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.