Leptospirosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Leptospirosis is a zoonotic disease caused by Leptospira sps. that affects humans and a wide range of animals, including mammals, birds, amphibians, and reptiles.^[1] Even though leptospirosis is relatively rare in human, it is one of the world’s most common zoonotic disease. The infection is commonly transmitted to humans by carriers such as rodents and other mammals through contaminated water sources by animal urine to come in contact with unhealed breaks in the skin, eyes or with the mucous membranes. Due to the ability of leptospire, they can survive for a prolonged period outside the animal host, especially in the environment favored by warm moist conditions with a neutral pH, which makes the disease more prevalent in tropical and sub-tropical regions. Outside of tropical areas, leptospirosis cases have a relatively distinct seasonality with most of them occurring August-September/February-March.^[2] Recently, with the improved health and safety methods in the work place, more infections are occurring due to recreational activities rather than occupational exposure.^[3][4] Animal body fluids such as urine, semen and products of conception with pathogenic leptospires, pose a potential risk to humans through prolonged excretion of bacteria. Other less common mechanisms of transmission include direct infection from animal urine, human to human spread, sexual transmission and via breast milk.^[5][6][7]

Adof Weil is the first physician described about the severe form of leptospirosis and the name Weil’s disease is named after him in the year 1886. He also described the jaundice with splenomegaly, renal failure, skin rash and conjunctival suffusion.^[8] Japanees scientists Kitamura and Hara named this disease as autumn fever and seven day disease in 1918.^[9]

Leptospirosis is classified into an anicteric and icteric form of leptospirosis based on the clinical presentation.

Pathological findings of leptospirosis are due to the development of the following:^{[12][13][14][15]}

• Vasculitis
• Endothelial damage
• Inflammatory infiltrates composed of monocytic cells, plasma cells, histiocytes and neutrophils.

Leptospirosis is caused by an infection with Leptospira. Several species of Leptospira have identified and have been classified, genotypically, which include both pathogenic and saprophytic species. Among the pathogenic species, over 300 serovars have been identified by serotyping methods.^[10]

Leptospirosis must be differentiated from other diseases that cause fever, diarrheanandausea and vomiting such as ebola, typhoid fever, malaria, yellow fever and other enteric bacterial infections. Moderate to severe leptospirosis must be differentiated from dengue fever.

Leptospirosis occurs worldwide but is most common in temperate or tropical climates. It is an occupational hazard for many people who work outdoors or with animals, for example: farmers, sewer workers, veterinarians, fish workers, dairy farmers or military personnel. It is a recreational hazard for campers or those who participate in outdoor sports in contaminated areas and has been associated with swimming, wading and whitewater rafting in contaminated lakes and rivers. The incidence is also increasing among urban children. Epidemiology of human leptospirosis is complex and dynamic, due to the interaction of pathogen, host, animal reservoir and environment. With the increase in urban population, occupational and recreational exposure to surface water and climatic changes results in the increase in the prevalence of leptospirosis recently.

The risk of acquiring leptospirosis is associated with contact with animals, which made leptospirosis as an important occupational disease, especially affecting farmers, slaughterhouse workers, pet traders, veterinarians, rodent catchers and sewer workers who are in contact with mammalian species which acts as a natural carriers of leptospires.^[11] According to World health organization survey highest risk groups are subsistence farmers and people living in urban slums.^[12] Common risk factors in the development of leptospirosis include occupational exposure to animals, tropical or temperate climates and water sports in contaminated lakes and rivers.

Leptospirosis is transported by the natural carriers such as feral, semi-domestic and farm and pet animals.^[11] Incubation period for leptospirosis varies between 3-20 days. The disease can cause wide range of symptoms from mild flu-like symptoms to severe disease with multi organ failure causing death. The first phase resolves and the patient is asymptomatic briefly before the second phase begins that is characterized by meningitis, liver damage (causing jaundice) and renal failure.^[13] The disease leptospirosis is poorly known and unaware of its natural history is mainly due to the wide range of non specific symptoms, subclinical nature of the disease in animals, and non specific laboratory tests making the disease difficult to diagnose.^[14] Outcome of the patient depends upon the pathogenic serovar and immunological status.

Clinical symptoms of leptospirosis are very wide, with mild anicteric presentation at one end to severe leptospirosis with severe jaundice and multiple organ involvement. Classic presentation of leptospirosis is a biphasic illness, and the onset of Symptoms within 2–30 days (incubation period) of exposure to the bacteria. Serious symptoms may manifest earlier on days 4–6 of the illness depending on the type of pathogen and host immunological status.^[15] As the clinical manifestations of the disease are non specific, the clinical diagnosis is difficult. The laboratory investigations for leptospirosis should be considered in patient with an abrupt onset of fever, chills, conjunctival suffusion, headache, myalgia and jaundice with history of occupational exposure to infected animals or contaminated with animal urine.^[16] The diagnosis of leptospirosis is based upon clinical suspicion and lab findings so, lab tests should be considered in a patient with a history of contact with potentially infected animals, soil or surface waters contaminated by animal urine.^[10] Leptospires can be found in blood and CSF for the first 7 to 10 days and then in the urine. Hence, in the early diagnosis, specimen of choice should be, blood or CSF for culture. From the second week onwards serological tests are useful in the diagnosis.

All patients with suspected leptospirosis require antimicrobial therapy. Antimicrobial therapy is the mainstay of therapy for Leptospirosis. Antimicrobial therapies include either penicillin, ampicillin, doxycycline or ceftriaxone. Patients with meningitis often require high-dose penicillin, whereas patients with Weil’s disease often require either azithromycin or doxycycline. Supportive measures include detoxification and normalization of electrolyte imbalances. Dialysis is reserved for patients with severe disease who fail antimicrobial therapy.

Leptospirosis can be prevented by avoiding the risk factors by practicing general measures, from contact with infected sources and animals. Also, it can be minimized by taking antibiotic prophylaxis in high-risk group who will have occupational exposure with infected sources.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Adof Weil is the first physician described about the severe form of leptospirosis and the name Weil’s disease is named after him in the year 1886. He also described the jaundice with splenomegaly, renal failure, skin rash and conjunctival suffusion.^[1] Japanees scientists Kitamura and Hara named this disease as autumn fever and seven day disease in 1918.^[2]

• The association between the disease prevalence and occupational status for leptospirosis is first described by Alston and Broom in 1958. They also found that it more prevalent in farmers who are working in cane farm and named the disease as cane cutter’s disease, swine-herd’s disease, Schlammfieber disease or mud fever.^[3]
• Leptospires are first demonstrated in the year 1907 by Stimson and he coined the name as Spirocheta interrogans.^[2]
• In 1915 German researchers Hubener, Uhlenhuth Fromme first time succeeded in transmitting the infection to guinea-pigs and demonstrating the leptospires in guinea-pig tissues and they named the organisms as Spirochaeta nodosa and Spirochaeta icterogenes.^[4]
• Japanese research group Ido et al. described the mechanism of transmission from rats to humans in 1917 and research groups Noguchi and Stokes et al. from Europe and United States respectively confirmed the same in 1917.^[5]
• Genus name Leptospira was coined to separate other spirochetes from Treponema pallidum by Noguchi in 1918.^[6]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Leptospirosis is classified into anicteric and icteric form of leptospirosis based on the clinical presentation.

• More common but serious illness is uncommon^[1]
• Most of cases present either subclinical or of very mild severity.
• Few cases present with a febrile illness of sudden onset.
• Other symptoms include chills, headache (severe with retro-orbital pain and photophobia), myalgia, abdominal pain, conjunctival suffusion, and skin rash (transient and last < 24 hours)
• May progress to aseptic meningitis in ≤ 25% of patients and more common in younger age group than the patients with icteric leptospirosis.
• Mortality is very less when compared to icteric leptospirosis

• Rapidly progressive and severe form of leptospirosis (Weil’s disease)
• In the severe form of leptospirosis renal failure, hepatic failure and pulmonary hemorrhage can occur and associate with Icterohemorrhagiae.^[2]
• Less common form of leptospirosis with incidence of 5%-10%.
• Jaundice is not associate with hepatocellular injury, eventually LFT returns to normal after recovery.
• High mortality rate with a range of 5%-15%.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Leptospires shed in the urine of animals to the environment from where humans are infected by incidental hosts. In Carriers these bacteria harbor in the renal tubules and can persist in soil or surface water and then transmits to human hosts via mucous membranes or abraded skin.^[1][2] Pathogen transmit through various mechanisms such as broken skin, mucus membranes and the conjunctivae, exposure to contaminated water are at risk of contracting leptospirosis.^[3]

The disease leptospirosis involves a spectrum of symptoms ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality and Weil’s disease represents only the most severe presentation. Severe leptospirosis is frequently caused by serovars of the icterohaemorrhagiae serogroup. The presentation of leptospirosis is biphasic, with the acute or septicemic phase lasting about a week, followed by the immune phase, characterized by antibody production and excretion of leptospires in the urine.^[4]

The major reservoir for leptospirosis is rat and small rodents that appear to harbour more virulent strains of the disease.^[5]

Domestic animals such as dogs,cattle and pigs acts as potential carriers that increases the risk of leptospirosis in humans. These carriers are generally asymptomatic.^[6][7]

1. Direct contact with urine or tissue of infected animal: Through skin abrasions and intact mucus membrane
2. Indirect contact: Broken skin with infected soil, water or vegetation, Through ingestion of contaminated food and water
3. Droplet infection: Inhalation of droplets of infected urine

Infection can occurs either by direct contact with the carrier’s urine or through indirect transmission via urine-contaminated environment. Infection due to direct transmission through direct oral intake of contaminated drinking water or food is very rare.^[8] Pathogenic leptospires live in the renal system and the genital tracts of domestic animals which act as sites of persistence.^[9][10] Bacteria shed from the infected animals such as rodents and domesticat animals through urine. These animals may not show signs of disease but humans shows signs of illness after contact with infected urine, or through contact with water, soil or food that has been contaminated and the outbreaks are associates with floodwaters. The major route of infection by leptospires is probably by transmission through indirect contact with leptospires secreted into the environment. Humans are considered dead end hosts, but sometimes they also act as carriers. Mammalian species (e.g. rodents, insectivores, dogs, pigs and cattle) act as the main carriers of the disease.^[11] Leptospires are excreted in urine into the environment, where they can survive for several months, depending on favourable environmental conditions such as humid and temperate areas. The pathogen may also be excreted in the products of abortion in mammalian animal species.^[9]

Pathological findings of leptospirosis are due to the development of the following:^{[12][13][14][15]}

• Vasculitis
• Endothelial damage
• Inflammatory infiltrates composed of monocytic cells, plasma cells, histiocytes, and neutrophils.

Gross findings of various organ systems are present as:^[16]

• Extensive petechial hemorrhages are common.
• Discoloration of organs is seen in severe cases of icteric leptospirosis.

• No significant structural destruction is seen^[16][17]
• Intrahepatic cholestasis is seen in few cases
• Hypertrophy and hyperplasia of Kupffer cells
• Erythrophagocytosis

• Common histopathological presentation in kidney includes interstitial nephritis with infiltration of neutrophils and monocytes.^[16]
• Leptospires are seen in renal tubules.
• Electron microscopy findings include:^[18][19]

• • Thickened tubular basement membrane
  • Denuded tubular brush borders
  • Mitochondrial depletion in tubular cells
• Glomerular destruction associated with proteinuria is seen in few cases.

Leptospirosis is associate with interstitial myocarditis.^{[20][21][22][23]}

• Cellular infiltration predominantly with lymphocytes and plasma cells.
• Petechial hemorrhages (epicardial hemorrhages are common)
• Epicardial infiltration of mononuclear cells.
• Pericardial effusion
• Coronary arteritis

Common pulmonary presentation in leptospirosis are pulmonary congestion and hemorrhage.^{[16][23][24][25]}

• Alveolar infiltration by monocytes and neutrophils.
• Hyaline membrane formation.
• Leptospires are seen within the endothelial cells in interalveolar septa, and also attached to capillary endothelial cells.

• Focal necrosis of muscle fibers with infiltration of histiocytes, neutrophils, and plasma cells.

• Perivascular cuffing is seen.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

For more information about Leptospira click here

Leptospirosis is caused by an infection with Leptospira. Several species of Leptospira have identified and have been classified, genotypically, which include both pathogenic and saprophytic species. Among the pathogenic species, over 300 serovars have been identified by serotyping methods.^[1]

• Phylum: Spirochaetes
• Class: Spirochaetes
• Order: Spirochaetales
• Species: Leptospira
• Family: Leptospiraceae

Leptospirosis is caused by a spirochaete bacterium called Leptospira spp. that has at 5 different serovars of importance in the United States causing disease (icterohaemorrhagiae, canicola, pomona, grippotyphosa and bratislava).^[2] There are other (less common) infectious strains. It should however be noted that genetically different leptospira organisms may be identical serologically and vice versa. Hence, an argument exists on the basis of strain identification. The traditional serologic system is seemingly more useful from diagnostic and epidemiologic standpoint at the moment (which may change with further development and spread of technologies like PCR).

Leptospirosis is transmitted by the urine of an infected animal, and is contagious as long as it is still moist. Although rats, mice and voles are important primary hosts, a wide range of other mammals including dogs, deer, rabbits, hedgehogs, cows, sheep, raccoons, possums, skunks and even certain marine mammals are also able to carry and transmit the disease as secondary hosts. Dogs may lick the urine of an infected animal off the grass or soil, or drink from an infected puddle. There have been reports of “house dogs” contracting leptospirosis apparently from licking the urine of infected mice that entered the house. The type of habitats most likely to carry infective bacteria are muddy riverbanks, ditches, gulleys and muddy livestock rearing areas where there is regular passage of either wild or farm mammals. There is a direct correlation between the amount of rainfall and the incidence of leptospirosis, making it seasonal in temperate climates and year-round in tropical climates.

Leptospirosis is also transmitted by the semen of infected animals^[3]. Abattoir workers can contract the disease through contact with infected blood or body fluids.

Humans become infected through contact with water, food, or soil containing urine from these infected animals. This may happen by swallowing contaminated food or water or through skin contact. The disease is not known to be spread from person to person and cases of bacterial dissemination in convalescence are extremely rare in humans. Leptospirosis is common among watersport enthusiasts in specific areas as prolonged immersion in water is known to promote the entry of the bacteria. Occupational risk factors include veterinarians, slaughter house workers, farmers and sewer workers. An outbreak in an inner city environment has been linked to contact with rat urine.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Leptospirosis must be differentiated from other diseases that cause fever, diarrhea, nausea and vomiting, such as ebola, typhoid fever, malaria, yellow fever, and other enteric bacterial infections. Moderate to severe leptospirosis must be differentiated from dengue fever.

Differential diagnosis list for leptospirosis is very large due to diverse symptomatics. For forms with middle to high severity, the list includes dengue fever and other hemorrhagic fevers, hepatitis of various etiologies, viral meningitis, malaria and typhoid fever. Light forms should be distinguished from influenza and other related viral diseases. Specific tests are a must for proper diagnosis of leptospirosis. Under circumstances of limited access (e.g., developing countries) to specific diagnostic means, close attention must be paid to anamnesis of the patient. Factors like certain dwelling areas, seasonality, contact with stagnant water (swimming, working on flooded meadows, etc) and/or rodents in the medical history support the leptospirosis hypothesis and serve as indications for specific tests (if available).

Differentiating psittacosis from other diseases

Key;

+, occurs in some cases

++, occurs in many cases,

+++, occurs frequently

Leptospirosis must be differentiated from other diseases that cause atypical pneumonia such as Q fever and legionella pneumonia:

Disease	Prominent clinical features	Lab findings	Chest X-ray
Q fever	Q fever is characterized by abrupt onset of fever, myalgia, headache, and other constitutional symptoms. Cough is the most prominent respiratory symptom and it is usually dry.[1] Cough is associated with dyspnea and pleuritic chest pain.	Antibody detection using indirect immunofluorescence (IIF) is the preferred method for diagnosis. PCR can be used if IIF is negative, or very early once disease is suspected. C. burnetii does not grow on ordinary blood cultures, but can be cultivated on special media such as embryonated eggs or cell culture. A two-to-three fold increase in AST and ALT is seen in most patients.
Mycoplasma pneumonia	Mycoplasma pneumonia can be asymptomatic. Headache, nausea, and malaise usually precede the onset of symptoms.[1] Cough is intractable and nonproductive.	Postitve Coombs test Leukocytosis Thrombocytosis
Legionellosis	Legionellosis is characterized by cough that is slightly productive.[1] Constitutional symptoms such as chills, myalgia, and arthralgia. Gastrointestinal symptoms such as diarrhea, nausea, and vomiting.	Labs are nonspecific for diagnosing legionellosis Renal and hepatic dysfunction Thrombocytopenia and leukocytosis Hyponatremia
Chlamydia pneumonia	There are no specific clinical features of chlamydia pneumonia. Symptoms appear gradually. Chlamydia infection is usually associated with upper respiratory tract symptoms (pharyngitis, sinusitis, etc). It might be associated with extrapulmonary maifestations such as meningitis and Guillain-Barre syndrome.[1]	Chlamydia pneumonia is usually associated with normal WBC count. Diagnosed with the presence of antichlamydial antibody (through complement fixation or direct immunofluoroscence) or direct antigen detection.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Leptospirosis occurs worldwide but is most common in temperate or tropical climates. It is an occupational hazard for many people who work outdoors or with animals, for example, farmers, sewer workers, veterinarians, fish workers, dairy farmers, or military personnel. It is a recreational hazard for campers or those who participate in outdoor sports in contaminated areas and has been associated with swimming, wading and whitewater rafting in contaminated lakes and rivers. The incidence is also increasing among urban children. Epidemiology of human leptospirosis is complex and dynamic due to the interaction of pathogen, host, animal reservoir and environment. With the increase in urban population, occupational and recreational exposure to surface water and climatic changes results in increase in prevalence of leptospirosis recently.

Leptospirosis caused by pathogenic Leptospira species have been found worldwide, except in Antarctica. It is most common in warm, humid environments and in the areas with a high disease incidence in humans include the Caribbean and Latin America, Oceania and parts of Asia. During the past few decades, leptospirosis has become seriously neglected, especially in countries of temperate regions.
The main reasons for this situation are probably:

• A relatively less number of cases noted in the temperate climate zone
• Well established, quite effective methods of therapy and prevention of the disease
• Seemingly well-determined epidemiologic situation concerning the disease.^[1]

Leptospirosis, is a zoonotic emerging infectious disease with a worldwide distribution.^[2] Tropical climatic conditions are most favourable for survival of leptospires and the morbidity is high due to extreme weather events such as cyclones and floods occurring in recent years.^[3][4] Leptospirosis is particularly prevalent in wet tropical and subtropical regions as the pathogenic leptospires can survive longer in a warm and humid environment.

Leptospirosis is an increasing public health problem worldwide, evidenced by markedly increasing incidence rates and multiple outbreaks allover the world. Even though multiple outbreaks has been reported, the true spread and incidence of leptospirosis remains unknown, as the availability of diagnostic tests, testing facilities and surveillance systems are highly variable and frequently absent. Incidence rate in temperate climate is in a range of ~0.1–1 per 100000 per year and it is ~10–100 per 100 000 in the humid tropical regions. In high-exposure risk groups and during outbreaks, the incidence may be >100 per 100000.^[5]

Higher morbidity due to leptospirosis is observed in regions with higher proportion of surface fresh waters such as lakes, rivers, developed canal systems.^[6][7] Case fatality rate due to leptospirosis is > 10%, and > 500,000 cases of severe leptospirosis are reported each year. Worldwide case fatality rates range from 3%-50%.^[8]

Leptospirosis has no age predilection, but more sever form of the disease is common in the age group of ≤ 5 years or ≥ 65 years.^[9]

Gender

Leptospirosis has no gender predilection usually, but due to high occupational exposure in men lead to high risk of disease incidence in male than female.^[10]

Leptospirosis is a zoonotic disease with global distribution, commonly occurs in tropical and subtropical regions. In United States most reported cases are seen in Hawaii.^[11]

Leptospirosis is a neglected disease with a greatest burden on impoverished populations from developing countries and tropical regions.^[12] Most of the tropical regions are developing countries and there is higher risk of exposure to the human population from the infected animals such as livestock, domestic pets, wild or feral animals. It is a major public health problem in many developing countries, such as Latin America and South-East Asia where the climate is more favorable for leptospires.^[13] 90% of deaths due to leptospirosis occur due to pulmonary hemorrhage and acute renal failure.^[14]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

The risk of acquiring leptospirosis is associated with contact with animals, which made leptospirosis as an important occupational disease, especially affecting farmers, slaughterhouse workers, pet traders, veterinarians, rodent catchers and sewer workers who are in contact with mammalian species which acts as a natural carriers of leptospires.^[1] According to World health organization survey highest risk groups are subsistence farmers and people living in urban slums.^[2] Common risk factors in the development of leptospirosis include occupational exposure to animals, tropical or temperate climates, and water sports in contaminated lakes and rivers.

Leptospirosis occurs worldwide, but is most common in temperate or tropical climates. Severe form of leptospirosis is more common in the risk group of age < 5 or > 65 years with comorbid conditions, such as pneumonia, immunocompromised status, history of liver diseases such as alcoholic liver disease.^[3] It is an occupational hazard for many people who work outdoors or with animals, such as:^[4]

• Farmers
• Mine workers
• Sewer workers
• Slaughterhouse workers
• Veterinarians and animal caretakers
• Fish workers
• Dairy farmers
• Military personnel

The disease has also been associated with swimming, wading, kayaking, and rafting in contaminated lakes and rivers. As such, it is a recreational hazard for campers or those who participate in outdoor sports. The risk is likely greater for those who participate in these activities in tropical or temperate climates.

In addition, incidence of Leptospirosis infection among urban children appears to be increasing.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Venkata Sivakrishna Kumar Pulivarthi M.B.B.S [2]

Leptospirosis is transported by the natural carriers such as feral, semi-domestic, farm and pet animals.^[1] Incubation period for leptospirosis varies between 3-20 days. The disease can cause wide range of symptoms from mild flu-like symptoms to severe disease with multi organ failure causing death. The first phase resolves and the patient is asymptomatic briefly before the second phase begins that is characterized by meningitis, liver damage (causing jaundice), and renal failure.^[2] The disease leptospirosis is poorly known and unaware of its natural history is mainly due to the wide range of non specific symptoms, subclinical nature of the disease in animals and non specific laboratory tests making the disease difficult to diagnose.^[3] Outcome of the patient depends upon the pathogenic serovar and immunological status.

Natural history of leptospirosis varies with each patient. It might be mild or asymptomatic, and go unrecognized or in some patients the illness may progress to kidney or liver failure, aseptic meningitis, life-threatening pulmonary hemorrhage and other syndromes.

• Also known as septicemic phase or leptospiremic phase.
• Begins abruptly
• Bacteria are present in the blood and CSF of the patient
• Characterized by wide spectrum of nonspecific signs and symptoms such as fever, chills, headache and conjunctival suffusion making it very difficult to diagnose.^[4]
• Associate with severe myalgia
• Other less common findings include: Photophobia, lymphadenopathy, abdominal pain, nausea, vomiting, a transient rash, sore throat, coughing or chest pain.
• Characterestic of this phase also includes: Mild form of leptospirosis in ~90% cases which lasts several days to a week, followed by a brief remission, during which the temperature drops and the symptoms disappear

• It is also known as leptospiruric phase.
• Circulating (IgM) antibodies are produced and leptospires are present in the urine.
• Characterestic findings that differentiate from other febrile illnesses are myalgia and conjunctival suffusion.^[5]
• Myalgia often involves in calf muscles, less commonly involves abdominal and para-spinal muscles.

• More common but serious illness is uncommon.
• Most of cases present either subclinical or of very mild severity.
• Few cases present with a febrile illness of sudden onset.
• May progress to aseptic meningitis in ≤25% of patients and more common in younger age group than the patients with icteric leptospirosis.
• Mortality is very less when compared to icteric leptospirosis.

• Rapidly progressive and severe form of leptospirosis(Weil’s disease)
• In the severe form of leptospirosis renal failure, hepatic failure and pulmonary hemorrhage can occur and associate with Icterohaemorrhagiae.^[6]
• Less common form of leptospirosis with incidence of 5%-10%
• Jaundice is not associate with hepatocellular injury, eventually LFT returns to normal after recovery.
• High mortality rate with a range of 5%-15%.

Sever form of leptospirosis with organ failure including liver and kidney involvement is known as Weil’s disease.

• Hepatic: Mild to severe form of jaundice developed within 4-7 days after the initial clinical presentation that can progress to hepatic failure or hepatic encephalopathy.
• Renal: Very common presentation involving kidneys is acute interstitial nephritis, with cola colored urine, oliguria or anuria.
• Pulmonary: Milder form of leptospirosis presents with cough, chest pain and blood tinged sputum, where as in severe form present with cough, hemoptysis, rapidly increasing breathlessness which may lead to respiratory failure and death. Hemorrhagic pneumonitis with interstitial and intra alveolar hemorrhage is the commonest cause of death in leptospirosis with case fatality rate of 0%-15%.
• Cardiovascular: Arrhythmias present with syncope and palpitations.
• Nervous system: Meningitis, encephalitis, focal defecits, spasticity, paralysis, peripheral neuropathies, nerve palsies and radiculopathies.

Complications of leptospirosis are associated with localization of pathogen (leptospires) within the tissues during the immune phase, eventually present during the second week of the illness.

Life threatening complications

• Acute kidney injury
• Disseminated intravascular coagulation
• Gastrointestinal hemorrhage
• Hemorrhagic shock

Common Complications

• Pulmonary: Pulmonary hemorrhage^[7]
• Hematological: Thrombocytopenic purpura, Disseminated intravascular coagulation.
• Neurological: Mild meningitis, encephalitis, radiculopathies, transverse myelitis, cranial nerve palsies and Guillain-Barre syndrome.^[4]
• Cardiac: Myocarditis, pericarditis^[8][9]
  • Conduction abnormalities: First degree atrioventricular block, widespread T-wave inversion^[9][10]
  • Rhythm abnormalities: Atrial fibrillation.
• Renal: Myositis → Rhabdomyolysis → Interstitial nephritis → Renal failure
• Pregnancy: Miscarriages, active leptospirosis in fetus^[11][12]

Less Common Complications

• Cerebrovascular accidents
• Rhabdomyolysis
• Acute acalculous cholecystitis
• Erythema nodosum
• Aortic stenosis
• Kawasaki syndrome
• Reactive arthritis
• Epididymitis
• Nerve palsy
• Male hypogonadism

The prognosis of leptospirosis depends upon several known and unknown factors, among which the type of pathogenic serovar and the host’s immune status are the important factors which determines the outcome.^[1] Most patients recover completely from leptospirosis but the duration of recovery varies from months to years with or without late sequelae. The late sequelae may include neuropsychiatric problems such as paresis, paralysis, mood swings and depression. The major causes of death include renal failure, cardiopulmonary failure and hemorrhage. Patients with risk factors such as old age and multiple underlying co-morbid conditions are often associated with more severe leptospirosis and increased mortality.