Anti-inflammatory cytokine profile and Jarisch-Herxheimer reaction in Leptospirosis patients: a prospective case-series study in New Caledonia
Abstract
Background
Leptospirosis is a neglected zoonosis. This spirochetal disease is common in tropical countries where rainfall and poor sanitation facilitate skin contact with environmentalLeptospirashed 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 do not induce inflammation but a potent anti-inflammatory response. It rejects the cytokine storm hypothesis often cited in leptospirosis, and does not argue for the use of immunosuppressive drugs. The high incidence of JHR in New Caledonia could challenge the systematic use of ß- lactams as a first-line treatment.
Author summary
Leptospirosis is a neglected zoonosis caused by spirochetal bacteria. Antibiotics are effective against leptospires, but they can induce an adverse reaction, called the Jarish-Herxheimer reaction (JHR), which occurs in the hours following the initiation of treatment. The present study was conducted in several hospitals in New Caledonia to measure the JHR incidence and describe the cytokine evolution. We included 81 patients diagnosed with leptospirosis and treated with antibiotics. A very interesting result was the absence of inflammation in the blood of patients before antibiotic treatment, confirming that leptospires are stealth bacteria not responsible for inflammation. In contrast, antibiotic treatment triggered JHR in about 50 percent of patients and was associated with increased inflammation, but not with markers of leptospirosis severity, nor cytokine storm. This study may raise the alarm on JHR and question the use of anti-inflammatory drugs and the choice of antibiotics in leptospirosis.
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