Cecal Perforation in a COVID-19 Patient Treated with Tocilizumab: A Case Report

host immune response that characterizes the disease and initiates patients' lung damage. Herein we present the case of a cecal perforation in a patient treated with Tocilizumab for COVID-19. In such context, we expect that there may be an increase in the incidence of gastrointestinal perforation related to Tocilizumab.


Introduction
Interleukin-6 (IL-6) is a well-known pro-inflammatory cytokine produced by B and T cells, monocytes and fibroblasts, that mediate several biological functions, including T cell activation, the differentiation of activated B cells into Ig-producing plasma cells, the upregulation of acute-phase protein synthesis in hepatic and adipose tissues. IL-6 is also implicated in the pathogenesis of autoimmune diseases such as Rheumatoid Arthritis (RA) and Juvenile Idiopathic Arthritis [1]. Tocilizumab is an IgG1 recombinant humanized antiinterleukin-6 receptor monoclonal antibody, which is used as a secondline treatment for RA, administered intravenously or subcutaneously, at a dose of 8 mg per Kg every 4 weeks for intravenous administration. It specifically binds to the IL-6 receptor, blocking the IL-6 intracellular signaling pathway [1].
Patients with severe COVID-19 pneumonia present with massive, aberrant and ineffective immune response, mediated by a proinflammatory cytokine storm led by IL-6, whose high levels are found in peripheral blood. This hyperimmune response triggers inflammation, exudation, increased vascular permeability and alveolar-capillary membrane edema, compromising gas exchange. In the absence of specific antiviral drugs, Tocilizumab (1-2 intravenous doses of 400 mg) is currently being used to treat patients with severe COVID-19 pneumonia [2].
Chest X-ray showed diffuse, hazy pulmonary opacities predominantly involving the right lung suggestive of COVID-19 pneumonia; RT-PCR test and serologic test were therefore performed on the patient and they both resulted positive for SARS-CoV-2. Based on clinical and analytical data, suspecting a multiple organ dysfunction syndrome secondary to intestinal ischaemia computed tomography angiography (CTA) was performed, showing a markedly dilated colon with a fecaloma in the rectum. In addition, CTA showed a normal enhancement of the bowel wall, excluding the suspected diagnosis and furthermore, the scan showed bilateral ground-glass opacities predominantly involving the right lung, suggestive of COVID-19 pneumonia, as described in the chest X-ray ( Figure 1)  The patient was hospitalized in Internal Medicine to receive treatment for COVID-19 pneumonia, including hydroxychloroquine, high doses of methylprednisolone (initial dose of 250 mg/day per 3 days, then 40 mg/day), lopinavir, ritonavir and Tocilizumab (single IV dose of 400 mg on the first day of hospitalization). Constipation improved with enemas and laxatives. On hospitalization day eight, the patient presented with intense and diffuse abdominal pain with signs of peritoneal irritation. A new CTA was performed, showing a 9 cm dilation of the cecum with intestinal pneumatosis, pericolonic fat stranding, free intraperitoneal fluid and pneumoperitoneum, suggestive of cecal perforation secondary to mesenteric ischaemia ( Figure 2). Urgent exploratory laparotomy was performed, finding a cecal perforation of inflammatory aspect with no generalized peritonitis. Right hemicolectomy with terminal ileostomy and the mucous fistula was performed. The postoperative course was uneventful. Microscopically the inflammatory nature of the lesion was confirmed with no signs of malignancy.

Discussion
GIP has been described as a rare but severe complication in relation to Tocilizumab treatment. The incidence rate of GIP in RA patients treated with Tocilizumab, both with subcutaneous and intravenous administration, was 1.2-3.9 per 1000 patient-years, the highest compared with other biological therapies for RA, with an associated mortality of 4.8-46%. No incidence increase was observed with higher drug doses nor longer drug exposure time [3]. Most perforations (71-85%) have occurred in the lower GI tract (small intestine or colon), with an incidence of 2.7 events per 1000 patient-years, HR of 4.48 (95% CI 2.0-10.0), the highest compared to other biological therapies for RA. In such cases, the mortality rate reaches 46%. Previous biological therapies, history of diverticular or peptic ulcer disease, advanced age, tobacco use, glucocorticoid use >7.5mg/day and non-steroidal anti-inflammatory drugs use are well-known predictors of GIP associated with Tocilizumab [3][4][5]. The physiopathological mechanism of lower GIP in patients with diverticular disease treated with Tocilizumab is explained by the role of IL-6 and its receptor in undertaking intestinal epithelial repair. This is done by stimulating enterocyte proliferation and wound healing and mediating the coverage of an inflamed diverticulum by the surrounding adipose tissue, thus impeding the progression of transmural inflammation and subsequent intestinal perforation, similar to the mesenteric adipose tissue's role in Crohn's disease. Tocilizumab's blockade of the IL-6 pathway can affect this protective mechanism, increasing the risk of GIP [5]. Specifically, we are not able to determine to what degree both Tocilizumab and high doses of glucocorticoids contributed to the pathogenesis of GIP in this case. Although, based on the described physiopathological mechanism, by inhibiting the IL-6 pathway, Tocilizumab may have facilitated the transmural inflammatory progression and the subsequent intestinal perforation, even if its primary cause was the marked cecum dilatation. The half-life t1/2 of Tocilizumab after a single IV dose is 18 days [1]. GIP took place 7 days after its administration. Therefore, its implication in the etiopathology of this case is chronologically plausible.

Conclusion
GIP is a rare but severe complication in relation to Tocilizumab treatment. Although its pathogenic involvement is difficult to prove, given its emerging role as an alternative treatment for patients with severe COVID-19 pneumonia, an increase in the incidence of GIP related to Tocilizumab may occur in such a context.