Leptospirosis

Leptospirosis is a blood infection caused by the bacteria

Leptospirosis
Leptospira[8] that can infect humans, dogs, rodents and many other
Other names Rat fever,[1] field
wild and domesticated animals.[8] Signs and symptoms can range
fever,[2] rat
from none to mild (headaches, muscle pains, and fevers) to severe
catcher's
(bleeding in the lungs or meningitis).[5] Weil's disease (/ˈvaɪlz/
yellows,[3] pretibial
VILES),[12] the acute, severe form of leptospirosis, causes the
fever[4]
infected individual to become jaundiced (skin and eyes become
yellow), develop kidney failure, and bleed.[6] Bleeding from the
lungs associated with leptospirosis is known as severe pulmonary
haemorrhage syndrome.[5]

More than ten genetic types of Leptospira cause disease in

humans.[13] Both wild and domestic animals can spread the
disease, most commonly rodents.[8] The bacteria are spread to
humans through animal urine or feces, or water or soil
contaminated with animal urine and feces, coming into contact
with the eyes, mouth, nose or breaks in the skin.[8] In developing
countries, the disease occurs most commonly in pest control,
Leptospira magnified 200-fold with
farmers and low-income people who live in areas with poor
a dark-field microscope
sanitation.[5] In developed countries, it occurs during heavy
Specialty Infectious disease
downpours and is a risk to pest controllers, sewage workers[14] and
those involved in outdoor activities in warm and wet areas.[5] Symptoms None, headaches,
Diagnosis is typically by testing for antibodies against the bacteria muscle pains,
or finding bacterial DNA in the blood.[5] fevers[5]
Complications Bleeding from the
Efforts to prevent the disease include protective equipment to block lungs, meningitis,
contact when working with potentially infected animals, washing kidney failure[5][6]
after contact, and reducing rodents in areas where people live and
Usual onset One to two
work.[7] The antibiotic doxycycline is effective in preventing
weeks[7]
leptospirosis infection.[7] Human vaccines are of limited
Causes Leptospira
usefulness;[15] vaccines for other animals are more widely
typically spread
available.[16] Treatment when infected is with antibiotics such as
by rodents[8]
doxycycline, penicillin, or ceftriaxone.[8] The overall risk of death
is 5–10%.[10] However, when the lungs are involved, the risk of Risk factors Exposure to
death increases to the range of 50–70%.[8] infected animals,
especially their
It is estimated that one million severe cases of leptospirosis in urine, or fresh
humans occur every year, causing about 58,900 deaths.[11] The water or damp
disease is most common in tropical areas of the world but may soil contaminated
occur anywhere.[7] Outbreaks may arise after heavy rainfall.[7] The with infectious
disease was first described by physician Adolf Weil in 1886 in urine[8]
Germany.[17][18] Infected animals may have no, mild or severe Diagnostic Testing blood for
symptoms.[19] These may vary by the type of animal.[16][19] In method antibodies against
some animals Leptospira live in the reproductive tract, leading to the bacterium or
transmission during mating.[16] its DNA[5]
Differential Malaria, enteric
Signs and symptoms diagnosis fever, rickettsiosis,
dengue[9]
The symptoms of leptospirosis usually appear one to two weeks
Prevention Personal
after infection,[7] but the incubation period can be as long as a
protective
month.[21] The illness is biphasic in a majority of symptomatic
equipment,
cases. Symptoms of the first phase (acute or leptospiremic phase)
hygiene
last five to seven days. In the second phase (immune phase), the
measures,
symptoms resolve as antibodies against the bacteria are
doxycycline[7]
produced.[8] Additional symptoms develop in the second phase.[22]
The phases of illness may not be distinct, especially in patients with Treatment Doxycycline,
severe illness.[23] 90% of those infected experience mild symptoms penicillin,
while 10% experience severe leptospirosis.[24] ceftriaxone[8]
Prognosis Risk of death
Leptospiral infection in humans causes a range of symptoms, ~7.5%[10]
though some infected persons may have none. The disease begins Frequency One million
suddenly with fever accompanied by chills, intense headache, people per
severe muscle aches and abdominal pain.[5][21] A headache year[7][11]
brought on by leptospirosis causes throbbing pain and is
Deaths 58,900 per
characteristically located at the head's bilateral temporal or frontal
year[11]
regions. The person could also have pain behind the eyes and a
sensitivity to light. Muscle pain usually involves the
calf muscle and the lower back. The most characteristic
feature of leptospirosis is the conjunctival suffusion
(conjunctivitis without exudate) which is rarely found
in other febrile illnesses. Other characteristic findings
on the eye include subconjunctival bleeding and
jaundice. A rash is rarely found in leptospirosis. When
one is found alternative diagnoses such as dengue
fever and chikungunya fever should be considered.
Dry cough is observed in 20–57% of people with
leptospirosis. Thus, this clinical feature can mislead a
doctor to diagnose the disease as a respiratory illness.
Additionally, gastrointestinal symptoms such as
nausea, vomiting, abdominal pain, and diarrhoea
Schematic depiction of the symptoms and signs of
frequently occur. Vomiting and diarrhea may contribute
leptospirosis[20]
to dehydration. The abdominal pain can be due to
acalculous cholecystitis or inflammation of the
pancreas.[21] Rarely, the lymph nodes, liver, and spleen may be enlarged and palpable.[8]

There will be a resolution of symptoms for one to three days.[7] The immune phase starts after this and can
last from four to 30 days and can be anything from brain to kidney complications.[25] The hallmark of the
second phase is inflammation of the membranes covering the brain.[7] Signs and symptoms of meningitis
include severe headache and neck stiffness.[7] Kidney
involvement is associated with reduced or absent urine
output.[7]

The classic form of severe leptospirosis, known as Weil's

disease, is characterised by liver damage (causing jaundice),
kidney failure, and bleeding, which happens in 5–10% of those
infected.[7] Lung and brain damage can also occur. For those
with signs of inflammation of membranes covering the brain
and the brain itself, altered level of consciousness can happen. Conjunctival suffusion (red conjunctiva)
A variety of neurological problems such as paralysis of half of together with jaundice is a specific feature
the body, complete inflammation of a whole horizontal section of leptospirosis.[20]
of spinal cord, and Guillain-Barré syndrome are the
complications. Signs of bleeding such as petechiae,
ecchymoses, nose bleeding, blackish stools due to bleeding in the stomach, vomiting blood and bleeding
from the lungs can also be found. Prolongation of prothrombin time in coagulation testing is associated with
severe bleeding manifestation. However, low platelet count is not associated with severe bleeding.[21]
Pulmonary haemorrhage is alveolar haemorrhage (bleeding into the alveoli of the lungs) leading to massive
coughing up of blood, and causing acute respiratory distress syndrome, where the risk of death is more
than 50%.[21] Rarely, inflammation of the heart muscles, inflammation of membranes covering the heart,
abnormalities in the heart's natural pacemaker and abnormal heart rhythms may occur.[8]

Cause

Bacteria
Leptospirosis is caused by spirochaete bacteria that belong to
the genus Leptospira, which are aerobic,[8] right-handed
helical,[13] and 6–20 micrometers long.[7] Like Gram-negative
bacteria, Leptospira have an outer membrane studded with
lipopolysaccharide (LPS) on the surface, an inner membrane
and a layer of peptidoglycan cell wall. However, unlike Gram-
negative bacteria, the peptidoglycan layer in Leptospira lies
closer to the inner than the outer membrane. This results in a
Scanning electron micrograph of a number fluid outer membrane loosely associated with the cell wall.[26]
of Leptospira sp. bacteria atop a 0.1 μm In addition, Leptospira have a flagellum located in the
polycarbonate filter[20]
periplasm, associated with corkscrew style movement.[7]
Chemoreceptors at the poles of the bacteria sense various
substrates and change the direction of its movement.[13] The
bacteria are traditionally visualised using dark-field microscopy without staining.[7]

A total of 66 species of Leptospira has been identified. Based on their genomic sequence, they are divided
into two clades and four subclades: P1, P2, S1, and S2.[27] The 19 members of the P1 subclade include the
8 species that can cause severe disease in humans: L. alexanderi, L. borgpetersenii, L. interrogans,
L. kirschneri, L. mayottensis, L. noguchii, L. santarosai, and L. weilii.[13][27] The P2 clade comprises 21
species that may cause mild disease in humans. The remaining 26 species comprise the S1 and S2
subclades, which include "saprophytes" known to consume decaying matter (saprotrophic nutrition).[27]
Pathogenic Leptospira do not multiply in the environment. Leptospira require high humidity for survival
but can remain alive in environments such as stagnant water or contaminated soil. The bacterium can be
killed by temperatures of 50 °C (122 °F) and can be inactivated by 70% ethanol, 1% sodium hypochlorite,
formaldehyde, detergents and acids.[28]

Leptospira are also classified based on their serovar. The diverse sugar composition of the
lipopolysaccharide on the surface of the bacteria is responsible for the antigenic difference between
serovars.[13] About 300 pathogenic serovars of Leptospira are recognised. Antigenically related serovars
(belonging to the same serogroup) may belong to different species because of horizontal gene transfer of
LPS biosynthetic genes between different species. Currently, the cross agglutination absorption test and
DNA-DNA hybridisation are used to classify Leptospira species, but are time-consuming. Therefore, total
genomic sequencing could potentially replace these two methods as the new gold standard of classifying
Leptospira species.[13]

Transmission
The bacteria can be found in ponds, rivers, puddles,
sewers, agricultural fields and moist soil.[7] Pathogenic
Leptospira have been found in the form of aquatic
biofilms, which may aid survival in the
environment.[29]

The number of cases of leptospirosis is directly related

to the amount of rainfall, making the disease seasonal
in temperate climates and year-round in tropical
Working in a paddy field barefoot is a risk factor for
climates.[7] The risk of contracting leptospirosis
leptospirosis.[20]
depends upon the risk of disease carriage in the
community and the frequency of exposure.[21] In rural
areas, farming and animal husbandry are the major risk factors for contracting leptospirosis.[5] Poor housing
and inadequate sanitation also increase the risk of infection.[21] In tropical and semi-tropical areas, the
disease often becomes widespread after heavy rains or after flooding.[7]

Leptospira are found mostly in mammals.[5] However, reptiles and cold-blooded animals such as frogs,
snakes, turtles, and toads have been shown to have the infection.[16] Whether there are reservoirs of human
infection is unknown.[21][16] Rats, mice, and moles are important primary hosts, but other mammals
including dogs, deer, rabbits, hedgehogs, cows, sheep, swine, raccoons, opossums, and skunks can also
carry the disease.[16] In Africa, a number of wildlife hosts have been identified as carriers, including the
banded mongoose, Egyptian fox, Rusa deer, and shrews.[30] There are various mechanisms whereby
animals can infect each other. Dogs may lick the urine of an infected animal off the grass or soil, or drink
from an infected puddle. House-bound domestic dogs have contracted leptospirosis, apparently from licking
the urine of infected mice in the house.[31] Leptospirosis can also be transmitted via the semen of infected
animals.[16] The duration of bacteria being consistently present in animal urine may persist for years.[16]

Humans are the accidental host of Leptospira.[5] Humans become infected through contact with water or
moist soil that contains urine & feces from infected animals.[7] The bacteria enter through cuts, abrasions,[7]
ingestion of contaminated food, or contact with mucous membrane of the body (e.g. mouth, nose, and
eyes).[32] Occupations at risk of contracting leptospirosis include farmers, fishermen, garbage collectors and
sewage workers.[5] The disease is also related to adventure tourism and recreational activities.[5] It is
common among water-sports enthusiasts in specific areas, including triathlons, water rafting, canoeing and
swimming, as prolonged immersion in water promotes the entry of the bacteria.[5] However, Leptospira are
unlikely to penetrate intact skin.[8] The disease is not known to spread between humans, and bacterial
dissemination in recovery period is extremely rare in humans.[8] Once humans are infected, bacterial
shedding from the kidneys usually persists for up to 60 days.[28]

Rarely, leptospirosis can be transmitted through an organ transplant.[33] Infection through the placenta
during pregnancy is also possible.[34][35][36] It can cause miscarriage and infection in infants.[37]
Leptospirosis transmission through eating raw meat of wildlife animals have also been reported (e.g.
psychiatric patients with allotriophagy).[38]

Pathogenesis
When animals ingest the bacteria, they circulate in the
bloodstream, then lodge themselves into the kidneys
through the glomerular or peritubular capillaries. The
bacteria then pass into the lumens of the renal tubules
and colonise the brush border and proximal convoluted
tubule. This causes the continuous shedding of bacteria
in the urine without the animal experiencing significant
ill effects. This relationship between the animal and the
bacteria is known as a commensal relationship, and the
Ways of Leptospira bacteria infecting human cells
animal is known as a reservoir host.[21]
and blood stream[20]

Humans are the accidental host of Leptospira.[5] The

pathogenesis of leptospirosis remains poorly understood despite research efforts.[7][32] The bacteria enter
the human body through either breaches in the skin or the mucous membrane, then into the bloodstream.
The bacteria later attach to the endothelial cells of the blood vessels and extracellular matrix (complex
network of proteins and carbohydrates present between cells). The bacteria use their flagella for moving
between cell layers. They bind to cells such as fibroblasts, macrophages, endothelial cells, and kidney
epithelial cells. They also bind to several human proteins such as complement proteins, thrombin,
fibrinogen, and plasminogen using surface leptospiral immunoglobulin-like (Lig) proteins such as LigB and
LipL32, whose genes are found in all pathogenic species.[13][32]

Through the innate immune system, endothelial cells of the capillaries in the human body are activated by
the presence of these bacteria. The endothelial cells produce cytokines and antimicrobial peptides against
the bacteria. These products regulate the coagulation cascade and movements of white blood cells.[13]
Macrophages presented in humans are able to engulf Leptospira. However, Leptospira are able to reside
and proliferate in the cytoplasmic matrix after being ingested by macrophages.[13] Those with severe
leptospirosis can experience a high level of cytokines such as interleukin 6, tumor necrosis factor alpha
(TNF-α), and interleukin 10. The high level of cytokines causes sepsis-like symptoms which is life-
threatening instead of helping to fight against the infection.[24] Those who have a high risk of sepsis during
a leptospirosis infection are found to have the HLA-DQ6 genotype, possibly due to superantigen activation,
which damages bodily organs.[21]
Leptospira LPS only activates toll-like receptor 2 (TLR2) in monocytes in humans. The lipid A molecule of
the bacteria is not recognised by human TLR4 receptors. Therefore, the lack of Leptospira recognition by
TLR4 receptors probably contributes to the leptospirosis disease process in humans.[13]

Although there are various mechanisms in the human body to fight against the bacteria, Leptospira is well
adapted to such an inflammatory condition created by it. In the bloodstream, it can activate host
plasminogen to become plasmin that breaks down extracellular matrix, degrades fibrin clots and
complemental proteins (C3b and C5) to avoid opsonisation. It can also recruit complement regulators such
as Factor H, C4b-binding protein, factor H-like binding protein, and vitronectin to prevent the activation of
membrane attack complex on its surface. It also secretes proteases to degrade complement proteins such as
C3. It can bind to thrombin that decreases the fibrin formation. Reduced fibrin formation increases the risk
of bleeding.[13] Leptospira also secretes sphingomyelinase and haemolysin that target red blood cells.[7]

Leptospira spreads rapidly to all organs through the bloodstream.[13] They mainly affect the liver. They
invade spaces between hepatocytes, causing apoptosis. The damaged hepatocytes and hepatocyte
intercellular junctions cause leakage of bile into the bloodstream, causing elevated levels of bilirubin,
resulting in jaundice. Congested liver sinusoids and perisinusoidal spaces have been reported. Meanwhile,
in the lungs, petechiae or frank bleeding can be found at the alveolar septum and spaces between
alveoli.[21] Leptospira secretes toxins that cause mild to severe kidney failure or interstitial nephritis.[32] The
kidney failure can recover completely or lead to atrophy and fibrosis.[21] Rarely, inflammation of the heart
muscles, coronary arteries, and aorta are found.[25]

Diagnosis

Laboratory tests
For those who are infected, a complete blood count may show a
high white cell count and a low platelet count. When a low
haemoglobin count is present together with a low white cell count
and thrombocytopenia, bone marrow suppression should be
considered.[21] Erythrocyte sedimentation rate and C-reactive
protein may also be elevated.[8] Kidney tissue, using a silver staining
technique, revealing the presence of
The kidneys are commonly involved in leptospirosis. Blood urea Leptospira bacteria[20]
and creatinine levels will be elevated. Leptospirosis increases
potassium excretion in urine, which leads to a low potassium
level[21] and a low sodium level in the blood.[8][21] Urinalysis may reveal the presence of protein, white
blood cells, and microscopic haematuria.[8] Because the bacteria settle in the kidneys, urine cultures will be
positive for leptospirosis starting after the second week of illness until 30 days of infection.[8]

For those with liver involvement, transaminases and direct bilirubin are elevated in liver function tests. The
Icterohaemorrhagiae serogroup is associated with jaundice and elevated bilirubin levels. Hemolytic anemia
contributes to jaundice. A feature of leptospirosis is acute haemolytic anaemia and conjugated
hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase deficiency.[21]
Abnormal serum amylase and lipase levels (associated with pancreatitis) are found in those who are
admitted to hospital due to leptospirosis. Impaired kidney function with creatinine clearance less than 50
ml/min is associated with elevated pancreatic enzymes.[21]
For those with severe headache who show signs of meningitis, a
lumbar puncture can be attempted. If infected, cerebrospinal fluid
(CSF) examination shows lymphocytic predominance with a cell
count of about 500/mm3 , protein between 50 and 100 mg/mL and
normal glucose levels. These findings are consistent with aseptic
meningitis.[21]

Serological tests
Rapid detection of Leptospira can be done by quantifying the IgM
antibodies using an enzyme-linked immunosorbent assay (ELISA).
Typically, L. biflexa antigen is used to detect the IgM antibodies.
Diffuse lungs bleeding due to
This test can quickly determine the diagnosis and help in early
leptospirosis infection[20]
treatment. However, the test specificity depends upon the type of
antigen used and the presence of antibodies from previous
infections. The presence of other diseases such as Epstein–Barr virus infection, viral hepatitis, and
cytomegalovirus infection can cause false-positive results.[21] Other rapid screening tests have been
developed such as dipsticks, latex and slide agglutination tests.[8]

The microscopic agglutination test (MAT) is the reference test for the diagnosis of leptospirosis.[21] MAT is
a test where serial dilutions of patient sera are mixed with different serovars of Leptospira. The mixture is
then examined under a dark field microscope to look for agglutination. The highest dilution where
50% agglutination occurs is the result.[21] MAT titres of 1:100 to 1:800 are diagnostic of leptospirosis.[8] A
fourfold or greater rise in titre of two sera taken at symptoms' onset and three to 10 days of disease onset
confirms the diagnosis. During the acute phase of the disease, MAT is not specific in detecting a serotype of
Leptospira because of cross-reactivity between the serovars.[21] In the convalescent phase, MAT is more
specific in detecting the serovar types.[21] MAT requires a panel of live antigens and requires laborious
work.[25]

Molecular tests
Leptospiral DNA can be amplified by using polymerase chain reaction (PCR) from serum, urine, aqueous
humour, CSF, and autopsy specimens.[21] It detects the presence of bacteria faster than MAT during the first
few days of infection without waiting for the appearance of antibodies.[25] As PCR detects the presence of
leptospiral DNA in the blood it is useful even when the bacteria is killed by antibiotics.[39]

Imaging
In those who have lung involvement, a chest X-ray may demonstrate diffuse alveolar opacities.[21]

Diagnostic criteria
In 1982, the World Health Organization (WHO) proposed the Faine's criteria for the diagnosis of
leptospirosis. It consists of three parts: A (clinical findings), B (epidemiological factors), and C (lab findings
and bacteriological data). Since the original Faine's criteria only included culture and MAT in part C, which
is difficult and complex to perform, the modified Faine's criteria were proposed in 2004 to include ELISA
and slide agglutination tests which are easier to perform. In 2012, modified Faine's criteria (with
amendment) was proposed to include shortness of breath and coughing up blood in the diagnosis. In 2013,
India recommended modified Faine's criteria in the diagnosis of leptospirosis.[40]

Prevention
Rates of leptospirosis can be reduced by improving housing,
infrastructure, and sanitation standards. Rodent abatement efforts
and flood mitigation projects can also help to prevent it.[21] Proper
use of personal protective equipment (PPE) by people who have a
high risk of occupational exposure can prevent leptospirosis
infections in most cases.[21]

There is no human vaccine suitable for worldwide use.[15] Only a

few countries such as Cuba, Japan, France, and China have
approved the use of inactivated vaccines with limited protective
effects.[15][41] Side effects such as nausea, injection site redness and
swelling have been reported after the vaccine was injected. Since
the immunity induced by one Leptospiraserovar is only protective
against that specific one, trivalent vaccines have been
developed.[21] However, they do not confer long-lasting immunity
A notice board by a lakeside in
to humans or animals.[13] Vaccines for other animals are more
Sarawak, Malaysia, that warns
widely available.[16] against swimming in the lake as it
has tested positive for pathogenic
Doxycycline is given once a week as a prophylaxis and is effective Leptospira[20]
in reducing the rate of leptospirosis infections amongst high-risk
individuals in flood-prone areas.[42] In one study, it reduced the
number of leptospirosis cases in military personnel undergoing
exercises in the jungles. In another study, it reduced the number of
symptomatic cases after exposure to leptospirosis under heavy
rainfall in endemic areas.[21]

The prevention of leptospirosis from the environmental sources like

contaminated waterways, soil, sewers, and agricultural fields, is
disinfection used by effective microorganisms, which is mixed with Blood samples being taken from a
bokashi mudballs for the infected waterways & sewers. group of residents in Boyolali
Regency, Indonesia, for leptospirosis

Treatment screening tests[20]

Most leptospiral cases resolve spontaneously. Early initiation of

antibiotics may prevent the progression to severe disease. Therefore, in resource-limited settings, antibiotics
can be started once leptospirosis is suspected after history taking and examination.[21]

For mild leptospirosis, antibiotic recommendations such as doxycycline, azithromycin, ampicillin and
amoxicillin were based solely on in vitro testing.[8] In 2001, the WHO recommended oral doxycycline
(2 mg/kg up to 100 mg every 12 hours) for five to seven days for those with mild leptospirosis.
Tetracycline, ampicillin, and amoxicillin can also be used in such cases.[43] However, in areas where both
rickettsia and leptospirosis are endemic, azithromycin and doxycycline are the drugs of choice.[8] It should
be noted doxycycline is not used in cases where the patient suffers from liver damage as it has been linked
to hepatotoxicity.[44]

Based on a 1988 study, intravenous (IV) benzylpenicillin (also known as penicillin G) is recommended for
the treatment of severe leptospirosis.[8] Intravenous benzylpenicillin (30 mg/kg up to 1.2 g every six hours)
is used for five to seven days. Amoxicillin, ampicillin, and erythromycin may also be used for severe
cases.[43] Ceftriaxone (1 g IV every 24 hours for seven days) is also effective for severe
leptospirosis.[21][8][45] Cefotaxime (1 g IV every six hours for seven days) and doxycycline (200 mg
initially followed by 100 mg IV every 12 hours for seven days) are equally effective as benzylpenicillin
(1.5 million units IV every six hours for seven days).[8][46] Therefore, there is no evidence on differences in
death reduction when benzylpenicillin is compared with ceftriaxone or cefotaxime.[8] Another study
conducted in 2007 also showed no difference in efficacy between doxycycline (200 mg initially followed
by 100 mg orally every 12 hours for seven days) or azithromycin (2 g on day one followed by 1 g daily for
two more days) for suspected leptospirosis. There was no difference in the resolution of fever and
azithromycin is better tolerated than doxycycline.[47][48][49]

Outpatients are given doxycycline or azithromycin. Doxycycline can shorten the duration of leptospirosis
by two days, improve symptoms, and prevent the shedding of organisms in their urine. Azithromycin and
amoxicillin are given to pregnant women and children.[21] Rarely, a Jarisch–Herxheimer reaction can
develop in the first few hours after antibiotic administration.[8] However, according to a meta-analysis done
in 2012, the benefit of antibiotics in the treatment of leptospirosis was unclear although the use of antibiotics
may reduce the duration of illness by two to four days.[8][48] Another meta-analysis done in 2013 reached a
similar conclusion.[8][49]

For those with severe leptospirosis, including potassium wasting with high kidney output dysfunction,
intravenous hydration and potassium supplements can prevent dehydration and hypokalemia. When acute
kidney failure occurs, early initiation of haemodialysis or peritoneal dialysis can help to improve survival.
For those with respiratory failure, tracheal intubation with low tidal volume improves survival rates.[21]

Corticosteroids have been proposed to suppress inflammation in leptospirosis because Leptospira infection
can induce the release of chemical signals which promote inflammation of blood vessels in the lungs.
However, there is insufficient evidence to determine whether the use of corticosteroids is beneficial.[8][50]

Prognosis
The overall risk of death for leptospirosis is 5–10%.[10] For those with jaundice, the case fatality can
increase up to 15%.[28] For those infected who present with confusion and neurological signs, there is a
high risk of death.[21] Other factors that increase the risk of death include reduced urine output, age more
than 36 years, and respiratory failure.[21] With proper care, most of those infected will recover completely.
Those with acute kidney failure may develop persistent mild kidney impairment after they recover.[21] In
those with severe lung involvement, the risk of death is 50–70%.[8] Thirty percent of people with acute
leptospirosis complained of long-lasting symptoms characterised by weakness, muscle pain, and
headaches.[21]

Eye complications
Eye problems can occur in 10% of those who recovered from leptospirosis[28] in the range from two weeks
to a few years post-infection. Most commonly, eye complications can occur at six months after the infection.
This is due to the immune privilege of the eye which protects it from immunological damage during the
initial phase of leptospiral infection.[51] These complications can range from mild anterior uveitis to severe
panuveitis (which involves all three vascular layers of the eye).[28] The uveitis is more commonly happen in
young to middle-aged males and those working in agricultural farming.[51] In up to 80% of those infected,
Leptospira DNA can be found in the aqueous humour of the eye.[21] Eye problems usually have a good
prognosis following treatment or they are self-limiting.[28] In anterior uveitis, only topical steroids and
mydriatics (an agent that causes dilation of the pupil) are needed while in panuveitis, it requires periocular
corticosteroids.[51] Leptospiral uveitis is characterised by hypopyon, rapidly maturing cataract, free floating
vitreous membranes, disc hyperemia and retinal vasculitis.[51][52][53]

Epidemiology
It is estimated that one million severe cases of
leptospirosis occur annually, with 58,900 deaths.
Severe cases account for 5–15% of all leptospirosis
cases.[11] Leptospirosis is found in both urban and
rural areas in tropical, subtropical, and temperate
regions.[10] The global health burden for leptospirosis
can be measured by disability-adjusted life year Global burden of leptospirosis calculated as
(DALY). The score is 42 per 100,000 people per year, disability-adjusted life year (DALY) lost per 100,000
which is more than other diseases such as rabies and people per year[20]

filariasis.[7]

The disease is observed persistently in parts of Asia, Oceania, the Caribbean, Latin America and Africa.[28]
Antarctica is the only place not affected by leptospirosis.[28] In the United States, there were 100 to 150
leptospirosis cases annually.[54] In 1994, leptospirosis ceased to be a notifiable disease in the United States
except in 36 states/territories where it is prevalent such as Hawaii, Texas, California, and Puerto Rico.[55]
About 50% of the reported cases occurred in Puerto Rico. In January 2013, leptospirosis was reinstated as a
nationally notifiable disease in the United States.[54] Research on epidemiology of leptospirosis in high-risk
groups and risk factors is limited in India.[56]

The global rates of leptospirosis have been underestimated because most affected countries lack notification
or notification is not mandatory.[21] Distinguishing clinical signs of leptospirosis from other diseases and
lack of laboratory diagnostic services are other problems.[57] The socioeconomic status of many of the
world's population is closely tied to malnutrition; subsequent lack of micronutrients may lead to increased
risk of infection and death due to leptospirosis infection.[58] Micronutrients such as iron, calcium, and
magnesium represent important areas for future research.[58]

History
The disease was first described by Adolf Weil in 1886 when he reported an "acute infectious disease with
enlargement of spleen, jaundice, and nephritis."[18] Before Weil's description, the disease was known as
"rice field jaundice" in ancient Chinese text, "autumn fever", "seven-day fever",[59] and "nanukayami
fever"[60] in Japan; in Europe and Australia, the disease was associated with certain occupations and given
names such as "cane-cutter's disease", "swine-herd's disease", and "Schlammfieber" (mud fever).[59] It has
been known historically as "black jaundice",[61] or "dairy farm fever" in New Zealand.[62] Leptospirosis
was postulated as the cause of an epidemic among Native Americans along the coast of what is now New
England during 1616–1619. The disease was most likely brought to the New World by Europeans.[63]

Leptospira was first observed in 1907 in a post mortem kidney tissue slice by Arthur Stimson using silver
deposition staining technique. He called the organism Spirocheta interrogans because the bacteria
resembled a question mark.[59][64] In 1908, a Japanese research group led by Ryukichi Inada and Yutaka Ito
first identified this bacterium as the causative agent of leptospirosis[65] and noted its presence in rats in
1916.[66] Japanese coal mine workers frequently contracted leptospirosis. In Japan, the organism was
named Spirocheta icterohaemorrhagiae. The Japanese group also experimented with the first leptospiral
immunisation studies in guinea pigs. They demonstrated that by injecting the infected guinea pigs with sera
from convalescent humans or goats, passive immunity could be provided to the guinea pigs. In 1917, the
Japanese group discovered rats as the carriers of leptospirosis.[59] Unaware of the Japanese group's work,
two German groups independently and almost simultaneously published their first demonstration of
transmitting leptospiral infection in guinea pigs in October 1915. They named the organism Spirochaeta
nodosa and Spirochaeta Icterogenes respectively.[59]

Leptospirosis was subsequently recognised as a disease of all mammalian species. In 1933, Dutch workers
reported the isolation of Leptospira canicola which specifically infects dogs. In 1940, the strain that
specifically infects cattle was first reported in Russia.[59] In 1942, soldiers at Fort Bragg, North Carolina,
were recorded to have an infectious disease which caused a rash over their shinbones. This disease was
later known to be caused by leptospirosis.[21] By the 1950s, the number of serovars that infected various
mammals had expanded significantly. In the 1980s, leptospirosis was recognised as a veterinary disease of
major economic importance.[59]

In 1982, there were about 200 serovars of Leptospira available for classification. The International
Committee on Systematic Bacteriology's subcommittee on taxonomy of Leptospira proposed classifying
these serovars into two big groups: L. interrogans containing pathogenic serovars and L. biflexa containing
saprophytic serovars.[59] In 1979, the leptospiral family of Leptospiraceae was proposed. In the same year,
Leptospira illini was reclassified as the new genus Leptonema.[59] In 2002, "Lepthangamushi syndrome"
was coined to describe a series of overlapping symptoms of leptospirosis with Hantavirus hemorrhagic
fever with renal syndrome, and scrub typhus caused by Orientia tsutsugamushi.[67][68] In 2005, Leptospira
parva was classified as Turneriella.[59] With DNA-DNA hybridisation technology, L. interrogans was
divided into seven species. More Leptospira species have been discovered since then.[59] The WHO
established the Leptospirosis Burden Epidemiology Reference Group (LERG) to review the latest disease
epidemiological data of leptospirosis, formulate a disease transmission model, and identify gaps in
knowledge and research. The first meeting was convened in 2009. In 2011, LERG estimated that the global
yearly rate of leptospirosis is five to 14 cases per 100,000 population.[21]

Other animals
Infected animals can have no, mild, or severe symptoms;[19] the presenting symptoms may vary by the type
of animal.[16][19] In some animals the bacteria live in the reproductive tract, leading to transmission during
mating.[16]
Animals also present with similar clinical features
when compared to humans. Clinical signs can appear
in 5–15 days in dogs. The incubation period can be
prolonged in cats. Leptospirosis can cause abortions
after 2–12 weeks in cattle, and 1–4 weeks of infection
in pigs. The illness tends to be milder in reservoir
hosts. The most commonly affected organs are the
kidneys, liver, and reproductive system, but other
organs can be affected.[28] In dogs, the acute clinical
signs include fever, loss of appetite, shivering, muscle
pain, weakness, and urinary symptoms. Vomiting, Liver of an unknown animal with multiple blackish
diarrhea, and abdominal pain may also present. necrotic patches secondary to leptospirosis
Petechiae and ecchymoses may be seen on mucous infection[20]

membranes. Bleeding from the lungs may also be seen

in dogs. In chronic presentations, the affected dog may
have no symptoms. In animals that have died of
leptospirosis, their kidneys may be swollen with grey
and white spots, mottling, or scarring. Their liver may
be enlarged with areas of cell death. Petechiae and
ecchymoses may be found in various organs.[28][69]
Inflammation of the blood vessels, inflammation of the
heart, meningeal layers covering the brain and spinal
cord, and uveitis are also possible.[16] Equine recurrent
uveitis (ERU) is the most common disease associated
with Leptospira infection in horses in North America Lungs of a canine with multiple bleeding spots due
and may lead to blindness. [70][71] ERU is an to leptospirosis[20]
autoimmune disease involving antibodies against
Leptospira proteins LruA and LruB cross-reacting with
eye proteins.[70] Live Leptospira can be recovered from the aqueous or vitreous fluid of many horses with
Leptospira-associated ERU.[71] Risk of death or disability in infected animals varies depending upon the
species and age of the animals. In adult pigs and cattle, reproductive signs are the most common signs of
leptospirosis. Up to 40% of cows may have a spontaneous abortion. Younger animals usually develop more
severe disease. About 80% of dogs can survive with treatment, but the survival rate is reduced if the lungs
are involved.[28]

ELISA and microscopic agglutination tests are most commonly used to diagnose leptospirosis in animals.
The bacteria can be detected in blood, urine, and milk or liver, kidney, or other tissue samples by using
immunofluorescence or immunohistochemical or polymerase chain reaction techniques. Silver staining or
immunogold silver staining is used to detect Leptospira in tissue sections. The organisms stain poorly with
Gram stain. Dark-field microscopy can be used to detect Leptospira in body fluids, but it is neither sensitive
nor specific in detecting the organism. A positive culture for leptospirosis is definitive, but the availability is
limited, and culture results can take 13–26 weeks for a result, limiting its utility. Paired acute and
convalescent samples are preferred for serological diagnosis of leptospirosis in animals. A positive
serological sample from an aborted fetus is also diagnostic of leptospirosis.[28]
Various antibiotics such as doxycycline, penicillins, dihydrostreptomycin, and streptomycin have been used
to treat leptospirosis in animals. Fluid therapy, blood transfusion, and respiratory support may be required in
severe disease. For horses with ERU, the primary treatment is with anti-inflammatory drugs.[28][16]

Leptospirosis vaccines are available for animals such as pigs, dogs, cattle, sheep, and goats. Vaccines for
cattle usually contain Leptospira serovar Hardjo and Pomona, for dogs, the vaccines usually contain serovar
Icterohaemorrhagiae and Canicola. Vaccines containing multiple serovars do not work for cattle as well as
vaccines containing a single serovar, yet the multivalent vaccines continue to be sold.[16] Isolation of
infected animals and prophylactic antibiotics are also effective in preventing leptospirosis transmission
between animals. Environmental control and sanitation also reduce transmission rates.[28][16]

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This article was submitted to WikiJournal of Medicine for external academic peer review in 2019
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updated content was reintegrated into the Wikipedia page under a CC-BY-SA-3.0 license (2022 (https://en.
wikipedia.org/w/index.php?title=Leptospirosis&action=history&date-range-to=2022-08-14)). The version
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External links
"Leptospirosis" (https://www.cdc.gov/leptospirosis/index.html). U.S. Disease Control and
Prevention Center. 21 November 2018.
"Leptospira" (https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=1
71). NCBI Taxonomy Browser. 171.

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