Hydroxychloroquine

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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 62-year-old man developed hepatocellular type II fibrinogen inclusions following off-label treatment with hydroxychloroquine for Coronavirus disease (COVID-19).

The man was admitted to a regional hospital with a cough, high fever and shortness of breath. Subsequent investigation confirmed a diagnosis of COVID-19. Therefore, he was started on off-label treatment with atazanavir and ceftriaxone. However, 4 days later, his condition worsened and he required endotracheal intubation. His atazanavir and ceftriaxone treatment was replaced by off label therapy including remdesivir, hydroxychloroquine [route and dosage not stated] and piperacillin/tazobactam. Lung-protective ventilation was also initiated. Laboratory workup showed elevated ALT, AST and ALP with normal total bilirubin.

The man's hydroxychloroquine treatment was discontinued after 2 days of initiation. He was started on antithrombotic prophylaxis with heparin [unfractionated heparin]. On day 7 after, he developed a bilateral segmental pulmonary embolism and he was initiated on therapeutic anticoagulation. The coagulation tests showed slightly decreased prothrombin time. On day 20, an elevation in plasma fibrinogen was noted. He further developed ventilator-associated pneumonia, treated with cefepime and meropenem; he also developed polyneuropathy. His remdesivir treatment was stopped. On day 21, his COVID-19 test returned negative. On day 24, he underwent a tracheotomy. Concurrently, he also developed hepatitis. Meanwhile, his piperacillin/tazobactam therapy was discontinued. Subsequent workup showed a progressive elevation in ALT, AST, ALP and total bilirubin on day 25. Further investigations were found to be normal, except for positive cytomegalovirus (CMV). Therefore he was started on ganciclovir and within 10 days, a significant drop in viremia was noted. A liver biopsy showed mild lymphoplasmocytic infiltrate in the portal tracts, without interface hepatitis or fibrosis, together with a few apoptotic hepatocytes scattered throughout the lobules. The findings suggested that hepatitis had been ongoing for a while. Periodic Acid Schiff (PAS) stain with immunochemistry for hepatitis B and CMV was found to be negative. Electron microscopy showed inclusions containing a homogenous, moderately electron-dense granular material. The morphological features were indicative of hepatocellular type II fibrinogen inclusions [duration of treatment to reaction onset not stated]. In view of treatment and investigational findings, the abnormal cytoplasmic fibrinogen accumulation was attributed to the hydroxychloroquine therapy after ruling out known FGG mutation [outcome not stated].