paratuberculosis
Index
- Pictures
- Identity
- Pathogen/s
- Overview
- Host Animals
- Hosts/Species Affected
- Systems Affected
- Distribution
- Distribution Table
- Pathology
- Diagnosis
- List of Symptoms/Signs
- Disease Course
- Epidemiology
- Impact: Economic
- Zoonoses and Food Safety
- Disease Treatment
- Prevention and Control
- References
- Links to Websites
- Contributors
- Distribution Maps
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Top of pagePreferred Scientific Name
- paratuberculosis
International Common Names
- English: Johne's disease; johne's disease, mycobacterium avium subsp paratuberculosis in cattle; johne's disease, mycobacterium avium subsp paratuberculosis in goats; johne's disease, mycobacterium avium subsp paratuberculosis in sheep
English acronym
- PTB
Overview
Top of pageJohne's disease or paratuberculosis caused by Mycobacterium avium subspecies paratuberculosis, initially infects the ileum causing a granulomatous enteritis. It then gradually spreads to other parts of the intestine and regional lymph nodes. The disorder known as paratuberculosis or Johne's disease was first described in 1895 by Johne and Frothingham, who identified organisms in the granulomatous lesions in the intestines of affected cattle. These microorganisms stained acid-fast, indicating some type of mycobacterial organism. The bacteria were cultured from cattle in 1910, classified as a mycobacterium and named Mycobacterium chronicae pseudotuberculosae bovis Johne (Twort, 1910; Twort and Ingram, 1912). The organism was later named Mycobacterium paratuberculosis and the disease was referred to as Johne's disease or paratuberculosis (Bergey et al., 1923). In 1990, the organism was reclassified as M. avium subsp. paratuberculosis due to the close genetic relationship between M. paratuberculosis and M. avium (Thorel et al., 1990).
Paratuberculosis is widely distributed both nationally and internationally in domestic ruminants such as cattle, sheep and goats, as well as in wildlife such as deer, antelope and bison. The prevalence of the disease is difficult to ascertain because few comprehensive studies have been conducted. A review by Whittington et al. (2019) provides prevalence estimates for 32 countries. Very few countries have a low prevalence (<1%) in their dairy cattle herds (Norway, Sweden, Thailand) with most countries having >20%. In 2007, the National Animal Health Monitoring System conducted a survey of dairy farms in the USA using faecal environmental sampling and reported the apparent herd prevalence to be 70.4% and Bayesian estimates to be nearer 91% (Lombard et al., 2013). Corbett et al. (2018) used environmental sampling to estimate true herd prevalences ranging from 24-66% in dairy cattle across Canada. European countries have reported similar prevalence rates for paratuberculosis. True herd-level prevalence of M. avium subsp. paratuberculosis infected herds was estimated to be 28-43% of dairy herds in the UK, 20-71% of herds in The Netherlands and 85% of herds in Denmark (Geraghty et al., 2014). Approximately 19% of cattle (dairy and beef) herds were serologically positive for paratuberculosis in Austria in 2003 (Khol et al., 2007). Infection with M. avium subsp. paratuberculosis was reported to be endemic at high prevalence in sheep flocks and cattle and deer herds in New Zealand with 69% of farms reporting infection in at least one species (Verdugo et al., 2014). The accuracy of prevalence estimates from these studies is limited by the sensitivity of the diagnostic tests used, accurate recognition and reporting of the disease, and the number of animals sampled. It is estimated that annual losses in the USA from paratuberculosis in cattle herds may exceed US $220 million (Ott et al., 1999). This figure is extrapolated from estimated prevalence values together with computation of financial losses due to culling or death of clinically infected cows, and reduced reproductive efficiency, feed efficiency and decreased milk production in subclinically infected animals. The significance of subclinical infection on economic losses to the producer are detailed in a review (Johnson-Ifearulundu and Kaneene, 1997) with a 15-16% reduction in milk production accounting for the major portion of net monetary loss (Abbas et al., 1983; Benedictus et al., 1987). M. avium subsp. paratuberculosis-infected cows beyond the second lactation have demonstrated losses of 1300-2800 lb (590-1270 kg) of milk per lactation (Wilson et al., 1993).
Prevalence rates suggest that paratuberculosis can also be a significant economic factor in small ruminant populations. A survey in 2019 found that almost half of 11 countries with prevalence estimates of M. avium subsp. paratuberculosis in sheep based on objective criteria had >10% of flocks affected and almost one in five countries had >40% flock-level prevalence (Whittington et al., 2019). Studies have reported that 2-5% and 67% of sheep flocks in parts of Spain and Canada, respectively, were infected with M. avium subsp. paratuberculosis (Aduriz et al., 1994; Bauman et al., 2016). Paratuberculosis has had a major impact on the sheep industry in Australia and New Zealand (Sergeant, 2001; Verdugo et al., 2014). Similarly, reported herd-prevalence estimates for paratuberculosis in goats from 15 countries ranged from <1% to >40% (Whittington et al., 2019). Paratuberculosis has also been reported in farmed and free-ranging deer populations in Europe, New Zealand, and North America (Temple et al., 1979; Chiodini and Van Kruiningen, 1983; Power et al., 1993; Fawcett et al., 1995).
This disease is on the list of diseases notifiable to the World Organisation for Animal Health (OIE). The distribution section contains data from OIE's WAHID database on disease occurrence. For further information on this disease from OIE, see www.oie.int.
Host Animals
Top of pageAnimal name | Context | Life stage | System |
---|---|---|---|
Bison bonasus | Domesticated host; Wild host | Other|Juvenile | |
Bos indicus (zebu) | Domesticated host | Cattle and Buffaloes|All Stages; Cattle and Buffaloes|Calf; Cattle and Buffaloes|Heifer | |
Bos taurus (cattle) | Domesticated host | Cattle and Buffaloes|All Stages; Cattle and Buffaloes|Calf; Cattle and Buffaloes|Heifer | |
Bubalus bubalis (Asian water buffalo) | Domesticated host | Cattle and Buffaloes|Bull; Cattle and Buffaloes|Cow; Cattle and Buffaloes|Heifer; Cattle and Buffaloes|Steer | |
Camelus bactrianus (Bactrian camel) | Domesticated host | Other|Juvenile | |
Camelus dromedarius (dromedary camel) | Domesticated host | Other|Juvenile | |
Capra hircus (goats) | Domesticated host; Wild host | Sheep and Goats|Lamb | |
Cervidae | Domesticated host; Wild host | Other|Juvenile | |
Equus caballus (horses) | Domesticated host | Other|Juvenile | |
Gallus gallus domesticus (chickens) | Domesticated host; Experimental settings | Poultry|All Stages | |
Lama glama (llamas) | Domesticated host | Other|Juvenile | |
Lama pacos (alpacas) | Domesticated host | Other|Adult Female; Other|Adult Male; Other|Juvenile | |
Lepus europaeus (European hare) | Wild host | Other|Adult Female; Other|Adult Male; Other|Juvenile | |
Oryctolagus cuniculus (rabbits) | Domesticated host; Experimental settings; Wild host | Other|Juvenile | |
Ovis aries (sheep) | Domesticated host; Wild host | Sheep and Goats|All Stages | |
Rangifer tarandus (reindeer) | Domesticated host | Other|Adult Female; Other|Adult Male; Other|Juvenile | |
Sus scrofa (pigs) | Domesticated host; Experimental settings | Pigs|All Stages |
Hosts/Species Affected
Top of pageM. avium subsp. paratuberculosis can infect a wide range of hosts including non-ruminants (Fox et al., 2020) but causes disease in ruminants, camelids, rabbits and hares. Paratuberculosis is widely distributed in many species of domesticated and non-domesticated ruminants throughout the world. It is recognized that herd prevalence may vary widely for many of these species, depending upon a variety of factors such as environment, farm management and control procedures, and host animal genetics. Environmental factors such as soil iron content and soil pH have been implicated in the incidence of paratuberculosis in dairy cattle herds in Michigan (Johnson-Ifearulundu and Kaneene, 1997). Some differences in disease susceptibility have been reported in cattle breeds. A higher incidence of paratuberculosis has been reported for Channel Island breeds and in Shorthorns in the UK, USA and Canada (Withers, 1959; Julian, 1975; Sorge et al., 2011). A higher prevalence for paratuberculosis was noted for Holstein cattle compared to other dairy breeds in Austria (Gasteiner et al., 2000) and in Zebu cattle compared with crossbred and European breeds in Brazil (Vilar et al., 2015). In addition, a Danish study demonstrated the highest probability for infection in older cows (parity > 4) and the lowest probability in first parity, large-breed cows (Jakobsen et al., 2000). Paratuberculosis is reported most frequently in the Holstein breed in the USA, but this breed comprises a major portion of the dairy cattle population. Differences in breed susceptibility to paratuberculosis have also been reported for sheep. In a controlled experimental infection, Merino and Suffolk-Merino cross animals were found to be more susceptible to disease (Begg et al., 2017) and an on-farm study of different breeds found Dorset animals to be less susceptible (Hemalatha et al., 2013).
Genetic differences have been demonstrated between M. avium subsp. paratuberculosis isolates from different hosts and whole genome sequencing has confirmed that there are two major lineages, MAP-S and MAP-C (Bryant et al., 2016; Stevenson and Ahlstrom 2020). Different phenotypic, epidemiologic and pathogenic characteristics may be associated with the two lineages (Stevenson, 2015; Stevenson and Ahlstrom, 2020). Cross-species transmission of MAP-S and MAP-C strains has been reported in natural settings among domestic ruminants, between domestic ruminants and both ruminant and non-ruminant wildlife and among wildlife.
Systems Affected
Top of pagedigestive diseases of small ruminants
Distribution
Top of pageFor current information on disease incidence, see OIE's World Animal Health Information System (OIE-WAHIS).
Distribution Table
Top of pageThe distribution in this summary table is based on all the information available. When several references are cited, they may give conflicting information on the status. Further details may be available for individual references in the Distribution Table Details section which can be selected by going to Generate Report.
Last updated: 10 Dec 2021Continent/Country/Region | Distribution | Last Reported | Origin | First Reported | Invasive | Reference | Notes |
---|---|---|---|---|---|---|---|
Africa |
|||||||
Algeria | Present | ||||||
Botswana | Absent | Jul-Dec-2018 | |||||
Burundi | Absent | Jul-Dec-2018 | |||||
Cabo Verde | Absent | Jul-Dec-2019 | |||||
Cameroon | Present | ||||||
Central African Republic | Absent | Jul-Dec-2019 | |||||
Chad | Absent | Jul-Dec-2019 | |||||
Congo, Republic of the | Present | ||||||
Côte d'Ivoire | Absent, No presence record(s) | ||||||
Djibouti | Absent | Jul-Dec-2019 | |||||
Egypt | Present | ||||||
Eritrea | Absent | Jul-Dec-2019 | |||||
Ethiopia | Present | ||||||
Ghana | Absent | Jan-Jun-2019 | |||||
Kenya | Present | ||||||
Lesotho | Absent | Jan-Jun-2020 | |||||
Liberia | Absent | Jul-Dec-2018 | |||||
Libya | Present | ||||||
Madagascar | Absent, No presence record(s) | Jan-Jun-2019 | |||||
Mauritius | Absent | Jul-Dec-2019 | |||||
Mayotte | Absent, No presence record(s) | Jul-Dec-2019 | |||||
Morocco | Present | ||||||
Mozambique | Absent | Jul-Dec-2019 | |||||
Namibia | Absent | Jul-Dec-2019 | |||||
Niger | Present, Localized | Jul-Dec-2019 | |||||
Nigeria | Present | Jul-Dec-2019 | |||||
Réunion | Present | Jul-Dec-2019 | |||||
Rwanda | Absent, No presence record(s) | ||||||
Saint Helena | Absent, No presence record(s) | Jan-Jun-2019 | |||||
São Tomé and Príncipe | Absent, No presence record(s) | ||||||
Senegal | Present | ||||||
Seychelles | Absent, No presence record(s) | Jul-Dec-2018 | |||||
Sierra Leone | Absent | Jan-Jun-2018 | |||||
Somalia | Absent | Jul-Dec-2020 | |||||
South Africa | Present | ||||||
South Sudan | Present | ||||||
Sudan | Absent | Jul-Dec-2019 | |||||
Tanzania | Present | ||||||
Tunisia | Absent | Jul-Dec-2019 | |||||
Uganda | Present | ||||||
Zambia | Present | ||||||
Zimbabwe | Absent | Jul-Dec-2019 | |||||
Asia |
|||||||
Armenia | Absent | Jul-Dec-2019 | |||||
Azerbaijan | Absent | Jul-Dec-2019 | |||||
Bahrain | Absent | Jul-Dec-2020 | |||||
Bangladesh | Present | ||||||
Bhutan | Present | ||||||
Brunei | Absent, No presence record(s) | Jul-Dec-2019 | |||||
China | Present, Localized | Jul-Dec-2018 | |||||
Georgia | Absent, No presence record(s) | Jul-Dec-2019 | |||||
Hong Kong | Absent | Jul-Dec-2019 | |||||
India | Present | ||||||
-Assam | Present | ||||||
-Haryana | Present | ||||||
-Kerala | Present | ||||||
-Maharashtra | Present | ||||||
-Punjab | Present | ||||||
Indonesia | Present, Localized | Jul-Dec-2019 | |||||
Iran | Present, Localized | Jul-Dec-2018 | |||||
Iraq | Absent | Jul-Dec-2019 | |||||
Israel | Present | Jul-Dec-2020 | |||||
Japan | Present | Jan-Jun-2020 | |||||
Jordan | Absent | Jul-Dec-2018 | |||||
Kazakhstan | Absent | Jul-Dec-2019 | |||||
Kuwait | Absent | Jan-Jun-2019 | |||||
Kyrgyzstan | Absent | Jan-Jun-2019 | |||||
Laos | Absent | Jan-Jun-2019 | |||||
Lebanon | Absent, No presence record(s) | 1999 | |||||
Malaysia | Present, Localized | Jan-Jun-2019 | |||||
-Peninsular Malaysia | Present, Serological evidence and/or isolation of the agent | ||||||
-Sabah | Present | ||||||
-Sarawak | Present, Serological evidence and/or isolation of the agent | ||||||
Maldives | Absent, No presence record(s) | Jan-Jun-2019 | |||||
Mongolia | Present | ||||||
Myanmar | Absent | Jul-Dec-2019 | |||||
Nepal | Present | ||||||
North Korea | Absent, No presence record(s) | ||||||
Oman | Present | Jul-Dec-2019 | |||||
Pakistan | Absent | Jan-Jun-2020 | |||||
Palestine | Present, Localized | Jul-Dec-2019 | |||||
Philippines | Present | ||||||
Qatar | Absent | Jul-Dec-2019 | |||||
Saudi Arabia | Present | ||||||
Singapore | Absent, No presence record(s) | Jul-Dec-2019 | |||||
South Korea | Present | Jul-Dec-2019 | |||||
Sri Lanka | Absent, No presence record(s) | Jul-Dec-2018 | |||||
Syria | Absent | Jul-Dec-2019 | |||||
Taiwan | Present, Localized | Jul-Dec-2019 | |||||
Tajikistan | Absent | Jan-Jun-2019 | |||||
Thailand | Present | ||||||
Turkey | Present | ||||||
Turkmenistan | Absent | Jan-Jun-2019 | |||||
United Arab Emirates | Present | Jul-Dec-2020 | |||||
Uzbekistan | Absent | Jul-Dec-2019 | |||||
Vietnam | Absent | Jul-Dec-2019 | |||||
Europe |
|||||||
Albania | Absent | Jul-Dec-2019 | |||||
Andorra | Absent | Jul-Dec-2019 | |||||
Austria | Present | Jul-Dec-2019 | |||||
Belarus | Absent, No presence record(s) | Jul-Dec-2019 | |||||
Belgium | Present | ||||||
Bosnia and Herzegovina | Present | Jul-Dec-2019 | |||||
Bulgaria | Absent | Jul-Dec-2018 | |||||
Croatia | Present, Localized | Jul-Dec-2019 | |||||
Cyprus | Present | Jul-Dec-2019 | |||||
Czechia | Absent | Jul-Dec-2019 | |||||
Denmark | Present | Jul-Dec-2018 | |||||
Estonia | Present | Jul-Dec-2019 | |||||
Faroe Islands | Present | Jul-Dec-2018 | |||||
Finland | Absent | Jul-Dec-2019 | |||||
France | Present | Jul-Dec-2019 | |||||
Germany | Present | Jul-Dec-2019 | |||||
Greece | Present | ||||||
Hungary | Present, Localized | Jul-Dec-2019 | |||||
Iceland | Present | Jul-Dec-2019 | |||||
Ireland | Present | ||||||
Isle of Man | Present | ||||||
Italy | Present, Localized | Jul-Dec-2020 | |||||
Jersey | Present | CAB Abstracts Data Mining | |||||
Latvia | Absent | Jul-Dec-2020 | |||||
Liechtenstein | Absent | Jul-Dec-2019 | |||||
Lithuania | Absent | Jul-Dec-2019 | |||||
Luxembourg | Present | ||||||
Malta | Absent | Jan-Jun-2019 | |||||
Moldova | Absent | Jan-Jun-2020 | |||||
Montenegro | Present, Localized | Jul-Dec-2019 | |||||
Netherlands | Present | ||||||
North Macedonia | Absent | Jul-Dec-2019 | |||||
Norway | Present | Jul-Dec-2020 | |||||
Poland | Absent | Jan-Jun-2019 | |||||
Portugal | Present | Jul-Dec-2019 | |||||
Romania | Present, Localized | Jul-Dec-2018 | |||||
Russia | Present, Localized | Jan-Jun-2020 | |||||
-Russia (Europe) | Present | ||||||
San Marino | Absent, No presence record(s) | Jan-Jun-2019 | |||||
Serbia | Absent, No presence record(s) | Jul-Dec-2019 | |||||
Slovakia | Absent | Jul-Dec-2020 | |||||
Slovenia | Present | ||||||
Spain | Present | ||||||
Sweden | Absent | Jul-Dec-2020 | |||||
Switzerland | Present | ||||||
Ukraine | Absent | Jul-Dec-2020 | |||||
United Kingdom | Present | ||||||
-Northern Ireland | Present | ||||||
North America |
|||||||
Bahamas | Absent, No presence record(s) | Jul-Dec-2018 | |||||
Barbados | Absent | Jul-Dec-2020 | |||||
Belize | Absent | Jul-Dec-2019 | |||||
Bermuda | Absent, No presence record(s) | ||||||
British Virgin Islands | Absent, No presence record(s) | ||||||
Canada | Present | Jul-Dec-2019 | |||||
-Ontario | Present | ||||||
-Prince Edward Island | Present | Original citation: van Leeuwen et al. (2001) | |||||
Cayman Islands | Absent | Jan-Jun-2019 | |||||
Costa Rica | Present | Jul-Dec-2019 | |||||
Cuba | Absent | Jan-Jun-2019 | |||||
Curaçao | Absent, No presence record(s) | ||||||
Dominica | Absent, No presence record(s) | ||||||
Dominican Republic | Absent, No presence record(s) | Jan-Jun-2019 | |||||
El Salvador | Absent | Jul-Dec-2019 | |||||
Greenland | Absent, No presence record(s) | ||||||
Guatemala | Absent, No presence record(s) | Jan-Jun-2019 | |||||
Haiti | Absent, No presence record(s) | Jul-Dec-2019 | |||||
Jamaica | Absent | Jul-Dec-2018 | |||||
Martinique | Absent, Unconfirmed presence record(s) | ||||||
Mexico | Present, Localized | Jul-Dec-2019 | |||||
Nicaragua | Absent | Jul-Dec-2019 | |||||
Panama | Present | ||||||
Saint Kitts and Nevis | Absent, No presence record(s) | ||||||
Saint Lucia | Absent, No presence record(s) | Jul-Dec-2018 | |||||
Saint Vincent and the Grenadines | Absent, No presence record(s) | Jan-Jun-2019 | |||||
Trinidad and Tobago | Absent | Jan-Jun-2018 | |||||
United States | Present | Jul-Dec-2019 | |||||
-Arizona | Present | Original citation: Kopecky and (1973) | |||||
-Arkansas | Present | ||||||
-California | Present | ||||||
-Colorado | Present | ||||||
-Connecticut | Present | Original citation: Kopecky and (1973) | |||||
-Florida | Present | ||||||
-Georgia | Present | ||||||
-Illinois | Present | ||||||
-Indiana | Present | Original citation: Kopecky and (1973) | |||||
-Iowa | Present | Original citation: Kopecky and (1973) | |||||
-Kansas | Present | ||||||
-Kentucky | Present | ||||||
-Louisiana | Present | Original citation: Kopecky and (1973) | |||||
-Maine | Present | ||||||
-Maryland | Present | Original citation: Kopecky and (1973) | |||||
-Massachusetts | Present | Original citation: Kopecky and (1973) | |||||
-Michigan | Present | ||||||
-Minnesota | Present | ||||||
-Mississippi | Present | Original citation: Kopecky and (1973) | |||||
-Missouri | Present | ||||||
-Nebraska | Present | ||||||
-Nevada | Present | Original citation: Kopecky and (1973) | |||||
-New Jersey | Present | Original citation: Kopecky and (1973) | |||||
-New Mexico | Present | Original citation: Kopecky and (1973) | |||||
-New York | Present | ||||||
-North Carolina | Present | Original citation: Kopecky and (1973) | |||||
-North Dakota | Present | Original citation: Kopecky and (1973) | |||||
-Ohio | Present | ||||||
-Oklahoma | Present | ||||||
-Oregon | Present | ||||||
-Pennsylvania | Present | ||||||
-South Carolina | Present | Original citation: Kopecky and (1973) | |||||
-South Dakota | Present | Original citation: Kopecky and (1973) | |||||
-Tennessee | Present | ||||||
-Texas | Present | ||||||
-Utah | Present | Original citation: Kopecky and (1973) | |||||
-Virginia | Present | ||||||
-Washington | Present | ||||||
-West Virginia | Present | Original citation: Kopecky and (1973) | |||||
-Wisconsin | Present | ||||||
Oceania |
|||||||
Australia | Present | ||||||
-New South Wales | Present | ||||||
-Queensland | Present | ||||||
-South Australia | Present | ||||||
-Tasmania | Present | ||||||
-Victoria | Present | ||||||
Cook Islands | Absent | Jul-Dec-2018 | |||||
Federated States of Micronesia | Absent, No presence record(s) | Jan-Jun-2019 | |||||
Fiji | Absent | Jan-Jun-2019 | |||||
French Polynesia | Absent | Jul-Dec-2018 | |||||
Kiribati | Absent, No presence record(s) | Jan-Jun-2018 | |||||
Marshall Islands | Absent, No presence record(s) | Jan-Jun-2019 | |||||
New Caledonia | Present | Jul-Dec-2019 | |||||
New Zealand | Present | ||||||
Palau | Absent | Jul-Dec-2020 | |||||
Samoa | Absent, No presence record(s) | Jan-Jun-2019 | |||||
Timor-Leste | Absent, No presence record(s) | Jul-Dec-2018 | |||||
Tonga | Absent | Jul-Dec-2019 | |||||
Vanuatu | Absent, No presence record(s) | Jan-Jun-2019 | |||||
South America |
|||||||
Argentina | Present | ||||||
Bolivia | Absent | Jan-Jun-2019 | |||||
Brazil | Present | ||||||
-Santa Catarina | Present | ||||||
-Sao Paulo | Present | ||||||
Chile | Present | ||||||
-Easter Island | Present | ||||||
Colombia | Present | ||||||
Ecuador | Present | ||||||
Falkland Islands | Absent, No presence record(s) | Jul-Dec-2019 | |||||
French Guiana | Absent | Jul-Dec-2019 | |||||
Guyana | Absent, No presence record(s) | ||||||
Paraguay | Absent | Jul-Dec-2019 | |||||
Peru | Absent | Jan-Jun-2019 | |||||
Suriname | Absent, No presence record(s) | Jan-Jun-2019 | |||||
Uruguay | Present | ||||||
Venezuela | Present | Jan-Jun-2019 |
Pathology
Top of pageGross pathology of affected animals is primarily associated with the lower small intestine and regional lymph nodes. Paratuberculosis is characterized by a granulomatous inflammation involving, mainly the ileo-caecal valve, ileum, and associated lymph nodes (Chiodini et al., 1984). This inflammation makes the intestinal wall appear thickened and corrugated, associated lymph nodes become enlarged and oedematous. However, in advanced stages of clinical disease, infection may become systemic and affect many tissues including the mammary gland, kidneys, liver, and male and female reproductive organs (Doyle, 1954; Kopecky et al., 1967; Larsen and Kopecky, 1970; Larsen et al., 1981; Hines et al., 1987). Atherosclerosis and calcification of the aorta and heart have been observed in cattle with end-stage clinical disease (Buergelt et al., 1978).
Tissue changes are accompanied by increased leakage of plasma proteins across the intestinal wall and malabsorption of amino acids and other nutrients from the intestine, with little or no evidence of mucosal necrosis. A decrease of calcium total protein and albumin has been observed in serum from cattle and sheep with clinical paratuberculosis (Jones and Kay, 1996). Accumulations of lymphocytes, macrophages, epithelioid cells, and other inflammatory cells are found in the lamina propria. Microscopic lesions consist primarily of macrophage infiltrate; they are multifocal in the early stages of disease but become more diffuse as the disease progresses to more advanced stages. Giant cells are a characteristic of paratuberculosis and occur more frequently in advanced clinical disease.
In some clinical cases, inflammatory cells may be observed in the submucosa as a band of epithelioid cells and lymphocytes along the muscularis mucosa. In general, granulomas or diffuse cellular infiltrates containing numerous acid-fast bacilli are present in clinical cases. Villi become blunt and may fuse together. It should be noted that cases with severe lesions and few bacilli can be observed, mainly in sheep (Marin et al., 1992; Pérez et al., 1996; Clarke, 1997). Caseous necrosis has been observed in paratuberculous lesions most frequently in goats, and certain captive wild species such as deer (Stehman, 1996). In sheep and goats lymphangiectasia, is most often observed in clinical cases (Marin et al., 1992; Perez et al., 1996; Clarke, 1997). Moreover, in sheep and goats gross changes associated with a thickening of the ileum and jejunum are sometimes difficult to detect, and do not resemble those observed in cattle (Marin et al., 1992; Clarke, 1997).
Diagnosis
Top of pageHost immunity
Diagnosis of paratuberculosis is difficult because of the fastidious growth pattern of the microorganism and because of the paradoxical pattern of the host animal immune response to infection. Efforts to control paratuberculosis in cattle and other species has been limited by the lack of rapid, reliable diagnostic tests for identifying all M. avium subsp. paratuberculosis-infected animals. Moreover, the sensitivity of different diagnostic methods is influenced by the prevalence of the infection in the herd and by the stage of the disease, depending on the individual host response (Clarke, 1997; Marin et al., 1992; Sweeney et al., 1995; Pérez et al., 1997; Pérez et al., 1999).
During the early subclinical stages of infection, the microorganism elicits a cell-mediated response that can be characterized by strong delayed type IV hypersensitivity reactions, lymphocyte proliferative responses to mitogens and production of cytokines by stimulated T lymphocytes (Kormendy et al., 1990; Stabel, 1996; Perez et al., 1999; Stabel et al., 2020). When the disease progresses from subclinical to clinical stages, the cell-mediated immune response wanes and a strong humoral response predominates. The presence of antibody to M. avium subsp. paratuberculosis does not protect the host against the disease; indeed, active cell-mediated immunity appears to be essential to keep the infection in check. During the final stages of disease, lack of antigen-specific cell-mediated immune responses or complete anergy may result, allowing for rapid dissemination of the infection throughout the host (Bendixen, 1978).
Clinical diagnosis
The most characteristic sign of paratuberculosis in cattle is the occurrence of profuse, watery diarrhoea in infected animals. The diarrhoea does not respond to treatment and may be chronic or appear intermittently over more protracted periods. In the early stages of clinical disease, the animal may continue to eat well but the diarrhoea causes a rapid weight loss. Because of the malabsorption of nutrients, animals begin to show signs of unthriftiness such as rough hair coat and dry skin. At the end stage of clinical disease, severe emaciation and submandibular oedema or ‘bottle-jaw’ may develop due to the leaking of serum proteins across capillary walls. In sheep and goats, diarrhoea is not a characteristic sign but some softening of the stool is observed; however, weight loss and unthriftiness do occur. Fever has been reported in some cases but is not a consistent sign of infection with M. avium subsp. paratuberculosis.
Laboratory diagnosis
Bacterial culture is the most definitive method of ante mortem diagnosis because it can detect animals that are subclinically infected and also animals in advanced stages of disease. Use of faecal samples in mycobacteriologic culture is routine in many countries to confirm diagnosis of M. avium subsp. paratuberculosis. Subclinically infected animals shed low numbers of M. avium subsp. paratuberculosis in their faeces and usually shed intermittently over time. During the clinical phase of infection, faecal shedding of the microorganism is quite high and may exceed 108 cfu per gram of faeces (Chiodini et al., 1984). Primary culture of the bacilli is very time-consuming, typically requiring 12-20 weeks of incubation, depending on the strain and culture medium and not all media support the growth of all M. avium subsp. paratuberculosis strains (Whittington, 2020). Culture is also labour intensive. Contamination by other fungal and bacterial microorganisms is often a problem when M. avium subsp. paratuberculosis is being cultured from faecal specimens, so incorporation of a decontamination procedure before culture is standard protocol for diagnostic laboratories. Because infected animals may shed the organism intermittently in their faeces, use of faecal culture alone as a diagnostic tool may result in misrepresentation of infection within the herd; only about 50% of M. avium subsp. paratuberculosis infection is detected by faecal culture (Sanftleben, 1990). For surveillance purposes detection of M. avium subsp. paratuberculosis in environmental or pooled faecal samples is an efficient procedure (van Schaik et al., 2007; Aly et al., 2009; Lavers et al., 2013).
Though several serologic tests have been developed for detecting antibodies in sera of cattle experimentally or naturally exposed to M. avium subsp. paratuberculosis, many of these tests have not been widely used under field conditions. Serological tests for diagnosis of paratuberculosis, such as agar gel immunodiffusion (AGID), enzyme-linked immunosorbent assay (ELISA) and complement fixation (CF), are relatively easy to perform but sensitivity of detection is only moderate (Colgrove et al., 1989). AGID is most often used as a rapid diagnostic method for confirmation of clinical paratuberculosis in small ruminants.
Most widely used is the ELISA, sometimes in conjunction with other diagnostic methods such as faecal culture or direct faeces PCR. Reported sensitivity values for ELISA are 15-57% for subclinically infected cattle shedding low numbers of organisms in their faeces; the average is 88% for clinically infected cattle shedding high numbers of organisms (Collins and Sockett, 1993; Sweeney et al., 1995). A multi-university study also demonstrated that several ELISA tests (three on serum and one on milk) had sensitivities ranging from 27.8-28.9% (Collins et al., 2005). A review of accuracies of ELISA tests indicated that sensitivity and specificity estimates vary greatly within and between tests making it impossible to provide point estimates (Nielsen and Toft, 2008). Milk ELISA testing is an attractive low cost method for diagnosing paratuberculosis in large scale monitoring systems (van Weering et al., 2007). The CF test is most frequently used to test cattle for import and export purposes, yet has a lower specificity than the AGID or ELISA tests. A study of sera from cattle in herds with a previous diagnosis of paratuberculosis provided additional evidence about the sensitivity of ELISA in cattle with clinical disease (Thoen and Moore, 1989). However, a high percentage of subclinically affected cattle, sheep and goats, in which M. avium subsp. paratuberculosis was isolated from tissue specimens at necropsy failed to have detectable mycobacterial antibodies in sera. Therefore, although serologic tests are useful in detecting cattle with clinical paratuberculosis, the application of ELISA for identifying cattle in the early stages of infection or shedding small numbers of organisms in the faeces is of limited value (Clarke, 1997; Sweeney et al., 1995; Perez et al., 1997). The AGID is more efficient in small ruminants than in cattle; the sensitivity is related with the stage of the infection, (high in clinical or preclinical cases and very low in the early stages of the infection) (Marin et al., 1992; Shulaw et al., 1993; Perez et al., 1997).
Intradermal injection of PPD prepared from the culture filtrate of M. avium subsp. paratuberculosis has been used to detect cattle with paratuberculosis. Although some cattle that respond to such an injection have been suggested to be only sensitized and not infected, reports indicate the organism is isolated in a high percentage of skin test positive animals. This test requires a veterinarian to inject the animal with johnin and read the change in skin thickness 24-48 h after injection. Although the test is inexpensive and rapid, it does require two visits by the veterinarian and has a low sensitivity of detection compared to other techniques. The specificity of the test may be improved markedly by the use of purified antigens. The skin test was used more frequently in the past, less so now due to the availability of the interferon-gamma (IFN-γ) release assay (Kalis et al., 2003).
In vitro lymphocyte blastogenic assays, which are considered an in vitro correlate of delayed-type hypersensitivity, have been developed for use in the diagnosis of paratuberculosis and seem to be valuable in detecting some cattle with subclinical disease. The measure of IFN-γ has been evaluated as a diagnostic tool for paratuberculosis (Billman-Jacobe et al., 1992). IFN-γ is a protein that is released by activated T cells after stimulation with mycobacterial antigens (Wood et al., 1990). The assay showed promise for identifying animals in the early subclinical stages of disease, but is problematic in terms of cost and interpretation of results. Sensitivity and specificity estimates of between 13% and 85% and 88% and 94%, respectively, have been reported for IFN-γ tests (Nielsen and Toft, 2008). The individual IFN-γ assay result of an individual animal cannot establish that the animal is infected or predict disease progression (Jungersen et al., 2012). Therefore, the IFN-γ assay should be used to test the level of exposure to M. avium subsp. paratuberculosis the animals have experienced, and thereby assist in maintaining rational in-herd management procedures and in the establishment of paratuberculosis status of a given herd. Combining the ELISA and IFN-γ tests to screen herds infected with M. avium subsp. paratuberculosis resulted in the identification of 70-90% of infected animals based upon faecal culture, indicating that using a combination of cellular and antibody assays may improve the detection of M. avium subsp. paratuberculosis-infected cattle.
Specific gene probes and polymerase chain reaction (PCR) are now routinely used for confirming the identity of cultured isolates and for rapid detection of M. avium subsp. paratuberculosis in clinical specimens (Giessen et al., 1992; Collins et al., 1993; Wentink et al., 1994; Theon and Haagsma, 1996; Plain et al., 2020; Whittington, 2020). These techniques provide for reporting of results to the clinician in 4 to 5 days, and are valuable when purchasing replacement cattle, where obtaining results in a short time is necessary. Because false-positive reactions have been observed in reference laboratories conducting PCR analysis, it is necessary to include suitable controls to validate results (Cousins et al., 1999). The most commonly used gene sequence for PCR detection of M. avium subsp. paratuberculosis is the insertion element, IS900 (Vary et al., 1990). Other genes specific for M. avium subsp. paratuberculosis can be used but are present at a lower copy number affecting sensitivity, although their inclusion in multiplex assays can increase specificity (Sevilla et al., 2014). Nested PCR has increased the sensitivity of this technique several fold over conventional PCR, detecting 104 organisms per gram of faeces versus 50 organisms per gram of faeces (Collins et al., 1993). This technique has a higher risk for cross contamination but is still used in some situations such as detection of M. avium subsp. paratuberculosis in tissues of Crohn’s patients (Zarei-Kordshouli et al., 2019). Currently, the greatest sensitivity is achieved using real time, quantitative PCR (qPCR), which is now commonly used for paratuberculosis diagnostic testing. Recent advances have focussed on more efficient techniques to isolate nucleic acids from clinical samples while limiting extraction of PCR inhibitors, thus further increasing sensitivity of these techniques for practical purposes (Okwumabua et al., 2010; Plain et al., 2020). Commercial kits are now available for a range of sample types. With all of these improvements, the sensitivity of direct PCR detection can exceed that of detection by culture and most countries implementing a paratuberculosis control programme utilise a PCR faecal diagnostic test (Whittington et al., 2019). The use of PCR on blood samples for the detection of M. avium subsp. paratuberculosis in macrophages is possible however only in a limited number of cases of advanced paratuberculosis (Giessen et al., 1992; Zhong et al., 2009).
PCR does not differentiate between live or dead organisms and with the ongoing discussions regarding the association of M. avium subsp. paratuberculosis and Crohn’s disease, this has raised concerns. Intercalating dye based PCR assays have been developed in which DNA from dead bacteria cannot be amplified but this compromises sensitivity and such assays have been restricted to research use (Kralik et al., 2010). More recently, phage-based assays have been developed and are being evaluated for commercial testing (Swift et al., 2020).
Restriction fragment length polymorphism analysis, PGFE, MIRU-VNTR, SSR, SNP typing and whole genome sequencing have provided for the differentiation of M. avium subsp. paratuberculosis isolates from animals, and are valuable in epidemiological investigations (Collins et al., 1990; Pavlik et al., 1995; Sevilla et al., 2008; Pradhan et al., 2011; van Hulzen et al., 2011; Bryant et al., 2016; Leão et al., 2016; Stevenson and Ahlstrom, 2020). However, the cost of these molecular techniques limits their use on a herd basis.
For practical purposes the present day challenge for practitioners is to select the appropriate test for the intended purpose. The intended purposes range from testing in control programs in M. avium subsp. paratuberculosis infected high prevalence herds, with the absorbed ELISA as the preferred test,to surveillance and confirming clinical diagnoses. If the primary aim is surveillance then environmental or pooled faecal samples should be used (van Schaik et al., 2007; Aly et al., 2009). For eradication strategies the pooled faecal culture or pooled faecal PCR are the test of choice. In case of confirmation of a clinical diagnoses in unsuspect herds necropsy, faecal culture or faecal PCR should be chosen. In cases of confirmation of a clinical diagnosis in herds with endemic paratuberculosis, ELISA, faecal culture or faecal PCR can be used. (Collins, 2011).
List of Symptoms/Signs
Top of pageSign | Life Stages | Type |
---|---|---|
Cardiovascular Signs / Tachycardia, rapid pulse, high heart rate | Sign | |
Digestive Signs / Anorexia, loss or decreased appetite, not nursing, off feed | Cattle and Buffaloes|Cow | Diagnosis |
Digestive Signs / Dark colour stools, faeces | Sign | |
Digestive Signs / Diarrhoea | Cattle and Buffaloes|Cow | Diagnosis |
Digestive Signs / Parasites passed per rectum, in stools, faeces | Cattle and Buffaloes|All Stages | Diagnosis |
Digestive Signs / Polyphagia, excessive appetite | Sign | |
General Signs / Dehydration | Cattle and Buffaloes|Cow | Sign |
General Signs / Fever, pyrexia, hyperthermia | Sign | |
General Signs / Generalized weakness, paresis, paralysis | Cattle and Buffaloes|All Stages | Sign |
General Signs / Head, face, ears, jaw, nose, nasal, swelling, mass | Sign | |
General Signs / Inability to stand, downer, prostration | Sign | |
General Signs / Lack of growth or weight gain, retarded, stunted growth | Sign | |
General Signs / Pale mucous membranes or skin, anemia | Sign | |
General Signs / Polydipsia, excessive fluid consumption, excessive thirst | Sign | |
General Signs / Underweight, poor condition, thin, emaciated, unthriftiness, ill thrift | Cattle and Buffaloes|Cow | Diagnosis |
General Signs / Weight loss | Cattle and Buffaloes|Cow | Diagnosis |
Nervous Signs / Dullness, depression, lethargy, depressed, lethargic, listless | Sign | |
Reproductive Signs / Abortion or weak newborns, stillbirth | Sign | |
Reproductive Signs / Agalactia, decreased, absent milk production | Sign | |
Reproductive Signs / Anestrus, absence of reproductive cycle, no visible estrus | Cattle and Buffaloes|Cow; Cattle and Buffaloes|Heifer | Sign |
Reproductive Signs / Decreased in size, small ovary, ovaries | Cattle and Buffaloes|Cow; Cattle and Buffaloes|Heifer | Sign |
Reproductive Signs / Female infertility, repeat breeder | Sign | |
Reproductive Signs / Male infertility | Cattle and Buffaloes|Bull | Sign |
Skin / Integumentary Signs / Alopecia, thinning, shedding, easily epilated, loss of, hair | Cattle and Buffaloes|All Stages | Sign |
Skin / Integumentary Signs / Decreased hair pigment, general or focal, poliosis | Cattle and Buffaloes|All Stages | Sign |
Skin / Integumentary Signs / Dryness of skin or hair | Sign | |
Skin / Integumentary Signs / Rough hair coat, dull, standing on end | Cattle and Buffaloes|Cow | Sign |
Skin / Integumentary Signs / Skin edema | Sign |
Disease Course
Top of pageThe clinical signs that occur, following a prolonged incubation period of one to ten years, include gradual weight loss despite a normal appetite. Other than the loose consistency the faeces appear normal. As the disease progresses, the affected animals become increasingly lethargic and emaciated. Cachexia and ‘waterhose’ diarrhoea characterize the terminal stages of the disease in cattle, but diarrhoea is not a common feature in sheep and goats (Chiodini et al., 1984; Marin et al., 1992). The main clinical signs of the disease are progressive weight loss and a decrease in milk production; therefore, most farmers cull the animals before severe clinical signs are present and before the diagnosis of paratuberculosis is made. Consequently, the number of clinical cases of paratuberculosis may be underestimated (Chiodini et al., 1984; Marin et al., 1992).
Transmission of M. avium subsp. paratuberculosis in cattle herds varies considerably, depending on the management practices followed. In some herds, the disease may persist for years before clinical signs appear. The most common route of exposure of calves to M. avium subsp. paratuberculosis is by ingestion of contaminated faeces on the surface of the dam’s mammary gland during suckling (Chiodini and Davis, 1992; Thoen and Haagsma, 1996). Young calves, seem to be more susceptible to the infection than older or adult cows (Hagan, 1938; Payne and Rankin, 1961; Larsen et al., 1975). Faeces contaminate pastures so feed and water are sources of infection. M. avium subsp. paratuberculosis can resist destruction for several months in the natural environment, making prevention and control difficult (Jorgensen, 1977). Moreover, colostrum, placenta and uterus as well as the foetus may be infected adding to the difficulty in the control of paratuberculosis (McQueen and Russell, 1979; Seitz et al., 1989; Rohde and Shulaw, 1990; Sweeney et al., 1992a,b; Streeter et al., 1995). The primary route of infection is through ingestion of faecal material, milk or colostrum containing M. avium subsp. paratuberculosis microorganisms (Chiodini et al., 1984) which, once ingested, survive and replicate within macrophages of the small intestine and in regional lymph nodes. The organisms have been isolated from semen and reproductive organs of bulls, but the importance of these findings in transmission is unclear. The incubation period, which is the interval between infection and the observation of clinical disease (diarrhoea and weight loss), usually varies from 1 to 5 years or more. Cattle become infected with M. avium subsp. paratuberculosis usually as calves but often do not develop clinical signs until 2-5 years old.
It is most important to emphasize that clinical disease may be observed in less than 30% of the M. avium subsp. paratuberculosis-infected cattle in a herd. Some animals remain subclinically infected throughout their lifetime and never show clinical signs of disease. Clinical disease is most often observed in cattle 3 to 6 years old. While in sheep and goats, most of the cases are present in animals 2 to 4 years of age or mainly during the first and second lactation (Clarke, 1997). Stress is an important factor that may contribute to the onset of clinical disease; the stress may be related to parturition and/or increased milk production. In beef bulls, stress may be associated with the breeding season.
When clinical signs are evident, the animal usually sheds M. avium subsp. paratuberculosis in the faeces; however, some animals shed intermittently and micro-organisms may not be found on the examination of a single faecal sample. M. avium subsp. paratuberculosis has been isolated from the milk of cows with clinical paratuberculosis and from milk samples and supra-mammary lymph node specimens in cows with subclinical infection (Taylor et al., 1981; Sweeney et al., 1992a; Streeter et al., 1995).
After an incubation period of several years, extensive granulomatous inflammation occurs in the terminal small intestine, leading to malabsorption of nutrients and protein-losing enteropathy. During this period the animal may suffer from chronic watery diarrhoea, rapid weight loss, diffuse oedema and rough hair coat. The chronic diarrhoea fails to respond to antibiotic treatment and animals continue to lose weight, despite adequate food intake. Clinical disease may persist for 6 months or more; diarrhoea may be intermittent and cattle sometimes seem to recover for a few weeks. In terminal stages, diarrhoea results in emaciation and death. However, in small ruminants diarrhoea can be absent in a high percentage of clinical cases (Stamp and Watt, 1954; Clarke, 1997).
A decrease in total serum protein, albumin, triglycerides and cholesterol concomitant with increased creatine kinase and aldolase may occur in the latter stages of disease due to muscle damage (Patterson et al., 1965, 1967, 1968). Some animals will progress rapidly to an end-stage of recumbency and death, whereas others may go into remission for a period of time, although generally these animals will succumb to clinical signs at a later date. Clinical signs of paratuberculosis in sheep, goats and deer are limited to weight loss, unthriftiness and slight softening of their stools. Poor condition of wool is associated with end-stage disease in sheep (Cranwell, 1993). Intestinal thickening is variable in these species with some enlargement of lymph nodes.
Pathogenesis
M. avium subsp. paratuberculosis penetrates the intestinal epithelial layers primarily through the follicle-associated epithelium or M cells (Momotani et al., 1988) but also via regional enterocytes (Sigurðardóttir et al., 2005; Ponnusamy et al., 2013) and possibly dendritic cells. Phagocytes engulf the organisms and are usually unable to degrade them and they remain viable and protected from humoral factors. The first small and limited granulomatous lesion is detected in the ileo-caecal and jejunal Peyers patches, and can persist as latent infection for long periods of time, as has been observed in experimental infections in sheep and goats as well as in natural infections (Pérez et al., 1996). If the infection progresses, lesions spread to mucosa affecting different parts of the small intestine and associated lymph nodes (Juste et al., 1994; Pérez et al., 1996).
During early infection, a cell-mediated immunity (CMI) is predominant, but, as the lesions and disease progresses a humoral response appears due to the presence of large numbers of bacilli released by dying macrophages. The first response is a cell-mediated type Th1 with cytokines such as IL-2 and IFN-γ, as reported in other mycobacterial infections. The progression of the disease is associated with the T-gamma delta cell which inhibits CD4 and helper lymphocytes (Chiodini and Davis, 1992). Th2-like cytokines (IL-4 and IL-10) are predominant in clinical cases with multibacillary and non-lymphocytic lesions (Wards et al., 1995; Little et al., 1996; Burrells et al., 1998; Navarro et al., 1998).
In natural cases a similar situation has been reported with cellular immune response associated with latent-focal subclinical lesions and humoral immunity with high antibody response in diffuse-severe and multibacillary cases (Bendixen, 1978; Clarke, 1997; Pérez et al., 1997; Pérez et al., 1999). However, in some clinical cases with severe disease animals can show a strong CMI response (skin hypersensitivity and low antibody response) with predominant presence of lymphocytes in the lesion and few bacilli (Clarke, 1997; Pérez et al., 1997; Pérez et al., 1999). This is more common in sheep. Therefore, in M. avium subsp. paratuberculosis. infections it has been proposed that an immunopathological spectrum develops, which depends on the host response (Pérez et al., 1999). A clear relationship with pathology, number of bacilli, and the cellular or humoral immune mediated response has been established in sheep (Clarke, 1997; Pérez et al., 1997; Pérez et al., 1999).
Epidemiology
Top of pageParatuberculosis is observed in cattle and small ruminants worldwide (Chiodini et al., 1984). Prevalence of the disease, on the basis of mycobacteriologic examination of tissue specimens collected from adult cattle at slaughter or on histopathological and serological studies (i.e., ELISA), varies considerably. A review by Whittington et al. (2019) provides prevalence estimates for 32 countries. Very few countries have a low prevalence (<1%) in their dairy cattle herds (Norway, Sweden, Thailand) with most countries having >20%. In 2007, the National Animal Health Monitoring System conducted a survey of dairy farms in the USA using faecal environmental sampling and reported the apparent herd prevalence to be 70.4% and Bayesian estimates to be nearer 91% (Lombard et al., 2013). Corbett et al. (2018) used environmental sampling to estimate true herd prevalences ranging from 24-66% in dairy cattle across Canada. These data may, however, markedly underestimate the true incidence of infection in animal populations. In Europe, true herd-level prevalences of 85% of dairy herds in Denmark and 28-43% of herds in the UK were estimated (Geraghty et al., 2014). A survey in 2019 found that almost half of 11 countries with prevalence estimates of M. avium subsp. paratuberculosis in sheep based on objective criteria had >10% of flocks affected and almost one in five countries had >40% flock-level prevalence (Whittington et al., 2019). Similarly, reported herd-prevalence estimates for paratuberculosis in goats from 15 countries ranged from <1% to >40%.
Cattle usually become infected with M. avium subsp. paratuberculosis as calves, but often do not develop clinical signs until 2-5 years of age (Larsen et al., 1975). Calves may become infected in utero or as neonates through ingestion of faecal material, milk or colostrum containing M. avium subsp. paratuberculosis microorganisms. Once ingested, it is believed that the M cells of the Peyer's patches serve as the primary portals of entry for M. avium subsp. paratuberculosis into the lymphatic system, as they do for other enteric intracellular pathogens such as Salmonella (Momotani et al., 1988). Live M. avium subsp. paratuberculosis will then traverse the M cell by transcytosis and be expelled on the basolateral side of the cell to be scavenged by the macrophages or dendritic cells. M. avium subsp. paratuberculosis may survive and replicate within the macrophages of the intestine and regional lymph nodes of the host animal, leading to a protracted subclinical phase of infection. Cattle shed minimal amounts of M. avium subsp. paratuberculosis in their faeces in the subclinical phase of infection, yet, over time, this shedding can lead to significant contamination of the environment and an insidious spread of infection throughout the herd. After an incubation period of several years, the immune system of the host animal may become compromised and the animal is no longer able to contain the infection. At this point, extensive granulomatous inflammation occurs in the terminal small intestine due to an influx of macrophages. Thickening of the intestinal epithelium occurs, resulting in malabsorption of nutrients and protein-losing enteropathy. The terminal stage of disease is characterized by chronic diarrhoea, rapid weight loss, diffuse oedema and inappetence.
Transplacental infection of foetuses with M. avium subsp. paratuberculosis occurs most frequently in foetuses from infected cows in the clinical stage of disease. A study examining infection of foetuses from cows with clinical signs of paratuberculosis found that 26.4% of foetuses had tissues that were culture-positive (Seitz et al., 1989). A lower level of foetal infection was noted in a more recent study evaluating foetal infection in cows that were faecal-culture positive for M. avium subsp. paratuberculosis but asymptomatic for clinical signs (Sweeney et al., 1992a). Foetal tissues were positive for M. avium subsp. paratuberculosis in only 8.6% of infected cows and these cows were shedding high numbers of the bacterium in their faeces. Results from these studies suggest that foetal infection is highly correlated with the level of faecal shedding of M. avium subsp. paratuberculosis and most commonly associated with cows demonstrating clinical signs of disease.
Faecal contamination of the environment poses the most likely threat for calfhood infection. In the clinical stage of disease, cows may shed up to 108 organisms per gram of faeces (Chiodini et al., 1984). Contamination of the maternity pen is a primary source for calves to gain contact with the bacterium. However, contamination of water sources, feed troughs and pasture may also contribute to transmission of infection. Early studies established that M. avium subsp. paratuberculosis is capable of surviving in water, soil and manure for periods up to 1 year. A recent study, however, indicates that the organism does not survive in high numbers during composting and liquid manure storage methods (Grewal et al., 2006). M. avium subsp. paratuberculosis is also shed in the colostrum and milk of infected dams, albeit in low numbers. Although shedding of the bacterium in colostrum has not been adequately quantified it is highly correlated with heavy shedding in the faeces of infected dams (Streeter et al., 1995). Shedding of M. avium subsp. paratuberculosis in the milk of infected dams is also associated with the degree of faecal shedding by the dam, and M. avium subsp. paratuberculosis has been found in viable numbers at low concentrations (5-8 cfu/50 ml of milk) (Sweeney et al., 1992b).
Viable M. avium subsp. paratuberculosis organisms have also been isolated from the reproductive organs of infected females and the reproductive organs and semen of infected bulls, which may contribute to disease transmission (Philpott, 1993). Although it is unclear whether embryo transfer contributes to the incidence of disease, viable M. avium subsp. paratuberculosis organisms have been cultured from uterine washings of clinically infected dams (Rohde and Shulaw, 1990). Experimental evidence also indicates that M. avium subsp. paratuberculosis may attach to bovine ova, suggesting a potential source of uterine infection of the recipient cow (Rohde et al., 1990).
Impact: Economic
Top of pageEconomic losses caused by paratuberculosis are attributable to decreased value of breeding stock, lower milk production, reduced salvage or slaughter value of animals with advanced clinical disease, increased cull rates of high-producing animals, decreased feed conversion rates, and reduced fertility (Merkal et al., 1987; Thoen and Moore, 1989). The significance of subclinical paratuberculosis on economic losses to the producer are detailed in a review by Johnson-Ifearulundu and Kaneene; a reduction in milk production of 15-16% accounts for the major portion of net monetary loss (Johnson-Ifearulundu and Kaneene, 1997). Cows that are infected with M. avium subsp. paratuberculosis beyond second lactation have demonstrated losses of 1300-2800 lb (590-1270 kg) of milk per lactation (Wilson et al., 1993).
Although the estimated losses from paratuberculosis vary, in commercial dairy herds in which M. avium subsp. paratuberculosis infection persists, losses are considerable. Decreases in milk production have been estimated between 4% to 18% in subclinical infected animals and about 20% or higher in clinical cows (Buergelt and Duncan, 1978; Goodger et al., 1996; Spangler et al., 1992). A survey of dairy herds in the USA suggested an annual loss of more than US $200 per cow for positive herds with at least 10% of their cull cows showing clinical signs of paratuberculosis (Ott et al., 1999). Most of this cost could be attributed to a significant reduction in milk production per cow (1500 lb; 680 kg). The national average cost across all herds in the USA was US $22 per cow with an economic loss of US $220 million per year to the dairy industry. Other studies have reported costs per cow ranging from US $145 to US $1094 per cow with paratuberculosis. Among Canadian herds with a within-herd seroprevalence of 12.7%, the average loss was approximately CDN$50 per cow per year with 46% of the cost attributed to additional culling (Tiwari et al., 2008). A recent survey of the profitability of dairy farms in Victoria, Australia, reported that respondents who declared participation in paratuberculosis control programs made an additional net profit of $43.80 per cow per year compared with non-participants and respondents also using a vaccine gained an additional $35.84 per cow per year compared to non-users (Burden and Hall, 2021).
Reduced production of meat, wool and milk has been reported for sheep with paratuberculosis, together with increased mortality rates (Aduriz et al., 1994; Chaitaweesub et al., 1999). An average loss of $29 per sheep was reported for flocks with paratuberculosis in Australia, but some highly infected flocks demonstrated losses of $64 per sheep.
Zoonoses and Food Safety
Top of pageIt is not clear whether M. avium subsp. paratuberculosis is a human pathogen and what potential danger it may present to consumers exposed to dairy or meat products from infected animals. Several species of mycobacteria, including M. fortuitum, M. avium-intracellulare, M. cheloni and M. kansasaii, have been found in intestinal biopsy tissue from Crohn's disease patients (Chiodini, 1989). M. avium subsp. paratuberculosis has also been identified by primary isolation from intestinal tissue and by PCR analysis of DNA specific for this organism. Because the clinical symptoms of Crohn's disease closely mimic those found in animals with paratuberculosis in the late stages of disease, it has been proposed by a number of investigators that M. avium subsp. paratuberculosis may be a causative agent of this disorder in humans (Sanderson et al., 1992; Mishina et al., 1996). An up to date review of the evidence for and against the potential relationship between M. avium subsp. paratuberculosis and Crohn’s disease has been written by Duffy and Behr (2020). A recent study employing three different culture techniques, a phage assay and four antibody assays performed in separate laboratories on parallel blood samples, revealed that viable M. avium subsp. paratuberculosis bacteraemia was widespread in a significant number of humans including Crohn’s and ulcerative colitis patients, those with other autoimmune disorders and asymptomatic healthy individuals (Kuenstner et al., 2020).
The potential relationship between Crohn's disease and M. avium subsp. paratuberculosis has become an issue for the dairy industry since the publication of a report in 1994 by a group in the UK that suggested that viable M. avium subsp. paratuberculosis organisms were present in pasteurized milk purchased from retail markets (Millar et al., 1996). Studies evaluating the optimal time and temperature for heat inactivation of M. avium subsp. paratuberculosis have followed (Grant et al., 1996; Hope et al., 1996; Stabel et al., 1997; Sung and Collins, 1998; Keswani and Frank, 1998). Viable M. avium subsp. paratuberculosis has been detected in retail pasteurized milk in the USA, Brazil and Argentina (Ellingson et al, 2005; Carvalho et al., 2012; Paolicchi et al., 2012) and also in infant formula (Botsaris et al., 2016) and calf milk replacer (Grant et al., 2017).
Further concerns regarding exposure of humans to M. avium subsp. paratuberculosis have been raised by observations of viable M. avium subsp. paratuberculosis in cheese (Spahr and Schafroth, 2001; Williams and Withers, 2010); meat (Mutharia et al., 2010; Whittington et al., 2010), dust (Eisenberg et al., 2010) and water (reviewed in Gill et al., 2011).
Despite the enduring controversy on the causal etiological role of M. avium subsp. paratuberculosis in the development of Crohn’s disease in humans (BANR, 2003b) the concerns have been instrumental in the establishment of national control programmes in multiple countries including, Australia, Denmark, the Netherlands and the United States.
Disease Treatment
Top of pageAntimicrobial therapy for treatment of animals infected with M. avium subsp. paratuberculosis is not recommended unless the animal has a high genetic value. There is no cure for paratuberculosis, so drug therapy is used only to prolong the life of an infected animal and reduce clinical signs of disease. Standard antituberculosis drugs such as clofazimine, isoniazid, rifabutin, rifampin, and streptomycin have been tested both in vitro and in vivo for effects on M. avium subsp. paratuberculosis (St. Jean, 1996). Although many in vivo studies have demonstrated an improvement in clinical signs of paratuberculosis after treatment, the organism may be still be shed in the faeces. Combination therapy with two or more of the antimycobacterial agents has proven to be more effective than one compound (Rankin, 1955; Slocombe, 1982; Das et al., 1992). Treatment times are protracted and treatment may be necessary for the remainder of the animal's life. This is a significant disadvantage because the cost of therapy can range from US $1.00 to US $219.00 per animal per day, depending upon the compound used (St. Jean, 1996).
Prevention and Control
Top of pageFarm level control
The economic impact of paratuberculosis in cattle herds can be greatly minimized when suitable control programmes are followed (Thoen and Moore, 1989). Control programs should control three major critical points in disease transmission. They should prevent exposure of susceptible animals, in particular young stock, to the infectious agent. They should enable the identification and stimulate the eradication of infected animals from the herd. Finally they should prevent entry of infected animals into the herd.
These programmes involve application of recognized tests and new molecular techniques to identify and remove cattle that have subclinical disease and shed M. avium subsp. paratuberculosis. Moreover, initiating changes in management is often necessary to prevent exposure of replacement heifers to the organism. Cattle to be introduced into the herd should be free of paratuberculosis and herd replacements should originate from herds without a history of paratuberculosis. When the status of the source herd is unknown, the purchased replacements should be quarantined for 3-4 months and retested for evidence of M. avium subsp. paratuberculosis infection. Thorough cleaning and disinfecting of pens is an essential part of a control program (Rossiter, 1996; Eisenberg et al., 2011a; Garry, 2011).
Within the herd, neonates are the most susceptible group of animals to infection with M. avium subsp. paratuberculosis; therefore, one recommendation is to remove the calf from the dam immediately after birth (Whitlock et al., 1994). Because M. avium subsp. paratuberculosis is shed into the colostrum and milk of clinically infected cows, the stockperson should ensure that calves are fed uncontaminated colostrum (from test-negative animals and pasteurised) and milk replacer to prevent infection. The maternity pen is also an excellent site for neonatal exposure to contaminated faecal matter in bedding, feed and on the dam's udder. In addition M. avium subsp. paratuberculosis can be transmitted from infected to susceptible individuals via bioaerosols such as dust (Eisenberg et al., 2010; Eisenberg et al., 2011b). Separate housing of calves in separate buildings is called for to prevent bioaerosol transmission.
Segregation of infected animals from uninfected animals is a good idea at any age, and the manure of each group should be disposed of separately. A common flaw of many dairy operations is the use of the same skid loader for feeding and manure disposal (Goodger et al., 1996). Cross-contamination of feed is a major contributor to the spread of paratuberculosis, and faeces are the major source of the causative organism. Use of improperly treated manure solids to fertilize pastures on the farm is another source of M. avium subsp. paratuberculosis infection because the organism can survive in the soil for up to 1 year. Co-grazing and sequential grazing of infected with uninfected stock can also potentiate transmission. Farm level control can fail if, for example, infection is controlled in cattle but not in sheep co-grazing the same pastures where inter-species transmission can occur. Furthermore, stagnant water sources are excellent reservoirs for numerous bacteria, and M. avium subsp. paratuberculosis has been found to survive in pond water for 270 days (Lovell et al., 1944). Therefore, it is advisable to prevent access to stagnant water. Preferably, a clean water source should be provided for each age group of animals.
Control of paratuberculosis should include procedures to identify and remove adult cattle shedding M. avium subsp. paratuberculosis in faeces (Moyle, 1975). Microbial culture of faecal samples or faecal PCR should be used. Although faecal cultures can have prolonged incubation periods, these can be timed so that results are available for making management decisions. Direct faecal PCR is much quicker and cheaper. Cattle that shed organisms intermittently or in low numbers may not be identified on bacteriologic examination. The problem is further complicated because cattle in early stages of infection usually do not shed bacteria in their faeces, which is particularly important when faecal testing is used in attempts to eliminate paratuberculosis from a herd or to select replacement cattle free of disease. Therefore, recommendations are to test animals annually and make purchases based on herd level testing, not individual animal test results. This is especially true when purchasing young stock, in which infection is less likely to be identified by current testing methods. Due to M. avium subsp. paratuberculosis strain differences, care must be taken in culturing samples from small ruminant species. Culture and qPCR techniques using environmental (Raizman et al., 2004) and pooled faecal samples (Wells et al., 2002; Whittington et al., 2000) provide more economical means of detecting the disease and estimating prevalence in surveillance strategies.
Vaccines
Vaccination of calves, using a whole bacterin vaccine at less than 35 days of age is practised in several countries (Thoen and Moore, 1989; Körmendy, 1994), however banned in others due to interference with tuberculosis control programmes. In one study, the prevalence of paratuberculosis, as assessed by faecal microscopic tests, decreased from 48 to 1.4% in vaccinated cattle, whereas in non-vaccinated cattle, prevalence was maintained at about 30% (Körmendy, 1994). Others studies in vaccinated young cattle reported a decrease in number of shedder animals and the level of excretion (Jorgensen, 1984; Whipple et al., 1992). There is consensus that in vaccinated herds clinical cases markedly decrease or disappear and is therefore economically attractive despite the fact that this vaccination procedure does not prevent transmission of infection (Benedictus et al., 1988; van Schaik et al., 1996; Kalis et al., 2001). A recent survey reported seven countries using vaccination control studies (Whittington et al., 2019).
Vaccine is used in several countries for the control of paratuberculosis in sheep and goats. Vaccination performed in these species, either in young or adult animals, has been useful to eliminate clinical cases and to reduce infection (Sigurdsson, 1960; Crowther et al., 1976; Pérez et al., 1995; Saxegaard and Fodstad, 1985; Corpa et al., 2000). In experimental studies, it has been shown that vaccination modifies the pathology of infection to regressive forms (Juste et al., 1994). A vaccine trial in sheep (Reddacliff et al, 2006), demonstrated that sheep vaccinated against ovine Johne’s disease (OJD) had 90% reductions in mortality, number of animals shedding and amount of organisms shed. However, successful control requires long term vaccination (Dhand et al., 2016).
In dairy cattle a significant economic benefit was reported in the herd using vaccine (Spangler et al., 1991). Vaccination should be recommended as a means of reducing disease in herds in which the infection rate is greater than 5% based on faecal culture and/or management changes cannot be implemented. The products used for vaccination vary from killed to attenuated live organisms, with or without adjuvant. In most of the countries, the use of vaccine requires official approval from regulatory officials. Regulatory officials often require tuberculin testing of adult cattle prior to approving use of vaccine, to exclude the presence of M. bovis infection. Vaccination is not recommended in herds in which M. bovis persists. In herds in which animals have been vaccinated serologic tests are of no value in identifying M. avium subsp. paratuberculosis-infected animals (Momotani et al., 1988; Spangler et al., 1992). Skin tests also should not be used, because false-positive reactions may be observed for several months or more (Inglies and Weipers, 1963). Due to the influence vaccine has on the immune system, Johne’s diagnostics in vaccinated herds should use organism detection based tests such as culture or PCR.
The search for a vaccine that will prevent infection and transmission continues, employing new technologies to generate subunit vaccines, replication deficient delivery vectors and live attenuated vaccines (Bull, 2020).
Other recommendations for control
Other recommendations for control include (BANR, 2003a):
- Prevent introduction of disease through purchased animals
- Isolate and slaughtering clinically affected animals
- Culling most recent offspring of clinical cases as soon as possible
- Removing calves from dams immediately upon birth (before suckling)
- Isolating calves in separate calf-rearing area
- Harvesting colostrum from cows with cleaned and sanitized udders
- Feeding colostrum from test-negative cows to calves then only feed milk replacer or pasteurized milk
- Preventing the contamination of calf feedstuffs, water, or bedding by adult cow manure
- Do not apply manure to land that will be harvested for forage within the same season
Diagnostic testing can be a useful tool in controlling the spread of paratuberculosis within and between farms. A number of factors including species, estimated herd/flock prevalence, farm goals, and cost against benefit of testing, all play into the decision of whether to test and which test to use on an individual operation. Conducting a herd risk assessment and making a herd management plan are valuable practices in helping to make these decisions.
Calving pens and facilities should be properly cleaned and disinfected periodically with a cresylic or substituted cresylic disinfectant that kills M. avium subsp. paratuberculosis. This is probably the most important management change that can be readily made on most premises with little expense to the owner, but is often ignored by many producers.
In most commercial dairy herds, control of paratuberculosis can often be accomplished by changes in management. New molecular techniques provide for more rapid identification of cattle shedding M. avium subsp. paratuberculosis and subsequent removal of such cattle from the herd, but the potential for false-positive and false-negative results must be considered by the veterinarian and client. Eradication of paratuberculosis will depend on development of sensitive immunological procedures (e.g. skin tests or IFN-γ with species-specific antigens) for detecting all M. avium subsp. paratuberculosis-infected animals.
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Talatchian M, 1965. First report of Johne's disease in Iran. Bull. Off. Int. Epizoot., 64:779-782
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Tsellarius IK, 1969. Vivcenija paratuberkul'ozu velikoj rogatoj chudobi na Ukrajni [Bovine paratuberculosis in the Ukraine]. Vertinariya (Kiev), 24:31-37
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Distribution References
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Paily EP, Georgekutty PT, Venugopal K, 1979. Incidence of Johne's disease in cattle and buffaloes in livestock farms of the Kerala Agricultural University. In: Kerala J. Vet. Sci. 10 (2) 344-345.
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Ramisz A, 1970. An outbreak of Johne's disease in Krakow province (Poland). (Przypadek choroby Johnego u bydla na terenie Wojewodztwa Krakowskiego). In: Med. Weteryn. 26 203-206.
Ramos Saco T, 1953. Bovine paratuberculosis (Johne's disease or paratuberculosis enteritis), a new disease of cattle in Peru. Preliminary note. (La paratuberculosis bovis (enfermedad de Johne o enteritis paratuberculosa), nueve enfermedad halada en el ganado lechero en el Peru. Nota preliminar). In: Vida. Agric. 30 Lima, 829-830.
Talatchian M, 1965. First report of Johne's disease in Iran. In: Bull. Off. Int. Epizoot. 64 779-782.
Tsellarius IK, 1969. Bovine paratuberculosis in the Ukraine. (Vivcenija paratuberkul'ozu velikoj rogatoj chudobi na Ukrajni). In: Vertinariya (Kiev), 24 31-37.
Ubach FA, 1941. Observations on Johne's disease and coccidial enteritis in cattle, sheep and goats in the Republic of Argentina. In: Revta. Med. Vet. Buenos Aires, 23 3-45.
Vavako D, 1942. Bovine paratuberculosis enteritis in Albania. (L'enterite paratubercolare dei bovini in Albania). In: Clinica. Vet. Milano, 65 291-293.
Zamora J, Kruze J, Schifferli C, 1975. Johne's disease of sheep: first case described in Chile. In: Arch. Med. Vet. 7 (1) 15-17.
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OIE: paratuberculosis | https://www.oie.int/en/animal-health-in-the-world/animal-diseases/Paratuberculosis/ |
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