HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH LEPTOSPIROSIS IN A CRITICAL CARE SETTING: A CASE SERIES OF FIVE PATIENTS

Abstract

Background: Leptospirosis is a zoonotic spirochaetal infection endemic across tropical low- and middle-income countries. In its severe form it generates an IL-1/IL-6/TNF-driven hyperinflammatory state that can, on rare occasions, tip over into secondary haemophagocytic lymphohistiocytosis (HLH). The two share a clinical picture — fever, cytopenias, organomegaly and multi-organ dysfunction — which means HLH is easily overlooked in this population.

Methods: We retrospectively describe five patients — four adults and one child — with serologically confirmed leptospirosis and HLH who were managed in the intensive care unit of a tertiary hospital. Each was scored against both the HLH-2004 criteria and the HScore.

Results: The patients were aged 12–39 years and all were male. Ferritin ranged from 2,065 to 8,219 ng/mL, triglycerides from 275 to 390 mg/dL and fibrinogen from 110 to 140 mg/dL; every patient had splenomegaly and cytopenias. Bone marrow haemophagocytosis was found in four of the five (marrow was not examined in Case 5, where consent was declined). The presentations varied widely: meningoencephalitis with herpes simplex virus type 1 (HSV-1) co-infection (Case 1); fever of unknown origin with cardiogenic shock and an ejection fraction of 20% (Case 2); a petechial rash with a platelet count of 5 × 10³/µL and hepatorenal dysfunction (Case 3); meningoencephalitis with right thalamic and left cerebellar infarcts (Case 4); and extensively drug-resistant (XDR) Salmonella Typhi co-infection in a 12-year-old boy (Case 5). Every patient was screened on admission for dengue (NS1 antigen and IgM) and for malaria under the institutional protocol for acute undifferentiated febrile illness, and both were negative throughout. Four patients met at least five of the eight HLH-2004 criteria, and Case 5 met five of eight even without bone marrow confirmation. All five cleared the HScore diagnostic threshold of 169, with totals of 187–244. Soluble CD25 and natural killer (NK) cell activity assays were not available. Every patient received five sessions of therapeutic plasma exchange and pulsed methylprednisolone (1–2 g/day for five days) alongside pathogen-directed antimicrobial therapy; none received etoposide. All five survived to intensive care discharge after stays of 6–14 days.

Conclusions: HLH should be actively ruled out before multi-organ failure in leptospirosis is put down to the infection alone. In resource-limited units where sCD25 and NK-cell assays are unavailable, the HScore can still be calculated in full, and it was diagnostic in all five patients — including the one in whom bone marrow was not examined. Dengue and malaria, the two leading competing febrile illnesses here and both recognised triggers of secondary HLH, were excluded in every case; dengue is, in addition, a known cause of false-positive anti-Leptospira antibody. Even so, Leptospira infection rested on a single positive IgM, without microscopic agglutination testing or PCR, and two patients carried a competing infectious trigger, so the relationship we report is best read as association rather than proven causation.