Leptospirosis, an infectious disease that affects humans and animals, is considered the most common zoonosis in the world.

[1] Leptospirosis is often referred to as swineherd's disease, swamp fever, or mud fever. The organism enters the body when mucous membranes or abraded skin come in contact with contaminated environmental sources. The infection causes a systemic illness that often leads to renal and hepatic dysfunction. The disease was first recognized as an occupational disease of sewer workers in 1883. In 1886, Weil described the clinical manifestations in 4 men who had severe jaundice, fever, and hemorrhage with renal involvement. Inada et al identified the causal agent in Japan in 1916.[2] Occupational exposure probably accounts for 30-50% of human cases. 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. Studies in sewer workers show greater prevalence of leptospira antibodies than in controls. Infected rats may contaminate sewer water. Partial or total immersion in mud and water plays a role in facilitating infection in sewer workers and rice field workers. Milkers may be splattered in the face, causing subsequent infection via the conjunctivae. Infection of military troops occurs as a result of direct exposure to infected urine or indirect contact with contaminated soil and water. Seroprevalence surveys of livestock workers have shown ranges of positive antibody titers at 8-29%. Although leptospirosis continues to be predominantly an occupational disease since 1970, it has also increasingly been recognized as a disease of recreation. Recreational activities that present some risk include traveling to tropical areas, canoeing, hiking, kayaking, fishing, windsurfing, swimming, waterskiing, wading, riding trail-bikes through puddles, white-water rafting, and other outdoor sports played in contaminated water. Camping by and traveling to endemic areas also add some risk. An outbreak of an acute febrile illness occurred among athletes competing in the Eco-ChallengeSabah 2000 in Malaysia; 44% of those who reported feeling ill met the case definition of leptospirosis.[3] Significant risk factors included kayaking and swimming in and swallowing water from the Segama River. In 1998, athletes who participated in a triathlon in Springfield, Illinois, and who swam in Lake Springfield developed leptospirosis.[4] Other athletes who participated in the same event, although asymptomatic, were found to have laboratory evidence of the disease. Prolonged water exposure, in the form of a 1.5-mile swim in Lake Springfield, was the epidemiologic association among the sick athletes. In 1997, US travelers who visited Costa Rica and engaged in white-water rafting contracted the disease.[5] Leptospirosis may be spread epidemically in large populations in conditions of widespread flooding, as occurred in Nicaragua in 1995.[6] In Brazil, the highest incidence of leptospirosis occurs during the summer months when heavy rains and floods occur in urban areas. Flooding in the Philippines in 2009 led to more than 2000 cases of leptospirosis infection, resulting in more than 100 deaths. Flooding on a smaller scale may also lead to individuals contracting the disease. For example, in 2004, a stream overflowed and caused flooding on the University of Hawaii campus.[7] Leptospirosis cases were found among those involved in the clean-up process. Urban dwellers are also at increased risk because these residents may be sporadically exposed to rat urine as inner cities deteriorate. The incidence is increasing in urban children. However, human disease remains mainly related to occupation. The prevalence is higher in males because they tend to be engaged in outdoor work more frequently than females. Leptospirosis is caused by pathogenic spiral bacteria that belong to the genusLeptospira, the family Leptospiraceae, and the order Spirochaetales. These spirochetes are finely coiled, thin, motile, obligate, slow-growing anaerobes.

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.)

Their flagella allow them to burrow into tissue. The genus Leptospira was originally thought to comprise only 2 species: L interrogans, which is pathogenic, and L biflexa, which is saprophytic. More recent work has identified 7 distinct species of pathogenic leptospires, which appear as more than 250 serologic variants (serovars). 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, and other animals. 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 and L 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 include autumnalis, hebdomidis, and australis. 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 animal bedding, soil, mud, and aborted tissue. The organism enters the body via abraded skin or mucous membranes, such as the conjunctiva or alimentary tract. Occasionally, the organism may even enter the body through intact skin. Infection has occurred after animal and rodent bites, after contact with abortion products of infected animals, and after ingestion of contaminated food and water. The latter route of infection is believed to occur via the mucosa of the mouth and the esophagus because leptospires cannot survive in an acidic environment. 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. Most cases occur in the warm season and in rural areas because leptospires can persist in water for many month. The leptospires from infected animals contaminate the warm lake water. They survive best in freshwater, damp alkaline soil, vegetation, and mud with temperatures higher than 22C. Mucous surfaces of the mouth, pharynx, and esophagus may be crossed easily by pathogenic leptospires, as are mucous membranes of the bronchial tree and lung alveoli. A waterborne outbreak occurred in Italy in the summer of 1984 when a contaminated water fountain was used as a source of drinking water.[8] Transmission via laboratory accidents may occur but is rare.

Pathophysiology

After the organism gains entry via intact skin or mucosa, it multiplies in blood and tissue. The resulting leptospiremia can spread to any part of the body but particularly affects the liver and kidney. After the organism gains access to the kidney, it migrates to the interstitium, renal tubules, and tubular lumen, causing interstitial nephritis and tubular necrosis. When renal failure develops, it is usually due to tubular damage, but hypovolemia from dehydration and from altered capillary permeability can also contribute to renal failure. Liver involvement is seen as centrilobular necrosis with proliferation of Kupffer cells. Jaundice may occur as a result of hepatocellular dysfunction. Leptospires may also invade skeletal muscle, causing edema, vacuolization of myofibrils, and focal necrosis. Muscular microcirculation is impaired and capillary permeability is increased, with resultant fluid leakage and circulatory hypovolemia. In severe disease, a disseminated vasculitic syndrome may result from damage to the capillary endothelium. Leptospires may invade the aqueous humor of the eye, where they may persist for many months, occasionally leading to chronic or recurrent uveitis. Despite the possibility of severe complications, the disease is most often self-limited and nonfatal. Over time, a systemic immune response may eliminate the organism from the body but may also lead to a symptomatic inflammatory reaction that can produce secondary end-organ injury.

Epidemiology
Frequency
United States Leptospirosis is a zoonosis with worldwide distribution. Specific serovars vary with locality. The incidence varies from sporadic in temperate zones to endemic in a few tropical countries. The disease 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 incidence of leptospirosis within the United States steadily increased during the first decades of the 20th century but has remained stable more recently. From 1987-1993, 43-93 cases were reported annually. Leptospirosis is generally underdiagnosed and underreported because many cases are asymptomatic or mildly symptomatic, self-limited, and nonfatal. In 1995, the Council of State and Territorial Epidemiologists and the US Centers for Disease Control and Prevention (CDC) removed leptospirosis from the US list of notifiable diseases. 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. International Leptospirosis is generally associated with tropical countries and heavy rainfall, but most cases actually occur in temperate climates, probably because of underreporting in some countries.

Sex
Most cases occur in middle-aged men, probably because they are employed in at-risk occupations. However, with the change in social roles and the increased exposure during leisure activities, more cases are now reported in women.

History

Leptospirosis infection has protean manifestations. As a result, it is frequently misdiagnosed. Approximately 15-40% of exposed patients who do not become ill have serologic evidence of past infection. This statistic includes 15% of abattoir workers, packinghouse workers, and veterinarians.

The incubation period is usually 7-12 days, with a range of 2-20 days. Approximately 90% of patients manifest a mild anicteric form of the [disease, and approximately 5-10% have the severe form with jaundice, otherwise known as Weil disease. The natural course of leptospirosis falls into 2 distinct phases: septicemic and immune. During a brief period of 1-3 days between the 2 phases, the patient shows some improve ment. o First stage This stage is called the septicemic or leptospiremic stage because the organism may be isolated from blood cultures, cerebrospinal fluid (CSF), and most tissues. During this stage, which lasts about 4-7 days, the patient develops a nonspecific flu like illness of varying severity. It is characterized by fever, chills, weakness, and myalgias, primarily affecting the calves, back, and abdomen. Other symptoms include sore throat, cough, chest pain, hemoptysis, rash, frontal headache, photophobia, mental confusion, and other symptoms of meningitis. Because of the abrupt nature of the onset, the patient can often tell exactly when the symptoms started. During the 1-3 day period of improvement that follows the first stage, the temperature curve falls and the patient may become afebrile and relatively asymptomatic. The fever then recurs, indicating the onset of the second stage when clinical or subclinical meningitis appears. o Second stage This stage is called the immune or leptospiruric stage because circulating antibodies may be detected or the organism may be isolated from urine; it may not be recoverable from blood or CSF. This stage occurs as a consequence of the body's immunologic response to infection and lasts 0-30 days or more. Disease referable to specific organs is seen. These organs include the meninges, liver, eyes, and kidney. An example of leptospirosis affecting the liver is seen in 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.)

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, encephalitis, and changes in consciousness are less common. Mild delirium may also be seen. Symptoms may be nonspecific, and a viral etiology may be suspected. Meningitis usually lasts a few days but occasionally lasts 1-2 weeks. Death is extremely rare in the anicteric cases. Leptospires may be isolated from the blood for 24-48 hours after jaundice appears6. Abdominal pain with diarrhea or constipation (30%), hepatosplenomegaly, nausea, vomiting, and anorexia are also seen. 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. Leptospires may be present in the aqueous humor.

Renal symptoms (eg, azotemia, pyuria, hematuria, proteinuria, and oliguria are seen in 50% of patients with leptospirosis. Leptospires may be present in the kidney. Pulmonary manifestations occur in 20-70% of patients, usually have a benign course, and may occur in both the icteric and anicteric forms of the disease. However, pulmonary involvement is the main cause of death due to leptospirosis in some countries, usually as a result of pulmonary hemorrhage or acute respiratory distress syndrome. Indeed, the severe pulmonary form of leptospirosis (SPFL) is considered to be one of the major causes of death in patients with severe leptospirosis. Adenopathy, rashes, and muscular pain are also seen. Clinical syndromes are not specific to the serotype, although some manifestations may be seen more commonly with some serotypes. Often, the serovar helps determine some of the more characteristic clinical manifestations, but any leptospiral serovar can lead to the signs and symptoms seen with this disease. For example, jaundice is seen in 83% of patients with L icterohaemorrhagiae infection and in 30% of patients infected with L pomona. A characteristic pretibial erythematous rash is seen in patients with L autumnalis infection. Similarly, GI symptoms predominate in patients infected with L grippotyphosa. Aseptic meningitis commonly occurs in those infected with L pomona or L canicola. Weil syndrome is the severe form of leptospirosis and primarily manifests as profound jaundice, renal dysfunction, hepatic necrosis, pulmonary dysfunction, and hemorrhagic diathesis. o It occurs at the end of the first stage and peaks in the second stage; however, the patient's condition can deteriorate suddenly at any time. Often, the transition between the stages is obscured. o Fever may be marked during the second stage. o Criteria to determine the development of Weil disease are not well defined. o Pulmonary manifestations include cough, dyspnea, chest pain, bloodstained sputum, hemoptysis, and respiratory failure. o Vascular and renal dysfunction accompanied by jaundice develop 4-9 days after onset of disease, and jaundice may persist for weeks. o Patients with severe jaundice are more likely to develop renal failure, hemorrhage, and cardiovascular collapse. Hepatomegaly and tenderness in the right upper quadrant may be present. o Oliguric or anuric acute tubular necrosis may occur during the second week due to hypovolemia and decreased renal perfusion. o Multiorgan failure, rhabdomyolysis, adult respiratory distress syndrome, hemolysis, splenomegaly, congestive heart failure,myocarditis, and pericarditis may also occur. o Weil syndrome carries a mortality rate of 5-10%. The most severe cases of Weil syndrome, with hepatorenal involvement and jaundice, have a case-fatality rate of 20-40%. The mortality rate is usually higher for older patients. Leptospirosis may present with a macular or maculopapular rash, abdominal pain that resembles acute appendicitis, or generalized enlargement of lymphoid glands, resembling infectious mononucleosis. It may also present as aseptic meningitis, encephalitis, or fever of unknown origin. Leptospirosis should be considered when a patient has a flulike disease with aseptic meningitis or disproportionately severe myalgia.

Physical

First stage: Common physical findings include fever; subconjunctival suffusion; pharyngeal injection; splenomegaly; hepatomegaly; mild jaundice; muscle tenderness; lymphadenopathy; and a macular, maculopapular, erythematous, urticarial, or hemorrhagic rash. Second stage: Physical findings depend on organ involvement. General - Adenopathy, rash, fever, bleeding, signs of hypovolemia/cardiogenic shock Icteric - Jaundice, hepatomegaly, abdominal tenderness, signs of coagulopathy Pulmonary - Cough, hemoptysis, dyspnea, respiratory distress Neurologic - Cranial nerve palsies, confusion, changes in consciousness, delirium, other signs of meningitis

Ocular - Subconjunctival hemorrhage, uveitis, signs of iridocyclitis or chorioretinitis Hematologic - Bleeding, petechiae, purpura, ecchymosis, splenomegaly, abdominal tenderness Cardiac - Signs of congestive heart failure, pericarditis

Differentials

Dengue Fever Encephalitis Hantavirus Cardiopulmonary Syndrome Hepatitis Malaria Meningitis Mononucleosis

Laboratory Studies
Definitive diagnosis is suggested by isolation of the organism by culture or a positive result on the microscopic agglutination test (MAT). An example of this is shown in the image below.

Darkfield microscopy of leptospiral microscopic agglutination test. (This image is in the public domain and thus free of any copyright restrictions. Courtesy of the Centers for Disease Control/Mrs. M. Gatton.)

Only specialized laboratories perform serologic tests; hence, the decision to treat should not be delayed while waiting for the test results.
o o

o o o o o o o o o

Cultures 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. MAT A 4-fold rise in convalescent titers is considered a positive result. A presumed diagnosis is made by observing an antibody titer of greater than or equal to 1:100 in the MAT in conjunction with symptoms consistent with the disease. The MAT uses a battery of live leptospiral strains. The antibody response does not reach detectable levels until the second week of illness, and it can be affected by treatment. Macroscopic slide agglutination test This test allows a presumptive diagnosis. Clinical illness consistent with leptospirosis must be present to support the diagnosis. This test, which uses killed antigen, is useful for screening but is not specific. Other tests: Other tests include an indirect hemagglutination test, a microcapsule agglutination test, an immunoglobulin M (IgM) enzyme-linked immunoabsorbent assay (ELISA), and a darkfield examination of blood or urine.

More recently, rapid commercial tests have been made available, such as the Dip-S-Ticks (PanBio, Inc; Baltimore, Maryland), which detects leptospira antibodies. o Nucleic acid amplification (polymerase chain reaction [PCR])based techniques have been developed to diagnose leptospirosis. PCR-based techniques are unable to identify the infecting serovar. This factor reduces its epidemiologic and public health value o The dark-field examination frequently leads to misdiagnosis and should not be used. o The ELISA uses a broadly reactive antigen and is a standard serologic procedure, as is the MAT.[9] Because it detects IgM, it may be useful for diagnosis of new infections within 3-5 days. Laboratory studies (general) o 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. o Aminotransferases may be mildly elevated up to 200 U/L; serum bilirubin and alkaline phosphatase levels may also be elevated. o Urinalysis may reveal the following: Proteinuria may be present. Leukocytes, erythrocytes, hyaline casts, and granular casts may be present in the urinary sediment. o CSF studies may reveal the following: When the CNS becomes involved, 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. Laboratory studies (Weil disease) o Patients may exhibit mild thrombocytopenia (as many as 50%), which is often accompanied by renal failure. o Azotemia and renal failure are other prominent characteristics. o Marked leukocytosis may be present. o Prothrombin times may be elevated. o Creatine phosphokinase (CPK) levels are elevated in as many as 50% of patients; acutely, jaundice in Weil disease is associated with very high CPK level, but transaminases are only modestly elevated.

Imaging Studies In severe disease, a patchy alveolar pattern may be revealed on lung radiography findings, corresponding to alveolar hemorrhage. Most radiographic changes occur in the periphery of the lower lobes. Other Tests Electrocardiographic (ECG) abnormalities are common during the leptospiremic phase of Weil syndrome. In severe cases, congestive heart failure and cardiogenic shock may occur. Emergency Department Care Treatment of leptospirosis should be started as soon as possible and may be effective even after the first 4 days of illness.

Antimicrobial therapy is indicated for the severe form of leptospirosis, but its use is controversial for the mild form of leptospirosis. The Cochrane Database of Systematic Reviews concluded that evidence from randomized clinical trials is insufficient to provide clear guidelines for the treatment of leptospirosis.[10] The trials suggest that antibiotics could be useful. The Cochrane Database of Systematic Reviews also concluded that prophylaxis may be achieved by administering

doxycycline to soldiers training in endemic areas with a high risk of exposure to leptospirosis. They were unable to extrapolate prophylaxis to other settings. A Jarisch-Herxheimer reaction rarely develops. It should be treated supportively if it does develop. Patients with renal failure may require dialysis; renal function is restored in most. Those with Weil syndrome may need transfusions of whole blood, platelets, or both. Supportive therapy and careful management of renal, hepatic, hematologic, and CNS complications are important.

Medication Summary
Currently, no human vaccine against leptospirosis is available. Mild leptospirosis is treated with doxycycline, ampicillin, or amoxicillin. For severe leptospirosis, the primary therapy is penicillin G, which is used widely in clinical practice. Alternative regimens are ampicillin, amoxicillin, or erythromycin. Several other antibiotics, including cephalosporins, may be useful, but clinical experience with these is more limited.

Antibiotics
Class Summary
Therapy must cover all likely pathogens in the context of the clinical setting.
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Doxycycline (Bio-Tab, Doryx, Vibramycin)

Should be considered for treatment of mild cases. Hepatobiliary and renally excreted.
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Ampicillin (Omnipen, Marcillin)

Some ampicillin metabolized by liver, although primarily renally excreted.
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Amoxicillin (Amoxil, Polymox, Trimox)

Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible bacteria.
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Penicillin G (Pfizerpen)

Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.
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Erythromycin (EES, E-Mycin, Ery-Tab)

Inhibits RNA-dependent protein synthesis, possibly by stimulating dissociation of peptidyl t-RNA from ribosomes. This inhibits bacterial growth. Excreted into bile via liver. Previous
Deterrence/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). Vaccines are not used in the United States. Human vaccines are serovar specific and must be repeated yearly. They are associated with painful swelling, especially after revaccination. Vaccinations are available to domestic livestock and to help prevent infection in animals. This intervention has reduced transmission in the United States, although one study in Australia showed no difference in seroprevalence between farmers associated with vaccinated herds and those with unvaccinated herds. 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 useful 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 be given to help prevent the disease in those exposed. This regimen is recommended for those with short-term exposure and is not for repeated exposure over protracted periods of time.

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