In the past decade, leptospirosis has emerged as a globally important infectious disease. It occurs in urban environments of industrialised and developing countries, as well as in rural regions worldwide. Mortality remains significant, related both to delays in diagnosis due to lack of infrastructure and adequate clinical suspicion, and to other poorly understood reasons that may include inherent pathogenicity of some leptospiral strains or genetically determined host immunopathological responses. Pulmonary haemorrhage is recognised increasingly as a major, often lethal, manifestation of leptospirosis, the pathogenesis of which remains unclear. The completion of the genome sequence of Leptospira interrogans serovar lai, and other continuing leptospiral genome sequencing projects, promise to guide future work on the disease. Mainstays of treatment are still tetracyclines and beta-lactam/cephalosporins. No vaccine is available. Prevention is largely dependent on sanitation measures that may be difficult to implement, especially in developing countries.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(03)00830-2.pdf

Leptospirosis: a zoonotic disease of global importance

Evidence-based guidelines for the management of patients with Lyme disease, human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis), and babesiosis were prepared by an expert panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 31[Suppl 1]:1-14). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. For each of these Ixodes tickborne infections, information is provided about prevention, epidemiology, clinical manifestations, diagnosis, and treatment. Tables list the doses and durations of antimicrobial therapy recommended for treatment and prevention of Lyme disease and provide a partial list of therapies to be avoided. A definition of post-Lyme disease syndrome is proposed.

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The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America

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 Pena-Moctezuma 2010; Bharti et al. 2003; Hartskeerl et al. 2011; Ko et al. 2009; Levett 2001; McBride et al. 2005).

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Leptospirosis in Humans

In October 1995, epidemic "hemorrhagic fever," without jaundice or renal manifestations, was reported in rural Nicaragua following heavy flooding; 2259 residents were evaluated for nonmalarial febrile illnesses (cumulative incidence, 6.1%) and 15 (0.7%) died with pulmonary hemorrhage. A case-control study found that case-patients were more likely than controls to have ever walked in creeks (matched odds ratio [MOR], 15.0; 95% confidence interval [CI], 1.7-132.3), have household rodents (MOR, 10.4; 95% CI, 1.1-97.1), or own dogs with titers >/=400 to Leptospira species (MOR, 23.4; 95% CI, 3.6-infinity). Twenty-six of 51 case-patients had serologic or postmortem evidence of acute leptospirosis. Leptospira species were isolated from case-patients and potential animal reservoirs. This leptospirosis epidemic likely resulted from exposure to flood waters contaminated by urine from infected animals, particularly dogs. Leptospirosis should be included in the differential diagnosis for nonmalarial febrile illness, particularly during periods of flooding or when pulmonary hemorrhage occurs.

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Epidemic Leptospirosis Associated with Pulmonary Hemorrhage—Nicaragua, 1995

Overview of the epidemiology, microbiology, and pathogenesis of Leptospira spp. in humans

A prospective, controlled randomized study of penicillin therapy in icteric human leptospirosis was carried out between 1 October 1983 and 31 December 1986. Thirty-eight patients received intravenous crystalline penicillin for 5 days, while 41 assigned to a control group received intravenous fluids only. A comparison of the results of laboratory tests made on the day of admission revealed no significant differences between the 2 groups. There was no significant difference in time for defervescence, return of biochemical parameters to normal, incidence of iritis, or mortality in the 2 groups. Three patients (7.3%) in the control group and 1 patient (2.6%) in the treatment group died. The overall mortality rate was 5.9%. Leptospira were recovered from urine cultures in 6 control patients but from none of the treated patients' post-treatment cultures. We conclude that penicillin has little effect on clinical outcome in icteric leptospirosis.

Penicillin therapy in icteric leptospirosis.

In a prospective study of human leptospirosis, thrombocytopenia was demonstrated in 54% of 24 cases The only additional laboratory evidence suggestive of disseminated intravascular coagulation lay in a mild elevation of fibrinogen degradation products, but this occurred with equal frequency in nonthrombocytopenic patients There is therefore no causal relationship between disseminated intravascular coagulation and the thrombocytopenia of human leptospirosis

Thrombocytopenia in leptospirosis: the absence of evidence for disseminated intravascular coagulation.

A 39-month clinical study of leptospirosis was undertaken at the Queen Elizabeth Hospital, Barbados. Eighty-eight patients had a confirmed diagnosis of the disease during the period. The major serogroups identified were autumnalis (including a new serovar bim), icterohaemorrhagiae, ballum and canicola. The majority of patients presented with jaundice (95%,) anorexia and headaches (85%), fever (76%) and conjunctival suffusion (54%). While abnormal creatinine levels were seen in 49% of patients on admission, only 16% were judged to have had renal failure. The urine to plasma urea ratio showed high sensitivity and specificity in the diagnosis of pre-renal azotemia. Cardiac arrhythmias and myocarditis occurred in 18% of patients and pericarditis in 6%. An elevated serum amylase was found in 65% of cases. The bilirubin level took 5.5 weeks to return to normal. Thrombocytopenia was shown not to be due to a disseminated intravascular coagulation, and a randomised trial of high dose penicillin did not reveal any benefit to jaundiced patients. The overall mortality during the study was 5.7%.

Leptospirosis in Barbados (a clinical study)

Between November 1979 and the end of December 1986 (7.17 years), 248 cases of leptospirosis were confirmed among hospital patients on Barbados (mean 35 per year; range 25-57). Considering the 235 who were greater than or equal to 15 years of age, the annual incidence of leptospirosis was 19.2/100,000 population (14.0 for all age groups). There were 173 males and 62 females, and for cases aged 15-34 leptospirosis was 9.6 times more common in men than women. Among men, incidence increased fairly steadily with age, and an even steadier increase was apparent in women up to age 64, with some decline in later years. The incidence of disease was much higher among agricultural than other workers and the non-employed. Highest case numbers were recorded in the parishes of St Michael (65 or 28%) and Christ Church (36 or 15%), though the incidence was lowest in these two parishes (13.1/100,000 and 17.4/100,000, respectively). The highest incidence rates were in St Andrew and St Joseph (50.2 and 36.1/100,000, respectively). The incidence in areas with rainfall greater than or equal to 1600 mm (32.6/100,000) was nearly twice that in areas with rainfall less than 1600 mm (17.3/100,000). There is a clear link between cases of severe disease and recent rainfall. Using 134 patients greater than or equal to 15 years of age with fever due to other illnesses as controls, a higher proportion of cases than controls came from rural areas. The risk of contracting leptospirosis was increased for all categories of manual workers relative to the group at lowest risk (non-manual indoor workers). Sugar-cane workers were five times more likely to contract leptospirosis than were non-manual indoor workers, while those whose families minded livestock were 2.5 times more likely, and those with rodents in their garden/yard were 1.8 times more likely to do so. Other risk factors examined did not show significant associations with the disease. Despite increasing mechanization and the use of more protective clothing, agricultural workers are still at high risk from leptospirosis. The annual range of cases is likely to stay much as it is in the foreseeable future.

An investigation of some risk factors for severe leptospirosis on Barbados.

Cases of leptospirosis admitted to the Queen Elizabeth Hospital (QEH), Barbados, were assessed for the presence of "pre-renal azotaemia" (NON-ARF) as opposed to "acute renal failure" (ARF). Distinction between the two diagnoses was made on the basis of clinical course. Peritoneal dialysis was inappropriately utilised in 26% of patients receiving such therapy. This study evaluates diagnostic tests for pre-renal azotaemia, and acute renal failure in leptospirosis, and indicates guidelines for the management of azotaemia in such patients. U/P urea and osmolar ratios show high sensitivity and specificity in diagnosing pre-renal azotaemia. While "early" dialysis is essential for patients with acute leptospiral renal failure, in those with plasma creatinines less than 600 mumol/litre on entry and indices indicating NON-ARF, decisions regarding dialysis can safely be delayed for 48-72 hours while the effect of rehydration is assessed.

T. A. Hassell

Papers

Penicillin therapy in icteric leptospirosis.

Thrombocytopenia in leptospirosis: the absence of evidence for disseminated intravascular coagulation.

Leptospirosis in Barbados (a clinical study)

An investigation of some risk factors for severe leptospirosis on Barbados.

Urinary diagnostic indices in the management of leptospirosis. Selection of patients for dialysis therapy.