantly perivascular, dermal-cell infiltration with lymphocytes and numerous eosinophils (hematoxylin-eosin-saffron, original magnification ×100).
FIGURE 1. Morbilliform maculopapular eruption. Histopathology shows mild dermal cell spongiosis and diffuse, predominantly perivascular, dermal-cell infiltration with lymphocytes and numerous eosinophils (hematoxylin-eosin-saffron, original magnification ×100).

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

 

 

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-1913 and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,19 which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.30

Chilblainlike lesions (so-called COVID toes) manifested with red-violaceous macules over the distal toes.
FIGURE 2. Chilblainlike lesions (so-called COVID toes) manifested with red-violaceous macules over the distal toes.

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Histopathology of chilblainlike lesions (so-called COVID toes) shows scattered epidermal keratinocyte necroses, severe edema of the papillary dermis, and dermal lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×100).
FIGURE 3. Histopathology of chilblainlike lesions (so-called COVID toes) shows scattered epidermal keratinocyte necroses, severe edema of the papillary dermis, and dermal lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×100).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Acro-ischemia livedoid lesions from an elderly patient with severe COVID-19 manifested histologically with epidermal necrosis, dermal capillary thromboses and necroses, red blood cell extravasation (purpura), and a moderately dense diffuse lymphocytic
FIGURE 4. Acro-ischemia livedoid lesions from an elderly patient with severe COVID-19 manifested histologically with epidermal necrosis, dermal capillary thromboses and necroses, red blood cell extravasation (purpura), and a moderately dense diffuse lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×200).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

Erythema multiforme–like eruption following COVID-19 infection manifesting histologically with epidermal keratinocyte necroses and dermoepidermal bullae (hematoxylin-eosin-saffron, original magnification ×200).
FIGURE 5. Erythema multiforme–like eruption following COVID-19 infection manifesting histologically with epidermal keratinocyte necroses and dermoepidermal bullae (hematoxylin-eosin-saffron, original magnification ×200).

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.33

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.34

 

 

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).35 Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance36; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.39 It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.40 Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.41 Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.42

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children43 and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).44 Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).45

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.46

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.47 This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,3 a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.48 In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals51; 54.4% of 879 health care professionals in one study reported such events.52 These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

 

 

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).53,54

Follicular papulopustular eruption (so-called maskne) distributed over the facial zones covered by a surgical mask.
FIGURE 6. Follicular papulopustular eruption (so-called maskne) distributed over the facial zones covered by a surgical mask.

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.55 Psoriasis and acrodermatitis continua of Hallopeau,56 which may progress into generalized, pustular, or erythrodermic forms,57 have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.57 Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.58 The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.59 Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,60 possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.61 Lupus erythematosus, which may relapse in the form of Rowell syndrome,62 and livedoid vasculopathy63 also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,4 an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.65 Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.70 Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.70
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.70

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.70

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.70

 

 

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.70

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.71

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.72

• Chilblainlike lesions: several such cases have been reported so far73; they constitute 0.03% of postvaccination reactions.70 Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.76

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).70

• Severe reactions: these include acute generalized exanthematous pustulosis77 and Stevens-Johnson syndrome.78 One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,79,80 leukocytoclastic vasculitis,81,82 lymphocytic83 or urticarial84 vasculitis, Sweet syndrome,85 lupus erythematosus, dermatomyositis,86,87 alopecia,37,88 infection with Trichophyton rubrum,89 Grover disease,90 and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30+], and de novo development of lymphomatoid papulosis).91

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.92 Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

COVID-19 is a potentially severe systemic disease caused by SARS-CoV-2. SARS-CoV and Middle East respiratory syndrome (MERS-CoV) caused fatal epidemics in Asia in 2002 to 2003 and in the Arabian Peninsula in 2012, respectively. In 2019, SARS-CoV-2 was detected in patients with severe, sometimes fatal pneumonia of previously unknown origin; it rapidly spread around the world, and the World Health Organization declared the disease a pandemic on March 11, 2020. SARS-CoV-2 is a β-coronavirus that is genetically related to the bat coronavirus and SARS-CoV; it is a single-stranded RNA virus of which several variants and subvariants exist. The SARS-CoV-2 viral particles bind via their surface spike protein (S protein) to the angiotensin-converting enzyme 2 receptor present on the membrane of several cell types, including epidermal and adnexal keratinocytes.1,2 The α and δ variants, predominant from 2020 to 2021, mainly affected the lower respiratory tract and caused severe, potentially fatal pneumonia, especially in patients older than 65 years and/or with comorbidities, such as obesity, hypertension, diabetes, and (iatrogenic) immunosuppression. The ο variant, which appeared in late 2021, is more contagious than the initial variants, but it causes a less severe disease preferentially affecting the upper respiratory airways.3 As of April 5, 2023, more than 762,000,000 confirmed cases of COVID-19 have been recorded worldwide, causing more than 6,800,000 deaths.4

Early studies from China describing the symptoms of COVID-19 reported a low frequency of skin manifestations (0.2%), probably because they were focused on the most severe disease symptoms.5 Subsequently, when COVID-19 spread to the rest of the world, an increasing number of skin manifestations were reported in association with the disease. After the first publication from northern Italy in spring 2020, which was specifically devoted to skin manifestations of COVID-19,6 an explosive number of publications reported a large number of skin manifestations, and national registries were established in several countries to record these manifestations, such as the American Academy of Dermatology and the International League of Dermatological Societies registry,7,8 the COVIDSKIN registry of the French Dermatology Society,9 and the Italian registry.10 Highlighting the unprecedented number of scientific articles published on this new disease, a PubMed search of articles indexed for MEDLINE search using the terms SARS-CoV-2 or COVID-19, on April 6, 2023, revealed 351,596 articles; that is more than 300 articles published every day in this database alone, with a large number of them concerning the skin.

SKIN DISEASSES ASSOCIATED WITH COVID-19

There are several types of COVID-19–related skin manifestations, depending on the circumstances of onset and the evolution of the pandemic.

Skin Manifestations Associated With SARS-CoV-2 Infection

The estimated incidence varies greatly according to the published series of patients, possibly depending on the geographic location. The estimated incidence seems lower in Asian countries, such as China (0.2%)5 and Japan (0.56%),11 compared with Europe (up to 20%).6 Skin manifestations associated with SARS-CoV-2 infection affect individuals of all ages, slightly more females, and are clinically polymorphous; some of them are associated with the severity of the infection.12 They may precede, accompany, or appear after the symptoms of COVID-19, most often within a month of the infection, of which they rarely are the only manifestation; however, their precise relationship to SARS-CoV-2 is not always well known. They have been classified according to their clinical presentation into several forms.13-15

Morbilliform Maculopapular Eruption—Representing 16% to 53% of skin manifestations, morbilliform and maculopapular eruptions usually appear within 15 days of infection; they manifest with more or less confluent erythematous macules that may be hemorrhagic/petechial, and usually are asymptomatic and rarely pruritic. The rash mainly affects the trunk and limbs, sparing the face, palmoplantar regions, and mucous membranes; it appears concomitantly with or a few days after the first symptoms of COVID-19 (eg, fever, respiratory symptoms), regresses within a few days, and does not appear to be associated with disease severity. The distinction from maculopapular drug eruptions may be subtle. Histologically, the rash manifests with a spongiform dermatitis (ie, variable parakeratosis; spongiosis; and a mixed dermal perivascular infiltrate of lymphocytes, eosinophils and histiocytes, depending on the lesion age)(Figure 1). The etiopathogenesis is unknown; it may involve immune complexes to SARS-CoV-2 deposited on skin vessels. Treatment is not mandatory; if necessary, local or systemic corticosteroids may be used.

Morbilliform maculopapular eruption. Histopathology shows mild dermal cell spongiosis and diffuse, predominantly perivascular, dermal-cell infiltration with lymphocytes and numerous eosinophils (hematoxylin-eosin-saffron, original magnification ×100).
FIGURE 1. Morbilliform maculopapular eruption. Histopathology shows mild dermal cell spongiosis and diffuse, predominantly perivascular, dermal-cell infiltration with lymphocytes and numerous eosinophils (hematoxylin-eosin-saffron, original magnification ×100).

Vesicular (Pseudovaricella) Rash—This rash accounts for 11% to 18% of all skin manifestations and usually appears within 15 days of COVID-19 onset. It manifests with small monomorphous or varicellalike (pseudopolymorphic) vesicles appearing on the trunk, usually in young patients. The vesicles may be herpetiform, hemorrhagic, or pruritic, and appear before or within 3 days of the onset of mild COVID-19 symptoms; they regress within a few days without scarring. Histologically, the lesions show basal cell vacuolization; multinucleated, dyskeratotic/apoptotic or ballooning/acantholytic epidermal keratinocytes; reticular degeneration of the epidermis; intraepidermal vesicles sometimes resembling herpetic vesicular infections or Grover disease; and mild dermal inflammation. There is no specific treatment.

Urticaria—Urticarial rash, or urticaria, represents 5% to 16% of skin manifestations; usually appears within 15 days of disease onset; and manifests with pruritic, migratory, edematous papules appearing mainly on the trunk and occasionally the face and limbs. The urticarial rash tends to be associated with more severe forms of the disease and regresses within a week, responding to antihistamines. Of note, clinically similar rashes can be caused by drugs. Histologically, the lesions show dermal edema and a mild perivascular lymphocytic infiltrate, sometimes admixed with eosinophils.

 

 

Chilblainlike Lesions—Chilblainlike lesions (CBLLs) account for 19% of skin manifestations associated with COVID-1913 and present as erythematous-purplish, edematous lesions that can be mildly pruritic or painful, appearing on the toes—COVID toes—and more rarely the fingers (Figure 2). They were seen epidemically during the first pandemic wave (2020 lockdown) in several countries, and clinically are very similar to, if not indistinguishable from, idiopathic chilblains, but are not necessarily associated with cold exposure. They appear in young, generally healthy patients or those with mild COVID-19 symptoms 2 to 4 weeks after symptom onset. They regress spontaneously or under local corticosteroid treatment within a few days or weeks. Histologically, CBLLs are indistinguishable from chilblains of other origins, namely idiopathic (seasonal) ones. They manifest with necrosis of epidermal keratinocytes; dermal edema that may be severe, leading to the development of subepidermal pseudobullae; a rather dense perivascular and perieccrine gland lymphocytic infiltrate; and sometimes with vascular lesions (eg, edema of endothelial cells, microthromboses of dermal capillaries and venules, fibrinoid deposits within the wall of dermal venules)(Figure 3).16-18 Most patients (>80%) with CBLLs have negative serologic or polymerase chain reaction tests for SARS-CoV-2,19 which generated a lively debate about the role of SARS-CoV-2 in the genesis of CBLLs. According to some authors, SARS-CoV-2 plays no direct role, and CBLLs would occur in young people who sit or walk barefoot on cold floors at home during confinement.20-23 Remarkably, CBLLs appeared in patients with no history of chilblains during a season that was not particularly cold, namely in France or in southern California, where their incidence was much higher compared to the same time period of prior years. Some reports have supported a direct role for the virus based on questionable observations of the virus within skin lesions (eg, sweat glands, endothelial cells) by immunohistochemistry, electron microscopy, and/or in situ hybridization.17,24,25 A more satisfactory hypothesis would involve the role of a strong innate immunity leading to elimination of the virus before the development of specific antibodies via the increased production of type 1 interferon (IFN-1); this would affect the vessels, causing CBLLs. This mechanism would be similar to the one observed in some interferonopathies (eg, Aicardi-Goutières syndrome), also characterized by IFN-1 hypersecretion and chilblains.26-29 According to this hypothesis, CBLLs should be considered a paraviral rash similar to other skin manifestations associated with COVID-19.30

Chilblainlike lesions (so-called COVID toes) manifested with red-violaceous macules over the distal toes.
FIGURE 2. Chilblainlike lesions (so-called COVID toes) manifested with red-violaceous macules over the distal toes.

Acro-ischemia—Acro-ischemia livedoid lesions account for 1% to 6% of skin manifestations and comprise lesions of livedo (either reticulated or racemosa); necrotic acral bullae; and gangrenous necrosis of the extremities, especially the toes. The livedoid lesions most often appear within 15 days of COVID-19 symptom onset, and the purpuric lesions somewhat later (2–4 weeks); they mainly affect adult patients, last about 10 days, and are the hallmark of severe infection, presumably related to microthromboses of the cutaneous capillaries (endothelial dysfunction, prothrombotic state, elevated D-dimers). Histologically, they show capillary thrombosis and dermoepidermal necrosis (Figure 4).

Histopathology of chilblainlike lesions (so-called COVID toes) shows scattered epidermal keratinocyte necroses, severe edema of the papillary dermis, and dermal lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×100).
FIGURE 3. Histopathology of chilblainlike lesions (so-called COVID toes) shows scattered epidermal keratinocyte necroses, severe edema of the papillary dermis, and dermal lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×100).

Other Reported Polymorphic or Atypical Rashes—Erythema multiforme–like eruptions may appear before other COVID-19 symptoms and manifest as reddish-purple, nearly symmetric, diffuse, occasionally targetoid bullous or necrotic macules. The eruptions mainly affect adults and most often are seen on the palms, elbows, knees, and sometimes the mucous membranes. The rash regresses in 1 to 3 weeks without scarring and represents a delayed cutaneous hypersensitivity reaction. Histologically, the lesions show vacuolization of basal epidermal keratinocytes, keratinocyte necrosis, dermoepidermal detachment, a variably dense dermal T-lymphocytic infiltrate, and red blood cell extravasation (Figure 5).

Acro-ischemia livedoid lesions from an elderly patient with severe COVID-19 manifested histologically with epidermal necrosis, dermal capillary thromboses and necroses, red blood cell extravasation (purpura), and a moderately dense diffuse lymphocytic
FIGURE 4. Acro-ischemia livedoid lesions from an elderly patient with severe COVID-19 manifested histologically with epidermal necrosis, dermal capillary thromboses and necroses, red blood cell extravasation (purpura), and a moderately dense diffuse lymphocytic infiltration (hematoxylin-eosin-saffron, original magnification ×200).

Leukocytoclastic vasculitis may be generalized or localized. It manifests clinically by petechial/purpuric maculopapules, especially on the legs, mainly in elderly patients with COVID-19. Histologically, the lesions show necrotizing changes of dermal postcapillary venules, neutrophilic perivascular inflammation, red blood cell extravasation, and occasionally vascular IgA deposits by direct immunofluorescence examination. The course usually is benign.

Erythema multiforme–like eruption following COVID-19 infection manifesting histologically with epidermal keratinocyte necroses and dermoepidermal bullae (hematoxylin-eosin-saffron, original magnification ×200).
FIGURE 5. Erythema multiforme–like eruption following COVID-19 infection manifesting histologically with epidermal keratinocyte necroses and dermoepidermal bullae (hematoxylin-eosin-saffron, original magnification ×200).

The incidence of pityriasis rosea and of clinically similar rashes (referred to as “pityriasis rosea–like”) increased 5-fold during the COVID-19 pandemic.31,32 These dermatoses manifest with erythematous, scaly, circinate plaques, typically with an initial herald lesion followed a few days later by smaller erythematous macules. Histologically, the lesions comprise a spongiform dermatitis with intraepidermal exocytosis of red blood cells and a mild to moderate dermal lymphocytic infiltrate.

Erythrodysesthesia, or hand-foot syndrome, manifests with edematous erythema and palmoplantar desquamation accompanied by a burning sensation or pain. This syndrome is known as an adverse effect of some chemotherapies because of the associated drug toxicity and sweat gland inflammation; it was observed in 40% of 666 COVID-19–positive patients with mild to moderate pneumonitis.33

“COVID nose” is a rare cutaneous manifestation characterized by nasal pigmentation comprising multiple coalescent frecklelike macules on the tip and wings of the nose and sometimes the malar areas. These lesions predominantly appear in women aged 25 to 65 years and show on average 23 days after onset of COVID-19, which is usually mild. This pigmentation is similar to pigmentary changes after infection with chikungunya; it can be treated with depigmenting products such as azelaic acid and hydroquinone cream with sunscreen use, and it regresses in 2 to 4 months.34

 

 

Telogen effluvium (excessive and temporary shedding of normal telogen club hairs of the entire scalp due to the disturbance of the hair cycle) is reportedly frequent in patients (48%) 1 month after COVID-19 infection, but it may appear later (after 12 weeks).35 Alopecia also is frequently reported during long (or postacute) COVID-19 (ie, the symptomatic disease phase past the acute 4 weeks’ stage of the infection) and shows a female predominance36; it likely represents the telogen effluvium seen 90 days after a severe illness. Trichodynia (pruritus, burning, pain, or paresthesia of the scalp) also is reportedly common (developing in more than 58% of patients) and is associated with telogen effluvium in 44% of cases. Several cases of alopecia areata (AA) triggered or aggravated by COVID-19 also have been reported37,38; they could be explained by the “cytokine storm” triggered by the infection, involving T and B lymphocytes; plasmacytoid dendritic cells; natural killer cells with oversecretion of IL-6, IL-4, tumor necrosis factor α, and IFN type I; and a cytotoxic reaction associated with loss of the immune privilege of hair follicles.

Nail Manifestations

The red half-moon nail sign is an asymptomatic purplish-red band around the distal margin of the lunula that affects some adult patients with COVID-19.39 It appears shortly after onset of symptoms, likely the manifestation of vascular inflammation in the nail bed, and regresses slowly after approximately 1 week.40 Beau lines are transverse grooves in the nail plate due to the temporary arrest of the proximal nail matrix growth accompanying systemic illnesses; they appear approximately 2 to 3 weeks after the onset of COVID-19.41 Furthermore, nail alterations can be caused by drugs used to treat COVID-19, such as longitudinal melanonychia due to treatment with hydroxychloroquine or fluorescence of the lunula or nail plate due to treatment with favipiravir.42

Multisystem Inflammatory Syndrome

Multisystem inflammatory syndrome (MIS) is clinically similar to Kawasaki disease; it typically affects children43 and more rarely adults with COVID-19. It manifests with fever, weakness, and biological inflammation and also frequently with skin lesions (72%), which are polymorphous and include morbilliform rash (27%); urticaria (24%); periorbital edema (24%); nonspecific erythema (21.2%); retiform purpura (18%); targetoid lesions (15%); malar rash (15.2%); and periareolar erythema (6%).44 Compared to Kawasaki disease, MIS affects slightly older children (mean age, 8.5 vs 3 years) and more frequently includes cardiac and gastrointestinal manifestations; the mortality rate also is slightly higher (2% vs 0.17%).45

Confirmed COVID-19 Infection

At the beginning of the pandemic, skin manifestations were reported in patients who were suspected of having COVID-19 but did not always have biological confirmation of SARS-CoV-2 infection due to the unavailability of diagnostic tests or the physical impossibility of testing. However, subsequent studies have confirmed that most of these dermatoses were indeed associated with COVID-19 infection.9,46 For example, a study of 655 patients with confirmed COVID-19 infection reported maculopapular (38%), vascular (22%), urticarial (15%), and vesicular (15%) rashes; erythema multiforme or Stevens-Johnson–like syndrome (3%, often related to the use of hydroxychloroquine); generalized pruritus (1%); and MIS (0.5%). The study confirmed that CBLLs were mostly seen in young patients with mild disease, whereas livedo (fixed rash) and retiform purpura occurred in older patients with a guarded prognosis.46

Remarkably, most dermatoses associated with SARS-CoV-2 infection were reported during the initial waves of the pandemic, which were due to the α and δ viral variants. These manifestations were reported more rarely when the ο variant was predominant, even though most patients (63%) who developed CBLLs in the first wave also developed them during the second pandemic wave.47 This decrease in the incidence of COVID-19–associated dermatoses could be because of the lower pathogenicity of the o variant,3 a lower tropism for the skin, and variations in SARS-CoV-2 antigenicity that would induce a different immunologic response, combined with an increasingly stronger herd immunity compared to the first pandemic waves achieved through vaccination and spontaneous infections in the population. Additional reasons may include different baseline characteristics in patients hospitalized with COVID-19 (regarding comorbidities, disease severity, and received treatments), and the possibility that some of the initially reported COVID-19–associated skin manifestations could have been produced by different etiologic agents.48 In the last 2 years, COVID-19–related skin manifestations have been reported mainly as adverse events to COVID-19 vaccination.

CUTANEOUS ADVERSE EFFECTS OF DRUGS USED TO TREAT COVID-19

Prior to the advent of vaccines and specific treatments for SARS-CoV-2, various drugs were used—namely hydroxychloroquine, ivermectin, and tocilizumab—that did not prove efficacious and caused diverse adverse effects, including cutaneous eruptions such as urticaria, maculopapular eruptions, erythema multiforme or Stevens-Johnson syndrome, vasculitis, longitudinal melanonychia, and acute generalized exanthematous pustulosis.49,50 Nirmatrelvir 150 mg–ritonavir 100 mg, which was authorized for emergency use by the US Food and Drug Administration for the treatment of COVID-19, is a viral protease inhibitor blocking the replication of the virus. Ritonavir can induce pruritus, maculopapular rash, acne, Stevens-Johnson syndrome, and toxic epidermal necrolysis; of note, these effects have been observed following administration of ritonavir for treatment of HIV at higher daily doses and for much longer periods of time compared with treatment of COVID-19 (600–1200 mg vs 200 mg/d, respectively). These cutaneous drug side effects are clinically similar to the manifestations caused either directly or indirectly by SARS-CoV-2 infection; therefore, it may be difficult to differentiate them.

DERMATOSES DUE TO PROTECTIVE DEVICES

Dermatoses due to personal protective equipment such as masks or face shields affected the general population and mostly health care professionals51; 54.4% of 879 health care professionals in one study reported such events.52 These dermatoses mainly include contact dermatitis of the face (nose, forehead, and cheeks) of irritant or allergic nature (eg, from preservatives releasing formaldehyde contained in masks and protective goggles). They manifest with skin dryness; desquamation; maceration; fissures; or erosions or ulcerations of the cheeks, forehead, and nose. Cases of pressure urticaria also have been reported. Irritant dermatitis induced by the frequent use of disinfectants (eg, soaps, hydroalcoholic sanitizing gels) also can affect the hands. Allergic hand dermatitis can be caused by medical gloves.

 

 

The term maskne (or mask acne) refers to a variety of mechanical acne due to the prolonged use of surgical masks (>4 hours per day for ≥6 weeks); it includes cases of de novo acne and cases of pre-existing acne aggravated by wearing a mask. Maskne is characterized by acne lesions located on the facial area covered by the mask (Figure 6). It is caused by follicular occlusion; increased sebum secretion; mechanical stress (pressure, friction); and dysbiosis of the microbiome induced by changes in heat, pH, and humidity. Preventive measures include application of noncomedogenic moisturizers or gauze before wearing the mask as well as facial cleansing with appropriate nonalcoholic products. Similar to acne, rosacea often is aggravated by prolonged wearing of surgical masks (mask rosacea).53,54

Follicular papulopustular eruption (so-called maskne) distributed over the facial zones covered by a surgical mask.
FIGURE 6. Follicular papulopustular eruption (so-called maskne) distributed over the facial zones covered by a surgical mask.

DERMATOSES REVEALED OR AGGRAVATED BY COVID-19

Exacerbation of various skin diseases has been reported after infection with SARS-CoV-2.55 Psoriasis and acrodermatitis continua of Hallopeau,56 which may progress into generalized, pustular, or erythrodermic forms,57 have been reported; the role of hydroxychloroquine and oral corticosteroids used for the treatment of COVID-19 has been suspected.57 Atopic dermatitis patients—26% to 43%—have experienced worsening of their disease after symptomatic COVID-19 infection.58 The incidence of herpesvirus infections, including herpes zoster, increased during the pandemic.59 Alopecia areata relapses occurred in 42.5% of 392 patients with preexisting disease within 2 months of COVID-19 onset in one study,60 possibly favored by the psychological stress; however, some studies have not confirmed the aggravating role of COVID-19 on alopecia areata.61 Lupus erythematosus, which may relapse in the form of Rowell syndrome,62 and livedoid vasculopathy63 also have been reported following COVID-19 infection.

SKIN MANIFESTATIONS ASSOCIATED WITH COVID-19 VACCINES

In parallel with the rapid spread of COVID-19 vaccination,4 an increasing number of skin manifestations has been observed following vaccination; these dermatoses now are more frequently reported than those related to natural SARS-CoV-2 infection.64-70 Vaccine-induced skin manifestations have a reported incidence of approximately 4% and show a female predominance.65 Most of them (79%) have been reported in association with messenger RNA (mRNA)–based vaccines, which have been the most widely used; however, the frequency of side effects would be lower after mRNA vaccines than after inactivated virus-based vaccines. Eighteen percent occurred after the adenoviral vector vaccine, and 3% after the inactivated virus vaccine.70 Fifty-nine percent were observed after the first dose. They are clinically polymorphous and generally benign, regressing spontaneously after a few days, and they should not constitute a contraindication to vaccination.Interestingly, many skin manifestations are similar to those associated with natural SARS-CoV-2 infection; however, their frequency and severity does not seem to depend on whether the patients had developed skin reactions during prior SARS-CoV-2 infection. These reactions have been classified into several types:

• Immediate local reactions at the injection site: pain, erythema, or edema represent the vast majority (96%) of reactions to vaccines. They appear within 7 days after vaccination (average, 1 day), slightly more frequently (59%) after the first dose. They concern mostly young patients and are benign, regressing in 2 to 3 days.70
 

• Delayed local reactions: characterized by pain or pruritus, erythema, and skin induration mimicking cellulitis (COVID arm) and represent 1.7% of postvaccination reactions. They correspond to a delayed hypersensitivity reaction and appear approximately 7 days after vaccination, most often after the first vaccine dose (75% of cases), which is almost invariably mRNA based.70

• Urticarial reactions corresponding to an immediate (type 1) hypersensitivity reaction: constitute 1% of postvaccination reactions, probably due to an allergy to vaccine ingredients. They appear on average 1 day after vaccination, almost always with mRNA vaccines.70

• Angioedema: characterized by mucosal or subcutaneous edema and constitutes 0.5% of postvaccination reactions. It is a potentially serious reaction that appears on average 12 hours after vaccination, always with an mRNA-based vaccine.70

 

 

• Morbilliform rash: represents delayed hypersensitivity reactions (0.1% of postvaccination reactions) that appear mostly after the first dose (72%), on average 3 days after vaccination, always with an mRNA-based vaccine.70

• Herpes zoster: usually develops after the first vaccine dose in elderly patients (69% of cases) on average 4 days after vaccination and constitutes 0.1% of postvaccination reactions.71

• Bullous diseases: mainly bullous pemphigoid (90%) and more rarely pemphigus (5%) or bullous erythema pigmentosum (5%). They appear in elderly patients on average 7 days after vaccination and constitute 0.04% of postvaccination reactions.72

• Chilblainlike lesions: several such cases have been reported so far73; they constitute 0.03% of postvaccination reactions.70 Clinically, they are similar to those associated with natural COVID-19; they appear mostly after the first dose (64%), on average 5 days after vaccination with the mRNA or adenovirus vaccine, and show a female predominance. The appearance of these lesions in vaccinated patients, who are a priori not carriers of the virus, strongly suggests that CBLLs are due to the immune reaction against SARS-CoV-2 rather than to a direct effect of this virus on the skin, which also is a likely scenario with regards to other skin manifestations seen during the successive COVID-19 epidemic waves.73-75

• Reactions to hyaluronic acid–containing cosmetic fillers: erythema, edema, and potentially painful induration at the filler injection sites. They constitute 0.04% of postvaccination skin reactions and appear 24 hours after vaccination with mRNA-based vaccines, equally after the first or second dose.76

• Pityriasis rosea–like rash: most occur after the second dose of mRNA-based vaccines (0.023% of postvaccination skin reactions).70

• Severe reactions: these include acute generalized exanthematous pustulosis77 and Stevens-Johnson syndrome.78 One case of each has been reported after the adenoviral vector vaccine 3 days after vaccination.

Other more rarely observed manifestations include reactivation/aggravation or de novo appearance of inflammatory dermatoses such as psoriasis,79,80 leukocytoclastic vasculitis,81,82 lymphocytic83 or urticarial84 vasculitis, Sweet syndrome,85 lupus erythematosus, dermatomyositis,86,87 alopecia,37,88 infection with Trichophyton rubrum,89 Grover disease,90 and lymphomatoid reactions (such as recurrences of cutaneous T-cell lymphomas [CD30+], and de novo development of lymphomatoid papulosis).91

FINAL THOUGHTS

COVID-19 is associated with several skin manifestations, even though the causative role of SARS-CoV-2 has remained elusive. These dermatoses are highly polymorphous, mostly benign, and usually spontaneously regressive, but some of them reflect severe infection. They mostly were described during the first pandemic waves, reported in several national and international registries, which allowed for their morphological classification. Currently, cutaneous adverse effects of vaccines are the most frequently reported dermatoses associated with SARS-CoV-2, and it is likely that they will continue to be observed while COVID-19 vaccination lasts. Hopefully the end of the COVID-19 pandemic is near. In January 2023, the International Health Regulations Emergency Committee of the World Health Organization acknowledged that the COVID-19 pandemic may be approaching an inflexion point, and even though the event continues to constitute a public health emergency of international concern, the higher levels of population immunity achieved globally through infection and/or vaccination may limit the impact of SARS-CoV-2 on morbidity and mortality. However, there is little doubt that this virus will remain a permanently established pathogen in humans and animals for the foreseeable future.92 Therefore, physicians—especially dermatologists—should be aware of the various skin manifestations associated with COVID-19 so they can more efficiently manage their patients.

References
  1. Ashraf UM, Abokor AA, Edwards JM, et al. SARS-CoV-2, ACE2 expression, and systemic organ invasion. Physiol Genomics. 2021;53:51-60.
  2. Ganier C, Harun N, Peplow I, et al. Angiotensin-converting enzyme 2 expression is detectable in keratinocytes, cutaneous appendages, and blood vessels by multiplex RNA in situ hybridization. Adv Skin Wound Care. 2022;35:219-223.
  3. Ulloa AC, Buchan SA, Daneman N, et al. Estimates of SARS-CoV-2 omicron variant severity in Ontario, Canada. JAMA. 2022;327:1286-1288.
  4. World Health Organization. Coronavirus (COVID-19) Dashboard. Accessed April 6, 2023. https://covid19.who.int
  5. Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert Group for COVID-19. clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-1720.
  6. Recalcati S. Cutaneous manifestations in COVID-9: a first perspective. J Eur Acad Dermatol Venereol. 2020;34:E212-E213.
  7. Freeman EE, McMahon DE, Lipoff JB, et al. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries. J Am Acad Dermatol. 2020;83:1118-1129.
  8. Freeman EE, Chamberlin GC, McMahon DE, et al. Dermatology COVID-19 registries: updates and future directions. Dermatol Clin. 2021;39:575-585.
  9. Guelimi R, Salle R, Dousset L, et al. Non-acral skin manifestations during the COVID-19 epidemic: COVIDSKIN study by the French Society of Dermatology. J Eur Acad Dermatol Venereol. 2021;35:E539-E541.
  10. Marzano AV, Genovese G, Moltrasio C, et al; Italian Skin COVID-19 Network of the Italian Society of Dermatology and Sexually Transmitted Diseases. The clinical spectrum of COVID-19 associated cutaneous manifestations: an Italian multicenter study of 200 adult patients. J Am Acad Dermatol. 2021;84:1356-1363.
  11. Sugai T, Fujita Y, Inamura E, et al. Prevalence and patterns of cutaneous manifestations in 1245 COVID-19 patients in Japan: a single-centre study. J Eur Acad Dermatol Venereol. 2022;36:E522-E524.
  12. Holmes Z, Courtney A, Lincoln M, et al. Rash morphology as a predictor of COVID‐19 severity: a systematic review of the cutaneous manifestations of COVID‐19. Skin Health Dis. 2022;2:E120. doi:10.1002/ski2.120
  13. Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020;183:71-77.
  14. Garduño‑Soto M, Choreño-Parra JA, Cazarin-Barrientos J. Dermatological aspects of SARS‑CoV‑2 infection: mechanisms and manifestations. Arch Dermatol Res. 2021;313:611-622.
  15. Huynh T, Sanchez-Flores X, Yau J, et al. Cutaneous manifestations of SARS-CoV-2 Infection. Am J Clin Dermatol. 2022;23:277-286.
  16. Kanitakis J, Lesort C, Danset M, et al. Chilblain-like acral lesions during the COVID-19 pandemic (“COVID toes”): histologic, immunofluorescence, and immunohistochemical study of 17 cases. J Am Acad Dermatol. 2020;83:870-875.
  17. Kolivras A, Thompson C, Pastushenko I, et al. A clinicopathological description of COVID-19-induced chilblains (COVID-toes) correlated with a published literature review. J Cutan Pathol. 2022;49:17-28.
  18. Roca-Ginés J, Torres-Navarro I, Sánchez-Arráez J, et al. Assessment of acute acral lesions in a case series of children and adolescents during the COVID-19 pandemic. JAMA Dermatol. 2020;156:992-997.
  19. Le Cleach L, Dousset L, Assier H, et al; French Society of Dermatology. Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing. Br J Dermatol. 2020;183:866-874.
  20. Discepolo V, Catzola A, Pierri L, et al. Bilateral chilblain-like lesions of the toes characterized by microvascular remodeling in adolescents during the COVID-19 pandemic. JAMA Netw Open. 2021;4:E2111369.
  21. Gehlhausen JR, Little AJ, Ko CJ, et al. Lack of association between pandemic chilblains and SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2022;119:e2122090119.
  22. Neri I, Virdi A, Corsini I, et al. Major cluster of paediatric ‘true’ primary chilblains during the COVID-19 pandemic: a consequence of lifestyle changes due to lockdown. J Eur Acad Dermatol Venereol. 2020;34:2630-2635.
  23. De Greef A, Choteau M, Herman A, et al. Chilblains observed during the COVID-19 pandemic cannot be distinguished from the classic, cold-related chilblains. Eur J Dermatol. 2022;32:377-383.
  24. Colmenero I, Santonja C, Alonso-Riaño M, et al. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol. 2020;183:729-737.
  25. Quintero-Bustos G, Aguilar-Leon D, Saeb-Lima M. Histopathological and immunohistochemical characterization of skin biopsies from 41 SARS-CoV-2 (+) patients: experience in a Mexican concentration institute: a case series and literature review. Am J Dermatopathol. 2022;44:327-337.
  26. Arkin LM, Moon JJ, Tran JM, et al; COVID Human Genetic Effort. From your nose to your toes: a review of severe acute respiratory syndrome coronavirus 2 pandemic-associated pernio. J Invest Dermatol. 2021;141:2791-2796.
  27. Frumholtz L, Bouaziz JD, Battistella M, et al; Saint-Louis CORE (COvid REsearch). Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak. Br J Dermatol. 2021;185:1176-1185.
  28. Hubiche T, Cardot-Leccia N, Le Duff F, et al. Clinical, laboratory, and interferon-alpha response characteristics of patients with chilblain-like lesions during the COVID-19 pandemic. JAMA Dermatol. 2021;157:202-206.
  29. Lesort C, Kanitakis J, Villani A, et al. COVID-19 and outbreak of chilblains: are they related? J Eur Acad Dermatol Venereol. 2020;34:E757-E758.
  30. Sanchez A, Sohier P, Benghanem S, et al. Digitate papulosquamous eruption associated with severe acute respiratory syndrome coronavirus 2 infection. JAMA Dermatol. 2020;156:819-820.
  31. Drago F, Broccolo F, Ciccarese G. Pityriasis rosea, pityriasis rosea-like eruptions, and herpes zoster in the setting of COVID-19 and COVID-19 vaccination. Clin Dermatol. 2022;S0738-081X(22)00002-5.
  32. Dursun R, Temiz SA. The clinics of HHV-6 infection in COVID-19 pandemic: pityriasis rosea and Kawasaki disease. Dermatol Ther. 2020;33:E13730.
  33. Nuno-Gonzalez A, Magaletsky K, Feito Rodríguez M, et al. Palmoplantar erythrodysesthesia: a diagnostic sign of COVID-19. J Eur Acad Dermatol Venereol. 2021;35:e247-e249.
  34. Sil A, Panigrahi A, Chandra A, et al. “COVID nose”: a unique post-COVID pigmentary sequelae reminiscing Chik sign: a descriptive case series. J Eur Acad Dermatol Venereol. 2022;36:E419-E421.
  35. Starace M, Iorizzo M, Sechi A, et al. Trichodynia and telogen effluvium in COVID-19 patients: results of an international expert opinion survey on diagnosis and management. JAAD Int. 2021;5:11-18.
  36. Wong-Chew RM, Rodríguez Cabrera EX, Rodríguez Valdez CA, et al. Symptom cluster analysis of long COVID-19 in patients discharged from the Temporary COVID-19 Hospital in Mexico City. Ther Adv Infect Dis. 2022;9:20499361211069264.
  37. Bardazzi F, Guglielmo A, Abbenante D, et al. New insights into alopecia areata during COVID-19 pandemic: when infection or vaccination could play a role. J Cosmet Dermatol. 2022;21:1796-1798.
  38. Christensen RE, Jafferany M. Association between alopecia areata and COVID-19: a systematic review. JAAD Int. 2022;7:57-61.
  39. Wollina U, Kanitakis J, Baran R. Nails and COVID-19: a comprehensive review of clinical findings and treatment. Dermatol Ther. 2021;34:E15100.
  40. Méndez-Flores S, Zaladonis A, Valdes-Rodriguez R. COVID-19 and nail manifestation: be on the lookout for the red half-moon nail sign. Int J Dermatol. 2020;59:1414.
  41. Alobaida S, Lam JM. Beau lines associated with COVID-19. CMAJ. 2020;192:E1040.
  42. Durmaz EÖ, Demirciog˘lu D. Fluorescence in the sclera, nails, and teeth secondary to favipiravir use for COVID-19 infections. J Clin Aesthet Dermatol. 2022;15:35-37.
  43. Brumfiel CM, DiLorenzo AM, Petronic-Rosic VM. Dermatologic manifestations of COVID-19-associated multisystem inflammatory syndrome in children. Clin Dermatol. 2021;39:329-333.
  44. Akçay N, Topkarcı Z, Menentog˘lu ME, et al. New dermatological findings of MIS-C: can mucocutaneous involvement be associated with severe disease course? Australas J Dermatol. 2022;63:228-234. doi:10.1111/ajd.13819
  45. Vogel TP, Top KA, Karatzios C, et al. Multisystem inflammatory syndrome in children and adults (MIS-C/A): case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2021;39:3037-3049.
  46. Conforti C, Dianzani C, Agozzino M, et al. Cutaneous manifestations in confirmed COVID-19 patients: a systematic review. Biology (Basel). 2020;9:449.
  47. Hubiche T, Le Duff F, Fontas E, et al. Relapse of chilblain-like lesions during the second wave of the COVID-19 pandemic: a cohort follow-up. Br J Dermatol. 2021;185:858-859.
  48. Fernandez-Nieto D, Ortega-Quijano D, Suarez-Valle A, et al. Lack of skin manifestations in COVID-19 hospitalized patients during the second epidemic wave in Spain: a possible association with a novel SARS-CoV-2 variant: a cross-sectional study. J Eur Acad Dermatol Venereol. 2021;35:E183-E185.
  49. Martinez-Lopez A, Cuenca-Barrales C, Montero-Vilchez T, et al. Review of adverse cutaneous reactions of pharmacologic interventions for COVID-19: a guide for the dermatologist. J Am Acad Dermatol. 2020;83:1738-1748.
  50. Türsen Ü, Türsen B, Lotti T. Cutaneous side-effects of the potential COVID-19 drugs. Dermatol Ther. 2020;33:E13476.
  51. Mawhirt SL, Frankel D, Diaz AM. Cutaneous manifestations in adult patients with COVID-19 and dermatologic conditions related to the COVID-19 pandemic in health care workers. Curr Allerg Asthma Rep. 2020;20:75.
  52. Nguyen C, Young FG, McElroy D, et al. Personal protective equipment and adverse dermatological reactions among healthcare workers: survey observations from the COVID-19 pandemic. Medicine (Baltimore). 2022;101:E29003.
  53. Rathi SK, Dsouza JM. Maskne: a new acne variant in COVID-19 era. Indian J Dermatol. 2022;67:552-555.
  54. Damiani G, Girono L, Grada A, et al. COVID-19 related masks increase severity of both acne (maskne) and rosacea (mask rosacea): multi-center, real-life, telemedical, and observational prospective study. Dermatol Ther. 2021;34:E14848.
  55. Aram K, Patil A, Goldust M, et al. COVID-19 and exacerbation of dermatological diseases: a review of the available literature. Dermatol Ther. 2021;34:E15113.
  56. Samotij D, Gawron E, Szcze˛ch J, et al. Acrodermatitis continua of Hallopeau evolving into generalized pustular psoriasis following COVID-19: a case report of a successful treatment with infliximab in combination with acitretin. Biologics. 2021;15:107-113.
  57. Demiri J, Abdo M, Tsianakas A. Erythrodermic psoriasis after COVID-19 [in German]. Hautarzt. 2022;73:156-159.
  58. de Wijs LEM, Joustra MM, Olydam JI, et al. COVID-19 in patients with cutaneous immune-mediated diseases in the Netherlands: real-world observational data. J Eur Acad Dermatol Venereol. 2021;35:E173-E176.
  59. Marques NP, Maia CMF, Marques NCT, et al. Continuous increase of herpes zoster cases in Brazil during the COVID-19 pandemic. Oral Surg Oral Med Oral Pathol Oral Radiol. 2022;133:612-614.
  60. Rinaldi F, Trink A, Giuliani G, et al. Italian survey for the evaluation of the effects of coronavirus disease 2019 (COVID-19) pandemic on alopecia areata recurrence. Dermatol Ther (Heidelb). 2021;11:339-345.
  61. Rudnicka L, Rakowska A, Waskiel-Burnat A, et al. Mild-to-moderate COVID-19 is not associated with worsening of alopecia areata: a retrospective analysis of 32 patients. J Am Acad Dermatol. 2021;85:723-725.
  62. Drenovska K, Shahid M, Mateeva V, et al. Case report: Rowell syndrome-like flare of cutaneous lupus erythematosus following COVID-19 infection. Front Med (Lausanne). 2022;9:815743.
  63. Kawabe R, Tonomura K, Kotobuki Y, et al. Exacerbation of livedoid vasculopathy after coronavirus disease 2019. Eur J Dermatol. 2022;32:129-131. doi:10.1684/ejd.2022.4200
  64. McMahon DE, Kovarik CL, Damsky W, et al. Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: a registry-based study. J Am Acad Dermatol. 2022;86:113-121.
  65. Avallone G, Quaglino P, Cavallo F, et al. SARS-CoV-2 vaccine-related cutaneous manifestations: a systematic review. Int J Dermatol. 2022;61:1187-1204. doi:10.1111/ijd.16063
  66. Gambichler T, Boms S, Susok L, et al. Cutaneous findings following COVID-19 vaccination: review of world literature and own experience. J Eur Acad Dermatol Venereol. 2022;36:172-180.
  67. Kroumpouzos G, Paroikaki ME, Yumeen S, et al. Cutaneous complications of mRNA and AZD1222 COVID-19 vaccines: a worldwide review. Microorganisms. 2022;10:624.
  68. Robinson L, Fu X, Hashimoto D, et al. Incidence of cutaneous reactions after messenger RNA COVID-19 vaccines. JAMA Dermatol. 2021;157:1000-1002.
  69. Wollina U, Chiriac A, Kocic H, et al. Cutaneous and hypersensitivity reactions associated with COVID-19 vaccination: a narrative review. Wien Med Wochenschr. 2022;172:63-69.
  70. Wei TS. Cutaneous reactions to COVID-19 vaccines: a review. JAAD Int. 2022;7:178-186.
  71. Katsikas Triantafyllidis K, Giannos P, Mian IT, et al. Varicella zoster virus reactivation following COVID-19 vaccination: a systematic review of case reports. Vaccines (Basel). 2021;9:1013.
  72. Maronese CA, Caproni M, Moltrasio C, et al. Bullous pemphigoid associated with COVID-19 vaccines: an Italian multicentre study. Front Med (Lausanne). 2022;9:841506.
  73. Cavazos A, Deb A, Sharma U, et al. COVID toes following vaccination. Proc (Bayl Univ Med Cent). 2022;35:476-479.
  74. Lesort C, Kanitakis J, Danset M, et al. Chilblain-like lesions after BNT162b2 mRNA COVID-19 vaccine: a case report suggesting that ‘COVID toes’ are due to the immune reaction to SARS-CoV-2. J Eur Acad Dermatol Venereol. 2021;35:E630-E632.
  75. Russo R, Cozzani E, Micalizzi C, et al. Chilblain-like lesions after COVID-19 vaccination: a case series. Acta Derm Venereol. 2022;102:adv00711. doi:10.2340/actadv.v102.2076
  76. Ortigosa LCM, Lenzoni FC, Suárez MV, et al. Hypersensitivity reaction to hyaluronic acid dermal filler after COVID-19 vaccination: a series of cases in São Paulo, Brazil. Int J Infect Dis. 2022;116:268-270.
  77. Agaronov A, Makdesi C, Hall CS. Acute generalized exanthematous pustulosis induced by Moderna COVID-19 messenger RNA vaccine. JAAD Case Rep. 2021;16:96-97.
  78. Dash S, Sirka CS, Mishra S, et al. COVID-19 vaccine-induced Stevens-Johnson syndrome. Clin Exp Dermatol. 2021;46:1615-1617.
  79. Huang Y, Tsai TF. Exacerbation of psoriasis following COVID-19 vaccination: report from a single center. Front Med (Lausanne). 2021;8:812010.
  80. Elamin S, Hinds F, Tolland J. De novo generalized pustular psoriasis following Oxford-AstraZeneca COVID-19 vaccine. Clin Exp Dermatol 2022;47:153-155.
  81. Abdelmaksoud A, Wollina U, Temiz SA, et al. SARS-CoV-2 vaccination-induced cutaneous vasculitis: report of two new cases and literature review. Dermatol Ther. 2022;35:E15458.
  82. Fritzen M, Funchal GDG, Luiz MO, et al. Leukocytoclastic vasculitis after exposure to COVID-19 vaccine. An Bras Dermatol. 2022;97:118-121.
  83. Vassallo C, Boveri E, Brazzelli V, et al. Cutaneous lymphocytic vasculitis after administration of COVID-19 mRNA vaccine. Dermatol Ther. 2021;34:E15076.
  84. Nazzaro G, Maronese CA. Urticarial vasculitis following mRNA anti-COVID-19 vaccine. Dermatol Ther. 2022;35:E15282.
  85. Hoshina D, Orita A. Sweet syndrome after severe acute respiratory syndrome coronavirus 2 mRNA vaccine: a case report and literature review. J Dermatol. 2022;49:E175-E176.
  86. Lemoine C, Padilla C, Krampe N, et al. Systemic lupus erythematous after Pfizer COVID-19 vaccine: a case report. Clin Rheumatol. 2022;41:1597-1601.
  87. Nguyen B, Lalama MJ, Gamret AC, et al. Cutaneous symptoms of connective tissue diseases after COVID-19 vaccination: a systematic review. Int J Dermatol. 2022;61:E238-E241.
  88. Gallo G, Mastorino L, Tonella L, et al. Alopecia areata after COVID-19 vaccination. Clin Exp Vaccine Res. 2022;11:129-132.
  89. Norimatsu Y, Norimatsu Y. A severe case of Trichophyton rubrum-caused dermatomycosis exacerbated after COVID-19 vaccination that had to be differentiated from pustular psoriasis. Med Mycol Case Rep. 2022;36:19-22.
  90. Yang K, Prussick L, Hartman R, et al. Acantholytic dyskeratosis post-COVID vaccination. Am J Dermatopathol. 2022;44:E61-E63.
  91. Koumaki D, Marinos L, Nikolaou V, et al. Lymphomatoid papulosis (LyP) after AZD1222 and BNT162b2 COVID-19 vaccines. Int J Dermatol. 2022;61:900-902.
  92. World Health Organization. Statement on the fourteenth meeting of the International Health Regulations (2005) Emergency Committee regarding the coronavirus disease (COVID-19) pandemic. Published January 30, 2023. Accessed April 12, 2023. https://www.who.int/news/item/30-01-2023-statement-on-the-fourteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic
References
  1. Ashraf UM, Abokor AA, Edwards JM, et al. SARS-CoV-2, ACE2 expression, and systemic organ invasion. Physiol Genomics. 2021;53:51-60.
  2. Ganier C, Harun N, Peplow I, et al. Angiotensin-converting enzyme 2 expression is detectable in keratinocytes, cutaneous appendages, and blood vessels by multiplex RNA in situ hybridization. Adv Skin Wound Care. 2022;35:219-223.
  3. Ulloa AC, Buchan SA, Daneman N, et al. Estimates of SARS-CoV-2 omicron variant severity in Ontario, Canada. JAMA. 2022;327:1286-1288.
  4. World Health Organization. Coronavirus (COVID-19) Dashboard. Accessed April 6, 2023. https://covid19.who.int
  5. Guan WJ, Ni ZY, Hu Y, et al; China Medical Treatment Expert Group for COVID-19. clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-1720.
  6. Recalcati S. Cutaneous manifestations in COVID-9: a first perspective. J Eur Acad Dermatol Venereol. 2020;34:E212-E213.
  7. Freeman EE, McMahon DE, Lipoff JB, et al. The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries. J Am Acad Dermatol. 2020;83:1118-1129.
  8. Freeman EE, Chamberlin GC, McMahon DE, et al. Dermatology COVID-19 registries: updates and future directions. Dermatol Clin. 2021;39:575-585.
  9. Guelimi R, Salle R, Dousset L, et al. Non-acral skin manifestations during the COVID-19 epidemic: COVIDSKIN study by the French Society of Dermatology. J Eur Acad Dermatol Venereol. 2021;35:E539-E541.
  10. Marzano AV, Genovese G, Moltrasio C, et al; Italian Skin COVID-19 Network of the Italian Society of Dermatology and Sexually Transmitted Diseases. The clinical spectrum of COVID-19 associated cutaneous manifestations: an Italian multicenter study of 200 adult patients. J Am Acad Dermatol. 2021;84:1356-1363.
  11. Sugai T, Fujita Y, Inamura E, et al. Prevalence and patterns of cutaneous manifestations in 1245 COVID-19 patients in Japan: a single-centre study. J Eur Acad Dermatol Venereol. 2022;36:E522-E524.
  12. Holmes Z, Courtney A, Lincoln M, et al. Rash morphology as a predictor of COVID‐19 severity: a systematic review of the cutaneous manifestations of COVID‐19. Skin Health Dis. 2022;2:E120. doi:10.1002/ski2.120
  13. Galván Casas C, Català A, Carretero Hernández G, et al. Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases. Br J Dermatol. 2020;183:71-77.
  14. Garduño‑Soto M, Choreño-Parra JA, Cazarin-Barrientos J. Dermatological aspects of SARS‑CoV‑2 infection: mechanisms and manifestations. Arch Dermatol Res. 2021;313:611-622.
  15. Huynh T, Sanchez-Flores X, Yau J, et al. Cutaneous manifestations of SARS-CoV-2 Infection. Am J Clin Dermatol. 2022;23:277-286.
  16. Kanitakis J, Lesort C, Danset M, et al. Chilblain-like acral lesions during the COVID-19 pandemic (“COVID toes”): histologic, immunofluorescence, and immunohistochemical study of 17 cases. J Am Acad Dermatol. 2020;83:870-875.
  17. Kolivras A, Thompson C, Pastushenko I, et al. A clinicopathological description of COVID-19-induced chilblains (COVID-toes) correlated with a published literature review. J Cutan Pathol. 2022;49:17-28.
  18. Roca-Ginés J, Torres-Navarro I, Sánchez-Arráez J, et al. Assessment of acute acral lesions in a case series of children and adolescents during the COVID-19 pandemic. JAMA Dermatol. 2020;156:992-997.
  19. Le Cleach L, Dousset L, Assier H, et al; French Society of Dermatology. Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing. Br J Dermatol. 2020;183:866-874.
  20. Discepolo V, Catzola A, Pierri L, et al. Bilateral chilblain-like lesions of the toes characterized by microvascular remodeling in adolescents during the COVID-19 pandemic. JAMA Netw Open. 2021;4:E2111369.
  21. Gehlhausen JR, Little AJ, Ko CJ, et al. Lack of association between pandemic chilblains and SARS-CoV-2 infection. Proc Natl Acad Sci U S A. 2022;119:e2122090119.
  22. Neri I, Virdi A, Corsini I, et al. Major cluster of paediatric ‘true’ primary chilblains during the COVID-19 pandemic: a consequence of lifestyle changes due to lockdown. J Eur Acad Dermatol Venereol. 2020;34:2630-2635.
  23. De Greef A, Choteau M, Herman A, et al. Chilblains observed during the COVID-19 pandemic cannot be distinguished from the classic, cold-related chilblains. Eur J Dermatol. 2022;32:377-383.
  24. Colmenero I, Santonja C, Alonso-Riaño M, et al. SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol. 2020;183:729-737.
  25. Quintero-Bustos G, Aguilar-Leon D, Saeb-Lima M. Histopathological and immunohistochemical characterization of skin biopsies from 41 SARS-CoV-2 (+) patients: experience in a Mexican concentration institute: a case series and literature review. Am J Dermatopathol. 2022;44:327-337.
  26. Arkin LM, Moon JJ, Tran JM, et al; COVID Human Genetic Effort. From your nose to your toes: a review of severe acute respiratory syndrome coronavirus 2 pandemic-associated pernio. J Invest Dermatol. 2021;141:2791-2796.
  27. Frumholtz L, Bouaziz JD, Battistella M, et al; Saint-Louis CORE (COvid REsearch). Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak. Br J Dermatol. 2021;185:1176-1185.
  28. Hubiche T, Cardot-Leccia N, Le Duff F, et al. Clinical, laboratory, and interferon-alpha response characteristics of patients with chilblain-like lesions during the COVID-19 pandemic. JAMA Dermatol. 2021;157:202-206.
  29. Lesort C, Kanitakis J, Villani A, et al. COVID-19 and outbreak of chilblains: are they related? J Eur Acad Dermatol Venereol. 2020;34:E757-E758.
  30. Sanchez A, Sohier P, Benghanem S, et al. Digitate papulosquamous eruption associated with severe acute respiratory syndrome coronavirus 2 infection. JAMA Dermatol. 2020;156:819-820.
  31. Drago F, Broccolo F, Ciccarese G. Pityriasis rosea, pityriasis rosea-like eruptions, and herpes zoster in the setting of COVID-19 and COVID-19 vaccination. Clin Dermatol. 2022;S0738-081X(22)00002-5.
  32. Dursun R, Temiz SA. The clinics of HHV-6 infection in COVID-19 pandemic: pityriasis rosea and Kawasaki disease. Dermatol Ther. 2020;33:E13730.
  33. Nuno-Gonzalez A, Magaletsky K, Feito Rodríguez M, et al. Palmoplantar erythrodysesthesia: a diagnostic sign of COVID-19. J Eur Acad Dermatol Venereol. 2021;35:e247-e249.
  34. Sil A, Panigrahi A, Chandra A, et al. “COVID nose”: a unique post-COVID pigmentary sequelae reminiscing Chik sign: a descriptive case series. J Eur Acad Dermatol Venereol. 2022;36:E419-E421.
  35. Starace M, Iorizzo M, Sechi A, et al. Trichodynia and telogen effluvium in COVID-19 patients: results of an international expert opinion survey on diagnosis and management. JAAD Int. 2021;5:11-18.
  36. Wong-Chew RM, Rodríguez Cabrera EX, Rodríguez Valdez CA, et al. Symptom cluster analysis of long COVID-19 in patients discharged from the Temporary COVID-19 Hospital in Mexico City. Ther Adv Infect Dis. 2022;9:20499361211069264.
  37. Bardazzi F, Guglielmo A, Abbenante D, et al. New insights into alopecia areata during COVID-19 pandemic: when infection or vaccination could play a role. J Cosmet Dermatol. 2022;21:1796-1798.
  38. Christensen RE, Jafferany M. Association between alopecia areata and COVID-19: a systematic review. JAAD Int. 2022;7:57-61.
  39. Wollina U, Kanitakis J, Baran R. Nails and COVID-19: a comprehensive review of clinical findings and treatment. Dermatol Ther. 2021;34:E15100.
  40. Méndez-Flores S, Zaladonis A, Valdes-Rodriguez R. COVID-19 and nail manifestation: be on the lookout for the red half-moon nail sign. Int J Dermatol. 2020;59:1414.
  41. Alobaida S, Lam JM. Beau lines associated with COVID-19. CMAJ. 2020;192:E1040.
  42. Durmaz EÖ, Demirciog˘lu D. Fluorescence in the sclera, nails, and teeth secondary to favipiravir use for COVID-19 infections. J Clin Aesthet Dermatol. 2022;15:35-37.
  43. Brumfiel CM, DiLorenzo AM, Petronic-Rosic VM. Dermatologic manifestations of COVID-19-associated multisystem inflammatory syndrome in children. Clin Dermatol. 2021;39:329-333.
  44. Akçay N, Topkarcı Z, Menentog˘lu ME, et al. New dermatological findings of MIS-C: can mucocutaneous involvement be associated with severe disease course? Australas J Dermatol. 2022;63:228-234. doi:10.1111/ajd.13819
  45. Vogel TP, Top KA, Karatzios C, et al. Multisystem inflammatory syndrome in children and adults (MIS-C/A): case definition & guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2021;39:3037-3049.
  46. Conforti C, Dianzani C, Agozzino M, et al. Cutaneous manifestations in confirmed COVID-19 patients: a systematic review. Biology (Basel). 2020;9:449.
  47. Hubiche T, Le Duff F, Fontas E, et al. Relapse of chilblain-like lesions during the second wave of the COVID-19 pandemic: a cohort follow-up. Br J Dermatol. 2021;185:858-859.
  48. Fernandez-Nieto D, Ortega-Quijano D, Suarez-Valle A, et al. Lack of skin manifestations in COVID-19 hospitalized patients during the second epidemic wave in Spain: a possible association with a novel SARS-CoV-2 variant: a cross-sectional study. J Eur Acad Dermatol Venereol. 2021;35:E183-E185.
  49. Martinez-Lopez A, Cuenca-Barrales C, Montero-Vilchez T, et al. Review of adverse cutaneous reactions of pharmacologic interventions for COVID-19: a guide for the dermatologist. J Am Acad Dermatol. 2020;83:1738-1748.
  50. Türsen Ü, Türsen B, Lotti T. Cutaneous side-effects of the potential COVID-19 drugs. Dermatol Ther. 2020;33:E13476.
  51. Mawhirt SL, Frankel D, Diaz AM. Cutaneous manifestations in adult patients with COVID-19 and dermatologic conditions related to the COVID-19 pandemic in health care workers. Curr Allerg Asthma Rep. 2020;20:75.
  52. Nguyen C, Young FG, McElroy D, et al. Personal protective equipment and adverse dermatological reactions among healthcare workers: survey observations from the COVID-19 pandemic. Medicine (Baltimore). 2022;101:E29003.
  53. Rathi SK, Dsouza JM. Maskne: a new acne variant in COVID-19 era. Indian J Dermatol. 2022;67:552-555.
  54. Damiani G, Girono L, Grada A, et al. COVID-19 related masks increase severity of both acne (maskne) and rosacea (mask rosacea): multi-center, real-life, telemedical, and observational prospective study. Dermatol Ther. 2021;34:E14848.
  55. Aram K, Patil A, Goldust M, et al. COVID-19 and exacerbation of dermatological diseases: a review of the available literature. Dermatol Ther. 2021;34:E15113.
  56. Samotij D, Gawron E, Szcze˛ch J, et al. Acrodermatitis continua of Hallopeau evolving into generalized pustular psoriasis following COVID-19: a case report of a successful treatment with infliximab in combination with acitretin. Biologics. 2021;15:107-113.
  57. Demiri J, Abdo M, Tsianakas A. Erythrodermic psoriasis after COVID-19 [in German]. Hautarzt. 2022;73:156-159.
  58. de Wijs LEM, Joustra MM, Olydam JI, et al. COVID-19 in patients with cutaneous immune-mediated diseases in the Netherlands: real-world observational data. J Eur Acad Dermatol Venereol. 2021;35:E173-E176.
  59. Marques NP, Maia CMF, Marques NCT, et al. Continuous increase of herpes zoster cases in Brazil during the COVID-19 pandemic. Oral Surg Oral Med Oral Pathol Oral Radiol. 2022;133:612-614.
  60. Rinaldi F, Trink A, Giuliani G, et al. Italian survey for the evaluation of the effects of coronavirus disease 2019 (COVID-19) pandemic on alopecia areata recurrence. Dermatol Ther (Heidelb). 2021;11:339-345.
  61. Rudnicka L, Rakowska A, Waskiel-Burnat A, et al. Mild-to-moderate COVID-19 is not associated with worsening of alopecia areata: a retrospective analysis of 32 patients. J Am Acad Dermatol. 2021;85:723-725.
  62. Drenovska K, Shahid M, Mateeva V, et al. Case report: Rowell syndrome-like flare of cutaneous lupus erythematosus following COVID-19 infection. Front Med (Lausanne). 2022;9:815743.
  63. Kawabe R, Tonomura K, Kotobuki Y, et al. Exacerbation of livedoid vasculopathy after coronavirus disease 2019. Eur J Dermatol. 2022;32:129-131. doi:10.1684/ejd.2022.4200
  64. McMahon DE, Kovarik CL, Damsky W, et al. Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: a registry-based study. J Am Acad Dermatol. 2022;86:113-121.
  65. Avallone G, Quaglino P, Cavallo F, et al. SARS-CoV-2 vaccine-related cutaneous manifestations: a systematic review. Int J Dermatol. 2022;61:1187-1204. doi:10.1111/ijd.16063
  66. Gambichler T, Boms S, Susok L, et al. Cutaneous findings following COVID-19 vaccination: review of world literature and own experience. J Eur Acad Dermatol Venereol. 2022;36:172-180.
  67. Kroumpouzos G, Paroikaki ME, Yumeen S, et al. Cutaneous complications of mRNA and AZD1222 COVID-19 vaccines: a worldwide review. Microorganisms. 2022;10:624.
  68. Robinson L, Fu X, Hashimoto D, et al. Incidence of cutaneous reactions after messenger RNA COVID-19 vaccines. JAMA Dermatol. 2021;157:1000-1002.
  69. Wollina U, Chiriac A, Kocic H, et al. Cutaneous and hypersensitivity reactions associated with COVID-19 vaccination: a narrative review. Wien Med Wochenschr. 2022;172:63-69.
  70. Wei TS. Cutaneous reactions to COVID-19 vaccines: a review. JAAD Int. 2022;7:178-186.
  71. Katsikas Triantafyllidis K, Giannos P, Mian IT, et al. Varicella zoster virus reactivation following COVID-19 vaccination: a systematic review of case reports. Vaccines (Basel). 2021;9:1013.
  72. Maronese CA, Caproni M, Moltrasio C, et al. Bullous pemphigoid associated with COVID-19 vaccines: an Italian multicentre study. Front Med (Lausanne). 2022;9:841506.
  73. Cavazos A, Deb A, Sharma U, et al. COVID toes following vaccination. Proc (Bayl Univ Med Cent). 2022;35:476-479.
  74. Lesort C, Kanitakis J, Danset M, et al. Chilblain-like lesions after BNT162b2 mRNA COVID-19 vaccine: a case report suggesting that ‘COVID toes’ are due to the immune reaction to SARS-CoV-2. J Eur Acad Dermatol Venereol. 2021;35:E630-E632.
  75. Russo R, Cozzani E, Micalizzi C, et al. Chilblain-like lesions after COVID-19 vaccination: a case series. Acta Derm Venereol. 2022;102:adv00711. doi:10.2340/actadv.v102.2076
  76. Ortigosa LCM, Lenzoni FC, Suárez MV, et al. Hypersensitivity reaction to hyaluronic acid dermal filler after COVID-19 vaccination: a series of cases in São Paulo, Brazil. Int J Infect Dis. 2022;116:268-270.
  77. Agaronov A, Makdesi C, Hall CS. Acute generalized exanthematous pustulosis induced by Moderna COVID-19 messenger RNA vaccine. JAAD Case Rep. 2021;16:96-97.
  78. Dash S, Sirka CS, Mishra S, et al. COVID-19 vaccine-induced Stevens-Johnson syndrome. Clin Exp Dermatol. 2021;46:1615-1617.
  79. Huang Y, Tsai TF. Exacerbation of psoriasis following COVID-19 vaccination: report from a single center. Front Med (Lausanne). 2021;8:812010.
  80. Elamin S, Hinds F, Tolland J. De novo generalized pustular psoriasis following Oxford-AstraZeneca COVID-19 vaccine. Clin Exp Dermatol 2022;47:153-155.
  81. Abdelmaksoud A, Wollina U, Temiz SA, et al. SARS-CoV-2 vaccination-induced cutaneous vasculitis: report of two new cases and literature review. Dermatol Ther. 2022;35:E15458.
  82. Fritzen M, Funchal GDG, Luiz MO, et al. Leukocytoclastic vasculitis after exposure to COVID-19 vaccine. An Bras Dermatol. 2022;97:118-121.
  83. Vassallo C, Boveri E, Brazzelli V, et al. Cutaneous lymphocytic vasculitis after administration of COVID-19 mRNA vaccine. Dermatol Ther. 2021;34:E15076.
  84. Nazzaro G, Maronese CA. Urticarial vasculitis following mRNA anti-COVID-19 vaccine. Dermatol Ther. 2022;35:E15282.
  85. Hoshina D, Orita A. Sweet syndrome after severe acute respiratory syndrome coronavirus 2 mRNA vaccine: a case report and literature review. J Dermatol. 2022;49:E175-E176.
  86. Lemoine C, Padilla C, Krampe N, et al. Systemic lupus erythematous after Pfizer COVID-19 vaccine: a case report. Clin Rheumatol. 2022;41:1597-1601.
  87. Nguyen B, Lalama MJ, Gamret AC, et al. Cutaneous symptoms of connective tissue diseases after COVID-19 vaccination: a systematic review. Int J Dermatol. 2022;61:E238-E241.
  88. Gallo G, Mastorino L, Tonella L, et al. Alopecia areata after COVID-19 vaccination. Clin Exp Vaccine Res. 2022;11:129-132.
  89. Norimatsu Y, Norimatsu Y. A severe case of Trichophyton rubrum-caused dermatomycosis exacerbated after COVID-19 vaccination that had to be differentiated from pustular psoriasis. Med Mycol Case Rep. 2022;36:19-22.
  90. Yang K, Prussick L, Hartman R, et al. Acantholytic dyskeratosis post-COVID vaccination. Am J Dermatopathol. 2022;44:E61-E63.
  91. Koumaki D, Marinos L, Nikolaou V, et al. Lymphomatoid papulosis (LyP) after AZD1222 and BNT162b2 COVID-19 vaccines. Int J Dermatol. 2022;61:900-902.
  92. World Health Organization. Statement on the fourteenth meeting of the International Health Regulations (2005) Emergency Committee regarding the coronavirus disease (COVID-19) pandemic. Published January 30, 2023. Accessed April 12, 2023. https://www.who.int/news/item/30-01-2023-statement-on-the-fourteenth-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-coronavirus-disease-(covid-19)-pandemic
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  • During the COVID-19 pandemic, several skin diseases were reported in association with this new infectious disease and were classified mainly according to their morphologic aspect. However, the pathogenetic mechanisms often are unclear and the causal link of the culprit virus (SARS-CoV-2) not always well established.
  • Currently, most skin manifestations related to COVID-19 are reported after vaccination against COVID-19; remarkably, many of them are similar to those attributed to the natural infection.
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Chilblainlike lesions (so-called COVID toes) manifested with red-violaceous macules over the distal toes.
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SARS-CoV-2 crosses placenta and infects brains of two infants: ‘This is a first’

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Marcia Frellick

Researchers have found for the first time that COVID infection has crossed the placenta and caused brain damage in two newborns, according to a study published online today in Pediatrics .

One of the infants died at 13 months and the other remained in hospice care at time of manuscript submission.

Lead author Merline Benny, MD, with the division of neonatology, department of pediatrics at University of Miami, and colleagues briefed reporters today ahead of the release.

Zelda Calvert
Dr. Shahnaz Duara

“This is a first,” said senior author Shahnaz Duara, MD, medical director of the Neonatal Intensive Care Unit at Holtz Children’s Hospital, Miami, explaining it is the first study to confirm cross-placental SARS-CoV-2 transmission leading to brain injury in a newborn.
 

Both infants negative for the virus at birth

The two infants were admitted in the early days of the pandemic in the Delta wave to the neonatal ICU at Holtz Children’s Hospital at University of Miami/Jackson Memorial Medical Center.

Both infants tested negative for the virus at birth, but had significantly elevated SARS-CoV-2 antibodies in their blood, indicating that either antibodies crossed the placenta, or the virus crossed and the immune response was the baby’s.

Dr. Benny explained that the researchers have seen, to this point, more than 700 mother/infant pairs in whom the mother tested positive for COVID in Jackson hospital.

Most who tested positive for COVID were asymptomatic and most of the mothers and infants left the hospital without complications.

“However, (these) two babies had a very unusual clinical picture,” Dr. Benny said.

Those infants were born to mothers who became COVID positive in the second trimester and delivered a few weeks later.

Seizures started on day 1 of life

The babies began to seize from the first day of life. They had profound low tone (hypotonia) in their clinical exam, Dr. Benny explained.

“We had absolutely no good explanation for the early seizures and the degree of brain injury we saw,” Dr. Duara said.

Dr. Benny said that as their bodies grew, they had very small head circumference. Unlike some babies born with the Zika virus, these babies were not microcephalic at birth. Brain imaging on the two babies indicated significant brain atrophy, and neurodevelopment exams showed significant delay.

Discussions began with the center’s multidisciplinary team including neurologists, pathologists, neuroradiologists, and obstetricians who cared for both the mothers and the babies.

The experts examined the placentas and found some characteristic COVID changes and presence of the COVID virus. This was accompanied by increased markers for inflammation and a severe reduction in a hormone critical for placental health and brain development.

Examining the infant’s autopsy findings further raised suspicions of maternal transmission, something that had not been documented before.

Coauthor Ali G. Saad, MD, pediatric and perinatal pathology director at Miami, said, “I have seen literally thousands of brains in autopsies over the last 14 years, and this was the most dramatic case of leukoencephalopathy or loss of white matter in a patient with no significant reason. That’s what triggered the investigation.”
 

 

 

Mothers had very different presentations

Coauthor Michael J. Paidas, MD, with the department of obstetrics, gynecology, and reproductive sciences at Miami, pointed out that the circumstances of the two mothers, who were in their 20s, were very different.

One mother delivered at 32 weeks and had a very severe COVID presentation and spent a month in the intensive care unit. The team decided to deliver the child to save the mother, Dr. Paidas said.

In contrast, the other mother had asymptomatic COVID infection in the second trimester and delivered at full term.

He said one of the early suspicions in the babies’ presentations was hypoxic ischemic encephalopathy. “But it wasn’t lack of blood flow to the placenta that caused this,” he said. “As best we can tell, it was the viral infection.”
 

Instances are rare

The researchers emphasized that these instances are rare and have not been seen before or since the period of this study to their knowledge.

Dr. Duara said, “This is something we want to alert the medical community to more than the general public. We do not want the lay public to be panicked. We’re trying to understand what made these two pregnancies different, so we can direct research towards protecting vulnerable babies.”

Previous data have indicated a relatively benign status in infants who test negative for the COVID virus after birth. Dr. Benny added that COVID vaccination has been found safe in pregnancy and both vaccination and breastfeeding can help passage of antibodies to the infant and help protect the baby. Because these cases happened in the early days of the pandemic, no vaccines were available.

Dr. Paidas received funding from BioIncept to study hypoxic-ischemic encephalopathy with Preimplantation Factor, is a scientific advisory board member, and has stock options. Dr. Paidas and coauthor Dr. Jayakumar are coinventors of SPIKENET, University of Miami, patent pending 2023. The other authors have no conflicts of interest to disclose.

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Author(s)
Marcia Frellick
Author(s)
Marcia Frellick

Researchers have found for the first time that COVID infection has crossed the placenta and caused brain damage in two newborns, according to a study published online today in Pediatrics .

One of the infants died at 13 months and the other remained in hospice care at time of manuscript submission.

Lead author Merline Benny, MD, with the division of neonatology, department of pediatrics at University of Miami, and colleagues briefed reporters today ahead of the release.

Zelda Calvert
Dr. Shahnaz Duara

“This is a first,” said senior author Shahnaz Duara, MD, medical director of the Neonatal Intensive Care Unit at Holtz Children’s Hospital, Miami, explaining it is the first study to confirm cross-placental SARS-CoV-2 transmission leading to brain injury in a newborn.
 

Both infants negative for the virus at birth

The two infants were admitted in the early days of the pandemic in the Delta wave to the neonatal ICU at Holtz Children’s Hospital at University of Miami/Jackson Memorial Medical Center.

Both infants tested negative for the virus at birth, but had significantly elevated SARS-CoV-2 antibodies in their blood, indicating that either antibodies crossed the placenta, or the virus crossed and the immune response was the baby’s.

Dr. Benny explained that the researchers have seen, to this point, more than 700 mother/infant pairs in whom the mother tested positive for COVID in Jackson hospital.

Most who tested positive for COVID were asymptomatic and most of the mothers and infants left the hospital without complications.

“However, (these) two babies had a very unusual clinical picture,” Dr. Benny said.

Those infants were born to mothers who became COVID positive in the second trimester and delivered a few weeks later.

Seizures started on day 1 of life

The babies began to seize from the first day of life. They had profound low tone (hypotonia) in their clinical exam, Dr. Benny explained.

“We had absolutely no good explanation for the early seizures and the degree of brain injury we saw,” Dr. Duara said.

Dr. Benny said that as their bodies grew, they had very small head circumference. Unlike some babies born with the Zika virus, these babies were not microcephalic at birth. Brain imaging on the two babies indicated significant brain atrophy, and neurodevelopment exams showed significant delay.

Discussions began with the center’s multidisciplinary team including neurologists, pathologists, neuroradiologists, and obstetricians who cared for both the mothers and the babies.

The experts examined the placentas and found some characteristic COVID changes and presence of the COVID virus. This was accompanied by increased markers for inflammation and a severe reduction in a hormone critical for placental health and brain development.

Examining the infant’s autopsy findings further raised suspicions of maternal transmission, something that had not been documented before.

Coauthor Ali G. Saad, MD, pediatric and perinatal pathology director at Miami, said, “I have seen literally thousands of brains in autopsies over the last 14 years, and this was the most dramatic case of leukoencephalopathy or loss of white matter in a patient with no significant reason. That’s what triggered the investigation.”
 

 

 

Mothers had very different presentations

Coauthor Michael J. Paidas, MD, with the department of obstetrics, gynecology, and reproductive sciences at Miami, pointed out that the circumstances of the two mothers, who were in their 20s, were very different.

One mother delivered at 32 weeks and had a very severe COVID presentation and spent a month in the intensive care unit. The team decided to deliver the child to save the mother, Dr. Paidas said.

In contrast, the other mother had asymptomatic COVID infection in the second trimester and delivered at full term.

He said one of the early suspicions in the babies’ presentations was hypoxic ischemic encephalopathy. “But it wasn’t lack of blood flow to the placenta that caused this,” he said. “As best we can tell, it was the viral infection.”
 

Instances are rare

The researchers emphasized that these instances are rare and have not been seen before or since the period of this study to their knowledge.

Dr. Duara said, “This is something we want to alert the medical community to more than the general public. We do not want the lay public to be panicked. We’re trying to understand what made these two pregnancies different, so we can direct research towards protecting vulnerable babies.”

Previous data have indicated a relatively benign status in infants who test negative for the COVID virus after birth. Dr. Benny added that COVID vaccination has been found safe in pregnancy and both vaccination and breastfeeding can help passage of antibodies to the infant and help protect the baby. Because these cases happened in the early days of the pandemic, no vaccines were available.

Dr. Paidas received funding from BioIncept to study hypoxic-ischemic encephalopathy with Preimplantation Factor, is a scientific advisory board member, and has stock options. Dr. Paidas and coauthor Dr. Jayakumar are coinventors of SPIKENET, University of Miami, patent pending 2023. The other authors have no conflicts of interest to disclose.

Researchers have found for the first time that COVID infection has crossed the placenta and caused brain damage in two newborns, according to a study published online today in Pediatrics .

One of the infants died at 13 months and the other remained in hospice care at time of manuscript submission.

Lead author Merline Benny, MD, with the division of neonatology, department of pediatrics at University of Miami, and colleagues briefed reporters today ahead of the release.

Zelda Calvert
Dr. Shahnaz Duara

“This is a first,” said senior author Shahnaz Duara, MD, medical director of the Neonatal Intensive Care Unit at Holtz Children’s Hospital, Miami, explaining it is the first study to confirm cross-placental SARS-CoV-2 transmission leading to brain injury in a newborn.
 

Both infants negative for the virus at birth

The two infants were admitted in the early days of the pandemic in the Delta wave to the neonatal ICU at Holtz Children’s Hospital at University of Miami/Jackson Memorial Medical Center.

Both infants tested negative for the virus at birth, but had significantly elevated SARS-CoV-2 antibodies in their blood, indicating that either antibodies crossed the placenta, or the virus crossed and the immune response was the baby’s.

Dr. Benny explained that the researchers have seen, to this point, more than 700 mother/infant pairs in whom the mother tested positive for COVID in Jackson hospital.

Most who tested positive for COVID were asymptomatic and most of the mothers and infants left the hospital without complications.

“However, (these) two babies had a very unusual clinical picture,” Dr. Benny said.

Those infants were born to mothers who became COVID positive in the second trimester and delivered a few weeks later.

Seizures started on day 1 of life

The babies began to seize from the first day of life. They had profound low tone (hypotonia) in their clinical exam, Dr. Benny explained.

“We had absolutely no good explanation for the early seizures and the degree of brain injury we saw,” Dr. Duara said.

Dr. Benny said that as their bodies grew, they had very small head circumference. Unlike some babies born with the Zika virus, these babies were not microcephalic at birth. Brain imaging on the two babies indicated significant brain atrophy, and neurodevelopment exams showed significant delay.

Discussions began with the center’s multidisciplinary team including neurologists, pathologists, neuroradiologists, and obstetricians who cared for both the mothers and the babies.

The experts examined the placentas and found some characteristic COVID changes and presence of the COVID virus. This was accompanied by increased markers for inflammation and a severe reduction in a hormone critical for placental health and brain development.

Examining the infant’s autopsy findings further raised suspicions of maternal transmission, something that had not been documented before.

Coauthor Ali G. Saad, MD, pediatric and perinatal pathology director at Miami, said, “I have seen literally thousands of brains in autopsies over the last 14 years, and this was the most dramatic case of leukoencephalopathy or loss of white matter in a patient with no significant reason. That’s what triggered the investigation.”
 

 

 

Mothers had very different presentations

Coauthor Michael J. Paidas, MD, with the department of obstetrics, gynecology, and reproductive sciences at Miami, pointed out that the circumstances of the two mothers, who were in their 20s, were very different.

One mother delivered at 32 weeks and had a very severe COVID presentation and spent a month in the intensive care unit. The team decided to deliver the child to save the mother, Dr. Paidas said.

In contrast, the other mother had asymptomatic COVID infection in the second trimester and delivered at full term.

He said one of the early suspicions in the babies’ presentations was hypoxic ischemic encephalopathy. “But it wasn’t lack of blood flow to the placenta that caused this,” he said. “As best we can tell, it was the viral infection.”
 

Instances are rare

The researchers emphasized that these instances are rare and have not been seen before or since the period of this study to their knowledge.

Dr. Duara said, “This is something we want to alert the medical community to more than the general public. We do not want the lay public to be panicked. We’re trying to understand what made these two pregnancies different, so we can direct research towards protecting vulnerable babies.”

Previous data have indicated a relatively benign status in infants who test negative for the COVID virus after birth. Dr. Benny added that COVID vaccination has been found safe in pregnancy and both vaccination and breastfeeding can help passage of antibodies to the infant and help protect the baby. Because these cases happened in the early days of the pandemic, no vaccines were available.

Dr. Paidas received funding from BioIncept to study hypoxic-ischemic encephalopathy with Preimplantation Factor, is a scientific advisory board member, and has stock options. Dr. Paidas and coauthor Dr. Jayakumar are coinventors of SPIKENET, University of Miami, patent pending 2023. The other authors have no conflicts of interest to disclose.

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Nurse makes millions selling her licensing exam study sheets

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Marcia Frellick

Emergency nurse Stephanee Beggs, RN, BSN, has made more than $2 million in three years selling her handwritten guides to study for the National Council Licensure Examination (NCLEX).

Ms. Beggs, 28, sells one-page study sheets or bundles of sheets, sometimes with colorful drawings, conversation bubbles and underlining, that boil down concepts for particular conditions into easy-to-understand language.

The biggest seller on Ms. Beggs’ online marketplace Etsy site, RNExplained, is a bundle of study guides covering eight core nursing classes. The notes range in price from $2 to $150. More than 70,000 customers have bought the $60 bundle, according to the website.

Ms. Beggs’ business developed in a “very unintentional” way when COVID hit with just months left in her nursing program at Mount Saint Mary’s University, Los Angeles, she told this news organization.

Classes had switched to Zoom, and she had no one to study with as she prepared to take her board exams.

“The best way I know how to study is to teach things out loud. But because I had nobody to teach out loud to, I would literally teach them to the wall,” Ms. Beggs said. “I would record myself so I could play it back and teach myself these topics that were hard for me to understand.”

Just for fun, she says, she posted them on TikTok and the responses started flowing in, with followers asking where she was selling the sheets. She now has more than 660,000 TikTok followers and 9 million likes.

Ms. Beggs said that every sheet highlights a condition, and she has made 308 of them.

Traditional classroom lessons typically teach one medical condition in 5-6 pages, Ms. Beggs said. “I go straight to the point.”

One reviewer on Ms. Beggs’ Etsy site appreciated the handwritten notes, calling them “simplified and concise.” Another commented: “Definitely helped me pass my last exam.”

Ms. Beggs says that her notes may seem simple, but each page represents comprehensive research.

“I have to go through not just one source of information to make sure my information is factual,” Ms. Beggs says. “What you teach in California might be a little different than what you teach in Florida. It’s very meticulous. The lab values will be a little different everywhere you go.”

She acknowledges her competition, noting that there are many other study guides for the NCLEX and nursing courses.
 

Nursing groups weigh in

Dawn Kappel, spokesperson for the National Council of State Boards of Nursing, which oversees NCLEX, said in an interview that “NCSBN has no issue with the current content of Stephanee Beggs’ business venture.”

For many students, the study guides will be helpful, especially for visual learners, said Carole Kenner, PhD, RN, dean and professor in the School of Nursing and Health Sciences at The College of New Jersey.

But for students “who are less confident in their knowledge, I would want to see a lot more in-depth explanation and rationale,” Dr. Kenner said.

“Since the NCLEX is moving to more cased-based scenarios, the next-gen unfolding cases, you really have to understand a lot of the rationale.”

The notes remind Dr. Kenner of traditional flash cards. “I don’t think it will work for all students, but even the fanciest of onsite review courses are useful to everyone,” she said.
 

 

 

‘Not cutting corners’

As an emergency nurse, Ms. Beggs said, “I have the experience as a nurse to show people that what you are learning will be seen in real life.”

“The way I teach my brand is not to take shortcuts. I love to teach to understand rather than teaching to memorize for an exam.”

She said she sees her guides as a supplement to learning, not a replacement.

“It’s not cutting corners,” she says. “I condense a medical condition that could take a very long time to understand and break it into layman’s terms.”

Ms. Beggs said when people hear about the $2 million, they often ask her whether she plans to give up her shifts in the emergency department for the more lucrative venture.

The answer is no, at least not yet.

“Aside from teaching, I genuinely love being at the bedside,” Ms. Beggs said. “I don’t foresee myself leaving that for good for as long as I can handle both.” She acknowledged, though, that her business now takes up most of her time.  

“I love everything about both aspects, so it’s hard for me to choose.”

A version of this article first appeared on Medscape.com.

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Emergency nurse Stephanee Beggs, RN, BSN, has made more than $2 million in three years selling her handwritten guides to study for the National Council Licensure Examination (NCLEX).

Ms. Beggs, 28, sells one-page study sheets or bundles of sheets, sometimes with colorful drawings, conversation bubbles and underlining, that boil down concepts for particular conditions into easy-to-understand language.

The biggest seller on Ms. Beggs’ online marketplace Etsy site, RNExplained, is a bundle of study guides covering eight core nursing classes. The notes range in price from $2 to $150. More than 70,000 customers have bought the $60 bundle, according to the website.

Ms. Beggs’ business developed in a “very unintentional” way when COVID hit with just months left in her nursing program at Mount Saint Mary’s University, Los Angeles, she told this news organization.

Classes had switched to Zoom, and she had no one to study with as she prepared to take her board exams.

“The best way I know how to study is to teach things out loud. But because I had nobody to teach out loud to, I would literally teach them to the wall,” Ms. Beggs said. “I would record myself so I could play it back and teach myself these topics that were hard for me to understand.”

Just for fun, she says, she posted them on TikTok and the responses started flowing in, with followers asking where she was selling the sheets. She now has more than 660,000 TikTok followers and 9 million likes.

Ms. Beggs said that every sheet highlights a condition, and she has made 308 of them.

Traditional classroom lessons typically teach one medical condition in 5-6 pages, Ms. Beggs said. “I go straight to the point.”

One reviewer on Ms. Beggs’ Etsy site appreciated the handwritten notes, calling them “simplified and concise.” Another commented: “Definitely helped me pass my last exam.”

Ms. Beggs says that her notes may seem simple, but each page represents comprehensive research.

“I have to go through not just one source of information to make sure my information is factual,” Ms. Beggs says. “What you teach in California might be a little different than what you teach in Florida. It’s very meticulous. The lab values will be a little different everywhere you go.”

She acknowledges her competition, noting that there are many other study guides for the NCLEX and nursing courses.
 

Nursing groups weigh in

Dawn Kappel, spokesperson for the National Council of State Boards of Nursing, which oversees NCLEX, said in an interview that “NCSBN has no issue with the current content of Stephanee Beggs’ business venture.”

For many students, the study guides will be helpful, especially for visual learners, said Carole Kenner, PhD, RN, dean and professor in the School of Nursing and Health Sciences at The College of New Jersey.

But for students “who are less confident in their knowledge, I would want to see a lot more in-depth explanation and rationale,” Dr. Kenner said.

“Since the NCLEX is moving to more cased-based scenarios, the next-gen unfolding cases, you really have to understand a lot of the rationale.”

The notes remind Dr. Kenner of traditional flash cards. “I don’t think it will work for all students, but even the fanciest of onsite review courses are useful to everyone,” she said.
 

 

 

‘Not cutting corners’

As an emergency nurse, Ms. Beggs said, “I have the experience as a nurse to show people that what you are learning will be seen in real life.”

“The way I teach my brand is not to take shortcuts. I love to teach to understand rather than teaching to memorize for an exam.”

She said she sees her guides as a supplement to learning, not a replacement.

“It’s not cutting corners,” she says. “I condense a medical condition that could take a very long time to understand and break it into layman’s terms.”

Ms. Beggs said when people hear about the $2 million, they often ask her whether she plans to give up her shifts in the emergency department for the more lucrative venture.

The answer is no, at least not yet.

“Aside from teaching, I genuinely love being at the bedside,” Ms. Beggs said. “I don’t foresee myself leaving that for good for as long as I can handle both.” She acknowledged, though, that her business now takes up most of her time.  

“I love everything about both aspects, so it’s hard for me to choose.”

A version of this article first appeared on Medscape.com.

Emergency nurse Stephanee Beggs, RN, BSN, has made more than $2 million in three years selling her handwritten guides to study for the National Council Licensure Examination (NCLEX).

Ms. Beggs, 28, sells one-page study sheets or bundles of sheets, sometimes with colorful drawings, conversation bubbles and underlining, that boil down concepts for particular conditions into easy-to-understand language.

The biggest seller on Ms. Beggs’ online marketplace Etsy site, RNExplained, is a bundle of study guides covering eight core nursing classes. The notes range in price from $2 to $150. More than 70,000 customers have bought the $60 bundle, according to the website.

Ms. Beggs’ business developed in a “very unintentional” way when COVID hit with just months left in her nursing program at Mount Saint Mary’s University, Los Angeles, she told this news organization.

Classes had switched to Zoom, and she had no one to study with as she prepared to take her board exams.

“The best way I know how to study is to teach things out loud. But because I had nobody to teach out loud to, I would literally teach them to the wall,” Ms. Beggs said. “I would record myself so I could play it back and teach myself these topics that were hard for me to understand.”

Just for fun, she says, she posted them on TikTok and the responses started flowing in, with followers asking where she was selling the sheets. She now has more than 660,000 TikTok followers and 9 million likes.

Ms. Beggs said that every sheet highlights a condition, and she has made 308 of them.

Traditional classroom lessons typically teach one medical condition in 5-6 pages, Ms. Beggs said. “I go straight to the point.”

One reviewer on Ms. Beggs’ Etsy site appreciated the handwritten notes, calling them “simplified and concise.” Another commented: “Definitely helped me pass my last exam.”

Ms. Beggs says that her notes may seem simple, but each page represents comprehensive research.

“I have to go through not just one source of information to make sure my information is factual,” Ms. Beggs says. “What you teach in California might be a little different than what you teach in Florida. It’s very meticulous. The lab values will be a little different everywhere you go.”

She acknowledges her competition, noting that there are many other study guides for the NCLEX and nursing courses.
 

Nursing groups weigh in

Dawn Kappel, spokesperson for the National Council of State Boards of Nursing, which oversees NCLEX, said in an interview that “NCSBN has no issue with the current content of Stephanee Beggs’ business venture.”

For many students, the study guides will be helpful, especially for visual learners, said Carole Kenner, PhD, RN, dean and professor in the School of Nursing and Health Sciences at The College of New Jersey.

But for students “who are less confident in their knowledge, I would want to see a lot more in-depth explanation and rationale,” Dr. Kenner said.

“Since the NCLEX is moving to more cased-based scenarios, the next-gen unfolding cases, you really have to understand a lot of the rationale.”

The notes remind Dr. Kenner of traditional flash cards. “I don’t think it will work for all students, but even the fanciest of onsite review courses are useful to everyone,” she said.
 

 

 

‘Not cutting corners’

As an emergency nurse, Ms. Beggs said, “I have the experience as a nurse to show people that what you are learning will be seen in real life.”

“The way I teach my brand is not to take shortcuts. I love to teach to understand rather than teaching to memorize for an exam.”

She said she sees her guides as a supplement to learning, not a replacement.

“It’s not cutting corners,” she says. “I condense a medical condition that could take a very long time to understand and break it into layman’s terms.”

Ms. Beggs said when people hear about the $2 million, they often ask her whether she plans to give up her shifts in the emergency department for the more lucrative venture.

The answer is no, at least not yet.

“Aside from teaching, I genuinely love being at the bedside,” Ms. Beggs said. “I don’t foresee myself leaving that for good for as long as I can handle both.” She acknowledged, though, that her business now takes up most of her time.  

“I love everything about both aspects, so it’s hard for me to choose.”

A version of this article first appeared on Medscape.com.

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COVID can mimic prostate cancer symptoms

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David King Keller, PhD

If a patient’s prostate-specific antigen (PSA) spikes 2 points in just 90 days, what is your first thought? This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter  painkillers are not helping, you’d think, “check for metastases,” right?

That patient was me in late January 2023.

As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.

With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.

To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6. 

But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit. 
 

The COVID effect

I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.

Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.

That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
 

COVID-19 pain

What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.

To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.

References

1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.

2. Cinislioglu AE et al. Urology. 2022;159:16-21.

3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.

Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.

A version of this article first appeared on Medscape.com.

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Author(s)
David King Keller, PhD
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David King Keller, PhD

If a patient’s prostate-specific antigen (PSA) spikes 2 points in just 90 days, what is your first thought? This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter  painkillers are not helping, you’d think, “check for metastases,” right?

That patient was me in late January 2023.

As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.

With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.

To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6. 

But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit. 
 

The COVID effect

I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.

Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.

That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
 

COVID-19 pain

What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.

To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.

References

1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.

2. Cinislioglu AE et al. Urology. 2022;159:16-21.

3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.

Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.

A version of this article first appeared on Medscape.com.

If a patient’s prostate-specific antigen (PSA) spikes 2 points in just 90 days, what is your first thought? This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter  painkillers are not helping, you’d think, “check for metastases,” right?

That patient was me in late January 2023.

As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.

With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.

To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6. 

But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit. 
 

The COVID effect

I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.

Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.

That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
 

COVID-19 pain

What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.

To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.

References

1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.

2. Cinislioglu AE et al. Urology. 2022;159:16-21.

3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.

Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.

A version of this article first appeared on Medscape.com.

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NOVIDs: Do some have the genes to dodge COVID?

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Kathleen Doheny

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

 

 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

 

 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

A version of this article first appeared on Medscape.com.

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As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

 

 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

 

 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

A version of this article first appeared on Medscape.com.

As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.

There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”

Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.

He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
 

How many NOVIDs?

As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.

As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.

While the exact number of people who have remained uninfected isn’t known with certainty, a review of comprehensive serologic data shows about 15% of Americans may not have gotten infected with COVID, Eric Topol, MD, editor-in-chief of Medscape (WebMD’s sister site for medical professionals) wrote in his substack Ground Truths.

But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.

Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
 

Resistance research

In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”

Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.

Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.

“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’

“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.

He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.

“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.

Genetic resistance has been found for other diseases, such as HIV.

“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.

However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”

What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”

Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.

The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.

The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
 

 

 

The testing ... or lack thereof factor

The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.

“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”

Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
 

Susceptibility research

“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.

Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.

More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
 

NOVIDs’ habits run the gamut

As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.

Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.

He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”

And does he worry his number will eventually be up? “Not at this point, no,” he said.

Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.

“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”

However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.

Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.

Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.

Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.

When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”

One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.

In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.

She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”

Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.

At this point, she said she doesn’t worry about getting infected but remains careful.

Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
 

 

 

Bragging rights?

Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it. 

And what about those who wear a “NOVID” T-shirt?

“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”

Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.

Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■

A version of this article first appeared on Medscape.com.

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Factors linked with increased VTE risk in COVID outpatients

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Marcia Frellick

Overall risk for venous thromboembolism (VTE) in nonhospitalized COVID-19 patients is low, but some of those patients may have factors that increase the risk and warrant more surveillance, according to a new retrospective cohort study.

Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.

The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
 

Nearly 400,000 patients studied

Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.

VTE risk was low overall for ambulatory COVID patients.

“It is a reassuring study,” Dr. Fang said in an interview.

The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
 

Factors linked with high VTE risk

They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.

The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
 

Are routine anticoagulants justified?

Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.

“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
 

Mild COVID VTE risk similar to general population

The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.

Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.

Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
 

Physicians should inform patients of their higher risk

“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.

”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.

Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
 

 

 

Unanswered questions

Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.

However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.

One is the change in the COVID variant landscape.

“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.

The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.

Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”

Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.

Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.

The research was funded through Patient-Centered Outcomes Research Institute.

Dr. Hopkins reports no relevant financial relationships.

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Marcia Frellick
Author(s)
Marcia Frellick

Overall risk for venous thromboembolism (VTE) in nonhospitalized COVID-19 patients is low, but some of those patients may have factors that increase the risk and warrant more surveillance, according to a new retrospective cohort study.

Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.

The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
 

Nearly 400,000 patients studied

Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.

VTE risk was low overall for ambulatory COVID patients.

“It is a reassuring study,” Dr. Fang said in an interview.

The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
 

Factors linked with high VTE risk

They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.

The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
 

Are routine anticoagulants justified?

Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.

“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
 

Mild COVID VTE risk similar to general population

The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.

Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.

Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
 

Physicians should inform patients of their higher risk

“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.

”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.

Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
 

 

 

Unanswered questions

Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.

However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.

One is the change in the COVID variant landscape.

“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.

The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.

Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”

Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.

Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.

The research was funded through Patient-Centered Outcomes Research Institute.

Dr. Hopkins reports no relevant financial relationships.

Overall risk for venous thromboembolism (VTE) in nonhospitalized COVID-19 patients is low, but some of those patients may have factors that increase the risk and warrant more surveillance, according to a new retrospective cohort study.

Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.

The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
 

Nearly 400,000 patients studied

Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.

VTE risk was low overall for ambulatory COVID patients.

“It is a reassuring study,” Dr. Fang said in an interview.

The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
 

Factors linked with high VTE risk

They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.

The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
 

Are routine anticoagulants justified?

Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.

“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
 

Mild COVID VTE risk similar to general population

The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.

Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.

Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
 

Physicians should inform patients of their higher risk

“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.

”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.

Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
 

 

 

Unanswered questions

Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.

However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.

One is the change in the COVID variant landscape.

“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.

The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.

Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”

Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.

Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.

The research was funded through Patient-Centered Outcomes Research Institute.

Dr. Hopkins reports no relevant financial relationships.

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‘Breakthrough’ study: Diabetes drug helps prevent long COVID

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Carolyn Crist

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

A version of this article first appeared on WebMD.com.

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Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

A version of this article first appeared on WebMD.com.

Metformin appears to play a role in preventing long COVID when taken early during a COVID-19 infection, according to preprints with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.

In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection. 

“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.

Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.

The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.

The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.

The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.

Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant. 

The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.

Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.

The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.

When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.

Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.

At the same time, the study authors caution that more research is needed. 

“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”

Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.

Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.

The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.

“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals. 

Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.

“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”

Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19. 

Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”

“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”

A version of this article first appeared on WebMD.com.

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Effect of the COVID-19 Pandemic on Resources, Other Diseases, and Healthcare Workers’ Experience

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Viren Kaul, MD, FCCP, FACP

 

Introduction

The COVID-19 pandemic has changed the healthcare system in a multitude of ways, affecting healthcare capacity, treatment of other illnesses, and wellness as well as professional retention of healthcare workers.1-3 During the peak of the COVID-19 pandemic, healthcare capacity was tested and resources were used up quickly.1 As the pandemic has progressed, healthcare systems have had to decide how to proceed with lessons learned, reassessing the environment of care delivery, healthcare supply chains, workforce structures, communication systems, and scientific collaboration as well as policy frameworks in healthcare.4 

There have been both immediate effects and long-term consequences of the delay in care for other conditions.2,5 One stark example of this is in cancer care, where screening and procedures were postponed or canceled due to the pandemic with a resulting predicted 2% increase in cancer mortality in the next 10 years.2 The care of heart disease, chronic illnesses, and other viruses has also been similarly negatively impacted by the COVID-19 pandemic due to similar delays in diagnosis and treatment.5-7 

The impact on healthcare workers has also been profound.3 Occupational stress from the pandemic has correlated with increased depression and posttraumatic stress disorder (PTSD) among other mental health diseases in healthcare workers.3 In a survey of neurosurgery residents, 26.1% of physicians reported feeling burnt out, and 65.8% were worried that they would not be able to reach surgical milestones.8,9 Among respiratory therapists, a hard hit group during this time, 79% reported burnout.10 Additionally, more healthcare workers left the field during the pandemic, with 15 million lost jobs. Future recovery of jobs looks bleak in some settings, like long-term care and among assistants and aides.11 Overall, the long-term outcomes of these resource, disease, and mental health disruptions need to be assessed and solutions created to maintain a quality and effective healthcare system, with ample resources and measures to account for disease increases and address the impact on providers. 

Healthcare Capacity and Resources 

With COVID-19 affecting over 100 million in the United States as of March 1, 2023, the impact on healthcare resources since the start of the pandemic has been immense.12 With 5% to 38% of hospitalized patients being admitted to the intensive care unit (ICU) and 75% to 88% of those patients requiring mechanical ventilation, a huge strain was placed on resources during and after the pandemic.1 

The question of balancing resources for other hospital needs while tending to patients with COVID-19 has been an ongoing discussion at many levels.1 One core resource concern is the lack of staff. In a survey of 77 different countries, including physicians (41%), nurses (40%), respiratory therapists (11%), and advanced practice providers (8%), 15% reported insufficient intensivists and 32% reported insufficient ICU nursing staff during March and April of 2020.1 A lack of hospital and care space that led to reallocation of limited-care acute care space was a concern. Thirteen percent reported a shortage of hospital ICU beds, while others reported the conversion of postoperative recovery rooms (20%) and operating rooms (12%) for patients with COVID-19.1 

Along with staff and care space concerns, hospital survey respondents reported that healthcare equipment was also challenged. Access to COVID-19 testing was one concern, with only 35% of respondents reporting availability for all patients at the beginning of the pandemic, and 56% reporting availability for only select patients based on symptom severity.1 Access to personal protective equipment (PPE) was also affected, with PPE always available according to 83% to 95% of respondents but just 35% having access to N95 masks.1 Additionally, 26% reported that there were no respirators in their hospital, and 11% reported limited ventilators.1 

Although resource depletion is a problem, studies have looked at public health measures that helped to mitigate this issue. With proper public health planning and implementation, such as physical distancing, aggressive testing, contact tracing, and increased hospital capacity, by freeing up existing resources or adding additional support, public health modeling showed that resources may be able to withstand the increase.13 Development of reallocation models at local, state, national, and international levels is an important step to be able to deal with future public health crises.14

The long-term impact from the pandemic includes disruption in the physical environment of healthcare, production, supply chain, staff structure, and workforce alterations.4 For example, the physical shape of healthcare facilities is changing to accommodate increasing volumes and decrease the risk of spreading disease.4 To accommodate the burden on staffing structure and workforce alteration, telehealth gained a prominent role.4 All in all, the pandemic has changed the healthcare system; however, institutions, organizations, and policy makers need to evaluate which measures were impactful and should be considered for long-term inclusion in healthcare practice. 

Impact on Other Diseases: Cancer, Heart Disease, Chronic Illnesses, and Other Viruses 

The treatment of other new and existing conditions has also been affected by the pandemic. Cancer, especially, is a disease of concern. Elective surgeries and screening were halted or altered during the pandemic, which is modeled to lead to higher cancer mortality in years to come.2 The most affected cancers were breast, lung, and colorectal cancer.2 A study of colorectal cancer screening showed that colonoscopies were delayed due to COVID-19 and that gastroenterology visits declined by 49% to 61%.15 This will likely lead to delayed cancer diagnoses and possible increases in mortality.15 Breast cancer screening was also delayed and many patients continued to avoid it for various reasons such as fears of contracting COVID-19 infection in healthcare facilities, and the economic effects of the pandemic such as job loss and healthcare coverage loss.16 These delays will result in an estimated potential 0.52% overall increase in breast cancer deaths by 2030.17

A study of 368 patients from Spain showed a 56.5% decrease in hospital admissions, usually related to heart attacks, in March and April of 2020, compared to January and February 2020.18,19 For other chronic illnesses, the pandemic resulted in decreased preventative care and management.20 The care of other infections similarly suffered. The World Health Organization announced that the number of patients receiving treatment for tuberculosis (TB) dropped by 1 million, setting the disease mitigation back considerably.20 An estimated 500,000 more people died in 2020 from TB.21 The drastic shift in focus to COVID-19 care during this period will continue to have a profound impact on other diseases like these for many years post-pandemic.

Provider Experience and Mental Health Outcomes 

The impact on provider experiences and mental health has been immense. One study of 510 healthcare providers (HCPs) and first responders found that occupational stress from the pandemic correlated with psychiatric symptoms, including depression, PTSD, insomnia, and generalized anxiety.3 Occupational stress also correlated with one’s likelihood to leave the medical field and trouble doing work they had once loved.3 Half of the healthcare workers surveyed indicated a decreased likelihood of staying in their current profession after the pandemic.3 

Other studies have also looked at specific subspecialties and impact on trainees during the pandemic. In neurosurgery, for example, resident burnout is high, at 26.1%.9 Additionally, the lack of surgeries in the pandemic made 65.8% of neurosurgery residents anxious about meeting career milestones.9 Respiratory therapists, a highly impacted group, also experienced burnout, reporting higher levels in those who worked more in the ICU. Another study identified several themes in the concerns reported by healthcare workers during the pandemic era including “changes in personal life and enhanced negative affect,” “gaining experience, normalization, and adaptation to the pandemic,” and “mental health considerations.”22 

Some studies have investigated ways to mitigate this dissatisfaction with the healthcare field post-pandemic. Intrapreneurship, reverse mentoring, and democratized learning all had a reported positive impact on employee experience and retention during this time.23 Intrapreneurship describes entrepreneurship within an existing organization, while reverse mentoring and democratized learning refer to newer employees teaching older employees and communicative learning on a breadth of topics. Other studies have examined the necessity of having mental health resources available, and that these resources need to be multi-stage and individualistic as well as specific to certain stressors HCPs faced during the pandemic.22 

Conclusion and Future Directions

The COVID-19 pandemic had stark effects on the healthcare system, impacting resources and capacity, care of other diseases, and provider mental health and experiences.1-3 After the chaos of the pandemic, many questions remain. What needs to be done now by health systems and HCPs? How can we learn from the challenges and the effects on capacity to change the healthcare workflow in times of crisis and in the present? How do we mitigate the impact of the pandemic on diagnosis and management of diseases? And how do we continue to provide healthcare workers with proper mental health and professional resources now, not just in times of stress, and encourage the future generation to pursue careers in healthcare? 

These are all the questions the pandemic has left us with, and more studies and initiatives are needed to investigate solutions to these issues. The COVID-19 pandemic left behind valuable lessons and changed the healthcare system, disease management, and staffing for many. Now is the time to pick up the pieces and strategize on how to make our existing system more effective for workers and patients post pandemic. 

References

  1. Wahlster S, Sharma M, Lewis AK, et al. The coronavirus disease 2019 pandemic's effect on critical care resources and health-care providers: a global survey. Chest. 2021;159(2):619-633. doi:10.1016/j.chest.2020.09.070

  2. Malagón T, Yong JHE, Tope P, Miller WH Jr, Franco EL; McGill task force on the impact of COVID-19 on cancer control and care. Predicted long-term impact of COVID-19 pandemic-related care delays on cancer mortality in Canada. Int J Cancer. 2022;150(8):1244-1254. doi:10.1002/ijc.33884

  3. Hendrickson RC, Slevin RA, Hoerster KD, et al. The impact of the COVID-19 pandemic on mental health, occupational functioning, and professional retention among health care workers and first responders. J Gen Intern Med. 2022;37(2):397-408. doi:10.1007/s11606-021-07252-z

  4. Davis B, Bankhead-Kendall BK, Dumas RP. A review of COVID-19's impact on modern medical systems from a health organization management perspective. Health Technol (Berl). 2022;12(4):815-824. doi:10.1007/s12553-022-00660-z

  5. Rosenbaum L. The untold toll - the pandemic's effects on patients without COVID-19. N Engl J Med. 2020;382(24):2368-2371. doi:10.1056/NEJMms2009984

  6. Hacker KA, Briss PA, Richardson L, Wright J, Petersen R. COVID-19 and chronic disease: the impact now and in the future. Prev Chronic Dis. 2021;18:E62. doi:10.5888/pcd18.210086

  7. Roberts L. How COVID hurt the fight against other dangerous diseases. Nature. 2021;592(7855):502-504. doi:10.1038/d41586-021-01022-x

  8. Jalili M, Niroomand M, Hadavand F, Zeinali K, Fotouhi A. Burnout among healthcare professionals during COVID-19 pandemic: a cross-sectional study. Int Arch Occup Environ Health. 2021;94(6):1345-1352. doi:10.1007/s00420-021-01695-x

  9. Khalafallah AM, Lam S, Gami A, et al. A national survey on the impact of the COVID-19 pandemic upon burnout and career satisfaction among neurosurgery residents. J Clin Neurosci. 2020;80:137-142. doi:10.1016/j.jocn.2020.08.012

  10. Miller AG, Roberts KJ, Smith BJ, et al. Prevalence of burnout among respiratory therapists amidst the COVID-19 pandemic. Respir Care. 2021;respcare.09283. doi:10.4187/respcare.09283

  11. Frogner BK, Dill JS. Tracking turnover among health care workers during the COVID-19 pandemic: a cross-sectional study. JAMA Health Forum. 2022;3(4):e220371. doi:10.1001/jamahealthforum.2022.0371

  12. CDC COVID data tracker. Centers for Disease Control and Prevention. Accessed December 22, 2022. http://covid-data-tracker/#datatracker-home. 

  13. Barrett K, Khan YA, Mac S, Ximenes R, Naimark DMJ, Sander B. Estimation of COVID-19-induced depletion of hospital resources in Ontario, Canada. CMAJ. 2020;192(24):E640-E646. doi:10.1503/cmaj.200715

  14. Kaul V, Chahal J, Schrarstzhaupt IN, et al. Lessons learned from a global perspective of COVID-19. Clin Chest Med. 2022 Nov. 24. [online ahead of print]. doi:10.1016/j.ccm.2022.11.020

  15. Issaka RB, Somsouk M. Colorectal cancer screening and prevention in the COVID-19 Era. JAMA Health Forum. 2020;1(5):e200588. doi:10.1001/jamahealthforum.2020.0588

  16. Freer PE. The impact of the COVID-19 pandemic on breast imaging. Radiol Clin North Am. 2021;59(1):1-11. doi:10.1016/j.rcl.2020.09.008

  17. Alagoz O, Lowry KP, Kurian AW, et al. Impact of the COVID-19 pandemic on breast cancer mortality in the US: estimates from collaborative simulation modeling. J Natl Cancer Inst. 2021;113(11):1484-1494. doi:10.1093/jnci/djab097

  18. Jiménez-Blanco Bravo M, Cordero Pereda D, Sánchez Vega D, et al. Heart failure in the time of COVID-19. Cardiology. 2020;145(8):481-484. doi:10.1159/000509181

  19. Frankfurter C, Buchan TA, Kobulnik J, et al. Reduced rate of hospital presentations for heart failure during the COVID-19 pandemic in Toronto, Canada. Can J Cardiol. 2020;36(10):1680-1684. doi:10.1016/j.cjca.2020.07.006

  20. Hacker KA, Briss PA, Richardson L, Wright J, Petersen R. COVID-19 and chronic disease: The impact now and in the future. Prev Chronic Dis. 2021;18:E62. doi:10.5888/pcd18.210086

  21. Roberts L. How COVID hurt the fight against other dangerous diseases. Nature. 2021;592(7855):502-504. doi:10.1038/d41586-021-01022-x

  22. Eftekhar Ardebili M, Naserbakht M, Bernstein C, Alazmani-Noodeh F, Hakimi H, Ranjbar H. Healthcare providers experience of working during the COVID-19 pandemic: a qualitative study. Am J Infect Control. 2021;49(5):547-554. doi:10.1016/j.ajic.2020.10.001

  23. Jayathilake HD, Daud D, Eaw HC, Annuar N. Employee development and retention of generation-Z employees in the post-covid-19 workplace: a conceptual framework. Benchmarking: An International Journal. 2021;28(7):2343-2364. doi:10.1108/bij-06-2020-0311 


 

Author and Disclosure Information

Viren Kaul, MD, FCCP, FACP 

Division Chief, Pulmonary Medicine and Intensivist 
Crouse Health Clinical Assistant Professor of Medicine 
Upstate Medical University 

Syracuse, NY

Dr. Viren Kaul has no disclosures to report. 

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Viren Kaul, MD, FCCP, FACP 

Division Chief, Pulmonary Medicine and Intensivist 
Crouse Health Clinical Assistant Professor of Medicine 
Upstate Medical University 

Syracuse, NY

Dr. Viren Kaul has no disclosures to report. 

Author and Disclosure Information

Viren Kaul, MD, FCCP, FACP 

Division Chief, Pulmonary Medicine and Intensivist 
Crouse Health Clinical Assistant Professor of Medicine 
Upstate Medical University 

Syracuse, NY

Dr. Viren Kaul has no disclosures to report. 

 

Introduction

The COVID-19 pandemic has changed the healthcare system in a multitude of ways, affecting healthcare capacity, treatment of other illnesses, and wellness as well as professional retention of healthcare workers.1-3 During the peak of the COVID-19 pandemic, healthcare capacity was tested and resources were used up quickly.1 As the pandemic has progressed, healthcare systems have had to decide how to proceed with lessons learned, reassessing the environment of care delivery, healthcare supply chains, workforce structures, communication systems, and scientific collaboration as well as policy frameworks in healthcare.4 

There have been both immediate effects and long-term consequences of the delay in care for other conditions.2,5 One stark example of this is in cancer care, where screening and procedures were postponed or canceled due to the pandemic with a resulting predicted 2% increase in cancer mortality in the next 10 years.2 The care of heart disease, chronic illnesses, and other viruses has also been similarly negatively impacted by the COVID-19 pandemic due to similar delays in diagnosis and treatment.5-7 

The impact on healthcare workers has also been profound.3 Occupational stress from the pandemic has correlated with increased depression and posttraumatic stress disorder (PTSD) among other mental health diseases in healthcare workers.3 In a survey of neurosurgery residents, 26.1% of physicians reported feeling burnt out, and 65.8% were worried that they would not be able to reach surgical milestones.8,9 Among respiratory therapists, a hard hit group during this time, 79% reported burnout.10 Additionally, more healthcare workers left the field during the pandemic, with 15 million lost jobs. Future recovery of jobs looks bleak in some settings, like long-term care and among assistants and aides.11 Overall, the long-term outcomes of these resource, disease, and mental health disruptions need to be assessed and solutions created to maintain a quality and effective healthcare system, with ample resources and measures to account for disease increases and address the impact on providers. 

Healthcare Capacity and Resources 

With COVID-19 affecting over 100 million in the United States as of March 1, 2023, the impact on healthcare resources since the start of the pandemic has been immense.12 With 5% to 38% of hospitalized patients being admitted to the intensive care unit (ICU) and 75% to 88% of those patients requiring mechanical ventilation, a huge strain was placed on resources during and after the pandemic.1 

The question of balancing resources for other hospital needs while tending to patients with COVID-19 has been an ongoing discussion at many levels.1 One core resource concern is the lack of staff. In a survey of 77 different countries, including physicians (41%), nurses (40%), respiratory therapists (11%), and advanced practice providers (8%), 15% reported insufficient intensivists and 32% reported insufficient ICU nursing staff during March and April of 2020.1 A lack of hospital and care space that led to reallocation of limited-care acute care space was a concern. Thirteen percent reported a shortage of hospital ICU beds, while others reported the conversion of postoperative recovery rooms (20%) and operating rooms (12%) for patients with COVID-19.1 

Along with staff and care space concerns, hospital survey respondents reported that healthcare equipment was also challenged. Access to COVID-19 testing was one concern, with only 35% of respondents reporting availability for all patients at the beginning of the pandemic, and 56% reporting availability for only select patients based on symptom severity.1 Access to personal protective equipment (PPE) was also affected, with PPE always available according to 83% to 95% of respondents but just 35% having access to N95 masks.1 Additionally, 26% reported that there were no respirators in their hospital, and 11% reported limited ventilators.1 

Although resource depletion is a problem, studies have looked at public health measures that helped to mitigate this issue. With proper public health planning and implementation, such as physical distancing, aggressive testing, contact tracing, and increased hospital capacity, by freeing up existing resources or adding additional support, public health modeling showed that resources may be able to withstand the increase.13 Development of reallocation models at local, state, national, and international levels is an important step to be able to deal with future public health crises.14

The long-term impact from the pandemic includes disruption in the physical environment of healthcare, production, supply chain, staff structure, and workforce alterations.4 For example, the physical shape of healthcare facilities is changing to accommodate increasing volumes and decrease the risk of spreading disease.4 To accommodate the burden on staffing structure and workforce alteration, telehealth gained a prominent role.4 All in all, the pandemic has changed the healthcare system; however, institutions, organizations, and policy makers need to evaluate which measures were impactful and should be considered for long-term inclusion in healthcare practice. 

Impact on Other Diseases: Cancer, Heart Disease, Chronic Illnesses, and Other Viruses 

The treatment of other new and existing conditions has also been affected by the pandemic. Cancer, especially, is a disease of concern. Elective surgeries and screening were halted or altered during the pandemic, which is modeled to lead to higher cancer mortality in years to come.2 The most affected cancers were breast, lung, and colorectal cancer.2 A study of colorectal cancer screening showed that colonoscopies were delayed due to COVID-19 and that gastroenterology visits declined by 49% to 61%.15 This will likely lead to delayed cancer diagnoses and possible increases in mortality.15 Breast cancer screening was also delayed and many patients continued to avoid it for various reasons such as fears of contracting COVID-19 infection in healthcare facilities, and the economic effects of the pandemic such as job loss and healthcare coverage loss.16 These delays will result in an estimated potential 0.52% overall increase in breast cancer deaths by 2030.17

A study of 368 patients from Spain showed a 56.5% decrease in hospital admissions, usually related to heart attacks, in March and April of 2020, compared to January and February 2020.18,19 For other chronic illnesses, the pandemic resulted in decreased preventative care and management.20 The care of other infections similarly suffered. The World Health Organization announced that the number of patients receiving treatment for tuberculosis (TB) dropped by 1 million, setting the disease mitigation back considerably.20 An estimated 500,000 more people died in 2020 from TB.21 The drastic shift in focus to COVID-19 care during this period will continue to have a profound impact on other diseases like these for many years post-pandemic.

Provider Experience and Mental Health Outcomes 

The impact on provider experiences and mental health has been immense. One study of 510 healthcare providers (HCPs) and first responders found that occupational stress from the pandemic correlated with psychiatric symptoms, including depression, PTSD, insomnia, and generalized anxiety.3 Occupational stress also correlated with one’s likelihood to leave the medical field and trouble doing work they had once loved.3 Half of the healthcare workers surveyed indicated a decreased likelihood of staying in their current profession after the pandemic.3 

Other studies have also looked at specific subspecialties and impact on trainees during the pandemic. In neurosurgery, for example, resident burnout is high, at 26.1%.9 Additionally, the lack of surgeries in the pandemic made 65.8% of neurosurgery residents anxious about meeting career milestones.9 Respiratory therapists, a highly impacted group, also experienced burnout, reporting higher levels in those who worked more in the ICU. Another study identified several themes in the concerns reported by healthcare workers during the pandemic era including “changes in personal life and enhanced negative affect,” “gaining experience, normalization, and adaptation to the pandemic,” and “mental health considerations.”22 

Some studies have investigated ways to mitigate this dissatisfaction with the healthcare field post-pandemic. Intrapreneurship, reverse mentoring, and democratized learning all had a reported positive impact on employee experience and retention during this time.23 Intrapreneurship describes entrepreneurship within an existing organization, while reverse mentoring and democratized learning refer to newer employees teaching older employees and communicative learning on a breadth of topics. Other studies have examined the necessity of having mental health resources available, and that these resources need to be multi-stage and individualistic as well as specific to certain stressors HCPs faced during the pandemic.22 

Conclusion and Future Directions

The COVID-19 pandemic had stark effects on the healthcare system, impacting resources and capacity, care of other diseases, and provider mental health and experiences.1-3 After the chaos of the pandemic, many questions remain. What needs to be done now by health systems and HCPs? How can we learn from the challenges and the effects on capacity to change the healthcare workflow in times of crisis and in the present? How do we mitigate the impact of the pandemic on diagnosis and management of diseases? And how do we continue to provide healthcare workers with proper mental health and professional resources now, not just in times of stress, and encourage the future generation to pursue careers in healthcare? 

These are all the questions the pandemic has left us with, and more studies and initiatives are needed to investigate solutions to these issues. The COVID-19 pandemic left behind valuable lessons and changed the healthcare system, disease management, and staffing for many. Now is the time to pick up the pieces and strategize on how to make our existing system more effective for workers and patients post pandemic. 

 

Introduction

The COVID-19 pandemic has changed the healthcare system in a multitude of ways, affecting healthcare capacity, treatment of other illnesses, and wellness as well as professional retention of healthcare workers.1-3 During the peak of the COVID-19 pandemic, healthcare capacity was tested and resources were used up quickly.1 As the pandemic has progressed, healthcare systems have had to decide how to proceed with lessons learned, reassessing the environment of care delivery, healthcare supply chains, workforce structures, communication systems, and scientific collaboration as well as policy frameworks in healthcare.4 

There have been both immediate effects and long-term consequences of the delay in care for other conditions.2,5 One stark example of this is in cancer care, where screening and procedures were postponed or canceled due to the pandemic with a resulting predicted 2% increase in cancer mortality in the next 10 years.2 The care of heart disease, chronic illnesses, and other viruses has also been similarly negatively impacted by the COVID-19 pandemic due to similar delays in diagnosis and treatment.5-7 

The impact on healthcare workers has also been profound.3 Occupational stress from the pandemic has correlated with increased depression and posttraumatic stress disorder (PTSD) among other mental health diseases in healthcare workers.3 In a survey of neurosurgery residents, 26.1% of physicians reported feeling burnt out, and 65.8% were worried that they would not be able to reach surgical milestones.8,9 Among respiratory therapists, a hard hit group during this time, 79% reported burnout.10 Additionally, more healthcare workers left the field during the pandemic, with 15 million lost jobs. Future recovery of jobs looks bleak in some settings, like long-term care and among assistants and aides.11 Overall, the long-term outcomes of these resource, disease, and mental health disruptions need to be assessed and solutions created to maintain a quality and effective healthcare system, with ample resources and measures to account for disease increases and address the impact on providers. 

Healthcare Capacity and Resources 

With COVID-19 affecting over 100 million in the United States as of March 1, 2023, the impact on healthcare resources since the start of the pandemic has been immense.12 With 5% to 38% of hospitalized patients being admitted to the intensive care unit (ICU) and 75% to 88% of those patients requiring mechanical ventilation, a huge strain was placed on resources during and after the pandemic.1 

The question of balancing resources for other hospital needs while tending to patients with COVID-19 has been an ongoing discussion at many levels.1 One core resource concern is the lack of staff. In a survey of 77 different countries, including physicians (41%), nurses (40%), respiratory therapists (11%), and advanced practice providers (8%), 15% reported insufficient intensivists and 32% reported insufficient ICU nursing staff during March and April of 2020.1 A lack of hospital and care space that led to reallocation of limited-care acute care space was a concern. Thirteen percent reported a shortage of hospital ICU beds, while others reported the conversion of postoperative recovery rooms (20%) and operating rooms (12%) for patients with COVID-19.1 

Along with staff and care space concerns, hospital survey respondents reported that healthcare equipment was also challenged. Access to COVID-19 testing was one concern, with only 35% of respondents reporting availability for all patients at the beginning of the pandemic, and 56% reporting availability for only select patients based on symptom severity.1 Access to personal protective equipment (PPE) was also affected, with PPE always available according to 83% to 95% of respondents but just 35% having access to N95 masks.1 Additionally, 26% reported that there were no respirators in their hospital, and 11% reported limited ventilators.1 

Although resource depletion is a problem, studies have looked at public health measures that helped to mitigate this issue. With proper public health planning and implementation, such as physical distancing, aggressive testing, contact tracing, and increased hospital capacity, by freeing up existing resources or adding additional support, public health modeling showed that resources may be able to withstand the increase.13 Development of reallocation models at local, state, national, and international levels is an important step to be able to deal with future public health crises.14

The long-term impact from the pandemic includes disruption in the physical environment of healthcare, production, supply chain, staff structure, and workforce alterations.4 For example, the physical shape of healthcare facilities is changing to accommodate increasing volumes and decrease the risk of spreading disease.4 To accommodate the burden on staffing structure and workforce alteration, telehealth gained a prominent role.4 All in all, the pandemic has changed the healthcare system; however, institutions, organizations, and policy makers need to evaluate which measures were impactful and should be considered for long-term inclusion in healthcare practice. 

Impact on Other Diseases: Cancer, Heart Disease, Chronic Illnesses, and Other Viruses 

The treatment of other new and existing conditions has also been affected by the pandemic. Cancer, especially, is a disease of concern. Elective surgeries and screening were halted or altered during the pandemic, which is modeled to lead to higher cancer mortality in years to come.2 The most affected cancers were breast, lung, and colorectal cancer.2 A study of colorectal cancer screening showed that colonoscopies were delayed due to COVID-19 and that gastroenterology visits declined by 49% to 61%.15 This will likely lead to delayed cancer diagnoses and possible increases in mortality.15 Breast cancer screening was also delayed and many patients continued to avoid it for various reasons such as fears of contracting COVID-19 infection in healthcare facilities, and the economic effects of the pandemic such as job loss and healthcare coverage loss.16 These delays will result in an estimated potential 0.52% overall increase in breast cancer deaths by 2030.17

A study of 368 patients from Spain showed a 56.5% decrease in hospital admissions, usually related to heart attacks, in March and April of 2020, compared to January and February 2020.18,19 For other chronic illnesses, the pandemic resulted in decreased preventative care and management.20 The care of other infections similarly suffered. The World Health Organization announced that the number of patients receiving treatment for tuberculosis (TB) dropped by 1 million, setting the disease mitigation back considerably.20 An estimated 500,000 more people died in 2020 from TB.21 The drastic shift in focus to COVID-19 care during this period will continue to have a profound impact on other diseases like these for many years post-pandemic.

Provider Experience and Mental Health Outcomes 

The impact on provider experiences and mental health has been immense. One study of 510 healthcare providers (HCPs) and first responders found that occupational stress from the pandemic correlated with psychiatric symptoms, including depression, PTSD, insomnia, and generalized anxiety.3 Occupational stress also correlated with one’s likelihood to leave the medical field and trouble doing work they had once loved.3 Half of the healthcare workers surveyed indicated a decreased likelihood of staying in their current profession after the pandemic.3 

Other studies have also looked at specific subspecialties and impact on trainees during the pandemic. In neurosurgery, for example, resident burnout is high, at 26.1%.9 Additionally, the lack of surgeries in the pandemic made 65.8% of neurosurgery residents anxious about meeting career milestones.9 Respiratory therapists, a highly impacted group, also experienced burnout, reporting higher levels in those who worked more in the ICU. Another study identified several themes in the concerns reported by healthcare workers during the pandemic era including “changes in personal life and enhanced negative affect,” “gaining experience, normalization, and adaptation to the pandemic,” and “mental health considerations.”22 

Some studies have investigated ways to mitigate this dissatisfaction with the healthcare field post-pandemic. Intrapreneurship, reverse mentoring, and democratized learning all had a reported positive impact on employee experience and retention during this time.23 Intrapreneurship describes entrepreneurship within an existing organization, while reverse mentoring and democratized learning refer to newer employees teaching older employees and communicative learning on a breadth of topics. Other studies have examined the necessity of having mental health resources available, and that these resources need to be multi-stage and individualistic as well as specific to certain stressors HCPs faced during the pandemic.22 

Conclusion and Future Directions

The COVID-19 pandemic had stark effects on the healthcare system, impacting resources and capacity, care of other diseases, and provider mental health and experiences.1-3 After the chaos of the pandemic, many questions remain. What needs to be done now by health systems and HCPs? How can we learn from the challenges and the effects on capacity to change the healthcare workflow in times of crisis and in the present? How do we mitigate the impact of the pandemic on diagnosis and management of diseases? And how do we continue to provide healthcare workers with proper mental health and professional resources now, not just in times of stress, and encourage the future generation to pursue careers in healthcare? 

These are all the questions the pandemic has left us with, and more studies and initiatives are needed to investigate solutions to these issues. The COVID-19 pandemic left behind valuable lessons and changed the healthcare system, disease management, and staffing for many. Now is the time to pick up the pieces and strategize on how to make our existing system more effective for workers and patients post pandemic. 

References

  1. Wahlster S, Sharma M, Lewis AK, et al. The coronavirus disease 2019 pandemic's effect on critical care resources and health-care providers: a global survey. Chest. 2021;159(2):619-633. doi:10.1016/j.chest.2020.09.070

  2. Malagón T, Yong JHE, Tope P, Miller WH Jr, Franco EL; McGill task force on the impact of COVID-19 on cancer control and care. Predicted long-term impact of COVID-19 pandemic-related care delays on cancer mortality in Canada. Int J Cancer. 2022;150(8):1244-1254. doi:10.1002/ijc.33884

  3. Hendrickson RC, Slevin RA, Hoerster KD, et al. The impact of the COVID-19 pandemic on mental health, occupational functioning, and professional retention among health care workers and first responders. J Gen Intern Med. 2022;37(2):397-408. doi:10.1007/s11606-021-07252-z

  4. Davis B, Bankhead-Kendall BK, Dumas RP. A review of COVID-19's impact on modern medical systems from a health organization management perspective. Health Technol (Berl). 2022;12(4):815-824. doi:10.1007/s12553-022-00660-z

  5. Rosenbaum L. The untold toll - the pandemic's effects on patients without COVID-19. N Engl J Med. 2020;382(24):2368-2371. doi:10.1056/NEJMms2009984

  6. Hacker KA, Briss PA, Richardson L, Wright J, Petersen R. COVID-19 and chronic disease: the impact now and in the future. Prev Chronic Dis. 2021;18:E62. doi:10.5888/pcd18.210086

  7. Roberts L. How COVID hurt the fight against other dangerous diseases. Nature. 2021;592(7855):502-504. doi:10.1038/d41586-021-01022-x

  8. Jalili M, Niroomand M, Hadavand F, Zeinali K, Fotouhi A. Burnout among healthcare professionals during COVID-19 pandemic: a cross-sectional study. Int Arch Occup Environ Health. 2021;94(6):1345-1352. doi:10.1007/s00420-021-01695-x

  9. Khalafallah AM, Lam S, Gami A, et al. A national survey on the impact of the COVID-19 pandemic upon burnout and career satisfaction among neurosurgery residents. J Clin Neurosci. 2020;80:137-142. doi:10.1016/j.jocn.2020.08.012

  10. Miller AG, Roberts KJ, Smith BJ, et al. Prevalence of burnout among respiratory therapists amidst the COVID-19 pandemic. Respir Care. 2021;respcare.09283. doi:10.4187/respcare.09283

  11. Frogner BK, Dill JS. Tracking turnover among health care workers during the COVID-19 pandemic: a cross-sectional study. JAMA Health Forum. 2022;3(4):e220371. doi:10.1001/jamahealthforum.2022.0371

  12. CDC COVID data tracker. Centers for Disease Control and Prevention. Accessed December 22, 2022. http://covid-data-tracker/#datatracker-home. 

  13. Barrett K, Khan YA, Mac S, Ximenes R, Naimark DMJ, Sander B. Estimation of COVID-19-induced depletion of hospital resources in Ontario, Canada. CMAJ. 2020;192(24):E640-E646. doi:10.1503/cmaj.200715

  14. Kaul V, Chahal J, Schrarstzhaupt IN, et al. Lessons learned from a global perspective of COVID-19. Clin Chest Med. 2022 Nov. 24. [online ahead of print]. doi:10.1016/j.ccm.2022.11.020

  15. Issaka RB, Somsouk M. Colorectal cancer screening and prevention in the COVID-19 Era. JAMA Health Forum. 2020;1(5):e200588. doi:10.1001/jamahealthforum.2020.0588

  16. Freer PE. The impact of the COVID-19 pandemic on breast imaging. Radiol Clin North Am. 2021;59(1):1-11. doi:10.1016/j.rcl.2020.09.008

  17. Alagoz O, Lowry KP, Kurian AW, et al. Impact of the COVID-19 pandemic on breast cancer mortality in the US: estimates from collaborative simulation modeling. J Natl Cancer Inst. 2021;113(11):1484-1494. doi:10.1093/jnci/djab097

  18. Jiménez-Blanco Bravo M, Cordero Pereda D, Sánchez Vega D, et al. Heart failure in the time of COVID-19. Cardiology. 2020;145(8):481-484. doi:10.1159/000509181

  19. Frankfurter C, Buchan TA, Kobulnik J, et al. Reduced rate of hospital presentations for heart failure during the COVID-19 pandemic in Toronto, Canada. Can J Cardiol. 2020;36(10):1680-1684. doi:10.1016/j.cjca.2020.07.006

  20. Hacker KA, Briss PA, Richardson L, Wright J, Petersen R. COVID-19 and chronic disease: The impact now and in the future. Prev Chronic Dis. 2021;18:E62. doi:10.5888/pcd18.210086

  21. Roberts L. How COVID hurt the fight against other dangerous diseases. Nature. 2021;592(7855):502-504. doi:10.1038/d41586-021-01022-x

  22. Eftekhar Ardebili M, Naserbakht M, Bernstein C, Alazmani-Noodeh F, Hakimi H, Ranjbar H. Healthcare providers experience of working during the COVID-19 pandemic: a qualitative study. Am J Infect Control. 2021;49(5):547-554. doi:10.1016/j.ajic.2020.10.001

  23. Jayathilake HD, Daud D, Eaw HC, Annuar N. Employee development and retention of generation-Z employees in the post-covid-19 workplace: a conceptual framework. Benchmarking: An International Journal. 2021;28(7):2343-2364. doi:10.1108/bij-06-2020-0311 


 

References

  1. Wahlster S, Sharma M, Lewis AK, et al. The coronavirus disease 2019 pandemic's effect on critical care resources and health-care providers: a global survey. Chest. 2021;159(2):619-633. doi:10.1016/j.chest.2020.09.070

  2. Malagón T, Yong JHE, Tope P, Miller WH Jr, Franco EL; McGill task force on the impact of COVID-19 on cancer control and care. Predicted long-term impact of COVID-19 pandemic-related care delays on cancer mortality in Canada. Int J Cancer. 2022;150(8):1244-1254. doi:10.1002/ijc.33884

  3. Hendrickson RC, Slevin RA, Hoerster KD, et al. The impact of the COVID-19 pandemic on mental health, occupational functioning, and professional retention among health care workers and first responders. J Gen Intern Med. 2022;37(2):397-408. doi:10.1007/s11606-021-07252-z

  4. Davis B, Bankhead-Kendall BK, Dumas RP. A review of COVID-19's impact on modern medical systems from a health organization management perspective. Health Technol (Berl). 2022;12(4):815-824. doi:10.1007/s12553-022-00660-z

  5. Rosenbaum L. The untold toll - the pandemic's effects on patients without COVID-19. N Engl J Med. 2020;382(24):2368-2371. doi:10.1056/NEJMms2009984

  6. Hacker KA, Briss PA, Richardson L, Wright J, Petersen R. COVID-19 and chronic disease: the impact now and in the future. Prev Chronic Dis. 2021;18:E62. doi:10.5888/pcd18.210086

  7. Roberts L. How COVID hurt the fight against other dangerous diseases. Nature. 2021;592(7855):502-504. doi:10.1038/d41586-021-01022-x

  8. Jalili M, Niroomand M, Hadavand F, Zeinali K, Fotouhi A. Burnout among healthcare professionals during COVID-19 pandemic: a cross-sectional study. Int Arch Occup Environ Health. 2021;94(6):1345-1352. doi:10.1007/s00420-021-01695-x

  9. Khalafallah AM, Lam S, Gami A, et al. A national survey on the impact of the COVID-19 pandemic upon burnout and career satisfaction among neurosurgery residents. J Clin Neurosci. 2020;80:137-142. doi:10.1016/j.jocn.2020.08.012

  10. Miller AG, Roberts KJ, Smith BJ, et al. Prevalence of burnout among respiratory therapists amidst the COVID-19 pandemic. Respir Care. 2021;respcare.09283. doi:10.4187/respcare.09283

  11. Frogner BK, Dill JS. Tracking turnover among health care workers during the COVID-19 pandemic: a cross-sectional study. JAMA Health Forum. 2022;3(4):e220371. doi:10.1001/jamahealthforum.2022.0371

  12. CDC COVID data tracker. Centers for Disease Control and Prevention. Accessed December 22, 2022. http://covid-data-tracker/#datatracker-home. 

  13. Barrett K, Khan YA, Mac S, Ximenes R, Naimark DMJ, Sander B. Estimation of COVID-19-induced depletion of hospital resources in Ontario, Canada. CMAJ. 2020;192(24):E640-E646. doi:10.1503/cmaj.200715

  14. Kaul V, Chahal J, Schrarstzhaupt IN, et al. Lessons learned from a global perspective of COVID-19. Clin Chest Med. 2022 Nov. 24. [online ahead of print]. doi:10.1016/j.ccm.2022.11.020

  15. Issaka RB, Somsouk M. Colorectal cancer screening and prevention in the COVID-19 Era. JAMA Health Forum. 2020;1(5):e200588. doi:10.1001/jamahealthforum.2020.0588

  16. Freer PE. The impact of the COVID-19 pandemic on breast imaging. Radiol Clin North Am. 2021;59(1):1-11. doi:10.1016/j.rcl.2020.09.008

  17. Alagoz O, Lowry KP, Kurian AW, et al. Impact of the COVID-19 pandemic on breast cancer mortality in the US: estimates from collaborative simulation modeling. J Natl Cancer Inst. 2021;113(11):1484-1494. doi:10.1093/jnci/djab097

  18. Jiménez-Blanco Bravo M, Cordero Pereda D, Sánchez Vega D, et al. Heart failure in the time of COVID-19. Cardiology. 2020;145(8):481-484. doi:10.1159/000509181

  19. Frankfurter C, Buchan TA, Kobulnik J, et al. Reduced rate of hospital presentations for heart failure during the COVID-19 pandemic in Toronto, Canada. Can J Cardiol. 2020;36(10):1680-1684. doi:10.1016/j.cjca.2020.07.006

  20. Hacker KA, Briss PA, Richardson L, Wright J, Petersen R. COVID-19 and chronic disease: The impact now and in the future. Prev Chronic Dis. 2021;18:E62. doi:10.5888/pcd18.210086

  21. Roberts L. How COVID hurt the fight against other dangerous diseases. Nature. 2021;592(7855):502-504. doi:10.1038/d41586-021-01022-x

  22. Eftekhar Ardebili M, Naserbakht M, Bernstein C, Alazmani-Noodeh F, Hakimi H, Ranjbar H. Healthcare providers experience of working during the COVID-19 pandemic: a qualitative study. Am J Infect Control. 2021;49(5):547-554. doi:10.1016/j.ajic.2020.10.001

  23. Jayathilake HD, Daud D, Eaw HC, Annuar N. Employee development and retention of generation-Z employees in the post-covid-19 workplace: a conceptual framework. Benchmarking: An International Journal. 2021;28(7):2343-2364. doi:10.1108/bij-06-2020-0311 


 

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Even mild COVID is hard on the brain

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Megan Brooks

Even mild cases of COVID-19 can affect the function and structure of the brain, early research suggests.

“Our results suggest a severe pattern of changes in how the brain communicates as well as its structure, mainly in people with anxiety and depression with long-COVID syndrome, which affects so many people,” study investigator Clarissa Yasuda, MD, PhD, from University of Campinas, São Paulo, said in a news release.

“The magnitude of these changes suggests that they could lead to problems with memory and thinking skills, so we need to be exploring holistic treatments even for people mildly affected by COVID-19,” Dr. Yasuda added.

The findings were released March 6 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Brain shrinkage

Some studies have shown a high prevalence of symptoms of anxiety and depression in COVID-19 survivors, but few have investigated the associated cerebral changes, Dr. Yasuda told this news organization.

The study included 254 adults (177 women, 77 men, median age 41 years) who had mild COVID-19 a median of 82 days earlier. A total of 102 had symptoms of both anxiety and depression, and 152 had no such symptoms.

On brain imaging, those with COVID-19 and anxiety and depression had atrophy in the limbic area of the brain, which plays a role in memory and emotional processing.

No shrinkage in this area was evident in people who had COVID-19 without anxiety and depression or in a healthy control group of individuals without COVID-19.

The researchers also observed a “severe” pattern of abnormal cerebral functional connectivity in those with COVID-19 and anxiety and depression. 

In this functional connectivity analysis, individuals with COVID-19 and anxiety and depression had widespread functional changes in each of the 12 networks assessed, while those with COVID-19 but without symptoms of anxiety and depression showed changes in only 5 networks.
 

Mechanisms unclear

“Unfortunately, the underpinning mechanisms associated with brain changes and neuropsychiatric dysfunction after COVID-19 infection are unclear,” Dr. Yasuda told this news organization.

“Some studies have demonstrated an association between symptoms of anxiety and depression with inflammation. However, we hypothesize that these cerebral alterations may result from a more complex interaction of social, psychological, and systemic stressors, including inflammation. It is indeed intriguing that such alterations are present in individuals who presented mild acute infection,” Dr. Yasuda added.

“Symptoms of anxiety and depression are frequently observed after COVID-19 and are part of long-COVID syndrome for some individuals. These symptoms require adequate treatment to improve the quality of life, cognition, and work capacity,” she said.

Treating these symptoms may induce “brain plasticity, which may result in some degree of gray matter increase and eventually prevent further structural and functional damage,” Dr. Yasuda said. 

A limitation of the study was that symptoms of anxiety and depression were self-reported, meaning people may have misjudged or misreported symptoms.

Commenting on the findings for this news organization, Cyrus Raji, MD, PhD, with the Mallinckrodt Institute of Radiology, Washington University, St. Louis, said the idea that COVID-19 is bad for the brain isn’t new. Dr. Raji was not involved with the study.

Early in the pandemic, Dr. Raji and colleagues published a paper detailing COVID-19’s effects on the brain, and Dr. Raji followed it up with a TED talk on the subject.

“Within the growing framework of what we already know about COVID-19 infection and its adverse effects on the brain, this work incrementally adds to this knowledge by identifying functional and structural neuroimaging abnormalities related to anxiety and depression in persons suffering from COVID-19 infection,” Dr. Raji said.

The study was supported by the São Paulo Research Foundation. The authors have no relevant disclosures. Raji is a consultant for Brainreader, Apollo Health, Pacific Neuroscience Foundation, and Neurevolution LLC.

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Even mild cases of COVID-19 can affect the function and structure of the brain, early research suggests.

“Our results suggest a severe pattern of changes in how the brain communicates as well as its structure, mainly in people with anxiety and depression with long-COVID syndrome, which affects so many people,” study investigator Clarissa Yasuda, MD, PhD, from University of Campinas, São Paulo, said in a news release.

“The magnitude of these changes suggests that they could lead to problems with memory and thinking skills, so we need to be exploring holistic treatments even for people mildly affected by COVID-19,” Dr. Yasuda added.

The findings were released March 6 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Brain shrinkage

Some studies have shown a high prevalence of symptoms of anxiety and depression in COVID-19 survivors, but few have investigated the associated cerebral changes, Dr. Yasuda told this news organization.

The study included 254 adults (177 women, 77 men, median age 41 years) who had mild COVID-19 a median of 82 days earlier. A total of 102 had symptoms of both anxiety and depression, and 152 had no such symptoms.

On brain imaging, those with COVID-19 and anxiety and depression had atrophy in the limbic area of the brain, which plays a role in memory and emotional processing.

No shrinkage in this area was evident in people who had COVID-19 without anxiety and depression or in a healthy control group of individuals without COVID-19.

The researchers also observed a “severe” pattern of abnormal cerebral functional connectivity in those with COVID-19 and anxiety and depression. 

In this functional connectivity analysis, individuals with COVID-19 and anxiety and depression had widespread functional changes in each of the 12 networks assessed, while those with COVID-19 but without symptoms of anxiety and depression showed changes in only 5 networks.
 

Mechanisms unclear

“Unfortunately, the underpinning mechanisms associated with brain changes and neuropsychiatric dysfunction after COVID-19 infection are unclear,” Dr. Yasuda told this news organization.

“Some studies have demonstrated an association between symptoms of anxiety and depression with inflammation. However, we hypothesize that these cerebral alterations may result from a more complex interaction of social, psychological, and systemic stressors, including inflammation. It is indeed intriguing that such alterations are present in individuals who presented mild acute infection,” Dr. Yasuda added.

“Symptoms of anxiety and depression are frequently observed after COVID-19 and are part of long-COVID syndrome for some individuals. These symptoms require adequate treatment to improve the quality of life, cognition, and work capacity,” she said.

Treating these symptoms may induce “brain plasticity, which may result in some degree of gray matter increase and eventually prevent further structural and functional damage,” Dr. Yasuda said. 

A limitation of the study was that symptoms of anxiety and depression were self-reported, meaning people may have misjudged or misreported symptoms.

Commenting on the findings for this news organization, Cyrus Raji, MD, PhD, with the Mallinckrodt Institute of Radiology, Washington University, St. Louis, said the idea that COVID-19 is bad for the brain isn’t new. Dr. Raji was not involved with the study.

Early in the pandemic, Dr. Raji and colleagues published a paper detailing COVID-19’s effects on the brain, and Dr. Raji followed it up with a TED talk on the subject.

“Within the growing framework of what we already know about COVID-19 infection and its adverse effects on the brain, this work incrementally adds to this knowledge by identifying functional and structural neuroimaging abnormalities related to anxiety and depression in persons suffering from COVID-19 infection,” Dr. Raji said.

The study was supported by the São Paulo Research Foundation. The authors have no relevant disclosures. Raji is a consultant for Brainreader, Apollo Health, Pacific Neuroscience Foundation, and Neurevolution LLC.

Even mild cases of COVID-19 can affect the function and structure of the brain, early research suggests.

“Our results suggest a severe pattern of changes in how the brain communicates as well as its structure, mainly in people with anxiety and depression with long-COVID syndrome, which affects so many people,” study investigator Clarissa Yasuda, MD, PhD, from University of Campinas, São Paulo, said in a news release.

“The magnitude of these changes suggests that they could lead to problems with memory and thinking skills, so we need to be exploring holistic treatments even for people mildly affected by COVID-19,” Dr. Yasuda added.

The findings were released March 6 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
 

Brain shrinkage

Some studies have shown a high prevalence of symptoms of anxiety and depression in COVID-19 survivors, but few have investigated the associated cerebral changes, Dr. Yasuda told this news organization.

The study included 254 adults (177 women, 77 men, median age 41 years) who had mild COVID-19 a median of 82 days earlier. A total of 102 had symptoms of both anxiety and depression, and 152 had no such symptoms.

On brain imaging, those with COVID-19 and anxiety and depression had atrophy in the limbic area of the brain, which plays a role in memory and emotional processing.

No shrinkage in this area was evident in people who had COVID-19 without anxiety and depression or in a healthy control group of individuals without COVID-19.

The researchers also observed a “severe” pattern of abnormal cerebral functional connectivity in those with COVID-19 and anxiety and depression. 

In this functional connectivity analysis, individuals with COVID-19 and anxiety and depression had widespread functional changes in each of the 12 networks assessed, while those with COVID-19 but without symptoms of anxiety and depression showed changes in only 5 networks.
 

Mechanisms unclear

“Unfortunately, the underpinning mechanisms associated with brain changes and neuropsychiatric dysfunction after COVID-19 infection are unclear,” Dr. Yasuda told this news organization.

“Some studies have demonstrated an association between symptoms of anxiety and depression with inflammation. However, we hypothesize that these cerebral alterations may result from a more complex interaction of social, psychological, and systemic stressors, including inflammation. It is indeed intriguing that such alterations are present in individuals who presented mild acute infection,” Dr. Yasuda added.

“Symptoms of anxiety and depression are frequently observed after COVID-19 and are part of long-COVID syndrome for some individuals. These symptoms require adequate treatment to improve the quality of life, cognition, and work capacity,” she said.

Treating these symptoms may induce “brain plasticity, which may result in some degree of gray matter increase and eventually prevent further structural and functional damage,” Dr. Yasuda said. 

A limitation of the study was that symptoms of anxiety and depression were self-reported, meaning people may have misjudged or misreported symptoms.

Commenting on the findings for this news organization, Cyrus Raji, MD, PhD, with the Mallinckrodt Institute of Radiology, Washington University, St. Louis, said the idea that COVID-19 is bad for the brain isn’t new. Dr. Raji was not involved with the study.

Early in the pandemic, Dr. Raji and colleagues published a paper detailing COVID-19’s effects on the brain, and Dr. Raji followed it up with a TED talk on the subject.

“Within the growing framework of what we already know about COVID-19 infection and its adverse effects on the brain, this work incrementally adds to this knowledge by identifying functional and structural neuroimaging abnormalities related to anxiety and depression in persons suffering from COVID-19 infection,” Dr. Raji said.

The study was supported by the São Paulo Research Foundation. The authors have no relevant disclosures. Raji is a consultant for Brainreader, Apollo Health, Pacific Neuroscience Foundation, and Neurevolution LLC.

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Prone positioning curbs need for intubation in nonintubated COVID-19 patients

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Heidi Splete

Prone positioning significantly reduced the need for intubation among nonintubated adults with COVID-19, as indicated by data from a new meta-analysis of more than 2,000 individuals.

The use of prone positioning for nonintubated patients (so-called “awake prone positioning”) has been common since the early days of the COVID-19 pandemic. Prone positioning is more comfortable for patients, and it entails no additional cost. Also, awake prone positioning is less labor intensive than prone positioning for intubated patients, said Jie Li, PhD, in a presentation at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

However, data on the specific benefits of prone positioning are lacking and contradictory, said Dr. Li, a respiratory care specialist at Rush University, Chicago.

Dr. Li and colleagues from a multinational research group found that outcomes were improved for patients who were treated with awake prone positioning – notably, fewer treatment failures at day 28 – but a pair of subsequent studies by other researchers showed contradictory outcomes.

For more definitive evidence, Dr. Li and colleagues conducted a systematic review and meta-analysis of 11 randomized, controlled trials and one unpublished study of awake prone positioning for patients with COVID-19. The studies were published between Jan. 1, 2020, and July 1, 2022, and included a total of 2,886 adult patients.

The primary outcome was the reported cumulative risk of intubation among nonintubated COVID-19 patients. Secondary outcomes included mortality, the need for escalating respiratory support, length of hospital length of stay, ICU admission, and adverse events.

Overall, awake prone positioning significantly reduced the intubation risk among nonintubated patients compared to standard care (risk ratio, 0.85).

A further subgroup analysis showed a significant reduction in risk for intubation among patients supported by high-flow nasal cannula or noninvasive ventilation (RR, 0.83).

However, no additional reduction in intubation risk occurred among patients who received conventional oxygen therapy (RR, 1.02).

Mortality rates were similar for patients who underwent awake prone positioning and those who underwent supine positioning (RR, 0.96), as was the need for additional respiratory support (RR, 1.03). The length of hospital stay, ICU admission, and adverse events were similar between the patients who underwent prone positioning and those who underwent supine positioning.

The findings were limited by several factors. There was a potential for confounding by disease severity, which may have increased the use of respiratory support devices, Li said in her presentation.

“Another factor we should not ignore is the daily duration of prone positioning,” said Dr. Li. More research is needed to identify which factors play the greatest roles in treatment success.

The current study was important in that it evaluated the current evidence of awake prone positioning, “particularly to identify the patients who benefit most from this treatment, in order to guide clinical practice,” Dr. Li said in an interview.

“Since early in the pandemic, awake prone positioning has been broadly utilized to treat patients with COVID-19,” she said. “In 2021, we published a multinational randomized controlled trial with over 1,100 patients enrolled and reported lower treatment failure. However, no significant differences of treatment failure were reported in several subsequent multicenter randomized, controlled trials published after our study.”

Dr. Li said she was not surprised by the findings, which reflect those of her team’s previously published meta-analysis. “The increased number of patients helps confirm our previous finding, even with the inclusion of several recently published randomized controlled trials,” she said.

For clinicians, “the current evidence supports the use of awake prone positioning for patients with COVID-19, particularly those who require advanced respiratory support from high-flow nasal cannula or noninvasive ventilation,” Dr. Li said.

The study received no outside funding. Dr. Li has relationships with AARC, Heyer, Aeorgen, the Rice Foundation, and Fisher & Paykel Healthcare.

A version of this article first appeared on Medscape.com.

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Prone positioning significantly reduced the need for intubation among nonintubated adults with COVID-19, as indicated by data from a new meta-analysis of more than 2,000 individuals.

The use of prone positioning for nonintubated patients (so-called “awake prone positioning”) has been common since the early days of the COVID-19 pandemic. Prone positioning is more comfortable for patients, and it entails no additional cost. Also, awake prone positioning is less labor intensive than prone positioning for intubated patients, said Jie Li, PhD, in a presentation at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

However, data on the specific benefits of prone positioning are lacking and contradictory, said Dr. Li, a respiratory care specialist at Rush University, Chicago.

Dr. Li and colleagues from a multinational research group found that outcomes were improved for patients who were treated with awake prone positioning – notably, fewer treatment failures at day 28 – but a pair of subsequent studies by other researchers showed contradictory outcomes.

For more definitive evidence, Dr. Li and colleagues conducted a systematic review and meta-analysis of 11 randomized, controlled trials and one unpublished study of awake prone positioning for patients with COVID-19. The studies were published between Jan. 1, 2020, and July 1, 2022, and included a total of 2,886 adult patients.

The primary outcome was the reported cumulative risk of intubation among nonintubated COVID-19 patients. Secondary outcomes included mortality, the need for escalating respiratory support, length of hospital length of stay, ICU admission, and adverse events.

Overall, awake prone positioning significantly reduced the intubation risk among nonintubated patients compared to standard care (risk ratio, 0.85).

A further subgroup analysis showed a significant reduction in risk for intubation among patients supported by high-flow nasal cannula or noninvasive ventilation (RR, 0.83).

However, no additional reduction in intubation risk occurred among patients who received conventional oxygen therapy (RR, 1.02).

Mortality rates were similar for patients who underwent awake prone positioning and those who underwent supine positioning (RR, 0.96), as was the need for additional respiratory support (RR, 1.03). The length of hospital stay, ICU admission, and adverse events were similar between the patients who underwent prone positioning and those who underwent supine positioning.

The findings were limited by several factors. There was a potential for confounding by disease severity, which may have increased the use of respiratory support devices, Li said in her presentation.

“Another factor we should not ignore is the daily duration of prone positioning,” said Dr. Li. More research is needed to identify which factors play the greatest roles in treatment success.

The current study was important in that it evaluated the current evidence of awake prone positioning, “particularly to identify the patients who benefit most from this treatment, in order to guide clinical practice,” Dr. Li said in an interview.

“Since early in the pandemic, awake prone positioning has been broadly utilized to treat patients with COVID-19,” she said. “In 2021, we published a multinational randomized controlled trial with over 1,100 patients enrolled and reported lower treatment failure. However, no significant differences of treatment failure were reported in several subsequent multicenter randomized, controlled trials published after our study.”

Dr. Li said she was not surprised by the findings, which reflect those of her team’s previously published meta-analysis. “The increased number of patients helps confirm our previous finding, even with the inclusion of several recently published randomized controlled trials,” she said.

For clinicians, “the current evidence supports the use of awake prone positioning for patients with COVID-19, particularly those who require advanced respiratory support from high-flow nasal cannula or noninvasive ventilation,” Dr. Li said.

The study received no outside funding. Dr. Li has relationships with AARC, Heyer, Aeorgen, the Rice Foundation, and Fisher & Paykel Healthcare.

A version of this article first appeared on Medscape.com.

Prone positioning significantly reduced the need for intubation among nonintubated adults with COVID-19, as indicated by data from a new meta-analysis of more than 2,000 individuals.

The use of prone positioning for nonintubated patients (so-called “awake prone positioning”) has been common since the early days of the COVID-19 pandemic. Prone positioning is more comfortable for patients, and it entails no additional cost. Also, awake prone positioning is less labor intensive than prone positioning for intubated patients, said Jie Li, PhD, in a presentation at the Critical Care Congress sponsored by the Society of Critical Care Medicine.

However, data on the specific benefits of prone positioning are lacking and contradictory, said Dr. Li, a respiratory care specialist at Rush University, Chicago.

Dr. Li and colleagues from a multinational research group found that outcomes were improved for patients who were treated with awake prone positioning – notably, fewer treatment failures at day 28 – but a pair of subsequent studies by other researchers showed contradictory outcomes.

For more definitive evidence, Dr. Li and colleagues conducted a systematic review and meta-analysis of 11 randomized, controlled trials and one unpublished study of awake prone positioning for patients with COVID-19. The studies were published between Jan. 1, 2020, and July 1, 2022, and included a total of 2,886 adult patients.

The primary outcome was the reported cumulative risk of intubation among nonintubated COVID-19 patients. Secondary outcomes included mortality, the need for escalating respiratory support, length of hospital length of stay, ICU admission, and adverse events.

Overall, awake prone positioning significantly reduced the intubation risk among nonintubated patients compared to standard care (risk ratio, 0.85).

A further subgroup analysis showed a significant reduction in risk for intubation among patients supported by high-flow nasal cannula or noninvasive ventilation (RR, 0.83).

However, no additional reduction in intubation risk occurred among patients who received conventional oxygen therapy (RR, 1.02).

Mortality rates were similar for patients who underwent awake prone positioning and those who underwent supine positioning (RR, 0.96), as was the need for additional respiratory support (RR, 1.03). The length of hospital stay, ICU admission, and adverse events were similar between the patients who underwent prone positioning and those who underwent supine positioning.

The findings were limited by several factors. There was a potential for confounding by disease severity, which may have increased the use of respiratory support devices, Li said in her presentation.

“Another factor we should not ignore is the daily duration of prone positioning,” said Dr. Li. More research is needed to identify which factors play the greatest roles in treatment success.

The current study was important in that it evaluated the current evidence of awake prone positioning, “particularly to identify the patients who benefit most from this treatment, in order to guide clinical practice,” Dr. Li said in an interview.

“Since early in the pandemic, awake prone positioning has been broadly utilized to treat patients with COVID-19,” she said. “In 2021, we published a multinational randomized controlled trial with over 1,100 patients enrolled and reported lower treatment failure. However, no significant differences of treatment failure were reported in several subsequent multicenter randomized, controlled trials published after our study.”

Dr. Li said she was not surprised by the findings, which reflect those of her team’s previously published meta-analysis. “The increased number of patients helps confirm our previous finding, even with the inclusion of several recently published randomized controlled trials,” she said.

For clinicians, “the current evidence supports the use of awake prone positioning for patients with COVID-19, particularly those who require advanced respiratory support from high-flow nasal cannula or noninvasive ventilation,” Dr. Li said.

The study received no outside funding. Dr. Li has relationships with AARC, Heyer, Aeorgen, the Rice Foundation, and Fisher & Paykel Healthcare.

A version of this article first appeared on Medscape.com.

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