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Acetylcysteine/hydroxychloroquine Haemolysis and inflammation following off-label use of hydroxychloroquine and acetylcysteine: 7 case reports

In case series, seven men aged 38-71 year were described. A man developed haemolysis during off-label treatment with hydroxychloroquine, and the remining six men developed elevated inflammatory markers C-reactive protein (CRP) and ferritin due to rebound effect of off-label use of acetylcysteine as therapeutic blockade of inflammation in severe COVID-19 infection [not all routes and frequency stated; time to reaction onset not stated]. Patient 1: A 44-year-old man, who had fever, cough and shortness of breath for 5 days, presented to the emergency department on 20 March 2020. He had a significant history of G6PD deficiency following haemolytic reaction to sulfa drugs. At presentation, he was tested positive for SARS-CoV-2 by PCR test. Additionally, his inflammatory markers including C-reactive protein (CRP), ferritin, and D-dimer, neutrophil to lymphocyte ratio (NLR) were elevated. On the next day, he received off-label treatment with hydroxychloroquine 400mg (only1 dose). However, his respiratory status continued to deteriorate. Therefore, he was intubated on 24 March 2020. Further he required veno-venous extracorporeal membrane oxygenator (VV ECMO) for oxygenation. Further laboratory investigation revealed a low level of Hb (7.9 g/dL) and elevated level of direct bilirubin (6.0 mg/dL), total bilirubin (9.0 mg/dL), alanine aminotransferase (263U/L) and aspartate aminotransferase (338U/L). Additionally, he was found to have a low level of G6PD (0.5 U/g Hb) and haptoglobin (2 mg/dL). Subsequent blood smear revealed bell cells suggesting G6PD-deficiency haemolysis. On 30 March 2020, he started receiving IV acetylcysteine [N-acetylcysteine] 30000mg 3 times/24 hours. His haemolysis indices improved with the acetylcysteine treatment. It was found that, bilirubin (total and direct) level increased following discontinuation of acetylcysteine, but it reduced with re-administration of acetylcysteine 600 mg/12 hours. Thus, it was concluded that, acetylcysteine therapy was associated with resolution of haemolysis as evident by a sustained reduction in total and direct bilirubin. His symptoms improved and he was discharged to the rehabilitation centre on 27 April 2020. On 30 April 2020, he was discharged to home with unspecified steroids. At the time of IV acetylcysteine therapy, reduction in inflammatory markers (CRP and ferritin) was also observed. Patient 3: A 48-year-old man was admitted with COVID-19 infection. His C-reactive protein (CRP) level was 243 mg/mL and ferritin was 5900 ng/mL. On 10 April 2020, he started receiving off-label treatment with IV acetylcysteine [N-acetylcysteine] 600 mg/12 hours for 7 days. During the treatment, the inflammatory markers CRP and ferritin were decreased to 72 mg/mL and 2700 ng/mL, respectively. However, the rebound of inflammation was noted following discontinuation of acetylcysteine. Therefore, on 28 Apr 2020, acetylcysteine was restart