Leptospirosis in humans

Abstract

Leptospirosis is a widespread and potentially fatal zoonosis that is endemic in many tropical regions and causes large epidemics after heavy rainfall and flooding. Infection results from direct or indirect exposure to infected reservoir host animals that carry the pathogen in their renal tubules and shed pathogenic leptospires in their urine. Although many wild and domestic animals can serve as reservoir hosts, the brown rat (Rattus norvegicus) is the most important source of human infections. Individuals living in urban slum environments characterized by inadequate sanitation and poor housing are at high risk of rat exposure and leptospirosis. The global burden of leptospirosis is expected to rise with demographic shifts that favor increases in the number of urban poor in tropical regions subject to worsening storms and urban flooding due to climate change. Data emerging from prospective surveillance studies suggest that most human leptospiral infections in endemic areas are mild or asymptomatic. Development of more severe outcomes likely depends on three factors: epidemiological conditions, host susceptibility, and pathogen virulence (Fig. 1). Mortality increases with age, particularly in patients older than 60 years of age. High levels of bacteremia are associated with poor clinical outcomes and, based on animal model and in vitro studies, are related in part to poor recognition of leptospiral LPS by human TLR4. Patients with severe leptospirosis experience a cytokine storm characterized by high levels of IL-6, TNF-alpha, and IL-10. Patients with the HLA DQ6 allele are at higher risk of disease, suggesting a role for lymphocyte stimulation by a leptospiral superantigen. Leptospirosis typically presents as a nonspecific, acute febrile illness characterized by fever, myalgia, and headache and may be confused with other entities such as influenza and dengue fever. Newer diagnostic methods facilitate early diagnosis and antibiotic treatment. Patients progressing to multisystem organ failure have widespread hematogenous dissemination of pathogens. Nonoliguric (high output) renal dysfunction should be supported with fluids and electrolytes. When oliguric renal failure occurs, prompt initiation of dialysis can be life saving. Elevated bilirubin levels are due to hepatocellular damage and disruption of intercellular junctions between hepatocytes, resulting in leaking of bilirubin out of bile caniliculi. Hemorrhagic complications are common and are associated with coagulation abnormalities. Severe pulmonary hemorrhage syndrome due to extensive alveolar hemorrhage has a fatality rate of >50 %. Readers are referred to earlier, excellent summaries related to this subject (Adler and de la Peña-Moctezuma 2010; Bharti et al. 2003; Hartskeerl et al. 2011; Ko et al. 2009; Levett 2001; McBride et al. 2005).

Figures

Fig. 1

Factors contributing to leptospirosis. Development of leptospirosis depends on three types of factors (epidemiology, host, and pathogen) and their interactions. Epidemiologic factors include sanitation, housing, rainfall, and whether flooding occurs. Incidence is linked to income level, occupation, and travel, representing epidemiologic factors linked to specific hosts. Hosts vary in susceptibility depending on age, genetic factors (e.g., HLA-DQ6), skin integrity, and whether protective clothing (e.g., gloves and boots) are worn. The ways in which the host and leptospires interact determine the route, exposure, and dose of the pathogen. Leptospiral pathogens differ in their ability to cause disease, a reflection of their virulence, motility, and ability to survive in the host, a reflection (at least in part) of complement resistance. The types of reservoir hosts determine the types of pathogens present in a particular epidemiologic setting

Fig. 2

Epidemiologic settings for leptospirosis. a A high proportion of contestants in the 2000 Eco-Challenge multisport race held in Malaysian Borneo developed leptospirosis. Of 189 participants contacted by the Centers for Disease Control, 80 (42 %) met the case definition for leptospirosis. Risk factors included exposure for extended periods of time to the rain-swollen Segama river (photograph credit Reed Hoffmann). b This rural village in Laos is a typical epidemiologic setting for leptospirosis. Residents of tropical regions of the world with high levels of rainfall are at increased risk of leptospirosis, particularly when standing water is contaminated by urine from wild or domesticated animals, which may serve as reservoir hosts for pathogenic Leptospira species (photograph credit Ben Adler)

Fig. 3

Histopathology of leptospirosis. a Histology of the liver typically shows lack of the normal adhesion between hepatocytes, a hallmark of the disease (photograph credit Thales De Brito). b Typical renal histopathology showing acute tubular necrosis and interstitial nephritis. The glomerulus is essentially unremarkable. Reproduced from Abdulkader and Silva, The kidney in leptospirosis. Pediatr Nephrol 2008; 23:2111–2120, with permission of the publisher, Springer

Fig. 4

Clinical presentation of leptospirosis. a Subconjunctival hemorrhages and icterus in a 37-year-old man who kept pet rats presented with sudden onset of fever, myalgia, and severe headache. On admission he had abnormal liver and kidney function. Serological tests for leptospiral antibodies converted from negative to positive 1 week after presentation. He was treated with intravenous penicillin and recovered completely. Reproduced from Jansen and Schneider, Weil’s disease in a rat owner. Lancet Infect Dis 2011; 11:152, with permission of the publisher, Elsevier Ltd. b Severe pulmonary hemorrhage in a 50-year-old man who had recently returned from vacation in Malaysia where he had waded through mangrove forests. Respiratory deterioration occurred on day 2 of hospitalization requiring mechanical ventilation complicated by severe hemoptysis requiring blood transfusion. He was treated initially with doxycycline followed by amoxicillin and made a slow but complete recovery. Blood culture in leptospiral growth medium became positive 4 months after inoculation. Reproduced from Wagenaar et al. Leptospirosis with pulmonary hemorrhage, caused by a new strain of serovar Lai: Langkawi. J Travel Med 2004; 11:379–382. With permission of the publisher, John Wiley and sons. No portion of this figure may be reproduced without permission of the publisher

Fig. 5

Biphasic nature of leptospirosis and relevant investigations at different stages of disease. Specimens 1 and 2 for serology are acute-phase specimens, 3 is a convalescent-phase sample which may facilitate detection of a delayed immune response, and 4 and 5 are follow-up samples which can provide epidemiological information, such as the presumptive infecting serogroup. Adapted from Turner LH (1969). Leptospirosis. Br Med J i:231–235, with permission of the publisher. Copyright © American Society for Microbiology, (Clin Microbiol Rev 2001, 14 (2):296–326. doi:10.1128/CMR.14.2.296-326.2001)