Pathways Case Record: An Immunocompetent Patient With Disseminated CMV

A 49-year-old male with a history of type 2 diabetes presented to Massachusetts General Hospital with one week of chest pain and shortness of breath. He was positive for rhino/enterovirus and was found to have new heart failure with a reduced ejection fraction and pericardial effusion. The cardiac work-up suggested myopericarditis, and he was admitted to the Cardiac Care Unit (CCU) for further assessment.

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During his admission, he developed acute onset, non-bloody diarrhea. Infectious stool studies were negative, an esophagogastroduodenoscopy (EGD; endoscopic procedure to visualize the upper components of the digestive system) showed diffuse esophageal candidiasis, and pathology from his colonoscopy revealed atypical changes that potentially related to an infection. He was discharged from the CCU on fluconazole and loperamide.

He then re-presented with hypotension in the setting of severe ongoing diarrhea. He reported 5-6 watery bowel movements per day. Repeat stool studies were consistent with inflammatory diarrhea. The patient's echocardiogram now showed recovery of his ejection fraction, but repeat EGD/colonoscopy revealed an elevated cytomegalovirus (CMV) viral load. Furthermore, an eye exam was consistent with CMV retinitis. Immunology was consulted for diagnostic work-up and management of disseminated CMV. His immunologic work-up was largely unremarkable, including negative testing for HIV and normal CD4+ T cell counts. He notably had low titers to the PSV23 Streptococcus pneumoniae vaccine, which he had reportedly received three years prior.

The Pathways Consult Service in the Department of Medicine at Mass General was consulted and focused on the following question:

1. How does a previously immunocompetent individual develop CMV reactivation?

Background and Diagnosis

CMV is an infectious double-stranded DNA virus and the largest member of the Herpesviridae family. The prevalence of CMV is 80% in developed countries (America, Europe) and approximately 100% in developing areas (Africa, Asia) (Rev Med Virol). CMV is a life-long infection, transmitted through direct and prolonged contact with bodily fluids, such as saliva and urine. CMV infects a wide array of cell types including endothelial cells, epithelial cells, smooth muscle cells, hepatocytes, leukocytes, and fibroblasts. An initial CMV infection is typically subclinical in immunocompetent individuals. Antigen-presenting cells present CMV antigens to CD4⁺ Helper T cells via the major histocompatibility complex (MHC) II receptor. In the presence of IL-2, IFNγ, and TNFα, cytotoxic CD8⁺ and NK CD16/56⁺ cells target and eliminate CMV-infected cells. CMV remains dormant in myeloid progenitor cells and tissue endothelial cells via control of host cellular differentiation and repression of CMV-lytic gene expression. While this describes the typical course of CMV infection in most immunocompetent individuals, CMV can reactivate with myeloid progenitor differentiation and inflammatory signaling in certain cell types (i.e., fibroblasts). Common pro-inflammatory conditions that lead to CMV reactivation include ischemia, concomitant infection, DNA damage, and oxidative stress (Front Cell Infect Microbiol). Like many other viruses, CMV can lead to extensive and impressive immunomodulation of the host's innate and adaptive immune systems (Front Immunol). Impairment of immune cells and cytokine signaling predispose patients towards developing other opportunistic infections via fungal and bacterial pathogens. Given the absence of primary immunodeficiency or acquired immunosuppression, our Pathways team examined how our patient's initial rhino/picornavirus infection may have affected his immune system.

Picornaviridae (e.g., enteroviruses, rhinovirus) encompass a family of single-stranded RNA viruses with a predilection to infect epithelial cells. Rhino/enterovirus positivity was confirmed in our patient at the time of his presentation to the hospital. Therefore, we sought to investigate whether this infection may have played a role in his subsequent CMV reactivation leading to a dissemination. We propose that picornavirus infection may predispose to CMV reactivation in a susceptible host through several immunomodulatory mechanisms. Like other viral infections, Picornaviridae viruses promote a strong pro-inflammatory response from the immune system via cellular signaling pathways (e.g., interferons). Latent CMV can then leverage this pro-inflammatory signaling to trigger reactivation. Specifically, TNFα and IFNγ turn on pathways for CMV gene expression that result in reactivation and replication of the virus (Front Cell Infect Microbiol). Therefore, an individual with a symptomatic enteroviral infection causing upregulation of these pro-inflammatory cytokines may encourage CMV reactivation in cells harboring latent infection.

Additionally, enteroviral infections have been shown to have immuno-modulatory effects. In infected cells, enteroviral proteins themselves can interfere with the expression of MHC class I and class II on the cell surface, which decreases the ability of the immune system to recognize these infected cells (Front Microbiol). Importantly, CMV and picornaviruses can infect the same cell types (e.g., epithelial cells). If cells are co-infected with CMV and picornavirus, it is possible that this downregulation of antigen-presenting capabilities could enhance CMV immune evasion capabilities and dampen recognition of CMV reactivation.

Finally, picornavirus strains have been shown to alter the balance of T cells in the immune response. For instance, T regulatory cells, which generally dampen the immune response, may be upregulated in picornavirus infections. As a result, Th1- and Th2-associated cytokines that are important in fighting viral infections are reduced in these infections (Front Immunol).

Cumulatively, the effects of pro-inflammatory signaling that occurs in secondary picornavirus infection, decreased antigen presentation in cells co-infected with CMV and picornavirus, and virally induced alteration of the immune system may result in a predilection for CMV reactivation in patients with picornavirus infections.

Summary and Future Steps

Although our patient had no history of immunosuppression, we hypothesize that the dissemination of CMV was triggered by the presence of an initial yet distinct viral infection, creating a pro-inflammatory landscape that promoted latent CMV reactivation. To determine if there is an association between picornavirus infections and CMV reactivation, we propose measuring CMV viral loads in patients with symptomatic picornavirus infections (e.g., positive for rhino/enterovirus on viral PCR). Viral loads of CMV can be compared to the CMV viral loads in these same individuals after they have cleared their picornavirus infections.

If there is indeed an association between picornavirus infections and CMV reactivation, we propose an experiment in which whole blood samples from individuals with picornavirus infections are stimulated with CMV lysate. A cytokine release assay can then be performed to quantify inflammatory cytokine release after stimulation. T-cell subsets could also be isolated and evaluated for proliferation and activation markers using flow cytometry. This assay could be repeated in the same patients once they have cleared their picornavirus infections.

Lastly, further studies could then be performed to interrogate specific immunologic pathways that may be impaired in picornavirus infections and predispose certain individuals, such as our patient, to CMV reactivation.

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