COVID‐19‐associated secondary hemophagocytic lymphohistiocytosis requiring hematopoietic cell transplant

Abstract Coronavirus disease 2019 (COVID‐19) infection causes a variety of extrapulmonary complications in pediatric patients. Multisystem inflammatory syndrome and hemophagocytic lymphohistiocytosis (HLH) are related to hypercytokinemia in COVID‐19 patients. HLH is a disorder of exaggerated inflammation resulting in a cytokine storm and unrestricted hemophagocytosis. HLH can be primary (familial) or secondary (acquired). Secondary HLH (sHLH) can occur in patients with rheumatologic, oncologic, or infectious diseases. The link between COVID‐19 and HLH has been reported in pediatric patients. Here we report a case of a pediatric patient who developed refractory sHLH secondary to COVID‐19 infection and required a hematopoietic cell transplant for the cure.

HLH is a hematologic disorder of exaggerated inflammation that results in a sepsis-like cytokine storm and unrestricted hemophagocytosis [5]. HLH can be primary (familial) or secondary (acquired). Secondary HLH (sHLH) can occur in patients with rheumatologic, oncologic, or infectious diseases [5]. A case of COVID-19 inducing HLH has previously been reported in a 6-week-old infant with Chediak-Higashi syndrome [6]. Here we report a case of a pediatric patient who developed refractory sHLH to COVID-19 infection and required a hematopoietic cell transplant (HCT) for the cure.
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CASE
A 5-year-old female presented to her pediatrician with fevers (101-105 • F) and papular rash for three days and was subsequently diagnosed with polymerase chain reaction (PCR) positive COVID-19. A chest X-ray was unremarkable, and she was treated empirically with cefdinir and azithromycin. After 4.5 weeks of persistent fevers despite antibiotic therapy, she was transferred to a tertiary center for further evaluation with concern for further evaluation of her hyperinflammatory state.
Labs at the time of re-evaluation are summarized in Table 1 Although the identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is temporally related with the hyperinflammation, it is possible that other unfound causes may have been at play.
Strong consideration was given to MIS-C, which was the leading differential diagnosis at repeat evaluation. The diagnosis of MIS-C requires (1) fever, inflammation, and multisystem (>2) involvement, toms that require intensive support [8]. Third, while anemia classifies as a hematologic manifestation, lymphocytopenia and thrombocytopenia are more characteristic of MIS-C [9]. Fourth, while ferritin is often elevated in severe, MIS-C, the elevation of ferritin is frequently much more modest [10]. In a study that evaluated features of MIS-C with cytokine storm syndrome scoring systems, the highest reported ferritin level was 1527.6 ng/ml [10]. We considered HLH as an alternative diagnosis based on absence of clinical gastrointestinal and cardiac symptoms, prolonged hemodynamic stability, absence of leukopenia, and profound hyperferritinemia.
multiple areas of mild lymphadenopathy. An echocardiogram and EKG were normal.
The diagnostic criteria for HLH include fever, splenomegaly, hypertriglyceridemia, elevated ferritin, hemophagocytosis, decreased NK cell activity, and elevated sIL-2R (Table 2) [11,12]. This case met 7/8 diagnostic criteria for HLH with only 5/8 being necessary for diagnosis (Table 2). H-Score was 236, which portends a 98%-99% probability of HLH [13]. Of note, in the cohort reported by Reiff and Cron, the median H-Score in patients with MIS-C was 68 with an interquartile range of 49-79 and there were zero patients with MIS-C that had an H-Score > 169 [10].
Based on our diagnosis of HLH, a comprehensive inherited HLH genetic panel of 21 genes associated with familial HLH was negative for pathogenic variants (Table S1) [11,12]. Therefore, the patient was considered to have acquired HLH secondary to COVID-19. By contrast, the case described by Lange was a case of fHLH (Chediak-Higashi syndrome) triggered by COVID-19 [6].
Intrathecal methotrexate was not initiated given lack of CNS involvement. Within 2 days, her fevers resolved, laboratory parameters improved, and she was discharged home.

DISCUSSION
HLH is a disorder of uninhibited inflammation and hemophagocytosis that can be secondary to infection such as COVID-19. To our knowledge, this is the first case of a pediatric patient with COVID-19 associated sHLH successfully treated with Emapalumab followed by HCT. Hence, similarly to other infections, COVID-19 can cause refractory sHLH unresponsive to standard therapy, ultimately requiring HCT in pediatric patients. This report highlights the potential severity of COVID-19 in pediatric patients, despite its otherwise typical mild course.

LIMITATIONS
While we excluded numerous causes of hyperinflammation and identified SARS-CoV-2 as an etiology in this case, we cannot definitively exclude the possibility of other contributors to hyperinflammation in this patient.