We identified relevant English language publications from 1966 onwards through Pubmed searches. Keywords used were “leptospirosis” and “leptospira”. To look for reports of human vaccine clinical trials in all languages we used keywords “vaccine”, “leptospirosis”, and “clinical trials”. We also examined reference lists of major reviews, a reference database compiled by Solomon Faine, and the compendium of references by E Ryu, Chronological references of zoonoses: leptospires and
ReviewLeptospirosis: a zoonotic disease of global importance
Section snippets
Microbiology and taxonomy
Leptospires are spirochetes (figure 1), a group of bacteria that diverged early in bacterial evolution.10 The family leptospiraceae includes two genera, Leptospira and Leptonema. Typically, leptospires were classified according to antigenic determinants.11, 12 More recently, a molecular classification has been described that divides the Leptospira genus into several species on the basis of DNA relatedness.13, 14, 15, 16 The reclassification of leptospires using genetic determinants provides
Microbiology
The leptospiral genome consists of two circular chromosomes17 and its entire sequence was recently established.18 The genome is large compared with the genomes of other spirochetes such as Treponema spp19 and Borrelia spp,20 which indicates the ability of Leptospira spp to live within diverse environments: animal hosts and freely in the environment. Little is known about genetic exchange among the Leptospira, although lateral transfer has been suggested.21 Tools for genetic manipulation of
Taxonomy
The species classification of the genus Leptospira is based on DNA relatedness (table 1).13, 14, 15, 16 The genus is divided into 17 species, defined as being at least 70% DNA—related and whose related DNA sequences contain at most 5% unpaired bases (divergence).15 This classification coexists with the older serological classification in which antisera are used to establish antigenic relatedness between isolates.11 Leptospiral strains are still commonly referred to by serovar (Table 1, Table 2
Epidemiology
Leptospirosis has a worldwide distribution. The incidence of human infection is higher in the tropics than in temperate regions but transmission occurs in both industrialised and developing countries. Incidence rates are underestimated due to lack of awareness of the disease and relatively inaccessible and insufficiently rapid diagnostics. Symptom—less or subclinical infection is common in endemic regions.34,35 We have seen that a surprisingly high proportion (20–30%) of patients presenting
Pathogenesis
Host infection by pathogenic Leptospira produces a diverse array of clinical manifestations ranging from subclinical infection to undifferentiated febrile illness to jaundice, renal failure, and potentially lethal pulmonary haemorrhage. Our understanding of mechanisms of leptospirosis pathogenesis is limited. Answers to the most basic questions, such as whether the outcome of infection (mild or severe disease) is due to direct pathogen effects or genetically determined host immune responses,
Clinical features
Leptospirosis has protean manifestations, and mimics the clinical presentations of many other diseases.32, 96 Consequently, mechanisms of the clinical manifestations of leptospirosis remain obscure. Typical descriptions97 include a biphasic illness (anicteric form, figure 10) and fulminant disease (icterohaemorrhagic form, figure 11).9 In the biphasic illness the initial acute or septicaemic phase is characterised by bacteraemia that typically lasts about 1 week. Most of the recognised cases
General laboratory tests
Diagnosis of leptospirosis depends on simple diagnostic tests, which are often not done because of a low index of clinical suspicion. Laboratory diagnosis of leptospirosis can be made either by showing the organism or by serological tests that detect leptospiral antibodies.122 Several non—specific findings may include increased ESR, mild increases in transaminases, alkaline phosphatase, and bilirubin; abnormal urinanalysis showing proteinuria, pyuria, and microscopic haematuria. CSF protein may
Treatment
There remains some controversy about whether antimicrobial treatment of severe leptospirosis should even be initiated since most cases of acute leptospirosis resolve spontaneously.140 However, most experts would not withhold antimicrobial treatment when clinical findings and epidemiological exposure history suggest leptospirosis.140 In the case series reported from Hawaii from 1974–1998, no significant difference was seen between use and non—use of antibiotics and duration of illness.100 In a
Chemoprophylaxis
In a now classic study, a clinical trial comparing doxycycline (200 mg/week) with placebo was done in Panama in 1982 involving 940 US soldiers deployed for jungle training98 22 cases of leptospirosis occurred in the placebo group (attack rate of 4·2%), which was significantly different from the single case in the doxycycline group (attack rate of 0·2%, p<0·001). A randomised clinical trial done on the North Andaman islands of India examined doxycycline prophylaxis against leptospirosis in
Vaccine development
Vaccines to prevent human leptospirosis are available in some countries and large—scale clinical trials have been reported from Cuba,149, 150 Russia,151 and China152 in non—English language journals. In Cuba, there was not a single reported side—effect in more than 100 000 people vaccinated and protection was reported to be 100%.149, 150 Only a few patients developed MAT antibodies to the serovars in the preparation,149, 150 so that in—vitro tests did not correlate with protective immunity.
Search strategy and selection criteria
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