The risk of melanoma was increased among patients taking biologics for immune-mediated inflammatory diseases, compared with biologic-naive patients on conventional systemic therapy, but the association was not statistically significant in a systematic review and meta-analysis published in JAMA Dermatology.

The studies included in the analysis, however, had limitations, including a lack of those comparing biologic and conventional systemic therapy in psoriasis and inflammatory bowel disease (IBD), according to Shamarke Esse, MRes, of the division of musculoskeletal and dermatological sciences at the University of Manchester (England) and colleagues. “We advocate for more large, well-designed studies of this issue to be performed to help improve certainty” regarding this association, they wrote.

Previous studies that have found an increased risk of melanoma in patients on biologics for psoriasis, rheumatoid arthritis, and IBD have “typically used the general population as the comparator,” they noted. There is a large amount of evidence that has established short-term efficacy and safety of biologics, compared with conventional systemic treatments, but concerns about longer-term cancer risk associated with biologics remains a concern. Moreover, they added, “melanoma is a highly immunogenic skin cancer and therefore of concern to patients treated with TNFIs [tumor necrosis factor inhibitors] because melanoma risk increases with suppression of the immune system and TNF-alpha plays an important role in the immune surveillance of tumors.12,13

In their review, the researchers identified seven cohort studies from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases published between January 1995 and February 2019 that evaluated melanoma risk in about 34,000 patients receiving biologics and 135,370 patients who had never been treated with biologics, and were receiving conventional systemic therapy for psoriasis, RA, or IBD. Of these, four studies were in patients with RA, two studies were in patients with IBD, and a single study was in patients with psoriasis. Six studies examined patients taking TNF inhibitors, but only one of six studies had information on specific TNF inhibitors (adalimumab, etanercept, and infliximab) in patients with RA. One study evaluated abatacept and rituximab in RA patients.

The researchers analyzed the pooled relative risk across all studies. Compared with patients who received conventional systemic therapy, there was a nonsignificant association with risk of melanoma in patients with psoriasis (hazard ratio, 1.57; 95% confidence interval, 0.61-4.09), RA (pooled relative risk, 1.20; 95% CI, 0.83-1.74), and IBD (pRR, 1.20; 95% CI, 0.60-2.40).

Among RA patients who received TNF inhibitors only, there was a slightly elevated nonsignificant risk of melanoma (pRR, 1.08; 95% CI, 0.81-1.43). Patients receiving rituximab had a pRR of 0.73 (95% CI, 0.38-1.39), and patients taking abatacept had a pRR of 1.43 (95% CI, 0.66-3.09), compared with RA patients receiving conventional systemic therapy. When excluding two major studies in the RA subgroup of patients in a sensitivity analysis, pooled risk estimates varied from 0.91 (95% CI, 0.69-1.18) to 1.95 (95% CI, 1.16- 3.30). There were no significant between-study heterogeneity or publication bias among the IBD and RA studies.

Mr. Esse and colleagues acknowledged the small number of IBD and psoriasis studies in the meta-analysis, which could affect pooled risk estimates. “Any future update of our study through the inclusion of newly published studies may produce significantly different pooled risk estimates than those reported in our meta-analysis,” they said. In addition, the use of health insurance databases, lack of risk factors for melanoma, and inconsistent information about treatment duration for patients receiving conventional systemic therapy were also limitations.

“Prospective cohort studies using an active comparator, new-user study design providing detailed information on treatment history, concomitant treatments, biologic and conventional systemic treatment duration, recreational and treatment-related UV exposure, skin color, and date of melanoma diagnosis are required to help improve certainty. These studies would also need to account for key risk factors and the latency period of melanoma,” the researchers said.

Mr. Esse disclosed being funded by a PhD studentship from the Psoriasis Association. One author disclosed receiving personal fees from Janssen, LEO Pharma, Lilly, and Novartis outside the study; another disclosed receiving grants and personal fees from those and several other pharmaceutical companies during the study, and personal fees from several pharmaceutical companies outside of the submitted work; the fourth author had no disclosures.

SOURCE: Esse S et al. JAMA Dermatol. 2020 May 20;e201300.

The risk of melanoma was increased among patients taking biologics for immune-mediated inflammatory diseases, compared with biologic-naive patients on conventional systemic therapy, but the association was not statistically significant in a systematic review and meta-analysis published in JAMA Dermatology.

The studies included in the analysis, however, had limitations, including a lack of those comparing biologic and conventional systemic therapy in psoriasis and inflammatory bowel disease (IBD), according to Shamarke Esse, MRes, of the division of musculoskeletal and dermatological sciences at the University of Manchester (England) and colleagues. “We advocate for more large, well-designed studies of this issue to be performed to help improve certainty” regarding this association, they wrote.

Previous studies that have found an increased risk of melanoma in patients on biologics for psoriasis, rheumatoid arthritis, and IBD have “typically used the general population as the comparator,” they noted. There is a large amount of evidence that has established short-term efficacy and safety of biologics, compared with conventional systemic treatments, but concerns about longer-term cancer risk associated with biologics remains a concern. Moreover, they added, “melanoma is a highly immunogenic skin cancer and therefore of concern to patients treated with TNFIs [tumor necrosis factor inhibitors] because melanoma risk increases with suppression of the immune system and TNF-alpha plays an important role in the immune surveillance of tumors.12,13

In their review, the researchers identified seven cohort studies from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases published between January 1995 and February 2019 that evaluated melanoma risk in about 34,000 patients receiving biologics and 135,370 patients who had never been treated with biologics, and were receiving conventional systemic therapy for psoriasis, RA, or IBD. Of these, four studies were in patients with RA, two studies were in patients with IBD, and a single study was in patients with psoriasis. Six studies examined patients taking TNF inhibitors, but only one of six studies had information on specific TNF inhibitors (adalimumab, etanercept, and infliximab) in patients with RA. One study evaluated abatacept and rituximab in RA patients.

The researchers analyzed the pooled relative risk across all studies. Compared with patients who received conventional systemic therapy, there was a nonsignificant association with risk of melanoma in patients with psoriasis (hazard ratio, 1.57; 95% confidence interval, 0.61-4.09), RA (pooled relative risk, 1.20; 95% CI, 0.83-1.74), and IBD (pRR, 1.20; 95% CI, 0.60-2.40).

Among RA patients who received TNF inhibitors only, there was a slightly elevated nonsignificant risk of melanoma (pRR, 1.08; 95% CI, 0.81-1.43). Patients receiving rituximab had a pRR of 0.73 (95% CI, 0.38-1.39), and patients taking abatacept had a pRR of 1.43 (95% CI, 0.66-3.09), compared with RA patients receiving conventional systemic therapy. When excluding two major studies in the RA subgroup of patients in a sensitivity analysis, pooled risk estimates varied from 0.91 (95% CI, 0.69-1.18) to 1.95 (95% CI, 1.16- 3.30). There were no significant between-study heterogeneity or publication bias among the IBD and RA studies.

Mr. Esse and colleagues acknowledged the small number of IBD and psoriasis studies in the meta-analysis, which could affect pooled risk estimates. “Any future update of our study through the inclusion of newly published studies may produce significantly different pooled risk estimates than those reported in our meta-analysis,” they said. In addition, the use of health insurance databases, lack of risk factors for melanoma, and inconsistent information about treatment duration for patients receiving conventional systemic therapy were also limitations.

“Prospective cohort studies using an active comparator, new-user study design providing detailed information on treatment history, concomitant treatments, biologic and conventional systemic treatment duration, recreational and treatment-related UV exposure, skin color, and date of melanoma diagnosis are required to help improve certainty. These studies would also need to account for key risk factors and the latency period of melanoma,” the researchers said.

Mr. Esse disclosed being funded by a PhD studentship from the Psoriasis Association. One author disclosed receiving personal fees from Janssen, LEO Pharma, Lilly, and Novartis outside the study; another disclosed receiving grants and personal fees from those and several other pharmaceutical companies during the study, and personal fees from several pharmaceutical companies outside of the submitted work; the fourth author had no disclosures.

SOURCE: Esse S et al. JAMA Dermatol. 2020 May 20;e201300.

The risk of melanoma was increased among patients taking biologics for immune-mediated inflammatory diseases, compared with biologic-naive patients on conventional systemic therapy, but the association was not statistically significant in a systematic review and meta-analysis published in JAMA Dermatology.

The studies included in the analysis, however, had limitations, including a lack of those comparing biologic and conventional systemic therapy in psoriasis and inflammatory bowel disease (IBD), according to Shamarke Esse, MRes, of the division of musculoskeletal and dermatological sciences at the University of Manchester (England) and colleagues. “We advocate for more large, well-designed studies of this issue to be performed to help improve certainty” regarding this association, they wrote.

Previous studies that have found an increased risk of melanoma in patients on biologics for psoriasis, rheumatoid arthritis, and IBD have “typically used the general population as the comparator,” they noted. There is a large amount of evidence that has established short-term efficacy and safety of biologics, compared with conventional systemic treatments, but concerns about longer-term cancer risk associated with biologics remains a concern. Moreover, they added, “melanoma is a highly immunogenic skin cancer and therefore of concern to patients treated with TNFIs [tumor necrosis factor inhibitors] because melanoma risk increases with suppression of the immune system and TNF-alpha plays an important role in the immune surveillance of tumors.12,13

In their review, the researchers identified seven cohort studies from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases published between January 1995 and February 2019 that evaluated melanoma risk in about 34,000 patients receiving biologics and 135,370 patients who had never been treated with biologics, and were receiving conventional systemic therapy for psoriasis, RA, or IBD. Of these, four studies were in patients with RA, two studies were in patients with IBD, and a single study was in patients with psoriasis. Six studies examined patients taking TNF inhibitors, but only one of six studies had information on specific TNF inhibitors (adalimumab, etanercept, and infliximab) in patients with RA. One study evaluated abatacept and rituximab in RA patients.

The researchers analyzed the pooled relative risk across all studies. Compared with patients who received conventional systemic therapy, there was a nonsignificant association with risk of melanoma in patients with psoriasis (hazard ratio, 1.57; 95% confidence interval, 0.61-4.09), RA (pooled relative risk, 1.20; 95% CI, 0.83-1.74), and IBD (pRR, 1.20; 95% CI, 0.60-2.40).

Among RA patients who received TNF inhibitors only, there was a slightly elevated nonsignificant risk of melanoma (pRR, 1.08; 95% CI, 0.81-1.43). Patients receiving rituximab had a pRR of 0.73 (95% CI, 0.38-1.39), and patients taking abatacept had a pRR of 1.43 (95% CI, 0.66-3.09), compared with RA patients receiving conventional systemic therapy. When excluding two major studies in the RA subgroup of patients in a sensitivity analysis, pooled risk estimates varied from 0.91 (95% CI, 0.69-1.18) to 1.95 (95% CI, 1.16- 3.30). There were no significant between-study heterogeneity or publication bias among the IBD and RA studies.

Mr. Esse and colleagues acknowledged the small number of IBD and psoriasis studies in the meta-analysis, which could affect pooled risk estimates. “Any future update of our study through the inclusion of newly published studies may produce significantly different pooled risk estimates than those reported in our meta-analysis,” they said. In addition, the use of health insurance databases, lack of risk factors for melanoma, and inconsistent information about treatment duration for patients receiving conventional systemic therapy were also limitations.

“Prospective cohort studies using an active comparator, new-user study design providing detailed information on treatment history, concomitant treatments, biologic and conventional systemic treatment duration, recreational and treatment-related UV exposure, skin color, and date of melanoma diagnosis are required to help improve certainty. These studies would also need to account for key risk factors and the latency period of melanoma,” the researchers said.

Mr. Esse disclosed being funded by a PhD studentship from the Psoriasis Association. One author disclosed receiving personal fees from Janssen, LEO Pharma, Lilly, and Novartis outside the study; another disclosed receiving grants and personal fees from those and several other pharmaceutical companies during the study, and personal fees from several pharmaceutical companies outside of the submitted work; the fourth author had no disclosures.

SOURCE: Esse S et al. JAMA Dermatol. 2020 May 20;e201300.

An estimated 30 million cases of acute rhinosinusitis (ARS) occur every year in the United States.¹ More than 80% of people with ARS are prescribed antibiotics in North America, accounting for 15% to 20% of all antibiotic prescriptions in the adult outpatient setting.^2,3 Many of these prescriptions are unnecessary, as the most common cause of ARS is a virus.^4,5 Evidence consistently shows that symptoms of ARS will resolve spontaneously in most patients and that only those patients with severe or prolonged symptoms require consideration of antibiotic therapy.^1,2,4,6 Nearly half of all patients will improve within 1 week and two-thirds of patients will improve within 2 weeks without the use of antibiotics.⁷ In children, only about 6% to 7% presenting with upper respiratory symptoms meet the criteria for acute bacterial rhinosinusitis (ABRS),⁸ which we’ll detail in a bit. For most patients, treatment should consist of symptom management.⁵

But what about the minority who require antibiotic therapy? This article reviews how to evaluate patients with ARS, identify those who require antibiotics, and prescribe the most appropriate antibiotic treatment regimens.

Diagnosis: Distinguishing viral from bacterial disease

ARS is defined as the sudden onset of purulent nasal discharge plus either nasal blockage or facial pressure/pain lasting < 4 weeks.^3,9 Additional signs and symptoms may include postnasal drip, a reduced sense of smell, sinus tenderness to palpation, and maxillary toothaches.^10,11

ARS may be viral or bacterial in etiology, with the most common bacterial organisms being Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.^1,3,5 The most common viral causes are influenza, parainfluenza, and rhinovirus. Approximately 90% to 98% of cases of ARS are viral^6,11; only about 0.5% to 2% of viral rhinosinusitis episodes are complicated by bacterial infection.^1,10-12

Diagnose ABRS when symptoms of ARS fail to improve after 10 days or symptoms of ARS worsen within 10 days after initial improvement (“double sickening”).^1,11 Symptoms that are significantly associated with ABRS are unilateral sinus pain and reported maxillary pain. The presence of facial or dental pain correlates with ABRS but does not identify the specific sinus involved.¹

Approximately 90% to 98% of cases of acute rhinosinusitis are viral; only about 0.5% to 2% of viral rhinosinusitis episodes are complicated by bacterial infection.

There isn’t good correlation between patients saying they have sinusitis and actually having it.¹³ A 2019 meta-analysis by Ebell et al¹⁴ reported that based on limited data, the overall clinical impression, fetid odor on the breath, and pain in the teeth are the best individual clinical predictors of ABRS.

As recommended by the Infectious Disease Society of America (IDSA), a diagnosis of ABRS is also reasonable in patients who present with severe symptoms at the onset.⁶ Although there is no consensus about what constitutes “severe symptoms,” they are often described as a temperature ≥ 102°F (39°C) plus 3 to 4 days of purulent nasal drainage.^1,4,6

Continue to: Additional symptoms of ABRS may include...

Additional symptoms of ABRS may include cough, fatigue, decreased or lack of sense of smell (hyposmia or anosmia), and ear pressure.¹⁰ Another sign of “double sickening” is the development of a fever after several days of symptoms.^1,9,15 Viral sinusitis typically lasts 5 to 7 days with a peak at days 2 to 3.^1,15 If symptoms continue for 10 days, there is a 60% chance of bacterial sinusitis, although some viral rhinosinusitis symptoms persist for > 14 days.^1,5 Beyond 4 to 12 weeks, sinusitis is classified as subacute or chronic.³

Physical exam findings and the limited roles of imaging and labs

Common physical exam findings associated with the diagnosis of ABRS include altered speech indicating nasal obstruction; edema or erythema of the skin indicating congested capillaries; tenderness to palpation over the cheeks or upper teeth; odorous breath; and purulent drainage from the nose or in the posterior pharynx.

In a study by Hansen et al¹³ (N = 174), the only sign that showed significant association with ABRS (diagnosed by sinus aspiration or lavage) was unilateral tenderness of the maxillary sinuses. The presence of purulent drainage in the nose or posterior pharynx also has significant diagnostic value, as it predicts the presence of bacteria on antral aspiration.¹ Purulent discharge in the pharynx is associated with a higher likelihood of benefit from antibiotic therapy compared to placebo (number needed to treat [NNT] = 8).¹⁶ However, colored nasal discharge indicates the presence of neutrophils—not bacteria—and does not predict the likelihood of bacterial sinus infection.^14,17 Therefore, the history and physical exam should focus on location of pain (sinus and/or teeth), duration of symptoms, presence of fever, change in symptom severity, attempted home therapies, sinus tenderness on exam, breath odor, and purulent drainage seen in the nasal cavity or posterior pharynx.^13,14

Radiographic imaging has no role in the diagnosis or treatment of uncomplicated ABRS because viral and bacterial etiologies have similar radiographic appearances. Additionally, employing radiologic imaging would increase health care costs by at least 4-fold.^5,6,8,17 The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) clinical practice guidelines recommend against radiographic imaging for patients who meet the diagnostic criteria for ABRS unless concern exists for a complication or an alternate diagnosis is suspected.¹ Computed tomography (CT) imaging of the sinuses may be warranted in patients with severe headaches, facial swelling, cranial nerve palsies, or bulging of the eye (proptosis), all of which indicate a potential complication of ABRS.¹

Laboratory evaluations. ABRS is a clinical diagnosis; therefore, routine lab work, such as a white blood cell count, C-­reactive protein (CRP) level, and/or erythrocyte sedimentation rate (ESR), are not indicated unless an alternate diagnosis is suspected.^1,5,13,18,19

Continue to: In one study...

In one study, CRP > 10 mg/L and ESR > 10 mm/h were the strongest individual predictors of purulent antral puncture aspirate or positive bacterial culture of aspirate, which is considered diagnostic for ABRS. ²⁰ However, CRP and ESR by themselves are not adequate to diagnose ABRS.²⁰ This study developed a clinical decision rule that used symptoms, signs, and laboratory values to rate the likelihood of ABRS as being either low, moderate, or high. However, this clinical decision rule has not been prospectively validated.

Thus, CRP and ESR elevations can support the diagnosis of ABRS, but the low sensitivity of these tests precludes their use as a screening tool for ABRS.^14,18 Studies by Ebell¹⁹ and Huang²¹ have shown some benefit to dipstick assay of nasal secretions for the diagnosis of ABRS, but this method is not validated or widely used.^19,21

Treatment: From managing symptoms to prescribing antibiotics

Overprescribing antibiotics for ARS is a prominent health care issue. In fact, 5 of 9 placebo-controlled studies showed that most people improve within 2 weeks regardless of antibiotic use (N = 1058).³ Therefore, weigh the decision to treat ABRS with antibiotics against the risk for potential adverse reactions and within the context of antibiotic stewardship.^2,9,12,22-24 Consider antibiotics only if patients meet the diagnostic criteria for ABRS (TABLE 1^1,6) or, occasionally, for patients with severe symptoms upon presentation, such as a temperature ≥ 102°F (39°C) plus purulent nasal discharge for 3 to 4 days.¹ The most commonly reported adverse effects of antibiotics are gastrointestinal in nature and include nausea, vomiting, and diarrhea.^2,9

Symptomatic management for both ARS and ABRS is recommended as first-line therapy; it should be offered to patients before making a diagnosis of ABRS.^1,5,9,25 Consider using analgesics, topical intranasal steroids, and/or nasal saline irrigation to alleviate symptoms and improve quality of life.^1,5,25 Interventions with questionable or unproven efficacy include the use of antihistamines, systemic steroids, decongestants, and mucolytics, but they may be considered on an individual basis.¹ A systematic review found that topical nasal steroids relieved facial pain and nasal congestion in patients with rhinitis and acute sinusitis (NNT = 14).^1,26

Even after diagnosing ABRS, clinicians should offer watchful waiting and symptomatic therapies as long as patients have adequate access to follow-up (TABLE 2,^1,15FIGURE^1,6). Antibiotic therapy can then be initiated if symptoms do not improve after an additional 7 days of watchful waiting or if symptoms worsen at any time. It is reasonable to give patients a prescription to keep on hand to be used if symptoms worsen, with instructions to notify the provider if antibiotics are started.¹

Continue to: Antibiotic therapy

Antibiotic therapy. The rationale for treating ABRS with antibiotics is to expedite recovery and prevent complications such as periorbital or orbital cellulitis, meningitis, frontal osteomyelitis, cavernous sinus thrombosis, and other serious illness.²⁷ Antibiotic treatment is associated with a shorter duration of symptoms (NNT = 19) but an increased risk of adverse events (NNH = 8).^7,19

Diagnose acute bacterial rhinosinusitis when symptoms of acute rhinosinusitis fail to improve after 10 days or symptoms of ARS worsen within 10 days after initial improvement.

Amoxicillin with or without clavulanate for 5 to 10 days is first-line antibiotic therapy for most adults with ABRS.^1,3,5,8,9,11 Per ­AAO-HNS, the “justification for amoxicillin as first-line treatment relates to its safety, efficacy, low cost, and narrow microbiologic spectrum.”¹ Amoxicillin may be dosed 500 mg tid for 5 to 10 days. Amoxicillin/clavulanate (Augmentin) is recommended for patients with comorbid conditions or with increased risk of bacterial resistance. Dosing for amoxicillin/clavulanate is 500/125 mg tid or 875/125 mg bid for 5 to 10 days. Duration of therapy should be determined by the severity of symptoms.⁵

For penicillin-allergic patients, doxycycline or a respiratory fluoroquinolone (levofloxacin or moxifloxacin) is considered first-line treatment.^1,6 Doxycycline is preferred because of its narrower spectrum and fewer adverse effects than the fluoroquinolones. Fluoroquinolones should be reserved for patients who fail first-line treatment and are penicillin allergic.¹ Because of the high rates of resistance among S pneumoniae and H influenzae, macrolides, trimethoprim/sulfamethoxazole (TMP/SMX), and cephalosporins are not recommended as first-line therapy.^1,5

How antibiotic options compare. A Cochrane review of 54 studies comparing different antibiotics showed no antibiotic was superior.³ Of the 54 studies, 6 studies (N = 1887) were pooled to compare cephalosporins to amoxicillin/clavulanate at 7 to 15 days. The findings indicated a statistically significant difference for amoxicillin/clavulanate with a relative risk (RR) of 1.37 (confidence interval [CI], 1.04-1.8).³ However, none of these 6 studies were graded as having a low risk of bias; therefore, confidence in this finding was deemed limited due to the quality of included studies. The failure rate for cephalosporins was 12% vs 8% for amoxicillin/clavulanate.³

Colored nasal discharge indicates the presence of neutrophils—not bacteria—and does not predict the likelihood of bacterial sinus infection.

Treatment failure is considered when a patient has not improved by Day 7 after ABRS diagnosis (with or without medication) or when symptoms worsen at any time. If watchful waiting was chosen and a safety net prescription was provided, the antibiotics should be filled and started. If no antibiotic was prescribed at the time watchful waiting commenced, the patient should return for further evaluation and be started on antibiotics. If antibiotics were prescribed initially for severe symptoms, a change in antibiotic therapy is indicated, and a broader-spectrum antibiotic should be chosen. If amoxicillin was prescribed, the patient should be switched to amoxicillin/clavulanate, doxycycline, a respiratory fluoroquinolone, or a combination of clindamycin plus a third-generation cephalosporin.¹

Continue to: Diagnosis and management of pediatric patients

Diagnosis and management of pediatric patients

Diagnosis of ABRS in children is defined as an acute upper respiratory infection (URI) accompanied by persistent nasal discharge, daytime cough for ≥ 10 days without improvement, an episode of “double sickening,” or severe onset with a temperature ≥ 102°F and purulent nasal discharge for 3 days.¹⁵

Weigh the decision to treat acute bacterial rhinosinusitis with antibiotics against the risk for potential adverse reactions and within the context of antibiotic stewardship.

Initial presentations of viral URIs and ABRS are almost identical; thus, persistence of symptoms is key to diagnosis.⁶ Nasal ­discharge tends to appear several days after initial symptoms manifest for viral infections including influenza. In children < 5 years of age, the most common complication involves the orbit.¹⁵ Orbital complications generally manifest with eye pain and/or periorbital swelling and may be accompanied by proptosis or decreased functioning of ­extraocular musculature. The differential diagnosis for orbital complications includes cavernous sinus thrombosis, orbital cellulitis/abscess, subperiosteal abscess, and inflammatory edema.^27,28 Intracranial complications are also possible with severe ABRS.¹²

Radiology studies are not recommended for the initial diagnosis of ABRS in children, as again, imaging does not differentiate between viral and bacterial etiologies. However, in children with complications such as orbital or cerebral involvement, a contrast-enhanced CT scan of the paranasal sinuses is indicated.¹⁵

Antibiotic therapy is indicated in children with a diagnosis of severe ABRS or in cases of “double sickening.” Clinicians may consider watchful waiting for 3 additional days before initiating antibiotics in patients meeting criteria for ABRS.Amoxicillin with or without clavulanate is the antibiotic of choice.¹⁵

For penicillin-allergic children without a history of anaphylactoid reaction, treatment with cefpodoxime, cefdinir, or cefuroxime is appropriate. For children with a history of anaphylaxis, treatment with a combination of clindamycin (or linezolid) and cefixime is indicated. Alternatively, a fluoroquinolone such as levofloxacin may be used, but adverse effects and emerging resistance limit its use.¹⁵

Continue to: Specialist referral

 

 

Specialist referral

Referral to Otolaryngology is indicated for patients with > 3 episodes of clinically diagnosed bacterial sinusitis in 1 year, evidence of fungal disease (which is outside the scope of this article), immunocompromised status, or a persistent temperature ≥ 102°F despite antibiotic therapy. Also consider otolaryngology referral for patients with a history of sinus surgery.^2,5,6

CORRESPONDENCE
Pamela R. Hughes, Family Medicine Residency Clinic, Mike O’Callaghan Military Medical Center, 4700 Las Vegas Boulevard North, Nellis AFB, NV 89191; pamela.r.hughes4.mil@mail.mil.

An estimated 30 million cases of acute rhinosinusitis (ARS) occur every year in the United States.¹ More than 80% of people with ARS are prescribed antibiotics in North America, accounting for 15% to 20% of all antibiotic prescriptions in the adult outpatient setting.^2,3 Many of these prescriptions are unnecessary, as the most common cause of ARS is a virus.^4,5 Evidence consistently shows that symptoms of ARS will resolve spontaneously in most patients and that only those patients with severe or prolonged symptoms require consideration of antibiotic therapy.^1,2,4,6 Nearly half of all patients will improve within 1 week and two-thirds of patients will improve within 2 weeks without the use of antibiotics.⁷ In children, only about 6% to 7% presenting with upper respiratory symptoms meet the criteria for acute bacterial rhinosinusitis (ABRS),⁸ which we’ll detail in a bit. For most patients, treatment should consist of symptom management.⁵

But what about the minority who require antibiotic therapy? This article reviews how to evaluate patients with ARS, identify those who require antibiotics, and prescribe the most appropriate antibiotic treatment regimens.

Diagnosis: Distinguishing viral from bacterial disease

ARS is defined as the sudden onset of purulent nasal discharge plus either nasal blockage or facial pressure/pain lasting < 4 weeks.^3,9 Additional signs and symptoms may include postnasal drip, a reduced sense of smell, sinus tenderness to palpation, and maxillary toothaches.^10,11

ARS may be viral or bacterial in etiology, with the most common bacterial organisms being Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.^1,3,5 The most common viral causes are influenza, parainfluenza, and rhinovirus. Approximately 90% to 98% of cases of ARS are viral^6,11; only about 0.5% to 2% of viral rhinosinusitis episodes are complicated by bacterial infection.^1,10-12

Diagnose ABRS when symptoms of ARS fail to improve after 10 days or symptoms of ARS worsen within 10 days after initial improvement (“double sickening”).^1,11 Symptoms that are significantly associated with ABRS are unilateral sinus pain and reported maxillary pain. The presence of facial or dental pain correlates with ABRS but does not identify the specific sinus involved.¹

Approximately 90% to 98% of cases of acute rhinosinusitis are viral; only about 0.5% to 2% of viral rhinosinusitis episodes are complicated by bacterial infection.

There isn’t good correlation between patients saying they have sinusitis and actually having it.¹³ A 2019 meta-analysis by Ebell et al¹⁴ reported that based on limited data, the overall clinical impression, fetid odor on the breath, and pain in the teeth are the best individual clinical predictors of ABRS.

As recommended by the Infectious Disease Society of America (IDSA), a diagnosis of ABRS is also reasonable in patients who present with severe symptoms at the onset.⁶ Although there is no consensus about what constitutes “severe symptoms,” they are often described as a temperature ≥ 102°F (39°C) plus 3 to 4 days of purulent nasal drainage.^1,4,6

Continue to: Additional symptoms of ABRS may include...

Additional symptoms of ABRS may include cough, fatigue, decreased or lack of sense of smell (hyposmia or anosmia), and ear pressure.¹⁰ Another sign of “double sickening” is the development of a fever after several days of symptoms.^1,9,15 Viral sinusitis typically lasts 5 to 7 days with a peak at days 2 to 3.^1,15 If symptoms continue for 10 days, there is a 60% chance of bacterial sinusitis, although some viral rhinosinusitis symptoms persist for > 14 days.^1,5 Beyond 4 to 12 weeks, sinusitis is classified as subacute or chronic.³

Physical exam findings and the limited roles of imaging and labs

Common physical exam findings associated with the diagnosis of ABRS include altered speech indicating nasal obstruction; edema or erythema of the skin indicating congested capillaries; tenderness to palpation over the cheeks or upper teeth; odorous breath; and purulent drainage from the nose or in the posterior pharynx.

In a study by Hansen et al¹³ (N = 174), the only sign that showed significant association with ABRS (diagnosed by sinus aspiration or lavage) was unilateral tenderness of the maxillary sinuses. The presence of purulent drainage in the nose or posterior pharynx also has significant diagnostic value, as it predicts the presence of bacteria on antral aspiration.¹ Purulent discharge in the pharynx is associated with a higher likelihood of benefit from antibiotic therapy compared to placebo (number needed to treat [NNT] = 8).¹⁶ However, colored nasal discharge indicates the presence of neutrophils—not bacteria—and does not predict the likelihood of bacterial sinus infection.^14,17 Therefore, the history and physical exam should focus on location of pain (sinus and/or teeth), duration of symptoms, presence of fever, change in symptom severity, attempted home therapies, sinus tenderness on exam, breath odor, and purulent drainage seen in the nasal cavity or posterior pharynx.^13,14

Radiographic imaging has no role in the diagnosis or treatment of uncomplicated ABRS because viral and bacterial etiologies have similar radiographic appearances. Additionally, employing radiologic imaging would increase health care costs by at least 4-fold.^5,6,8,17 The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) clinical practice guidelines recommend against radiographic imaging for patients who meet the diagnostic criteria for ABRS unless concern exists for a complication or an alternate diagnosis is suspected.¹ Computed tomography (CT) imaging of the sinuses may be warranted in patients with severe headaches, facial swelling, cranial nerve palsies, or bulging of the eye (proptosis), all of which indicate a potential complication of ABRS.¹

Laboratory evaluations. ABRS is a clinical diagnosis; therefore, routine lab work, such as a white blood cell count, C-­reactive protein (CRP) level, and/or erythrocyte sedimentation rate (ESR), are not indicated unless an alternate diagnosis is suspected.^1,5,13,18,19

Continue to: In one study...

In one study, CRP > 10 mg/L and ESR > 10 mm/h were the strongest individual predictors of purulent antral puncture aspirate or positive bacterial culture of aspirate, which is considered diagnostic for ABRS. ²⁰ However, CRP and ESR by themselves are not adequate to diagnose ABRS.²⁰ This study developed a clinical decision rule that used symptoms, signs, and laboratory values to rate the likelihood of ABRS as being either low, moderate, or high. However, this clinical decision rule has not been prospectively validated.

Thus, CRP and ESR elevations can support the diagnosis of ABRS, but the low sensitivity of these tests precludes their use as a screening tool for ABRS.^14,18 Studies by Ebell¹⁹ and Huang²¹ have shown some benefit to dipstick assay of nasal secretions for the diagnosis of ABRS, but this method is not validated or widely used.^19,21

Treatment: From managing symptoms to prescribing antibiotics

Overprescribing antibiotics for ARS is a prominent health care issue. In fact, 5 of 9 placebo-controlled studies showed that most people improve within 2 weeks regardless of antibiotic use (N = 1058).³ Therefore, weigh the decision to treat ABRS with antibiotics against the risk for potential adverse reactions and within the context of antibiotic stewardship.^2,9,12,22-24 Consider antibiotics only if patients meet the diagnostic criteria for ABRS (TABLE 1^1,6) or, occasionally, for patients with severe symptoms upon presentation, such as a temperature ≥ 102°F (39°C) plus purulent nasal discharge for 3 to 4 days.¹ The most commonly reported adverse effects of antibiotics are gastrointestinal in nature and include nausea, vomiting, and diarrhea.^2,9

Symptomatic management for both ARS and ABRS is recommended as first-line therapy; it should be offered to patients before making a diagnosis of ABRS.^1,5,9,25 Consider using analgesics, topical intranasal steroids, and/or nasal saline irrigation to alleviate symptoms and improve quality of life.^1,5,25 Interventions with questionable or unproven efficacy include the use of antihistamines, systemic steroids, decongestants, and mucolytics, but they may be considered on an individual basis.¹ A systematic review found that topical nasal steroids relieved facial pain and nasal congestion in patients with rhinitis and acute sinusitis (NNT = 14).^1,26

Even after diagnosing ABRS, clinicians should offer watchful waiting and symptomatic therapies as long as patients have adequate access to follow-up (TABLE 2,^1,15FIGURE^1,6). Antibiotic therapy can then be initiated if symptoms do not improve after an additional 7 days of watchful waiting or if symptoms worsen at any time. It is reasonable to give patients a prescription to keep on hand to be used if symptoms worsen, with instructions to notify the provider if antibiotics are started.¹

Continue to: Antibiotic therapy

Antibiotic therapy. The rationale for treating ABRS with antibiotics is to expedite recovery and prevent complications such as periorbital or orbital cellulitis, meningitis, frontal osteomyelitis, cavernous sinus thrombosis, and other serious illness.²⁷ Antibiotic treatment is associated with a shorter duration of symptoms (NNT = 19) but an increased risk of adverse events (NNH = 8).^7,19

Diagnose acute bacterial rhinosinusitis when symptoms of acute rhinosinusitis fail to improve after 10 days or symptoms of ARS worsen within 10 days after initial improvement.

Amoxicillin with or without clavulanate for 5 to 10 days is first-line antibiotic therapy for most adults with ABRS.^1,3,5,8,9,11 Per ­AAO-HNS, the “justification for amoxicillin as first-line treatment relates to its safety, efficacy, low cost, and narrow microbiologic spectrum.”¹ Amoxicillin may be dosed 500 mg tid for 5 to 10 days. Amoxicillin/clavulanate (Augmentin) is recommended for patients with comorbid conditions or with increased risk of bacterial resistance. Dosing for amoxicillin/clavulanate is 500/125 mg tid or 875/125 mg bid for 5 to 10 days. Duration of therapy should be determined by the severity of symptoms.⁵

For penicillin-allergic patients, doxycycline or a respiratory fluoroquinolone (levofloxacin or moxifloxacin) is considered first-line treatment.^1,6 Doxycycline is preferred because of its narrower spectrum and fewer adverse effects than the fluoroquinolones. Fluoroquinolones should be reserved for patients who fail first-line treatment and are penicillin allergic.¹ Because of the high rates of resistance among S pneumoniae and H influenzae, macrolides, trimethoprim/sulfamethoxazole (TMP/SMX), and cephalosporins are not recommended as first-line therapy.^1,5

How antibiotic options compare. A Cochrane review of 54 studies comparing different antibiotics showed no antibiotic was superior.³ Of the 54 studies, 6 studies (N = 1887) were pooled to compare cephalosporins to amoxicillin/clavulanate at 7 to 15 days. The findings indicated a statistically significant difference for amoxicillin/clavulanate with a relative risk (RR) of 1.37 (confidence interval [CI], 1.04-1.8).³ However, none of these 6 studies were graded as having a low risk of bias; therefore, confidence in this finding was deemed limited due to the quality of included studies. The failure rate for cephalosporins was 12% vs 8% for amoxicillin/clavulanate.³

Colored nasal discharge indicates the presence of neutrophils—not bacteria—and does not predict the likelihood of bacterial sinus infection.

Treatment failure is considered when a patient has not improved by Day 7 after ABRS diagnosis (with or without medication) or when symptoms worsen at any time. If watchful waiting was chosen and a safety net prescription was provided, the antibiotics should be filled and started. If no antibiotic was prescribed at the time watchful waiting commenced, the patient should return for further evaluation and be started on antibiotics. If antibiotics were prescribed initially for severe symptoms, a change in antibiotic therapy is indicated, and a broader-spectrum antibiotic should be chosen. If amoxicillin was prescribed, the patient should be switched to amoxicillin/clavulanate, doxycycline, a respiratory fluoroquinolone, or a combination of clindamycin plus a third-generation cephalosporin.¹

Continue to: Diagnosis and management of pediatric patients

Diagnosis and management of pediatric patients

Diagnosis of ABRS in children is defined as an acute upper respiratory infection (URI) accompanied by persistent nasal discharge, daytime cough for ≥ 10 days without improvement, an episode of “double sickening,” or severe onset with a temperature ≥ 102°F and purulent nasal discharge for 3 days.¹⁵

Weigh the decision to treat acute bacterial rhinosinusitis with antibiotics against the risk for potential adverse reactions and within the context of antibiotic stewardship.

Initial presentations of viral URIs and ABRS are almost identical; thus, persistence of symptoms is key to diagnosis.⁶ Nasal ­discharge tends to appear several days after initial symptoms manifest for viral infections including influenza. In children < 5 years of age, the most common complication involves the orbit.¹⁵ Orbital complications generally manifest with eye pain and/or periorbital swelling and may be accompanied by proptosis or decreased functioning of ­extraocular musculature. The differential diagnosis for orbital complications includes cavernous sinus thrombosis, orbital cellulitis/abscess, subperiosteal abscess, and inflammatory edema.^27,28 Intracranial complications are also possible with severe ABRS.¹²

Radiology studies are not recommended for the initial diagnosis of ABRS in children, as again, imaging does not differentiate between viral and bacterial etiologies. However, in children with complications such as orbital or cerebral involvement, a contrast-enhanced CT scan of the paranasal sinuses is indicated.¹⁵

Antibiotic therapy is indicated in children with a diagnosis of severe ABRS or in cases of “double sickening.” Clinicians may consider watchful waiting for 3 additional days before initiating antibiotics in patients meeting criteria for ABRS.Amoxicillin with or without clavulanate is the antibiotic of choice.¹⁵

For penicillin-allergic children without a history of anaphylactoid reaction, treatment with cefpodoxime, cefdinir, or cefuroxime is appropriate. For children with a history of anaphylaxis, treatment with a combination of clindamycin (or linezolid) and cefixime is indicated. Alternatively, a fluoroquinolone such as levofloxacin may be used, but adverse effects and emerging resistance limit its use.¹⁵

Continue to: Specialist referral

 

 

Specialist referral

Referral to Otolaryngology is indicated for patients with > 3 episodes of clinically diagnosed bacterial sinusitis in 1 year, evidence of fungal disease (which is outside the scope of this article), immunocompromised status, or a persistent temperature ≥ 102°F despite antibiotic therapy. Also consider otolaryngology referral for patients with a history of sinus surgery.^2,5,6

CORRESPONDENCE
Pamela R. Hughes, Family Medicine Residency Clinic, Mike O’Callaghan Military Medical Center, 4700 Las Vegas Boulevard North, Nellis AFB, NV 89191; pamela.r.hughes4.mil@mail.mil.

An estimated 30 million cases of acute rhinosinusitis (ARS) occur every year in the United States.¹ More than 80% of people with ARS are prescribed antibiotics in North America, accounting for 15% to 20% of all antibiotic prescriptions in the adult outpatient setting.^2,3 Many of these prescriptions are unnecessary, as the most common cause of ARS is a virus.^4,5 Evidence consistently shows that symptoms of ARS will resolve spontaneously in most patients and that only those patients with severe or prolonged symptoms require consideration of antibiotic therapy.^1,2,4,6 Nearly half of all patients will improve within 1 week and two-thirds of patients will improve within 2 weeks without the use of antibiotics.⁷ In children, only about 6% to 7% presenting with upper respiratory symptoms meet the criteria for acute bacterial rhinosinusitis (ABRS),⁸ which we’ll detail in a bit. For most patients, treatment should consist of symptom management.⁵

But what about the minority who require antibiotic therapy? This article reviews how to evaluate patients with ARS, identify those who require antibiotics, and prescribe the most appropriate antibiotic treatment regimens.

Diagnosis: Distinguishing viral from bacterial disease

ARS is defined as the sudden onset of purulent nasal discharge plus either nasal blockage or facial pressure/pain lasting < 4 weeks.^3,9 Additional signs and symptoms may include postnasal drip, a reduced sense of smell, sinus tenderness to palpation, and maxillary toothaches.^10,11

ARS may be viral or bacterial in etiology, with the most common bacterial organisms being Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.^1,3,5 The most common viral causes are influenza, parainfluenza, and rhinovirus. Approximately 90% to 98% of cases of ARS are viral^6,11; only about 0.5% to 2% of viral rhinosinusitis episodes are complicated by bacterial infection.^1,10-12

Diagnose ABRS when symptoms of ARS fail to improve after 10 days or symptoms of ARS worsen within 10 days after initial improvement (“double sickening”).^1,11 Symptoms that are significantly associated with ABRS are unilateral sinus pain and reported maxillary pain. The presence of facial or dental pain correlates with ABRS but does not identify the specific sinus involved.¹

Approximately 90% to 98% of cases of acute rhinosinusitis are viral; only about 0.5% to 2% of viral rhinosinusitis episodes are complicated by bacterial infection.

There isn’t good correlation between patients saying they have sinusitis and actually having it.¹³ A 2019 meta-analysis by Ebell et al¹⁴ reported that based on limited data, the overall clinical impression, fetid odor on the breath, and pain in the teeth are the best individual clinical predictors of ABRS.

As recommended by the Infectious Disease Society of America (IDSA), a diagnosis of ABRS is also reasonable in patients who present with severe symptoms at the onset.⁶ Although there is no consensus about what constitutes “severe symptoms,” they are often described as a temperature ≥ 102°F (39°C) plus 3 to 4 days of purulent nasal drainage.^1,4,6

Continue to: Additional symptoms of ABRS may include...

Additional symptoms of ABRS may include cough, fatigue, decreased or lack of sense of smell (hyposmia or anosmia), and ear pressure.¹⁰ Another sign of “double sickening” is the development of a fever after several days of symptoms.^1,9,15 Viral sinusitis typically lasts 5 to 7 days with a peak at days 2 to 3.^1,15 If symptoms continue for 10 days, there is a 60% chance of bacterial sinusitis, although some viral rhinosinusitis symptoms persist for > 14 days.^1,5 Beyond 4 to 12 weeks, sinusitis is classified as subacute or chronic.³

Physical exam findings and the limited roles of imaging and labs

Common physical exam findings associated with the diagnosis of ABRS include altered speech indicating nasal obstruction; edema or erythema of the skin indicating congested capillaries; tenderness to palpation over the cheeks or upper teeth; odorous breath; and purulent drainage from the nose or in the posterior pharynx.

In a study by Hansen et al¹³ (N = 174), the only sign that showed significant association with ABRS (diagnosed by sinus aspiration or lavage) was unilateral tenderness of the maxillary sinuses. The presence of purulent drainage in the nose or posterior pharynx also has significant diagnostic value, as it predicts the presence of bacteria on antral aspiration.¹ Purulent discharge in the pharynx is associated with a higher likelihood of benefit from antibiotic therapy compared to placebo (number needed to treat [NNT] = 8).¹⁶ However, colored nasal discharge indicates the presence of neutrophils—not bacteria—and does not predict the likelihood of bacterial sinus infection.^14,17 Therefore, the history and physical exam should focus on location of pain (sinus and/or teeth), duration of symptoms, presence of fever, change in symptom severity, attempted home therapies, sinus tenderness on exam, breath odor, and purulent drainage seen in the nasal cavity or posterior pharynx.^13,14

Radiographic imaging has no role in the diagnosis or treatment of uncomplicated ABRS because viral and bacterial etiologies have similar radiographic appearances. Additionally, employing radiologic imaging would increase health care costs by at least 4-fold.^5,6,8,17 The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) clinical practice guidelines recommend against radiographic imaging for patients who meet the diagnostic criteria for ABRS unless concern exists for a complication or an alternate diagnosis is suspected.¹ Computed tomography (CT) imaging of the sinuses may be warranted in patients with severe headaches, facial swelling, cranial nerve palsies, or bulging of the eye (proptosis), all of which indicate a potential complication of ABRS.¹

Laboratory evaluations. ABRS is a clinical diagnosis; therefore, routine lab work, such as a white blood cell count, C-­reactive protein (CRP) level, and/or erythrocyte sedimentation rate (ESR), are not indicated unless an alternate diagnosis is suspected.^1,5,13,18,19

Continue to: In one study...

In one study, CRP > 10 mg/L and ESR > 10 mm/h were the strongest individual predictors of purulent antral puncture aspirate or positive bacterial culture of aspirate, which is considered diagnostic for ABRS. ²⁰ However, CRP and ESR by themselves are not adequate to diagnose ABRS.²⁰ This study developed a clinical decision rule that used symptoms, signs, and laboratory values to rate the likelihood of ABRS as being either low, moderate, or high. However, this clinical decision rule has not been prospectively validated.

Thus, CRP and ESR elevations can support the diagnosis of ABRS, but the low sensitivity of these tests precludes their use as a screening tool for ABRS.^14,18 Studies by Ebell¹⁹ and Huang²¹ have shown some benefit to dipstick assay of nasal secretions for the diagnosis of ABRS, but this method is not validated or widely used.^19,21

Treatment: From managing symptoms to prescribing antibiotics

Overprescribing antibiotics for ARS is a prominent health care issue. In fact, 5 of 9 placebo-controlled studies showed that most people improve within 2 weeks regardless of antibiotic use (N = 1058).³ Therefore, weigh the decision to treat ABRS with antibiotics against the risk for potential adverse reactions and within the context of antibiotic stewardship.^2,9,12,22-24 Consider antibiotics only if patients meet the diagnostic criteria for ABRS (TABLE 1^1,6) or, occasionally, for patients with severe symptoms upon presentation, such as a temperature ≥ 102°F (39°C) plus purulent nasal discharge for 3 to 4 days.¹ The most commonly reported adverse effects of antibiotics are gastrointestinal in nature and include nausea, vomiting, and diarrhea.^2,9

Symptomatic management for both ARS and ABRS is recommended as first-line therapy; it should be offered to patients before making a diagnosis of ABRS.^1,5,9,25 Consider using analgesics, topical intranasal steroids, and/or nasal saline irrigation to alleviate symptoms and improve quality of life.^1,5,25 Interventions with questionable or unproven efficacy include the use of antihistamines, systemic steroids, decongestants, and mucolytics, but they may be considered on an individual basis.¹ A systematic review found that topical nasal steroids relieved facial pain and nasal congestion in patients with rhinitis and acute sinusitis (NNT = 14).^1,26

Even after diagnosing ABRS, clinicians should offer watchful waiting and symptomatic therapies as long as patients have adequate access to follow-up (TABLE 2,^1,15FIGURE^1,6). Antibiotic therapy can then be initiated if symptoms do not improve after an additional 7 days of watchful waiting or if symptoms worsen at any time. It is reasonable to give patients a prescription to keep on hand to be used if symptoms worsen, with instructions to notify the provider if antibiotics are started.¹

Continue to: Antibiotic therapy

Antibiotic therapy. The rationale for treating ABRS with antibiotics is to expedite recovery and prevent complications such as periorbital or orbital cellulitis, meningitis, frontal osteomyelitis, cavernous sinus thrombosis, and other serious illness.²⁷ Antibiotic treatment is associated with a shorter duration of symptoms (NNT = 19) but an increased risk of adverse events (NNH = 8).^7,19

Diagnose acute bacterial rhinosinusitis when symptoms of acute rhinosinusitis fail to improve after 10 days or symptoms of ARS worsen within 10 days after initial improvement.

Amoxicillin with or without clavulanate for 5 to 10 days is first-line antibiotic therapy for most adults with ABRS.^1,3,5,8,9,11 Per ­AAO-HNS, the “justification for amoxicillin as first-line treatment relates to its safety, efficacy, low cost, and narrow microbiologic spectrum.”¹ Amoxicillin may be dosed 500 mg tid for 5 to 10 days. Amoxicillin/clavulanate (Augmentin) is recommended for patients with comorbid conditions or with increased risk of bacterial resistance. Dosing for amoxicillin/clavulanate is 500/125 mg tid or 875/125 mg bid for 5 to 10 days. Duration of therapy should be determined by the severity of symptoms.⁵

For penicillin-allergic patients, doxycycline or a respiratory fluoroquinolone (levofloxacin or moxifloxacin) is considered first-line treatment.^1,6 Doxycycline is preferred because of its narrower spectrum and fewer adverse effects than the fluoroquinolones. Fluoroquinolones should be reserved for patients who fail first-line treatment and are penicillin allergic.¹ Because of the high rates of resistance among S pneumoniae and H influenzae, macrolides, trimethoprim/sulfamethoxazole (TMP/SMX), and cephalosporins are not recommended as first-line therapy.^1,5

How antibiotic options compare. A Cochrane review of 54 studies comparing different antibiotics showed no antibiotic was superior.³ Of the 54 studies, 6 studies (N = 1887) were pooled to compare cephalosporins to amoxicillin/clavulanate at 7 to 15 days. The findings indicated a statistically significant difference for amoxicillin/clavulanate with a relative risk (RR) of 1.37 (confidence interval [CI], 1.04-1.8).³ However, none of these 6 studies were graded as having a low risk of bias; therefore, confidence in this finding was deemed limited due to the quality of included studies. The failure rate for cephalosporins was 12% vs 8% for amoxicillin/clavulanate.³

Colored nasal discharge indicates the presence of neutrophils—not bacteria—and does not predict the likelihood of bacterial sinus infection.

Treatment failure is considered when a patient has not improved by Day 7 after ABRS diagnosis (with or without medication) or when symptoms worsen at any time. If watchful waiting was chosen and a safety net prescription was provided, the antibiotics should be filled and started. If no antibiotic was prescribed at the time watchful waiting commenced, the patient should return for further evaluation and be started on antibiotics. If antibiotics were prescribed initially for severe symptoms, a change in antibiotic therapy is indicated, and a broader-spectrum antibiotic should be chosen. If amoxicillin was prescribed, the patient should be switched to amoxicillin/clavulanate, doxycycline, a respiratory fluoroquinolone, or a combination of clindamycin plus a third-generation cephalosporin.¹

Continue to: Diagnosis and management of pediatric patients

Diagnosis and management of pediatric patients

Diagnosis of ABRS in children is defined as an acute upper respiratory infection (URI) accompanied by persistent nasal discharge, daytime cough for ≥ 10 days without improvement, an episode of “double sickening,” or severe onset with a temperature ≥ 102°F and purulent nasal discharge for 3 days.¹⁵

Weigh the decision to treat acute bacterial rhinosinusitis with antibiotics against the risk for potential adverse reactions and within the context of antibiotic stewardship.

Initial presentations of viral URIs and ABRS are almost identical; thus, persistence of symptoms is key to diagnosis.⁶ Nasal ­discharge tends to appear several days after initial symptoms manifest for viral infections including influenza. In children < 5 years of age, the most common complication involves the orbit.¹⁵ Orbital complications generally manifest with eye pain and/or periorbital swelling and may be accompanied by proptosis or decreased functioning of ­extraocular musculature. The differential diagnosis for orbital complications includes cavernous sinus thrombosis, orbital cellulitis/abscess, subperiosteal abscess, and inflammatory edema.^27,28 Intracranial complications are also possible with severe ABRS.¹²

Radiology studies are not recommended for the initial diagnosis of ABRS in children, as again, imaging does not differentiate between viral and bacterial etiologies. However, in children with complications such as orbital or cerebral involvement, a contrast-enhanced CT scan of the paranasal sinuses is indicated.¹⁵

Antibiotic therapy is indicated in children with a diagnosis of severe ABRS or in cases of “double sickening.” Clinicians may consider watchful waiting for 3 additional days before initiating antibiotics in patients meeting criteria for ABRS.Amoxicillin with or without clavulanate is the antibiotic of choice.¹⁵

For penicillin-allergic children without a history of anaphylactoid reaction, treatment with cefpodoxime, cefdinir, or cefuroxime is appropriate. For children with a history of anaphylaxis, treatment with a combination of clindamycin (or linezolid) and cefixime is indicated. Alternatively, a fluoroquinolone such as levofloxacin may be used, but adverse effects and emerging resistance limit its use.¹⁵

Continue to: Specialist referral

 

 

Specialist referral

Referral to Otolaryngology is indicated for patients with > 3 episodes of clinically diagnosed bacterial sinusitis in 1 year, evidence of fungal disease (which is outside the scope of this article), immunocompromised status, or a persistent temperature ≥ 102°F despite antibiotic therapy. Also consider otolaryngology referral for patients with a history of sinus surgery.^2,5,6

CORRESPONDENCE
Pamela R. Hughes, Family Medicine Residency Clinic, Mike O’Callaghan Military Medical Center, 4700 Las Vegas Boulevard North, Nellis AFB, NV 89191; pamela.r.hughes4.mil@mail.mil.

As part of the COVID-19 pandemic, I see signs everywhere saying they have perks for health care workers. I can go to the front of the line at Costco, or for takeout at a restaurant, or to checkout at the grocery store. Certainly it would be easy, I always have my hospital ID in my car.

I have no interest in doing so. None.

As I’ve previously written, I’m in the back seat right now. For me to take out my hospital ID and grandstand to get in front of the line is not only a lie, but takes away from someone – a nurse, a paramedic, another doctor, whatever – who actually is on the front line of the pandemic and may be in a hurry to get home or back to work.

Me? I may be a doctor, but certainly not part of fighting the pandemic (unless you count wearing a mask and washing my hands frequently as such). I’m here for anyone who needs a neurologist, and my office is open, but that’s always been my normal day at work. I’m not at the hospital, or a screening center, or urgent care.

To me it seems pretty hypocritical, or at least inappropriate, for me to take advantage of a “FastPass” (as Disneyland calls it) when I’m really not one of the people it is intended for.

Perhaps it’s a minor point, but I feel like our society already has too many people taking advantage of the system in ways that, while not illegal, don’t seem fair, either. I have three kids, and part of raising them is leading by example. Don’t take something that isn’t yours.

Which is what it would feel like to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

As part of the COVID-19 pandemic, I see signs everywhere saying they have perks for health care workers. I can go to the front of the line at Costco, or for takeout at a restaurant, or to checkout at the grocery store. Certainly it would be easy, I always have my hospital ID in my car.

I have no interest in doing so. None.

As I’ve previously written, I’m in the back seat right now. For me to take out my hospital ID and grandstand to get in front of the line is not only a lie, but takes away from someone – a nurse, a paramedic, another doctor, whatever – who actually is on the front line of the pandemic and may be in a hurry to get home or back to work.

Me? I may be a doctor, but certainly not part of fighting the pandemic (unless you count wearing a mask and washing my hands frequently as such). I’m here for anyone who needs a neurologist, and my office is open, but that’s always been my normal day at work. I’m not at the hospital, or a screening center, or urgent care.

To me it seems pretty hypocritical, or at least inappropriate, for me to take advantage of a “FastPass” (as Disneyland calls it) when I’m really not one of the people it is intended for.

Perhaps it’s a minor point, but I feel like our society already has too many people taking advantage of the system in ways that, while not illegal, don’t seem fair, either. I have three kids, and part of raising them is leading by example. Don’t take something that isn’t yours.

Which is what it would feel like to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

As part of the COVID-19 pandemic, I see signs everywhere saying they have perks for health care workers. I can go to the front of the line at Costco, or for takeout at a restaurant, or to checkout at the grocery store. Certainly it would be easy, I always have my hospital ID in my car.

I have no interest in doing so. None.

As I’ve previously written, I’m in the back seat right now. For me to take out my hospital ID and grandstand to get in front of the line is not only a lie, but takes away from someone – a nurse, a paramedic, another doctor, whatever – who actually is on the front line of the pandemic and may be in a hurry to get home or back to work.

Me? I may be a doctor, but certainly not part of fighting the pandemic (unless you count wearing a mask and washing my hands frequently as such). I’m here for anyone who needs a neurologist, and my office is open, but that’s always been my normal day at work. I’m not at the hospital, or a screening center, or urgent care.

To me it seems pretty hypocritical, or at least inappropriate, for me to take advantage of a “FastPass” (as Disneyland calls it) when I’m really not one of the people it is intended for.

Perhaps it’s a minor point, but I feel like our society already has too many people taking advantage of the system in ways that, while not illegal, don’t seem fair, either. I have three kids, and part of raising them is leading by example. Don’t take something that isn’t yours.

Which is what it would feel like to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; sbschrag@wisc.edu.

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; sbschrag@wisc.edu.

CASE

Sara T* recently moved back to the area to be closer to her family. The 34-year-old patient visited our office to discuss the benefits and potential risks of genetic counseling. She explained that her aunt had just died at age 64 of ovarian cancer. Also, her maternal cousin had been diagnosed at age 42 with breast cancer, and her maternal grandmother had died at age 45 of an unknown “female cancer.” She was scared to find out if she had high-risk genes because she felt it would change her life forever. However, if she ignored the issue, she thought she might worry too much.

We discussed the implications of a positive result, such as having to live with the knowledge and to make decisions about potential screening and risk-reducing surgery. On the other hand, not knowing could allow for the undetected growth of cancer that might otherwise be mitigated to some degree if she knew her risk status and pursued an aggressive screening program.

We worked with Ms. T to map out her next steps.

*The patient’s name has been changed to protect her identity.

Breast cancer is the most commonly diagnosed cancer in women worldwide, representing nearly one-quarter of all female cancer diagnoses in 2018.¹ It is the second-leading cause of cancer death in women in developed nations and the leading cause of cancer death in women in developing nations.¹ In the United States, 1 in 8 women will develop breast cancer in her lifetime.² By comparison, the rate of ovarian cancer is much lower, with a lifetime prevalence of 1 in 70 to 80 women.^3,4 Although ovarian cancer is less common than breast cancer, its associated mortality is high, and most cases are discovered at advanced stages.

The outsized threat of BRCA mutations. It is estimated that 5% to 10% of all breast cancers are hereditary, with 80% of these attributable to BRCA1 (45%) and BRCA2 (35%).⁵ These autosomal dominant mutations occur at the germline level, within the egg or sperm, and are therefore incorporated into the DNA of every cell and passed from one generation to the next. Families with BRCA mutations have much higher lifetime rates of cancer. The lifetime risk of breast cancer due to BRCA mutations is estimated at > 80% (BRCA1) and 45% (BRCA2).⁵BRCA mutations account for between 10% and 18% of all ovarian cancers⁶ and convey a lifetime risk of 40% (BRCA1) and 15% (BRCA2) to carriers.⁵

USPSTF now also recommends BRCA1/2 screening for any woman with a family history of tubal or peritoneal cancer.

Male BRCA carriers have a lifetime breast cancer risk of 1% to 5% with BRCA1 and 5% to 10% with BRCA2,^7,8 compared with about 1:1000 lifetime incidence in the unselected male population. Male carriers are also at risk for more aggressive prostate cancers.^7,8

Continue to: Certain populatiosn carry undue burden of BRCA-related disease

Certain populations carry undue burden of BRCA-related disease due to specific founder mutations. While the estimated global prevalence of BRCA mutations is 0.2% to 1%, for those of Ashkenazi Jewish descent the range is 2% to 3%, representing a relative risk up to 15 times that of the general population.⁹ Hispanic Americans also appear to have higher rates of BRCA-related cancers.¹⁰ Ongoing genetics research continues to identify founder mutations worldwide,¹⁰ which may inform future screening guidelines.

In addition to BRCA mutations, there are other, less common mutations (TABLE 1⁵) known to cause hereditary breast and ovarian cancer.

Identifying BRCA genes enables treatment planning. Compared with sporadic cancers, BRCA-related breast cancers are diagnosed at earlier ages,¹¹are more likely to have lymph node involvement at time of discovery,¹²are more likely to be triple negative (no expression of estrogen, progesterone, or HER2 receptors),^11,12 and are associated with worse overall and breast cancer–specific survival.¹³

Similarly, BRCA-related ovarian cancer is more likely to be high-grade and endometrioid or serous subtype.¹⁴Knowledge of BRCA carrier status allows for risk-reducing strategies that are effective in reducing the incidence of cancer and improving cancer-­specific survival.^15,16As such, it is crucial that the primary care provider understand guidelines to help identify this high-risk population and work with patients on risk-reducing strategies.

Shared decision-making helps give clarity to the way forward

Shared decision-making is a process of communication whereby the clinician and the patient identify a decision to be made, review data relevant to clinical options, discuss patient perspectives and preferences regarding each option, and arrive at the decision together.¹⁷ Shared decision-making is important when treating women with BRCA mutations because there is no single correct plan. Individual values and competing medical issues may strongly guide each woman’s decisions about screening and cancer prevention treatment decisions.

Continue to: Shared decision-making in this situation...

Shared decision-making in this situation is a strategy to use the evidence of risk along with patient preferences around fertility issues to help come to a decision that is the right one for the patient. Primary care clinicians aware of the general risks and benefits of each available option can refer women at high risk for breast or ovarian cancer to a specialist multidisciplinary clinic that can provide tailored risk assessment and risk reduction counseling as needed.^18-20

Genetic screening recommendations

Screening is recommended for women who have any 1 of several family risk factors (TABLE 2²¹). A number of risk assessment tools are available for primary care clinicians to determine which patients are at high enough risk for a hereditary breast or ovarian cancer to warrant referral to a genetic counselor.^22-25 If screening suggests high risk, the US Preventive Services Task Force (USPSTF) recommends (Grade B) referral for genetic counseling.²¹

Explain to patients who are candidates for further investigation that a genetic counselor will review their family history and recommend testing for the specific mutations that increase cancer risk. Discuss potential benefits and harms of genetic testing. A benefit of genetic testing is that aggressive screening may suggest preventive procedures to reduce the risk of future cancer. Most tests come back definitively positive or negative, but an indeterminate result may cause harm. A small minority of results may indicate a genetic variant of unknown significance. The ramifications of this variant may not be known. Some women will experience anxiety about nonspecific test results and will be afraid to share them with family members. There is also some concern about privacy issues, potential insurance bias, and coverage of any preventive strategies.²⁶

CASE

Based on Ms. T’s family history and her desire to know more, we referred her to a genetic counselor and she decided to undergo genetic testing. She screened positive for BRCA1. Ms. T was in a serious relationship and thought she would like to have children at some point. She returned to our office after receiving the positive genetic test results, wondering about screening for breast and ovarian cancer.

Breast cancer screening and risk-reduction strategies

Screening. Because the risk of breast cancer is high in women with BRCA mutations, and because cancer in these women is more likely to be advanced at diagnosis, starting a screening program at an early age is prudent. Observational studies suggest that breastfeeding reduces the risk of breast and ovarian cancer in women with BRCA mutations, as it does for women in the general population.²⁷ Women should return for a clinical breast exam every 6 to 12 months starting at age 25; they should start radiologic screening with magnetic resonance imaging at age 25 and mammography at age 30 (TABLE 3^27,28).

Continue to: Risk-reduction strategies

Risk-reduction strategies. There is weak evidence to support the use of tamoxifen or other synthetic estrogen reuptake modulators (SERMs) to reduce breast cancer risk in women with BRCA mutations. Many of these cancers do not express estrogen receptors, which may explain the lack of efficacy in certain cases. Several observational studies have shown that tamoxifen can reduce the risk of contralateral breast cancer in women with BRCA mutations who have already been diagnosed with cancer in the other breast.^29-31 However, tamoxifen does not reduce a patient’s risk of ovarian cancer, and it may increase her risk of uterine cancer.

Shared decisionmaking is important when treating women with BRCA mutations because there is no single correct plan.

Prophylactic bilateral mastectomy is the mainstay of breast cancer prevention in this population. Data from a systematic review suggest that this surgery may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.³² However, this review did not demonstrate a reduction in mortality from breast cancer, likely due to poor data quality.³² The National Comprehensive Cancer Network (NCCN) recommends discussing prophylactic mastectomy with all women who have BRCA mutations.²⁸ Further conversations are important to review the risk of tissue left behind and quality-of-life issues, including the inability to breastfeed if the woman wants more children and the cosmetic changes with reconstruction.

Ovarian cancer screening and risk-reduction strategies

Screening. No effective screening strategy has been endorsed for ovarian cancer, as most previous studies have shown screening to be ineffective.^26,33 Recently, studies both in the United Kingdom and the United States have investigated a screening strategy using the risk-of-ovarian-cancer algorithm (ROCA), which calculates an individual’s risk based on serum levels of cancer antigen 125 (CA-125).^34,35 These studies measured CA-125 levels every 3 to 4 months followed by transvaginal ultrasound if CA-125 increased substantially (as determined by ROCA). Absent an abnormal increase in CA-125, transvaginal ultrasound was performed annually. These screening strategies showed improved specificity over annual screening programs, and the cancers detected were more likely to be diagnosed at an early stage (stage II vs stage III) and had higher rates of zero residual disease after surgery compared with those detected 1 year after screening ended.^34,35 However, survival data are not yet available. More research is needed to determine if more frequent screening approaches could improve survival in high-risk women.

Prophylactic bilateral mastectomy may prevent the incidence of breast cancer in women with BRCA mutations by 90% to 95%.

NCCN and the American College of Obstetricians and Gynecologists (ACOG) do not endorse routine screening with transvaginal ultrasound and serum CA-125 for high-risk women, as the benefits are uncertain. However, they do advise that these screens may be considered as a short-term strategy for women ages 30 to 35 who defer risk-reducing surgery.^26,36 The USPSTF does not make a recommendation regarding ovarian cancer screening in high-risk women.³⁷

Risk-reduction strategies. Risk-reducing bilateral salpingo-oophorectomy (RRSO) is the only recommended technique for reducing the risk of ovarian cancer in women at high risk.^26,33,36 Meta-analyses have shown an 80% reduction in ovarian cancer risk¹⁶ and 68% reduction in all-cause mortality with this approach.³⁸ The NCCN recommends RRSO for women with a known BRCA1 mutation between the ages of 35 and 40 who have completed childbearing.³⁶ Since the onset of ovarian cancer tends to be later in women with BRCA2 mutations, it is reasonable to delay RRSO until age 40 to 45 in this population if they have taken other steps to maximize breast cancer prevention (ie, bilateral mastectomy).³⁶

Continue to: Adverse effects of RRSO...

Adverse effects of RRSO include surgery complications (wound infection, small bowel obstruction, bladder perforation) and effects of early menopause (vasomotor symptoms, decreased sexual functioning, and increased risk of osteoporosis, cardiovascular disease, and all-cause mortality).^39-41 In the absence of contraindications, ACOG recommends using hormone therapy in women undergoing RRSO until the natural age of menopause,⁴² particularly if their breast tissue has been removed.

Salpingectomy as an alternative. In an attempt to reduce these adverse effects of early menopause, and because a large proportion of high-grade serous tumors originate in the fallopian tube,⁴³ interest has increased in the use of risk-reducing salpingectomy (removal of fallopian tubes) and delayed oophorectomy in women at high risk of ovarian cancer.⁴² Studies have shown this may be a cost-effective approach and an acceptable alternative in BRCA mutation carriers who are unwilling to undergo RRSO.^44,45 A clinical trial investigating this approach in women with BRCA mutations is currently underway in the United States.⁴⁶ Many centers offer salpingectomy to high-risk patients < 40 years old, understanding that ovary removal is an eventuality for these patients.

When oral contraceptive pills might be beneficial. In younger women with BRCA mutations, there may also be a role for oral contraceptive pills (OCPs) as a risk-reducing strategy. Meta-analyses have shown an approximately 50% reduction in the risk of ovarian cancer among women with BRCA mutations who use OCPs.^47-49

ACOG advises that it is appropriate for women with BRCA mutations to use oral contraceptives if indicated (for pregnancy prevention or menstrual cycle regulation), and that it is reasonable to use them for cancer prevention.²⁶ NCCN does not make a formal recommendation, although it does state OCPs may reduce the risk of ovarian cancer in women with a BRCA mutation.³⁶ Case-control studies have produced conflicting data on the association between OCP use and breast cancer risk in BRCA mutation carriers,^50-53 although 2 meta-analyses found no significant association in this population.^47,48

Decision aids for women with BRCA mutations

Decision aids are visual displays of risk that help patients work through complex decisions. Most decision aids are in print or digital format and include information about the decision to be made as well as pictorial examples of possible outcomes. Pictographs are especially helpful in communicating information. Some decision aids for women with BRCA mutations can be complicated with multiple outcomes (ie, breast cancer and ovarian cancer) and multiple potential interventions (risk-reducing surgery, enhanced screening options).⁵⁴

Continue to: A Cochrane review...

A Cochrane review found that decision aids increased patients’ knowledge, helped patients clarify their values, and may improve value-concordant decisions.⁵⁵ Two papers describing the use of decision aids for women with BRCA mutations^56,57 documented decreased decisional conflict and increased satisfaction.

CASE

Ms. T underwent the recommended mammogram and MRI screening for breast ­cancer, as well as testing with serum CA-125 and ultrasound examinations for ovarian cancer. Her initial mammogram and MRI revealed early stage, triple-negative right breast cancer. She chose to undergo bilateral mastectomy and reconstruction. She has now completed treatment and continues to work closely with her oncology team for appropriate breast ­follow-up.

Two papers describing the use of decision aids for women with BRCA mutations documented decreased decisional conflict and increased satisfaction.

One year after her initial diagnosis, at the age of 35, she returned to discuss fertility. She was recently married, and she and her husband wanted to start having children. She was concerned about a safe timeline for her to pursue pregnancy, saying she felt “like a ticking time-bomb” given her prior cancer and carrier status. She wanted to discuss the risks and benefits of pregnancy and when she should consider prophylactic oophorectomy. She had a few options. She could have a baby and then undergo an RRSO, or she could talk to her gynecologist about having a salpingectomy to reduce her risk now and use assisted reproductive technology to get pregnant. She could also freeze eggs or embryos, have an RRSO, and then use a surrogate to get pregnant. We informed her that pregnancy would not affect her risk of ovarian cancer and discussed the options for pre-implantation genetic testing to assure that her children would not carry the genetic mutation.⁵⁸

We provided Ms. T and her husband with a decision aid to help them navigate the decision. They are currently evaluating the options and said they would let us know when they made a decision.

CORRESPONDENCE
Sarina Schrager, MD, MS, Northeast Family Medicine Center, 3209 Dryden Drive, Madison, WI, 53704; sbschrag@wisc.edu.

Almost 8% of Americans ages ≥ 12 years have depression and 19.1% of Americans ages ≥ 18 years have experienced an anxiety disorder in the past year.^1,2 Furthermore, suicide, which can result from depression and anxiety, is the 10th leading cause of death in the United States, claiming about 40,000 to 49,000 lives per year since 2012, with increasing yearly rates.³ While multiple conventional medication and therapy treatments are available, patients remain interested in complementary and alternative medicine (CAM) options. According to the National Center for Complementary and Integrative Health, more than 30% of American adults use CAM treatments.⁴

This article provides an overview of the evidence for commonly used CAM treatments for unipolar depression and anxiety in adults. It is designed to serve as a useful resource when patients are interested in looking beyond conventional medications.

St. John’s wort: ‘Yes’ for depression; ‘no’ for anxiety

Hypericum perforatum, more commonly known as St. John’s wort, is a widely used antidepressant, especially in Europe where it is prescribed, rather than offered over the counter as it is here. Its mechanism of action is not completely understood because its various constituents have different neuropharmacologic activities.^5,6

A 2008 Cochrane review evaluated 29 randomized, double-blind studies (N = 5489) that compared St. John’s wort with placebo or standard antidepressants in the treatment of depression.⁷ St. John’s wort was found to be superior to placebo and comparable to standard antidepressants. More recently, a 2017 meta-analysis of 27 studies (N = 3808) had similar findings.⁸ In patients with mild-to-moderate depression, St. John’s wart produced rates of remission that were comparable to those produced by selective serotonin reuptake inhibitors (SSRIs) but with a lower discontinuation rate.

Mood disorders other than depression. Studies do not support a role for St. John’s wort in the treatment of anxiety disorders. There are no trials that assess the efficacy of St. John’s wort for the reduction of symptoms of general anxiety disorder as a primary outcome of treatment. Some small clinical trials have investigated the efficacy of St. John’s wort in obsessive-compulsive disorder and social anxiety disorder. In those studies, St. John’s wort performed no better than placebo.^9,10

A few words of caution. Preparations of St. John’s wort in the United States are not standardized, so St. John’s wort should be used in America with caution. Furthermore, long-term use of St. John’s wort for depression is questionable given that most studies have evaluated only up to 12 weeks of use.⁸

In patients with mildto-moderate depression, St. John’s wort produced rates of remission that were comparable to those produced by SSRIs— with a lower discontinuation rate.

If used, studies indicate that the St. John’s wort extract that should be used is 0.3% hypericin or 5% hyperforin administered in a dosage of 300 to 400 mg tid.^7,8,11 Physicians and patients can use www.consumerlabs.com to find St. John’s wort brands that have met specified quality criteria based on independent laboratory studies. This Web site can also be used to investigate the quality of the brands available for the other supplements discussed in this article.

Continue to: Adverse effects

Adverse effects. St. John’s wort and an SSRI can lead to serotonin syndrome, which is a constellation of symptoms involving mental status changes and autonomic and neuromuscular hyperactivity caused by serotonin overactivity.¹² Furthermore, treatment failures with anticoagulants, digoxin, hormonal contraceptives, immunosuppressants, and narcotics due to concomitant use with St. John’s wort have been reported.¹³

The most common adverse reactions to St. John’s wort include gastrointestinal symptoms, dizziness, sedation, photosensitivity, dry mouth, urinary frequency, anorgasmia, and swelling.¹⁴ However, multiple studies have supported St. John’s wort to be equally or better tolerated than conventional antidepressants.^7,8

Certain forms of folate can be adjunctive treatment for depression

Methylfolate is the form of folate that crosses the blood–brain barrier. A prospective observational study evaluated the cerebral spinal fluid of 33 patients with refractory depression. The authors found metabolic abnormalities in the cerebrospinal fluid of most of those patients, the most common of which was folate deficiency in 12 patients despite normal serum folate levels.¹⁵

Additionally, current understanding of the role of the Methylenetetrahydrofolate reductase (MTHFR) gene and the folate cycle in depression supports a potential role of methylfolate in depression treatment.¹⁶ The MTHFR gene encodes for an enzyme called MTHFR. The MTHFR enzyme converts 5,10-MTHF to 5-MTHF, which then crosses the blood–brain barrier and donates a methyl group for the conversion of homocysteine to methionine. Methionine is a precursor to monoamine neurotransmitters. Thus, decreased expression of the MTHFR gene leads to decreased methylfolate levels, which, in turn, potentially leads to insufficient neurotransmitter synthesis and homocysteine excess.

MTHFR gene polymorphisms and increased homocysteine levels have been found to be associated with the occurrence of depression. One thought is that methylfolate supplementation compensates for an underlying MTHFR enzyme deficiency in patients with depression. Further studies are needed to determine if screening depressed patients for MTHFR gene polymorphisms is of benefit.¹⁶

Continue to: A 2012 randomized controlled trial...

A 2012 randomized controlled trial (RCT) (N = 75) compared L-methylfolate 15 mg/d plus an SSRI with placebo plus an SSRI in patients with SSRI-resistant major depression.¹⁷ The trial found that a reduction of baseline symptoms by ≥ 50% occurred in more patients who received adjunctive L-methylfolate than placebo (32% vs 15%) and tolerability was comparable. These findings were again supported in 2016 with a 12-month study showing L-methylfolate to have long-term tolerability comparable to placebo,¹⁸ and in 2017 with a randomized trial (N = 260) that found escitalopram 10 mg/d plus L-methylfolate 15 mg/d to be significantly more effective at treating depression than escitalopram 10 mg/d alone.¹⁹ Thus, methylfolate may be an effective adjunctive treatment for depression at a dosage of 15 mg/d.

S-adenosyl methionine (SAMe) is a metabolite of folate derived from methionine that facilitates the synthesis of neurotransmitters including dopamine, norepinephrine, and serotonin. In Europe, as is the case with St. John’s wort, it is a prescription medication.

A randomized trial (N = 73) compared adjunctive SAMe 800 mg bid with placebo in the treatment of patients with unipolar major depression who did not experience improvement with SSRI treatment alone.²⁰ The investigators found that more patients who received SAMe than who received placebo had improvement in their depression (36.1% vs 17.6%), and more patients who received SAMe compared to placebo went into depression remission (25.8% vs 11.7%).

Adverse effects were comparable in both groups. Thus, SAMe at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.^20,21 The findings of 1 study (N = 65) suggest that patients could experience further improvement in their depression symptoms with SAMe at doses of as much as 3200 mg/d; however, 3200 mg/d increased the occurrence of gastrointestinal adverse effects (31.3% in the SAMe arm vs 3.8% in the placebo group).²¹

Folate. With regard to folate itself, randomized trials have not supported its efficacy in the treatment of depression in the general population.²²

Continue to: VItamin D may improve anxiety/depression in those with low levels

Vitamin D may improve anxiety/depression in those with low levels

Vitamin D supplementation is also being used more frequently in the treatment of depression. Case-control, cross-sectional, and cohort studies have linked low vitamin D levels to the occurrence of depression. A 2013 systematic review of 14 such studies (N = 31,424) found lower vitamin D levels in people with depression compared with controls.²³ Further studies are needed to determine if this relationship is causal, and quality RCTs investigating the effect of vitamin D supplementation on depression are lacking.

S-adenosyl methionine (SAMe) at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.

A 2019 study (N = 30) evaluated the ­impact of vitamin D supplementation on generalized anxiety disorder in patients with co-occurring vitamin D deficiency. Half received standard-of-care general anxiety disorder treatment plus 50,000 IU of vitamin D weekly for 3 months, while the other half received standard of care alone. Significant improvements in anxiety scores, increases in serum serotonin, and decreases in serum neopterin (an inflammatory marker) were observed in the vitamin D–treated group compared to the group that did not receive vitamin D.²⁴

It is not currently standard of care to check vitamin D levels in all patients presenting with mood disorders. However, if screening is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/or depressive symptoms. Despite this, no evidence exists to support vitamin D supplementation for depression or anxiety in patients with normal vitamin D levels.^24,25

The effects of omega-3 fatty acids are largely unclear

Research has shown that omega-3 polyunsaturated fatty acids (n-3 PUFA), which are found in fish oil, protect glutamatergic neurotransmission from glucocorticoids, which are released in the body during a stress response.²⁶ Small clinical trials have found n-3 PUFAs to reduce the symptoms of anxiety compared with placebo, but the acids have not been studied directly for anxiety disorders.^27,28

With regard to depression, evidence is conflicting as to whether n-3 PUFAs are of any benefit in treatment.²⁹ Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are hypothesized to be the components in omega-3 fatty acid preparations that could lead to a reduction in depressive symptoms. However, randomized trials have shown that EPA-predominant omega-3 fatty acid formulations have only a moderate or no clinically significant effect on depression over placebo, and that DHA-predominant omega-3 fatty acid formulations are only comparable or inferior to placebo.³⁰

Continue to: Response to EPA...

Response to EPA may be greater in patients with depression who have high levels of inflammatory biomarkers, such as interleuken (IL)-1 receptor antagonist (1Ra), IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin, and adiponectin, than in patients with low levels. An 8-week trial randomly assigned patients with unipolar major depression (N = 155) to receive either EPA, DHA, or placebo and found that improvement for the 3 groups was comparable; however, in the subgroup of patients with high levels of inflammatory markers, improvement in depressive symptoms was significantly greater with EPA than with either DHA or placebo.³¹

If screening for vitamin D levels is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/ or depression symptoms.

It is unclear whether different sources of n-3 PUFA, such as whole fish vs fish oil vs prescription omega-3 acid ethyl esters (Lovaza), are more or less efficacious in the treatment of anxiety or depression. Furthermore, there is no standard dosing for n-3 PUFA in the treatment of mood disorders. Given that the US Food and Drug Administration recommends no more than 2 g/d of combined EPA and DHA supplementation, we recommend using 2 g/d if one decides to treat depression/anxiety with n-3 PUFA.³²

N-3 PUFA supplementation is fairly benign. There have been previous concerns about n-3 PUFA supplementation increasing patients’ risk for gastrointestinal bleeding, but a 2006 systematic review that included 9 trials (N = 2612) that looked at clinically significant bleeding episodes found that even patients at high risk for bleeding (ie, those taking aspirin or warfarin) had no increased bleeding risk from taking n-3 PUFA supplementation at up to 4 g/d.³³

Don’t underestimate exercise and meditation; consider acupuncture

Exercise. Multiple practice guidelines, including the American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Major Depressive Disorder,” and meta-analyses have supported the use of exercise to treat unipolar major depression and anxiety.^34-37 However, only about 26% of American men and 19% of American women met the US Department of Health and Human Services’ “Federal Physical Activity Guidelines for Americans” in 2016.³⁸

Exercise alone is a reasonable monotherapy, as long as patients are monitored closely for worsening symptoms. Additionally, exercise as an add-on treatment can be helpful for more severe depression or anxiety.³⁹ The best type, duration, and frequency of exercise specifically for the treatment of depression or anxiety has yet to be determined, but physicians may base their exercise recommendations on the “Federal Physical Activity Guidelines for Americans” for general good health (TABLE).³⁸

Continue to: Meditation

Meditation, especially mindfulness meditation, is another strategy that has gained popularity in the treatment of anxiety and depression. Mindfulness has been defined as “the practice of maintaining a nonjudgmental state of heightened or complete awareness of one’s thoughts, emotions, or experiences on a moment-to-moment basis.”⁴⁰ A 2014 systematic review and meta-analysis of 47 trials with 3515 participants found that mindfulness meditation programs led to clinically significant moderate reductions in anxiety.⁴¹ Smaller effects were found for depression.

Nevertheless, meditation may be beneficial as an adjunctive treatment for depression. A small randomized trial (N = 25) compared an adjunctive breathing-based meditation intervention with a waitlist control (delayed yoga) in patients with unipolar major depression who failed to respond to at least 8 weeks of antidepressant treatment.⁴² The meditation intervention consisted of a group program with sitting meditation, breathing exercises, and yoga postures. Participants engaged in the meditation intervention for 2 to 3.5 hours per day for 8 weeks and demonstrated significant improvement in depression symptoms compared with the control group.⁴²

Acupuncture. A 2018 meta-analysis of 64 studies (N = 7104) suggests that acupuncture results in a small-to-moderate reduction in depressive symptoms when compared to no treatment, control/sham acupuncture, or medication.⁴³ Furthermore, acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.⁴³

Additionally, a 2019 analysis of 10 systematic reviews found acupuncture to be more effective than control/sham acupuncture in the treatment of general anxiety.⁴⁴ It should be noted, however, that a lot of heterogeneity and potential for bias existed across all of the studies. The studies analyzed were very low to low in quality. Thus, the evidence is insufficient to strongly recommend the use of acupuncture for depression or anxiety, although acupuncture is a safe intervention with low rates of adverse events.

Emotional support animals: Beneficial, but evidence is weak

Emotional support animals are gaining in popularity with Americans who have mood disorders. An important distinction must be made, however, between service animals and emotional support animals. A service animal is one “that is individually trained to do work or perform tasks for the benefit of an individual with a disability, including a physical, sensory, psychiatric, intellectual, or other mental disability.”⁴⁵ Under the Americans with Disabilities Act (ADA), service animals are limited to dogs, and, in some cases, specially trained miniature horses. Psychiatric service dogs can be trained to do anything from reminding their owner to take medicine to stopping self-mutilation activities.

Continue to: Emotional support animals...

Emotional support animals are not specially trained to perform tasks to help with disabilities. It’s their companionship that helps relieve symptoms of depression and/or anxiety.⁴⁵ Thus, emotional support animals are not covered under federal laws that apply to service animals. However, the Air Carrier Access Act does require airlines to allow emotional support animals to fly in the cabin for free. Furthermore, the Fair Housing Act allows emotional support animals to circumvent no-pet rules in housing and dorms. Airplanes and housing are the only places legally required to allow the unrestricted presence of emotional support animals.⁴⁶

Also, there are important distinctions between emotional support animals and pets. While anyone can own a pet, an emotional support animal is prescribed by a licensed mental health professional as a treatment for a mood disorder. Housing facilities and airlines will usually require an emotional support animal “prescription” or letter from a physician to recognize animals as such.

Exercise alone is a reasonable monotherapy for depression or anxiety as long as patients are monitored closely for worsening symptoms.

A 2018 systematic review evaluated the evidence behind emotional support animals, which included 17 peer-reviewed journal articles, conference papers, and research dissertations (N = 1727) mostly containing qualitative evidence.⁴⁷ Unfortunately, there are no RCTs, and there are limited case-control and cohort studies evaluating the effect of an emotional support animal on mood disorders. Based on the available evidence, there does seem to be a psychological benefit to owning an animal for both those with a diagnosable mental health disorder and the general population. This benefit seems to stem from a perceived reduction in social isolation and an increase in emotional support. Factors that determine the psychological benefit of emotional support animals include the type of pet, the number of pets, the attachment to the pet, and the perceived friendliness of the pet.⁴⁷

Animal-assisted therapy. A 2014 systematic review evaluated higher-level evidence behind animal-assisted therapy (AAT).⁴⁸ Although participating in therapy that involves interaction with animals is not the same as owning an emotional support animal, the concept—using an animal to improve mental health—is the same. The systematic review looked at 11 RCTs (N = 411) that studied the effect of AAT on mental health. Animals studied included dogs, cats, dolphins, birds, cows, rabbits, ferrets, and guinea pigs. Mental health disorders studied included schizophrenia, depression, anxiety, alcohol/drug abuse, and other addictive behaviors.

Acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.

Therapeutic animal exposure led to reported improvements in mood, quality of life, and social behavior. These improvements were attributed to the animals buffering people’s reactions to mental stressors. The animals provided a sense of comfort and safety and diverted attention away from immediate stressors. Furthermore, the memory of the animals brought participants a sense of comfort/happiness when they were later without the animal. However, the majority of participants were people who liked animals at baseline.⁴⁸

CORRESPONDENCE
Amanda E. Olagunju, DO, Operational Medicine Clinic, Langley AFB Hospital, 77 Nealy Avenue, Langley AFB, VA 23665; amanda.olagunju@gmail.com.

Almost 8% of Americans ages ≥ 12 years have depression and 19.1% of Americans ages ≥ 18 years have experienced an anxiety disorder in the past year.^1,2 Furthermore, suicide, which can result from depression and anxiety, is the 10th leading cause of death in the United States, claiming about 40,000 to 49,000 lives per year since 2012, with increasing yearly rates.³ While multiple conventional medication and therapy treatments are available, patients remain interested in complementary and alternative medicine (CAM) options. According to the National Center for Complementary and Integrative Health, more than 30% of American adults use CAM treatments.⁴

This article provides an overview of the evidence for commonly used CAM treatments for unipolar depression and anxiety in adults. It is designed to serve as a useful resource when patients are interested in looking beyond conventional medications.

St. John’s wort: ‘Yes’ for depression; ‘no’ for anxiety

Hypericum perforatum, more commonly known as St. John’s wort, is a widely used antidepressant, especially in Europe where it is prescribed, rather than offered over the counter as it is here. Its mechanism of action is not completely understood because its various constituents have different neuropharmacologic activities.^5,6

A 2008 Cochrane review evaluated 29 randomized, double-blind studies (N = 5489) that compared St. John’s wort with placebo or standard antidepressants in the treatment of depression.⁷ St. John’s wort was found to be superior to placebo and comparable to standard antidepressants. More recently, a 2017 meta-analysis of 27 studies (N = 3808) had similar findings.⁸ In patients with mild-to-moderate depression, St. John’s wart produced rates of remission that were comparable to those produced by selective serotonin reuptake inhibitors (SSRIs) but with a lower discontinuation rate.

Mood disorders other than depression. Studies do not support a role for St. John’s wort in the treatment of anxiety disorders. There are no trials that assess the efficacy of St. John’s wort for the reduction of symptoms of general anxiety disorder as a primary outcome of treatment. Some small clinical trials have investigated the efficacy of St. John’s wort in obsessive-compulsive disorder and social anxiety disorder. In those studies, St. John’s wort performed no better than placebo.^9,10

A few words of caution. Preparations of St. John’s wort in the United States are not standardized, so St. John’s wort should be used in America with caution. Furthermore, long-term use of St. John’s wort for depression is questionable given that most studies have evaluated only up to 12 weeks of use.⁸

In patients with mildto-moderate depression, St. John’s wort produced rates of remission that were comparable to those produced by SSRIs— with a lower discontinuation rate.

If used, studies indicate that the St. John’s wort extract that should be used is 0.3% hypericin or 5% hyperforin administered in a dosage of 300 to 400 mg tid.^7,8,11 Physicians and patients can use www.consumerlabs.com to find St. John’s wort brands that have met specified quality criteria based on independent laboratory studies. This Web site can also be used to investigate the quality of the brands available for the other supplements discussed in this article.

Continue to: Adverse effects

Adverse effects. St. John’s wort and an SSRI can lead to serotonin syndrome, which is a constellation of symptoms involving mental status changes and autonomic and neuromuscular hyperactivity caused by serotonin overactivity.¹² Furthermore, treatment failures with anticoagulants, digoxin, hormonal contraceptives, immunosuppressants, and narcotics due to concomitant use with St. John’s wort have been reported.¹³

The most common adverse reactions to St. John’s wort include gastrointestinal symptoms, dizziness, sedation, photosensitivity, dry mouth, urinary frequency, anorgasmia, and swelling.¹⁴ However, multiple studies have supported St. John’s wort to be equally or better tolerated than conventional antidepressants.^7,8

Certain forms of folate can be adjunctive treatment for depression

Methylfolate is the form of folate that crosses the blood–brain barrier. A prospective observational study evaluated the cerebral spinal fluid of 33 patients with refractory depression. The authors found metabolic abnormalities in the cerebrospinal fluid of most of those patients, the most common of which was folate deficiency in 12 patients despite normal serum folate levels.¹⁵

Additionally, current understanding of the role of the Methylenetetrahydrofolate reductase (MTHFR) gene and the folate cycle in depression supports a potential role of methylfolate in depression treatment.¹⁶ The MTHFR gene encodes for an enzyme called MTHFR. The MTHFR enzyme converts 5,10-MTHF to 5-MTHF, which then crosses the blood–brain barrier and donates a methyl group for the conversion of homocysteine to methionine. Methionine is a precursor to monoamine neurotransmitters. Thus, decreased expression of the MTHFR gene leads to decreased methylfolate levels, which, in turn, potentially leads to insufficient neurotransmitter synthesis and homocysteine excess.

MTHFR gene polymorphisms and increased homocysteine levels have been found to be associated with the occurrence of depression. One thought is that methylfolate supplementation compensates for an underlying MTHFR enzyme deficiency in patients with depression. Further studies are needed to determine if screening depressed patients for MTHFR gene polymorphisms is of benefit.¹⁶

Continue to: A 2012 randomized controlled trial...

A 2012 randomized controlled trial (RCT) (N = 75) compared L-methylfolate 15 mg/d plus an SSRI with placebo plus an SSRI in patients with SSRI-resistant major depression.¹⁷ The trial found that a reduction of baseline symptoms by ≥ 50% occurred in more patients who received adjunctive L-methylfolate than placebo (32% vs 15%) and tolerability was comparable. These findings were again supported in 2016 with a 12-month study showing L-methylfolate to have long-term tolerability comparable to placebo,¹⁸ and in 2017 with a randomized trial (N = 260) that found escitalopram 10 mg/d plus L-methylfolate 15 mg/d to be significantly more effective at treating depression than escitalopram 10 mg/d alone.¹⁹ Thus, methylfolate may be an effective adjunctive treatment for depression at a dosage of 15 mg/d.

S-adenosyl methionine (SAMe) is a metabolite of folate derived from methionine that facilitates the synthesis of neurotransmitters including dopamine, norepinephrine, and serotonin. In Europe, as is the case with St. John’s wort, it is a prescription medication.

A randomized trial (N = 73) compared adjunctive SAMe 800 mg bid with placebo in the treatment of patients with unipolar major depression who did not experience improvement with SSRI treatment alone.²⁰ The investigators found that more patients who received SAMe than who received placebo had improvement in their depression (36.1% vs 17.6%), and more patients who received SAMe compared to placebo went into depression remission (25.8% vs 11.7%).

Adverse effects were comparable in both groups. Thus, SAMe at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.^20,21 The findings of 1 study (N = 65) suggest that patients could experience further improvement in their depression symptoms with SAMe at doses of as much as 3200 mg/d; however, 3200 mg/d increased the occurrence of gastrointestinal adverse effects (31.3% in the SAMe arm vs 3.8% in the placebo group).²¹

Folate. With regard to folate itself, randomized trials have not supported its efficacy in the treatment of depression in the general population.²²

Continue to: VItamin D may improve anxiety/depression in those with low levels

Vitamin D may improve anxiety/depression in those with low levels

Vitamin D supplementation is also being used more frequently in the treatment of depression. Case-control, cross-sectional, and cohort studies have linked low vitamin D levels to the occurrence of depression. A 2013 systematic review of 14 such studies (N = 31,424) found lower vitamin D levels in people with depression compared with controls.²³ Further studies are needed to determine if this relationship is causal, and quality RCTs investigating the effect of vitamin D supplementation on depression are lacking.

S-adenosyl methionine (SAMe) at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.

A 2019 study (N = 30) evaluated the ­impact of vitamin D supplementation on generalized anxiety disorder in patients with co-occurring vitamin D deficiency. Half received standard-of-care general anxiety disorder treatment plus 50,000 IU of vitamin D weekly for 3 months, while the other half received standard of care alone. Significant improvements in anxiety scores, increases in serum serotonin, and decreases in serum neopterin (an inflammatory marker) were observed in the vitamin D–treated group compared to the group that did not receive vitamin D.²⁴

It is not currently standard of care to check vitamin D levels in all patients presenting with mood disorders. However, if screening is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/or depressive symptoms. Despite this, no evidence exists to support vitamin D supplementation for depression or anxiety in patients with normal vitamin D levels.^24,25

The effects of omega-3 fatty acids are largely unclear

Research has shown that omega-3 polyunsaturated fatty acids (n-3 PUFA), which are found in fish oil, protect glutamatergic neurotransmission from glucocorticoids, which are released in the body during a stress response.²⁶ Small clinical trials have found n-3 PUFAs to reduce the symptoms of anxiety compared with placebo, but the acids have not been studied directly for anxiety disorders.^27,28

With regard to depression, evidence is conflicting as to whether n-3 PUFAs are of any benefit in treatment.²⁹ Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are hypothesized to be the components in omega-3 fatty acid preparations that could lead to a reduction in depressive symptoms. However, randomized trials have shown that EPA-predominant omega-3 fatty acid formulations have only a moderate or no clinically significant effect on depression over placebo, and that DHA-predominant omega-3 fatty acid formulations are only comparable or inferior to placebo.³⁰

Continue to: Response to EPA...

Response to EPA may be greater in patients with depression who have high levels of inflammatory biomarkers, such as interleuken (IL)-1 receptor antagonist (1Ra), IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin, and adiponectin, than in patients with low levels. An 8-week trial randomly assigned patients with unipolar major depression (N = 155) to receive either EPA, DHA, or placebo and found that improvement for the 3 groups was comparable; however, in the subgroup of patients with high levels of inflammatory markers, improvement in depressive symptoms was significantly greater with EPA than with either DHA or placebo.³¹

If screening for vitamin D levels is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/ or depression symptoms.

It is unclear whether different sources of n-3 PUFA, such as whole fish vs fish oil vs prescription omega-3 acid ethyl esters (Lovaza), are more or less efficacious in the treatment of anxiety or depression. Furthermore, there is no standard dosing for n-3 PUFA in the treatment of mood disorders. Given that the US Food and Drug Administration recommends no more than 2 g/d of combined EPA and DHA supplementation, we recommend using 2 g/d if one decides to treat depression/anxiety with n-3 PUFA.³²

N-3 PUFA supplementation is fairly benign. There have been previous concerns about n-3 PUFA supplementation increasing patients’ risk for gastrointestinal bleeding, but a 2006 systematic review that included 9 trials (N = 2612) that looked at clinically significant bleeding episodes found that even patients at high risk for bleeding (ie, those taking aspirin or warfarin) had no increased bleeding risk from taking n-3 PUFA supplementation at up to 4 g/d.³³

Don’t underestimate exercise and meditation; consider acupuncture

Exercise. Multiple practice guidelines, including the American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Major Depressive Disorder,” and meta-analyses have supported the use of exercise to treat unipolar major depression and anxiety.^34-37 However, only about 26% of American men and 19% of American women met the US Department of Health and Human Services’ “Federal Physical Activity Guidelines for Americans” in 2016.³⁸

Exercise alone is a reasonable monotherapy, as long as patients are monitored closely for worsening symptoms. Additionally, exercise as an add-on treatment can be helpful for more severe depression or anxiety.³⁹ The best type, duration, and frequency of exercise specifically for the treatment of depression or anxiety has yet to be determined, but physicians may base their exercise recommendations on the “Federal Physical Activity Guidelines for Americans” for general good health (TABLE).³⁸

Continue to: Meditation

Meditation, especially mindfulness meditation, is another strategy that has gained popularity in the treatment of anxiety and depression. Mindfulness has been defined as “the practice of maintaining a nonjudgmental state of heightened or complete awareness of one’s thoughts, emotions, or experiences on a moment-to-moment basis.”⁴⁰ A 2014 systematic review and meta-analysis of 47 trials with 3515 participants found that mindfulness meditation programs led to clinically significant moderate reductions in anxiety.⁴¹ Smaller effects were found for depression.

Nevertheless, meditation may be beneficial as an adjunctive treatment for depression. A small randomized trial (N = 25) compared an adjunctive breathing-based meditation intervention with a waitlist control (delayed yoga) in patients with unipolar major depression who failed to respond to at least 8 weeks of antidepressant treatment.⁴² The meditation intervention consisted of a group program with sitting meditation, breathing exercises, and yoga postures. Participants engaged in the meditation intervention for 2 to 3.5 hours per day for 8 weeks and demonstrated significant improvement in depression symptoms compared with the control group.⁴²

Acupuncture. A 2018 meta-analysis of 64 studies (N = 7104) suggests that acupuncture results in a small-to-moderate reduction in depressive symptoms when compared to no treatment, control/sham acupuncture, or medication.⁴³ Furthermore, acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.⁴³

Additionally, a 2019 analysis of 10 systematic reviews found acupuncture to be more effective than control/sham acupuncture in the treatment of general anxiety.⁴⁴ It should be noted, however, that a lot of heterogeneity and potential for bias existed across all of the studies. The studies analyzed were very low to low in quality. Thus, the evidence is insufficient to strongly recommend the use of acupuncture for depression or anxiety, although acupuncture is a safe intervention with low rates of adverse events.

Emotional support animals: Beneficial, but evidence is weak

Emotional support animals are gaining in popularity with Americans who have mood disorders. An important distinction must be made, however, between service animals and emotional support animals. A service animal is one “that is individually trained to do work or perform tasks for the benefit of an individual with a disability, including a physical, sensory, psychiatric, intellectual, or other mental disability.”⁴⁵ Under the Americans with Disabilities Act (ADA), service animals are limited to dogs, and, in some cases, specially trained miniature horses. Psychiatric service dogs can be trained to do anything from reminding their owner to take medicine to stopping self-mutilation activities.

Continue to: Emotional support animals...

Emotional support animals are not specially trained to perform tasks to help with disabilities. It’s their companionship that helps relieve symptoms of depression and/or anxiety.⁴⁵ Thus, emotional support animals are not covered under federal laws that apply to service animals. However, the Air Carrier Access Act does require airlines to allow emotional support animals to fly in the cabin for free. Furthermore, the Fair Housing Act allows emotional support animals to circumvent no-pet rules in housing and dorms. Airplanes and housing are the only places legally required to allow the unrestricted presence of emotional support animals.⁴⁶

Also, there are important distinctions between emotional support animals and pets. While anyone can own a pet, an emotional support animal is prescribed by a licensed mental health professional as a treatment for a mood disorder. Housing facilities and airlines will usually require an emotional support animal “prescription” or letter from a physician to recognize animals as such.

Exercise alone is a reasonable monotherapy for depression or anxiety as long as patients are monitored closely for worsening symptoms.

A 2018 systematic review evaluated the evidence behind emotional support animals, which included 17 peer-reviewed journal articles, conference papers, and research dissertations (N = 1727) mostly containing qualitative evidence.⁴⁷ Unfortunately, there are no RCTs, and there are limited case-control and cohort studies evaluating the effect of an emotional support animal on mood disorders. Based on the available evidence, there does seem to be a psychological benefit to owning an animal for both those with a diagnosable mental health disorder and the general population. This benefit seems to stem from a perceived reduction in social isolation and an increase in emotional support. Factors that determine the psychological benefit of emotional support animals include the type of pet, the number of pets, the attachment to the pet, and the perceived friendliness of the pet.⁴⁷

Animal-assisted therapy. A 2014 systematic review evaluated higher-level evidence behind animal-assisted therapy (AAT).⁴⁸ Although participating in therapy that involves interaction with animals is not the same as owning an emotional support animal, the concept—using an animal to improve mental health—is the same. The systematic review looked at 11 RCTs (N = 411) that studied the effect of AAT on mental health. Animals studied included dogs, cats, dolphins, birds, cows, rabbits, ferrets, and guinea pigs. Mental health disorders studied included schizophrenia, depression, anxiety, alcohol/drug abuse, and other addictive behaviors.

Acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.

Therapeutic animal exposure led to reported improvements in mood, quality of life, and social behavior. These improvements were attributed to the animals buffering people’s reactions to mental stressors. The animals provided a sense of comfort and safety and diverted attention away from immediate stressors. Furthermore, the memory of the animals brought participants a sense of comfort/happiness when they were later without the animal. However, the majority of participants were people who liked animals at baseline.⁴⁸

CORRESPONDENCE
Amanda E. Olagunju, DO, Operational Medicine Clinic, Langley AFB Hospital, 77 Nealy Avenue, Langley AFB, VA 23665; amanda.olagunju@gmail.com.

Almost 8% of Americans ages ≥ 12 years have depression and 19.1% of Americans ages ≥ 18 years have experienced an anxiety disorder in the past year.^1,2 Furthermore, suicide, which can result from depression and anxiety, is the 10th leading cause of death in the United States, claiming about 40,000 to 49,000 lives per year since 2012, with increasing yearly rates.³ While multiple conventional medication and therapy treatments are available, patients remain interested in complementary and alternative medicine (CAM) options. According to the National Center for Complementary and Integrative Health, more than 30% of American adults use CAM treatments.⁴

This article provides an overview of the evidence for commonly used CAM treatments for unipolar depression and anxiety in adults. It is designed to serve as a useful resource when patients are interested in looking beyond conventional medications.

St. John’s wort: ‘Yes’ for depression; ‘no’ for anxiety

Hypericum perforatum, more commonly known as St. John’s wort, is a widely used antidepressant, especially in Europe where it is prescribed, rather than offered over the counter as it is here. Its mechanism of action is not completely understood because its various constituents have different neuropharmacologic activities.^5,6

A 2008 Cochrane review evaluated 29 randomized, double-blind studies (N = 5489) that compared St. John’s wort with placebo or standard antidepressants in the treatment of depression.⁷ St. John’s wort was found to be superior to placebo and comparable to standard antidepressants. More recently, a 2017 meta-analysis of 27 studies (N = 3808) had similar findings.⁸ In patients with mild-to-moderate depression, St. John’s wart produced rates of remission that were comparable to those produced by selective serotonin reuptake inhibitors (SSRIs) but with a lower discontinuation rate.

Mood disorders other than depression. Studies do not support a role for St. John’s wort in the treatment of anxiety disorders. There are no trials that assess the efficacy of St. John’s wort for the reduction of symptoms of general anxiety disorder as a primary outcome of treatment. Some small clinical trials have investigated the efficacy of St. John’s wort in obsessive-compulsive disorder and social anxiety disorder. In those studies, St. John’s wort performed no better than placebo.^9,10

A few words of caution. Preparations of St. John’s wort in the United States are not standardized, so St. John’s wort should be used in America with caution. Furthermore, long-term use of St. John’s wort for depression is questionable given that most studies have evaluated only up to 12 weeks of use.⁸

In patients with mildto-moderate depression, St. John’s wort produced rates of remission that were comparable to those produced by SSRIs— with a lower discontinuation rate.

If used, studies indicate that the St. John’s wort extract that should be used is 0.3% hypericin or 5% hyperforin administered in a dosage of 300 to 400 mg tid.^7,8,11 Physicians and patients can use www.consumerlabs.com to find St. John’s wort brands that have met specified quality criteria based on independent laboratory studies. This Web site can also be used to investigate the quality of the brands available for the other supplements discussed in this article.

Continue to: Adverse effects

Adverse effects. St. John’s wort and an SSRI can lead to serotonin syndrome, which is a constellation of symptoms involving mental status changes and autonomic and neuromuscular hyperactivity caused by serotonin overactivity.¹² Furthermore, treatment failures with anticoagulants, digoxin, hormonal contraceptives, immunosuppressants, and narcotics due to concomitant use with St. John’s wort have been reported.¹³

The most common adverse reactions to St. John’s wort include gastrointestinal symptoms, dizziness, sedation, photosensitivity, dry mouth, urinary frequency, anorgasmia, and swelling.¹⁴ However, multiple studies have supported St. John’s wort to be equally or better tolerated than conventional antidepressants.^7,8

Certain forms of folate can be adjunctive treatment for depression

Methylfolate is the form of folate that crosses the blood–brain barrier. A prospective observational study evaluated the cerebral spinal fluid of 33 patients with refractory depression. The authors found metabolic abnormalities in the cerebrospinal fluid of most of those patients, the most common of which was folate deficiency in 12 patients despite normal serum folate levels.¹⁵

Additionally, current understanding of the role of the Methylenetetrahydrofolate reductase (MTHFR) gene and the folate cycle in depression supports a potential role of methylfolate in depression treatment.¹⁶ The MTHFR gene encodes for an enzyme called MTHFR. The MTHFR enzyme converts 5,10-MTHF to 5-MTHF, which then crosses the blood–brain barrier and donates a methyl group for the conversion of homocysteine to methionine. Methionine is a precursor to monoamine neurotransmitters. Thus, decreased expression of the MTHFR gene leads to decreased methylfolate levels, which, in turn, potentially leads to insufficient neurotransmitter synthesis and homocysteine excess.

MTHFR gene polymorphisms and increased homocysteine levels have been found to be associated with the occurrence of depression. One thought is that methylfolate supplementation compensates for an underlying MTHFR enzyme deficiency in patients with depression. Further studies are needed to determine if screening depressed patients for MTHFR gene polymorphisms is of benefit.¹⁶

Continue to: A 2012 randomized controlled trial...

A 2012 randomized controlled trial (RCT) (N = 75) compared L-methylfolate 15 mg/d plus an SSRI with placebo plus an SSRI in patients with SSRI-resistant major depression.¹⁷ The trial found that a reduction of baseline symptoms by ≥ 50% occurred in more patients who received adjunctive L-methylfolate than placebo (32% vs 15%) and tolerability was comparable. These findings were again supported in 2016 with a 12-month study showing L-methylfolate to have long-term tolerability comparable to placebo,¹⁸ and in 2017 with a randomized trial (N = 260) that found escitalopram 10 mg/d plus L-methylfolate 15 mg/d to be significantly more effective at treating depression than escitalopram 10 mg/d alone.¹⁹ Thus, methylfolate may be an effective adjunctive treatment for depression at a dosage of 15 mg/d.

S-adenosyl methionine (SAMe) is a metabolite of folate derived from methionine that facilitates the synthesis of neurotransmitters including dopamine, norepinephrine, and serotonin. In Europe, as is the case with St. John’s wort, it is a prescription medication.

A randomized trial (N = 73) compared adjunctive SAMe 800 mg bid with placebo in the treatment of patients with unipolar major depression who did not experience improvement with SSRI treatment alone.²⁰ The investigators found that more patients who received SAMe than who received placebo had improvement in their depression (36.1% vs 17.6%), and more patients who received SAMe compared to placebo went into depression remission (25.8% vs 11.7%).

Adverse effects were comparable in both groups. Thus, SAMe at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.^20,21 The findings of 1 study (N = 65) suggest that patients could experience further improvement in their depression symptoms with SAMe at doses of as much as 3200 mg/d; however, 3200 mg/d increased the occurrence of gastrointestinal adverse effects (31.3% in the SAMe arm vs 3.8% in the placebo group).²¹

Folate. With regard to folate itself, randomized trials have not supported its efficacy in the treatment of depression in the general population.²²

Continue to: VItamin D may improve anxiety/depression in those with low levels

Vitamin D may improve anxiety/depression in those with low levels

Vitamin D supplementation is also being used more frequently in the treatment of depression. Case-control, cross-sectional, and cohort studies have linked low vitamin D levels to the occurrence of depression. A 2013 systematic review of 14 such studies (N = 31,424) found lower vitamin D levels in people with depression compared with controls.²³ Further studies are needed to determine if this relationship is causal, and quality RCTs investigating the effect of vitamin D supplementation on depression are lacking.

S-adenosyl methionine (SAMe) at a dosage of 400 to 1600 mg/d may be effective in the treatment of depression.

A 2019 study (N = 30) evaluated the ­impact of vitamin D supplementation on generalized anxiety disorder in patients with co-occurring vitamin D deficiency. Half received standard-of-care general anxiety disorder treatment plus 50,000 IU of vitamin D weekly for 3 months, while the other half received standard of care alone. Significant improvements in anxiety scores, increases in serum serotonin, and decreases in serum neopterin (an inflammatory marker) were observed in the vitamin D–treated group compared to the group that did not receive vitamin D.²⁴

It is not currently standard of care to check vitamin D levels in all patients presenting with mood disorders. However, if screening is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/or depressive symptoms. Despite this, no evidence exists to support vitamin D supplementation for depression or anxiety in patients with normal vitamin D levels.^24,25

The effects of omega-3 fatty acids are largely unclear

Research has shown that omega-3 polyunsaturated fatty acids (n-3 PUFA), which are found in fish oil, protect glutamatergic neurotransmission from glucocorticoids, which are released in the body during a stress response.²⁶ Small clinical trials have found n-3 PUFAs to reduce the symptoms of anxiety compared with placebo, but the acids have not been studied directly for anxiety disorders.^27,28

With regard to depression, evidence is conflicting as to whether n-3 PUFAs are of any benefit in treatment.²⁹ Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are hypothesized to be the components in omega-3 fatty acid preparations that could lead to a reduction in depressive symptoms. However, randomized trials have shown that EPA-predominant omega-3 fatty acid formulations have only a moderate or no clinically significant effect on depression over placebo, and that DHA-predominant omega-3 fatty acid formulations are only comparable or inferior to placebo.³⁰

Continue to: Response to EPA...

Response to EPA may be greater in patients with depression who have high levels of inflammatory biomarkers, such as interleuken (IL)-1 receptor antagonist (1Ra), IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin, and adiponectin, than in patients with low levels. An 8-week trial randomly assigned patients with unipolar major depression (N = 155) to receive either EPA, DHA, or placebo and found that improvement for the 3 groups was comparable; however, in the subgroup of patients with high levels of inflammatory markers, improvement in depressive symptoms was significantly greater with EPA than with either DHA or placebo.³¹

If screening for vitamin D levels is indicated for another reason and low levels are confirmed, vitamin D replacement may improve anxiety and/ or depression symptoms.

It is unclear whether different sources of n-3 PUFA, such as whole fish vs fish oil vs prescription omega-3 acid ethyl esters (Lovaza), are more or less efficacious in the treatment of anxiety or depression. Furthermore, there is no standard dosing for n-3 PUFA in the treatment of mood disorders. Given that the US Food and Drug Administration recommends no more than 2 g/d of combined EPA and DHA supplementation, we recommend using 2 g/d if one decides to treat depression/anxiety with n-3 PUFA.³²

N-3 PUFA supplementation is fairly benign. There have been previous concerns about n-3 PUFA supplementation increasing patients’ risk for gastrointestinal bleeding, but a 2006 systematic review that included 9 trials (N = 2612) that looked at clinically significant bleeding episodes found that even patients at high risk for bleeding (ie, those taking aspirin or warfarin) had no increased bleeding risk from taking n-3 PUFA supplementation at up to 4 g/d.³³

Don’t underestimate exercise and meditation; consider acupuncture

Exercise. Multiple practice guidelines, including the American Psychiatric Association’s “Practice Guideline for the Treatment of Patients with Major Depressive Disorder,” and meta-analyses have supported the use of exercise to treat unipolar major depression and anxiety.^34-37 However, only about 26% of American men and 19% of American women met the US Department of Health and Human Services’ “Federal Physical Activity Guidelines for Americans” in 2016.³⁸

Exercise alone is a reasonable monotherapy, as long as patients are monitored closely for worsening symptoms. Additionally, exercise as an add-on treatment can be helpful for more severe depression or anxiety.³⁹ The best type, duration, and frequency of exercise specifically for the treatment of depression or anxiety has yet to be determined, but physicians may base their exercise recommendations on the “Federal Physical Activity Guidelines for Americans” for general good health (TABLE).³⁸

Continue to: Meditation

Meditation, especially mindfulness meditation, is another strategy that has gained popularity in the treatment of anxiety and depression. Mindfulness has been defined as “the practice of maintaining a nonjudgmental state of heightened or complete awareness of one’s thoughts, emotions, or experiences on a moment-to-moment basis.”⁴⁰ A 2014 systematic review and meta-analysis of 47 trials with 3515 participants found that mindfulness meditation programs led to clinically significant moderate reductions in anxiety.⁴¹ Smaller effects were found for depression.

Nevertheless, meditation may be beneficial as an adjunctive treatment for depression. A small randomized trial (N = 25) compared an adjunctive breathing-based meditation intervention with a waitlist control (delayed yoga) in patients with unipolar major depression who failed to respond to at least 8 weeks of antidepressant treatment.⁴² The meditation intervention consisted of a group program with sitting meditation, breathing exercises, and yoga postures. Participants engaged in the meditation intervention for 2 to 3.5 hours per day for 8 weeks and demonstrated significant improvement in depression symptoms compared with the control group.⁴²

Acupuncture. A 2018 meta-analysis of 64 studies (N = 7104) suggests that acupuncture results in a small-to-moderate reduction in depressive symptoms when compared to no treatment, control/sham acupuncture, or medication.⁴³ Furthermore, acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.⁴³

Additionally, a 2019 analysis of 10 systematic reviews found acupuncture to be more effective than control/sham acupuncture in the treatment of general anxiety.⁴⁴ It should be noted, however, that a lot of heterogeneity and potential for bias existed across all of the studies. The studies analyzed were very low to low in quality. Thus, the evidence is insufficient to strongly recommend the use of acupuncture for depression or anxiety, although acupuncture is a safe intervention with low rates of adverse events.

Emotional support animals: Beneficial, but evidence is weak

Emotional support animals are gaining in popularity with Americans who have mood disorders. An important distinction must be made, however, between service animals and emotional support animals. A service animal is one “that is individually trained to do work or perform tasks for the benefit of an individual with a disability, including a physical, sensory, psychiatric, intellectual, or other mental disability.”⁴⁵ Under the Americans with Disabilities Act (ADA), service animals are limited to dogs, and, in some cases, specially trained miniature horses. Psychiatric service dogs can be trained to do anything from reminding their owner to take medicine to stopping self-mutilation activities.

Continue to: Emotional support animals...

Emotional support animals are not specially trained to perform tasks to help with disabilities. It’s their companionship that helps relieve symptoms of depression and/or anxiety.⁴⁵ Thus, emotional support animals are not covered under federal laws that apply to service animals. However, the Air Carrier Access Act does require airlines to allow emotional support animals to fly in the cabin for free. Furthermore, the Fair Housing Act allows emotional support animals to circumvent no-pet rules in housing and dorms. Airplanes and housing are the only places legally required to allow the unrestricted presence of emotional support animals.⁴⁶

Also, there are important distinctions between emotional support animals and pets. While anyone can own a pet, an emotional support animal is prescribed by a licensed mental health professional as a treatment for a mood disorder. Housing facilities and airlines will usually require an emotional support animal “prescription” or letter from a physician to recognize animals as such.

Exercise alone is a reasonable monotherapy for depression or anxiety as long as patients are monitored closely for worsening symptoms.

A 2018 systematic review evaluated the evidence behind emotional support animals, which included 17 peer-reviewed journal articles, conference papers, and research dissertations (N = 1727) mostly containing qualitative evidence.⁴⁷ Unfortunately, there are no RCTs, and there are limited case-control and cohort studies evaluating the effect of an emotional support animal on mood disorders. Based on the available evidence, there does seem to be a psychological benefit to owning an animal for both those with a diagnosable mental health disorder and the general population. This benefit seems to stem from a perceived reduction in social isolation and an increase in emotional support. Factors that determine the psychological benefit of emotional support animals include the type of pet, the number of pets, the attachment to the pet, and the perceived friendliness of the pet.⁴⁷

Animal-assisted therapy. A 2014 systematic review evaluated higher-level evidence behind animal-assisted therapy (AAT).⁴⁸ Although participating in therapy that involves interaction with animals is not the same as owning an emotional support animal, the concept—using an animal to improve mental health—is the same. The systematic review looked at 11 RCTs (N = 411) that studied the effect of AAT on mental health. Animals studied included dogs, cats, dolphins, birds, cows, rabbits, ferrets, and guinea pigs. Mental health disorders studied included schizophrenia, depression, anxiety, alcohol/drug abuse, and other addictive behaviors.

Acupuncture plus medication compared to medication alone results in a higher reduction in depressive symptoms without an increase in adverse events.

Therapeutic animal exposure led to reported improvements in mood, quality of life, and social behavior. These improvements were attributed to the animals buffering people’s reactions to mental stressors. The animals provided a sense of comfort and safety and diverted attention away from immediate stressors. Furthermore, the memory of the animals brought participants a sense of comfort/happiness when they were later without the animal. However, the majority of participants were people who liked animals at baseline.⁴⁸

CORRESPONDENCE
Amanda E. Olagunju, DO, Operational Medicine Clinic, Langley AFB Hospital, 77 Nealy Avenue, Langley AFB, VA 23665; amanda.olagunju@gmail.com.

Treatment with oral tafamidis at 80 mg/day provided a significantly greater survival benefit than dosing at 20 mg/day in patients with transthyretin amyloid cardiomyopathy in the long-term extension of the landmark ATTR-ACT trial, Thibaud Damy, MD, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Moreover, the superior survival benefit achieved by taking four 20-mg capsules of tafamidis (Vyndaqel) once daily – or its more convenient once-daily, single-capsule, 61-mg bioequivalent formulation marketed as Vyndamax – came at no cost in terms of side effects and toxicity, compared with low-dose therapy for this progressive multisystem disease, according to Dr. Damy, professor of cardiology at the University of Paris and head of the French National Referral Center for Cardiac Amyloidosis at Henri Mondor University Hospital, Créteil, France.

“There are no side effects with tafamidis,” he said. “It doesn’t act on any receptors, it just acts on the formation of amyloid fibrils, so there are no side effects at whatever dosage is used. And in ATTR-ACT there was actually a trend towards increased side effects in the placebo group because the amyloidosis is everywhere, so by decreasing the amyloidosis process you improve not only the heart but all the organs, and the patient has a better quality of life.”

ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) was a phase 3, double-blind study in which 441 patients with transthyretin amyloidosis cardiomyopathy (TAC) in 13 countries were randomized to tafamidis at either 80 mg or 20 mg per day or placebo and followed prospectively for 30 months. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a statistically significant and clinically important 30% relative risk reduction, establishing tafamidis as the first disease-modifying therapy for this disease (N Engl J Med. 2018 Sep 13;379[11]:1007-16).

Patients in the 80-mg group had a 20% reduction in the risk of death, compared with the 20-mg group, at 30 months in an analysis adjusted for baseline age, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, all of which are known to impact survival in TAC. This between-group survival difference wasn’t statistically significant, providing one impetus for the subsequent long-term extension study, in which patients remained on their original dose of tafamidis, and the controls who’d been on placebo for 30 months were randomized 2:1 to tafamidis at 80 mg or 20 mg per day.

The primary endpoint in the long-term extension was a composite of all-cause mortality, heart transplantation, or implantation of a ventricular assist device. At a median follow-up of 39 months since ATTR-ACT began, the high-dose tafamidis group had an adjusted 33% reduction in the risk of this endpoint, compared with patients on 20 mg per day, a difference that barely missed statistical significance. At that point, everyone in the long-term extension was switched to the once-daily 61-mg formulation of tafamidis free acid, which is bioequivalent to four 20-mg capsules of tafamidis.

Dr. Damy’s key message: At a median of 51 months of follow-up, the group originally on 80 mg of tafamidis displayed a highly significant adjusted 43% reduction in risk of the composite endpoint, compared with those who had been on 20 mg per day.

Session chair Petar M. Seferovic, MD, PhD, pronounced the ATTR-ACT trial and its long-term extension “a breakthrough advancement.”

“This is the first time in human medical history that we have a drug which improves the long-term outcome, including survival, in patients with this form of hypertrophic cardiomyopathy. So this is extremely important. It’s one of the major steps forward in the treatment of patients with myocardial disease,” said Dr. Seferovic, president of the European Society of Cardiology Heart Failure Association and professor of internal medicine at the University of Belgrade, Serbia.

Discussant Loreena Hill, PhD, of Queen’s University in Belfast, Northern Ireland, observed that TAC is a devastating disease with a formidable symptom burden and an average survival of just 2-5 years after diagnosis.

“It is often underdiagnosed, and yet it is estimated to account for up to 13% of patients with heart failure and preserved ejection fraction,” she said, adding that she considers the long-term extension results “extremely positive.”
 

Nailing down the prevalence of hereditary TAC: the DISCOVERY study

TAC occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium and elsewhere. In the heart, the result is progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive nonischemic heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild-type protein.

Dr. Damy was a coinvestigator in the recently published multicenter DISCOVERY study, in which 1,001 patients with clinically suspected cardiac amyloidosis, the great majority of them from the United States, were screened for pathogenic transthyretin genetic mutations. The overall prevalence of such mutations was 8% in the American patients, with the Val122Ile mutation being identified in 11% of African Americans (Amyloid. 2020 May 26;1-8).

The prevalence of wild-type amyloidosis causing TAC hasn’t yet been studied with anything approaching the rigor of DISCOVERY, but the available evidence suggests the wild-type version is roughly as common as the hereditary forms.

Although DISCOVERY and other studies indicate that TAC is far more common than generally realized, Pfizer has priced Vyndaqel and Vyndamax as though TAC is a rare disease, with a U.S. list price of around $225,000 per year.

“Obviously, the cost will go down over time,” Dr. Seferovic predicted.
 

Diagnosing TAC

Audience members mostly wanted to know how to identify individuals with TAC who are buried within the huge population of patients with heart failure with preserved ejection fraction. Dr. Damy said it’s actually a simple matter using a screening framework developed by an 11-member TAC expert panel on which he served. A definitive diagnosis can usually be achieved noninvasively at a low cost using bone scintigraphy, he added.

The panel recommended screening via bone scintigraphy in patients with an increased left ventricular wall thickness of 14 mm or more in men over age 65 and women older than 70 who either have heart failure or red flag symptoms.

These red flags for TAC include an echocardiographic finding of reduced longitudinal strain with relative apical sparing, a discrepancy between left ventricular wall thickness on imaging and normal or low-normal voltages on a standard 12-lead ECG, diffuse gadolinium enhancement or marked extracellular volume expansion on cardiac magnetic resonance imaging, a history of bilateral carpal tunnel syndrome, symptoms of polyneuropathy, and mildly increased serum troponin levels on multiple occasions (JACC Heart Fail. 2019 Aug;7[8]:709-16).

Dr. Damy reported receiving institutional research grant support from Pfizer, the study sponsor, and serving on a scientific advisory board for the company.

bjancin@mdedge.com

Treatment with oral tafamidis at 80 mg/day provided a significantly greater survival benefit than dosing at 20 mg/day in patients with transthyretin amyloid cardiomyopathy in the long-term extension of the landmark ATTR-ACT trial, Thibaud Damy, MD, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Moreover, the superior survival benefit achieved by taking four 20-mg capsules of tafamidis (Vyndaqel) once daily – or its more convenient once-daily, single-capsule, 61-mg bioequivalent formulation marketed as Vyndamax – came at no cost in terms of side effects and toxicity, compared with low-dose therapy for this progressive multisystem disease, according to Dr. Damy, professor of cardiology at the University of Paris and head of the French National Referral Center for Cardiac Amyloidosis at Henri Mondor University Hospital, Créteil, France.

“There are no side effects with tafamidis,” he said. “It doesn’t act on any receptors, it just acts on the formation of amyloid fibrils, so there are no side effects at whatever dosage is used. And in ATTR-ACT there was actually a trend towards increased side effects in the placebo group because the amyloidosis is everywhere, so by decreasing the amyloidosis process you improve not only the heart but all the organs, and the patient has a better quality of life.”

ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) was a phase 3, double-blind study in which 441 patients with transthyretin amyloidosis cardiomyopathy (TAC) in 13 countries were randomized to tafamidis at either 80 mg or 20 mg per day or placebo and followed prospectively for 30 months. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a statistically significant and clinically important 30% relative risk reduction, establishing tafamidis as the first disease-modifying therapy for this disease (N Engl J Med. 2018 Sep 13;379[11]:1007-16).

Patients in the 80-mg group had a 20% reduction in the risk of death, compared with the 20-mg group, at 30 months in an analysis adjusted for baseline age, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, all of which are known to impact survival in TAC. This between-group survival difference wasn’t statistically significant, providing one impetus for the subsequent long-term extension study, in which patients remained on their original dose of tafamidis, and the controls who’d been on placebo for 30 months were randomized 2:1 to tafamidis at 80 mg or 20 mg per day.

The primary endpoint in the long-term extension was a composite of all-cause mortality, heart transplantation, or implantation of a ventricular assist device. At a median follow-up of 39 months since ATTR-ACT began, the high-dose tafamidis group had an adjusted 33% reduction in the risk of this endpoint, compared with patients on 20 mg per day, a difference that barely missed statistical significance. At that point, everyone in the long-term extension was switched to the once-daily 61-mg formulation of tafamidis free acid, which is bioequivalent to four 20-mg capsules of tafamidis.

Dr. Damy’s key message: At a median of 51 months of follow-up, the group originally on 80 mg of tafamidis displayed a highly significant adjusted 43% reduction in risk of the composite endpoint, compared with those who had been on 20 mg per day.

Session chair Petar M. Seferovic, MD, PhD, pronounced the ATTR-ACT trial and its long-term extension “a breakthrough advancement.”

“This is the first time in human medical history that we have a drug which improves the long-term outcome, including survival, in patients with this form of hypertrophic cardiomyopathy. So this is extremely important. It’s one of the major steps forward in the treatment of patients with myocardial disease,” said Dr. Seferovic, president of the European Society of Cardiology Heart Failure Association and professor of internal medicine at the University of Belgrade, Serbia.

Discussant Loreena Hill, PhD, of Queen’s University in Belfast, Northern Ireland, observed that TAC is a devastating disease with a formidable symptom burden and an average survival of just 2-5 years after diagnosis.

“It is often underdiagnosed, and yet it is estimated to account for up to 13% of patients with heart failure and preserved ejection fraction,” she said, adding that she considers the long-term extension results “extremely positive.”
 

Nailing down the prevalence of hereditary TAC: the DISCOVERY study

TAC occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium and elsewhere. In the heart, the result is progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive nonischemic heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild-type protein.

Dr. Damy was a coinvestigator in the recently published multicenter DISCOVERY study, in which 1,001 patients with clinically suspected cardiac amyloidosis, the great majority of them from the United States, were screened for pathogenic transthyretin genetic mutations. The overall prevalence of such mutations was 8% in the American patients, with the Val122Ile mutation being identified in 11% of African Americans (Amyloid. 2020 May 26;1-8).

The prevalence of wild-type amyloidosis causing TAC hasn’t yet been studied with anything approaching the rigor of DISCOVERY, but the available evidence suggests the wild-type version is roughly as common as the hereditary forms.

Although DISCOVERY and other studies indicate that TAC is far more common than generally realized, Pfizer has priced Vyndaqel and Vyndamax as though TAC is a rare disease, with a U.S. list price of around $225,000 per year.

“Obviously, the cost will go down over time,” Dr. Seferovic predicted.
 

Diagnosing TAC

Audience members mostly wanted to know how to identify individuals with TAC who are buried within the huge population of patients with heart failure with preserved ejection fraction. Dr. Damy said it’s actually a simple matter using a screening framework developed by an 11-member TAC expert panel on which he served. A definitive diagnosis can usually be achieved noninvasively at a low cost using bone scintigraphy, he added.

The panel recommended screening via bone scintigraphy in patients with an increased left ventricular wall thickness of 14 mm or more in men over age 65 and women older than 70 who either have heart failure or red flag symptoms.

These red flags for TAC include an echocardiographic finding of reduced longitudinal strain with relative apical sparing, a discrepancy between left ventricular wall thickness on imaging and normal or low-normal voltages on a standard 12-lead ECG, diffuse gadolinium enhancement or marked extracellular volume expansion on cardiac magnetic resonance imaging, a history of bilateral carpal tunnel syndrome, symptoms of polyneuropathy, and mildly increased serum troponin levels on multiple occasions (JACC Heart Fail. 2019 Aug;7[8]:709-16).

Dr. Damy reported receiving institutional research grant support from Pfizer, the study sponsor, and serving on a scientific advisory board for the company.

bjancin@mdedge.com

Treatment with oral tafamidis at 80 mg/day provided a significantly greater survival benefit than dosing at 20 mg/day in patients with transthyretin amyloid cardiomyopathy in the long-term extension of the landmark ATTR-ACT trial, Thibaud Damy, MD, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Moreover, the superior survival benefit achieved by taking four 20-mg capsules of tafamidis (Vyndaqel) once daily – or its more convenient once-daily, single-capsule, 61-mg bioequivalent formulation marketed as Vyndamax – came at no cost in terms of side effects and toxicity, compared with low-dose therapy for this progressive multisystem disease, according to Dr. Damy, professor of cardiology at the University of Paris and head of the French National Referral Center for Cardiac Amyloidosis at Henri Mondor University Hospital, Créteil, France.

“There are no side effects with tafamidis,” he said. “It doesn’t act on any receptors, it just acts on the formation of amyloid fibrils, so there are no side effects at whatever dosage is used. And in ATTR-ACT there was actually a trend towards increased side effects in the placebo group because the amyloidosis is everywhere, so by decreasing the amyloidosis process you improve not only the heart but all the organs, and the patient has a better quality of life.”

ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) was a phase 3, double-blind study in which 441 patients with transthyretin amyloidosis cardiomyopathy (TAC) in 13 countries were randomized to tafamidis at either 80 mg or 20 mg per day or placebo and followed prospectively for 30 months. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a statistically significant and clinically important 30% relative risk reduction, establishing tafamidis as the first disease-modifying therapy for this disease (N Engl J Med. 2018 Sep 13;379[11]:1007-16).

Patients in the 80-mg group had a 20% reduction in the risk of death, compared with the 20-mg group, at 30 months in an analysis adjusted for baseline age, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, all of which are known to impact survival in TAC. This between-group survival difference wasn’t statistically significant, providing one impetus for the subsequent long-term extension study, in which patients remained on their original dose of tafamidis, and the controls who’d been on placebo for 30 months were randomized 2:1 to tafamidis at 80 mg or 20 mg per day.

The primary endpoint in the long-term extension was a composite of all-cause mortality, heart transplantation, or implantation of a ventricular assist device. At a median follow-up of 39 months since ATTR-ACT began, the high-dose tafamidis group had an adjusted 33% reduction in the risk of this endpoint, compared with patients on 20 mg per day, a difference that barely missed statistical significance. At that point, everyone in the long-term extension was switched to the once-daily 61-mg formulation of tafamidis free acid, which is bioequivalent to four 20-mg capsules of tafamidis.

Dr. Damy’s key message: At a median of 51 months of follow-up, the group originally on 80 mg of tafamidis displayed a highly significant adjusted 43% reduction in risk of the composite endpoint, compared with those who had been on 20 mg per day.

Session chair Petar M. Seferovic, MD, PhD, pronounced the ATTR-ACT trial and its long-term extension “a breakthrough advancement.”

“This is the first time in human medical history that we have a drug which improves the long-term outcome, including survival, in patients with this form of hypertrophic cardiomyopathy. So this is extremely important. It’s one of the major steps forward in the treatment of patients with myocardial disease,” said Dr. Seferovic, president of the European Society of Cardiology Heart Failure Association and professor of internal medicine at the University of Belgrade, Serbia.

Discussant Loreena Hill, PhD, of Queen’s University in Belfast, Northern Ireland, observed that TAC is a devastating disease with a formidable symptom burden and an average survival of just 2-5 years after diagnosis.

“It is often underdiagnosed, and yet it is estimated to account for up to 13% of patients with heart failure and preserved ejection fraction,” she said, adding that she considers the long-term extension results “extremely positive.”
 

Nailing down the prevalence of hereditary TAC: the DISCOVERY study

TAC occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium and elsewhere. In the heart, the result is progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive nonischemic heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild-type protein.

Dr. Damy was a coinvestigator in the recently published multicenter DISCOVERY study, in which 1,001 patients with clinically suspected cardiac amyloidosis, the great majority of them from the United States, were screened for pathogenic transthyretin genetic mutations. The overall prevalence of such mutations was 8% in the American patients, with the Val122Ile mutation being identified in 11% of African Americans (Amyloid. 2020 May 26;1-8).

The prevalence of wild-type amyloidosis causing TAC hasn’t yet been studied with anything approaching the rigor of DISCOVERY, but the available evidence suggests the wild-type version is roughly as common as the hereditary forms.

Although DISCOVERY and other studies indicate that TAC is far more common than generally realized, Pfizer has priced Vyndaqel and Vyndamax as though TAC is a rare disease, with a U.S. list price of around $225,000 per year.

“Obviously, the cost will go down over time,” Dr. Seferovic predicted.
 

Diagnosing TAC

Audience members mostly wanted to know how to identify individuals with TAC who are buried within the huge population of patients with heart failure with preserved ejection fraction. Dr. Damy said it’s actually a simple matter using a screening framework developed by an 11-member TAC expert panel on which he served. A definitive diagnosis can usually be achieved noninvasively at a low cost using bone scintigraphy, he added.

The panel recommended screening via bone scintigraphy in patients with an increased left ventricular wall thickness of 14 mm or more in men over age 65 and women older than 70 who either have heart failure or red flag symptoms.

These red flags for TAC include an echocardiographic finding of reduced longitudinal strain with relative apical sparing, a discrepancy between left ventricular wall thickness on imaging and normal or low-normal voltages on a standard 12-lead ECG, diffuse gadolinium enhancement or marked extracellular volume expansion on cardiac magnetic resonance imaging, a history of bilateral carpal tunnel syndrome, symptoms of polyneuropathy, and mildly increased serum troponin levels on multiple occasions (JACC Heart Fail. 2019 Aug;7[8]:709-16).

Dr. Damy reported receiving institutional research grant support from Pfizer, the study sponsor, and serving on a scientific advisory board for the company.

bjancin@mdedge.com

Foot and ankle injuries are among the most common conditions evaluated at primary care visits; the differential diagnosis of such injury is broad.¹ Although many of these injuries are easily identified on imaging studies, a number of subtle, yet important, conditions can be easily missed, especially if you do not routinely encounter them. Given that broad differential, a high degree of suspicion is required to make an accurate diagnosis, which allows appropriate treatment within a reasonable time frame and minimizes the risk of long-term morbidity.

This article outlines the diagnosis and initial management of 5 important, yet often elusive, types of foot and ankle conditions: Achilles tendon rupture, injury to the syndesmosis, ankle fracture, Lisfranc injury, and proximal fracture of the fifth metatarsal.

© Ken Jacobsen

Achilles tendon rupture

The Achilles tendon is the most frequently ruptured tendon in the body (approximately 20% of all large-tendon injuries)²; as many as 25% of cases are initially misdiagnosed.³

Presentation. Patients frequently present with pain at the Achilles tendon—2 to 6 cm above the insertion into the calcaneus—and an inability to fully bear weight.^4,5 A small percentage of patients are able to ambulate on the affected side, albeit with minor pain, which likely contributes to the rate of missed diagnosis. Absence of difficulty bearing weight is due to the presence of secondary plantar flexors, which can compensate for loss of chief plantar flexor function by the Achilles tendon.²

Although many of these injuries are easily identified on imaging studies, a number of subtle conditions can be easily missed, especially if you do not routinely encounter them.

Examination of a patient with an Achilles tendon rupture typically reveals edema, bruising, and a palpable gap within the tendon, 2 to 6 cm proximal to insertion.^3,4 The Thompson test—squeezing the calf with the patient prone and the knee on the affected side flexed—can aid in diagnosis. When the Achilles tendon is intact, plantar flexion occurs at the ankle; when the tendon is ruptured, plantar flexion is absent.⁵ The test can be modified when examining a patient who is unable to lie prone by having them rest the flexed knee on a chair while standing on the unaffected leg.

A diagnosis of Achilles tendon rupture is supported when at least 2 of the following conditions are met^4,5:

• positive Thompson test
• decreased strength during plantar flexion of the ankle
• palpable gap or pain at the typical location (2-6 cm above insertion)
• increased passive ankle dorsiflexion upon gentle ranging of the ankle joint.

Imaging has a limited role in the diagnosis of Achilles tendon rupture; because the findings of the physical examination are reliable, reserve x-rays for cases in which the diagnosis remains uncertain after examination.² Consider ordering plain x-rays to rule out an avulsion fracture at the insertion of the Achilles tendon; ultrasonography or magnetic resonance imaging (MRI) might assist you in detecting the rupture proper, along with the location of the tear for surgical planning, if surgery is deemed necessary by an orthopedic surgeon.^3-5

Continue to: Management

Management. Some degree of controversy surrounds preferred treatment of Achilles tendon rupture, although available evidence demonstrates that these injuries can be effectively managed by surgical repair or nonoperative treatment, as outcomes are comparable.^3,5 Operative management tends to reduce the risk of repeat rupture, compared to nonoperative treatment; however, the potential for surgical complications, including wound infection, sensory disturbance, and adhesions favors nonoperative treatment.^3,4,6

Nonoperative treatment consists of referral to a functional rehabilitation program, without which outcomes are, on the whole, less favorable than with surgery.^3,6 Surgery is preferred if functional rehabilitation is unavailable, 6 months of conservative management fails, or there is avulsion injury.^3,4,6

Injury to the syndesmosis

A complex of ligaments that provide dynamic stability to the ankle joint, the tibiofibular syndesmosis comprises:

• the anterior inferior tibiofibular ligament
• the posterior inferior tibiofibular ligament
• the inferior transverse tibiofibular ligament
• the interosseous membrane.

These structures are further supported by the deltoid ligament.^7,8

Some patients with Achilles tendon rupture can walk on the affected side, even with minor pain; the diagnosis might be missed without further in-depth evaluation.

Commonly referred to as a “high ankle sprain,” a syndesmotic injury is present in as many as 20% of ankle fractures and 5% to 10% of ankle sprains. Injury typically results from external rotation with hyperdorsiflexion of the ankle. Recovery is typically prolonged (ie, twice as long as recovery from a lateral ankle sprain). The diagnosis is missed in as many as 20% of patients; failure to recognize and treat syndesmotic instability appropriately can lead to posttraumatic arthritis.^7,9

Continue to: Presentation

Presentation. Patients generally present with ankle pain, swelling, instability, pain when walking on uneven terrain, and pain upon push-off.⁹

Examination reveals reduced passive ankle dorsiflexion and tenderness upon palpation of individual ligaments. Several clinical tests have been described to aid in detecting this often-elusive diagnosis^7,9,10,11:

• Squeeze test. The patient sits with the knee on the affected side bent at a 90° degree angle while the examiner applies compression, with one or both hands, to the tibia and fibula at midcalf. The test is positive when pain is elicited at the level of the syndesmosis just above the ankle joint.^9,11
• External rotation test. External rotation of the foot and ankle relative to the tibia reproduces pain.
• Crossed leg test. The affected ankle is crossed over the opposite knee in a figure-4 position. The test is positive when pain is elicited at the syndesmosis.¹⁰
• Cotton test. The proximal lower leg is steadied with 1 hand and the plantar heel grasped with the other hand. Pain when the heel is externally rotated (and radiographic widening of the syndesmosis under fluoroscopy) signal syndesmotic instability.
• Fibular translation test. When anterior or posterior drawer force is applied to the fibula, pain and increased translation of the fibula (compared to the contralateral side) suggest instability.

With the Cotton and fibular translation tests, interexaminer technique is more variable and findings are less reproducible.⁸ Taken alone, none of the above-listed tests are diagnostic; they can, however, assist in making a diagnosis of an injury to the syndesmosis.¹¹

Imaging typically involves anteroposterior [AP], lateral, and mortise plain films of the ankle and weight-bearing AP and lateral views of the tibia and fibula.⁹ Important measures on weight-bearing AP x-rays are the tibiofibular clear space (abnormal, > 6 mm) and the tibiofibular overlap (abnormal, < 6 mm) (both abnormalities shown in FIGURE 1). Comparing films of the affected ankle with views of the contralateral ankle is often useful.

Management of syndesmotic injuries depends on degree of disruption:

• Grade 1 injury is a sprain without diastasis on imaging. Management is conservative, with immobilization in a splint or boot for 1 to 3 weeks, followed by functional rehabilitation over 3 to 6 weeks.¹⁰
• Grade 2 injury is demonstrated by ­diastasis on a stress radiograph. Although evidence to guide successful identification of a grade 2 injury is lacking, it is clinically important to make that identification because these injuries might require surgical intervention, due to instability. Because the diagnosis of this injury can be challenging in primary care, high clinical suspicion of a grade 2 injury makes it appropriate to defer further evaluation to an orthopedic surgeon. On the other hand, if suspicion of a grade 2 injury is low, a trial of conservative management, with weekly clinical assessment, can be considered. A diagnosis of grade 2 injury can be inferred when a patient is unable to perform a single-leg hop after 3 weeks of immobilization; referral to an orthopedic surgeon is then indicated.¹²
• Grade 3 injury is frank separation at the distal tibiofibular joint that is detectable on a routine plain film. Management—surgical intervention to address instability—is often provided concurrently with the treatment for a Danis-Weber B or C fracture, which tends to coexist with grade 3 syndesmotic injury. (The Danis-Weber A–B–C classification of lateral ankle fracture will be discussed in a bit.)

Continue to: Ankle fracture

Ankle fracture

Fracture of the ankle joint is among the more common fractures in adults, comprising 10% of all fractures.^13,14 The ankle joint is defined as the junction of 3 bony structures: (1) the distal ends of the tibia and fibula and (2) the trochlea of the talus, all stabilized by (3) the collateral ligament complex. Appropriate diagnosis and timely intervention are needed to prevent long-term posttraumatic joint degeneration.

Presentation, examination, and imaging. In addition to difficulty bearing (or inability to bear) weight, patients with suspected ankle fracture can present with tenderness or pain, swelling (generally, the more severe the injury, the more severe the swelling, although this finding is time-dependent), and ecchymosis. However, distinguishing fracture from a ligamentous injury is often difficult by physical examination alone; the evidence-based Ottawa Ankle Rules can guide determination of the need for radiographic imaging, although this tool is less reliable in certain patient populations (TABLE^15-17).^13,15-17

Management. A widely used classification system for guiding ankle fracture management is the Danis-Weber classification (FIGURE 2). In this scheme, type A fractures (distal to the level of the tibial plafond) are managed with ankle stabilization bracing without immobilization. Nondisplaced type B and C fractures (at the level of the tibial plafond and proximal to it, respectively) should be treated with 6 weeks of immobilization in a walking boot; close follow-up within 1 week of injury is recommended to ensure that no displacement of fragments has occurred. Type B and C fractures need to be followed until bony union is achieved. If there is radiologic evidence of a fracture line after 3 months, referral to an orthopedic surgeon is indicated for management of delayed union.

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Common indications for referral to Orthopedics for surgical intervention of ankle fracture include open fracture, bimalleolar and trimalleolar fracture, posterior malleolar fracture, medial malleolar displacement > 2 mm, and lateral malleolar displacement > 3 mm.¹⁸

Special concern: Talar fracture. Although talar fracture is rare, the injury is important to detect because a limited blood supply places fragments at risk of avascular necrosis.¹⁹ Talus fracture is frequently confused with ankle sprain because initial x-rays are not always revelatory.²⁰ A high index of suspicion is required to make the diagnosis, which should be suspected in high-energy injuries that result in pain and swelling of the ankle accompanied by difficulty weight-bearing, severely reduced range of motion, and tenderness to palpation at different areas of the talus.¹ Computed tomography (CT) or MRI might be necessary to detect a talar fracture if initial x-rays are negative. A low threshold for surgical management of talar fracture means that referral to Orthopedics is indicated once this injury is diagnosed.²¹

Continue to: Other frequently missed types of ankle fracture

Other frequently missed types of ankle fracture are shown in FIGURE 3.²² These are relatively uncommon injuries that can be missed for a number of reasons, alone or in combination, including their subtlety on radiography, their often vague clinical presentation, and providers’ lack of awareness of these types. Identification or strong suspicion of fracture at any of these sites (ie, in a patient who is persistently unable to bear weight) should prompt orthopedic referral.

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Lisfranc injury

The tarsometatarsal joint comprises 3 cuneiforms, the cuboid, and 5 metatarsals. Stability is maintained by an intricate ligamentous complex. Lisfranc injury comprises a spectrum of midfoot injuries in which 1 or more metatarsals are displaced from the tarsus. These injuries are both rare and notoriously difficult to diagnose: As many as 20% of cases are missed on initial assessment. Without proper treatment, long-term disability and deformity, such as pes planus, can result.^22-24 Lisfranc injuries typically result from a direct blow to the midfoot or excessive pronation or supination in a plantarflexed foot.²³

Presentation. A historical clue to Lisfranc injury is a report of pain while walking down stairs. Patients can present with pain, swelling, and tenderness to palpation over the dorsal aspect of the Lisfranc joint. Weight-bearing on the injured foot frequently cannot be tolerated but is occasionally possible in some patients, especially those who have diabetes or other baseline neuropathy.²³

Examination. Physical examination can also reveal plantar ecchymosis, which is considered pathognomonic. Another highly supportive maneuver is passive abduction and pronation of the forefoot, which can elicit pain.^25,26

Imaging. Lisfranc injury can be diagnosed on weight-bearing x-rays; as many as one-half of cases are missed when only non-weight-bearing films are obtained. If initial weight-bearing cannot be tolerated by the patient, another attempt at imaging can be made after 1 week of rest.²⁴

Continue to: Distance > 2 mm between the base...

Distance > 2 mm between the base of the first and second metatarsals (FIGURE 4) or an avulsion fracture at the medial base of the second metatarsal or distal lateral corner of the medial cuneiform (the “fleck sign”) supports a disturbance of the Lisfranc joint complex.²⁴ Imaging of the contralateral foot might highlight the injury in subtle cases, followed by CT when diagnostic uncertainty persists.^24,25

IMAGE COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Management of Lisfranc injury depends on the stability of the joint complex. Stable injury without diastasis can be managed conservatively with immobilization in a short walker boot and limited weight-bearing for 2 weeks, followed by weight-bearing as tolerated in the boot if tenderness has improved.²⁴ After 6 to 8 weeks, if the patient is pain-free with abduction stress, weight-bearing without the boot (but with a rigid-sole shoe) is permissible for an additional 6 months. Sport-specific rehabilitation for an athlete can begin once the patient can walk down multiple flights of stairs without pain.²⁴

Orthopedic referral for surgical evaluation is recommended for all patients who have any radiographic evidence of dynamic instability, indicated by the fleck sign; displacement; or obvious diastasis between the metatarsals on imaging. A delay of 1 to 2 weeks from injury to fixation has not been associated with a negative outcome; delay as long as 6 weeks is permissible in some cases. Longer delay in surgical treatment (≥ 6 months) can be associated with posttraumatic arthritis and the need for Lisfranc fusion.^24-26

Whether a syndesmotic injury is managed conservatively (immobilization, rehabilitation) or surgically depends on the degree (grade 1, 2, or 3) of disruption.

Proximal fifth-metatarsal fractures

These common fractures are classified in 3 broad categories: tuberosity avulsion fracture, proximal diaphyseal (Jones) fracture, and stress fractures of the diaphysis (immediately distal to the site of the Jones fracture zone).^27-29 Differentiating an acute Jones fracture and other fracture types is clinically important because the watershed area at the metaphysis–diaphysis junction results in a higher risk of delayed union and nonunion of Jones fractures, compared to other fractures in this region (FIGURE 5).^28,29

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Presentation. Proximal fifth-metatarsal fractures generally present with lateral foot pain and tenderness at the base of the fifth metatarsal, made worse by inversion of the foot, and inability to bear weight on the lateral aspect of the foot. Acute pain can follow a more insidious course of lateral foot pain in stress fracture.

Continue to: Examination

Examination. On exam, there might be swelling and ecchymosis over the lateral foot, with sharp tenderness to palpation at the base of the fifth metatarsal.

Imaging. Most fractures are revealed on standing AP, oblique, and lateral x-rays. Plain films are often falsely negative early in stress fracture; MRI is the gold standard of diagnosis.^27,30

Management. Preferred treatment for a nondisplaced tuberosity avulsion fracture is typically 2-pronged: compressive dressings or casting for pain control and weight-bearing and range-of-motion exercises as tolerated.¹ Follow-up every 2 to 3 weeks is recommended to ensure appropriate healing—ie, pain nearly resolved by 3 weeks post-injury and radiographic union evident at 8 weeks. If displacement is > 3 mm, > 60% of the metatarsal–cuboid joint surface is affected, or there is a 1 to 2 mm step-off on the cuboid articular surface, consider referral to an orthopedist.^1,29

Jones fractures can be managed initially with posterior splinting, non-weight-bearing, and close follow-up. When radiographic healing has not been achieved by 6 to 8 weeks, non-weight-bearing status can be extended by another 4 weeks. When displacement is > 2 mm, or there is no healing after 12 weeks of immobilization and delayed union on x-rays, referral for surgical management is indicated.¹ In select cases, when earlier return to activity is desired, referral for early surgical fixation is appropriate.²⁷

Surgical referral is indicated in all cases of diaphysial stress fracture because of the high rate of nonunion and refracture. Conservative management, based on the orthopedic surgeon’s assessment, might be an option in a minority of patients.²⁹

CORRESPONDENCE
Aileen Roman, MD, Boston University Medical School, Department of Family Medicine, 11 Melnea Cass Boulevard, Boston MA, 02119; aileen.roman@bmc.org

Foot and ankle injuries are among the most common conditions evaluated at primary care visits; the differential diagnosis of such injury is broad.¹ Although many of these injuries are easily identified on imaging studies, a number of subtle, yet important, conditions can be easily missed, especially if you do not routinely encounter them. Given that broad differential, a high degree of suspicion is required to make an accurate diagnosis, which allows appropriate treatment within a reasonable time frame and minimizes the risk of long-term morbidity.

This article outlines the diagnosis and initial management of 5 important, yet often elusive, types of foot and ankle conditions: Achilles tendon rupture, injury to the syndesmosis, ankle fracture, Lisfranc injury, and proximal fracture of the fifth metatarsal.

© Ken Jacobsen

Achilles tendon rupture

The Achilles tendon is the most frequently ruptured tendon in the body (approximately 20% of all large-tendon injuries)²; as many as 25% of cases are initially misdiagnosed.³

Presentation. Patients frequently present with pain at the Achilles tendon—2 to 6 cm above the insertion into the calcaneus—and an inability to fully bear weight.^4,5 A small percentage of patients are able to ambulate on the affected side, albeit with minor pain, which likely contributes to the rate of missed diagnosis. Absence of difficulty bearing weight is due to the presence of secondary plantar flexors, which can compensate for loss of chief plantar flexor function by the Achilles tendon.²

Although many of these injuries are easily identified on imaging studies, a number of subtle conditions can be easily missed, especially if you do not routinely encounter them.

Examination of a patient with an Achilles tendon rupture typically reveals edema, bruising, and a palpable gap within the tendon, 2 to 6 cm proximal to insertion.^3,4 The Thompson test—squeezing the calf with the patient prone and the knee on the affected side flexed—can aid in diagnosis. When the Achilles tendon is intact, plantar flexion occurs at the ankle; when the tendon is ruptured, plantar flexion is absent.⁵ The test can be modified when examining a patient who is unable to lie prone by having them rest the flexed knee on a chair while standing on the unaffected leg.

A diagnosis of Achilles tendon rupture is supported when at least 2 of the following conditions are met^4,5:

• positive Thompson test
• decreased strength during plantar flexion of the ankle
• palpable gap or pain at the typical location (2-6 cm above insertion)
• increased passive ankle dorsiflexion upon gentle ranging of the ankle joint.

Imaging has a limited role in the diagnosis of Achilles tendon rupture; because the findings of the physical examination are reliable, reserve x-rays for cases in which the diagnosis remains uncertain after examination.² Consider ordering plain x-rays to rule out an avulsion fracture at the insertion of the Achilles tendon; ultrasonography or magnetic resonance imaging (MRI) might assist you in detecting the rupture proper, along with the location of the tear for surgical planning, if surgery is deemed necessary by an orthopedic surgeon.^3-5

Continue to: Management

Management. Some degree of controversy surrounds preferred treatment of Achilles tendon rupture, although available evidence demonstrates that these injuries can be effectively managed by surgical repair or nonoperative treatment, as outcomes are comparable.^3,5 Operative management tends to reduce the risk of repeat rupture, compared to nonoperative treatment; however, the potential for surgical complications, including wound infection, sensory disturbance, and adhesions favors nonoperative treatment.^3,4,6

Nonoperative treatment consists of referral to a functional rehabilitation program, without which outcomes are, on the whole, less favorable than with surgery.^3,6 Surgery is preferred if functional rehabilitation is unavailable, 6 months of conservative management fails, or there is avulsion injury.^3,4,6

Injury to the syndesmosis

A complex of ligaments that provide dynamic stability to the ankle joint, the tibiofibular syndesmosis comprises:

• the anterior inferior tibiofibular ligament
• the posterior inferior tibiofibular ligament
• the inferior transverse tibiofibular ligament
• the interosseous membrane.

These structures are further supported by the deltoid ligament.^7,8

Some patients with Achilles tendon rupture can walk on the affected side, even with minor pain; the diagnosis might be missed without further in-depth evaluation.

Commonly referred to as a “high ankle sprain,” a syndesmotic injury is present in as many as 20% of ankle fractures and 5% to 10% of ankle sprains. Injury typically results from external rotation with hyperdorsiflexion of the ankle. Recovery is typically prolonged (ie, twice as long as recovery from a lateral ankle sprain). The diagnosis is missed in as many as 20% of patients; failure to recognize and treat syndesmotic instability appropriately can lead to posttraumatic arthritis.^7,9

Continue to: Presentation

Presentation. Patients generally present with ankle pain, swelling, instability, pain when walking on uneven terrain, and pain upon push-off.⁹

Examination reveals reduced passive ankle dorsiflexion and tenderness upon palpation of individual ligaments. Several clinical tests have been described to aid in detecting this often-elusive diagnosis^7,9,10,11:

• Squeeze test. The patient sits with the knee on the affected side bent at a 90° degree angle while the examiner applies compression, with one or both hands, to the tibia and fibula at midcalf. The test is positive when pain is elicited at the level of the syndesmosis just above the ankle joint.^9,11
• External rotation test. External rotation of the foot and ankle relative to the tibia reproduces pain.
• Crossed leg test. The affected ankle is crossed over the opposite knee in a figure-4 position. The test is positive when pain is elicited at the syndesmosis.¹⁰
• Cotton test. The proximal lower leg is steadied with 1 hand and the plantar heel grasped with the other hand. Pain when the heel is externally rotated (and radiographic widening of the syndesmosis under fluoroscopy) signal syndesmotic instability.
• Fibular translation test. When anterior or posterior drawer force is applied to the fibula, pain and increased translation of the fibula (compared to the contralateral side) suggest instability.

With the Cotton and fibular translation tests, interexaminer technique is more variable and findings are less reproducible.⁸ Taken alone, none of the above-listed tests are diagnostic; they can, however, assist in making a diagnosis of an injury to the syndesmosis.¹¹

Imaging typically involves anteroposterior [AP], lateral, and mortise plain films of the ankle and weight-bearing AP and lateral views of the tibia and fibula.⁹ Important measures on weight-bearing AP x-rays are the tibiofibular clear space (abnormal, > 6 mm) and the tibiofibular overlap (abnormal, < 6 mm) (both abnormalities shown in FIGURE 1). Comparing films of the affected ankle with views of the contralateral ankle is often useful.

Management of syndesmotic injuries depends on degree of disruption:

• Grade 1 injury is a sprain without diastasis on imaging. Management is conservative, with immobilization in a splint or boot for 1 to 3 weeks, followed by functional rehabilitation over 3 to 6 weeks.¹⁰
• Grade 2 injury is demonstrated by ­diastasis on a stress radiograph. Although evidence to guide successful identification of a grade 2 injury is lacking, it is clinically important to make that identification because these injuries might require surgical intervention, due to instability. Because the diagnosis of this injury can be challenging in primary care, high clinical suspicion of a grade 2 injury makes it appropriate to defer further evaluation to an orthopedic surgeon. On the other hand, if suspicion of a grade 2 injury is low, a trial of conservative management, with weekly clinical assessment, can be considered. A diagnosis of grade 2 injury can be inferred when a patient is unable to perform a single-leg hop after 3 weeks of immobilization; referral to an orthopedic surgeon is then indicated.¹²
• Grade 3 injury is frank separation at the distal tibiofibular joint that is detectable on a routine plain film. Management—surgical intervention to address instability—is often provided concurrently with the treatment for a Danis-Weber B or C fracture, which tends to coexist with grade 3 syndesmotic injury. (The Danis-Weber A–B–C classification of lateral ankle fracture will be discussed in a bit.)

Continue to: Ankle fracture

Ankle fracture

Fracture of the ankle joint is among the more common fractures in adults, comprising 10% of all fractures.^13,14 The ankle joint is defined as the junction of 3 bony structures: (1) the distal ends of the tibia and fibula and (2) the trochlea of the talus, all stabilized by (3) the collateral ligament complex. Appropriate diagnosis and timely intervention are needed to prevent long-term posttraumatic joint degeneration.

Presentation, examination, and imaging. In addition to difficulty bearing (or inability to bear) weight, patients with suspected ankle fracture can present with tenderness or pain, swelling (generally, the more severe the injury, the more severe the swelling, although this finding is time-dependent), and ecchymosis. However, distinguishing fracture from a ligamentous injury is often difficult by physical examination alone; the evidence-based Ottawa Ankle Rules can guide determination of the need for radiographic imaging, although this tool is less reliable in certain patient populations (TABLE^15-17).^13,15-17

Management. A widely used classification system for guiding ankle fracture management is the Danis-Weber classification (FIGURE 2). In this scheme, type A fractures (distal to the level of the tibial plafond) are managed with ankle stabilization bracing without immobilization. Nondisplaced type B and C fractures (at the level of the tibial plafond and proximal to it, respectively) should be treated with 6 weeks of immobilization in a walking boot; close follow-up within 1 week of injury is recommended to ensure that no displacement of fragments has occurred. Type B and C fractures need to be followed until bony union is achieved. If there is radiologic evidence of a fracture line after 3 months, referral to an orthopedic surgeon is indicated for management of delayed union.

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Common indications for referral to Orthopedics for surgical intervention of ankle fracture include open fracture, bimalleolar and trimalleolar fracture, posterior malleolar fracture, medial malleolar displacement > 2 mm, and lateral malleolar displacement > 3 mm.¹⁸

Special concern: Talar fracture. Although talar fracture is rare, the injury is important to detect because a limited blood supply places fragments at risk of avascular necrosis.¹⁹ Talus fracture is frequently confused with ankle sprain because initial x-rays are not always revelatory.²⁰ A high index of suspicion is required to make the diagnosis, which should be suspected in high-energy injuries that result in pain and swelling of the ankle accompanied by difficulty weight-bearing, severely reduced range of motion, and tenderness to palpation at different areas of the talus.¹ Computed tomography (CT) or MRI might be necessary to detect a talar fracture if initial x-rays are negative. A low threshold for surgical management of talar fracture means that referral to Orthopedics is indicated once this injury is diagnosed.²¹

Continue to: Other frequently missed types of ankle fracture

Other frequently missed types of ankle fracture are shown in FIGURE 3.²² These are relatively uncommon injuries that can be missed for a number of reasons, alone or in combination, including their subtlety on radiography, their often vague clinical presentation, and providers’ lack of awareness of these types. Identification or strong suspicion of fracture at any of these sites (ie, in a patient who is persistently unable to bear weight) should prompt orthopedic referral.

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Lisfranc injury

The tarsometatarsal joint comprises 3 cuneiforms, the cuboid, and 5 metatarsals. Stability is maintained by an intricate ligamentous complex. Lisfranc injury comprises a spectrum of midfoot injuries in which 1 or more metatarsals are displaced from the tarsus. These injuries are both rare and notoriously difficult to diagnose: As many as 20% of cases are missed on initial assessment. Without proper treatment, long-term disability and deformity, such as pes planus, can result.^22-24 Lisfranc injuries typically result from a direct blow to the midfoot or excessive pronation or supination in a plantarflexed foot.²³

Presentation. A historical clue to Lisfranc injury is a report of pain while walking down stairs. Patients can present with pain, swelling, and tenderness to palpation over the dorsal aspect of the Lisfranc joint. Weight-bearing on the injured foot frequently cannot be tolerated but is occasionally possible in some patients, especially those who have diabetes or other baseline neuropathy.²³

Examination. Physical examination can also reveal plantar ecchymosis, which is considered pathognomonic. Another highly supportive maneuver is passive abduction and pronation of the forefoot, which can elicit pain.^25,26

Imaging. Lisfranc injury can be diagnosed on weight-bearing x-rays; as many as one-half of cases are missed when only non-weight-bearing films are obtained. If initial weight-bearing cannot be tolerated by the patient, another attempt at imaging can be made after 1 week of rest.²⁴

Continue to: Distance > 2 mm between the base...

Distance > 2 mm between the base of the first and second metatarsals (FIGURE 4) or an avulsion fracture at the medial base of the second metatarsal or distal lateral corner of the medial cuneiform (the “fleck sign”) supports a disturbance of the Lisfranc joint complex.²⁴ Imaging of the contralateral foot might highlight the injury in subtle cases, followed by CT when diagnostic uncertainty persists.^24,25

IMAGE COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Management of Lisfranc injury depends on the stability of the joint complex. Stable injury without diastasis can be managed conservatively with immobilization in a short walker boot and limited weight-bearing for 2 weeks, followed by weight-bearing as tolerated in the boot if tenderness has improved.²⁴ After 6 to 8 weeks, if the patient is pain-free with abduction stress, weight-bearing without the boot (but with a rigid-sole shoe) is permissible for an additional 6 months. Sport-specific rehabilitation for an athlete can begin once the patient can walk down multiple flights of stairs without pain.²⁴

Orthopedic referral for surgical evaluation is recommended for all patients who have any radiographic evidence of dynamic instability, indicated by the fleck sign; displacement; or obvious diastasis between the metatarsals on imaging. A delay of 1 to 2 weeks from injury to fixation has not been associated with a negative outcome; delay as long as 6 weeks is permissible in some cases. Longer delay in surgical treatment (≥ 6 months) can be associated with posttraumatic arthritis and the need for Lisfranc fusion.^24-26

Whether a syndesmotic injury is managed conservatively (immobilization, rehabilitation) or surgically depends on the degree (grade 1, 2, or 3) of disruption.

Proximal fifth-metatarsal fractures

These common fractures are classified in 3 broad categories: tuberosity avulsion fracture, proximal diaphyseal (Jones) fracture, and stress fractures of the diaphysis (immediately distal to the site of the Jones fracture zone).^27-29 Differentiating an acute Jones fracture and other fracture types is clinically important because the watershed area at the metaphysis–diaphysis junction results in a higher risk of delayed union and nonunion of Jones fractures, compared to other fractures in this region (FIGURE 5).^28,29

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Presentation. Proximal fifth-metatarsal fractures generally present with lateral foot pain and tenderness at the base of the fifth metatarsal, made worse by inversion of the foot, and inability to bear weight on the lateral aspect of the foot. Acute pain can follow a more insidious course of lateral foot pain in stress fracture.

Continue to: Examination

Examination. On exam, there might be swelling and ecchymosis over the lateral foot, with sharp tenderness to palpation at the base of the fifth metatarsal.

Imaging. Most fractures are revealed on standing AP, oblique, and lateral x-rays. Plain films are often falsely negative early in stress fracture; MRI is the gold standard of diagnosis.^27,30

Management. Preferred treatment for a nondisplaced tuberosity avulsion fracture is typically 2-pronged: compressive dressings or casting for pain control and weight-bearing and range-of-motion exercises as tolerated.¹ Follow-up every 2 to 3 weeks is recommended to ensure appropriate healing—ie, pain nearly resolved by 3 weeks post-injury and radiographic union evident at 8 weeks. If displacement is > 3 mm, > 60% of the metatarsal–cuboid joint surface is affected, or there is a 1 to 2 mm step-off on the cuboid articular surface, consider referral to an orthopedist.^1,29

Jones fractures can be managed initially with posterior splinting, non-weight-bearing, and close follow-up. When radiographic healing has not been achieved by 6 to 8 weeks, non-weight-bearing status can be extended by another 4 weeks. When displacement is > 2 mm, or there is no healing after 12 weeks of immobilization and delayed union on x-rays, referral for surgical management is indicated.¹ In select cases, when earlier return to activity is desired, referral for early surgical fixation is appropriate.²⁷

Surgical referral is indicated in all cases of diaphysial stress fracture because of the high rate of nonunion and refracture. Conservative management, based on the orthopedic surgeon’s assessment, might be an option in a minority of patients.²⁹

CORRESPONDENCE
Aileen Roman, MD, Boston University Medical School, Department of Family Medicine, 11 Melnea Cass Boulevard, Boston MA, 02119; aileen.roman@bmc.org

Foot and ankle injuries are among the most common conditions evaluated at primary care visits; the differential diagnosis of such injury is broad.¹ Although many of these injuries are easily identified on imaging studies, a number of subtle, yet important, conditions can be easily missed, especially if you do not routinely encounter them. Given that broad differential, a high degree of suspicion is required to make an accurate diagnosis, which allows appropriate treatment within a reasonable time frame and minimizes the risk of long-term morbidity.

This article outlines the diagnosis and initial management of 5 important, yet often elusive, types of foot and ankle conditions: Achilles tendon rupture, injury to the syndesmosis, ankle fracture, Lisfranc injury, and proximal fracture of the fifth metatarsal.

© Ken Jacobsen

Achilles tendon rupture

The Achilles tendon is the most frequently ruptured tendon in the body (approximately 20% of all large-tendon injuries)²; as many as 25% of cases are initially misdiagnosed.³

Presentation. Patients frequently present with pain at the Achilles tendon—2 to 6 cm above the insertion into the calcaneus—and an inability to fully bear weight.^4,5 A small percentage of patients are able to ambulate on the affected side, albeit with minor pain, which likely contributes to the rate of missed diagnosis. Absence of difficulty bearing weight is due to the presence of secondary plantar flexors, which can compensate for loss of chief plantar flexor function by the Achilles tendon.²

Although many of these injuries are easily identified on imaging studies, a number of subtle conditions can be easily missed, especially if you do not routinely encounter them.

Examination of a patient with an Achilles tendon rupture typically reveals edema, bruising, and a palpable gap within the tendon, 2 to 6 cm proximal to insertion.^3,4 The Thompson test—squeezing the calf with the patient prone and the knee on the affected side flexed—can aid in diagnosis. When the Achilles tendon is intact, plantar flexion occurs at the ankle; when the tendon is ruptured, plantar flexion is absent.⁵ The test can be modified when examining a patient who is unable to lie prone by having them rest the flexed knee on a chair while standing on the unaffected leg.

A diagnosis of Achilles tendon rupture is supported when at least 2 of the following conditions are met^4,5:

• positive Thompson test
• decreased strength during plantar flexion of the ankle
• palpable gap or pain at the typical location (2-6 cm above insertion)
• increased passive ankle dorsiflexion upon gentle ranging of the ankle joint.

Imaging has a limited role in the diagnosis of Achilles tendon rupture; because the findings of the physical examination are reliable, reserve x-rays for cases in which the diagnosis remains uncertain after examination.² Consider ordering plain x-rays to rule out an avulsion fracture at the insertion of the Achilles tendon; ultrasonography or magnetic resonance imaging (MRI) might assist you in detecting the rupture proper, along with the location of the tear for surgical planning, if surgery is deemed necessary by an orthopedic surgeon.^3-5

Continue to: Management

Management. Some degree of controversy surrounds preferred treatment of Achilles tendon rupture, although available evidence demonstrates that these injuries can be effectively managed by surgical repair or nonoperative treatment, as outcomes are comparable.^3,5 Operative management tends to reduce the risk of repeat rupture, compared to nonoperative treatment; however, the potential for surgical complications, including wound infection, sensory disturbance, and adhesions favors nonoperative treatment.^3,4,6

Nonoperative treatment consists of referral to a functional rehabilitation program, without which outcomes are, on the whole, less favorable than with surgery.^3,6 Surgery is preferred if functional rehabilitation is unavailable, 6 months of conservative management fails, or there is avulsion injury.^3,4,6

Injury to the syndesmosis

A complex of ligaments that provide dynamic stability to the ankle joint, the tibiofibular syndesmosis comprises:

• the anterior inferior tibiofibular ligament
• the posterior inferior tibiofibular ligament
• the inferior transverse tibiofibular ligament
• the interosseous membrane.

These structures are further supported by the deltoid ligament.^7,8

Some patients with Achilles tendon rupture can walk on the affected side, even with minor pain; the diagnosis might be missed without further in-depth evaluation.

Commonly referred to as a “high ankle sprain,” a syndesmotic injury is present in as many as 20% of ankle fractures and 5% to 10% of ankle sprains. Injury typically results from external rotation with hyperdorsiflexion of the ankle. Recovery is typically prolonged (ie, twice as long as recovery from a lateral ankle sprain). The diagnosis is missed in as many as 20% of patients; failure to recognize and treat syndesmotic instability appropriately can lead to posttraumatic arthritis.^7,9

Continue to: Presentation

Presentation. Patients generally present with ankle pain, swelling, instability, pain when walking on uneven terrain, and pain upon push-off.⁹

Examination reveals reduced passive ankle dorsiflexion and tenderness upon palpation of individual ligaments. Several clinical tests have been described to aid in detecting this often-elusive diagnosis^7,9,10,11:

• Squeeze test. The patient sits with the knee on the affected side bent at a 90° degree angle while the examiner applies compression, with one or both hands, to the tibia and fibula at midcalf. The test is positive when pain is elicited at the level of the syndesmosis just above the ankle joint.^9,11
• External rotation test. External rotation of the foot and ankle relative to the tibia reproduces pain.
• Crossed leg test. The affected ankle is crossed over the opposite knee in a figure-4 position. The test is positive when pain is elicited at the syndesmosis.¹⁰
• Cotton test. The proximal lower leg is steadied with 1 hand and the plantar heel grasped with the other hand. Pain when the heel is externally rotated (and radiographic widening of the syndesmosis under fluoroscopy) signal syndesmotic instability.
• Fibular translation test. When anterior or posterior drawer force is applied to the fibula, pain and increased translation of the fibula (compared to the contralateral side) suggest instability.

With the Cotton and fibular translation tests, interexaminer technique is more variable and findings are less reproducible.⁸ Taken alone, none of the above-listed tests are diagnostic; they can, however, assist in making a diagnosis of an injury to the syndesmosis.¹¹

Imaging typically involves anteroposterior [AP], lateral, and mortise plain films of the ankle and weight-bearing AP and lateral views of the tibia and fibula.⁹ Important measures on weight-bearing AP x-rays are the tibiofibular clear space (abnormal, > 6 mm) and the tibiofibular overlap (abnormal, < 6 mm) (both abnormalities shown in FIGURE 1). Comparing films of the affected ankle with views of the contralateral ankle is often useful.

Management of syndesmotic injuries depends on degree of disruption:

• Grade 1 injury is a sprain without diastasis on imaging. Management is conservative, with immobilization in a splint or boot for 1 to 3 weeks, followed by functional rehabilitation over 3 to 6 weeks.¹⁰
• Grade 2 injury is demonstrated by ­diastasis on a stress radiograph. Although evidence to guide successful identification of a grade 2 injury is lacking, it is clinically important to make that identification because these injuries might require surgical intervention, due to instability. Because the diagnosis of this injury can be challenging in primary care, high clinical suspicion of a grade 2 injury makes it appropriate to defer further evaluation to an orthopedic surgeon. On the other hand, if suspicion of a grade 2 injury is low, a trial of conservative management, with weekly clinical assessment, can be considered. A diagnosis of grade 2 injury can be inferred when a patient is unable to perform a single-leg hop after 3 weeks of immobilization; referral to an orthopedic surgeon is then indicated.¹²
• Grade 3 injury is frank separation at the distal tibiofibular joint that is detectable on a routine plain film. Management—surgical intervention to address instability—is often provided concurrently with the treatment for a Danis-Weber B or C fracture, which tends to coexist with grade 3 syndesmotic injury. (The Danis-Weber A–B–C classification of lateral ankle fracture will be discussed in a bit.)

Continue to: Ankle fracture

Ankle fracture

Fracture of the ankle joint is among the more common fractures in adults, comprising 10% of all fractures.^13,14 The ankle joint is defined as the junction of 3 bony structures: (1) the distal ends of the tibia and fibula and (2) the trochlea of the talus, all stabilized by (3) the collateral ligament complex. Appropriate diagnosis and timely intervention are needed to prevent long-term posttraumatic joint degeneration.

Presentation, examination, and imaging. In addition to difficulty bearing (or inability to bear) weight, patients with suspected ankle fracture can present with tenderness or pain, swelling (generally, the more severe the injury, the more severe the swelling, although this finding is time-dependent), and ecchymosis. However, distinguishing fracture from a ligamentous injury is often difficult by physical examination alone; the evidence-based Ottawa Ankle Rules can guide determination of the need for radiographic imaging, although this tool is less reliable in certain patient populations (TABLE^15-17).^13,15-17

Management. A widely used classification system for guiding ankle fracture management is the Danis-Weber classification (FIGURE 2). In this scheme, type A fractures (distal to the level of the tibial plafond) are managed with ankle stabilization bracing without immobilization. Nondisplaced type B and C fractures (at the level of the tibial plafond and proximal to it, respectively) should be treated with 6 weeks of immobilization in a walking boot; close follow-up within 1 week of injury is recommended to ensure that no displacement of fragments has occurred. Type B and C fractures need to be followed until bony union is achieved. If there is radiologic evidence of a fracture line after 3 months, referral to an orthopedic surgeon is indicated for management of delayed union.

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Common indications for referral to Orthopedics for surgical intervention of ankle fracture include open fracture, bimalleolar and trimalleolar fracture, posterior malleolar fracture, medial malleolar displacement > 2 mm, and lateral malleolar displacement > 3 mm.¹⁸

Special concern: Talar fracture. Although talar fracture is rare, the injury is important to detect because a limited blood supply places fragments at risk of avascular necrosis.¹⁹ Talus fracture is frequently confused with ankle sprain because initial x-rays are not always revelatory.²⁰ A high index of suspicion is required to make the diagnosis, which should be suspected in high-energy injuries that result in pain and swelling of the ankle accompanied by difficulty weight-bearing, severely reduced range of motion, and tenderness to palpation at different areas of the talus.¹ Computed tomography (CT) or MRI might be necessary to detect a talar fracture if initial x-rays are negative. A low threshold for surgical management of talar fracture means that referral to Orthopedics is indicated once this injury is diagnosed.²¹

Continue to: Other frequently missed types of ankle fracture

Other frequently missed types of ankle fracture are shown in FIGURE 3.²² These are relatively uncommon injuries that can be missed for a number of reasons, alone or in combination, including their subtlety on radiography, their often vague clinical presentation, and providers’ lack of awareness of these types. Identification or strong suspicion of fracture at any of these sites (ie, in a patient who is persistently unable to bear weight) should prompt orthopedic referral.

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Lisfranc injury

The tarsometatarsal joint comprises 3 cuneiforms, the cuboid, and 5 metatarsals. Stability is maintained by an intricate ligamentous complex. Lisfranc injury comprises a spectrum of midfoot injuries in which 1 or more metatarsals are displaced from the tarsus. These injuries are both rare and notoriously difficult to diagnose: As many as 20% of cases are missed on initial assessment. Without proper treatment, long-term disability and deformity, such as pes planus, can result.^22-24 Lisfranc injuries typically result from a direct blow to the midfoot or excessive pronation or supination in a plantarflexed foot.²³

Presentation. A historical clue to Lisfranc injury is a report of pain while walking down stairs. Patients can present with pain, swelling, and tenderness to palpation over the dorsal aspect of the Lisfranc joint. Weight-bearing on the injured foot frequently cannot be tolerated but is occasionally possible in some patients, especially those who have diabetes or other baseline neuropathy.²³

Examination. Physical examination can also reveal plantar ecchymosis, which is considered pathognomonic. Another highly supportive maneuver is passive abduction and pronation of the forefoot, which can elicit pain.^25,26

Imaging. Lisfranc injury can be diagnosed on weight-bearing x-rays; as many as one-half of cases are missed when only non-weight-bearing films are obtained. If initial weight-bearing cannot be tolerated by the patient, another attempt at imaging can be made after 1 week of rest.²⁴

Continue to: Distance > 2 mm between the base...

Distance > 2 mm between the base of the first and second metatarsals (FIGURE 4) or an avulsion fracture at the medial base of the second metatarsal or distal lateral corner of the medial cuneiform (the “fleck sign”) supports a disturbance of the Lisfranc joint complex.²⁴ Imaging of the contralateral foot might highlight the injury in subtle cases, followed by CT when diagnostic uncertainty persists.^24,25

IMAGE COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Management of Lisfranc injury depends on the stability of the joint complex. Stable injury without diastasis can be managed conservatively with immobilization in a short walker boot and limited weight-bearing for 2 weeks, followed by weight-bearing as tolerated in the boot if tenderness has improved.²⁴ After 6 to 8 weeks, if the patient is pain-free with abduction stress, weight-bearing without the boot (but with a rigid-sole shoe) is permissible for an additional 6 months. Sport-specific rehabilitation for an athlete can begin once the patient can walk down multiple flights of stairs without pain.²⁴

Orthopedic referral for surgical evaluation is recommended for all patients who have any radiographic evidence of dynamic instability, indicated by the fleck sign; displacement; or obvious diastasis between the metatarsals on imaging. A delay of 1 to 2 weeks from injury to fixation has not been associated with a negative outcome; delay as long as 6 weeks is permissible in some cases. Longer delay in surgical treatment (≥ 6 months) can be associated with posttraumatic arthritis and the need for Lisfranc fusion.^24-26

Whether a syndesmotic injury is managed conservatively (immobilization, rehabilitation) or surgically depends on the degree (grade 1, 2, or 3) of disruption.

Proximal fifth-metatarsal fractures

These common fractures are classified in 3 broad categories: tuberosity avulsion fracture, proximal diaphyseal (Jones) fracture, and stress fractures of the diaphysis (immediately distal to the site of the Jones fracture zone).^27-29 Differentiating an acute Jones fracture and other fracture types is clinically important because the watershed area at the metaphysis–diaphysis junction results in a higher risk of delayed union and nonunion of Jones fractures, compared to other fractures in this region (FIGURE 5).^28,29

IMAGES COURTESY OF HANS P. VAN LANCKER, MD, FRCSC

Presentation. Proximal fifth-metatarsal fractures generally present with lateral foot pain and tenderness at the base of the fifth metatarsal, made worse by inversion of the foot, and inability to bear weight on the lateral aspect of the foot. Acute pain can follow a more insidious course of lateral foot pain in stress fracture.

Continue to: Examination

Examination. On exam, there might be swelling and ecchymosis over the lateral foot, with sharp tenderness to palpation at the base of the fifth metatarsal.

Imaging. Most fractures are revealed on standing AP, oblique, and lateral x-rays. Plain films are often falsely negative early in stress fracture; MRI is the gold standard of diagnosis.^27,30

Management. Preferred treatment for a nondisplaced tuberosity avulsion fracture is typically 2-pronged: compressive dressings or casting for pain control and weight-bearing and range-of-motion exercises as tolerated.¹ Follow-up every 2 to 3 weeks is recommended to ensure appropriate healing—ie, pain nearly resolved by 3 weeks post-injury and radiographic union evident at 8 weeks. If displacement is > 3 mm, > 60% of the metatarsal–cuboid joint surface is affected, or there is a 1 to 2 mm step-off on the cuboid articular surface, consider referral to an orthopedist.^1,29

Jones fractures can be managed initially with posterior splinting, non-weight-bearing, and close follow-up. When radiographic healing has not been achieved by 6 to 8 weeks, non-weight-bearing status can be extended by another 4 weeks. When displacement is > 2 mm, or there is no healing after 12 weeks of immobilization and delayed union on x-rays, referral for surgical management is indicated.¹ In select cases, when earlier return to activity is desired, referral for early surgical fixation is appropriate.²⁷

Surgical referral is indicated in all cases of diaphysial stress fracture because of the high rate of nonunion and refracture. Conservative management, based on the orthopedic surgeon’s assessment, might be an option in a minority of patients.²⁹

CORRESPONDENCE
Aileen Roman, MD, Boston University Medical School, Department of Family Medicine, 11 Melnea Cass Boulevard, Boston MA, 02119; aileen.roman@bmc.org

In a difficult field like medicine, it’s always nice when people appreciate what you’re trying to do. Even if things are good or bad in a case, it means a lot when they know you’re trying your best and are grateful for it.

I’m not saying I expect it (I don’t), but it’s still nice when it happens.

Most of the time someone will say thank you. Occasionally I’ll get a card, or rarely a small gift or box of candy at the holidays. I’m not asking for them, but it’s thoughtful when they do that.

But perhaps the most meaningful way I realize people like and trust me is when they refer a family member. Or two. Or three.

Last week I had a nice college kid in to see me. I’d seen his mother in the past. And both of her parents.

When you have a third generation of a family coming in ... you must be doing something right.

I got curious, began looking through my charts, and was surprised by how many different families had two to three generations seeing me. In several cases the original patient had passed on, but obviously the family had felt good enough about me to come here when the need arose.

That really means a lot when you think about it. In a world in which many see doctors as interchangeable with each other and physician extenders, and where insurance plans seem to drop and sign practices at random, people have a lot of doctors to choose from. The fact that a family thinks highly enough of me to keep returning is flattering.

Medicine is never an easy job, even outside the endless paperwork and other, often pointless, things it requires. In spite of this, we all work hard to care for patients to the best of our ability. It’s nice when they feel we are, too, and trust us enough to share that sentiment with loved ones.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In a difficult field like medicine, it’s always nice when people appreciate what you’re trying to do. Even if things are good or bad in a case, it means a lot when they know you’re trying your best and are grateful for it.

I’m not saying I expect it (I don’t), but it’s still nice when it happens.

Most of the time someone will say thank you. Occasionally I’ll get a card, or rarely a small gift or box of candy at the holidays. I’m not asking for them, but it’s thoughtful when they do that.

But perhaps the most meaningful way I realize people like and trust me is when they refer a family member. Or two. Or three.

Last week I had a nice college kid in to see me. I’d seen his mother in the past. And both of her parents.

When you have a third generation of a family coming in ... you must be doing something right.

I got curious, began looking through my charts, and was surprised by how many different families had two to three generations seeing me. In several cases the original patient had passed on, but obviously the family had felt good enough about me to come here when the need arose.

That really means a lot when you think about it. In a world in which many see doctors as interchangeable with each other and physician extenders, and where insurance plans seem to drop and sign practices at random, people have a lot of doctors to choose from. The fact that a family thinks highly enough of me to keep returning is flattering.

Medicine is never an easy job, even outside the endless paperwork and other, often pointless, things it requires. In spite of this, we all work hard to care for patients to the best of our ability. It’s nice when they feel we are, too, and trust us enough to share that sentiment with loved ones.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In a difficult field like medicine, it’s always nice when people appreciate what you’re trying to do. Even if things are good or bad in a case, it means a lot when they know you’re trying your best and are grateful for it.

I’m not saying I expect it (I don’t), but it’s still nice when it happens.

Most of the time someone will say thank you. Occasionally I’ll get a card, or rarely a small gift or box of candy at the holidays. I’m not asking for them, but it’s thoughtful when they do that.

But perhaps the most meaningful way I realize people like and trust me is when they refer a family member. Or two. Or three.

Last week I had a nice college kid in to see me. I’d seen his mother in the past. And both of her parents.

When you have a third generation of a family coming in ... you must be doing something right.

I got curious, began looking through my charts, and was surprised by how many different families had two to three generations seeing me. In several cases the original patient had passed on, but obviously the family had felt good enough about me to come here when the need arose.

That really means a lot when you think about it. In a world in which many see doctors as interchangeable with each other and physician extenders, and where insurance plans seem to drop and sign practices at random, people have a lot of doctors to choose from. The fact that a family thinks highly enough of me to keep returning is flattering.

Medicine is never an easy job, even outside the endless paperwork and other, often pointless, things it requires. In spite of this, we all work hard to care for patients to the best of our ability. It’s nice when they feel we are, too, and trust us enough to share that sentiment with loved ones.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Recent concerns surrounding coronavirus disease 2019 (COVID-19) make it timely to reexamine the complex findings related to eating disorders and the immune system, and the risks for and detection of infection in patients with anorexia nervosa (AN) and similar disorders. To date, there are no published studies evaluating patients with eating disorders and COVID-19. However, it may be helpful to review the data on the infectious process in this patient population to improve patient communication, enhance surveillance and detection, and possibly reduce morbidity and mortality.

The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) issued warnings that individuals who are older, have underlying medical conditions, and/or are immunocompromised face the greatest risk of serious complications and death as a result of COVID-19, the disease process caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to malnutrition, patients with eating disorders, especially AN, may be perceived to have an increased risk of medical conditions and infection. Despite many studies on specific changes and differences in the immune system of patients with eating disorders, the consequences of these changes remain controversial and inconclusive.

This article reviews research on eating disorders, focusing on published data regarding the effects of AN on the immune system, susceptibility to infections, infectious detection, and morbidity. We also discuss clinical considerations related to COVID-19 and patients with AN.

Infection risks: Conflicting data

In a 1981 study that included 9 participants, Golla et al¹ concluded that patients with AN may have “resistance” to infections based on a suggested protective factor within the immune system of these patients. Because this study has been cited repeatedly in multiple articles about AN and cell-mediated immunity,^2-7 some clinicians have accepted this evidence of resistance to infection in patients with AN, which may lower their suspicion for and detection of infections in patients with AN.

However, studies published both before and after Golla et al¹ have shown statistically significant results that contradict those researchers’ conclusion. A study that compared the medical records of 68 patients with AN with those who did not have AN found no significant difference, and concluded that the rate of infection among patients with AN is the same as among controls.⁸ These researchers noted that infection rates may be higher among patients with later-stage, more severe AN. In a 1986 study of 12 patients with AN, Cason et al⁹ concluded that while cellular immunity function is abnormal in patients with AN, their results were not compatible with prior studies that suggested AN patients were more resistant to infection.^1,2,8

More recently, researchers compared 1,592 patients with eating disorders with 6,368 matched controls; they reviewed prescriptions of antibacterial, antifungal, and antiviral medications as a measure of infection rates.¹⁰ Compared with controls, patients with binge eating disorder (BED), patients with bulimia nervosa (BN), and males with AN more often received prescriptions for antimicrobial medications. There was no statistically significant difference between controls and females with AN, which is consistent with other reports of no increased or decreased risk of infection among females with AN. In terms of antiviral use, this study showed an increased prescription of antivirals only in the BN group.

Several other studies examining the rate of infection in patients with AN concluded that there is neither an increased nor decreased rate of infection in patients with AN, and that the rate of infection in this population is similar to that of the general population.^8,10-12 Because studies that have included patients with AN have evaluated only symptomatic viral infections, some researchers have proposed that patients with AN may show lower rates of symptomatic viral infection but higher rates of asymptomatic infection, as evidenced by higher viral titers.⁶ Further research is required. Despite controversy regarding infection rates, studies have found that patients with AN have increased rates of morbidity and mortality from infections.^6,12-16

Continue to: Obstacles to detecting infections

Obstacles to detecting infections

Several factors can complicate the surveillance and detection of infections in patients with eating disorders, especially those with AN. These include:

• an accepted predisposition to infection secondary to malnutrition
• a lack of visual or reported infectious symptoms
• misrepresentation and assumptions from published research.

Clinicians who report fewer observed cases of infections among patients with AN may be overlooking comorbid disease processes due to a bias from the literature and/or a lack of awareness of symptom parameters in patients with AN.

Features of AN include a loss of adipose tissue responsible for pro-inflammatory cytokines, and excessive exercise, which stimulates anti-inflammatory myokines. This can modulate the experience of illness that impacts the core features of disease,¹⁷ possibly reducing symptomatic presentation of infections.

Fever. The presence and intensity of fever may be altered in patients with eating disorders, especially those with AN. In a study of 311 inpatients with AN, researchers found that patients with AN had a significant delay in fever response in AN.¹² Of 23 patients with an active bacterial infection, all but 5 had a fever <37°C, with some as low as 35.5°C. A detectable fever response and unexplained fevers were found in 2 of the 6 patients with a viral infection. A series of case studies found that patients with AN with bacterial infections also had a delayed fever response.¹⁸

For patients with infections that commonly present with fever, such as COVID-19, a delayed fever response can delay or evade the detection of infection, thus increasing potential complications as well viral exposure to others. Thus, clinicians should use caution when ruling out COVID-19 or other infections because of a lack of significant fever.

Continue to: Overlapping symptoms

Overlapping symptoms. The symptoms of viral infection can mimic the symptoms of AN, which further complicates screening and diagnosis of infection in these patients. Although up to 80% of individuals infected with COVID-19 may be asymptomatic or have a mild presentation, the most common reported symptoms are fever (92.6%), shortness of breath (50.8%), expectoration (41.4%), fatigue (46.4%), dry cough (33.3%), and myalgia (21.4%).^19-21 Gastrointestinal (GI) symptoms have been reported in patients with COVID-19, as well as a loss of taste and smell.

Commonly reported physical symptoms of AN include an intolerance to cold, general fatigue, muscle aches and pains, restlessness, emesis, and a multitude of GI complaints. Patients with AN also have been reported to experience shortness of breath due to conditions such as respiratory muscle weakness,²² nutritional emphysema,²³ and anxiety and panic attack.²⁴ These conditions could lead to an increased susceptibility to COVID-19 and increased complications during treatment. Cardiac abnormalities, which are common in patients with AN and BN, may increase the risk of adverse events. While these symptoms may be an important part of screening for diseases such as COVID-19, suspicion of infection also may be lower because of the overlap of AN symptomology, underlying conditions, and a delayed fever response.

Laboratory findings. Laboratory testing results for patients with COVID-19 include lower lymphocyte counts, higher leukocyte counts, elevated levels of infection-related biomarkers and inflammatory cytokines, and significantly decreased T-cell counts.¹⁹ Similar values are also found in patients with AN.

The similar clinical presentations and laboratory values of AN and COVID-19 could lead to delayed diagnosis, increased disease transmission, cross-contamination of facilities, and higher incidences of medical complications and mortality.

The immunology of AN and correlations with COVID-19

Many studies examining the immune system of patients with eating disorders, especially those with AN, have discovered changes and differences in both cell-mediated and humoral response to infections.^{1,3,5,7,9,11,16,21,25-27} Whether these differences represent a dysfunctional immune system, an immunocompromised state, or even a protective factor remains unclear.

Continue to: While some studies have reported...

While some studies have reported that AN represents an immunocompromised state, others describe the immune system of patients with AN as dysfunctional or simply altered.^9,11,22,28 Some studies have found that patients with AN had delayed reactions to pathogen skin exposures compared with healthy controls, which provides evidence of an impaired cell-mediated immune system.^9,27,29

Some studies have considered the consequences of infection and immunologic findings as markers of or contributing to the onset of AN.^2,30,31 Numerous studies have noted abnormalities in AN with regards to cell-mediated immunity, the humoral system, the lymphoreticular system, and the innate immune system, and potential contributions from increased oxidative stress, a chronically activated sympathetic nervous system and hypothalamic-pituitary-adrenal axis, altered intestinal microbiota, and an abnormal bone marrow microenvironment.²

Box 1

Box 1^19,25,32-34 describes some of the initial immunologic findings reported in patients with COVID-19. In Box 2,^{5,8,11,13,14,19,26,28,35-40} we discuss reports that describe the immunologic overlay of COVID-19 and AN.

Box 2

Malnutrition and the immune system

Differences in the type of malnutrition observed in low-weight patients with AN may help explain why patients with AN can maintain a relatively intact cell-mediated immune system.¹ Protein-energy malnutrition (PEM), which is found in typical states of starvation, consists of deficiencies in multiple vitamins, protein, and energy (caloric content), whereas the dietary habits of patients with AN usually result in a deficiency of carbohydrates and fats.⁴¹ Studies that examined the impact of PEM on immunity to influenza infection have suggested that balanced protein energy replenishment may be a strategy for boosting immunity against influenza viral infections.⁴² However, carbohydrates are the primary nutrients for human bone marrow fat cells, which play a crucial role in the maturation of white blood cells. This may account for the leukopenia that is common in patients with AN.^6,43 The protein-sparing aspect of the typical AN diet may account for the immune system changes observed in patients with AN.⁴⁴

Although some studies have proposed that immune deficiencies observed in patients with AN are secondary to malnutrition and return to normal with refeeding,^5,40,45 others have concluded that immune function is not compromised by factors such as nutritional status or body weight in AN.^26,43,46

Continue to: Clinical considerations

 

 

Clinical considerations

Neither the CDC nor the WHO have issued a specific protocol for monitoring for and treating COVID-19 in patients with eating disorders; however, the guidelines offered by these organizations for the general population should be followed for patients with eating disorders.

When screening a patient with an eating disorder, keep in mind that the symptoms of eating disorders, such as AN, may mimic an infectious process. Mood symptoms, such as depression or anxiety, could represent physiological responses to infection. Patients with GI symptoms that typically are considered part of the pathology of an eating disorder should be more carefully considered for COVID-19. Monitor a patient’s basal body temperature, and be mindful that a patient with AN may exhibit a delayed fever response. Be vigilant for a recent loss of taste or smell, which should raise suspicion for COVID-19. When monitoring vital signs, pay careful attention for any decompensation in a patient’s pulse oximetry. Whenever possible, order COVID-19 testing for any patient you suspect may be infected.

Outpatient clinicians should work closely in a collaborative manner with a patient’s eating disorder treatment team. Psychiatrists, primary care physicians, psychotherapists, nutritionists, and other clinicians should all follow CDC/WHO guidelines regarding COVID-19, provide surveillance, and communicate any suspicions to the medical team. Eating disorder treatment programs, including residential centers, partial hospital programs (PHP), and intensive outpatient programs (IOP), must enhance monitoring for COVID-19, and exercise caution by practicing social distancing and providing adequate personal protective equipment for patients and staff. To reduce the spread of COVID-19, many IOPs and PHPs have transitioned to virtual treatment. Residential centers must carefully screen patients before admission to weigh the risks and benefits of inpatient vs outpatient care.

Bottom Line

Differences in the immune system of patients with an eating disorder do not necessarily confer a higher or lower risk of infection. Symptoms of some infections can mimic the symptoms of anorexia nervosa. Recognizing infections in patients with eating disorders is critical because compared with the general population, they have higher rates of infection-related morbidity and mortality.

Related Resources

• Congress J, Madaan V. 6 ‘M’s to keep in mind when you next see a patient with anorexia nervosa. Current Psychiatry. 2014;13(5):58-59.
• Westmoreland P. Eating disorders: Masterclass lecture part I. Psychcast (podcast). https://www.mdedge.com/podcasts/psychcast/eating-disorders-masterclass-lecture-part-i.

Recent concerns surrounding coronavirus disease 2019 (COVID-19) make it timely to reexamine the complex findings related to eating disorders and the immune system, and the risks for and detection of infection in patients with anorexia nervosa (AN) and similar disorders. To date, there are no published studies evaluating patients with eating disorders and COVID-19. However, it may be helpful to review the data on the infectious process in this patient population to improve patient communication, enhance surveillance and detection, and possibly reduce morbidity and mortality.

The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) issued warnings that individuals who are older, have underlying medical conditions, and/or are immunocompromised face the greatest risk of serious complications and death as a result of COVID-19, the disease process caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to malnutrition, patients with eating disorders, especially AN, may be perceived to have an increased risk of medical conditions and infection. Despite many studies on specific changes and differences in the immune system of patients with eating disorders, the consequences of these changes remain controversial and inconclusive.

This article reviews research on eating disorders, focusing on published data regarding the effects of AN on the immune system, susceptibility to infections, infectious detection, and morbidity. We also discuss clinical considerations related to COVID-19 and patients with AN.

Infection risks: Conflicting data

In a 1981 study that included 9 participants, Golla et al¹ concluded that patients with AN may have “resistance” to infections based on a suggested protective factor within the immune system of these patients. Because this study has been cited repeatedly in multiple articles about AN and cell-mediated immunity,^2-7 some clinicians have accepted this evidence of resistance to infection in patients with AN, which may lower their suspicion for and detection of infections in patients with AN.

However, studies published both before and after Golla et al¹ have shown statistically significant results that contradict those researchers’ conclusion. A study that compared the medical records of 68 patients with AN with those who did not have AN found no significant difference, and concluded that the rate of infection among patients with AN is the same as among controls.⁸ These researchers noted that infection rates may be higher among patients with later-stage, more severe AN. In a 1986 study of 12 patients with AN, Cason et al⁹ concluded that while cellular immunity function is abnormal in patients with AN, their results were not compatible with prior studies that suggested AN patients were more resistant to infection.^1,2,8

More recently, researchers compared 1,592 patients with eating disorders with 6,368 matched controls; they reviewed prescriptions of antibacterial, antifungal, and antiviral medications as a measure of infection rates.¹⁰ Compared with controls, patients with binge eating disorder (BED), patients with bulimia nervosa (BN), and males with AN more often received prescriptions for antimicrobial medications. There was no statistically significant difference between controls and females with AN, which is consistent with other reports of no increased or decreased risk of infection among females with AN. In terms of antiviral use, this study showed an increased prescription of antivirals only in the BN group.

Several other studies examining the rate of infection in patients with AN concluded that there is neither an increased nor decreased rate of infection in patients with AN, and that the rate of infection in this population is similar to that of the general population.^8,10-12 Because studies that have included patients with AN have evaluated only symptomatic viral infections, some researchers have proposed that patients with AN may show lower rates of symptomatic viral infection but higher rates of asymptomatic infection, as evidenced by higher viral titers.⁶ Further research is required. Despite controversy regarding infection rates, studies have found that patients with AN have increased rates of morbidity and mortality from infections.^6,12-16

Continue to: Obstacles to detecting infections

Obstacles to detecting infections

Several factors can complicate the surveillance and detection of infections in patients with eating disorders, especially those with AN. These include:

• an accepted predisposition to infection secondary to malnutrition
• a lack of visual or reported infectious symptoms
• misrepresentation and assumptions from published research.

Clinicians who report fewer observed cases of infections among patients with AN may be overlooking comorbid disease processes due to a bias from the literature and/or a lack of awareness of symptom parameters in patients with AN.

Features of AN include a loss of adipose tissue responsible for pro-inflammatory cytokines, and excessive exercise, which stimulates anti-inflammatory myokines. This can modulate the experience of illness that impacts the core features of disease,¹⁷ possibly reducing symptomatic presentation of infections.

Fever. The presence and intensity of fever may be altered in patients with eating disorders, especially those with AN. In a study of 311 inpatients with AN, researchers found that patients with AN had a significant delay in fever response in AN.¹² Of 23 patients with an active bacterial infection, all but 5 had a fever <37°C, with some as low as 35.5°C. A detectable fever response and unexplained fevers were found in 2 of the 6 patients with a viral infection. A series of case studies found that patients with AN with bacterial infections also had a delayed fever response.¹⁸

For patients with infections that commonly present with fever, such as COVID-19, a delayed fever response can delay or evade the detection of infection, thus increasing potential complications as well viral exposure to others. Thus, clinicians should use caution when ruling out COVID-19 or other infections because of a lack of significant fever.

Continue to: Overlapping symptoms

Overlapping symptoms. The symptoms of viral infection can mimic the symptoms of AN, which further complicates screening and diagnosis of infection in these patients. Although up to 80% of individuals infected with COVID-19 may be asymptomatic or have a mild presentation, the most common reported symptoms are fever (92.6%), shortness of breath (50.8%), expectoration (41.4%), fatigue (46.4%), dry cough (33.3%), and myalgia (21.4%).^19-21 Gastrointestinal (GI) symptoms have been reported in patients with COVID-19, as well as a loss of taste and smell.

Commonly reported physical symptoms of AN include an intolerance to cold, general fatigue, muscle aches and pains, restlessness, emesis, and a multitude of GI complaints. Patients with AN also have been reported to experience shortness of breath due to conditions such as respiratory muscle weakness,²² nutritional emphysema,²³ and anxiety and panic attack.²⁴ These conditions could lead to an increased susceptibility to COVID-19 and increased complications during treatment. Cardiac abnormalities, which are common in patients with AN and BN, may increase the risk of adverse events. While these symptoms may be an important part of screening for diseases such as COVID-19, suspicion of infection also may be lower because of the overlap of AN symptomology, underlying conditions, and a delayed fever response.

Laboratory findings. Laboratory testing results for patients with COVID-19 include lower lymphocyte counts, higher leukocyte counts, elevated levels of infection-related biomarkers and inflammatory cytokines, and significantly decreased T-cell counts.¹⁹ Similar values are also found in patients with AN.

The similar clinical presentations and laboratory values of AN and COVID-19 could lead to delayed diagnosis, increased disease transmission, cross-contamination of facilities, and higher incidences of medical complications and mortality.

The immunology of AN and correlations with COVID-19

Many studies examining the immune system of patients with eating disorders, especially those with AN, have discovered changes and differences in both cell-mediated and humoral response to infections.^{1,3,5,7,9,11,16,21,25-27} Whether these differences represent a dysfunctional immune system, an immunocompromised state, or even a protective factor remains unclear.

Continue to: While some studies have reported...

While some studies have reported that AN represents an immunocompromised state, others describe the immune system of patients with AN as dysfunctional or simply altered.^9,11,22,28 Some studies have found that patients with AN had delayed reactions to pathogen skin exposures compared with healthy controls, which provides evidence of an impaired cell-mediated immune system.^9,27,29

Some studies have considered the consequences of infection and immunologic findings as markers of or contributing to the onset of AN.^2,30,31 Numerous studies have noted abnormalities in AN with regards to cell-mediated immunity, the humoral system, the lymphoreticular system, and the innate immune system, and potential contributions from increased oxidative stress, a chronically activated sympathetic nervous system and hypothalamic-pituitary-adrenal axis, altered intestinal microbiota, and an abnormal bone marrow microenvironment.²

Box 1

Box 1^19,25,32-34 describes some of the initial immunologic findings reported in patients with COVID-19. In Box 2,^{5,8,11,13,14,19,26,28,35-40} we discuss reports that describe the immunologic overlay of COVID-19 and AN.

Box 2

Malnutrition and the immune system

Differences in the type of malnutrition observed in low-weight patients with AN may help explain why patients with AN can maintain a relatively intact cell-mediated immune system.¹ Protein-energy malnutrition (PEM), which is found in typical states of starvation, consists of deficiencies in multiple vitamins, protein, and energy (caloric content), whereas the dietary habits of patients with AN usually result in a deficiency of carbohydrates and fats.⁴¹ Studies that examined the impact of PEM on immunity to influenza infection have suggested that balanced protein energy replenishment may be a strategy for boosting immunity against influenza viral infections.⁴² However, carbohydrates are the primary nutrients for human bone marrow fat cells, which play a crucial role in the maturation of white blood cells. This may account for the leukopenia that is common in patients with AN.^6,43 The protein-sparing aspect of the typical AN diet may account for the immune system changes observed in patients with AN.⁴⁴

Although some studies have proposed that immune deficiencies observed in patients with AN are secondary to malnutrition and return to normal with refeeding,^5,40,45 others have concluded that immune function is not compromised by factors such as nutritional status or body weight in AN.^26,43,46

Continue to: Clinical considerations

 

 

Clinical considerations

Neither the CDC nor the WHO have issued a specific protocol for monitoring for and treating COVID-19 in patients with eating disorders; however, the guidelines offered by these organizations for the general population should be followed for patients with eating disorders.

When screening a patient with an eating disorder, keep in mind that the symptoms of eating disorders, such as AN, may mimic an infectious process. Mood symptoms, such as depression or anxiety, could represent physiological responses to infection. Patients with GI symptoms that typically are considered part of the pathology of an eating disorder should be more carefully considered for COVID-19. Monitor a patient’s basal body temperature, and be mindful that a patient with AN may exhibit a delayed fever response. Be vigilant for a recent loss of taste or smell, which should raise suspicion for COVID-19. When monitoring vital signs, pay careful attention for any decompensation in a patient’s pulse oximetry. Whenever possible, order COVID-19 testing for any patient you suspect may be infected.

Outpatient clinicians should work closely in a collaborative manner with a patient’s eating disorder treatment team. Psychiatrists, primary care physicians, psychotherapists, nutritionists, and other clinicians should all follow CDC/WHO guidelines regarding COVID-19, provide surveillance, and communicate any suspicions to the medical team. Eating disorder treatment programs, including residential centers, partial hospital programs (PHP), and intensive outpatient programs (IOP), must enhance monitoring for COVID-19, and exercise caution by practicing social distancing and providing adequate personal protective equipment for patients and staff. To reduce the spread of COVID-19, many IOPs and PHPs have transitioned to virtual treatment. Residential centers must carefully screen patients before admission to weigh the risks and benefits of inpatient vs outpatient care.

Bottom Line

Differences in the immune system of patients with an eating disorder do not necessarily confer a higher or lower risk of infection. Symptoms of some infections can mimic the symptoms of anorexia nervosa. Recognizing infections in patients with eating disorders is critical because compared with the general population, they have higher rates of infection-related morbidity and mortality.

Related Resources

• Congress J, Madaan V. 6 ‘M’s to keep in mind when you next see a patient with anorexia nervosa. Current Psychiatry. 2014;13(5):58-59.
• Westmoreland P. Eating disorders: Masterclass lecture part I. Psychcast (podcast). https://www.mdedge.com/podcasts/psychcast/eating-disorders-masterclass-lecture-part-i.

Recent concerns surrounding coronavirus disease 2019 (COVID-19) make it timely to reexamine the complex findings related to eating disorders and the immune system, and the risks for and detection of infection in patients with anorexia nervosa (AN) and similar disorders. To date, there are no published studies evaluating patients with eating disorders and COVID-19. However, it may be helpful to review the data on the infectious process in this patient population to improve patient communication, enhance surveillance and detection, and possibly reduce morbidity and mortality.

The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) issued warnings that individuals who are older, have underlying medical conditions, and/or are immunocompromised face the greatest risk of serious complications and death as a result of COVID-19, the disease process caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to malnutrition, patients with eating disorders, especially AN, may be perceived to have an increased risk of medical conditions and infection. Despite many studies on specific changes and differences in the immune system of patients with eating disorders, the consequences of these changes remain controversial and inconclusive.

This article reviews research on eating disorders, focusing on published data regarding the effects of AN on the immune system, susceptibility to infections, infectious detection, and morbidity. We also discuss clinical considerations related to COVID-19 and patients with AN.

Infection risks: Conflicting data

In a 1981 study that included 9 participants, Golla et al¹ concluded that patients with AN may have “resistance” to infections based on a suggested protective factor within the immune system of these patients. Because this study has been cited repeatedly in multiple articles about AN and cell-mediated immunity,^2-7 some clinicians have accepted this evidence of resistance to infection in patients with AN, which may lower their suspicion for and detection of infections in patients with AN.

However, studies published both before and after Golla et al¹ have shown statistically significant results that contradict those researchers’ conclusion. A study that compared the medical records of 68 patients with AN with those who did not have AN found no significant difference, and concluded that the rate of infection among patients with AN is the same as among controls.⁸ These researchers noted that infection rates may be higher among patients with later-stage, more severe AN. In a 1986 study of 12 patients with AN, Cason et al⁹ concluded that while cellular immunity function is abnormal in patients with AN, their results were not compatible with prior studies that suggested AN patients were more resistant to infection.^1,2,8

More recently, researchers compared 1,592 patients with eating disorders with 6,368 matched controls; they reviewed prescriptions of antibacterial, antifungal, and antiviral medications as a measure of infection rates.¹⁰ Compared with controls, patients with binge eating disorder (BED), patients with bulimia nervosa (BN), and males with AN more often received prescriptions for antimicrobial medications. There was no statistically significant difference between controls and females with AN, which is consistent with other reports of no increased or decreased risk of infection among females with AN. In terms of antiviral use, this study showed an increased prescription of antivirals only in the BN group.

Several other studies examining the rate of infection in patients with AN concluded that there is neither an increased nor decreased rate of infection in patients with AN, and that the rate of infection in this population is similar to that of the general population.^8,10-12 Because studies that have included patients with AN have evaluated only symptomatic viral infections, some researchers have proposed that patients with AN may show lower rates of symptomatic viral infection but higher rates of asymptomatic infection, as evidenced by higher viral titers.⁶ Further research is required. Despite controversy regarding infection rates, studies have found that patients with AN have increased rates of morbidity and mortality from infections.^6,12-16

Continue to: Obstacles to detecting infections

Obstacles to detecting infections

Several factors can complicate the surveillance and detection of infections in patients with eating disorders, especially those with AN. These include:

• an accepted predisposition to infection secondary to malnutrition
• a lack of visual or reported infectious symptoms
• misrepresentation and assumptions from published research.

Clinicians who report fewer observed cases of infections among patients with AN may be overlooking comorbid disease processes due to a bias from the literature and/or a lack of awareness of symptom parameters in patients with AN.

Features of AN include a loss of adipose tissue responsible for pro-inflammatory cytokines, and excessive exercise, which stimulates anti-inflammatory myokines. This can modulate the experience of illness that impacts the core features of disease,¹⁷ possibly reducing symptomatic presentation of infections.

Fever. The presence and intensity of fever may be altered in patients with eating disorders, especially those with AN. In a study of 311 inpatients with AN, researchers found that patients with AN had a significant delay in fever response in AN.¹² Of 23 patients with an active bacterial infection, all but 5 had a fever <37°C, with some as low as 35.5°C. A detectable fever response and unexplained fevers were found in 2 of the 6 patients with a viral infection. A series of case studies found that patients with AN with bacterial infections also had a delayed fever response.¹⁸

For patients with infections that commonly present with fever, such as COVID-19, a delayed fever response can delay or evade the detection of infection, thus increasing potential complications as well viral exposure to others. Thus, clinicians should use caution when ruling out COVID-19 or other infections because of a lack of significant fever.

Continue to: Overlapping symptoms

Overlapping symptoms. The symptoms of viral infection can mimic the symptoms of AN, which further complicates screening and diagnosis of infection in these patients. Although up to 80% of individuals infected with COVID-19 may be asymptomatic or have a mild presentation, the most common reported symptoms are fever (92.6%), shortness of breath (50.8%), expectoration (41.4%), fatigue (46.4%), dry cough (33.3%), and myalgia (21.4%).^19-21 Gastrointestinal (GI) symptoms have been reported in patients with COVID-19, as well as a loss of taste and smell.

Commonly reported physical symptoms of AN include an intolerance to cold, general fatigue, muscle aches and pains, restlessness, emesis, and a multitude of GI complaints. Patients with AN also have been reported to experience shortness of breath due to conditions such as respiratory muscle weakness,²² nutritional emphysema,²³ and anxiety and panic attack.²⁴ These conditions could lead to an increased susceptibility to COVID-19 and increased complications during treatment. Cardiac abnormalities, which are common in patients with AN and BN, may increase the risk of adverse events. While these symptoms may be an important part of screening for diseases such as COVID-19, suspicion of infection also may be lower because of the overlap of AN symptomology, underlying conditions, and a delayed fever response.

Laboratory findings. Laboratory testing results for patients with COVID-19 include lower lymphocyte counts, higher leukocyte counts, elevated levels of infection-related biomarkers and inflammatory cytokines, and significantly decreased T-cell counts.¹⁹ Similar values are also found in patients with AN.

The similar clinical presentations and laboratory values of AN and COVID-19 could lead to delayed diagnosis, increased disease transmission, cross-contamination of facilities, and higher incidences of medical complications and mortality.

The immunology of AN and correlations with COVID-19

Many studies examining the immune system of patients with eating disorders, especially those with AN, have discovered changes and differences in both cell-mediated and humoral response to infections.^{1,3,5,7,9,11,16,21,25-27} Whether these differences represent a dysfunctional immune system, an immunocompromised state, or even a protective factor remains unclear.

Continue to: While some studies have reported...

While some studies have reported that AN represents an immunocompromised state, others describe the immune system of patients with AN as dysfunctional or simply altered.^9,11,22,28 Some studies have found that patients with AN had delayed reactions to pathogen skin exposures compared with healthy controls, which provides evidence of an impaired cell-mediated immune system.^9,27,29

Some studies have considered the consequences of infection and immunologic findings as markers of or contributing to the onset of AN.^2,30,31 Numerous studies have noted abnormalities in AN with regards to cell-mediated immunity, the humoral system, the lymphoreticular system, and the innate immune system, and potential contributions from increased oxidative stress, a chronically activated sympathetic nervous system and hypothalamic-pituitary-adrenal axis, altered intestinal microbiota, and an abnormal bone marrow microenvironment.²

Box 1

Box 1^19,25,32-34 describes some of the initial immunologic findings reported in patients with COVID-19. In Box 2,^{5,8,11,13,14,19,26,28,35-40} we discuss reports that describe the immunologic overlay of COVID-19 and AN.

Box 2

Malnutrition and the immune system

Differences in the type of malnutrition observed in low-weight patients with AN may help explain why patients with AN can maintain a relatively intact cell-mediated immune system.¹ Protein-energy malnutrition (PEM), which is found in typical states of starvation, consists of deficiencies in multiple vitamins, protein, and energy (caloric content), whereas the dietary habits of patients with AN usually result in a deficiency of carbohydrates and fats.⁴¹ Studies that examined the impact of PEM on immunity to influenza infection have suggested that balanced protein energy replenishment may be a strategy for boosting immunity against influenza viral infections.⁴² However, carbohydrates are the primary nutrients for human bone marrow fat cells, which play a crucial role in the maturation of white blood cells. This may account for the leukopenia that is common in patients with AN.^6,43 The protein-sparing aspect of the typical AN diet may account for the immune system changes observed in patients with AN.⁴⁴

Although some studies have proposed that immune deficiencies observed in patients with AN are secondary to malnutrition and return to normal with refeeding,^5,40,45 others have concluded that immune function is not compromised by factors such as nutritional status or body weight in AN.^26,43,46

Continue to: Clinical considerations

 

 

Clinical considerations

Neither the CDC nor the WHO have issued a specific protocol for monitoring for and treating COVID-19 in patients with eating disorders; however, the guidelines offered by these organizations for the general population should be followed for patients with eating disorders.

When screening a patient with an eating disorder, keep in mind that the symptoms of eating disorders, such as AN, may mimic an infectious process. Mood symptoms, such as depression or anxiety, could represent physiological responses to infection. Patients with GI symptoms that typically are considered part of the pathology of an eating disorder should be more carefully considered for COVID-19. Monitor a patient’s basal body temperature, and be mindful that a patient with AN may exhibit a delayed fever response. Be vigilant for a recent loss of taste or smell, which should raise suspicion for COVID-19. When monitoring vital signs, pay careful attention for any decompensation in a patient’s pulse oximetry. Whenever possible, order COVID-19 testing for any patient you suspect may be infected.

Outpatient clinicians should work closely in a collaborative manner with a patient’s eating disorder treatment team. Psychiatrists, primary care physicians, psychotherapists, nutritionists, and other clinicians should all follow CDC/WHO guidelines regarding COVID-19, provide surveillance, and communicate any suspicions to the medical team. Eating disorder treatment programs, including residential centers, partial hospital programs (PHP), and intensive outpatient programs (IOP), must enhance monitoring for COVID-19, and exercise caution by practicing social distancing and providing adequate personal protective equipment for patients and staff. To reduce the spread of COVID-19, many IOPs and PHPs have transitioned to virtual treatment. Residential centers must carefully screen patients before admission to weigh the risks and benefits of inpatient vs outpatient care.

Bottom Line

Differences in the immune system of patients with an eating disorder do not necessarily confer a higher or lower risk of infection. Symptoms of some infections can mimic the symptoms of anorexia nervosa. Recognizing infections in patients with eating disorders is critical because compared with the general population, they have higher rates of infection-related morbidity and mortality.

Related Resources

• Congress J, Madaan V. 6 ‘M’s to keep in mind when you next see a patient with anorexia nervosa. Current Psychiatry. 2014;13(5):58-59.
• Westmoreland P. Eating disorders: Masterclass lecture part I. Psychcast (podcast). https://www.mdedge.com/podcasts/psychcast/eating-disorders-masterclass-lecture-part-i.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²

The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The FDA has approved rTMS for the treatment of MDD and for at least 4 device manufacturers. The treatment has been studied in multiple clinical trials.³ An overview of these trials, additional rTMS training and educational materials, and device information can be accessed at www.mirecc.va.gov/visn21/education/tms_education.asp. rTMS for MDD administers a personalized dose with stimulation delivered over the dorsolateral prefrontal cortex. A typical clinical course runs for 40 minutes a day for 20 to 30 sessions. In addition to studies of depression,^1,4-7 rTMS has been studied for the following diseases and conditions:

• Headache (especially migraine)⁸
• Alzheimer disease⁹
• Obsessive compulsive disorder (OCD)¹⁰
• Obesity¹¹
• Schizophrenia¹²
• Posttraumatic stress disorder (PTSD)¹³
• Alcohol and nicotine dependence¹⁴

The FDA also has approved the use of rTMS for OCD. In addition, some health care providers (HCPs) are treating depression with rTMS in conjunction with electroconvulsive therapy (ECT).

Treatment for Veterans

MDD is one of the most significant risk factors for suicide. Therefore, treating depression with rTMS would likely diminish suicide risk. The annual suicide rate among veterans has been higher than the national average.¹⁵ However, most of these veterans are not getting their care at the Veterans Health Administration (VHA). Major efforts at the VA have been made to address this problem, including modification and promotion of the Veterans Crisis Line, increased mental health clinic hours, mental health same-day appointment availability for veterans, as well as raising awareness of suicide and suicidal ideation.¹⁶ George and colleagues showed that it is safe and feasible to treat acutely suicidal inpatients at a VA or US Department of Defense hospital over an intensive 3 day, 3 treatments per day regimen. This regimen would be potentially useful in a suicidal inpatient population, a technically and ethically difficult group to study.¹⁷

MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.¹⁷ There clearly is a need for additional treatment options. MDD and OCD are the only indications that have received FDA approval for rTMS use. The initial FDA approval for MDD was based on a 2007 study of medication-free patients who had failed previous therapy and found a significant effect of rTMS compared with a sham procedure.⁷ MDD remains a common problem among veterans who have failed one or more antidepressant medications. Such patients might benefit from rTMS.^6,18

rTMS has several advantages over ECT, another significant FDA-approved, nonpharmacologic treatment alternative for medication-refractory MDD. rTMS is less invasive, requires fewer resources, does not require anesthesia or restrict activities, and does not cause memory loss. After an rTMS treatment, the patient can drive home.

Nationwide Pilot Program

The VA pilot program was created to supply rTMS machines nationwide to VHA sites and to offer a framework for establishing a clinical program. Preliminary program evaluation data suggest patients experienced a reduction in depression and suicidal ideation.

There were many challenges to implementation; for example, one VA site was eager to start using the device but could not secure space or personnel. An interdisciplinary team consisting of physicians, nurses, psychologists, suicide prevention coordinators, and others in the VA Palo Alto Health Care System (VAPAHCS) Precision Neurostimulation Clinic (PNC) has been instrumental in overcoming these challenges. VAPAHCS oversees the pilot and employs the national director.

Thirty-five sites nationwide were initially selected due to their ability to provide space for a rTMS machine and appropriate staffing to set up and run a Clinic (Figure 3). The pilot started with tertiary care VA medical centers then expanded to include community-based outpatient clinics as resources permitted. Sites that were unable to meet these standards were not included. Of these 35 original sites, 26 are treating patients and collecting data. Some early delays were due to unassigned relative value units (RVUs) to rTMS, which since have been revised as imputed RVU values. The American Medical Association established and defined RVUs to compare the value of different health care roles.¹⁹ The clinics have been established with smooth operations as the pilot program has provided the infrastructure.

REDCap (www.project-redcap.org), a data collection tool used primarily in academic research settings, was selected to gather program evaluation data through patient questionnaires informed by the VHA measurement-based care initiative. Standard psychometrics were readily available in the VHA application and REDCap Mental Health Assistant includes the Patient Health Questionnaire 9 (PHQ-9) Brief Symptom Inventory 18, Posttraumatic Checklist 5, Beck Scale for Suicidal Ideation, and Quality of Life Inventory. The Timberlawn Couple and Family Evaluation Scale (TCFES), which can be completed in 30 to 35 minutes and is a measure of overall function of relevant relationships, also may be added. Future studies are needed to confirm psychometrics of this scale in this setting, but the TCFES metric is widely used for similar purposes.

Nationwide, more than 950 patients have started treatment (ie, including active, completed, and discontinued treatment) and 412 veterans have completed the rTMS treatment. The goal of the program evaluation is to examine large scale rTMS efficacy in a large veteran population as well as determine predictors of individual patient response. Nationwide, PHQ-9 depression scores declined from a pretreatment average (SD) of 18.2 (5.5; range, 5-27) to a posttreatment average (SD) of 11.0 (7.1; range, 0-27). Patients also have indicated a high level of satisfaction with the treatment (Figure 4). Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response that might be lost in a smaller subset of cases.

Implementation

It took 11 months for the VA contracting department to determine which machine to buy. However, the lengthy process assured that the equipment selected met all standards for clinical safety and efficacy. Furthermore, provision was made to allow for additional orders as new sites came online as well as upgrading the equipment for advances in technology.

The PNC set up several training programs to ensure proper use of this novel treatment. The education is ongoing and available as new sites are identified and initiated. The education includes, but is not limited to, in-person onsite and offsite training programs, online training modules that are available in the VA Electronic Educational Services (EES), and video telehealth consultations. Participants can view online lectures and then receive hands-on training as part of the educational program. Up to 3 HCPs for each site can receive funding to attend. Online programs also are available for new material to support continuing medical education. However, hands-on training is essential to understand how to obtain the motor threshold, which is used to determine the strength of the rTMS stimulus dose. Furthermore, hands-on training is essential for the proper localization of the stimulus, which is determined by certain anatomical landmarks. A phantom mannequin (ERIK [Evaluating Resting motor threshold and Insuring Kappa]) has been developed to assist in the hands-on learning.²⁰

Relative Value Units

The VHA uses RVUs to properly account for workload and clinician activities. As a result, RVUs play an essential role as a currency that denotes the relative value of one type of clinical activity when compared with other activities. Depending on the treating specialty, clinicians generally use procedure codes outlined in the Current Procedural Terminology (CPT) code set or the Healthcare Common Procedure Coding System (HCPCS) for medical billing. Most insurance carriers use RVUs set by the Centers for Medicare and Medicaid Services (CMS) system as a standard system to determine HCP reimbursement for medical procedures.

The CPT codes associated with rTMS currently are 90867 to 90869. CMS had initially assigned a zero RVU to these CPT codes due to wide variations in the cost of performing rTMS. When we began implementing rTMS in the VHA, the lack of RVUs for rTMS rendered it impossible to show clinical workload for this activity using established VHA clinical accounting methods. The lack of RVUs assigned to rTMS CPT codes made justification for this treatment to clinical management difficult, which limited its clinical use in the VHA. In addition, HCPs who were using rTMS to treat severely ill veterans appeared artificially unproductive despite a significant patient workload. As we and VHA leadership became aware the program could not be staffed locally without getting workload credit for work done, the value was raised to 1.37 for treatment (90868) and 2.12 and 1.93 for evaluations (90867) and reevaluations (90869), respectively, thus reducing a potential roadblock to implementation.

Challenges as the Program Expands

Future challenges include upgrading machines to do intermittent θ burst stimulation (iTBS), which decreases the standard treatment time from 37.5 minutes to 3 minutes. Both patients and HCPs find iTBS to have similar tolerability to standard rTMS but in much less time. iTBS mimics endogenous θ rhythms and has been shown to be noninferior to rTMS for depression.^21,22 Several devices have received FDA approval to treat MDD, including the Magstim and MagVenture TMS devices used in this program.

A major challenge for the VHA with rTMS will be to maintain a consistent level of competence and training. There is a need for continued maintenance of staff competence with ongoing training and training for new staff. Novel ways of training operators have been developed including ERIK.

Determining treatment interaction with other psychotherapies and pharmacotherapies is another challenge. Currently, rTMS is considered an adjunctive treatment added to the current patient treatment plan. We do not know yet how best to incorporate this somatic treatment with other approaches, and further research is necessary. A key issue is to determine which approach provides the best long-term results for a patient at risk for recurrence of depression. In addition, more research into maintaining healthy relationships for veterans with both MDD and PTSD is needed.

Many misconceptions exist about rTMS and HCPs need to be educated about the benefits of this modality. In addition, patients should understand the differences between rTMS and ECT. Even with newer approaches that streamline rTMS, the therapy remains costly in terms of direct costs as well as patient and HCP time.

Streamlining rTMS treatment remains an important concern. Compressing treatment schedules (ie, many treatments delivered to a patient in a single day) would allow the entire process to be delivered in days, not weeks. This would be especially advantageous to patients who live far from a treatment site. Performing multiple rTMS daily treatments is especially feasible with iTBS with its short treatment time.

Conclusions

rTMS is an emerging modality with both established and novel applications. The best studied application is treatment resistant MDD. Currently, rTMS has only been approved by the FDA for treatment of MDD. A pilot program was established by the VHA to distribute 30 rTMS machines sites nationwide. Results from data collected by these sites have shown patients improving on standard psychometric scales. Future changes include upgrading the machines to provide θ bursts, which has been shown to be faster and noninferior. Integrating rTMS with other pharmacotherapies and psychotherapies remains poorly understood and needs more research.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²

The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The FDA has approved rTMS for the treatment of MDD and for at least 4 device manufacturers. The treatment has been studied in multiple clinical trials.³ An overview of these trials, additional rTMS training and educational materials, and device information can be accessed at www.mirecc.va.gov/visn21/education/tms_education.asp. rTMS for MDD administers a personalized dose with stimulation delivered over the dorsolateral prefrontal cortex. A typical clinical course runs for 40 minutes a day for 20 to 30 sessions. In addition to studies of depression,^1,4-7 rTMS has been studied for the following diseases and conditions:

• Headache (especially migraine)⁸
• Alzheimer disease⁹
• Obsessive compulsive disorder (OCD)¹⁰
• Obesity¹¹
• Schizophrenia¹²
• Posttraumatic stress disorder (PTSD)¹³
• Alcohol and nicotine dependence¹⁴

The FDA also has approved the use of rTMS for OCD. In addition, some health care providers (HCPs) are treating depression with rTMS in conjunction with electroconvulsive therapy (ECT).

Treatment for Veterans

MDD is one of the most significant risk factors for suicide. Therefore, treating depression with rTMS would likely diminish suicide risk. The annual suicide rate among veterans has been higher than the national average.¹⁵ However, most of these veterans are not getting their care at the Veterans Health Administration (VHA). Major efforts at the VA have been made to address this problem, including modification and promotion of the Veterans Crisis Line, increased mental health clinic hours, mental health same-day appointment availability for veterans, as well as raising awareness of suicide and suicidal ideation.¹⁶ George and colleagues showed that it is safe and feasible to treat acutely suicidal inpatients at a VA or US Department of Defense hospital over an intensive 3 day, 3 treatments per day regimen. This regimen would be potentially useful in a suicidal inpatient population, a technically and ethically difficult group to study.¹⁷

MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.¹⁷ There clearly is a need for additional treatment options. MDD and OCD are the only indications that have received FDA approval for rTMS use. The initial FDA approval for MDD was based on a 2007 study of medication-free patients who had failed previous therapy and found a significant effect of rTMS compared with a sham procedure.⁷ MDD remains a common problem among veterans who have failed one or more antidepressant medications. Such patients might benefit from rTMS.^6,18

rTMS has several advantages over ECT, another significant FDA-approved, nonpharmacologic treatment alternative for medication-refractory MDD. rTMS is less invasive, requires fewer resources, does not require anesthesia or restrict activities, and does not cause memory loss. After an rTMS treatment, the patient can drive home.

Nationwide Pilot Program

The VA pilot program was created to supply rTMS machines nationwide to VHA sites and to offer a framework for establishing a clinical program. Preliminary program evaluation data suggest patients experienced a reduction in depression and suicidal ideation.

There were many challenges to implementation; for example, one VA site was eager to start using the device but could not secure space or personnel. An interdisciplinary team consisting of physicians, nurses, psychologists, suicide prevention coordinators, and others in the VA Palo Alto Health Care System (VAPAHCS) Precision Neurostimulation Clinic (PNC) has been instrumental in overcoming these challenges. VAPAHCS oversees the pilot and employs the national director.

Thirty-five sites nationwide were initially selected due to their ability to provide space for a rTMS machine and appropriate staffing to set up and run a Clinic (Figure 3). The pilot started with tertiary care VA medical centers then expanded to include community-based outpatient clinics as resources permitted. Sites that were unable to meet these standards were not included. Of these 35 original sites, 26 are treating patients and collecting data. Some early delays were due to unassigned relative value units (RVUs) to rTMS, which since have been revised as imputed RVU values. The American Medical Association established and defined RVUs to compare the value of different health care roles.¹⁹ The clinics have been established with smooth operations as the pilot program has provided the infrastructure.

REDCap (www.project-redcap.org), a data collection tool used primarily in academic research settings, was selected to gather program evaluation data through patient questionnaires informed by the VHA measurement-based care initiative. Standard psychometrics were readily available in the VHA application and REDCap Mental Health Assistant includes the Patient Health Questionnaire 9 (PHQ-9) Brief Symptom Inventory 18, Posttraumatic Checklist 5, Beck Scale for Suicidal Ideation, and Quality of Life Inventory. The Timberlawn Couple and Family Evaluation Scale (TCFES), which can be completed in 30 to 35 minutes and is a measure of overall function of relevant relationships, also may be added. Future studies are needed to confirm psychometrics of this scale in this setting, but the TCFES metric is widely used for similar purposes.

Nationwide, more than 950 patients have started treatment (ie, including active, completed, and discontinued treatment) and 412 veterans have completed the rTMS treatment. The goal of the program evaluation is to examine large scale rTMS efficacy in a large veteran population as well as determine predictors of individual patient response. Nationwide, PHQ-9 depression scores declined from a pretreatment average (SD) of 18.2 (5.5; range, 5-27) to a posttreatment average (SD) of 11.0 (7.1; range, 0-27). Patients also have indicated a high level of satisfaction with the treatment (Figure 4). Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response that might be lost in a smaller subset of cases.

Implementation

It took 11 months for the VA contracting department to determine which machine to buy. However, the lengthy process assured that the equipment selected met all standards for clinical safety and efficacy. Furthermore, provision was made to allow for additional orders as new sites came online as well as upgrading the equipment for advances in technology.

The PNC set up several training programs to ensure proper use of this novel treatment. The education is ongoing and available as new sites are identified and initiated. The education includes, but is not limited to, in-person onsite and offsite training programs, online training modules that are available in the VA Electronic Educational Services (EES), and video telehealth consultations. Participants can view online lectures and then receive hands-on training as part of the educational program. Up to 3 HCPs for each site can receive funding to attend. Online programs also are available for new material to support continuing medical education. However, hands-on training is essential to understand how to obtain the motor threshold, which is used to determine the strength of the rTMS stimulus dose. Furthermore, hands-on training is essential for the proper localization of the stimulus, which is determined by certain anatomical landmarks. A phantom mannequin (ERIK [Evaluating Resting motor threshold and Insuring Kappa]) has been developed to assist in the hands-on learning.²⁰

Relative Value Units

The VHA uses RVUs to properly account for workload and clinician activities. As a result, RVUs play an essential role as a currency that denotes the relative value of one type of clinical activity when compared with other activities. Depending on the treating specialty, clinicians generally use procedure codes outlined in the Current Procedural Terminology (CPT) code set or the Healthcare Common Procedure Coding System (HCPCS) for medical billing. Most insurance carriers use RVUs set by the Centers for Medicare and Medicaid Services (CMS) system as a standard system to determine HCP reimbursement for medical procedures.

The CPT codes associated with rTMS currently are 90867 to 90869. CMS had initially assigned a zero RVU to these CPT codes due to wide variations in the cost of performing rTMS. When we began implementing rTMS in the VHA, the lack of RVUs for rTMS rendered it impossible to show clinical workload for this activity using established VHA clinical accounting methods. The lack of RVUs assigned to rTMS CPT codes made justification for this treatment to clinical management difficult, which limited its clinical use in the VHA. In addition, HCPs who were using rTMS to treat severely ill veterans appeared artificially unproductive despite a significant patient workload. As we and VHA leadership became aware the program could not be staffed locally without getting workload credit for work done, the value was raised to 1.37 for treatment (90868) and 2.12 and 1.93 for evaluations (90867) and reevaluations (90869), respectively, thus reducing a potential roadblock to implementation.

Challenges as the Program Expands

Future challenges include upgrading machines to do intermittent θ burst stimulation (iTBS), which decreases the standard treatment time from 37.5 minutes to 3 minutes. Both patients and HCPs find iTBS to have similar tolerability to standard rTMS but in much less time. iTBS mimics endogenous θ rhythms and has been shown to be noninferior to rTMS for depression.^21,22 Several devices have received FDA approval to treat MDD, including the Magstim and MagVenture TMS devices used in this program.

A major challenge for the VHA with rTMS will be to maintain a consistent level of competence and training. There is a need for continued maintenance of staff competence with ongoing training and training for new staff. Novel ways of training operators have been developed including ERIK.

Determining treatment interaction with other psychotherapies and pharmacotherapies is another challenge. Currently, rTMS is considered an adjunctive treatment added to the current patient treatment plan. We do not know yet how best to incorporate this somatic treatment with other approaches, and further research is necessary. A key issue is to determine which approach provides the best long-term results for a patient at risk for recurrence of depression. In addition, more research into maintaining healthy relationships for veterans with both MDD and PTSD is needed.

Many misconceptions exist about rTMS and HCPs need to be educated about the benefits of this modality. In addition, patients should understand the differences between rTMS and ECT. Even with newer approaches that streamline rTMS, the therapy remains costly in terms of direct costs as well as patient and HCP time.

Streamlining rTMS treatment remains an important concern. Compressing treatment schedules (ie, many treatments delivered to a patient in a single day) would allow the entire process to be delivered in days, not weeks. This would be especially advantageous to patients who live far from a treatment site. Performing multiple rTMS daily treatments is especially feasible with iTBS with its short treatment time.

Conclusions

rTMS is an emerging modality with both established and novel applications. The best studied application is treatment resistant MDD. Currently, rTMS has only been approved by the FDA for treatment of MDD. A pilot program was established by the VHA to distribute 30 rTMS machines sites nationwide. Results from data collected by these sites have shown patients improving on standard psychometric scales. Future changes include upgrading the machines to provide θ bursts, which has been shown to be faster and noninferior. Integrating rTMS with other pharmacotherapies and psychotherapies remains poorly understood and needs more research.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²