Virus-Associated Hemophagocytic Syndrome Contributes to Fatal Outcome In Critical Ill Patients with 2009 Influenza A (H1N1) Infection.

Virus-associated hemophagocytic syndrome (VAHS) is a severe complication of various viral infections often resulting in multiple organ failure syndrome and death. Based on previous experience with seasonal (H3N2) and avian (H5N1) infections the 2009 influenza A (H1N1) virus offers the potency of VAHS-development resulting in an aggressive and life-threatening disease. Most patients infected by the novel human influenza A (H1N1) experienced a mild clinical course; however some patients become critically ill with respiratory failure requiring intensive care and ventilator support. Multiple organ failure was one of the leading causes of death suggesting that patients with severe influenza A (H1N1) infection may develop a virus-associated hemophagocytic syndrome (VAHS).

To evaluate frequency, clinical course and outcome of VAHS in critically ill patients a prospective observational study was performed at a single center intensive care unit in Hannover, Germany. Collected data include demographics, comorbid conditions, viral shedding, diagnosis of VAHS, illness progression, treatments and survival. VAHS was suspected when patients developed fever, cytopenia affecting at least two lineages, hepatitis or splenomegaly, hemophagocytosis in bone marrow samples and/or increased serum levels of sIL-2R and ferritin. Diagnosis of VAHS was made according to established HLH-diagnostic criteria. Primary outcome variables were the development of VAHS and VAHS-associated mortality.

Between October 5, 2009 and January 4, 2010 twenty five consecutive critically ill patients with RT-PCR confirmed 2009 influenza A (H1N1) infection and respiratory failure were identified. VAHS developed in nine out of 25 (36%) patients. Treatment of VAHS was started in 6 out of the 9 patients; three patients showed terminal disease and were no longer considered candidates for treatment with etoposide and dexamethasone. Despite VAHS-directed therapy, 5 out of the 6 patients died from uncontrolled progress leading to multiorgan failure. Overall, 8 out of the nine patients (89%) with confirmed VAHS died. In contrast, the mortality rate in the remaining 16 patients without VAHS was 25% (p=0.004). Patients were young (median, 45 [IQR, 35–56] years), however 18 (72%) presented one or more risk factors for a severe course of influenza illness. All 25 patients received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia with duration of mechanical ventilation of median (IQR) 19 (13-26) days. Additionally 17 patients (68%) required extracorporeal membrane oxygenation for median (IQR) 10 (6-19) days. Oseltamivir and zanamivir were used as antiviral treatment in 24 patients (96%) for a median (IQR) of 7 (4-10) days and in 15 patients (60%) for a median (IQR) of 7 (5-12) days, respectively. The median (IQR) duration of viral shedding from disease-onset to the last positive H1N1 RT-PCR was 19 (14-26) days. In patients without VAHS the median (IQR) viral shedding time was 15 (12-22) days as opposed to 21 (14-26) days (p=0.13) in patients with VAHS.

The present case series confirms previous post mortem analysis that severe influenza A (H1N1) infection is an important contributor to the development of VAHS in critically ill patients. Development of VAHS was associated with fatal outcome showing rapid clinical deterioration and multi organ failure syndrome and either contributes greatly to, or is itself causative of death in this patient population. Our findings are preliminary but potentially have important implications for future management of patients with influenza A (H1N1) disease as well as other severe virus infections which can induce secondary hemophagocytic syndromes.

No relevant conflicts of interest to declare.