Leptospirosis

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Background

Leptospirosis is a disease that is caused by pathogenic spirochetes of the genus Leptospira. It is considered the most common zoonosis in the world. Leptospirosis has recently been recognized as a re-emerging infectious disease among animals and humans[1] and has the potential to become even more prevalent with anticipated global warming. Leptospirosis is distributed worldwide (sparing the polar regions) but is most common in the tropics.

Humans and a wide range of animals, including mammals, birds, amphibians, and reptiles can develop Leptospira infection. However, humans are rarely chronic carriers and are therefore considered accidental hosts. Leptospirosis is transmitted via direct contact with the body fluid of an acutely infected animal or by exposure to soil or fresh water contaminated with the urine of an animal that is a chronic carrier.

Human leptospirosis is often acquired via contact with fresh water contaminated by bovine, rat, or canine urine as part of occupational contact with these animals. The disease is also acquired during adventure travel or vacations that involve water sports or hiking, or even as a consequence of flooding.

The burgeoning exotic-pet trade further increases the likelihood of transmission. In 2005, leptospirosis was transmitted from southern flying squirrels imported from Miami, Florida, to two Japanese animal handlers employed by an importer of exotic pets. Endemic canine leptospirosis is becoming more common in the United States, and California has seen a re-emergence of disease since 2000.

Leptospirosis in humans is characterized by an acute febrile illness followed by mild self-limiting sequelae or an even more severe, and often fatal, multiorgan involvement. The disease was first described by Larrey in 1812 of fièvre jaune among Napoleon's troops at the siege of Cairo. It was initially believed to be related to the plague but not as contagious. Throughout the remainder of the 19th century, the illness was known in Europe as bilious typhoid.

A little over 100 years ago, Adolph Weil published his historic paper describing the most severe form of infection that would be later known as Weil disease.

In 1907, special staining techniques were used to confirm that a spirochete was responsible for this illness. A postmortem examination of the kidney of a person with Weil disease contained a spiral organism with hooked ends, which was first named Spirochaeta interrogans.

Pathophysiology

The leptospires are thin, coiled, gram-negative, aerobic organisms 6-20 µm in length. They are motile, with hooked ends and paired axial flagella (one on each end), enabling them to burrow into tissue. Motion is marked by continual spinning on the long axis. They are unique among the spirochetes in that they can be isolated on artificial media.

Leptospires belong to the order Spirochaetales and the family Leptospiraceae. Traditionally, the organisms are classified based on antigenic differences in the lipopolysaccharide envelopes that surround the cell wall. Serologic detection of these differences, therefore, is based on identifying serovars within each species. Based on this system, the genus Leptospira contains two species—the pathogenic Leptospira interrogans, with at least 218 serovars, and the nonpathogenic, free-living, saprophytic Leptospira biflexa, which has at least 60 serovars.

Current studies that classify the organisms based on DNA relatedness identify at least 7 pathogenic species of leptospires. However, organisms that are identical serologically may be different genetically, and organisms with the same genetic makeup may differ serologically. Therefore, some authors feel that the traditional serologic system is the most useful from a diagnostic and epidemiologic standpoint.

Although not fully understood, leptospires are believed to enter the host through abrasions in healthy skin, through sodden and waterlogged skin, directly through intact mucus membranes or conjunctiva, through the nasal mucosa and cribriform plate, through the lungs (after inhalation of aerosolized body fluid), or through the placenta during pregnancy. Virulent organisms in a susceptible host gain rapid access to the bloodstream through the lymphatics, resulting in leptospiremia and spread to all organs. The incubation period is usually 5-14 days but has been described from 72 hours to a month or more.

If the host survives the acute infection, septicemia and multiplication of the organism persist until the development of opsonizing immunoglobulin in the plasma, followed by rapid immune clearance. However, after clearance from the blood, leptospires remain in immunologically privileged sites, including the renal tubules, brain, and anterior chamber of the eye, for weeks to months. In humans, leptospires in the renal tubules and resulting leptospiruria rarely persist longer than 60 days.

During acute infection, leptospires are thought to multiply in the small blood vessel endothelium, resulting in damage and vasculitis. The major clinical manifestations of the disease are believed to be secondary to this mechanism, which can affect nearly any organ system.

Clinical manifestations of leptospirosis after the acute infection are the result of the inflammatory response, as well as action of the remaining organisms in the aqueous humor.

Epidemiology

Frequency

United States

Leptospirosis is a ubiquitous disease found throughout the world. Leptospirosis is no longer a reportable disease in the United States; however, numerous states, including Hawaii, continue to report. An estimated 100-200 cases are identified annually in the United States, with about 50% of cases occurring in Hawaii. The state of Hawaii is affected more than any other state.

Over the past 20 years, epidemiology has begun to shift from primarily recreational water exposures to an increasing number of occupational exposures related to farm and agricultural activities.[4]

Because most cases are self-limiting and unreported, underreported, or even misdiagnosed, the true incidence is difficult to determine.

International

Up to 80% of individuals in tropical areas are estimated to have positive seroconversion rates, indicating either past or present infection.

Mortality/Morbidity

The mortality rate in severe leptospirosis has been described as ranging from 5-40%. The mild form of the illness is rarely fatal, and an estimated 90% of cases fall into this category. Elderly and immunocompromised people are at the highest risk of mortality overall.

Subclinical infection is controversial. Evidence from limited population studies during epidemics have indicated agglutination titers are elevated in more people than are clinically infected with the disease.

Sex

Although leptospirosis is rare in pregnancy, acute infection without fever may mimic the clinical pattern of HELLP (hemolytic anemia, elevated liver enzymes, low platelet count) syndrome or acute fatty liver of pregnancy, and the diagnosis may be a challenge.[5]

Age

No evidence suggests that leptospirosis affects persons of various races, ages, or sexes differently. However, because occupational exposure constitutes a major risk for development of disease, a disproportionate number of working-aged males seem to be affected.

In addition, immunosuppressed patients may develop a fulminant course of leptospirosis. Two cases of Weil syndrome in transplant patients have been described.[6]

History

A good clinical history is often the key to accurate diagnosis in leptospirosis. Important features include a plausible exposure history and a clinical picture consistent with the disease.

Leptospirosis occurs worldwide wherever risk of contact with the urine, kidneys, or conception products of infected animals exists. Typically, rodents, dogs, cattle, and pigs are considered reservoirs for this organism; however, increasing diversity of travel and exotic-pet trade are expanding the list. The leptospires may live for years in the renal tubules of animals and are excreted in the urine into standing water or soil. This explains sources of both direct infection (eg, body fluids or organs of infected animals) and indirect infection (eg, inoculated soil or water). In 2004, cases were linked to flood water in urban endemic regions of Hawaii. In tropical settings, leptospirosis is becoming more prevalent among travelers and residents. For example, recreational activities in rivers (eg, white-water rafting) may be a significant risk factor for infection with leptospires.

Leptospires can live outside the body for several weeks. They enter the body through disrupted skin or mucosal barriers, such as abrasions or waterlogged skin. Other means of infection have been documented, including inhalation of aerosolized leptospires and direct infection across intact mucus membranes or conjunctivae. After an incubation period of 2-30 days (typically 5-14 d), clinical symptoms ensue. A plausible history of possible exposure must precede clinical symptoms in order to consider the diagnosis of leptospirosis.

Expert consensus is that leptospirosis occurs as two recognizable clinical syndromes. A third syndrome of asymptomatic infection is more controversial. Anicteric leptospirosis is a self-limited disease similar to a mild flulike illness. Icteric leptospirosis, also known as Weil disease, is a severe illness characterized by multiorgan involvement or even failure. Two distinct phases of illness are observed in the mild form—the septicemic (acute) phase and the immune (delayed) phase. In icteric leptospirosis, the 2 phases of illness are often continuous and indistinguishable. At disease onset, clinically predicting the severity of disease is not possible. Subsequent sequelae depend on the serovar involved and the health, nutritional status, and age of the patient, as well as the rapidity of definitive and supportive treatment.

An acute illness follows any infection with any serovar of leptospirosis. Most of the following symptoms develop in varying degrees: high temperature (38-40°C), rigors, sudden headache, nausea and vomiting, anorexia, diarrhea, cough, pharyngitis, nonpruritic skin rash, and muscle pain. Muscle pains are typically localized to the calf and lumbar areas. This phase of illness lasts 5-7 days and either regresses to a relatively asymptomatic period or progresses to a more severe illness. In anicteric leptospirosis, the acute illness is followed by 1-3 days without fever and then progresses to 4-30 days of the immune (delayed) phase of the illness.

Physical

The physical examination findings differ depending on the severity of disease and the time from onset of symptoms. Patients may appear mildly ill or toxic. Early in the disease, temperatures as high as 40°C and tachycardia are common. Hypotension, oliguria, and abnormal chest auscultation at presentation may portend severe illness. When fever is severe and prolonged, hypotension and shock due to volume depletion may also occur. The fever typically subsides within 7 days.

Early in the disease, the skin is warm and flushed. Additional skin findings include a transient petechial eruption that can involve the palate. Later in severe disease, jaundice and purpura can develop. The classic ocular finding of conjunctival suffusion occurs early irrespective of disease severity. Conjunctival suffusion is characterized by redness of the conjunctiva that resembles conjunctivitis but that does not involve inflammatory exudates.

Uveitis is a common feature following acute leptospirosis; however, patients who receive antibiotics during the acute phase of illness may develop only mild uveitis.[7]

Muscle tenderness can occur with the myositis of early infection. This can be particularly prominent in the paraspinal and calf muscles but can involve any muscle. Neurologic examination can reveal signs of meningitis, including neck stiffness and rigidity and photophobia. Early in the disease, the stiffness on neck examination can be confused as muscular in origin; however, this symptom may actually represent early meningismus.

Lung examination results may be normal in early or mild illness. In severe illness, signs of consolidation due to alveolar hemorrhage may be found. In patients with cardiac-related pulmonary edema, rales and wheezes can be heard.

The incidence of pulmonary involvement has increased over the past few years, affecting up to 70% patients. Alveolar hemorrhage that manifests as dyspnea and hemoptysis is the main pulmonary manifestation. This clinical manifestation may be severe and can occur in the absence of typical presentations of Weil disease.

Pulmonary involvement has emerged as a serious cause of mortality, becoming the main cause of leptospirosis-associated death in some countries.[8, 9]

Myocarditis may occur in severe disease. All of the physical findings of biventricular heart failure can be found, including elevated jugular venous pulsations; a new S3 gallop; and dysrhythmias, including atrial fibrillation, heart blocks of varying severity, and ventricular ectopy.

Abdominal examination may reveal liver enlargement and tenderness due to hepatitis. Acalculous cholecystitis, which may be suggested by a positive Murphy sign, is a finding of profound systemic illness. Pancreatitis has also been described in severe cases.[10]

Heme-positive stool and even gross blood can be found on rectal examination in patients with DIC and bleeding.

In severe disease, delirium may develop either as a consequence of shock or independent of it. Delirium may be an early finding in severe disease. Late in disease and into convalescence, prolonged mental symptoms may persist, including depression, anxiety, irritability, psychosis, and even dementia.

Laboratory Studies

Laboratory studies are used for two purposes—to confirm the diagnosis and to determine the extent of organ involvement and severity of complications. Laboratory confirmation of leptospirosis can be accomplished in 2 different ways.

Isolation of the leptospires from human tissue or body fluids is the criterion standard. Urine is the most reliable body fluid to study because the urine contains leptospires from the onset of clinical symptoms until the third week of infection. Other body fluids (eg, blood, cerebrospinal fluid [CSF]) contain the organism, but the window of opportunity to isolate them is shorter.

Tissues (ie, liver, muscle, kidney, skin, eyes) are also sources of identification of the leptospires but are obviously more complicated to acquire. Isolation of leptospires can be difficult and time consuming, involving reference laboratories and often taking several months to complete.

More often, paired acute and convalescent serum specimens are used to confirm the diagnosis. Again, this is a delayed means of confirmation because the acute sera are collected 1-2 weeks after onset of symptoms, and the convalescent sera are collected 2 weeks afterward. Antileptospire antibodies in these samples are detected using the microscopic agglutination test (MAT). The Centers for Disease Control and Prevention (CDC) laboratory in Atlanta, Georgia, performs the MAT using 23 leptospire antigens. A 4-fold rise in MAT titer between acute and convalescent sera with any of these antigens confirms the diagnosis of leptospirosis.

See the image below.


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Darkfield microscopy of leptospiral microscopic agglutination test. (This image is in the public domain and thus free of any copyright restrictions. C....

Faster laboratory methods may strongly suggest the diagnosis of leptospirosis, but they may be no more readily available than the CDC laboratory in Atlanta. A single MAT titer of 1:800 on any sera or identification of spirochetes on dark-field microscopy, when accompanied by the appropriate clinical scenario, is strongly suggestive.

In suspected leptospirosis, further laboratory studies should be routinely performed to determine the extent and severity of organ involvement after the acute phase of illness. A CBC count is necessary.

See the image below.


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A scanning electron micrograph depicting Leptospira atop a 0.1-µm polycarbonate filter. (This image is in the public domain and thus free of any copyr....

Significant anemia due to pulmonary and gastrointestinal hemorrhage can occur. The platelet count may be diminished as a component of DIC.

Levels of blood urea nitrogen and serum creatinine may be profoundly elevated in the anuric or oliguric phase. Tubulointerstitial nephritis is the main cause of acute renal injury in Weil disease. In addition, renal magnesium and potassium wasting is common in persons with leptospirosis.[11]

Serum bilirubin levels elevate as part of the obstructive disease due to capillaritis in the liver. Levels of hepatocellular transaminases are elevated less often and less significantly (usually < 200 U/L). Jaundice and bilirubinemia disproportional to hepatocellular damage is common in leptospirosis; alkaline phosphatase levels may be elevated 10-fold.

Coagulation times may be elevated in patients with hepatic dysfunction and/or DIC.

Serum creatine kinase levels (MM fraction) are often elevated in patients with muscular involvement.

Analysis of the CSF is useful only in excluding other causes of bacterial meningitis. Leptospires is routinely isolated from the CSF, but this finding does not change management of the disease.

Imaging Studies

Imaging studies are also useful in determining the extent and severity of organ involvement.

The most common abnormality on chest radiography is bilateral diffuse airspace disease. Chest radiography may also reveal cardiomegaly and pulmonary edema due to myocarditis. In patients with alveolar hemorrhage due to pulmonary capillaritis, the lung parenchyma may contain multiple patchy infiltrates.

Biliary tract ultrasonography can reveal an acalculous cholecystitis.

Histologic Findings

Shortly after inoculation and during the incubation period, leptospires are actively replicating in the liver. The leptospires then disseminate throughout the body and infect multiple tissues.

Silver staining and immunofluorescence are used to identify leptospires in the liver, spleen, kidney, CNS, muscles, and heart. During this acute phase, histology reveals these organisms without much inflammatory infiltrate. In addition to the finding of leptospires during histologic examination, the pathologic effects of leptospiral toxins are also apparent. See the image below.


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Silver stain, liver, fatal human leptospirosis. (This image is in the public domain and thus free of any copyright restrictions. Courtesy of the Cente....

Leptospirosis may be seen as an infective systemic vasculitis.[12] Leptospiral toxins break down endothelial cell membranes of capillaries. This toxin-mediated process allows for extravasation of blood and leptospires from blood vessels into the supported parenchyma. Secondarily, because the capillaries are no longer functional, ischemia and cell death can occur. Later in infection, mononuclear cells predominate in the areas of this focal cell necrosis.

Leptospires can be identified in immunologically privileged sites, such as renal tubules, CNS, and the anterior chamber of the eyes, for weeks to months after the initial infection. In nonhuman animals, the intended hosts of infection, the leptospires establish residence in these immunologically privileged sites. Provided that the animal survives the initial infection, a chronic carrier state is then established, and histology reveals leptospires at these sites for years after initial infection.

Medical Care

Leptospirosis is treated primarily with antimicrobial therapy. In uncomplicated infections that do not require hospitalization, oral doxycycline has been shown to decrease duration of fever and most symptoms. Hospitalized patients should be treated with intravenous penicillin G therapy, the treatment of choice. A recent clinical trial showed that third-generation cephalosporins are as effective as doxycycline and penicillin in the treatment of acute disease. A review of 7 randomized clinical trials comparing penicillin to no treatment or placebo, as well as penicillin to other agents, yielded inconclusive support for or against antibiotic therapy, especially in severe leptospirosis. A suggestion of shortened duration of illness with IV penicillin did not achieve statistical significance, nor was a difference demonstrated by any intervention in mortality or fever duration.[13]

Severe cases of leptospirosis can affect any organ system and can lead to multiorgan failure. In addition to antimicrobials, therapy is supportive. Patients should be managed in a monitored setting because their condition can rapidly progress to cardiovascular collapse and shock. Renal function should be evaluated carefully and dialysis considered in cases of renal failure. In most cases, the renal damage is reversible if the patient survives the acute illness. Access to mechanical ventilation and airway protection should be available in the event of respiratory compromise. Continuous cardiac monitoring should be attained; arrhythmias, including ventricular tachycardia and premature ventricular contractions, as well as atrial fibrillation, flutter, and tachycardia, can occur.

A few cases in the literature have reported that plasma exchange, corticosteroids, and intravenous immunoglobulin may be beneficial in selected patients in whom conventional therapy does not elicit a response.[14, 15, 16]

Consultations

In severe cases of leptospirosis, several specialty consultations may aid in proper patient management. An infectious disease specialist may assist in differentiating leptospirosis from diseases with similar presentations but that may have significantly different treatments. A nephrologist should be alerted early in the course because the need for dialysis may present rapidly. If available, critical care specialists may be best prepared to manage patients with affected multiple systems. Finally, for assistance with laboratory diagnosis, the CDC or the World Health Organization (WHO) can aid the clinician in obtaining samples and ordering test.

Diet

In mild cases, patients should be encouraged to maintain adequate fluid intake to avoid volume depletion. In more severe cases, diets appropriate for the clinical picture should be ordered, eg, electrolyte and protein restriction in cases of renal insufficiency. Patients with hypotension or clinical shock should not be fed enterally until adequate perfusion is restored.

Activity

Patients with severe disease should be placed on bed rest until adequately resuscitated and treated. Those with mild disease can pursue activity as tolerated.

Medication Summary

In general, antibiotic therapy should be effective against leptospirosis and against the other pathogens considered in the differential diagnoses. However, what follows is a description of therapy specific to leptospirosis only.

Penicillin G (Pfizerpen, Permapen)

Clinical Context:  First-line antibiotic therapy. Interferes with synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.

Doxycycline (Vibramycin, Doryx)

Clinical Context:  Inhibits protein synthesis, and thus bacterial growth, by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Erythromycin (E.E.S., E-Mycin, Eryc)

Clinical Context:  In pregnant patients who are allergic to penicillin, erythromycin is the therapy of choice.

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Amoxicillin (Amoxil, Trimox)

Clinical Context:  Alternative therapy. Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Cefotaxime (Claforan)

Clinical Context:  Third-generation cephalosporin with broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, which in turn inhibits bacterial growth. Used for septicemia and treatment of gynecologic infections caused by susceptible organisms.

Ceftriaxone (Rocephin)

Clinical Context:  Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Bactericidal activity results from inhibiting cell wall synthesis by binding to one or more penicillin-binding proteins. Exerts antimicrobial effect by interfering with synthesis of peptidoglycan, a major structural component of bacterial cell wall. Bacteria eventually lyse owing to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.

Highly stable in presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of dose excreted unchanged in urine, and remainder secreted in bile and ultimately in feces as microbiologically inactive compounds. Reversibly binds to human plasma proteins, and binding have been reported to decrease from 95% bound at plasma concentrations < 25 mcg/mL to 85% bound at 300 mcg/mL.

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.

Further Inpatient Care

Further Outpatient Care

Transfer

Deterrence/Prevention

Complications

Prognosis

Author

Sandra G Gompf, MD, FACP, FIDSA, Associate Professor of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Ana Paula Velez, MD, Assistant Professor of Medicine, Division of Infectious Disease and International Medicine, University of South Florida College of Medicine and James A Haley Veterans Affairs Medical Center; Attending Physician, Moffitt Cancer Center

Disclosure: Nothing to disclose.

Specialty Editors

Maria D Mileno, MD, Associate Professor of Medicine, Division of Infectious Diseases, The Warren Alpert Medical School of Brown University

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Charles V Sanders, MD, Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthors Juan D Diaz, DO; Matthew R Jezior, MD; Cecily K Peterson, MD; and Joseph T Morris, MD, to the development and writing of this article.

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

A scanning electron micrograph depicting Leptospira atop a 0.1-µm polycarbonate filter. (This image is in the public domain and thus free of any copyright restrictions. Courtesy of the Centers for Disease Control/Rob Weyant)

Silver stain, liver, fatal human leptospirosis. (This image is in the public domain and thus free of any copyright restrictions. Courtesy of the Centers for Disease Control/Dr. Martin Hicklin)

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

A scanning electron micrograph depicting Leptospira atop a 0.1-µm polycarbonate filter. (This image is in the public domain and thus free of any copyright restrictions. Courtesy of the Centers for Disease Control/Rob Weyant)

Silver stain, liver, fatal human leptospirosis. (This image is in the public domain and thus free of any copyright restrictions. Courtesy of the Centers for Disease Control/Dr. Martin Hicklin)