Ulcerative Colitis With an Unexpected Cause

A 50-year-old male patient presented to an outpatient clinic in the spring of 2020 with fever and dyspnea; he told clinicians that the symptoms had persisted for the past 3 days.

Physical examination findings included a fever of 37.8°C (100°F), respiratory rate of 24 breaths/min, and heart rate of 105 beats/min. There was no organomegaly, and the patient was a non-smoker.

Initial laboratory test findings included:

• White blood cell count: 6.4 × 109/L
• C-reactive protein (CRP): 4.6 mg/L
• Ferritin: 162 ng/mL
• D-dimer: 842 ng/mL

Findings of a polymerase chain reaction (PCR) test for SARS-CoV-2 were negative. However, the patient's wife and two children had positive PCR test results; and the patient's CT chest scan revealed diffuse ground-glass opacities consistent with viral pneumonia. Clinicians diagnosed him with COVID-19, and he was started on a now-debunked 7-day regimen of hydroxychloroquine and azithromycin. Once he was clinically stable, he was released with instructions to return for a follow-up assessment.

He returned several weeks later with bloody diarrhea, which he explained had come on about 2 weeks after he completed COVID-19 treatment. Stool analysis revealed 10 to 12 erythrocytes and five to six leukocytes. However, there was no evidence of amoebas or Clostridium difficile A+B. Complete blood count and CRP were within normal ranges. Clinicians prescribed treatment with ciprofloxacin, metronidazole, and probiotics.

On follow-up assessment 1 week later, the patient reported no improvement in symptoms. His stool calprotectin level was 1800 μg/g (normal range: 0-50 μg/g). Endoscopy revealed a diffuse, micro-ulcerated, granulated appearance that clinicians noted continued uninterrupted from the dentate line to the sigmoid colon, as well as distortion of the submucosal vascularization.

Based on presumed diagnoses of infectious colitis and ulcerative colitis, biopsies were taken. Pathology findings included mucin loss and distortion in the colonic glands, as well as evidence of polymorphonuclear leukocytes (PMNL) and plasma cell infiltration. Clinicians also noted cryptitis and a crypt abscess between the glands; no granulomatous or specific micro-organisms were detected.

The patient was diagnosed with ulcerative colitis, which clinicians believed had been triggered by COVID-19. The patient was prescribed treatment with 5-aminosalicylic acid (5-ASA) therapy, initiated orally and by enema. After 3 days of this drug therapy, his bloody diarrhea and other symptoms resolved.

On testing, the patient's anti-SARS-CoV-2 antibodies were found to be IgG positive and IgM weak positive. A subsequent CT scan revealed significant improvement from the initial findings and evidence of a sequela lesion.

Discussion

Clinicians presenting this case – which they believe is the second documentation of ulcerative colitis with COVID-19 in the literature – made the report "to show that COVID-19 can appear with other organ pathologies, in addition to upper and lower respiratory tract complaints."

The group noted that initial reports of COVID-19 from China around the time this patient was diagnosed focused only on its respiratory manifestations, so the absence of reports of diarrhea or other gastrointestinal complaints may have "led to under-recognition of these symptoms."

They noted that several studies have since reported the involvement of other organs and diarrhea symptoms. For example, a single-center study of 95 COVID-19 patients admitted to the hospital found GI symptoms in 61% (n=58) of patients overall. Of those symptomatic patients, about 12% were symptomatic on admission, and the remaining 49% developed symptoms (primarily elevated bilirubin and, to a lesser extent, diarrhea) during hospitalization, possibly aggravated by various medications, including antibiotics, researchers reported.

Those researchers found "no statistically significant difference in the general demographics or clinical outcomes between patients with and without GI symptoms." Of the 58 patients with GI manifestations, impaired hepatic function occurred in about 31% during hospitalization, compared with only 1% who were affected on initial presentation.

The next most common symptom, diarrhea (two to 10 loose or watery stools a day) was noted in 24% overall, followed by anorexia and nausea, each affecting 18%. Vomiting affected just 4% of patients.

The researchers noted that antibiotic treatment was associated with development of diarrhea (P=0.034) and elevated bilirubin levels (P=0.028) during hospitalization, effects that were not noted with antiviral treatment. Importantly, of the 11 patients with GI symptoms only, 12% had no evidence of COVID-19 pneumonia on imaging, that paper stated.

Authors of the current case report noted that while "COVID-19 RNA can be detected by PCR tests in the stool after respiratory samples become negative in some infected patients," it is not known how long the COVID-19 virus can remain viable in the stool.

They referred to a recent study conducted at China's Wuhan Inflammatory Bowel Disease (IBD) Center which suggested that the prompt measures taken to prevent the spread of the virus may explain why none of the 318 registered IBD patients developed COVID-19. While another case series noted diarrhea in just 3% to 5% of patients, authors of the current case report wrote that "clinicians have begun to question the prevalence of IBD as a symptom of COVID-19," citing another report in which 31% of 84 patients with COVID-19 pneumonia had diarrhea.

Case authors pointed to the other report of COVID-19 and ulcerative colitis in which a 19-year-old female from Italy "presented with fever, vomiting, bloody diarrhea, and loss of taste and smell ... a positive PCR test but no CT evidence of pneumonia, and contrast enhancement in the ileum and colon." She recovered fully, returned a negative PCR test, and was diagnosed with ulcerative colitis following an ultrasound of the small bowel on day 16, with no evidence of COVID-19 in stool samples.

Likewise, case authors noted that their patient also tested negative for COVID-19, despite CT evidence of diffuse ground-glass opacities, "the most common manifestation of COVID-19"; he also developed GI symptoms after finishing treatment for COVID-19, which improved on CT.

While noting that their patient's clinical picture was not compatible with ischemic colitis, case authors advised clinicians to also "consider ischemic colitis in the differential diagnosis of antibiotic-induced colitis." Regarding the latter, the group noted that while "late-onset antibiotic-induced colitis can occur on rare occasions," that did not apply in the current case, given his lack of symptoms for 2 weeks after antibiotic treatment, and the absence of amoeba and C. difficile toxins in stool analyses.

In this case, authors noted that their patient's clinical parameters, the presence of bloody diarrhea in the absence of a toxic condition (such as ischemia or necrosis), endoscopic and pathological findings, plus his "very rapid response to 5-ASA treatment for ulcerative colitis, and the onset of complaints after recovery from COVID-19" suggest his ulcerative colitis may have been due to an immune response triggered by COVID-19.

The group explained that the etiology of ulcerative colitis is unknown -- the disease may be induced by inflammation triggered by any condition. That their patient had no history of GI complaints; developed bloody diarrhea and abdominal pain shortly after the onset of COVID-19 symptoms; and had imaging and pathology findings compatible with ulcerative colitis "might suggest that the disease could be triggered by COVID-19," the group noted.

The high levels of angiotensin-converting enzyme-2 (ACE-2) and transmembrane serine protease required for the COVID-19 virus to enter cells are expressed by human intestines, they noted, citing emerging data suggesting the virus's effect on the GI system and liver may also be associated with hepatic cells' expression of ACE-2, "a major receptor for gastrointestinal epithelial cells and COVID-19."

Case authors observed that, while little is known about COVID-19 and inflammatory bowel disease (IBD), "the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) ... recently recommended reducing corticosteroid therapy and maintaining thiopurines and biologics." In 2021, that group also released consensus recommendations regarding SARS-CoV-2 vaccination for IBD patients.

Given the dynamic course seen in COVID-19 and the increasing range of clinical symptoms being reported, "there is an urgent need to properly determine the clinical features of COVID-19," case authors wrote. They acknowledged that while the lack of PCR investigations in stool or tissue samples was a limitation in this case, there was considerable evidence to suggest that the patient did experience COVID-19.

They concluded by urging further study of the association between COVID-19 and IBD, especially ulcerative colitis, and COVID-19 testing in patients presenting with gastrointestinal complaints.

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