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This previously healthy 61-year-old man presented with jaundice as well as features of both cholestasis and hepatocellular injury weeks after having Covid-19. Viral, autoimmune, and drug- or alcohol-associated hepatitis were ruled out. The unclear cause of jaundice in the presence of features of systemic inflammation aroused suspicion for HLH. The patient’s symptoms met the diagnostic criteria for secondary HLH, and in the absence of other causes, post–Covid-19 HLH was diagnosed. HLH is diagnosed when patients have at least five of eight diagnostic criteria that include physical examination findings, laboratory tests including elevated inflammatory markers, and histologic findings. Our patient’s fever, hypertriglyceridemia, hemophagocytosis on a bone marrow biopsy, high level of ferritin, and elevated level of soluble interleukin-2 receptor α were consistent with the diagnosis of HLH, even in the absence of other criteria (splenomegaly, cytopenias, and low or absent NK-cell activity).1 In addition, this patient had an H score of 189, which was strongly suggestive of secondary HLH. In a retrospective study, the best cutoff value for diagnosis was an H score of 169, which had a sensitivity of 93% and specificity of 86% for HLH.2 Details about H scores are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

hich was strongly suggestive of secondary HLH. In a retrospective study, the best cutoff value for diagnosis was an H score of 169, which had a sensitivity of 93% and specificity of 86% for HLH.2 Details about H scores are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. A hyperinflammatory syndrome may occur during severe Covid-19 illness or after Covid-19 has resolved.3-5 “Cytokine storm” is an umbrella term that encompasses the exaggerated activation of the immune system, systemic inflammation, and life-threating multiorgan failure that may follow SARS-CoV-2 infection. Although there has been no broadly accepted definition of cytokine storm, three criteria have been proposed for the diagnosis: elevated circulating cytokine levels, acute systemic inflammatory symptoms, and cytokine-driven organ dysfunction.6 Profound leukopenia is common, and mononuclear cell infiltrates in the lungs, spleen, heart, and lymph nodes have been observed on postmortem analyses. The pattern of elevations in cytokine levels seen in severe Covid-19 most often includes elevations in interleukin-6, interleukin-7, TNF, interleukin-2 receptor α, and inflammatory cytokines such as CCL2, CCL3, and CXCL10 — all of which are products of hyperactivated monocytes and macrophages. Indeed, in single-cell analysis of bronchoalveolar lavage fluid samples, patients with severe Covid-19 have been found to have higher numbers of inflammatory macrophages than those with mild disease or healthy controls, an observation that supports a central role of macrophage activation in the pathogenesis of severe Covid-19 disease.7 HLH associated with viral infections or autoimmune disorders is similarly characterized by macrophage polarization toward a hyperinflammatory phenotype and thus has pathophysiological overlap with Covid-19 pathogenesis.

at supports a central role of macrophage activation in the pathogenesis of severe Covid-19 disease.7 HLH associated with viral infections or autoimmune disorders is similarly characterized by macrophage polarization toward a hyperinflammatory phenotype and thus has pathophysiological overlap with Covid-19 pathogenesis. The clinical manifestations of Covid-19–associated cytokine storm include fever, fatigue, anorexia, acute respiratory distress syndrome, liver injury, and multiorgan failure (Figure 3).6 These features are apparent in patients with severe Covid-19 pneumonia8 and overlap with clinical features associated with the two well-characterized, immune-mediated, severe systemic inflammatory syndromes that may follow Covid-19 illness. HLH usually occurs less than 14 days after the onset of infection,3 and MIS-C and MIS-A typically occur several weeks after Covid-19. The delayed manifestation of HLH in our patient highlights the fact that immune-mediated complications probably represent a spectrum of disorders rather than distinct syndromes. The timeline, symptoms, and laboratory features of prolonged hyperinflammatory Covid-19 may also overlap with those of HLH and MIS-A, sometimes making distinguishing the conditions difficult.8 Among reported patients with HLH associated with Covid-19, most were male, with a median age of 56 years; many cases occurred in the context of prolonged severe acute Covid-19. Most patients received care in an intensive care unit, and overall mortality was 46%, similar to that reported in severe Covid-19.9-12 Hyperferritinemia, elevated AST levels, and fever were the main presenting features. Hemophagocytosis was present in 83% of cases in which a biopsy was performed. However, only eight patients met at least five of the eight criteria required to make a diagnosis of HLH; thus, treatment with glucocorticoids should be considered even if patients do not meet the required diagnostic criteria.

nting features. Hemophagocytosis was present in 83% of cases in which a biopsy was performed. However, only eight patients met at least five of the eight criteria required to make a diagnosis of HLH; thus, treatment with glucocorticoids should be considered even if patients do not meet the required diagnostic criteria. Prompt identification of cytokine storm is critical for management. Aside from supportive care, immunosuppressive therapy is necessary to contain the damage induced by the exaggerated immune response. Case series have shown that in patients with secondary HLH-associated cytokine storm, treatment with glucocorticoids, interleukin-1β inhibitors, or Janus kinase (JAK) inhibitors JAK1 and JAK2 provides benefits.13,14 Although patients with HLH and hepatic involvement may have prompt overall improvement after glucocorticoid therapy, persistent AST and ALT elevation for more than 1 year after hospital discharge has been reported.15 Weeks after this patient had Covid-19, a severe hyperinflammatory syndrome consistent with HLH developed. The prompt alleviation of the constellation of symptoms and signs after immunosuppressive therapy was started underscores the importance of early recognition of this entity.