Leptospirosis

Overview
Leptospirosis (also known as Weil's disease, canicola fever, canefield fever, nanukayami fever, 7-day fever and many more ) is a bacterial zoonotic  disease caused by spirochaetes of the genus Leptospira that affects humans and a wide range of animals, including mammals, birds, amphibians, and reptiles. It was first described by Adolf Weil in 1886 when he reported an "acute infectious disease with enlargement of spleen, jaundice and nephritis". Leptospira was first observed in 1907 from a post mortem renal tissue slice.

Though being recognised among the world's most common zoonoses, leptospirosis is a relatively rare bacterial infection in humans. The infection is commonly transmitted to humans by allowing fresh water that has been contaminated by animal urine to come in contact with unhealed breaks in the skin, eyes or with the mucous membranes. Outside of tropical areas, leptospirosis cases have a relatively distinct seasonality with most of them occurring August-September/February-March.

Where is leptospirosis found?
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.

Causes
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). 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. 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.

How do people get leptospirosis?
Outbreaks of leptospirosis are usually caused by exposure to water contaminated with the urine of infected animals. Many different kinds of animals carry the bacterium; they may become sick but sometimes have no symptoms. Leptospira organisms have been found in cattle, pigs, horses, dogs, rodents, and wild animals. 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, especially with mucosal surfaces, such as the eyes or nose, or with broken skin. The disease is not known to be spread from person to person.

How long is it between the time of exposure and when people become sick?
The time between a person's exposure to a contaminated source and becoming sick is 2 days to 4 weeks. Illness usually begins abruptly with fever and other symptoms. Leptospirosis may occur in two phases; after the first phase, with fever, chills, headache, muscle aches, vomiting, or diarrhea, the patient may recover for a time but become ill again. If a second phase occurs, it is more severe; the person may have kidney or liver failure or meningitis. This phase is also called Weil's disease.

The illness lasts from a few days to 3 weeks or longer. Without treatment, recovery may take several months.

Symptoms
In animals, the incubation period (time of exposure to first symptoms) is anywhere from 2 to 20 days. In dogs, the liver and kidney are most commonly damaged by leptospirosis. Vasculitis can occur, causing edema and potentially disseminated intravascular coagulation (DIC). Myocarditis, pericarditis, meningitis, and uveitis are also possible sequelae. One should strongly suspect leptospirosis and include it as part of a differential diagnosis if the sclerae of the dog's eyes appear jaundiced (even slightly yellow), though the absence of jaundice does not eliminate the possibility of leptospirosis, and its presence could indicate hepatitis or other liver pathology rather than leptospirosis. Vomiting, fever, failure to eat, reduced urine output, unusually dark or brown urine, and lethargy are also indications of the disease.

In humans, leptospiral infection causes a wide range of symptoms, and some infected persons may have no symptoms at all. Leptospirosis is a biphasic disease that begins with flu-like symptoms (fever, chills, myalgias, intense headache). 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. Because of the wide range of symptoms the infection is often wrongly diagnosed. This leads to a lower registered number of cases than there really are. Symptoms of leptospirosis include high fever, severe headache, chills, muscle aches, and vomiting, and may include jaundice, red eyes, abdominal pain, diarrhea, and/or a rash. The symptoms in humans appear after a 4-14 day incubation period.

Complications
Complications include meningitis, respiratory distress and renal interstitial tubular necrosis, which results in renal failure and often liver failure (the severe form of this disease is known as Weil's disease, though it is sometimes named Weil Syndrome ). Cardiovascular problems are also possible. Approximately 5-50% of severe leptospirosis cases are fatal, however, such cases only constitute about 10% of all registered incidents.

Diagnostics
On infection the microorganism can be found in blood for the first 7 to 10 days (invoking serologically identifiable reactions) and then moving to the kidneys. After 7 to 10 days the microorganism can be found in fresh urine. Hence, early diagnostic efforts include testing a serum or blood sample serologically with a panel of different strains. It is also possible to culture the microorganism from blood, serum, fresh urine and possibly fresh kidney biopsy. Kidney function tests (Blood Urea Nitrogen and creatinine) as well as blood tests for liver functions are performed. The later reveal a moderate elevation of transaminases. Brief elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (GGT) levels are relatively mild. These levels may be normal, even in children with jaundice. Diagnosis of leptospirosis is  confirmed with tests such as Enzyme-Linked Immunosorbent Assay (ELISA) and PCR. Serological testing, the MAT (microscopic agglutination test), is considered the gold standard in diagnosing leptospirosis. As a large panel of different leptospira need to be subcultured frequently, which is both laborious and expensive, it is underused, mainly in developing countries.

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).

Leptospira can be cultured in [[Ellinghausen-McCullough-Johnson-Harris medium], which is incubated at 28 to 30ºC. The median time to positivity is three weeks with a maximum of 3 months. This makes culture techniques useless for diagnostic purposes, but is commonly used in research.

Treatment
Leptospirosis treatment is a relatively complicated process comprising two main components - suppressing the  causative agent and  fighting possible complications. Aetiotropic drugs are antibiotics, such as doxycycline, penicillin, ampicillin, and amoxicillin (doxycycline can also be used as a prophylaxis). There are no human vaccines; animal vaccines are only for a few strains, and are only effective for a few months. Human therapeutic dosage of drugs is as follows: doxycycline 100 mg orally every 12 hours for 1 week or penicillin 1-1.5 MU every 4 hours for 1 week. Doxycycline 200-250 mg once a week is administered as a prophylaxis. In dogs, penicillin is most commonly used to end the leptospiremic phase (infection of the blood), and doxycycline is used to eliminate the carrier state.

Supportive therapy measures (esp. in severe cases) include detoxication and normalization of the hydro-electrolytic balance. Glucose and salt solution infusions may be administered; dialysis is used in serious cases. Elevations of serum potassium are common and if the potassium level gets too high special measures must be taken. Serum phosphorus levels may likewise increase to unacceptable levels due to renal failure. Treatment for hyperphosphatemia consists of treating the underlying disease, dialysis where appropriate, or oral administration of calcium carbonate, but not without first checking the serum calcium levels (these two levels are related). Corticosteroids administration in gradually reduced doses (e.g., prednisolone starting from 30-60 mg) during 7-10 days is recommended by some specialists in cases of severe haemorrhagic effects.

Research
Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis. 2003 Dec;3(12):757-71 Bharti AR, Nally JE, Ricaldi JN, Matthias MA, Diaz MM, Lovett MA, Levett PN, Gilman RH, Willig MR, Gotuzzo E, Vinetz JM; Peru-United States Leptospirosis Consortium.

In the past decade, leptospirosis has emerged as a globally important infectious disease. It occurs in urban environments of industrialised and developing countries, as well as in rural regions worldwide. Mortality remains significant, related both to delays in diagnosis due to lack of infrastructure and adequate clinical suspicion, and to other poorly understood reasons that may include inherent pathogenicity of some leptospiral strains or genetically determined host immunopathological responses. Pulmonary haemorrhage is recognised increasingly as a major, often lethal, manifestation of leptospirosis, the pathogenesis of which remains unclear. The completion of the genome sequence of Leptospira interrogans serovar lai, and other continuing leptospiral genome sequencing projects, promise to guide future work on the disease. Mainstays of treatment are still tetracyclines and beta-lactam/cephalosporins. No vaccine is available. Prevention is largely dependent on sanitation measures that may be difficult to implement, especially in developing countries.

In a study of 38 dogs diagnosed and properly treated for leptospirosis published in the February 2000 issue of the Journal of the American Veterinary Association, the survival rate for the dialysis patients was slightly higher than the ones not put on dialysis, but both were in the 85% range (plus or minus). Of the dogs in this study that did not die, most recovered adequate kidney function, although one had chronic renal problems.

Can leptospirosis be prevented?
The risk of acquiring leptospirosis can be greatly reduced by not swimming or wading in water that might be contaminated with animal urine. Protective clothing or footwear should be worn by those exposed to contaminated water or soil because of their job or recreational activities.