Viêm ruột cấp tính thể nặng do biến thể HSV-1 ở bệnh nhân trẻ có hệ miễn dịch khỏe mạnh

Abstract

We present a unique case of a 26-year-old man who is immunocompetent with severe abdominal pain and diarrhea, diagnosed with acute severe enteritis caused by a herpes simplex virus type 1 (HSV-1) variant, with intestinal inflammatory changes observed through computed tomography imaging, necessitating an empirical antibiotic. Biopsies from the esophagus and terminal ileum confirmed the presence of HSV-1, with immunostaining highlighting viral inclusion bodies. Notably, the genomic characterization of the HSV-1 variant was elucidated through next-generation sequencing analysis of mucosal biopsy samples from the gastrointestinal tract. The findings contribute to understanding atypical presentations of HSV-1 infection in patients who are immunocompetent and the role of advanced molecular techniques in HSV tropism.

Background

Herpes simplex virus (HSV) is a ubiquitous DNA virus that is well known to cause infection in patients who are immunologically compromised. The HSV has 2 distinct strains, HSV-1 and HSV-2. It has been reported that HSV infects more than 66% of the U.S. population under 50 years of age, with an estimated prevalence of HSV-1 being approximately 48%, and for HSV-2, it is about 12% (1). It is noteworthy that HSV-2 is transmitted almost exclusively by sexual contact, while HSV-1 is usually transmitted by intimate but nonsexual contact (2). Involvement of the small intestine by HSV infection is rare and has been reported only in patients who are immunologically compromised (3–7).

In this report, we describe a 26-year-old man who is immunocompetent and who presented with severe abdominal pain and diarrhea, which turned out to be acute severe enteritis. Immunostaining and metagenomic sequencing of esophageal, ileal, and colonic mucosal biopsy samples identified infection with a unique HSV-1 variant.

Case Report

A 26-year-old man with a medical history of Wolff–Parkinson–White (WPW) syndrome and eczema presented to the emergency department with abdominal pain and episodes of vomiting for 1 week. The patient was afebrile and physical examination revealed a mildly distended and diffusely tender abdomen with hypoactive bowel sounds. His abdominal pain was 8/10 in severity, with diffuse tenderness in all quadrants without aggravating or relieving factors. He had no personal history of inflammatory bowel disease. His family history was significant for heart disease in his father and systemic lupus erythematosus in his mother. He has a history of marijuana intake 3 to 5 times per week. Initial clinical chemistry was remarkable for hypochloremic metabolic alkalosis, a normal hemoglobin level of 160 g/L, leukocyte count of 17.13 × 109/L, a lactate level of 4.2 mmol/L, and a C-reactive protein level of 256.0 mg/L. A computed tomography (CT) scan of the abdomen showed inflammatory mucosal changes around the distal esophagus, distal stomach, proximal duodenum, terminal ileum, and colon (Figure 1).

The patient continued to have abdominal pain and worsening leukocytosis despite initial empirical antibiotics (piperacillin/tazobactam). On day 7 of hospitalization due to persistent abdominal pain, he experienced a drop in hemoglobin levels (105 g/L), worsening leukocytosis (32.79 × 109/L), and he received esophagogastroduodenoscopy (EGD) and colonoscopy. An EGD revealed multiple esophageal ulcerations in the middle and lower third of the esophagus (Figure 2, A). Colonoscopy findings included erythema and edema, involving the ileocecal valve and terminal ileum (Figure 2, B). Biopsies from the esophagus and terminal ileum revealed multinucleated cells with viral inclusion bodies, consistent with herpes simplex infection, and immunostaining was positive for HSV-1 (Figure 2, C). Immunostaining for HSV-2, cytomegalovirus (CMV), and periodic acid-Schiff (PAS) were negative. Serology results were positive for HSV-1 IgG and Epstein–Barr virus (EBV) IgG antibodies. Extensive work-up for infectious and autoimmune diseases was negative, including stool studies for culture, viral, and parasites. To further evaluate the genomic nature of the HSV, we performed next-generation sequencing (NGS) analysis on several mucosal biopsies obtained from different parts of the intestine.

Discussion

In immunocompetent hosts, HSV causes spontaneously resolving cutaneous lesions. Herpes simplex virus type 1 tends to affect oropharyngeal areas, while HSV-2 more commonly involves genital areas. With both types of HSV strains, severe and disseminated infection is observed mostly in patients who are immunocompromised. Diagnosis is usually made by type-specific serologic tests, immunohistochemical stain, and polymerase chain reaction tests on the tissue samples or swabs, which are considered to be the gold standard to confirm the diagnosis of HSV infection.

Herpes enteritis and colitis has been previously reported only in patients who are immunocompromised (Table 1). Immunocompetency is defined as having the ability to produce a normal immune response to environmental antigen or pathogen. To establish immunocompetency in our patient from a clinical point of view, a comprehensive work-up, including HIV serology, CD4 and CD8+ T-cell count, B-cell count, hepatitis B surface antigen, antibody to hepatitis C virus, antibody to CMV, HSV-1 IgM, HSV-2 IgM, and IgG tests, was performed. Serology results were positive for HSV-1 IgG and EBV IgG antibodies. Based on these observations, it was inferred that this case represented a rare presentation of HSV esophagitis and enteritis in a patient who is immunocompetent.

Herpes simplex virus type 1–infected neurons presumably recruit inflammatory macrophages through the CCL2/CCR2 pathway that releases reactive oxidative species, which in turn modulates enteric nervous system (ENS) neuroplasticity, causing gastrointestinal dysmotility 8. A study from the University of Padova, Italy, demonstrated that orogastric administration of HSV-1 in mice resulted in infection of enteric neurons 9. By immunohistochemistry, HSV-1 antigens were detected in the ileal myenteric ganglia of the HSV-infected mice but not of the sham-infected mice 9. Thus, several lines of evidence suggest that HSV-1 disturbs the immune cells and neurons of the ENS, presumably leading to enteritis.

We decided to examine the nature of this HSV-1 strain using NGS metagenomic analysis (Table 2). Following read alignment to the HSV-1 strain 17 reference genome, high-quality reads containing single-nucleotide polymorphisms and insertion/deletions (SNPs/indels) were BLAST (basic local alignment search tool) queried to identify the closest matching HSV strain genome deposited in the NCBI database. This search identified human alphaherpes virus 1 strain 2011-5409 as a close match, which was previously identified from an oral lesion of a patient with HSV infection at the University of Washington Virology Clinic 10. After alignment to this strain genome, 39 SNPs/indels were identified, which did not match any previously deposited strain genome by BLAST search. This suggests the presence of a novel, previously uncharacterized strain of human alphaherpes virus 1.

These observations suggest the presence of a unique variant of the HSV-1 virus.

Indicates HSV-1 strain.

Metagenomic sequencing of the mucosal biopsy of the esophagus sample identified the presence of human endogenous retrovirus K113 (HERV-K113). The role of HERV-K113 is not fully understood. The expression of HERV proteins is being studied for acting as onco-proteins, inducing autoantibodies/autoimmune disease 11–13. It is possible that the combination of a novel HSV-1 strain combined with upregulated HERV-K113 expression resulted in the unusual HSV enteritis observed in this patient.

The role of chronic cannabis use in the development of acute severe HSV enteritis is unclear at the current time. In most viral infections we studied, cannabinoid treatment has demonstrated a significant influence on virus–host cell interactions. Notably, cannabinoid exposure resulted in a marked increase in viral replication and other surrogate measures of infection caused by HSV-2, HIV-1, Kaposi sarcoma–associated herpes virus, influenza, and vesicular stomatitis virus 14, 15. Furthermore, tetrahydrocannabinol has been shown to decrease CD8 and cytotoxic T lymphocyte activity in mice models. There seems to be a worsened disease outcome in the setting of cannabinoid use and the possibility of latent infection caused by HSV-1. These observations suggest that cannabinoids can enhance the susceptibility to infections such as HSV.

Our patient also had a history of eczema. However, he had no active cutaneous lesion identified at the time of admission. Development of herpeticum dermatitis is well defined when Herpes virus comes in contact with eczematous skin.

Our patient responded to intravenous acyclovir (700 mg, every 8 hours for 21 days), and a repeat small bowel enterostomy showed complete healing of the esophageal ulcer (Figure 2, D). Biopsies from the upper gastrointestinal tract (stomach and small bowel) were negative for HSV-1 immunostaining. This indicates that this variant of HSV-1 was responsive to current antiviral therapy (acyclovir). A clinic visit 8 weeks after discharge revealed that the patient had recovered from his acute illness and was completely asymptomatic. This case illustrates development of acute severe enteritis in a young immunocompetent individual by a unique variant of HSV-1.