Masterclass 8 - Mycobacteria: the Past, Present and Future

Tuberculosis (TB) is an ancient disease but humanity still suffers from it. Prevention of infection and progression to TB disease is crucial in controlling the global TB epidemic. Though BCG is still the only licensed TB vaccine available, promising work is in progress in the development of novel effective and safe TB vaccine. Newer diagnostics like IGRA and TBST could facilitate the identification of high-risk people infected by TB who will benefit from preventive TB treatment (PTT). Shorter rifamycin containing regime for PTT could enhance patient adherence and ensure completion of the planned treatment. Molecular based technique has revolutionized the diagnosis of drug resistant, especially MDR-TB which conventionally required phenotypic, culture-based method with delay in commencement of appropriate anti-TB treatment. Newer and shorter regimens of anti-TB treatment for both drug sensitive and drug resistant TB have been shown to be effective and safe and incorporated into the latest guidelines. Multiple studies on new and repurposed anti-TB drugs are in the pipeline. Video or electronic supported directly observed therapy is advocated to enhance patient adherence to anti-TB treatment. Host directed therapy opens a new window for the effective treatment of TB. Application of artificial intelligence in management of TB patients from screening, diagnosis, prognostication and regimen determination brings hope to accomplish the goal of TB elimination.   

Drug-resistant tuberculosis (DR-TB) is still a significant global health threat, posing challenges to public health systems worldwide. The emergence of DR-TB is primarily driven by delayed diagnosis, inadequate treatment regimens and poor drug adherence. Since rifampicin is the key first-line drug for shortening treatment duration, the impact of mycobacterium tuberculosis resistant to rifampicin is crucial.
Globally, the treatment success rate of rifampicin-resistant/multidrug-resistant TB (RR/MDR-TB) patients has been low. The long treatment duration and toxicities associated with second-line regimens are well-known barriers that hinder drug compliance and favourable treatment outcomes. Although recent advancements in molecular testing and the development of novel medications offer hope for better control of RR/MDR-TB, their accessibility remains problematic. While recent clinical trials, such as the ZeNix, TB-PRACTECAL, BEAT-TB and EndTB, have identified shorter and safer all-oral regimens, further evidence for generalizing these promising results to diverse populations is awaiting.
There have also been reports of emerging resistance to newer drugs (e.g. linezolid, bedaquiline resistance), highlighting the need to strengthen drug susceptibility testing to second line drugs. When a substantial rate of resistance to these novel drugs is observed, the development of the next cascade of new drugs and regimens will be imperative. 
In Hong Kong, with all the concerted efforts, the rate of RR/MDR-TB has remained low at around 1% of all culture-confirmed TB cases. The main strategies of local RR/MDR-TB control include early identification of RR/MDR-TB by molecular testing, prompt initiation of effective second-line treatment regimen, strictly implemented directly observed therapy and the adoption of a close surveillance system. Our local experience in using the new RR/MDR-TB regimens will be discussed in the meeting.

Non-tuberculous Mycobacteria (NTM) represent an escalating public health challenge that warrant attention from clinicians, researches, and public health officials. Alongside the notorious tuberculosis and leprosy, NTM belong to the same family of Mycobacteriaceae. Unlike their pathogenic relatives, NTM represents a diverse group of free-living environmental organisms that were once considered harmless saprophytes, but they are now recognized as significant opportunistic pathogens capable of causing a wide range of infections, most commonly causing NTM pulmonary disease (NTM-PD) in susceptible hosts, and less commonly in otherwise healthy individuals. Extra-pulmonary NTM diseases are increasingly reported, which are often related to medical procedures. With improved diagnostic techniques, heightened awareness among healthcare providers, changes in environmental exposure, and an aging population with more individuals susceptible to NTM infections, its global incidence has been on a rise. However, the published data may have underestimated its true incidence due to underdiagnoses and it not being a notifiable disease. 


To date, approximately 200 different species of NTM have been identified. The clinical management of NTM-PD could be challenging. The presenting symptoms are often non-specific. Isolation of NTM from respiratory samples does not always indicate active disease, complicating treatment decisions. Diagnosing NTM-PD requires combination of clinical, radiological, and microbiological assessment, which could be complex and require input from respiratory specialist. Furthermore, they are notoriously difficult to treat, with high rates of antibiotic resistance and require prolonged, complex treatment regimens which could lead to significant side effects and poor patient adherence. Variable treatment response and reinfection could be frustrating to both physicians and patients. 


As such, NTM infection represent a significant public health concern that requires ongoing researches to improve diagnostic efficacy, develop new effective therapeutic strategies, and identify efficient preventive strategies. Multidisciplinary collaboration among clinicians, epidemiologists, and microbiologists would be essential in tackling this growing burden. 

结核病（TB）是全球重大公共卫生挑战之一。团队以临床问题为导向，针对结核病防治中的"卡脖子"问题，聚焦结核发病机制和诊治新技术，借助"国家感染性疾病临床医学研究中心"这一高端平台，整合资源，协同攻关，在结核病原创性研究中取得一定成绩，学术贡献如下：（1）阐明干扰素应答在结核免疫应答中的调控作用和机制；（2）鉴定多个结核易感基因及宿主定向治疗靶点，提出靶向"肺-肠轴"控制结核感染的理论并完成概念验证；（3）开发基于CRISPR和全基因测序的结核诊断技术，制定基于γδT细胞的结核病宿主定向治疗新策略。团队研究成果入选教育部、广东省、深圳市等各级奖励，为结核病的精准防控和个体化治疗提供重要理论依据和科学支撑。Tuberculosis (TB) is one of the major public health challenges. The team is guided by clinical issues and focuses on the "bottleneck" problems in TB. Under the platform of National Clinical Research Center for Infectious Diseases, it integrates resources and collaborates with partners to make innovative achievements in TB research. The academic contributions are as follows: (1) Clarify the regulatory roles and mechanism of interferon response in TB; (2) Identify multiple TB susceptible genes and host-directed therapy targets, propose the theory of targeting the "lung-intestine axis" to control TB and complete the proof of concept; (3) Develop TB diagnostic technology based on CRISPR and whole-genome sequencing, formulate a new cellular therapy strategy for TB using γδT cells. The research achievements were selected into awards at various levels such as the Ministry of Education, Guangdong Province, Shenzhen City, etc., providing important theoretical basis for the precise prevention and individualized treatment of TB.

Macao has achieved a sustained downward trend in TB incidence, with an average annual decline rate of 4%. Treatment coverage and success rates remain high, while drug resistance, mortality, and loss to follow-up rates are comparatively low.


But TB continues to be a major public health challenge in Macao, driven by an aging population, a large migrant workforce, and increasing comorbidities. To address these issues, key strategies have been implemented, including screening of contactor and high-risk groups, and the expansion of LTBI treatment, etc.