Haiqing Chu (PhD), Professor, Chief Physician, Doctoral Supervisor
Head of Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital

Academic Positions：
Executive Member of the Non-Tuberculous Mycobacteria (NTM) Committee, Chinese Medical Association Tuberculosis Branch
Executive Member of the Tuberculosis Translational Medicine Professional Committee, China Anti-Tuberculosis Association
Member of the Infection and Chemotherapy Committee, Shanghai Medical Association
Member of the Internal Medicine Committee, Shanghai Medical Association
Member of the Sports Medicine Committee, Shanghai Medical Doctor Association
Member of the Critical Care Medicine Management Professional Committee, Shanghai Hospital Association
Expert in the Shanghai Science and Technology Expert Database

Major Achievements：
Led over 12 national and provincial-level projects, including those funded by the National Natural Science Foundation
Published over 50 SCI papers as the first or corresponding author in journals such as AAC, JCM, JID, IJAA
Recipient of the Third Prize of the Shanghai Medical Science and Technology Award

Introduction: The diagnosis and treatment of NTM disease should adhere to guidelines and be personalized based on individual patient responses.

Nontuberculous mycobacteria (NTM) constitute a diverse group of mycobacteria, excluding the Mycobacterium tuberculosis complex and Mycobacterium leprae. NTM disease is an infection caused by NTM, characterized by pathological changes in tissues and organs¹, with NTM pulmonary disease being the most common manifestation.

In recent years, advancements in diagnostic competencies have led to increasing reports of the incidence and prevalence of NTM disease. In certain countries and regions, NTM infection has surpassed tuberculosis, emerging as a significant public health concern. In this edition, we have invited Professor Haiqing Chu from the Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, to share her insights on the diagnosis and anti-infective treatment for NTM disease.

Rising trend in NTM disease calls for attention to at-risk groups
Professor Haiqing Chu highlighted that international studies have indicated a continuous rise in the incidence of NTM. However, as NTM disease is not a notifiable disease in China, coupled with the lack of recent large-scale epidemiological studies, the exact epidemiological data for NTM disease remains unknown. According to the National Tuberculosis Epidemiological Survey conducted in 2010, the isolation rate of NTM is as high as 22.9%¹, significantly surpassing the rates reported in 1979 (4.3%) and 2000 (11.1%). This indicates a rising trend for the prevalence of NTM disease.

NTM comprise a diverse group, with over 190 species. Since the majority of these pathogens are considered opportunistic, the risk of infection is strongly associated with host and environmental factors. Host factors include underlying lung diseases (such as bronchiectasis, cystic fibrosis, interstitial lung disease, pulmonary alveolar proteinosis, chronic obstructive pulmonary disease, asthma, etc.), connective tissue diseases, gastroesophageal reflux, tumors, organ transplantation, as well as radiotherapy, chemotherapy and immunotherapy. Environmental factors include trauma, plastic surgery, injections, acupuncture, etc.

It should be noted that some conditions that may seem unrelated to NTM diseases can act as both causative factors and consequences of NTM disease, establishing a bidirectional cause-and-effect relationship. As an example, structural changes after chest surgery may lead to poor chest drainage, creating conditions predisposing patients to NTM infection. Patients undergoing tumor-related radiotherapy, chemotherapy and organ transplantation may experience impaired immune function, which increase their risk of NTM infection. Notably, NTM disease is one of the most significant death-related factors for organ transplant recipients.

Professor Haiqing Chu emphasized that, given the diversity of risk factors, clinicians should be vigilant about the possibility of NTM diseases when treating certain patients. For instance, patients undergoing non-standard invasive plastic surgeries or acupuncture procedures with non-disposable needles should be monitored for potential NTM infections due to inadequate disinfection. Specific populations such as fishermen and agricultural workers should also be mindful of NTM disease caused by environmental factors.

Standardizing the diagnosis of NTM disease: From clinical practice to guidelines
Currently, the diagnosis and treatment of NTM pulmonary disease mainly refer to the “Guidelines for diagnosis and treatment of non-tuberculous mycobacteria disease (2020 Edition)” by the Tuberculosis Branch of the Chinese Medical Association¹, as well as the “Treatment of non-tuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline” ² issued in 2020.

The diagnosis of NTM pulmonary disease necessitate a comprehensive assessment of clinical manifestations, radiological findings, microbiology, and pathological examination results. Common clinical symptoms of NTM pulmonary disease include cough, sputum production, chest tightness, chest pain, night sweats, low-grade fever, and poor appetite. Symptoms vary in severity, and some patients may be asymptomatic. Radiological findings in the chest are diverse, including multiple small nodules, bronchiectasis (especially in the right middle lobe and left lingular segment), cavities, and other lesions that may indicate NTM pulmonary disease.

Microbiological examinations are essential for the diagnosis of NTM pulmonary disease. The specimen sources primarily fall into four categories: 1) Sputum specimens, two independent sputum samples must be tested positive for NTM culture and be identified as the same species; 2) Bronchoalveolar lavage fluid specimens, a single positive result in NTM culture and/or molecular biology detection is required; 3) Lung biopsy specimens exhibiting characteristic histopathological changes of NTM disease (granulomatous inflammation or acid-fast staining positivity), with a positive NTM culture and/or molecular biology detection; 4) Lung biopsy specimens exhibiting characteristic histopathological changes of NTM disease (granulomatous inflammation or acid-fast staining positivity), with one or more positive NTM culture and/or molecular biology detection results in sputum/bronchial flushing fluid/bronchoalveolar lavage fluid.

It should be emphasized that although NTM and tuberculosis are both acid-fast positive mycobacteria, tuberculosis is infectious, whereas NTM are typically non-communicable opportunistic pathogens. Despite this distinction, they share similar clinical symptoms and manifestations on radiology, making clinical differential diagnosis challenging. Tests such as T-cell interferon-gamma release assays (T-SPOT test) and X-pert MTB/RIF can be helpful in distinguishing tuberculosis. The most important aspect is to clearly identify the pathogen. Obtaining high-quality specimens is crucial, including uncontaminated tissue specimens obtained through techniques such as bronchoscopy-guided lung biopsy, endobronchial ultrasound-guided transbronchial needle aspiration, percutaneous lung puncture, bronchoalveolar lavage fluid, and lower respiratory tract specimens.

Historically, the diagnosis of NTM diseases has been challenging due to the need for precise and specific culture processes, which may take up to two months, a period unrealistically lengthy for patients. Moreover, specimen acquisition posed a major problem, prompting many hospitals to abandon auxiliary diagnostic techniques for NTM disease. However, with the advent of next-generation sequencing (NGS) and improvements in molecular biology techniques, rapid and optimized diagnosis of NTM disease has been made possible.

Can a positive culture result for NTM alone confirm the diagnosis of NTM disease? Professor Haiqing Chu pointed out that it is necessary to consider the type of specimen, bacterial colonization, and the possibility of specimen contamination. Furthermore, the interpretation of results must adhere to the principles of etiological diagnosis. Relying solely on a single positive sputum culture result is insufficient for diagnosis. If NTM is cultured from bronchoalveolar lavage fluid, blood, or tissue fluid, diagnosis can be established through comprehensive assessment of clinical and radiological findings. Thus, clinicians must meticulously diagnose NTM disease, avoiding both overdiagnosis and missed diagnosis.

Breakthroughs in treating NTM disease in a high drug-resistance environment
There are two standard criteria for the resolution of NTM pulmonary disease: clinical cure and absence of pathogenic microorganism growth, the latter being pivotal. Currently, NTM is being categorized as highly drug-resistant. Faced with this clinical challenge, Professor Haiqing Chu emphasized the need to differentiate between different types of NTM, including rapidly growing mycobacteria (represented by Mycobacterium abscessus) and slow growing mycobacteria (including Mycobacterium intracellulare, Mycobacterium avium, Mycobacterium kansasii, etc.). Treatment regimens should be tailored to the specific pathogen, as detailed in the “Guidelines for diagnosis and treatment of non-tuberculous mycobacteria disease (2020 Edition)”. For instance, for Mycobacterium kansasii infection, rifampin susceptibility testing is recommended for treatment-naïve patients. For patients insensitive or resistant to rifampin, different treatment drugs are recommended. Sensitive patients may opt for rifampin, isoniazid /clarithromycin, or ethambutol, while resistant patients are recommended to administer moxifloxacin, azithromycin/clarithromycin, ethambutol, and clofazimine/linezolid. Considering community resistance to moxifloxacin, alternative quinolones may be considered. The guidelines advocate substitution with a similar drug in the presence of resistance.

Similarly, treatment approach for Mycobacterium abscessus complex should be selected based on the sensitivity or resistance to macrolides (Daley et al, 2020). For macrolide-sensitive patients, the initial treatment phase should include a combination of at least three active drugs including macrolides, including at least one injectable drug (amikacin, imipenem/cefepime, tigecycline), and oral drugs (azithromycin/clarithromycin, clofazimine, linezolid), with a treatment course of at least one month. The continuation phase should include 2-3 oral/inhaled active drugs. For macrolide-resistant patients, one or more active drug should be added in both the initial and continuation phases. Despite macrolide resistance, macrolides such as azithromycin/clarithromycin should still be included in the treatment plan due to their immunomodulatory activity. The guidelines stipulated the treatment duration as one year following the conversion of sputum culture to a negative status. Due to the lengthy treatment course, adverse reactions such as impaired liver and kidney functions, hematologic abnormalities, peripheral neuropathy, etc., should be monitored. If a patient cannot tolerate the treatment, strict adherence to the guidelines should not be mandatory; instead, the treatment plan should be adjusted based on drug susceptibility tests.

Regarding the quinolones recommended in the guidelines, Professor Haiqing Chu’s team conducted a research on nine quinolones, including sitafloxacin, nemonoxacin, moxifloxacin, levofloxacin, gatifloxacin, garenoxacin, ciprofloxacin, sparfloxacin, and delafloxacin. They conducted in vitro and cellular tests on NTM, revealing that sitafloxacin exhibited favorable Minimum Inhibitory Concentration (MIC) results against rapidly growing mycobacteria as Mycobacterium abscessus and slow growing mycobacteria such as Mycobacterium intracellulare, Mycobacterium avium ─ being only 1/4 or even 1/16 of similar drugs. Intracellular experiments on Mycobacterium abscessus suggested that the intracellular action of sitafloxacin is equivalent to clarithromycin, rendering it suitable for continuous treatment and as an equivalent alternative to the recommended quinolones in the guidelines.

Summary
Given the complexity and challenges of treating NTM pulmonary disease, adherence to guidelines and standardization of treatment are especially crucial. Clinical treatment plans should take into account factors such as the patient’s condition, NTM drug sensitivity, comorbidities, and drug tolerance. This approach aims to optimize treatment regimens and deliver precise therapies, which potentially leads to the cure of NTM pulmonary disease and enhancing the well-being of patients with NTM.

References：
1. Chinese Medical Association Tuberculosis Branch. [Guidelines for the Diagnosis and Treatment of Non-Tuberculous Mycobacterial Diseases (2020 edition)]. Chin J Tuberc Respir Dis. 2020, 43(11): 918-946.
2. Daley CL, Iaccarino JM, et al. Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline. Clin Infect Dis. 2020 Aug 14;71(4):e1-e36.