Pathophysiology

Infection is initiated through direct or indirect contact with urine of infected animals.
Other sources of exposure include contact with blood or fluids, or tissues of
parturition of infected animals. Leptospira are maintained in nature by means of
chronic renal infection in host animals. Rodents and small mammals are the most
common hosts but infection can also be acquired after contact with cattle, pigs, and
other domestic and wild animals. Once these animals get infected, they will excrete
or shed leptospires in their urine for the remainder of their life. Leptospires
penetrate through broken skin, mucous membranes, inhalation of respiratory
droplets, and waterlogged contact with intact skin and conjunctivae. The incubation
period is generally 7 to 14 days but ranges between 2 and 30 days. Dissemination
of leptospires is probably a result of motility of the organism. Virulence factors have
not been well described; however, it has been postulated that pathogenic
leptospires release haemolysins, sphingomyelinases, and phospholipases. Additional
potential virulence factors include toxin production, immune mechanisms, and
surface proteins. A well-described major surface lipoprotein is LipL32, which is
present in pathogenic strains. [33] LipL32 is a target of the immune response and is
involved in the development of tubulointerstitial nephritis in patients with renal
insufficiency. [1] [2] TLR2 (toll-like receptor 2) has an important role in leptospiral
protein and lipopolysaccharide recognition. [34] Disease presents in 2 phases: the
acute/initial (or septicaemic) phase characterised by high fevers, malaise,
headache, myalgia, and abdominal pain followed 5 to 7 days later by the second,
immune phase associated with antibody production and excretion of the organism
in urine. During the immune phase, patients suffer from severe systemic
manifestations, such as renal failure, hepatic failure, and pulmonary haemorrhages,
which can be fatal.
Leptospirosis is an infectious disease of humans and animals that is caused by pathogenic spirochetes of
the genus Leptospira. It is considered the most common zoonosis in the world.

Signs and symptoms

Leptospirosis occurs as two recognizable clinical syndromes: anicteric and icteric. Anicteric leptospirosis
is a self-limited, mild flulike illness characterized by sudden onset of some combination of the following:

Headache
Fever (38-40C)
Rigors
Muscle pain (typically localized to the calf and lumbar areas)
Nausea and vomiting
Anorexia
Diarrhea
Cough
Pharyngitis
Conjunctivitis
Nonpruritic rash
Icteric leptospirosis, also known as Weil disease, is a severe illness whose classic manifestations include
the following:

Fever
Jaundice
Renal failure
Hemorrhage
Other organ systems (ie, pulmonary, cardiac system, central nervous system) are also frequently
involved.
See Clinical Presentation for more detail.

Diagnosis
Laboratory studies used to confirm the diagnosis include the following:

Culture of leptospires from body fluids or tissue (criterion standard)

Microscopic agglutination testing (MAT; the criterion standard for serologic identification of
leptospires, available only at reference laboratories)
Studies to determine the extent of organ involvement and severity of complications may include the
following, depending on the clinical presentation:

CBC
Renal function studies
Coagulation studies
Liver function studies
CSF analysis
Chest radiography
Biliary tract ultrasonography
ECG
See Workup for more detail.

Management
Use of antibiotics in mild leptospirosis is controversial. If used, antibiotic treatment may include the
following:

Doxycycline
Ampicillin
Amoxicillin
Antibiotics for severe leptospirosis include the following:

IV penicillin G (long the drug of choice)

Third-generation cephalosporins (cefotaxime and ceftriaxone)
Ampicillin or amoxicillin (second-line agents)
Erythromycin (in penicillin-allergic pregnant women)
Patients with severe cases also require supportive therapy and careful management of renal, hepatic,
hematologic, and central nervous system complications. If renal failure ensues, corticosteroids may be
considered. Additional supportive care may include inotropic agents, diuretics, or ophthalmic drops.
See Treatment and Medication for more detail.

Image library

A scanning electron micrograph depicting Leptospira atop a 0.1-m polycarbonate

filter. (This image is in the public domain and thus free of any copyright restrictions. Courtesy of the Centers for Disease
Control/Rob Weyant)

Leptospirosis is an infectious disease of humans and animals that is caused by pathogenic spirochetes of
the genus Leptospira. It is considered the most common zoonosis in the world. [1] Leptospirosis has been
recognized as a re-emerging infectious disease among animals and humans [2] and has the potential to
become even more prevalent with anticipated global warming. Leptospirosis is distributed worldwide
(sparing the Polar Regions) but is most common in the tropics.
Leptospira species infect a wide range of animals, including mammals, birds, amphibians, and reptiles.
Humans are rarely chronic carriers and are therefore considered accidental hosts. The organism is
typically transmitted via exposure of mucous membranes or abraded skin to the body fluid of an acutely
infected animal or by exposure to soil or fresh water contaminated with the urine of an animal that is a
chronic carrier.

Occupational exposure probably accounts for 30-50% of human cases of leptospirosis. The main
occupational groups at risk include farm workers, veterinarians, pet shop owners, field agricultural
workers, abattoir workers, plumbers, meat handlers and slaughterhouse workers, coal miners, workers in
the fishing industry, military troops, milkers, and sewer workers.
Although leptospirosis continues to be predominantly an occupational disease, in recent decades it has
also increasingly been recognized as a disease of recreation. The disease may be acquired during
adventure travel or vacations that involve water sports or hiking, or even as a consequence of flooding. [3, 4,
5, 6]
The burgeoning exotic-pet trade further increases the likelihood of transmission.
Widespread flooding may lead to epidemic spread of leptospirosis in large populations. [7] Flooding on a
smaller scale may also lead to individuals contracting the disease. [8] Urban dwellers in economically
deprived areas may contract the disease through exposure to rat urine. [9]
In 90% of cases, leptospirosis manifests as an acute febrile illness with a biphasic course and an
excellent prognosis. Nonspecific signs and symptoms of leptospirosis (eg, fever, headache, nausea,
vomiting) are often confused with viral illness.
In 10% of cases, the presentation is more dramatic, and the infection has a mortality rate of 10%. Known
as Weil disease or icteric leptospirosis, the classic definition of this form of leptospirosis includes fever,
jaundice, renal failure, and hemorrhage. Other organ systems (ie, pulmonary system, cardiac system,
central nervous system) are also frequently involved. (See Clinical Presentation.)
Treatment of leptospirosis should be started as soon as possible. Treatment is begun empirically in
patients with a plausible exposure history and compatible symptoms, as culture times for Leptospira are
long and recovery rates are low. The criterion standard for serologic identification of leptospires,
microscopic agglutination testing (MAT), is available only at reference laboratories. Paired acute and
convalescent serum specimens can provide delayed confirmation of the diagnosis.
In uncomplicated infections that do not require hospitalization, oral doxycycline has been shown to
decrease duration of fever and most symptoms. However, use of antimicrobial therapy is controversial for
the mild form of the disease. In hospitalized patients, intravenous penicillin G has been the treatment of
choice. Patients with severe leptospirosis (Weil disease) require supportive therapy and careful
management of renal, hepatic, hematologic, and central nervous system complications. (See Treatment.)

Historical background
In ancient China, a disease that was certainly leptospirosis was recognized as an occupational hazard of
rice harvesters. In Japan, leptospirosis was called akiyami, or autumn fever, a term still used for this
disease.[10]
In the West, Leptospirosis was described by Larrey in 1812 as fivre jaune among Napoleon's troops at
the siege of Cairo. The disease was initially believed to be related to the plague but not as contagious.
Throughout the remainder of the 19th century, leptospirosis was known in Europe as bilious typhoid.
Leptospirosis was recognized as an occupational disease of sewer workers in 1883. In 1886, Adolph Weil
published his historic paper describing the most severe form of leptospirosis that would be later known as
Weil disease. Weil described the clinical manifestations in 4 men who had severe jaundice, fever, and
hemorrhage with renal involvement.[11]
In 1907, Stimson used special staining techniques in the postmortem examination of a kidney from a
person with Weil disease and found a spiral organism with hooked ends, which was named Spirochaeta
interrogans because its shape resembled that of a question mark . Inada et al identified the causal agent
of infectious jaundice in Japan in 1916, naming the organism Spirochaeta icterohaemorrhagiae.[11]
Leptospires are thin, coiled, gram-negative, aerobic organisms 6-20 m in length (see the image below).
They are motile, with hooked ends and paired axial flagella (one on each end), enabling them to burrow

into tissue. Motion is marked by continual spinning on the long axis. They are unique among the
spirochetes in that they can be isolated on artificial media.

A scanning electron micrograph depicting Leptospira atop a 0.1-m polycarbonate

filter. (This image is in the public domain and thus free of any copyright restrictions. Courtesy of the Centers for Disease
Control/Rob Weyant)

Leptospires belong to the order Spirochaetales and the family Leptospiraceae. Traditionally, the
organisms are classified based on antigenic differences in the lipopolysaccharide envelopes that surround
the cell wall. Serologic detection of these differences, therefore, is based on identifying serovars within
each species. Based on this system, the genus Leptospira contains two species: the
pathogenicLeptospira interrogans, with at least 218 serovars; and the nonpathogenic, free-living,
saprophytic Leptospira biflexa, which has at least 60 serovars.
Current studies that classify the organisms based on DNA relatedness identify at least 7 pathogenic
species of leptospires. However, organisms that are identical serologically may be different genetically,
and organisms with the same genetic makeup may differ serologically. Therefore, some authors feel that
the traditional serologic system is the most useful from a diagnostic and epidemiologic standpoint.

Animal reservoirs
Most leptospiral serovars have their primary reservoir in wild mammals, which continually reinfect
domestic populations. The organism affects at least 160 mammalian species and has been recovered
from rats, swine, dogs, cats, raccoons, cattle, mongooses, and bandicoots. [12, 13] The most important
reservoirs are rodents, and rats are the most common source worldwide. In the United States, important
leptospiral sources include dogs, livestock, rodents, wild animals, and cats.
Many serovars are associated with particular animals. For example, L pomona andL interrogans are seen
in cattle and pigs; L grippotyphosa is seen in cattle, sheep, goats, and voles; L ballum and L
icterohaemorrhagiae are associated with rats and mice; and L canicola is associated with dogs. Other
important serotypes includeLautumnalis, Lhebdomidis, and Laustralis. Leptospiral species' and
serogroups' host animals vary from region to region. Individual animals may carry several serovars.
Leptospirosis in animals is often subclinical. Leptospires may persist for long periods in the renal tubules
of animals by establishing a symbiotic relationship with no evidence of disease or pathological changes in
the kidney. As a result, animals that serve as reservoirs of host-adapted serovars can shed high
concentrations of the organism in their urine without showing clinical evidence of disease.
This leptospiruria in animals often occurs for months after the initial infection. Leptospiruria also has been
found to occur in healthy immunized dogs. Leptospiruria in humans is more transient, rarely lasting more
than 60 days. Humans and nonadapted animals are incidental hosts. With rare exceptions, man
represents a dead end in the chain of infection because person-to-person spread of the disease is rare.

Transmission and incubation

Urinary shedding of organisms from infected animals is the most important source of these bacterial
pathogens. Contact with the organism via infected urine or urine-contaminated media results in human
infection. Such media include contaminated water and food, as well as animal bedding, soil, mud, and
aborted tissue. Under favorable conditions, leptospires can survive in fresh water for as many as 16 days
and in soil for as many as 24 days.[14]

Leptospires are believed to enter the host through the following:

Abrasions in healthy skin

Animal and rodent bites
Sodden and waterlogged skin
Mucous membranes or conjunctiva
Lungs (after inhalation of aerosolized body fluid) [15]
The placenta during pregnancy
Virulent organisms in a susceptible host gain rapid access to the bloodstream through the lymphatics,
resulting in leptospiremia and spread to all organs, but particularly the liver and kidney. The incubation
period is usually 5-14 days but has been described from 72 hours to a month or more.

Pathologic effects
Although direct invasion of tissue may cause some pathologic effects, researchers note that the marked
degree of multiorgan tissue injury appears inconsistent with the number of leptospires found on
microscopic examination of tissue. Other mediators induced by the leptospire are the suspected causes
of the disease's various manifestations. Research has suggested endotoxin, hemolysin, and lipase as
possible sources of pathogenicity. However, the true mechanism of host tissue injury remains unclear and
likely involves a complex set of interactions.
The most consistent pathologic finding in leptospirosis is vasculitis of capillaries, manifested by
endothelial edema, necrosis, and lymphocytic infiltration. Capillary vasculitis is found in every affected
organ system. The resulting loss of red blood cells and fluid through enlarged junctions and fenestrae,
which cause secondary tissue injury, probably accounts for many of the clinical findings.
In the kidneys, leptospires migrate to the interstitium, renal tubules, and tubular lumen, causing interstitial
nephritis and tubular necrosis. Capillary vasculitis is readily identified. Although the glomeruli are spared,
the progression from normal renal function to decreased glomerular filtration rate to renal failure requiring
dialysis can be rapid. Renal failure is usually due to tubular damage, but hypovolemia from dehydration
and from altered capillary permeability can also contribute to renal failure.
Liver involvement is marked by centrilobular necrosis and Kupffer cell proliferation. Jaundice may occur
as a result of hepatocellular dysfunction.
Pulmonary involvement is secondary to alveolar and interstitial vascular damage resulting in hemorrhage.
This complication is considered to be the major cause of leptospirosis-associated death.
Cardiac lesions have been identified in postmortem examinations. In an autopsy series of fatal cases of
leptospirosis in Mumbai, India in 2005, involvement of the cardiovascular system was found in 41 of 44
cases. Interstitial myocarditis was the predominant feature on histopathological examination. These
authors suggested that leptospirosis be viewed as an infective systemic vasculitis. [16]
Hemorrhage, focal necrosis, and inflammatory infiltration have been documented within the adrenal
gland. Although these complications do not appear clinically, some researchers speculate that adrenal
insufficiency may mediate, in part, the final vascular collapse associated with fatal leptospirosis.
The skin is affected by epithelial vascular insult. Skeletal muscle involvement is secondary to edema,
myofibril vacuolization, and vessel damage. Muscular microcirculation is impaired and capillary
permeability is increased, with resultant fluid leakage and circulatory hypovolemia.
The damage to the vascular system as a whole can result in capillary leakage, hypovolemia, and shock.
Patients with leptospirosis may develop disseminated intravascular coagulation (DIC), hemolytic uremic
syndrome (HUS), or thrombotic thrombocytopenic purpura (TTP). Thrombocytopenia indicates severe
disease and should raise suspicion for a risk of bleeding. [17, 18]

If the host survives the acute infection, septicemia and multiplication of the organism persist until the
development of opsonizing immunoglobulin in the plasma, followed by rapid immune clearance. Although
the systemic immune response may eliminate the organism from the body, it may also lead to a
symptomatic inflammatory reaction that can produce secondary end-organ injury.
Despite clearance from the blood, leptospires may remain in immunologically privileged sites, including
the renal tubules, brain, and aqueous humor of the eye, for weeks to months. Persistent leptospires in the
eye occasionally lead to chronic or recurrent uveitis. In humans, leptospires in the renal tubules and
resulting leptospiruria rarely persist longer than 60 days.

ETIOLOGY
Leptospirosis is caused by spiral bacteria that belong to the genus Leptospira, the
family Leptospiraceae, and the order Spirochaetales. These spirochetes are finely coiled, thin, motile,
obligate, slow-growing anaerobes.
The nomenclature system used to organize leptospires has been revised, making review of the literature
often confusing. The traditional system divided the genus into 2 species: the pathogenic Leptospira
interrogans and the nonpathogenicLeptospira biflexa. These species were divided further into serogroups,
serovars, and strains based on shared antigens. L interrogans included more than 250 serovars.
The current classification system is based on DNA homology and recognizes the heterogeneity of the
classic leptospires, dividing L interrogans and L biflexa into 20 named species.[19] Within these species,
leptospires are further grouped by serogroups, serovars, and strains on the basis of microscopic
agglutination testing (MAT).
Serologic grouping may, however, cross DNA-based species boundaries, and both pathogenic and
nonpathogenic serovars may be found within the same species. Although certain species (eg, L
interrogans) have a classic association with Weil disease, knowledge of the species type does not
necessarily help predict disease severity.
Particular serovars may be associated with specific clinical manifestations. For example, a characteristic
pretibial erythematous rash is seen in patients with L autumnalis infection, and gastrointestinal symptoms
predominate in patients infected with L grippotyphosa.
Nevertheless, any leptospiral serovar can lead to the signs and symptoms seen with this disease. For
example, jaundice occurs in 83% of patients with L icterohaemorrhagiae infection and in 30% of patients
infected with L pomona. Aseptic meningitis commonly occurs in those infected with L pomona or L
canicola.
Transmission of leptospires to humans typically occurs by invasion across mucosal surfaces or nonintact
skin. Infection may occur via direct contact with infected animals or their tissues or urine or through
contact with contaminated water and soil.

EPIDEMIOLOGY

United States statistics

Leptospirosis, as a clinical entity, is underdiagnosed and underreported. From 1985-1994, the reported
annual incidence ranged from 0.02-0.04 cases per 100,000 persons. In 1994, 38 leptospirosis cases were
reported nationwide, and the Council of State and Territorial Epidemiologists recommended removing
leptospirosis from the list of notifiable diseases.[20]
Because reliable diagnostic testing was not readily available and organized reporting had not resulted in
implementation of methods to control the disease, many states stopped reporting leptospirosis.
Nevertheless, numerous states, including Hawaii, continue to report.

In Hawaii, which reports the highest annual occurrence rate, 405 suspected cases of leptospirosis were
reported between June 1998 and February 1999; 61 of those cases were confirmed. [21] Case numbers
widely varied from island to island within the state. Incidence rates ranged from 2.3-40.2 cases per
100,000 persons, with the highest numbers of cases on Kauai and Hawaii.
These reported cases starkly contrast with the prevalence rates found under active surveillance. [22] Using
active surveillance measures, Hawaiian researchers projected the state's true local incidence at
approximately 128 cases per 100,000 persons. Major risk factors identified in Hawaii include the use of
water catchment systems, wild pig hunting, and the presence of skin wounds.
An estimated 100-200 cases are identified annually in the United States, with about 50% of cases
occurring in Hawaii. Endemic canine leptospirosis is becoming more common in the United States, and
California has seen a re-emergence of disease since 2000. Over the past 20 years, epidemiology has
begun to shift from primarily recreational water exposures to an increasing number of occupational
exposures related to farm and agricultural activities. [23]
Although less dramatic and often unrecognized, people with no obvious risk factor have significantly
higher background infection rates than reports often indicate. Approximately 30% of children in urban
Detroit[24] and 16% of adults in Baltimore[25] demonstrated serologic evidence of past infection. The Detroit
study also showed correlation between degree of rat infestation and seropositivity rates. This finding
suggests rats are major, if not the most important, vectors for human leptospirosis in the mainland United
States.
Leptospirosis has a seasonal incidence. Most cases occur during the rainy season in the tropics and
during the late summer or early fall in Western countries, when the soil is moist and alkaline. The
leptospires from infected animals survive best in fresh water, damp alkaline soil, vegetation, and mud with
temperatures higher than 22C.

International statistics
Leptospirosis is a ubiquitous disease found throughout the world. Specific serovars vary with locality. The
incidence varies from sporadic in temperate zones to endemic in a few tropical countries. Up to 80% of
individuals in tropical areas are estimated to have positive seroconversion rates, indicating either past or
present infection. Although leptospirosis is generally associated with tropical countries and heavy rainfall,
most cases actually occur in temperate climates, probably because of underreporting in some countries.
High-risk areas include the Caribbean islands, Central and South America, Southeast Asia, and the
Pacific islands. Frequently, the disease gains public attention when outbreaks occur in association with
natural disasters, such as flooding in Nicaragua in 1995[7] or among foreign travelers, as with extreme
athletes competing in tropical rainforests.

Sexual and age-related differences in incidence

No evidence suggests that leptospirosis affects persons of various races, ages, or sexes differently.
However, because occupational exposure constitutes a major risk for development of disease, a
disproportionate number of working-aged males seem to be affected.
On the other hand, the rates may be different because some practitioners are more likely to look for and,
hence, diagnose the disease in patients who have obvious risk factors. When population groups other
than adult males are actively surveyed, their rates are higher than those previously reported.
In addition, outbreaks have been reported in which more than 40% of patients were younger than 15
years, a reversal of traditional prevalence rates. Potential explanations in such cases include childhood
predilections to play with suspected vectors (eg, dogs) or indiscriminate contact with water. Active
surveillance measures have detected leptospire antibodies in as many as 30% of children in some urban
American populations.

Seasonal variation in incidence

Leptospirosis has a seasonal incidence. Most cases occur during the rainy season in the tropics and
during the late summer or early fall in Western countries, as leptospires survive best in fresh water, damp
alkaline soil, vegetation, and mud with temperatures higher than 22C.
Seasonal outbreaks associated with changes in local water levels have been described. Flood conditions
increase risk of exposure to the population at large, and drought causes leptospire concentrations to peak
in isolated pools.[26, 27]
Seasonal variation also correlates with participation in activities that increase exposure to leptospires. For
example, outbreaks have been reported in triathlon athletes and white-water rafters. [4, 5, 6]

PROGNOSIS
The mild form of leptospirosis is rarely fatal, and an estimated 90% of cases fall into this category. The
mortality rate in severe leptospirosis averages approximately 10%, but has been described as ranging
from 5-40%. Elderly and immunocompromised people are at the highest risk of mortality overall. Most
deaths occur from renal failure, massive hemorrhage, or acute respiratory distress syndrome (ARDS).
The incidence of pulmonary involvement has increased over the past few years, affecting up to 70%
patients. Pulmonary involvement has emerged as a serious cause of mortality, becoming the main cause
of leptospirosis-associated death in some countries.[28, 29]
Leptospirosis occurring during pregnancy is ominous. In a review of 16 cases, spontaneous abortion was
likely during the first 2 trimesters.[30] When disease occurred in the third trimester, a third of pregnancies
ended in abortion or perinatal death.
In general, survivors of leptospirosis experience little long-term morbidity, regardless of disease severity.
Hepatic and renal functions return to normal, despite severe dysfunction during acute illness, even among
patients who required dialysis.
Approximately a third of patients with documented aseptic meningitis may continue to complain of
periodic headaches of varying severities. Patients who have had leptospiral uveitis may experience
persistent visual acuity loss (caused by lens pigmentation following anterior uveitis) and blurry vision
(associated with keratic precipitates in the anterior chamber).

HISTORY
A good clinical history is often the key to accurate diagnosis in leptospirosis. Important features include a
plausible exposure history and a clinical picture consistent with the disease.
The exposure history may reveal direct contact with body fluids or organs of infected animals, or indirectly
(eg, via contaminated soil or water). Direct exposure often occurs in occupational cases, while indirect
exposure is more typical of cases contracted during travel or recreational activities rivers (eg, white-water
rafting). Onset of clinical illness occurs abruptly, after an incubation period of 2-30 days (typically 5-14 d).
Expert consensus is that leptospirosis occurs as two recognizable clinical syndromes: anicteric and icteric
(the existence of a third syndrome of asymptomatic infection is more controversial). Anicteric leptospirosis
is a self-limited, mild flulike illness. Icteric leptospirosis, also known as Weil disease, is a severe illness
characterized by multiorgan involvement or even failure.
Two distinct phases of illness are observed in the mild form: the septicemic (acute) phase and the
immune (delayed) phase. In icteric leptospirosis, the 2 phases of illness are often continuous and
indistinguishable. At disease onset, clinically predicting the severity of disease is not possible.
An acute illness follows infection with any serovar of leptospirosis. Most of the following signs and
symptoms may develop in varying degrees:

Headache
Fever (38-40C)
Rigors
Muscle pain (typically localized to the calf and lumbar areas)
Nausea and vomiting
Anorexia

Diarrhea
Cough
Pharyngitis
Conjunctivitis
Nonpruritic skin rash
Despite reports of fever as a cardinal symptom, research by the Hawaii Department of Health found that
the presence of fever varied.[22, 31] In serologically confirmed cases, 5% of patients gave no history of fever,
and 55% were afebrile at the time of presentation. Myalgias and headache were universally reported at
the time of presentation and were the chief complaint in 25% of patients.
The natural course of leptospirosis falls into 2 distinct phases. The acute phase of illness lasts 5-7 days
and is followed by a 1-3 day period of improvement in which the temperature curve falls and the patient
may become afebrile and relatively asymptomatic. Subsequently, leptospirosis either regresses to a
relatively asymptomatic illness or progresses to a more severe illness.
Recurrence of fever indicates the onset of the second, immune stage. Nonspecific symptoms, such as
fever and myalgia, may be less severe than in the first stage and last a few days to a few weeks. Many
patients (77%) experience headache that is intense and poorly controlled by analgesics; this often heralds
the onset of meningitis.
Aseptic meningitis is the most important clinical syndrome observed in the immune anicteric stage.
Meningeal symptoms develop in 50% of patients. Cranial nerve palsies, peripheral facial palsy,
[32]
encephalitis, and changes in consciousness are less common. Mild delirium may also be seen.
Meningitis usually lasts a few days but occasionally lasts 1-2 weeks. Death is extremely rare in anicteric
cases.
Abdominal pain with diarrhea or constipation (30%), hepatosplenomegaly, nausea, vomiting, and anorexia
are also seen. Acalculous cholecystitis may be seen rarely but is clinically significant. [33]
Uveitis (2-10%) can develop early or late in the disease and has been reported to occur as late as one
year after initial illness. Iridocyclitis and chorioretinitis are other late complications that may persist for
years. These symptoms first manifest 3 weeks to 1 month after exposure. Subconjunctival hemorrhage is
the most common ocular complication of leptospirosis, occurring in as many as 92% of patients.
Renal manifestations include hematuria. Oliguric or anuric acute tubular necrosis may occur during the
second week due to hypovolemia and decreased renal perfusion.
Weil syndrome, the severe form of leptospirosis, primarily manifests as profound jaundice, renal
dysfunction, hepatic necrosis, pulmonary dysfunction, and hemorrhagic diathesis. Pulmonary
manifestations include cough, dyspnea, chest pain, bloodstained sputum, hemoptysis, and respiratory
failure.

P.A.
The physical examination findings differ depending on the severity of disease and the time from onset of
symptoms. Patients may appear mildly ill or toxic. Early in the disease, temperatures as high as 40C and
tachycardia are common. Hypotension, oliguria, and abnormal chest auscultation findings at presentation
may portend severe illness. When fever is severe and prolonged, hypotension and shock due to volume
depletion may also occur. The fever typically subsides within 7 days.
Early in the disease, the skin is warm and flushed. Additional skin findings include a transient petechial
eruption that can involve the palate. Later in severe disease, jaundice and purpura can develop. The
classic ocular finding of conjunctival suffusion occurs early irrespective of disease severity. Conjunctival
suffusion is characterized by redness of the conjunctiva that resembles conjunctivitis but that does not
involve inflammatory exudates.
Uveitis is a common feature following acute leptospirosis. However, patients who receive antibiotics
during the acute phase of illness may develop only mild uveitis. [34]
Muscle tenderness can occur with the myositis of early infection. This can be particularly prominent in the
paraspinal and calf muscles but can involve any muscle.
Neurologic examination can reveal signs of meningitis, including neck stiffness and rigidity and
photophobia. Early in the disease, the stiffness on neck examination can be confused as muscular in
origin; however, this symptom may actually represent early meningismus.

Lung examination results may be normal in early or mild illness. In severe illness, signs of consolidation
due to alveolar hemorrhage may be found. In patients with cardiac-related pulmonary edema, rales and
wheezes can be heard.
Alveolar hemorrhage that manifests as dyspnea and hemoptysis is the main pulmonary manifestation.
This clinical manifestation may be severe and can occur in the absence of typical presentations of Weil
disease.
Myocarditis may occur in severe disease. All of the physical findings of biventricular heart failure can be
found, including elevated jugular venous pulsations; a new S3gallop; and dysrhythmias, including atrial
fibrillation, heart blocks of varying severity, and ventricular ectopy.
Abdominal examination may reveal liver enlargement and tenderness due to hepatitis. Acalculous
cholecystitis, which may be suggested by a positive Murphy sign, is a finding of profound systemic
illness. Pancreatitis has also been described in severe cases.[35, 36, 37] Heme-positive stool and even gross
blood can be found on rectal examination in patients with DIC and bleeding.
In severe disease, delirium may develop either as a consequence of shock or independent of it. Delirium
may be an early finding in severe disease. Late in disease and into convalescence, prolonged mental
symptoms may persist, including depression, anxiety, irritability, psychosis, and even dementia.
Rash may present as a macular or maculopapular eruption with erythematous, urticarial, petechial, or
desquamative lesions. Adenopathy may be noted.

DXXX
The differential diagnosis of leptospirosis is confoundingly broad. The flulike illness that characterizes mild
cases may resemble a benign viral syndrome, while more severe cases may resemble meningitis or
sepsis.
Recognizing and addressing the differential diagnoses when evaluating a patient suspected of having
leptospirosis is critical. Missing other life-threatening illnesses, such as bacterial meningitis, acute toxininduced hepatitis, pancreatitis, cholangitis, or Goodpasture disease, can be devastating, particularly
because each of those diseases has a specific and entirely different necessary therapy. In addition,
delayed treatment for severe leptospirosis may negatively affect patient outcome.
A possible key to correct diagnosis is a thorough history focusing on the patient's travel history, activities,
and exposure to animals. Case clusters, if present, may suggest a common exposure.
Other problems to be considered may include the following:

Enteric fever
Infantile polyarteritis nodosa
Kawasaki disease
Primary HIV infection
Typhoid fever
Yellow fever
Mononucleosis
Cholecystitis
Pancreatitis and pancreatic pseudocyst
Differentials
Brucellosis
Dengue
Enteroviral Infections
Hantavirus Pulmonary Syndrome
Hepatitis A
Malaria
Meningitis
Q Fever
Rickettsial Infection
Viral Hemorrhagic Fevers

Leptospires grow slowly in culture, and recovery rates are low. Serologic tests are available only in
specialized laboratories, and the sensitivity of acute serologic tests is low. Consequently, those tests
should not be the basis on which treatment is initiated. In a patient with compatible symptoms and a
plausible exposure history, empiric therapy should be started.
Laboratory studies are used for two purposes: to confirm the diagnosis and to determine the extent of
organ involvement and severity of complications. Laboratory confirmation of leptospirosis can be
accomplished through isolation of the pathogen or by serologic testing.
Isolation of the leptospires from human tissue or body fluids is the criterion standard. Consultation with
the local microbiology laboratory is essential, because processing requires specialized techniques. Urine
is the most reliable body fluid to study because the urine contains leptospires from the onset of clinical
symptoms until at least the third week of infection.
Other body fluids contain the organism, but the window of opportunity to isolate them is shorter. Blood
and CSF may produce positive cultures during the first 7-10 days of symptoms.
Tissues (ie, liver, muscle, kidney, skin, eyes) are also sources of identification of the leptospires but are
obviously more complicated to acquire. Isolation of leptospires can be difficult and time consuming,
involving reference laboratories and often taking several months to complete.
More often, paired acute and convalescent serum specimens are used to confirm the diagnosis. Again,
this is a delayed means of confirmation because the acute sera are collected 1-2 weeks after onset of
symptoms, and the convalescent sera are collected 2 weeks afterward.
Antileptospire antibodies in these samples are detected using the microscopic agglutination test (MAT).
The Centers for Disease Control and Prevention (CDC) laboratory in Atlanta, Georgia, performs the MAT
using 23 leptospire antigens. A 4-fold rise in MAT titer between acute and convalescent sera with any of
these antigens confirms the diagnosis of leptospirosis.
Faster laboratory methods may strongly suggest the diagnosis of leptospirosis, but they may be no more
readily available than the CDC laboratory in Atlanta. A single MAT titer of 1:800 on any sera or
identification of spirochetes on dark-field microscopy, when accompanied by the appropriate clinical
scenario, is strongly suggestive.
In suspected leptospirosis, further laboratory studies should be routinely performed to determine the
extent and severity of organ involvement after the acute phase of illness. A complete blood cell count
(CBC) is necessary. Findings on general laboratory studies are as follows:

In patients with mild disease, elevated erythrocyte sedimentation rates and peripheral
leukocytosis (3,000-26,000 x 109/L) with a left shift are noted
Significant anemia due to pulmonary and gastrointestinal hemorrhage can occur
The platelet count may be diminished as a component of disseminated intravascular coagulation
(DIC)
levels of blood urea nitrogen and serum creatinine may be profoundly elevated in the anuric or
oliguric phase
Serum creatine kinase levels (MM fraction) are often elevated in patients with muscular
involvement.
Coagulation times may be prolonged in patients with hepatic dysfunction and/or DIC On liver
function testing, serum bilirubin levels elevate as part of the obstructive disease due to capillaritis in the
liver. levels of hepatocellular transaminases are elevated less often and less significantly (usually < 200
U/L). Jaundice and bilirubinemia disproportional to hepatocellular damage is common in leptospirosis;
alkaline phosphatase levels may be elevated 10-fold.
On urinalysis, proteinuria may be present. Leukocytes, erythrocytes, hyaline casts, and granular casts
may be present in the urinary sediment.
Analysis of the CSF is useful only in excluding other causes of bacterial meningitis. When the CNS
becomes involved in leptospirosis, polymorphonuclear leukocytes initially predominate and are later
replaced by monocytes. CSF protein may be normal or elevated, whereas glucose levels remain normal.
CSF pressure is normal, but a lumbar puncture can relieve the headache. Leptospires are routinely
isolated from the CSF, but this finding does not change management of the disease.
Imaging studies are useful in determining the extent and severity of organ involvement. This may include
chest radiography to evaluate lung disease and biliary tract ultrasonography in suspected acalculous
cholecystitis.
Electrocardiographic (ECG) abnormalities are common during the leptospiremic phase of Weil syndrome.
In severe cases, congestive heart failure and cardiogenic shock may occur.

CULTURE

Isolating the organism by culture allows definitive diagnosis. Leptospires remain viable in anticoagulated
blood for as long as 11 days; hence, specimens can be mailed to a reference laboratory for culture. The
infecting serovar can be isolated only by culture.
Blood cultures may be negative if drawn too early or too late. Leptospires may not be detected in the
blood until 4 days after the onset of symptoms (7-14 d after exposure). Once the immune system is
activated, blood cultures may again become negative. Leptospires may be isolated from the cerebrospinal
fluid (CSF) within the first 10 days.
Leptospires may be isolated from the urine for several weeks after the initial infection. In some patients,
urine cultures may remain positive for months or years after the onset of illness. Positive urine cultures
may take as long as 8 weeks to grow.
Microscopic agglutination testing (MAT) uses a battery of antigens taken from common (frequently locally
endemic) leptospire serovars. MAT is available only at reference laboratories, such as the Centers for
Disease Control and Prevention (CDC).
In a patient with clinical findings consistent with the disease, a single titer exceeding 1:200 or serial titers
exceeding 1:100 suggest leptospirosis; however, neither is diagnostic. A 4-fold rise in titer between acute
and convalescent specimens is considered a positive result. The antibody response does not reach
detectable levels until the second week of illness, and it can be affected by treatment.
False-negative MAT findings may result from testing a single specimen obtained before the immune
phase of disease. Test accuracy is also affected by appropriate selection of antigens for the battery,
necessitating discussion with the laboratory about which serovars are suspected or predominate in the
region where the case originated. False-positive MAT results may occur with cases
of Legionella infection, Lyme disease, and syphilis.
Screening tests for leptospirosis, which are easy to perform and provide results relatively rapidly, include
the macroscopic slide agglutination test, the Patoc-slide agglutination test, the microcapsule agglutination
test, latex agglutination tests, dipstick tests, and the indirect hemagglutination test. Confirmation of
screening test results (positive or negative) is advisable, however, preferably with MAT.[38]
An immunoglobulin M (IgM) enzyme-linked immunoabsorbent assay (ELISA) has been developed. The
ELISA uses a broadly reactive antigen and is a standard serologic procedure, as is the MAT.[39] Because it
detects IgM, it may be useful for diagnosis of new infections within 3-5 days. Positive results should be
referred for confirmatory testing.
Nucleic acid amplification (polymerase chain reaction [PCR])based techniques have been developed to
diagnose leptospirosis. PCR can confirm the diagnosis rapidly during the early phase of the disease,
when leptospires may be present and before antibody titers are detectable, but it requires adequate
infrastructure such as appropriate equipment, laboratory space, and skilled personnel. In addition, PCRbased techniques are unable to identify the infecting serovar, which reduce their epidemiologic and public
health value.
Dark-field examination of blood or urine has been used to identify leptospires. However, this technique
cannot be recommended, as it frequently leads to misdiagnosis.
Screening tests for leptospirosis, which are easy to perform and provide results relatively rapidly, include
the macroscopic slide agglutination test, the Patoc-slide agglutination test, the microcapsule agglutination
test, latex agglutination tests, dipstick tests, and the indirect hemagglutination test. Confirmation of
screening test results (positive or negative) is advisable, however, preferably with MAT.[38]
An immunoglobulin M (IgM) enzyme-linked immunoabsorbent assay (ELISA) has been developed. The
ELISA uses a broadly reactive antigen and is a standard serologic procedure, as is the MAT.[39] Because it
detects IgM, it may be useful for diagnosis of new infections within 3-5 days. Positive results should be
referred for confirmatory testing.

Nucleic acid amplification (polymerase chain reaction [PCR])based techniques have been developed to
diagnose leptospirosis. PCR can confirm the diagnosis rapidly during the early phase of the disease,
when leptospires may be present and before antibody titers are detectable, but it requires adequate
infrastructure such as appropriate equipment, laboratory space, and skilled personnel. In addition, PCRbased techniques are unable to identify the infecting serovar, which reduce their epidemiologic and public
health value.
Dark-field examination of blood or urine has been used to identify leptospires. However, this technique
cannot be recommended, as it frequently leads to misdiagnosis.
Shortly after inoculation and during the incubation period, leptospires actively replicate in the liver. The
leptospires then disseminate throughout the body and infect multiple tissues.
Silver staining and immunofluorescence can identify leptospires in the liver, spleen, kidney, CNS,
muscles, and heart. During the acute phase of leptospirosis, histology reveals these organisms without
much inflammatory infiltrate. In addition to the finding of leptospires during histologic examination, the
pathologic effects of leptospiral toxins are also apparent. See the image below.

Silver stain, liver, fatal human leptospirosis. (This image is in the public domain and
thus free of any copyright restrictions. Courtesy of the Centers for Disease Control/Dr. Martin Hicklin)

Leptospirosis may be seen as an infective systemic vasculitis. [16] Leptospiral toxins break down endothelial
cell membranes of capillaries. This toxin-mediated process allows for extravasation of blood and
leptospires from blood vessels into the supported parenchyma. Secondarily, because the capillaries are
no longer functional, ischemia and cell death can occur. Later in infection, mononuclear cells predominate
in the areas of this focal cell necrosis.
Leptospires can be identified in immunologically privileged sites, such as renal tubules, CNS, and the
anterior chamber of the eyes, for weeks to months after the initial infection. In nonhuman animals, the
intended hosts of infection, the leptospires establish residence in these immunologically privileged sites.
Provided that the animal survives the initial infection, a chronic carrier state is then established, and
histology reveals leptospires at these sites for years after initial infection.
Previous
Antimicrobial therapy is indicated for the severe form of leptospirosis, but its use is controversial for the
mild form of leptospirosis. A Cochrane Review found insufficient evidence to advocate for or against the
use of antibiotics in the therapy for leptospirosis.[40]
If antibiotics are used, they should be initiated as soon as the diagnosis of leptospirosis is considered and
should be continued for a full course despite initial serologic results, because most patients are diagnosed
only through acute and convalescent testing. Early treatment has been shown to offer the best clinical
outcomes; results from controlled studies of treatment during the immune phase have yielded mixed
results.[41, 42]
Mild leptospirosis is treated with doxycycline, ampicillin, or amoxicillin. For severe leptospirosis,
intravenous penicillin G has long been the drug of choice, although the third-generation cephalosporins
cefotaxime and ceftriaxone have become widely used. Alternative regimens are ampicillin, amoxicillin, or
erythromycin. Several other antibiotics may be usefulfor example, broth microdilution testing has shown
sensitivity to macrolides, fluoroquinolones, and carbapenems[43] but clinical experience with these
agents is more limited.
Severe cases of leptospirosis can affect any organ system and can lead to multiorgan failure. Supportive
therapy and careful management of renal, hepatic, hematologic, and central nervous system
complications are important.

Patients should be managed in a monitored setting because their condition can rapidly progress to
cardiovascular collapse and shock. Access to mechanical ventilation and airway protection should be
available in the event of respiratory compromise. Continuous cardiac monitoring should be attained;
arrhythmias, including ventricular tachycardia and premature ventricular contractions, as well as atrial
fibrillation, flutter, and tachycardia, can occur.
Renal function should be evaluated carefully and dialysis considered in cases of renal failure. In most
cases, the renal damage is reversible if the patient survives the acute illness. A few cases in the literature
have reported that plasma exchange, corticosteroids, and intravenous immunoglobulin may be beneficial
in selected patients in whom conventional therapy does not elicit a response. [44, 45, 46]
Corticosteroid therapy with high-dose pulsed methylprednisolone (30 mg/kg/d, not to exceed 1500 mg
has been used successfully to treat patients with leptospiral renal failure without dialysis. This approach
may have an important role in areas of the world with limited resources where dialysis treatment is
unavailable and would involve lengthy medical transport. The use of renal-dose dopamine in conjunction
with steroids or diuretics has also been described.[21]
Pulse-dose steroids may also play a role in the management of severe pulmonary disease. [47, 45] Patients
with Weil syndrome may need transfusions of whole blood, platelets, or both. Ophthalmic drops of
mydriatics and corticosteroids have been used for relief of ocular symptoms. [48]
Patients with severe disease should remain hospitalized until adequate resolution of organ failure and
clinical infection. Outpatient follow-up may include an assessment of renal function to ensure ongoing
reversal of any damage. A cardiac assessment may be indicated in patients with symptoms suggestive of
heart involvement.

DIET AND ACTIVITY

In mild cases, patients should be encouraged to maintain adequate fluid intake to avoid volume depletion.
In more severe cases, diets appropriate for the clinical picture should be ordered (eg, electrolyte and
protein restriction in cases of renal insufficiency). Patients with hypotension or clinical shock should not be
fed enterally until adequate perfusion is restored.
Patients with severe disease should be placed on bed rest until adequately resuscitated and treated.
Those with mild disease can pursue activity as tolerated.

PREVENTION
Prevention of leptospirosis is difficult because the organism has not been eradicated from wild animals,
which constantly infect domestic animals. Important control measures include control of livestock infection
with good sanitation, immunization, and proper veterinary care.
Preventing infected animals from urinating in waters where humans have contact, disinfecting
contaminated work areas, providing worker education, practicing good personal hygiene, and using
personal protective equipment (PPE) when handling infected animals or tissues are important actions for
prevention of the disease. Examples of PPE include gloves and face shields for veterinarians and rubber
boots for sewer workers and agricultural workers who wade in rodent urine-contaminated water.
Public health measures include investigation of cases in an effort to detect common source outbreaks and
implementation of appropriate control measures to prevent further cases. Other public health measures
include identification of contaminated water supplies, rodent control, prohibition of swimming in streams
where risk of infection may be high, and informing people of risk when they are involved in recreational
activities.
Vaccines are offered to high-risk workers in some European and Asian countries (eg, rice workers in
Italy). Human vaccines are serovar specific and must be repeated yearly. They are associated with painful
swelling, especially after revaccination. Vaccines are not used in the United States.

However, renal infection and persistent leptospiruria can occur in immunized dogs. Human infection has
occurred from asymptomatic immunized dogs that still shed leptospires in their urine. Also, these animal
vaccines are serovar specific and thus are useful only where one or a few serovars are present. Hence,
the vaccine given should contain the serovars known to be prevalent in the area.
Doxycycline, in the dose of 200 mg every week, has demonstrated efficacy of 95% against leptospirosis
and may help prevent the disease in exposed adults. [49, 50]This regimen is recommended for those with
short-term exposure and is not for repeated or long-term exposure. The role of prophylaxis in children has
not been adequately studied.

MEDICATION
Treatment for leptospirosis consists of empiric antibiotic therapy. In general, antibiotic therapy should be
effective against leptospirosis and against the other pathogens considered in the differential diagnoses. If
renal failure ensues, corticosteroids may be considered. Additional supportive care may include inotropic
agents, diuretics, or ophthalmic drops. Currently, no human vaccine against leptospirosis is available.
ANTIBIOTICS

Class Summary
For severe leptospirosis, intravenous penicillin G has long been considered the drug of choice.
Doxycycline is used for the treatment of mild leptospirosis. Ampicillin or amoxicillin are alternatives for the
treatment of mild leptospirosis. Erythromycin is the therapy of choice in pregnant patients who are allergic
to penicillin. Third-generation cephalosporins have become widely used for intravenous antibiotic
treatment in patients with severe leptospirosis.
View full drug information

Penicillin G aqueous (Pfizerpen-G)

Intravenous penicillin is first-line antibiotic therapy for severe leptospirosis. Penicillin interferes with
synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against
susceptible microorganisms.
View full drug information

Doxycycline (Vibramycin, Doryx, Adoxa)

Doxycycline inhibits protein synthesis, and thus bacterial growth, by binding to 30S and possibly 50S
ribosomal subunits of susceptible bacteria. Excretion is hepatobiliary and renal.
View full drug information

Ampicillin
Ampicillin is a second-line agent or for patients younger than 8 years of age, in whom doxycycline is
contraindicated. This agent interferes with synthesis of cell-wall mucopeptides during active multiplication,
resulting in bactericidal activity. Excretion is primarily renal, although some ampicillin is metabolized by
the liver.
View full drug information

Amoxicillin (Moxatag)
Amoxicillin is a second-line agent or for patients younger than 8 years of age, in whom doxycycline is
contraindicated. This agent interferes with synthesis of cell wall mucopeptides during active multiplication,
resulting in bactericidal activity against susceptible bacteria.
View full drug information

Erythromycin ethylsuccinate (E.E.S., EryPed, Erythrocin, PCE, Ery-Tab)

Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes,
causing RNA-dependent protein synthesis to arrest. In pregnant patients who are allergic to penicillin,
erythromycin is the therapy of choice.

Cefotaxime (Claforan)
A third-generation cephalosporin with broad gram-negative spectrum, cefotaxime has lower efficacy
against gram-positive organisms and higher efficacy against resistant organisms. This agent arrests
bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, which in turn
inhibits bacterial growth.

View full drug information

Ceftriaxone (Rocephin)
Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower
efficacy against gram-positive organisms and higher efficacy against resistant organisms.
Ceftriaxone exerts its bactericidal effect by interfering with the synthesis of peptidoglycan, a major
structural component of bacterial cell walls. Bacteria eventually lyse owing to the ongoing activity of cell
wall autolytic enzymes while cell wall assembly is arrested.
Ceftriaxone is highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase,
produced by gram-negative and gram-positive bacteria. Approximately 33-67% of the dose is excreted
unchanged in urine; the remainder is secreted in bile and ultimately in feces as microbiologically inactive
compounds.
This agent reversibly binds to human plasma proteins. Binding has been reported to decrease with
increasing plasma concentrations of the drug, from 95% bound at plasma concentrations < 25 mcg/mL to
85% bound at 300 mcg/mL.

CORTICOSTEROID

Class Summary
In patients with leptospirosis, corticosteroids are indicated to improve renal failure outcome.
View full drug information

Methylprednisolone (A-Methapred, Medrol, Depo-Medrol, Solu-Medrol)

Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear
leukocytes and reversing increased capillary permeability. High-dose pulsed methylprednisolone (30
mg/kg/d, not to exceed 1500 mg) has been used successfully to treat patients with leptospiral renal failure
without dialysis.