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Feline Mycobacterial Disease: Determining Which Bug Really Matters

Feline mycobacterioses present veterinary practitioners with a conundrum. An overlap in the clinical presentation of disease, regardless of which species of mycobacteria is involved, can make definitive diagnosis challenging. Since different species of mycobacteria vary in terms of the zoonotic risk they carry, as well as optimal antibiotic treatment selection and prognosis, accurate diagnosis and species discrimination are fundamental clinical priorities.

Feline Mycobacteriosis—Some Key Players

Mycobacterial infections in cats are increasingly recognized throughout many parts of the world, including the United States.1 Mycobacteria can be divided into two groups: the non-tuberculous mycobacteria (NTM) and the Mycobacterium tuberculosis complex, which includes the causative agents of tuberculosis (TB) in cats such as Mycobacterium bovis and Mycobacterium microti.2,3 Another type of mycobacteria is Mycobacterium lepraemurium, which causes the feline leprosy syndrome.4


Mycobacterium avium complex (MAC) is a group of slow-growing mycobacteria that cause opportunistic infections.5 Mycobacterium avium complex infection is the most frequently confirmed NTM infection in companion animals, and the third most common mycobacterial species detected in cats in the UK, following M. microti and M. bovis.3 A recent study by Munro et al looking at mycobacterial infections in cats in northern California reported that the most common rapid-growing (in culture) mycobacterial species included M. smegmatis and M. fortuitum as well as MAC infections.1 Cats seem to be at higher risk for NTM than other species and some breeds such as the Siamese, Abyssinian, and Somali might be predisposed to MAC infections.6

Unlike in humans, where HIV co-infection is an important risk factor for developing active TB, co-infection of mycobacteria and immunodeficiency viruses such as feline leukemia virus and feline immunodeficiency virus is rare in cats, but it has been reported.1 Administration of immunosuppressive drugs could also predispose cats to mycobacterial infections and recently a disseminated MAC infection was reported in a cat on long-term therapy with cyclosporine.3,7

Clinical Presentation

M. avium is more pathogenic than other NTM, and has been associated with cutaneous lesions, ocular involvement (Figure 1), generalized lymph node and pulmonary involvement, gastrointestinal disease, and disseminated disease. Granulomatous panniculitis, which can present as subcutaneous nodules with multiple draining tracts and large areas of ulcerated, non-healing tissue, is most commonly associated with rapid-growing species such as M. fortuitum and M. smegmatis, and Mycobacterium chelonae.


There can be an overlap in the clinical presentation of feline mycobacteriosis, regardless of which species of mycobacteria is involved, which can make obtaining a definitive etiological diagnosis challenging. Hematological and serum biochemistry changes, if present, are non-specific and vary with the severity of disease; hypercalcemia may be identified and appears to correlate with extensive or disseminated granulomatous disease.3 Radiography is useful for identifying lung involvement; however, changes can be variable and include lymphadenopathy, interstitial or miliary lung infiltration, localized lung consolidation, or pleural effusion (Figure 2). Bone lesions tend to consist of areas of bony lysis. CT imaging has higher sensitivity for detection of lung changes. Abdominal ultrasonography may show hepato- or splenomegaly (and structural changes in the spleen; Figure 3), abdominal masses, mineralized mesenteric lymph nodes, and/or ascites.

Figure 1. Cutaneous and ocular lesions in a cat with M. avium infection. Image courtesy of Petra Černá.
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B
Figure 2. Lateral (A) and ventrodorsal (B) thoracic radiographs showing a moderate to severe bronchial pattern, patchy interstitial regions, and pleural effusion in a cat with Mycobacterium avium complex infection. Images courtesy of Petra Černá.
Figure 3. Abdominal ultrasound examination revealing numerous hypoechoic nodules in the spleen of a cat with Mycobacterium avium complex infection. Image courtesy of Petra Černá.
Cytological and histological samples show granulomatous to pyogranulomatous inflammation, predominated by macrophages, which may be foamy in appearance. Necrosis may also be present.8 Additional tests are described in the section below on diagnostics.

Mycobacterium species Diagnostics

Since different species of mycobacteria vary in terms of the zoonotic risk they carry, as well as optimal antibiotic treatment selection and prognosis, accurate diagnosis and species discrimination are important. Unfortunately, diagnosis of mycobacterial infections is always challenging. This is because many of the mycobacteria do not grow in culture; the ones that do grow, with the exception of rapid-growing species, can take weeks to months to be identified. Moreover, molecular diagnostics are not always available and can be very expensive.

Specific tests:

  • The interferon-gamma (IFNγ) release assay, adapted for use in cats from cattle and humans, is a highly sensitive immunological test for Mycobacterium tuberculosis complex infections, although it is limited in its ability to diagnose and discriminate between infections with NTM, and is currently not available in the United States.9
  • Unlike other species, cats do not react strongly to intradermally administered tuberculin and the results from intradermal skin testing are not reliable.10

Identification of Mycobacteria

  1. Fine-needle aspiration and/or biopsy provide samples for histopathology and cytology. Histopathology is frequently the first-line diagnostic investigation for suspected mycobacterial cases, and most often performed on either an incisional or excisional biopsy sample of any non-healing skin lesions, abscesses that do not or only partially respond to antibiotic therapy, and/or enlarged peripheral lymph nodes. Histopathology typically reveals granulomatous inflammation, with foamy macrophages containing variable numbers of acid-fast bacteria. Romanowsky-stained cytology samples may show macrophages containing negatively stained organisms (Figure 4A). Ziehl–Neelsen (ZN) staining (Figure 4B) may be used to confirm the presence of acid-fast bacilli; however, approximately two-thirds of biopsy specimens from cats with histopathological changes indicative of mycobacterial infection are negative on ZN staining.11 Therefore, a negative ZN stain cannot be used to rule out feline mycobacteriosis.
  2. Culture is needed to determine which species of mycobacterium is involved. However, approximately half of samples fail to grow3 and it can take more than three months for colonies of some mycobacterial species to be identified (e.g., M. microti).12 Members of the Mycobacterium avium complex despite being slow-growing can often be detected on culture. Antibiotic susceptibility testing can be also performed at specialized laboratories, such as Colorado State University’s Veterinary Diagnostic Laboratories, which offer culture and antibiotic susceptibility for Mycobacterium species (see ‘More information’ below).
  3. Molecular PCR techniques can identify mycobacterial DNA and may allow speciation.13 Fresh or fresh-frozen tissue is better for PCR, as formalin-fixed, paraffin-embedded tissue samples have poor sensitivity in comparison.14
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Figure 4: Samples collected by fine-needle aspiration from a soft tissue mass of cat. (A) May-Grünwald-Giemsa staining: note the presence of negative-staining linear to comma-shaped microorganisms (arrows) within macrophages. (B) Ziehl-Neelsen staining: the microorganisms were positive for acid-fast staining (arrows), confirming the suspicion of Mycobacterium species. Pictures were taken using a 100× oil objective for a total magnification of 1000×. Images courtesy of Petra Černá.

Correct Handling of Biopsy/Aspirate Material

For any case where mycobacterial disease is suspected, wear gloves and use routine aseptic practices when handling the biopsy material and the biopsy site.

  1. Biopsy material should be cut into two or three pieces, with one submitted for histological examination and the rest frozen for further testing (culture, PCR), if required.
    • Ship overnight on ice to the laboratory for PCR and culture.
  2. Fine-needle aspirates should be collected for cytological analysis as well as for additional diagnostics (culture, PCR), if needed.
    • Flush the needle hub with sterile saline and empty into a sterile tube (e.g., red top tube) for PCR and culture. Store in a refrigerator or freezer if not being submitted immediately.
    • Ship overnight on ice to the laboratory for PCR and culture.

Treatment of Mycobacterial Infections

Correct diagnosis of mycobacterial infections is a prerequisite for determining appropriate treatment, which in most cases involves antimicrobial therapy for several months. Culture and susceptibility testing is useful to identify the right antimicrobials for treatment; however, in the above-mentioned study by Munro et al on cats in northern California, susceptibility to prescribed antimicrobials did not appear to guarantee treatment success.1

Recommended doses and possible side effects of antibiotics for treatment of mycobacterial infections are listed in Table 1. Pradofloxacin is usually recommended as it is more effective against mycobacteria than other fluoroquinolones, such as marbofloxacin.15 With more extensive disease, triple antimicrobial therapy is advised, as more than one drug generally gives the best chance of clinical resolution and decreases the potential for development of antimicrobial resistance. Antimicrobial resistance can be a particular problem when treating TB or MAC infections. Triple drug antimicrobial therapy should be continued for four to six months, depending on the extent of disease, and always for at least two months following complete resolution of the lesions.

In humans, the first-line treatment for TB consists of combinations of rifampicin, isoniazid, ethambutol, dihydrostreptomycin, and pyrazinamide; however, most of these drugs are very toxic to cats.

MAC infections in cats are particularly difficult to treat and fluoroquinolones generally have poorer efficacy for these mycobacteria.6 In cases where resistance develops, replacing either pradofloxacin or azithromycin with ethambutol may work, although toxicity can be severe.16 For resistant and extensive disease, two or three drug combinations of clarithromycin, rifampicin, ethambutol, clofazimine, or amikacin can be considered.17 Surgical excision of small cutaneous lesions can be considered in some patients; however, debulking of larger lesions risks wound dehiscence and local recurrence of infection.

Table 1: Potentially useful drugs for the treatment of feline mycobacterial disease. Adapted, with permission, from Gunn-Moore (2014).10
CNS = central nervous system; GI = gastrointestinal; IM = intramuscularly; IV = intravenously; NTM = non-tuberculous mycobacteria; PO = orally; SC = subcutaneously

Prognosis

The prognosis depends on the type of mycobacteria involved, and the extent and severity of the infection; it is also influenced by the appropriate length of treatment. In a retrospective study of 184 cats with mycobacterial infection, approximately 40% of cats achieved cure or long-term remission but around 60% responded temporarily or poorly to treatment or did not respond at all; notably, many cats in this study were treated suboptimally, with few receiving more than one drug, many receiving inappropriate antibiotics (e.g., β-lactam drugs) and around 60% of cats being treated for less than one month.8

Disease due to NTM has a more variable prognosis, which is very dependent on the extent of disease and the specific mycobacteria involved.18 Systemic disease caused by M. avium and extensive granulomatous panniculitis caused by mycobacteria are typically difficult to treat.19 Munro et al’s study looking at cats infected with rapid-growing mycobacteria species reported death or euthanasia in 3/ 4 M. avium cases, and only 4/12 cats with rapid-growing mycobacteria species where follow-up was available achieved remission.1 However, if the disease is diagnosed early and treated appropriately, cats can achieve full remission.

Zoonotic Risk

The perceived zoonotic risk of feline mycobacterial infections is often low, with only few recorded cases of feline-to-human transmission of M. bovis. 20 The common feature in each of these cases was purulent draining lesions. Zoonotic transmission of the other major causes of feline mycobacteriosis, namely M. microti and M. avium, has not been identified.

Conclusion

Mycobacterial infections in cats are increasingly recognized throughout many parts of the world, including the United States, and can present both diagnostic and treatment challenges. Correct diagnosis is required for appropriate treatment, which in most cases requires triple antimicrobial therapy for several months. The prognosis for cats with mycobacteriosis depends on the mycobacterial species involved, the extent and severity of the infection, as well as compliance with the appropriate length of treatment.

More information can be found here.

References

  1. Munro MJ, Byrne BA and Sykes JE. Feline mycobacterial disease in northern California: Epidemiology, clinical features, and antimicrobial susceptibility. J Vet Intern Med 2021; 35: 273–283. DOI: 10.1111/jvim.16013.

  2. O’Halloran C and Gunn‐Moore D. Mycobacteria in cats: An update. In Practice 2017; 39: 399–406. DOI: 10.1136/inp.j4155.

  3. Gunn-Moore DA, McFarland SE, Brewer JI, et al. Mycobacterial disease in cats in Great Britain: I. Culture results, geographical distribution and clinical presentation of 339 cases. J Feline Med Surg 2011; 13: 934–944. DOI: 10.1016/j.jfms.2011.07.012.

  4. O’Brien CR, Malik R, Globan M,et al. Feline leprosy due to Mycobacterium lepraemurium: Further clinical and molecular characterisation of 23 previously reported cases and an additional 42 cases. J Feline Med Surg 2017; 19: 737–746. DOI: 10.1177/1098612X17706469.

  5. Gunn‐Moore D, Jenkins P and Lucke V. Feline tuberculosis: A literature review and discussion of 19 cases caused by an unusual mycobacterial variant. Vet Rec 1996; 138: 53–58. DOI: 10.1136/vr.138.3.53.

  6. Jordan H, Cohn L and Armstrong P. Disseminated Mycobacterium avium complex infection in three Siamese cats. J Am Vet Med Assoc 1994; 204: 90–93.

  7. Webster J, Marchesi F, Gunn-Moore D, et al. Disseminated Mycobacterium avium infection in a cat on long-term ciclosporin therapy and potential latent infection of an in-contact cat. JFMS Open Rep 2022; 8. DOI: 10.1177/20551169221109442.

  8. Gunn-Moore DA, McFarland SE, Schock A, et al. Mycobacterial disease in a population of 339 cats in Great Britain: II. Histopathology of 225 cases, and treatment and outcome of 184 cases. J Feline Med Surg 2011; 13: 945–952. DOI: 10.1016/j.jfms.2011.09.009.

  9. Rhodes SG, Gunn-Moore D, Boschiroli ML, et al. Comparative study of IFNγ and antibody tests for feline tuberculosis. Vet Immunol Immunopathol 2011; 144: 129–134. DOI: 10.1016/j.vetimm.2011.07.020.

  10. Gunn-Moore DA. Feline mycobacterial infections. Vet J. 2014; 201: 230–238. DOI: 10.1016/j.tvjl.2014.02.014.

  11. Gunn‐Moore D, Gaunt C and Shaw D. Incidence of mycobacterial infections in cats in Great Britain: Estimate from feline tissue samples submitted to diagnostic laboratories. Transbound Emerg Dis 2013; 60: 338–344. DOI: 10.1111/j.1865-1682.2012.01352.x.

  12. Smith N, Crawshaw T, Parry J, et al. Mycobacterium microti: more diverse than previously thought. J Clin Microbiol 2009; 47: 2551–2559. DOI: 10.1128/JCM.00638-09.

  13. Aranaz A, Liébana E, Pickering X, et al. Use of polymerase chain reaction in the diagnosis of tuberculosis in cats and dogs. Vet Rec 1996; 138: 276–280. DOI: 10.1136/vr.138.12.276.

  14. Reppas G, Fyfe J, Foster S, et al. Detection and identification of mycobacteria in fixed stained smears and formalin‐fixed paraffin‐embedded tissues using PCR. J Small Anim Pract 2013; 54: 638–646. DOI: 10.1111/jsap.12149.

  15. Govendir M, Norris J, Hansen T, et al. Susceptibility of rapidly growing mycobacteria and Nocardia isolates from cats and dogs to pradofloxacin. Vet Microbiol 2011; 153: 240–245. DOI: 10.1016/j.vetmic.2011.06.001.

  16. Gunn-Moore D, Dean R and Shaw S. Mycobacterial infections in cats and dogs. In Practice 2010; 32: 444–452. DOI: 10.1136/inp.c5313.

  17. Baral RM, Metcalfe SS, Krockenberger MB, et al. Disseminated Mycobacterium avium infection in young cats: overrepresentation of Abyssinian cats. J Feline Med Surg 2006; 8: 23–24. DOI: 10.1016/j.jfms.2005.06.004.

  18. Horne KS and Kunkle GA. Clinical outcome of cutaneous rapidly growing mycobacterial infections in cats in the south-eastern United States: a review of 10 cases (1996–2006). J Feline Med Surg 2009; 11: 627–632. DOI: 10.1016/j.jfms.2008.10.008.

  19. Malik R, Hunt G, Goldsmid S, et al. Diagnosis and treatment of pyogranulomatous panniculitis due to Mycobacterium smegmatis in cats. J Small Anim Pract 1994; 35: 524–530. DOI: 10.1111/j.1748-5827.1994.tb03806.x.

  20. Gunn-Moore DA and Lalor S. Tuberculosis in companion animal species. In: Mukundan H, Chambers MA, Waters WR, et al. Tuberculosis, leprosy and mycobacterial diseases of man and animals: the many hosts of mycobacteria. Wallingford, UK; CABI, 2015, pp 235–258.