Multi-organ involvement secondary to varicella zoster virus, herpes simplex virus and cytomegalovirus in an immunocompromised patient

Abstract

The use of immunosuppressing agents can act as a catalyst for viral reactivation, promoting systemic infection with organ involvement. Current literature remains sparse on this topic but does provide individual case reports involving single viruses. We present the case of an immunocompromised patient with skin lesions, pancreatitis, colitis and hepatitis. Work-up revealed varicella zoster virus, which likely put the patient at risk for multi-organ involvement, as well as clinical suspicion of other implicated viruses, specifically herpes simplex virus and cytomegalovirus. A high clinical index of suspicion along with biopsy guidance for viral involvement in immunocompromised patients is crucial for early diagnosis and treatment of these conditions.

Background

Herpes simplex virus (HSV) 1 and 2 infections are common, with an estimated seroprevalence of 50% and 15%, respectively, in the general US population.¹ HSV can be reactivated throughout life but usually presents as a mild disease, such as mucocutaneous involvement in immunocompetent patients. Varicella zoster virus (VZV) can reactivate and spread along a dermatome with the potential for additional dermatomal involvement.² VZV can remain dormant at the dorsal ganglia for decades until there are immune changes that constitute reactivation. Cytomegalovirus (CMV) commonly affects patients of all ages and has a seroprevalence of 30%–100%.^{3 4} Once inside a patient’s body, CMV will remain there for life and has the potential for reactivation.⁴

The use of certain immunomodulatory agents can act as a catalyst for HSV, VZV or CMV reactivation and promote systemic infection, including organ involvement.1 3 5 6 Current literature remains sparse but does provide individual case reports involving one virus. The combination of multiple viruses contributing to systemic involvement has been infrequently published.

We present a case of an immunocompromised patient who developed disseminated multi-organ involvement due primarily to VZV, with some contribution from HSV and likely also CMV. This case presentation adds to the body of literature regarding extracutaneous viral manifestations that can occur in immunocompromised individuals.

Case presentation

Our patient was a 64-year-old woman who transferred to our institution for evaluation of disseminated bullous skin eruptions involving her face and body. Her medical history was significant for chronic obstructive pulmonary disease, asthma, rheumatoid arthritis (previously treated with methotrexate and rituximab), osteoarthritis, type-2 diabetes mellitus, gastroesophageal reflex disease and non-Hodgkin’s lymphoma (diagnosed in 2001 with recurrence in 2006; last round of chemotherapy with fludarabine, cyclophosphamide and rituximab 5 months prior).

She initially presented to an outside institution with nausea and left-sided abdominal pain radiating towards her back. During her outside hospital course, she continued to have persistent abdominal pain without notable improvement. Initially, a rash was not detected on physical exam; however, she developed diffuse dusky appearing vesicles and bullae with violaceous bases and central necrosis of varying size and in various stages of evolution, involving nearly all areas of her body including head/neck, torso and extremities, but sparing the palms and soles (figure 1). They were painful, non-pruritic and rapidly progressive. Of note, she had a history of chickenpox as a child but denied history of HSV, cold sores or genital lesions. She also had white velvety lesions on her tongue and her lips. Her initial labs were notable for aspartate aminotransferase of 214 U/L, alanine aminotransferase of 130 U/L, total bilirubin of 4.2 mg/dL, alkaline phosphatase of 797 U/L and lipase of 853 U/L. Her complete blood count (CBC) panel was within normal limits, with the exception of haemoglobin and platelet count. The CBC with differential included the following lab values: white cell count 5.84×10⁹/L; haemoglobin 136 g/L; haematocrit 39.7%; platelet count 53×10⁹/L; neutrophils 91%; metamyelocyte 3%; lymphocytes 5%; basophils 1%.

Figure 1.

Patient’s back with numerous skin lesions.

A hepatitis panel was obtained and was negative. A CT scan of her abdomen revealed findings of acute pancreatitis, primarily in the body and tail of the pancreas with a possible lesion, as well as diffuse colitis and mesenteric lymphadenopathy. A CT scan of her lungs was unremarkable except for small unchanged pulmonary nodules. An MRCP was performed, showing no definite obstruction of the pancreatic duct. Due to difficulties performing a skin biopsy, the patient was transferred to our facility for dermatologic evaluation.

On arrival, the patient’s vital signs showed a blood pressure of 109/74 mm Hg, heart rate of 137 beats/min, respiratory rate at 15 breaths/min and afebrile (98°F). She was first admitted to the medical floor but transferred to the intensive care unit the following day for hypotension (95/79 mm Hg, mean arterial pressure <60) and tachycardia (heart rate of 152 beats/min). Unroofed bulla fluid swabs from the patient’s face and trunk tested positive for both HSV-1 and VZV by viral PCR (figure 2). She was started on acyclovir 10 mg/kg intravenous every 8 hours. During her hospital course, she continued to report back and abdominal pain. Serum CMV-PCR was collected the next morning, resulting with >1 million copies/mL and acyclovir was then adjusted to ganciclovir 5 mg/kg intravenous every 12 hours. Dermatology was consulted and performed four biopsies (two shave and two punch) of the right back. Histology demonstrated vesicle formation and epidermal necrosis with the classic HSV-associated cytopathic effects (the three M’s), namely multinucleated cells, with moulding of the nuclei around each other and marginated chromatin around the edge of the nucleus, located at the leading edge of the lesion (figure 3). Immunohistochemistry performed with adequate controls showed strong positivity for VZV (figure 4), while HSV 1 and 2 as well as CMV were negative.

Figure 2.

Patient’s mouth showing lesions on lips, tongue and palate.

Figure 3.

History with H&E stain of biopsy from back.

Figure 4.

Immunohistochemistry performed with adequate controls showed strong positivity for varicella zoster.

Her clinical course deteriorated quickly, with progressive respiratory distress requiring intubation along with maximum vasopressor support 3 days after hospital transfer. A chest radiograph post-intubation revealed bilateral perihilar airspace disease, worse on the right side. In addition, an abdominal CT scan revealed diffuse bowel wall thickening, possibly infectious/inflammatory enteritis/colitis with noted perihepatic ascites. Given her critical status, gastrointestinal intervention, such as colonoscopy with biopsy or endoscopic ultrasonography, was not able to be performed. Bronchoscopy revealed edematous mucosa in the right middle and lower lobes. A bronchoalveolar lavage was performed and resulted positive HSV-1 PCR and >1 million copies/mL CMV but negative for malignant cells and Pneumocystis jirovecii pneumonia.

Outcome and follow-up

After discussion with critical care and palliative care, she was transitioned to comfort measures only and expired with no autopsy performed. IgG subclasses 1–4 were ordered 1 day prior to the patient’s expiration and revealed significantly low levels for all results (table 1).

Table 1.

Immunoglobulin levels by subtype

IgG subtype	Result (mg/dL)	Normal range (mg/dL)
IgG subtype 1	88	382–929
IgG subtype 2	57	241–700
IgG subtype 3	10	22–178
IgG subtype 4	3.5	4.0–86.0

Discussion

This report describes a chronically immunocompromised woman with a disseminated viral infection that led to suspected viral involvement of the pancreas, colon and liver.

Most of the time herpes zoster can be diagnosed clinically, but not in our case. Her skin lesions were distributed across the body without any dermatomal pattern. She also had lesions on her buccal mucosa, which supports disseminated disease. From the patient’s face and trunk, a swab of the unroofed bulla fluid was positive for both HSV-1 and VZV. The immunohistochemistry stain on skin biopsy clearly confirms VZV but not HSV. We believe that HSV might represent shedding of the skin but did not contribute to her rash. Her initial presentation with abdominal pain could be explained by VZV infection, which could cause several days of abdominal pain on the affected dermatome, followed by vesicular eruption.

Overall, there are various aetiologies and conditions that can contribute to acute pancreatitis, colitis and hepatitis. The implication of HSV or VZV being involved with these manifestations have been rarely highlighted in the available literature. The combination of multiple viruses affecting one or multiple organs with dermatologic findings further exemplifies the rare encounter that we observed in our patient. Given the disseminated nature of this patient’s cutaneous viral infection, it raises further clinical suspicion that there could be visceral involvement, especially with VZV.⁷

Our patient presented with traditional signs and symptoms of acute pancreatitis with elevated amylase and lipase values. However, she lacked traditional risk factors for pancreatitis, such as chronic alcohol use or gallbladder involvement.⁸ She presented with skin lesions in the abdominal area and did consistently complain of abdominal pain. In one case report, a 44-year-old immunocompetent woman was diagnosed with VZV-associated pancreatitis.² Though this is rare, this patient exhibited a rash as well as abdominal pain similar to our case. In addition, a possible lesion was noted in the pancreas tail on outside facility imaging. It is possible the lesion could have been HSV based on a small case series. In this case series, HSV pancreatitis was confirmed by immunohistochemistry studies and imaging supporting an identified lesion, which was likely a result from intense necrosis of acinar cells due to a direct cytopathic effect of HSV.⁹

In addition, our patient may have had colitis and hepatitis secondary to viral involvement. Her CT abdomen/pelvis at our facility indicated bowel thickening. HSV can induce colonic ulcerations as well as diarrhoea.^{1 5} However, the signs of HSV colitis are non-specific and the role of serology testing is not helpful, as this is a commonly encountered virus.⁶ In our patient, she did not endorse signs of diarrhoea. Regarding VZV, there is very little published on complications of VZV in immunocompromised hosts.¹⁰ One published case report focused on an infant with this diagnosis, yet they were not immunocompromised nor had irritable bowel disease.¹¹ We also suspect our patient’s liver function was impacted by the viruses. She consistently had transaminitis at both institutions and had a negative hepatitis panel at the outside facility. HSV hepatitis is rare but disseminated disease will include dermatologic findings.¹² However, the clinical presentation of this is non-specific and if left untreated, it can progress to fulminant liver failure.¹² The proposed mechanism for hepatic involvement is a high initial viral inoculum which interacts with impaired T-cell and macrophage immunity to promote dissemination.¹² VZV has been associated with mild hepatitis and can lead to fulminant liver dysfunction.¹³ VZV-associated hepatitis may not always include cutaneous involvement and immunocompromised patients should be carefully monitored.¹³ In addition, disseminated zoster can occur with age-related decreased cellular immunity.⁷

Impaired immunity may have predisposed our patient to viral infections and associated complications. Though she had not received recent chemotherapy, reactivation of HSV can occur in cancer patients with a history of lymphoma and leukaemia.^{5 7} She received her last chemotherapy regimen months before her hospital admissions, which included fludarabine therapy. Fludarabine can cause severe bone marrow toxicity and its immunosuppressive effect can be prolonged.^{14 15} The fludarabine effects may have contributed to viral reactivation.

In addition, our patient had evidence of low IgG levels, which play an integral role in fighting against bacterial and viral infections. IgG is an abundant protein found in human proteins and helps with the immune system response.¹⁶ IgG1 and IgG3 have been identified as potent triggers of immune-related mechanisms, while IgG2 and IgG4 will induce less of an immune response in general but can help in certain situations, such as with neutralising viral particles and toxins.¹⁶ In our patient, she exhibited abnormally low levels of all subtypes of IgG, reinforcing her significantly immunosuppressed state.

Because of this patient’s significantly depressed immune system, CMV was also isolated. Traditionally, CMV reaction can occur in critically ill ICU patients who are otherwise immunocompetent.⁵ However, the clinical significance of CMV reactivation is unclear if CMV acts as a bystander versus a pathogen in this particular population.¹⁷ In contrast, CMV infection can result in end organ disease or opportunistic infection in an immunocompromised individual, such as a solid organ transplant recipient or HIV-positive patient with a CD4+ lymphocyte count less than 50 cells/mm³.¹⁸ It is unclear the role that CMV played in this case, as we had no tissue available through interventional biopsies or on post-mortem autopsy to conclusively link her deteriorations to this specific virus. Yet, it is plausible that CMV played some role in her clinical course, as CMV can contribute to colitis, pancreatitis, hepatitis and pneumonia.

In review of the literature, it has been established that disseminated VZV infection can occur in individuals who have undergone autologous and allogeneic stem cell transplantation due to disruption of the cellular immune response in combination with VZV reactivation.¹⁹ While disseminated viral infections and/or multi-viral involvement following conventional chemotherapy have been highlighted in the literature, overall data is sparse. In a report of three patients who underwent conventional chemotherapy, disseminated VZV infection occurred in all cases.¹⁹ These patients were undergoing treatment for follicular lymphoma, diffuse large B-cell lymphoma and peripheral T-cell lymphoma. All patients developed abdominal pain and two of the patients developed hepatitis secondary to VZV.¹⁹ In a similar fashion, our patient presented with abdominal pain and hepatitis. Additionally, HSV can also be disseminated and occur after receiving chemotherapy, especially in those with mouth ulcers.²⁰ In our patient, HSV was not a surprising finding, as HSV can be found in the oral cavity in addition to other cutaneous manifestations.

We acknowledge the limitations of this case report, as an autopsy was not performed nor additional biopsy studies. Viral cytopathology was noted in this patient’s biopsy report and reinforces the extent of infection and her immunosuppressed state. The use of biopsies and swabs of the skin lesions were helpful in the workup of her diagnosis. Unfortunately, it is unknown if VZV, HSV and/or CMV were responsible for the patient’s presentation of acute pancreatitis, colitis, and hepatitis; however, with the skin biopsy findings revealing disseminated viral involvement, we suspect VZV, with potential contributions by HSV and possibly CMV, likely affected her other organ systems, leading to her unfortunate expiration.

Learning points.

• This case highlights the need to consider viral involvement as part of the differential diagnosis of disseminated skin rash, acute pancreatitis, colitis and/or hepatitis.

• Immunocompromised patients are at risk for viral involvement of multiple organ systems.

• The use of biopsies and swabs on skin lesions can assist with a patient’s diagnosis.

• Since these infections are treatable, a high index of suspicion for viral involvement in immunosuppressed hospitalised patients is crucial for early diagnosis and treatment.