Cytomegalovirus skin disease in a kidney transplant patient

Abstract

A 44-year-old man with a history of renal transplantation presented with right lower abdominal wall swelling, redness and pain. A bacterial abscess was drained, and he was discharged home with oral antibiotics. After failing to improve, he returned to the hospital, where he was briefly treated with intravenous antibiotics and discharged home again. The patient returned 5 days later, reporting worsening right groin swelling that extended into the ipsilateral scrotum. Imaging revealed a persistent fluid collection in the region, and he was taken for surgical debridement. Tissue immunochemistry and histopathological evaluation identified cytomegalovirus infection. Plasma quantitative PCR for cytomegalovirus demonstrated high viraemia. The patient was successfully treated with intravenous ganciclovir, followed by oral valganciclovir, with resolution of the skin changes. Persistent hydrocele with epididymitis on imaging suggests that this process may have been the source of the cutaneous cytomegalovirus infection.

Background

Cytomegalovirus (CMV) is a human herpesvirus that commonly causes a latent and asymptomatic infection. However, immunocompromised patients, such as those living with HIV or receiving organ transplantation, are particularly susceptible to more severe disease.¹ In solid organ transplant (SOT) recipients, CMV remains a major contributor to morbidity and mortality despite preventive strategies.² Manifestations of CMV infection in SOT recipients range from a viral syndrome with fever, myalgias and laboratory abnormalities to tissue-invasive disease that frequently affects the allograft.³ CMV infection of the skin is rare. When present, CMV infection of the skin usually manifests as a rash, nodules or ulcers and has been associated with poor prognosis.⁴ We present a case of cutaneous CMV disease in a kidney transplant patient. This report underscores the importance of specific microbiological diagnosis and understanding the net state of immunosuppression in transplant recipients.⁵

Case presentation

A 44-year-old man presented to the emergency department (ED) with right lower abdominal wall swelling, redness and pain for 3 days. Physical examination was notable for a superficial abscess, and a bedside incision and drainage was performed. Purulent material was sent for culture, and the patient was sent home on a 7-day course of oral cephalexin and trimethoprim–sulfamethoxazole. The patient returned to the ED 2 days later having worsening swelling of the affected region, and he was admitted to the hospital for intravenous antibiotics. On hospital day 3, he was discharged home to complete a course of oral antibiotics. The patient returned 5 days later, again reporting worsening right groin swelling that now extended into the ipsilateral scrotum. He was readmitted and infectious diseases was consulted. He was initiated on empiric antibiotics with levofloxacin and doxycycline to cover typical skin flora.

His medical history included type 2 diabetes, hypertension, gout and kidney transplant 14 months prior to presentation. At the time of transplantation, the patient was CMV‐seropositive and received an organ from a deceased CMV‐seronegative donor. His post-transplant course had been complicated by allograft rejection requiring pulse glucocorticoids and antithymocyte globulin 1 month after transplantation. Ten months post-transplant, he developed focal segmental glomerulosclerosis of the graft and required treatment with plasmapheresis and high-dose prednisone. His medications at the time of hospital presentation included tacrolimus, mycophenolate, prednisone, atovaquone, nystatin, insulin, nifedipine, metoprolol and aspirin. Valganciclovir prophylaxis had been discontinued 6 months after renal transplantation.

The patient reported no prior trauma to the affected skin region. Of note, 1 month after transplantation, he developed a perianal abscess that was treated with incision and fistulotomy. Abscess cultures grew Streptococcus constellatus.

He was born in the Caribbean but had been living in the USA for several decades. He was in a monogamous relationship with his wife and reported no history of sexually transmitted infections.

On admission, the patient’s vital signs were as follows: temperature 37°C, blood pressure 130/80 mm Hg, heart rate 65 bpm. Skin examination revealed swelling, erythema and tenderness of the right lower quadrant abdominal wall that extended into the right groin and scrotum. Examination of the allograft region was notable for a mature scar. The remainder of the physical examination was unremarkable.

Investigations

Initial laboratory testing was notable for a white cell count of 7.8 cells x 10⁹/L and serum creatinine of 6.9 mg/dL (baseline 3.1). Cultures from the drainage performed in the ED (10 days earlier) revealed susceptible Streptococcus anginosus. Nucleic acid amplification testing of urine was negative for Neisseria gonorrhoeae and Chlamydia trachomatis.

A CT with contrast of the abdomen and pelvis showed a 4.4×4.5×2.3 cm fluid collection and inflammation of the subcutaneous soft tissues at the right lower quadrant extending into the inguinal region that was suggestive of cellulitis. A Doppler ultrasound of the scrotum was compatible with right-sided epididymo-orchitis.

Treatment

The patient was taken to the operating room for the surgical debridement of the abdominal wall. During the procedure, purulent fluid was drained, and subcutaneous tissue was sent for culture and histopathology. Bacterial cultures were negative. However, tissue biopsy identified CMV by inclusions and positive immunohistochemistry staining (figure 1). A plasma quantitative PCR for CMV was elevated, with a viral load of 11 225 IU/mL. The patient was started on intravenous ganciclovir, and antibiotic therapy with levofloxacin and doxycycline was continued.

Figure 1.

(A) H&E stain of tissue from debridement of groin wound. Cytopathic effect of cytomegalovirus (CMV) is demonstrated by a cell (centre of the image) with cytomegaly and a large, single intranuclear inclusion surrounded by a clear halo in the periphery. Prominent acute inflammation is also present. (B) Immunohistochemical staining for CMV. Positive cells are shown staining dark brown.

Outcome and follow-up

After 10 days of ganciclovir therapy, the patient’s plasma CMV viral load became undetectable, and he was transitioned to oral valganciclovir for secondary prophylaxis. A repeat CT of the abdomen and pelvis demonstrated no residual fluid collections in the abdominal wall; however, persistent right scrotal swelling was noted on exam and ultrasonography. Urology consultants attributed the groin swelling to a reactive hydrocele, and no further surgical intervention was recommended.

After a 20-day hospital stay, the patient was discharged home on valganciclovir prophylaxis and a 2-week course of doxycycline and amoxicillin–clavulanate with resolution of his symptoms. At 4 months of follow-up, the patient had no recurrence of the abdominal wall infection. Elective hydrocelectomy was offered for his persistent right scrotal swelling, but the patient declined. Unfortunately, posthospitalisation, the patient developed renal allograft failure and was restarted on haemodialysis. He is currently listed for a second transplant.

Discussion

CMV tissue-invasive disease in SOT recipients commonly presents after antiviral prophylaxis has been discontinued and is characterised by fever, malaise, leucopaenia, thrombocytopaenia, elevated liver function tests and signs of end-organ inflammation (eg, colitis, pneumonitis, etc). In the most cases, CMV identification on histopathology is necessary for diagnosis and, while CMV viraemia is often present in tissue-invasive disease, its absence does not exclude the diagnosis. Ganciclovir and valganciclovir are first-line treatments for CMV disease, and clinical resolution of symptoms and virological clearance should dictate treatment duration.^{2 6} In our patient, we initially treated with intravenous ganciclovir for 10 days and then transitioned to oral valganciclovir when he displayed clinical improvement and declining plasma viral load. Once he achieved an undetectable CMV viral load, we continued him on secondary prophylaxis with valganciclovir, though the optimal strategy for preventing recurrence has not been established.²

CMV infection can present with protean manifestations, including, in some cases, skin eruptions. However, invasive skin disease proven by histopathology is rare.⁴ Our patient’s presentation is particularly notable because cellulitis and abscess have not previously been reported in CMV skin disease, to our knowledge. The typical histopathological findings in the stromal layer argue for true cutaneous infection, as opposed to other cases where haematogenous dissemination may have accounted for CMV localisation in the skin.⁷ On the other hand, it is unlikely that CMV alone caused his clinical presentation. Instead, a concurrent bacterial and viral infection is a more plausible scenario.

We performed a literature review of all published case reports of CMV skin infection in SOT recipients. The results of our review are shown in table 1. To the best of our knowledge, there have been 29 cases of CMV skin disease in SOT recipients reported to date. The mean age at diagnosis was 48 years (IQR 36.5–61), and the majority were male (20/28, 71.4%). Kidney transplantation was the most common SOT (19/29, 65.5%) among reported cases. The mean time to presentation after transplant was 23.7 months (IQR 1–30), the most frequent localisation was the anogenital region (14/28, 50%), and the most common skin lesion was an ulcer (21/28, 75%). Patients frequently presented with concurrent infections. Reported overall mortality in these cases was 28.5% (8/28), although most deaths were reported before adequate antiviral therapy was available.^{4 8–28} The predominant type (ulcer) and location (perianal) of cutaneous CMV manifestations noted in SOT recipient reports are echoed in a large review on the topic that included non-immunocompromised hosts, suggesting similar clinical presentation regardless of immune function. However, a specific comparison between SOT and immunocompetent hosts was not performed.²⁹

Table 1.

Clinical characteristics and outcomes of reported cases of cutaneous cytomegalovirus disease in solid organ transplant recipients

Reference	Year	Age, sex	Transplant	Post-transplant	Localisation	Clinical description	Extracutaneous CMV	Coinfection	Treatment	Outcome
Minars et al22	1977	24, F	Kidney	1 year	Elbow, thigh	Necrotic ulcer	Lungs, liver, kidneys, breast, ovaries, adrenals, parathyroids, eyes	Escherichia coli bacteraemia	None	Died
Pariser et al23	1983	32, M	Kidney	3 months	Generalised, genital	Maculopapular rash, ulcer	Liver, bone marrow, lungs	–	None	Died
Patterson et al24	1988	39, F	Liver	1 month	Chest, arm, thighs	Necrotic ulcer	Liver, blood	Sepsis	G	Died
Elenitsas et al20	1988	7, M	Liver	10 days	Generalised	Purpura	Liver, lung, urine	Sepsis	G	Died
Lee4	1989	40, M	Liver	1 month	Supraclavicular	Ulcer	–	–	None	Alive
		53, M	Heart	2.5 years	Hip / wound	Ulcer	Liver, blood	Sepsis, Candida (ulcer), dissem. HSV	None	Died
		29, M	Heart, Lung	3 months	Generalised	Purpura	Lung, urine, throat	Pseudomonas sepsis	None	Died
Rees et al*26	1991	–	Heart	–	–	–	Lung	Toxoplasmosis	G	–
Trimarchi et al10	2001	56, M	Kidney	4 months	Trunk	Maculopapular rash, ulcer	Liver, bone marrow, blood	–	G	Alive
Ruiz et al14	2002	70, F	Kidney	20 days	Leg	Plaque	Blood	Pseudomonas perirenal abscess	G	Alive
Choi et al9	2006	54, M	Liver	–	Gluteal	Ulcer	Enterocolitis	–	G	Alive
		54, M	Liver	–	Gluteal	Ulcer	–	–	G	Alive
		31, M	Kidney	–	Genital	Ulcer	–	–	G	Alive
		62, F	Kidney	–	Genital	Ulcer	–	HSV-2 (ulcer)	G	Alive
Kaisar et al15	2007	39, F	Kidney	7 years	Perianal	Ulcer	–	–	G, V	Alive
		34, M	Kidney	6 months	Ear	Nodule	Tongue, blood	Pseudomonas osteomyelitis	G, V	Died
Reino et al27	2008	29, M	Kidney	4 months	Ureterostomy site	Ulcer	–	Pseudomonas UTI	G	Alive
Moscarelli et al17	2010	54, F	Kidney	1 month	Perianal	Ulcer	Blood	HSV-2 (ulcer)	G, V	Alive
Ryan et al28	2011	57, F	Liver	–	Perianal	Ulcer	Blood	–	V	Alive
Prasad et al25	2010	52, M	Kidney	2.5 years	Axilla, genital	Ulcer	Blood	Pseudomonas (ulcer)	G, V	Alive
Garib et al21	2013	50, F	Kidney	–	Thighs, abdomen, genital	Exophytic plaques	Blood	HSV (skin)	G	Alive
		62, M	Kidney	–	Genital	Verrucous nodule	–	HSV-2 (skin)	V	Alive
Lloret-Ruiz et al16	2015	60, M	Heart	10 years	Arm	Ulcer	–	Pseudomonas sepsis and skin	V	Alive
Pinca et al19	2016	65, M	Kidney	1 month	Scrotal	Ulcer	Blood	–	V	Alive
Ezzatzadegan et al11	2016	67, M	Kidney	1 month	Face	Ulcer	Kidney, blood	E. coli UTI, HSV (ulcer)	G	Alive
Neumann et al18	2016	68, M	Kidney	2 months	Genital	Ulcer	Tongue, blood	Pulmonary sepsis	G	Died
Mena Lora et al12	2017	47, M	Kidney	5 years	Elbow	Ulcer	–	–	V	Alive
Wang et al13	2018	67, M	Kidney	10 years	Leg/wound	Ulcer	Eye, blood	–	G, V, FN, CMV-IG	Alive
Present case		44, M	Kidney	14 months	Abdomen	Cellulitis	Blood	Streptococcus anginosus cellulitis	G, V	Alive

*Unable to retrieve for review.

CMV, cytomegalovirus; F, female; FN, foscarnet; G, ganciclovir; HSV, herpes simplex virus; IG, immune globulin; M, male; UTI, urinary tract infection; V, valganciclovir.

Given the paucity of cases, other authors have proposed that the skin offers an unwelcoming environment for CMV.¹⁰ Several factors appear to be necessary for infection to occur, including local and systemic inflammation and host immunosuppression. Early works reported that damaged or coinfected tissue might be more susceptible to CMV.⁴ More recent research has better elucidated the inflammatory milieu that favours reactivation of latent virus. Specifically, stimuli by tumor necrosis factor alpha (TNF‐α), prostaglandins and stress catecholamines appear to be involved.^30–33 Many of the cases in SOT recipients presented with either sepsis, concurrent bacterial skin infection, or previous tissue damage. The case we present here had purulent cellulitis with S. anginosus and was severely immunosuppressed.

Finally, our patient presented with right scrotal swelling and ultrasonographic evidence of epididymo-orchitis that was managed expectantly. Epididymo-orchitis caused by CMV in SOT recipients has been rarely reported.^{34 35} Given the contiguous nature of the abdominal cellulitis, it is possible that CMV was also involved in this process. However, scrotal tissue was not available to reach a definitive diagnosis.

In conclusion, we present a case of CMV cutaneous disease in a kidney transplant recipient presenting as cellulitis of the abdominal wall. Though the patient likely had a concurrent bacterial skin infection, he failed to improve with antibiotics and drainage alone, suggesting that CMV played a causative role in his presentation. This case underscores the importance of specific microbiological diagnosis and maintaining a high index of suspicion for atypical organisms when evaluating SOT patients.

Learning points.

• Histopathological identification of cytomegalovirus (CMV) inclusions and positive immunohistochemical staining in the stromal layer is critically important in diagnosing invasive cutaneous CMV disease.

• Cutaneous disease is a rare manifestation of CMV infection in immunocompromised patients; in addition to ulcers, it can present with cellulitis and abscess.

• Cutaneous CMV infection may be more common in younger patients and those with a history of renal transplant. It may be associated with a concurrent bacterial skin infection and is often found in the anogenital region.

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