Abstract
History of Tuberculosis Treatment Guidelines and Working Group
Tuberculosis (TB) “emerged” as a disease of concern for captive elephants in 1996 when two privately owned elephants died due to Mycobacterium tuberculosis (M. tuberculosis). Following these deaths, an Elephant TB Advisory Panel was formed to develop a diagnostic and treatment plan for the remaining 18 elephants in this herd. The diagnosis of M. tuberculosis in five additional elephants in 1996 and 19971 raised concerns that the disease might be more prevalent in the captive population than suggested by a retrospective study of elephants compiled from available current and historic records in North American zoos.7 The latter review, published in 1994, had noted only eight deaths from TB among 379 elephants for a prevalence of 2.1%.
The Elephant TB Advisory Panel (comprised of veterinarians from the zoo and academic communities and the United States Department of Agriculture, APHIS, Veterinary Services), together with the National Tuberculosis Working Group for Zoo and Wildlife Species (formed in 1997 primarily to address tuberculosis in non-domestic hoofstock) subsequently developed recommendations to address the issue of TB in elephants. “Guidelines for the Control of Tuberculosis in Elephants” served as the basis for Policy #21, “Control of Tuberculosis in Regulated Elephants,” issued by APHIS in April 1998 under the Animal Welfare Act (AWA).13 With knowledge gained from the index elephant herd and eight additional elephant TB cases, diagnosed between 1998–1999, the group revised the guidelines in 2000.12 Recent cases of tuberculosis resistant to the first-line anti-tuberculous drugs prompted a reanalysis of the guidelines. The group was reconvened in January 2002, and new guidelines were formulated.14 This paper will discuss the new guidelines formulated to continue the goal to eradicate TB from elephants and to limit the emergence of drug-resistant strains of M. tuberculosis in elephants.
The guidelines specify criteria for the testing, surveillance, and treatment of elephants for TB. Annual testing of all elephants by culture is required. Based on current data, while intradermal tuberculin testing and ELISA have been evaluated as diagnostic techniques,3,5,8 sputum culture is considered the current gold standard.6 Because mycobacterial numbers may markedly differ in individual samples of sputum as a result of differences in techniques and/or temporal variations in shedding, a series of three sputa must be submitted. Samples for culture should be collected using the trunk wash technique.2 Samples collected on culture swabs are not adequate. Despite current limitations, the submission of samples for ancillary tests listed in the protocol is strongly recommended to assist in the development of ancillary testing methods.
According to the guidelines, elephants are placed in one of four groups based on culture results and exposure history. Included are recommendations on monitoring, treatment, and restrictions on travel. For treatment, the guidelines have been patterned after protocols known to be effective in humans.10,11 To ensure adequate absorption, tuberculosis treatment regimens include mandatory testing for serum drug levels. Blood levels comparable to those in humans9 can be achieved in elephants with all first-line anti-tuberculosis drugs isoniazid (INH), rifampin, pyrazinamide, and ethambutol (Mikota et al., 2001; Maslow, unpublished). To date, no idiosyncratic reactions have been observed in elephants. Adverse effects have included inanition, INH and rifampin-related hepatitis, and INH-related neutropenia (observed in one elephant).
“Guidelines for the Control of Tuberculosis in Elephants—2002” can be accessed at the following websites: www.aazv.org, www.aphis.usda.gov/aphis/banner/help (VIN editor: Original link was modified as of 2-23-21), and elephantcare.org (VIN editor: Original link was modified as of 2-23-21).
Prevalence of TB Among Elephants Regulated in America
Between 1996 and April 2002, 26 confirmed cases of tuberculosis (including the seven initial cases above) have been diagnosed in elephants in North America among 539 animals tested for a prevalence of 4.8%. Mycobacterium tuberculosis was isolated from 23 female and two male Asian elephants (Elephas maximus), and M. bovis was isolated from one female African elephant (Loxodonta africana). Six zoological (AZA-accredited) and seven private (non-AZA-accredited) facilities were affected.
Ten of the 26 infected animals have died. Six animals died with extensive pulmonary and/or visceral disease, two had localized pulmonary disease associated with fibrosis, and two had disease isolated to a single lymph node that was diagnosed incidentally at necropsy.
Human Health Considerations
Transmission of TB between an elephant and a human has been reported.4 While animal-to-human transmission was suspected, this was not confirmed. In this report, three handlers were documented as converting from skin-test negative to positive.
In general, handlers in close daily contact with infected elephants would be at greatest risk. However, since elephants may be at risk of contracting TB from infected humans, handlers and others in close contact with elephants should undergo periodic skin testing to minimize risks to elephant health.
To minimize potential aerosol exposures, handlers should wear HEPA filtered masks when in proximity (<30 feet) to known positive animals and during procedures that generate significant aerosolized sputa with herds with a prior history of TB disease or exposure. Animals should be maintained in well-ventilated areas to minimize risk to humans and other animals. Other infection control procedures used in hospitals, such as HEPA filtration of air from the containment barns and installation of UV lights, have not been tested but are considerations. Use of gowns, gloves, and protective footwear is recommended to prevent skin and/or mucous membrane contamination and to prevent spread to other animal quarters.
Critical Issues
Of great concern is the recent identification of antibiotic-resistant strains of M. tuberculosis isolated from elephants. To date, the isolates from four animals have been confirmed as resistant to INH (one animal), rifampin (one animal), or both INH and streptomycin (two animals). To address this fact, treatment regimens are constructed of at least three or four agents to which the strains are susceptible. To minimize future emergence of resistant strains, drug concentration monitoring is mandated.
Based on the observation that four animals had isolated disease, it seems likely that the pathogenesis of TB for elephants is similar to humans: initial exposure with subclinical disease for most and reactivation in a minority of animals. Moreover, intermittent shedding appears to occur based on necropsy data and clinical experience in at least two animals. Therefore, the development of ancillary tests to identify latently infected animals is crucial. Latently infected animals can then be treated prior to the development of clinical disease and thus prevent spread to humans and other animals. Such a strategy would maximize human contact for elephants with public exposure.
To date, there have been no documented or suspected cases of TB transmission from elephants to the general public. To minimize potential spread to the public, culture-positive animals are restricted from travel during the period of antibiotic treatment and 6 months thereafter. Animals exposed to a known case are also restricted from travel during evaluation and the early stages of treatment. Exposed animals are administered prophylactic antibiotics to treat potential, undiagnosed latent infection; antibiotic choices are based on susceptibilities of the index case.
Conclusions
Tuberculosis in elephants is a significant problem but is not epidemic. Antemortem diagnosis continues to be challenging. Although identification of M. tuberculosis or M. bovis definitively establishes the presence of infection, failure to isolate the organism does not rule out infection. Annual testing remains essential. Better diagnostic tests are needed. Preliminary ELISA results are promising. The cooperation of the zoo community to provide samples for this and other ancillary diagnostic tests will facilitate this research effort.
Long-term monitoring of affected individuals and exposed herds is essential for determining the success of TB treatment in elephants. It is possible to administer anti-tuberculosis drugs that achieve blood levels consistent with human therapeutic levels; however, the long-term efficacy of current treatment protocols remains to be documented.
All elephants that die should receive a thorough postmortem examination. A search for TB lesions should be conducted, even if the disease is not suspected. The Elephant Necropsy Protocol (available on the above websites) outlines appropriate samples to submit for laboratory evaluation. In cases of euthanasia, a diagnostic workup for TB (including ancillary tests as outlined in the guidelines) should be performed premortem so that results can be correlated with postmortem findings.
Literature Cited
1. Binkley, M. 1997. Tuberculosis in captive elephants. Proc. Am. Assoc. Zoo Vet.
2. Isaza, R., and C. Ketz. 1999. Proc. 39th International Symposium of European Zoo and Wildlife Medicine.
3. Larsen, R. S., M. D. Salman, S. K. Mikota, R. Isaza, R. J. Montali, and J. Triantis. 2000. Evaluation of a multiple-antigen enzyme-linked immunosorbent assay (ELISA) for detection of Mycobacterium tuberculosis in captive elephants. J. Zoo Wildl. Med. 31:291–302.
4. Michalak, K., C. Austin, S. Diesel, J. M. Bacon, P. Zimmerman, and J. N. Maslow. 1998. Mycobacterium tuberculosis infection as a zoonotic disease: transmission between humans and elephants. Emerg. Infect. Dis. 4:283–287.
5. Mikota, S. K., R. S. Larsen, and R. J. Montali. 2000. Tuberculosis in elephants in North America. Zoo Biol. 19:393–403.
6. Mikota, S. K., L. Peddie, J. Peddie, R. Isaza, F. Dunker, G. West, W. Lindsay, S. Larsen, M. Salman, D. Chatterjee, J. Payeur, D. Whipple, C. Thoen, D. S. Davis, C. Sedgwick, R. J. Montali, M. Ziccardi, and J. N. Maslow. 2001. Epidemiology and diagnosis of Mycobacterium tuberculosis in captive Asian elephants (Elephas maximus). J. Zoo Wildl. Med. 32:1–16.
7. Mikota, S. K., E. L. Sargent, and G. Ranglack, S. 1994. Medical Management of the Elephant. Indira Publishing House, West Bloomfield.
8. Montali, R. J., L. H. Spelman, R. J. Cambre, D. Chatterjee, and S. K. Mikota. 1999. Presented at the Proc. Amer. Assoc. Zoo Vet.
9. Peloquin, C. A. 1997. Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin. Chest Med. 18:79–87.
10. American Thoracic Society. 2000. Diagnostic standards and classification of tuberculosis in adults and children. Am. J. Respir. Crit. Care Med. 161:1376–1395.
11. American Thoracic Society. 1994. Treatment of tuberculosis and tuberculosis infection in adults and children. Am. J. Respir. Crit. Care Med. 149:1359–1374.
12. National Tuberculosis Working Group for Zoo and Wildlife Species. 2000. Guidelines for the control of tuberculosis in elephants, United States Department of Agriculture, Animal and Plant Inspection Service, Animal Care Policies ed.
13. National Tuberculosis Working Group for Zoo and Wildlife Species. 1998. Guidelines for the control of tuberculosis in elephants, vol. policy #21.
14. National Tuberculosis Working Group for Zoo and Wildlife Species. 2002. Guidelines for the control of tuberculosis in elephants, United States Department of Agriculture, Animal and Plant Inspection Service, Animal Care Policies ed, vol. policy #21.