<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Frostbite and explain in detail? [/INST] Frostbite is a skin injury that occurs when exposed to extreme low temperatures, causing the freezing of the skin or other tissues, commonly affecting the fingers, toes, nose, ears, cheeks and chin areas. Most often, frostbite occurs in the hands and feet. The initial symptom is typically numbness. This may be followed by clumsiness with a white or bluish color to the skin. Swelling or blistering may occur following treatment. Complications may include hypothermia or compartment syndrome.People who are exposed to low temperatures for prolonged periods, such as winter sports enthusiasts, military personnel, and homeless individuals, are at greatest risk. Other risk factors include drinking alcohol, smoking, mental health problems, certain medications, and prior injuries due to cold. The underlying mechanism involves injury from ice crystals and blood clots in small blood vessels following thawing. Diagnosis is based on symptoms. Severity may be divided into superficial (1st and 2nd degree) or deep (3rd and 4th degree). A bone scan or MRI may help in determining the extent of injury.Prevention is by wearing proper, fully-covering clothing, maintaining hydration and nutrition, avoiding low temperatures, and minimizing strenuous physical activity while maintaining a sufficient core temperature. Treatment is by gradual rewarming, generally from cold to warm water, and should only be done when consistent temperature can be maintained and refreezing is not a concern. Rapid heating or cooling should be avoided since it could potentially cause heart stress or cause burning. Rubbing or applying force to the affected areas should be avoided as it may cause further damage such as abrasions. The use of ibuprofen and tetanus toxoid is recommended for pain relief or to reduce swelling or inflammation. For severe injuries, iloprost or thrombolytics may be used. Surgery is sometimes necessary. Amputation should be considered a few months after exposure in order to consider whether the extent of injury is permanent damage and thus necessitates drastic treatment.Evidence of frostbite occurring in people dates back 5,000 years. Evidence was documented in a pre-Columbian mummy discovered in the Andes. The number of cases of frostbite is unknown. Rates may be as high as 40% a year among those who mountaineer. The most common age group affected is those 30 to 50 years old. Frostbite has also played an important role in a number of military conflicts. The first formal description of the condition was in 1813 by Dominique Jean Larrey, a physician in Napoleons army, during its invasion of Russia.

Signs and symptoms
Areas that are usually affected include cheeks, ears, nose and fingers and toes. Frostbite is often preceded by frostnip. The symptoms of frostbite progress with prolonged exposure to cold. Historically, frostbite has been classified by degrees according to skin and sensation changes, similar to burn classifications. However, the degrees do not correspond to the amount of long term damage. A simplification of this system of classification is superficial (first or second degree) or deep injury (third or fourth degree).

First degree
First degree frostbite is superficial, surface skin damage that is usually not permanent.
Early on, the primary symptom is loss of feeling in the skin. In the affected areas, the skin is numb, and possibly swollen, with a reddened border.
In the weeks after injury, the skins surface may slough off.

Second degree
In second degree frostbite, the skin develops clear blisters early on, and the skins surface hardens.
In the weeks after injury, this hardened, blistered skin dries, blackens, and peels.
At this stage, lasting cold sensitivity and numbness can develop.

Third degree
In third degree frostbite, the layers of tissue below the skin freeze.
Symptoms include blood blisters and "blue-grey discoloration of the skin".
In the weeks after injury, pain persists and a blackened crust (eschar) develops.
There can be longterm ulceration and damage to growth plates.

Fourth degree
In fourth degree frostbite, structures below the skin are involved like muscles, tendon, and bone.
Early symptoms include a colorless appearance of the skin, a hard texture, and painless rewarming.
Later, the skin becomes black and mummified. The amount of permanent damage can take one month or more to determine. Autoamputation can occur after two months.

Causes
Risk factors
The major risk factor for frostbite is exposure to cold through geography, occupation and/or recreation. Inadequate clothing and shelter are major risk factors. Frostbite is more likely when the bodys ability to produce or retain heat is impaired. Physical, behavioral, and environmental factors can all contribute to the development of frostbite. Immobility and physical stress (such as malnutrition or dehydration) are also risk factors. Disorders and substances that impair circulation contribute, including diabetes, Raynauds phenomenon, tobacco and alcohol use. Homeless individuals and individuals with some mental illnesses may be at higher risk.

Mechanism
Freezing
In frostbite, cooling of the body causes narrowing of the blood vessels (vasoconstriction). Temperatures below −23 °C (−9 °F) are required to form ice crystals in the tissues. The process of freezing causes ice crystals to form in the tissue, which in turn causes damage at the cellular level. Ice crystals can damage cell membranes directly. In addition, ice crystals can damage small blood vessels at the site of injury. Scar tissue forms when fibroblasts replace the dead cells.

Rewarming
Rewarming causes tissue damage through reperfusion injury, which involves vasodilation, swelling (edema), and poor blood flow (stasis). Platelet aggregation is another possible mechanism of injury. Blisters and spasm of blood vessels (vasospasm) can develop after rewarming.

Non-freezing cold injury
The process of frostbite differs from the process of non-freezing cold injury (NFCI). In NFCI, temperature in the tissue decreases gradually. This slower temperature decrease allows the body to try to compensate through alternating cycles of closing and opening blood vessels (vasoconstriction and vasodilation). If this process continues, inflammatory mast cells act in the area. Small clots (microthrombi) form and can cut off blood to the affected area (known as ischemia) and damage nerve fibers. Rewarming causes a series of inflammatory chemicals such as prostaglandins to increase localized clotting.

Pathophysiology
The pathological mechanism by which frostbite causes body tissue injury can be characterized by four stages: Prefreeze, freeze-thaw, vascular stasis, and the late ischemic stage.
Prefreeze phase: involves the cooling of tissues without ice crystal formation.
Freeze-thaw phase: ice-crystals form, resulting in cellular damage and death.
Vascular stasis phase: marked by blood coagulation or the leaking of blood out of the vessels.
Late ischemic phase: characterized by inflammatory events, ischemia and tissue death.

Diagnosis
Frostbite is diagnosed based on signs and symptoms as described above, and by patient history. Other conditions that can have a similar appearance or occur at the same time include:

Frostnip is similar to frostbite, but without ice crystal formation in the skin. Whitening of the skin and numbness reverse quickly after rewarming.
Trench foot is damage to nerves and blood vessels that results exposure to wet, cold (non-freezing) conditions. This is reversible if treated early.
Pernio or chilblains are inflammation of the skin from exposure to wet, cold (non-freezing) conditions. They can appear as various types of ulcers and blisters.
Bullous pemphigoid is a condition that causes itchy blisters over the body that can mimic frostbite. It does not require exposure to cold to develop.
Levamisole toxicity is a vasculitis that can appear similar to frostbite. It is caused by contamination of cocaine by levamisole. Skin lesions can look similar those of frostbite, but do not require cold exposure to occur.People who have hypothermia often have frostbite as well. Since hypothermia is life-threatening this should be treated first. Technetium-99 or MR scans are not required for diagnosis, but might be useful for prognostic purposes.

Prevention
The Wilderness Medical Society recommends covering the skin and scalp, taking in adequate nutrition, avoiding constrictive footwear and clothing, and remaining active without causing exhaustion. Supplemental oxygen might also be of use at high elevations. Repeated exposure to cold water makes people more susceptible to frostbite. Additional measures to prevent frostbite include:
Avoiding temperatures below −23 °C (-9 °F)
Avoiding moisture, including in the form of sweat and/or skin emollients
Avoiding alcohol and drugs that impair circulation or natural protective responses
Layering clothing
Using chemical or electric warming devices
Recognizing early signs of frostnip and frostbite

Treatment
Individuals with frostbite or potential frostbite should go to a protected environment and get warm fluids. If there is no risk of re-freezing, the extremity can be exposed and warmed in the groin or underarm of a companion. If the area is allowed to refreeze, there can be worse tissue damage. If the area cannot be reliably kept warm, the person should be brought to a medical facility without rewarming the area. Rubbing the affected area can also increase tissue damage. Aspirin and ibuprofen can be given in the field to prevent clotting and inflammation. Ibuprofen is often preferred to aspirin because aspirin may block a subset of prostaglandins that are important in injury repair.The first priority in people with frostbite should be to assess for hypothermia and other life-threatening complications of cold exposure. Before treating frostbite, the core temperature should be raised above 35 °C. Oral or intravenous (IV) fluids should be given.Other considerations for standard hospital management include:

wound care: blisters can be drained by needle aspiration, unless they are bloody (hemorrhagic). Aloe vera gel can be applied before breathable, protective dressings or bandages are put on.
antibiotics: if there is trauma, skin infection (cellulitis) or severe injury
tetanus toxoid: should be administered according to local guidelines. Uncomplicated frostbite wounds are not known to encourage tetanus.
pain control: NSAIDs or opioids are recommended during the painful rewarming process.

Rewarming
If the area is still partially or fully frozen, it should be rewarmed in the hospital with a warm bath with povidone iodine or chlorhexidine antiseptic. Active rewarming seeks to warm the injured tissue as quickly as possible without burning. The faster tissue is thawed, the less tissue damage occurs.  According to Handford and colleagues, "The Wilderness Medical Society and State of Alaska Cold Injury Guidelines recommend a temperature of 37–39 °C, which decreases the pain experienced by the patient whilst only slightly slowing rewarming time." Warming takes 15 minutes to 1 hour. The faucet should be left running so the water can circulate. Rewarming can be very painful, so pain management is important.

Medications
People with potential for large amputations and who present within 24 hours of injury can be given TPA with heparin. These medications should be withheld if there are any contraindications. Bone scans or CT angiography can be done to assess damage.Blood vessel dilating medications such as iloprost may prevent blood vessel blockage. This treatment might be appropriate in grades 2–4 frostbite, when people get treatment within 48 hours. In addition to vasodilators, sympatholytic drugs can be used to counteract the detrimental peripheral vasoconstriction that occurs during frostbite.A systematic review and metaanalysis revealed that  iloprost alone or  iloprost plus recombinant tissue plasminogen activator (rtPA) may decrease amputation rate in case of severe frostbite in comparison to buflomedil alone with no major adverse events reported from iloprost or iloprost plus rtPA in the included studies.

Surgery
Various types of surgery might be indicated in frostbite injury, depending on the type and extent of damage. Debridement or amputation of necrotic tissue is usually delayed unless there is gangrene or systemic infection (sepsis). This has led to the adage "Frozen in January, amputate in July". If symptoms of compartment syndrome develop, fasciotomy can be done to attempt to preserve blood flow.

Prognosis
Tissue loss and autoamputation are potential consequences of frostbite. Permanent nerve damage including loss of feeling can occur. It can take several weeks to know what parts of the tissue will survive. Time of exposure to cold is more predictive of lasting injury than temperature the individual was exposed to. The classification system of grades, based on the tissue response to initial rewarming and other factors is designed to predict degree of longterm recovery.

Grades
Grade 1: if there is no initial lesion on the area, no amputation or lasting effects are expected
Grade 2: if there is a lesion on the distal body part, tissue and fingernails can be destroyed
Grade 3: if there is a lesion on the intermediate or near body part, auto-amputation and loss of function can occur
Grade 4: if there is a lesion very near the body (such as the carpals of the hand), the limb can be lost. Sepsis and/or other systemic problems are expected.A number of long term sequelae can occur after frostbite </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Meningitis and explain in detail? [/INST] Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or altered consciousness, nausea, vomiting, and an inability to tolerate light or loud noises. Young children often exhibit only nonspecific symptoms, such as irritability, drowsiness, or poor feeding. A non-blanching rash (a rash that does not fade when a glass is rolled over it) may also be present.The inflammation may be caused by infection with viruses, bacteria or other microorganisms. Non-infectious causes include malignancy (cancer), subarachnoid haemorrhage, chronic inflammatory disease (sarcoidosis) and certain drugs. Meningitis can be life-threatening because of the inflammations proximity to the brain and spinal cord; therefore, the condition is classified as a medical emergency. A lumbar puncture, in which a needle is inserted into the spinal canal to collect a sample of cerebrospinal fluid (CSF), can diagnose or exclude meningitis.Some forms of meningitis are preventable by immunization with the meningococcal, mumps, pneumococcal, and Hib vaccines. Giving antibiotics to people with significant exposure to certain types of meningitis may also be useful. The first treatment in acute meningitis consists of promptly giving antibiotics and sometimes antiviral drugs. Corticosteroids can also be used to prevent complications from excessive inflammation. Meningitis can lead to serious long-term consequences such as deafness, epilepsy, hydrocephalus, or cognitive deficits, especially if not treated quickly.In 2019, meningitis was prevalent in about 7.7 million people worldwide. This resulted in 236,000 deaths, down from 433,000 deaths in 1990. With appropriate treatment, the risk of death in bacterial meningitis is less than 15%. Outbreaks of bacterial meningitis occur between December and June each year in an area of sub-Saharan Africa known as the meningitis belt. Smaller outbreaks may also occur in other areas of the world. The word meningitis comes from the Greek μῆνιγξ meninx, "membrane", and the medical suffix -itis, "inflammation".

Signs and symptoms
Clinical features
In adults, the most common symptom of meningitis is a severe headache, occurring in almost 90% of cases of bacterial meningitis, followed by neck stiffness (the inability to flex the neck forward passively due to increased neck muscle tone and stiffness). The classic triad of diagnostic signs consists of neck stiffness, sudden high fever, and altered mental status; however, all three features are present in only 44–46% of bacterial meningitis cases. If none of the three signs are present, acute meningitis is extremely unlikely. Other signs commonly associated with meningitis include photophobia (intolerance to bright light) and phonophobia (intolerance to loud noises). Small children often do not exhibit the aforementioned symptoms, and may only be irritable and look unwell. The fontanelle (the soft spot on the top of a babys head) can bulge in infants aged up to 6 months. Other features that distinguish meningitis from less severe illnesses in young children are leg pain, cold extremities, and an abnormal skin color.Nuchal rigidity occurs in 70% of bacterial meningitis in adults. Other signs include the presence of positive Kernigs sign or Brudziński sign. Kernigs sign is assessed with the person lying supine, with the hip and knee flexed to 90 degrees. In a person with a positive Kernigs sign, pain limits passive extension of the knee. A positive Brudzinskis sign occurs when flexion of the neck causes involuntary flexion of the knee and hip. Although Kernigs sign and Brudzinskis sign are both commonly used to screen for meningitis, the sensitivity of these tests is limited. They do, however, have very good specificity for meningitis: the signs rarely occur in other diseases. Another test, known as the "jolt accentuation maneuver" helps determine whether meningitis is present in those reporting fever and headache. A person is asked to rapidly rotate the head horizontally; if this does not make the headache worse, meningitis is unlikely.Other problems can produce symptoms similar to those above, but from non-meningitic causes. This is called meningism or pseudomeningitis.Meningitis caused by the bacterium Neisseria meningitidis (known as "meningococcal meningitis") can be differentiated from meningitis with other causes by a rapidly spreading petechial rash, which may precede other symptoms. The rash consists of numerous small, irregular purple or red spots ("petechiae") on the trunk, lower extremities, mucous membranes, conjunctiva, and (occasionally) the palms of the hands or soles of the feet. The rash is typically non-blanching; the redness does not disappear when pressed with a finger or a glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is relatively specific for the disease; it does, however, occasionally occur in meningitis due to other bacteria. Other clues on the cause of meningitis may be the skin signs of hand, foot and mouth disease and genital herpes, both of which are associated with various forms of viral meningitis.

Early complications
Additional problems may occur in the early stage of the illness. These may require specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may trigger sepsis, a systemic inflammatory response syndrome of falling blood pressure, fast heart rate, high or abnormally low temperature, and rapid breathing. Very low blood pressure may occur at an early stage, especially but not exclusively in meningococcal meningitis; this may lead to insufficient blood supply to other organs. Disseminated intravascular coagulation, the excessive activation of blood clotting, may obstruct blood flow to organs and paradoxically increase the bleeding risk. Gangrene of limbs can occur in meningococcal disease. Severe meningococcal and pneumococcal infections may result in hemorrhaging of the adrenal glands, leading to Waterhouse-Friderichsen syndrome, which is often fatal.The brain tissue may swell, pressure inside the skull may increase and the swollen brain may herniate through the skull base. This may be noticed by a decreasing level of consciousness, loss of the pupillary light reflex, and abnormal posturing. The inflammation of the brain tissue may also obstruct the normal flow of CSF around the brain (hydrocephalus). Seizures may occur for various reasons; in children, seizures are common in the early stages of meningitis (in 30% of cases) and do not necessarily indicate an underlying cause. Seizures may result from increased pressure and from areas of inflammation in the brain tissue. Focal seizures (seizures that involve one limb or part of the body), persistent seizures, late-onset seizures and those that are difficult to control with medication indicate a poorer long-term outcome.Inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves arising from the brain stem that supply the head and neck area and which control, among other functions, eye movement, facial muscles, and hearing. Visual symptoms and hearing loss may persist after an episode of meningitis. Inflammation of the brain (encephalitis) or its blood vessels (cerebral vasculitis), as well as the formation of blood clots in the veins (cerebral venous thrombosis), may all lead to weakness, loss of sensation, or abnormal movement or function of the part of the body supplied by the affected area of the brain.

Causes
Meningitis is typically caused by an infection with microorganisms. Most infections are due to viruses, with bacteria, fungi, and protozoa being the next most common causes. It may also result from various non-infectious causes. The term aseptic meningitis refers to cases of meningitis in which no bacterial infection can be demonstrated. This type of meningitis is usually caused by viruses but it may be due to bacterial infection that has already been partially treated, when bacteria disappear from the meninges, or pathogens infect a space adjacent to the meninges (e.g. sinusitis). Endocarditis (an infection of the heart valves which spreads small clusters of bacteria through the bloodstream) may cause aseptic meningitis. Aseptic meningitis may also result from infection with spirochetes, a group of bacteria that includes Treponema pallidum (the cause of syphilis) and Borrelia burgdorferi (known for causing Lyme disease). Meningitis may be encountered in cerebral malaria (malaria infecting the brain) or amoebic meningitis, meningitis due to infection with amoebae such as Naegleria fowleri, contracted from freshwater sources.

Bacterial
The types of bacteria that cause bacterial meningitis vary according to the infected individuals age group.

In premature babies and newborns up to three months old, common causes are group B streptococci (subtypes III which normally inhabit the vagina and are mainly a cause during the first week of life) and bacteria that normally inhabit the digestive tract such as Escherichia coli (carrying the K1 antigen). Listeria monocytogenes (serotype IVb) can be contracted when consuming improperly prepared food such as dairy products, produce and deli meats, and may cause meningitis in the newborn.
Older children are more commonly affected by Neisseria meningitidis (meningococcus) and Streptococcus pneumoniae (serotypes 6, 9, 14, 18 and 23) and those under five by Haemophilus influenzae type B (in countries that do not offer vaccination).
In adults, Neisseria meningitidis and Streptococcus pneumoniae together cause 80% of bacterial meningitis cases. Risk of infection with Listeria monocytogenes is increased in persons over 50 years old. The introduction of pneumococcal vaccine has lowered rates of pneumococcal meningitis in both children and adults.Recent skull trauma potentially allows nasal cavity bacteria to enter the meningeal space. Similarly, devices in the brain and meninges, such as cerebral shunts, extraventricular drains or Ommaya reservoirs, carry an increased risk of meningitis. In these cases, the persons are more likely to be infected with Staphylococci, Pseudomonas, and other Gram-negative bacteria. These pathogens are also associated with meningitis in people with an impaired immune system.  An infection in the head and neck area, such as otitis media or mastoiditis, can lead to meningitis in a small proportion of people. Recipients of cochlear implants for hearing loss are more at risk for pneumococcal meningitis.Tuberculous meningitis, which is meningitis caused by Mycobacterium tuberculosis, is more common in people from countries in which tuberculosis is endemic, but is also encountered in persons with immune problems, such as AIDS.Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or acquired, or by disorders of the immune system. Anatomical defects allow continuity between the external environment and the nervous system. The most common cause of recurrent meningitis is a skull fracture, particularly fractures that affect the base of the skull or extend towards the sinuses and petrous pyramids. Approximately 59% of recurrent meningitis cases are due to such anatomical abnormalities, 36% are due to immune deficiencies (such as complement deficiency, which predisposes especially to recurrent meningococcal meningitis), and 5% are due to ongoing infections in areas adjacent to the meninges.

Viral
Viruses that cause meningitis include enteroviruses, herpes simplex virus (generally type 2, which produces most genital sores; less commonly type 1), varicella zoster virus (known for causing chickenpox and shingles), mumps virus, HIV, LCMV, Arboviruses (acquired from a mosquito or other insect), and the Influenza virus.  Mollarets meningitis is a chronic recurrent form of herpes meningitis; it is thought to be caused by herpes simplex virus type 2.

Fungal
There are a number of risk factors for fungal meningitis, including the use of immunosuppressants (such as after organ transplantation), HIV/AIDS, and the loss of immunity associated with aging. It is uncommon in those with a normal immune system but has occurred with medication contamination. Symptom onset is typically more gradual, with headaches and fever being present for at least a couple of weeks before diagnosis. The most common fungal meningitis is cryptococcal meningitis due to Cryptococcus neoformans. In Africa, cryptococcal meningitis is now the most common cause of meningitis in multiple studies, and it accounts for 20–25% of AIDS-related deaths in Africa. Other less common fungal pathogens which can cause meningitis include: Coccidioides immitis,  Histoplasma capsulatum, Blastomyces dermatitidis, and Candida species.

Parasitic
A parasitic cause is often assumed when there is a predominance of eosinophils (a type of white blood cell) in the CSF. The most common parasites implicated are Angiostrongylus cantonensis, Gnathostoma spinigerum, Schistosoma, as well as the conditions cysticercosis, toxocariasis, baylisascariasis, paragonimiasis, and a number of rarer infections and noninfective conditions.

Non-infectious
Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges (malignant or neoplastic meningitis) and certain drugs (mainly non-steroidal anti-inflammatory drugs, antibiotics and intravenous immunoglobulins). It may also be caused by several inflammatory conditions, such as sarcoidosis (which is then called neurosarcoidosis), connective tissue disorders such as systemic lupus erythematosus, and certain forms of vasculitis (inflammatory conditions of the blood vessel wall), such as Behçets disease. Epidermoid cysts and dermoid cysts may cause meningitis by releasing irritant matter into the subarachnoid space. Rarely, migraine may cause meningitis, but this diagnosis is usually only made when other causes have been eliminated.

Mechanism
The meninges comprise three membranes that, together with the cerebrospinal fluid, enclose and protect the brain and spinal cord (the central nervous system). The pia mater is a delicate impermeable membrane that firmly adheres to the surface of the brain, following all the minor contours. The arachnoid mater (so named because of its spider-web-like appearance) is a loosely fitting sac on top of the pia mater. The subarachnoid space separates the arachnoid and pia mater membranes and is filled with cerebrospinal fluid. The outermost membrane, the dura mater, is a thick durable membrane, which is attached to both the arachnoid membrane and the skull.
In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream (hematogenous spread) or through direct contact between the meninges and either the nasal cavity or the skin. In most cases, meningitis follows invasion of the bloodstream by organisms that live on mucosal surfaces such as the nasal cavity. This is often in turn preceded by viral infections, which break down the normal barrier provided by the mucosal surfaces. Once bacteria have entered the bloodstream, they enter the subarachnoid space in places where the blood–brain barrier is vulnerable – such as the choroid plexus. Meningitis occurs in 25% of newborns with bloodstream infections due to group B streptococci; this phenomenon is much less common in adults. Direct contamination of the cerebrospinal fluid may arise from indwelling devices, skull fractures, or infections of the nasopharynx or the nasal sinuses that have formed a tract with the subarachnoid space (see above); occasionally, congenital defects of the dura mater can be identified.The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result of bacterial infection but can rather largely be attributed to the response of the immune system to the entry of bacteria into the central nervous system. When components of the bacterial cell membrane are identified by the immune cells of the brain (astrocytes and microglia), they respond by releasing large amounts of cytokines, hormone-like mediators that recruit other immune cells and stimulate other tissues to participate in an immune response. The blood–brain barrier becomes more permeable, leading to "vasogenic" cerebral edema (swelling of the brain due to fluid leakage from blood vessels). Large numbers of white blood cells enter the CSF, causing inflammation of the meninges and leading to "interstitial" edema (swelling due to fluid between the cells). In addition, the walls of the blood vessels themselves become inflamed (cerebral vasculitis), which leads to decreased blood flow and a third type of edema, "cytotoxic" edema. The three forms of cerebral edema all lead to increased intracranial pressure; together with the lowered blood pressure often encountered in sepsis, this means that it is harder for blood to enter the brain; consequently brain cells are deprived of oxygen and undergo apoptosis (programmed cell death).It is recognized that administration of antibiotics may initially worsen the process outlined above, by increasing the amount of bacterial cell membrane products released through the destruction of bacteria. Particular treatments, such as the use of corticosteroids, are aimed at dampening the immune systems response to this phenomenon.

Diagnosis
Diagnosing meningitis as promptly as possible can improve outcomes. There is no specific sign or symptom that can diagnose meningitis and a lumbar puncture (spinal tap) to examine the cerebrospinal fluid is recommended for diagnosis. Lumbar puncture is contraindicated if there is a mass in the brain (tumor or abscess) or the intracranial pressure (ICP) is elevated, as it may lead to brain herniation. If someone is at risk for either a mass or raised ICP (recent head injury, a known immune system problem, localizing neurological signs, or evidence on examination of a raised ICP), a CT or MRI scan is recommended prior to the lumbar puncture. This applies in 45% of all adult cases.There are no physical tests that can rule out or determine if a person has meningitis. The jolt accentuation test is not specific or sensitive enough to completely rule out meningitis.If someone is suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. C-reactive protein, complete blood count), as well as blood cultures. If a CT or MRI is required before LP, or if LP proves difficult, professional guidelines suggest that antibiotics should be administered first to prevent delay in treatment, especially if this may be longer than 30 minutes. Often, CT or MRI scans are performed at a later stage to assess for complications of meningitis.In severe forms of meningitis, monitoring of blood electrolytes may be important; for example, hyponatremia is common in bacterial meningitis. The cause of hyponatremia, however, is controversial and may include dehydration, the inappropriate secretion of the antidiuretic hormone (SIADH), or overly aggressive intravenous fluid administration.

Lumbar puncture
A lumbar puncture is done by positioning the person, usually lying on the side, applying local anesthetic, and inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When this has been achieved, the "opening pressure" of the CSF is measured using a manometer. The pressure is normally between 6 and 18 cm water (cmH2O); in bacterial meningitis the pressure is usually elevated. In cryptococcal meningitis, intracranial pressure is markedly elevated.  The initial appearance of the fluid may prove an indication of the nature of the infection: cloudy CSF indicates higher levels of protein, white and red blood cells and/or bacteria, and therefore may suggest bacterial meningitis.The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content and glucose level. Gram staining of the sample may demonstrate bacteria in bacterial meningitis, but absence of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure is reduced by a further 20% if antibiotics were administered before the sample was taken. Gram staining is also less reliable in particular infections such as listeriosis. Microbiological culture of the sample is more sensitive (it identifies the organism in 70–85% of cases) but results can take up to 48 hours to become available. The type of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually neutrophil-predominant) or viral (usually lymphocyte-predominant), although at the beginning of the disease this is not always a reliable indicator. Less commonly, eosinophils predominate, suggesting parasitic or fungal etiology, among others.The concentration of glucose in CSF is normally above 40% of that in blood. In bacterial meningitis it is typically lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum glucose ratio). A ratio ≤0.4 is indicative of bacterial meningitis; in the newborn, glucose levels in CSF are normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal. High levels of lactate in CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count. If lactate levels are less than 35 mg/dl and the person has not previously received antibiotics then this may rule out bacterial meningitis.Various other specialized tests may be used to distinguish between different types of meningitis. A latex agglutination test may be positive in meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli and group B streptococci; its routine use is not encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic. Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of limited use unless other tests have been unhelpful. Polymerase chain reaction (PCR) is a technique used to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in cerebrospinal fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agents DNA is required. It may identify bacteria in bacterial meningitis and may assist in distinguishing the various causes of viral meningitis (enterovirus, herpes simplex virus 2 and mumps in those not vaccinated for this). Serology (identification of antibodies to viruses) may be useful in viral meningitis. If tuberculous meningitis is suspected, the sample is processed for Ziehl–Neelsen stain, which has a low sensitivity, and tuberculosis culture, which takes a long time to process; PCR is being used increasingly. Diagnosis of cryptococcal meningitis can be made at low cost using an India ink stain of the CSF; however, testing for cryptococcal antigen in blood or CSF is more sensitive.A diagnostic and therapeutic difficulty is "partially treated meningitis", where there are meningitis symptoms after receiving antibiotics (such as for presumptive sinusitis). When this happens, CSF findings may resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is definitive positive evidence of a viral cause (e.g. a positive enterovirus PCR).

Postmortem
Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a widespread inflammation of the pia mater and arachnoid layers of the meninges. Neutrophil granulocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along with cranial nerves and the spinal cord, may be surrounded with pus – as may the meningeal vessels.

Prevention
For some causes of meningitis, protection can be provided in the long term through vaccination, or in the short term with antibiotics. Some behavioral measures may also be effective.

Behavioral
Bacterial and viral meningitis are contagious, but neither is as contagious as the common cold or flu. Both can be transmitted through droplets of respiratory secretions during close contact such as kissing, sneezing or coughing on someone, but bacterial meningitis cannot be spread by only breathing the air where a person with meningitis has been. Viral meningitis is typically caused by enteroviruses, and is most commonly spread through fecal contamination. The risk of infection can be decreased by changing the behavior that led to transmission.

Vaccination
Since the 1980s, many countries have included immunization against Haemophilus influenzae type B in their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis in young children in those countries. In the countries in which the disease burden is highest, however, the vaccine is still too expensive. Similarly, immunization against mumps has led to a sharp fall in the number of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of mumps.Meningococcus vaccines exist against groups A, B, C, W135 and Y.  In countries where the vaccine for meningococcus group C was introduced, cases caused by this pathogen have decreased substantially. A quadrivalent vaccine now exists, which combines four vaccines with the exception of B; immunization with this ACW135Y vaccine is now a visa requirement for taking part in Hajj. Development of a vaccine against group B meningococci has proved much more difficult, as its surface proteins (which would normally be used to make a vaccine) only elicit a weak response from the immune system, or cross-react with normal human proteins. Still, some countries (New Zealand, Cuba, Norway and Chile) have developed vaccines against local strains of group B meningococci; some have shown good results and are used in local immunization schedules. Two new vaccines, both approved in 2014, are effective against a wider range of group B meningococci strains. In Africa, until recently, the approach for prevention and control of meningococcal epidemics was based on early detection of the disease and emergency reactive mass vaccination of the at-risk population with bivalent A/C or trivalent A/C/W135 polysaccharide vaccines, though the introduction of MenAfriVac (meningococcus group A vaccine) has demonstrated effectiveness in young people and has been described as a model for product development partnerships in resource-limited settings.Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV), which is active against seven common serotypes of this pathogen, significantly reduces the incidence of pneumococcal meningitis. The pneumococcal polysaccharide vaccine, which covers 23 strains, is only administered to certain groups (e.g. those who have had a splenectomy, the surgical removal of the spleen); it does not elicit a significant immune response in all recipients, e.g. small children. Childhood vaccination with Bacillus Calmette-Guérin has been reported to significantly reduce the rate of tuberculous meningitis, but its waning effectiveness in adulthood has prompted a search for a better vaccine.

Antibiotics
Short-term antibiotic prophylaxis is another method of prevention, particularly of meningococcal meningitis. In cases of meningococcal meningitis, preventative treatment in close contacts with antibiotics (e.g. rifampicin, ciprofloxacin or ceftriaxone) can reduce their risk of contracting the condition, but does not protect against future infections. Resistance to rifampicin has been noted to increase after use, which has caused some to recommend considering other agents. While antibiotics are frequently used in an attempt to prevent meningitis in those with a basilar skull fracture there is not enough evidence to determine whether this is beneficial or harmful. This applies to those with or without a CSF leak.

Management
Meningitis is potentially life-threatening and has a high mortality rate if untreated; delay in treatment has been associated with a poorer outcome. Thus, treatment with wide-spectrum antibiotics should not be delayed while confirmatory tests are being conducted. If meningococcal disease is suspected in primary care, guidelines recommend that benzylpenicillin be administered before transfer to hospital. Intravenous fluids should be administered if hypotension (low blood pressure) or shock are present. It is not clear whether intravenous fluid should be given routinely or whether this should be restricted. Given that meningitis can cause a number of early severe complications, regular medical review is recommended to identify these complications early and to admit the person to an intensive care unit if deemed necessary.Mechanical ventilation may be needed if the level of consciousness is very low, or if there is evidence of respiratory failure. If there are signs of raised intracranial pressure, measures to monitor the pressure may be taken; this would allow the optimization of the cerebral perfusion pressure and various treatments to decrease the intracranial pressure with medication (e.g. mannitol). Seizures are treated with anticonvulsants. Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or long-term drainage device, such as a cerebral shunt. The osmotic therapy, glycerol, has an unclear effect on mortality but may decrease hearing problems.

Bacterial meningitis
Antibiotics
Empiric antibiotics (treatment without exact diagnosis) should be started immediately, even before the results of the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely on the kind of bacteria that cause meningitis in a particular place and population. For instance, in the United Kingdom, empirical treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone. In the US, where resistance to cefalosporins is increasingly found in streptococci, addition of vancomycin to the initial treatment is recommended. Chloramphenicol, either alone or in combination with ampicillin, however, appears to work equally well.Empirical therapy may be chosen on the basis of the persons age, whether the infection was preceded by a head injury, whether the person has undergone recent neurosurgery and whether or not a cerebral shunt is present. In young children and those over 50 years of age, as well as those who are immunocompromised, the addition of ampicillin is recommended to cover Listeria monocytogenes. Once the Gram stain results become available, and the broad type of bacterial cause is known, it may be possible to change the antibiotics to those likely to deal with the presumed group of pathogens. The results of the CSF culture generally take longer to become available (24–48 hours). Once they do, empiric therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its sensitivities to antibiotics. For an antibiotic to be effective in meningitis it must not only be active against the pathogenic bacterium but also reach the meninges in adequate quantities; some antibiotics have inadequate penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis have not been tested directly on people with meningitis in clinical trials. Rather, the relevant knowledge has mostly derived from laboratory studies in rabbits. Tuberculous meningitis requires prolonged treatment with antibiotics. While tuberculosis of the lungs is typically treated for six months, those with tuberculous meningitis are typically treated for a year or longer.

Fluid Therapy
Fluid given intravenously are an essential part of treatment of bacterial meningitis. There is no difference in terms of mortality or acute severe neurological complications in children given a maintenance regimen over restricted-fluid regimen, but evidence is in favor of the maintenance regimen in terms of  emergence of chronic severe neurological complications.

Steroids
Additional treatment with corticosteroids (usually dexamethasone) has shown some benefits, such as a reduction of hearing loss, and better short term neurological outcomes in adolescents and adults from high-income countries with low rates of HIV. Some research has found reduced rates of death while other research has not. They also appear to be beneficial in those with tuberculosis meningitis, at least in those who are HIV negative.Professional guidelines therefore recommend the commencement of dexamethasone or a similar corticosteroid just before the first dose of antibiotics is given, and continued for four days. Given that most of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines suggest that dexamethasone be discontinued if another cause for meningitis is identified. The likely mechanism is suppression of overactive inflammation.Additional treatment with corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids has been demonstrated in adults as well as in children from high-income countries, their use in children from low-income countries is not supported by the evidence; the reason for this discrepancy is not clear. Even in high-income countries, the benefit of corticosteroids is only seen when they are given prior to the first dose of antibiotics, and is greatest in cases of H. influenzae meningitis, the incidence of which has decreased dramatically since the introduction of the Hib vaccine. Thus, corticosteroids are recommended in the treatment of pediatric meningitis if the cause is H. influenzae, and only if given prior to the first dose of antibiotics; other uses are controversial.

Viral meningitis
Viral meningitis typically only requires supportive therapy; most viruses responsible for causing meningitis are not amenable to specific treatment. Viral meningitis tends to run a more benign course than bacterial meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral drugs such as aciclovir, but there are no clinical trials that have specifically addressed whether this treatment is effective. Mild cases of viral meningitis can be treated at home with conservative measures such as fluid, bedrest, and analgesics.

Fungal meningitis
Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of high dose antifungals, such as amphotericin B and flucytosine. Raised intracranial pressure is common in fungal meningitis, and frequent (ideally daily) lumbar punctures to relieve the pressure are recommended, or alternatively a lumbar drain.

Prognosis
Untreated, bacterial meningitis is almost always fatal. Viral meningitis, in contrast, tends to resolve spontaneously and is rarely fatal. With treatment, mortality (risk of death) from bacterial meningitis depends on the age of the person and the underlying cause. Of newborns, 20–30% may die from an episode of bacterial meningitis. This risk is much lower in older children, whose mortality is about 2%, but rises again to about 19–37% in adults.Risk of death is predicted by various factors apart from age, such as the pathogen and the time it takes for the pathogen to be cleared from the cerebrospinal fluid, the severity of the generalized illness, a decreased level of consciousness or an abnormally low count of white blood cells in the CSF. Meningitis caused by H. influenzae and meningococci has a better prognosis than cases caused by group B streptococci, coliforms and S. pneumoniae. In adults, too, meningococcal meningitis has a lower mortality (3–7%) than pneumococcal disease.In children there are several potential disabilities which may result from damage to the nervous system, including sensorineural hearing loss, epilepsy, learning and behavioral difficulties, as well as decreased intelligence. These occur in about 15% of survivors. Some of the hearing loss may be reversible. In adults, 66% of all cases emerge without disability. The main problems are deafness (in 14%) and cognitive impairment (in 10%).Tuberculous meningitis in children continues to be associated with a significant risk of death even with treatment (19%), and a significant proportion of the surviving children have ongoing neurological problems. Just over a third of all cases survives with no problems.

Epidemiology
Although meningitis is a notifiable disease in many countries, the exact incidence rate is unknown. In 2013 meningitis resulted in 303,000 deaths – down from 464,000 deaths in 1990. In 2010 it was estimated that meningitis resulted in 420,000 deaths, excluding cryptococcal meningitis.Bacterial meningitis occurs in about 3 people per 100,000 annually in Western countries. Population-wide studies have shown that viral meningitis is more common, at 10.9 per 100,000, and occurs more often in the summer. In Brazil, the rate of bacterial meningitis is higher, at 45.8 per 100,000 annually. Sub-Saharan Africa has been plagued by large epidemics of meningococcal meningitis for over a century, leading to it being labeled the "meningitis belt". Epidemics typically occur in the dry season (December to June), and an epidemic wave can last two to three years, dying out during the intervening rainy seasons. Attack rates of 100–800 cases per 100,000 are encountered in this area, which is poorly served by medical care. These cases are predominantly caused by meningococci. The largest epidemic ever recorded in history swept across the entire region in 1996–1997, causing over 250,000 cases and 25,000 deaths.Meningococcal disease occurs in epidemics in areas where many people live together for the first time, such as army barracks during mobilization, university and college campuses and the annual Hajj pilgrimage. Although the pattern of epidemic cycles in Africa is not well understood, several factors have been associated with the development of epidemics in the meningitis belt. They include: medical conditions (immunological susceptibility of the population), demographic conditions (travel and large population displacements), socioeconomic conditions (overcrowding and poor living conditions), climatic conditions (drought and dust storms), and concurrent infections (acute respiratory infections).There are significant differences in the local distribution of causes for bacterial meningitis. For instance, while N </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Epiglottitis and explain in detail? [/INST] Epiglottitis is the inflammation of the epiglottis—the flap at the base of the tongue that prevents food entering the trachea (windpipe). Symptoms are usually rapid in onset and include trouble swallowing which can result in drooling, changes to the voice, fever, and an increased breathing rate. As the epiglottis is in the upper airway, swelling can interfere with breathing. People may lean forward in an effort to open the airway. As the condition worsens stridor and bluish skin may occur.Epiglottitis was historically mostly caused by infection by H. influenzae type b. With vaccination it is now more often caused by other bacteria. Other possible causes include burns and trauma to the area. The most accurate way to make the diagnosis is to look directly at the epiglottis. X-rays of the neck from the side may show a "thumbprint sign" but the lack of this sign does not mean the condition is absent.An effective vaccine, the Hib vaccine, has been available since the 1980s. The antibiotic rifampicin may also be used to prevent the disease among those who have been exposed to the disease and are at high risk. The most important part of treatment involves securing the airway, which is often done by endotracheal intubation. Intravenous antibiotics such as ceftriaxone and possibly vancomycin or clindamycin is then given. Corticosteroids are also typically used. With appropriate treatment, the risk of death among children with the condition is about one percent and among adults is seven percent.With the use of the Hib vaccine, the number of cases of epiglottitis has decreased by more than 95%. While, historically, young children were mostly affected, it is now more common among older children and adults. In the United States it affects about 1.3 per 100,000 children a year. In adults between 1 and 4 per 100,000 are affected a year. It occurs more commonly in the developing world. In children the risk of death is about 6%; however, if they are intubated early it is less than 1%.

Signs and symptoms
Epiglottitis is associated with fever, throat pain, difficulty in swallowing, drooling, hoarseness of voice, and stridor. Onset is typically over a day. The throat itself may appear normal.Stridor is a sign of upper airways obstruction and is a surgical emergency. The child often appears acutely ill, anxious, and will have very quiet shallow breathing often keeping the head held forward and insisting on sitting up in bed. The early symptoms are usually insidious but rapidly progressive, and swelling of the throat may lead to cyanosis and asphyxiation.

Causes
Epiglottitis is primarily caused by an acquired bacterial infection of the epiglottis. Historically it was most often caused by Haemophilus influenzae type B, but with the availability of immunization this is no longer the case. Presently the bacteria most often causing infection are Streptococcus pneumoniae, Streptococcus pyogenes, or Staphylococcus aureus.Alternate risk factors and causes associated with infection include burns and other trauma to the area. Medical research has also identified a link between epiglottitis and crack cocaine usage.  Underlying health conditions, such as Graft-versus-host disease and Lymphoproliferative disorders, have also been identified as contributors of increased risk for developing the infection .  This is in part caused by the hosts decreased immune response coupled with the common sites targeting the soft tissue of the lymphatic system, both of which are already negatively impacted by the pre-existing illnesses.

Diagnosis
Diagnosis may be confirmed by direct inspection using a laryngoscope, although this may provoke airway spasm. If epiglottitis is suspected, attempts to visualise the epiglottis using a tongue depressor are discouraged for this reason; therefore, diagnosis is made on basis of indirect fiberoptic laryngoscopy carried out in a controlled environment like an operating room. Imaging is rarely useful, and treatment should not be delayed for this test to be carried out.

Imaging
On lateral C-spine X-ray, the thumbprint sign describes a swollen, enlarged epiglottis. A normal X-ray, however, does not exclude the diagnosis. An ultrasound may be helpful if specific changes are present, but its use (as of 2018) is in the early stages of study.On CT imaging, the "Halloween sign" describes an epiglottis of normal thickness. It can safely exclude the acute epiglottitis. Furthermore, CT imaging can help to diagnose other conditions such as peritonsillar abscess or retropharyngeal abscess which have similar clinical features.

Prevention
An effective vaccine, the Hib vaccine, has been available since the 1980s. The antibiotic rifampicin may also be used to prevent the disease among those who have been exposed to the disease and are at high risk.

Management
Airway management
The most important part of treatment involves securing the airway </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Leptospirosis and explain in detail? [/INST] Leptospirosis is a blood infection caused by the bacteria Leptospira. Signs and symptoms can range from none to mild (headaches, muscle pains, and fevers) to severe (bleeding in the lungs or meningitis). Weils disease, the acute, severe form of leptospirosis, causes the infected individual to become jaundiced (skin and eyes become yellow), develop kidney failure, and bleed. Bleeding from the lungs associated with leptospirosis is known as severe pulmonary haemorrhage syndrome.More than ten genetic types of Leptospira cause disease in humans. Both wild and domestic animals can spread the disease, most commonly rodents. The bacteria are spread to humans through animal urine, or water and soil contaminated with animal urine, coming into contact with the eyes, mouth, nose or breaks in the skin. In developing countries, the disease occurs most commonly in farmers and low-income people who live in areas with poor sanitation. In developed countries, it occurs during heavy downpours and is a risk to sewage workers and those involved in outdoor activities in warm and wet areas. Diagnosis is typically by testing for antibodies against the bacteria or finding bacterial DNA in the blood.Efforts to prevent the disease include protective equipment to block contact when working with potentially infected animals, washing after contact, and reducing rodents in areas where people live and work. The antibiotic doxycycline is effective in preventing leptospirosis infection. Human vaccines are of limited usefulness; vaccines for other animals are more widely available. Treatment when infected is with antibiotics such as doxycycline, penicillin, or ceftriaxone. The overall risk of death is 5–10%. However, when the lungs are involved, the risk of death increases to the range of 50–70%.It is estimated that one million severe cases of leptospirosis occur every year, causing about 58,900 deaths. The disease is most common in tropical areas of the world but may occur anywhere. Outbreaks may arise after heavy rainfall. The disease was first described by physician Adolf Weil in 1886 in Germany. Infected animals may have no, mild or severe symptoms. These may vary by the type of animal. In some animals Leptospira live in the reproductive tract, leading to transmission during mating.

Signs and symptoms
The symptoms of leptospirosis usually appear one to two weeks after infection, but the incubation period can be as long as a month. The illness is biphasic in a majority of symptomatic cases. Symptoms of the first phase (acute or leptospiremic phase) last five to seven days. In the second phase (immune phase), the symptoms resolve as antibodies against the bacteria are produced. Additional symptoms develop in the second phase. The phases of illness may not be distinct, especially in patients with severe illness. 90% of those infected experience mild symptoms while 10% experience severe leptospirosis.Leptospiral infection in humans causes a range of symptoms, though some infected persons may have none. The disease begins suddenly with fever accompanied by chills, intense headache, severe muscle aches and abdominal pain. A headache brought on by leptospirosis causes throbbing pain and is characteristically located at the heads bilateral temporal or frontal regions. The person could also have pain behind the eyes and a sensitivity to light. Muscle pain usually involves the calf muscle and the lower back. The most characteristic feature of leptospirosis is the conjunctival suffusion (conjunctivitis without exudate) which is rarely found in other febrile illnesses. Other characteristic findings on the eye include subconjunctival bleeding and jaundice. A rash is rarely found in leptospirosis. When one is found alternative diagnoses such as dengue fever and chikungunya fever should be considered. Dry cough is observed in 20–57% of people with leptospirosis. Thus, this clinical feature can mislead a doctor to diagnose the disease as a respiratory illness. Additionally, gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhoea frequently occur. Vomiting and diarrhea may contribute to dehydration. The abdominal pain can be due to acalculous cholecystitis or inflammation of the pancreas. Rarely, the lymph nodes, liver, and spleen may be enlarged and palpable.There will be a resolution of symptoms for one to three days. The immune phase starts after this and can last from four to 30 days and can be anything from brain to kidney complications. The hallmark of the second phase is inflammation of the membranes covering the brain. Signs and symptoms of meningitis include severe headache and neck stiffness. Kidney involvement is associated with reduced or absent urine output.The classic form of severe leptospirosis, known as Weils disease, is characterised by liver damage (causing jaundice), kidney failure, and bleeding, which happens in 5–10% of those infected. Lung and brain damage can also occur. For those with signs of inflammation of membranes covering the brain and the brain itself, altered level of consciousness can happen. A variety of neurological problems such as paralysis of half of the body, complete inflammation of a whole horizontal section of spinal cord, and muscle weakness due to immune damage of the nerves supplying the muscles are the complications. Signs of bleeding such as non-traumatic bruises at 1 mm (0.039 in), non-traumatic bruises more than 1 cm (0.39 in), nose bleeding, blackish stools due to bleeding in the stomach, vomiting blood and bleeding from the lungs can also be found. Prolongation of prothrombin time in coagulation testing is associated with severe bleeding manifestation. However, low platelet count is not associated with severe bleeding. Pulmonary haemorrhage is alveolar haemorrhage (bleeding into the alveoli of the lungs) leading to massive coughing up of blood, and causing acute respiratory distress syndrome, where the risk of death is more than 50%. Rarely, inflammation of the heart muscles, inflammation of membranes covering the heart, abnormalities in the hearts natural pacemaker and abnormal heart rhythms may occur.

Cause
Bacteria
Leptospirosis is caused by spirochaete bacteria that belong to the genus Leptospira, which are aerobic, right-handed helical, and 6–20 micrometers long. Like Gram-negative bacteria, Leptospira have an outer membrane studded with lipopolysaccharide (LPS) on the surface, an inner membrane and a layer of peptidoglycan cell wall. However, unlike Gram-negative bacteria, the peptidoglycan layer in Leptospira lies closer to the inner than the outer membrane. This results in a fluid outer membrane loosely associated with the cell wall. In addition, Leptospira have a flagellum located in the periplasm, associated with corkscrew style movement. Chemoreceptors at the poles of the bacteria sense various substrates and change the direction of its movement. The bacteria are traditionally visualised using dark-field microscopy without staining.A total of 66 species of Leptospira has been identified. Based on their genomic sequence, they are divided into two clades and four subclades: P1, P2, S1, and S2. The 19 members of the P1 subclade include the 8 species that can cause severe disease in humans: L. alexanderi, L. borgpetersenii, L. interrogans, L. kirschneri, L. mayottensis, L. noguchii, L. santarosai, and L. weilii. The P2 clade comprises 21 species that may cause mild disease in humans. The remaining 26 species comprise the S1 and S2 subclades, which include "saprophytes" known to consume decaying matter (saprotrophic nutrition). Pathogenic Leptospira do not multiply in the environment. Leptospira require high humidity for survival but can remain alive in environments such as stagnant water or contaminated soil. The bacterium can be killed by temperatures of 50 °C (122 °F) and can be inactivated by 70% ethanol, 1% sodium hypochlorite, formaldehyde, detergents and acids.Leptospira are also classified based on their serovar. The diverse sugar composition of the lipopolysaccharide on the surface of the bacteria is responsible for the antigenic difference between serovars. About 300 pathogenic serovars of Leptospira are recognised. Antigenically related serovars (belonging to the same serogroup) may belong to different species because of horizontal gene transfer of LPS biosynthetic genes between different species. Currently, the cross agglutination absorption test and DNA-DNA hybridisation are used to classify Leptospira species, but are time consuming. Therefore, total genomic sequencing could potentially replace these two methods as the new gold standard of classifying Leptospira species.

Transmission
The bacteria can be found in ponds, rivers, puddles, sewers, agricultural fields and moist soil. Pathogenic Leptospira have been found in the form of aquatic biofilms, which may aid survival in the environment.The number of cases of leptospirosis is directly related to the amount of rainfall, making the disease seasonal in temperate climates and year-round in tropical climates. The risk of contracting leptospirosis depends upon the risk of disease carriage in the community and the frequency of exposure. In rural areas, farming and animal husbandry are the major risk factors for contracting leptospirosis. Poor housing and inadequate sanitation also increase the risk of infection. In tropical and semi-tropical areas, the disease often becomes widespread after heavy rains or after flooding.Leptospira are found mostly in mammals. However, reptiles and cold-blooded animals such as frogs, snakes, turtles, and toads have been shown to have the infection. Whether there are reservoirs of human infection is unknown. Rats, mice, and moles are important primary hosts, but other mammals including dogs, deer, rabbits, hedgehogs, cows, sheep, swine, raccoons, opossums, and skunks can also carry the disease. In Africa, a number of wildlife hosts have been identified as carriers, including the banded mongoose, Egyptian fox, Rusa deer, and shrews. There are various mechanisms whereby animals can infect each other. 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. Leptospirosis can also be transmitted via the semen of infected animals. The duration of bacteria being consistently present in animal urine may persist for years.Humans are the accidental host of Leptospira. Humans become infected through contact with water or moist soil that contains urine from infected animals. The bacteria enter through cuts, abrasions, ingestion of contaminated food, or contact with mucous membrane of the body (e.g. mouth, nose, and eyes). Occupations at risk of contracting leptospirosis include farmers, fishermen, garbage collectors and sewage workers. The disease is also related to adventure tourism and recreational activities. It is common among water-sports enthusiasts in specific areas, including triathlons, water rafting, canoeing and swimming, as prolonged immersion in water promotes the entry of the bacteria. However, Leptospira are unlikely to penetrate intact skin. The disease is not known to spread between humans, and bacterial dissemination in recovery period is extremely rare in humans. Once humans are infected, bacterial shedding from the kidneys usually persists for up to 60 days.Rarely, leptospirosis can be transmitted through an organ transplant. Infection through the placenta during pregnancy is also possible. It can cause miscarriage and infection in infants. Leptospirosis transmission through eating raw meat of wildlife animals have also been reported (e.g. psychiatric patients with allotriophagy).

Pathogenesis
When animals ingest the bacteria, they circulate in the bloodstream, then lodge themselves into the kidneys through the glomerulular or peritubular capillaries. The bacteria then pass into the lumens of the renal tubules and colonise the brush border and proximal convoluted tubule. This causes the continuous shedding of bacteria in the urine without the animal experiencing significant ill effects. This relationship between the animal and the bacteria is known as a commensal relationship, and the animal is known as a reservoir host.Humans are the accidental host of Leptospira. The pathogenesis of leptospirosis remains poorly understood despite research efforts. The bacteria enter the human body through either breaches in the skin or the mucous membrane, then into the bloodstream. The bacteria later attach to the endothelial cells of the blood vessels and extracellular matrix (complex network of proteins and carbohydrates present between cells). The bacteria use their flagella for moving between cell layers. They bind to cells such as fibroblasts, macrophages, endothelial cells, and kidney epithelial cells. They also bind to several human proteins such as complement proteins, thrombin, fibrinogen, and plasminogen using surface leptospiral immunoglobulin-like (Lig) proteins such as LigB and LipL32, whose genes are found in all pathogenic species.Through innate immune system, endothelial cells of the capillaries in the human body are activated by the presence of these bacteria. The endothelial cells produce cytokines and antimicrobial peptides against the bacteria. These products regulate the coagulation cascade and movements of white blood cells. Macrophages presented in humans are able to engulf Leptospira. However, Leptospira are able to reside and proliferate in the cytoplasmic matrix after being ingested by macrophages. Those with severe leptospirosis can experience a high level of cytokines such as interleukin 6, tumor necrosis factor alpha (TNF-α), and interleukin 10. The high level of cytokines causes sepsis-like symptoms which is life-threatening instead of helping to fight against the infection. Those who have a high risk of sepsis during a leptospirosis infection are found to have the HLA-DQ6 genotype, possibly due to superantigen activation, which damages bodily organs.Leptospira LPS only activates toll-like receptor 2 (TLR2) in monocytes in humans. The lipid A molecule of the bacteria is not recognised by human TLR4 receptors. Therefore, the lack of Leptospira recognition by TLR4 receptors probably contributes to the leptospirosis disease process in humans.Although there are various mechanisms in the human body to fight against the bacteria, Leptospira is well adapted to such an inflammatory condition created by it. In the bloodstream, it can activate host plasminogen to become plasmin that breaks down extracellular matrix, degrades fibrin clots and complemental proteins (C3b and C5) to avoid opsonisation. It can also recruit complement regulators such as Factor H, C4b-binding protein, factor H-like binding protein, and vitronectin to prevent the activation of membrane attack complex on its surface. It also secretes proteases to degrade complement proteins such as C3. It can bind to thrombin that decreases the fibrin formation. Reduced fibrin formation increases the risk of bleeding. Leptospira also secretes sphingomyelinase and haemolysin that target red blood cells.Leptospira spreads rapidly to all organs through the bloodstream. They mainly affect the liver. They invade spaces between hepatocytes, causing apoptosis. The damaged hepatocytes and hepatocyte intercellular junctions cause leakage of bile into the bloodstream, causing elevated levels of bilirubin, resulting in jaundice. Congested liver sinusoids and perisinusoidal spaces have been reported. Meanwhile, in the lungs, petechiae or frank bleeding can be found at the alveolar septum and spaces between alveoli. Leptospira secretes toxins that cause mild to severe kidney failure or interstitial nephritis. The kidney failure can recover completely or lead to atrophy and fibrosis. Rarely, inflammation of the heart muscles, coronary arteries, and aorta are found.

Diagnosis
Laboratory tests
For those who are infected, a complete blood count may show a high white cell count and a low platelet count. When a low haemoglobin count is present together with a low white cell count and thrombocytopenia, bone marrow suppression should be considered. Erythrocyte sedimentation rate and C-reactive protein may also be elevated.The kidneys are commonly involved in leptospirosis. Blood urea and creatinine levels will be elevated. Leptospirosis increases potassium excretion in urine, which leads to a low potassium level and a low sodium level in the blood. Urinalysis may reveal the presence of protein, white blood cells, and microscopic haematuria. Because the bacteria settle in the kidneys, urine cultures will be positive for leptospirosis starting after the second week of illness until 30 days of infection.For those with liver involvement, transaminases and direct bilirubin are elevated in liver function tests. The Icterohaemorrhagiae serogroup is associated with jaundice and elevated bilirubin levels. Hemolytic anemia contributes to jaundice. A feature of leptospirosis is acute haemolytic anaemia and conjugated hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase deficiency. Abnormal serum amylase and lipase levels (associated with pancreatitis) are found in those who are admitted to hospital due to leptospirosis. Impaired kidney function with creatinine clearance less than 50 ml/min is associated with elevated pancreatic enzymes.For those with severe headache who show signs of meningitis, a lumbar puncture can be attempted. If infected, cerebrospinal fluid (CSF) examination shows lymphocytic predominance with a cell count of about 500/mm3, protein between 50 and 100 mg/ml and normal glucose levels. These findings are consistent with aseptic meningitis.

Serological tests
Rapid detection of Leptospira can be done by quantifying the IgM antibodies using ELISA. Typically, L. biflexa antigen is used to detect the IgM antibodies. This test can quickly determine the diagnosis and help in early treatment. However, the test specificity depends upon the type of antigen used and the presence of antibodies from previous infections. The presence of other diseases such as Epstein–Barr virus infection, viral hepatitis, and cytomegalovirus infection can cause false-positive results. Other rapid screening tests have been developed such as dipsticks, latex and slide agglutination tests.The microscopic agglutination test (MAT) is the reference test for the diagnosis of leptospirosis. MAT is a test where serial dilutions of patient sera are mixed with different serovars of Leptospira. The mixture is then examined under a dark field microscope to look for agglutination. The highest dilution where 50% agglutination occurs is the result. MAT titres of 1:100 to 1:800 are diagnostic of leptospirosis. A fourfold or greater rise in titre of two sera taken at symptoms onset and three to 10 days of disease onset confirms the diagnosis. During the acute phase of the disease, MAT is not specific in detecting a serotype of Leptospira because of cross-reactivity between the serovars. In the convalescent phase, MAT is more specific in detecting the serovar types. MAT requires a panel of live antigens and requires laborious work.

Molecular tests
Leptospiral DNA can be amplified by using polymerase chain reaction (PCR) from serum, urine, aqueous humour, CSF, and autopsy specimens. It detects the presence of bacteria faster than MAT during the first few days of infection without waiting for the appearance of antibodies. As PCR detects the presence of leptospiral DNA in the blood it is useful even when the bacteria is killed by antibiotics.

Imaging
In those who have lung involvement, a chest X-ray may demonstrate diffuse alveolar opacities.

Diagnostic criteria
In 1982, the World Health Organization (WHO) proposed the Faines criteria for the diagnosis of leptospirosis. It consists of three parts: A (clinical findings), B (epidemiological factors), and C (lab findings and bacteriological data). Since the original Faines criteria only included culture and MAT in part C, which is difficult and complex to perform, the modified Faines criteria was proposed in 2004 to include ELISA and slide agglutination tests which are easier to perform. In 2012, modified Faines criteria (with amendment) was proposed to include shortness of breath and coughing up blood in the diagnosis. In 2013, India recommended modified Faines criteria in the diagnosis of leptospirosis.

Prevention
Rates of leptospirosis can be reduced by improving housing, infrastructure, and sanitation standards. Rodent abatement efforts and flood mitigation projects can also help to prevent it. Proper use of personal protective equipment (PPE) by people who have a high risk of occupational exposure can prevent leptospirosis infections in most cases.There is no human vaccine suitable for worldwide use. Only a few countries such as Cuba, Japan, France, and China have approved the use of inactivated vaccines with limited protective effects. Side effects such as nausea, injection site redness and swelling have been reported after the vaccine was injected. Since the immunity induced by one Leptospiraserovar is only protective against that specific one, trivalent vaccines have been developed. However, they do not confer long-lasting immunity to humans or animals. Vaccines for other animals are more widely available.Doxycycline is given once a week as a prophylaxis and is effective in reducing the rate of leptospirosis infections amongst high-risk individuals in flood-prone areas. In one study, it reduced the number of leptospirosis cases in military personnel undergoing exercises in the jungles. In another study, it reduced the number of symptomatic cases after exposure to leptospirosis under heavy rainfall in endemic areas.

Treatment
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 leptospirosis is suspected after history taking and examination.For mild leptospirosis, antibiotic recommendations such as doxycycline, azithromycin, ampicillin and amoxicillin were based solely on in vitro testing. In 2001, the WHO recommended oral doxycycline (2 mg/kg up to 100 mg every 12 hours) for five to seven days for those with mild leptospirosis. Tetracycline, ampicillin, and amoxicillin can also be used in such cases. However, in areas where rickettsia and leptospirosis are both endemic, azithromycin and doxycycline are the drugs of choice.Based on a 1988 study, intravenous (IV) benzylpenicillin (also known as penicillin G) is recommended for the treatment of severe leptospirosis. Intravenous benzylpenicillin (30 mg/kg up to 1.2 g every six hours) is used for five to seven days. Amoxicillin, ampicillin, and erythromycin may also be used for severe cases. Ceftriaxone (1 g IV every 24 hours for seven days) is also effective for severe leptospirosis. Cefotaxime (1 g IV every six hours for seven days) and doxycycline (200 mg initially followed by 100 mg IV every 12 hours for seven days) are equally effective as benzylpenicillin (1.5 million units IV every six hours for seven days). Therefore, there is no evidence on differences in death reduction when benzylpenicillin is compared with ceftriaxone or cefotaxime. Another study conducted in 2007 also showed no difference in efficacy between doxycycline (200 mg initially followed by 100 mg orally every 12 hours for seven days) or azithromycin (2 g on day one followed by 1 g daily for two more days) for suspected leptospirosis. There was no difference in the resolution of fever and azithromycin is better tolerated than doxycycline.Outpatients are given doxycycline or azithromycin. Doxycycline can shorten the duration of leptospirosis by two days, improve symptoms, and prevent the shedding of organisms in their urine. Azithromycin and amoxicillin are given to pregnant women and children. Rarely, a Jarisch–Herxheimer reaction can develop in the first few hours after antibiotic administration. However, according to a meta-analysis done in 2012, the benefit of antibiotics in the treatment of leptospirosis was unclear although the use of antibiotics may reduce the duration of illness by two to four days. Another meta-analysis done in 2013 reached a similar conclusion.For those with severe leptospirosis, including potassium wasting with high kidney output dysfunction, intravenous hydration and potassium supplements can prevent dehydration and hypokalemia. When acute kidney 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.Corticosteroids have been proposed to suppress inflammation in leptospirosis because Leptospira infection can induce the release of chemical signals which promote inflammation of blood vessels in the lungs. However, there is insufficient evidence to determine whether the use of corticosteroids is beneficial.

Prognosis
The overall risk of death for leptospirosis is 5–10%. For those with jaundice, the case fatality can increase up to 15%. For those infected who present with confusion and neurological signs, there is a high risk of death. Other factors that increase the risk of death include reduced urine output, age more than 36 years, and respiratory failure. With proper care, most of those infected will recover completely. Those with acute kidney failure may develop persistent mild kidney impairment after they recover. In those with severe lung involvement, the risk of death is 50–70%. Thirty percent of people with acute leptospirosis complained of long-lasting symptoms characterised by weakness, muscle pain, and headaches.

Eye complications
Eye problems can occur in 10% of those who recovered from leptospirosis in the range from two weeks to a few years post-infection. Most commonly, eye complications can occur at six months after the infection. This is due to the immune privilege of the eye which protects it from immunological damage during the initial phase of leptospiral infection. These complications can range from mild anterior uveitis to severe panuveitis (which involves all three vascular layers of the eye). The uveitis is more commonly happen in young to a middle-aged man and those working in agricultural farming. In up to 80% of those infected, Leptospira DNA can be found in the aqueous humour of the eye. Eye problems usually have a good prognosis following treatment or they are self-limiting. In anterior uveitis, only topical steroids and mydriatics (an agent that causes dilation of the pupil) are needed while in panuveitis, it requires periocular corticosteroids. Leptospiral uveitis is characterised by hypopyon, rapidly maturing cataract, free floating vitreous membranes, disc hyperemia and retinal vasculitis.

Epidemiology
It is estimated that one million severe cases of leptospirosis occur annually, with 58,900 deaths. Severe cases account for 5–15% of all leptospirosis cases. Leptospirosis is found in both urban and rural areas in tropical, subtropical, and temperate regions. The global health burden for leptospirosis can be measured by disability-adjusted life year (DALY). The score is 42 per 100,000 people per year, which is more than other diseases such as rabies and filariasis.The disease is observed persistently in parts of Asia, Oceania, the Caribbean, Latin America and Africa. Antarctica is the only place not affected by leptospirosis. In the United States, there were 100 to 150 leptospirosis cases annually. In 1994, leptospirosis ceased to be a notifiable disease in the United States except in 36 states/territories where it is prevalent such as Hawaii, Texas, California, and Puerto Rico. About 50% of the reported cases occurred in Puerto Rico. In January 2013, leptospirosis was reinstated as a nationally notifiable disease in the United States. Research on epidemiology of leptospirosis in high-risk groups and risk factors is limited in India.The global rates of leptospirosis have been underestimated because most affected countries lack notification or notification is not mandatory. Distinguishing clinical signs of leptospirosis from other diseases and lack of laboratory diagnostic services are other problems. The socioeconomic status of many of the worlds population is closely tied to malnutrition; subsequent lack of micronutrients may lead to increased risk of infection and death due to leptospirosis infection. Micronutrients such as iron, calcium, and magnesium represent important areas for future research.

History
The disease was first described by Adolf Weil in 1886 when he reported an "acute infectious disease with enlargement of spleen, jaundice, and nephritis." Before Weils description, the disease was known as "rice field jaundice" in ancient Chinese text, "autumn fever", "seven-day fever", and "nanukayami fever" in Japan; in Europe and Australia, the disease was associated with certain occupations and given names such as "cane-cutters disease", "swine-herds disease", and "Schlammfieber" (mud fever). It has been known historically as "black jaundice", or "dairy farm fever" in New Zealand. Leptospirosis was postulated as the cause of an epidemic among Native Americans along the coast of what is now New England during 1616–19. The disease was most likely brought to the New World by Europeans.Leptospira was first observed in 1907 in a post mortem kidney tissue slice by Arthur Stimson using silver deposition staining technique. He called the organism Spirocheta interrogans because the bacteria resembled a question mark. In 1908, a Japanese research group led by Ryukichi Inada and Yutaka Ito first identified this bacterium as the causative agent of leptospirosis and noted its presence in rats in 1916. Japanese coal mine workers frequently contracted leptospirosis. In Japan, the organism was named Spirocheta icterohaemorrhagiae. The Japanese group also experimented with the first leptospiral immunisation studies in guinea pigs. They demonstrated that by injecting the infected guinea pigs with sera from convalescent humans or goats, passive immunity could be provided to the guinea pigs. In 1917, the Japanese group discovered rats as the carriers of leptospirosis. Unaware of the Japanese groups work, two German groups independently and almost simultaneously published their first demonstration of transmitting leptospiral infection in guinea pigs in October 1915. They named the organism Spirochaeta nodosa and Spirochaeta Icterogenes respectively.Leptospirosis was subsequently recognised as a disease of all mammalian species. In 1933, Dutch workers reported the isolation of Leptospira canicola which specifically infects dogs. In 1940, the strain that specifically infects cattle was first reported in Russia. In 1942, soldiers at Fort Bragg, North Carolina, were recorded to have an infectious disease which caused a rash over their shinbones. This disease was later known to be caused by leptospirosis. By the 1950s, the number of serovars that infected various mammals had expanded significantly. In the 1980s, leptospirosis was recognised as a veterinary disease of major economic importance.In 1982, there were about 200 serovars of Leptospira available for classification. The International Committee on Systematic Bacteriologys subcommittee on taxonomy of Leptospira proposed classifying these serovars into two big groups: L. interrogans containing pathogenic serovars and L. biflexa containing saprophytic serovars. In 1979, the leptospiral family of Leptospiraceae was proposed. In the same year, Leptospira illini was reclassified as the new genus Leptonema. In 2002, "Lepthangamushi syndrome" was coined to describe a series of overlapping symptoms of leptospirosis with Hantavirus hemorrhagic fever with renal syndrome, and scrub typhus caused by Orientia tsutsugamushi. In 2005, Leptospira parva was classified as Turneriella. With DNA-DNA hybridisation technology, L. interrogans was divided into seven species. More Leptospira species have been discovered since then. The WHO established the Leptospirosis Burden Epidemiology Reference Group (LERG) to review the latest disease epidemiological data of leptospirosis, formulate a disease transmission model, and identify gaps in knowledge and research. The first meeting was convened in 2009. In 2011, LERG estimated that the global yearly rate of leptospirosis is five to 14 cases per 100,000 population.

Other animals
Infected animals can have no, mild, or severe symptoms; the presenting symptoms may vary by the type of animal. In some animals the bacteria live in the reproductive tract, leading to transmission during mating.Animals also present with similar clinical features when compared to humans. Clinical signs can appear in 5–15 days in dogs. The incubation period can be prolonged in cats. Leptospirosis can cause abortions after 2–12 weeks in cattle, and 1–4 weeks of infection in pigs. The illness tends to be milder in reservoir hosts. The most commonly affected organs are the kidneys, liver, and reproductive system, but other organs can be affected. In dogs, the acute clinical signs include fever, loss of appetite, shivering, muscle pain, weakness, and urinary symptoms. Vomiting, diarrhea, and abdominal pain may also present. Petechiae and ecchymoses may be seen on mucous membranes. Bleeding from the lungs may also be seen in dogs. In chronic presentations, the affected dog may have no symptoms. In animals that have died of leptospirosis, their kidneys may be swollen with grey and white spots, mottling, or scarring. Their liver may be enlarged with areas of cell death. Petechiae and ecchymoses may be found in various organs. Inflammation of the blood vessels, inflammation of the heart, meningeal layers covering the brain and spinal cord, and uveitis are also possible. Equine recurrent uveitis (ERU) is the most common disease associated with Leptospira infection in horses in North America and may lead to blindness. ERU is an autoimmune disease involving antibodies against Leptospira proteins LruA and LruB cross-reacting with eye proteins. Live Leptospira can be recovered from the aqueous or vitreous fluid of many horses with Leptospira-associated ERU. Risk of death or disability in infected 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. Up to 40% of cows may have a spontaneous abortion. Younger animals usually develop more severe disease. About 80% of dogs can survive with treatment, but the survival rate is reduced if the lungs are involved.ELISA and microscopic agglutination tests are most commonly used to diagnose leptospirosis in animals. The 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 techniques. Silver staining or immunogold silver staining is used to detect Leptospira in tissue sections. The organisms stain poorly with Gram stain. Dark-field microscopy can be used to detect Leptospira in body fluids, but it is neither sensitive nor specific in detecting the organism. A positive culture for leptospirosis is definitive, but the availability is limited, and culture results can take 13–26 weeks for a result, limiting its utility. Paired acute and convalescent samples are preferred for serological diagnosis of leptospirosis in animals. A positive serological sample from an aborted fetus is also diagnostic of leptospirosis.Various antibiotics such as doxycycline, penicillins, dihydrostreptomycin, and streptomycin have been used to treat leptospirosis in animals. Fluid therapy, blood transfusion, and respiratory support may be required in severe disease. For horses with ERU, the primary treatment is with anti-inflammatory drugs.Leptospirosis vaccines are available for animals such as pigs, dogs, cattle, sheep, and goats. Vaccines for cattle usually contain Leptospira serovar Hardjo and Pomona, for dogs, the vaccines usually contain serovar Icterohaemorrhagiae and Canicola. Vaccines containing multiple serovars do not work for cattle as well as vaccines containing a single serovar, yet the multivalent vaccines continue to be sold. Isolation of infected animals and prophylactic antibiotics are also effective in preventing leptospirosis transmission between animals. Environmental control and sanitation also reduce transmission rates.

References
This article was submitted to WikiJournal of Medicine for external academic peer review in 2019 (reviewer reports). The updated content was reintegrated into the Wikipedia page under a CC-BY-SA-3.0 license (2022). The version of record as reviewed is:
Siang Ching Raymond Chieng;  et al. (21 June 2022). "Leptospirosis" </s>