Influenza as a less commonly recognized cause of hemophagocytic lymphohistiocytosis: A systematic review of case reports and case series Free

Introduction

Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory condition that can lead to multi-organ failure and death. Secondary HLH is known to be triggered by infections, including viruses. However, influenza is not commonly recognized as a cause of HLH, and there is no comprehensive synthesis of influenza-associated HLH in the literature to guide clinicians. We conducted a systematic review of case reports and case series to characterize demographics, clinical features, treatment, and outcomes of influenza-associated HLH.

Methods

We systematically searched PubMed and Embase from inception to June 21, 2025, using MeSH/Emtree terms for “Influenza” and “Hemophagocytic Lymphohistiocytosis”. We included original case reports and case series describing influenza-associated HLH, with no restrictions on language or geographic location. Editorials and conference abstracts were excluded. Two independent reviewers screened all the articles for eligibility. Data from the included studies were extracted and summarized using descriptive methods.

Results

Of 148 articles screened, 29 articles (21 case reports, 8 case series) involving 47 patients met inclusion criteria. Patients ranged in age from 2 months to 72 years (median age: 26 years), with 67% being male. Thirteen percent of patients had comorbid conditions leading to immunosuppression. Twenty-eight percent of them had bacterial co-infections, one-third of which were due to Staphylococcus aureus. Influenza A accounted for 91.3% of the cases, with H1N1 being the predominant subtype (90.2%). The remaining 8.7% of cases were due to Influenza B.

Diagnosis of HLH was most often based on HLH 2004 criteria (91.1%), with 55.3% patients meeting 5 or more criteria. All patients had fever, 60% had anemia, 84.4% had thrombocytopenia, 53.3% had leukopenia, 61.3% had splenomegaly, 71.4% had hypertriglyceridemia, and 94.7% had elevated ferritin levels (range: 169-95,703 ng/ml). Evidence of hemophagocytosis on biopsy was present in 97.6% patients. Only 34% underwent testing for soluble IL2 receptor (sCD25), all of whom had elevated levels. A smaller proportion (15%) were tested for NK cell activity, and half of them had low activity levels. Genetic testing was performed in 4 patients, and 50% of them had pathogenic variants in PRF1 and LYST.

Antiviral therapy was administered in 89.5% patients, most commonly with Oseltamivir (88.2%). Seventeen percent of patients were diagnosed with HLH post-mortem and therefore did not receive HLH-directed therapy. Seventy-seven percent received corticosteroids, 36% received intravenous immunoglobulin (IVIG), one patient received rituximab, and another patient underwent plasmapheresis. Etoposide was administered to 9 patients, and cyclosporine to 2 patients. Intensive care was required in 95.2% of cases, with 74.5% requiring mechanical ventilation and 44.7% requiring extracorporeal membrane oxygenation (ECMO). Overall survival was 53.2%. Survival rates were 61.8% among patients who received antiviral therapy, 65.6% among those who received immunosuppressive therapy, and 65.4% among those who received both.

Conclusion

Influenza, particularly H1N1, is a notable but under-recognized trigger for HLH. Most patients required critical care, and mortality was high. Corticosteroids were the most frequently used HLH-directed therapy, with occasional use of Etoposide and Cyclosporine. Survival appeared generally favorable among patients who received antiviral and/or immunosuppressive therapy. Further studies are necessary to establish standardized diagnostic and therapeutic protocols for influenza-associated HLH.