GUIDELINE for Mycobacterioses in cats

Visceral (gastrointestinal or respiratory) or systemic forms of mycobacteriosis

The MTBC (especially M. bovis) and MAC species are the most common mycobacteria producing visceral or systemic lesions in cats (Gunn-Moore et al., 1996; Barry et al., 2002; De Lorenzi and Solano-Gallego, 2009; de Groot et al., 2010; Riviere et al., 2011). With these species, common clinical signs and abnormalities include gastrointestinal (weight loss, mesenteric lymphadenopathy, intestinal thickening, diarrhoea, vomiting) or respiratory (tachypnoea, dyspnoea and/or coughing due to pneumonia, hilar lymphadenopathy, pneumothorax, pleural or pericardial effusions) signs. Whether intestinal, or respiratory, signs predominate can depend on the route of infection i.e. ingestion (via contaminated raw meat or unpasteurised milk), or inhalation, respectively. However, pulmonary signs in cats with mycobacterial infections are more likely to have arisen following haematogenous spread to the lungs rather than inhalation of infection (O’Brien et al., 2023); respiratory signs secondary to inhalation of MTBC organisms can cause the formation of classic tubercles in the lungs with hilar lymphadenopathy, rather than the more diffuse interstitial patterns seen with haematogenous spread to the lungs (O’Brien et al., 2023). The diffuse patterns due to haematogenous spread are more common (Peterhans et al., 2020). Regional and generalised lymphadenopathy is very common with MTBC infections, and in one study, these signs were more common than cutaneous changes (Mitchell et al., 2021c)

Other systemic signs can also be present such as: pyrexia, ocular signs (e.g. chorioretinitis, conjunctivitis, occasionally blindness), splenomegaly, hepatomegaly, generalised lymphadenopathy, bone lesions (lameness or pain due to arthritis, osteomyelitis) and neurological signs (Barry et al., 2002; Malik et al., 2002; Baral et al., 2006; Burthe et al., 2008; de Groot et al., 2010; Riviere et al., 2011; Rufenacht et al., 2011; Lo et al., 2012; Lalor et al., 2017; Madarame et al., 2017; Manou et al., 2021). Within the MTBC, involvement of internal lymph nodes is more common with M. bovis infections (21% of cats) than with M. microti infections (9% of cats) (Gunn-Moore et al., 2011a).

Neurological signs (e.g. nystagmus) are only usually present alongside other systemic signs (Baral et al., 2006) and have been reported mostly with MAC infections. However, one cat with M. avium subsp. hominissuis infection presented with neurological signs only due to a pyogranulomatous meningoencephalitis (Madarame et al., 2017). However, following necropsy and histopathological studies, mycobacteria were identified in several other organs and granulomatous lymphadenitis was also evident (Madarame et al., 2017), so infection was not localised to the nervous system.

A case series of feline ocular mycobacteriosis (Stavinohova et al., 2019) showed that approximately 25% of the cats presented only with ocular signs, emphasizing the importance of including these infections in the differential list of potential causes of ocular disease, even in cats with only ocular signs apparent. The most common signs were uveitis and blindness, but some cats also showed corneal, conjunctival and eyelid proliferative lesions. Cataracts, lens subluxation and glaucoma secondary to uveitis were present in some cats. In 80% of the cats, ocular disease was unilateral at presentation (Stavinohova et al., 2019).

Cats in the outbreaks of M. bovis infection associated with ingestion of contaminated raw food were presented with unusual, severe (with lethargy, anorexia, weight loss, pyrexia) and rapidly progressive clinical disease, with a high mortality rate even after attempting treatment. It may be that gastrointestinal infection produces more severe disease compared to infections associated with skin exposure, and it has been suggested also that these aggressive infections might be caused by more virulent M. bovis strains (O’Halloran et al., 2019; O’Halloran et al., 2021). A severe rapid course of M. bovis disease was also reported in a group of young Abyssinian cats in Italy (Černá et al., 2019); the source of infection was a cat imported from Eastern Europe and spread of infection in the household was extremely rapid, although the route of infection between the cats was not known.

Slow-growing and fastidious NTM infections rarely produce disseminated disease, but several case reports of disseminated infection (e.g. pyrexia, thin body condition, abdominal lymphadenopathy, renomegaly, hepatomegaly, tachypnoea, and/or increased lung sounds) do exist (O’Brien et al., 2023), including in immunocompetent cats (Couto and Artacho, 2007; Lee et al., 2017; O’Brien et al., 2017c; Pekkarinen et al., 2018). Cats severely affected by rapid-growing NTM can also show systemic signs (e.g. pyrexia, anorexia, pain) (O’Brien et al., 2023).

Diagnosis

Diagnosis of mycobacteriosis can be difficult, especially when skin lesions are absent, and is based on a clinical suspicion when the presentation is indicative and other diseases have been ruled out.

Many differential diagnoses need to be considered but include neoplasia (lymphoma, mast cell tumours), feline infectious peritonitis (Paharsingh et al., 2020), nocardiosis (these are also AFB), actinomycosis, fungal infections, Rhodococcus spp. (these are also AFB), Pasteurella luteola (Milliron et al., 2020), toxoplasmosis (Černá et al., 2020), Amycolatopsis spp. (Cole et al., 2022) and oomycete infections (Bowman et al., 2023).

The traditional tuberculin skin-testing technique used in other species (e.g. humans, where the test is known as the Mantoux test) (O’Brien et al., 2023) is insensitive in domestic cats (Broughan et al., 2013a). Therefore, diagnosis should focus on identifying appropriate sampling sites to collect samples for cytology and/or histopathology (including acid-fast staining for AFB), culture and PCR.

An IGRA test is available in some countries, which measures the T-cell response of the cat’s blood mononuclear cells, when they are stimulated by three different mycobacterial protein antigens/peptides; the IGRA can be used as an adjunct test when non-invasive sampling is required and/or when cytology samples are non-diagnostic, or tissue samples are not available. A comparative purified protein derivative (PPD) enzyme-linked immunosorbent assay (ELISA) to facilitate the diagnosis of feline MTBC has also been described (Mitchell et al., 2023), and may be a useful adjunct test for cases of feline MTBC due to M. bovis missed by the IGRA.

Laboratory changes

Haematology and biochemistry changes are non-specific, suggesting a chronic inflammatory condition.

A mild anaemia of inflammatory disease may be present, but the indoor-only cats that presented with suspected M. bovis infection due to ingestion (O’Halloran et al., 2018a; O’Halloran and Gunn-Moore, 2019; O’Halloran et al., 2019) often showed severe anaemia and marked neutrophilia.

Serum biochemistry is often normal (O’Halloran et al., 2021). Hypercalcaemia due to granulomatous disease has been reported with disseminated MAC (Malik et al., 2002) and M. microti infections (Gunn-Moore et al., 2011a), and is believed to be associated with extensive disease or severe panniculitis. The hypercalcaemia (ionised calcium is also elevated) is thought to be due to calcitriol (1,25-OH₂VitD) production by activated macrophages. Cats infected with mycobacteria can also show reduced serum levels of calcifediol (25-OHVitD) compared to healthy cats, as occurs in humans (Lalor et al., 2012), although the clinical significance of this is unknown. Mild hyperglobulinaemia (Han and Gunn-Moore, 2023) and hypoalbuminaemia may be present.

Testing for retroviruses (feline leukaemia virus or FIV) may be indicated for NTM cases, but most affected cats are negative, as outlined in the section on Epidemiology.

Diagnostic imaging changes

Thoracic radiography changes are variable and non-specific (Figure 5). In one study (Bennett et al., 2011), 21 of 24 cats with mycobacterial infections had abnormalities; bronchial, alveolar, nodular structured interstitial or non-structured (absence of miliary pattern, nodules or masses) interstitial patterns were visible, with possible perihilar or sternal lymphadenopathy too. Others have reported that bronchial and interstitial thoracic patterns are most common (Mitchell et al., 2021c). But many infected cats will not have thoracic changes.

Abdominal radiographic changes are uncommon but can include hepatomegaly and/or splenomegaly, mineralised mesenteric lymph nodes, or ascites (MacWilliams et al., 1998; Černá et al., 2020).

Appendicular radiographs can show bone osteolytic lesions, and (less frequently) osteoproliferative changes, associated with systemic mycobacterial infections (Bennett et al., 2011; Lo et al., 2012). Overlying soft tissue changes (and cutaneous lesions) and lymphadenopathy may also be visible.

Abdominal ultrasonography may show abdominal lymphadenopathy, hepatomegaly, splenomegaly, renal changes and can be useful to find evidence of mesenteric lymphadenopathy or granulomatous lesions, via changes in the echogenicity of tissues. Ultrasonography can then be used as a guide to obtain a window for collecting fine needle aspirates (FNAs) for diagnostic purposes (Griffin et al., 2003).

Computed tomography (CT) scan abnormalities were also reported in a group of 20 cats with mycobacterial infections (including six cats with M. bovis infection and six with M. microti infection) (Major et al., 2016). Interstitial lung patterns, mediastinal and/or mesenteric lymphadenopathy (such as lymphadenomegaly) and osteolytic or proliferative skeletal lesions were the most frequent abnormalities seen (Major et al., 2016). Again, thoracic abnormalities predominated (19 of the 20 cats) with structured interstitial (15 of 20), bronchial (nine of 20), alveolar (eight of 20) and ground glass (non-structured interstitial) (six of 20) patterns visible, which were often mixed. Other CT changes that were reported include abdominal or peripheral lymphadenopathy, osteolytic or proliferative lesions (Černá et al., 2020) and cutaneous or subcutaneous soft tissues masses and nodules. Mild lymphadenopathy was appreciated more in post-contrast studies, so use of contrast to evaluate systemic mycobacteriosis cases should be considered with CT. A study of feline MTBC (primarily M. microti) cases that were sequentially monitored by CT, showed that imaging abnormalities only resolved in a minority of cases, with very variable changes in CT findings over time and with treatment (Major et al., 2018). However, the report of two cats with extensive changes due to M. kansasii NTM infection showed resolution of osteolytic lesions on repeated CTs (Černá et al., 2020), showing that these changes can sometimes be reversible.

Fig. 5. Mixed bronchial-interstitial pattern in the lung of a cat with a Mycobacterium tuberculosis complex group infection (courtesy of Richard Malik, University of Sydney Veterinary School)

Direct detection of mycobacterial infection

Please note that when obtaining samples for mycobacterial organism detection, one must remember that some of the infections are potentially zoonotic, particularly M. bovis. Thus gloves, a mask and aseptic practice are required to handle samples whenever mycobacteria are suspected. Samples being sent to the laboratory should be labelled as possible or suspected mycobacterial infection too (see the Zoonotic section later).

Cytology

FNAs or smears obtained from skin lesions (e.g. nodules, ulcers, draining tracts) or other affected tissues (e.g. enlarged lymph nodes or those lymph nodes draining lesions, liver) or bronchoalveolar lavage (BAL) samples from cats with pulmonary changes should be evaluated for granulomatous changes, consistent with mycobacterial infections. If the cytology suggests granulomatous inflammation, the cytology samples should always be stained for AFB in macrophages using e.g. Ziehl-Nielsen (ZN) staining. The AFB are usually rod-shaped but M. microti bacteria can be curved or S-shaped (Peterhans et al., 2020; Mitchell et al., 2021b). The number of AFB is very variable and can be very sparse, reducing sensitivity; the number was thought to be dependent on the infecting mycobacterial species but the cat’s immune response is now thought to be important too (O’Halloran et al., 2016). The MTBC species were commonly associated with only very low numbers of AFB compared to NTM infections, but this is not always the case (Mitchell et al., 2021b). However, with NTM infections in particular, AFB are often lost from within the lipid droplets during processing of cytology (and biopsy) samples, and so alternative staining methods may be needed (e.g. rapid ZN or modified Fite’s stain).

The presence of AFB, with appropriate cytological changes and morphology, confirms the presence of mycobacterial infection but does not identify the species present. Species identification relies on submission of samples for culture or PCR. Although not ideal, due to the small sample size reducing sensitivity, FNAs and cytology slides can be submitted for PCR (see PCR section) and FNAs for culture, which may help species identification. If no AFB are present, but cytology changes are consistent with mycobacterial infection i.e. granulomatous inflammation, mycobacterial disease should remain a differential diagnosis and biopsy and/or culture, or even IGRA, should be performed i.e. negative ZN staining cannot be used to rule out mycobacteriosis (Gunn-Moore et al., 2013).

Histopathology

Histopathology is useful for the diagnosis of mycobacterial infections. It allows the assessment of the inflammatory pattern, which can vary with the mycobacterial species involved, e.g. the presence of pyogranulomatous, rather than granulomatous, inflammation, the presence of granulation tissue and/or mixed inflammatory response, necrosis, panniculitis. Histopathology also allows acid-fast staining with ZN stain (Kipar et al., 2003; Gunn-Moore et al., 2011b) (Figure 6).

On histopathology, large multi-layered granulomas with central necrosis are more commonly seen with M. bovis infection than M. microti (Mitchell et al., 2021b); this may help pathologists suspect one of these two infections above the other. However, sometimes only a few bacteria are present and they are not detected by ZN staining (particularly with M. microti infections and some NTM rapid-growing species), although culture or PCR on biopsy samples may still give a positive result in such cases (Gunn-Moore et al., 2011b; Gunn-Moore et al., 2013).

Positive AFB staining, with appropriate bacterial morphology, and histopathological changes allows confirmation of the presence of mycobacterial infection but does not allow identification (speciation) of the mycobacterial species; culture and/or PCR is required to speciate.

It is important to remember that if mycobacterial infection is suspected, not all of the sample should be placed into formalin for histopathology. Some sections of fresh biopsy samples should be immediately frozen at -20°C after collection (wrap the biopsy samples in sterile gauze moistened with sterile saline) without formalin, so that they can be submitted for subsequent culture and/or PCR if needed and / or if histopathology suggests mycobacteriosis (O’Brien et al., 2023). Another fresh sample can also be submitted for routine culture and sensitivity. This is because formalin-fixed samples can no longer be used for culture, and formalin also reduces PCR sensitivity (although PCR may still be possible; see PCR section).

Fig. 6. Large numbers of pink acid-fast bacteria as shown using the Ziehl–Neelsen stain (courtesy of Richard Malik, University of Sydney Veterinary School)

Culture

A positive culture from a fresh tissue sample or FNA or BAL is the most reliable way to confirm mycobacterial infection, and identify the species involved which has implications for treatment, prognosis and assessment of zoonotic risk. However, culture has poor sensitivity and is only possible for those mycobacterial species that grow in culture, such as the MTBC species and some of the NTM species. Only ~50% of mycobacteria in cats are said to grow in culture (Gunn-Moore et al., 2011a). Swabs of draining wounds should be avoided as these are usually contaminated with secondary bacteria.

Culture also carries risks in laboratory personnel and is carried out in specialised diagnostic laboratories under containment. It is important to contact a specialised laboratory to ask for the correct procedures and requirements before sample submission. Culture, other than for the rapid-growing species, can also take a long time, especially for MTBC species (M. bovis typically takes six to eight weeks to grow, and M. microti can be four to 12 or more weeks (Peterhans et al., 2020). Importantly, some of the fastidious species (the feline leprosy-like syndrome species and some other NTM infections) never grow in culture, even when ZN staining is positive (Malik et al., 2000; Gunn-Moore et al., 2011a; Gunn-Moore et al., 2013), and it takes a long time for laboratories to be able to say that the culture is definitely negative. Due to these limitations, it is advisable, if affordable, to simultaneously submit fresh samples for PCR as quicker results are usually obtained.

PCR

PCR is recommended for a more rapid diagnosis of mycobacterial infections (Kipar et al., 2003; Biet et al., 2005; Rufenacht et al., 2011), if available and affordable. It allows confirmation of the diagnosis more rapidly than culture and is especially useful for species that cannot be grown in culture. Fresh tissue or cytology samples (incl. FNAs and BALs) are preferred for PCR testing, but frozen tissue samples, cytology slides (even if fixed) and formalin-fixed paraffin-embedded tissues (Reppas et al., 2013) have also been used to generate positive results if fresh tissue is not available.

Not all commercial PCR assays can determine the species of mycobacteria present when a generic PCR assay yields a positive result, but some can determine if the DNA from a MTBC species is present, depending on the PCR assay used. PCR methods that include sequencing of a portion of the rpoB gene can be useful in assigning a species identity, particularly for members of the MAC (Higgins et al., 2011). Spacer oligonucleotide typing (spoligotyping) is the widely used PCR-based method for genotyping MTBC organisms, and is used primarily for research or epidemiological studies. Extensive sequencing is required for full speciation but has been performed to determine the epidemiology of infections in outbreaks (Roberts et al., 2014), or occasionally in individual cases (Lalor et al., 2017; Černá et al., 2019).

However, the availability of veterinary PCR testing for mycobacteriosis can be limited, depending on the commercial diagnostic laboratories available in an area; otherwise samples could be submitted to an official national human laboratory for mycobacterial diagnosis, after contacting them for advice regarding submission of samples.

Indirect detection of mycobacterial infection

Interferon-gamma release assay (IGRA)

The IGRA test (Rhodes et al., 2011) is especially useful for the diagnosis of MTBC group infections. IGRA can reduce the lag time between clinical presentation and diagnosis.

IGRA measures the T-cell response (CMI) of heparinised peripheral blood mononuclear cells (PBMCs), by measuring the release of interferon-gamma (IFN-γ) from the PBMCs, when they are stimulated by control reagents (O’Brien et al., 2023) and by three different mycobacterial protein antigens/peptides, namely:

• PPDA; purified protein derivative from avium
• PPDB; purified protein derivative from bovis
• ESAT-6/CFP-10; an antigenic peptide cocktail of the region of difference-1 proteins 6 kDa early secreted antigenic target and 10 kDa culture filtrate protein.

The response determines whether the cat has previously been infected with mycobacterial species containing these peptides. If a positive result is obtained, the pattern of the positive results classifies the cat in one of three ways i.e. the cat is likely to:

• be affected with a pathogenic MTBC species i.e. bovis (or theoretically M. tuberculosis, but as this species is very rare in cats, a positive result is likely to reflect M. bovis infection)
• be affected with a less-pathogenic MTBC species i.e. microti
• have been exposed to a saprophytic / environmental NTM species.

The IGRA has been evaluated for its usefulness in the diagnosis of mycobacterial infections and had a sensitivity of 94.0% and specificity of 90.0% (Mitchell et al., 2021d) (see Table 2) in research that optimised the cut-off for the IGRA assays. The sensitivity and specificity values for detection of the different types of mycobacterial infection are shown in Table 2.

Table 2: Sensitivity & specificity values for the Interferon-gamma release assay (IGRA)*

*IGRA performed on cats with different mycobacterial infections and negative control cats (Mitchell et al., 2021d)
MTBC = Mycobacterium tuberculosis complex group
CI = Confidence intervals.

As shown in Table 2, and as previously reported (O’Halloran and Gunn‐Moore, 2017; O’Halloran et al., 2018b), IGRA is less sensitive for the detection of NTM (66.7%, although only low numbers of cats were in the study) than MTBC (90.2%) infections, although the sensitivity for M. bovis infection (68.8%) is far less than for M. microti (90.0%) too. Thus, some cats with MTBC are IGRA negative. A separate study reported a sensitivity of only 50% for the detection of M. avium infections (O’Halloran and Gunn‐Moore, 2017). Sensitivity may be affected by cats being tested early in infection or due to the type of monocyte cell populations present in cats; age of cat was not found to be a factor. If an IGRA negative result is obtained in a cat with ZN positive results, culture and/or PCR should be performed, and/or repeat IGRA if the blood sample was believed to be taken early in disease. In the future, such cases could be subjected to a comparative PPD ELISA (Mitchell et al., 2023) as an adjunct test for cases of feline MTBC, due to some M. bovis infections being missed by the IGRA (see below).

IGRA specificity values tend to be higher than sensitivity values, so that a positive IGRA result for M. bovis or M. microti can be trusted (Mitchell et al., 2021d). However, IGRA can also be positive in clinically healthy cats exposed to mycobacteria without clinical signs, so results should be interpreted together with the cat’s presentation and following careful selection of cases for IGRA testing (Rhodes et al., 2008; Fenton et al., 2010; O’Halloran et al., 2018b; O’Halloran et al., 2021). Although NTM infections in 10 cats all generated positive IGRA results in a recent study (Mitchell et al., 2021d), IGRA was limited in its ability to diagnose and discriminate between the types of NTM infection (Černá et al., 2020). It is therefore recommended that positive NTM results by IGRA are followed up with PCR and/or culture to try and help confirm the identity of the infecting NTM.

Others have also found IGRA testing useful for mycobacteria diagnosis (Peterhans et al., 2020); positive results were obtained for both of the two M. microti infected cats in the study, but not in any of the 12 healthy control cats tested.

The IGRA has the advantage of being quicker and cheaper than culture and can be performed using a heparinised blood sample (i.e. is non-invasive). IGRA could also be useful as a screening test when no discernible lesions are available to sample in a cat (Mitchell et al., 2021d) e.g. to test in-contact animals that have no clinical signs. However, the test must be interpreted with caution as the proportion of subclinical but IGRA-positive patients that go on to develop active clinical disease is unknown (O’Brien et al., 2023).

One must remember that the IGRA is an indirect method of diagnosis, and does not absolutely confirm the presence of mycobacterial infection, as culture or PCR would do. This IGRA test is currently commercially available only in the UK, although samples can be submitted from abroad.

Although it was hoped that IGRA might be useful to monitor treatment (O’Halloran and Gunn‐Moore, 2017), this was not found to be the case (Mitchell et al., 2021c), as IGRA results were not associated with clinical remission nor prediction of recurrence of disease in cats. It was found that IGRA results remain persistently positive following clinical remission, as is the case in human TB cases.

Comparative purified protein derivative (PPD) ELISA

One study (Mitchell et al., 2023) reported the development of an ELISA test as an adjunct test to help the diagnosis of feline MTBC, although it is not yet commercially available. The ELISA was optimised for use on serum and plasma, and was tested on samples from 14 cats with culture-confirmed MTBC and 24 uninfected controls. It showed a sensitivity of 64.3% (nine of 14 cats) and specificity of 100% (no positive antibody results were recorded in the 24 uninfected cats); but sensitivity was poorer for MTBC cases diagnosed by PCR without culture (15.4%, two of 13 cats). Additionally, rates of antibody positivity were higher in cats with culture or PCR-diagnosed M. bovis (66.7%, eight of 12) than M. microti infection (two of five cats). The authors reported that the test had reasonable performance for identifying cases of MTBC, particularly those caused by infection with M. bovis. Since negative IGRA results can occur in cases of MTBC (Mitchell et al., 2021c), a concurrent antibody test, such as with this ELISA (Mitchell et al., 2023), could facilitate the earlier identification of such cases missed by the IGRA, if the test becomes further validated and commercially available.

Treatment

Treatment of mycobacterial infections is generally challenging. There have been no prospective, controlled clinical trials, and recommendations are based on case reports or retrospective studies. Good outcomes have been reported after identification of the mycobacterial species and treatment with a long (several months in duration) course of an appropriate antibiotic combination (O’Brien et al., 2023). Surgery is indicated when local skin lesions can be removed; more diffuse lesions may be treated with surgical debridement and subsequent antibiotic treatment (Baral et al., 2006; Elsner et al., 2008; Horne and Kunkle, 2009).

Before starting mycobacterial treatment, five important issues must be considered:

• Firstly, if a diagnosis of bovis has been made, is treatment of the cat allowed in the country in which the cat resides? If not, euthansia is required alongside counselling of the owner regarding the loss of their cat and zoonotic risks (see next point).
• Secondly, the potential zoonotic risk (particularly for the MTBC group, including  microti, but also for MAC species) must be discussed with the owner (Xavier Emmanuel et al., 2007), especially, but not only, if the owner is immunocompromised or if there are very young or old people in the household. In such cases, treatment of the cat might not be recommended, and euthanasia might be considered as an option. The client needs to be advised to talk to their own doctor too regarding risks and potential screening for MTBC infection (this usually includes Mantoux testing and thoracic radiographs).
• Thirdly, confirmation (by culture or PCR) of the mycobacterial species might take time; in this case, the zoonotic risk (especially in the case of  tuberculosis, which is very rare in cats) of M. bovis, more commonly encountered in cats, can be unacceptable, and inappropriate initial antibiotic selection can lead to the development of mycobacterial antibiotic resistance (Masur, 1993; Gunn-Moore et al., 2011b; Gunn-Moore et al., 2013; O’Brien et al., 2023).
• Fourthly, treatment requires several months of an antibiotic combination regime; compliance, adverse effects and financial issues must be discussed with the owners. The cat should ideally be kept indoors during treatment and separated from other cats to prevent any possible transmission.
• Fifthly, a final diagnosis should always be based on culture and/or PCR tests, but in some situations the clinical context and IGRA can be helpful to suggest the mycobacteria species involved and to evaluate the zoonotic risk and guide initial discussions or treatment. For example, in non-TB endemic areas, cats with mycobacterial infection will be less of a zoonotic risk, especially if the lesions are cutaneous with no evidence of systemic infection, and cats with diffuse panniculitis due to rapidly-growing mycobacteria species pose even less of a zoonotic risk.

An overview of treatments used for each type of feline mycobacteriosis is shown in Table 1, whilst Table 3 shows dosages and possible adverse effects (O’Brien et al., 2023).

Table 3: Drugs used for treatment of feline mycobacteriosis – dosages and possible adverse effects. Adapted from (O’Brien et al., 2023) and (O’Halloran and Gunn‐Moore, 2017).

* Note that different licensed dosages exist for some agents (e.g. pradofloxacin, marboflaxocin) in different countries and for some different formulations (e.g. pradofloxacin tablets and suspension). Please check manufacturer’s recommendations.

MTBC group treatment

For the MTBC group, double or triple antibiotic therapy is currently recommended (Tables 1 and 3): rifampicin plus a fluoroquinolone (marbofloxacin may be effective but pradofloxacin is now often preferred if available) plus a macrolide (clarithromycin or azithromycin) for six to nine months. Previously, it was suggested that three drugs (triple therapy) should be administered during an initial phase for two months, followed by two of the drugs (dual therapy) for four to seven months (Gunn-Moore et al., 1996; Baral et al., 2006; Gunn-Moore et al., 2011a; O’Brien et al., 2023). However, an alternative treatment protocol has been suggested which comprises longer triple therapy (rifampicin plus a fluoroquinolone plus a macrolide, as above) for at least four months (and six months if pulmonary involvement), with continued therapy two to three months beyond resolution of clinical signs or beyond static thoracic imaging abnormalities. This protocol has been described in reports of MTBC cases (O’Halloran and Gunn‐Moore, 2017; Major et al., 2018; Albuquerque et al., 2021), although not much follow up information on this protocol is yet available. The rationale for this treatment protocol is based on recommendations from human medicine where at least three or four antibiotics are given in combination for longer to reduce the development of multi-drug resistant mycobacteria.

The newer fluoroquinolones (moxifloxacin and pradofloxacin) might be more effective than older ones (Malik et al., 2002; Horne and Kunkle, 2009). Unpublished clinical experience suggests that pradofloxacin is a good choice; in confirmed localised disease, pradofloxacin could be a good initial treatment pending species confirmation (Smith et al., 2009), but multiple antibiotic therapy is often indicated for mycobacterial treatment, even pending confirmation of diagnosis to avoid antibiotic resistance developing (see below).

In some cats, an oesophageal feeding tube is needed to allow prolonged and intensive drug administration (O’Brien et al., 2023).  Reformulations of drugs (e.g. rifampicin and azithromycin) into one capsule are available from some manufacturers (Mitchell et al., 2019) to allow for easier dosing and compliance. Alternatively, tablets can be combined into a single gelatine capsule for easier administration. Liquid formulations can also be used in preference for some cats, when available. Short courses of antibiotic and/or monotherapy (e.g. with fluoroquinolones or beta-lactams) can be associated with an initial clinical response and remission, but there is a high risk of relapse, which can be followed by systemic spread and possible mycobacterial antibiotic resistance (Gunn-Moore et al., 2011b). It is therefore recommended to always start complete multiple antibiotic treatment whilst awaiting diagnosis confirmation and species identification.

Adverse effects (see Table 3) (cutaneous, hepatic) are not uncommon. Repeat examinations are important, and haematology and biochemistry should be monitored two weeks after starting treatment, and every two months thereafter, to monitor for possible side effects, especially hepatotoxicity with rifampicin. Some vets administer S-adenosylmethionine (SAMe) during rifampicin treatment to reduce its potential hepatotoxicity effects (Černá et al., 2020), but no controlled studies have been performed to confirm a beneficial effect. Rifampicin can also discolour body fluids orange, which necessitates warning of owners, and cause anorexia, erythema, pruritus and anaphylaxis, whilst clarithromycin can result in pinnal or generalised erythema (Table 3). These adverse effects usually require the need to stop these medications. Although azithromycin can be used in place of clarithromycin, and other second line anti-MTBC drugs exit (Table 3) such as isoniazid and ethambutol, there are not many practical alternatives to rifampicin.

NTM: MAC, slow-growing and rapid-growing infection treatment

Disseminated MAC infections usually respond poorly to treatment, and old generation fluoroquinolones are not very effective (Jordan et al., 1994; Burthe et al., 2008; Gunn-Moore et al., 2013; Munro et al., 2021). The recommended first choice treatment is clarithromycin, and clofazimine or rifampicin, alongside doxycycline if possible or pradofloxacin, based on the few cases reported with good outcomes (Kaufman et al., 1995; Aranaz et al., 1996; Malik et al., 2000; Biet et al., 2005; Sieber-Ruckstuhl et al., 2007). Limited clinical experience with pradofloxacin suggests that it is more effective than the older fluoroquinolones (Smith et al., 2009), especially for rapid-growing NTM species (Govendir et al., 2011b), although resistance to fluoroquinolones and aminoglycosides has been found to be common among M. avium isolates (Munro et al., 2021).

One cat, that presented with chronic, progressive multinodular to generalised subcutaneous nodules covering much of its body due to Mycobacterium intracellulare infection, failed to respond to doxycycline alone nor to triple therapy with rifampicin, azithromycin and pradofloxacin (Han and Gunn-Moore, 2023); a clinical response occurred when treatment was changed to triple therapy, with clofazimine, clarithromycin and doxycycline (based on culture and sensitivity results), which was given for three months after which long-term therapy with clofazimine and clarithromycin was continued.

Treatment of NTM infections is ideally based on individual culture and sensitivity tests (Han and Gunn-Moore, 2023), as different mycobacterial species or strains can have different antibiotic sensitivity (Munro et al., 2021). However, this is not always possible, as specific culture systems are unavailable or results take too long. Other NTM species show variable responses to antibiotics, but generally dual or triple antibiotic treatment is given. Dual clarithromycin and pradofloxacin treatment is good for certain species (e.g. M. chelonae-abscessus) whilst dual fluoroquinolone and doxycycline is better for others (e.g. M. smegmatis). Periods of eight-months and eleven-months of triple treatment with rifampicin, azithromycin and pradofloxacin were effective at treating M. kansasii in two sibling cats (Černá et al., 2020), whereas another report documented M. kansasii treatment success with six months of rifampicin and clarithromycin (Fukano et al., 2021). In one case of M. kansasii infection (Černá et al., 2020), N-acetyl cysteine (NAC) (600 mg/cat PO q 12 hr) was added to the treatment protocol for the last five months to try to speed resolution due to its direct antimycobacterial effects, as well as its hepatoprotective activity, but its efficacy in treatment has not been further evaluated. Treatment of NTM infections should continue one to two months beyond clinical resolution; up to 12 months of treatment is needed for extensive or systemic infections.

Surgical resection may comprise part of the treatment for severe panniculitis case, with reconstructive surgery sometimes needed to maximise healing.

NTM: Fastidious species (feline leprosy-like syndromes) treatment

Surgical removal of solitary lesions may be curative; occasionally spontaneous resolution of lesions can occur (Roccabianca et al., 1996; Ghielmetti et al., 2021). If further treatment is required, dual or triple antibiotic treatment should include clarithromycin, rifampicin, pradofloxacin /  moxifloxacin and / or clofamazine typically for three to six months (Horne and Kunkle, 2009), although one case responded to just a four-week course of rifampicin and clarithromycin (Ghielmetti et al., 2021).

Reviews of feline leprosy provide interesting information on treatment and response of the different types of feline leprosy-like syndrome NTMs due to different infecting species (O’Brien et al., 2017a; O’Brien et al., 2017b; O’Brien et al., 2017c).

Response to treatment

As mentioned earlier, prediction of response to treatment based on clinical presentation is difficult, and IGRA was not useful as a marker of disease remission in cats (Mitchell et al., 2021c), with 78% of cases remaining persistently IGRA positive despite clinical remission. However, the same study noted that all (100%) of the cases that had recurrence of clinical signs had pulmonary changes at diagnosis compared to only 54% of those cats that did not, suggesting that pulmonary changes may be associated with increased likelihood of recurrence, although further work with larger numbers is required for validation. Additionally, a M. microti case report (Albuquerque et al., 2021) described a cat that had at least six episodes of disease (including pulmonary changes and negative IGRA results after long-term antibiotic treatment courses) over a 10-year period, seemingly due to reinfections, rather than relapses, emphasizing that long-term response to treatment is difficult to predict.

Prognosis

Prognosis must be considered guarded in general but depends on the mycobacterial species and the extent and severity of the disease.

In a study of 184 feline mycobacterial cases (Gunn-Moore et al., 2011b), around 40% responded well to treatment long-term (remission or cure), whilst the remainder responded temporarily, poorly, or not at all. However, the infecting mycobacterial species was not always determined and appropriate treatment was not given in all cases (e.g. many were given only a single fluoroquinolone for less than a month and others were also given steroids). Another study of 18 cats (many with MTBC infections, but infecting species was not determined in all) reported a 72% response rate in cats generally treated with triple (i.e. rifampicin, a fluoroquinolone and a macrolide) therapy (Mitchell et al., 2021c).

Disseminated infections (MTBC, MAC and ‘Candidatus M. lepraefelis’ species) are associated with a poorer prognosis (Gunn-Moore et al., 1996; Barry et al., 2002; De Lorenzi and Solano-Gallego, 2009; Smith et al., 2009; de Groot et al., 2010; Riviere et al., 2011). Outbreaks in younger cats may be associated with a poorer prognosis too, due to more severe disease (Černá et al., 2019; O’Halloran et al., 2019).

Localised skin disease due to NTM, M. microti infections and leprosy-like syndromes can have a good prognosis with appropriate treatment (Baral et al., 2006; Horne and Kunkle, 2009; Gunn-Moore et al., 2011b).

Vaccination

No vaccinations for mycobacterial infections exist for cats.

Prevention

Keeping a cat indoors, and avoiding hunting and fighting or feeding raw meat diets, are measures available for preventing mycobacterial infection.

Disease control in specific situations

No reliable protocols exist for management of cats that have been in contact with a cat with confirmed mycobacterial infection. IGRA tests can be used to test in-contact animals that have no clinical signs. However, the test must be interpreted with caution as the proportion of subclinical but IGRA-positive patients that go on to develop active clinical disease is unknown (O’Brien et al., 2023).

Where more than one cat in a household is affected, cat-to-cat transmission may be possible but other considerations, including exposure to the same infection source (e.g. infected rodents through hunting, raw meat diet), or a genetic predisposition to infection, as suspected in certain lines of Abyssinians and Somalis as a result of immunodeficiency (Baral et al., 2006).

Zoonotic risk

General zoonotic considerations

All members of the MTBC are potentially zoonotic (Roberts et al., 2014; O’Connor et al., 2019), including M. microti. However, the risk of transmission from cats (and dogs) to humans is very low (Public Health News & Reports 2014), as they are spillover hosts (Biet et al., 2005; Baral et al., 2006; Couto and Artacho, 2007).

An unusual cluster of M. bovis infection in cats was reported from the UK in 2012 to 2013. Cat-to-cat transmission was suspected, and zoonotic infection of two humans was documented (O’Connor et al., 2019). Similarly, cat-to-human transmission was suspected in Texas, USA (Ramdas et al., 2015). After the documented evidence of cat-to-human transmission in the UK, the risk of spread of M. bovis from cats to their human contacts was increased from negligible to very low in the UK (Human Animal Infections and Risk Surveillance Group 2014). Cats with clinical signs compatible with disseminated disease, before treatment is started, are believed to pose the greatest risk to humans, most likely by ingestion from a contaminated environment, following handling of discharges from exudative tuberculous lesions, or by aerosols from cats with respiratory signs or aerosol-generating procedures. Cutaneous inoculation of humans via cuts or skin breakages following handling of mycobacterial discharges is also possible.

In the published outbreaks in cats with M. bovis infection that were likely infected following the consumption of contaminated raw food, no transmission to owners was observed. However, there is concern about the potential risk of infection to owners by them handling contaminated raw food during meal preparation, as well as home environment contamination by M. bovis faecal shedding by the cats.

M. tuberculosisis the main cause of human TB. Dogs, rather than cats, are more likely to become infected with M. tuberculosis and when this occurs, it is more often caught from infected humans than the other way round (Parsons et al., 2012). Indeed, in one case of a dog with disseminated M. tuberculosis disease (Posthaus et al., 2011), none of the humans (including the owners) in contact with the dog when it was alive became infected, but zoonotic M. tuberculosis infection was reported in three vet pathologists who subsequently performed necropsy on the dog (see below) (Posthaus et al., 2011).

MAC species, particularly M. avium subsp. hominissuis, are potentially transmissible from cat-to-human, but so far there have been no reports of cat-to-human cases (Biet et al., 2005). There is a published case report from Australia of a local skin infection infected with Mycobacterium marinum (a NTM pathogen of fish) in a human (Phan and Relic, 2010) where the person had been scratched by her cat. It is possible that the cat acted as a vector for M. marinum through its contact with fish tank water in the house and then the scratch to the human, but an alternative explanation is that the cat scratch predisposed the human to subsequent inoculation with fish tank water during cleaning of the tank (Phan and Relic, 2010). Another NTM, M. kansasii, is also a potential zoonotic agent, as this species is a human NTM pathogen; one report found an isolate in an indoor only cat in Japan that was genetically identical to human isolates (Fukano et al., 2021) (Table 1).

In some countries, such as Italy, euthanasia of cats with confirmed M. bovis (or M. tuberculosis) infection is required by the government. In others, different regulations prevail. A country’s regulation should be consulted to determine if any health or government authorities need to be notified if mycobacterial disease (e.g. due to M. tuberculosis or M. bovis) is confirmed in a cat (O’Brien et al., 2023). For example, in the UK (2024), Public Health England now advises that all close contacts of household companion animals with confirmed M. bovis infections be assessed by a public health professional and receive guidance on how best to minimise zoonotic transmission. Additionally, as part of an enhanced surveillance system in England and Wales, newly diagnosed human patients with M. bovis infection are asked explicitly about contact with pets with suspected or confirmed M. bovis disease (O’Connor et al., 2019). Similar examples likely exist in other countries.

Over and above a vet following government rules, euthanasia or treatment of cats with confirmed M. bovis (or M. tuberculosis) infection, or cats with any of the other potential zoonotic mycobacterial species, namely M. microti and MAC species, should be a shared decision between the owner and the vet. Euthanasia might be the most appropriate option. Owners in close contact with the cat will have probably already been exposed to infection before the cat visits the vet. As soon as effective treatment has started, the risk of infection transmission from cat-to-human will reduce. It is generally thought that protracted exposure is required to transmit infection transmission, but a single inoculation with a high dose could result in infection transmission, so care is always required.

People considered to be at increased risk of mycobacterial infection (O’Halloran and Gunn‐Moore, 2017; O’Brien et al., 2023) are those:

• under 5 years old (some sources suggest 12 years)
• pregnant
• HIV-infected
• substance abusers
• with diabetes mellitus
• with cystic fibrosis
• with kidney disease
• solid organ transplant receivers
• with cancer, receiving chemotherapy or radiotherapy
• require systemic corticosteroid treatment
• require tumour necrosis factor antagonist treatment
• specialised treatment for rheumatoid arthritis or Crohn’s disease
• history of gastrectomy or jejunoileal bypass
• silicosis

Zoonotic considerations in the veterinary practice

Zoonotic potential must be considered when collecting samples from cats in the clinic, especially in endemic areas. Inhalation of organisms from cats with respiratory signs with a possibility of mycobacterial infection, or contact with organisms in draining wounds via open skin sores or wounds on people, could allow transmission to humans. Protective personal equipment (PPE) is important; gloves and protective clothing must be used when handling cases with draining skin lesions to avoid spread to other cats, as well as covering of any open sores/wounds in personnel to prevent zoonotic transmission. PPE is also important when taking and processing biopsy or other clinical samples, including FNAs and BALs. A fitted facial filtration particle 3 (FFP3), equivalent of N95, facemask (fitting should be done by a trained individual) should be worn when in close proximity to the face of cases with respiratory signs (e.g. coughing cats, during intubation for anaesthesia or collecting FNAs, BALs) to prevent inhalation of organisms. Veterinary practice staff should take care to avoid needle-stick injuries or cutaneous inoculation when collecting specimens (such as FNAs of lymph nodes) from cats with NTM infections because of the possibility that disease might occur after cutaneous inoculation. Sedation is recommended whenever lymph node aspiration is indicated for an animal with an unknown cause of lymphadenopathy. Care should also be taken not to aerosolise tissues at necropsy when mycobacterial disease is suspected (such as that occurring with the use of electric saws); zoonotic M. tuberculosis infection was reported in three pathologists who performed necropsy on a M. tuberculosis-infected dog, likely due to inhalation of M. tuberculosis-containing aerosols created using an electric saw to open the dog’s brain cavity (Posthaus et al., 2011).

Strict asepsis is very important as nosocomial spread of mycobacterial infections has been reported when cats that were undergoing neutering in a veterinary practice were infected with M. bovis via contact with contaminated staff uniform and / or hands (Murray et al., 2015). Hand washes and disinfectants must be mycobacteriocidal e.g. high (60-90) percentage alcohols, halogenated tertiary amines and 3% iodine preparations are mycobacteriocidal but 4% chlorhexidine is not mycobacteriocidal. Breathing systems and endotracheal tubes used for suspected cases should be disposed of after use in clinical waste (double bagged) and investigations on suspected cases should be performed at the end of the day in well ventilated rooms. If open surgery is required on a suspected TB patient, in addition to the PPE mentioned above, an appropriately filtered airflow helmet respirator is required e.g. Dustmaster Powered Respiration kit. Additionally, necropsy examination of granulomatous disease in cats should be performed in a dedicated isolation unit in which more stringent personal protective measures are required (e.g. FFP3 or N95 facemasks or powered air-purifying respirators), and a logging system for all personnel entering the isolation unit kept (Haydock et al., 2022). Following euthanasia of a TB patient, cremation rather than burial should be recommended to reduce the risk of environmental contamination.

Acknowledgement

ABCD Europe gratefully acknowledges the support of Boehringer Ingelheim (the founding sponsor of the ABCD), Virbac and MSD Animal Health.

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