HLH Syndrome in a Community Hospital: The Challenge of an Early Diagnosis

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory cytokine storm.It can be secondary to infections, malignancies, autoimmune diseases, or the manifestation of genetic disorders, including primary immune deficiency.HLH requires a high index of suspicion and is challenging for community hospitals.Methods: Medical records of children with HLH admitted to the Meir Medical Center in Israel between 2014 and 2017 were reviewed.Results: Nine children met ≥5/8 HLH-2004 criteria.The median age was 1.1 year, and 78% of the patients were aged <2 years.All patients had prolonged fever, cytopenia, and elevated soluble interleukin-2 receptor, and 89% had elevated ferritin levels.Of three children who underwent gene panel evaluation, one had heterozygote genetic variants of UNC13D and STXBP2 of unclear significance, whereas the other two had no variants.Infection was identified in 8 of 9 patients: adenovirus, HHV6, EBV, and Streptococcus Group A. Only 2 patients received HLH-2004 therapy (dexamethasone, etoposide, cyclosporin-A) and the others received dexamethasone and/or intravenous gamma globulins (IVIG), with rapid resolution of fever (median 2 days).One patient (11%) died of Pseudomonas septicemia and multiorgan failure.At a median follow-up of 7 years (range 2.6-8.1 years), all others (8/9) are long-term survivors with no recurrent HLH, but 2 patients developed adenovirus-related bronchiolitis obliterans. Conclusion:Children presenting with prolonged fever and abnormal blood counts should be evaluated with ferritin, triglycerides, and fibrinogen levels which indicate possible HLH.Early intervention with corticosteroids and/or IVIG may prevent deterioration, spare them from chemotherapy and provide time for more elaborate testing to identify true HLH.Unfortunately, mortality remains a significant risk for these children.Plain Language Summary: In the emergency department, children with common infections may have a severe complication called Hemophagocytic Lymphohistiocytosis or HLH.HLH can be life threatening if not rapidly recognized.HLH is rare and challenging for doctors in community hospitals.We describe nine patients who presented to a community hospital who were later diagnosed with HLH, posing a dilemma for physicians.Most (78%) were less than 2 years, all had prolonged fever, abnormal blood counts, elevated marker of HLH called soluble interleukin-2 receptor and 8 of 9 had elevated ferritin, which can be a marker of HLH.HLH could be genetic therefore three children had genetic studies, with one having minor abnormalities, but the contribution to HLH is unclear.Infection as cause for HLH was identified in 8 of 9 patients.Chemotherapy that is used for severe HLH was required for 2 patients and the others received steroids and/or intravenous gamma globulin with rapid improvement.One patient who received chemotherapy and had suppressed immunity died of a severe bacterial infection.Others (8 of 9) are long-term survivors with no evidence of recurrent HLH.Two patients developed a pulmonary complication from adenovirus known as bronchiolitis obliterans.We conclude that children presenting with prolonged fever and abnormal blood counts should be evaluated with ferritin and other markers of possible HLH.Early intervention may prevent deterioration, may spare them from chemotherapy, and allow further assessment of true HLH.However, the death of one (11%), demonstrates the significant risks to these children.