This manuscript presents a report of bullous pemphigoid rash associated with COVID-19 for the first time. The objective of this manuscript is to present a unique dermatological case in the setting of a COVID-19-positive infection to further recognize the virus symptomatology. A 37-year-old female with a past medical history of class III obesity, type II diabetes mellitus, and hypertension presented to the emergency department in September 2020 with inpatient and outpatient follow-up through to November 2020. The patient denied any personal or family history of skin disorders. The patient tested positive for COVID-19 prior to hospitalization and presented to the hospital with severe, persistent, pruritic rash meeting dermatopathological, serologic, and clinical criteria for bullous pemphigoid diagnosis. Histopathology H&E punch biopsy from her left flexor wrist demonstrated epidermal keratinocyte necrosis, subepidermal vesiculation with eosinophils, gossamer stranding of the papillary dermis, and subepidermal edema. Direct immunofluorescence punch biopsy from her left flexor wrist demonstrated strong linear IgG staining at the dermoepidermal junction, with weaker and focal linear C3 staining. Antigen-specific serology was consistent with bullous pemphigoid. There was no previously reported cutaneous association of COVID-19 infection with bullous pemphigoid making this case an important addition to the body of evidence helping to identify bullous pemphigoid in the setting of viral infection.
In 2019, a (Novel) coronavirus emerged in Wuhan, China. The virus has been found to cause severe pneumonia and has affected 35 million people, resulting in 1.5 million deaths worldwide since its emergence. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus that spreads via aerosolized droplets and enters host cells through the angiotensin-converting enzyme 2 (ACE2) receptor [
Our patient is a 37-year-old female with a past medical history of type II diabetes mellitus, hypertension, and class III obesity who presented to the emergency department in September 2020 with a worsening rash. On the day of admission, she noted the development of red, raised lesions on her arms over the course of the last week. The lesions were mildly pruritic and nontender. The following day, she began experiencing typical COVID-19 symptoms (fever, shortness of breath, and muscle aches) and tested positive for COVID-19 on day 3 of her symptoms. She had no personal or family history of dermatologic or autoimmune conditions. No recent changes in the environment, detergent, soaps, or lotions were reported. No recent immunizations or changes in medications were reported. Medications included lisinopril 20 mg QD since February 2020 for hypertension and metformin 500 mg BID since February 2020 for type II diabetes mellitus.
The rash spread to her lower extremities, torso, and ultimately onto her neck and chin over the ten days before she presented to the ED. The lesions became larger, and some started to blister. The severity of the pruritus and discomfort motivated her to come to the emergency department. She was found to be tachypneic but oxygenated well on room air. Supplemental oxygen was given at 1-2 L by using a nasal cannula to relieve tachypnea with no hypoxia noted during hospitalization.
On examination, the patient reported negative Nikolsky sign, blanching, blisters tense and tender to palpation, and scaly lesions nontender to palpation. No mucosal involvement was observed on physical exam (Figure
(a) Left hip with blanching and tense blisters that are tender to palpation. (b) Bilateral lower extremities with erythematous, scaly annular lesions which are pruritic and at varying stages of the disease.
Hematologic studies for the patient were found to be normal. On admission, she did demonstrate mild hypokalemia (which resolved during her hospital stay), elevated blood glucose (serum ranged from 134 mg/dL to 146 mg/dL and HbA1C 5.8%), hypoalbuminemia, and elevated liver enzymes (ALT and AST). A D-dimer and C-reactive protein were also ordered and found to be elevated. Figures
Laboratory results. (a) Complete blood count. (b) Complete metabolic panel. (c) D-dimer. (d) C-reactive protein. (e) Hemoglobin A1C.
Table
Patient lab results.
Diagnostic | Location/type | Result | Normal value |
---|---|---|---|
Biopsy | Left flexor wrist | Epidermal keratinocyte necrosis, subepidermal vesiculation with eosinophils, gossamer stranding of the papillary dermis, subepidermal edema | <20 RU/mL (negative) |
Direct immunofluorescence | Left flexor wrist | Strong linear IgG staining at the dermoepidermal junction, with weaker and focal linear C3 staining | ≥20 RU/mL (positive) |
Antigen-specific serologic testing | Bullous pemphigoid 180 IgG Abs | 211.4 RU/mL | <20 RU/mL (negative) |
Bullous pemphigoid 230 IgG Abs | <1.0 RU/mL | ≥20 RU/mL (positive) |
Differential diagnoses were erythema multiforme, chemical burn or exposure, leukocytoclastic vasculitis, drug reaction, granulomatosis with polyangiitis, urticarial vasculitis, and other viral exanthems.
She was treated with oral diphenhydramine, topical diphenhydramine, triamcinolone 0.5% cream, and IV dexamethasone 6 mg. Her home medications (metformin and lisinopril) were held during her hospital stay, and the patient was placed on sliding-scale correctional insulin for persistently elevated blood glucose values. Lisinopril was withheld due to the association with bullous pemphigoid, though the patient had been taking it without issues for years. She was discharged on oral dexamethasone 6 mg to complete a 10-day course in addition to topical diphenhydramine and triamcinolone. Since discharge, she has repeated multiple steroid courses due to the persistent discomfort associated with the rash as it improves with steroids and then flares back up upon completion of steroid courses. She has also been taking nicotinamide to help with her rash. Her dyspnea, body aches, and fever resolved shortly after discharge, and the rash was her only remaining symptom.
The patient has completed multiple steroid courses with continued exacerbations of the rash. At the end of November 2020, she was starting her third prednisone taper since discharge in addition to doxycycline. At the time of publication, immune-modulating therapies were under consideration but not yet initiated.
Pathological disease course since initial admission is as follows: First clinic visit on 11/17/2020: the patient was started on doxycycline 100 mg BID and nicotinamide 500 mg TID, and prednisone taper was initiated. She initially declined immunosuppressive agents given the COVID-19 pandemic. Telehealth visit on 12/9/2020: the patient stopped doxycycline and nicotinamide as per the provider’s recommendation. The patient was admitted on 12/11–12/14 for bullous pemphigoid flare requiring hospitalization for pain control and wound care. Office visit on 12/29/2020: the patient noted worsening with the painful blister formation on the face, arms, groin, legs, and back, with interference with the ability to sleep and work. The patient received two rituximab infusions on 1/11/2021 and 1/25/2021. She continued hydroxyzine 25–50 mg nightly QHS for pruritus. Pt was seen at dermatology clinic on 3/23 and is doing very well after the second rituximab infusion. Has no blisters and is down to 7.5 mg prednisone. Will continue to slowly decrease dose. Patient to follow up in 4 weeks.
Verbal consent for the use of images and the case report was obtained from the patient. No written consent has been obtained from the patient as there are no identifiable data included in this case report.
This submission presents a review of the current literature related to cutaneous manifestations of SARS-CoV-2 and the case of a woman who tested positive for COVID-19 after she noticed an annular, bullous, pruritic rash on her extremities two days prior to her diagnosis. The clinical picture of her rash was consistent with bullous pemphigoid, a condition which, to date, has not been associated with COVID-19.
In a recent literature review, Gisondi et al. reported on novel cutaneous manifestations of COVID-19 and discovered several dermatological presentations. These included exanthems (varicella-like, papulovesicular, and morbilliform rash), vascular (chilblain-like, purpuric/petechial, and livedoid lesions), urticarial, and acropapular eruption [
A popular opinion among cutaneous involvement of COVID-19 is that patients experience varying types of vasculitis, one being its effect on the dermal/epidermal junction of the skin. Becker examined the effects of COVID-19 on the circulatory system and found multiple case reports in which urticarial vasculitis was implicated [
There have also been numerous case studies that have described dermatologic conditions associated with COVID-19, which do not necessarily fall under the category of vasculitis. Due to the difficulty in accessing dermatology consultation during the pandemic, skin manifestations of the disease may be underrecognized, and it is important to study them further.
While COVID-19-related dermatologic conditions have been relatively well documented in the literature, our patient’s presentation of bullous pemphigoid has not previously been associated with COVID-19 infection. Bullous pemphigoid is an uncommon intraepidermal blistering disease caused by autoantibodies to adhesion molecules expressed in the skin and mucous membranes. The bullae appear spontaneously and are painful when they rupture. Bullous pemphigoid is a relatively benign pruritic disease characterized by tense blisters most commonly seen in flexural areas, with a course characterized by exacerbations and remissions [
Bullous pemphigoid flares are associated with the binding of autoantibodies to the proteins of hemidesmosomes triggering an inflammatory pathophysiological process ultimately leading to dermal-epidermal junction cleavage and blister formation [
It is well understood that the underlying cause of bullous pemphigoid is due to autoantibodies that are directed at adherence proteins within the skin; however, little evidence exists that discusses the triggering factors for the development of such autoantibodies [
There have been case reports of patients developing bullous pemphigoid following vaccine administration and viral infection [
Though recent literature reports a strong correlation between viral infections and the development of BP, it is prudent to consider that most patients diagnosed with pemphigus rashes have a genetic predisposition to the development of autoantibodies directed towards the dermal proteins BP180 and BP230, which play a critical role in maintaining epidermal adhesion [
Recent studies have reported that nearly all patients who develop pemphigoid rash have an increased frequency of the DQB1
The role of complement deposits found within the blister fluid is also an important consideration in the etiology of BP, especially in our patient who was newly diagnosed with COVID-19. Romeijn et al. cited that complement deposits are found in the blister fluid of 83.1% of the skin biopsies of patients diagnosed with bullous pemphigoid [
It is important to note that it is entirely possible that our patient had developed both conditions simultaneously without one precipitating the other. It would be prudent to consider the possibility that the two disease processes were unrelated conditions in this patient. Further investigation for a causative relationship between COVID-19 and BP is warranted.
This case presents a unique dermatologic presentation of COVID-19 and recent literature on potential pathophysiology of BP in COVID-19-positive patients. SARS-CoV-2 enters the host cell through the ACE2 receptor, which is found on multiple cell types including dermatological cells. Once it enters into a host cell, the virus activates complement, and, in turn, inflammatory cells are recruited to the cell eliciting a response [
This research is important for medical practitioners to continue to understand COVID-19 and associated dermatological manifestations. The pathogenesis of both COVID-19 and bullous pemphigoid is complex. Perhaps, their relation to one another as in this case will allow for a deeper understanding of each disease and the mechanisms by which they evolve and progress.
“It’s been really horrible and difficult. The itching and the pain have been difficult to deal with. The outcome of having bullous pemphigoid so young makes me worried. It’s supposed to take years to fully go away and usually happens to older people. It’s embarrassing when the blisters are on my arms and people can see them. If it is from COVID, then people should really listen when they tell us not to attend group gatherings.
I experience worsening symptoms whenever I take less than 30 mg of prednisone.
It’s difficult to sleep at night because the blisters on my back are so itchy and it’s hard to lay on them. Insurance only pays for a small amount of topical creams and I need to use so much over my whole body, so it doesn’t really work as an option. Hot showers sometimes help the itching, but I still don’t sleep well. It’s just so difficult and I hope it gets better.”
The case report, meta-analysis, and scientific data used to support the findings of this study are included within this study. These prior studies are cited at relevant places within the text as references [
This study was approved by the Rocky Vista University IRB (RVU IRB no. 2020-0123 Exempt Category).
The authors declare no conflicts of interest.
The authors wish to thank Kelsey Sherman, Bradley Brown, Jonathan Dill, Kimberly Insel, Trevor Harrington, Tom Califf, and Zoey Thompson for providing care for their patient and for informative discussions which helped shape this manuscript. Images were provided by Tom Califf and Angela Delano.