Survival outcomes in tickborne infection-associated hemophagocytic lymphohistiocytosis treated with antibiotics alone versus antibiotics and HLH-directed therapy: A multicenter real-world study

Abstract Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome marked by excessive immune activation and cytokine storm. While HLH-directed therapies such as corticosteroids, etoposide, and cytokine inhibitors are standard in malignancy- or virus-associated HLH, their benefit in tickborne infection-associated cases remains unclear. In settings where the inciting pathogen is treatable, the additional role of targeted immunosuppression is uncertain. We conducted a multicenter real-world study to compare survival outcomes in patients treated with antimicrobial therapy alone versus those receiving antibiotics and HLH-directed therapy. Methods: Using the TriNetX, we identified adult patients with a diagnosis of HLH and a concurrent infection caused by Ehrlichia, Babesia, Anaplasma, Borrelia, Lyme, or Rickettsia species. Patients were stratified into two treatment groups: (1) antimicrobial therapy alone (e.g., doxycycline, atovaquone), and (2) antimicrobial therapy plus HLH-directed therapy (defined as corticosteroids, etoposide, IVIG, or anakinra). Cohorts were propensity score–matched for age, sex, comorbidities, and other potential causes of HLH, including underlying malignancy and viral infections, resulting in two cohorts of 206 patients each. We analyzed 14-, 30- and 90-days time points for survival. Time-to-event analyses were performed using Kaplan-Meier survival curves with log-rank testing. Hazard ratios (HRs) were estimated using Cox proportional hazards models, and odds ratios (ORs) were calculated to compare mortality rates at fixed time points. Results: Thirty-day and 90-day mortality were significantly higher among patients receiving HLH-directed therapy compared to those treated with antibiotics alone. At 14 days, the odds ratio for death was 3.37 (95% CI 1.69–6.70, p < 0.0001). By 30 days, mortality remained elevated (OR 4.33, 95% CI 2.48–7.57, p < 0.0001), and at 90 days, mortality remained significantly worse in the HLH therapy group (OR 6.60, 95% CI 3.24–13.45, p < 0.0001). Kaplan-Meier analysis demonstrated similar early survival between groups, but survival curves began to diverge after day 10 and remained significantly different at days 14 and 30 (log-rank p < 0.001; HR 5.01, 95% CI 2.55–9.88). The difference in survival persisted through day 90 (log-rank p < 0.001; HR 3.42, 95% CI 2.04–5.71). No median survival was met at any time point. No significant differences were observed in ICU admissions or inpatient hospitalization rates between the two treatment groups. Conclusions: In our study, HLH-directed therapy in the context of tickborne infection–associated HLH was associated with worse survival compared to antimicrobial therapy alone. The difference in survival became increasingly apparent after 10 days from diagnosis, with persistent separation in time-to-death analysis at 14, 30 and 90 days. Higher rates of organ dysfunction in the HLH therapy group may reflect underlying disease severity, treatment-related toxicity, or inappropriate immunosuppression. While it is possible that patients receiving HLH-directed therapy were more critically ill at baseline, these findings raise the concern that adding immunosuppressive therapy in tickborne HLH may not improve outcomes and could increase risk. Given that the underlying trigger is a treatable infection, antimicrobial therapy alone may be sufficient in select cases. Prospective studies are needed to determine optimal treatment strategies for tickborne-associated HLH.