Tocilizumab
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Acute terminal ileum and perforated caecal ulceration following off label use: case report A 43-year-old man developed acute terminal ileum and perforated caecal ulceration during off label therapy with tocilizumab for COVID-19. The man presented to hospital in Singapore with a 1-week history of high fever, cough and anosmia. He had a history of hypertension, gout, chronic kidney disease (CKD-3) and unprovoked lower limb venous thromboembolism (VTE). On day 1 of hospitalisation, he required intubation due to respiratory failure, and on day 2, he started receiving norepinephrine for refractory shock. He also received continuous renal replacement therapy. Further, COVID-19 acute respiratory distress syndrome (H-type CARDS) was noted along with paralysis, and his condition continued to worsen. On day 2 of hospitalisation, off label therapy with IV tocilizumab 800mg was initiated. Concurrently, he also received heparin and off label therapy with hydrocortisone from day 2 to day 5. Tocilizumab doses were withheld because of improvement in clinical status. Later, gastrointestinal (GI) bleeding occurred. Two days before overt GI bleeding, he had high-volume diarrhoea, requiring rectal tube insertion. On day 17, CT mesenteric angiogram (CTMA) revealed arterial blush in the caecum and thickening of the terminal ileum. The bleeding continued on day 18 of admission. Repeated CTMA showed new areas of active bleeding in the ascending colon. Therefore, a second embolisation of a separate culprit vessel was performed. However, bleeding continued, necessitating significant amounts of blood transfusion. On day 20, colonoscopy was performed with attempted endostasis. Endoscopy showed erythematous friable ileal mucosa and luminal bleeding up to at least 15cm proximal to the ileocecal valve. Additionally, colitis of the caecum and ascending colon along with large ulcerations were noted [time to reaction onset not stated]. Because of endostasis failure, the man underwent a right-sided hemicolectomy and segmental resection of the terminal ileum. The gross examination demonstrated extensive ulceration of the terminal ileum associated with the thickened dusky wall, fat encroachment and mesenteric stranding. The caecum had three deep linear circumferential ulcers with bowel wall perforation (perforated caecal ulceration). Microscopic examination showed extensive ulceration of the terminal ileum and deep fissuring caecum ulceration associated with perforation. The mucosa at the ulcer edges demonstrated irregular, branching and disordered crypts, which were compatible with regenerative changes. Smaller vessels around ulcerative sites contained scattered fibrin microthrombi; however, the overall burden was low with no ischaemic changes. Drug chart review identified only tocilizumab as culprit drug. Tissue bacterial culture showed light growth of multidrug-resistant Pseudomonas, and it had also identified from the respiratory tract. Fungal cultures showed a light growth of Candida glabrata, which was considered non-pathogenic. A stool PCR
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