Cutaneous Cytomegalovirus Infection Presenting As Recalcitrant Bullous Pemphigoid Lesion

Abstract

Cytomegalovirus (CMV) infection is common among immunocompromised hosts; however, its cutaneous manifestation is considered rare in comparison to internal organ involvement. Clinical manifestations of cutaneous CMV infection generally include perioral or perianal ulcerations. On the other hand, autoimmune bullous dermatosis can have bullae and ulcerations similar to those caused by cutaneous CMV infection. Autoimmune bullous dermatosis requires treatment with immunosuppressive agents for relatively long periods, which may cause reduction of immunocompetence. Because of this iatrogenic immunosuppression, patients with autoimmune bullous dermatosis subsequently acquire increased risk for opportunistic infections. However, cases of bullous pemphigoid (BP) complicated by cutaneous CMV infection are rarely reported. Herein, we report the case of an 88-year-old male who had BP and subsequently recalcitrant perianal skin lesions, which were eventually diagnosed as cutaneous CMV infections.

INTRODUCTION

Cytomegalovirus (CMV) persists among infected individuals in a latent state, usually without symptoms across its host’s lifetime¹. It reactivates when the infected host develops an immunosuppressed state which is followed by various breakthrough presentations of CMV-related diseases. Cutaneous manifestations of CMV infections are rare, especially among patients who do not have acquired immune deficiency syndrome². It can present with diverse clinical manifestations such as plaques or erosions, petechiae, purpura, vesicles, and bullae, impending its accurate clinical diagnosis. The most common form of CMV’s cutaneous manifestation is ulceration around the periorificial area. However, when accompanied by underlying dermatologic disease, further challenges may complicate diagnosis, especially if the concomitant disease is bullous dermatosis.

CASE REPORT

An 88-year-old male with bullous pemphigoid (BP) was admitted to our hospital with chief complaints of aggravated skin lesions from BP and severe pain. Multiple bullae and erosions caused by BP were ubiquitously distributed across the skin. His BP had histopathologic confirmation prior to his admission, with epidermal spongiosis and subepidermal blister formation with cellular infiltration consisting of eosinophils and neutrophils on lesional skin biopsy. Direct immunofluorescence showed linear deposition of immunoglobulin (Ig) G and C3 in the dermoepidermal junction, consistent with BP. The patient had been treated with oral prednisolone (PD) and mycophenolate mofetil (MMF). Most of the patient’s skin lesions had improved following the use of systemic immunosuppressants with careful wound dressing. However, the lesions on the buttocks remained relatively unchanged (Fig. 1A), prompting further evaluation. Potential infection with the herpes simplex virus (HSV) was excluded through examination by real-time polymerase chain reaction (RT-PCR) of the skin swab sample. An additional skin biopsy from the edge of the lesion revealed endothelial cells with large nuclei and basophilic intranuclear inclusions (Fig. 2A). Immunohistochemistry for CMV infection was found to be positive (Fig. 2B). RT-PCR for CMV in a blood sample showed negative results and serology for CMV infection showed positive IgG and negative IgM. Based on clinical presentation and histopathological findings, the recalcitrant skin lesions on the buttocks were diagnosed as cutaneous CMV infection, superimposed over BP, and he was treated with intravenous ganciclovir at 2.5 mg/kg daily. The lesions rapidly improved in 1 week and were completely resolved at 4 weeks following initiation of treatment (Fig. 1B).

Fig. 1. (A) Remaining refractory ulcerations on the buttock after systemic treatment with immunosuppressors in a patient with bullous pemphigoid. (B) Improved ulcerations on the buttock after 1 week of systemic ganciclovir treatment, same patient.

Fig. 2. (A) A skin biopsy sample taken from ulceration on the buttock showed endothelial cells with large nuclei and basophilic intranuclear inclusions (H&E, ×400). (B) Immunohistochemistry for cytomegalovirus infection was positive, same biopsy sample (×400).

We received the patient’s consent form about publishing all photographic materials.

DISCUSSION

Autoimmune bullous dermatosis inevitably requires long-term treatment with immunosuppressants, even in elderly patients despite its possible risk of treatment-related complications including iatrogenic immunosuppression. Autoimmune bullous diseases are usually controlled with PD in conjunction with other immunosuppressive agents such as MMF or azathioprine (AZA), for their steroid-sparing effect. MMF is preferred over AZA because of its higher immunosuppressive potency, and better safety profile. MMF has a wide therapeutic index and low incidence of grave side effects such as serious infections, and major end-organ toxicity. However, MMF can increase the risk of CMV-related disease³. The detailed mechanism by which MMF reactivates CMV has not yet been defined. However, few hypotheses have been proposed; the ability of MMF to modify cytokine profiles related to viral replication may impact CMV disease⁴ or the inhibitory potential of MMF against both T and B lymphocytes may play a role in immunity against CMV⁵,⁶. The use of immunosuppressants in patients with a defective skin barrier can promote cutaneous viral infections, such as CMV or HSV infections⁷.

Cutaneous CMV infection concurrent with the bullous disease has rarely been reported, which may be partly due to cutaneous CMV disease’s diverse, non-specific clinical features and the difficulties in differentiating between underlying bullae and CMV-induced erosions. There are three case reports about simultaneous presentation of both BP and CMV infection. Two of them were focused on systemic, instead of cutaneous manifestations of CMV⁸,⁹, while the other one described a case of a BP patient with oral ulcerations¹⁰. Our patient did not have any systemic features of CMV infection including gastroenteritis, hepatitis, or pneumonitis and showed skin lesions analogous to BP which were confirmed through lesional biopsy. Furthermore, we observed improvement following ganciclovir therapy. Viral infections including CMV have been suggested to trigger BP¹¹; however, based on our patient’s clinical course, we believe that cutaneous CMV infection, in this case, clinically overlapped with BP. The patient presented with lesions typical of BP and the diagnosis was confirmed upon skin biopsy and histopathology. Majority of cutaneous ulcers and bullae were resolved following systemic immunosuppressant except for the perianal lesions, and these perianal lesions resolved following administration of antiviral therapy for CMV infection. In our case, the use of MMF in an elderly patient over 80 years of age, with impaired skin barrier from by BP, may have synergistically precipitated CMV reactivation.

This emphasizes the importance of differential diagnose for possible cutaneous co-infections, especially CMV-associated diseases in patients with autoimmune bullous dermatosis who have been treated with MMF but were unresponsive to conventional therapies.