The complex dance of immunity: A review of secondary HLH in HIV (2000-2025)

Abstract Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory syndrome marked by severe immune dysregulation. Secondary HLH typically arises in association with viral infections, malignancies, or autoimmune diseases. While it has also been sporadically reported in people living with HIV (PWH), the underlying mechanisms driving its co-occurrence with HIV remain poorly understood. Its epidemiology and clinical outcomes might also possibly diverge from those seen in other causes of secondary HLH. Methods: We searched PubMed in early July 2025 to identify cases of HLH diagnosed in PWH and published as case reports, case series, or short retrospective cohorts between January 2000 and June 2025. We only included manuscripts that did not contain possible instances of primary HLH, and ensured that studies involving younger patients (18 years old) or those that were missing comprehensive clinical and hematological data were excluded. Eventually, we were able to identify 20 PWH from 20 studies who had been diagnosed with HLH between 2000 and 2025. Demographic, clinical, and hematological data were extracted, including HLH-2004 diagnostic criteria fulfillment and suspected precipitants besides HIV. Patients were stratified by survival status. Continuous variables were analyzed using the Wilcoxon rank-sum test, while categorical variables were interrogated via Fisher's exact test. Logistic regression was used to explore mortality predictors. Results: Among 20 identified individuals, 12 survived while 8 died from their disease. The median age at diagnosis of HLH was 35 years (range: 27-61), and 90% were men. Patients represented diverse nationalities, predominantly from West Africa and Asia. Besides their HIV diagnoses, PWH were most commonly found to have had tuberculosis (25%) in the past. The most frequent HLH precipitants identified in our review were: CMV (40%), tuberculosis (25%), and lymphoma (15%). Clinically, PWH with HLH presented with: fever (85%), cytopenias (75%), splenomegaly (60%), and liver dysfunction (40%). Bone marrow biopsies were performed in 17 out of the 20 patients, with hemophagocytosis noted in the majority (80%). Fifteen patients (75%) fulfilled ≥5 HLH-2004 criteria for diagnosis. Nine (45%) received HLH-directed therapy, including corticosteroids, IVIG, ruxolitinib, and/or etoposide. We found that no individual laboratory variable (e.g. AST, ALT, ferritin, and HIV viral load) significantly predicted mortality. However, LDH values 1000 IU/L were associated with a trend toward increased mortality (p = 0.055). Interestingly, a patient's age, CD4 counts, or having fulfilled at least 5 HLH-2004 criteria for diagnosis were not associated with mortality amongst PWH. Conclusions: In our limited yet detailed analysis of published case reports on HIV-associated HLH, no single variable predicted mortality. Although LDH elevation trended toward significance, larger studies are needed to validate prognostic indicators and guide therapy in this complex population with morbid mortality rates despite treatment.