"Toci Associated Toxicity" - A Report of Tocilizumab Associated Bowel Perforation in Two Critically Ill Patients with COVID-19 Pneumonia

Abstract

INTRODUCTION:The advent of corona virus disease as a global health emergency has resulted in the trial of several empiric pharmacological regimens, many of which are associated with deleterious adverse effects. However, because of the lack of viable treatments and rapidity of spread, physicians around the world have used them in an attempt to improve survival in critically ill patients. One such drug is Tocilizumab, which was hypothesized to have a role in managing the cytokine release syndrome ("Cytokine storm") associated with this illness. We report our experience with 2 critically ill patients with COVID-19 who received Tocilizumab and subsequently developed intestinal perforation. CASE PRESENTATION: Patient A was a 74-year-old gentleman with COVID-19 pneumonia whose hospitalization was complicated by development of adynamic ileus presumed secondary to sepsis, that was conservatively managed. Due to worsening tachypnea, tachycardia and higher oxygen requirements, he was given Tocilizumab. 2 weeks into his hospital stay, his surveillance imaging demonstrated small bowel perforation with free intraperitoneal air and intrabdominal abscesses. He was started on antibiotics, total parenteral nutrition and obtained 2 intraperitoneal drains. His further hospital stay was complicated by development of hypotension and asystole cardiac arrest. Patient B was a 65-year-old renal transplant recipient with COVID-19 pneumonia who received Remdesivir, Dexamethasone, convalescent plasma and Tocilizumab. During his hospital stay, he had worsening hypoxic respiratory failure requiring mechanical ventilation. Subsequently, patient developed fevers with worsening leukocytosis and new pressor requirements. He was started on broad spectrum antibiotic coverage and imaging demonstrated pneumatosis of ascending colon concerning for impending perforation. After discussion with family members, patient was transitioned towards comfort measures. DISCUSSION: Tocilizumab is an Interleukin-6 receptor antagonist which was used for the profound inflammatory state associated with COVID-19. Recent studies have demonstrated its ineffectiveness in preventing further clinical deterioration, intubation or death in moderately ill hospitalized patients with COVID-19. In prior studies in rheumatoid arthritis, Tocilizumab was noted to have a higher incidence of lower gastrointestinal perforations, especially with preexisting diverticulitis or steroid use. The exact mechanism of bowel perforation is unclear and is likely multifactorial. Early after bowel injury, there is a substantial increase in Interleukin-6 expression that stimulates epithelial proliferation. Absence of this, in combination with intestinal hypoperfusion seen in critically ill patients may potentially increase the risk of intestinal perforation. Our cases emphasize the importance of close monitoring and caution while using lesser known and more risky medications without clearly established guidelines.

A Case of Abdominal Perforation in a COVID+ Patient Treated With Tocilizumab and Corticosteroids

“… 4 With concerns to abdominal perforation in COVID-19 patients, tocilizumab, an approved treatment by the CDC, has been linked to such adverse effects. Asharaf and Papierniak 6 note a higher incidence for GI perforation in patients with previous corticosteroid use or preexisting diverticulitis. In addition, they state that increased expression of IL-6 stimulates epithelial proliferation, which was significantly reduced in patients at higher risk of intestinal perforation.…”

“…In addition, they state that increased expression of IL-6 stimulates epithelial proliferation, which was significantly reduced in patients at higher risk of intestinal perforation. 6 It is also important to mention that no adverse GI effects have been reported using convalescent plasma. 7 Tocilizumab, an IL-6 receptor antagonist, was initially approved by the Food and Drug Administration (FDA) for adults with moderate to severe rheumatoid arthritis and children ages 2 and old with either active Polyarticular Juvenile Idiopathic Arthritis or active Systemic Juvenile Idiopathic Arthritis.…”

“…In addition, they state that increased expression of IL-6 stimulates epithelial proliferation, which was significantly reduced in patients at higher risk of intestinal perforation. 6 It is also important to mention that no adverse GI effects have been reported using convalescent plasma. 7 …”