Diseases

Small ruminant mastitis (M. agalactiae)

Download as PDF Download as XLS

Chapter select

Control Tools

  • Diagnostics availability

  • Commercial diagnostic kits available worldwide

    Standard laboratory procedures are available for identifying the invading pathogen and its sensitivity to antibiotics.

    GAPS: Commercial ELISA kits for serological monitoring are available from M agalactiae. Diagnostic agar medium plates are also available for detection of M agalactiae.

  • Commercial diagnostic kits available in Europe

    Standard laboratory procedures are available for identifying the invading pathogen and its sensitivity to antibiotics.

    GAPS: Commercial ELISA kits for serological monitoring are available from M agalactiae. Diagnostic agar medium plates are also available for detection of M agalactiae.

  • Diagnostic kits validated by International, European or National Standards

    No.

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

    No.

  • Commercial potential for diagnostic kits in Europe

    With the advent of marker vaccines that are efficacious then there would be potential for diagnostic kits.

    GAP: P48 is a prospective marker vaccine, but to-date has only been tested experimentally.

  • DIVA tests required and/or available

    None.

  • Vaccines availability

  • Commercial vaccines availability (globally)

    Live vaccines are not permitted in Europe but formalin inactivated, adjuvanted vaccines are available. Globally live attenuated vaccines are available.

  • Commercial vaccines authorised in Europe

    In Europe formalin inactivated, adjuvanted vaccines are available. There appears to be little data available on the efficacy of these inactivated vaccines. A multivalent formalin inactivated vaccine incorporating all four causative mycoplasmas and adjuvanted with saponin and aluminium hydroxide appears to show some promise.

    GAP: Very little data on vaccine efficacy.

  • Marker vaccines available worldwide

    Currently there are no marker vaccines available.

  • Marker vaccines authorised in Europe

    Currently there are no marker vaccines available.

  • Effectiveness of vaccines / Main shortcomings of current vaccines

    Inactivated and live attenuated vaccines are available. There is doubt regarding the efficacy of the inactivated vaccines and a number of countries do not allow the use of live vaccines.

    GAP: Use of attenuated vaccines in males and non-lactating females for the control of disease should be assessed.

  • Commercial potential for vaccines in Europe

    There is potential in some European countries for vaccination and if there were marker vaccines of proven efficacy available there could be significant commercial potential for them in these countries.

  • Regulatory and/or policy challenges to approval

    For those countries that have eradicated the disease or where the disease does not currently occur there will be policy challenges for approval.

  • Commercial feasibility (e.g manufacturing)

    Dependant on what is developed but initially there would appear to be no hindrance to commercial manufacturing of marker vaccines.

  • Opportunity for barrier protection

    No.

  • Pharmaceutical availability

  • Current therapy (curative and preventive)

    Antibiotics are used, mainly tetracycline, macrolide, florfenicol, tiamulin and fluoroquinolones. Disinfection and fly control can be used as adjuncts and milking machine maintenance should be given priority.

  • Future therapy

    Future therapy is likely to remain with the use of antibiotics and although new antibiotics may become available they are liable to be restricted for human use initially.

  • Commercial potential for pharmaceuticals in Europe

    May be significant in those countries affected.

  • Regulatory and/or policy challenges to approval

    None known.

  • Commercial feasibility (e.g manufacturing)

    Feasible.

  • New developments for diagnostic tests

  • Requirements for diagnostics development

    The development of rapid identification and sensitivity testing methods may be beneficial. Should marker vaccines become available then diagnostic kits based on serology that can distinguish between vaccinated and infected animals would be useful.

    GAPS: Development of penside tests for testing milk/sera would improve diagnosis and may help increase awareness of this disease.

  • Time to develop new or improved diagnostics

    In relation to a proposed marker vaccines the diagnostic kits would probably be developed alongside.

  • Cost of developing new or improved diagnostics and their validation

    This could be significant.

  • Technology to determine virus freedom in animals

    N/A.

  • New developments for vaccines

  • Requirements for vaccines development / main characteristics for improved vaccines

    Vaccine development needs to emphasise the development of marker vaccines that are both efficacious and permit ready analysis of vaccinated as opposed to infected animals. It is conceivable that global warming will encourage the spread of the disease to other countries who may currently not allow vaccination and it will be imperative to distinguish vaccinated as opposed to infected animals in order to allow use of such vaccines.

    GAPS:

    • Not sure why global warming would encourage spread. Diversification by farmers in small ruminant dairy farming would increase risk not weather.
    • Much current research is focused on identifying immunogenic proteins that can be utilized in subunit vaccines. In addition, recent developments in epitope mapping are making it much easier to identify immunogenic proteins that may have uses in vaccine development. A strongly immunogenic lipoprotein protein (AvgC) has been identified in M. agalactiae and shown to be “surface-exposed” by antibodies to it in the sera of infected sheep. This protein may be of value in future subunit vaccines (Santona et al., 2002)
  • Time to develop new or improved vaccines

    This will be significant – the collection of the data necessary to gain approval will probably be years rather than months and the registration process in Europe would take a minimum of one year.

  • Cost of developing new or improved vaccines and their validation

    This is also liable to be significant and since the disease is often present in countries with a generally lower socio-economic structure the potential for recuperation of the investment would need careful consideration.

  • New developments for pharmaceuticals

  • Requirements for pharmaceuticals development

    There is potential for antibiotics with increased efficacy/distribution that could prevent the continued excretion of mycoplasma.

    GAP: Screening of novel chemicals and plant extracts against CA mycoplasmas (Momani et al 2007).

  • Time to develop new or improved pharmaceuticals

    This will be significant – the collection of the data necessary to gain approval will probably be years rather than months and the registration process in Europe would take a minimum of one year.

  • Cost of developing new or improved pharmaceuticals and their validation

    This is also liable to be significant and since the disease is often present in countries with a generally lower socio-economic structure the potential for recuperation of the investment would need careful consideration.

Disease details

  • Description and characteristics

  • Pathogen

    The main pathogen is Mycoplasma agalactiae although recently M. capricolum subsp. capricolum and M. mycoides subsp. capri have also been implicated along with M. putrefaciens which causes mastitis and arthritis in goats.

    GAPS: Not so recent now. Expert COST group in 1999 confirmed clinical findings in diseases caused by the 4 pathogens was difficult to differentiate. M capricolum subsp capricolum is very rare in Europe.

  • Variability of the disease

    Mastitis, arthritis, keratoconjunctivitis and blindness can occur in both male and female sheep and goats. The major pathogen (M. agalactiae) was considered to be unusually homogenous but more recent work with variable number tandem repeat analysis of the genome has revealed unexpected diversity which it is believed is sufficient to distinguish the geographical location of any particular outbreak. Clinical disease can be manifested in an acute, sub-acute or chronic form. A sporadic occurrence of atypical or asymptomatic forms has also been reported.

    GAPS:

    • The disease presents itself differently in sheep and goats. CA in sheep is a less severe disease and is caused almost always by M. agalactiae, while in the goats is a serious illness that can be caused by M. agalactiae and other agents such as M. mycoides subsp. capri, M. capricolum subsp. capricolum and M. putrefaciens. A complication is that M mycoides subsp. capri is also a cause of caprine pleuropneumonia. which is found worldwide.
    • Subclinical CA is one of the main problem regarding transmission risk: rapid (but sensitive) lab detection is essential
    • The role of pneumonia as part of the infectious / transmission process for M. agalactiae has not been clearly defined. Furthermore the presence of M agalactiae in the brain requires further investigated and may be responsible for ataxia seen in newly born lambs and kids.
    • Outbreaks of severe arthritis have lately been associated with M mycoides subsp capri in kids with little effect on adults.
    • M putrefaciens is more associated with a sudden drop in milk production without other clinical signs.
    • Evidence for pathogenic strains still anecdotal and requires animal infections studies. So called apathogenic strain of M mycoides subsp. capri sill capable of causing death and disease.
    • M. agalactiae previously thought to be very homogeneous but new molecular typing tools have detected some variation between geographically diverse areas (McAuliffe et al 2011) but subtyping is difficult within enzootic areas (for outbreaks tracing).
  • Stability of the agent/pathogen in the environment

    M. agalactiae can survive for one or two weeks at room temperature but is sensitive to osmotic shock, the effect of detergents and ultraviolet radiation. However, M. agalactiae and M. putrefaciens produce prolific biofilms which are considerably more resistant to stress including heat and desiccation.

    GAPS:

    • New data from biofilm study may account for “mal di sito” first reported over 100 years ago whereby flocks could become infected from a contaminated environment. Further work needed to investigate whether biofilm grown strains are more virulent.
    • Occurrence of biofilm formation in vivo, on milking machine and in the environment needs to be investigated.
  • Species involved

  • Animal infected/carrier/disease

    Sheep and goats are the species involved. It has been shown that other animal species, such as camels, cattle, or small wild ruminants (deer, ibexes) can function as infection reservoirs. Antibodies have also been detected in South American camelids, (Llamas, Alpacas, Vicunas).

    GAPS:

    • Precise reservoir role of common European wild animals (mammalians, birds,…) in enzootic areas is unknown
    • Further work needed to verify camelid infection as the CA mycoplasmas have never been isolated.
  • Human infected/disease

    M. agalactiae is currently not thought to be pathogenic to humans.

    GAP: No evidence of zoonosis from CA mycoplasmas though unconfirmed reports of sickness in humans working with calves fed goat milk naturally affected with M m. capri (Goncalves 2009).

  • Vector cyclical/non-cyclical

    Insects can act as vectors along with milking equipment and the hands of milkers.

    GAP: Further work needed to confirm whether insects (often present in the ears) are capable of infecting rather than just carrying the mycoplasmas.

  • Reservoir (animal, environment)

    Both other animals and the environment can act as reservoirs. Dissemination into the environment occurs by means of ocular and nasal discharge, milk, faeces, urine and excretions from open joints or the male genitourinary tract. Asymptomatic carriers in a herd appear to be a serious risk.

    GAPS:

    • Environmental persistence and re-infection require investigation. There is little transmission of mycoplasma via urine and faeces compared to milk.
    • Importance of artificial insemination and natural mating in transmission?
  • Description of infection & disease in natural hosts

  • Transmissibility

    Horizontal transmission occurs by contact between infected animals and/or the environment shared with infected animals. Vertical transmission can occur by means of suckling milk from infected mothers. Animals become infected by ingestion or occasionally by inhalation. Aerosol transmission is possible over short distances. Transmission via fomites, (milking equipment or milker’s hands) is possible.

    GAPS:

    • Vertical transmission can also occur through the transplacental route and give birth to kids with swollen joints or cause abortions.
    • In utero transmission for kids is described but what is the incidence of ante partum and per partum transmission in lambs ?
    • Immunity effectors and pathways are not well described (particularly for lambs not experiencing disease nor milk shedding within positive flocks with adult shedding).
  • Signs/Morbidity

    Generally more severe in goats. Acute infections begin with a transient fever followed by malaise, inappetance and mastitis. The udder becomes hot and swollen and the milk is usually greenish-yellow or greyish-blue and watery at first before becoming lumpy. Polyarthritis is also common especially in the tarsal and carpel joints and this may be the major clinical sign in male goats. Keratoconjunctivitis develops in approximately half of all infections and is usually transient but may become chronic and can cause blindness. Abortions can occur in chronically infected animals.

    GAPS: Generally arthritis and septicaemia in kids is a feature of M mycoides subsp. capri without clinically affecting adults. Often very little ocular involvement in M. mycoides capri infections. Some disagreement about relative severity of disease in small ruminants with sheep in southern Italy presenting more severe signs from infection with M agalactiae.

  • Incubation period

    The incubation period may last from one week to two months, its duration being related to the degree of virulence of the infectious agent and the overall resistance of the host.

    GAPS:

    • Very long incubation periods occur for at least some strains (sometimes for the whole life of animal),: Factors associated with reactivation of mycoplasma are not well known.
    • The incubation period may also be affected by immune status and stress of the host.
  • Mortality

    When an organism is first introduced into a susceptible flock or herd the morbidity rate is approximately 30 – 60% and the mortality rate is often less than 20%, however it may reach 40 – 70% in young animals with septicaemia.

    GAP: In flocks in S Italy morbidity may exceed 80% but mortality less than 10%.

  • Shedding kinetic patterns

    The infectious organism is shed during infection. Following the disease the causal agent is excreted with milk for a minimum of 12 months and a maximum of 8 years. Asymptomatic carriers may harbour the infectious agent in their genital tracts and in goats it is thought the infection can be present in the external auditory canal.

    GAPS:

    • Excretion from eyes and nose is very transient-1-2 weeks
    • While not thought to be significant, faecal and respiratory carriage/shedding in sheep should be addressed.
  • Mechanism of pathogenicity

    In animals infected orally it is assumed that the primary site of adhesion and subsequent invasion is the small intestine. In natural conditions it is difficult to determine if the infection was acquired via the respiratory route but experimental infection via this route has been achieved. Infection and colonisation of the mammary gland is thought to be via defective or poorly cleaned milking equipment. Infected animals develop bacteraemia and the infectious agent is transferred via the blood to the target organs.

    GAPS:

    • Little known of pathogencity mechanisms in particular role of lymphatic and intracellular dissemination
    • Little evidence for intestinal route of infection. More likely to be invasion of lymph glands/palatal tonsils.
    • The contribution of the host immune response to lesion development (in mammary gland and lung?) and disease requires investigation?
  • Zoonotic potential

  • Reported incidence in humans

    There is no evidence to date that M. agalactiae is a threat to human health.

    GAP: No evidence of zoonosis from CA mycoplasmas though unconfirmed reports of sickness in humans working with calves fed goat milk naturally affected with M m. capri (Goncalves 2009).

  • Risk of occurence in humans, populations at risk, specific risk factors

    N/A.

  • Symptoms described in humans

    N/A.

  • Estimated level of under-reporting in humans

    N/A.

  • Likelihood of spread in humans

    N/A.

  • Impact on animal welfare and biodiversity

  • Both disease and prevention/control measures related

    Contagious agalactia can cause serious economic losses and certainly has a serious affect on animal welfare. Prevention may be by biosecurity measures and vaccination and control is by the use of antibiotics although these normally leave treated animals as carriers.

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

    Various wild small ruminants can be infected and act as carriers but not considered a particular problem among endangered species.

    GAP: Clinical CA occurs at least in ibex in French and Italian Alps, but potential aetiological cofactors and favourable conditions to the disease expression should be studied.

  • Slaughter necessity according to EU rules or other regions

    In those countries clear of the disease slaughter can be used in any outbreak. Euthanasia is used for acute cases if death does not intervene already.

    GAP: In some countries CA by M agalactiae is notifiable but not when caused by other mycoplasmas so slaughter would not necessarily follow in disease-free countries.

  • Geographical distribution and spread

  • Current occurence/distribution

    The disease occurs in Europe, Western Asia, the United States of America and North Africa.

    GAP: Generally occurs in southern Europe where small ruminants are kept for milking. Major outbreaks of M agalactiae in Mongolia and reports in China and South America. M mycoides subsp. capri present on all continents though usually as a cause of caprine pleuropneumonia.

  • Epizootic/endemic- if epidemic frequency of outbreaks

    Endemic in Europe, Western Asia, the United States of America and North Africa.

    GAP: New outbreaks in Corsica and disease spreading in southern France.

  • Seasonality

    Seasonal by association with young offspring.

    GAP: Milking period is time of greatest risk.

  • Speed of spatial spread during an outbreak

    Dependant on animal welfare and the removal or minimising of risk factors in the environment.

    GAP: spatial spread of clinical forms is observable but very few data are available for infection spread.

  • Transboundary potential of the disease

    Environmental and aerosol transmission can occur along with carrier animals brought in so there is a trans-boundary potential.

    GAP: Disease is spread invariably by animal movements.

  • Seasonal cycle linked to climate

    Not generally recognised but bearing in mind the geographical distribution this may be a possibility.

  • Distribution of disease or vector linked to climate

    Not generally recognised but bearing in mind the geographical distribution this may be a possibility.

  • Outbreaks linked to extreme weather

    No.

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

    Not generally recognised but bearing in mind the geographical distribution this may be a possibility.

  • Route of Transmission

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

    Horizontal by animal or environmental contact and vertical via suckling of young.

    GAPS:

    • Mycoplasma spread in the herd accelerated during milking.
    • Importance of spread by normal human activity (vets, tech, milk tank trucks,…) is unknown.
    • Length of long-term silent carriage is not known.
  • Occasional mode of transmission

    It is considered that aerosol transmission may occur.

    GAPS:

    • The significance of aerosol transmission and pneumonia preceding bacteraemia and development of mastitis should be investigated.
    • Transmission of infectious fluids from the eye may occur by contact and/or by flies.
    • Natural or artificial genital transmission.
  • Conditions that favour spread

    Poor husbandry and hygiene, improper maintenance of milking equipment.

    GAP: Analysis in Middle East also shows purchase of replacement animals and visits by veterinarians and other workers may also increase risk.

  • Detection and Immune response to infection

  • Mechanism of host response

    Following bacteraemia a serological response is noted although in view of the prolonged shedding post infection this response is potentially inadequate.

    GAP: Humoral response is not believed to be protective. Data from cell mediated immunity studies is unclear.

  • Immunological basis of diagnosis

    Serology.

    GAP: However, asymptomatic carriers of the herds tend to be serologically negative.

  • Main means of prevention, detection and control

  • Sanitary measures

    Disinfection can be effective against mycoplasmas.

    GAP: In view of increased persistence seen in biofilm grown mycoplasmas, studies should be conducted to assess effect of disinfectants.

  • Mechanical and biological control

    Adequate maintenance of milking equipment and the use of antibiotics and vaccination may be used.

    GAP: Insecticides may be additional control method.

  • Diagnostic tools

    Definitive diagnosis is mainly by isolation of the organism. Serological methods for identification include growth inhibition, metabolism inhibition, epi-immunofluorescence and peroxidase tests. PCR techniques are also available.

    GAPS:

    • Serological screening by ELISA offers most cost effective and sensitive method of preliminary diagnosis as well as monitoring disease absence.
    • Improvements needed in sensitivity to detect healthy carriers.
    • Conventional serological tests for identification of mycoplasmas are slow and laborious and are being replaced by molecular methods.
  • Vaccines

    Live attenuated and inactivated vaccines are available.

    GAPS:

    • Live vaccines are not used in Europe despite good results in Turkey. Very little data on effectiveness of a commercial inactivated vaccines though recent unpublished study show lack of protection in multivalent CA vaccine.
    • Improved (DIVA) vaccines needed.
  • Therapeutics

    Antibiotics are used, mainly tetracycline, macrolide, florfenicol, tiamulin and fluoroquinolones.

    GAPS:

    • Rarely completely eliminates causative mycoplasmas though can resolve clinical signs.
    • May encourage carrier state but studies needed.
    • Expensive.
  • Biosecurity measures effective as a preventive measure

    Beneficial in minimising the risk of introducing asymptomatic carriers.

    GAP: Serological screening of flocks prior to purchase would greatly reduce risk.

  • Border/trade/movement control sufficient for control

    The OIE Animal Health code recommends animals should have an international veterinary certificate certifying the animal showed no clinical signs on day of shipment; that the animal was kept since birth or for 6 months prior to shipment in an establishment where no case was officially reported during the period; and that the animal was kept in a quarantine station for 21 days prior to shipment.

    GAPS:

    • Serological detection before shipment should be performed (with improved Elisa kits).
    • Incidence and significance of ear carriage in goats should be defined.
  • Prevention tools

    General hygiene and maintenance of milking equipment are important.

    GAPS:

    • Vaccination of replacement or new stock before introduction to herd.
    • Systematic detection of the mycoplasmas should be performed at the flock/herd level before animal introduction into a free area/flock.
    • In enzootic areas, extension of systematic infectious status definition for flocks is limited by the cost of direct/indirect detection.
  • Surveillance

    Contagious agalactia is an OIE notifiable disease included in List B of dangerous infections.

    GAP: List B category discontinued by OIE. CA not notifiable in all countries in particular France.

  • Past experiences on success (and failures) of prevention, control, eradication in regions outside Europe

    Although contagious agalactia has been eradicated from some countries it may be difficult to control where it is widespread.

    GAPS:

    • Eradication (without vaccination) was achieved 9 years ago in French Alps (goats), but is difficult in Pyrenees due to the density of sheep population.
    • Reasons for failures include difficulty of applying sanitary measures, absence of efficient vaccine and costs of lab diagnosis.
  • Costs of above measures

    The costs of treating or preventing the disease are significant.

    GAPS:

    • Cost of disease to Greece was estimated at 25 euro million pa in 1995. Costs of enforcing regulations in Italy are high requiring the slaughter of stock when disease confirmed.
    • PCR is necessary but expensive and stamping out is genetically and financially expensive.
  • Disease information from the OIE

  • OIE disease card available

    No

  • Socio-economic impact

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

    Not relevant except that an increased use of antibiotics to treat the disease could lead to increased resistance among human pathogens.

  • Zoonosis: cost of treatment and control of the disease in humans

    N/A.

  • Direct impact (a) on production

    Loss of production and mortality has a serious impact on farms in the endemic areas.

    GAP: Recording of milk yield needed to assess economic cost at a flock/herd level.

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

    Significant.

  • Indirect impact

    In the endemic areas it is not considered that a significant fall in tourism, security in food supply or constraints on livestock production would be significant.

  • Trade implications

  • Impact on international trade/exports from the EU

    For those EU countries where the disease is present the OIE Animal Health Code regarding transporting animals would need to be addressed.

    GAP: Does this include serological testing?

  • Impact on EU intra-community trade

    For those EU countries where the disease is present the OIE Animal Health Code regarding transporting animals would need to be addressed.

  • Impact on national trade

    For those EU countries where the disease is present the OIE Animal Health Code regarding transporting animals would need to be addressed.

  • Main perceived obstacles for effective prevention and control

    Sub-clinically infected animals and carriers among those infected bearing in mind the extended period of shedding (potentially up to 8 years).

    GAP: The significance of ear carriage and pneumonia as sources of spread needs to be addressed.

  • Main perceived facilitators for effective prevention and control

    Vaccination is considered appropriate however the efficacy of vaccination is widely disputed. Live attenuated vaccines are considered more effective than inactivated vaccines but live vaccines are not permitted in some of the affected countries.

Risk

  • Contagious agalactia is a highly infectious disease of sheep and goats which has been included in List B of dangerous infections of the OIE. The current geographical location of the disease suggests it is prevalent in sub-tropical regions and should climate warmer significantly alter the climate there is potential for this to spread to currently clear areas. The current use of antibiotics to treat the disease also may lead to increased resistance among human pathogens and is an indirect risk.

    GAPS:

    Not sure why global warming would encourage spread. Diversification by farmers in small ruminant dairy farming would increase risk not weather

    Much current research is focused on identifying immunogenic proteins that can be utilized in subunit vaccines. In addition, recent developments in epitope mapping are making it much easier to identify immunogenic proteins that may have uses in vaccine development. A strongly immunogenic lipoprotein protein (AvgC) has been identified in M. agalactiae and shown to be “surface-exposed” by antibodies to it in the sera of infected sheep. This protein may be of value in future subunit vaccines (Santona et al., 2002)

Main critical gaps

Conclusion

  • It appears that antibiotic therapy may clear the clinical signs of this debilitating disease but often the organism is not cleared and the sub-clinically infected animal goes on shedding the organism for potentially years afterwards. The use of live vaccines, whilst being the most antigenic, is banned in some countries and the efficacy of inactivated vaccines is a matter for debate. It appears, therefore, that there is a desperate need for a marker vaccine together with a suitable diagnostic means of distinguishing between vaccinated and infected animals. Sheep and goats are not farm animals with the greatest return and therefore there will be a limit on the price for such vaccines which could make them unviable for commercial development.

    GAPS:

    • Greater awareness of this little known but economically important disease should be encouraged
    • Easing of severe regulations in Italy would improve farmers’ incomes

Sources of information

  • Expert group composition

    Expert group members are included where permission has been given

    Robin A.J. Nicholas, Animal Health and Veterinary Laboratories Agency (AHVLA), UK - [Leader]Jose Poveda , University of Gran Canaria, SpainUmit Ozdemir , PENDIK VETERINARY CONTROL INSTITUTE, TurkeyGuido Loria, IZS Palermo, Italy

     

  • Reviewed by

    Project Management Board.

  • Date of submission by expert group

    31st August, 2011.

  • References

    30th September, 2011.