The incidence and prevalence of nontuberculous mycobacterial pulmonary disease (NTM-PD) is on the rise. Even so, NTM-PD is often overlooked as a differential diagnosis by clinicians and radiologists because of its nonspecific clinical features, broad gamut of radiological findings, and the challenges involved in identifying the causative organism.¹

NTM-PD was a principal focus of the 6^th World Bronchiectasis & NTM Conference, which was held in New York City from July 18 to 20, 2023. The conference brought together health care professionals, innovators, and researchers from around the globe for numerous sessions discussing NTM management and research; highlights of those sessions are presented here. Next year’s conference will be held July 4 to 6, 2024, in Dundee, Scotland.

The Respiratory Microbiome as a Target

The respiratory microbiome plays a role in NTM-PD symptoms, pathogenesis, and progression. Moreover, common treatments such as azithromycin, inhaled steroids, and long-acting beta agonists (LABAs) can alter the respiratory microbiome and thus affect treatment response.

“With the addition of inhaled corticosteroids on top of a LABA, you see a change in bacterial load, change in alpha diversity, and an increase in some taxa, such as Streptococcus. CFTR [cystic fibrosis transmembrane conductance regulator] modulators alter the microbiome as well,” said conference presenter Imran Sulalman, MD, PhD, a respiratory physician and member of the Division of Respiratory Medicine at Beaumont Hospital/RCSI in Dublin, Ireland, who spoke on Clinical Application of the Microbiome. “You get a reduction in Pseudomonas and a change in sputum cytokines with these medications. A lot of people love azithromycin but there is a difference in alpha diversity and a significant difference in inflammatory cytokines….Non-pathogenic organisms also affect the response to pathogenic organisms,” he added.

Next-generation sequencing (NGS) is a useful tool for pathogen isolation, and combining whole genome sequencing with RNA sequencing offers data on the airway microbiome, the pathogen, and the host response.

An integrated omics approach, as well as the use of prebiotics and probiotics, could help with the management of NTM-PD, said Dr. Sulalman. Nevertheless, many questions require elucidation including the use of biomarkers in evaluating the respiratory microbiome, what species should be targeted, and whether live microbes should be introduced into the airway.

“The respiratory microbiome is a novel and modifiable therapeutic target. Precision microbiology may represent the next frontier of respiratory medicine,” he reflected.

Medication Burden: 2 vs 3 Drugs

One of the top patient priorities for NTM is to decrease the medication burden, said conference presenter Kevin L. Winthrop, MD, MPH, professor at the School of Public Health at Oregon Health & Science University in Portland. His research comparing 2- vs 3-antibiotic therapy for Mycobacterium Avian complex (MAC)-PD (ClinicalTrials.gov Identifier: NCT03672630) focuses on patient priorities via patient-expert panels and is sponsored by the Patient-Centered Outcomes Research Institute of the US Department of Health and Human Services.

“If you listen to patients, [they will tell you,] ‘We don’t want to take therapy for 18 months. We don’t want to take so many drugs. Do we really need to take so many drugs?’ So we went back and looked at evidence, and there was no evidence for taking any of these drugs except for the macrolides,” he said.

The standard 3-drug regimen is azithromycin/ethambutol/rifampin, whereas the 2-drug regimen consists of azithromycin/ethambutol. Half of patients start with triple therapy, as this is guideline recommended. However, this may be unnecessary, said Dr. Winthrop. There are similar kill rates between the 2 regimens, as well as equal macrolide resistance suppression, per the data. Patients also prefer the 2-drug regimen.

Rifampin increased the risk of adverse effects such as gastrointestinal disturbance, influenza-like symptoms, hypersensitivity, and hepatitis. Dr. Winthrop stressed that because half of his patients are taking clopidogrel (Plavix) or other antiplatelet therapy, rifampin is not an option. Of note, rifabutin is a poor substitute and is poorly tolerated, said Dr. Winthrop.

“The bottom line is that the AUC/MIC [area under the curve/minimum inhibitory concentration] is unattainable with rifampin, given the MIC structure,” stated Dr. Winthrop.

Clinical trial data is limited, although in 2014, Japanese researchers did find that sputum conversion was higher in those taking the 2- vs 3-drug regimen (clarithromycin/ethambutol/rifampin), with sputum conversion rates of 55% vs 40%, respectively. The 2-drug regimen was more tolerable, with 37% discontinuing the 3 drug-regimen vs 26% discontinuing the 2-drug regimen.

“It’s very clear that the preclinical data suggests that rifampin doesn’t do anything. I think the data suggests that rifampin is hard to tolerate and the drug-drug interactions make it difficult to use. I think there is limited human clinical data to support the 2-drug regimen but hopefully in another year, I’ll have some data to show you,” he concluded.

It should be noted that standard antibiotic therapy is not the first step in managing NTM; there are months of preparation first. Patients engage in clearance, hygiene, and education as initial steps. Antibiotics are started after 3 to 6 months, unless the case is severe or there is cavitary disease.²

The Importance of PROs

There’s a growing interest in using patient-reported outcomes (PROs) in the assessment and clinical care of NTM-PD. Currently, PROs are extensively used in cancer trials/clinical practice, rheumatology, and orthopedics. Emily Henkle, PhD, MPH, of the Oregon Health & Science University-Portland State University School of Public Health made the case for the use PROs in NTM-PD during a conference session titled Patient-Centered Research Priorities.

“PROs are a key component of patient-centeredness,” she said. “They are easy and patient-friendly to measure with electronic administration. They are central to clinical care where health-related quality of life (HRQoL) is critical to management.”

PROs are currently the preferred primary outcome for US Food and Drug Administration (FDA) registration trials for MAC-PD. Importantly, the FDA’s draft guidance for MAC-PD from 2021 values clinical vs microbiologic outcomes. PROs need to be reliable, valid, fit-for-purpose, and sensitive to change, and to result in meaningful change for the patient.

“There’s room for the biomarkers, microbiome — all of that is critical. There are a number of places PROS can be used. This is a complementary way to monitor and evaluate patients and track how patients are doing,” said Dr. Henkle.

PROs can measure disease progression, symptoms, health perceptions, fatigue, vitality, symptomatic adverse effects, and so forth. These measures assess how the patient feels, functions, and survives.

Although no PRO for NTM-PD is fully validated, Dr. Henkle’s team is currently working on developing a HRQoL tool based on QOL-Bronchiectasis, NTM Symptoms Module, and PROs-Common Terminology Criteria for Adverse Events (PRO-CTCAE). 

Bottom line

The treatment of NTM-PD is rapidly advancing, with the leverage of omics technology and patient-centered measures like PROs on the horizon. Importantly, the treatment of this underrecognized condition is favoring patient concerns, including preferences for decreased medication burdens such as 2-treatment regimens without rifampin.