Tocilizumab

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

A 38-year-old man developed decrease in WBC count following an off-label use of tocilizumab, indicated for COVID-19 pneumonia and acute pancreatitis.

The man had underlying oedematous moderate acute pancreatitis, hepatic steatosis, hepatosplenomegaly and alcohol dependence. On 4 April 2020, he was admitted in hospital of Poland, with positive SARS-CoV-2 (molecular test result obtained on 3 April 2020). He had previously been hospitalised for 2 weeks in another medical centre due to severe acute pancreatitis, presenting with acute-onset upper abdominal pain, metabolic acidosis and features of multi-organ failure. Empiric antimicrobial therapy with vancomycin and imipenem/cilastatin and total parenteral nutrition (TPN) were administered that time. On 27 March 2020, he underwent chest high-resolution CT-scan and abdomen-pelvis contrast-enhanced CT scans, which showed diffuse enlargement, shaggy contour of the pancreas without contrast enhancement of pancreatic neck, body and tail, oedema and blurring of peripancreatic fat planes, acute peripancreatic and intraperitoneal fluid collection, bilateral atelectasis in lower lung segments and pleural fluid collections up to 24mm on the left side and up to 18mm on the right side. No COVID-19 imaging findings were noted. He was then transferred to the latest hospital (latest presentation) to continue the treatment due to SARS-CoV-2 infection. Following admission, he received IV paracetamol 1000mg four times daily and oxygen supplementation through a nasal cannula, and his oxygen saturation increased to 95%. Off-label therapy with vancomycin 1000mg twice daily, IV meropenem 1000mg three times a day and SC dalteparin sodium [dalteparin] 7500 IU once daily were administered for COVID-19. He received off-label oral chloroquine 500mg twice a day for COVID-19. Blood and urine culture tests were negative. Of note, hepatitis B surface antigen, hepatitis C antibodies and HIV antigen were all negative. He was provided with a mechanical soft diet, with good clinical tolerance. On day 2, his vital parameters were stable, and he received off-label oral azithromycin 500mg daily for COVID-19. On days 3 through six of hospitalization, vital parameters remained stable except fever (despite paracetamol and dipyrone [metamizole] treatment), mild dry cough and shortness of breath with oxygen saturation at 91−94%, while breathing ambient air. Investigations showed necrosis of more than 50% of pancreatic parenchyma (body and tail), peripancreatic and along Gerota's fascia fluid collections, and acute necrosis collection (ANC) along the greater curvature of the stomach. On day 5 a chest X-ray demonstrated diffused bilateral alveolar consolidations. On day 6, an abdominal ultrasound and emergency chest high resolution (HR) CT were performed. The HRCT showed widespread, multifocal, bilateral groundglass opacities (GGO) typical for COVID-19 pneumonia and ultrasound showed hepatic enlargement up to 180mm, enlargement of pancreas up to 30mm and fluid collection located around head of pancreas and along the left anterior renal fascia. On the same day vancomycin was discontinued, and he received off-label oral lopinavir/ritonavir lopinavir 400mg/ritonavir 100mg twice a day for COVID-19. The next day his body temperature was still increased. Later at night, due to persistent fever, increased serum IL-6 level and after multidisciplinary consultation, he received off-label IV tocilizumab 800mg to inhibit cytokine storm syndrome in COVID-19 pneumonia. On day 2, he developed decrease in WBC count due to tocilizumab.

On day 8 the man's condition improved, and body temperature was normal. On day 10 CRP level dramatically decreased, and oxygen saturation improved to 98%, while breathing ambient air. Meropenem was discontinued, and oral rifaximin 400mg twice a day was administered. On day 12, an abdominal ultrasound showed peripancreatic fluid collection (as in previous abdominal ultrasound examination), parenchymal heterogenicity of body and tail of pancreas, and spleen enlargement up to 127mm. On day 13, a nasopharyngeal swab test for SARS-CoV-2 nucleic acid returned negative. Additionally, his CRP level decreased, and RBC morphology improved, showing elevation of RBC count, and haematocrit and Hb level. Chloroquine was discontinued. The next day, retesting of nasopharyngeal swabs for SARS-CoV-2 nucleic acid was negative and control chest HRCT showed significant regression of GGO and reduction of pleural fluid collection. On day 15 (18 April 2020), due to clinical and laboratory improvement without the need for oxygen supplementation and negative SARS-CoV-2 swabs tests, he was discharged from the hospital with advice of undertaking control abdominal ultrasound within 3−4 weeks, and chest HRCT and blood tests within 2 months. Control ambulatory abdominal ultrasound, performed on 3 June 2020 revealed inflammatory changes around the head of the pancreas, body and tail heterogenous necrosis, and peripancreatic and along anterior renal fascia fluid collection. CRP level, blood morphology parameters, sodium, potassium, transaminases, ALP, GGTP, bilirubin, amylase, lipase, creatinine, urea, and TSH were within normal range. On 1 July 2020, control chest HRCT, abdomen-pelvis contrast enhanced CT (CECT), and blood tests were performed. Chest HRCT showed no pulmonary consolidations. Abdomen-pelvis CECT revealed regression of pancreatic oedema and peripancreatic fluid collection, necrosis of more than 50% of pancreatic parenchyma (poor contrast enhancement of body and tail parenchyma as previously), 61×42×38mm encapsulated wall-off necrosis (WON) along the greater gastric curvature (previously ANC 88×70×125mm), encapsulated 78×32×180 mm WON along the left anterior renal fascia down to the descending colon, and splenic vein thrombosis with collateral vessel compensation. After hospital discharge, he experienced only mild abdominal pain periodically a couple of times a month, mainly after dietary mistakes. No other symptoms were reported, and his physical examination showed no significant abnormalities. Outpatient follow-up was continued for 2.5 months, with good outcome.