The story of Professor Lu Shuihua's team's efforts to tackle tuberculosis

Professor Lu Shuihua

The history of human struggle against tuberculosis is also the history of blood and tears of medical progress. While TB threatens human life and health, it also promotes scientific and technological progress and technological innovation. The theme slogan of the 2022 World Tuberculosis Day issued by the National Health Commission is "Life first, all people take action, share health, and end tuberculosis", which is the call of the motherland and the inevitability of history. Whether mankind can eventually defeat it depends on the close combination of the public's knowledge and action of tuberculosis and the scientific and technological innovation tools for tuberculosis. On the occasion of the 27th "World Tuberculosis Day", the "China Medical Forum" specially invited Professor Lu Shuihua, the incoming chairman of the Tuberculosis Branch of the Chinese Medical Association, deputy director of the National Clinical Medical Research Center for Infectious Diseases, and director of the Department of Pulmonary Medicine of Shenzhen Third People's Hospital, to share the results of innovation and transformation in the field of tuberculosis prevention and control over the years, look forward to the future development direction of tuberculosis scientific and technological innovation, and send a message to young medical workers fighting on the front line of tuberculosis prevention and control, to maintain the spirit of exploration, improve innovation, and strive to provide more powerful scientific and technological innovation tools for defeating tuberculosis.

Part I

Eliminating the dross and retaining the essence, opening a new chapter in tuberculosis immunodiagnosis

In recent years, Professor Lu Shuihua's team has conducted systematic and detailed research on the immune diagnosis of tuberculosis, localized the immune diagnosis technology in light of China's national conditions, and achieved breakthrough progress in early diagnosis, precise diagnosis, precise intervention of latent infection and preventive medication, as well as the innovation, transformation and promotion of tuberculosis vaccines.

Three innovative tools break through the defense line, making early diagnosis and accurate diagnosis a reality

China is one of the countries with a high burden of tuberculosis. The population of tuberculosis and latent tuberculosis infection (LTBI) is huge, which brings great challenges to tuberculosis prevention and control in my country. Effective identification of tuberculosis and LTBI is of great significance to the control of tuberculosis epidemic. Early diagnosis and forward-moving the checkpoints are important aspects of tuberculosis control in my country at present, and are also a highland of scientific research innovation.

Recombinant Mycobacterium tuberculosis EAST6-CFP10 allergen, aimed at early and rapid diagnosis of tuberculosis infection

The diagnosis of sputum-negative pulmonary tuberculosis and LTBI relies on the immunological diagnostic method of Mycobacterium tuberculosis (MTB) infection. The current immunological detection methods for tuberculosis infection are mainly tuberculin skin test (TST), interferon-γ release assay (IGRA) and antigen-antibody detection. Based on the above three methods, Professor Lu Shuihua's team innovatively developed EC with high sensitivity, strong specificity, simple operation, and can be used for the diagnosis of tuberculosis and LTBI. At present, the product has completed phase I, II and III national multicenter clinical studies, and has been approved by the State Food and Drug Administration for marketing as the first national Class I new drug in the field of tuberculosis. In addition, Professor Lu Shuihua also took the lead in organizing the writing and release of the expert consensus on the clinical application of EC.

Domestic IGRA assay forms a diagnostic tool with Chinese characteristics

Peripheral blood-based IGRA has been shown to be useful for diagnosing tuberculosis infection with high sensitivity and specificity, but imported IGRA assays (Tuberculosis-infected T lymphocyte spot test, T-SPOT.TB) are expensive. In order to promote advanced diagnostic technology, Professor Lu Shuihua's team verified a domestically produced IGRA assay (TS-SPOT) through a multicenter clinical study. The results showed that this method has a diagnostic efficacy for active tuberculosis (ATB) similar to that of T-SPOT.TB, and is economical and efficient.

Repeated identification of infection antigens to fill clinical screening gaps

Neither the allergen skin test (IA) nor the IGRA can distinguish LTBI from ATB. Professor Lu Shuihua's team screened and identified multiple antigens, including the Mycobacterium tuberculosis antigen heparin-binding hemagglutinin (HBHA), the Mycobacterium tuberculosis surface liposome protein (LppZ), and the Mycobacterium tuberculosis Rv3841 gene-encoded protein (BfrB), to explore their possibility of being used for tuberculosis infection screening. Among them, HBHA can be used in combination with IGRA to identify ATB, which has potential clinical application prospects.

An innovative model returns to the clinic to solve the problem of immune diagnosis in medical institutions at all levels

To promote medical progress, we must not only achieve technological innovation, but also work hard to transform and promote new technologies and new projects. The ultimate goal of scientific research innovation is to return to the clinic and serve the people. Professor Lu Shuihua took the lead in proposing a stratified solution for immune diagnosis of tuberculosis infection that is in line with my country's national conditions, and successfully transformed it into an innovative model, perfectly demonstrating the close combination of achievement transformation and implementation for the benefit of the people. This model is a stratified solution for immune diagnosis of tuberculosis infection suitable for medical institutions of different levels.

Tuberculosis infection screening technology suitable for primary care hospitals or community hospitals

The key to controlling the spread of tuberculosis and improving the cure rate of tuberculosis lies in the first diagnosis at the grassroots or community level, early detection and early treatment. Early tuberculosis screening conducted by grassroots and community medical institutions requires economical, simple and highly sensitive technology. The EC test combines the advantages of IGRA and tuberculin test (PPD test), which is safe, simple, highly sensitive and highly specific, and is very suitable for screening at the grassroots and community level.

Tuberculosis infection screening technology suitable for small and medium-sized hospitals

my country's small and medium-sized hospitals have certain testing equipment and technical capabilities, which can meet the laboratory conditions required for IGRA. However, the high cost of imported IGRA reagents limits their widespread application in clinical diagnosis and treatment in small and medium-sized hospitals. Professor Lu has always strived to bring high-tech to the grassroots level. The domestic IGRA assay TS-SPOT verified by his team is both economical and efficient, and is suitable for promotion and application in my country's small and medium-sized hospitals as an effective auxiliary means for rapid diagnosis of tuberculosis infection.

Precision diagnosis technology for tuberculosis infection suitable for large hospitals

The in-depth promotion of hierarchical diagnosis and treatment has put forward higher requirements for the precision diagnosis capabilities of large hospitals. Professor Lu Shuihua's team has screened and identified multiple antigens that can be used for tuberculosis infection screening. Among them, the combined use of HABA and IGRA is expected to fill the limitation that IA and IGRA cannot distinguish LTBI from ATB, and meet the clinical needs of large hospitals for precision diagnosis.

New drugs and vaccines are launched to precisely intervene in the immune response to tuberculosis

Professor Lu Shuihua suggested that a "one-size-fits-all" chemical prevention should not be used for LTBI populations, but precise intervention should be carried out for susceptible populations after differential diagnosis based on their immune function status or imaging manifestations. Professor Lu Shuihua's team also designed and synthesized small molecule compounds and successfully transformed them.

In addition, Professor Lu Shuihua's team used Sendai virus as a vector subunit for the first time to construct a new tuberculosis vaccine. The induced lung tissue-resident memory cells can quickly initiate an immune response and control the infection in the early stages of tuberculosis infection.

Part II

Focus on the future,
Explore the direction of innovation and transformation

Under the shadow of the COVID-19 pandemic, tuberculosis is prevalent worldwide, and the challenges of tuberculosis prevention and control have increased dramatically. In this special period, clinical research staff in the field of tuberculosis need to be more determined, and on the basis of doing a good job in daily clinical and scientific research, they should focus on innovation and transformation in tuberculosis prevention and treatment, and provide new and powerful weapons for controlling, curbing and ending tuberculosis as soon as possible.

The road to innovation begins with overcoming difficulties

Drug-resistant tuberculosis still faces bottlenecks such as difficult diagnosis, low treatment success rate and lack of prevention methods. Diagnostic markers for drug-resistant tuberculosis and new targets for treatment and prevention are the entry points for future scientific research innovation. The diagnosis and cell therapy of difficult, rare and genetically related tuberculosis have been rarely studied in China and even the world, but Professor Lu Shuihua's team has been deeply involved in this field for many years. Professor Lu Shuihua believes that the most daunting field is the high ground that should be explored the most, the most cutting-edge direction of scientific and technological innovation and transformation, and the most needed results in clinical practice.

The road to innovation complements discipline construction

China is a country with a high incidence of tuberculosis. With the changes in people's living habits and environmental factors, people's understanding of tuberculosis has continued to deepen, and their perspective on tuberculosis has become more comprehensive and systematic, and more and more tuberculosis comorbidities have received attention. Paying attention to tuberculosis comorbidities is the only way to end tuberculosis. While tuberculosis comorbidities bring huge challenges to the diagnosis and treatment of tuberculosis, they also require tuberculosis specialists to develop in the direction of combining internal and external medicine, comprehensive coverage, and fine sub-specialty division. The difficulty in the diagnosis and treatment of tuberculosis comorbidities is the starting point for scientific research innovation. Scientific research innovation not only provides new impetus for the construction of tuberculosis comorbidity disciplines, but also provides new ideas, methods and solutions for solving clinical problems.

Part III

For the country and the people,
The driving force of persistence and innovation

Professor Lu Shuihua said in summarizing his work: "Only after working hard do you realize that many things can be overcome with persistence."

Professor Lu Shuihua has been engaged in clinical, scientific research and teaching work for more than 30 years, and has dedicated his best years to the cause of public health. He focuses on the diagnosis, treatment and prevention of tuberculosis, is keen on solving difficult and complicated cases of tuberculosis, and has saved countless families on the verge of breaking up. From a single person's hard work to a team's tireless and full struggle, to the concerted efforts of a national research center, Professor Lu Shuihua has come a long way and encountered countless difficulties and challenges in the process of clinical diagnosis and treatment and scientific research innovation and transformation. Many people are curious about what force supports him to never give up and always maintain his fighting spirit and creativity.

One of Professor Lu's students once said that when he first listened to Professor Lu's academic lecture on scientific research and innovation, he was touched by his words from the beginning. Professor Lu said: "Chinese people must first love their country when doing scientific research. This is the fundamental basis."

Professor Lu Shuihua sent a message to young people fighting on the front line of tuberculosis prevention and control: if doctors put the country in their hearts, they will put the people and patients in their hearts. After experiencing various hardships and setbacks on the road of scientific research and innovation, the joy of helping patients will become a source of nourishment for doctors, nourishing the strength of firmness and persistence. Continuous learning and in-depth thinking are the source of innovation. Of course, it is also necessary to deliberately practice and cultivate one's ability in time management, energy management, physical management, efficiency management, emotional and mental management, etc.

Although MTB is an ancient pathogen, it has been innovating itself. Therefore, in order to defeat it and maintain lasting combat effectiveness, doctors also need to continue to innovate themselves, step out of their comfort zone, and explore more scientific and technological innovations. Ending the tuberculosis epidemic is a long way to go, but it will eventually be achieved.