Probable collagenous gastritis via Epstein–Barr virus reactivation in the setting of coronavirus disease 2019: a case report

Abstract

Background

Recent biomedical research has shown the unusual, multisystem effects of coronavirus disease 2019 in humans. One specific sequela of a primary severe acute respiratory syndrome coronavirus 2 infection is the reactivation of latent viruses in various tissues, such as Epstein–Barr virus. Epstein–Barr virus has been identified in many inflammatory gastrointestinal lesions, such as microscopic gastritides and colitides. One subtype of these diseases is collagenous disease. “Long COVID” may be related to the reactivation of these latent viruses, and the following case describes a patient who developed vague symptoms consistent with “long COVID.”

Case presentation

A non-Hispanic white male in his 50s, with previous collagenous gastritis and colitis, developed a 10-kg weight loss and diffuse leg cramps over 3 months. The patient had coronavirus disease 2019 about 3 months prior to presentation. He had iron deficiency and tested positive for human immunodeficiency virus antibody. His heterophile antibody was also positive. Confirmatory testing for human immunodeficiency virus was negative, and his Epstein–Barr virus antibody panel was positive for early antigen immunoglobulin G. His Epstein–Barr virus viral load was undetectable. Minimal improvement was achieved with a 4-week course of oral budesonide, and upper endoscopy showed diffuse gastritis. He is now improving with proton pump inhibitor therapy and ferrous sulfate supplementation.

Conclusion

This case report explores outpatient management of microscopic gastritides and colitides. The evidence around coronavirus disease 2019 causing reactivation of Epstein–Barr virus, and Epstein–Barr virus’ presence in chronic gastrointestinal inflammatory lesions, is discussed. Practice recommendations include corticosteroid and acid-suppression therapy for patients suspected of having a recurrence of inflammatory lesions.

Background

Few viruses have the potential to cause such severe and complex diseases as the Epstein–Barr virus (EBV), which has been implicated in the pathogenesis of diseases such as infectious mononucleosis and Burkitt lymphoma [1]. The current literature on EBV demonstrates its existence in many chronic inflammatory gastrointestinal lesions, such as microscopic gastritides and colitides [2,3,4]. One subtype of these inflammatory conditions is collagenous disease, characterized by dense subepithelial collagen in addition to inflammatory infiltrates [2]. Although a rare disease entity, it is important for clinicians to be aware of it because of its tendency to flare up intermittently, which can be associated with the reactivation of EBV in its latent form.

Recent biomedical research has shown the unusual, multisystem effects of coronavirus disease 2019 (COVID-19) on the body [5]. One specific sequela of a primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the reactivation of latent viruses in various tissues, such as EBV [5,6,7,8]. It is theorized that “long COVID” may be related to the reactivation of these latent viruses, and that the hyperinflammation phase of COVID-19 that occurs around 10 days after the initial infection mediates this phenomenon [9]. Moreover, COVID-19 has been associated with gastrointestinal manifestations [10], which makes the theoretical foundation of COVID-19 leading to exacerbation of underlying gastrointestinal diseases more plausible. This case report describes a patient who developed vague, systemic symptoms consistent with “long COVID” symptomatology based on the World Health Organization criteria [11]. His history of chronic gastrointestinal disease raised the clinical suspicion of COVID-19 reactivating a latent virus in his upper tract.

Case presentation

History and physical

A non-Hispanic white male manual laborer in his 50s, with a history of collagenous gastritis and colitis diagnosed on direct mucosal biopsy in 2019, presented to the clinic in late 2022 with complaints of a 10-kg weight loss over 3 months and diffuse leg cramps. On chart review, the patient tested positive for COVID-19 based on in-clinic rapid antigen testing about 3 months prior to presentation, which resolved spontaneously without any respiratory sequelae. The patient described a new intolerance to spicy foods over the past month. He denied having night sweats, constipation, diarrhea, melena, early satiety, odynophagia, dysphagia, abdominal pain, hematochezia, and dyschezia. He further denied any family history of cancers, autoimmune disorders, or gastrointestinal diseases. He noted that he drinks one to two alcoholic beverages weekly, does not use any tobacco products, and does not use any illicit substances. When his collagenous gastritis and colitis were discovered in 2019, he reportedly received oral steroids and sucralfate, which improved his abdominal symptoms.

His vital signs were all within normal limits during the visit. On chart review, it was confirmed that the patient had lost about 13.5 kg since the end of 2021. Physical examination revealed an anxious-appearing male who appeared at his stated age. Cardiopulmonary auscultation revealed no abnormalities. He had mildly pale skin and palpebral conjunctivae without jaundice or cutaneous lesions. Abdominal examination revealed normoactive bowel sounds, no hepatosplenomegaly, mild left upper quadrant abdominal tenderness to percussion, and no palpable intraabdominal masses. His bilateral lower extremities were mildly tender to palpation along the calves, with normal bilateral popliteal, dorsalis pedis, and posterior tibial pulses.

Investigations

On chart review, the patient had undergone Helicobacter pylori stool antigen testing about 6 months prior to presentation, which was negative. In the initial basic and symptom-specific laboratory work (Tables 1 and 2), the patient was found to be iron deficient without microcytic anemia, and had a positive human immunodeficiency virus (HIV) screening test. On further investigation, his heterophile antibody test was also positive. Confirmatory testing for HIV was negative, and his EBV antibody panel was positive for EBV early antigen (EA) immunoglobulin G (IgG) and negative for EBV nuclear antigen (EBNA) IgG (Table 3). His EBV viral load was undetectable.

Table 1 Selected initial basic laboratory studies, including complete blood count and metabolic panel results

Table 2 Symptom-specific laboratory studies demonstrating iron deficiency, positive human immunodeficiency virus antibody, and positive heterophile antibody

Table 3 Confirmatory laboratory studies showing positive Epstein–Barr virus immunoglobulin G

Differential diagnosis

In the beginning, the differential diagnosis consisted of HIV infection, gastritis, esophagitis secondary to gastroesophageal reflux disease, intestinal malabsorption, autoimmune condition (nonspecific), syphilis, iron deficiency, electrolyte deficiency, and hyperthyroidism. The initial investigation revealed the underlying iron deficiency, positive heterophile antibody, and false-positive HIV screening test. The differential diagnosis at this point included active EBV infection and intestinal malabsorption, secondary to reactivated collagenous gastritis with distal extension of inflammation. Active EBV was ruled out with the subsequent workup.

Treatment

After getting the results from the patient’s laboratory investigations, it was decided to start the patient on ferrous sulfate 325 mg daily for his iron deficiency without anemia, and oral budesonide 9 mg daily because we had a high clinical suspicion of recurrent collagenous gastritis with a possible colitis component. Treatment was started before further investigations could be performed owing to the severity of his symptoms.

Outcome and follow-up

His leg cramps resolved with 3 months of ferrous sulfate supplementation. He was treated with oral budesonide 9 mg daily for 4 weeks with a 4-week taper, during which time he also received prophylactic famotidine therapy. The patient experienced minimal improvement after the course of budesonide. He underwent esophagogastroduodenoscopy and colonoscopy at the end of 2022, which showed diffuse gastritis and normal colonic mucosa (Fig. 1). His symptoms are now improving—including steady but slow weight gain—with ongoing proton pump inhibitor therapy with omeprazole 40 mg daily.

Fig. 1

Upper and lower endoscopy findings

Discussion

Our patient exhibited clinical symptoms consistent with collagenous gastritis and reported fatigue, weight loss, and leg cramps, which may also be sequelae of COVID-19 [12]. In this case, early EBV antigen antibodies, without nuclear antigen antibodies, indicate the possibility of either coinfection of EBV and SARS-CoV-2 or a chronic, low-grade immune system stimulation by EBV. HIV screening was positive, but further investigation revealed that the result was a false positive. The cross-reactivity of EBV and SARS-CoV-2 with many HIV screening assays can explain this [13]. Treatment with oral budesonide for 4 weeks resulted in minimal improvement, but a combination of proton pump inhibitor therapy and ferrous sulfate supplementation eventually led to improvement. One possibility is that the patient experienced COVID-19 inflammation-induced EBV reactivation, which could have contributed to developing collagenous gastritis symptoms and a slower recovery. Although the exact role of COVID-19 and EBV reactivation in relapsing collagenous gastritis is unknown, chronic inflammation could impact clinical outcomes and potentially exacerbate preexisting gastrointestinal disorders. Pathophysiologic research on “long COVID” reveals that immune dysregulation—including subclinical overproduction of cytokines—is likely responsible for this increased inflammation [14].

Collagenous gastritis is a rare inflammatory disorder of unclear etiology and pathogenesis. Its clinical symptoms are related to the gastrointestinal tract zone involved, and both pediatric and adult phenotypes have been documented [15]. Only one case of collagenous gastritis with a concomitant EBV infection has been published among adult cases [16,17,18,19,20,21]. Narsai et al. presented the case of a 53-year-old man with selective immunoglobulin M (IgM) deficiency and isolated collagenous gastritis that transitioned to gastric adenocarcinoma [21]. After undergoing a polyp biopsy, the patient was diagnosed with gastric adenocarcinoma and EBV infection. Of note, the patient did not report experiencing any new symptoms. His serum EBV viral capsid antigen (VCA) IgM antibodies were undetected, VCA IgG and EBNA IgG antibodies were positive, and EA antibodies and polymerase chain reaction (PCR) were negative.

In contrast to that case report, we describe a patient who probably redeveloped collagenous gastritis in the setting of EBV reactivation following COVID-19, as suggested by his serologic studies. According to Meng et al. [5], EBV reactivation is common in individuals with COVID-19 and may be associated with the severity of illness and poor clinical outcomes. They also observed a statistically significant correlation between EBV reactivation and age [5]. In addition, Manoharan and Ying found in a comparative meta-analysis that EBV reactivation resulted in significantly higher mortality rates among hospitalized patients admitted for symptomatic COVID-19 [22]. Some individuals with COVID-19 may experience persistent symptoms beyond the acute phase of the disease, which researchers and clinicians commonly refer to as “long COVID” [23]. Gold et al. suggested that many “long COVID” symptoms are not necessarily an immediate result of SARS-CoV-2 but rather the likely reactivation of EBV, induced by COVID-19-related inflammation [22]. The published article identified common clinical manifestations in “long COVID” patients with positive EBV reactivation, such as skin rashes and lesions, hearing loss, and tinnitus [6].

Conclusion

Clinicians should consider the possibility of exacerbated underlying chronic gastrointestinal disorders when encountering nonspecific gastrointestinal symptoms suggestive of post-viral syndromes. This is an essential consideration for the appropriate management and treatment of patients. Although clear clinical guidelines for the treatment of collagenous gastritis and colitis do not exist, the current practice recommendations include a trial of oral corticosteroid therapy (that is budesonide for coverage of colonic inflammation) and standard acid-suppression therapy for patients suspected of having reactivation of their inflammatory lesions [15, 24].