Leptospirosis

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Leptospirosis
SynonymsRat fever,[1] field fever,[2] rat catcher's yellows,[3] pretibial fever[4]
Leptospirosis darkfield.jpg
Leptospira magnified 200-fold with dark-field microscope
SpecialtyInfectious disease
SymptomsNone, headaches, muscle pains, fevers[5]
ComplicationsBleeding from the lungs, meningitis, kidney failure[5][6]
CausesLeptospira typically spread by rodents[5][7]
Diagnostic methodTesting blood for antibodies against the bacterium or its DNA[8]
Differential diagnosisMalaria, enteric fever, rickettsiosis, dengue[9]
TreatmentDoxycycline, penicillin, ceftriaxone[5]
Frequency~8.5 million people per year[10]
DeathsUnknown[10]

Leptospirosis is an infection caused by corkscrew-shaped bacteria called Leptospira.[5] Signs and symptoms can range from none to mild such as headaches, muscle pains, and fevers to severe with bleeding from the lungs or meningitis.[5][6] If the infection causes the person to turn yellow, have kidney failure and bleeding, it is then known as Weil's disease.[6] If it also causes bleeding into the lungs then it is known as severe pulmonary hemorrhage syndrome.[6]

Up to 10 different genetic types of Leptospira may cause disease in humans.[11] It is transmitted by both wild and domestic animals.[6] The most common animals that spread the disease are rodents.[7] It is often transmitted by animal urine or by water or soil containing animal urine coming into contact with breaks in the skin, eyes, mouth, or nose.[5][12] In the developing world the disease most commonly occurs in farmers and low-income people who live in cities.[6] In the developed world it most commonly occurs in those involved in outdoor activities in warm and wet areas of the world.[5] Diagnosis is typically by looking for antibodies against the bacterium or finding its DNA in the blood.[8]

Efforts to prevent the disease include protective equipment to prevent contact when working with potentially infected animals, washing after this contact, and reducing rodents in areas where people live and work.[5] The antibiotic doxycycline, when used in an effort to prevent infection among travellers, is of unclear benefit.[5] Vaccines for animals exist for certain type of Leptospira which may decrease the risk of spread to humans.[5] Treatment if infected is with antibiotics such as: doxycycline, penicillin, or ceftriaxone.[5] Weil's disease and severe pulmonary haemorrhage syndrome result in death rates greater than 10% and 50%, respectively, even with treatment.[6]

It is estimated that seven to ten million people are infected by leptospirosis per year.[10] The number of deaths this causes is not clear.[10] The disease is most common in tropical areas of the world but may occur anywhere.[5] Outbreaks may occur in slums of the developing world.[6] The disease was first described by physician Adolf Weil in 1886 in Germany.[5][13] Animals which are infected may have no symptoms, mild symptoms, or severe symptoms.[14] Symptoms may vary by the type of animal.[14] In some animals Leptospira live in the reproductive tract, leading to transmission during mating.[15]

Signs and symptoms[edit]

The symptoms appear after an incubation period of 7–12 days.[16] However, the incubation period can vary from 6 days to 29 days.[17] The first phase (acute or septic phase) ends after 3–7 days of illness.[16] The second phase (immune phase) starts with the resolution of symptoms and appearance of antibodies.[18] Ninety percent of cases of the disease are mild leptospirosis. The rest experience severe disease, which develops during the second stage or occurs as a single progressive illness.[19]

Leptospiral infection in humans causes a range of symptoms, and some infected persons may have no symptoms at all. Leptospirosis is a biphasic disease that begins suddenly with fever accompanied by chills, intense headache, severe myalgia (muscle ache), abdominal pain, and occasionally a skin rash.[20] These symptoms are non-specific to Leptospirosis and can occur in other infectious diseases. The headache in Leptospirosis characteristically located at the bilateral temporal regions, or frontal headache with throbbing pain, associated with pain behind the eyes and photophobia.[17] Muscle pain usually involves the calf muscle and the lower back.[17] The most characteristic feature of Leptospirosis is the conjunctival suffusion (conjunctivitis without exudate) which is not commonly found in other febrile illnesses. Other characteristic findings on the eye includes subconjunctival bleeding and jaundice.[17] Rash is rarely found in leptospirosis. When rash is found, other alternative diagnoses such as Dengue fever and Chikungunya fever should be considered. However, rashes can be found in front of the shinbone in the case of “Fort Bragg Fever” which was recorded among the soldiers at North Carolina in 1942.[17] Cough without any sputum is observed in 20 to 57% of the people with leptospirosis. Thus, this clinical feature can mislead the diagnosis to respiratory illnesses. Besides, gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea frequently occurred. Vomiting and diarrhea may contribute to dehydration in conjunction with high-output renal failure in leptospirosis.[17] The abdominal pain can be due to acalculous cholecystitis or pancreatitis.[17] Rarely, lymph nodes, liver, spleen may be palpable.[18]

The disappearance of symptoms coincides with the appearance of antibodies against Leptospira and the disappearance of all the bacteria from the bloodstream. The patient is asymptomatic for 3–4 days until the second phase begins with another episode of fever.[20] The hallmark of the second phase is meningitis (inflammation of the membranes covering the brain).[21] Signs and symptoms of meningitis includes severe headache and neck stiffness. In 5 to 10% of those infected with jaundice, the disease can be rapidly progressive to multiorgan failure.[22]

The classic form of severe leptospirosis is known as Weil's disease, which is characterized by liver damage (causing jaundice), kidney failure, and bleeding.[23] Severe leptospirosis can cause liver, kidney, lungs, and brain damage. For those with signs of meningoencephalitis, altered level of consciousness can occur. A variety of neurological complications can occur such as hemiplegia, transverse myelitis, and Guillain-Barré syndrome.[17] Signs of bleeding such as petechiae (non traumatic bruises at 1 mm), ecchymoses (non-traumatic bruises more than 1 cm), epistaxis (nose bleeding), malena (blood in stools), haematemesis (vomiting blood) and pulmonary haemorrhage (bleeding from the lungs) can also be found. Prolongation of prothrombin time (PT) is associated with severe bleeding manifestation. However, low platelet count (thrombocytopenia) is not associated with severe bleeding.[17] In less than 5% of those infected, pulmonary haemorrhage can occur at 4th to 6th day of the illness and can be rapidly fatal.[22] Leptospira causes alveolar haemorrhage (bleeding into the alveoli of the lungs) and massive haemoptysis (cough up blood). This causes acute respiratory distress syndrome (ARDS). This feature increases the risk of death to more than 50%.[17] Rarely, myocarditis, pericarditis, heart block and arrhythmia may occur.[18]

Cause[edit]

Bacteria[edit]

Scanning electron micrograph of a number of Leptospira sp. bacteria atop a 0.1 µm polycarbonate filter

Leptospirosis is caused by aerobic,[18] right handed helical[11] bacteria belonging to the genus Leptospira; sized at 6 to 20 micrometers. Hooked ends of this bacterium gives it a "question mark" shape. Leptospira has both gram positive and gram negative features. It has a double membrane studded with lipopolysaccharide (LPS) which is characteristic of gram negative bacteria and a peptidoglycan cell wall which is characteristic of gram positive bacteria. In addition, Leptospira has two flagella located in the periplasm.[24] Chemoreceptors are located at the poles of the bacteria that sense various substrates and change the direction of the bacteria movement.[11] The advent of electron cryotomography allows detailed observation of leptospira structures.[11] A total of 22 species of Leptospira have been identified.[11] These can be divided into three clades and then can be further divided into four subgroups (I to IV). Of these, 10 species cause diseases in humans in one clade. In another clade, there are five species that can cause mild clinical manifestations in humans.[11] The remaining seven species of Leptospira in the third clade are known to consume decaying matter (saprotrophic nutrition).[11] Among the important species that cause diseases are: L. interrogans, L. borgpetersenii, and L. santarosai.[24] Pathogenic Leptospira does not multiply in the environment. Leptospira requires high humidity for survival and can remain alive in the environment in stagnant water or contaminated soil. The bacteria can be killed under temperatures of 50°C (122°F). Leptospira can be inactivated by 70% ethanol, 1% sodium hypochloride, formaldehyde, detergents and acids.[22]

Leptospira are also classified based on their serovar. About 300 pathogenic serovars of Leptospira are recognized.[11] Antigenically related serovars (belonging to the same serogroup) may belong to different species because of horizontal gene transfer between different serovars.[11] Currently, cross agglutination absorption test (CAAT) and DNA-DNA hybridisation are used to classify the Leptospira species but they are time consuming. Therefore, total genomic sequencing is could potentially replace the above two methods as the new gold standard of classifying leptospira species.[11]

Transmission[edit]

L. interrogans can survive in low nutrient environments such as moist soil and fresh water for prolonged periods. They are capable of aggregating together into a biofilm, which may aid survival in the environment. However, L. borgpetersenii is devoid of critical genes necessary for survival in the environment.[24] The type of habitats most likely to carry infective bacteria includes muddy riverbanks, ditches, gullies, and muddy livestock rearing areas where there is a regular passage of wild or farm mammals. The incidence of leptospirosis correlates directly with the amount of rainfall, making it seasonal in temperate climates and year-round in tropical climates.[25] In rural areas, farming and animal husbandry are the risk factors.[24] Poor housing and inadequate sanitation also increases risk of leptospirosis infection.[17]

When animals ingested the bacteria from the enivronment, it circulates in the blood stream, then lodged itself onto kidneys through glomerulus or peritubular capillaries. The bacteria then went into the renal tubular lumens of the kidneys and colonise the brush border and proximal convoluted tubule. This causes the continuous shedding of the bacteria in the urine without significant ill effects against the host. The relationship is known as commensal relationship and the animal is known as reservoir host.[17]

Thus, Leptospirosis is transmitted by the urine of an infected animal and is contagious as long as the urine is still moist. Although Leptospira has been detected in reptiles and birds, only mammals are able to transmit the bacterium to humans and other animals.[26] Rats, mice, and moles are important primary hosts—but a wide range of other mammals including dogs, deer, rabbits, hedgehogs, cows, sheep, swine, raccoons, opossums, skunks, and certain marine mammals carry and transmit the disease as secondary hosts. In Africa, the banded mongoose has been identified as a carrier of the pathogen, likely in addition to other African wildlife hosts.[27] Dogs may lick the urine of an infected animal off the grass or soil, or drink from an infected puddle. House-bound domestic dogs have contracted leptospirosis, apparently from licking the urine of infected mice in the house.[17] Leptospirosis also transmits via the semen of infected animals.[25] In some animals such as bulls and cows, the bacterial shedding can persists for one year.[22]

Humans become infected through contact with water, food, or soil that contains urine from these infected animals. This may happen by swallowing contaminated food or water or through skin contact. The disease is not known to spread between humans, and bacterial dissemination in convalescence is extremely rare in humans. Leptospirosis is common among water-sport enthusiasts in specific areas, as prolonged immersion in water promotes the entry of this bacterium. Surfers and whitewater paddlers[28] are at especially high risk in areas that have been shown to contain these bacteria, and can contract the disease by swallowing contaminated water, splashing contaminated water into their eyes or nose, or exposing open wounds to infected water.[29] However, Leptospira is unlikely to penetrate skin.[18] In humans, bacteria shedding usally persists for only 60 days.[22]

In tropical and semi tropical areas, like South and South-east Asia the disease is increasingly seen as epidemics after heavy rains, sometimes after flooding. Periods of heavy rain followed by days of little or no rain seemed to be the setting for leptospirosis epidemics in this part of the world. Most cases seemed to occur by cutaneous exposure of the legs while walking in stagnant water or moist soil.[30] The presence of wounds or fissures on the legs are a risk factor for acquiring the infection.[24] The risk of getting Leptospiral infection depends upon the risk of carriage in the community and the frequency of exposure.[17]

At-risk occupations[edit]

Occupations at risk include veterinarians, slaughterhouse workers, countryside rangers, farmers, sailors on rivers, sewer maintenance workers, waste disposal facility workers, and people who work on derelict buildings.[31] Slaughterhouse workers can contract the disease through contact with infected blood or body fluids. Rowers, kayakers and canoeists also sometimes contract the disease.[32] It was once mostly work-related but is now often also related to adventure tourism and recreational activities.[6]

Pathogenesis[edit]

L. interrogans serovar Pomona has SphA gene which codes for Sphingomyelinase C that break down red blood cells. L. interrogans serovar Lai has SphH gene which codes for pore-forming protein and sph2 gene where both of them damage the membranes of red blood cells.[24]

Mice are a reservoir host for Leptospira while humans are the accidental host for leptospirosis.[24] Humoral immunity is the main immune response against the Leptospira cells. Agglutinating antibodies such as Immunoglobulin M and Immunoglobulin G antibodies are produced against the bacteria. Such antibodies are mainly directed against the LPS.[24] Mice lacking Toll-like receptor (TLR)2 and TLR4 are susceptible to deadly leptospirosis. LPS activates TLR4 in mice. The lipid A molecule from Leptospira can be also be recognized by TLR4 receptors in mice. TLR4 mediates production of IgM by B cells against Leptospira in mice. However, in humans, Leptospira’s LPS only activates TLR2 in monocytes. The Lipid A molecule is not recognized by TLR4 receptors in humans.[24]

Macrophages presented in mice and humans are able to phagocytose Leptospires. For murine macrophages, Leptospires are degraded in lysosomes. In contrast, Leptospires after being ingested by macrophages in humans, are able to reside and proliferate in cytosol, which later results in the apoptosis of the macrophages.[24] Those with severe leptospirosis can experience a high level of cytokines such as Interleukin 6, Tumor necrosis factor alpha (TNF alpha), and Interleukin 10. The high level of cytokines causes sepsis-like symptoms which is life-threatening. Those who has HLA-DQ6 allele has higher risk of leptospirosis due to increased susceptibiliy to superantigen activation which further damages bodily organs.[17]

Leptospira mainly affects the liver. Congested liver sinusoid and perisinusoidal space had been reported. In an animal's liver, the Leptospires are particularly fond of invading spaces between hepatocytes. Hepatocyte apoptosis have also been reported. The damaged hepatocytes and hepatocyte intercellular junctions causes leakage of bile into blood, resulting in elevated level of bilirubin in those with jaundice. Meanwhile, in lungs, petechiae or frank haemorrhage can be found at alveolar septum and spaces between alveoli.[17] Leptospira can cause mild to severe kidney failure. This is possibly due to reduced expression of Sodium–hydrogen antiporter 3 at proximal renal tubule, causing reduced water absorption and increased urinary excretion. In humans, TLR2 detection of Leptospira causes inflammation of the kidney in the first two weeks of infection which results in interstitial nephritis. The kidney failure can recover completely or ended up as atrophy and fibrosis.[17]

Diagnosis[edit]

Kidney tissue, using a silver staining technique, revealing the presence of Leptospira bacteria

During the first 8 days of infection, the bacteria can be detected by quantitive Polymerase chain reaction (PCR) and can reach as high is 106 bacteria per ml of blood.[17] The inability of human TLR4 to recognise the Leptospires allows the bacterial titres to be significantly higher when compared to other Enterobacteriaceae infections.[17] Blood and cerebrospinal fluid (CSF) can be found during the first 7 to 10 days of illness. The bacteria then move into kidneys after 10 days. Therefore, urine culture will remain positive for leptospirosis from 10 days until 30 days.[18]

For those who are infected, full blood count may show high white cell count (leukocytosis) and low platelet count (thrombocytopenia). When anemia (low haemoglobin count) is present together with leukopenia (low white cell count) and thromobocytopenia, bone marrow suppression should be considered.[17] Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be also elevated.[18]

Kidneys are commonly involved in leptospirosis. Blood urea and creatinine levels will be elevated although the urine output is normal or high. Leptospirosis causes increase in potassium excretion in the urine, which leads to low potassium level in blood (hypokalemia)[17] and hyponatremia (low sodium level).[18] Thus, those infected who have poor oral intake and high urine output will cause severe dehydration and increases the risk of death.[17] Urine analysis may reveal the presence of protein (proteinuria), presence of pus cells (pyuria), and microscopic hematuria.[18]

For those with liver involvement, mild elevations of transaminases and direct bilirubin can be observed in liver function test. Leptospira Icterohaemorrhagiae serogroup is most commonly associated with jaundice and elevated bilirubin levels. In those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, leptospirosis can contribute to acute hemolytic anemia and conjugated jaundice.[17] Abnormal serum amylase and lipase levels (associated with pancreatitis) can be common in those who admitted into hospital due to leptospirosis. Impaired renal function with creatinine clearance less than 50 ml/min is associated with elevated pancreatic enzymes.[17]

In those who have lungs involvement, chest X-ray shows diffuse alveolar infiltrates.[17]

For those with severe headache that shows signs of meningitis, lumbar puncture can be attempted. Cerebrospinal fluid (CSF) examination shows lymphocytic predominance with cell count of 500/mm3, protein between 50 and 100 mg/ml, and normal glucose levels. These findings are consistent with aseptic meningitis.[17]

Rapid detection of Leptospira can be done by detecting the IgM antibodies using ELISA. Typically, isolates of L. biflexa is used to detect the IgM antibodies. Such test can quickly determine the diagnosis and help in early treatment of leptospirosis. However, the test specificity depends upon the type of antigen used, presence of the antibodies in previous infections, and the presence of other diseases can cause false positive results.[17] Other rapid screening test have been developed including dipsticks, latex and slide agglutination tests.[18]

Microscopic Agglutination Test (MAT) is a reference test for the diagnostic of leptospirosis.[17] MAT is a test where human or animal serum is mixed with various types of Leptospiral antigens serovars. The mixture is then examined under microscope to look for agglutination. The MAT is then read by dark field microscopy. The highest dilution where 50% agglutination occurs is the end result.[17] MAT titres of 1:100 to 1:800 is diagnostic of leptospirosis.[18] Four fold or greater rise in titre of two sera taken between the symptoms onset and 3 to 10 days after confirms the diagnosis. During acute phase of the disease, MAT is not specific in detecting a serotype of Leptospira because of cross-reactivitiy between the serovars.[17] Besides, antibodies only reach detection levels in the second week of illness.[18] In convalescent phase, MAT is more specific in detecting the serovar types. However, MAT cannot determine the infecting serotype unless the bacteria is isolated from culture.[17]

Leptospiral DNA can be amplified by using polymerase chain reaction (PCR) from serum, urine, aqueous humour, CSF, and autopsy specimens. Although PCR can detect more cases when compared to culture, it cannot detect specific serotype of Leptospira, thus affecting its value in epidemiological studies.[17] However, PCR can detect the presence of leptospiral DNA in blood even after the initiation of antibiotics.[18] MAT subsequently largely replaces PCR in detecting Leptospira infection.[17]

Differential diagnosis list for leptospirosis is very large due to diverse symptoms. For forms with middle to high severity, the list includes dengue fever and other hemorrhagic fevers, hepatitis of various causes, 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 the medical history of the patient. Factors such as certain dwelling areas, seasonality, contact with stagnant contaminated water (bathing, swimming, working on flooded meadows, etc.) or rodents in the medical history support the leptospirosis hypothesis and serve as indications for specific tests (if available).

Leptospira is a slow-growing bacteria. Blood samples containing Leptospira can be cultured in both liquid and solid medium with nutrients such as long-chain fatty acids, vitamins B1 and B12, and ammonium salts.[24] The most common medium used is Ellinghausen-McCullough-Johnson-Harris medium (EMJH), which contains oleic acid, bovine serum albumin, and polysorbate,[24] incubated at 28 to 30 °C.[33] Other samples that can be cultured are: CSF and peritoneal washings during the first week of infection, and urine samples from second week of infection. However, since survival of Leptospira is limited in urine, a phosphate buffered saline is used to enhance the bacteria growth in culture. Since contaimination is prevalent in urine culture, antibiotics such as fluorouracil is used to inhibit the growth of other bacteria in culture. The cultures are examined weekly under dark field microscope until 13 weeks of incubation.[17]

Prevention[edit]

Improving housing, infrastructure, and sanitation standards can help to reduce the number of leptospirosis cases. Rodent abatement effort and flood mitigation project can also help to prevent leptospirosis infection.[17] Wearing of Personal protective equipment (PPE) for those with high risk of occupational exposure can prevent the transmission of infections in most of the cases.[17] Effective rat control and avoidance of urine contaminated water sources are essential preventive measures.[6]

Human vaccines are available only in a few countries, such as Cuba and China.[6] Both human and animal vaccines only cover a few strains of the bacteria. Dog vaccines are effective for at least one year.[34] Side effects such as nausea, erythema and swelling have been reported after the vaccine was injected. Since the immunity induced by one serovar of Leptospirosis is only protective one serovar of leptospirosis, trivalent vaccines have been developed.[17]

Doxycycline has been provided once a week as a prophylaxis to minimize infections during outbreaks in endemic regions.[35] Doxycycline was effective in prevention of leptospirosis.[17] However, there is no evidence that chemoprophylaxis is effective in containing outbreaks of leptospirosis,[36] and use of antibiotics increases antibiotics resistance. Pre-exposure prophylaxis may be beneficial for individuals traveling to high-risk areas for a short stay.[37]

Treatment[edit]

Most leptospiral cases resolve spontaneously. Early initiation of antibiotics may prevent the progression to severe disease. Therefore, in resource limited settings, antibiotics can be started once leptopsirosis is suspected in history and examination.[17]

For those who are hospitalized, intravenous antibiotics such as penicillin, ampicillin, and in more severe cases, ceftriaxone, and cefotaxime are used.[38] Strong evidence for antibiotics, however, is lacking.[38] There is no evidence on reducing the risk of death when comparing the usage of intravenous benzylpenicillin with ceftriaxone or cefotaxime.[18] Those who can be treated as outpatients should receive doxycycline or azithromycin. Doxycycline can shorten the duration of leptospirosis by two days, improve symptoms, and prevent the shedding of organisms in urine. Azithromycin and amoxicillin are given to pregnant women and children.[17] Rarely, Jarisch–Herxheimer reaction can develop in the first few hours after antibiotics administration.[18]

For those with severe leptospirosis, such as potassium wasting with high renal output dysfunction, intravenous hydration and potassium supplements should be given to prevent dehydration and hypokalemia. When acute renal failure occurs, early initiation of haemodialysis or peritoneal dialysis can help to improve survival. For those with respiratory failure, tracheal intubation with low tidal volume improves survival rates.[17]

Prognosis[edit]

The overall case fatality rate for leptospirosis is 1% to 5%. For those with jaundice, the case fatality can increase to 5% to 15%.[22] Those with altered mental status have high risk of death. Other factors that increase the risk of death include: reduced urine output, age more than 36 years, and respiratory insufficiency. With proper care, most of those infected will recover completely. Those with acute renal failure may suffer persistent mild renal impairment post recovery.[17] In those with severe lungs involvement, the risk of death is 50 to 70%.[18] 30% of the people may suffer chronic leptospirosis syndrome up to 2 years which is characterized by weakness, muscle pain, and headache.[17] Eye problems can occur in 10% of those who recovered from leptospirosis.[22] Eye problems can range from mild anterior uveitis to severe panuveitis (which involves all the three vascular layers of the eye) post recovery. In up to 80% of those infected, leptospira DNA can be found in the aqueous humour of the eye.[17] The eye problems usually have good prognosis when being treated or they are self-limiting.[22]

Epidemiology[edit]

It is estimated that seven to ten million people are infected by leptospirosis annually.[10] One million cases of severe leptospirosis occur annually, with 58,900 deaths.[39] Leptospirosis is found in both urban and rural areas in tropical, subtropical, and temperate regions. The risk of death is 5 to 10%.[24]

Annual rates of infection vary from 0.02 per 100,000 in temperate climates to 10 to 100 per 100,000 in tropical climates.[35][40] This leads to a lower number of registered cases than likely exists. The highest estimates of disease morbidity and mortality were observed in South and Southeast Asia, Oceania, Caribbean,[24] Latin America and Africa.[22] Antarctica is the only place not affected by leptospirosis.[22]

The number of new cases of leptospirosis is difficult to estimate since many cases of the disease go unreported. There are many reasons for this, but the biggest issue is separating the disease from other similar conditions.[40] Laboratory testing is lacking in many areas.[40] The global incidence of leptospiroses have been underestimated because majority of the countries lack notification or notification is not mandatory.[17] In context of global epidemiology, the socioeconomic status of many of the world's population is closely tied to malnutrition; subsequent lack of micronutrients may lead to increased risk of infection and death due to leptospirosis infection.[41] Micronutrients such as iron, calcium, and magnesium represent important areas of future research.[41]

Outbreaks that occurred after the 1940s have happened mostly in the late summer seasons, which happens to be the driest part of the year. The people at the highest risk for leptospirosis are young people whose age ranges from 5–16 years old, and can also range to young adults.[42]

The number of cases increase during the rainy season in the tropics and during the late summer or early fall in Western countries. This happens because leptospires survive best in fresh water, damp alkaline soil, vegetation, and mud with temperatures higher than 22 °C.[43] This also leads to increased risk of exposure to populations during flood conditions, and leptospire concentrations to peak in isolated pools during drought. There is no evidence of leptospirosis having any effect on sexual and age-related differences.[43] However, a major risk factor for development of the disease is occupational exposure, a disproportionate number of working-aged males are affected.[43] There have been reported outbreaks where more than 40% of people are younger than 15. “Active surveillance measures have detected leptospire antibodies in as many as 30% of children in some urban American populations.”[43] Potential reasons for such cases include children playing with suspected vectors such as dogs or indiscriminate contact with water.

History[edit]

The disease was first described by Adolf Weil in 1886 when he reported an "acute infectious disease with enlargement of spleen, jaundice, and nephritis."[13] Leptospira was first observed in 1907 from a post mortem renal tissue slice.[44] In 1908, Inada and Ito first identified it as the causative organism[45] and in 1916 noted its presence in rats.[46]

Leptospirosis was postulated as the cause of an epidemic among American Indians along the coast of Massachusetts which occurred immediately before the arrival of the Pilgrims in 1620 and killed most of the population.[47] Earlier proposals included plague, yellow fever, smallpox, influenza, chickenpox, typhus, typhoid fever, trichinellosis, meningitis, and syndemic infection of hepatitis B with hepatitis D.[48][49][50][51] The disease may have been brought to the New World by Europeans and spread by the daily activities of the Indians.[47]

Before Weil's characterization in 1886, the disease known as infectious jaundice was very likely the same as Weil's disease or severe icteric leptospirosis. During the Egyptian campaign, Napoleon's army suffered from what was probably infectious jaundice.[52] Infectious jaundice occurred among troops during the American Civil War.[53]

It was also reported among troops at Gallipoli and other battles of World War I, where the sodden conditions of trench warfare favored infection. Terms used in early 20th century descriptions of leptospirosis include the pseudo-dengue of Java, seven-day fever, autumn fever, Akiyama disease, and marsh or swamp fever. L icterohaemorrhagiae was identified as the causative agent in pre-World War II outbreaks in Japan, which were characterized by jaundice and a high mortality rate.

WHO established Leptospirosis Burden Epidemiology Reference Group (LERG) to review the latest disease epidemiological data of leptospirosis, formulating a disease transmission model, and to identify gaps in knowledge and research. The first meeting was convened in 2009. In 2011, LERG estimated that the global annual incidence of leptospirosis is 5 to 14 cases per 100,000 population.[17]

In October 2010 British rower Andy Holmes died after contracting Weil's Disease.[54] His death has raised awareness of the disease among the public and medical professionals.[55]

Names[edit]

Leptospirosis has many different names including: "7-day fever",[2] "harvest fever",[2] "field fever",[2] "canefield fever",[2] "mild fever",[2] "rat catcher's yellows",[3] "Fort Bragg fever",[4] and "pretibial fever".[4] It has historically been known as "black jaundice",[56] or "dairy farm fever" in New Zealand.[57] In Japan it is called "nanukayami fever".[58] Weil's disease or Weil's syndrome is also known as spirochaetosis icterohaemorrhagica.[59]

Other animals[edit]

Incubation (time of exposure to first symptoms) in animals is anywhere from 2 to 20 days.[60] Clinical signs can appear in 5 to 15 days of incubation period in dogs. Incubation period can be prolonged in cats. Leptospirosis can cause abortions after 2 to 12 weeks in cattle, and 1 to 4 weeks of infection in pigs. The illness tends to be milder in reservoir host. Most commonly affected organs are: kidneys, liver, and reproductive system but other organs can be affected.[22] In dogs, the acute clinical signs are: fever, loss of appetite, shivering, muscle pain, weakness, and urinary symptoms. Vomiting, diarrhea, and abdominal pain may also present. Petechiae and ecchymoses could be seen on mucous membranes. Pulmonary haemorrhages could also be seen in dogs. In chronic presentations, the dog could be asymptomatic. In animals died of leptospirosis, their kidney specimens could be swollen with grey and white spots, mottling, or fibrotic scarring. Their liver may be enlarged with areas of necrosis. Petechiae and ecchymoses may be found in various organs.[22][60][61] Vasculitis may occur, causing edema and potentially disseminated intravascular coagulation (DIC). Myocarditis, pericarditis, meningitis, and uveitis are also possible sequelae.[32] Risk of death or disability in animals varies depending upon the species and age of the animals. In adult pigs and cattle, reproductive signs are the most common signs of leptospirosis infection. Up to 40% of the cows may have abortion. Younger animals usually develop more severe diseases. 80% of the dogs can survive with treatment but the survival rates is reduced if the lungs are involved.[22]

At least five important serovars exist in the United States and Canada, all of which cause disease in dogs: Icterohaemorrhagiae, Canicola, Pomona, Grippotyphosa, and Bratislava.[32][60][61] In dogs when leptospirosis is caused by L. interrogans it may be referred to as "canicola fever".[58]

ELISA and Microscopic Agglutination Tests (MAT) are most commonly used in the leptospirosis diagnosis in animals. The Leptospira bacteria can be detected in blood, urine, and milk or liver, kidney, or other tissue samples by using immunofluorescence or immunohistochemical or polymerase chain reaction (PCR) techniques. The organisms stained poorly with gram stain, therefore, silver staining or immunogold silver staining are used for staining leptospira. Dark field microscopy can be used to detect leptospira but it is not very sensitive nor specific in detecting the organism.[22] Culture for leptospirosis is definitive but the availability is limited. The culture can take 13 to 26 weeks for result to turn positive.[22] Paired acute and convalescent samples are perferred for serological diagnosis of leptospirosis in animals. However, a positive serological sample from an aborted fetus is diagnostic of leptospirosis.[22]

Various antibiotics such as doxycycline, penicillins, dihydrostreptomycin, and streptomycin has been used to treat leptospirosis in animals. Fluid therapy, blood transfusion, and respiratory support may be required in severe disease.[22] For horses, the primary treatment are anti-inflammatory drugs.[22]

Leptospirosis vaccines are available for animals such as pigs, dogs, cattle, sheep, and goats. Vaccines for cattle usually contains Leptospira serovar Hardjo and Pomona, for dogs, the vaccines usually contains serovar Icterohaemorrhagiae and Canicola.[22] Isolation of infected animals and prophylactic antibiotics are also effective in preventing leptospirosis in animals. Environmental control and sanitation also helps to reduce transmission rates.[22]

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