Shari R. Lipner, MD, PhD

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Implantation mycoses such as chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma are a diverse group of fungal diseases that occur when a break in the skin allows the entry of the causative fungus. These diseases disproportionately affect individuals in low- and middle-income countries causing substantial disability, decreased quality of life, and severe social stigma.^1-3 Timely diagnosis and appropriate treatment are critical.

Chromoblastomycosis and mycetoma are designated as neglected tropical diseases, but research to improve their management is sparse, even compared to other neglected tropical diseases.^4,5 Since there are no global diagnostic and treatment guidelines to date, we outline steps to diagnose and manage chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma.

Chromoblastomycosis

Chromoblastomycosis is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Chromoblastomycosis is distinguished from subcutaneous phaeohyphomycosis by microscopically visualizing the characteristic thick-walled, single, or multicellular clusters of pigmented fungal cells (also known as medlar bodies, muriform cells, or sclerotic bodies).⁶ In phaeohyphomycosis, short hyphae and pseudohyphae plus some single cells typically are seen.

Epidemiology—Globally, the distribution and burden of chromoblastomycosis are relatively unknown. Infections are more common in tropical and subtropical areas but can be acquired anywhere. A literature review conducted in 2021 identified 7740 cases of chromo­blastomycosis, mostly reported in South America, Africa, Central America and Mexico, and Asia.⁷ Most of the patients were male, and the median age was 52 years. One study found an incidence of 14.7 per 1,000,000 patients in the United States for both chromoblastomycosis and phaeohyphomycotic abscesses (which included both skin and brain abscesses).⁸ Most patients were aged 65 years or older, with a higher incidence in males. Geographically, the incidence was highest in the Northeast followed by the South; patients in rural areas also had higher incidence of disease.⁸

Causative Organisms—Causative species cannot reliably distinguish between chromoblastomycosis and subcutaneous phaeohyphomycosis, as some species overlap. Cladophialophora carrionii, Fonsecaea species, Phialophora verrucosa species complex, and Rhinocladiella aquaspersa most commonly cause chromoblastomycosis.^9,10

Clinical Manifestations—Chromoblastomycosis initially manifests as a solitary erythematous macule at a site of trauma (often not recalled by the patient) that can evolve to a smooth pink papule and may progress to 1 of 5 morphologies: nodular, verrucous, tumorous, cicatricial, or plaque.⁶ Patients may present with more than one morphology, particularly in long-standing or advanced disease. Lesions commonly manifest on the arms and legs in otherwise healthy individuals in environments (eg, rural, agricultural) that have more opportunities for injury and exposure to the causative fungi. Affected individuals often have small black specks on the lesion surface that are visible with the naked eye.⁶

Diagnosis—Common differential diagnoses include cutaneous blastomycosis, fixed sporotrichosis, warty tuberculosis nocardiosis, cutaneous leishmaniasis, human papillomavirus (HPV) infection, podoconiosis, lymphatic filariasis, cutaneous tuberculosis, and psoriasis.⁶ Squamous cell carcinoma is both a differential diagnosis as well as a potential complication of the disease.¹¹

Potassium hydroxide preparation with skin scapings or a biopsy from the lesion has high sensitivity and quick turnaround times. There often is a background histopathologic reaction of pseudoepitheliomatous hyperplasia. Examining samples taken from areas with the visible small black dots on the skin surface can increase the likelihood of detecting fungal elements (Figure 1). Clinicians also may choose to obtain a 6- to 8-mm deep skin biopsy from the lesion and splice it in half, with one sample sent for histopathology and the other for culture (Figure 2). Skin scrapings can be sent for culture instead. In the case of verrucous lesions, biopsy is preferred if feasible. 

Treatment should not be delayed while awaiting the culture results if infection is otherwise confirmed by direct microscopy or histopathology. The treatment approach remains similar regardless of the causative species. If the culture results are positive, the causative genus can be identified by the microscopic morphology; however, molecular diagnostic tools are needed for accurate species identification.^12,13

Antifungal Susceptibility Testing—For most dematiaceous fungi, interpreting minimum inhibitory concentrations (MICs) is challenging due to a lack of data from multicenter studies. One report examined sequential isolates of Fonsecaea pedrosoi and demonstrated both high MIC values and clinical resistance to itraconazole in some cases, likely from treatment pressure.¹⁴ Clinical Laboratory Standards Institute–approved epidemiologic cutoff values (ECVs) are established for F pedrosoi for commonly used antifungals including itraconazole (0.5 µg/mL), terbinafine (0.25 µg/mL), and posaconazole (0.5 µg/mL).¹⁵ Clinicians may choose to obtain sequential isolates for any causative fungi in recalcitrant disease to monitor for increases in MIC.

Management—In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. If antifungals are needed, itraconazole is the most commonly prescribed agent, typically at a dose of 100 to 200 mg twice daily. Terbinafine also has been used first-line at a dose of 250 to 500 mg per day. Voriconazole and posaconazole also may be suitable options for first-line or for refractory disease treatment. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy usually is several months, but many patients require years of therapy until resolution of lesions. 

Clinicians can consider combination therapy with an antifungal and a topical immunomodulator such as imiquimod (applied topically 3 times per week); this combination can be considered in refractory disease and even upon initial diagnosis, especially in severe disease.^17,18 Nonpharmacologic interventions such as cryotherapy, heat, and light-based therapies have been used, but outcome data are scarce.^19-23

Subcutaneous Phaeohyphomycosis

Subcutaneous phaeohyphomycosis also is caused by dematiaceous fungi that typically affect the skin and subcutaneous tissue. Subcutaneous phaeohyphomycosis is distinguished from chromoblastomycosis by short hyphae and hyphal fragments usually seen microscopically instead of visualizing thick-walled, single, or multicellular clusters of pigmented fungal cells.⁶

Epidemiology—Globally, the burden and distribution of phaeohyphomycosis, including its cutaneous manifestations, are not well understood. Infections are more common in tropical and subtropical areas but can be acquired anywhere. Phaeohyphomycosis is a generic term used to describe infections caused by pigmented hyphal fungi that can manifest on the skin (subcutaneous phaeohyphomycosis) but also can affect deep structures including the brain (systemic phaeohyphomycosis).²⁴

Causative Organisms—Alternaria, Bipolaris, Cladosporium, Curvularia, Exophiala, and Exserohilum species most commonly cause subcutaneous phaeohyphomycosis. Alternaria infections manifesting with skin lesions often are referred to as cutaneous alternariosis.²⁵

Clinical Manifestations—The most common skin manifestation of phaeohyphomycosis is a subcutaneous cyst (cystic phaeohyphomycosis)(Figure 2). Subcutaneous phaeohyphomycosis also may manifest with nodules or plaques (Figure 3). Phaeohyphomycosis appears to occur more commonly in individuals who are immunosuppressed, those in whom T-cell function is affected, in congenital immunodeficiency states (eg, individuals with CARD9 mutations).²⁶

Diagnosis—Culture is the gold standard for confirming phaeohyphomycosis.²⁷ For cystic phaeohyphomycosis, clinicians can consider aspiration of the cyst for direct microscopic examination and culture. Histopathology may be utilized but can have lower sensitivity in showing dematiaceous hyphae and granulomatous inflammation; using the Masson-Fontana stain for melanin can be helpful. Molecular diagnostic tools including metagenomics applied directly to the tissue may be useful but are likely to have lower sensitivity than culture and require specialist diagnostic facilities.

Management—The approaches to managing chromoblastomycosis and subcutaneous phaeohyphomycosis are similar, though the preferred agents often differ. In early-stage disease, excision of the skin nodule may be curative, although concomitant treatment for several months with an antifungal is advised. In localized forms, itraconazole usually is used, but in those cases associated with immunodeficiency states, voriconazole may be necessary. Fluconazole does not have good activity against dematiaceous fungi and should be avoided.¹⁶ Topical antifungals will not reach the site of infection in adequate concentrations. Topical corticosteroids can make the disease worse and should be avoided. The duration of therapy may be substantially longer for chromoblastomycosis (months to years) compared to subcutaneous phaeohyphomycosis (weeks to months), although in immunocompromised individuals treatment may be even more prolonged.

Mycetoma

Mycetoma is caused by one of several different types of fungi (eumycetoma) and bacteria (actinomycetoma) that lead to progressively debilitating yet painless subcutaneous tumorlike lesions. The lesions usually manifest on the arms and legs but can occur anywhere.

Epidemiology—Little is known about the true global burden of mycetoma, but it occurs more frequently in low-income communities in rural areas.²⁸ A retrospective review identified 19,494 cases published from 1876 to 2019, with cases reported in 102 countries.²⁹ The countries with the highest numbers of cases are Sudan and Mexico, where there is more information on the distribution of the disease. Cases often are reported in what is known as the mycetoma belt (between latitudes 15° south and 30° north) but are increasingly identified outside this region.²⁸ Young men aged 20 to 40 years are most commonly affected.

In the United States, mycetoma is uncommon, but clinicians can encounter locally acquired and travel-associated cases; hence, taking a good travel history is essential. One study specifically evaluating eumycetoma found a prevalence of 5.2 per 1,000,000 patients.⁸ Women and those aged 65 years or older had a higher incidence. Incidence was similar across US regions, but a higher incidence was reported in nonrural areas.⁸

Causative Organisms—More than 60 different species of fungi can cause eumycetoma; most cases are caused by Madurella mycetomatis, Trematosphaeria grisea (formerly Madurella grisea); Pseudallescheria boydii species complex, and Falciformispora (formerly Leptosphaeria) senegalensis.³⁰ Actinomycetoma commonly is caused by Nocardia species (Nocardia brasiliensis, Nocardia asteroides, Nocardia otitidiscaviarum, Nocardia transvalensis, Nocardia harenae, and Nocardia takedensis), Streptomyces somaliensis, and Actinomadura species (Actinomadura madurae, Actinomadura pelletieri).³¹

Clinical Manifestations—Mycetoma is a chronic granulomatous disease with a progressive inflammatory reaction (Figures 4 and 5). Over the course of years, mycetoma progresses from small nodules to large, bone-invasive, mutilating lesions. Mycetoma manifests as a triad of painless firm subcutaneous masses, formation of multiple sinuses within the masses, and a purulent or seropurulent discharge containing sandlike visible particles (grains) that can be white, yellow, red, or black.²⁸ Lesions usually are painless in early disease and are slowly progressive. Large lesion size, bone destruction, secondary bacterial infections, and actinomycetoma may lead to higher likelihood of pain.³²

Diagnosis—Other conditions that could manifest with the same triad seen in mycetoma such as botryomycosis should be included in the differential. Other differential diagnoses include foreign body granuloma, filariasis, mycobacterial infection, skeletal tuberculosis, and yaws. 

Proper treatment requires an accurate diagnosis that distinguishes actinomycetoma from eumycetoma.³³ Culturing of grains obtained from deep lesion aspirates enables identification of the causative organism (Figure 6). The color of the grains may provide clues to their etiology: black grains are caused by fungus, red grains by a bacterium (A pelletieri), and pale (yellow or white) grains can be caused by either one.³¹Nocardia mycetoma grains are very small and usually cannot be appreciated with the naked eye. Histopathology of deep biopsy specimens (biopsy needle or surgical biopsy) stained with hematoxylin and eosin can diagnose actinomycetoma and eumycetoma. Punch biopsies often are not helpful, as the inflammatory mass is too deeply located. Deep surgical biopsy is preferred; however, species identification cannot be made without culture. Molecular tests for certain causative organisms of mycetoma have been developed but are not readily available.^34,35 Currently, no serologic tests can diagnose mycetoma reliably. Ultrasonography can be used to diagnose mycetoma and, with appropriate training, distinguish between actinomycetoma and eumycetoma; it also can be combined with needle aspiration for taking grain samples.³⁶

Treatment—Treatment of mycetoma depends on identification of the causal etiology and requires long-term and expensive drug regimens. It is not possible to determine the causative organism clinically. Actinomycetoma generally responds to medical treatment, and surgery rarely is needed. The current first-line treatment is co-trimoxazole (trimethoprim/sulfamethoxazole) in combination with amoxicillin and clavulanate acid or co-trimoxazole and amikacin for refractory disease; linezolid also may be a promising option for refractory disease.³⁷

Eumycetoma is less responsive to medical therapies, and recurrence is common. Current recommended therapy is itraconazole for 9 to 12 months; however, cure rates ranging from 26% to 75% in combination with surgery have been reported, and fungi often can still be cultured from lesions posttreatment.^38,39 Surgical excision often is used following 6 months of treatment with itraconazole to obtain better outcomes. Amputation may be required if the combination of antifungals and surgical excision fails. Fosravuconazole has shown promise in one clinical trial, but it is not approved in most countries, including the United States.³⁹

Final Thoughts

Chromoblastomycosis, subcutaneous phaeohyphomycosis, and mycetoma can cause devastating disease. Patients with these conditions often are unable to carry out daily activities and experience stigma and discrimination. Limited diagnostic and treatment options hamper the ability of clinicians to respond appropriately to suspect and confirmed disease. Effectively examining the skin is the starting point for diagnosing and managing these diseases and can help clinicians to care for patients and prevent severe disease.

Measles, also known as rubeola, is a highly contagious paramyxovirus that has neared elimination in the United States since 2000 due to widespread adoption of the measles vaccine; however, measles recently has made a comeback, with outbreaks reported in more than 60 countries. In the United States, vaccine hesitancy coupled with decreasing vaccination rates, international travel to endemic areas, and decreased funding and resources for monitoring and immunization programs likely led to a re-emergence of measles cases.^1,2 The resurgence of measles is troubling given its infectiousness and potential severity in at-risk populations. Since measles has a basic reproduction number of 12 to 18 (ie, 1 infected individual will on average infect 12 to 18 others³), it has the capacity to spread quickly. This is why, prior to the development of the measles vaccine in the 1960s, it was responsible for millions of deaths across the globe.

Prior to the introduction of the measles vaccine, both physicians and the public generally were aware of the signs and symptoms of measles due to its prevalence; however, since there have been so few cases in recent decades, images and descriptions of patients presenting with measles can be found only in textbooks, and many physicians are ill-prepared to diagnose the disease.⁴ In response to the recent surge in measles cases, dermatologists—who often are among the first medical professionals to encounter febrile patients with rashes—must be prepared to bridge this divide. Herein, we review the clinical signs, diagnostic approach, operational precautions, and public health responsibilities that dermatologists must relearn amid the current measles outbreak.

Background

Measles is primarily transmitted via respiratory droplets and may remain airborne for up to 2 hours.⁵ It also can be transmitted through direct contact with secretions such as mucus. Indirect transmission via fomites, while certainly plausible, is thought to be the least effective mechanism of transmission.⁶ Following exposure, the incubation period ranges from 7 to 21 days, during which the virus replicates asymptomatically before causing clinical disease.⁷ Herd immunity for measles requires 93% immunity in the population; public health agencies typically target greater than 95% immunity.⁸ Humans are the only reservoir for the measles virus, making eradication possible.

The road to eradication began with the introduction of the measles vaccine in 1963 and subsequent development of the combined measles-mumps-rubella (MMR) vaccine in 1971. As MMR is a live vaccine, 2 doses confer approximately 97% protection.⁹ The first dose is given at 12 to 15 months of age, and the second dose is given at 4 to 6 years of age. Immunity is considered lifelong, and the Centers for Disease Control and Prevention and the World Health Organization do not recommend routine measles boosters for individuals who have completed the primary 2-dose series.^10,11

Widespread vaccination led to a dramatic reduction in incidence, with many countries eliminating measles infections.⁷ The United States declared measles eliminated in 2000, with confirmed cases between 2000 and 2020 ranging from 37 to 1282.¹² Vaccination progress stalled in the late 1990s due to vaccine hesitancy resulting from (subsequently debunked) reports of an association between the MMR vaccine and autism.¹³ Despite efforts to correct this misinformation, many patients continue to espouse these concerns.

Recognizing Measles: Clinical Presentation

Measles, which most often manifests in childhood but also can occur in adults, follows a distinctive clinical course. The prodromal phase is characterized by high fever, cough, coryza (nasal congestion), and conjunctivitis— conjunctivitis—the 3 “Cs” that serve as early warning signs of the disease. Patients may develop small white macules on the buccal mucosa known as Koplik spots (phonetically the fourth “C”), which appear just before the rash. Three to 5 days after the onset of systemic symptoms, patients will develop a classic morbilliform exanthem. In some cases, the exanthem manifests on the head and neck (Figure 1)—first behind the ears and along the hairline, then spreading caudally to the trunk and extremities. The lesions may become confluent, with patients presenting with diffuse erythema. The exanthem fades over several days to weeks, often accompanied by superficial desquamation.¹⁴

Given the nonspecificity of the early symptoms of measles, a high index of suspicion is needed for patients presenting with a febrile illness and a morbilliform eruption (Figure 2). Consideration of MMR vaccination status, exposure history, and local outbreak patterns can help guide risk stratification and the need for testing. Immunocompromised individuals, including those receiving immunosuppressive therapies for dermatologic conditions, may present atypically, lacking the prototypical exanthem or displaying milder signs and further complicating the diagnosis.¹⁵ The differential diagnosis for measles includes a drug reaction or other viral exanthem, and a detailed history may help elucidate the culprit.

Evaluation and Diagnosis

Definitive diagnosis of measles relies on both molecular and serologic testing. Nasopharyngeal swabs for measles polymerase chain reaction testing are obtained using synthetic (noncotton) swabs placed in a viral transport medium. Serum samples also should be collected for measles IgM and IgG antibody testing. Importantly, measles is a reportable illness, and testing may be coordinated with local departments of health.

Determining a patient’s immune status may be important for certain populations. Patients with documented 2-dose MMR vaccination, positive measles IgG serology, or a prior confirmed measles infection are considered immune. While a positive measles IgG indicates immunity, a negative result in an exposed patient should prompt consideration of postexposure prophylaxis with intravenous immunoglobulin.

Many patients, specifically those presenting to dermatology, are taking immunomodulatory or immunosuppressive medications—a contraindication for vaccination with the live MMR vaccine. At the time of publication, there was a single reported case of a patient taking a tumor necrosis factor α inhibitor for rheumatoid arthritis who had acquired measles.¹⁶ While the benefits of titer assessment in patients who are starting or continuing immunomodulatory therapy are not known and currently it is not recommended by the Centers for Disease Control and Prevention, dermatologists might consider checking MMR titers and vaccinating (or referring for vaccination) nonimmune patients.¹⁷

Infection Control

Early identification of a suspected measles case is paramount. Patients in whom measles is a possibility should be isolated as quickly as possible, and the patient and accompanying caregivers should be masked. Clinical staff should don appropriate personal protective equipment, including an N95 mask. Coordination with the local department of health must occur as soon as measles is suspected.

If testing is an option in the outpatient setting, a nasopharyngeal viral swab and serologic titers can be obtained. If testing is not available on site, patients should be sent to appropriate care facilities; prenotification is critical to prevent nosocomial outbreaks. Patients should be encouraged to isolate and avoid public spaces and/or public transport for 4 days following development of an exanthem.¹⁸ Offices should develop clinical protocols for suspected measles cases with training for clinical and office staff.

Final Thoughts

As measles outbreaks become more prevalent, it is incumbent upon physicians to remind ourselves of the signs and symptoms of this largely eliminated disease so that we may pursue early detection and intervention strategies. The primary cutaneous manifestations of measles make dermatologists critical to early recognition and containment efforts. Dermatologists should prepare for the arrival of patients with measles by maintaining vigilance for the classic signs of the disease, implementing stringent isolation protocols, verifying patient immunity when appropriate, and partnering closely with public health authorities.

More broadly, efforts to contain and re-establish a paradigm for eliminating measles outbreaks must be pursued. Encouraging vaccination and developing programs to help combat misinformation surrounding vaccines are critical to this effort. In an era of vaccine hesitancy, measles is a multidisciplinary public health emergency. Dermatologists must remain ready.

Measles, also known as rubeola, is a highly contagious paramyxovirus that has neared elimination in the United States since 2000 due to widespread adoption of the measles vaccine; however, measles recently has made a comeback, with outbreaks reported in more than 60 countries. In the United States, vaccine hesitancy coupled with decreasing vaccination rates, international travel to endemic areas, and decreased funding and resources for monitoring and immunization programs likely led to a re-emergence of measles cases.^1,2 The resurgence of measles is troubling given its infectiousness and potential severity in at-risk populations. Since measles has a basic reproduction number of 12 to 18 (ie, 1 infected individual will on average infect 12 to 18 others³), it has the capacity to spread quickly. This is why, prior to the development of the measles vaccine in the 1960s, it was responsible for millions of deaths across the globe.

Prior to the introduction of the measles vaccine, both physicians and the public generally were aware of the signs and symptoms of measles due to its prevalence; however, since there have been so few cases in recent decades, images and descriptions of patients presenting with measles can be found only in textbooks, and many physicians are ill-prepared to diagnose the disease.⁴ In response to the recent surge in measles cases, dermatologists—who often are among the first medical professionals to encounter febrile patients with rashes—must be prepared to bridge this divide. Herein, we review the clinical signs, diagnostic approach, operational precautions, and public health responsibilities that dermatologists must relearn amid the current measles outbreak.

Background

Measles is primarily transmitted via respiratory droplets and may remain airborne for up to 2 hours.⁵ It also can be transmitted through direct contact with secretions such as mucus. Indirect transmission via fomites, while certainly plausible, is thought to be the least effective mechanism of transmission.⁶ Following exposure, the incubation period ranges from 7 to 21 days, during which the virus replicates asymptomatically before causing clinical disease.⁷ Herd immunity for measles requires 93% immunity in the population; public health agencies typically target greater than 95% immunity.⁸ Humans are the only reservoir for the measles virus, making eradication possible.

The road to eradication began with the introduction of the measles vaccine in 1963 and subsequent development of the combined measles-mumps-rubella (MMR) vaccine in 1971. As MMR is a live vaccine, 2 doses confer approximately 97% protection.⁹ The first dose is given at 12 to 15 months of age, and the second dose is given at 4 to 6 years of age. Immunity is considered lifelong, and the Centers for Disease Control and Prevention and the World Health Organization do not recommend routine measles boosters for individuals who have completed the primary 2-dose series.^10,11

Widespread vaccination led to a dramatic reduction in incidence, with many countries eliminating measles infections.⁷ The United States declared measles eliminated in 2000, with confirmed cases between 2000 and 2020 ranging from 37 to 1282.¹² Vaccination progress stalled in the late 1990s due to vaccine hesitancy resulting from (subsequently debunked) reports of an association between the MMR vaccine and autism.¹³ Despite efforts to correct this misinformation, many patients continue to espouse these concerns.

Recognizing Measles: Clinical Presentation

Measles, which most often manifests in childhood but also can occur in adults, follows a distinctive clinical course. The prodromal phase is characterized by high fever, cough, coryza (nasal congestion), and conjunctivitis— conjunctivitis—the 3 “Cs” that serve as early warning signs of the disease. Patients may develop small white macules on the buccal mucosa known as Koplik spots (phonetically the fourth “C”), which appear just before the rash. Three to 5 days after the onset of systemic symptoms, patients will develop a classic morbilliform exanthem. In some cases, the exanthem manifests on the head and neck (Figure 1)—first behind the ears and along the hairline, then spreading caudally to the trunk and extremities. The lesions may become confluent, with patients presenting with diffuse erythema. The exanthem fades over several days to weeks, often accompanied by superficial desquamation.¹⁴

Given the nonspecificity of the early symptoms of measles, a high index of suspicion is needed for patients presenting with a febrile illness and a morbilliform eruption (Figure 2). Consideration of MMR vaccination status, exposure history, and local outbreak patterns can help guide risk stratification and the need for testing. Immunocompromised individuals, including those receiving immunosuppressive therapies for dermatologic conditions, may present atypically, lacking the prototypical exanthem or displaying milder signs and further complicating the diagnosis.¹⁵ The differential diagnosis for measles includes a drug reaction or other viral exanthem, and a detailed history may help elucidate the culprit.

Evaluation and Diagnosis

Definitive diagnosis of measles relies on both molecular and serologic testing. Nasopharyngeal swabs for measles polymerase chain reaction testing are obtained using synthetic (noncotton) swabs placed in a viral transport medium. Serum samples also should be collected for measles IgM and IgG antibody testing. Importantly, measles is a reportable illness, and testing may be coordinated with local departments of health.

Determining a patient’s immune status may be important for certain populations. Patients with documented 2-dose MMR vaccination, positive measles IgG serology, or a prior confirmed measles infection are considered immune. While a positive measles IgG indicates immunity, a negative result in an exposed patient should prompt consideration of postexposure prophylaxis with intravenous immunoglobulin.

Many patients, specifically those presenting to dermatology, are taking immunomodulatory or immunosuppressive medications—a contraindication for vaccination with the live MMR vaccine. At the time of publication, there was a single reported case of a patient taking a tumor necrosis factor α inhibitor for rheumatoid arthritis who had acquired measles.¹⁶ While the benefits of titer assessment in patients who are starting or continuing immunomodulatory therapy are not known and currently it is not recommended by the Centers for Disease Control and Prevention, dermatologists might consider checking MMR titers and vaccinating (or referring for vaccination) nonimmune patients.¹⁷

Infection Control

Early identification of a suspected measles case is paramount. Patients in whom measles is a possibility should be isolated as quickly as possible, and the patient and accompanying caregivers should be masked. Clinical staff should don appropriate personal protective equipment, including an N95 mask. Coordination with the local department of health must occur as soon as measles is suspected.

If testing is an option in the outpatient setting, a nasopharyngeal viral swab and serologic titers can be obtained. If testing is not available on site, patients should be sent to appropriate care facilities; prenotification is critical to prevent nosocomial outbreaks. Patients should be encouraged to isolate and avoid public spaces and/or public transport for 4 days following development of an exanthem.¹⁸ Offices should develop clinical protocols for suspected measles cases with training for clinical and office staff.

Final Thoughts

As measles outbreaks become more prevalent, it is incumbent upon physicians to remind ourselves of the signs and symptoms of this largely eliminated disease so that we may pursue early detection and intervention strategies. The primary cutaneous manifestations of measles make dermatologists critical to early recognition and containment efforts. Dermatologists should prepare for the arrival of patients with measles by maintaining vigilance for the classic signs of the disease, implementing stringent isolation protocols, verifying patient immunity when appropriate, and partnering closely with public health authorities.

More broadly, efforts to contain and re-establish a paradigm for eliminating measles outbreaks must be pursued. Encouraging vaccination and developing programs to help combat misinformation surrounding vaccines are critical to this effort. In an era of vaccine hesitancy, measles is a multidisciplinary public health emergency. Dermatologists must remain ready.

Measles, also known as rubeola, is a highly contagious paramyxovirus that has neared elimination in the United States since 2000 due to widespread adoption of the measles vaccine; however, measles recently has made a comeback, with outbreaks reported in more than 60 countries. In the United States, vaccine hesitancy coupled with decreasing vaccination rates, international travel to endemic areas, and decreased funding and resources for monitoring and immunization programs likely led to a re-emergence of measles cases.^1,2 The resurgence of measles is troubling given its infectiousness and potential severity in at-risk populations. Since measles has a basic reproduction number of 12 to 18 (ie, 1 infected individual will on average infect 12 to 18 others³), it has the capacity to spread quickly. This is why, prior to the development of the measles vaccine in the 1960s, it was responsible for millions of deaths across the globe.

Prior to the introduction of the measles vaccine, both physicians and the public generally were aware of the signs and symptoms of measles due to its prevalence; however, since there have been so few cases in recent decades, images and descriptions of patients presenting with measles can be found only in textbooks, and many physicians are ill-prepared to diagnose the disease.⁴ In response to the recent surge in measles cases, dermatologists—who often are among the first medical professionals to encounter febrile patients with rashes—must be prepared to bridge this divide. Herein, we review the clinical signs, diagnostic approach, operational precautions, and public health responsibilities that dermatologists must relearn amid the current measles outbreak.

Background

Measles is primarily transmitted via respiratory droplets and may remain airborne for up to 2 hours.⁵ It also can be transmitted through direct contact with secretions such as mucus. Indirect transmission via fomites, while certainly plausible, is thought to be the least effective mechanism of transmission.⁶ Following exposure, the incubation period ranges from 7 to 21 days, during which the virus replicates asymptomatically before causing clinical disease.⁷ Herd immunity for measles requires 93% immunity in the population; public health agencies typically target greater than 95% immunity.⁸ Humans are the only reservoir for the measles virus, making eradication possible.

The road to eradication began with the introduction of the measles vaccine in 1963 and subsequent development of the combined measles-mumps-rubella (MMR) vaccine in 1971. As MMR is a live vaccine, 2 doses confer approximately 97% protection.⁹ The first dose is given at 12 to 15 months of age, and the second dose is given at 4 to 6 years of age. Immunity is considered lifelong, and the Centers for Disease Control and Prevention and the World Health Organization do not recommend routine measles boosters for individuals who have completed the primary 2-dose series.^10,11

Widespread vaccination led to a dramatic reduction in incidence, with many countries eliminating measles infections.⁷ The United States declared measles eliminated in 2000, with confirmed cases between 2000 and 2020 ranging from 37 to 1282.¹² Vaccination progress stalled in the late 1990s due to vaccine hesitancy resulting from (subsequently debunked) reports of an association between the MMR vaccine and autism.¹³ Despite efforts to correct this misinformation, many patients continue to espouse these concerns.

Recognizing Measles: Clinical Presentation

Measles, which most often manifests in childhood but also can occur in adults, follows a distinctive clinical course. The prodromal phase is characterized by high fever, cough, coryza (nasal congestion), and conjunctivitis— conjunctivitis—the 3 “Cs” that serve as early warning signs of the disease. Patients may develop small white macules on the buccal mucosa known as Koplik spots (phonetically the fourth “C”), which appear just before the rash. Three to 5 days after the onset of systemic symptoms, patients will develop a classic morbilliform exanthem. In some cases, the exanthem manifests on the head and neck (Figure 1)—first behind the ears and along the hairline, then spreading caudally to the trunk and extremities. The lesions may become confluent, with patients presenting with diffuse erythema. The exanthem fades over several days to weeks, often accompanied by superficial desquamation.¹⁴

Given the nonspecificity of the early symptoms of measles, a high index of suspicion is needed for patients presenting with a febrile illness and a morbilliform eruption (Figure 2). Consideration of MMR vaccination status, exposure history, and local outbreak patterns can help guide risk stratification and the need for testing. Immunocompromised individuals, including those receiving immunosuppressive therapies for dermatologic conditions, may present atypically, lacking the prototypical exanthem or displaying milder signs and further complicating the diagnosis.¹⁵ The differential diagnosis for measles includes a drug reaction or other viral exanthem, and a detailed history may help elucidate the culprit.

Evaluation and Diagnosis

Definitive diagnosis of measles relies on both molecular and serologic testing. Nasopharyngeal swabs for measles polymerase chain reaction testing are obtained using synthetic (noncotton) swabs placed in a viral transport medium. Serum samples also should be collected for measles IgM and IgG antibody testing. Importantly, measles is a reportable illness, and testing may be coordinated with local departments of health.

Determining a patient’s immune status may be important for certain populations. Patients with documented 2-dose MMR vaccination, positive measles IgG serology, or a prior confirmed measles infection are considered immune. While a positive measles IgG indicates immunity, a negative result in an exposed patient should prompt consideration of postexposure prophylaxis with intravenous immunoglobulin.

Many patients, specifically those presenting to dermatology, are taking immunomodulatory or immunosuppressive medications—a contraindication for vaccination with the live MMR vaccine. At the time of publication, there was a single reported case of a patient taking a tumor necrosis factor α inhibitor for rheumatoid arthritis who had acquired measles.¹⁶ While the benefits of titer assessment in patients who are starting or continuing immunomodulatory therapy are not known and currently it is not recommended by the Centers for Disease Control and Prevention, dermatologists might consider checking MMR titers and vaccinating (or referring for vaccination) nonimmune patients.¹⁷

Infection Control

Early identification of a suspected measles case is paramount. Patients in whom measles is a possibility should be isolated as quickly as possible, and the patient and accompanying caregivers should be masked. Clinical staff should don appropriate personal protective equipment, including an N95 mask. Coordination with the local department of health must occur as soon as measles is suspected.

If testing is an option in the outpatient setting, a nasopharyngeal viral swab and serologic titers can be obtained. If testing is not available on site, patients should be sent to appropriate care facilities; prenotification is critical to prevent nosocomial outbreaks. Patients should be encouraged to isolate and avoid public spaces and/or public transport for 4 days following development of an exanthem.¹⁸ Offices should develop clinical protocols for suspected measles cases with training for clinical and office staff.

Final Thoughts

As measles outbreaks become more prevalent, it is incumbent upon physicians to remind ourselves of the signs and symptoms of this largely eliminated disease so that we may pursue early detection and intervention strategies. The primary cutaneous manifestations of measles make dermatologists critical to early recognition and containment efforts. Dermatologists should prepare for the arrival of patients with measles by maintaining vigilance for the classic signs of the disease, implementing stringent isolation protocols, verifying patient immunity when appropriate, and partnering closely with public health authorities.

More broadly, efforts to contain and re-establish a paradigm for eliminating measles outbreaks must be pursued. Encouraging vaccination and developing programs to help combat misinformation surrounding vaccines are critical to this effort. In an era of vaccine hesitancy, measles is a multidisciplinary public health emergency. Dermatologists must remain ready.

Worldwide, it is estimated that up to 1 in 5 individuals will experience a dermatophyte infection (commonly called ringworm or tinea infection) in their lifetime.¹ Historically, dermatophyte infections have been considered relatively minor conditions usually treated with short courses of topical antifungals.² Oral antifungals historically were needed only for patients with nail or hair shaft infections or extensive cutaneous fungal infections, which typically occurred in immunosuppressed patients.² However, the landscape is changing rapidly due to the global emergence of severe dermatophyte infections that frequently are resistant to first-line antifungal medications.^3-5 In this article, we aimed to review the epidemiology of emerging dermatophyte infections and provide dermatologists with information needed for effective diagnosis and management.

Emergence of Trichophyton indotineae

In recent decades, public health officials and dermatologists have noted with concern the spread of the recently emerged dermatophyte species Trichophyton indotineae in South Asia.^3,6 This species (previously known as Trichophyton mentagrophytes genotype VIII) usually is transmitted from person to person, either through direct skin-to-skin contact or by fomites.^4,6 Potential sexual transmission of T indotineae infections also has been reported,⁷ and it is possible that animals may serve as reservoirs for this pathogen, although there are no known reports of direct spread from animals to humans.^8,9 Major outbreaks of T indotineae are ongoing in South Asia, and cases have been documented in 6 continents.^10-12 In the United States, most but not all cases have occurred in immigrants from or recently returned travelers to South Asia.^6,13 The emergence and spread of T indotineae is hypothesized to be promoted by the misuse and overuse of topical antifungal products, particularly those containing combinations of potent corticosteroids with other antimicrobial drugs.^14,15

Cutaneous manifestations of T indotineae infections tend to cover large body surface areas, recur frequently, and pose substantial treatment challenges.^6,13,16 Several clinical presentations have been documented, including erythematous, scaly concentric plaques; papulosquamous lesions; pustular forms; and corticosteroid-modified disease (Figure 1).^6,16 Affected patients seldom are immunocompromised and often have a history of multiple failed courses of topical or oral antifungals, including oral terbinafine.¹³ Many also have been prescribed topical corticosteroids or have used over-the-counter topical corticosteroids, which worsen the rash.¹⁷

Direct microscopy with potassium hydroxide could be used to confirm the diagnosis of dermatophyte infection, but it does not distinguish T indotineae from other dermatophyte species.^2,6 Importantly, culture-based testing usually will misidentify T indotineae as other Trichophyton species such as the more common T mentagrophytes or Trichophyton interdigitale. Definitive identification of T indotineae requires advanced molecular techniques that are available only at select laboratories.⁶ Unfortunately, availability of such testing is limited (Table), and results may take several weeks; therefore, it is suggested that dermatologists who suspect T indotineae infections based on the patient’s history and clinical presentation begin antifungal treatment after confirmation of dermatophyte infection but not wait for definitive confirmation of the causative organism.¹⁶

Itraconazole is considered the first-line therapy for T indotineae infection, as terbinafine usually is ineffective due to mutations in the squalene epoxidase gene.¹⁶ Dermatologists should be aware that itraconazole is available in different formulations that can affect absorption. The oral solution has greater bioavailability and should be taken on an empty stomach, whereas the capsules are required to be taken with food for effective absorption; the capsules also should be taken with an acidic beverage such as orange juice. Dermatologists should carefully assess for drug-drug interactions when prescribing itraconazole, given its extensive interaction profile with numerous other medications. Patients may require treatment with itraconazole (100 mg/d or 200 mg/d) for a minimum of 6 to 8 weeks until complete clearance has been achieved and ideally a negative potassium hydroxide preparation of skin scrapings has been obtained. A longer treatment period (eg, ≥3 months) frequently is needed, and relapses are common.^6,16,18 Regular follow-up is needed to monitor for infection clearance and recurrences. It is important to note that cases of itraconazole resistance have been reported, although this currently appears to be uncommon.^19,20

Other Emerging Dermatophytes to Watch

Trichophyton rubrum is the most common cause of dermatophyte infections among humans,²¹ and cases of terbinafine-resistant T rubrum infections have been reported increasingly in the United States and Canada.^5,22-24 Onychomycosis caused by terbinafine-resistant T rubrum has been documented, and patients may have infections that do not respond to terbinafine given at the standard dose and duration.^22,23 Case reports have indicated successful treatment using itraconazole 200 mg/d and posaconazole 300 mg/d.^5,23

Trichophyton mentagrophytes genotype VII (TMVII) is an emerging dermatophyte that recently has been reported as a cause of sexually transmitted dermatophyte infections in Europe and the United States primarily affecting men who have sex with men.^25-27 Patients may present with pruritic, annular, scaly patches and plaques involving the trunk, groin, genital region, or face (Figure 2). Although closely related to T indotineae, TMVII differs in that it more often affects the genital region, generally is susceptible to terbinafine, and in the United States and Europe usually is not related to travel or immigration involving South Asia.²⁶ Although TMVII has not been associated with antifungal resistance, awareness among dermatologists is important because patients may experience inflamed, painful, and persistent rashes that can lead to secondary bacterial infection or scarring, and physicians might mistake it for mimics including eczema or psoriasis.^25,26

Importance of Judicious Antifungal Use

Optimizing the use of antifungals is critical to improving patient outcomes and preserving available treatment options.^28,29 A retrospective analysis of commercial health insurance data estimated that topical antifungal prescriptions were potentially unnecessary for more than half of the more than 560,000 patients who were prescribed these medications in 2023. In this study, it also was observed that only 16% of patients prescribed a topical antifungal had received diagnostic testing, with low rates across specialties.³⁰ This is concerning because even among board-certified dermatologists, incorrect diagnosis of suspected fungal skin infections can occur; in one survey-based study of board-certified dermatologists who were presented with dermatomycosis images, respondents categorized cases with greater than 75% accuracy in only 31% (4/13) of instances.³¹ Clotrimazole-betamethasone is among the most commonly prescribed topical antifungals in the United States,^14,32 and 2 recent retrospective analyses highlighted that the majority of patients prescribed this medication did not receive any fungal diagnostic testing.^33,34

Final Thoughts

In an era of emerging antifungal-resistant dermatophyte infections, it is important for dermatologists to educate nondermatologists about the importance of using diagnostic testing for suspected dermatophyte infections.^14,28 Dermatologists also can educate nondermatologist colleagues on the importance of avoiding the use of topical combination antifungal/corticosteroid medications and referring for dermatologic evaluation when diagnoses are uncertain.^33,34 Strategies for education by dermatologists could include giving workshops, creating educational materials, and fostering open communication about optimal treatment practices and referral parameters for suspected dermatophyte infections.

Worldwide, it is estimated that up to 1 in 5 individuals will experience a dermatophyte infection (commonly called ringworm or tinea infection) in their lifetime.¹ Historically, dermatophyte infections have been considered relatively minor conditions usually treated with short courses of topical antifungals.² Oral antifungals historically were needed only for patients with nail or hair shaft infections or extensive cutaneous fungal infections, which typically occurred in immunosuppressed patients.² However, the landscape is changing rapidly due to the global emergence of severe dermatophyte infections that frequently are resistant to first-line antifungal medications.^3-5 In this article, we aimed to review the epidemiology of emerging dermatophyte infections and provide dermatologists with information needed for effective diagnosis and management.

Emergence of Trichophyton indotineae

In recent decades, public health officials and dermatologists have noted with concern the spread of the recently emerged dermatophyte species Trichophyton indotineae in South Asia.^3,6 This species (previously known as Trichophyton mentagrophytes genotype VIII) usually is transmitted from person to person, either through direct skin-to-skin contact or by fomites.^4,6 Potential sexual transmission of T indotineae infections also has been reported,⁷ and it is possible that animals may serve as reservoirs for this pathogen, although there are no known reports of direct spread from animals to humans.^8,9 Major outbreaks of T indotineae are ongoing in South Asia, and cases have been documented in 6 continents.^10-12 In the United States, most but not all cases have occurred in immigrants from or recently returned travelers to South Asia.^6,13 The emergence and spread of T indotineae is hypothesized to be promoted by the misuse and overuse of topical antifungal products, particularly those containing combinations of potent corticosteroids with other antimicrobial drugs.^14,15

Cutaneous manifestations of T indotineae infections tend to cover large body surface areas, recur frequently, and pose substantial treatment challenges.^6,13,16 Several clinical presentations have been documented, including erythematous, scaly concentric plaques; papulosquamous lesions; pustular forms; and corticosteroid-modified disease (Figure 1).^6,16 Affected patients seldom are immunocompromised and often have a history of multiple failed courses of topical or oral antifungals, including oral terbinafine.¹³ Many also have been prescribed topical corticosteroids or have used over-the-counter topical corticosteroids, which worsen the rash.¹⁷

Direct microscopy with potassium hydroxide could be used to confirm the diagnosis of dermatophyte infection, but it does not distinguish T indotineae from other dermatophyte species.^2,6 Importantly, culture-based testing usually will misidentify T indotineae as other Trichophyton species such as the more common T mentagrophytes or Trichophyton interdigitale. Definitive identification of T indotineae requires advanced molecular techniques that are available only at select laboratories.⁶ Unfortunately, availability of such testing is limited (Table), and results may take several weeks; therefore, it is suggested that dermatologists who suspect T indotineae infections based on the patient’s history and clinical presentation begin antifungal treatment after confirmation of dermatophyte infection but not wait for definitive confirmation of the causative organism.¹⁶

Itraconazole is considered the first-line therapy for T indotineae infection, as terbinafine usually is ineffective due to mutations in the squalene epoxidase gene.¹⁶ Dermatologists should be aware that itraconazole is available in different formulations that can affect absorption. The oral solution has greater bioavailability and should be taken on an empty stomach, whereas the capsules are required to be taken with food for effective absorption; the capsules also should be taken with an acidic beverage such as orange juice. Dermatologists should carefully assess for drug-drug interactions when prescribing itraconazole, given its extensive interaction profile with numerous other medications. Patients may require treatment with itraconazole (100 mg/d or 200 mg/d) for a minimum of 6 to 8 weeks until complete clearance has been achieved and ideally a negative potassium hydroxide preparation of skin scrapings has been obtained. A longer treatment period (eg, ≥3 months) frequently is needed, and relapses are common.^6,16,18 Regular follow-up is needed to monitor for infection clearance and recurrences. It is important to note that cases of itraconazole resistance have been reported, although this currently appears to be uncommon.^19,20

Other Emerging Dermatophytes to Watch

Trichophyton rubrum is the most common cause of dermatophyte infections among humans,²¹ and cases of terbinafine-resistant T rubrum infections have been reported increasingly in the United States and Canada.^5,22-24 Onychomycosis caused by terbinafine-resistant T rubrum has been documented, and patients may have infections that do not respond to terbinafine given at the standard dose and duration.^22,23 Case reports have indicated successful treatment using itraconazole 200 mg/d and posaconazole 300 mg/d.^5,23

Trichophyton mentagrophytes genotype VII (TMVII) is an emerging dermatophyte that recently has been reported as a cause of sexually transmitted dermatophyte infections in Europe and the United States primarily affecting men who have sex with men.^25-27 Patients may present with pruritic, annular, scaly patches and plaques involving the trunk, groin, genital region, or face (Figure 2). Although closely related to T indotineae, TMVII differs in that it more often affects the genital region, generally is susceptible to terbinafine, and in the United States and Europe usually is not related to travel or immigration involving South Asia.²⁶ Although TMVII has not been associated with antifungal resistance, awareness among dermatologists is important because patients may experience inflamed, painful, and persistent rashes that can lead to secondary bacterial infection or scarring, and physicians might mistake it for mimics including eczema or psoriasis.^25,26

Importance of Judicious Antifungal Use

Optimizing the use of antifungals is critical to improving patient outcomes and preserving available treatment options.^28,29 A retrospective analysis of commercial health insurance data estimated that topical antifungal prescriptions were potentially unnecessary for more than half of the more than 560,000 patients who were prescribed these medications in 2023. In this study, it also was observed that only 16% of patients prescribed a topical antifungal had received diagnostic testing, with low rates across specialties.³⁰ This is concerning because even among board-certified dermatologists, incorrect diagnosis of suspected fungal skin infections can occur; in one survey-based study of board-certified dermatologists who were presented with dermatomycosis images, respondents categorized cases with greater than 75% accuracy in only 31% (4/13) of instances.³¹ Clotrimazole-betamethasone is among the most commonly prescribed topical antifungals in the United States,^14,32 and 2 recent retrospective analyses highlighted that the majority of patients prescribed this medication did not receive any fungal diagnostic testing.^33,34

Final Thoughts

In an era of emerging antifungal-resistant dermatophyte infections, it is important for dermatologists to educate nondermatologists about the importance of using diagnostic testing for suspected dermatophyte infections.^14,28 Dermatologists also can educate nondermatologist colleagues on the importance of avoiding the use of topical combination antifungal/corticosteroid medications and referring for dermatologic evaluation when diagnoses are uncertain.^33,34 Strategies for education by dermatologists could include giving workshops, creating educational materials, and fostering open communication about optimal treatment practices and referral parameters for suspected dermatophyte infections.

Worldwide, it is estimated that up to 1 in 5 individuals will experience a dermatophyte infection (commonly called ringworm or tinea infection) in their lifetime.¹ Historically, dermatophyte infections have been considered relatively minor conditions usually treated with short courses of topical antifungals.² Oral antifungals historically were needed only for patients with nail or hair shaft infections or extensive cutaneous fungal infections, which typically occurred in immunosuppressed patients.² However, the landscape is changing rapidly due to the global emergence of severe dermatophyte infections that frequently are resistant to first-line antifungal medications.^3-5 In this article, we aimed to review the epidemiology of emerging dermatophyte infections and provide dermatologists with information needed for effective diagnosis and management.

Emergence of Trichophyton indotineae

In recent decades, public health officials and dermatologists have noted with concern the spread of the recently emerged dermatophyte species Trichophyton indotineae in South Asia.^3,6 This species (previously known as Trichophyton mentagrophytes genotype VIII) usually is transmitted from person to person, either through direct skin-to-skin contact or by fomites.^4,6 Potential sexual transmission of T indotineae infections also has been reported,⁷ and it is possible that animals may serve as reservoirs for this pathogen, although there are no known reports of direct spread from animals to humans.^8,9 Major outbreaks of T indotineae are ongoing in South Asia, and cases have been documented in 6 continents.^10-12 In the United States, most but not all cases have occurred in immigrants from or recently returned travelers to South Asia.^6,13 The emergence and spread of T indotineae is hypothesized to be promoted by the misuse and overuse of topical antifungal products, particularly those containing combinations of potent corticosteroids with other antimicrobial drugs.^14,15

Cutaneous manifestations of T indotineae infections tend to cover large body surface areas, recur frequently, and pose substantial treatment challenges.^6,13,16 Several clinical presentations have been documented, including erythematous, scaly concentric plaques; papulosquamous lesions; pustular forms; and corticosteroid-modified disease (Figure 1).^6,16 Affected patients seldom are immunocompromised and often have a history of multiple failed courses of topical or oral antifungals, including oral terbinafine.¹³ Many also have been prescribed topical corticosteroids or have used over-the-counter topical corticosteroids, which worsen the rash.¹⁷

Direct microscopy with potassium hydroxide could be used to confirm the diagnosis of dermatophyte infection, but it does not distinguish T indotineae from other dermatophyte species.^2,6 Importantly, culture-based testing usually will misidentify T indotineae as other Trichophyton species such as the more common T mentagrophytes or Trichophyton interdigitale. Definitive identification of T indotineae requires advanced molecular techniques that are available only at select laboratories.⁶ Unfortunately, availability of such testing is limited (Table), and results may take several weeks; therefore, it is suggested that dermatologists who suspect T indotineae infections based on the patient’s history and clinical presentation begin antifungal treatment after confirmation of dermatophyte infection but not wait for definitive confirmation of the causative organism.¹⁶

Itraconazole is considered the first-line therapy for T indotineae infection, as terbinafine usually is ineffective due to mutations in the squalene epoxidase gene.¹⁶ Dermatologists should be aware that itraconazole is available in different formulations that can affect absorption. The oral solution has greater bioavailability and should be taken on an empty stomach, whereas the capsules are required to be taken with food for effective absorption; the capsules also should be taken with an acidic beverage such as orange juice. Dermatologists should carefully assess for drug-drug interactions when prescribing itraconazole, given its extensive interaction profile with numerous other medications. Patients may require treatment with itraconazole (100 mg/d or 200 mg/d) for a minimum of 6 to 8 weeks until complete clearance has been achieved and ideally a negative potassium hydroxide preparation of skin scrapings has been obtained. A longer treatment period (eg, ≥3 months) frequently is needed, and relapses are common.^6,16,18 Regular follow-up is needed to monitor for infection clearance and recurrences. It is important to note that cases of itraconazole resistance have been reported, although this currently appears to be uncommon.^19,20

Other Emerging Dermatophytes to Watch

Trichophyton rubrum is the most common cause of dermatophyte infections among humans,²¹ and cases of terbinafine-resistant T rubrum infections have been reported increasingly in the United States and Canada.^5,22-24 Onychomycosis caused by terbinafine-resistant T rubrum has been documented, and patients may have infections that do not respond to terbinafine given at the standard dose and duration.^22,23 Case reports have indicated successful treatment using itraconazole 200 mg/d and posaconazole 300 mg/d.^5,23

Trichophyton mentagrophytes genotype VII (TMVII) is an emerging dermatophyte that recently has been reported as a cause of sexually transmitted dermatophyte infections in Europe and the United States primarily affecting men who have sex with men.^25-27 Patients may present with pruritic, annular, scaly patches and plaques involving the trunk, groin, genital region, or face (Figure 2). Although closely related to T indotineae, TMVII differs in that it more often affects the genital region, generally is susceptible to terbinafine, and in the United States and Europe usually is not related to travel or immigration involving South Asia.²⁶ Although TMVII has not been associated with antifungal resistance, awareness among dermatologists is important because patients may experience inflamed, painful, and persistent rashes that can lead to secondary bacterial infection or scarring, and physicians might mistake it for mimics including eczema or psoriasis.^25,26

Importance of Judicious Antifungal Use

Optimizing the use of antifungals is critical to improving patient outcomes and preserving available treatment options.^28,29 A retrospective analysis of commercial health insurance data estimated that topical antifungal prescriptions were potentially unnecessary for more than half of the more than 560,000 patients who were prescribed these medications in 2023. In this study, it also was observed that only 16% of patients prescribed a topical antifungal had received diagnostic testing, with low rates across specialties.³⁰ This is concerning because even among board-certified dermatologists, incorrect diagnosis of suspected fungal skin infections can occur; in one survey-based study of board-certified dermatologists who were presented with dermatomycosis images, respondents categorized cases with greater than 75% accuracy in only 31% (4/13) of instances.³¹ Clotrimazole-betamethasone is among the most commonly prescribed topical antifungals in the United States,^14,32 and 2 recent retrospective analyses highlighted that the majority of patients prescribed this medication did not receive any fungal diagnostic testing.^33,34

Final Thoughts

In an era of emerging antifungal-resistant dermatophyte infections, it is important for dermatologists to educate nondermatologists about the importance of using diagnostic testing for suspected dermatophyte infections.^14,28 Dermatologists also can educate nondermatologist colleagues on the importance of avoiding the use of topical combination antifungal/corticosteroid medications and referring for dermatologic evaluation when diagnoses are uncertain.^33,34 Strategies for education by dermatologists could include giving workshops, creating educational materials, and fostering open communication about optimal treatment practices and referral parameters for suspected dermatophyte infections.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful recurrent abscesses. Several autoimmune and endocrine diseases are associated with HS, including inflammatory bowel disease and diabetes mellitus (DM).¹ Notably, the association between HS and thyroid disorders is poorly characterized,² and there are no known nationwide studies exploring this potential association in the hospital setting. In this cross-sectional matched cohort study, we aimed to characterize HS patients with comorbid thyroid disorders as well as to explore whether thyroid disease is associated with comorbidities and hospital outcome measures in these patients.

The 2019 National Inpatient Sample (NIS) was weighted in accordance with NIS-assigned weight variables and queried for HS, hypothyroidism, and hyperthyroidism cases using International Classification of Diseases, Tenth Revision, codes L73.2, E03, and E05, respectively. Propensity score matching based on age and sex was performed using a nearest-neighbor method in the MatchIt statistical R package. Patient demographics, comorbidities, and outcome variables were collected. Univariable analysis of HS patients with thyroid disease vs those without thyroid disease vs controls without HS were performed using X² and t-test functions in SPSS statistical software (IBM). A series of multivariate analyses were performed using SPSS logistic and linear regression models to examine the effect of thyroid disease on hospital outcome measures and comorbidities in HS patients, with statistical significance set at P=.05.

A total of 1720 HS patients with comorbid thyroid disease (hyperthyroidism/hypothyroidism), 23,785 HS patients without thyroid disease, and 25,497 age- and sex-matched controls were included in the analysis. On average, HS patients with comorbid thyroid disease were older than HS patients without thyroid disease and controls (49.36 years vs 42.17 years vs 42.66 years [P<.001]), more likely to be female (75.58% vs 58.67% vs 59.81% [P<.001]), more likely to be in the highest income quartile (17.52% vs 12.18% vs 8.14% [P<.001]), and more likely to be Medicare insured (39.07% vs 27.47% vs 18.02% [P<.001])(eTable).

On univariate analysis of hospital outcome measures, HS patients with comorbid thyroid disease had the highest frequency of extreme likelihood of dying compared with HS patients without thyroid disease and with controls (6.40% vs 5.38% vs 2.47% [P<.001]), the highest mean number of diagnoses (18.31 vs 14.14 vs 8.57 [P<.001]), and the longest mean length of hospital stay (6.03 days vs 5.94 days vs 3.73 days [P<.001]). On univariate analysis of comorbidities, HS patients with thyroid disease had the highest incidence of the following comorbidities compared with HS patients without thyroid disease and controls: hypertension (34.01% vs 28.55% vs 22.39% [P<.001]), DM (48.26% vs 35.63% vs 18.05% [P<.001]), obesity (46.80% vs 39.65% vs 11.70% [P<.001]), and acute kidney injury (AKI)(21.80% vs 13.10% vs 6.33% [P<.001])(eTable).

A multivariate analysis adjusting for multiple potential confounders including age, sex, race, median income quartile, disposition/discharge location, and primary payer was performed for hospital outcome measures and comorbidities. There were no significant differences in hospital outcome measures between HS patients with comorbid thyroid disease vs those without thyroid disease (P>.05)(Table 1). Thyroid disease was associated with increased odds of comorbid DM (odds ratio [OR], 1.242 [95% CI, 1.113-1.386]), obesity (OR, 1.173 [95% CI, 1.057-1.302]), and AKI (OR, 1.623 [95% CI, 1.423-1.851]) and decreased odds of comorbid nicotine dependence (OR, 0.609 [95% CI, 0.540-0.687]), skin and soft tissue infections (OR, 0.712 [95% CI, 0.637-0.797]), and sepsis (OR, 0.836 [95% CI, 0.717-0.973]) in HS patients (Table 2).

We found that HS patients with thyroid disease had increased odds of comorbid obesity, DM, and AKI compared with HS patients without thyroid disease when adjusting for potential confounders on multivariate analysis. A 2019 nationwide cross-sectional study of 18,224 patients with thyroid disease and 72,896 controls in Taiwan showed a higher prevalence of obesity (1.26% vs 0.57% [P<.0001]) and a higher hazard ratio (HR) of type 2 DM (HR, 1.23 [95% CI, 1.16-1.31]) in the thyroid disease group vs the controls.³ In a 2024 claims-based national cohort study of 4,152,830 patients with 2 or more consecutive thyroid-stimulating hormone measurements in the United States, patients with hypothyroidism and hyperthyroidism had a higher incidence risk for kidney dysfunction vs patients with euthyroidism (HRs, 1.37 [95% CI, 1.34–1.40] and 1.42 [95% CI, 1.39-1.45]).⁴ In addition, patients with and without DM and thyroid disease had increased risk for kidney disease compared to patients with and without DM and euthyroidism (hypothyroidism: HRs, 1.17 [95% CI, 1.13-1.22] and 1.52 [95% CI, 1.49-1.56]; hyperthyroidism: HRs, 1.34 [95% CI, 1.29-1.38] and 1.36 [95% CI, 1.33-1.39]). Furthermore, patients with and without obesity and thyroid disease had increased risk for kidney disease compared to patients with and without obesity and with euthyroidism (hypothyroidism: HRs, 1.40 [95% CI, 1.36-1.45] and 1.26 [95% CI, 1.21-1.32]; hyperthyroidism: HRs, 1.34 [95% CI, 1.30-1.39] and 1.35 [95% CI, 1.30-1.40]).⁴ However, these studies did not focus on HS patients.⁵

Hidradenitis suppurativa has a major comorbidity burden, including obesity, DM, and kidney disease.⁵ Our findings suggest a potential additive risk for these conditions in HS patients with comorbid thyroid disease; therefore, heightened surveillance for obesity, DM, and AKI in this population is encouraged. Prospective and retrospective studies in HS patients assessing the risk for each comorbidity while controlling for the others may help to better characterize these relationships.

Using multivariate analysis, we found that HS patients with comorbid thyroid disease had no significant differences in hospital outcome measures compared with HS patients without thyroid disease despite significant differences on univariate analysis (P<.05). Similarly, in a 2018 cross-sectional study of 430 HS patients and 20,780 controls in Denmark, the HS group had 10% lower thyroid-stimulating hormone levels vs the control group, but this did not significantly affect HS severity and thyroid function on multivariate analysis.⁶ In a 2020 cross-sectional analysis of 290 Greek HS patients, thyroid disease was associated with higher HS severity using Hurley classification (OR, 1.19 [95% CI, 1.03-1.51]) and International Hidradenitis Suppurativa Severity Score System 4 classification (OR, 1.29 [95% CI, 1.13-1.62]); however, this analysis was univariate and did not account for confounders.⁷ Taken together, our study and previous research suggest that thyroid disease is not an independent prognostic indicator for hospital outcome measures in HS patients when cofounders are considered and therefore may not warrant extra caution when treating hospitalized HS patients.

Nicotine dependence was an important potential confounder with regard to the effects of comorbid thyroid disease on outcomes of HS patients in our study. While we found that the prevalence of nicotine dependence was higher in HS patients vs matched controls, HS patients with comorbid thyroid disease had a lower prevalence of nicotine dependence than HS patients without thyroid disease. Furthermore, thyroid disease was associated with decreased odds of nicotine dependence in HS patients when adjusting for confounders. Previous studies have shown an association between cigarette smoking and HS. Smoking also may affect thyroid function via thiocyanate, sympathetic activation, or immunologic disturbances. Smoking may have both prothyroid and antithyroid effects.⁶ In a 2023 cross-sectional study of 108 HS patients and 52 age- and sex-matched controls in Germany, HS patients had higher thyroid antibody (TRAb) levels compared with controls (median TRAb level, 15.4 vs 14.2 [P=.026]), with even greater increases in TRAb in HS patients who were smokers or former smokers vs never smokers (median TRAb level, 1.18 vs 1.08 [P=.042]).²

There was a lower frequency of thyroid disease in our HS cohort compared with our matched controls cohort. While there are conflicting reports on the association between HS and thyroid disease in the literature, 2 recent meta-analyses of 5 and 6 case-control studies, respectively, found an association between HS and thyroid disease (OR, 1.36 [95% CI, 1.13-1.64] and 1.88 [95% CI, 1.25-2.81]).^1,8 Notably, these studies were either claims or survey based, included outpatients, or were unspecified. One potential explanation for the difference in our findings vs those of other studies could be underdiagnosis of thyroid disease in hospitalized HS patients. We found that HS patients were most frequently Medicaid or Medicare insured compared to controls, who most frequently were privately insured. Increased availability and ease of access to outpatient medical care through private health insurance may be a possible contributor to the higher frequency of diagnosed thyroid disease in control patients in our study; therefore, awareness of potential underdiagnosis of thyroid disease in hospitalized HS patients is recommended.

Limitations of our study included those inherent to the NIS database, including potential miscoding and lack of data on pharmacologic treatments. Outcome measures assessed were limited by inclusion of both primary and secondary diagnoses of HS and thyroid disease in our cohort and may have been affected by other conditions. As with any observational study, there was a possibility of unidentified confounders unaccounted for in our study.

In conclusion, in this national inpatient-matched cohort study, thyroid disease was associated with increased odds of obesity, DM, and AKI in HS inpatients but was not an independent risk factor for worse hospital outcome measures. Therefore, while increased surveillance of associated comorbidities is appropriate, thyroid disease may not be a cause for increased concern for dermatologists treating hospitalized HS patients. Prospective studies are necessary to better characterize these findings.

To the Editor:

Scabies infestation, which has been recognized as a neglected tropical disease by the World Health Organization since 2017, is caused by the human itch mite (Sarcoptes scabiei var hominis).¹ Infected individuals experience a pruritic papular rash when the mite burrows into the epidermis, where it lives and lays eggs.^2,3 Infected individuals also may develop bacterial superinfections if the skin barrier becomes compromised, leading to systemic complications and considerable morbidity.³

In countries with high human development indices, scabies outbreaks are linked to densely populated living conditions, such as those found in nursing homes or prisons.^3,4 Scabies also is transmitted via sexual contact in adults. Beyond immunosuppression, little is known about other comorbid conditions or lifestyle risk factors associated with scabies infestation.² Because scabies can mimic a range of other dermatologic conditions such as folliculitis, atopic dermatitis, and arthropod bites, misdiagnosis is common and can lead to delayed treatment and increased transmission risk.⁴ In this study, we sought to examine comorbid conditions and/or lifestyle risk factors associated with scabies infestation.

A matched case-control study was performed using the Registered Tier dataset of the National Institutes of Health All of Us Research Program Curated Data Repository version 7, which includes more than 400,000 unique participants aged 18 years or older from across the United States. The All of Us Research Program excludes adults who are unable to consent independently as well as incarcerated populations and children younger than 18 years. Participants diagnosed with scabies were identified using SNOMED code 62752005 and compared to a control group matched 1:4 based on age, sex, and selfidentified race. SNOMED codes also were used to identify various comorbidities and lifestyle risk factors, including depression, bipolar disorder, anxiety, schizophrenia, peripheral vascular disease (PVD), HIV, type 2 diabetes mellitus (T2DM), unsheltered status, tobacco use, difficulty with activities of daily living, insurance status, and any recent travel history. Logistic regression models were used to calculate odds ratios (ORs) and estimate effect sizes, with statistical significance set at P<.05.

We identified 691 cases of scabies infestation and 2073 controls. The average age of the patients diagnosed with scabies was 55.1 years. Seventy percent (481/691) identified as female and 32.4% (224/491) identified as Black or African American. Matched controls were similar for all analyzed demographic characteristics (P=1.0)(eTable 1). Patients diagnosed with scabies were more likely to be unsheltered (OR, 2.33 [95% CI, 1.91-2.85]), use tobacco (OR 1.77 [95% CI, 1.48-2.11]) and have a comorbid diagnosis of HIV (OR, 3.08 [95% CI, 2.03-4.66]), T2DM (OR, 2.05 [95% CI, 1.57- 2.66]) or PVD (OR, 2.06 [95% CI, 1.43-2.97]) compared with controls (P<.001). Psychiatric comorbidities were more common in the patients diagnosed with scabies, including depression (OR, 3.07 [95% CI, 2.54-3.72]), anxiety (OR, 2.48 [95% CI, 2.06-2.98]), bipolar disorder (OR, 3.08 [95% CI, 2.34-4.05]), and schizophrenia (OR, 4.68 [95% CI, 2.93-7.49])(P<.001). Difficulties with activities of daily living, including running errands alone (OR, 2.32 [95% CI, 1.43-3.76]) and concentrating (OR, 5.78; 95% CI, 3.86-8.64), were more prevalent in the scabies group compared to controls (both P<.05). In a multivariate logistic regression model including unsheltered status as a covariate, all associations remained statistically significant (P<.05)(eTable 2).

This large diverse study demonstrated an association between scabies infestation and unsheltered status. Previous studies have shown that unsheltered populations are at increased risk for many dermatologic conditions, perhaps due to decreased access to health care and social support, lack of access to hygiene facilities (eg, public showers), and increased prevalence of substance use and psychiatric disorders among this population.⁵ In a cross-sectional analysis of hospitalized patients, 8.6% of unsheltered patients (n=197) had an ectoparasitic disease (including scabies) compared with 1.0% of patients with stable housing (n=1018), with a 9.43-fold increased risk for ectoparasitic infestation among unsheltered patients (95% CI, 3.79-23.47; P<.001).⁶ Increased attention to public health initiatives among unsheltered populations— including access to hygiene facilities and increased dermatologic services—are needed, as ectoparasitic infections are both preventable and treatable, and these initiatives could reduce morbidity associated with superimposed bacterial infections for which unsheltered patients are at increased risk.⁶

Our results also showed that individuals diagnosed with scabies were more likely than the controls to have been diagnosed with HIV, T2DM, and PVD. Our findings are similar to those of a systematic review of immunosuppressive factors associated with crusted scabies (a severe form of scabies infestation) in which 10.2% and 15.7% of patients (n=683) had comorbid HIV and T2DM, respectively.⁷ A functioning cell-mediated response to scabies mite antigens limits proliferation of the human itch mite; thus, infection with HIV/AIDS, which induces the destruction of CD4+ T cells, limits the immune system’s ability to mount an effective response against these antigens. The association of scabies with T2DM likely is multifactorial; for example, chronic hyperglycemia may lead to immune system impairment, and peripheral neuropathy may reduce the itch sensation, allowing scabies mites to proliferate without removal by scratching.⁷ In a descriptive epidemiologic study in Japan, 11.7% of patients with scabies (N=857) had comorbid PVD.⁸ Peripheral vascular disease can lead to the development of ulcers, gangrene, and stasis dermatitis, all of which compromise the skin barrier and increase susceptibility to infection.⁹ Notably, these associations remained even when unsheltered status was considered as a confounding variable. Because individuals with HIV, T2DM, and PVD may be at higher risk for serious complications of scabies infestation (eg, secondary bacterial infections, invasive group A streptococcal infections), prompt detection and treatment of scabies are crucial in curbing morbidity in these at-risk populations.

Our study also demonstrated that psychiatric comorbidities including depression, anxiety, bipolar disorder, and schizophrenia were associated with scabies infestation, even when controlling for unsheltered status, which may have a bidirectional relationship with mental health disorders.¹⁰ In a cross-sectional study of 83 adult patients diagnosed with scabies, 72.2% (60/83) reported moderate to extremely large effect of scabies infestation on quality of life using the Dermatology Life Quality Index, and these scores positively correlated with increased Beck Depression Scale and Beck Anxiety Scale scores (r_s=0.448 and r_s=0.456 0.456, respectively; both P=.000). The results of this study suggest that scabies negatively impacts quality of life, which might increase symptoms of depression and anxiety.¹¹

Studies are needed to assess whether patients with pre-existing depression and anxiety face increased risk for scabies infestation. In a retrospective case-control study using data from the National Health Insurance Research Database of Taiwan, 0.8% (58/7096) of patients with scabies (n=7096) and 0.4% of controls (n=28,375) were newly diagnosed with bipolar disorder over a 7-year period, indicating a 1.55-fold increased risk for bipolar disorder in patients with scabies compared to those without (95% CI, 1.12-2.09; P<.05).¹² Future studies are needed to determine whether the relationship between bipolar disorder and scabies is bidirectional, with pre-existing bipolar disorder evaluated as a risk factor for subsequent scabies infestation. Increased difficulties with activities of daily living, including running errands independently and concentrating, were associated with scabies. These difficulties may reflect sequelae of psychiatric illness or pruritus associated with scabies affecting daily living.

Physician awareness of comorbidities and lifestyle risk factors associated with scabies infestation may improve diagnosis and prevent treatment delays. In a retrospective study at a single dermatology outpatient clinic, 45.3% of patients with scabies (n=428) had previously been misdiagnosed with another dermatologic condition, and the most common erroneous diagnosis was atopic dermatitis.¹³ Our study provides a framework of comorbidities and lifestyle risk factors associated with scabies infestation that dermatologists can use to stratify patients who may be at greater risk for this condition, allowing dermatologists to select appropriate treatment when clinical signs are ambiguous.

Limitations of our study included the potential for miscoding in the database, lack of information about treatment regimens employed (if any), and lack of information about the temporal relationship between associations.

In summary, it is recommended that patients with pruritus and other characteristic clinical findings of scabies receive appropriate workup for scabies regardless of risk factors; however, the medical and psychiatric comorbidities and lifestyle risk factors identified in this study may help to identify at-risk patients. Our study showed that unsheltered patients are at increased risk for scabies, potentially due to unique dermatologic challenges and lack of access to health care and hygiene facilities. Positive correlations between scabies and HIV, T2DM, and PVD suggest that patients with chronic immunocompromising illnesses who live in group homes or other crowded quarters and present with symptoms could be evaluated for scabies infestation to prevent widespread and difficult- to-control outbreaks in these communities. Based on our findings, scabies also should be included in the differential diagnosis for patients with psychiatric illness and suggestive symptoms. Early identification and treatment of scabies infestation could prevent misdiagnosis and treatment delays.

To the Editor:

Scabies infestation, which has been recognized as a neglected tropical disease by the World Health Organization since 2017, is caused by the human itch mite (Sarcoptes scabiei var hominis).¹ Infected individuals experience a pruritic papular rash when the mite burrows into the epidermis, where it lives and lays eggs.^2,3 Infected individuals also may develop bacterial superinfections if the skin barrier becomes compromised, leading to systemic complications and considerable morbidity.³

In countries with high human development indices, scabies outbreaks are linked to densely populated living conditions, such as those found in nursing homes or prisons.^3,4 Scabies also is transmitted via sexual contact in adults. Beyond immunosuppression, little is known about other comorbid conditions or lifestyle risk factors associated with scabies infestation.² Because scabies can mimic a range of other dermatologic conditions such as folliculitis, atopic dermatitis, and arthropod bites, misdiagnosis is common and can lead to delayed treatment and increased transmission risk.⁴ In this study, we sought to examine comorbid conditions and/or lifestyle risk factors associated with scabies infestation.

A matched case-control study was performed using the Registered Tier dataset of the National Institutes of Health All of Us Research Program Curated Data Repository version 7, which includes more than 400,000 unique participants aged 18 years or older from across the United States. The All of Us Research Program excludes adults who are unable to consent independently as well as incarcerated populations and children younger than 18 years. Participants diagnosed with scabies were identified using SNOMED code 62752005 and compared to a control group matched 1:4 based on age, sex, and selfidentified race. SNOMED codes also were used to identify various comorbidities and lifestyle risk factors, including depression, bipolar disorder, anxiety, schizophrenia, peripheral vascular disease (PVD), HIV, type 2 diabetes mellitus (T2DM), unsheltered status, tobacco use, difficulty with activities of daily living, insurance status, and any recent travel history. Logistic regression models were used to calculate odds ratios (ORs) and estimate effect sizes, with statistical significance set at P<.05.

We identified 691 cases of scabies infestation and 2073 controls. The average age of the patients diagnosed with scabies was 55.1 years. Seventy percent (481/691) identified as female and 32.4% (224/491) identified as Black or African American. Matched controls were similar for all analyzed demographic characteristics (P=1.0)(eTable 1). Patients diagnosed with scabies were more likely to be unsheltered (OR, 2.33 [95% CI, 1.91-2.85]), use tobacco (OR 1.77 [95% CI, 1.48-2.11]) and have a comorbid diagnosis of HIV (OR, 3.08 [95% CI, 2.03-4.66]), T2DM (OR, 2.05 [95% CI, 1.57- 2.66]) or PVD (OR, 2.06 [95% CI, 1.43-2.97]) compared with controls (P<.001). Psychiatric comorbidities were more common in the patients diagnosed with scabies, including depression (OR, 3.07 [95% CI, 2.54-3.72]), anxiety (OR, 2.48 [95% CI, 2.06-2.98]), bipolar disorder (OR, 3.08 [95% CI, 2.34-4.05]), and schizophrenia (OR, 4.68 [95% CI, 2.93-7.49])(P<.001). Difficulties with activities of daily living, including running errands alone (OR, 2.32 [95% CI, 1.43-3.76]) and concentrating (OR, 5.78; 95% CI, 3.86-8.64), were more prevalent in the scabies group compared to controls (both P<.05). In a multivariate logistic regression model including unsheltered status as a covariate, all associations remained statistically significant (P<.05)(eTable 2).

This large diverse study demonstrated an association between scabies infestation and unsheltered status. Previous studies have shown that unsheltered populations are at increased risk for many dermatologic conditions, perhaps due to decreased access to health care and social support, lack of access to hygiene facilities (eg, public showers), and increased prevalence of substance use and psychiatric disorders among this population.⁵ In a cross-sectional analysis of hospitalized patients, 8.6% of unsheltered patients (n=197) had an ectoparasitic disease (including scabies) compared with 1.0% of patients with stable housing (n=1018), with a 9.43-fold increased risk for ectoparasitic infestation among unsheltered patients (95% CI, 3.79-23.47; P<.001).⁶ Increased attention to public health initiatives among unsheltered populations— including access to hygiene facilities and increased dermatologic services—are needed, as ectoparasitic infections are both preventable and treatable, and these initiatives could reduce morbidity associated with superimposed bacterial infections for which unsheltered patients are at increased risk.⁶

Our results also showed that individuals diagnosed with scabies were more likely than the controls to have been diagnosed with HIV, T2DM, and PVD. Our findings are similar to those of a systematic review of immunosuppressive factors associated with crusted scabies (a severe form of scabies infestation) in which 10.2% and 15.7% of patients (n=683) had comorbid HIV and T2DM, respectively.⁷ A functioning cell-mediated response to scabies mite antigens limits proliferation of the human itch mite; thus, infection with HIV/AIDS, which induces the destruction of CD4+ T cells, limits the immune system’s ability to mount an effective response against these antigens. The association of scabies with T2DM likely is multifactorial; for example, chronic hyperglycemia may lead to immune system impairment, and peripheral neuropathy may reduce the itch sensation, allowing scabies mites to proliferate without removal by scratching.⁷ In a descriptive epidemiologic study in Japan, 11.7% of patients with scabies (N=857) had comorbid PVD.⁸ Peripheral vascular disease can lead to the development of ulcers, gangrene, and stasis dermatitis, all of which compromise the skin barrier and increase susceptibility to infection.⁹ Notably, these associations remained even when unsheltered status was considered as a confounding variable. Because individuals with HIV, T2DM, and PVD may be at higher risk for serious complications of scabies infestation (eg, secondary bacterial infections, invasive group A streptococcal infections), prompt detection and treatment of scabies are crucial in curbing morbidity in these at-risk populations.

Our study also demonstrated that psychiatric comorbidities including depression, anxiety, bipolar disorder, and schizophrenia were associated with scabies infestation, even when controlling for unsheltered status, which may have a bidirectional relationship with mental health disorders.¹⁰ In a cross-sectional study of 83 adult patients diagnosed with scabies, 72.2% (60/83) reported moderate to extremely large effect of scabies infestation on quality of life using the Dermatology Life Quality Index, and these scores positively correlated with increased Beck Depression Scale and Beck Anxiety Scale scores (r_s=0.448 and r_s=0.456 0.456, respectively; both P=.000). The results of this study suggest that scabies negatively impacts quality of life, which might increase symptoms of depression and anxiety.¹¹

Studies are needed to assess whether patients with pre-existing depression and anxiety face increased risk for scabies infestation. In a retrospective case-control study using data from the National Health Insurance Research Database of Taiwan, 0.8% (58/7096) of patients with scabies (n=7096) and 0.4% of controls (n=28,375) were newly diagnosed with bipolar disorder over a 7-year period, indicating a 1.55-fold increased risk for bipolar disorder in patients with scabies compared to those without (95% CI, 1.12-2.09; P<.05).¹² Future studies are needed to determine whether the relationship between bipolar disorder and scabies is bidirectional, with pre-existing bipolar disorder evaluated as a risk factor for subsequent scabies infestation. Increased difficulties with activities of daily living, including running errands independently and concentrating, were associated with scabies. These difficulties may reflect sequelae of psychiatric illness or pruritus associated with scabies affecting daily living.

Physician awareness of comorbidities and lifestyle risk factors associated with scabies infestation may improve diagnosis and prevent treatment delays. In a retrospective study at a single dermatology outpatient clinic, 45.3% of patients with scabies (n=428) had previously been misdiagnosed with another dermatologic condition, and the most common erroneous diagnosis was atopic dermatitis.¹³ Our study provides a framework of comorbidities and lifestyle risk factors associated with scabies infestation that dermatologists can use to stratify patients who may be at greater risk for this condition, allowing dermatologists to select appropriate treatment when clinical signs are ambiguous.

Limitations of our study included the potential for miscoding in the database, lack of information about treatment regimens employed (if any), and lack of information about the temporal relationship between associations.

In summary, it is recommended that patients with pruritus and other characteristic clinical findings of scabies receive appropriate workup for scabies regardless of risk factors; however, the medical and psychiatric comorbidities and lifestyle risk factors identified in this study may help to identify at-risk patients. Our study showed that unsheltered patients are at increased risk for scabies, potentially due to unique dermatologic challenges and lack of access to health care and hygiene facilities. Positive correlations between scabies and HIV, T2DM, and PVD suggest that patients with chronic immunocompromising illnesses who live in group homes or other crowded quarters and present with symptoms could be evaluated for scabies infestation to prevent widespread and difficult- to-control outbreaks in these communities. Based on our findings, scabies also should be included in the differential diagnosis for patients with psychiatric illness and suggestive symptoms. Early identification and treatment of scabies infestation could prevent misdiagnosis and treatment delays.

To the Editor:

Scabies infestation, which has been recognized as a neglected tropical disease by the World Health Organization since 2017, is caused by the human itch mite (Sarcoptes scabiei var hominis).¹ Infected individuals experience a pruritic papular rash when the mite burrows into the epidermis, where it lives and lays eggs.^2,3 Infected individuals also may develop bacterial superinfections if the skin barrier becomes compromised, leading to systemic complications and considerable morbidity.³

In countries with high human development indices, scabies outbreaks are linked to densely populated living conditions, such as those found in nursing homes or prisons.^3,4 Scabies also is transmitted via sexual contact in adults. Beyond immunosuppression, little is known about other comorbid conditions or lifestyle risk factors associated with scabies infestation.² Because scabies can mimic a range of other dermatologic conditions such as folliculitis, atopic dermatitis, and arthropod bites, misdiagnosis is common and can lead to delayed treatment and increased transmission risk.⁴ In this study, we sought to examine comorbid conditions and/or lifestyle risk factors associated with scabies infestation.

A matched case-control study was performed using the Registered Tier dataset of the National Institutes of Health All of Us Research Program Curated Data Repository version 7, which includes more than 400,000 unique participants aged 18 years or older from across the United States. The All of Us Research Program excludes adults who are unable to consent independently as well as incarcerated populations and children younger than 18 years. Participants diagnosed with scabies were identified using SNOMED code 62752005 and compared to a control group matched 1:4 based on age, sex, and selfidentified race. SNOMED codes also were used to identify various comorbidities and lifestyle risk factors, including depression, bipolar disorder, anxiety, schizophrenia, peripheral vascular disease (PVD), HIV, type 2 diabetes mellitus (T2DM), unsheltered status, tobacco use, difficulty with activities of daily living, insurance status, and any recent travel history. Logistic regression models were used to calculate odds ratios (ORs) and estimate effect sizes, with statistical significance set at P<.05.

We identified 691 cases of scabies infestation and 2073 controls. The average age of the patients diagnosed with scabies was 55.1 years. Seventy percent (481/691) identified as female and 32.4% (224/491) identified as Black or African American. Matched controls were similar for all analyzed demographic characteristics (P=1.0)(eTable 1). Patients diagnosed with scabies were more likely to be unsheltered (OR, 2.33 [95% CI, 1.91-2.85]), use tobacco (OR 1.77 [95% CI, 1.48-2.11]) and have a comorbid diagnosis of HIV (OR, 3.08 [95% CI, 2.03-4.66]), T2DM (OR, 2.05 [95% CI, 1.57- 2.66]) or PVD (OR, 2.06 [95% CI, 1.43-2.97]) compared with controls (P<.001). Psychiatric comorbidities were more common in the patients diagnosed with scabies, including depression (OR, 3.07 [95% CI, 2.54-3.72]), anxiety (OR, 2.48 [95% CI, 2.06-2.98]), bipolar disorder (OR, 3.08 [95% CI, 2.34-4.05]), and schizophrenia (OR, 4.68 [95% CI, 2.93-7.49])(P<.001). Difficulties with activities of daily living, including running errands alone (OR, 2.32 [95% CI, 1.43-3.76]) and concentrating (OR, 5.78; 95% CI, 3.86-8.64), were more prevalent in the scabies group compared to controls (both P<.05). In a multivariate logistic regression model including unsheltered status as a covariate, all associations remained statistically significant (P<.05)(eTable 2).

This large diverse study demonstrated an association between scabies infestation and unsheltered status. Previous studies have shown that unsheltered populations are at increased risk for many dermatologic conditions, perhaps due to decreased access to health care and social support, lack of access to hygiene facilities (eg, public showers), and increased prevalence of substance use and psychiatric disorders among this population.⁵ In a cross-sectional analysis of hospitalized patients, 8.6% of unsheltered patients (n=197) had an ectoparasitic disease (including scabies) compared with 1.0% of patients with stable housing (n=1018), with a 9.43-fold increased risk for ectoparasitic infestation among unsheltered patients (95% CI, 3.79-23.47; P<.001).⁶ Increased attention to public health initiatives among unsheltered populations— including access to hygiene facilities and increased dermatologic services—are needed, as ectoparasitic infections are both preventable and treatable, and these initiatives could reduce morbidity associated with superimposed bacterial infections for which unsheltered patients are at increased risk.⁶

Our results also showed that individuals diagnosed with scabies were more likely than the controls to have been diagnosed with HIV, T2DM, and PVD. Our findings are similar to those of a systematic review of immunosuppressive factors associated with crusted scabies (a severe form of scabies infestation) in which 10.2% and 15.7% of patients (n=683) had comorbid HIV and T2DM, respectively.⁷ A functioning cell-mediated response to scabies mite antigens limits proliferation of the human itch mite; thus, infection with HIV/AIDS, which induces the destruction of CD4+ T cells, limits the immune system’s ability to mount an effective response against these antigens. The association of scabies with T2DM likely is multifactorial; for example, chronic hyperglycemia may lead to immune system impairment, and peripheral neuropathy may reduce the itch sensation, allowing scabies mites to proliferate without removal by scratching.⁷ In a descriptive epidemiologic study in Japan, 11.7% of patients with scabies (N=857) had comorbid PVD.⁸ Peripheral vascular disease can lead to the development of ulcers, gangrene, and stasis dermatitis, all of which compromise the skin barrier and increase susceptibility to infection.⁹ Notably, these associations remained even when unsheltered status was considered as a confounding variable. Because individuals with HIV, T2DM, and PVD may be at higher risk for serious complications of scabies infestation (eg, secondary bacterial infections, invasive group A streptococcal infections), prompt detection and treatment of scabies are crucial in curbing morbidity in these at-risk populations.

Our study also demonstrated that psychiatric comorbidities including depression, anxiety, bipolar disorder, and schizophrenia were associated with scabies infestation, even when controlling for unsheltered status, which may have a bidirectional relationship with mental health disorders.¹⁰ In a cross-sectional study of 83 adult patients diagnosed with scabies, 72.2% (60/83) reported moderate to extremely large effect of scabies infestation on quality of life using the Dermatology Life Quality Index, and these scores positively correlated with increased Beck Depression Scale and Beck Anxiety Scale scores (r_s=0.448 and r_s=0.456 0.456, respectively; both P=.000). The results of this study suggest that scabies negatively impacts quality of life, which might increase symptoms of depression and anxiety.¹¹

Studies are needed to assess whether patients with pre-existing depression and anxiety face increased risk for scabies infestation. In a retrospective case-control study using data from the National Health Insurance Research Database of Taiwan, 0.8% (58/7096) of patients with scabies (n=7096) and 0.4% of controls (n=28,375) were newly diagnosed with bipolar disorder over a 7-year period, indicating a 1.55-fold increased risk for bipolar disorder in patients with scabies compared to those without (95% CI, 1.12-2.09; P<.05).¹² Future studies are needed to determine whether the relationship between bipolar disorder and scabies is bidirectional, with pre-existing bipolar disorder evaluated as a risk factor for subsequent scabies infestation. Increased difficulties with activities of daily living, including running errands independently and concentrating, were associated with scabies. These difficulties may reflect sequelae of psychiatric illness or pruritus associated with scabies affecting daily living.

Physician awareness of comorbidities and lifestyle risk factors associated with scabies infestation may improve diagnosis and prevent treatment delays. In a retrospective study at a single dermatology outpatient clinic, 45.3% of patients with scabies (n=428) had previously been misdiagnosed with another dermatologic condition, and the most common erroneous diagnosis was atopic dermatitis.¹³ Our study provides a framework of comorbidities and lifestyle risk factors associated with scabies infestation that dermatologists can use to stratify patients who may be at greater risk for this condition, allowing dermatologists to select appropriate treatment when clinical signs are ambiguous.

Limitations of our study included the potential for miscoding in the database, lack of information about treatment regimens employed (if any), and lack of information about the temporal relationship between associations.

In summary, it is recommended that patients with pruritus and other characteristic clinical findings of scabies receive appropriate workup for scabies regardless of risk factors; however, the medical and psychiatric comorbidities and lifestyle risk factors identified in this study may help to identify at-risk patients. Our study showed that unsheltered patients are at increased risk for scabies, potentially due to unique dermatologic challenges and lack of access to health care and hygiene facilities. Positive correlations between scabies and HIV, T2DM, and PVD suggest that patients with chronic immunocompromising illnesses who live in group homes or other crowded quarters and present with symptoms could be evaluated for scabies infestation to prevent widespread and difficult- to-control outbreaks in these communities. Based on our findings, scabies also should be included in the differential diagnosis for patients with psychiatric illness and suggestive symptoms. Early identification and treatment of scabies infestation could prevent misdiagnosis and treatment delays.