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 "Leptospirosis: Treatment and prevention".)
EPIDEMIOLOGY — Leptospirosis is a widespread and prevalent zoonotic disease; it occurs in both temperate and tropical regions. It is an under-reported infection, and there are no reliable global incidence figures. A systematic review and modeling exercise estimated that there were 1.03 million cases worldwide annually with 58,900 deaths associated with the loss of 2.9 million disability-adjusted life years [1,2]. This burden fell disproportionately on males (80 percent) and in tropical rather than temperate regions.
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 [3]. 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. A leptospirosis outbreak was also reported among adventure race participants in Florida [4].
In the tropics, endemic leptospirosis is mainly a disease of poverty (including low education, poor housing, absence of sanitation, and poor income) [5,6]. It is acquired through occupational exposure (subsistence farming) and living in rodent-infested, flood-prone, overcrowded urban areas [7]. Large outbreaks affecting thousands of people and leading to hundreds of deaths are common occurrences. These are often associated with increased rainfall or flooding, which presumably increased the risk of exposure to contaminated water [8-12]. In Thailand between 1995 and 2005, there was a particularly large sustained outbreak caused by the spread of a single ecologically successful pathogenic clone [13].
Risk factors for infection include [14-18]:
●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
●Low socioeconomic status – Living in overcrowded urban areas with poor sanitation
●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 [19-22]. 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 [19]. Another outbreak among swimmers occurred in Borneo, Malaysia, in 2000; 44 percent of 158 athletes met the case definition [20]. Swimming in the Segama River was associated with a 38 percent attributable risk of acquiring leptospirosis, which was endemic in the area. Other notable outbreaks have occurred in Germany and Austria (following triathlons) and in Israel (in association with recreational water exposure) [21-23].
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.
MICROBIOLOGY — The phylogeny of Leptospira has undergone a major overhaul since 2018, due to large-scale whole-genome sequencing.
There are 64 recognized species (60 of these have been published under the rules of the International Code of Nomenclature of Bacteria), split into two clades and four subclades [24,25]. Subclade P1(17 species) contains, alongside newly described species, those species traditionally recognized as pathogenic (Leptospira interrogans, L. kirschneri, L. noguchii, L. alexanderi, L. weilii, L. alstonii, L. borgpetersenii, L. santarosai, L. kmetyi, and L. mayottensis). Subclade P2 contains 20 species, including those species previously regarded as of intermediate or unclear pathogenicity. Subclades S1 and S2 contain 22 and 5 species, respectively, and include those species previously categorized as ‘saprophytes.’
There is an older 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 and Multiple-Locus Variable-number Tandem Repeat Analysis [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 [28].
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 FEATURES
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, characterized by conjunctival redness (picture 2), is an important but frequently overlooked sign; in one case series, it occurred in 55 percent of patients [30]. 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 [33]. Acalculous cholecystitis and pancreatitis have been described in children [34]. Leptospirosis has been described as a biphasic illness. The first phase consists of an acute febrile bacteremic phase lasting two to nine days, after which there may be a period with little or no fever and apparent improvement. The second phase consists of an "immune" phase characterized by renewed fever and development of complications. During the immune phase, leptospires are absent from the blood but may appear in the urine. The two phases may overlap clinically, particularly in the setting of 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 [32]; however, in one study including 39 CSF samples from patients with meningeal abnormalities in Brazil, Leptospira DNA was detectable in the CSF by polymerase chain reaction in 59 percent of cases [35].
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 [36-40].
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 [41]. However, leptospirosis exposure (as determined by serology) has been associated with chronic kidney disease in an endemic area in Taiwan [42]. Liver failure is generally reversible and not a cause of death. Vasculitis with necrosis of extremities may be seen in severe cases [43]. Mortality rates in hospitalized patients with leptospirosis range from 4 to 52 percent [37,44-47].
Severe pulmonary disease, characterized by pulmonary hemorrhage, is a serious complication of leptospirosis; it may be underdiagnosed in highly endemic regions [48]. 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) [49].
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 [46]. 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) [50]. 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 [44]. 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 [51].
There are few reported cases of leptospirosis in HIV-infected patients [52-54]; the clinical manifestations in HIV-infected patients are similar to those in immunocompetent patients. Among patients with solid organ transplants, a review of case reports of leptospirosis concluded that occurrence of leptospirosis was more likely related to epidemiologic exposure than to increased risk of infection in the setting of immunosuppression [55]; the disease progression and outcome in the cases reviewed was similar to that seen in other cases of severe leptospirosis.
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 [56]. Pancytopenia has been reported as the presenting manifestation in case reports [57].
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 [32]. 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 [60].
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 [61].
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].
Findings associated with adverse outcomes include oliguria, WBC count above 12,900/mm3, repolarization abnormalities on electrocardiogram, and alveolar infiltrates on chest radiography.
Manifestations in pregnancy — Leptospirosis in pregnancy may be misdiagnosed as it can mimic other infections, pregnancy-associated hypertension, acute fatty liver, hemolysis, elevated liver enzymes, and low platelet count syndrome [63]. Transplacental infection occurs, but the rate of fetal transmission and the type and frequency of fetal complications are unknown [63-65]. In one review of 14 pregnancies with active maternal infection, there were 8 spontaneous abortions, 4 infants with active infection, and 2 healthy neonates [64]. Another series of 11 cases noted risk of abortion or fetal death of over 50 percent [65]. Information on sequelae in surviving neonates is sparse.
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 [66]. (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Dengue virus infection: Clinical manifestations and diagnosis" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)
●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 enteric (typhoid and paratyphoid) 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 "Seasonal influenza in adults: Clinical manifestations and diagnosis".)
●Hantavirus can cause a renal syndrome and/or pulmonary syndrome similar to the renal and/or pulmonary complications observed in leptospirosis. (See "Kidney involvement in hantavirus infections".)
DIAGNOSIS
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 often nonspecific in acute infection.
Nucleic acid detection is most sensitive in bacteremic phase of infection, with antibodies becoming detectable by serologic methods after the first week. Hence, for timely diagnosis of patients with suspected leptospirosis, a combined serologic/molecular diagnostics approach is increasingly used [67,68]. The exact combination of tests used depends on local availability.
The organism may be cultured from blood (during the bacteremic phase) and urine (after the first week), but growth may 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 "Leptospirosis: Treatment and prevention".)
Diagnostic tools
Molecular tests — Molecular techniques such as real time polymerase chain reaction (PCR) and loop-mediated isothermal amplification have been developed for diagnosis of leptospirosis [69]. These are increasingly available and useful for rapid, accurate diagnosis of acute leptospirosis and have the advantage over serology of earlier positivity, and hence not requiring paired acute and convalescent samples and the consequent delay in diagnosis when the acute sample is seronegative for anti-leptospire antibodies samples [70-75]. Leptospire DNA can be detected in blood (whole blood, buffy coat, or plasma) during the initial bacteremic phase of the illness, and in cerebrospinal fluid (CSF) and urine a few days after the onset of symptoms.
PCR assays target genes unique to pathogenic leptospire species (eg, LipL32, ligA, ligB, lfb1) or housekeeping/ribosomal RNA genes (eg, rrs, gyrB, secY). In one study using a combined rrs/LipL32 qPCR on acute clinical samples from 787 febrile patients in Laos, estimated sensitivities and specificities were 54 and 99 percent for serum, 59 and 100 percent for buffy coat, and 45 and 99 percent for urine [76]. This compared favorably with MAT and culture which both had much lower sensitivities (16 and 25 percent, respectively). Sensitivity of qPCR and culture may have been compromised by prereferral antibiotic use (57 percent in this study), but the results are consistent with other studies reporting sensitivities on acute samples of 40 to 60 percent for various PCR assays. With the recognition that both subclade P1 and subclade P2 Leptospira species may cause clinical disease, a validated multiplex qPCR assay targeting specific regions of the rrs gene has been developed to target and distinguish these [77].
Serology — Serologic tests are used most frequently for diagnosis of leptospirosis [78]. Their use in acute diagnosis is limited by background seropositivity in endemic areas and by the fact that in naïve individuals, antibodies only appear from day 5 to 7 of illness. Paired acute and convalescent samples are therefore preferable. Assays include the microscopic agglutination test (MAT), macroscopic agglutination test, indirect hemagglutination, and enzyme-linked immunosorbent assay (ELISA) [79,80]. A number of immunoglobulin (Ig)M ELISAs have been developed, both in-house and commercially available, though many have been inadequately validated and their diagnostic performance in an endemic setting is variable [81-83].
There are a number of serologically based lateral flow rapid tests available for the diagnosis of leptospirosis [70]. One meta-analysis of point-of-care rapid lateral flow assays (based on heat-treated whole cell Leptospira biflexa serovar Patoc) found a pooled sensitivity and specificity of 79 percent (95% CI 70-86 percent) and 92 percent (95% CI 85-96 percent) respectively, but the evidence base was limited and in many cases the reference tests were imperfect [84].
The MAT a reference assay, which provides information on both antibody titer and serovar, although its status as a ‘gold standard’ for diagnosis has been questioned in a large comparative study analyzed using Bayesian latent class modelling [85]. 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 [86,87]. Cross-reactive antibodies have been associated with syphilis, relapsing fever, Lyme disease, and legionellosis.
Since the MAT is not available outside of reference centers, another serology assay is typically performed first in suspected cases of leptospirosis. This is usually either an IgM ELISA or conventional or real time PCR, and ideally both. If one of these is positive, acute and convalescent sera for MAT can then be sent to the CDC for serovar determination. Hopefully in the near future, more accurate rapid diagnostic tests or antigen detection ELISAs will be validated and become widely available [78].
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 [33].
Antigen detection — Antigen detection in blood using a monoclonal anti-LipL32 antibody-based antigen capture ELISA has been developed and validated against PCR [88]. In the future this may provide a cost-effective alternative to PCR-based early diagnosis.
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 UpToDate editorial staff acknowledges Dr. E Dale Everett, who contributed to an earlier version of this topic review.
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29 : Unique physiological and pathogenic features of Leptospira interrogans revealed by whole-genome sequencing.
30 : Clinical characteristics and risk factors of human leptospirosis in Argentina (1999-2005).
31 : Leptospirosis--time for a booster.
32 : Sporadic anicteric leptospirosis in South Vietnam. A study in 150 patients.
33 : Assessment of the clinical presentation and treatment of 353 cases of laboratory-confirmed leptospirosis in Hawaii, 1974-1998.
34 : Acute acalculous cholecystitis in leptospirosis.
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37 : Leptospirosis: prognostic factors associated with mortality.
38 : Uveitis associated with an epidemic outbreak of leptospirosis.
39 : Acute renal failure: a common manifestation of leptospirosis.
40 : Acute kidney injury requiring hemodialysis in patients with anicteric leptospirosis.
41 : Pattern of renal function recovery after leptospirosis acute renal failure.
42 : Overlooked Risk for Chronic Kidney Disease after Leptospiral Infection: A Population-Based Survey and Epidemiological Cohort Evidence.
43 : Leptospirosis: a childhood disease.
44 : Epidemic of leptospirosis: an ICU experience.
45 : Leptospirosis during dengue outbreak, Bangladesh.
46 : Risk factors for mortality in patients with leptospirosis during an epidemic in northern Kerala.
47 : Outbreak of leptospirosis after flood, the Philippines, 2009.
48 : Anicteric leptospirosis-associated severe pulmonary hemorrhagic syndrome: a case series study.
49 : Clinical spectrum of pulmonary involvement in leptospirosis in a region of endemicity, with quantification of leptospiral burden.
50 : A Systematic Review of the Mortality from Untreated Leptospirosis.
51 : Risk factors and predictors of severe leptospirosis in New Caledonia.
52 : Mild, self-resolving acute leptospirosis in an HIV-infected patient in the Peruvian Amazon.
53 : Leptospirosis patient with AIDS: the first case reported.
54 : Fulminant leptospirosis in a patient with human immunodeficiency virus infection: case report and review of the literature.
55 : A first report of leptospirosis after liver transplantation.
56 : Activation of the coagulation cascade in patients with leptospirosis.
57 : Leptospirosis and pancytopenia: two case reports and review of the literature.
58 : Reduced renal Na+-K+-Cl- co-transporter activity and inhibited NKCC2 mRNA expression by Leptospira shermani: from bed-side to bench.
59 : Paralysis due to renal potassium wasting: an unusual presentation of leptospirosis.
60 : Serum creatine phosphokinase in leptospirosis.
61 : Letter: Hypoglycorrachia in leptospirosis.
62 : Pulmonary complications of leptospirosis.
63 : Leptospirosis in pregnancy.
64 : Leptospirosis in pregnancy and its effect on the fetus: case report and review.
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66 : Concurrent outbreak of leptospirosis and dengue in Mumbai, India, 2002.
67 : Combined PCR and MAT improves the early diagnosis of the biphasic illness leptospirosis.
68 : Combined antibody and DNA detection for early diagnosis of leptospirosis after a disaster.
69 : Nucleic acid and antigen detection tests for leptospirosis.
70 : Rapid tests for diagnosis of leptospirosis: current tools and emerging technologies.
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78 : Leptospirosis: current situation and trends of specific laboratory tests.
79 : Evaluation of the indirect hemagglutination assay for diagnosis of acute leptospirosis.
80 : Detection of LipL32-specific IgM by ELISA in sera of patients with a clinical diagnosis of leptospirosis.
81 : Accuracy of a commercial IgM ELISA for the diagnosis of human leptospirosis in Thailand.
82 : Evaluation of the Standard Diagnostics Leptospira IgM ELISA for diagnosis of acute leptospirosis in Lao PDR.
83 : An Improved Enzyme-Linked Immunoassay for the Detection of Leptospira-Specific Antibodies.
84 : Diagnostic accuracy of rapid diagnostic tests for the early detection of leptospirosis.
85 : Fool's gold: Why imperfect reference tests are undermining the evaluation of novel diagnostics: a reevaluation of 5 diagnostic tests for leptospirosis.
86 : Usefulness of serologic analysis as a predictor of the infecting serovar in patients with severe leptospirosis.
87 : The microscopic agglutination test (MAT) is an unreliable predictor of infecting Leptospira serovar in Thailand.
88 : Development and evaluation of monoclonal antibody-based antigen capture enzyme-linked immunosorbent assay for the diagnosis of acute leptospirosis in humans.
