NTM: The Macrophage Invader
How does NTM cause infection?
Equal in prevalence to pseudomonas and potentially severely impacting both health-related quality and length of life, yet not receiving the same degree of attention, Non-tuberculous mycobacteria (NTM) could be considered the poor relation of lower respiratory tract infections (LRTIs). Responsible for exacerbating underlying respiratory disease, increasing hospital admissions and leaving patients housebound due to persistent symptoms, NTM pulmonary disease is chronic, isolating and can be debilitating. This is an extremely dire situation for both patients living with the disease and the healthcare practitioners involved in its management.
NTM are naturally occurring organisms capable of causing serious infections, the most common manifestation of which is in the lungs accounting for 70-80% of all NTM infections.1 2 3 4 The incidence of pathogenic NTM isolates in the UK was 6.3 per 100,000 which is comparable to that of Pseudomonas Spp. at 6.4 per 100,000, recorded in 2012 and 2013 respectively.5 6 Species within the genus Pseudomonas are amongst the most researched bacteria in the scientific community, meaning that awareness is high.7 Although rising, awareness of NTM on the other hand, is still suboptimal and compliance with guidelines is very poor globally.8
Most evidence suggests that NTM infections are not transmitted from person to person and are instead acquired from the environment, leading to lung entry.1 2 9 Whereas, in healthy individuals, NTM organisms are cleared from the lungs naturally and do not cause infection, patients with underlying lung disease may be predisposed to NTM pulmonary disease due to chronic epithelial cell inflammation and impaired mucociliary clearance.1 2 9 10 11 12
NTM bacteria can invade lung tissue and intracellular pulmonary compartments, specifically macrophages, where they can subvert normal cellular defence mechanisms, replicate, and cause chronic infections. Additionally, NTM may also live as planktonic mycobacteria and assemble in biofilm colonies in the mucus and alveolar walls of lung tissue.13 14 15 16 17 Find out more about the mechanism of disease action by watching this short video.
Some would say, the only thing worse than having NTM, is not knowing you have NTM. Why? NTM pulmonary disease follows a chronic course with the occurrence of progressive structural lung damage, leading to symptomatic and radiological deterioration, and in a significant proportion of patients, mortality.18 However, variable rates of testing combined with symptoms being similar to underlying lung disease leads to significant numbers of patients being either misdiagnosed or not diagnosed at all.1 2 3 19 20 For example, in bronchiectasis patients, who are recommended to be tested for NTM by both British Thoracic Society (BTS) and European Respiratory Society (ERS) guidelines, only 17.2% of UK patients enrolled in the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) registry were actually tested for NTM at least once. The percentage of patients tested varied substantially between regions, with the lowest rate being 8.3% in Northern Ireland, and the highest rate being 35.5% in Scotland.20
Due to the fact that NTM invades macrophages, treatment can be complex. The majority of antibiotics used in the treatment of NTM pulmonary disease display poor intracellular activity as a result of their hydrophilicity leading to poor diffusion through cell membranes.21 NTM pulmonary disease is therefore treated with a combination of drugs which are dependent on the species of NTM present.10 Although cure rates are dependent on both the species of NTM and the regimen used,22 23 some studies suggest that treatment provides improved radiological and mortality outcomes compared to no treatment and a delay in commencing recommended therapy can lead to severe consequences.18 24 25 In one particular study of 40 untreated nodular bronchiectatic Mycobacterium avium complex (MAC) pulmonary disease patients who did not receive NTM therapy due to minimal symptoms, 97.5% experienced radiographic disease progression over an average of 6 years.25 Another study investigating radiographic changes in MAC pulmonary disease patients found that persistent culture positivity is associated with increased rates of radiographic progression compared to conversion to culture negative status.26
Despite the significant impact NTM pulmonary disease can have on health-related quality of life and the deterioration witnessed when therapy is delayed, adherence to treatment guidelines in the UK is poor. Approximately half of the patients in primary care are not receiving guideline recommended therapy for NTM pulmonary disease and 14% of patients are receiving no treatment at all.27