Elephant Disease Fact sheets       

Tuberculosis
Elephant Care International Fact Sheet

Susan Mikota DVM


Etiology

  • Mycobacterium tuberculosis (most cases); humans are natural reservoir

  • M. bovis; (cattle are natural reservoir

  • atypical  mycobacteria (non-tuberculous) (1 case)

 Epizootiology

  • Asian and African elephants susceptible

  • chronic, progressive, debilitating disease

 Transmission and Pathogenesis

  • aerosol transmission assumed

  • transmission from human to elephant or elephant to elephant

  • diagnosed in captive elephants in the U.S. and Europe

  •   not yet  found in free-ranging elephants

  • M.tb has been isolated from feces (coughed and swallowed)

 Clinical signs in elephants

  • clinical signs may be absent

  • weight loss,  wasting syndrome

  • lethargy

  • exercise intolerance

  • discharge from trunk

  • dyspnea

Diagnosis

  • see TB Guidelines*

  • isolation of organism by culture

  • trunk wash technique

  • intermittent shedding so  need 3 samples / test

  • new serological tests promising


Differential diagnosis

  • dental disease

  • neoplasia

  • major organ disease

 Management

  • see TB Guidelines for current Rx recommendations*

  • based on human protocols

  • expensive

 Zoonotic potential conversion on PPD (skin test)

  • possible following exposure

  • one human case of active TB documented (same strain as elephant)

  • take appropriate precautions (use personal protective equipment)

                        

 Links for general information about TB

 1. Todarís On-line Textbook of Bacteriology:

http://textbookofbacteriology.net/tuberculosis.html

 2. Medical Microbiology: http://gsbs.utmb.edu/microbook/ch033.htm

 3. WHO: http://www.who.int/tb/en/

4. Supercourse TB epidemiology lecture:

http://www.pitt.edu/~super1/lecture/lec0711/index.htm

 5. CDC: http://www.cdc.gov/nchstp/tb/tims/default.htm

 6. American Thoracic Society http://www.thoracic.org/statements/

 
* Guidelines for the Control of Tuberculosis in Elephants:

Available on the Internet at the following sites:

1.  www.aphis.usda.gov/ac/ElephTBGuidelines2003.html  (available to the public)

2.  www.aazv.org  (available to AAZV members by password)

3.  www.elephantcare.org/protoman.htm  (available to the public)

Elephant Tuberculosis References with Abstracts June 2005

Elephant Care International Bibliographic Database (www.elephantcare.org)

 

   1.   Lewerin,S.S., Olsson,S.L., Eld,K., Roken,B., Ghebremichael,S., Koivula,T., Kallenius,G., and Bolske,G. 2005. Outbreak of Mycobacterium tuberculosis infection among captive Asian elephants in a Swedish zoo. Vet Rec. 156(6):171-175.
Abstract: Between 2001 and 2003, there was an outbreak of tuberculosis in a Swedish zoo which involved elephants, giraffes, rhinoceroses and buffaloes. Cultures of trunk lavages were used to detect infected elephants, tuberculin testing was used in the giraffes and buffaloes, and tracheal lavage and tuberculin testing were used in the rhinoceroses. The bacteria isolated were investigated by spoligotyping and restriction fragment length polymorphism. Five elephants and one giraffe were found to have been infected by four different strains of Mycobacterium tuberculosis. National Veterinary Institute, SE-751 89 Uppsala, Sweden.

   2.   Maslow,J.N., Mikota,S.K., Zhu,M., Riddle,H., and Peloquin,CA. 2005. Pharmacokinetics of ethambutol (EMB) in elephants. J Vet Pharmacol Ther. 28:321-323.

   3.   Maslow,J.N., Mikota,S.K., Zhu,M., Isaza,R., Peddie,L.R., Dunker,F., Peddie,J., Riddle,H., and Peloquin,CA. 2005. Population pharmacokinetics of isoniazid in the treatment of Mycobacterium tuberculosis among Asian and African elephants (Elephas maximus and Loxodonta
africana). J Vet Pharmacol Ther. 28(1):1-7.
Abstract: We recently described the clinical presentation and treatment of 18 elephants from six herds infected with TB. Treatment protocols and methods varied between
herds to include both oral and rectal dosing using multiple drug doses and formulations. In this paper we present information regarding the pharmacokinetics (PK) of isoniazid (INH) in elephants and provide suggestions regarding initial treatment regimens. Forty-one elephants received INH daily by either oral or rectal administration with different formulations. Population PK analysis was performed using Non-linear Mixed Effect Modeling (NONMEM). Results of oral administration indicated that compared with premixed INH solution, the drug exposure was highest with a suspension prepared freshly with INH powder. When INH was concomitantly given as an admixture over food, Tmax was delayed and variability in drug absorption was significantly increased. Compared with oral administration, similar drug exposures were found when INH was dosed rectally. The data generated suggest that a starting dose of 7.5 mg/kg of INH is appropriate for initial TB treatment in elephants when premixed solution is administered directly into the oropharynx or rectal vault and 4 mg/kg are when INH is administered following immediate suspension from powdered form.  Section of Infectious Diseases, VA Medical Center, Division of Infectious Diseases, University of Pennsylvania, Philadelphia, PA, USA. jol.maslow@med.va.gov

   4.   Pandey,R. and Khuller,G.K. 2005. Antitubercular inhaled therapy: opportunities, progress and challenges. Journal of Antimicrobial Therapy 55:430-435.

      5.         Zhu,M., Maslow,J.N., Mikota,S.K., Isaza,R., Dunker,F., and Peloquin,C.A. 2005. Population pharmacokinetics of pyrazinamide in elephants. Journal of Veterinary Pharmacology and Therapeutics. Accepted for publication Dec 2004.  In press.

   6.   Guidelines for the control of tuberculosis in elephants. 2003. http://www.aphis.usda.gov/ac/TBGuidelines2003.pdf.

   7.   Chakraborty,A. 2003. Diseases of elephants (Elephas maximus) in India-A Review. Indian Wildlife Year Book 2:74-82.

   8.   Michel,A.L., Venter,L., Espie,I.W., and Coetzee,M.L. 2003. Mycobacterium tuberculosis infections in eight species at the National Zoological Gardens of South Africa, 1991-2001. Journal of Zoo and Wildlife Medicine 34(4):364-370.
Abstract: Between 1991 and 2001 a total of 12 cases of Mycobacterium tuberculosis infection in eight different species were recorded in the National Zoological Gardens of South Africa in Pretoria (Tshwane). The genetic relatedness between seven of the M. tuberculosis isolates was determined by IS6110 restriction fragment length polymorphism analysis. For the majority of the isolates that were analyzed, a high degree of polymorphism suggested different sources of infection. Evidence of M. tuberculosis transmission between animals is reported in two chimpanzees (Pan troglodytes)  housed together, from which samples were collected for analysis 29 mo apart.

   9.   Pavlik,I., Ayele,W.Y., Parmova,I., Melicharek,I., Hanzlikova,M., Svejnochova,M., and Kormendy,B. 2003. Mycobacterium tuberculosis in animal and human populations in six Central European countries during 1990-1999. Veterinarni Medicina 48(4):83-89.
Abstract:  Results of Mycobacterium tuberculosis detection in animals from six Central European countries (Croatia, the Czech Republic, Hungary, Poland, Slovakia and Slovenia) spreading over 610402 km2 with a population of 11.8 million heads of cattle were analysed. In the monitoring period between 1990 and 1999, M. tuberculosis from animals was isolated only in two countries (Poland and Slovak Republic) from 16 animals with tuberculous lesions. These comprise 9 cattle (Bos taurus), 4 domestic pigs (Sus scrofa f. domestica) and three wild animals, an African elephant (Loxodonta africana), agouti (Dasyprocta aguti) and terrestrial tapir (Tapirus terrestris) from a zoological garden Gdansk in Poland. A steady decrease in the incidence of tuberculosis in humans was recorded during the monitoring period in all countries. The human population of the study countries was 68.03 million. In the period monitored, infection caused by M. tuberculosis was identified in a total of 241040 patients with a decreasing incidence of tuberculosis found in all countries. The lowest relative bacteriologically confirmed disease was found in the Czech Republic, Slovak Republic and Slovenia. Given the low number of infected domestic and wild animals, the epidemiological and epizootiological situation may be considered auspicious.

10.   Rahman,T., 2003. Infectious and non-infectious disease of elephants. In Das,D. (Editor). Healthcare, Breeding and Management of Asian Elephants.New Delhi Project Elephant. Govt. of India, pp. 108-118.

11.   Ziccardi,M., Wong,H.N., Tell,L.A., Fritcher,D., Blanchard,J., Kilbourn,A., and Godfrey,H.P. 2003. Further optimization and validation of the antigen 85 immunoassay for diagnosing mycobacteriosis in wildlife. Proc Amer Assoc Zoo Vet, pp. 219-220.
Abstract: Mycobacteriosis caused by Mycobacterium bovis, M. tuberculosis and M. avium has been a well-documented health problem for zoological collections as long ago as the late 19th century.  Prevalence estimation in these captive wildlife populations, however, has been hampered by diagnostic test methods that are oftentimes difficult or impossible to conduct and/or interpret (due to the requirement for multiple immobilizations for measurement of response), the occurrence of non-specific results with methods such as the intradermal skin test, and/or the near-total lack of validation, optimization and standardization of any of the available test methods in the species of interest.  Additionally, because intradermal skin testing is the primary screening method for many of these species, the ability to compare exposure in captive wildlife with exposure in free-ranging populations has been limited due to the difficulty with follow-up in free-ranging populations.  Lastly, unlike testing methods that use serological techniques, skin testing precludes retrospective studies of banked samples to determine onset of reactivity.

Recently, human tuberculosis researchers working with tuberculosis in humans have developed an immunoassay that detects a serum protein complex (the antigen 85, or Ag85, complex) produced by mycobacteria in the early stages of mycobacterial infections1.  Previous work has shown that this method is a promising diagnostic tool in the evaluation of tuberculosis exposure in some primate (including orangutan (Pongo pygmaeus), a species known for non-specific tuberculin responses)2  and captive hoofstock species3.  In order to determine the feasibility and applicability of a widespread use of this method for captive and free-ranging wildlife species, we have undertaken a number of pilot studies on different populations of interest, with the goals of optimizing and validating the immunoassay through analysis of serum from known infected and non-infected individuals and through comparisons with other diagnostic methods.  Thus far, we have begun evaluating the applicability of the antigen 85 immunoassay in various avian, primate, rhinoceros and hoofstock species for detecting tuberculosis and/or paratuberculosis (Johne's disease) infections.  Preliminary results, a summary of which will be presented, indicate that this method may be a valuable adjunct to other testing methods (including gamma interferon and multiple-antigen ELISA) to allow a better evaluation of true mycobacterial status in these species.

LITERATURE CITED

1.Bentley-Hibbert, S. I., X. Quan, T. G. Newman, K. Huygen and H. P. Godfrey. 1999.  Pathophysiology of Antigen 85 in patients with active tuberculosis. Infect Immun. 67(2):581-8.
2.Kilbourn, A. M., H. P. Godfrey, R. A. Cook, P. P. Calle, E. J. Bosi, S. I. Bentley-Hibbert, K. Huygen, M. Andau, M. Ziccardi and W. B. Karesh.  2001.  Serum Antigen 85 levels in adjunct testing for active mycobacterial infections in orangutans.  J. Wildl. Dis. 37(1): 65-71.
3.Mangold, B. J., R. A. Cook, M. R. Cranfield, K. Huygen, and H. P. Godfrey.  1999.  Detection of elevated levels of circulating antigen 85 by dot immunobinding assay in captive wild animals with tuberculosis.  J. Zoo Wildl. Med. 30(4): 477-483.

12.   Chandrasekharan,K. 2002. Specific diseases of Asian elephants. Journal of Indian Veterinary Association Kerala 7(3):31-34.
Abstract: The earliest writing describing the diseases of elephants in ancient literature said to be the works on "Gajasastra" (Elephantology) written in Sanskrit by authors like Gautama, Narada, Mrigacharma, Rajaputra and Vyasa. "Hasthyayurveda" a legendary book in Sanskrit written by a safe Palakapya deals with some diseases, treatment, desirable and undesirable points of selection, management practices and some mythological aspects on the origin of elephants. The earliest book in English dealing with diseases of elephants seems to be that of W. Gilchrist "A practical treatise on the treatment of diseases of elephants" published in 1848. Later Slym (1873), Sanderson (1878), Steel (1885), Evans (1910), Herpburn (1913), Milroy (1922), Ptaff (1940), Ferrier (1947), Utoke Gale (1974), Chandrasekharan (1979) and Panicker (1985) have documented their findings on the incidence, etiology and control of diseases of Asian elephants.

13.   Mikota,S.K. and Maslow,J. 2002. Epidemiology and Treatment of Tuberculosis in Elephants: 2002. American Association of Zoo Veterinarians Annual Conference, pp. 384-387.

14.   Oh,P., Granich,R., Scott,J., Sun,B., Joseph,M., Stringfield,C., Thisdell,S., Staley,J., Workman-Malcolm,D., Borenstein,L., Lehnkering,E., Ryan,P., Soukup,J., Nitta,A., and Flood,J. 2002. Human exposure following Mycobacterium tuberculosis infection of multiple animal species in a Metropolitan Zoo. Emerg Infect Dis 8(11):1290-1293.
Abstract: From 1997 to 2000, Mycobacterium tuberculosis was diagnosed in two Asian elephants (Elephas maximus), three Rocky Mountain goats (Oreamnos americanus), and one black rhinoceros (Diceros bicornis) in the Los Angeles Zoo. DNA fingerprint patterns suggested recent transmission. An investigation found no active cases of tuberculosis in humans; however, tuberculin skin-test conversions in humans were associated with training elephants and attending an elephant necropsy.

15.   Payeur,J.B., Jarnagin,J.L., Marquardt,J.G., and Whipple,D.L. 2002. Mycobacterial isolations in captive elephants in the United States. Ann N Y Acad Sci 969:256-258.
Abstract: Interest in tuberculosis in elephants has been increasing over the past several years in the United States. Several techniques have been used to diagnose mammalian tuberculosis. Currently, the test considered most reliable for diagnosis of TB in elephants is based on the culture of respiratory secretions obtained by trunk washes.

16.   Peloquin,CA. 2002. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 62(15):2169-2183.

17.   Turenne,C., Chedore,P., Wolfe,J., Jamieson,F., May,K., and Kabani,A. 2002. Phenotypic and molecular characterization of clinical isolates of Mycobacterium elephantis from human specimens. J Clin Microbiol 40(4):1230-1236.
Abstract: Eleven strains of a rapidly growing mycobacterium were isolated from patient specimens originating from various regions of the province of Ontario, Canada, over a 2-year period. Unique high-performance liquid chromatography (HPLC) and PCR-restriction enzyme pattern analysis (PRA) profiles initially suggested a new Mycobacterium species, while sequencing of the 16S rRNA gene revealed a sequence match with Mycobacterium sp. strain MCRO 17 (GenBank accession no. X93028), an isolate determined to be unique which is to date uncharacterized, and also a close similarity to M. elephantis (GenBank accession no. AJ010747), with six base pair variations. A complete biochemical profile of these isolates revealed a species of mycobacteria with phenotypic characteristics similar to those of M. flavescens. HPLC, PRA, and 16S rRNA sequencing of strain M. elephantis DSM 44368(T) and result comparisons with the clinical isolates revealed that these strains were in fact M. elephantis, a newly described species isolated from an elephant. All strains were isolated from human samples, 10 from sputum and 1from an axillary lymph node.

18.   Clifton-Hadley,R.S., Sauter-Louis,C.M., Lugton,I.W., Jacson,R., Durr,P.A., and Wilesmith,J.W., 2001. Mycobacterial diseases. In Williams,E.S. (Editor). Infectious Diseases of Wild Mammals.Ames, Iowa Iowa State University Press, pp. 340-361.

19.   Davis,M. 2001. Mycobacterium tuberculosis risk for elephant handlers and veterinarians. Appl Occup Environ Hyg 16(3):350-353.

20.   Harr,K., Isaza,R., and Harvey,J. 2001. Clinicopathological findings in Mycobacterium tuberculosis culture-positive elephants (Elephas maximus) in comparison to clinically normal elephants. Proceedings American Association of Zoo Veterinarians, American Association of Wildlife Veterinarians, Association of Reptilian and Amphibian Veterinarians and the National Association of Zoo and Wildlife Veterinarians Joint Conference  2001, pp. 209-211.

21.   Isaza,R. 2001. The elephant trunk wash - An update. ProcElephant Mangers Association Annual Conference.

22.   Mikota,S.K., Peddie,L., Peddie,J., Isaza,R., Dunker,F., West,G., Lindsay,W., Larsen,R.S., Salman,M.D., Chatterjee,D., Payeur,J., Whipple,D., Thoen,C., Davis,D.S., Sedgwick,C., Montali,R., Ziccardi,M., and Maslow,J. 2001. Epidemiology and diagnosis of Mycobacterium tuberculosis in captive Asian elephants (Elephas maximus). Journal of Zoo and Wildlife Medicine 32(1):1-16.
Abstract: The deaths of two Asian elephants (Elephas maximus) in August 1996 led the United States Department of Agriculture to require the testing and treatment of elephants for tuberculosis. From August 1996 to September 1999. Mycobacterium tuberculosis infection was confirmed by culture in 12 of 118 elephants in six herds. Eight diagnoses were made antemortem on the basis of isolation of M. tuberculosis by culture of trunk wash samples; the remainder (including the initial two) were diagnosed postmortem. We present the case histories, epidemiologic characteristics, diagnostic test results, and therapeutic plans from these six herds. The intradermal tuberculin test, enzyme-linked immunosorbent assay serology, the blood tuberculosis test, and nucleic acid amplification and culture are compared as methods to diagnose M. tuberculosis infection in elephants.

23.   Montali,R.J., Mikota,S.K., and Cheng,L.I. 2001. Mycobacterium tuberculosis in zoo and wildlife species. Revue Scientifique et Technique Office International des Epizooties 20(1):291-303.
Abstract: Tuberculosis caused by Mycobacterium tuberculosis, and M. tuberculosis-like organisms has been identified in a wide range of species: non-human primates, exotic ungulates and carnivores, elephants, marine mammals, and psittacine birds.  Disease associated with M. tuberculosis has occurred mostly in captive settings and does not appear to  occur naturally in free-living mammals. Mycobacterium tuberculosis is probably a zooanthroponosis of humans but from the zoonotic standpoint, non-human primates, Asian elephants and psittacine birds have the  potential of transmitting this disease to humans. However, its overall prevalence in these target species has been low and documented transmissions of M. tuberculosis between animals and humans are uncommon. M. tuberculosis causes progressive pulmonary disease in mammals and a muco-cutaneous disease in parrots, and  in all cases it can disseminate and be shed into the environment. Diagnosis in living animals has been based on intradermal tuberculin testing in non-human primates, culturing trunk secretions in elephants, and biopsy and culture of external lesions in parrots.   Ancillary testing with DNA probes and nucleic acid  amplification, and enzyme-linked immunoabsorbent (ELISA) tests have been adapted to some of these species with promising results. Additionally, new guidelines for controlling tuberculosis in elephants in the U.S.,  and programs for tuberculosis prevention in animal handlers have been established.

24.   Ratanakorn,P. 2001. Elephant Health Problems and Management in Cambodia, Lao and Thailand. A Research Update on Elephants and Rhinos; Proceedings of the International Elephant and Rhino Research Symposium, Vienna, June 7-11, 2001, pp. 111-114.

25.   Larsen,R.S., Salman,M.D., Mikota,S.K., Isaza,R., Montali,R.J., and Triantis,J. 2000. Evaluation of a multiple-antigen enzyme-linked immunosorbent assay for detection of Mycobacterium tuberculosis infection in captive elephants. Journal of Zoo and Wildlife Medicine 31(3):291-302.
Abstract: Mycobacterium tuberculosis has become an important agent of disease in the captive elephant population of the United States, although current detection methods appear to be inadequate for effective disease management. This investigation sought to validate a multiple-antigen enzyme-linked immunosorbent assay (ELISA) for screening of M. tuberculosis infection in captive elephants and to document the elephant's serologic response over time using a cross-sectional observational study design. Serum samples were collected from 51 Asian elephants (Elephas maximus) and 26 African elephants (Loxodonta africana) from 16 zoos and circuses throughout the United States from February 1996 to March 1999. Infection status of each animal was determined by mycobacterial culture of trunk washes. Reactivity of each serum sample against six antigens was determined, and the linear combination of antigens that accurately predicted the infection status of the greatest number of animals was determined by discriminant analysis. The resulting classification functions were used to calculate the percentage of animals that were correctly classified (i.e., specificity and sensitivity). Of the 77 elephants sampled, 47 fit the criteria for inclusion in discriminant analysis. Of these, seven Asian elephants were considered infected; 25 Asian elephants and 15 African elephants were considered noninfected. The remaining elephants had been exposed to one or more infected animals. The specificity and sensitivity of the multiple-antigen ELISA were both 100% (91.9-100% and 54.4-100%, respectively) with 95% confidence intervals. M. bovis culture filtrate showed the highest individual antigen specificity (95%; 83.0-100%) and sensitivity (100%; 54.4-100%). Serum samples from 34 elephants were analyzed over time by the response to the culture filtrate antigen; four of these elephants were culture positive and had been used to calculate the discriminant function. Limitations such as sample size, compromised ability to ascertain each animal's true infection status, and absence of known-infected African elephants suggest that much additional research needs to be conducted regarding the use of this ELISA. However, the results indicate that this multiple-antigen ELISA would be a valuable screening test for detecting M. tuberculosis infection in elephant herds.

26.   Larsen,R.S., Salman,M.D., Mikota,S.K., Isaza,R., and Triantis,J. 2000. Validation and use of a multiple-antigen ELISA for detection of tuberculosis infections in elephants. Proc. AAZV and IAAAM Joint Conf., pp. 231-233.

27.   Lyashchenko,K., Singh,M., Colangeli,R., and Gennaro,M.L. 2000. A multi-antigen print immunoassay for the development of serological diagnosis of infectious disease. ournal of Immunological Methods 242:91-100.

28.   Mikota,S.K., Larsen,R.S., and Montali,R.J. 2000. Tuberculosis in Elephants in North America. Zoo Biology 19:393-403.
Abstract: Within the past 4 years, TB has emerged as a disease of concern in elephants. The population of elephants in North America is declining (Weise,1997), and transmissible diseases such as TB may exacerbate this trend. Guidelines for all elephants for TB, were instituted in 1997 (USDA, 1997, 2000). Between August 1996 and May 2000, Mycobacterium tuberculosis was isolated form 18 of 539 elephants in North America, indicating an estimated prevalence of 3.3%. Isolation of the TB organism by culture is the currently recommended test to establish a diagnosis of TB; however, culture requires 8 weeks. Further research is essential to validate other diagnostic tests and treatment protocols.

29.   Shojaei,H., Magee,J.G., Freeman,R., Yates,M., Horadagoda,N.U., and Goodfellow,M. 2000. Mycobacterium elephantis sp. nov., a rapidly growing non-chromogenic Mycobacterium isolated from an elephant. International Journal of Systematic and Evolutionary Microbiology 50(5):1817-1820.
Abstract: A strain isolated from a lung abscess in an elephant that died from chronic respiratory disease was found to have properties consistent with its classification in the genus Mycobacterium. An almost complete sequence of the 16S rDNA of the strain was determined following the cloning and sequencing of the amplified gene. The sequence was aligned with those available on mycobacteria and phylogenetic trees inferred by using three tree-making algorithms. The organism, which formed a distinct phyletic line within the evolutionary radiation occupied by rapidly growing mycobacteria, was readily distinguished from members of validly described species of rapidly growing mycobacteria on the basis of its mycolic acid pattern and by a number of other phenotypic features, notably its ability to grow at higher temperatures. The type strain is Mycobacterium elephantis DSM 44368T. The EMBL accession number for the 16S rDNA sequence of strain 484T is AJ010747.

30.   Ziccardi,M., Mikota,S.K., Barbiers,R.B., and Norton,T.M. 2000. Tuberculosis in zoo ungulates:Survey results and surveillance plan. Proc. AAZV and IAAAM Joint Conf., pp. 438-441.

31.   Bhat,M.N., Manickam,R., and Ramkrishna,J. 1999. Screening of captive wild animals for tuberculosis. Indian Veterinary Journal 76(11):959-961.
Abstract: The passive haemagglutination (PHA) test was used to test 109 captive elephants (Elephas maximus), and spotted deer (Cervus axis), blackbuck (Antilope cervicapra) and common langurs (Semnopithecus entellus?) (4 of each) for tuberculosis; 51 of the elephants and the 4 langurs were also assessed by the tuberculin test. PHA titres of 1:16 or 1:32 were found in 4 elephants, 1 deer and 2 langurs, but all were apparently healthy except 1 langur that had clinical signs indicative of tuberculosis. There were 4 positive reactors in the tuberculin tests, all elephants, but these animals did not have significant PHA titres. It is concluded that the procedures and reagents used for the diagnosis of tuberculosis in domestic animals are not reliable for testing wild animals.

32.   Biberstein,E.L. and Hirsch,D.C., 1999. Mycobacterium species: The agents of animal tuberculosis. In Veterinary Microbiology.Maiden, MA Blackwell Science, pp. 158-172.

33.   Isaza,R. and Ketz,C.J. 1999. A Trunk Wash Technique for the Diagnosis of Tuberculosis in Elephants. Verh.ber.Erkrg.Zootiere 39:121-124.

34.   Mangold,B.J., Cook,R.A., Cranfield,M.R., Huygen,K., and Godfrey,H.P. 1999. Detection of elevated levels of circulating antigen 85 by dot immunobinding assay in captive wild animals with tuberculosis. Journal of Zoo and Wildlife Medicine 30(4):477-483.
Abstract: Antemortem diagnosis of tuberculosis in captive wild animals is often difficult. In addition to the variability of host cellular immune response, which does not always indicate current active infection, reactivity to saprophytic or other mycobacteria is common and may interfere with the interpretation of the intradermal tuberculin skin test. Furthermore, the immobilization required for administrating the test and evaluating skin reactions in these animals may result in unacceptable levels of morbidity and mortality, of particular concern in individuals of rare or endangered species. Proteins of the antigen 85 (Ag85) complex are major secretory products of actively metabolizing mycobacteria in vitro. Production of these proteins by mycobacteria during growth in vivo could result in increases in circulating levels of Ag85 in hosts with active tuberculosis. A dot blot immunoassay has been used to detect and quantify circulating Ag85 in captive wild animals with tuberculosis. Elevated levels of Ag85 were observed in animals with active tuberculosis as compared with uninfected animals. Study populations included a herd of nyala (Tragelaphus angasi) (n=9) with no history of exposure to Mycobacterium bovis. Serum Ag85 levels ranged from <5 to 15 uU/ml (median, 5 uU/ml). The other group included 11 animals from a mixed collection with a documented history of an M. bovis outbreak. Animals with pulmonary granulomatous lesions (n=3) had serum Ag85 levels ranging from 320 to 1,280 uU/ml (median, 320 uU/ml). Animals with only chronic mediastinal or mesenteric lymphadenitis (n=4) had serum Ag85 levels ranging from <5 to 80 uU/ml (median, <5 uU/ml). This assay could provide an important adjunct to intradermal skin testing for antemortem diagnosis of tuberculosis in nondomestic species.

35.   Mikota,S.K. 1999. Diseases of the Elephant: A Review. Verh.ber.Erkrg.Zootiere 39:1-15.

36.   Anonymous. 1998. TB in elephants. Communique 18.

37.   Dunker,F. and Rudovsky,M. 1998. Management and treatment of a Mycobacterium tuberculosis positive elephant at the San Francisco Zoo.  Proceedings AAZV and AAWV Joint Conference, pp. 122-123.

38.   Mahato,G., Rahman,H., Sharma,K.K., and Pathak,S.C. 1998. Tuberculin testing in captive Indian elephants (Elephas maximus) of a national park. Indian Journal of Comparative Microbiology, Immunology and Infectious Diseases 19(1):63.
Abstract: Full text:Tuberculosis, an important zoonotic disease, has been reported in wild African and Asian domestic elephants (Seneviratna and Seneviratna, 1966). Under this communication 25 cative Indian elephants of Kaziranga National Park, Assam, were tested for allergic reaction by injecting 0.1 ml PPD at the base of ear tip. The thickness of skin was measured after 48 and 72 h and an increase of 4 mm or more was taken as positive. Out of 25 elephants tested, 3 adults were found reactors. Base of the ear was found more appropriate site as it remained protected from rubbing against hard object due to irritation caused by the tuberculin and needle. The trunk also could not disturb this inoculation site.

39.   Michalak,K., Austin,C., Diesel,S., Bacon,M.J., Zimmerman,P., and Maslow,J.N. 1998. Mycobacterium tuberculosis infection as a zoonotic disease: transmission between humans and elephants. Emerg Infect Dis 4(2):283-287.
Abstract: Between 1994 and 1996, three elephants from an exotic animal farm in Illinois died of pulmonary disease due to Mycobacterium tuberculosis. In October 1996, a fourth living elephant was culture-positive for M. tuberculosis. Twenty-two handlers at the farm were screened for tuberculosis (TB); eleven had positive reactions to intradermal injection with purified protein derivative. One had smear-negative, culture-positive active TB. DNA fingerprint comparison by IS6110 and TBN12 typing showed that the isolates from the four elephants and the handler with active TB were the same strain. This investigation indicates transmission of M. tuberculosis between humans and elephants.

40.   Montali,R.J., Spelman,L.H., Cambre,R.C., Chattergee,D., and Mikota,S.K. 1998. Factors influencing interpretation of indirect testing methods for tuberculosis in elephants. Proceedings AAZV and AAWV Joint Conference, pp. 109-112.
Abstract: Serologic and other laboratory tests (such as BTB, ELISA, and gamma interferon) are often used in conjunction with the intradermal tuberculin test to detect tuberculosis (TB) in animals.  The skin test is considered the "gold standard" in domestic cattle and humans, and the BTB test has been highly rated for use in cervid species.  However, these indirect methods for TB diagnosis have not been proven valid in most exotic species susceptible to Mycobacterium tuberculosis complex (which includes M. bovis) infection.  In addition, many of the tuberculin skin testing methods used in exotic species are not uniform in terms of tuberculin type(s) and sites used and interpretation of the end points.

41.   Binkley,M. 1997. Tuberculosis in captive elephants. Proceedings American Association of Zoo Veterinarians, pp. 116-119.

42.   Essey,M.A. and Davis,J.P. 1997. Status of the National cooperative state-federal bovine tuberculosis eradication program fiscal year 1997. Proceedings United States Animal Health Association, pp. 564.

43.   Furley,C.W. 1997. Tuberculosis in elephants. Lancet British edition 350(9072):224.
Abstract: Tests on 171 elephants in zoos and circuses in the USA revealed that 33% were positive to one or more skin tests and 11% were positive by ELISA. As there is no standard procedure for testing elephants caution should be used when interpreting the results.

44.   Maslow,J. 1997. Tuberculosis and other mycobacteria as zoonoses. Proceedings American Association of Zoo Veterinarians, pp. 110-115.
Abstract: Mycobacterial infections are common among humans.  Of theses, infection with Mycobacterium tuberculosis (TB) is the most common and of greatest concern. Non-tuberculous species of mycobacteria may also cause infections in man, especially among immunosuppressed individuals.  Human TB is typically acquired by inhalation of aerosols carrying tubercle bacilli fowwoing exposure to a person with active pulmonary infection; non-tuberculous species of mycobacteria are acquired from environmental sources.  Since zoonotic transmission of TB does occur, the identification of acid fast bacilli (AFB) in clinical specimens from animals is a cause of concern, unease, and occasionally misconception for animal care handlers and zoo personnel.

45.   Mikota,S.K. and Maslow,J. 1997. Theoretical and technical aspects of diagnostic techniques for mammalian tuberculosis. Proceedings, American Association Zoo Veterinarians, pp. 162-165.

46.   Peloquin,CA. 1997. Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clinics in Chest Medicine 18:79-97.

47.   Whipple,D.L., Meyer,R.M., Berry,D.F., Jarnagin,J.L., and Payeur,J.B. 1997. Molecular epidemiology of tuberculosis in wild white-tailed deer in michigan and elephants. Proceedings One Hundred and First Annual Meeting of the United States Animal Health Association, Louisville, Kentucky, USA, 18-24 October, 1997, pp. 543-546.

48.   Dalovision,J.R., Montenegro-James,S., Kemmerly,S.A., Genre,C.F., Chambers,R., Pankey,G.A., Failla,D.M., Haydel,K.G., Hutchinson,L., Lindley,M.F., Praba,A., Eisenach,K.D., and Cooper,E.S. 1996. Comparison of the amplified Mycobacterium tuberculosis (MTB) direct test, aplicor MTB PCR and IS6, 110-PCR for detection of MTB in respiratory specimens. Clin.Infect.Dis. 23:1099-1106.

49.   Moda,G., Daborn,C.J., Grange,J.M., and Cosivi,O. 1996. The zoonotic importance of Mycobacterium bovis. Tubercle and Lung Disease 77:103-108.
Abstract: The zoonotic importance of Mycobacterium bovis has been the subject of renewed interest in the wake of the increasing incidence of tuberculosis in the human population. This paper considers some of the conditions under which transmission of M. bovis from animals to humans occurs and reviews current information on the global distribution of the disease. The paper highlights the particular threat posed by this zoonotic disease in developing countries and lists the veterinary and human public health measures that need to be adopted if the disease is to contained. The association of tuberculosis with malnutrition and poverty has long been recognized and the need to address these basic issues as as crucial as specific measures against the disease itself.

50.   Sandin,R.L. 1996. Polymerase chain reaction and other amplification techniques in mycobacteriology. Clinical Mycobacteriology 16(3):617-639.

51.   Chandrasekharan,K., Radhakrishnan,K., Cheeran,J.V., Nair,K.N.M., and Prabhakaran,T., 1995. Review of the Incidence, Etiology and Control of Common Diseases of Asian Elephants with Special Reference to Kerala. In Daniel,J.C. (Editor). A Week with Elephants; Proceedings of the International Seminar on Asian Elephants.Bombay, India Bombay Natural History Society; Oxford University Press, pp. 439-449.
Abstract: Incidence, etiology, symptoms and control of specific and non-specific diseases of captive and wild elephants have been reviewed. Asian elephants have been observed to be susceptible to various parasitic diseases such as helminthiasis, trypanosomiasis and ectoparasitic infestations, bacterial diseases such as tetanus, tuberculosis, haemorrhagic septicemia, salmonellosis and anthrax, viral diseases such as foot and mouth disease, pox and rabies and non-specific diseases like impaction of colon, foot rot and corneal opacity. A detailed study extending over two decades on captive and wild elephants in Kerala, revealed high incidence of helminthiasis (285), ectoparasitic infestation (235), impaction of colon (169) and foot rot (125). Diseases such as trypanosomiasis (21), tetanus (8), tuberculosis (5) pox (2) and anthrax (1) were also encountered. The line of treatment against the diseases mentioned, have been discussed in detail.

52.    1994. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Respir Crit Care Med 149:1359-1374.

53.   Chandrasekharan,K., 1992. Prevalence of infectious diseases in elephants in Kerala and their treatment. In Silas,E.G., Nair,M.K., and Nirmalan,G. (Editors). The Asian Elephant: Ecology, Biology, Diseases, Conservation and Management (Proceedings of the National Symposium on the Asian Elephant held at the Kerala Agricultural University, Trichur, India, January 1989).Trichur, India Kerala Agricultural University, pp. 148-155.

54.   Fowler,M.E. 1991. Tuberculosis in zoo ungulates. Bovine tuberculosis in cervidae: Proceedings of a symposium, pp. 37-41.

55.   Ilnitskii,I.G. 1991. Chemo-tuberculin therapy in association with tissue electrophoresis in the management of patients with recently detected destructive pulmonary tuberculosis. Vrach.Delo. 0(11):59-61.

56.   John,M.C., Nedunchelliyan,S., and Raghvan,N. 1991. Tuberculin testing in Indian elephants. Indian Journal of Veterinary Medicine 11(1-2):48-49.

57.   Thoen,C.O. 1988. Tuberculosis. Journal of the American Veterinary Medical Association 193(9):1045-1048.

58.   Arora,B.M. 1986. Tuberculosis in wildlife in India. Summer Institute on Health, Production and Management in Wildlife, pp. 67-78.

59.   Snider,D.E., Jr., Jones,W.D., and Good,R.C. 1984. The usefulness of phage typing Mycobacterium tuberculosis isolates. Am.Rev.Respir.Dis. 130:1095-1099.
Abstract: Mycobacteriophage typing of Mycobacterium tuberculosis isolates was used as an epidemiologic aid in investigating the transmission of tuberculosis in community, industrial, and institutional outbreaks. The technique was also useful in other situations, e.g., documenting congenital transmission of infection and distinguishing exogenous reinfection from endogenous reactivation. Additional studies are indicated to further explore the value of phage typing for tracking the transmission of tuberculosis in the community

60.   Devine,J.E., Boever,W.J., and Miller,E. 1983. Isoniazid therapy in an Asiatic elephant (Elephas maximus). Journal of Zoo and Wildlife Medicine 14:130-133.

61.   Saunders,G. 1983. Pulmonary Mycobacterium tuberculosis infection in a circus elephant. Journal of the American Veterinary Medical Association 183(11):1311-1312.

62.   Wallach,J.D. and Boever,W.J., 1983. Tuberculosis. In Diseases of Exotic Animals. pp. 791-792.

63.   Jones,W.D., Jr. and Good,R.C. 1982. Hazel elephant redux (letter). Am.Rev.Respir.Dis. 125(2):270.
Abstract: Full text.  A recent letter from Greenberg, Jung and Gutter reported the untimely death of Hazel Elephant with Mycobacterium tuberculosis infection.  The authors concluded that the animal trainer, who was found to have cavitary tuberculosis, was probably the source of infection.  The conclusion was based on data available at the time.  The isolates from Hazel Elephant and the animal trainer were submitted to us for further study the state health departments of Louisiana and Florida.  Using the methodology and classification scheme previously described, we found that the cultures were of different phage types.  The isolate from the elephant was type A0 (7), and the isolate from the trainer was type A1 (7,13,14).  The isolates differed by lysis with one major phage (MTPH 5) and two auxiliary phages (MTPH 13 and 14). We have previously used phage typing of M. tuberculosis in several well-defined outbreaks as an adjunct to other epidemiologic procedures.  The isolates were typed without the laboratory's knowing epidemiologic relationships between cases.  The results indicated that M. tuberculosis transmitted from one individual to another retained the same phage-type characteristics.  In the present study, our phage-type results suggest that the animal trainer and the elephant were infected from two different sources and that occurrence of disease in the animal and the trainer was coincidental.  We are still evaluating page typing as a procedure for use in tuberculosis epidemiology and can accept selected cultures for phage typing in special situations if we are contacted before the cultures are submitted.

64.   Woodford,M.H. 1982. Tuberculosis in wildlife in the Ruwenzori National Park, Uganda (Part II). Trop.Anim.Hlth.Prod. 14(3):155-160.
Abstract: The results of post-mortem examinations of 90 warthog (Phacochoerus aethiopicus) conducted in the Ruwenzori National Park, Uganda during a survey of tuberculous infection in wildlife are described. Nine per cent of warthog were found to show gross lesions on autopsy and of these organisms which could by typed, Mycobacterium bovis was isolated in 2 of 6 cases and 5 atypical mycobacterial strains were isolated from the remaining 4. The distribution and character of the lesions is described and it is concluded that the route of infection in the warthog is alimentary. A mycobacterial survey of 8 other species of mammals, 7 species of birds, 5 species of fish and 1 species of amphibian is described. None of the mammals (except possibly 1 elephant), birds, fish or amphibia was harbour atypical, probably saprophytic, mycobacterial types. The origin of tuberculosis in buffalo and warthog in the Ruwenzori National Park is discussed and is concluded to have been previous contact with domestic cattle.

65.   Greenberg,H.B., Jung,R.C., and Gutter,A.E. 1981. Hazel Elephant is dead (of tuberculosis) (letter). Am.Rev.Respir.Dis. 124(3):341.
Abstract: Full text.  Hazel Elephant was only 35 years old (by our estimate) when she died.  She was cooperative and trusting to the last.  Had we known about her illness sooner, we could have saved her.  The Mycobacterium tuberculosis, var hominis that killed Hazel was sensitive to our drugs at the following levels: INH to 0.2mcg/ml; PAS to 2 mcg/ml; R to 1 mcg/ml; and MAB to 5 mcg/ml.  Hazel worked and performed for a travelling circus. Ordinarily good-humored and loving, she had been off her feed for weeks.  She became listless and apathetic, her eyes lost their sparkle, and she lacked her customary elan.  Nonetheless, Hazel continued to perform for the children and do her other chores until she came to New Orleans.  When Hazel got to New Orleans, she could barely move.  The circus's bosses called for help.  The brought her to the hospital at the Audubon Park and Zoological Garden.  As soon as we saw Hazel, we admitted her to the isolation ward.  We have her fluids, electrolytes, and antibiotics.  We got cultures and other clinical laboratory tests.  We comforted Hazel and tried to put her at ease.  It was too late.  She fell to the ground, her rheumy eyes gazed at us pitifully, her respirations failed, and she died.  Hazel's postmortem examination took six hours.  She was an emaciated Asian elephant whose lungs were filled with caseating granulomata.  Since microscopy showed myriads of acid-fast bacilli, we examined everyone who had, or who thought they had, contact with Hazel.  We found three persons with positive tuberculin skin test results.  None had tuberculous disease. Fortunately, Hazel had been kept away from other animals. Hazel's circus did not wait for the results of our autopsy.  It left Louisiana.  The U.S. Public Health Service tracked it down and found the man, an animal trainer with cavitary tuberculosis, who probably gave Hazel her fatal disease.  Now another health department will have to deal with the circus and its animals.

66.   Gutter,A. 1981. Mycobacterium tuberculosis in an Asian elephant. Proc.Am.Assoc.Zoo Vet., pp. 105-106.

67.   Mann,P.C., Bush,M., Janssen,D.L., Frank,E.S., and Montali,R.J. 1981. Clinicopathologic correlations of tuberculosis in large zoo mammals. Journal of the American Veterinary Medical Association 179(11):1123-1129.
Abstract: In August 1978, a black rhinoceros at the National Zoological Park died with generalized tuberculosis caused by Mycobacterium bovis. A 2nd black rhinoceros was euthanatized 9 months after M bovis was cultured from its lungs. After these 2 deaths, numerous large zoo mammals that had been potentially exposed were subjected to various procedures to ascertain their status regarding tuberculosis. The procedures were: intradermal tuberculin testing, evaluation of delayed hypersensitivity reaction on biopsy specimens, enzyme-linked immunosorbent assay (ELISA) testing, and culture of various secretions and organs. Several of the animals in this series died during the study. These were necropsied and examined for evidence of mycobacterial infection. The results of tuberculin testing varied from species to species and from site to site within a species. Delayed hypersensitivity responses generally correlated well with the amount of swelling at the tuberculin site. In some cases, however, positive reactions were found without any delayed hypersensitivity response. Results of ELISA testing were confirmatory in tuberculous animals. Several species were judged to be nonspecific reactors, based on positive or suspect tuberculin test results, with negative ELISA results and necropsy findings.

68.   Thoen,C.O. and Himes,E.M., 1981. Tuberculosis. In Davis,J.W., Karstad,L.H., and Trainer,D.O. (Editors). Infectious diseases of wild mammals.Ames, Iowa The University of Iowa Press.

69.   Thoen,C.O., Mills,K., and Hopkins,M.P. 1980. Enzyme linked protein A: An enzyme-linked immunosorbent assay reagent for detecting antibodies in tuberculous exotic animals. American Journal of Veterinary Research 41(5):833-835.
Abstract: An enzyme-linked immunosorbent assay (ELISA) was developed, using protein A labeled with horseradish peroxidase for detecting antibodies in tuberculous exotic animals (llamas, rhinoceroses, elephants).  The modified ELISA provides a rapid procedure for screening several animal species simultaneously for tuberculosis without the production of specific anti-species conjugates.  Heat-killed cells of Mycobacterium bovis and M. avium and purified protein-derivative tuberculin of M. bovis were used as antigens for ELISA.

70.   Thoen,C.O. and Himes,E.M., 1980. Mycobacterial infections in exotic animals. In Montali,R.J. and Migaki,G. (Editors). The comparative pathology of zoo animals.Washington,D.C. Smithsonian Institution Press, pp. 241-245.
Abstract:  Mycobacteria were isolated from 59% of the 826 specimens submitted from exotic animals suspected of having tuberculosis.  Mycobacterium bovis and Mycobacterium tuberculosis accounted for 61% of the isolations from nonhuman primates.  Mycobacterium bovis was the organism most frequently isolated from hoofed animals and Mycobacterium avium was most commonly isolated from birds.  The distribution, pathogenesis, diagnosis, and control of tuberculosis in exotic animals is discussed.

71.   Chandrasekharan,K. 1979. Common diseases of elephants. State Level Workshop on Elephants, pp. 51-61.

72.   Thoen,C.O., Richards,W.D., and Jarnagin,J.L. 1977. Mycobacteria isolated from exotic animals. Journal of the American Veterinary Medical Association 170(9):987-990.

73.   von Benten,K., Fiedler,H.H., Schmidt,U., Schultz,L.C., Hahn,G., and Dittrich,L. 1975. Occurrence of tuberculosis in zoo mammals; a critical evaluation of autopsy material from 1970 to the beginning of 1974. Deutsche Tierarztliche Wochenschrift 82(8):316-318.

74.   Pinto,M.R.M., Jainudeen,M.R., and Panabokke,R.G. 1973. Tuberculosis in a domesticated Asiatic elephant Elephas maximus. Veterinary Record 93(26):662-664.
Abstract: A case of tuberculosis in a domesticated Asiatic elephant, Elephas maximus, was diagnosed on post-mortem examination.  The causal organism was identified as Mycobacterium tuberculosis var hominis on the basis of cultural, biochemical and virulence studies.  Microscopically, the lesions resembled tuberculous lesions as seen in man and other domestic animals, but an important difference was the apparent absence of Langerhan's type giant cells.  The problems associated with the clinical diagnosis of tuberculosis in the elephant are discussed.

75.   Gorovitz,C. 1969. Tuberculosis in an African elephant. American Association of Zoo Veterinarians Newsletter January 20.

76.   Seneviratna,P., Wettimuny,S.G., and Seneviratna,D. 1966. Fatal tuberculosis pneumonia in an elephant. Veterinary Medicine Small Animal Clinician 60:129-132.
Abstract: A fatal case of tuberculosis pneumonia with anemia and helminthiasis in a Ceylon elephant is reported. Acid-fast organisms resembling Mycobacterium tuberculosis and tubercular nodules were seen in large numbers in sections of the lung.

77.   Gorovitz,C. 1962. Tuberculosis in an African elephant. Nord Vet Med 14(Supl 1):351-352.

78.   Halloran,P.O. 1955. A bibliography of references to diseases in wild mammals and birds. American Journal of Veterinary Research 16(part 2):161.

79.   Curasson,G., 1942. Traite de pathologie exotique veterinaire et comparee. Vigot Freres, Paris.

80.   Griffith,A.S. 1939. Infections of wild animals with tubercle and other acid-fast bacilli. Proceedings of the Royal Society of Medicine 32:1405-1412.

81.   Urbain,A. 1938. Tuberculosis in wild animals in captivity. Annales de L'Institute Pasteur 61:705-730.

82.   Winogradradsky,S. 1938. La microbiologie ecologique ses principes - son procede. Annales de L'Institute Pasteur 64(6):715-730.

83.   Iyer,A.K. 1937. Veterinary science in India, ancient and modern with special reference to tuberculosis. Agric.Livest.India 7:718-724.

84.   Curasson,G., 1936. Treatise on the pathology of exotic animals. Vigot Freres, Paris.

85.   Datta,S.C.A. 1934. Report of the pathology section. Ann.Rep.Imp.Inst.Vet.Research Muktesar:25-33.

86.   Baldrey,F.S.H. 1930.  Tuberculosis in an elephant. J.R.Army Vet.Corp. 1:252.

87.   Bopayya,A.B. 1928. Tuberculosis in an elephant. Indian Veterinary Journal 5:142-145.

88.   Narayanan,R.S. 1925. A case of tuberculosis in an elephant. Journal of Comparative Pathology 38:96-97.

89.   Thieringer,H. 1911. About tuberculosis in an elephant. Berl.Tierarztl.Wschr. 27:234-235.

90.   Damman and Stedefeder. 1909. Tuberculosis diseases in elephants with human type mycobacterium. Deutsche Tierarztliche Wochenschrift 17:345.

91.   Garrod,A.H. 1875. Report on the Indian elephant which died in the society's gardens on July 7th, 1875. Procedings of the Zoological Society of London 1875:542-543.

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