Benefits of early treatment initiation in non-tuberculous mycobacterial pulmonary disease (NTM-PD)

Treatment of non-tuberculous mycobacterial pulmonary disease (NTM-PD) with antimicrobial agents offers the possibility of cure.¹ In patients who meet the clinical, radiographical and microbiological diagnostic criteria for NTM-PD, the 2020 ATS/ERS/ESCMID/IDSA clinical practice guideline for NTM-PD recommend initiation of treatment rather than watchful waiting.¹ Initiation is especially important in the context of positive acid-fast bacilli sputum smears and/or cavitary lung disease¹as there may be an increased rate of progression and poor treatment outcomes if treatment is delayed.¹

Evidence of disease progression in untreated MAC-PD

Several studies have shown that most patients diagnosed with Mycobacterium avium complex pulmonary disease (MAC-PD) have progressive disease resulting in the need for antibiotic treatment.^2,3 In a recent study of 488 newly diagnosed patients at the Asan Medical Center in South Korea, 305 (62.5%) patients showed progressive MAC-PD resulting in treatment initiation within 3 years of diagnosis.² Similarly, in another study of 40 untreated patients with the nodular bronchiectatic form of MAC-PD (most with minimal symptoms), who underwent serial chest computed tomography (CT) scans for a minimum of 4 years, 39 (97.5%) experienced disease progression with a significant increase in overall CT score.³ It is noted in the 2020 NTM-PD guidelines that some subgroups (minimal nodular/bronchiectatic disease) may be safely, but regularly, followed without antimicrobial therapy; however, those with cavity disease should always receive prompt antibiotic treatment.¹

Factors influencing the decision to initiate treatment

The decision to treat may be influenced by both host factors and infecting bacterial species. Certain factors like cavitary disease and low body mass index have been associated with progressive disease and may necessitate earlier consideration of antibiotic treatment.² In very frail patients with very mild nodular bronchiectatic disease, the balance between efficacy and tolerability may favour watchful waiting.¹

The clinical relevance of NTM varies significantly between species (Figure 1) and may also differ geographically.^1,4 For example, species such as M. gordonae have low pathogenicity and rarely cause disease in humans, whereas M. kansasii is highly pathogenic.^1,4  

Figure 1. Clinical relevance (the percentage of patients with isolates of these species that meet the ATS/IDSA diagnostic criteria) of non-tuberculous mycobacterial species. M., Mycobacterium. Adapted from Zweijpfenning (2018).⁵

The most common NTM pathogens include MAC, M. kansasii and M. xenopi among the slowly growing NTM and M. abscessus among the rapidly growing NTM.¹

Meeting the guideline-recommended diagnostic criteria for NTM-PD

Diagnostic criteria within the guideline is based on:

• Clinical symptoms e.g. worsening of symptoms of underlying lung conditions, or onset of new, persistent symptoms in patients at risk of NTM-PD e.g. haemoptysis, weight loss, fatigue
• Radiological findings on X-ray or hight-resolution CT scan such as nodular or cavitary opacities
• Microbiological findings from a) at least two expectorated sputum or b) positive culture from at least one bronchial wash or lavage or c) positive culture for NTM and biopsy from transbronchial or lung biopsy plus one or more culture positive sputa or bronchial washing.

Patients suspected of having NTM-PD who do not meet the diagnostic criteria should be actively managed and followed with serial CT scans until the diagnosis is firmly established or excluded and should start or continue recommended techniques such as airway clearance.⁶

The decision to initiate antibiotic treatment

NTM-PD is associated with diminished health-related quality of life that correlates with severity of lung impairment;⁷ antimicrobial treatment may be associated with improvement.⁸

NTM-PD treatment decisions are often difficult and require experience in managing the disease. This can mean that it may be necessary for a peer consultation or referral to a pulmonologist or infectious disease specialist with experience in NTM-PD.^1,9 The virulence and potential for progressive disease must be evaluated once the NTM species is identified in order to determine treatment. In the 2020 ATS/ERS/ESCMID/IDSA clinical practice guideline for NTM-PD for example, it is recommended that for species of low pathogenicity such as M. gordonae, treatment is only indicated if repeated positive cultures over several months are observed, along with strong clinical and radiological evidence of disease whereas in many patients only one positive M. kansasii sputum culture may be required in order to initiate treatment.¹ Similarly, clinically significant MAC-PD is unlikely in patients who have a single positive sputum culture during the initial evaluation but can be as high as 98% in those with ≥2 positive cultures.¹ Two or more MAC-positive cultures indicate active MAC infection requiring a treatment decision, whereas for patients identified with M. kansasii, treatment should be initiated as soon as a single positive culture is obtained.¹

Regardless of the infecting organism, the decision to initiate antibiotic treatment should be individualised considering the patient’s symptoms, the pathogenicity of the organism, radiological findings, microbiological results and importantly, the patient’s wish and ability to receive treatment as well as the goals of therapy.¹ Any treatment decision should include a discussion with the patient that outlines the potential side-effects of antimicrobial therapy, the uncertainties surrounding the benefits of antimicrobial therapy and the potential for recurrence including reinfection (particularly in the setting of nodular/bronchiectatic disease).¹ Guidelines recommend regular sputum cultures and routine monitoring to assess disease progression.¹

Following treatment initiation, sputum specimens should be obtained for culture every 1 to 2 months to document when sputum cultures become negative and to survey for the appearance of other organisms. ¹

Clinical and radiographical assessments should be performed alongside the microbiological assessments to determine if the patient is responding to therapy.¹

Retrospective studies have shown that most patients with MAC-PD who convert on treatment do so within 6 months of starting treatment.^11–13

If you decide not to initiate antibiotic treatment, an active monitoring plan is recommended by the guidelines.¹ Study data suggest that untreated NTM-PD could progress.^2,3

References:

1. Daley Cl, et al. Clin Infect Dis 2020;71:e1–e36.
2. Hwang JA, et al. Eur Respir J 2017;49:1600537.
3. Park TY, et al. PLoS One 2017;12:e0185774.
4. van Ingen J, et al. Thorax 2009;64:502–6.
5. Zweijpfenning SMH, et al. Semin Respir Crit Care Med 2018;39:336–42.
6. Lipman M, et al. BMJ Open Respir Res 2020 ;7 :e000591
7. Mehta M, Marras TK. Respir Med 2011;105:1718–25.
8. Czaja CA, et al. Ann Am Thorac Soc 2016;13:40–8.
9. Ryu YJ, et al. Tuberc Respir Dis 2016;79:74–84.
10. Lee MR, et al. Clin Microbiol Infect 2015;21:250.e1–250.e7.
11. Furuuchi K, et al. Chest 2020;157:1442–5.
12. Koh WJ, et al. Eur Respir J 2017;50:1602503.
13. Moon SM, et al. Eur Respir J 2019;53;1801636.

Medical writing and editorial support was provided by Highfield, Oxford, UK. This support was sponsored by Insmed.

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Impact of non-tuberculous mycobacteria (NTM) on at-risk patients

Non-tuberculous mycobacteria (NTM) can cause serious pulmonary disease in at-risk patients, which can have a significant impact on health-related quality of life, morbidity and mortality, and increase disease progression in patients with structural lung diseases. Understanding who is at risk can facilitate earlier diagnosis and treatment, which is crucial in preventing disease progression and lung function decline.

Non-tuberculous mycobacteria (NTM) are opportunistic infections that can cause infection at a wide range of body sites in patients who have underlying disease or are immunosuppressed.¹ Inhalation of some NTM species in vulnerable people can cause non-tuberculous mycobacterial pulmonary disease (NTM-PD)². NTM-PD can be caused by a variety of mycobacterial species, the most common of which is the Mycobacterium avium complex (MAC), which comprises two main species M. avium and M. intracellulare. In one study of 62 centres in 30 countries of 18,418 isolates MAC-PD accounted for 47% of incidences of NTM-PD.³ 

How does NTM-PD have an impact on quality of life?

NTM-PD can be a significant burden on patients. Patients with NTM-PD, including MAC-PD, may have reduced lung function, increased morbidity and mortality, and reduced health-related quality of life (HRQoL) compared with the general population.^3,4–11

All-cause mortality in patients with NTM-PD can be up to four times higher than the general population, independent of other factors.^10–12 For MAC-PD, studies showed a pooled estimate of five-year all-cause 5-year mortality of 27%.² NTM-PD can also cause a significant reduction in patients’ lung function.^7–9 Patients with NTM-PD have been shown to experience a more substantial reduction in forced expiratory volume in 1 sec (FEV₁) compared with those without NTM-PD.⁸ In one study where patients with mild disease were considered not to require treatment, chronic NTM infection caused a substantial decline in lung function over time.⁷ NTM-PD is associated with a lower HRQoL compared with the general population, with these patients demonstrating higher scores using the St. George’s Respiratory Questionnaire (SGRQ) and lower scores using the Medical Outcomes Study 36-item Short Form Survey (SF-36).^4,13 In one study, SGRQ scores in patients with NTM-PD were over 25 points worse compared with normal values.¹³ Another study showed that patients eventually requiring treatment for their NTM-PD had worsening SGRQ scores, suggesting an association between disease progression and lower HRQoL.⁴

Who is most at risk of NTM-PD?

Understanding who is at increased risk of NTM-PD can help in early recognition and diagnosis of disease. High-risk groups include tall, elderly women with a low body mass index (BMI) and abnormalities of the skeleton for example, conditions such as abnormal spinal curvatures (scoliosis, kyphosis) and structural abnormality of the chest where the sternum is pressed inward (pectus excavatum) – so-called Lady Windermere syndrome – patients with underlying lung conditions such as bronchiectasis and chronic obstructive pulmonary disease (COPD), and immunocompromised and immunosuppressed patients; exposure to NTM species is much more likely to cause disease in these groups.^6,14–16

Patients with low BMI

There is an association between NTM-PD and marfanoid characteristics of elderly female patients who are taller than average with low body weight, as well as those with thoracic skeletal abnormalities; low body weight alone increases risk of NTM-PD by three-fold and thoracic abnormalities five-fold.^17,18 In patients with NTM-PD, low BMI (<18.5 kg/m²) has been associated with the presence of multiple NTM isolates as well as a lower chance of treatment success.^4,5 In addition, patients with lower BMI are more likely to fail treatment for their NTM-PD.⁴

Transplant recipients

NTM can also cause disease in immunosuppressed patients who are recipients of organ or stem cell transplants.⁶ Rates of NTM infections in lung transplant recipients are particularly high, and have been shown to increase post-transplant mortality, with an estimated 5-year mortality of 50%.⁶

Patients with structural lung diseases

NTM can cause pulmonary disease in patients with pre-existing underlying lung conditions, such as those with bronchiectasis (44.0–187.5 increased risk) and COPD (2.0–10.0 increased risk).^15,16 Infection and inflammation caused by NTM in such patients can lead to deterioration of pulmonary function, causing faster disease progression compared with patients without NTM-PD.⁵ In one study, the presence of multiple NTM isolates in patients with COPD has been associated with a greater decline in FEV₁ as well as an increase in exacerbations requiring hospitalisation compared with the absence of isolates.⁵

Act now for your at-risk patients

Early diagnosis and treatment of NTM-PD is crucial in preventing disease progression and declining lung function.¹⁹

NTM-PD is often misdiagnosed or diagnosed late, as symptoms of NTM-PD are similar to those of coexisting lung disease and may be present for more than 10 years before diagnosis; increasing testing for your at-risk patients may lead to a higher chance of spotting NTM-PD early.^20,21 In a survey of 280 hospital-based physicians, the majority perceived NTM-PD as a significant factor for worsening respiratory function, increasing morbidity and hospitalisation in patients with bronchiectasis, although fewer perceived NTM-PD as having a significant impact on mortality.²² However, the mortality rate for NTM-PD and in particular MAC-PD is high (up to 27%),² so recognising the risk of NTM-PD and testing your at-risk patients is important, as missing a diagnosis can lead to worse long-term outcomes for your patients, including increased risk of death.

At-risk patients with underlying lung conditions such as COPD or bronchiectasis may receive long-term macrolide monotherapy to prevent exacerbations of underlying disease.²³ One study indicated that 42% of patients with bronchiectasis received macrolide monotherapy, however, macrolide monotherapy is not recommended in patients with NTM-PD because of the increased chance of macrolide resistance.²²

Guidelines for managing bronchiectasis outline that any patient being considered for macrolide therapy for exacerbations should be screened for underlying NTM to rule out infection and protect antimicrobial susceptibility for NTM therapy.²³ 

Currently, 68% of healthcare professionals do not test their patients for NTM-PD prior to initiating macrolide treatment, despite 87% perceiving these patients to be at particular risk of NTM infection.²² In fact, macrolide monotherapy is one of the major predispositions for macrolide-resistant MAC,²⁴ so testing your at-risk patients for NTM-PD prior to initiating macrolide monotherapy is essential to reduce the emergence of macrolide-resistant NTM-PD and to increase the chance of cure. In patients with macrolide-resistant NTM-PD, treatment outcomes are poor, with an estimated all-cause 5-year mortality rate of 47%.²⁵

References:

1. Centers for Disease Control and Prevention. Nontuberculous mycobacteria (NTM) infections. https://www.cdc.gov/hai/organisms/nontuberculous-mycobacteria.html [Accessed March 2021]
2. Diel R, et al. BMC Infect Dis 2018;18:206.
3. Hoefsloot W, et al. Eur Respir J 2013;42:1604–13.
4. Kwak N, et al. BMC Pulm Med 2020;20:126.
5. Huang CT, et al. Int J Tuberc Lung Dis 2012;16:539–45.
6. Friedman DZP, et al. Transpl Infec Dis 2020;22:e13229.
7. Park HY, et al. Chest 2016;150:1222–32.
8. Kobayashi T, et al. J Clin Tuberc Other Mycobact Dis 2018;11:17–21.
9. Lee MR, et al. PLoS One 2013;8(3):e58214.
10. Marras TK, et al. Respir Med 2018;145:80–8.
11. Fleshner M, et al. Int J Tuberc Lung Dis 2016;20:582–7.
12. Diel R, et al. Eur Resp J 2017;49:1602109.
13. Mehta M, et al. Resp Med 2011;105:1718–25.
14. Aksamit TR, et al. Chest 2017;151:982–92.
15. Andrejak C, et al. Thorax 2013;68:256–62.
16. Prevots DR, et al. Clin Chest Med 2015;36:13–34.
17. Dirac MA, et al. Am J Respir Crit Care Med 2012;186:684–91.
18. Axson EL, et al. Eur J Clin Microbiol Infect Dis 2019;38:117–24.
19. Park TY, et al. PLoS One 2017;12:e0185774.
20. Kotilainen H, et al. Eur J Clin Microbiol Infect Dis 2015;34:1909–18.
21. Griffith DE, et al. Am J Respir Crit Care Med 2007;175:367–416.
22. Wagner D, et al. BMJ Open Respir Res 2020;7:e000498.
23. Smith D, et al. BMJ Open Resp Res 2020;7:e000489.
24. Griffith DE, et al. Curr Opin Infect Dis 2012;25:218–27.
25. Moon SM, et al. Antimicrob Agents Chemother 2016;60:6758–65.

Medical writing and editorial support was provided by Highfield, Oxford, UK. This support was sponsored by Insmed.