What is Leptospirosis?

Leptospirosis is considered to be the most common and widespread disease transmissible to man from animal. Leptospirosis is an emerging infectious disease of global importance, as illustrated by recent large outbreaks in Asia, Central and South America, and the United States. Leptospirosis has varied clinical manifestations ranging from mild Leptospirosis with headache and myalgia to fatal disease. The severe form of Leptospirosis is known as Weil’s disease or Weil’s syndrome, which is characterized by jaundice, renal dysfunction, and hemorrhagic diathesis. Weil’s disease is just one form of human leptospirosis.

What is the causative agent of leptospirosis?

Leptospirosis is caused by spirochetes belonging to the order Spirochaetales and the family Leptospiraceae. Leptospira comprised of two species: the pathogenic Leptospira interrogans and the free-living L. biflexa (the current designations are L. interrogans sensu lato and L. biflexa sensu lato respectively). But DNA analysis of leptospira indicates that there are at least seventeen genomospecies of pathogenic leptospires, which are now identified.

The leptospires:

Leptospires are coiled, very thin, highly motile organism with hooked ends and two periplasmic flagella that are used for burrowing the tissue. The leptospires are 6-20 micrometer long and approximately 0.1 micrometer wide. The organisms stain poorly but can be seen microscopically by dark-field examination and after silver impregnation staining. Culture of leptospires is difficult and may take several weeks to grow in special culture media under optimal conditions.

The pathogenic leptospires are divided into serovars according to their antigenic composition and at present more than 250 serovars are identified which make up the 26 serogroups. The genome sequence of two strains of leptospires are already complete and others in progress, which will improve understanding of leptospirosis.

Problem statement of leptospirosis:

Leptospirosis has high prevalence in the warm tropical countries. It is considered to be the most widespread of the zoonotic diseases (transmitted from animal to humans) with worldwide distribution and infecting millions of people every year. Leptospirosis affects more than 160 mammalian species including humans. Rodents (mainly rats) are the main reservoir of leptospires, though other mammals can harbor leptospires including domestic animals. Leptospires can establish a symbiotic relationship with their host and can persist in the renal tubules for years without causing any apparent disease.

Leptospirosis in human is generally underestimated. Leptospirosis occurs mainly in poor tropical countries due to poor hygiene and the climate which is favorable for leptospires survival and distribution. The peak season for leptospirosis is summer or rainy season and in Western countries, fall. In an ongoing cohort study in Brazil, approximately 5% of the individuals studied have serological evidence of leptospirosis, whereas the incidence of severe leptospirosis (like Weil’s disease) is 9.5 per 100,000 cases. Case fatality ranges from less than 1% to approximately 8%. In the United States, the Centers for Disease Control and Prevention (CDC) reports 40–120 cases annually, but most experts agree that this is underestimation of the total number.

Outbreaks of leptospirosis are common during heavy rains and flood due to exposure to leptospires that are excreted in urine of infected animals. In India there were outbreaks of leptospirosis after the cyclone that hit the Indian state of Orissa in October 1999.

How leptospirosis is transmitted?

Leptospirosis can be transmitted by direct contact, indirect contact or by droplet infection. Leptospires can gain entry to the body through skin abrasions or through intact mucous membrane by direct contact with infected urine, blood of animals or tissues of infected animals. Leptospires can also gain entry via broken skin if it comes in contact with soil, water, vegetation etc. which is contaminated with infected urine. Leptospires may also enter by ingestion of food, drink contaminated with leptospires. Leptospirosis may also occur through inhalation as well as during milking infected cows or goats by breathing air polluted with droplets of infected urine. Leptospires excreted in urine can survive in water for several months and can cause transmission as seen during flood.

Direct man to man transmission of Leptospirosis is rare, but can occur.

Who are at risk of contacting leptospirosis?

Certain occupations are at greater risk of contacting leptospirosis. Veterinarians, agricultural workers, sewage workers, slaughterhouse employees, and workers in the fishing industry are at greater risk of contacting leptospirosis. The infection may occur through direct exposure to or contact with contaminated water and soil. Other than certain occupation, certain activities can also increase the risk of contacting leptospirosis, these include recreational exposures and animal contacts. Recreational water activities, such as canoeing, windsurfing, swimming, and waterskiing can increase the risk of leptospirosis. Several outbreaks have followed sporting events, e.g. in 1998 there was a large outbreak of leptospirosis among athletes after a triathlon in Illinois, and ingestion of one or more swallows of lake water was the risk factor for illness. Heavy rains that preceded the triathlon event in Illinois, with consequent agricultural runoff might have increased the level of leptospiral contamination in the lake water.

Travelers to the tropical countries, especially Southeast Asia are also a risk factor for leptospirosis. Sometimes leptospirosis can be contacted accidentally in laboratory.

How long is the incubation period of leptospirosis?

The usual incubation period (entry of organism to development of first clinical manifestation) of leptospirosis is 10 days, but can vary from 2 days to 20 days.

Pathogenesis of leptospirosis:

The pathogenesis of leptospirosis is not completely understood. Leptospires enter through abrasions in the skin or through intact mucous membranes (conjunctiva and the lining of the oro- pharynx and naso-pharynx). Leptospires may also gain entry through drinking of contaminated water, through the mouth, throat, or esophagus. Leptospiremia (presence of leptospires in blood) develops after leptospires gain entry to the body and subsequently spreads to all the organs. Leptospires multiply in the blood and tissues and can be isolated from blood and CSF (cerebrospinal fluid) during the first 4–10 days of illness. Leptospires (all forms and types of leptospires) can damage the walls of small blood vessel and cause vasculitis, which can lead to hemorrhage and leakage and extravasation of cells. Leptospires adhere to cell surface and cause cellular toxicity.

The major manifestations of leptospirosis are due to vasculitis. In the kidney, leptospires migrate to the interstitium of the kidney, renal tubules, and tubular lumen and cause interstitial nephritis and tubular necrosis. Hypovolemia due to dehydration may contribute to the development of renal failure. In the liver, necrosis with proliferation of Kupffer cells may be seen (severe hepatocellular necrosis is not seen with leptospirosis). In the lungs there is hemorrhage (not inflammation). Invasion of skeletal muscle by leptospires may cause swelling of the myofibrils, and focal necrosis. In severe leptospirosis, vasculitis may ultimately impair the microcirculation and increase capillary permeability which results in fluid leakage and hypovolemia.

Once body starts producing antibodies against leptospires, they are eliminated from all sites in the human host except the eye and the proximal renal tubules (may be in the brain), where they may persist for weeks or months. Presence of leptospires in the aqueous humor can cause chronic or recurrent uveitis in the eye. The immune response of the host can eliminate the leptospires from the body but may cause symptomatic inflammatory reactions.

Jarisch-Herxheimer reaction similar to that seen in other spirochetal diseases (syphilis, Yaws etc.) may develop, after the start of antimicrobial treatment for leptospirosis, but much less frequent in leptospirosis than in other spirochetal diseases.

What are the clinical manifestations of leptospirosis?

Many individuals infected with leptospires remain asymptomatic (as evident from serological findings of individuals never developed leptospirosis). In symptomatic leptospirosis the disease varies from mild clinical manifestations (more than 90% of clinical cases are anicteric form of leptospirosis, with or without meningitis) to serious or even fatal leptospirosis. The milder form of leptospirosis is known as anicteric leptospirosis and the severe form of leptospirosis is known as Weil's syndrome and occurs in 5-10% of infected individuals. Typically, an acute leptospiremic phase is followed by an immune leptospiruric phase known as convalescent stage. The two phases can not be always clearly distinguished, and in milder cases may not have the second phase.

Anicteric leptospirosis:

Mild leptospirosis may present as an acute influenza-like illness (fever, chills, severe headache, nausea, vomiting, and myalgias). Myalgia generally affects muscles of calves, back and abdomen is characteristic of leptospirosis. The headache which is usually frontal or retroorbital is generally intense with photophobia (sometimes). Sometimes there may be sore throat, skin rash, mental confusion, cough and chest pain (lung involvement). Rarely there may be hemoptysis (blood in sputum).

Most of the patients of leptospirosis become asymptomatic within a week and in some cases after an interval of 1–3 days the illness recurs (the second phase or convalescent phase), which coincides with the development of antibodies and in second phase the symptoms are more variable. The symptoms of second phase generally lasts for a few days only, but may last for weeks (sometimes). Symptoms are generally less severe in second phase than first phase. Some patients (less than 15%) of leptospirosis may develop aseptic meningitis in the second phase of the disease, with CSF pleocytosis. The symptoms of meningitis generally disappear within few days but may persist for several weeks in rare instances. Aseptic meningitis is more common among children than among adults. The late complications of leptospirosis are iritis, iridocyclitis, and chorioretinitis, may develop in the third week but often present several months after the initial illness and may persist for years. The death rates in anicteric leptospirosis are low and are generally less than 2.5% as reported in a Chinese outbreak and were due to lung hemorrhage.

Physical examination generally shows fever with conjunctiva involvement and sometimes jaundice. There may be muscle tenderness, lymphadenopathy, pharyngeal injection, skin rash, hepatomegaly (enlargement of liver), and splenomegaly (enlargement of speen). The rash may be macular, maculopapular, erythematous, urticarial, or hemorrhagic.

Weil’s Syndrome or severe leptospirosis:

The most severe form of leptospirosis is Weil’s Syndrome and characterized by jaundice, renal dysfunction, and hemorrhagic diathesis and pulmonary involvement in many cases with mortality rates of 5–15%. The onset of Weil’s Syndrome is same as that of milder form of leptospirosis, but 4-9 days after onset of illness renal and vascular dysfunction develop. The two phase pattern of illness is not seen in severe form of leptospirosis as seen in milder form (anicteric form). The jaundice is generally severe (give an orange cast to the skin) and not due to hepatic necrosis. There may be hepatomegaly, and splenomegaly.

Renal failure may develop during the second week of illness with hypovolemia and decreased renal perfusion that leads to the development of acute tubular necrosis with oliguria or anuria. Dialysis may be required sometimes. Renal function may be completely regained if there is recovery. Lung involvement is frequent and can be a major manifestation in some outbreaks, with cough, dyspnea, chest pain, and blood-stained sputum and sometimes in hemoptysis or even respiratory failure. Hemorrhagic manifestations of Weil's syndrome are epistaxis, petechiae, purpura, and ecchymoses. Severe gastrointestinal bleeding and adrenal or subarachnoid hemorrhage are detected rarely.

Rare but severe manifestations of severe leptospirosis are rhabdomyolysis, hemolysis, myocarditis, pericarditis, congestive heart failure, cardiogenic shock, adult respiratory distress syndrome, necrotizing pancreatitis, and multi-organ failure.

How leptospirosis is diagnosed?

Leptospirosis can not be diagnosed with clinical symptoms alone. Diagnosis of leptospirosis is based on isolation of leptospires from blood and/or CSF during the first 10 days of illness and from urine for several weeks beginning at approximately 1 week. Culture become positive after 2-4 weeks (may range from 1 week to 6 months), but urine culture may remain positive for several months to years after start of illness. Leptospires can be isolated using culture body fluids or tissues in Ellinghausen-McCullough-Johnson-Harris (EMJH) medium (Fletcher medium and Korthof medium can also be used). Body fluids or tissue specimens can be mailed to the referral laboratory for culture as leptospires remain viable in anticoagulated blood (heparin, EDTA, or citrate) for up to 11 days at room temperature. For correct diagnosis of leptospirosis, isolation of leptospires is essential, especially if serology of the patient shows positive for leptospirosis. Dark-field microscopy should not be used fro diagnosis of leptospirosis, as it frequently leads to misdiagnosis.

Diagnosis of leptospirosis can also be done by observing seroconversion or a rise in antibody titer in the microscopic agglutination test (MAT). MAT is performed in United States only in CDC.

In addition to MAT, other serological tests that can be used to diagnose leptospirosis are ELISA, various rapid tests (use lateral flow, agglutination methods) with diagnostic value that are commercially available and are quite useful in diagnosis of leptospirosis. Among rapid serological tests “leptodipstick” test is frequently used with satisfactory results.

Microscopic agglutination test (MAT) and PCR (polymerase chain reaction) are used only in research and reference laboratories. MAT uses a battery of live leptospiral strains and is used for determination of the antibody titer and for tentative identification of the serogroup, and in some cases the serovar involved. So it is important to use antigens representative of the serovars prevalent in the particular geographic area. Antibodies do not reach detectable levels until the second week of illness and also the antibody response can be affected by early treatment.

Differential diagnosis of leptospirosis:

There are several other febrile illnesses that should be differentiated from leptospirosis, especially with headache and muscle pain. Leptospirosis should be differentiated from, Hantavirus infections, malaria, enteric fever, viral hepatitis, and rickettsial diseases. Due to the strong similarity in epidemiology and clinical presentation between leptospirosis and Hantavirus infections and also reports of dual infection (leptospirosis and Hantavirus infections), it is advisable to test for Hantavirus infections in all suspected cases of leptospirosis.

How leptospirosis is treated?

The most commonly used antibiotics for treatement of leptospirosis based on clinical trials are penicillin (ampicillin, amoxicillin, penicillin G) and doxycycline. Cefotaxime, ceftriaxone and other cephalosporins can also be sued for treatment of leptospirosis. Treatment with appropriate antibiotic should be initiated as early as possible, (although treatment started after the first 4 days of illness is still effective). In milder cases, oral treatment with tetracycline, doxycycline, ampicillin, or amoxicillin can be used. Severe cases of leptospirosis should be treated with intravenous administration of penicillin G, amoxicillin, ampicillin, or erythromycin.

Sometimes Jarisch-Herxheimer reaction may develop which is treated with supportive measures. If there is renal failure it may require dialysis. Whole blood and/or platelets transfusion may be required in patients of leptospirosis with Weil's syndrome. ICU care is required for severe cases of leptospirosis.

Leptospirosis during pregnancy:

Leptospirosis during pregnancy is generally associated with high rates of fetal mortality. In general it does not have extra effects on the mother, other than fetal mortality. During pregnancy leptospirosis should be diagnosed as early as possible and treated with penicillin, as doxycycline is teratogenic (can cause fetal abnormality).

What is the prognosis of leptospirosis treatment?

Most of the patients with leptospirosis generally recover with very low mortality. The mortality from leptospirosis may be higher if the patients are elderly and those who have Weil's syndrome.

How to prevent leptospirosis?

In general control of rodents, avoidance of exposure to urine and tissues from infected animals, health education and proper hygienic disposal of wastes should be practiced to control leptospirosis. Individuals who may be exposed to leptospires through their occupations (veterinarians, agricultural workers, sewage workers, slaughterhouse employees) or their involvement in recreational water activities should be informed about the risks and should be vaccinated with the human vaccine against a specific serovar prevalent in an area. Vaccination of humans against a specific serovar prevalent in an area has been undertaken in some European (serovar Icterohaemorrhagiae/Copenhageni are the main cause of Weil’s syndrome in Europe) and Asian countries and has proved effective Chemoprophylaxis with doxycycline (200 mg once a week) is effective sometimes and is indicated in rare instances of sustained short-term exposure.

Animals also should be vaccinated with prevalent serovars in a given area. Unfortunately, some vaccinated animals still excrete leptospires in their urine and can cause leptospirosis.