Hepatitis B virus and cytomegalovirus coinfection in an older patient: a case report

Abstract

Cytomegalovirus (CMV) infection involving the skin is relatively rare. We herein report a case involving a man in his late 70s with positive hepatitis B surface antigen who presented with multiform skin lesions, including a papuloid rash, papular urticaria, and purpura. The patient had taken no antiviral drugs for nearly 13 years but had recently developed severe liver injury. Laboratory examination revealed positive CMV immunoglobulin M, CMV polymerase chain reaction result of 1.09 × 10² copies/mL, and a slightly decreased CD4+ cell count; however, the CD8+ T-cell count was within the normal range. A skin biopsy was performed in the region of the papular eruption on the left inner thigh, and the pathologic findings were consistent with CMV infection. After admission, the patient began a combination of antiviral therapy for hepatitis B virus and CMV. After 3 weeks of treatment, the patient was discharged with skin lesions, and his liver function recovered.

Introduction

Cytomegalovirus (CMV) belongs to the Herpesviridae family and induces latent infection after the primary phase. ¹ CMV infection with skin lesions is rarely reported and easily misdiagnosed because of its nonspecific clinical presentation and difficulty identifying pathological changes. Hepatitis B virus (HBV) is a hepatotropic virus that can lead to persistent and chronic infection in humans. Approximately 3.5% of people worldwide have chronic hepatitis B (CHB).^2,3 Mismanagement of HBV and CMV coinfection can lead to aggravation of hepatocyte damage and liver failure. ⁴ Proper treatment of HBV and CMV is required for an improved prognosis. ⁵ We herein describe an older man who presented with multiform skin lesions and progressive aggravation of liver function caused by CMV and HBV coinfection.

Case report

The reporting of this study conforms to the CARE guidelines. ⁶

A man in his late 70s who had been positive for hepatitis B surface antigen for nearly 13 years was admitted for evaluation of elevated liver function biomarkers [including alanine aminotransferase (ALT), aspartate transaminase (AST), and γ-glutamyl transferase (GGT)] and skin lesions that had been present for >10 days. His medical history included a >50-year history of smoking 20 cigarettes per day; however, he had not been smoking for the past 10 years. He also had a 60-year history of persistent moderate drinking.

The patient had been diagnosed with HBV infection with positive hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody in May 2008. He refused all antiviral medications for personal reasons. His liver function had been normal and stable before July 2020, and slight fluctuations in biomarker levels were observed from September to December 2020. He began treatment with entecavir (ETV) in December 2020. Five days after ETV initiation, he noticed three papular rashes on his left inner thigh. Therefore, he stopped using ETV himself and then his HBV DNA copy number had increased to 1.70 × 10⁸IU/mL. He followed the doctor's advice to use ETV again. Sixteen days after beginning treatment with ETV again, his laboratory examination results showed persistent increases in the ALT, AST, and GGT concentrations and an HBV DNA copy number of 2.12 × 10⁵IU/mL. He was also diagnosed with senile ecchymosis and an acute attack of chronic urticaria at a dermatology clinic. He was then admitted to our department for diagnosis and treatment.

Upon admission, the patient’s vital signs were stable. Physical examination showed a classic hepatic face without jaundice or scleral icterus, a non-distended jugular vein, and non-palpable lymph nodes throughout the whole body. Scattered spider angiomas were present in the precordial area, and the presence of palmar erythema led us to suspect liver disease. Three papular eruptions of approximately 0.8 to 1.5 cm in diameter with purulent exudate and ulceration were present on the left inner thigh, and these eruptions were slightly tender upon palpation (Figure 1(a)). Edema was observed in both lower limbs. In January 2021, the number of scattered purpura eruptions with a diameter of approximately 0.2 to 0.4 cm increased on the chest and abdomen within a couple of days. Some of them merged and gradually spread to the limbs (Figure 1(b)). In January 2021, erythematous papules appeared on the back with pruritus (Figure 1(c)). The patient was afebrile and had no cough, sneezing, or conjunctivitis.

Figure 1.

Skin manifestations. (a) Comparison of rashes on the left inner thigh before and after treatment. (b) Comparison of scattered purpura on the limbs before and after treatment. (c) Comparison of urticaria-like rash on the back before and after treatment and (d) viral inclusion body-like structures in skin biopsy (arrows) (hematoxylin–eosin, ×400).

Serologic testing revealed positivity for CMV immunoglobulin M. The polymerase chain reaction results were positive for CMV (1.09 × 10² copies/mL) and negative for Epstein–Barr virus. Autoimmune antibody spectrum and antineutrophil cytoplasmic antibodies were negative. Coagulation factors, coagulation function, and platelets were within the normal range. Hematoxylin–eosin staining of a skin biopsy specimen from the left inner thigh showed that the epidermis was hyperkeratotic with parakeratosis, and viral inclusion bodies were present near blood vessels (Figure 1(d)). Immunohistochemical staining was positive for CD3 and CD68 and sporadically positive for CD20, and the Ki-67 index was 20%. The CD4+ cell count was slightly decreased at 424/mm³ (reference range, 500–1440/mm³), while the CD8+ cell count was normal at 328/mm³ (reference range, 238–1250/mm³).

The patient’s final diagnosis was severe liver injury with HBV infection, CMV infection, and skin CMV infection. He began long-term treatment with 0.5 mg entecavir tablets every day under the guidance of specialists. Ganciclovir injection was implemented with an induction dose of 5 mg/kg every 12 hours for 14 days and a maintenance dose of 5 mg/kg every day for 7 days. Oral reduced glutathione and ademetionine succinate were administered to alleviate the hepatocyte damage. With this antiviral treatment, the rash gradually went into remission; the purpura diminished 5 days post-antiviral treatment, and the papuloid rash disappeared 14 days after treatment. The liver function biomarkers and HBV-DNA level also improved (Table 1). Two months after discharge, a follow-up laboratory examination showed that the ALT concentration had returned to the normal range and that the HBV-DNA level was below the lower limit. Although the other liver function biomarkers still exceeded the normal range, they had also decreased (Table 1).

Table 1.

Laboratory examination findings.

Date	ALT (<42 IU/L)	AST (<42 IU/L)	GGT (4–50 IU/L)	Alb (38–58 g/L)	TBIL (6–21 μmol/L)	DBIL(0–6μmol/L)	TG (0.4–1.73mmol/L)	HBV-DNA (minimum 50 IU/mL)	CMV-PCR (minimum 40 copies/mL)	CMV-IgM (0–0.8 COI)
March 2018 1	29	36	40	41.3	18	7	1.7	3.67 × 102
July 2020 1	43.8	51.3	37.04	46.1	13.4	4.1		1.02 × 102
September 2020 1	22.7	41	29.1	44.9	20	8.7
December 2020 1	329.8	392.1	548.2	31.13	38.41	27.6	2.22	1.70 × 108		1.43
December 2020 2	204.4	302	575.8	25.39	42.17	33	1.93	2.12 × 105	1.09 × 102	1.31
January 2021 2 (7 days after admission)	172.2	331.5	661.5	28.67	83.46	70		2.32 × 103
January 2021 2 (10 days after admission)	172.5	470	764.9	38	155.8	98.4			BDL
January 2021 2 (11 days after admission)	189	388.3	615	28.79	160.11	132.4
January 2021 2 (14 days after admission)	188.9	278.5	430	32.3	140.84	113.93	4.07			1.22
January 2021 2 (22 days after admission)	133.1	142.5	341.5	24.65	111.21	88.4	4.74			6.81
January 2021 2	97.9	112.4	266.9	30.54	86.6	66.4		7.08 × 10 2
March 2021 3	19.7	58.2	233.10	41.30	26.28	12.34	2.13	BDL	BDL

¹Examination results before admission.

²Examination results after admission.

³Examination results, discharge data, and follow-up data.

Alb, albumin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BDL, below detection limit; CMV, cytomegalovirus; COI, cut-off index; DBIL, direct bilirubin; GGT, γ-glutamyl transferase; HBV, hepatitis B virus; IgM, immunoglobulin M; TBIL, total bilirubin; TG, triglyceride.

Discussion

Coinfection of CMV and HBV

Previous studies have indicated that HBV and CMV coinfection can increase the ALT concentration and the incidence of cirrhosis and liver failure.^7,8 CMV can affect hepatocytes, aggravating the inflammation and clinical symptoms of CHB. ⁹ Our patient showed elevated concentrations of aminotransferases (ALT and AST), GGT, and bilirubin, possibly due to HBV reactivation caused by CMV infection. After admission, “bile enzyme separation” occurred, and the patient’s liver dysfunction rapidly worsened. Therefore, patients with severe clinical symptoms of CHB should be suspected to have CMV coinfection. Antiviral treatment for both CMV and HBV is necessary.

CMV infection and skin lesions

The American Association of Transplantation defines CMV infection as the presence of viral replication, regardless of clinical symptoms (this differs from latent CMV infection), and CMV disease as the existence of CMV replication with corresponding clinical symptoms and signs. CMV skin infection can be considered a subtype of CMV disease. ¹⁰ According to previous reports, skin lesions of CMV infection in immunocompromised patients may be an early manifestation of systemic diffuse CMV disease.^11,12 Without treatment, the 6-month mortality rate may reach 85%. In the present case, the CMV polymerase chain reaction result was positive. The CD4+ cell count was decreased at 424/mm³, but the CD8+ cell count was within the normal range. Advanced age and CHB may reduce immune function to different degrees. According to the order of eruptions, our patient’s rash was divided into three categories: papular lesions on the left inner thigh at admission (Figure 1(a)), which was the site of skin biopsy; purpura of the whole body and all limbs, which had been misdiagnosed as senile ecchymosis in the dermatology clinic; and erythematous papules on the back, which had been misdiagnosed as an acute attack of chronic urticaria at the dermatology clinic.

The clinical manifestations of skin CMV infection lack specificity and may include macules, papules, ulcers, nodules, verrucous plaques, hard spots, purpura, ecchymosis, blisters, and other skin lesions. ¹⁰ Our patient had a history of chronic urticaria with multiple rashes on the back and waist that only occurred in summer, which is inconsistent with the season during which the patient was admitted. In addition, he had a long-term history of senile ecchymosis, which was inconsistent with his new-onset skin rash before admission. With recovery of his liver disease, the ecchymosis also gradually decreased and partially subsided. Senile ecchymosis alone could not explain the rapid disappearance of all clinical manifestations of the rash. Additionally, all three types of skin lesions occurred simultaneously or after the positive CMV test, which could be explained by CMV viremia and possible endothelial cell involvement. ¹³ We still suspected a correlation between the skin lesions and CMV viremia, although we did not obtain biopsies from multiple sites. Drago et al. ⁴ reported that skin rashes of immunocompromised patients show various nonspecific papules, especially purpuric papules and ecchymosis on the legs. Systemic diffuse purpura may be the result of viral infection of vascular endothelial cells or hematogenous dissemination after viremia. ¹⁴ If we use clinical monism to explain these phenomena, the patient’s rashes may have been closely related to CMV infection in the context of CHB. Moreover, the viral inclusion bodies near the blood vessels on hematoxylin–eosin staining supported the diagnosis of CMV skin infection ¹² (Figure 1(d)).

CMV infection and the elderly

Patients at high risk of CMV infection are those with various immunodeficiencies and those undergoing long-term immunosuppressant therapy after organ transplantation or for treatment of systemic lupus erythematosus.^15,16 Infants and older individuals are also susceptible to CMV, and the mortality rate is high in these patients. ⁴ The present case involved a man in his late 70s with CHB. Although he refused antiviral medication, his liver function remained normal with low HBV-DNA replication until September 2020. At the onset of CMV reactivation, he had multiple skin lesions and declining liver function. Following successful treatment, the patient was discharged. Nevertheless, greater attention should be placed on patient education, especially for older patients with chronic diseases. China is one of the world’s most rapidly aging countries. ¹⁷ Given this problem, standardized training of general practitioners should be promoted and the family contract system should be strengthened. ¹⁸

Conclusion

Both HBV and CMV infections commonly aggravate liver injury, whereas skin injury is a relatively rare occurrence. Doctors are usually unaware of these skin presentations and underestimate the diversity of lesions caused by CMV infection. Thus, it is challenging to identify skin lesions in the clinical setting, and misdiagnosis is likely to occur. We have herein summarized the characteristics of skin CMV infection in HBV-infected patients. This may be helpful for the diagnosis and treatment of such cases, potentially improving patients’ prognosis in the future.

Data availability statement

All data generated or analyzed during this study are included in this published article.

Ethics approval and consent to participate

The study was approved by the Institutional Review Board of the First Affiliated Hospital of Army Medical University, PLA (KY201989). The patient was informed about the study protocol and provided consent for treatment and publication.

Patient consent for publication

Written consent for publication was obtained from the patient, and all details that could reveal the patient’s identity have been removed.