Leptospirosis, a
spirocheatal infection caused by Leptospira interrogans (1,2),
has been reported from all climatic zones of the world. It is primarily
an infection of mammalian species, in which the infection may manifest
in various clinical forms or may be totally unapparent. As in the case
of the other mammals, in humans also, the infection may result in a wide
spectrum of outcomes (3), ranging from completely assymptomatic state
(4,5) on one end to severe complications due to affliction and failure
of multiple organ systems culminating rapidly in death on the other. In
many ecological niches, particularly around the tropic where human
infection occurs very frequently, the disease is a common cause of
clinical syndromes such as renal failure (6,7,8) myocarditis (9,10) and
severe pulmonary haemorrhage (11,12,13) and deaths among young and
middle aged adults. Although the global burden of disease due to
leptospiral infection has not been estimated, the disease accounts for a
significant proportion of years of life lost (YLL) in high transmission
ecological niches.
History:
Adolf Weil described a
clinical syndrome of splenomegaly, jaundice, haemorrhages and nephritis,
which is now referred to as Weil's disease and is often used as a
synonym for leptospirosis (14,15) Such clinical syndromes were
recognized as occupational hazards among rice farmers in ancient China
(16) . Leptospires were first identified as the cause of Weil's disease
in Japan where it was common among coal miners.
In 1915, Inada and Ido
successfully transmitted infection to guinea pigs from a patient with
Weil's disease and grew the organism from the blood of the infected
animals. Independently, Huebener and Reiter reported the successful
transmission of Weil's disease to guinea pigs in October 1915 and
demonstrated flagella like bodies in blood smears. At almost the same
time Uhlenhuth and Fromme also reported similar findings. Several years
before, Stimson had reported the presence of spiral organisms in
Levadeti stained kidney specimens of a patient (17), and this is
considered by some as the first demonstration of leptospira (18).
Naguchi grew a spirochaete, which he named as Spirochaeta icteroids,
from the liver specimen of a patient, who had reportedly died of yellow
fever. However this organism closely resembled the causative organism of
Weil's disease even in cross-protection studies in guinea pigs. After
the discovery of yellow fever virus, it became clear that the two
organisms were the same and the patient might have had leptospirosis
rather than yellow fever.
Inada and Ido named the
causative organism of Weil's disease as Spirochaeta
icterohaemorrhagiae, though there were considerable differences in
the appearance and movement of this organism from other spirochaetes.
Stimson named the organisms he observed in the kidney specimens
provisionally as Spirochaeta interrogans. Huebener and Reiter
called the organism they grew Spirochaeta icterogenes and
Uhlenhuth and Fromme as Spirochaeta nodosa. Naguchi introduced
the genus Leptospira in 1917 on account of the difference in morphology
and movement. He described the characteristic feature of this organism
as 'long, slender, cylindrical, highly flexible filament with tightly
set, regular, shallow spirals'.
Leptospira:
Leptospires are flexible
helical rods that with active motility characterized by clockwise and
anti-clockwise rotation about its longitudinal axis and flexion and
extension. They are aerobes and utilize long-chain fatty acids as source
of carbon and energy (19). Till 1979, the genus Leptospira
contained two species, Leptospira interrogans containing 23
serogroups that are pathogenic either to humans or animals, and
Leptospira biflexa containing 28 serogroups (20) that are usually
found in fresh water and moist soil. In 1979, a new genus Leptonema
with a single species Leptonema illini was proposed and in 1981,
a third species of Leptospira, L. Parva. This was later found to
be sufficiently different from Leptospira and Leptonema to
merit the proposal for a new genus Turneria. DNA relatedness
studies during the past two decades have shown that the both L.
interrogans and L. biflexa are extremely heterogeneous and
therefore need to be reclassified into several new geno-species (1,2).
Leptospires exhibit vast
diversity in antigenic nature and based on antigenic similarities about
250 pathogenic serovars have been described. Although not much evidence
exists to support any association between antigenic type of leptospires
and the clinical outcome of infection, the antigenic diversity has great
implications in the diagnosis of the disease, epidemiology and
strategies for prevention and control.
Clinical presentation and
pathophysiology:
Majority of leptospiral
infections do not cause any clinical disease (21), however, about 10% -
20% of infected persons suffer mild flu-like symptoms. A small
proportion of the patients progresses to fulminant disease with fatal
complications including renal failure (6,7) severe pulmonary haemorrhage
(11,12,13) myocarditis (9,10) or acute respiratory distress syndrome (ARDS)
(22). The case fatality ratio in severe leptospirosis could be as high
as 40% - 50% (23) .
The pathogenic mechanisms
behind renal, pulmonary and cardiac injury in leptospirosis have not
been fully understood. Previously it was thought that direct cytotoxic/cytopathic
effect of the microorganisms or their lytic products were responsible
for the tissue injury (24,25,26). Later toxins including a glycoprotein
fraction (GLP), endotoxin with Na, K-ATPase inhibitor activity (27) and
a hemolysin (28) were incriminated as possible mediators in the
pathophysiilogy of leptospirosis. Various leptospiral proteins have also
been considered as potential virulence factors in the pathogenisis of
leptospirosis (29).
The availability of the whole genome sequence of leptospiral strains
(30) and functional analysis of
the genome and proteome (31) are major breakthroughs in leptospiral
research, particularly on the pathogenesis of the disease.
Diagnosis and treatment:
Diagnostic procedures for
leptospirosis are based on direct evidence of the presence leptospires
or its components in clinical specimens or by demonstration of antibody
response to leptospiral antigens (32). Tests that give direct evidence
include demonstration of leptospires in clinical specimens by darkground
microscopy (DGM), special staining techniques including
immunofluorescent staining, isolation and identification of leptospires,
demonstration of leptospiral DNA using polymerase chain reaction (PCR)
and animal inoculation. Although direct demonstration of leptospires in
blood using DGM has been shown to be highly unreliable (33) and
therefore not advocated as a diagnostic test (34), it is still being
used by some laboratories leading to misdiagnosis and over-diagnosis.
Other tests that give evidence of leptospires or their components in
clinical specimens, except PCR, are rarely used for diagnosis because of
various inherent limitations. Though attempts are being made to develop
a test that demonstrates leptospiral antigen in clinical specimens,
these have not been successful so far.
Serological tests that give
indirect evidence of leptospiral infection by demonstrating antibody
response in the host include microscopic agglutination test (MAT),
macroscopic agglutination tests employing sensitized latex particles or
killed leptospires, enzyme immune assay and immune-chromatography
techniques. MAT occupies a prominent position among the serological
procedures not only because of its reliability as a diagnostic test when
performed on paired specimens but also because of its ability to provide
additional information about the infecting serogroup of leptospires. It
is an indispensable procedure for serological characterization of
leptospiral isolates. The cut-off titre for categorizing a test as
positive or negative needs to be standardized taking into account the
background titre seen in an area (35). Leptospiral IgM and IgG ELISA are
commercially available and have been shown to have acceptable
reliability. Many rapid tests are currently available and among them
Lepto-lateral flow (36) or variations of it and some of the latex
agglutination tests, either commercially available or prepared in-house
by laboratories, have been found to give reliable results.
Leptospires are sensitive
to most of the antibiotics, except perhaps chloramphenicol (37).
However, there can be variations in the susceptibility of leptospiral
isolates from geographically diverse regions to the same antimicrobial
(38). Penicillin is the antibiotic of choice in the treatment of
leptospirosis, but at least one randomized controlled trial has shown
that penicillin therapy does not affect the time
for defervescence or mortality in icteric leptospirosis (39).
Cephalosporines and fluoro-quinolones have been shown to be as effective
as penicillin (40,41), and can be useful alternative drugs in patients
with hypersensitivity to penicillin.
In patients with renal,
pulmonary and cardiac complications, survival depends upon the
effectiveness of supportive therapy and treatment regimes aimed at
compensating for and reversing organ system malfunction/failure. There
has been a lot of debate about the effectiveness of various therapies in
patients with severe pulmonary haemorrhage, because of the very high
case fatality ratio in such patients and the increasing frequency with
which this is being encountered worldwide. There are conflicting reports
about the efficacy of desmopressin and pulsed dexamethosone (42,43)
therapy in reducing mortality in patients with pulmonary haemorrhage.
Plasma exchange has been tried in isolated patients with severe
pulmonary haemorrhage (44) as well as renal failure (45) and has been
shown to be effective. However, this has not yet been supported by
strong evidence from properly conducted randomized trials. The focus of
clinical research on leptospirosis today is on developing clinical
algorithims for early case detection and initiation of antibiotic
therapy to prevent progression of the disease to more severe and fatal
forms and on devising new treatment strategies for reducing mortality in
severe complicated leptospirosis.
Epidemiology, surveillance
and control
Leptospirosis is currently
identified as a worldwide public health problem (34). An increase in the
incidence of the disease has been recorded in some countries where
leptospirosis surveillance exists46. A multi-centric study in India
showed that leptospirosis accounts for about 12.7% of cases of acute
febrile illness attending hospitals (47). Several large outbreaks have
been reported in the recent years, particularly in Southeast Asian
countries and central and south America. Outbreaks during monsoon occur
regularly in endemic areas such as Gujarat (48), Kerala (49) and Andaman
Islands (23), where the disease was called Andaman Haemorrhagic Fever (AHF)
as the etiology remained unknown for several years in 1980s and 90s11.
Natural calamities such as floods and flash floods often trigger large
outbreaks (50,51,52).
In many tropical endemic
areas, a significant proportion of the population is exposed to
leptospires. Very high seroprevalence has been reported from such areas
(21,53,54). In spite of the short duration of bacteriaemia in
leptospirosis, a 9% prevalence of current assymptomatic infection has
been recorded in Seychelles Island (53), probably because a large
proportion of the population are exposed to leptospires and acquire
infection every year, particularly during the peak transmission season
(55). Burden of disease due to leptospirosis at global or national
levels has not been estimated as yet, but the World Health Organization
has constituted a Leptospira Burden Epidemiology Reference Group (LERG)
to conduct global research for providing necessary disease burden data
(http://www.who.int/zoonoses/diseases/lerg/en/).
The transmission cycle of
leptospirosis involves three entities viz. the carrier animals,
environment and humans. The natural habitat of leptospires is the renal
tubules of animals of various mammalian species. Although rodents are
often implicated, other mammals including farm animals and pets and
occasionally some exotic species such as opossums (56), sea lions (57),
flying foxes (58) and squirrel monkeys (59) have been found to carry
leptospires. Their role as a source of infection to human beings,
though, is likely to be negligible.
Leptospires shed in the
urine of carrier animals can survive for prolonged period in wet soil
and surface water under favourable conditions (60), which include
absence of salinity, neutral or slightly alkaline pH and absence of
detergents and other bactericidal agents. There is some evidence to
suggest that leptospires actually multiply in certain environmental
niches (61). People get infected when they are exposed to the urine
of carrier animals or contaminated soil or surface water. Because of
the chances of people coming into contact with environment is much
higher than they coming into contact with animal urine, indirect
transmission from contaminated environment is likely to be more frequent
than direct transmission from animals. Therefore, environmental
characteristics are central to the epidemiology of leptospirosis.
People of some occupational
groups, because of their higher chances of coming into contact with
source of infection, are at high risk of acquiring leptospiral
infection. This includes farmers and farm labourers, conservancy
workers, veterinarians, meat handlers and dairy workers. Risk factor
studies (62, 21, 46, 53) conducted in endemic areas and during epidemics
show, predictably, association between leptospiral infection and
occupational or behavioural factors that are likely to result in
exposure to sources of infection. In spite of the availability of such
information, studies on the impact of behaviour modification programmes
on leptospirosis incidence/mortality are scarce, perhaps because of low
community acceptance of measures to limit exposure in tropical
developing world where close interaction with environment and animals is
part of the way of life.
While exposure limiting
measures at community level and at workplace are dependant upon the
specific nature of transmission dynamics in the area, conferring
protection through vaccination/prophylaxis are not and therefore could
be a simpler public health strategy for leptospirosis prevention. A
major hurdle in developing an effective vaccine is the antigenic
variability among pathogenic leptospires. Polyvalent and monovalent
vaccines for animal use have been obtained and tested. Some such
vaccines are in routine use for pets and in some areas among domestic
animals. Besides conferring protection against leptospiral disease in
animals, these animal vaccines may also play a role in human
leptospirosis control as a source reduction strategy. In spite of
several decades of research human vaccine development has been
relatively unsuccessful (63). Various categories of vaccines such as
lipopolysaccharides (LPS), recombinant proteins, inactivated and
attenuated vaccines and DNA vaccines have been tried and several
molecules have been shown to be immunogenic in experimental studies.
Chemoprophylaxis is another possible method for prevention of
leptospirosis when a well defined population group is exposed to or
likely to be exposed to possible source of infection. Chemoprophylaxis
with doxycycline at a dose of 200 mg per week has been shown to be 100%
effective amongst US troops visiting Panama for training64. However, the
same strategy failed to prevent infection in an endemic area in Andaman
Islands, though it offered 54% protection against leptospiral disease
(55).
Leptospirosis has a
worldwide distribution. Countries around the tropic, particularly those
in South East Asia and in Amazon Basin in South America, are endemic to
the disease because of a suitable environment for the survival of
leptospires and transmission of infection and high degree of exposure of
the people to animals and environment. The monsoon in the South East
Asia cyclically makes the environment wet and water-logged further
facilitating transmission of infection. These countries are also prone
for tropical storms and flash floods that trigger widespread outbreaks
almost every year. The occurrence of leptospirosis is closely linked to
environmental factors such as temperature and rainfall. It is one of
the six diseases whose incidence or geographical distribution could
change by global warming phenomenon (65).
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