Leptospirosis-associated pulmonary hemorrhagic syndrome: immune mechanisms, clinical manifestations, and experimental models

ABSTRACT Leptospirosis is a neglected zoonotic disease caused by bacteria of the genus Leptospira, mainly acquired via direct contact with water and soil contaminated by the urine of infected animals. This is most observed in tropical and subtropical regions, and it is strongly associated with urban population growth in areas lacking adequate sanitation conditions. Leptospira infection can lead to several clinical manifestations in humans, ranging from a nonspecific febrile illness to severe complications such as jaundice, renal failure, and life-threatening pulmonary disease. One of the most severe forms is leptospirosis-associated pulmonary hemorrhagic syndrome (LPHS), characterized by coughing, chest pain, dyspnea, and massive pulmonary hemorrhage. The mortality rate of LPHS is approximately 50%, with death generally occurring within 72 hours after symptom onset. The etiopathogenesis of LPHS remains poorly understood. Some studies suggest that Leptospira spp. may directly damage blood capillaries and alter vascular permeability. Additionally, the host immune response, via the cytokine release, high expression of adhesion molecules, and activation of the Complement System, may further disrupt endothelial integrity, promoting vascular leakage and the systemic dissemination of leptospires. Animal models are essential for a better understanding of Leptospira transmission, colonization, and pathogenesis. This review aims to consolidate current understanding of LPHS, with emphasis on its pathogenesis, immune mechanisms, clinical manifestations, virulence factors, and experimental models.