Non-tuberculous mycobacteria (NTM) are a diverse group of complex bacteria that are found in environmental sites such as soil and water. They are generally not as pathogenic to humans as the Mycobacterium tuberculosis complex organisms, which result in tuberculosis (TB). For the purposes of classification, they also do not include Mycobacterium leprae, which cause leprosy.
This article will discuss why what was previously regarded as an unimportant and generally harmless organism is now seen as a serious healthcare issue. It will also map out the important role of nurses in the management of NTM-related infection and disease.
Epidemiology
There are over 170 different NTM species. This number continues to rise as improvements in diagnostic technology occur, for example the use of mycobacterial whole genome sequencing (where the full or near-complete DNA sequence of a mycobacteria is identified using molecular techniques) to distinguish strains that would have been previously considered the same organism. Also, the greater interest in the field means that researchers are now looking for NTM in a number of different clinical and environmental settings; while clinicians in both primary and secondary care are considering these organisms in diagnostic investigations.
Inevitably, the high number of species results in a need to classify them into more manageable groupings. One approach is to use the speed at which NTM can be cultured in the laboratory (Table 1). ‘Rapid growers’ are identifiable after a few days of growth. ‘Slow growers’ are usually identified after at least 1 week of culture. This distinction is helpful as the drugs used in treating rapid growers are often similar to standard antibiotics, whereas the slow growers have characteristics that respond better to treatment with anti-tuberculosis therapies.
Table 1. Classification of non-tuberculous mycobacteria by speed of growth
| Growth rate classification | Common non-tuberculous mycobacteria | Notes |
|---|---|---|
| Slow-growing mycobacteria (SGM) |
|
Colonies require >7 days to form mature colonies on solid media agar growth plates |
| Rapid-growing mycobacteria (RGM) |
|
Colonies formed on agar subculture in ≤7 days |
NTM are environmental organisms that adapted to living in harsh, often unstable natural settings outside of humans. They generally not pathogenic and therefore would be thought of as unlikely to cause disease. This was certainly the case until the advent of conditions such as HIV, the increasing use of chemotherapy for cancers and transplantation drug regimens which suppress immunity, enabling bacteria to thrive in the absence of good host defences. As a result, until about 20 years ago, NTM would generally be seen in the context of either disseminated illness in immunocompromised people, for example the presentation of disseminated M. avium complex (MAC) in people living with HIV and a very low blood cluster of differentiation 4 (CD4) T-cell count (usually less than 50 cells/μl, normal >400) and fevers, weight loss, diarrhoea, extensive lymphadenopathy and a positive mycobacterial blood culture (Hawkins et al, 1986).
Since then medicine has evolved. The widespread use of antiretroviral therapy has significantly reduced the frequency of NTM-related disease in HIV, and it is now people with structural lung disease who are at the greatest risk of NTM infection (Table 2). This is usually localised to the lung.
Table 2. Clinical presentation of non-tuberculous mycobacteria disease
| Clinical syndrome | Mycobacteria | Clinical setting |
|---|---|---|
| Pulmonary disease | M. avium complex (MAC) | MAC clinical phenotypes:
|
| M. kansasii | ||
| M. xenopi | ||
| M. abscessus | ||
| Lymphadenitis | M. avium complex | Cervical lymphadenitis in children |
| M. scrofulaceum | ||
| M. malmoense | ||
| Disseminated disease | MAC | Disseminated disease in patients with advanced HIV infection. Recent cases post-cardiac bypass surgery (not immunocompromised) |
| Skin and soft tissue infections | M. abscessus | Infected implants (eg pacemakers) |
| M. chelonae | Post-tattooing, post-surgery, post-skin trauma; injecting drug use | |
| M. fortuitum | Post-surgery | |
| M. marinum | Infection through breaks in the skin, may cause persistent sores (eg ‘fish tank granuloma’) | |
| M. ulcerans | Endemic in the tropics. Cause of Buruli ulcer |
A recent, important exception to this is the outbreak from 2013 in Europe and the US of over 100 cases of life-threatening prosthetic valve endocarditis and often disseminated M. chimaera disease in people who had previously had cardiac surgery (Kohler et al, 2015). This was linked to contaminated heater-cooler units used during the affected patient's surgery – which in some cases was several years previously. The likely source of the NTM contamination was the factory originally manufacturing the products.
Prevalence
Epidemiological analyses from across the world demonstrate an increasing prevalence of NTM isolates in local and national Mycobacterial Reference Laboratories (Hoefsloot et al, 2013). Although this in part may be related to an increased awareness of NTM (with clinicians sending more samples for mycobacterial culture), it appears to be a phenomenon that requires further explanation. Areas to consider for research include:
- NTM filling the ‘ecological niche’ that has been left by the decline of tuberculosis in many countries
- Changes in local environments (eg increased use of water storage facilities that enable NTM to grow and then spread via shower aerosols and air conditioning)
- A reduction in the temperature at which hot water tanks are kept in order to reduce fuel consumption, creating an environment that does not kill mycobacteria
- An increase in the number of people with chronic lung diseases that enable NTM to colonise and cause local disease.
Common examples of associated conditions are chronic obstructive pulmonary disease (COPD), bronchiectasis, including the changes from old tuberculosis, and, in younger people, cystic fibrosis.
An important issue when attempting to determine the frequency of NTM lung disease is what actually constitutes this condition. The diagnostic criteria will be discussed in this article, but the epidemiological implications are also important to note. NTM are often isolated over several months to years – which can be as repeated isolations of the same species as well as completely different ones isolated together or separately. Evidence suggests that, provided a standardised approach is used to record information, it is possible to understand and map epidemiological trends in NTM. Although the actual size of the problem is not known, data from large national bronchiectasis registries suggest that around 10% of patients will isolate NTM from their lungs (Faverio et al, 2016). This might indicate that NTM lung disease in many high income countries is now more common than tuberculosis.
Presentation
NTM-related disease is generally considered as either being pulmonary or extra pulmonary (Table 2). Pulmonary is the most common form, and in many global studies it is increasing at the fastest rate (Shah et al, 2016). Examples of extra pulmonary disease include isolated lymphadenopathy (often seen in children), skin infections with rapid growing organisms, which will have been inoculated into the skin (eg tattooing or trauma, infection of intravascular devices such as Hickman lines, and disseminated disease).
Respiratory disease can present late, which is often a consequence of the underlying NTM-related cause not having been considered and/or no diagnostic investigations being performed (Table 3). An example of this is a patient attending healthcare services with recurrent respiratory tract infections that only partially respond to standard antibiotics. NTM may lead to subtle changes in symptoms, for example a person with pre-existing COPD noting an increase in cough and sputum, plus associated fatigue and/or breathlessness. Not surprisingly, this can be taken to reflect progressive COPD rather than NTM disease.
Table 3. Clinical scenarios which suggest non-tuberculous mycobacteria infection/disease
| Scenario | Notes |
|---|---|
| Non-resolution of disease | Persistent skin or pulmonary disease despite standard treatment |
| Recurrent disease | Increase in frequency of chest infections in patient with known bronchiectasis or smoking related lung disease |
| Onset following a specific event | Surgery, tattoo, skin trauma. Chemotherapy with impaired immunity in particular low immunoglobulins |
Diagnosis
Given that NTM are low-grade pathogens, it is extremely rare for NTM-related disease to be diagnosed (and treated) without the organism being formally identified. This is unlike TB, where approximately one third of all notified cases are culture negative yet still receive treatment as a presumed case of TB (Public Health England, 2015). Therefore, it is crucial that if there is a concern about NTM, good-quality samples (usually sputum) are sent for specific mycobacterial culture, as well as for bacterial and fungal cultures.
As with TB diagnosis, the authors would recommend that at least two and preferably three sputum (either spontaneous or induced) samples are obtained in someone with respiratory symptoms. Should the patient be non-productive, or concerns persist about NTM despite negative sputum cultures, then bronchoscopy and broncho-alveolar lavage should be performed. Although more invasive than sputum sampling, it appears to increase the chance of a positive NTM culture.
As previously discussed, there is a difference between isolating NTM from someone's sputum and regarding it as the cause of disease in that person. Diagnostic criteria have been developed which are both useful and pragmatic (Table 4). These recommend that NTM lung disease is diagnosed when a patient has at least two positive similar sputum cultures (or one positive bronchoscopically-obtained sample), together with appropriate symptoms and radiological findings (Griffith et al, 2007; Haworth et al, 2017).
Table 4. Clinical and microbiological criteria for diagnosis
| Clinical (both required): |
|---|
|
| Microbiological: |
|
The radiology of pulmonary NTM disease is very variable. Chest X-rays (CXRs) are a relatively small dose of radiation and are also inexpensive. However, they are insensitive when diagnosing many cases of NTM lung disease. Generally, imaging findings can be categorised as being of a reticulo-nodular or cavitatory predominant pattern. The former may be extremely difficult to visualise on a standard CXR, in particular when there is co-existing lung disease such as COPD or bronchiectasis. Cavities associated with NTM are easier to see; however, they are a non-specific finding – for example, in a former smoker with COPD, they may represent lung cancer, old disease, or another inflammatory or infectious condition. Given the breadth and potential severity of the other possible diagnoses, it is important to perform diagnostic tests promptly to determine what is underlying the symptoms and radiology changes.
CT scans are helpful, and it is generally recommended that a patient with NTM lung disease should have at least one chest CT performed during their care (Haworth et al, 2017).
Management
Unlike tuberculosis, which typically affects younger people without other comorbid illness, NTM lung disease is most frequently seen in people who are aged 50 years or above, and may have other on-going conditions. Additionally, in contrast to tuberculosis, the drugs that are used to treat NTM are not particularly effective and can lead to a large number of adverse events.
Hence many clinicians will try and improve or manage specific factors that they feel are contributing to the NTM's persistence in the lung or associated symptoms. Examples of this include colonisation with pathogens such as Pseudomonas spp, and symptomatic gastroesophageal reflux and sinus disease. The authors would recommend that all patients with NTM lung disease are offered assessments for impaired immunity (Lake et al, 2016; Haworth et al, 2017). These should include a HIV test and measurement of immunoglobulin blood levels. Further testing can be undertaken as needed or if there are any concerns, generally in conjunction with an immunologist or specialist infection service.
Understanding how NTM itself is affecting the patient's health status is important. Here, nurses can make a considerable impact. For example, a patient with COPD may have long-standing breathlessness and use a large amount of inhaled steroids and start to isolate NTM from their sputum with an increase in productive cough. On review, they may report worsening sore throat and gastroesophageal reflux.
While the NTM may be responsible for breathlessness and increased sputum, the large dose of inhaled steroid that they are using (which may not necessarily be required in this patient) could be impairing the local immunity in the lung, leading to the environmental NTM being able to colonise and produce pulmonary infection. It may also be promoting gastroesophageal reflux. Hence treatment for both the patient's symptoms and the NTM may consider reducing the inhaled steroid dose, with careful patient monitoring. In this particular example, they could also be offered antigastroesophageal reflux management, as the reflux may be also contributing to their lung symptoms.
Another important area of management is ensuring that patients are shown how to effectively clear their sputum. This improves symptoms and quality of life. In many cases, this is likely to reduce their need for both short and long courses of antibiotics. As well as respiratory physiotherapy, services should review their patient's diet, lifestyle and concurrent medication – which may also be contributing to their symptoms and impaired quality of life.
Specific treatment
The decision to initiate specific antimycobacterial treatment should be taken following full discussion with the patient regarding the pros and cons of therapy. This should cover the chance of success, the frequency of adverse events, and the need for regular monitoring during treatment. Some clinicians will recommend the use of quality of life scores before, during, and after treatment. These are useful measures, as in particular frail or elderly people starting treatment can find the drugs difficult to tolerate. Again, nursing care and input is crucial, given that most treatment regimens are for a minimum of 12 months, and more often approaching 2 years, therefore the picture is closer to the management of multidrug resistant TB and requires long-term input and support. Examples of specific regimen are listed in Table 5.
Table 5. Treatment for common non-tuberculous mycobacteria disease
| NTM species | Antibiotic regimen | Comments |
|---|---|---|
| M. avium complex (MAC) |
|
Duration not definitively established (18–24 months) |
| M. kansasii |
|
Treat for 12 months after sputum cultures negative (often total 18–24 months) |
| Rapidly growing mycobacteria |
|
Minimum 6 months' treatment |
American Thoracic Society and Infectious Disease Society of America (2007); British Thoracic Society (2017)
‘Another important area of management is ensuring that patients are shown how to effectively clear their sputum. This improves symptoms and quality of life. In many cases is likely to reduce their need for both short and long courses of antibiotics. As well as respiratory physiotherapy, services should take the opportunity to review their patient's diet, lifestyle and concurrent medication – which may also be contributing to their symptoms and impaired quality of life.’
In general, surgery is used only in specific circumstances – such as when symptomatic, localised lung disease is persisting despite medical therapy.
Follow-up and outcome
People with suspected or known NTM lung disease will be followed up in clinical services for several years. This enables good and supportive links to be made between primary and secondary care. During treatment, monitoring should be performed for adverse events, and the opportunity taken to educate the patient and their carers about these.
As patients may have underlying structural lung disease or an immune deficiency that predisposes them to continued infection and disease, it is generally recommended that even if they are being monitored for NTM without receiving specific treatment, they are reviewed in a service that has an interest in NTM. As a minimum, provision should be made for the patient to get in touch in future with the NTM service should they have any concerns.
Unlike TB, there is limited evidence for transmission of NTM between patients. The reports of this occurring in Cystic Fibrosis Units are concerning, though may reflect transmission in the unit rather than between people attending the service (Bryant et al, 2016). This does, of course, highlight the importance of rigorous infection control and prevention in such settings.
Patient support
NTM management poses challenges for patients and clinicians alike. In response to this, the patient association NTM Patient Care UK was set up with the aim of working to improve the lives of people with NTM infection through education and information that can increase understanding for patients, carers and clinicians. It also seeks to develop a support network for NTM patient communities. Its model is based on the highly successful approach taken by NTM Information and Research in the US. Support networks such as these are crucial if we are to enable patients to understand their condition, and empower them to make educated choices regarding their healthcare.
Conclusion
NTM infection is increasingly recognised as a condition that can cause both pulmonary and extra-pulmonary disease. It is most frequently seen in people with underlying lung disease such as COPD and bronchiectasis. It can result in chronic or recurrent symptoms – the presence of which should trigger appropriate investigation for mycobacterial infection.
Treatment is prolonged and includes general measures such as physiotherapy to reduce ongoing infection and symptoms, as well as specific antimycobacterial therapy. The relatively poor response to the latter highlights the importance of patient-centred care and decision-making in NTM management.
KEY POINTS
- Non-tuberculous mycobacteria (NTM) lung disease is under recognised and an increasingly common respiratory problem. Sending appropriate mycobacterial samples is essential for diagnosis
- A management plan should be patient-centred, taking into account the length of treatment, its potential side-effects and that it may not result in a cure
- Patients require significant skills and support from a variety of clinicians for the duration of their treatment. NTM nursing care falls across a range of nursing specialities
- Patient support through self-help groups is an increasingly important aspect of holistic care and management
CPD reflective practice
- Review the clinical similarities and differences between non-tuberculous mycobacteria (NTM) and mycobacterium tuberculosis (the cause of TB)
- Reflect on the benefits of a multi-disciplinary team approach to the care of patients with NTM
- Consider the challenges a diagnosis of NTM lung disease presents to patients and how the primary care team can provide support