Anti-inflammatory cytokine profile and Jarisch-Herxheimer reaction in Leptospirosis patients: A prospective case-series study in New Caledonia

Background Leptospirosis is a neglected zoonosis. This spirochetal disease is common in tropical countries where rainfall and poor sanitation facilitate skin contact with environmental Leptospira shed in animal urine. Antibiotics are effective against spirochetes, although a harmful Jarisch-Herxheimer (JHR) reaction can occur within hours of treatment, with the onset of chills, fever and/or hypotension. However, the awareness and incidence of JHR in leptospirosis are poorly understood. Methods This prospective observational study enrolled 81 patients diagnosed with leptospirosis from four hospitals in New Caledonia between 2021 and 2024. To evaluate the patients’ inflammatory status and identify risk factors for JHR, we collected data on clinical, socioeconomic, and biological factors (including blood cytokine levels) at admission and during the hours following treatment with different regimens of β-lactam antibiotics. Main results The majority of the cohort were middle-aged men, most of them Melanesian farmers. They exhibited high levels of C-reactive protein (CRP), neutrophilia, thrombocytopenia, and elevated biochemical markers indicative of liver and kidney dysfunction, which are typical of leptospirosis. Unexpectedly, pro-inflammatory cytokine levels were low or undetectable upon admission, while high levels of the anti-inflammatory cytokine IL-10 were measured. After antibiotherapy, increased levels of the pro-inflammatory cytokines TNF and IL-6, as well as IL-10 were observed. Strikingly, there was no increase in IL-1ß, the main player in the “cytokine storm”. JHR, identified with a new clinical score, occurred in 48% (possibly 61%) of patients and was associated with higher cytokine levels, as expected. Conclusion/Significance This study confirms the stealth nature of leptospires, which induce a potent anti-inflammatory response rather than inflammation. It calls into question both the cytokine storm hypothesis, which is often cited in leptospirosis and the use of immunosuppressive drugs. The high incidence of JHR in New Caledonia suggests that the systematic use of ß-lactams as a first-line treatment should be reevaluated