AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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Background

Leptospirosis is a disease caused by pathogenic spirochetes of the genus Leptospira. It is considered the most common zoonosis in the world. Its distribution is worldwide (sparing the polar regions), occurring with the greatest frequency in the tropics.

Humans and a wide range of animals, including mammals, birds, amphibians, and reptiles are affected. However, humans rarely are chronic carriers and, therefore, are considered accidental hosts. Transmission occurs by 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 disease is often acquired via contact with fresh water contaminated by bovine, rat, or canine urine and may be encountered with increasing interest in adventure travel or vacations that involve water sports or hiking. Increasing exotic pet trade further enhances the likelihood of transmission. In 2005, leptospirosis was transmitted from southern flying squirrels imported from Miami, Fla, to two Japanese animal handlers employed by an importer of exotic pets. Endemic canine leptospirosis is on the rise in the United States, and California has seen 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. It was first described by Larrey in 1812 of fièvre jaune among Napoleon's troops at the siege of Cairo. It initially was thought 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 first was 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, identifies serovars within each species. Based on this system, 2 species exist within the genus Leptospira—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 be different 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 thought 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 usually is 5-14 days, but it 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 felt to be secondary to this mechanism, which can affect nearly any organ system.

• In the kidneys, interstitial nephritis, tubular necrosis, and impaired capillary permeability, as well as the associated hypovolemia, result in renal failure.
• Liver involvement is marked by centrilobular necrosis and Kupffer cell proliferation, with hepatocellular dysfunction.
• Pulmonary involvement is secondary to alveolar and interstitial vascular damage resulting in hemorrhage.
• The skin is affected by epithelial vascular insult.
• Skeletal muscle involvement is secondary to edema, myofibril vacuolization, and damage to vessels.
• The damage to the vascular system as a whole can result in capillary leakage, hypovolemia, and shock.

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

Frequency

United States

Leptospirosis is a ubiquitous disease found throughout the world, as well as within the United States. 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. Because most cases are self-limiting and unreported, underreported, or even misdiagnosed, the true incidence is difficult to determine.

International

As many as 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 rarely is fatal, and an estimated 90% of cases fall into this category. Elderly and immunocompromised people have the highest risk of mortality overall.

Controversy exists regarding the occurrence of subclinical infection. Evidence from limited population studies during epidemics indicates that more people have a rise in agglutination titers than are clinically infected with the disease.

Age

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

CLINICAL

Section 3 of 11  

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History

A good clinical history often is 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 regions of Hawaii where the illness is endemic. In tropical settings, leptospirosis is increasingly being recognized as affecting travelers and residents. For example, recreation in rivers such as white-water river rafting can 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 (most typically, time is 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 2 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 multiple multiorgan system involvement or even failure. Two distinct phases of illness are observed in the mild form—the septicemic (acute) phase and the immune phase (delayed). In icteric leptospirosis, the 2 phases of illness often are continuous and indistinguishable. At the time of onset, clinically predicting if a mild or severe form of the disease will develop 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. Some degree of most of the following symptoms will occur: high temperature (38-40°C), rigors, sudden headache, nausea and vomiting, anorexia, diarrhea, cough, pharyngitis, nonpruritic skin rash, and muscle pain. Muscle pains classically are localized to the calf and lumbar areas. This phase of illness will last 5-7 days and either will regress to a relatively asymptomatic period or will progress to a more severe illness. In anicteric leptospirosis, the acute illness is followed by 1-3 days without fever, and then it progresses to 4-30 days of the immune, or delayed, phase of the illness.

Physical

The physical examinations of patients differ depending on the severity of disease and the time from onset of symptoms. On general appearance, patients can present with symptoms that fall anywhere on the spectrum of a very mildly ill appearance to a toxic appearance. Early in the disease, temperatures as high as 40°C and tachycardia occur commonly. Hypotension, oliguria, and abnormal chest auscultation at time of presentation may predict severe illness. When fever is severe and prolonged, hypotension and shock also may occur from volume depletion. Typically, the fever 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 the severity of disease. Conjunctival suffusion is characterized by redness of the conjunctiva that is similar to conjunctivitis but without inflammatory exudates.

Muscle tenderness can occur with the myositis of early infection. This particularly can be 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 actually may represent early meningismus.

Lung examination results can be normal in early or mild illness. In severe illness, signs of consolidation can be found as a result of alveolar hemorrhage. In patients with cardiac-related pulmonary edema, rales and wheezes can be heard. Additionally, in the myocarditis of 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 can reveal liver enlargement and tenderness from hepatitis. A positive Murphy sign can be observed in patients who develop acalculous cholecystitis. The latter in particular is a finding of very severe systemic illness from leptospirosis. Heme-positive stool and even gross blood can be found on rectal examination in patients with disseminated intravascular coagulation (DIC) and bleeding.

Occasionally, in severe disease, delirium may develop either as a consequence of or independently of shock. Delirium can 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.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Enteric fever
Hantavirus
Rickettsial disease
Encephalitis
Primary HIV infection

WORKUP

Section 5 of 11  

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• Follow-up
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Lab Studies

• Laboratory studies are used for 2 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 leptospires are present in the urine at the start of clinical symptoms and persist into 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) also are sources of identification of the leptospires but obviously are 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 at 1-2 weeks after onset of symptoms and the convalescent sera are collected 2 weeks after that. Antileptospire antibodies in these samples are detected using the microscopic agglutination test (MAT). The Centers for Disease Control and Prevention (CDC) laboratory in Atlanta, Ga 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.
• Faster laboratory methods may suggest the diagnosis of leptospirosis strongly, 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 evaluated routinely to determine the extent and severity of organ involvement after the acute phase of illness. A complete blood count (CBC) is necessary.
• • Significant anemia can occur secondary to pulmonary and gastrointestinal hemorrhage. The platelet count can be diminished as a component of DIC. Blood urea nitrogen and serum creatinine can be profoundly elevated in the anuric or oliguric tubulointerstitial nephritis that can occur in Weil disease.
  • Serum bilirubin levels elevate as part of the obstructive disease that occurs as a result of the capillaritis in the liver. Hepatocellular transaminases are elevated less often and less significantly (usually <200 U/L).
  • Coagulation times can be elevated with hepatic dysfunction and/or DIC. Serum creatine kinase (MM fraction) often is elevated with muscular involvement.
• Analysis of the CSF is useful only in excluding other causes of bacterial meningitis. Leptospires can be isolated from the CSF routinely, but this finding does not change management of the disease.

Imaging Studies

• Imaging studies also are useful in determining the extent and severity of organ involvement.
• • The most common finding on an abnormal chest radiograph is bilateral diffuse air space disease. The chest radiograph can reveal cardiomegaly and pulmonary edema as a result of myocarditis. In alveolar hemorrhage from pulmonary capillaritis, multiple patchy infiltrates can be observed in the lung parenchyma.
  • 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 will identify leptospires in the liver, spleen, kidney, CNS, and muscles. 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 also can be observed.

Leptospiral toxins cause breakdown of 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 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 then is established, and histology will reveal leptospires at these sites for years after an initial infection.

TREATMENT

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Medical Care

• Antimicrobial therapy is the mainstay of treatment in leptospirosis. For uncomplicated infection not requiring hospitalization, oral doxycycline has been shown to decrease duration of fever as well as 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.
• 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 the progression towards cardiovascular collapse and shock can occur rapidly.
  • 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.

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 physicians may be best prepared to manage the patient 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

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

Drug Category: Antibiotics

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.

Drug Name	Doxycycline (Vibramycin, Doryx)
Description	Inhibits protein synthesis, and thus bacterial growth, by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Adult Dose	100 mg IV q12h 100 mg PO bid for outpatient oral therapy of less severe infection
Pediatric Dose	<8 years: Not recommended >8 years: Not established
Contraindications	Documented hypersensitivity; severe hepatic dysfunction
Interactions	Bioavailability is slightly decreased with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy
Pregnancy	D - Unsafe in pregnancy
Precautions	Photosensitivity rarely may occur; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth

Drug Name	Erythromycin (E.E.S., E-Mycin, Eryc)
Description	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.
Adult Dose	500 mg IV q6h 500 mg PO qid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hepatic impairment
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Drug Name	Amoxicillin (Amoxil, Trimox)
Description	Alternative therapy. Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.
Adult Dose	0.5-1 g PO q8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Reduces the efficacy of oral contraceptives
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; may enhance chance of candidiasis

FOLLOW-UP

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Further Inpatient Care

• Patients with severe disease should remain in a hospitalized setting until adequate resolution of organ failure and clinical infection.

Further Outpatient Care

• Outpatient follow-up may include an assessment of renal function to ensure ongoing reversal of any damage.
• A cardiac assessment may be indicated in patients with symptoms suggestive of heart involvement.

Transfer

• Transfer to a facility with an appropriate level of care should be considered in patients with severe disease.

Deterrence/Prevention

• Avoiding or reducing contact with either potentially affected animals or contaminated soil or water is the most effective deterrence. For persons at risk for occupational exposure, protective garments, including footwear, gloves, and eye protection, should be worn. Strict attention to hygiene and sanitation is important; rodent control, decontamination of affected surfaces, and control of livestock infection are examples.
• Vaccines are available for both humans and animals; however, their use is controversial. Internationally, certain workers at high risk, such as rice farmers in Asia or miners in Poland, have used immunizations that are specific to the serovars endemic to the local area. Vaccination of humans is not performed in the United States. Immunization of livestock and peridomestic animals is performed, either to prevent the spread of leptospires to other animals or for prevention of human disease.
• Chemoprophylaxis has been shown to be effective for persons with potential risk for exposure, such as military troops traveling to endemic areas or vacationers engaging in aquatic recreation. Doxycycline, 250 mg administered orally once a week, is shown to be highly efficacious. However, it is not recommended for persons with long-term or repeated exposure.

Complications

• Complications originate either from the natural history of the disease or the treatment.

Prognosis

• The prognosis for patients with mild infection is very good. More severe cases portend a much poorer outcome.

Patient Education

• Government officials, public health workers, and health care workers should educate all populations at risk about proper preventative measures.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Recognizing and addressing the differential diagnosis when evaluating a patient suspected of having leptospirosis is critical. Missing other life-threatening illnesses, such as bacterial meningitis, acute toxin-induced hepatitis, pancreatitis, cholangitis, or Goodpasture disease, can be devastating, particularly because each of these diseases has a specific and entirely different necessary therapy when compared to leptospirosis.

Special Concerns

• Sequelae of infection depend, in part, on the health, nutritional status, and age of the patient.
• • Extremes of age can result in more significant disease. The relatively poor resilience of elderly people produces a high mortality from Weil disease in this population.
  • In the pregnant patient, any outcome is possible. During the septicemic phase of the illness, leptospires can cross the placenta and infect the fetus. Capillaritis thus can occur in the placenta and in the organs of the fetus, which can result in fetal demise. Even without fetal septicemia and capillaritis, the fetus can be at risk for morbidity and mortality when the mother has severe complications of her infection, such as high fever and hemodynamic instability. The literature does support that pregnancies also can remain unaffected by the infection.

MULTIMEDIA

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• Miscellaneous
• Multimedia
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Media file 1:  A scanning electron micrograph depicting Leptospira sp. bacteria atop a 0.1. µm polycarbonate filter. (This image is in the public domain and thus free of any copyright restrictions. Content provider: Centers for Disease Control/Rob Weyant)
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Media file 2:  Darkfield microscopy of leptospiral microscopic agglutination test. (This image is in the public domain and thus free of any copyright restrictions. Content provider: Centers for Disease Control/Mrs. M. Gatton)
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Media type:  Image

Media file 3:  Silver stain, liver, fatal human Leptospirosis. (This image is in the public domain and thus free of any copyright restrictions. Content provider: Centers for Disease Control/Dr. Martin Hicklin)
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Miscellaneous
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• Boyer AS, Runyan RB. TGFbeta Type III and TGFbeta Type II receptors have distinct activities during epithelial-mesenchymal cell transformation in the embryonic heart. Dev Dyn. Aug 2001;221(4):454-9. [Medline].
• Centers for Disease Control and Prevention (CDC). Outbreak of leptospirosis among white-water rafters--Costa Rica, 1996. MMWR Morb Mortal Wkly Rep. Jun 27 1997;46(25):577-9. [Medline]. [Full Text].
• Centers for Disease Control and Prevention (CDC). Brief report: Leptospirosis after flooding of a university campus--Hawaii, 2004. MMWR Morb Mortal Wkly Rep. Feb 10 2006;55(5):125-7. [Full Text].
• Cox TE, Smythe LD, Leung LK. Flying foxes as carriers of pathogenic Leptospira species. J Wildl Dis. Oct 2005;41(4):753-7.
• Doudier B, Garcia S, Quennee V. Prognostic factors associated with severe leptospirosis. Clin Microbiol Infect. Apr 2006;12(4):299-300.
• Faine S. In: Leptospira and Leptospirosis. Boca Raton: CRC Press Inc;. 1994.
• Farr RW. Leptospirosis. Clin Infect Dis. Jul 1995;21(1):1-6; quiz 7-8. [Medline].
• Masuzawa T, Okamoto Y, Une Y. Leptospirosis in squirrels imported from United States to Japan. Emerg Infect Dis [serial on the Internet]. 2006;[Full Text].
• Moore GE, Guptill LF, Glickman NW. Canine leptospirosis, United States, 2002-2004. Emerg Infect Dis. Mar 2006;12(3):501-3.
• O''Neil KM, Rickman LS, Lazarus AA. Pulmonary manifestations of leptospirosis. Rev Infect Dis. Jul-Aug 1991;13(4):705-9. [Medline].
• Sanford JP. Leptospirosis. In: Harrison's Principles of Internal Medicine. 13th ed. New York, NY: McGraw-Hill, Inc;. 740-743.
• Sejvar J, Bancroft E, Winthrop K, et al. Leptospirosis in "Eco-Challenge" athletes, Malaysian Borneo, 2000. Emerg Infect Dis. Jun 2003;9(6):702-7. [Full Text].
• Speelman P. Leptospirosis. In: Harrison's Principle of Internal Medicine. 14th ed. New York, NY: McGraw-Hill, Inc;. 1036-38.
• Tappero J, Ashford D, Perkins N. Leptospira species (Leptospirosis). In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Philadelphia, Pa: Churchill Livingstone;. 2000:2495-2500.

Article Last Updated: Jun 29, 2006