Diseases

Leptospirosis

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Control Tools

  • Diagnostics availability

  • Commercial diagnostic kits available worldwide

    Commercial kits available for human and dog diseases comprising lateral flow and latex agglutination methodologies.There are commercial ELISA kits (species and serovar specific) for Leptospira serovars Hardjo infection in cattle and Leptospira interrogans serovar Bratislava infection in pigs. Commercial ELISA kits are also available for dogs.All these tests do measure anti-leptospiral antibodies.

    GAPS :

    • Lack of validated rapid tests.
    • Existing rapid tests (not all of them commercially available) cannot be applied to different endemic backgrounds and serovars and have to be locally evaluated.
    • Commercial kits are not available for other domestic species such as horses.
    • There are no commercial kits for detection of leptospiral DNA.
  • Diagnostic kits validated by International, European or National Standards

    No.Yes MAT.

    GAP :

    Diagnostic test kits are rarely validated by international standards. It is essential that reference material is available for their purpose of use, including validation of diagnostic kits/methods.

  • Diagnostic method(s) described by International, European or National standards

    Routine methods are described in the OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animals

    1. Identification of the agenta) The demonstration of Leptospira in blood and milk of animals showing clinical signs ;b) Culture ;c) Leptospira may also be demonstrated by a variety of immunochemical staining techniques, e.g. immunofluorescence and various immunohistochemical techniques ;d) PCR-based assays are used in some diagnostic and many reference laboratories for the detection of Leptospira in tissues and body fluids of animals.

    2. Serological testsa) Microscopic agglutination test (MAT) ;b) Enzyme-linked immunosorbent assays (ELISAs).

    GAP :

    Lack of validation by international standards.

  • Commercial potential for diagnostic kits in Europe

    Limited at present but growing demand particularly with concerns over side effects associated with canine leptospirosis vaccination. (L4 vs L2 formulation).

  • DIVA tests required and/or available

    Animals that have been vaccinated against a specific serovar may show cross reactions to other (related or non-related) serovars on MAT and ELISAs, which can make the interpretation of the test results difficult.

    GAP :

    Tests that can differentiate infected from vaccinated animals are not available.

  • Vaccines availability

  • Commercial vaccines availability (globally)

    Effective leptospirosis vaccines are available for use in pigs, cattle and dogs. Often combined with more than one serovar and other bacterial or viral vaccines.

    GAPS :

    Lack of human vaccine which contains enough serovars to protect across continents.Lack of animal vaccines which contain enough serovars to protect across continents.

    No vaccine against serovar Pomona in dogs available on EU market. However effective vaccines are available outside the EU, but not registered at the EU since these are not yet approved by the EMA.

    No vaccine available and authorized against any serovar on the EU market for the horse.

  • Marker vaccines available worldwide

    No.

  • Effectiveness of vaccines / Main shortcomings of current vaccines

    • Vaccines prevent disease but do not completely prevent infection or the shedding of the organisms.
    • Tendency for vaccinated animals to become carriers particularly where multivalent vaccines are used.
    • Vaccines tend to only generate serovar or closely related serovar specific immunity.

    GAP :

    Control interventions based on immunizing potential reservoirs are limited because a period of one month ++ is required to develop vaccine-mediated immunity and vaccines are serovar-specific and may not provide coverage against other serovars.

  • Commercial potential for vaccines in Europe

    Widely used in Europe.

  • Regulatory and/or policy challenges to approval

    The development of genetically modified vaccines might be problematic in some countries. The field trials may need specific regulation regarding the release of GMOs into the environment.

    GAP :

    Further data on the effectiveness/validity of mass prophylaxis (currently controversial) in outbreak settings would facilitate the development of alert response guidelines.

  • Commercial feasibility (e.g manufacturing)

    Commercially feasible but would depend on demand. Canine leptospirosis vaccines in most regions of the world not considered as “core vaccine”.

  • Opportunity for barrier protection

    May use vaccination to provide herd protection in areas where there is a high incidence of disease.

  • Pharmaceutical availability

  • Current therapy (curative and preventive)

    Antibiotics are used for care of human leptospirosis cases and may be used to tackle a clinical disease problem in animals (e.g. in the event of an abortion storm). However, efforts to reduce the use of antibiotics in the livestock industry to tackle antimicrobial resistance mean that preventive measures such as the addition of antibiotics to feed for chemoprophylaxis are not considered appropriate. Herd treatment may be indicated if there is a clear public health need but must be carefully justified.

    GAP :

    Clear guidance on chemoprophylaxis (e.g. doxycycline, cannot be used in animals from which milk is produced for human consumption or in horses of which the meat is used for human consumption) needed (only limited understanding whether pre-exposure doxy chemoprophylaxis is effective as a preventive measure during epidemics).

  • Future therapy

    Possible development of effective treatments against carrier animals but likely to rely on vaccines as an alternative to antibiotic treatment.

  • Commercial potential for pharmaceuticals in Europe

    Balance between use of vaccines or treatment. If vaccines widely used there will not be a major demand for pharmaceuticals.

  • Regulatory and/or policy challenges to approval

    None.

  • Commercial feasibility (e.g manufacturing)

    Dependent on demand.

  • New developments for diagnostic tests

  • Requirements for diagnostics development

    1. Serological tests.

    a) New ELISA tests.

    MAT is useful in diagnosis of infection. ELISA test seems to be a satisfactory method for identifying for population-level surveillance or identifying exposure in animals but cannot be used to identify chronic infection in carrier animals which act as a maintenance host. Many ELISAs for the detection of anti-leptospiral antibodies have been developed using a number of different antigen preparation and assay protocols. In contrast to the application of ELISA for diagnosis of human infection, where broadly reactive assay are generally desirable, veterinary applications should be directed towards detection of serovar specific antibodies such as ELISA for serovar Hardjo infection in cattle and serovar Bratislava infection in pigs.

    b) Distinguish vaccinated from naturally infected animals.Some studies have shown fundamental differences in the nature of the immune response in cattle that have been naturally infected and vaccinated with killed bacterin.

    2. Identification of the agent.

    PCR

    Most published PCRs have been validated under laboratory conditions using seeded urine or kidney material or using fresh tissue from experimentally infected laboratory animals. This unfortunately bears little relevance to its use in aborted fetal tissue and it has not been validated for the examination of fetuses. There are very few reports of real time PCR being used for abortion diagnosis (which is difficult due to lack of readily available aborted fetus material) and its comparison with other techniques of identification of agent.

    GAPS :

    Serovar specific ELISAs should be developed for detection serovar Pomona infection in cattle and serovar Hardjo infection in sheep. Could also be beneficial to extend canine ELISAs to include other serovars of concern in Europe (L. interrogans serovar Bratislava; L. kirschneri serovar Grippotyphosa), however the MAT is useful for this as well.Lack in well-defined banks of serum, urine and other specimens that would allow the development of new diagnostic tests, also to be used in a field context.

    Specific immuno-diagnostics that can discriminate between vaccinated and naturally infected animals.

    Lack of internationally validated guidelines (e.g. OIE or EU) on diagnosis of Leptospira-associated abortions in livestock.

    It is possible to determine the leptospiral species by molecular diagnostics, however there is a lack of molecular diagnostic tools which are able to determine the infecting serovar.

  • Time to develop new or improved diagnostics

    In general the development of tests is much faster and less expensive than developing vaccines. From development through validation to commercial availability will be time consuming and can take years.

  • Cost of developing new or improved diagnostics and their validation

    The development and validation of new tests is time consuming and labour intensive which is costly. Costs cannot be specified as they will depend on the nature of the test and the cost of producing reagents and supplying reading or processing machines if necessary. Once validated there will need to be a commercial company willing to market the test. One of the biggest hurdles to assay validation is the lack of samples from (confirmed) infected animals.

  • Research requirements for new or improved diagnostics

    Identification of specific and sensitive antigens, which may differentiate natural infection and vaccination. Availability of samples from (confirmed) infected animals and (confirmed) negative animals.

  • Technology to determine virus freedom in animals

    The MAT has limitations in the diagnosis of chronic infection in individual animals and in the diagnosis of endemic infections in herds.

  • New developments for vaccines

  • Requirements for vaccines development / main characteristics for improved vaccines

    Develop and standardise L. borgpetersenii serovar Hardjo sheep vaccine.

    New canine vaccines have been developed which include four serovars considered to be important in Europe: L. interrogans serovar Bratislava; L. interrogans serovar Canicola, L. interrogans serovar Icterohaemorrhagiae and L. kirschneri serovar Grippotyphosa.

    GAPS :

    Data regarding prevalence of Leptospira serovars in dogs and other domestic susceptible species in Europe is incomplete and monitoring is sporadic. This is mainly due to lack of awareness (professionals, authorities), which probably is caused by general underdiagnosis of the disease. There are no structured surveillance programmes.

    No canine Pomona vaccine on EU market.

  • Time to develop new or improved vaccines

    Depending on when a candidate vaccine could be identified the timescale will be 5-10 years. This will involve feasibility, development, clinical trials and licensing. Potential vaccines need to be identified and subjected to initial trials and depending on the outcome will determine the time to commercial availability.

  • Cost of developing new or improved vaccines and their validation

    Expensive with the need to develop and undertake all the relevant tests to provide data to enable the product to be authorised. Field trial will be difficult as will evaluating the results. In vaccine development also higher chance of conflicts between increasing licensing requirements (Ph Eur) and increasing animal welfare demands (in particular applicable to dogs).

  • Research requirements for new or improved vaccines

    Establish surveillance for monitoring introduction /existence of new Leptospira serovars not covered by improved vaccines given that these are serovar specific not protecting animals from unrelated strains. Periodic sampling of isolates could help understand the emergence of serovars not covered by available serovars. Target sampling for example of imported pets and domestic animals will help reveal new serovars.

    GAP :

    It might be useful to develop genetic tools for vector technology in order to develop better vaccines which in theory could induce a significant longer duration of immunity than 1 year.

  • New developments for pharmaceuticals

  • Requirements for pharmaceuticals development

    No requirements.

  • Time to develop new or improved pharmaceuticals

    Time to develop would depend on the product and the trials necessary to validate the efficacy and safety. Commercial production would then take further time. Five to 10 years seems a realistic timeframe.

  • Cost of developing new or improved pharmaceuticals and their validation

    Expensive and difficult to assess as it will depend on the product and the trials necessary to validate and license.

  • Research requirements for new or improved pharmaceuticals

    No requirements.

Disease details

  • Description and characteristics

  • Pathogen

    The classification of this organism is complex as Leptospira are antigenically complex. Leptospira are now identified in 17 pathogenic, 21 intermediate and 26 non-pathogenic species. There are over 260 known pathogenic serologic variants which are arranged in 26 serogroups. The current classification system can be confusing. There is poor correspondence between Leptospira serogroups and species, as defined by genetic or genomic methods. A single serovar can occur within multiple species.

  • Variability of the disease

    Leptospirosis is a geographically widespread disease of humans, livestock, pet animals and wildlife. Disease is usually endemic and sustained in a certain environment by variety of animal species with rodents as primary reservoirs. Different animal species can be maintenance hosts of distinct serovars or incidental hosts when infected with serovars carried by other domestic or free-living animals. In spite of the large number of known pathogenic serovars, only a limited number occur and circulate in certain geographical area. Humans are considered to be incidental hosts.

    GAP :

    Mapping of major maintenance hosts in different geographic areas needed to help pinpoint source of infections and suitable control intervention. The generalization of reservoir hosts hinders understanding the major source of transmission to humans as well other animals.

  • Stability of the agent/pathogen in the environment

    Commonly present in the urine or sometimes in the genital tract of infected animals. Leptospira can survive in moist conditions outside the host for many days or even weeks especially in fresh water, soil, and mud in tropical areas. Some species with larger genomes and wider host ranges e.g. L. interrogans can survive outside the host for longer periods than those with smaller genomes and narrow host range e.g. L. borgpetersenii. Leptospira are readily killed by drying, exposure to detergents, disinfectants, heating to 50°C for ten minutes and only survive for a few hours in salt water.

    GAP :

    Survival of Leptospira in the environment- potential factors: temperature, soil type, moisture and soil pH.

  • Species involved

  • Animal infected/carrier/disease

    Leptospira have been found in a variety of both wild and domestic animals, including rodents, insectivores, dogs, cats, cattle, pigs, sheep, goats and horses. Animals can become chronically infected and remain carriers for months to years following initial infection. As a result, animal carriers can remain reservoirs of infection for animals and humans.

    GAPS :

    Gap in knowledge on dynamics of leptospirosis in rodent carriers of disease and effect of rodent populations on disease transmission lifecycle in rodent carriers, e.g.

    • Role of rodents and interactions with other animal hosts in spreading serovars for which they are not maintenance reservoirs
    • Correlation of rodent populations dynamics (seasonality (breeding), migration) with leptospirosis incidence
    • In certain regions other reservoir animals than rodents have been reported to be relevant in disease transmission, e.g. raccoons in the USA. Also examples were published of re-introduction of endangered animal species that were found positive and could play a role in transmission of Leptospira serovars (e.g. beavers and water voles in the UK).
  • Human infected/disease

    Pathogenic serovars can cause illness in humans.

    GAP :

    Need for further revision of case definition in humans.

  • Vector cyclical/non-cyclical

    No.

  • Reservoir (animal, environment)

    Animals, including humans, can be divided into maintenance hosts and incidental hosts. The disease is maintained in nature by chronic infection of maintenance hosts who shed the bacteria in their urine for months to years following infection. Other animals may become incidentally infected by direct or indirect contact with the maintenance host. The major host maintained serovars include:

    • Rats: serogroups Icterohaemorrhagiae and Ballum
    • Mice, differs according to species e.gApodemus flavicollis, A. sylvaticus – serogroup Australis.Apodemus agrarius – serogroup Pomona.Voles (Microtis agrestis, M. arvalis or Myodes glareolus) – serogroup Grippotyphosa.Mus musculus – serogroups Sejroe, Ballum.
    • Cattle: serovar Hardjo type bovis.
    • Pigs: serovars Pomona, Tarassovi and Bratislava.
    • Dogs: serovar Canicola.
    • Insectivore species: e.g. shrews or hedgehogs can also harbour a broad range of serovars.

    GAP :

    • Not all animal reservoirs are responsible for the maintenance of the many different Leptospira strains and serovars are identified.
    • Mechanisms that underpin host/serovar relationships are poorly understood.
    • Host/serovar relationships may vary, with different associations reported in different geographic or environmental locations.
    • Climate or other environmental change may also be an important factor in driving the introduction of new serovars to animal populations but is hard to predict.
    • Active surveillance is important to detect the introduction of novel serovars but is lacking in many countries.
    • It is unclear whether some animals can act as a maintenance host for certain serovars (e.g. Dogs: serovar Bratislava or Sheep: serovar Hardjo)
  • Description of infection & disease in natural hosts

  • Transmissibility

    Infection may be spread by skin via a cut or abrasion, via the mucous membranes of the conjunctivae or oral cavity, contact with infected urine, semen, vaginal fluids or water or, less commonly, by ingesting food or water contaminated with urine.

    GAP :

    Data gaps on human to human as well as animal species to animal species transmissibility.

  • Pathogenic life cycle stages

    Not applicable.

  • Signs/Morbidity

    All mammals appear to be susceptible to at least one serovar of Leptospira. Clinical signs seen vary (from subclinical infections to severe conditions) depending on the species of animal affected, and the type of leptospiral organism involved. Severe disease is uncommon in livestock but can occur, especially in young animals. Clinical signs include pyrexia, jaundice, haemoglobinuria, and occasionally meningitis. Agalactia can occur in lactating cows. Clinical disease in dogs is very similar to that in humans. The most common severe clinical manifestations are related to acute kidney injury, and recently leptospirosis pulmonary haemorrhagic syndrome. Disease is rare in cats. Abortion, stillbirth, birth of weak offspring and infertility can all be associated with chronic infection, particularly in livestock species such as cattle or pigs. Chronic Leptospira infection can also be associated with recurrent uveitis in horses. In the chronic cases, Leptospira may localise and persist in the kidney or the male and female reproductive tracts with the consequence that diagnosis can be difficult.

    GAP :

    Typical signs presented in animals/humans in different geographic areas are needed and mapping of the causative Leptospira serovars. This could be achieved by prioritising the long list of associated symptoms/signs to few (major ones) which will also increase chances of pinpointing to this disease than now when it is easily confused with diseases presenting related broad range of signs.

  • Incubation period

    The incubation period is 4 to 12 days in dogs. Abortionsusually occur 3 to 10 weeks after infection in cattle, and 15 to 45 days after infection in pigs. In horses, most abortions occur after the 8th month of gestation. Recurrent uveitis develops 2-8 months after initial infection.

  • Mortality

    Generally thought to be low, however if intensive care treatment is lacking, more fatal cases will occur in humans as well as dogs.

    GAP :

    Scale of foetal or neonatal mortality as a result of abortion, still birth or neonatal death, are not well documented as these often go unreported, or are not investigated in farming systems. There is also a lack of guidance regarding diagnosis of leptospirosis-associated abortions in livestock.

  • Shedding kinetic patterns

    Shed in the urine of acutely infected animals and also in the urine of chronic carriers for many months.

  • Mechanism of pathogenicity

    Pathogenic Leptospira enter the body through mucous membranes (eyes, mouth, lips and reproductive organs) or skin abrasions, enter the blood stream and lymphatic system and are disseminated through various organs, such as the kidneys, liver, lungs, eyes, brain, muscles and heart). Leptospira cause vasculitis leading to damage of endothelial membranes and necrosis of organs. Acute infection induces an interstitial nephritis, whereas chronic carriers may have little to no renal pathology. Leptospirosis activates the coagulation cascade and causes disseminated intravascular coagulation in up to 50% of patients with severe disease manifestations. The immune response stimulates production of pro-inflammatory cytokines, causing inflammation and damage of organ tissues. TNF-alpha may be important in disease progression as levels of this cytokine are associated with poor clinical outcomes. Lipopolysaccharide (LPS) and surface proteins are to date the main discovered virulence factors, mediating the interaction between the host tissues and the bacterium. So a small number of essential virulence factors have been identified, though most do not have a clearly defined function. Significant advances have also been made in the in vitro characterization of leptospiral interaction with host structures although none of these in vitro findings has been translated to the host animal. Binding to host structures may permit colonization of the host, prevention of blood clotting by contribute to haemorrhage, while interaction with complement resistance mediators may contribute to survival in serum.

    GAP :

    While many advances have been made, there remains a lack of understanding how Leptospira causes tissue pathology.

  • Zoonotic potential

  • Reported incidence in humans

    Leptospirosis occurs worldwide with the total number of cases estimated to exceed one million each year. The highest estimates of morbidity and mortality are found in tropical or subtropical areas with Oceania, South-east Asia and the Caribbean having particularly high burden of human disease. By region, incidence estimates range from 1.4 cases per 100,000 per year in Eastern Europe to 151 cases per 100,000 per year in Oceania. During outbreaks and in high-risk groups, 100 or more per 100,000 may be infected. Leptospirosis continues to re-emerge as a notable source of morbidity and mortality in western Europe.

    High severity of under-diagnosis of leptospirosis and under-recognition occur in many developing countries. The number of human cases worldwide is not well-documented. The disease is underreported for many reasons, including difficulty in distinguishing clinical signs from those of other endemic diseases and a lack of appropriate diagnostic laboratory services.

    GAPS :

    • Lack of good quality large-scale studies in some parts of the world including the middle East and most parts of Africa.
    • Incidence estimates are predictions rather than observed figures due to low level of case detection and reporting in some regions.
    • Age and sex break down still poorly understood.
    • Understanding of resistance and susceptibility in humans to leptospirosis (naturally-acquired immunity to re-infection).
    • Poor notification (in many countries, no mandatory notification) even though leptospirosis is recognized as a major public health concern in several countries suffering from recent large outbreaks.
    • Lack of reliable point-of-care diagnostics with high sensitivity and specificity that could be used for rapid case detection.
  • Risk of occurence in humans, populations at risk, specific risk factors

    Infection in humans is from direct contact with urine of infected animals or indirect contact with contaminated environment. Less frequently animal bites or handling infected animal samples or tissues can cause infection. Rodents are implicated in many human cases. People who work outdoors or with animals, such as farmers, sewer workers, veterinarians, dairy workers etc. face leptospirosis as an occupational hazard. Swimming or wading in contaminated waters can pose a potential risk. Cases have been reported in association with recreational or sporting activities such as triathlon events.

    GAPS :

    • Infective dose especially during outbreaks and flooding.
    • Understanding of community risk factors (rodents, hygiene, water contamination) and risk linked socio cultural dimensions like livestock rearing systems, food storage practices, etc.
  • Symptoms described in humans

    The most common clinical presentation is acute undifferentiated fever. Further symptoms include headache, chills, muscle aches, vomiting, jaundice, anaemia, and sometimes a rash. The incubation period usually is 7 days, with a range of 2-29 days. If not treated, the patient could develop kidney damage, meningitis, liver failure, and respiratory distress. In rare cases, death occurs. Leptospirosis pulmonary haemorrhagic syndrome has been recently recognized as an emerging clinical manifestation.Leptospirosis can cause long-term sequels which can hamper individuals in their daily activities.

    GAPS :

    • Lack of clear case definitions within the broad spectrum of clinical manifestations which fall into a wide range of possible differential diagnosis (often misdiagnosed for malaria or dengue or hantavirus infection).
    • Need for outbreak response and clinical management protocols.
  • Likelihood of spread in humans

    Human-to-human transmission is rare.

    GAP :

    See Section “Description of infection & disease in natural hosts – Transmissibility”.

  • Impact on animal welfare and biodiversity

  • Both disease and prevention/control measures related

    Clinical disease impacts on the welfare of animals. Disease in animal hosts can range from asymptomatic or mild through to severe in young or naïve animals. Some animals appear to be adapted to particular serovars and show little evidence of disease when infected with these types.

  • Endangered wild species affected or not (estimation for Europe / worldwide)

    Wild species are known to be susceptible to infection but usually disease in animals is not fatal. Leptospirosis has also been identified as an important pathogen for surveillance in some wild animal reintroduction programmes (e.g. beavers and water voles in the UK).

    GAP :

    Little evidence or assessment of impacts of infection in vulnerable wild animal species.

  • Slaughter necessity according to EU rules or other regions

    No.

  • Geographical distribution and spread

  • Current occurence/distribution

    Leptospirosis occurs worldwide, in both rural and urban areas and in temperate and tropical climates. The predominant serovars vary by geographic region.

    GAP :

    Due to a global lack of epidemiological data, knowledge very limited, especially concerning many African regions.

  • Epizootic/endemic- if epidemic frequency of outbreaks

    Endemic in many areas. Introduction of organism into a naïve herds/flock can result in abortion storms.Human: generally leptospirosis has an endemic and seasonal pattern, but epidemics also occur after periods of heavy rain and/or flooding. Climate change is predicted to increase the frequency of outbreaks associated with adverse weather conditions.

  • Speed of spatial spread during an outbreak

    Variable.

    GAPS :

    • Lack of well-designed outbreak investigation protocols.
    • Lack of models estimating this type of data.
  • Transboundary potential of the disease

    Spread by carrier animals including free-living animals such as rodents and bats hence transboundary spread is likely.

    GAP :

    Introduction of screening of livestock in transboundary trade may reduce transmission/importation of the disease and enhance understand causes of potential vaccine failures if the imported strains are not covered by the vaccine.

  • Route of Transmission

  • Usual mode of transmission (introduction, means of spread)

    Leptospira are shed in the urine of acutely infected and chronically infected animals, which may carry the infection silently (see 2.4). They may also be found in the genital tract, semen and in aborted foetuses, vaginal discharges after parturition. Direct transmission occurs following contact with urine of infected animals. Indirect transmission occurs following contact with contaminated environments. Transmission pathways differ among animal species and between different landscapes (e.g. urban vs rural) and different environmental conditions.

    GAP :

    There is a need for improved understanding of the drivers of transmission in different settings to improve predictions of outbreaks and to improve the design of control programmes in endemic settings.

  • Occasional mode of transmission

    Leptospira is rarely spread through rat bites or ingestion of contaminated food or water.

    GAP :

    Studies needed to establish whether contamination of food (with favourable pH and temperature) is not responsible for transmission to humans.

  • Conditions that favour spread

    Favourable climatic condition (as described above), type of soil (alkaline, neutral), rodent abundance, floods?

    GAP :

    As above-identification of risk factors and dynamics in host animals and their transmission.

  • Detection and Immune response to infection

  • Mechanism of host response

    Leptospira induce a serovar-specific immune response consisting of a cellular (type 1) and humoral (type 2) mediated immunity. Sero-conversion may occur after 2 - 10 days after onset of disease, dependent on the individual’s immunological competence, infecting serovar, animal species and the infective dose. IgM class antibodies usually appear earlier than IgG class antibodies, and remain for months or years at a low detectable titre. IgG antibodies may not be detected at all, or for only a short period, or persist for several years. The antibodies are directed against both non-specific and serovar specific antigens. The primary immunological response is humoral mediated and the presence of immunoglobulin has shown to be protective in challenge trials. However, beef cattle have responded to vaccination with a cellular response (Naiman et al. 2001) and presence of antibodies were not always protective (Adler and de la Pena Moctezuma 2010). The level of antibody response is influenced by its initial level, the rates of decay, its continued production, the infected species, the age of the host and how well adapted the serovar is to its host (Faine et al. 1999). Leptospira can be isolated in urine from hosts that demonstrate a low or no detectable titre (Mackintosh et al. 1980a; Faine et al. 1999). Serovars that are more likely to cause clinical disease like Pomona and Copenhageni, may induce higher titres than Hardjo infections (Faine et al. 1999; Ayanegui-Alcérreca 2006).The duration of detectable antibodies in humans after natural infection with Leptospira varied substantially within and between studies, with sero-positive persons becoming sero-negative between 6 and 60 months after infection. The large range in titre duration is possibly related to re-exposure, infecting serovar and initial titre (Mackintosh et al. 1980b; Blackmore et al. 1984; Romero et al. 1998; Faine et al. 1999; Cumberland et al. 2001). It is important to note that protective serum antibodies to Leptospira can be present, even when the MAT does not detect antibodies, as was shown with passive immunisation of laboratory animals (Rodriguez-Gonzalez et al. 2004).

  • Immunological basis of diagnosis

    Serological testing is the most widely used means for diagnosing leptospirosis.

    GAP :

    Gap (window in early onset) in diagnostics between onset of undifferentiated symptoms to measurement of IgM. Early detection difficult at the beginning of outbreak for example. In early phase of infection (first 5-7 days after onset of symptoms) PCR on blood/serum is proposed as alternative for serology.

  • Main means of prevention, detection and control

  • Sanitary measures

      • Sanitation, including clean water, good drainage and cleaning of waste dumps can reduce the risk of infection in kennels, and in areas where livestock are bred or give birth.
      • Prevention of contact with contaminated environments or infected wildlife, particularly rodents.
      • Animals should not be allowed to drink from or enter contaminated bodies of water.

    GAPS :

    • Need for outbreak response and clinical management protocols.
    • Timing of rodent control measures before rainy season.

  • Mechanical and biological control

    • Isolation and treatment of infected animals,
    • Management, including the separation of young cattle from older animals prevents direct animal-to-animal transmission.
    • Measures to prevent contact with wildlife.
    • Prevention of access to contaminated water supplies.
    • Rodent control.
  • Prevention through breeding

    Some Leptospira serovars have been isolated from the genital tract of chronically infected animals e.g. L. borgpetersenii serovar Hardjo from infected cattle. Leptospira DNA has also been detected by PCR in semen collected for artificial insemination from infected cattle and horses. Venereal transmission is therefore considered to be likely for some serovars. Pre-breeding screening or screening of animals before introduction into a clean herd is recommended to help prevent introduction of infection.Placental fluid and vaginal discharges favour the persistence of Leptospira spp. in the environment.

    GAP :

    Importance of venereal transmission for animal-to-animal spread of infection remains unknown.

  • Diagnostic tools

    Laboratory diagnosis of leptospirosis can involve identification of the agent or serological testing.

    1. Test for the agent. Detection of Leptospira by culture or tests for leptospiral antigens e.g. immunofluorescence. Tests such as PCR based assays are now used by many laboratories in particular to detect leptospiral nucleic acid in tissues, urine or blood using primer sets that target pathogenic Leptospira species. PCR tests have particular value in helping to identify carrier animals that may act as reservoirs of infection.

    2. Tests designed to detect leptospiral antibodies

    a) Enzyme-linked immunosorbent assays (ELISAs): detect IgG or IgM from Leptospira spp. in people. Also species/serovar specific ELISA IgG tests available for animals e.g. Leptospira serovars Hardjo in cattle (milk or serum).

    b) The microscopic agglutination test (MAT) is the standard serological test. Antigens selected for use in the MAT should include representative strains of the serogroups known to exist in the particular region plus those known to be maintained elsewhere by the host species under test. For the evaluation of an acute infection using MAT, it is necessary to analyse two serum samples, collected at an interval of at least three weeks to verify an increase in antibody titre of at least 4 or more.

    c) Other serologic tests include radioimmunoassay, the microcapsule agglutination test, immunofluorescence, counter immunoelectrophoresis and thin-layer immunoassay.

    GAPS :

    • Difficult performance of existing "gold standard" serological tests (incl. background antibodies in endemic regions that may complicate discrimination between current and past infections).
    • MAT is problematic in detecting renal carriers.
    • Lacking sensitivity of antigen detection during active infection in routine diagnostics.
  • Vaccines

    Serovar-specific (monovalent, bivalent or polyvalent) vaccines are available for several domestic animal species including cattle, pigs and dogs.The majority of commercial vaccines used in animals are inactivated whole cell cultures of one or more serovars of Leptospira spp. Live attenuated vaccines have been developed but not licensed.For humans, inactivated whole cell vaccines are used in some high-risk populations e.g. sewer workers in France but not generally widely deployed.

    GAPS :

    There are some vaccines available for animals and some for humans that are based on locally circulating Leptospira serovars (autogenic vaccines). Characterisation of local serovars is required before transferring vaccines to new locations to ensure appropriate coverage.

    Little information about the use of vaccines to control human disease outbreaks following adverse weather events.

  • Therapeutics

    Antibiotics used to treat leptospirosis include the tetracyclines, penicillin/ampicillin, dihydrostreptomycin, streptomycin and the fluoroquinolones. The efficacy of treatment may depend on the serovar and the host response to infection.

    GAP :

    Suggested protocols for chemoprophylaxis are in use by some groups (e.g. military) but limited evidence of effectiveness.

  • Biosecurity measures effective as a preventive measure

    Prevent introduction of carrier animals into herd/flock.Replacement stock should be selected from herds negative for leptospirosis.Human aspects-limit exposure e.g. protective clothing when handling infected animals.

    GAP :

    Establish effective protocols, e.g. barrier approaches (protective clothing) and cleaning wounds after exposure.

  • Border/trade/movement control sufficient for control

    None specified in the OIE Terrestrial Animal Health code. Generally no restrictions on movements.

  • Prevention tools

    Prophylactic treatment of exposed animals with antibiotics can prevent clinical disease.Vaccination of domestic animals.

    GAPS :

    Clear guidance on chemoprophylaxis (e.g. doxycycline) needed (only limited understanding whether pre-exposure doxy chemoprophylaxis is effective as a preventive measure during epidemics).

    Does vaccination only prevent disease or also shedding?

  • Surveillance

    Investigation of abortions in livestock and sero-surveillance using MAT or ELISA. Use of PCR to monitor for prevalence of carriage amongst animal hosts e.g. through rodent trapping and testing or abattoir surveillance in livestock, has improved our understanding of the epidemiology of infection in animal hosts.Community and hospital based surveillance for humans: relies on effective health-care systems and access to reliable diagnostic testing.

    GAPS :

    • Human: Significant variation in surveillance and reporting among countries due to different regulations on notification (mandatory notification only in some countries) and limited by technically demanding standard diagnosis.
    • Human: Lack of low-cost effective surveillance systems and lack of resources for their implementation in endemic countries.
    • Low cost, reliable diagnostics for use in low-income countries are lacking.
    • Animal: Need to distinguish between passive, active, and sentinel surveillance.
    • Establish cut-off point titres for different geographic areas in order to understand better the disease situation in different setting e.g. Africa where there are few studies and little information is available.
    • Support isolation of local strains to enhance detection of infecting serovars.
  • Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

    Eradication has been accomplished in closed cattle herds by vaccination and testing over a five-year period. Similar measures can help to prevent or control leptospirosis in pigs and sheep.

  • Costs of above measures

    Unspecified but involve costs of purchase and application of vaccines and/or /treatment and testing.

    GAPS :

    • Cost of early detection and treatment versus intensive care of severely ill advanced disease.
    • Often the limiting factor during outbreak surges are sufficient numbers of ventilators and their appropriate use.
  • Disease information from the OIE

  • Disease notifiable to the OIE

    Leptospirosis is no longer an OIE listed disease (delisted in 2014).

    GAPS :

    • Lack of international system to support reporting of leptospirosis outbreaks hinders disease surveillance in animals.
    • Surveillance activities are now on a national level and hence vary from country to country.
  • OIE Terrestrial Animal Health Code

    Not available.

  • Socio-economic impact

  • Zoonosis: impact on affected individuals and/or aggregated DALY figures

    Leptospirosis is a bacterial disease that causes morbidity and mortality around the world. Global burden of disease estimates have improved awareness but are largely based on mortality estimates.Although it is endemic in many rural and urban slum communities and can also cause sporadic epidemics, little is actually known about the true morbidity impacts e.g. chronic disease or long term consequences and consequently, the disease has been neglected.

    GAPS :

    • Translation of burden of disease (BoD) estimates into policy and measurement of impact of policies on BoD
    • Geographic impact is not well known and the disease rather underestimated in many parts of the world, e.g. Africa or Eastern Mediterranean states.
    • Lack of data and approaches for modelling of the disease to estimate disease burden and epidemiological key figures.
  • Zoonosis: cost of treatment and control of the disease in humans

    Unspecified.

    GAP :

    Cost-benefit analyses of prevention-control options not available.

  • Direct impact (a) on production

    In newly infected cattle herds, up to 30% of the cows may abort, and overall calf production can decrease by up to 40%. In endemically infected herds, abortions are usually sporadic and occur mainly in younger animals. Infertility, with decreased pregnancy rates and increased culling, may also be noted. The estimated decrease in the first service conception rate is approximately 16-32%. Deaths can occur in calves; however, maternal antibodies are protective for around 6 months.

    GAP :

    Lack of information on all productivity losses. Current efforts to estimate the Global Burden of Animal Disease could help to tackle this knowledge gap.

  • Direct impact (b) cost of private and public control measures

    Costs of treatment and vaccination are currently borne by the animal keeper e.g. farmers and not well quantified on a national or regional level. Requirement for individuals to pay for control can hamper efforts to control infection for public health purposes.

  • Indirect impact

    Overall reduced productivity in affected animals leading to higher costs and environmental impact of production.Infections have been reported in association with adventure tourism e.g., in South-east Asia although these are typically small scale and unlikely to have major impacts on tourism.

    GAP :

    All over, there is too little information available (e.g. socio-economic impact, cost-benefit analysis of prevention/control measures, productivity losses) to be able to estimate the indirect economic impact.

  • Trade implications

  • Impact on international trade/exports from the EU

    None. There are no standards for trade in animals laid down in the OIE Terrestrial Animal Health Code.
  • Impact on EU intra-community trade

    None.

  • Impact on national trade

    None.

  • Links to climate

  • Seasonal cycle linked to climate

    This disease is often seasonal: it is most common during the rainy season in the tropics and in the summer and autumn in temperate regions. Linked to rainfall and temperature. Also evidence from New Caledonia that outbreaks are linked to El Niño oscillations.

    GAP :

    Further development and refinement of models can help with prediction of outbreaks; understanding transmission dynamics in relation to seasonal changes and measure impact of interventions.

  • Distribution of disease or vector linked to climate

    Related to conditions that facilitate the survival of Leptospira in water and the environment and conditions that are favourable for reservoir animal species populations.

  • Outbreaks linked to extreme weather

    Human cases of leptospirosis may peak during the rainy season in endemic areas and are associated with flooding events following heavy rainfall e.g. typhoons in the Philippines or Pacific Islands (e.g. Fiji); hurricanes in the Caribbean.

  • Sensitivity of disease or vectors to the effects of global climate change (climate/environment/land use)

    Extreme weather resulting in extensive flooding may result in the occurrence of more frequent epidemics.

Main critical gaps

    • Overall, poor surveillance and lack of public disease awareness, impeding the gathering of epidemiological data and thus the establishment of comprehensive models estimating disease burden, and its economic and ecologic impact.
    • Lack of rapid tests for different contexts, lack of clinical protocols as well as effective preventive and outbreak interventions/preparedness.
    • Need for a cross-sectoral multidisciplinary approach to the control and prevention of leptospirosis on the animal-human-ecosystem interface.

Sources of information

  • Expert group composition

    Marga G.A. Goris PhD, OIE and National Collaborating Centre for Reference and Research on Leptospirosis, Academic Medical Centre, Department of Medical Microbiology, The Netherlands – [Leader]

    Anou Dreyfus DVM, MSc, PhD, l`Unité Epidémiologie et de Recherche Clinique, Institut Pasteur de Madagascar, Madagascar

    Josipa Habus PhD DVM, Faculty of Veterinary Medicine University of Zagreb Department of Microbiology and Infectious Diseases, Croatia

    Georgies Mgode PhD, Pest Management Centre (SPMC), Sokoine University of Agriculture (SUA), Tanzania

    Eric Klaasen PhD DVM, MSD Animal Health, the Netherlands

    Kathryn Allan BSc BVM&S PhD MRCVS, School of Veterinary Medicine, University of Glasgow, United Kingdom

  • Date of submission by expert group

    04 October 2021.

  • References

    Internet Resources

    Publications

    • Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, Stein C, Abela-Ridder B, Ko AI. Global morbidity and mortality of leptospirosis: a systematic review. PLoS Negl Trop Dis. 2015;9(9)
    • Murray GL. The molecular basis of leptospiral pathogenesis. In: Adler B, editor. Leptospira and Leptospirosis. Current Topics in Microbiology and Immunology. 387. Berlin: Springer; 2015.
    • Picardeau M. Virulence of the zoonotic agent of leptospirosis: still terra incognita? Nature Reviews Microbiology. 2017;15:297.
    • Mwachui MA, Crump L, Hartskeerl R, Zinsstag J, Hattendorf J. Environmental and behavioural determinants of leptospirosis transmission: a systematic review. PLoS Negl Trop Dis. 2015;9(9)
    • Vincent AT, Schiettekatte O, Goarant C, et al. Revisiting the taxonomy and evolution of pathogenicity of the genus Leptospira through the prism of genomics. PLoS Negl Trop Dis. 2019;13(5)
    • Ellis WA. Animal Leptospirosis. In: Adler B, editor. Leptospira and Leptospirosis. Current Topics in Microbiology and Immunology. 387. Berlin: Springer; 2015
    • Goris MGA, Kikken V, Straetemans M, Alba S, Goeijenbier M, van Gorp ECM, et al.
    • Weinberger D, Baroux N, Grangeon J-P, Ko AI, Goarant C. El Niño Southern Oscillation and Leptospirosis Outbreaks in New Caledonia. PLoS Negl Trop Dis. 2014;8(4):e2798.
    • Rushton J, Bruce M, Bellet C, Torgerson P, Shaw A, Marsh T, Pigott D, Stone M, Pinto J, Mesenhowski S, Wood P. Initiation of Global Burden of Animal Diseases Programme. The Lancet. 2018;392(10147):538-40
    • Haake DA, Levett PN. Leptospirosis in humans. In: Adler B, editor. Leptospira and Leptospirosis. Current Topics in Microbiology and Immunology. 387. Berlin: Springer; 2015
    • Bharti AR et al. Leptospirosis: a zoonotic disease of global importance. Lancet Infect Dis. 2003 Dec;3(12):757-71. doi: 10.1016/s1473-3099(03)00830-2.
    • Chierakul W et al. Activation of the coagulation cascade in patients with leptospirosis. Clin Infect Dis. 2008 Jan 15;46(2):254-60. doi: 10.1086/524664.
    • Tajiki H, Salomão R. Association of plasma levels of tumor necrosis factor alpha with severity of disease and mortality among patients with leptospirosis. Clin Infect Dis. 1996 Nov;23(5):1177-8.
    • Naiman BM, Alt D, Bolin CA, Zuerner R, Baldwin CL. Protective killed Leptospira borgpetersenii vaccine induces potent Th1 immunity comprising responses by CD4 and gammadelta T lymphocytes.Infect Immun. 2001 Dec;69(12):7550-8. doi: 10.1128/IAI.69.12.7550-7558.2001.
    • Adler B, de la Peña Moctezuma A. Leptospira and leptospirosis. Vet Microbiol. 2010 Jan 27;140(3-4):287-96.
    • Mackintosh CG, Marshall RB, Broughton ES. The use of a hardjo-pomona vaccine to prevent leptospiruria in cattle exposed to natural challenge with Leptospira interrogans serovar hardjo. N Z Vet J. 1980 Sep;28(9):174-7.
    • Rodriguez-Gonzalez I, Fillonneau C, Blanchet B, Suard I, Catilina P, Andre-Fontaine G. Efficacy of the Spirolept® vaccine against human leptospirosis estimated by passive sera-protection of laboratory rodents. Médecine et maladies infectieuses 2004, 34, 196–200.
    • Vinod Kumar K, Lall C, Raj RV, Vedhagiri K, Sunish IP, Vijayachari P. In Vitro Antimicrobial Susceptibility of Pathogenic Leptospira Biofilm. (2016) Microbial Drug Resistance 2016, 22 (7), 511-514
    • Day MJ. The CALLISTO Project: A Summary. Journal of Comparative Pathology 2016, 155 (1), S1-S7.
    • Divers TJ, Chang YF, Irby NL, Smith JL, Carter CN. Leptospirosis: An important infectious disease in North American horses. Equine Vet J. 2019 May;51(3):287-292.

Conclusions

  • Leptospirosis is a neglected zoonosis that is poorly diagnosed in many parts of the world. It is an occupational hazard for those working with or near animals or water. Improved diagnosis of leptospirosis, notably in tropical endemic areas where sophisticated equipment is lacking and increasing awareness of leptospirosis worldwide are important.

  • Main perceived obstacles for effective prevention and control

    Number of different reservoir hosts.Variable epidemiology and transmission routes in different landscapes or environments.Potential for re-infection from the environment or other species.Limited surveillance in both humans and animals on a global scale.Cost of vaccination is borne by the individual.Use of multivalent vaccines –effective in canines against the serovar included.

    GAPS :

    • Lack of public awareness and sensitization of governments and further (health) agencies.
    • Often, lack of imminent diagnostic (absence of distinct, well-defined clinical signs, absence of performing rapid tests).
    • Lack of knowledge on effective intervention methods, even more hampered by the diversity of settings, epi- and endemic contexts and serovar specificities. Lack of knowledge of predominant serovars (in some areas).
    • Leptospirosis is not on the neglected tropical disease list of WHO with the consequence of research funding being very difficult to acquire.
  • Main perceived facilitators for effective prevention and control

    Improved vaccines and tests which discriminate between vaccinates and natural infection.

    GAPS :

    • Improvement of outbreak response and preparedness, e.g. through the spread of knowledge/lessons learnt from previous outbreaks (e.g. India, Thailand, Brazil) and experts involved to identify key issues to be addressed would be an important measure.
    • Improvement of case definition including better early diagnosis systems would be beneficial.