COVID-19 outbreak and autoimmune bullous diseases: A systematic review of published cases
Authors: Michael Kasperkiewicz
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: Autoimmune bullous diseases (AIBDs) are potentially life-threatening disorders requiring long-term immunomodulatory therapies.1Schmidt E. Kasperkiewicz M. Joly P. Pemphigus.Lancet. 2019; 394: 882-894Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar,2Schmidt E. Zillikens D. Pemphigoid diseases.Lancet. 2013; 381: 320-332Abstract Full Text Full Text PDF PubMed Scopus (801) Google Scholar As the coronavirus disease 2019 (COVID-19) has emerged as a widespread public health emergency since December 2019,3Sharma R. Agarwal M. Gupta M. et al.Clinical characteristics and differential clinical diagnosis of novel coronavirus disease 2019 (COVID-19).in: Saxena S. Coronavirus Disease 2019 (COVID-19). Medical Virology: From Pathogenesis to Disease Control. Springer, Singapore2020: 55-70Crossref Google Scholar we have published recommendations for their management during the outbreak.4Kasperkiewicz M. Schmidt E. Fairley J.A. et al.Expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic.J Eur Acad Dermatol Venereol. 2020; 34: e302-e303Crossref PubMed Scopus (50) Google Scholar However, there is currently only sparse evidence-based information on how the pandemic affects this special patient population, considering that AIBDs are rare conditions and that it is difficult to collect large cohorts. Therefore, a rapid systematic review of published cases has been conducted. Literature was comprehensively screened using the PubMed database from inception to July 28, 2020. Search terms were "pemphigus" or "pemphigoid" or "bullous" or "blistering" combined with "COVID-19" or "SARS-CoV-2" or "coronavirus." Inclusion criteria were English-language clinical and epidemiologic reports related to AIBD cases in association with the COVID-19 outbreak and indexed in the mentioned database. Pure review/recommendation articles and articles not related to both AIBDs and COVID-19/severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were excluded. The main endpoints were the proportion of patients with AIBDs with COVID-19 symptoms and confirmed COVID-19 as well as the rate of related hospitalizations and deaths. Screening and review of articles were performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig 1). Eight articles (7 case series and 1 case report) with a pooled total of 732 patients with AIBDs (211 pemphigus, 112 pemphigoid, 409 not specified) from 3 countries were included in the final analysis (Table I). Except for 1 report, all information was collected via telephone/telemedicine visits that have been performed instead of in-person encounters during the COVID-19 outbreak. COVID-19 symptoms were reported in 70 (9.5%) patients, and in 16 (2.1%) patients the diagnosis was confirmed. Six (0.8%) patients had severe symptoms requiring hospitalization, and 3 (0.4%) died of COVID-19, all of whom were elderly people and/or had comorbidities. Only 3 (0.4%) patients were reported to have some limited control of their AIBD.Table ISummary of published reports relating to COVID-19 and autoimmune bullous disease casesStudy type/originPatient populationDemographic characteristicsComorbiditiesTreatmentCOVID-19Course of AIBDOther main findingsCase series/Italy371 with AIBD (NS)202 women and 169 menMean age: 55.8 yDisease duration NRNRAzathioprine, cyclophosphamide, cyclosporine, dapsone, doxycycline, mycophenolate mofetil, methotrexate, prednisone/prednisolone, rituximab (n = 12), topical corticosteroidsSymptoms: 47 patients with COVID-19–related symptoms (NS)Confirmed diagnosis by PCR: 3 patients (NS)Hospitalization/death: NRNRNone of the patients had discontinued the prescribed therapies on their own accord or because urged by their general practitioners; none of the 12 patients actively on rituximab had COVID-19–related symptoms or positive testing results.Case series/Italy30 with BP, 9 with pemphigus (NS), and 4 with MMPPemphigus: 1 womanAge: 65 yDisease duration: 40 moOther patients NRNRMycophenolate mofetil (n = 1); other NRSymptoms: 1 patient with nausea, fever, anorexia, and asthenia; other patients NRConfirmed diagnosis by PCR: 1 patient (woman, 65 y) with pemphigus receiving mycophenolate mofetilHospitalization/death: NRRemission in the patient with confirmed COVID-19, some posterior tongue discomfort; other patients NR—Case series/Italy5 with BP and 4 with pemphigus (NS)7 women and 2 menAge range: 60-83 y (mean: 71.1 y)Disease duration NRNRPrednisone (n = 9), topical corticosteroids (n = 6), rituximab (n = 1)Symptoms: 8 patients with good general statusConfirmed diagnosis by PCR: 1 patient (NS)Hospitalization/death: NRStable disease (all)—Case series/Italy62 with BP and 31 with PVBP: 28 women and 34 menAge range: 52-98 y (mean: 78.6 y);Disease duration: 1-123 moPV: 14 women and 17 menAge: 19-95 y (mean: 62.5 y)Disease duration: 5-411 moBP: diabetes (n = 22), hypertension (n = 17), neurologic/psychiatric diseases (n = 14), cardiovascular diseases (n = 21), chronic kidney failure (n = 6), dyslipidemia (n = 9), neoplasia (n = 4)PV: diabetes (n = 3), hypertension (n = 1), neurologic/psychiatric diseases (n = 5), cardiovascular diseases (n = 2), dyslipidemia (n = 1), neoplasia (n = 2)BP: azathioprine (n = 4), doxycycline (n = 6), systemic corticosteroids (<20 mg/d prednisone equivalent; n = 52)PV: azathioprine (n = 3), cyclophosphamide (n = 4), dapsone (n = 2), rituximab (n = 1), systemic corticosteroids (<20 mg/d prednisone equivalent; n = 22)Symptoms (BP): 6 patients with mild/moderate symptoms (eg, flu-like symptoms, cough, low-grade fever, and/or anosmia/ageusia); 4 patients with severe symptoms (eg, pneumonia with respiratory failure)Confirmed diagnosis by PCR (BP): 4 patientsHospitalization/death (BP): 4 and 3 (mean age, 85 y; all 3 with severe cognitive impairment) patients, respectivelySymptoms (PV): 6 patients with mild/moderate symptoms (eg, flu-like symptoms, cough, low-grade fever, and/or anosmia/ageusia); 1 patient with severe symptoms (NS)Confirmed diagnosis by PCR (PV): 1 patient (69 y; previous breast cancer)Hospitalization/death (PV): 1 and 0 patients, respectivelyRemission (all)Main risk factor of developing suspected COVID-19 symptoms was contact between the patient and an individual with known/suspected COVID-19; longer disease duration was more frequently associated with suspected COVID-19 symptomatic patients.Case series/China38 with AIBD (NS)NRNRNRNRMild disease (all)17 patients discontinued their therapy; 21 patients admitted that they were worried about COVID-19 infection.Case report/Iran1 with MMP1 manAge: 43 yDisease duration: 4 moDiabetes, hypertension, and benign prostatic hypertrophyIntravenous immunoglobulins (5 × 30 g), mycophenolate mofetil (2 g/d), prednisolone (up to 50 mg/d), rituximab (4 × 500 mg)Symptoms: fever, chills, malaise, dry cough, dyspnea, dizziness, decreased oxygen saturation, pneumonia, and laboratory test result abnormalities (ie, lymphopenia, positive CRP, and high LDH and ESR)Confirmed diagnosis: yes (by spiral chest CT scan; PCR negative)Hospitalization/death: yes and no, respectivelyInitial disease progression, but improvement with intravenous immunoglobulinsImprovement of both MMP and COVID-19 with adjuvant intravenous immunoglobulinsCase series/Italy10 with BP6 women and 4 menMedian age: 68.5 yDisease duration: NRDiabetes, hypertension, malignancy (n = 3)Azathioprine (n = 3), systemic corticosteroids (n = 8), topical corticosteroids (n = 8)NRMild to moderate grade (n = 7) and severe grade (n = 3) of the disease; almost all patients (n = 8) had good control of their disease—Case series/Iran167 with PVMean age: 48.6 ySex and disease duration NR for most patientsNRRituximab (all), corticosteroids and other immunosuppressants (NS; n = 165)Symptoms: 4 patients with fever, nausea, vomiting, myalgia, dry cough, and/or dyspneaConfirmed diagnosis by CT scan: 5 patients, 1 of whom was asymptomatic (4 women and 1 man; mean age, 41.8 y; all without a past medical history)Hospitalization/death: NRNone of the patients with confirmed COVID-19 experienced disease recurrence45 (26.9%) patients received rituximab within 1 year of the pandemic, and none of them developed COVID-19; 150 (89.8%) patients adhered to home quarantine, and all used face masks in public places.AIBD, Autoimmune bullous disease; BP, bullous pemphigoid; CRP, C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; MMP, mucous membrane pemphigoid; mo, month; NR, not reported; NS, not specified; PCR, polymerase chain reaction; PV, pemphigus vulgaris, y, year.Due to the journal's policy, full references of the respective studies cannot be displayed due to limitation in citation numbers. Open table in a new tab AIBD, Autoimmune bullous disease; BP, bullous pemphigoid; CRP, C-reactive protein; CT, computed tomography; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; MMP, mucous membrane pemphigoid; mo, month; NR, not reported; NS, not specified; PCR, polymerase chain reaction; PV, pemphigus vulgaris, y, year. Due to the journal's policy, full references of the respective studies cannot be displayed due to limitation in citation numbers. Although old age and certain comorbidities such as hypertension and diabetes represent well-described risk factors for complicated COVID-19, the role of immunosuppression remains controversial.3Sharma R. Agarwal M. Gupta M. et al.Clinical characteristics and differential clinical diagnosis of novel coronavirus disease 2019 (COVID-19).in: Saxena S. Coronavirus Disease 2019 (COVID-19). Medical Virology: From Pathogenesis to Disease Control. Springer, Singapore2020: 55-70Crossref Google Scholar,5D'Antiga L. Coronaviruses and immunosuppressed patients: the facts during the third epidemic.Liver Transpl. 2020; 26: 832-834Crossref PubMed Scopus (521) Google Scholar Taking into account that approximately 15% of COVID-19 cases are of a severe nature in the general population and that the overall mortality rate associated with COVID-19 is 1.5% to 3.6%,3Sharma R. Agarwal M. Gupta M. et al.Clinical characteristics and differential clinical diagnosis of novel coronavirus disease 2019 (COVID-19).in: Saxena S. Coronavirus Disease 2019 (COVID-19). Medical Virology: From Pathogenesis to Disease Control. Springer, Singapore2020: 55-70Crossref Google Scholar this preliminary systematic analysis suggests that patients with AIBDs receiving immunomodulatory therapies are basically not at increased risk of severe or fatal COVID-19. This assumption, which may potentially be at least partly associated with enhanced disease prevention in this patient cohort, is in line with previous reports about other immunosuppressed patient populations during the present and past coronavirus outbreaks.5D'Antiga L. Coronaviruses and immunosuppressed patients: the facts during the third epidemic.Liver Transpl. 2020; 26: 832-834Crossref PubMed Scopus (521) Google Scholar The results further indicate that the pandemic generally does not seem to negatively affect the course of AIBDs. Therefore, although surveillance of and precautions for this particular patient group must remain, delays or obstructions in important immunomodulatory treatment should be avoided during the pandemic. Nevertheless, data from this brief systematic review need to be interpreted with caution until more comprehensive investigations such as international registries further define the influence of COVID-19 on patients with AIBDs.