key: cord-0712125-k6u6571y authors: Tarhini, Hassan; Husain, Maya; Poey, Nora; Lariven, Sylvie; Lescure, François-Xavier; Yazdanpanah, Yazdan; Gervais, Anne title: Jaundice in a patient treated with Anakinra in a context of Covid-19 date: 2020-09-30 journal: Med Mal Infect DOI: 10.1016/j.medmal.2020.09.011 sha: 673c1da32e6813cb534f79fb26837410e25ef138 doc_id: 712125 cord_uid: k6u6571y nan Anakinra, IL-1 receptor antagonist, is being used in the treatment of acute severe distress syndrome due to SARS-Cov-2 (1). Although this drug is associated with moderate elevation in transaminases, increased bilirubin is not documented as one of its adverse effects. We report a case of 87 years old woman with moderate COVID-19 infection treated by Anakinra. She had an elevation of the conjugated bilirubin 5 days after Anakinra treatment with clinical improvement and symptoms resolution one week after drug withdrawal. The pathophysiology behind Anakinra and an elevation of conjugated bilirubin is still not fully understood. An 87 year old female patient presented on April 2 to our hospital and was evaluated for a period of two weeks with upper respiratory symptoms, myalgia, headache, and worsening dyspnea over 3 days. Medical history is significant for longstanding hyperlipidemia treated with Fenofibrate and hypertension treated with indapamide and propranolol. She had no history of alcohol abuse or chronic liver disease. On presentation, the patient was afebrile and severely hypoxemic (oxygen saturation was 80 % on room air). Her physical exam was notable only for basilar crackles with no signs of cardiac decompensation. Initial laboratory evaluation showed elevated CRP (280 mg/L). No abnormalities were shown on liver, kidney, and hematological biological tests. Chest CT without contrast was compatible with COVID-19 infection with extensive involvement estimated at 45%. The patient's hypoxemia resolved with 15L/min oxygen therapy reaching 95% saturation. Initial regimen treatment was composed of Lopinavir /Ritonavir (10 days), Dexamethasone (6 days), and Ceftriaxone (total course of 7 days). Anakinra (Interleukin 1 receptor antagonist) was added to the initial regimen on April 4 for a total of 5 days. Since April 5, the patient had been clinically improving. Her oxygen requirements decreased and the inflammatory marker (CRP) was trending down to 16 mg/L on April 7. One week later, the patient's clinical status had improved dramatically. Her oxygen requirements decreased along with resolution of fever and respiratory symptoms. Her inflammatory markers and bilirubin trended down (Table 1) . Afterwards, the patient was sent to a rehabilitation center on oxygen 1L/min to attain full recovery before going home. In this report, we present a case of bilirubin elevation after 5 days of Anakinra treatment. There was no disturbance in either transaminases (AST/ALT) or in the activity of alkaline phosphatase (ALP). At the onset of this disturbance, the patient's clinical condition was improving, and her inflammatory markers were trending down. Therefore, the etiology of this perturbation is most likely related to the Anakinra treatment rather than the inflammatory syndrome. Even though the patient was on Fenofibrate, her baseline liver enzymes were normal. She also received steroids for six days only, in addition to Ceftriaxone for seven days and Lopinavir /Ritonavir for ten days, but none of these medications give jaundice without acute hepatitis after a short duration of treatment (2). No history of chronic or active viral infection (HBV, HCV, HAV), no autoantibodies found, and no morphological abnormalities in the biliary tract. An isolated increase of conjugated bilirubin has to be related to change in bilirubin secretion. Conjugated bilirubin is secreted by the multidrug resistance protein 2 (MRP2, gene ABCC2), through the canalicular membrane into bile (3). Two nuclear receptors, the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) supervise bilirubin metabolism (4) . Proinflammatory cytokine IL-1β leads to CAR downregulation and hyperbilirubinemia (5) . Therefore, an increase of bilirubin during Anakinra administration is not expected as Anakinra is the recombinant human IL-1Ra which inhibits the action of IL-1α and IL-1β. A delicate equilibrium exists between pro-inflammatory cytokines (IL-1, IL-12, IL-18, TNF-α, IFNγ, and GM-CSF) and anti-inflammatory cytokines (interleukin -1 receptor antagonist, IL-4, IL-6, IL-10, IL-13, IL-19, and IL-35). It is known that MRP2/ABCC2 is significantly downregulated by TNF-α, IL-6, and IL-1β (6) . During COVID, the cytokine's equilibrium is disrupted by excessive elevation of pro-inflammatory cytokines (7) . When pro-inflammatory cytokines are released, anti-inflammatory cytokines are subsequently secreted to restore the balance. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China National Institute of Diabetes and Digestive and Kidney Diseases Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance The Constitutive Androstane Receptor and Pregnane X Receptor Function Coordinately to Prevent Bile Acid-induced Hepatotoxicity Interleukin 1β inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance Regulation of MRP2/ABCC2 and BSEP/ABCB11 Expression in Sandwich Cultured Human and Rat Hepatocytes Exposed to Inflammatory Cytokines TNF-α, IL-6, and IL-1β Cytokine storm in COVID-19 LiverTox: Clinical and Research Information on Drug-Induced Liver Injury National Institute of Diabetes and Digestive and Kidney Diseases Anakinra Hepatotoxicity in a Patient With Adult-Onset Still's Disease. ACG Case Rep J Subacute Liver Failure Following Anakinra Treatment for Adult-onset Still Disease This equilibrium between early pro-inflammatory and late anti-inflammatory cytokines is disturbed through Anakinra administration. So even if Anakinra-induced liver injury is reported as mild elevations in aminotransferase levels except for some case reports (8) (9) (10) . This report, with isolated hyperbilirubinemia, suggests a modulation of MRP2 expression or function. This observation should prompt assessment of MRP2 polymorphism to fully understand the regulatory mechanism underlying such a change.