Leptospirosis, which is a major zoonotic health problem in developing countries, has been recognized as

an emerging infectious disease in developed countries. Infection with Leptospira spirochetes occurs
during contact with animal reservoirs or an environment contaminated with their urine. The clinical
course of leptospirosis ranges from a mild acute febrile illness to life-threatening manifestations such as
Weil's disease, which consists of the triad of jaundice, acute renal failure, and bleeding. Leptospirosis
has also been recognized as an important cause of severe pulmonary hemorrhage syndrome worldwide.
The Pathogen
The etiologic agent, which can be identified by darkfield microscopy or silver staining procedures, is a
motile spirochete 6 to 20 m in length and 0.1 m in diameter ( Fig. 344-1 ). Leptospires are obligate
aerobes whose relatively large genome (two chromosomes of 4.3 megabase and 350 kilobase) reflects
its ability to adapt to external and host environments. Leptospira are classified into 17 species and
genomospecies, 11 of which (L. interrogans, L. kirschneri, L. noguchii, L. weillii, L. borgspeterseni, L.
santarosai, L. fanei, L. inadai, L. broomii, L. alexandrii, and genomospecies 1) are pathogenic. Serologic
classification provides more useful epidemiologic information because serogroups and serovars, of
which there are more than 25 and 250, respectively, are associated with specific animal reservoirs.
Epidemiology
Leptospirosis has a worldwide distribution because of the broad spectrum of animal reservoirs, including
domestic and wild rodents, dogs, pigs, cattle, and sheep. Leptospires colonize the renal tubules, are
excreted in urine, and survive for weeks to months in the environment. Transmission to humans occurs
when leptospires penetrate the skin or mucous membranes during contact with contaminated water,
soil, or vegetation. Abrasions in the skin facilitate entry of the pathogen. Direct contact with urine and
tissues is an important mode of transmission in risk groups such as abattoir workers and veterinarians.
Ingestion of contaminated food, inhalation of droplet aerosols, or swallowing contaminated water, as
found during a 1998 outbreak among triathletes, occasionally causes infection. Humans are accidental
hosts and do not serve as reservoirs because sufficient concentrations of viable organisms are not
excreted in urine. Rare human-to-human transmission is associated with transplacental infection and
breast-feeding.
Leptospirosis is a major public health problem in developing countries, where it is an endemic disease
among subsistence farmers, sharecroppers, and livestock herders. Furthermore, it is the cause of large
epidemics in urban slums, where inadequate sanitation favors rodent-borne transmission. Although
leptospirosis has traditionally been a sporadic occupation-related disease in developed countries, it has
emerged to become a health problem associated with travel, water sports, and recreation (white water
rafting, swimming). Outbreaks frequently follow natural disasters, heavy seasonal rainfall, and flooding,
as seen during the aftermath of hurricanes in the Caribbean and monsoons in Mumbai. Leptospirosis
may also be an under-recognized problem in U.S. inner cities inasmuch as sporadic cases have been
reported in this setting.
Pathobiology
Leptospires disseminate rapidly to all tissues shortly after infection by means of direct tissue penetration
and hematogenous spread. Symptoms develop 5 to 14 days after exposure, although the incubation
period may vary from 2 to 30 days. Leptospires are cleared from the blood stream by agglutinating
antibodies, whose titers rise at the end of early-phase leptospiremic illness. The late-phase
immunopathogenic process is responsible for the severe manifestations of the disease. Leptospira
lipopolysaccharide and lipopeptides are potent stimulators of pro-inflammatory cytokines such as tumor
necrosis factor-, and these cytokines produce a septic shocklike picture. Damage to the vascular
endothelium, which is a hallmark of severe leptospirosis, causes capillary leakage, hemorrhage, and in a
subset of cases, vasculitis. Unlike gram-negative sepsis, systemic infection does not cause disseminated
intravascular coagulation. The pronounced disturbances in hepatic and renal function are believed to be
due to the toxic effects of products released from killed organisms because pathologic examination of
tissues reveals mild inflammatory cell infiltrates and sparse intact leptospires. Although the immune
response eventually eliminates the pathogen, leptospires may persist for prolonged periods in
immunoprivileged sites, such as the anterior chamber of the eye and the renal tubules, and then may be
shed in urine weeks after resolution of the illness.
Clinical Manifestations
The clinical findings in early-phase leptospirosis (initial 3 to 7 days of illness) are nonspecific. The onset
of high fever (38 to 40 C), myalgias, and headache (retro-orbital and frontal) may be abrupt and
accompanied by symptoms of nausea, vomiting, abdominal pain, diarrhea, cough, and photophobia.
Muscle tenderness is pronounced, especially in the calves and lumbar region; if muscle tenderness
involves the abdominal wall musculature, it can mimic the symptoms of an acute abdomen. Rash, which
occurs in 10 to 20% of patients, has erythematous macular, papular, urticarial, or purpuric components
distributed in a truncal or pretibial (Fort Bragg fever) pattern. Hepatomegaly, splenomegaly, and
lymphadenopathy are less common (<20%) findings. Conjunctival suffusion, which is a pathognomonic
symptom seen in about 30% of patients, develops toward the end of early-phase illness and is
characterized by hyperemia of the conjunctival vessels along the palpebral fissures and chemosis ( Fig.
344-2 ).
A minority (5 to 15%) of patients progress to severe late-phase disease. Jaundice is a poor prognostic
sign because acute renal failure and hemorrhage are frequently associated complications (Weil's
disease). Anicteric leptospirosis tends to be a milder late-phase finding characterized by prolonged fever
and aseptic meningitis. Life-threatening complications are hypotension, hemorrhage, and renal and
respiratory failure.
Leptospirosis causes nonoliguric, hypokalemic renal insufficiency, with impaired proximal sodium
reabsorption, increased distal sodium delivery, and potassium wasting. As volume loss progresses,
oliguric renal insufficiency develops as a result of prerenal azotemia and acute tubular necrosis. Cardiac
rhythm disturbances, precipitated by electrolyte imbalance, uremia, and pericarditis, are observed in 20
to 40% of patients and include atrial fibrillation, first-degree atrioventricular block, and alterations in
ventricular repolarization.
Severe thrombocytopenia and anemia secondary to hemolysis or blood loss are observed in up to 30%
of patients. The prothrombin and partial thromboplastin times remain normal or are only mildly
elevated. Leptospirosis is now recognized as an important cause of severe pulmonary hemorrhage
syndrome. Acute respiratory distress syndrome, which is a prominent feature of this manifestation, can
also occur in the absence of documented bleeding. In addition to pulmonary hemorrhage, massive
spontaneous gastrointestinal bleeding is a major cause of death. Other late-phase findings include
diffuse or focal interstitial pneumonitis and pneumonia, myocarditis, pancreatitis, and rhabdomyolysis.
Aseptic meningitis, which is the most frequent neurologic manifestation, is characterized by
cerebrospinal fluid pleocytosis with early neutrophilic and late mononuclear cell predominance.
Leptospirosis has also been reported to cause encephalitis, cerebral hemorrhage and arteritis
(Moyamoya disease), transverse myelitis, and cranial (Bell's palsy) and peripheral neuropathies.
Diagnosis
Few clinical or laboratory findings differentiate early-phase leptospirosis from other causes of an acute
febrile illness associated with myalgias and headache. Conjunctival suffusion is a highly specific, but
insensitive clinical finding. The white blood cell count may be mildly elevated or normal in early-phase
illness.
Severe leptospirosis is often recognized by the classic manifestations of Weil's disease, but severe
complications may occur in anicteric disease. Furthermore, aseptic meningitis and uveitis may develop
in patients with icteric leptospirosis, manifestations classically associated with anicteric disease.
Laboratory confirmation of leptospirosis is based on the presence of a four-fold rise in antibody titer in
the microagglutination test (MAT) or isolation of pathogenic leptospires from a normally sterile site.
However, these standard diagnostic methods provide only retrospective confirmation of the disease.
MAT requires acute- and convalescent-phase sera and is performed routinely in few reference
laboratories worldwide. A positive MAT titer (1:100 or greater) from a single acute-phase sample
provides suggestive evidence of leptospirosis but must be interpreted with caution in areas of high
endemic transmission. Isolation of Leptospira requires specific media (Ellinghausen-McCullough-
Johnson-Harris or Fletcher medium) and may take more than 4 weeks to identify a positive culture.
Commercial antiwhole Leptospira immunoglobulin M (IgM) detection kits in enzyme-linked
immunosorbent assays or rapid formats are used to provide presumptive confirmation of leptospirosis.
However, sensitivity is low (39 to 72%) during acute-phase illness. Polymerase chain reactionbased
diagnostic methods have been developed, but their use has been limited to reference laboratory
settings.
Differential Diagnosis
Leptospirosis is frequently confused with dengue ( Chapter 404 ) or malaria ( Chapter 366 ) in regions
where these diseases are endemic. Severe leptospirosis must be differentiated from other causes of
acute jaundice and acute renal failure, such as viral hepatitis; typhoid fever; rickettsial disease;
hantavirus-associated hemorrhagic fever renal syndrome and pulmonary syndrome; gram-negative
sepsis; endocarditis; and autoimmune disorders. Icteric leptospirosis is associated with elevated serum
conjugated bilirubin concentrations and can be differentiated from viral hepatitis by the findings of
elevated serum creatine phosphokinase and mild elevations (<400 U/L) in aminotransaminases. The
finding of moderate to severe hypokalemia is useful in distinguishing leptospirosis from other infectious
causes of acute renal failure.
Treatment
Antimicrobial therapy is efficacious for early and severe late-phase leptospirosis. Mild leptospirosis is
treated with oral doxycycline (100 mg twice a day) or ampicillin or amoxicillin (500 mg every 8 hours).
Severe leptospirosis is treated with intravenous penicillin (1.5 million U every 6 hours). Intravenous
ceftriaxone (1 g once a day) and cefotaxime (1 g every 6 hours) have equivalent efficacy as penicillin
for severe leptospirosis.
[1] [2]

Other antimicrobial agents may have potential therapeutic use, although at present their efficacy is
unproven. Leptospira organisms are susceptible in vitro to chloramphenicol and to quinolone and
macrolide agents. Azithromycin and clarithromycin are efficacious in experimental animals. The
duration of antimicrobial therapy is usually 7 days. Although patients require monitoring for Jarisch-
Herxheimer reactions during initiation of antimicrobial therapy, this complication is less frequently
observed than with other spirochetal infections.
Reducing mortality from severe leptospirosis requires prompt triage of high-risk patients and
aggressive supportive care for hypotension, renal and respiratory distress, and hemorrhage. Patients
with nonoliguric hypokalemic renal insufficiency have a better overall prognosis and can be treated by
volume and potassium repletion. Timely initiation of dialysis is critical to prevent mortality from
oliguric renal insufficiency. Continuous hemofiltration is more effective than peritoneal dialysis in
treating infection-associated acute renal failure.
Prevention
Prevention of leptospirosis is based on controlling animal reservoirs, interrupting transmission routes,
and preventing disease in humans. Control measures that target defined animal populations, such as
dogs, pigs, and cattle, are highly effective. Immunization of domestic animals and livestock may reduce
carriage and transmission to humans. Chemical pesticides and environmental control of the habitats of
domestic rodent reservoirs are important, but difficult to implement, especially in urban slum settings.
Control of sylvatic reservoirs is often not feasible. When possible, environmental sources of transmission
can be decontaminated with hypochlorite solution and isolated. Protective clothing such as gloves and
boots reduces the risk for occupational exposure. Although infection after exposure to human urine has
not been documented, precautions need to be taken when handling patients' secretions.
Doxycycline chemoprophylaxis (200 mg orally per week) is efficacious in preventing clinical disease but
not in reducing infection rates in endemic areas.
[3]
Doxycycline (100 mg orally twice a day for 3 to 7
days) or amoxicillin can be used for postexposure prophylaxis, although the efficacy of these regimens
has been not been evaluated. Bacterin-based vaccines have been used for high-risk groups in several
countries and in mass immunization campaigns in Cuba and China; at present, however, the
effectiveness and safety of these vaccines is uncertain.
Prognosis
Although leptospirosis is usually a self-limited illness, mortality is high in patients with severe disease
manifestations. Case-fatality rates in patients with Weil's disease and severe pulmonary hemorrhage
syndrome are 5 to 40% and higher than 50%, respectively. Prognostic predictors for death are older age
(>40 years), oliguria, respiratory insufficiency, pulmonary hemorrhage, cardiac arrhythmias, and altered
mental status. Follow-up of patients has found that hepatic and renal function typically returns to
baseline levels within 1 month and 6 months, respectively, after acute illness. However, unilateral or
bilateral uveitis characterized by iritis, iridocyclitis, and chorioretinitis may develop up to 18 months
after systemic illness and persist for years.