Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Leptospirosis

Nature Reviews Disease Primers volume 11, Article number: 32 (2025) Cite this article

Subjects

Abstract

Leptospirosis is a zoonotic bacterial infection that is prevalent across all continents and is caused by pathogenic spirochaetes of the genus Leptospira. Although infection can be asymptomatic, symptomatic disease can vary in severity from mild to severe illness, the latter characterized by icterus and/or multi-organ dysfunction and potentially death. An estimated one million cases of leptospirosis occur globally each year, resulting in ~60,000 deaths. The pathogenesis of severe leptospirosis is poorly understood but is believed to involve an interplay between genetic predisposition, pathogen virulence and dysregulated immune responses that trigger a cytokine storm with associated immunoparesis. Leptospira are susceptible to several low-cost antibiotics, including benzyl penicillin, doxycycline, cephalosporins and macrolides, when used in the early phase of infection. Late disease with organ dysfunction is treated with supportive care, and the benefit of antibiotics during late disease is doubtful. Very few countries have licensed a vaccine for human leptospirosis, and available vaccines only protect against rodent-associated serogroups. Exposure control by behavioural modifications and personal protective measures are the major preventative measures in leptospirosis, and the efficacy of prophylactic antibiotics has not been confirmed in clinical trials. Future research is needed to accurately estimate leptospirosis disease burden across the globe, to understand the pathophysiology of severe leptospirosis to inform the design of targeted immunotherapies and vaccines, and to develop cost-effective and accurate point-of-care diagnostics.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Transmission and clinical manifestations of leptospirosis in humans.
Fig. 2: Estimated worldwide incidence of leptospirosis.
Fig. 3: The pathogenesis of severe leptospirosis.
Fig. 4: Jaundice, conjunctival suffusion and haemorrhage in icteric leptospirosis.
Fig. 5: Laboratory diagnosis of leptospirosis.

Similar content being viewed by others

References

  1. European Centre for Disease Prevention and Control. Factsheet about leptospirosis. ECDC https://www.ecdc.europa.eu/en/leptospirosis/factsheet#:~:Text=Leptospirosis%20is%20the%20most%20widespread,Mediterranean%20and%20East%20European%20regions (2017).

  2. Haake, D. A. & Levett, P. N. Leptospirosis in humans. Curr. Top. Microbiol. Immunol. 387, 65–97 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bolin, C. A. & Koellner, P. Human-to-human transmission of Leptospira interrogans by milk. J. Infect. Dis. 158, 246–247 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Carles, G., Montoya, E., Joly, F. & Peneau, C. Leptospirosis and pregnancy. Eleven cases in French Guyana. J. Gynecol. Obstet. Biol. Reprod. 24, 418–421 (1995).

    CAS  Google Scholar 

  5. Evangelista, K. V. & Coburn, J. Leptospira as an emerging pathogen: a review of its biology, pathogenesis and host immune responses. Future Microbiol. 5, 1413–1425 (2010).

    Article  PubMed  Google Scholar 

  6. Raddi, G. et al. Three-dimensional structures of pathogenic and saprophytic leptospira species revealed by cryo-electron tomography. J. Bacteriol. 194, 1299–1306 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vincent, A. T. et al. Revisiting the taxonomy and evolution of pathogenicity of the genus Leptospira through the prism of genomics. PLoS Negl. Trop. Dis. 13, e0007270 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kędzierska-Mieszkowska, S. Sigma factors of RNA polymerase in the pathogenic spirochaete Leptospira interrogans, the causative agent of leptospirosis. FASEB J. 37, e23163 (2023).

    Article  PubMed  Google Scholar 

  9. Guglielmini, J. et al. Genus-wide Leptospira core genome multilocus sequence typing for strain taxonomy and global surveillance. PLoS Negl. Trop. Dis. 13, e0007374 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Costa, F. et al. Global morbidity and mortality of leptospirosis: a systematic review. PLoS Negl. Trop. Dis. 9, e0003898 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Weil, A. Ueber einer eigenhuemliche, mit milztumor, icterus un nephritis einhergehende, acute infektionskrankheit. Deutsch Arch. Klin. Med. 109, 209–232 (1886).

    Google Scholar 

  12. Clemente, B. M., Pineda-Cortel, M. R. & Villaflores, O. Evaluating immunochromatographic test kits for diagnosis of acute human leptospirosis: a systematic review. Heliyon 8, e11829 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Limmathurotsakul, D. et al. Fool’s gold: why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis. Clin. Infect. Dis. 55, 322–331 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Rajapakse, S., Rodrigo, C., Handunnetti, S. M. & Fernando, S. D. Current immunological and molecular tools for leptospirosis: diagnostics, vaccine design, and biomarkers for predicting severity. Ann. Clin. Microbiol. Antimicrob. 14, 2 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Boss, J. et al. Antimicrobial susceptibility testing of leptospira spp. in the Lao People’s Democratic Republic using disk diffusion. Am. J. Trop. Med. Hyg. 100, 1073–1078 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chawla, V., Trivedi, T. H. & Yeolekar, M. E. Epidemic of leptospirosis: an ICU experience. J. Assoc. Physicians India 52, 619–622 (2004).

    CAS  PubMed  Google Scholar 

  17. Levett, P. N. Leptospirosis. Clin. Microbiol. Rev. 14, 296–326 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bharti, A. R. et al. Leptospirosis: a zoonotic disease of global importance. Lancet Infect. Dis. 3, 757–771 (2003).

    Article  PubMed  Google Scholar 

  19. Munoz-Zanzi, C. et al. A systematic literature review of leptospirosis outbreaks worldwide, 1970–2012. Rev. Panam. Salud Publica 44, e78 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zeng, Z., Zhan, J., Chen, L., Chen, H. & Cheng, S. Global, regional, and national dengue burden from 1990 to 2017: a systematic analysis based on the global burden of disease study 2017. eClinicalMedicine https://doi.org/10.1016/j.eclinm.2020.100712 (2021).

  21. Allan, K. J. et al. Epidemiology of leptospirosis in Africa: a systematic review of a neglected zoonosis and a paradigm for ‘One Health’ in Africa. PLoS Negl. Trop. Dis. 9, e0003899 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gizamba, J. M. & Mugisha, L. Leptospirosis in humans and selected animals in sub-Saharan Africa, 2014–2022: a systematic review and meta-analysis. BMC Infect. Dis. 23, 649 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Beauté, J. et al. Epidemiology of reported cases of leptospirosis in the EU/EEA, 2010 to 2021. Euro Surveill. https://doi.org/10.2807/1560-7917.Es.2024.29.7.2300266 (2024).

  24. Lau, C. L., Smythe, L. D., Craig, S. B. & Weinstein, P. Climate change, flooding, urbanisation and leptospirosis: fuelling the fire? Trans. R. Soc. Trop. Med. Hyg. 104, 631–638 (2010).

    Article  PubMed  Google Scholar 

  25. Cann, K. F., Thomas, D. R., Salmon, R. L., Wyn-Jones, A. P. & Kay, D. Extreme water-related weather events and waterborne disease. Epidemiol. Infect. 141, 671–686 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Baharom, M. et al. Environmental and occupational factors associated with leptospirosis: a systematic review. Heliyon 10, e23473 (2024).

    Article  PubMed  Google Scholar 

  27. Mwachui, M. A., Crump, L., Hartskeerl, R., Zinsstag, J. & Hattendorf, J. Environmental and behavioural determinants of leptospirosis transmission: a systematic review. PLoS Negl. Trop. Dis. 9, e0003843 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Hartskeerl, R. A., Collares-Pereira, M. & Ellis, W. A. Emergence, control and re-emerging leptospirosis: dynamics of infection in the changing world. Clin. Microbiol. Infect. 17, 494–501 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Hagedoorn, N. N. et al. Global distribution of Leptospira serovar isolations and detections from animal host species: a systematic review and online database. Trop. Med. Int. Health 29, 161–172 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Allan, K. J. et al. Assessment of animal hosts of pathogenic Leptospira in northern Tanzania. PLoS Negl. Trop. Dis. 12, e0006444 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chadsuthi, S. et al. Investigation on predominant Leptospira serovars and its distribution in humans and livestock in Thailand, 2010–2015. PLoS Negl. Trop. Dis. 11, e0005228 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Casanovas-Massana, A. et al. Genetic evidence for a potential environmental pathway to spillover infection of rat-borne leptospirosis. J. Infect. Dis. 225, 130–134 (2022).

    Article  CAS  PubMed  Google Scholar 

  33. Faine, S., Adler, B., Bolin, C. & Perolat, P. Leptospira and Leptospirosis Vol. 2 (MediSci, 1999).

  34. Adler, B. & de la Pena Moctezuma, A. Leptospira and leptospirosis. Vet. Microbiol. 140, 287–296 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Bierque, E., Thibeaux, R., Girault, D., Soupé-Gilbert, M.-E. & Goarant, C. A systematic review of Leptospira in water and soil environments. PLoS ONE 15, e0227055 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Thibeaux, R. et al. Seeking the environmental source of Leptospirosis reveals durable bacterial viability in river soils. PLoS Negl. Trop. Dis. 11, e0005414 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hacker, K. P. et al. Influence of rainfall on leptospira infection and disease in a tropical urban setting, Brazil. Emerg. Infect. Dis. 26, 311–314 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rodríguez-Rodríguez, V. et al. Acute human leptospirosis in a Caribbean region of Colombia: from classic to emerging risk factors. Zoonoses Public Health 71, 107–119 (2024).

    Article  PubMed  Google Scholar 

  39. Susanna, D., Nova, R. I. T. & Rozek, L. Community behaviors that affect the incidence of leptospirosis in West Jakarta, Indonesia. Vector Borne Zoonotic Dis. 23, 29–34 (2023).

    Article  PubMed  Google Scholar 

  40. Amilasan, A. S. et al. Outbreak of leptospirosis after flood, the Philippines, 2009. Emerg. Infect. Dis. 18, 91–94 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sanders, E. J. et al. Increase of leptospirosis in dengue-negative patients after a hurricane in Puerto Rico in 1996 (correction of 1966). Am. J. Trop. Med. Hyg. 61, 399–404 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Dreesman, J. et al. Investigation and response to a large outbreak of leptospirosis in field workers in Lower Saxony, Germany. Zoonoses Public Health 70, 315–326 (2023).

    Article  CAS  PubMed  Google Scholar 

  43. Dreyfus, A. et al. Risk factors for new infection with Leptospira in meat workers in New Zealand. Occup. Environ. Med. 72, 219–225 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Pagès, F. et al. Investigation of a leptospirosis outbreak in triathlon participants, Réunion Island, 2013. Epidemiol. Infect. 144, 661–669 (2016).

    Article  PubMed  Google Scholar 

  45. Bradley, E. A. & Lockaby, G. Leptospirosis and the environment: a review and future directions. Pathogens https://doi.org/10.3390/pathogens12091167 (2023).

  46. Magalhães, A. R. et al. Neglected tropical diseases risk correlates with poverty and early ecosystem destruction. Infect. Dis. Poverty 12, 32 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Jeffree, M. S. et al. High incidence of asymptomatic leptospirosis among urban sanitation workers from Kota Kinabalu, Sabah, Malaysian Borneo. Sci. Rep. 10, 19442 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Khalil, H. et al. Poverty, sanitation, and Leptospira transmission pathways in residents from four Brazilian slums. PLoS Negl. Trop. Dis. 15, e0009256 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Reis, R. B. et al. Impact of environment and social gradient on Leptospira infection in urban slums. PLoS Negl. Trop. Dis. 2, e228 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Antima & Banerjee, S. Modeling the dynamics of leptospirosis in India. Sci. Rep. 13, 19791 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lingappa, J. et al. HLA-DQ6 and ingestion of contaminated water: possible gene–environment interaction in an outbreak of Leptospirosis. Genes Immun. 5, 197–202 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Agampodi, S. B., Matthias, M. A., Moreno, A. C. & Vinetz, J. M. Utility of quantitative polymerase chain reaction in leptospirosis diagnosis: association of level of leptospiremia and clinical manifestations in Sri Lanka. Clin. Infect. Dis. 54, 1249–1255 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cagliero, J., Villanueva, S. & Matsui, M. Leptospirosis pathophysiology: into the storm of cytokines. Front. Cell. Infect. Microbiol. 8, 204 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Nicodemo, A. C. et al. Lung lesions in human leptospirosis: microscopic, immunohistochemical, and ultrastructural features related to thrombocytopenia. Am. J. Trop. Med. Hyg. 56, 181–187 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Chierakul, W. et al. Activation of the coagulation cascade in patients with leptospirosis. Clin. Infect. Dis. 46, 254–260 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Yücel Koçak, S., Kudu, A., Kayalar, A., Yilmaz, M. & Apaydin, S. Leptospirosis with acute renal failure and vasculitis: a case report. Arch. Rheumatol. 34, 229–232 (2019).

    Article  PubMed  Google Scholar 

  57. De Brito, T., Silva, A. & Abreu, P. A. E. Pathology and pathogenesis of human leptospirosis: a commented review. Rev. Inst. Med. Trop. Sao Paulo 60, e23 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Shintaku, M., Itoh, H. & Tsutsumi, Y. Weil’s disease (leptospirosis) manifesting as fulminant hepatic failure: report of an autopsy case. Pathol. Res. Pract. 210, 1134–1137 (2014).

    Article  PubMed  Google Scholar 

  59. Arean, V. M. The pathologic anatomy and pathogenesis of fatal human leptospirosis (Weil’s disease). Am. J. Pathol. 40, 393–423 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sitprija, V. & Evans, H. The kidney in human leptospirosis. Am. J. Med. 49, 780–788 (1970).

    Article  CAS  PubMed  Google Scholar 

  61. Abdulkader, R. C. & Silva, M. V. The kidney in leptospirosis. Pediatr. Nephrol. 23, 2111–2120 (2008).

    Article  PubMed  Google Scholar 

  62. Dolhnikoff, M., Mauad, T., Bethlem, E. P. & Carvalho, C. R. Pathology and pathophysiology of pulmonary manifestations in leptospirosis. Braz. J. Infect. Dis. 11, 142–148 (2007).

    Article  PubMed  Google Scholar 

  63. Fernando, T. et al. Electrocardiographic and echocardiographic manifestations of cardiac involvement in leptospirosis. Trans. R. Soc. Trop. Med. Hyg. 107, 457–459 (2013).

    Article  PubMed  Google Scholar 

  64. Swarath, S. et al. Leptospirosis-induced myocarditis and arrhythmias. J. Investig. Med. High. Impact Case Rep. 11, 23247096231179450 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Silva, J. J. et al. Clinicopathological and immunohistochemical features of the severe pulmonary form of leptospirosis. Rev. Soc. Bras. Med. Trop. 35, 395–399 (2002).

    Article  PubMed  Google Scholar 

  66. Cédola, M. et al. Association of Toll-like receptor 2 Arg753Gln and Toll-like receptor 1 Ile602Ser single-nucleotide polymorphisms with leptospirosis in an Argentine population. Acta Trop. 146, 73–80 (2015).

    Article  PubMed  Google Scholar 

  67. Viriyakosol, S., Matthias, M. A., Swancutt, M. A., Kirkland, T. N. & Vinetz, J. M. Toll-like receptor 4 protects against lethal Leptospira interrogans serovar icterohaemorrhagiae infection and contributes to in vivo control of leptospiral burden. Infect. Immun. 74, 887–895 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Haake, D. A. & Zückert, W. R. Spirochetal lipoproteins in pathogenesis and immunity. Curr. Top. Microbiol. Immunol. 415, 239–271 (2018).

    CAS  PubMed  Google Scholar 

  69. Li, D. & Wu, M. Pattern recognition receptors in health and diseases. Signal. Transduct. Target. Ther. 6, 291 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Senavirathna, I., Rathish, D. & Agampodi, S. Cytokine response in human leptospirosis with different clinical outcomes: a systematic review. BMC Infect. Dis. 20, 268 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wang, H. et al. Leptospiral hemolysins induce proinflammatory cytokines through Toll-like receptor 2-and 4-mediated JNK and NF-κB signaling pathways. PLoS ONE 7, e42266 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Reis, E. A. et al. Cytokine response signatures in disease progression and development of severe clinical outcomes for leptospirosis. PLoS Negl. Trop. Dis. 7, e2457 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Nisansala, T. et al. Contributing role of TNF, IL-10, sTNFR1 and TNF gene polymorphisms in disease severity of leptospirosis. Med. Microbiol. Immunol. 210, 211–219 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hsu, S. H. et al. Peptidoglycan mediates Leptospira outer membrane protein Loa22 to toll-like receptor 2 for inflammatory interaction: a novel innate immune recognition. Sci. Rep. 11, 1064 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schuler, E. J. A., Patel, D. T. & Marconi, R. T. The leptospiral OmpA-like protein (Loa22) is a surface-exposed antigen that elicits bactericidal antibody against heterologous Leptospira. Vaccine X 15, 100382 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang, B., Sullivan, J. A., Sullivan, G. W. & Mandell, G. L. Role of specific antibody in interaction of leptospires with human monocytes and monocyte-derived macrophages. Infect. Immun. 46, 809–813 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Li, S. et al. Replication or death: distinct fates of pathogenic Leptospira strain Lai within macrophages of human or mouse origin. Innate Immun. 16, 80–92 (2010).

    Article  PubMed  Google Scholar 

  78. Eshghi, A. et al. Leptospira interrogans catalase is required for resistance to H2O2 and for virulence. Infect. Immun. 80, 3892–3899 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fernando, N. et al. Protein carbonyl as a biomarker of oxidative stress in severe leptospirosis, and its usefulness in differentiating leptospirosis from dengue infections. PLoS ONE 11, e0156085 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wang, B., Sullivan, J., Sullivan, G. W. & Mandell, G. L. Interaction of leptospires with human polymorphonuclear neutrophils. Infect. Immun. 44, 459–464 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Vieira, M. L. et al. Leptospira interrogans outer membrane protein LipL21 is a potent inhibitor of neutrophil myeloperoxidase. Virulence 9, 414–425 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Aratani, Y. Myeloperoxidase: its role for host defense, inflammation, and neutrophil function. Arch. Biochem. Biophys. 640, 47–52 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Jost, B. H., Adler, B., Vinh, T. & Faine, S. A monoclonal antibody reacting with a determinant on leptospiral lipopolysaccharide protects guinea pigs against leptospirosis. J. Med. Microbiol. 22, 269–275 (1986).

    Article  CAS  PubMed  Google Scholar 

  84. Rees, E. M. et al. Estimating the duration of antibody positivity and likely time of Leptospira infection using data from a cross-sectional serological study in Fiji. PLoS Negl. Trop. Dis. 16, e0010506 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Grillová, L. et al. Circulating genotypes of Leptospira in French Polynesia: an 9-year molecular epidemiology surveillance follow-up study. PLoS Negl. Trop. Dis. 14, e0008662 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Klimpel, G. R., Matthias, M. A. & Vinetz, J. M. Leptospira interrogans activation of human peripheral blood mononuclear cells: preferential expansion of TCR gamma delta+ T cells vs TCR alpha beta+ T cells. J. Immunol. 171, 1447–1455 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Krangvichian, P. et al. Impaired functions of human monocyte-derived dendritic cells and induction of regulatory T cells by pathogenic Leptospira. PLoS Negl. Trop. Dis. 17, e0011781 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sumaiya, K. & Natarajaseenivasan, K. Macrophage migration inhibitory factor gene promoter polymorphism (−173G/C SNP) determines host susceptibility and severity of leptospirosis. Microb. Pathog. 164, 105445 (2022).

    Article  CAS  PubMed  Google Scholar 

  89. Esteves, L. M. et al. Human leptospirosis: seroreactivity and genetic susceptibility in the population of São Miguel Island (Azores, Portugal). PLoS ONE 9, e108534 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Fialho, R. N. et al. Role of human leukocyte antigen, killer-cell immunoglobulin-like receptors, and cytokine gene polymorphisms in leptospirosis. Hum. Immunol. 70, 915–920 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Charon, N. W., Greenberg, E. P., Koopman, M. B. & Limberger, R. J. Spirochete chemotaxis, motility, and the structure of the spirochetal periplasmic flagella. Res. Microbiol. 143, 597–603 (1992).

    Article  CAS  PubMed  Google Scholar 

  92. Vieira, D. S., Chaurasia, R. & Vinetz, J. M. Comparison of the PF07598-encoded virulence-modifying proteins of L. interrogans and L. borgpetersenii. Trop. Med. Infect. Dis. 8, 14 (2023).

    Article  Google Scholar 

  93. Chaurasia, R. & Vinetz, J. M. In silico prediction of molecular mechanisms of toxicity mediated by the leptospiral PF07598 gene family-encoded virulence-modifying proteins. Front. Mol. Biosci. 9, 1092197 (2022).

    Article  CAS  PubMed  Google Scholar 

  94. Safiee, A. W. et al. Putative pathogenic genes of Leptospira interrogans and Leptospira weilii isolated from patients with acute febrile illness. Trop. Med. Infect. Dis. 7, 284 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Pinne, M., Choy, H. A. & Haake, D. A. The OmpL37 surface-exposed protein is expressed by pathogenic leptospira during infection and binds skin and vascular elastin. PLoS Negl. Trop. Dis. 4, e815 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Barbosa, A. S. & Isaac, L. Strategies used by Leptospira spirochetes to evade the host complement system. FEBS Lett. 594, 2633–2644 (2020).

    Article  CAS  PubMed  Google Scholar 

  97. Fraga, T. R., Barbosa, A. S. & Isaac, L. Leptospirosis: aspects of innate immunity, immunopathogenesis and immune evasion from the complement system. Scand. J. Immunol. 73, 408–419 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Ren, S. X. et al. Unique physiological and pathogenic features of Leptospira interrogans revealed by whole-genome sequencing. Nature 422, 888–893 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Carvalho, E. et al. Leptospiral TlyC is an extracellular matrix-binding protein and does not present hemolysin activity. FEBS Lett. 583, 1381–1385 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Segers, R. P., van Gestel, J. A., van Eys, G. J., van der Zeijst, B. A. & Gaastra, W. Presence of putative sphingomyelinase genes among members of the family Leptospiraceae. Infect. Immun. 60, 1707–1710 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Narayanavari, S. A., Sritharan, M., Haake, D. A. & Matsunaga, J. Multiple leptospiral sphingomyelinases (or are there?). Microbiology 158, 1137–1146 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chacko, C. S. et al. A short review on leptospirosis: clinical manifestations, diagnosis and treatment. Clin. Epidemiol. Glob. Health 11, 100741 (2021).

    Article  CAS  Google Scholar 

  103. Centers for Disease Control and Prevention. Leptospirosis. CDC https://www.cdc.gov/leptospirosis/ (2023).

  104. Ganoza, C. A. et al. Asymptomatic renal colonization of humans in the peruvian Amazon by Leptospira. PLoS Negl. Trop. Dis. 4, e612 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Ashford, D. A. et al. Asymptomatic infection and risk factors for leptospirosis in Nicaragua. Am. J. Trop. Med. Hyg. 63, 249–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Rajapakse, S. et al. Seroprevalence of leptospirosis in an endemic mixed urban and semi-urban setting — a community-based study in the district of Colombo, Sri Lanka. PLoS Negl. Trop. Dis. 14, e0008309 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Almeida, D. S. et al. Investigation of chronic infection by Leptospira spp. in asymptomatic sheep slaughtered in slaughterhouse. PLoS ONE 14, e0217391 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Boey, K., Shiokawa, K. & Rajeev, S. Leptospira infection in rats: a literature review of global prevalence and distribution. PLoS Negl. Trop. Dis. 13, e0007499 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Sant’Anna da Costa, R. et al. Persistent high leptospiral shedding by asymptomatic dogs in endemic areas triggers a serious public health concern. Animals https://doi.org/10.3390/ani11040937 (2021).

  110. Ko, A. I., Goarant, C. & Picardeau, M. Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen. Nat. Rev. Microbiol. 7, 736–747 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Rajapakse, S. Leptospirosis: clinical aspects. Clin. Med. 22, 14–17 (2022).

    Article  Google Scholar 

  112. Araujo, E. R. et al. Acute kidney injury in human leptospirosis: an immunohistochemical study with pathophysiological correlation. Virchows Arch. 456, 367–375 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Yang, C. W. Leptospirosis renal disease: understanding the initiation by Toll-like receptors. Kidney Int. 72, 918–925 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Rajapakse, S. et al. Clinical and laboratory associations of severity in a Sri Lankan cohort of patients with serologically confirmed leptospirosis: a prospective study. Trans. R. Soc. Trop. Med. Hyg. 109, 710–716 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Nicodemo, A. C. & Duarte-Neto, A. N. Pathogenesis of pulmonary hemorrhagic syndrome in human leptospirosis. Am. J. Trop. Med. Hyg. 104, 1970–1972 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Taylor, A. J., Paris, D. H. & Newton, P. N. A systematic review of the mortality from untreated leptospirosis. PLoS Negl. Trop. Dis. 9, e0003866 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Rajapakse, S., Rodrigo, C. & Haniffa, R. Developing a clinically relevant classification to predict mortality in severe leptospirosis. J. Emerg. Trauma Shock. 3, 213–219 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Bhatia, M., Umapathy, B. L. & Navaneeth, B. V. An evaluation of dark field microscopy, culture and commercial serological kits in the diagnosis of leptospirosis. Indian J. Med. Microbiol. 33, 416–421 (2015).

    Article  CAS  PubMed  Google Scholar 

  119. Guedes, I. B. et al. Leptospira transport medium (LTM): a practical tool for leptospires isolation. J. Microbiol. Methods 175, 105995 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Goarant, C., Girault, D., Thibeaux, R. & Soupé-Gilbert, M. E. Isolation and culture of leptospira from clinical and environmental samples. Methods Mol. Biol. 2134, 1–9 (2020).

    Article  CAS  PubMed  Google Scholar 

  121. Goris, M. G. & Hartskeerl, R. A. Leptospirosis serodiagnosis by the microscopic agglutination test. Curr. Protoc. Microbiol. 32, 12E.15 (2014).

    Article  Google Scholar 

  122. Guernier, V., Goarant, C., Benschop, J. & Lau, C. L. A systematic review of human and animal leptospirosis in the Pacific Islands reveals pathogen and reservoir diversity. PLoS Negl. Trop. Dis. 12, e0006503 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Signorini, M. L., Lottersberger, J., Tarabla, H. D. & Vanasco, N. B. Enzyme-linked immunosorbent assay to diagnose human leptospirosis: a meta-analysis of the published literature. Epidemiol. Infect. 141, 22–32 (2013).

    Article  CAS  PubMed  Google Scholar 

  124. Rosa, M. I. et al. IgM ELISA for leptospirosis diagnosis: a systematic review and meta-analysis. Cien. Saude Colet. 22, 4001–4012 (2017).

    Article  PubMed  Google Scholar 

  125. Sreevalsan, T. V. & Chandra, R. Relevance of polymerase chain reaction in early diagnosis of leptospirosis. Indian J. Crit. Care Med. 28, 290–293 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Croda, J. et al. Leptospira immunoglobulin-like proteins as a serodiagnostic marker for acute leptospirosis. J. Clin. Microbiol. 45, 1528–1534 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Picardeau, M. Diagnosis and epidemiology of leptospirosis. Med. Mal. Infect. 43, 1–9 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Levett, P. N. Usefulness of serologic analysis as a predictor of the infecting serovar in patients with severe leptospirosis. Clin. Infect. Dis. 36, 447–452 (2003).

    Article  PubMed  Google Scholar 

  129. Eugene, E. J. et al. Evaluation of two immunodiagnostic tests for early rapid diagnosis of leptospirosis in Sri Lanka: a preliminary study. BMC Infect. Dis. 15, 319 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Goris, M. G. et al. Prospective evaluation of three rapid diagnostic tests for diagnosis of human leptospirosis. PLoS Negl. Trop. Dis. 7, e2290 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Behera, S. K. et al. Diagnosis of human leptospirosis: comparison of microscopic agglutination test with recombinant LigA/B antigen-based in-house IgM dot ELISA dipstick test and latex agglutination test using bayesian latent class model and MAT as gold standard. Diagnostics 12, 1455 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Suwancharoen, D., Sittiwicheanwong, B. & Wiratsudakul, A. Evaluation of loop-mediated isothermal amplification method (LAMP) for pathogenic Leptospira spp. detection with leptospires isolation and real-time PCR. J. Vet. Med. Sci. 78, 1299–1302 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Podgoršek, D. et al. Evaluation of real-time PCR targeting the lipL32 gene for diagnosis of Leptospira infection. BMC Microbiol. 20, 59 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Castro-Wallace, S. L. et al. Nanopore DNA sequencing and genome assembly on the international space station. Sci. Rep. 7, 18022 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Chiu, C. Y. & Miller, S. A. Clinical metagenomics. Nat. Rev. Genet. 20, 341–355 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Allicock, O. M. et al. BacCapSeq: a platform for diagnosis and characterization of bacterial infections. mBio https://doi.org/10.1128/mBio.02007-18 (2018).

  137. Rajapakse, S. et al. A diagnostic scoring model for leptospirosis in resource limited settings. PLoS Negl. Trop. Dis. 10, e0004513 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Sigera, P. C. et al. Risk prediction for severe disease and better diagnostic accuracy in early dengue infection; the Colombo dengue study. BMC Infect. Dis. 19, 680 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Lau, C. L. & DePasquale, J. M. Leptospirosis, diagnostic challenges, American Samoa. Emerg. Infect. Dis. 18, 2079–2081 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  140. De Silva, N. L. et al. Changes in full blood count parameters in leptospirosis: a prospective study. Int. Arch. Med. 7, 31 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. de Silva, N. L. et al. Can findings on peripheral blood smear differentiate leptospirosis from other infections? A preliminary comparative study. Trans. R. Soc. Trop. Med. Hyg. 112, 94–96 (2018).

    Article  PubMed  Google Scholar 

  142. Sukmark, T. et al. Thai-Lepto-on-admission probability (THAI-LEPTO) score as an early tool for initial diagnosis of leptospirosis: result from Thai-Lepto AKI study group. PLoS Negl. Trop. Dis. 12, e0006319 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Temeiam, N., Jareinpituk, S., Phinyo, P., Patumanond, J. & Srisawat, N. Development and validation of a simple score for diagnosis of Leptospirosis at outpatient departments. PLoS Negl. Trop. Dis. 14, e0007977 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Al Hariri, Y. K., Sulaiman, S. A. S., Khan, A. H., Adnan, A. S. & Al Ebrahem, S. Q. Mortality of leptospirosis associated acute kidney injury (LAKI) & predictors for its development in adults: a systematic review. J. Infect. public. health 12, 751–759 (2019).

    Article  PubMed  Google Scholar 

  145. Smith, S. et al. A simple score to predict severe leptospirosis. PLoS Negl. Trop. Dis. 13, e0007205 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Galdino, G. S. et al. Development and validation of a simple machine learning tool to predict mortality in leptospirosis. Sci. Rep. 13, 4506 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Marotto, P. C. et al. Early identification of leptospirosis-associated pulmonary hemorrhage syndrome by use of a validated prediction model. J. Infect. 60, 218–223 (2010).

    Article  PubMed  Google Scholar 

  148. Pongpan, S., Thanatrakolsri, P., Vittaporn, S., Khamnuan, P. & Daraswang, P. Prognostic factors for leptospirosis infection severity. Trop. Med. Infect. Dis. https://doi.org/10.3390/tropicalmed8020112 (2023).

  149. So, R. A. Y. et al. A scoring tool to predict pulmonary complications in severe leptospirosis with kidney failure. Trop. Med. Infect. Dis. https://doi.org/10.3390/tropicalmed7010007 (2022).

  150. Ajjimarungsi, A., Bhurayanontachai, R. & Chusri, S. Clinical characteristics, outcomes, and predictors of leptospirosis in patients admitted to the medical intensive care unit: a retrospective analysis. J. Infect. Public Health 13, 2055–2061 (2020).

    Article  PubMed  Google Scholar 

  151. Guernier, V., Allan, K. J. & Goarant, C. Advances and challenges in barcoding pathogenic and environmental Leptospira. Parasitology 145, 595–607 (2018).

    Article  PubMed  Google Scholar 

  152. Goarant, C. Leptospirosis: risk factors and management challenges in developing countries. Res. Rep. Trop. Med. 7, 49–62 (2016).

    PubMed  PubMed Central  Google Scholar 

  153. World Health Organization. Human Leptospirosis: Guidance for Diagnosis, Surveillance and Control (WHO, 2003).

  154. Hancock, G. A., Wilks, C. R., Kotiw, M. & Allen, J. D. The long term efficacy of a hardjo-pomona vaccine in preventing leptospiruria in cattle exposed to natural challenge with Leptospira interrogans serovar hardjo. Aust. Vet. J. 61, 54–56 (1984).

    Article  CAS  PubMed  Google Scholar 

  155. Rinehart, C. L., Zimmerman, A. D., Buterbaugh, R. E., Jolie, R. A. & Chase, C. C. Efficacy of vaccination of cattle with the Leptospira interrogans serovar hardjo type hardjoprajitno component of a pentavalent Leptospira bacterin against experimental challenge with Leptospira borgpetersenii serovar hardjo type hardjo-bovis. Am. J. Vet. Res. 73, 735–740 (2012).

    Article  PubMed  Google Scholar 

  156. Nisa, S. et al. Diverse epidemiology of leptospira serovars notified in New Zealand, 1999–2017. Pathogens https://doi.org/10.3390/pathogens9100841 (2020).

  157. Win, T. Z. et al. Antibiotic prophylaxis for leptospirosis. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD014959.pub2 (2024).

  158. Alikhani, A. et al. Comparison of azithromycin vs doxycycline prophylaxis in leptospirosis, a randomized double blind placebo-controlled trial. J. Infect. Dev. Ctries 12, 991–995 (2018).

    Article  CAS  PubMed  Google Scholar 

  159. Gonsalez, C. R. et al. Use of doxycycline for leptospirosis after high-risk exposure in São Paulo, Brazil. Rev. Inst. Med. Trop. Sao Paulo 40, 59–61 (1998).

    Article  CAS  PubMed  Google Scholar 

  160. Illangasekera, V. L., Kularatne, S. A., Kumarasiri, P. V., Pussepitiya, D. & Premaratne, M. D. Is oral penicillin an effective chemoprophylaxis against leptospirosis? A placebo controlled field study in the Kandy District, Sri Lanka. Southeast. Asian J. Trop. Med. Public Health 39, 882–884 (2008).

    CAS  PubMed  Google Scholar 

  161. Sehgal, S. C., Sugunan, A. P., Murhekar, M. V., Sharma, S. & Vijayachari, P. Randomized controlled trial of doxycycline prophylaxis against leptospirosis in an endemic area. Int. J. Antimicrob. Agents 13, 249–255 (2000).

    Article  CAS  PubMed  Google Scholar 

  162. Takafuji, E. T. et al. An efficacy trial of doxycycline chemoprophylaxis against leptospirosis. N. Engl. J. Med. 310, 497–500 (1984).

    Article  CAS  PubMed  Google Scholar 

  163. Brett-Major, D. M. & Lipnick, R. J. Antibiotic prophylaxis for leptospirosis. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD007342.pub2 (2009).

  164. Yanagihara, Y., Villanueva, S. Y., Yoshida, S., Okamoto, Y. & Masuzawa, T. Current status of leptospirosis in Japan and Philippines. Comp. Immunol. Microbiol. Infect. Dis. 30, 399–413 (2007).

    Article  PubMed  Google Scholar 

  165. Martínez, R. et al. Efficacy and safety of a vaccine against human leptospirosis in Cuba. Rev. Panam. Salud Publica 15, 249–255 (2004).

    PubMed  Google Scholar 

  166. Laurichesse, H. et al. Safety and immunogenicity of subcutaneous or intramuscular administration of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae in healthy volunteers. Clin. Microbiol. Infect. 13, 395–403 (2007).

    Article  CAS  PubMed  Google Scholar 

  167. Yan, Y. et al. An evaluation of the serological and epidemiological effects of the outer envelope vaccine to leptospira. J. Chin. Med. Assoc. 66, 224–230 (2003).

    PubMed  Google Scholar 

  168. Koizumi, N. & Watanabe, H. Leptospirosis vaccines: past, present, and future. J. Postgrad. Med. 51, 210–214 (2005).

    CAS  PubMed  Google Scholar 

  169. Wunder, E. A. et al. A live attenuated-vaccine model confers cross-protective immunity against different species of the Leptospira genus. eLife 10, e64166 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Silveira, M. M. et al. DNA vaccines against leptospirosis: a literature review. Vaccine 35, 5559–5567 (2017).

    Article  CAS  PubMed  Google Scholar 

  171. Barazzone, G. C. et al. Revisiting the development of vaccines against pathogenic leptospira: innovative approaches, present challenges, and future perspectives. Front. Immunol. 12, 760291 (2021).

    Article  CAS  PubMed  Google Scholar 

  172. Lin, M. H. et al. LipL41, a hemin binding protein from Leptospira santarosai serovar Shermani. PLoS ONE 8, e83246 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Dellagostin, O. A. et al. Recombinant vaccines against leptospirosis. Hum. Vaccin. 7, 1215–1224 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. Haake, D. A. et al. Characterization of leptospiral outer membrane lipoprotein LipL36: downregulation associated with late-log-phase growth and mammalian infection. Infect. Immun. 66, 1579–1587 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Vijayachari, P. et al. Immunogenicity of a novel enhanced consensus DNA vaccine encoding the leptospiral protein LipL45. Hum. Vaccin. Immunother. 11, 1945–1953 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Buaklin, A. et al. Optimization of the immunogenicity of a DNA vaccine encoding a bacterial outer membrane lipoprotein. Mol. Biotechnol. 56, 903–910 (2014).

    Article  CAS  PubMed  Google Scholar 

  177. Faisal, S. M. et al. Evaluation of protective immunity of Leptospira immunoglobulin like protein A (LigA) DNA vaccine against challenge in hamsters. Vaccine 26, 277–287 (2008).

    Article  CAS  PubMed  Google Scholar 

  178. Feng, C. Y. et al. Immune strategies using single-component LipL32 and multi-component recombinant LipL32-41-OmpL1 vaccines against leptospira. Braz. J. Med. Biol. Res. 42, 796–803 (2009).

    Article  CAS  PubMed  Google Scholar 

  179. Umthong, S. et al. Immunogenicity of a DNA and recombinant protein vaccine combining LipL32 and Loa22 for leptospirosis using chitosan as a delivery system. J. Microbiol. Biotechnol. 25, 526–536 (2015).

    Article  CAS  PubMed  Google Scholar 

  180. Kumar, P., Lata, S., Shankar, U. N. & Akif, M. Immunoinformatics-based designing of a multi-epitope chimeric vaccine from multi-domain outer surface antigens of leptospira. Front. Immunol. https://doi.org/10.3389/fimmu.2021.735373 (2021).

  181. Validi, M., Karkhah, A., Prajapati, V. K. & Nouri, H. R. Immuno-informatics based approaches to design a novel multi epitope-based vaccine for immune response reinforcement against Leptospirosis. Mol. Immunol. 104, 128–138 (2018).

    Article  CAS  PubMed  Google Scholar 

  182. Techawiwattanaboon, T. et al. Designing adjuvant formulations to promote immunogenicity and protective efficacy of leptospira immunoglobulin-like protein a subunit vaccine. Front. Cell. Infect. Microbiol. https://doi.org/10.3389/fcimb.2022.918629 (2022).

  183. Varma, V. P., Kadivella, M., Kumar, A., Kavela, S. & Faisal, S. M. LigA formulated in AS04 or montanide ISA720VG induced superior immune response compared to alum, which correlated to protective efficacy in a hamster model of leptospirosis. Front. Immunol. https://doi.org/10.3389/fimmu.2022.985802 (2022).

  184. Yang, H. L. et al. In silico and microarray-based genomic approaches to identifying potential vaccine candidates against Leptospira interrogans. BMC Genomics https://doi.org/10.1186/1471-2164-7-293 (2006).

  185. Techawiwattanaboon, T. et al. Proteomic profile of naturally released extracellular vesicles secreted from leptospira interrogans serovar pomona in response to temperature and osmotic stresses. Sci. Rep.https://doi.org/10.1038/s41598-023-45863-0 (2023).

  186. Trott, D. J., Abraham, S. & Adler, B. Antimicrobial resistance in Leptospira, Brucella, and other rarely investigated veterinary and zoonotic pathogens. Microbiol. Spectr. https://doi.org/10.1128/microbiolspec.ARBA-0029-2017 (2018).

  187. Charan, J., Saxena, D., Mulla, S. & Yadav, P. Antibiotics for the treatment of leptospirosis: systematic review and meta-analysis of controlled trials. Int. J. Prev. Med. 4, 501–510 (2013).

    PubMed  PubMed Central  Google Scholar 

  188. Suputtamongkol, Y. et al. An open, randomized, controlled trial of penicillin, doxycycline, and cefotaxime for patients with severe leptospirosis. Clin. Infect. Dis. 39, 1417–1424 (2004).

    Article  CAS  PubMed  Google Scholar 

  189. Selvarajah, S., Ran, S., Roberts, N. W. & Nair, M. Leptospirosis in pregnancy: a systematic review. PLoS Negl. Trop. Dis. 15, e0009747 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Win, T. Z. et al. Antibiotics for treatment of leptospirosis. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD014960.pub2 (2024).

  191. Fernando, N. et al. Effect of antimicrobial agents on inflammatory cytokines in acute leptospirosis. Antimicrob. Agents Chemother. https://doi.org/10.1128/aac.02312-17 (2018).

  192. Zhang, W. et al. Doxycycline attenuates leptospira-induced IL-1β by suppressing nlrp3 inflammasome priming. Front. Immunol. 8, 857 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  193. Guerrier, G. & D’Ortenzio, E. The Jarisch–Herxheimer reaction in leptospirosis: a systematic review. PLoS ONE 8, e59266 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Takamizawa, S. et al. Leptospirosis and Jarisch–Herxheimer reaction. QJM 108, 967–968 (2015).

    Article  CAS  PubMed  Google Scholar 

  195. Guerrier, G., Lefèvre, P., Chouvin, C. & D’Ortenzio, E. Jarisch–Herxheimer reaction among patients with leptospirosis: incidence and risk factors. Am. J. Trop. Med. Hyg. 96, 791–794 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Smith, S. et al. Severe leptospirosis in tropical Australia: optimising intensive care unit management to reduce mortality. PLoS Negl. Trop. Dis. 13, e0007929 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Rodrigo, C. et al. High dose corticosteroids in severe leptospirosis: a systematic review. Trans. R. Soc. Trop. Med. Hyg. 108, 743–750 (2014).

    Article  CAS  PubMed  Google Scholar 

  198. Davoodi, L. et al. Evaluation of the effectiveness of N-acetylcysteine on accelerating the recovery of renal failure in patients with leptospirosis, a randomized clinical trial study. Ann. Med. Surg. 67, 102518 (2021).

    Article  Google Scholar 

  199. Herath, N. et al. Sequel and therapeutic modalities of leptospirosis associated severe pulmonary haemorrhagic syndrome (SPHS); a Sri Lankan experience. BMC Infect. Dis. 19, 451 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Trivedi, S. V. et al. Plasma exchange with immunosuppression in pulmonary alveolar haemorrhage due to leptospirosis. Indian J. Med. Res. 131, 429–433 (2010).

    PubMed  Google Scholar 

  201. Fonseka, C. L. & Lekamwasam, S. Role of plasmapheresis and extracorporeal membrane oxygenation in the treatment of leptospirosis complicated with pulmonary hemorrhages. J. Trop. Med. 2018, 4520185 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Biggs, H. M. et al. Leptospirosis among hospitalized febrile patients in Northern Tanzania. Am. J. Trop. Med. Hyg. 85, 275–281 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Ismail, T. F. et al. Retrospective serosurvey of leptospirosis among patients with acute febrile illness and hepatitis in Egypt. Am. J. Trop. Med. Hyg. 75, 1085–1089 (2006).

    Article  PubMed  Google Scholar 

  204. Crump, J. A. et al. Etiology of severe non-malaria febrile illness in Northern Tanzania: a prospective cohort study. PLoS Negl. Trop. Dis. 7, e2324 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Torgerson, P. R. et al. Global burden of leptospirosis: estimated in terms of disability adjusted life years. PLoS Negl. Trop. Dis. 9, e0004122 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Ellis, W. A. in Leptospira and Leptospirosis (ed. Adler, B.) 99–137 (Springer, 2015).

  207. Engida, H. A., Theuri, D. M., Gathungu, D. K. & Gachohi, J. Optimal control and cost-effectiveness analysis for leptospirosis epidemic. J. Biol. Dyn. 17, 2248178 (2023).

    Article  PubMed  Google Scholar 

  208. Sanhueza, J. M. et al. Estimation of the burden of leptospirosis in New Zealand. Zoonoses Public Health 67, 167–176 (2020).

    Article  PubMed  Google Scholar 

  209. Galloway, R. L., Levett, P. N., Tumeh, J. W. & Flowers, C. R. Assessing cost effectiveness of empirical and prophylactic therapy for managing leptospirosis outbreaks. Epidemiol. Infect. 137, 1323–1332 (2009).

    Article  CAS  PubMed  Google Scholar 

  210. Agampodi, S., Gunarathna, S., Lee, J. S. & Excler, J. L. Global, regional, and country-level cost of leptospirosis due to loss of productivity in humans. PLoS Negl. Trop. Dis. 17, e0011291 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Goris, M. G. et al. Towards the burden of human leptospirosis: duration of acute illness and occurrence of post-leptospirosis symptoms of patients in the Netherlands. PLoS ONE 8, e76549 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Cvejic, E. et al. Contribution of individual psychological and psychosocial factors to symptom severity and time-to-recovery after naturally-occurring acute infective illness: the Dubbo Infection Outcomes Study (DIOS). Brain Behav. Immun. 82, 76–83 (2019).

    Article  PubMed  Google Scholar 

  213. Chang, C. H. et al. Long-term outcome of leptospirosis infection with acute kidney injury. Biomedicines https://doi.org/10.3390/biomedicines10102338 (2022).

  214. Phannajit, J. et al. Long-term kidney outcomes after leptospirosis: a prospective multicentre cohort study in Thailand. Nephrol. Dial. Transpl. 38, 2182–2191 (2023).

    Article  Google Scholar 

  215. Premarathne, S. S. et al. Leptospirosis: a potential culprit for chronic kidney disease of uncertain etiology. Nephron 147, 510–520 (2023).

    Article  CAS  PubMed  Google Scholar 

  216. Carrillo-Larco, R. M., Altez-Fernandez, C., Acevedo-Rodriguez, J. G., Ortiz-Acha, K. & Ugarte-Gil, C. Leptospirosis as a risk factor for chronic kidney disease: a systematic review of observational studies. PLoS Negl. Trop. Dis. 13, e0007458 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Prado, L. G. & Barbosa, A. S. Understanding the renal fibrotic process in leptospirosis. Int. J. Mol. Sci. https://doi.org/10.3390/ijms221910779 (2021).

  218. Hotez, P. J., Aksoy, S., Brindley, P. J. & Kamhawi, S. What constitutes a neglected tropical disease? PLoS Negl. Trop. Dis. 14, e0008001 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Hotez, P. J., Woc-Colburn, L. & Bottazzi, M. E. Neglected tropical diseases in Central America and Panama: review of their prevalence, populations at risk and impact on regional development. Int. J. Parasitol. 44, 597–603 (2014).

    Article  PubMed  Google Scholar 

  220. Karpagam, K. B. & Ganesh, B. Leptospirosis: a neglected tropical zoonotic infection of public health importance — an updated review. Eur. J. Clin. Microbiol. Infect. Dis. 39, 835–846 (2020).

    Article  CAS  PubMed  Google Scholar 

  221. Costa, E. et al. Penicillin at the late stage of leptospirosis: a randomized controlled trial. Rev. Inst. Med. Trop. Sao Paulo 45, 141–145 (2003).

    Article  PubMed  Google Scholar 

  222. Daher, E. F. & Nogueira, C. B. Evaluation of penicillin therapy in patients with leptospirosis and acute renal failure. Rev. Inst. Med. Trop. Sao Paulo 42, 327–332 (2000).

    Article  CAS  PubMed  Google Scholar 

  223. Edwards, C. N., Nicholson, G. D., Hassell, T. A., Everard, C. O. & Callender, J. Penicillin therapy in icteric leptospirosis. Am. J. Trop. Med. Hyg. 39, 388–390 (1988).

    Article  CAS  PubMed  Google Scholar 

  224. Fairburn, A. C. & Semple, S. J. Chloramphenicol and penicillin in the treatment of leptospirosis among British troops in Malaya. Lancet 270, 13–16 (1956).

    Article  CAS  PubMed  Google Scholar 

  225. McClain, J. B., Ballou, W. R., Harrison, S. M. & Steinweg, D. L. Doxycycline therapy for leptospirosis. Ann. Intern. Med. 100, 696–698 (1984).

    Article  CAS  PubMed  Google Scholar 

  226. Panaphut, T., Domrongkitchaiporn, S., Vibhagool, A., Thinkamrop, B. & Susaengrat, W. Ceftriaxone compared with sodium penicillin g for treatment of severe leptospirosis. Clin. Infect. Dis. 36, 1507–1513 (2003).

    Article  CAS  PubMed  Google Scholar 

  227. Phimda, K. et al. Doxycycline versus azithromycin for treatment of leptospirosis and scrub typhus. Antimicrob. Agents Chemother. 51, 3259–3263 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Watt, G. et al. Placebo-controlled trial of intravenous penicillin for severe and late leptospirosis. Lancet 1, 433–435 (1988).

    Article  CAS  PubMed  Google Scholar 

  229. Russell, R. W. Treatment of leptospirosis with oxytetracycline. Lancet 2, 1143–1145 (1958).

    Article  CAS  PubMed  Google Scholar 

  230. Rajapakse, S., Rodrigo, C., Balaji, K. & Fernando, S. D. Atypical manifestations of leptospirosis. Trans. R. Soc. Trop. Med. Hyg. 109, 294–302 (2015).

    Article  PubMed  Google Scholar 

  231. Vilaichone, R. K., Mahachai, V. & Wilde, H. Acute acalculous cholecystitis in leptospirosis. J. Clin. Gastroenterol. 29, 280–283 (1999).

    Article  CAS  PubMed  Google Scholar 

  232. Ranawaka, N., Jeevagan, V., Karunanayake, P. & Jayasinghe, S. Pancreatitis and myocarditis followed by pulmonary hemorrhage, a rare presentation of leptospirosis — a case report and literature survey. BMC Infect. Dis. 13, 38 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  233. Solmazgul, E. et al. A case of Weil’s syndrome developing steroid resistant immune haemolytic anaemia. Scand. J. Infect. Dis. 37, 700–702 (2005).

    Article  PubMed  Google Scholar 

  234. Hanvanich, M., Moollaor, P., Suwangool, P. & Sitprija, V. Hemolytic uremic syndrome in leptospirosis bataviae. Nephron 40, 230–231 (1985).

    Article  CAS  PubMed  Google Scholar 

  235. Laing, R. W., Teh, C. & Toh, C. H. Thrombotic thrombocytopenic purpura (TTP) complicating leptospirosis: a previously undescribed association. J. Clin. Pathol. 43, 961–962 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Panicker, J. N., Mammachan, R. & Jayakumar, R. V. Primary neuroleptospirosis. Postgrad. Med. J. 77, 589–590 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Chandra, S. R. et al. Acute disseminated encephalomyelitis following leptospirosis. J. Assoc. Physicians India 52, 327–329 (2004).

    CAS  PubMed  Google Scholar 

  238. Sakellaridis, N., Panagopoulos, D. & Androulis, A. Neuroleptospirosis with hydrocephalus and very elevated cerebrospinal fluid protein. South. Med. J. 102, 549–550 (2009).

    Article  PubMed  Google Scholar 

  239. Dimopoulou, I. et al. Leptospirosis presenting with encephalitis-induced coma. Intensive Care Med. 28, 1682 (2002).

    Article  PubMed  Google Scholar 

  240. Kavitha, S. & Shastry, B. A. Leptospirosis with transverse myelitis. J. Assoc. Physicians India 53, 159–160 (2005).

    CAS  PubMed  Google Scholar 

  241. Bal, A. M., Bharadwaj, R. S., Gita, N., Joshi, S. A. & Thakare, J. P. Guillain–Barre syndrome in a pediatric patient following infection due to Leptospira. Jpn J. Infect. Dis. 56, 29–31 (2003).

    Article  PubMed  Google Scholar 

  242. Hancox, R. J., Karalus, N. & Singh, V. Mononeuritis multiplex in leptospirosis. Scand. J. Infect. Dis. 23, 395–396 (1991).

    Article  CAS  PubMed  Google Scholar 

  243. Turhan, V. et al. Cerebral venous thrombosis as a complication of leptospirosis. J. Infect. 53, e247–e249 (2006).

    Article  PubMed  Google Scholar 

  244. Chu, K. M., Rathinam, R., Namperumalsamy, P. & Dean, D. Identification of Leptospira species in the pathogenesis of uveitis and determination of clinical ocular characteristics in south India. J. Infect. Dis. 177, 1314–1321 (1998).

    Article  CAS  PubMed  Google Scholar 

  245. Levin, N. et al. Panuveitis with papillitis in leptospirosis. Am. J. Ophthalmol. 117, 118–119 (1994).

    Article  CAS  PubMed  Google Scholar 

  246. Faine, S., Adler, B., Christopher, W. & Valentine, R. Fatal congenital human leptospirosis. Zentralbl. Bakteriol. Mikrobiol. Hyg. A 257, 548 (1984).

    CAS  PubMed  Google Scholar 

  247. Sharma, K. K., Madhvilatha, P., Kalawat, U. & Sivakumar, V. Leptospirosis-induced still birth and postpartum sepsis. Indian J. Pathol. Microbiol. 54, 426–427 (2011).

    Article  PubMed  Google Scholar 

  248. Shaked, Y., Shpilberg, O., Samra, D. & Samra, Y. Leptospirosis in pregnancy and its effect on the fetus: case report and review. Clin. Infect. Dis. 17, 241–243 (1993).

    Article  CAS  PubMed  Google Scholar 

  249. Tramoni, G., Clément, H. J., Lopez, F. & Viale, J. P. An unusual case of post partum haemorrhage: leptospirosis infection [French]. Ann. Fr. Anesth. Reanim. 22, 363–365 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful to P. Ruwanpathirana for providing the clinical photographs used in Fig. 4.

Author information

Authors and Affiliations

  1. Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka

    Senaka Rajapakse

  2. Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, Colombo, Sri Lanka

    Narmada Fernando

  3. Section of Epidemiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland

    Anou Dreyfus

  4. Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK

    Chris Smith

  5. School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan

    Chris Smith

  6. Department of Pathology, School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia

    Chaturaka Rodrigo

Authors
  1. Senaka Rajapakse
    View author publications

    Search author on:PubMed Google Scholar

  2. Narmada Fernando
    View author publications

    Search author on:PubMed Google Scholar

  3. Anou Dreyfus
    View author publications

    Search author on:PubMed Google Scholar

  4. Chris Smith
    View author publications

    Search author on:PubMed Google Scholar

  5. Chaturaka Rodrigo
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Introduction (S.R., N.F. and C.R.); Epidemiology (A.D., S.R., N.F. and C.R.); Mechanisms/pathophysiology (S.R., N.F. and C.R.); Diagnosis, screening and prevention (S.R., N.F. A.D., C.S. and C.R.); Management (S.R., C.S. and C.R.); Quality of life (S.R.); Outlook (S.R., N.F., A.D. and C.R.); overview of the Primer (S.R., N.F. and C.R.).

Corresponding author

Correspondence to Senaka Rajapakse.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Disease Primers thanks Suneth Agampodi, Natarajaseenivasan Kalimuthusamy, Paluru Vijayachari and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Informed consent

The authors affirm that human research participants provided informed consent for publication of the images in Fig. 4.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rajapakse, S., Fernando, N., Dreyfus, A. et al. Leptospirosis. Nat Rev Dis Primers 11, 32 (2025). https://doi.org/10.1038/s41572-025-00614-5

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-025-00614-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research