Discussion
MOFS is a known catastrophic complication of SCD; however, aspects of this case of MOFS with severe encephalopathy secondary to acute liver failure with hyperammonemia, acute kidney injury, and neurologic insult present a diagnostic enigma. MOFS in SCD typically evolves from VOC progressing to fever, altered sensorium, significant rapid drop in hemoglobin and platelets, and acute failure of at least two of the following organs: liver, kidney, or lungs; it is often fatal without prompt RBCX8,9. While she had some classic features of SCD-related MOFS, hyperammonemia is not typical, and her anemia and thrombocytopenia were mild. While her low baseline hemoglobin S (<30%) is not fully protective, it reduces the likelihood that SCD alone is the culprit.
Her history of acute and chronic liver issues – poorly-controlled iron overload, history of hepatic crisis10,11, potential toxicity from DFX12,13 and/or hydroxychloroquine – certainly predispose to hepatic injury14; however, these are unlikely the sole cause. In the differential for her acute liver dysfunction and hyperbilirubinemia was acute SCD hepatopathy, a range of conditions including acute hepatic crisis, hepatic sequestration, or acute intra-hepatic cholestasis. Though her baseline hemoglobin S was kept low by chronic transfusion therapy, evidence suggests that low hemoglobin S may not be fully protective against SCD hepatopathy10,7. However, involvement of other organs and unusual presentation of hyperammonemia preceding AST/ALT increase argue against SCD hepatopathy alone. DFX-induced liver failure and hyperammonemia are reported though poorly understood; however additional findings of MOFS with multisystem hyperinflammatory disorder also suggest a pathophysiology beyond DFX toxicity alone8,9.
While SARS-CoV-2 PCR was negative immediately prior to developing MOFS, the short duration from initial diagnosis to MOFS is suspicious. Severe COVID-19 disease was initially described as primarily ARDS; however, multiple organ failure, diffuse thromboembolic disease, and hyperinflammatory response have more recently been reported. Overproduction of early pro-inflammatory cytokines, including TNF-α and IL-6, may occur, leading to hyperinflammation with increased vascular permeability, vasculitis, and multiorgan failure1. One such presentation has been described as multisystem inflammatory syndrome in children (MIS-C), a rare syndrome similar to Kawasaki Disease occurring one to six weeks following COVID-19 infection15-17. MIS-C has greater gastrointestinal symptoms, lesser respiratory symptoms, and greater risk for severe manifestations of toxic-shock-syndrome, cardiac involvement (coronary aneurysms, myocarditis, heart failure), and macrophage activation syndrome18,19.
COVID-19-related coagulopathy is also recognized, with severe cases showing increased D-dimer, initial increase with late decrease in fibrinogen, disseminated intravascular coagulation20or other thrombotic complications18. Among other COVID-19 manifestations, gastrointestinal symptoms and/or abnormal liver function tests are reported12,13,21. Though this patient initially presented with VOC and respiratory symptoms of COVID-19, her acute chest syndrome was mild, without progression to pneumonitis, pulmonary edema, or ARDS; later manifestations were abdominal pain, hyperammonemia, liver failure, acute kidney injury, and systemic inflammation. While this case is not consistent with MIS-C, it demonstrates that post-COVID-19 inflammation may include a spectrum of manifestations occurring after initial infection. Further observation supporting COVID-19-related multisystem hyperinflammatory disorder is her rapid improvement following TPE, observed in other COVID-19 patients22,23.
The pathophysiologic mechanism for this patient’s clinical course is likely multifactorial, with COVID-19-related multisystem hyperinflammatory disorder likely triggering SCD-related MOFS and DFX-induced hepatic injury with hyperammonemia in a patient with preceding liver disease. This novel case of MOFS with predominant hepatic involvement may represent another possible COVID-19 manifestation in SCD, preexisting liver disease, DFX therapy, or others without these conditions. We recommend monitoring liver function, coagulation profile, and ammonia levels in high risk COVID-19 patients with underlying liver disease (SCD or other causes). Hepatotoxic drugs like DFX may need to be held. Lastly, RBCX and TPE should be considered in SCD patients with MOFS and multisystem hyperinflammatory disorder secondary to current or recent COVID-19.
Conflict of Interest: The authors have no conflicts of interest to disclose.
Financial Disclosure: The authors have no financial relationships relevant to this article to disclose.