Infectious Complications in Patients with Hemophagocytic Lymphohistiocytosis: A Single Center Experience

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome characterized by fever, cytopenias, and activated macrophages in hemopoietic organs. HLH is commonly associated with underlying conditions such as infection, autoimmune disease, malignancy, or immunosuppressive therapy. Management of HLH includes treatment directed at the specific trigger, suppression of maladaptive cytokines, and inhibition of T cell and macrophage proliferation. While there has been a dramatically improved survival rate with the HLH-94 protocol, mortality remains high, with reports ranging from 20-80%. Impaired host immunity and treatment with immunosuppressive therapy predispose patients with HLH to secondary infections. A paucity of evidence is available on the incidence, prevention, and management of infectious complications in patients with HLH, with no consensus available to guide antimicrobial prophylaxis.

Aim: We sought to assess the incidence and characteristics of infectious complications in patients with HLH.

Methods: We performed a retrospective, single-center cohort study of patients aged 18 years or older admitted with a diagnosis code of HLH from July 1997 through March 2024. Each case was reviewed to confirm the diagnosis of HLH based on available diagnostic evaluation and the final discharge diagnoses as documented by the primary treating team. In cases indeterminate for HLH, a second independent reviewer performed additional evaluation to reach consensus. Data were collected beginning from the index admission for HLH and ended at one year from HLH diagnosis, or earlier if death or loss to follow up occurred. The primary outcome was the cumulative incidence of infection at one year, with infectious outcomes recorded on the basis of documented clinician suspicion or microbiologic evidence with pathogen isolation. Other examined outcomes included: number of patients with febrile neutropenia, number of infections per patient, type of infectious diagnoses (bacterial, viral, fungal, or parasitic), source of infection, time-to-first infection, and infection-related mortality. Fungal infections were classified as possible, probable, or proven as defined by previously outlined definitions. Overall survival (OS) was calculated using the Kaplan-Meier method.

Results: The study compromised of 143 patients with a diagnosis code of HLH, of which 79 patients met inclusion criteria. A total of 276 infections (187 bacterial, 31 viral, 56 fungal, and 2 parasitic) were documented. Seventy-four patients (93.7%) were diagnosed with an infection during the study period and the median number of infections per patient was 3 (interquartile range [IQR] 1 - 5). Sixty-one patients (77.2%) had an infection at the time of HLH diagnosis. Twenty-nine patients (36.7%) experienced at least one episode of febrile neutropenia. Seventy-three patients (92.4%) experienced at least one bacterial infection, 25 patients (31.6%) experienced at least one viral infection, and 38 patients (48.1%) experienced at least one fungal infection. Of the documented fungal infections, 20 were deemed possible, 23 were deemed probable, and 13 were deemed proven. Two patients experienced a parasitic infection, including one patient with pulmonary strongyloidiasis discovered at the time of HLH diagnosis and another patient with gastrointestinal toxoplasmosis occurring 346 days following HLH diagnosis. Thirty-eight patients died within one year of diagnosis, and the median OS for the cohort was 212 days, with a 12-month OS rate of 47.8%. Death attributable to infection occurred in 11 patients (13.9%), representing 28.9% of all documented deaths.

Conclusions: In this single center, retrospective cohort study of patients with HLH, infectious complications were ubiquitous, with the majority of patients experiencing at least one infection within one year of HLH diagnosis. Infection-related mortality was high. Our results highlight the need for further prospective investigation of infectious complications in this population in order to determine the most appropriate use of antimicrobial prophylaxis against viral, bacterial, and fungal pathogens, and to delineate management guidelines for infections that do occur.

No relevant conflicts of interest to declare.