As early as the 1990s, Zhang Wenhong, who had just entered Huashan Hospital, had his eye on tuberculosis and went to the University of Hong Kong and Harvard Medical School to conduct relevant academic research. This also makes him, like many infectious disease doctors, familiar with the past and present lives of tuberculosis.
One of Zhang Wenhong's scientific research achievements is the diagnosis and treatment of difficult tuberculosis such as drug-resistant tuberculosis. Zhang Wenhong's doctoral thesis of Shanghai Medical College (formerly Shanghai Medical University) of Fudan University, "A Series of Studies on the Mutation of mycobacterium tuberculosis katG gene and its mechanism of isoniazid tolerance", is also a study of tuberculosis.
Tuberculosis is a respiratory disease with strong transmission, in a sense, and it is a fight with the new crown. However, tuberculosis is not a viral disease, it will spread to many people, but many people have no symptoms after infection, and if the resistance is strong enough, it will become latent or secret tuberculosis.
The data show that about 360 million people in China are infected with Mycobacterium tuberculosis, and people who have been infected with tuberculosis bacteria are about 5% to 10% likely to develop tuberculosis in their lifetime. However, latently infected people have no signs and symptoms associated with TB and are not contagious.
At the beginning of the last century, the saying "ten tuberculosis and nine deaths" was popular, when tuberculosis was the most common disease in China. Today, tuberculosis still ranks second in china in terms of the number of cases and deaths of legally reported Class A and B infectious diseases.
"Arguably, COVID-19 has erased most of the gains we have made in global TB control over the past 10 to 15 years." Speaking at the 2nd TB and Lung Disease Prevention Forum hosted by the Chinese Journal of Tuberculosis prevention on 22 April, Qian Bingzhong, deputy director of the Gates Foundation's TB Programme, mentioned who estimates that TB mortality will rise for the first time since 2005.
"But covid-19 may be an opportunity for China to eliminate tuberculosis." Qian Bingzhong said that before the new crown pneumonia epidemic, many cities and counties in China did not have diagnostic networks for rapid molecular testing of tuberculosis and drug resistance, but the epidemic has prompted molecular testing capabilities almost everywhere in China, and China can now quickly collect thousands or even millions of clinical samples for high-throughput molecular testing.
Dr. Zhang Wenhong also participated in the Second Forum on Tuberculosis and Lung Disease Prevention and Control, and the following is a transcript of his speech (with a condensed version):
In December 2020, Zhang Wenhong came to a rural hospital in Yunnan to learn about the current situation of local MDR-TB patients. (Photo: Health number)
It is a great pleasure to meet you online today, Recently Shanghai has been fighting the epidemic, and everyone is very aware that our task of fighting the new crown is relatively heavy, and we are now in a very critical battle to clear zero and further prevent and control the new crown. At this point in time, I was working at the Shanghai Public Health Clinical Center and was invited by the Chinese Journal of Tuberculosis Prevention to talk about how to learn from the successful experience of the new crown prevention and control strategy to end the tuberculosis epidemic.
Almost every infectious disease is due to the fact that humans continue to live with animals or come into contact with the wild, and slowly enter human society from the animal kingdom.
These bacteria and viruses, after experiencing the expansion from the animal kingdom to humans, continue to evolve, causing outbreaks, long-term epidemics, and slowly beginning to weaken.
In our existing experience, how do many infectious diseases that have been prevalent, such as chronic hepatitis B and measles, slowly subside? There are several features:
First, the reservoir in nature has disappeared and will not be continuously released into humans, and there is a certain possibility of elimination. For example, chronic hepatitis B virus, hepatitis C, and HIV are all gone in nature.
Second, human beings need to gain long-term immunity, and vaccines must be effective for a long time. For example, measles vaccine and hepatitis B vaccine are effective for a long time, and the elimination of these infectious diseases is visible to everyone. Some infectious diseases do not have a vaccine or vaccines do not obtain effective immunity, such as tuberculosis, AIDS is very difficult.
Third, existing infected people can heal themselves or be treated well. After infection like hepatitis C, it can be treated with drugs.
What we're seeing is that HIV, malaria have drugs but no vaccines, hepatitis B has both drugs and good vaccines, tuberculosis treatment is not ideal in terms of drug resistance, and it may take a long time to treat sensitive tuberculosis, which makes our treatment delayed.
Malaria persists in some countries and regions of Africa, but malaria has been eliminated in China. Because after the infectivity is controlled by us, there are few mosquitoes that bite these sources of infection and form a reservoir. As a result, there is no longer a malaria reservoir for native mosquitoes in China, which makes malaria elimination possible.
From the 1940s when about 30 million malaria cases were reported annually, to 2017, when there have been no local cases on the mainland for five consecutive years, China was certified by the World Health Organization as a country for malaria elimination in 2021. These situations all tell us that in a given situation, an infectious disease has the ability to eliminate.
In December 2020, Zhang Wenhong came to a rural hospital in Yunnan to learn about the current situation of local MDR-TB patients. (Photo: Health number)
But what about tuberculosis? WHO has set the goal of "ending the TB epidemic": by 2035, the incidence of TB will be reduced by more than 90% from today, that is, to less than 10 per 10 000.
10 in 100,000 is a very important concept in epidemiology, and if the number of patients is consistently below this level, it will not cause a very large burden of disease.
Today, if the new crown in China has reached 10 per 100,000, why should it be strictly controlled? Because its reproduction rate is very high, 10 parts per 100,000 may soon become 100 parts per 100,000 and then 1,000 parts per 100,000.
However, the number of TB reproductions is not so high and will still persist for a long time. What we are doing now is how to make the decline in tuberculosis faster.
If the current worldwide reproduction index really drops below 10 per 10,000, it means that it will not be until 2182. So if you want to reach 10 per 100,000 by 2035, the decline will be even faster.
This task is very difficult to complete, especially in the past two years, the new crown epidemic, tuberculosis incidence has seen some resurgence, making it more difficult to eliminate tuberculosis.
It is recognized worldwide that the results of TUBERCULO have been set back by 5 years due to COVID-19. How should we do it? According to the existing technology and level, it must be reduced by 10% per year by 2025, for example, this year China is 60 per 100,000, and next year it is 54 per 100,000. After 2025, we will have to go down at the level of 17/100,000 to reach the level of low prevalence. The task is daunting.
In December 2020, Zhang Wenhong exchanged treatment plans with local MDR-TB patients in Yunnan. (Photo: Health number)
What are some ways to get rid of TB?
First, it is necessary to find enough patients, treat them, and cut off the source of infection;
Second, latent tuberculosis. Tuberculosis is not only contagious, there are many people who have already been infected who will continue to become active. We see a lot of asymptomatic COVID-19 infections, in fact, in a sense also hidden infections.
However, there is a huge difference between the hidden infection of tuberculosis and the hidden infection of the new crown: the hidden infection of the new crown, we do not intervene, it can be continuously eliminated by itself. Therefore, the continuous popularity of the new crown is the popularity of maintaining its survival in the world through continuous transmission and generation.
But tuberculosis is not the same, tuberculosis reproduction is low, but can be stored in the human body for a long time, which means that for such a latent infection intervention is also very important, otherwise a certain degree of tuberculosis stock will become active tuberculosis every year, making tuberculosis difficult to eliminate forever.
Therefore, we must strengthen measures in the elimination plan of tuberculosis in many ways: discover, diagnose, treat, and prevent it from spreading as soon as possible, and at the same time, we must detect latent tuberculosis and hidden tuberculosis infections, and also give a certain degree of intervention so that it does not turn into active tuberculosis.
WHO recently found in the process of developing policy guidelines for tuberculosis that many studies are lacking. What needs to be done? I asked my student, Ge Shijia, to comb through the evidence and research gaps identified by the World Health Organization in the development of TB policy guidelines.
This evidence is the basis for each time WHO develops new guidelines: for example, screening for latent TB, molecular testing for drug-resistant TB, changing our treatment strategies and shortening the course of treatment, or adopting a new treatment regimen for shortening the course of treatment for MDR-TB?
When it comes to the elimination of tuberculosis, the first is prevention. Crucially, vaccines have limited efficacy: there is no more evidence that new vaccines can replace BCG vaccines for TB, so there are now many scientific gaps about whether preventive treatment for TB can be effectively advanced.
Preventive treatment for tuberculosis is not very common in China. So what risks will WHO be very concerned about in the future? One is who is at risk of latent tuberculosis infection progressing to active tuberculosis, and who are students, the elderly, or immunocompromised people? Be clear and then intervene in key populations.
Second, preventive treatment for active tuberculosis, how to screen close contacts, and how to diagnose the process after screening.
Among high-risk groups, such as AIDS, silicosis and close contacts (mainly family contacts), what kind of test is the best? Skin tests and γ interferon release tests have been proposed, how can these be applied in the clinic? How can I effectively, easily and quickly diagnose latent TUBERCULO infection?
I will now tell you that the evidence for evidence-based medicine worldwide is generally considered insufficient and that much more needs to be done.
After extensive TB screening in the community, find people at high risk and find groups with latent TB infection.
The new crown has a very good measure - it should be inspected and collected.
The screening method is very particular, and there are many strategies for the impact of pan-community TB screening on the reporting rate of TUBERCULO cases. How is it screened? We have many good methods: tuberculosis symptom screening, screening for severe indicators, chest imaging testing, etc.
In addition, there is no rapid molecular biology test, which is very simple, preferably at home, or directly screened at rural service stations and health clinics.
Just like the new crown, this method, if fully developed, can find the patient in a very short time.
In December 2020, Zhang Wenhong exchanged treatment plans with local MDR-TB patients in Yunnan. (Photo: Health number)
The overall number of latent TB in China is now very high, and china's disease control has conducted a large screening in the countryside, and found that up to about 15% (13%-20%) in rural China, and the younger people will be lower, but as they get older, they will continue to be infected. Eventually, at the age of forty or fifty, it will reach the level of 20% latent infection. If China's 1.4 billion population is calculated at 20%, there will be close to 300 million or so latent TB infections.
300 million latent TB infections, how do we do it? Our team has done a lot of work, and I remember that before the above large-scale screening, in 2010, in the screening of healthy people, it was found that latent infections reached 18.9%, and the sensitivity and specificity were much higher than the skin tuberculosis test.
It is accepted worldwide that the lifetime prevalence of latent TB is 5% to 15% if there is no intervention. China should pay further attention to these special groups of people, how to screen out the points of latent tuberculosis, and further intervene after screening out.
Who is particularly important in this group? It is an HIV-infected person, an adult contact (close contact), a group receiving some immunosuppressant treatment, and a patient with silicosis.
How high can the incidence of HIV and close contacts be as high as? The overall incidence of latent TB is 14.5 per thousand and 21 per thousand. If 300 million people are multiplied by a certain percentage, we can see that a large number of people will develop into active TUBERCULO patients.
Therefore, WHO proposes to pay special attention to HIV patients, close contacts of bacterial-yang tuberculosis under 5 years of age, and patients with silicosis, immunosuppressant therapy, dialysis treatment, and these patients should also be treated with preventive treatment.
Our team has done a lot of work in this regard, and one of the jobs is to try to shorten the old international program – a treatment plan that lasts 6-9 months – for silicosis patients in high-risk groups. Because if interventions for latent TB can be undertaken, international data show that the incidence can be reduced by 50% in 5 days. Therefore, after completing a 3-month short course of treatment, the results of 3-year follow-up show that the incidence can be effectively reduced by more than 50%. This shows that the significance of preventive treatment is very large.
In addition, we are constantly exploring shorter courses of treatment, which can be treated for one month to reduce the incidence of latent tuberculosis.
We have also initiated a series of studies on MDR-TB interventions, with certain protocols based on the drug resistance of previous cases, and for close treatment, further onset of MDR-TB can also be reduced. Now there are many ways to intervene in latent tuberculosis infection as a whole in the world, the classic one is 6-9 months, the more isoniazid used in China is used for 6-9 months alone or a combination of 3-4 months, and there are also 3 months of use with rifapentin + isoniazid.
In fact, the future short-course treatment plan will continue to be updated, and the data on the past short-course treatment of HIV will slowly come out. In 2020, the latent TB guidelines have been updated, and I believe that there will be a new latent TB guideline update soon, making the treatment course shorter.
In December 2020, Zhang Wenhong came to a rural hospital in Yunnan to learn about the current situation of local MDR-TB patients. (Photo: Health number)
One clinical study we are doing now is initiating a one-month ultra-short course of treatment for latent TB.
First of all, the occurrence of adverse reactions will be greatly reduced, that is to say, compliance will reach more than 90%. If the old three-month regimen was adopted, compliance was only 54.7%.
Second, diagnosis. How to screen out more patients, if there is no new breakthrough in diagnosis, is very difficult. WHO highly recommends nucleic acid testing. We hope that these programmes will be rapidly rolled out to every TB site, even in county-level hospitals.
In addition, how can more patients be found? Now there is a lot of attention to exploring the detection of urine. In the urine, mainly in HIV patients, ring-mediated isothermal amplification (LAMP) testing has received good value, and WHO has been pushing.
How is urine testing used in HIV-negative people? Isn't this approach simpler? In addition to the tuberculosis ring-mediated isothermal amplification detection technology (TB-LAMP), WHO hopes to find more diagnostic techniques for tuberculosis for clinical use, that is, whether it is easier to popularize, less costly, and even in some tuberculosis hospitals or rural clinics where the equipment is very simple.
After the discovery of tuberculosis patients, it is very critical that resistance testing should be carried out in a timely manner. Molecular testing can only be done, not culture, so does the culture need to be? Cultured phenotypic susceptibility is of great significance for the final determination of drug resistance, and if there is no clinical microbiology laboratory for tuberculosis, it can be replaced by molecular testing.
If the elimination of tuberculosis is understood as a very large puzzle, think about whether the early screening is in place, whether it is preventive in advance after screening some infected people, whether it is vaccine or preventive treatment, whether the tuberculosis patient will be tested for drug resistance in the first time, and whether there can be better compliance and shorter treatment plans after treatment, these programs need to be done by us. So by 2035, I hope all tb people will come together and put together these puzzle pieces.
Thank you very much for listening.
(Yi Zhang, Professor of Social Media Research Center, Peking University, also contributed to this article)
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