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INTRODUCTION — Leptospirosis is a zoonosis with protean clinical manifestations caused by pathogenic spirochetes of the genus Leptospira. Synonyms for the disease include Weil's disease, Weil-Vasiliev disease, Swineherd's disease, rice-field fever, waterborne fever, nanukayami fever, cane-cutter fever, swamp fever, mud fever, Stuttgart disease, and Canicola fever.
The epidemiology, microbiology, clinical manifestations, and diagnosis of leptospirosis will be presented here. The treatment and prevention of this disease are discussed separately. (See "Treatment and prevention of leptospirosis".)
EPIDEMIOLOGY — Leptospirosis is a widespread and prevalent zoonotic disease. It occurs in both temperate and tropical regions; the incidence in the tropics is approximately 10 times higher than in temperate regions . Leptospirosis is an underreported disease, and there are no reliable global incidence figures. A modeling exercise by the World Health Organization's (WHO's) Leptospirosis Burden Epidemiology Group estimated that there were 873,000 cases worldwide annually with 48,600 deaths .
Various mammals are natural hosts; humans are infected incidentally after animal or environmental exposure.
Animal infection — The organism infects a variety of both wild and domestic mammals, especially rodents, cattle, swine, dogs, horses, sheep, and goats. The disease rarely occurs in cats. Animals can be asymptomatic or develop clinical infection, which can be fatal. Mortality in dogs is estimated at approximately 10 percent. Spontaneous abortion is a common outcome of leptospirosis in cattle, swine, sheep, and goats.
Rodents are the most important reservoirs for maintaining transmission in most settings. Infection in small rodents usually occurs during infancy, and, once infected, animals may shed the organism in their urine intermittently or continuously throughout life, resulting in contamination of the environment, particularly water . Organisms may remain viable for days to months in soil and water with a neutral pH. Some Leptospira serovars have become adapted to long-term carriage by particular host species; for example, serovar Icterohaemorrhagiae is carried by rats (Rattus rattus) and serovar Hardjo is carried by cattle.
Human infection — Human infection usually results from exposure to environmental sources, such as animal urine, contaminated water or soil, or infected animal tissue. Portals of entry include cuts or abraded skin, mucous membranes, or conjunctivae. The infection may rarely be acquired by ingestion of food contaminated with urine or via aerosols. Controversy exists as to whether Leptospira can penetrate the intact skin.
In the United States, the incidence of leptospirosis is relatively low; most cases are reported from the southern and Pacific coastal states. Hawaii consistently reports the most cases of any state, though this may be partly because leptospirosis ceased to be a notifiable disease nationally in 1995 but remains notifiable in Hawaii. A leptospirosis outbreak was also reported among adventure race participants in Florida .
In the tropics, endemic leptospirosis is mainly a disease of poverty (including low education, poor housing, absence of sanitation, and poor income) . It is acquired through occupational exposure (subsistence farming) and living in rodent-infested, flood-prone urban slums . Large outbreaks affecting thousands of people and leading to hundreds of deaths are common occurrences. These are often associated with increased rainfall [7,8] or flooding, such as the epidemics in Guyana  and Queensland, Australia , both of which presumably increased the risk of exposure to contaminated water. In Thailand between 1995 and 2005, there was a particularly large sustained outbreak caused by the spread of a single ecologically successful pathogenic clone .
Risk factors for infection include [12-16]:
●Occupational exposure – Farmers, ranchers, abattoir workers, trappers, veterinarians, loggers, sewer workers, rice farmers, pet traders, military personnel, laboratory workers
●Recreational activities – Freshwater swimming, canoeing, kayaking, trail biking
●Household exposure – Pet dogs, domesticated livestock, rainwater catchment systems, infestation by infected rodents
●Other – Walking barefoot through surface water, skin lesions, contact with wild rodents, accidental laboratory exposure
Disease in humans is often sporadic, although outbreaks may occur from common source exposures. Participation in a triathlon where the swimming portion was in fresh water has been responsible for several outbreaks of leptospirosis [17-20]. An outbreak occurred among 12 percent of individuals participating in an Illinois triathlon including 834 athletes, likely after exposure to lake water in the swimming phase of the event . Another outbreak among swimmers occurred in Borneo, Malaysia, in 2000; 44 percent of 158 athletes met the case definition . Swimming in the Segama River was associated with a 38 percent attributable risk of acquiring leptospirosis, which was endemic in the area. Other outbreaks occurred following triathlons in Germany in 2006 and Austria in 2010 [19,20].
Physicians caring for travelers following return from vacations involving recreational activities associated with potential environmental Leptospira exposure in high-risk regions such as Southeast Asia should consider the possibility of leptospirosis.
Transplacental infection occurs, but the rate of fetal transmission and the type and frequency of fetal complications are unknown [21-23]. In one review of 14 pregnancies with active maternal infection, there were 8 spontaneous abortions, 4 infants with active infection, and 2 healthy neonates . Another series of 11 cases noted risk of abortion or fetal death of over 50 percent . Information on sequelae in surviving neonates is sparse.
MICROBIOLOGY — The genus Leptospira contains 21 species; 9 are regarded as pathogenic (Leptospira interrogans, L. kirschneri, L. noguchii, L. alexanderi, L. weilii, L. alstonii, L. borgpetersenii, L. santarosai, and L. kmetyi), 5 are of intermediate or unclear pathogenicity (L. inadai, L. fainei, L. broomii, L. licerasiae, and L wolffii), and the remaining 7 are nonpathogenic free-living saprophytic species that do not infect animal hosts (L. biflexa, L. meyeri, L. wolbachii, L. vanthielii, L. terpstrae, L. yanagawae, and L. idonii) [24,25].
There is an older parallel classification system based on serology, with approximately 250 serovars of pathogenic Leptospira identified grouped into 24 serogroups; some serovars are found in more than one species of Leptospira. As a result, by convention, isolates are identified by both species and serovar (eg, L. interrogans serovar Copenhageni). Molecular methods have also been developed to classify Leptospira strains beyond the species level, including Multilocus Sequence Typing (MLST) and Multiple-Locus Variable-number Tandem Repeat Analysis (MLVA) [26,27].
Leptospira are spiral-shaped, highly motile aerobic spirochetes with 18 or more coils per cell. They tend to stain poorly with common laboratory stains and are best visualized by dark field microscopy, silver stain, or fluorescent microscopy. They can be distinguished morphologically from other spirochetes by their unique "question mark" hook at the end of the bacterium (picture 1).
Pathogenic Leptospira spp can be grown in vitro from clinical specimens including blood, urine, and cerebrospinal fluid. Special media are required for isolation such as Fletcher's, Ellinghausen-McCullough-Johnson-Harris, or polysorbate 80 media. Therefore, the laboratory needs to be notified if an attempt to isolate leptospires is desired. Growth is usually observed in one to two weeks but may take up to three months. A method of growing leptospires on solid agar has been developed to facilitate more rapid growth, isolation of single colonies, and simple antimicrobial sensitivity testing .
Whole-genome sequencing of strains of the pathogenic species L. interrogans and L. borgpetersenii and of the saprophytic species L. biflexa have identified a series of genes possibly related to adhesion, invasion, and the hematological changes that characterize leptospirosis, allowing in-depth studies of virulence and pathogenesis [3,29].
Clinical manifestations — The clinical course of leptospirosis is variable. Most cases are mild and self-limited or subclinical, while some are severe and potentially fatal. The illness generally presents with the abrupt onset of fever, rigors, myalgias, and headache in 75 to 100 percent of patients, following an incubation period of 2 to 26 days (average 10 days).
Conjunctival suffusion is an important but frequently overlooked sign (picture 2); in one case series, it occurred in 55 percent of patients . This is not a common finding in other infectious diseases, and its presence in a patient with a nonspecific febrile illness should raise the possibility of leptospirosis. Subconjunctival hemorrhages also occur.
Nonproductive cough occurs in 25 to 35 percent of cases; nausea, vomiting, and diarrhea occur in approximately 50 percent of cases. Muscle tenderness, splenomegaly, lymphadenopathy, pharyngitis, hepatomegaly, muscle rigidity, abnormal respiratory auscultation, or skin rash occur in 7 to 40 percent of patients [31,32].
Less common symptoms include arthralgias, bone pain, sore throat, and abdominal pain . Acalculous cholecystitis and pancreatitis have been described in children . Leptospirosis has been described as a biphasic illness (with an acute bacteremic phase followed by an "immune" phase); clinically, the two phases usually merge, particularly in severe disease.
Aseptic meningitis is observed in 50 to 85 percent of patients if cerebrospinal fluid (CSF) is examined after seven days of illness. In general, this finding has been attributed to a host immune response to the organism rather than to direct infection ; however, in one study, 89 percent of serologically confirmed cases of leptospirosis with CSF abnormalities had Leptospira DNA detectable in the CSF by polymerase chain reaction .
A case-control study in Taiwan during an outbreak of leptospirosis in adults identified the following clinical and laboratory findings associated with serologically confirmed cases :
●Hemorrhagic diathesis (odds ratio [OR] 10; 95% CI 1.1-90.8)
●Myalgias (OR 8.0; 95% CI 1.4-45.8)
●Bilateral enlarged kidneys (OR 7.5; 95% CI 2.5-22.7)
●Sterile pyuria (OR 6.3; 95% CI 1.4-27.8)
●Hypokalemia (OR 5.0; 95% CI 1.1-22.3)
●Thrombocytopenia (OR 4.8; 95% CI 1.1-21.1)
Leptospirosis may be complicated by jaundice and renal failure ("Weil's disease"), pulmonary hemorrhage, acute respiratory distress syndrome (ARDS), uveitis, optic neuritis, peripheral neuropathy, myocarditis, and rhabdomyolysis [37-41].
Renal failure is often nonoliguric and associated with hypokalemia. Supportive renal replacement therapy may be required during the acute phase; renal recovery is generally complete . However, leptospirosis exposure (as determined by serology) has been associated with chronic kidney disease in an endemic area in Taiwan . Liver failure is generally reversible and not a cause of death. Vasculitis with necrosis of extremities may be seen in severe cases . Mortality rates in hospitalized patients with leptospirosis range from 4 to 52 percent [38,45-48].
Severe pulmonary disease, characterized by pulmonary hemorrhage, is a serious complication of leptospirosis; it may be underdiagnosed in highly endemic regions . Among 321 patients with serologic and clinical evidence of leptospirosis in Peru, 3.7 percent had severe pulmonary manifestations; of these, 71 percent died (causes of death included pulmonary hemorrhage, ARDS, and multiorgan failure) .
In one retrospective review of 282 cases of leptospirosis during an outbreak in India, significant predictors of death in logistic regression analysis included pulmonary involvement and central nervous system disease . In another review of 35 studies, high case-fatality rates were associated with jaundice (median mortality 19 percent, range 0 to 39 percent), renal failure (12 percent, range 0 to 25 percent), and age >60 years (60 percent, range 33 to 60 percent) . Reported mortality rates for untreated anicteric patients were low (median 0 percent, range 0 to 2 percent).
The potential severity of leptospirosis was illustrated in a retrospective study of 60 patients with leptospirosis requiring intensive care unit (ICU) admission in India . Multiorgan failure developed in 46 patients (77 percent); the mortality for patients with leptospirosis requiring ICU admission was 52 percent. In one retrospective case-control study from New Caledonia, risk factors for the development of severe leptospirosis included a delay of >2 days following the start of symptoms in the initiation of antibiotics and infection due to Leptospira interrogans serogroup Icterohaemorrhagiae .
There are few reported cases of leptospirosis in HIV-infected patients [53-55]; the clinical manifestations in HIV-infected patients are similar to those in immunocompetent patients.
Laboratory studies and imaging — Routine laboratory tests may be nonspecific. White blood cell (WBC) counts are generally less than 10,000/microL but may range from 3000 to 26,000/microL; a left shift occurs in about two-thirds of patients. Thrombocytopenia can occur; in one series of 79 patients with leptospirosis in Thailand, thrombocytopenia was present in 38 percent of cases . Pancytopenia has been reported as the presenting manifestation in case reports .
Hyponatremia is common in severe leptospirosis. Leptospirosis has the capacity to act directly on electrolyte transport mechanisms, inducing derangements of sodium and potassium. Data suggest that an outer membrane protein of Leptospira inhibits the Na+-K+-Cl- cotransporter activity in the thick ascending limb of Henle, resulting in hypokalemia and sodium wasting [58,59].
Urinalysis frequently shows proteinuria, pyuria, granular casts, and occasionally microscopic hematuria . Renal failure may be observed in severe leptospirosis. Elevated creatine kinase is observed in approximately 50 percent of patients and may be a useful clue .
Approximately 40 percent of patients have minimal to moderate elevations of hepatic transaminases (usually <200 international units/L). Jaundice may be observed in severe leptospirosis. In some cases, the serum bilirubin concentration reaches 60 to 80 mg/dL (1026 to 1368 mmol/L).
The CSF may show a lymphocytic or neutrophilic pleocytosis with minimal to moderately elevated protein concentrations and normal glucose concentration; a low glucose concentration is seen rarely .
Chest radiography may demonstrate small nodular densities, which can progress to confluent consolidation or a ground-glass appearance . Pathologically, these infiltrates may represent alveolar hemorrhage, ARDS, or pulmonary edema [62,63].
Findings associated with adverse outcomes include oliguria, WBC count above 12,900/mm3, repolarization abnormalities on electrocardiogram, and alveolar infiltrates on chest radiography.
DIFFERENTIAL DIAGNOSIS — Leptospirosis may be difficult to distinguish from many other infectious illnesses. Conjunctival suffusion, when it occurs, is one of the most reliable distinguishing features since it rarely occurs with any infectious illness other than leptospirosis.
●Malaria, dengue, and chikungunya share some common clinical features and similar endemic patterns with leptospirosis . (See "Clinical manifestations of malaria in nonpregnant adults and children" and "Dengue virus infection: Clinical manifestations and diagnosis" and "Chikungunya fever".)
●Scrub typhus is a common disease in some tropical regions where leptospirosis also occurs. (See "Scrub typhus: Clinical features and diagnosis".)
●Other rickettsial disease, infections with Rickettsia typhi (murine typhus), or spotted fever group rickettsiae may mimic leptospirosis. (See "Other spotted fever group rickettsial infections".)
●Leptospirosis may mimic infection with Salmonella typhi in areas of the tropics where typhoid fever is common, particularly in patients with prominent gastrointestinal complaints. (See "Epidemiology, microbiology, clinical manifestations, and diagnosis of typhoid fever".)
●Ehrlichiosis may present with similar clinical manifestations, including fever and nonspecific complaints. (See "Human ehrlichiosis and anaplasmosis".)
●Acute viral illnesses including influenza may mimic leptospirosis, particularly in patients with prominent respiratory tract symptoms. (See "Clinical manifestations of seasonal influenza in adults".)
●Hantavirus can cause a renal syndrome and/or pulmonary syndrome similar to the renal and/or pulmonary complications observed in leptospirosis. (See "Renal involvement with hantavirus infection (hemorrhagic fever with renal syndrome)".)
Clinical approach — A high index of suspicion is required to make the diagnosis based on epidemiologic exposure and clinical manifestations, since clinical and laboratory findings are nonspecific. The diagnosis is made most frequently by serologic testing. Molecular techniques are promising for rapid diagnosis but are not widely available. The organism can be cultured, but this can take several weeks.
In the setting of moderate or high clinical suspicion for leptospirosis in the absence of a definitive laboratory diagnosis, administration of empiric treatment is appropriate. (See "Treatment and prevention of leptospirosis".)
Diagnostic tools — There is a lack of reference standard for diagnosis of leptospirosis; the microscopic agglutination test (MAT) and culture are both imperfect, either alone or in combination . This limitation has important implications for the assessment of new assays as they may perform poorly compared with the existing imperfect reference even if they are superior to the reference. In one assessment of diagnostic test results from 1652 patients with suspected leptospirosis , all patients had blood culture, MAT, immunofluorescence assay (IFA), lateral flow (LF), and/or polymerase chain reaction (PCR) targeting the 16S rRNA gene performed. Even a combination of blood culture and MAT had sensitivity of only 55.5 percent, although the specificity was 98.8 percent.
Serology — Serological tests are used most frequently for diagnosis of leptospirosis . Assays include the microscopic agglutination test, macroscopic agglutination test, indirect hemagglutination, and enzyme-linked immunosorbent assay (ELISA) [67,68]. A number of rapid immunoglobulin (Ig)M ELISA and lateral flow tests have been developed, though many have been inadequately validated and their diagnostic performance in an endemic setting is variable [69-71].
MAT is considered a reference standard for development of other assays . It requires live organisms, considerable expertise, and is performed only by reference laboratories such as the United States Centers for Disease Control and Prevention (CDC). MAT is most specific when a fourfold or greater rise in titer is detected between acute and convalescent serum specimens. A single titer of >1:800 is reasonable evidence of current or recent infection with Leptospira. The level of the antibody titers cannot be used to predict the infecting serovar, and false-negative results may occur if infection occurs with a serovar not included in the panel of organisms maintained at a particular reference center [72,73]. Cross-reactive antibodies have been associated with syphilis, relapsing fever, Lyme disease, and legionellosis.
Since the MAT is not readily available, another assay (serologic or molecular) is typically performed first in suspected cases of leptospirosis. If one of these is positive, serum for MAT can then be sent to the CDC. Hopefully in the near future, more accurate rapid diagnostic tests will be validated and become widely available .
Molecular tests — Molecular techniques such as real time PCR and loop-mediated isothermal amplification (LAMP) have been developed for diagnosis of leptospirosis. These are increasingly available and useful for rapid, accurate diagnosis [71,74-78].
Next-generation sequencing is a technology for determining DNA sequence by analyzing multiple DNA fragments in parallel; it allows sequencing of an exponentially greater number of genes than conventional DNA sequencing. Next-generation sequencing of the cerebrospinal fluid was used to diagnose neuroleptospirosis in a 14-year-old boy with severe combined immunodeficiency who had developed unexplained fever and progressive neurologic deterioration, after an extensive infectious disease evaluation (including 16S rRNA bacterial PCR testing) was unrevealing . Penicillin was initiated based on the next-generation sequencing result, with rapid clinical improvement. Subsequent testing (PCR, Sanger sequencing, and IgM antibody by latex agglutination ELISA) confirmed the diagnosis. (See "Principles and clinical applications of next-generation DNA sequencing".)
Culture — Leptospirosis can be confirmed by culture of the organism from clinical specimens in appropriate media if antibiotic therapy has not been administered before samples are taken. Blood and CSF specimens are generally positive during the first 10 days of the illness. Blood culture is insensitive; isolation of the organism is successful in 5 to 50 percent of cases and may take several weeks . Urine cultures become positive during the second week of the illness and remain positive for up to 30 days after the resolution of symptoms .
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Leptospirosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Leptospirosis is a zoonosis with protean manifestations caused by pathogenic spirochetes of the genus Leptospira. (See 'Introduction' above.)
●Leptospirosis is distributed worldwide, with the majority of clinical cases occurring in the tropics. In the United States, Hawaii consistently reports the most cases. (See 'Epidemiology' above.)
●The organism infects a variety of wild and domestic mammals, especially rodents, cattle, swine, dogs, horses, sheep, and goats. Animals can be asymptomatic or develop clinical infection, which can be fatal. Reservoir animals may shed the organism in their urine intermittently or continuously throughout life, resulting in contamination of the environment, particularly water. (See 'Animal infection' above.)
●Humans most often become infected after exposure to environmental sources, such as animal urine, contaminated water or soil, or infected animal tissue through cuts or abraded skin, mucous membranes, or conjunctiva. (See 'Human infection' above.)
●The clinical course is variable. Leptospirosis may manifest as a subclinical illness followed by seroconversion, a self-limited systemic infection, or a severe, potentially fatal illness accompanied by multiorgan failure. (See 'Clinical features' above.)
●Clinically apparent leptospirosis presents with the abrupt onset of fever, rigors, myalgias, and headache in 75 to 100 percent of patients. Conjunctival suffusion in a patient with a nonspecific febrile illness should raise suspicion for the diagnosis of leptospirosis (picture 2). (See 'Clinical features' above.)
●Most cases of leptospirosis are mild to moderate. However, the course may be complicated by renal failure, uveitis, hemorrhage, acute respiratory distress syndrome with pulmonary hemorrhage, myocarditis, and rhabdomyolysis. (See 'Clinical features' above.)
●A high index of suspicion is required to make the diagnosis based on epidemiologic exposure and clinical manifestations, since clinical and laboratory findings are nonspecific. The diagnosis is made most frequently by serologic testing, though molecular diagnostics have utility and are increasingly available. The microscopic agglutination test is a reference standard assay; it is performed by reference laboratories such as the United States Centers for Disease Control and Prevention. In the absence of a definitive laboratory diagnosis, administration of empiric treatment is appropriate. (See 'Diagnosis' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Dr. E Dale Everett, who contributed to an earlier version of this topic review.
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