Version May 2024
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, Fort Bragg fever, Stuttgart disease, Mgunda fever, 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".)
MICROBIOLOGY — Leptospira are spiral-shaped, highly motile aerobic spirochetes with 18 or more coils per cell.
The organism stains poorly with common laboratory stains and is best visualized by dark field microscopy, silver stain, or fluorescent microscopy. It can be distinguished morphologically from other spirochetes by its unique "question mark" hook at the end of the bacterium (picture 1).
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 [1,2]. 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 300 serovars of pathogenic Leptospira grouped into 32 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 [3,4].
Whole-genome sequencing of strains of the pathogenic species L. interrogans and L. borgpetersenii, and of the saprophytic species L. biflexa, has identified a series of genes possibly related to adhesion, invasion, and hematological findings in hosts [5,6].
EPIDEMIOLOGY
Prevalence and geography — Leptospirosis is thought to be the most widespread zoonosis in the world. It is an under-reported infection, and there are no reliable global incidence figures. A systematic review and modeling exercise estimated that more than one million human cases occur worldwide annually, including almost 60,000 deaths [7,8].
It is most prevalent in tropical regions but also occurs in temperate regions [7,8]. Regions with the highest incidence of infections include South and Southeast Asia, Oceania, the Caribbean, parts of sub-Saharan Africa, and parts of Latin America [9].
In the United States, the incidence of leptospirosis is relatively low (approximately 100 to 150 cases are reported annually) [10]. Puerto Rico and Hawaii consistently report the most cases.
Disease in humans is usually sporadic, although outbreaks may occur from common source exposures. (See 'Outbreaks' below.)
Animal and environmental reservoirs — Mammals act as the primary reservoir for Leptospira organisms. The environment can serve as a reservoir if it becomes contaminated by the urine of infected mammals.
●Animal reservoir – Approximately 160 mammalian species have been identified as natural carriers of pathogenic Leptospira species [11]. The organism lives in the renal tubules of infected mammals and is shed in the urine.
Rodents are the most important reservoirs for maintaining transmission in most settings. Infection in small rodents (eg, rats) usually occurs in utero, during birth, or during infancy from environmental contamination of the nest [12]. Once infected, rodents are asymptomatic carriers and shed the organism in their urine intermittently or continuously throughout life, resulting in contamination of the environment, particularly water [6].
In addition to rodents, the organism infects a variety of both wild and domestic mammals, especially cattle, swine, dogs, horses, sheep, and goats. It rarely occurs in cats. Animals can be asymptomatic carriers or can develop clinical infection, which may 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.
●Environmental reservoir – Organisms can survive for days to months in urine-contaminated soil and fresh water [10].
Contamination of water with animal urine can occur via several mechanisms:
•Following heavy rainfall or flooding that allows mixing of urine-contaminated soil or sewage with water, especially in areas with poor housing and sanitation/sewage conditions that propagate high rodent populations
•Animal excretion of urine into wet soil or bodies of fresh water, such as ponds, lakes, rivers, and streams
•Drainage of urine-contaminated soil or water into bodies of fresh water
Transmission to humans — Humans are accidental hosts, infected incidentally after animal or environmental exposure.
Transmission of the organism to humans occurs via portals of entry, including cuts or abraded skin, mucous membranes, or conjunctivae [10].
Human exposures that lead to infection include contact with urine-contaminated soil or water (eg, floodwater, ponds, rivers, streams, sewage), ingestion of food or water contaminated by urine or urine-contaminated water, or direct contact with the urine or reproductive fluids from infected animals [10]. Transmission has also rarely occurred through animal bites. Controversy exists as to whether Leptospira can penetrate intact skin.
Human-to-human transmission is very rare but has been documented through sexual intercourse and breastfeeding [10].
Risk factors — Risk factors primarily include direct animal exposure or activities that can lead to skin abrasions and water or soil exposure [10].
Specific risk factors for infection include the following [10,13-17]:
●Occupational exposure – Farmers, ranchers, abattoir workers, trappers, veterinarians, loggers, sewer workers, landscapers, rice farmers, pet traders, military personnel, laboratory workers
●Recreational activities – Freshwater swimming, canoeing, kayaking, trail biking, trekking, gardening
●Household exposure – Pet dogs, domesticated livestock, rainwater catchment systems, infestation by infected rodents
●Low socioeconomic status – Living in overcrowded urban areas with poor sanitation
●Travel to endemic areas (especially if travel occurs during or following heavy rainfall or flooding or involves high-risk activities) (see 'Prevalence and geography' above)
●Other – Walking barefoot through surface water, skin lesions, contact with wild rodents, accidental laboratory exposure
In the tropics, endemic leptospirosis is mainly a disease of poverty (including low education, poor housing, absence of sanitation, and poor income) [18,19]. It is usually acquired through occupational exposure (subsistence farming) or living in rodent-infested, flood-prone, overcrowded urban areas [20].
Outbreaks — Large outbreaks affecting thousands of people and causing tens and hundreds of deaths have been reported [21]. Outbreaks tend to occur after heavy rainfall or flooding in endemic areas, especially in areas with poor housing and sanitation conditions [10,22-26]. In 2022, an outbreak was reported in Tanzania among farmers [27].
Several outbreaks have been reported around the world in participants in triathlons where the swimming portion was in fresh water [28-31]. A leptospirosis outbreak was also reported among adventure race participants in a swamp in Florida [32]. In 2018, an outbreak in northern Israel was reported and was associated with recreational water exposure [33].
CLINICAL MANIFESTATIONS
Spectrum of illness — The clinical course of leptospirosis is variable. Most cases are mild and self-limited or asymptomatic, while some are severe and potentially fatal [34].
Syndromes caused by leptospirosis are often divided into two categories: anicteric leptospirosis and icteric leptospirosis. Icteric leptospirosis is the more severe form of disease and is associated with icterus and jaundice.
Anicteric leptospirosis — The majority of symptomatic patients with leptospirosis have the anicteric form of disease.
Anicteric leptospirosis has been described as a biphasic illness, with an acute phase and an "immune" phase. However, most patients never proceed to the immune phase of illness. In some cases, the two phases may overlap clinically.
Acute phase (first week of illness) — The acute phase of anicteric leptospirosis typically lasts two to nine days [10,28,34]. It usually begins 5 to 14 days after exposure, although the incubation period can range from 2 to 30 days.
●Symptoms – The acute phase is characterized by acute febrile bacteremia. Clinical features include abrupt onset of fever, rigors, myalgias (especially in the calves and lower back), and headache; these symptoms occur in 75 to 100 percent of patients [33,35]. Approximately half of patients experience nausea, vomiting, and diarrhea, and nonproductive cough occurs in 25 to 35 percent of cases.
Less common symptoms include arthralgias, bone pain, sore throat, and abdominal pain [36]. Acalculous cholecystitis and pancreatitis have been described in children [37].
Rarely, rapidly progressive pulmonary hemorrhage can occur during the acute phase, although this finding is more commonly associated with icteric leptospirosis. Symptoms include shortness of breath and hemoptysis. This syndrome is associated a high mortality rate. More details are found elsewhere. (See 'Icteric leptospirosis (Weil's disease)' below.)
●Physical examination – In addition to fever, a distinguishing, but often overlooked, finding is conjunctival hyperemia ('suffusion'), which has been reported in a majority of patients with leptospirosis in some case series [38,39]. It is characterized by bilateral dilation of conjunctival blood vessels causing conjunctival erythema without purulent discharge (in contrast to conjunctivitis, which includes purulent discharge) and is uncommon in other infectious diseases. In a minority of patients, subconjunctival hemorrhage (ie, focal, flat, bright red patches) occurs with or without conjunctival suffusion (picture 2).
In addition to the ophthalmologic findings described above, case series have also reported muscle tenderness, splenomegaly, lymphadenopathy, pharyngitis, hepatomegaly, muscle rigidity, abnormal respiratory auscultation, and/or skin rash in 7 to 40 percent of patients [34,40,41]. If present, the rash typically lasts one to two days and may be maculopapular, urticarial, petechial, or purpuric in nature; pretibial petechiae have been noted, especially from infections caused by the L. autumnalis serotype.
●Laboratory findings – Typical lab findings during the acute phase include neutrophilia, although the total white blood cell (WBC) count can be normal, low, or elevated. Thrombocytopenia and anemia are less common; pancytopenia has been reported as the presenting manifestation in case reports [42]. The erythrocyte sedimentation rate (ESR) is usually elevated, and mild elevation of liver aminotransferases may occur. Elevated creatine kinase (due to rhabdomyolysis) may occur in approximately half of patients [43].
Urinalysis frequently shows proteinuria, pyuria, granular casts, and occasionally microscopic hematuria [41]. Rarely, acute kidney injury occurs during this phase, although it is more commonly associated with icteric leptospirosis which is described elsewhere. (See 'Icteric leptospirosis (Weil's disease)' below.)
"Immune" phase (delayed phase of illness) — Following the acute phase, a minority of patients with anicteric leptospirosis experience an "immune" phase characterized by specific immune-mediated complications. Rarely, patients can present with the manifestations of the immune phase without experiencing a preceding symptomatic acute phase.
In those who do develop an immune phase, there is often a period of improvement between the end of the acute phase and the beginning of the immune phase. In others, the acute and immune phases may overlap. The immune phase typically lasts around one week, and no longer than 30 days, except for ophthalmologic complications, as described below.
During the immune phase, leptospires are absent from the blood, and antibodies to the organism are present. The organism may be detectable in the urine during this phase. Diagnostic testing of various bodily fluids is discussed elsewhere. (See 'Diagnosis' below.)
●Systemic symptoms – The immune phase usually begins with renewed fever, headache, and myalgia, sometimes accompanied by nausea, vomiting, and abdominal pain [34].
●Aseptic meningitis – Aseptic meningitis is a hallmark of the immune phase, with symptoms of headache and neck pain or stiffness occurring in approximately half of patients [44]. Physical examination findings include nuchal rigidity; papilledema is uncommon. Meningitis symptoms usually subside within one or two days and can rarely persist up to three weeks.
Typical cerebrospinal fluid (CSF) findings include neutrophilic or lymphocytic pleocytosis with mildly elevated protein and normal glucose; these findings are found in 50 to 85 percent of patients whose CSF is examined during the immune phase, including in patients without meningitis symptoms. Rarely, a low glucose concentration is present [45]. CSF pleocytosis may persist for up to three months [44].
In general, CSF abnormalities and meningitis symptoms have been attributed to the host immune response to the organism rather than to infection of the central nervous system [41]. However, in one study that included 15 patients with serologically confirmed leptospirosis and lymphocytic aseptic meningitis in Brazil, 14 (93 percent) had detectable Leptospira DNA in the CSF by polymerase chain reaction (PCR) [46].
●Uveitis – Unilateral or bilateral uveitis is another feature of the immune phase and may be recurrent. The most common presentation is anterior uveitis (ie, iritis, iridocyclitis), which manifests as acute-onset or insidious pain and redness of the eye(s), primarily at the limbus (the junction between the cornea and the sclera). Less commonly, posterior uveitis (eg, chorioretinitis) occurs and presents as painless visual changes (eg, floaters, decreased visual acuity) in one or both normal-appearing eyes. Both types of uveitis typically have a good prognosis and can be diagnosed by examination by an ophthalmologist [47]. More details regarding uveitis are found elsewhere. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)
Icteric leptospirosis (Weil's disease) — Icteric leptospirosis occurs in approximately 5 to 10 percent of symptomatic leptospirosis cases and is a rapidly progressive multisystem illness associated with mortality rates of 5 to 15 percent [34].
Usually, icteric leptospirosis is accompanied by fever, jaundice, and renal failure, a syndrome known as "Weil's disease." Pulmonary hemorrhage with acute respiratory distress syndrome (ARDS), myocarditis with electrocardiogram (EKG) abnormalities, and rhabdomyolysis may also occur as part of this syndrome [34,47-52]. Conjunctival suffusion is also common (picture 2).
●Hepatic findings – Physical examination reveals scleral icterus and jaundice, and conjugated bilirubin is elevated with normal or slightly elevated aminotransferases. In some cases, the serum bilirubin concentration reaches 60 to 80 mg/dL (1026 to 1368 mmol/L). Liver failure is rare, and liver enzymes and bilirubin abnormalities typically resolve without permanent liver damage.
●Renal findings – Renal failure may be oliguric or nonoliguric. The serum creatinine is often markedly elevated, and serum potassium abnormalities and hyponatremia are common [53,54]. Supportive renal replacement therapy (eg, hemodialysis) may be required for survival in up to half of patients with Weil’s disease, but complete renal recovery is typical after discontinuation of renal replacement therapy [55]. Although this manifestation is most commonly associated with icteric disease (Weil’s disease), some more recent reports suggest that acute kidney failure can sometimes occur in the absence of icterus and jaundice [51].
●Pulmonary findings – Severe pulmonary disease, characterized by pulmonary hemorrhage, is a serious complication of Weil's disease. This manifestation is seen in less than 5 percent of patients and has been reported to be fatal in 50 to 70 percent of patients [56]. Symptoms include shortness of breath, cough, and hemoptysis. Laboratory findings associated with pulmonary hemorrhage include thrombocytopenia, anemia, and results compatible with disseminated intravascular coagulation (DIC; elevated coagulation tests and D-dimer with low fibrinogen) [57]. Imaging typically reveals bilateral patchy peripheral infiltrates, often with a "snowflake" appearance, that can progress to confluent consolidation or a ground-glass appearance. Pathologically, these infiltrates may represent alveolar hemorrhage, ARDS, or pulmonary edema [58]. Death typically occurs within a few days of onset. This syndrome may be underdiagnosed in highly endemic regions and has sometimes been associated with nonicteric acute leptospirosis in recent reports [52,59].
●Cardiovascular findings – Cardiovascular abnormalities, including myocarditis with heart failure or cardiogenic shock, have been reported. EKG abnormalities have been reported in over half of patients with severe leptospirosis, with nonspecific ventricular repolarization disturbances being the most common finding [60]. Vasculitis with necrosis of extremities may also be seen in severe cases, including in children [52,61].
●Other findings – Other findings associated with icteric leptospirosis include neutrophilia (although the total WBC count can be normal, low, or elevated) and elevated creatine kinase consistent with rhabdomyolysis.
Special populations
Pregnant patients — Leptospirosis in pregnancy may be misdiagnosed as it can mimic other pregnancy-associated conditions, including other infections, pregnancy-associated hypertension, acute fatty liver, and HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome) [62]. Transplacental infection occurs, but the rate of fetal transmission and the type and frequency of fetal complications are unknown [62-64]. In one review of 14 pregnancies with active maternal infection, there were eight spontaneous abortions, four infants with active infection, and two healthy neonates [63]. Another series of 11 cases noted risk of abortion or fetal death of over 50 percent [64]. Information on sequelae in surviving neonates is sparse.
Immunocompromised patients — Limited data suggest that the clinical course and outcomes of leptospirosis in immunocompromised individuals is similar to that of immunocompetent individuals [65-67]. 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 [68].
DIAGNOSIS
Clinical suspicion — The level of suspicion for leptospirosis in a given patient depends primarily on the clinical syndrome and the local epidemiology of the infection.
Leptospirosis should be suspected in patients who have a compatible systemic febrile illness and no clear alternative explanation, especially if they have exposures to endemic or outbreak settings or have engaged in high-risk activities. In nonendemic areas, a high index of suspicion is necessary to make the diagnosis. A thorough history should be sought to assess for risk factors, including occupational hazards, exposures to bodies of fresh water, recent travel to endemic or flooded areas, or exposures to rats. The geographic prevalence and risk factors for infection are discussed in detail elsewhere. (See 'Epidemiology' above.)
Compatible syndromes include nonspecific febrile illness (especially if accompanied by conjunctival hyperemia or suffusion and calf myalgias), aseptic meningitis or uveitis (especially if preceded by a febrile illness), unexplained jaundice and acute kidney injury with fever, or unexplained pulmonary hemorrhage. The absence of conjunctival hyperemia or suffusion does not rule out the possibility of leptospirosis. In pregnant women, leptospirosis should be considered if similar syndromes occur along with spontaneous abortion or unexplained infection of the infant. Clinical manifestations are discussed in detail elsewhere. (See 'Clinical manifestations' above.)
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".)
Confirming the diagnosis — A definitive diagnosis is made by laboratory-based tests.
Approach to testing — When leptospirosis is suspected, we notify the microbiology laboratory prior to sending samples, so they can use specialized techniques. We send the following lab tests:
●Blood samples for polymerase chain reaction (PCR) and serology (immunoglobulin [Ig]M and IgG). We also send leptospire culture if available. We order follow-up serology 7 to 14 days after the initial serologic test.
●Urine samples for PCR (and leptospire culture if available). These are particularly valuable beyond one week after the onset of symptoms.
●Cerebrospinal fluid (CSF) for PCR (for patients with meningitis).
The diagnosis is confirmed by a positive PCR of blood or urine or by positive serologic testing; rarely, a diagnosis is made by a positive culture of blood or urine. The diagnosis is not ruled out by negative test results, because the sensitivity of leptospirosis testing is suboptimal.
Nucleic acid detection (eg, PCR) is most sensitive during the bacteremic phase (ie, the first week) of infection, with antibodies becoming detectable by serology after the first week. Hence, for timely diagnosis of patients with suspected leptospirosis, a combined serologic/molecular diagnostic approach is increasingly used [69,70]. The exact combination of tests used depends on local availability.
Details regarding each type of testing is found elsewhere. (See 'Molecular tests (eg, PCR)' below and 'Serology' below and 'Other tests' below.)
Molecular tests (eg, PCR) — Molecular tests, such as PCR, can provide rapid, accurate diagnosis of leptospirosis, especially early in the course of illness (ie, the acute phase) [71]. The tests are available commercially and from some public health laboratories, including the Centers for Disease Control and Prevention (CDC) in the United States.
A single positive PCR is confirmatory of leptospirosis infection. However, the sensitivity of PCR testing depends on the timing of collection of the sample relative to the onset of symptoms. Due to the transience of leptospires in bodily fluids, a negative PCR does not rule out leptospirosis.
PCR tests can be performed on multiple types of samples [10]:
●Blood – During the first four to six days of symptoms, leptospires are often detected by PCR in the blood.
●Urine – The organism may be intermittently identified by PCR in the urine during the first week of illness but is more reliably present after one week of illness.
●CSF – In patients with meningitis, PCR is often negative in the CSF, presumably because most cases of meningitis are due to immune-mediated mechanisms as opposed to ongoing active infection. CSF findings are discussed in detail above. (See '"Immune" phase (delayed phase of illness)' above.)
●Tissue – Although biopsy is rarely performed, PCR can be performed on tissue. From deceased patients, CDC suggests PCR testing of fresh frozen kidney (preferred) or liver samples.
The overall sensitivity of PCR tests in studies typically ranges from 40 to 60 percent in blood samples, and the specificity is above 95 percent [71-74]. In a meta-analysis of 11 studies categorized as having low risk of bias, conventional PCR performed on blood, urine, or both had a pooled sensitivity of 87 percent (95% CI, 44-98) and specificity of 97 percent (95% CI, 60-100) [71]. For real-time PCR, meta-analysis of 10 studies at low risk of bias revealed a median specificity of 92 percent, with significantly lower sensitivity (eg, sensitivity was only 40 percent when specificity was fixed at 90 percent on a receiver operating characteristic [ROC] curve). One of the main variables lending uncertainty in the included studies was lack of control for the timing of the testing relative to onset of symptoms.
Some molecular tests, such as real-time PCR and loop-mediated isothermal amplification, have the potential to be used as point-of-care tests in resource-limited settings because they don't require sophisticated microbiology laboratories and equipment. Sensitivity and specificity of such rapid tests has varied between studies [71,75-80].
Serology — Serologic tests measure specific immunoglobulin (Ig)M and IgG antibodies against Leptospira organisms [81].
To diagnose leptospirosis by serologic testing, one blood sample should be obtained upon presentation (ie, an acute sample) and a second sample should be obtained 7 to 14 days after the first antibody test is sent (ie, a convalescent sample). A four-fold change in IgG titer confirms infection.
If only one blood sample can be sent for serologic testing, a sample collected during the first 7 to 10 days of illness is preferred. A single IgG titer that is very high (eg, >1:800 on a microscopic agglutination test [MAT] test) is reasonable evidence of infection, although a single positive or negative IgM or IgG test cannot confirm or rule out infection.
Like PCR tests, serologic tests can be negative despite active or recent infection, particularly in specific situations:
●Antibodies to leptospirosis develop 3 to 10 days after onset of symptoms and may not reach detectable levels within the first week. Patients with negative initial serology can be confirmed to have infection if a subsequent convalescent sample shows a significant conversion from undetectable to a positive titer, as described above.
●Antibody tests that do not detect all serovars of Leptospira may produce negative results in the setting of true infection [82,83].
●In theory, antibiotic treatment may abort IgM and IgG production, which may prevent four-fold rises in convalescent titers, although this has not been specifically documented in studies.
Unlike PCR, serologic tests can be positive in the absence of ongoing infection, particularly in specific situations:
●Patients with past leptospirosis can have persistently positive IgG results, sometimes persisting for many years. As described above, correct timing of acute and convalescent titers can differentiate past from acute infection.
●Like IgG, a single positive IgM antibody titer should not be used to make a definitive diagnosis of acute or recent infection. IgM antibody tests are frequently offered by commercial labs, but many have been inadequately validated and their diagnostic performance is uncertain [84-86]. A positive IgM test can be suggestive of infection in the appropriate clinical setting and should prompt further confirmatory testing [10].
●In some situations, antibody tests can be positive due to cross-reactivity with other organisms (eg, syphilis). There are no definitive data that this occurs with leptospirosis antibody testing.
Serologic tests are available from multiple commercial laboratories and the United States CDC. Laboratories use different methodologies to perform serologic tests:
●Microscopic agglutination test (MAT) – The MAT is the historical reference standard for leptospirosis. The test requires live organisms, considerable expertise, and is performed only by reference laboratories, such as the CDC.
Despite its historical role as the reference standard, studies have suggested that MAT serologic testing may not be as sensitive as other diagnostic techniques and testing algorithms [74,82,83,87]. For instance, a meta-analysis of four studies involving over 1600 patients with suspected leptospirosis found a sensitivity for MAT of 50 percent (95% CI, 38-61) and a specificity of 99 percent (95% CI, 93-100); in this meta-analysis, the sensitivity of other types of serologic testing was higher and specificity was comparable [74].
●Other serologic tests – Serologic tests other than the MAT are widely available in commercial laboratories. Such tests include enzyme-linked immunosorbent assay (ELISA), immunofluorescence assay (IFA), lateral flow tests, and indirect hemagglutination tests [88,89].
Some serologic tests, such as the lateral flow assay, offer point-of-care testing. In a meta-analysis that compared a commonly used lateral flow assay with the MAT, the lateral flow assay had a pooled sensitivity and specificity of 75 percent (95% CI, 64-84) and 87 percent (95% CI, 77-94) respectively [90,91].
Other tests — Other tests that are used less frequently can be used to make a diagnosis.
●Culture – Although leptospirosis can be confirmed by culture of blood, urine, or CSF, the sensitivity of culture is suboptimal. Isolation of the organism is successful in 5 to 50 percent of cases and may take several weeks [74,92].
Blood and CSF specimens may be positive during the first 10 days of the illness. Urine cultures may become positive during the second week of the illness and remain positive for up to 30 days after the resolution of symptoms [36].
The laboratory needs to be notified prior to attempting to culture leptospires. Special media are required for isolation such as Fletcher's, Ellinghausen-McCullough-Johnson-Harris, or polysorbate-80 media. 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, identification of single colonies, and antimicrobial sensitivity testing [93].
●Antigen detection – Antigen detection in blood using a monoclonal anti-LipL32 antibody-based antigen capture ELISA has been developed and validated against PCR [94]. This test is not widely available but may provide a cost-effective alternative to PCR for diagnosis of early infection.
●Blood smears – Darkfield microscopic examination of a peripheral blood smear may sometimes reveal spirochetes during the first few days of infection. However, this test is hampered by low sensitivity and specificity, and it requires technical expertise and specialized laboratory equipment [95]. It is no longer recommended for routine diagnosis. The number of organisms in the blood must be substantial to visualize the organism: 104 leptospires/mL is necessary for one organism/field to be visible.
●Histopathology – Biopsies are rarely performed in patients suspected of leptospirosis infection. On formalin-fixed biopsied tissue, immunohistochemistry tests can confirm the diagnosis, including in deceased patients [10]. Acceptable tissues are kidney (preferred), liver, lung, heart, or spleen.
DIFFERENTIAL DIAGNOSIS — Leptospirosis may be difficult to distinguish from many other infectious illnesses and some noninfectious diseases. Conjunctival suffusion, when it occurs, is one of the most reliable distinguishing features since it rarely occurs with other infectious illnesses.
●Infectious etiologies
•Infections that also have conjunctival suffusion – These include measles, rubella, adenovirus, hantavirus, toxic shock syndrome, and Rocky Mountain spotted fever [96-98]. They each have distinguishing features (eg, rash) that may help differentiate them from leptospirosis. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Clinical manifestations' and "Rubella", section on 'Clinical manifestations' and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Clinical presentation' and "Hantavirus cardiopulmonary syndrome", section on 'Clinical features' and "Staphylococcal toxic shock syndrome", section on 'Clinical manifestations' and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever", section on 'Clinical manifestations'.)
•Severe sepsis and septic shock from common bacterial syndromes – Common infections such as bacterial pneumonia and bacteremia can cause multiorgan-system failure and sometimes are associated with jaundice. Blood and urine cultures, imaging, and other diagnostic tests can help to detect these infections. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Clinical presentation'.)
•Infections that are common in areas where leptospirosis is endemic
-Malaria – This infection can present with mild nonspecific febrile illness or multiorgan-system involvement, including jaundice. In areas where malaria is endemic, it should be ruled out by blood smear or polymerase chain reaction (PCR). (See "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)
-Dengue and chikungunya [99] – Dengue can be difficult to distinguish from leptospirosis because both are febrile illnesses that can range from mild disease to severe illness with hemorrhage and eye findings. Chikungunya is a typically mild, nonspecific febrile illness, although in some cases it can present with diffuse arthritis. Jaundice is uncommon in both infections. (See "Dengue virus infection: Clinical manifestations and diagnosis" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)
-Scrub typhus presents similarly to the acute phase of leptospirosis. A distinguishing feature is rash (often including the face), eschar at the site of a chigger bite, and regional lymphadenopathy. (See "Scrub typhus", section on 'Clinical manifestations'.)
-Other rickettsial disease, including Rickettsia typhi (murine typhus) or spotted fever group rickettsiae, may present with a broad range of infectious symptoms. Murine typhus may have ocular hemorrhage as well as rash. (See "Murine typhus" and "Other spotted fever group rickettsial infections".)
-Typhoid and paratyphoid fever can mimic leptospirosis, particularly in patients with prominent gastrointestinal complaints. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)
-Hantavirus and other hemorrhagic fevers can present with renal, pulmonary, and ophthalmologic complications similar to those observed in leptospirosis. Like leptospirosis, rodents are important reservoirs for hantavirus. (See "Kidney involvement in hantavirus infections" and "Hantavirus cardiopulmonary syndrome" and "Lassa fever", section on 'Clinical manifestations' and "Clinical manifestations and diagnosis of Ebola virus disease", section on 'Clinical manifestations' and "Yellow fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Crimean-Congo hemorrhagic fever", section on 'Clinical manifestations'.)
-Acute viral hepatitis, especially hepatitis A, can present with fever and jaundice. Renal and pulmonary involvement are uncommon. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Hepatitis B virus: Clinical manifestations and natural history", section on 'Acute hepatitis'.)
•Other infectious etiologies
-Tickborne infections – In addition to rickettsial infections, Ehrlichiosis, Anaplasma, and Babesia can present with nonspecific febrile syndromes. Renal involvement is uncommon but can occur in severe cases. Pulmonary involvement is rare. Jaundice may be present in babesiosis. (See "Human ehrlichiosis and anaplasmosis" and "Babesiosis: Clinical manifestations and diagnosis".)
-Acute viral illnesses – Common viral infections, including influenza, can mimic the acute phase of leptospirosis, particularly in patients with prominent respiratory tract symptoms. Kidney injury, jaundice, and pulmonary hemorrhage are uncommon. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)
●Noninfectious etiologies – Several noninfectious syndromes can be associated with fever and a combination of either kidney, liver, or pulmonary manifestations, including the following:
•Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome (TTP/HUS) – These syndromes are associated with fever, thrombocytopenia, acute kidney injury, and jaundice. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
•Vasculitic pulmonary-renal syndromes – Autoimmune vasculitic syndromes may be associated with fever, pulmonary hemorrhage, and acute kidney injury. Such syndromes include ANCA-associated vasculitis, anti-glomerular basement membrane disease, and systemic lupus erythematosus. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Clinical manifestations' and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies" and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)
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
●Microbiology – Leptospira are spiral-shaped, highly motile aerobic spirochetes with 18 or more coils per cell. (See 'Microbiology' above.)
●Epidemiology – Leptospirosis is a worldwide zoonotic infection but is most prevalent in tropical regions. Disease in humans is usually sporadic, although outbreaks may occur from common source exposures. (See 'Prevalence and geography' above and 'Outbreaks' above.)
●Transmission to humans – Mammals (especially rodents) act as the primary reservoir for Leptospira, and they shed the organism in their urine into the environment. Humans become infected via contact with urine-contaminated soil or freshwater through cuts or abraded skin, mucous membranes, or conjunctivae. (See 'Animal and environmental reservoirs' above and 'Transmission to humans' above.)
●Risk factors – Numerous risk factors have been identified, including occupation (eg, farming, sewer work, military), recreational activity (eg, freshwater swimming, kayaking, gardening), household (eg, pet dogs, infestation by rodents), travel to endemic areas, and living in overcrowded urban areas with poor sanitation. (See 'Risk factors' above.)
●Clinical manifestations – Most cases are mild or asymptomatic, although some are severe and potentially fatal. Two distinct syndromes have been identified:
•Anicteric leptospirosis – The majority of symptomatic patients have this form of disease. It is generally described as a biphasic illness, although most only experience the acute phase. (See 'Anicteric leptospirosis' above.)
-Acute phase – This phase typically lasts about one week and is a nonspecific febrile illness characterized by abrupt onset of fever, rigors, myalgias (especially in the calves and lower back), and headache. A distinguishing feature is conjunctival suffusion, which occurs in over half of patients. (See 'Acute phase (first week of illness)' above.)
-"Immune" phase – A minority of patients experience this phase, which is characterized by return of fever, headache, and myalgia that last about one week. Aseptic meningitis and uveitis can complicate this phase. (See '"Immune" phase (delayed phase of illness)' above.)
•Icteric leptospirosis (Weil's disease) – This rapidly progressive multisystem illness occurs in 5 to 10 percent of patients and has a mortality rate of 5 to 15 percent. Features include fever, jaundice, and renal failure. Pulmonary hemorrhage is a severe complication that has been reported to be fatal in 50 to 70 percent of affected patients. (See 'Icteric leptospirosis (Weil's disease)' above.)
●Diagnosis – Leptospirosis should be suspected in patients who have a compatible febrile illness with no clear alternative explanation, especially in endemic areas or outbreak settings. A high index of suspicion is necessary to make the diagnosis, and a thorough history should be performed to assess for risk factors. (See 'Clinical suspicion' above.)
The diagnosis is confirmed by a positive polymerase chain reaction (PCR) of blood or urine or by positive serologic testing; rarely, a diagnosis is made by a positive culture of blood or urine. The diagnosis is not ruled out by negative test results because the sensitivity of leptospirosis testing is suboptimal.
•Diagnostic evaluation – When leptospirosis is suspected, we send the following lab tests (see 'Confirming the diagnosis' above):
-Blood samples for PCR, serology (IgM and IgG), and culture, if available. We also send follow-up serology 7 to 14 days after the initial serologic test.
-Urine samples for PCR and culture, if available.
-CSF for PCR (for patients with meningitis).
We notify the microbiology laboratory prior to sending cultures so they can use specialized techniques to culture the organism, if available.
●Differential diagnosis – The differential diagnosis is broad and depends on the geographic location. In endemic areas, malaria, dengue, typhus, typhoid fever, hepatitis A, and hemorrhagic fevers should be considered, among numerous other infections.
Severe sepsis and septic shock from bacterial infections can mimic leptospirosis, especially in patients suspected of having icteric leptospirosis (Weil’s disease).
Noninfectious mimickers include thrombotic thrombocytopenic purpura (TTP) and vasculitic pulmonary-renal syndromes. (See 'Differential 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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