Intriguing Phase 1: Anti-multidrug-resistant pulmonary tuberculosis treatment plan curative effect detection prediction

The intriguing and intriguing youth podcast gathered the most promising young and middle-aged tuberculosis doctors in China.

The first episode will start from 20:00-21:00 on March 23.

The hosts and guests of the first podcast are: Fu Liang, Zhang Xiaolei, and Tang Zhigang.

Efficacy monitoring/pre-judgment of curative effect monitoring/pre-judgment of multi-drug-resistant pulmonary tuberculosis treatment The treatment course is long (short-term regimen 9-12 months; long-term regimen 18-20 months), and it is important to conduct active curative effect monitoring during the long anti-tuberculosis treatment process significance.

It is an important basis for us to identify patients with poor efficacy and high-risk groups of treatment failure in the early stage, timely conduct drug susceptibility testing and adjust treatment plans.

The WHO guidelines for the treatment of drug-resistant tuberculosis recommend sputum culture + sputum smear for efficacy monitoring in the intensive period once a month and once every 2 months in the continuation period.

In addition to the above methods, what other methods can be used to monitor efficacy? More importantly, how should we comprehensively evaluate the results of various efficacy monitoring and guide the next treatment? Discussion Points Discussion Points In this issue of the podcast forum, the host Fu Liang had a lively discussion with guests Zhang Xiaolei and Tang Zhigang on the diagnosis and treatment of multidrug-resistant tuberculosis.

They believe that the current monitoring of the efficacy of multi-drug-resistant tuberculosis is mostly based on the comprehensive judgment of the patient’s clinical manifestations, sputum and imaging test results, but it is not an ideal indicator, especially for patients with diabetic tuberculosis, it is difficult to determine the course of treatment and Timing of withdrawal.

If an ideal diagnostic kit can be established to quantify the various indicators of the patient, and quickly and accurately determine the efficacy, then it can help doctors better judge the patient's treatment course and timing of drug withdrawal, and predict the risk of recurrence.

The following is the text of the discussion between the host and the guests.

Fu Liang: The topic of this issue is about the monitoring of the therapeutic effect of multidrug-resistant pulmonary tuberculosis.

The treatment course of multidrug-resistant tuberculosis is longer, the short-term regimen takes 9-12 months, and the long-term regimen takes 10-20 months.
In this process, active monitoring of the therapeutic effect is essential to help early identification of poor therapeutic effects and treatment failures.
For patients with high risk, timely drug sensitivity testing can be performed to adjust the treatment plan.

However, there is still a lack of monitoring methods for the efficacy of multidrug-resistant tuberculosis.
Before discussing, we must understand the difference between active tuberculosis and inactive tuberculosis.

Zhang Xiaolei: There are three main differences between active and inactive tuberculosis.
One is the patient's symptoms, the other is smear examination, and the third is imaging findings.

If the patient has no symptoms, the smear test is negative for sputum, and imaging shows stable fibrosis, cords, or calcifications, then this is inactive, otherwise it is active.

Tang Zhigang: As mentioned by Teacher Zhang, active and inactive pulmonary tuberculosis are mainly distinguished from clinical symptoms, phlegmology and chest imaging.

What needs to be added is that patients with suspected tuberculosis who have not been treated should be treated with caution, and relevant pathogenic examinations, especially bronchoscopy, should be performed, combined with the patient's symptoms to judge tuberculosis and non-tuberculous tuberculosis.

Fu Liang: The process of judging curative effect is actually the process of distinguishing activity and inactivity.

In addition to the diagnosis, the identification of active and inactive pulmonary tuberculosis based on the patient’s symptoms, sputum, and imaging examinations also requires the patient to be treated after treatment according to whether the treatment can be stopped or whether there is recurrence after stopping the treatment to distinguish the activity And inactivity.

At the time of diagnosis, the identification of pulmonary tuberculosis as active is mainly based on the pathogenic test results.
There are four criteria: one is positive for smear, second is positive for culture, third is positive for molecular biology, and fourth is positive for pathology.

However, in the judgment of curative effect, if the patient's sputum bacterial load gradually decreases or even becomes negative, it cannot be differentiated by etiology.
At this time, clinical symptoms and imaging results are required, and there is a difference in subjective judgment.

Therefore, in the judgment of curative effect, etiological examination cannot be used as a good indicator to distinguish between activity and inactivity.

Tang Zhigang: In combination with the existing guidelines, whether it is short-term or long-term treatment, clinical symptoms, sputum and chest imaging are very important in judging the curative effect.

If the course of treatment is close to completion, two consecutive sputum cultures are negative, and the patient's clinical manifestations stop coughing and sputum, then this means that the patient’s lung lesions are also prone to calcification.
If the imaging examination results confirm this, then the course of treatment can be considered Stop the drug after the end.

It should be noted that it is necessary to use a bronchoscope to collect sputum from the deep part for sputum sputum examination, and it needs to be done more than twice in a row before the drug can be discontinued.

In addition, the patient needs to be re-examined three months after stopping the drug, including clinical symptoms, sputum and imaging examinations.

If there are no symptoms and the test is negative, the follow-up periodical review time can be gradually extended appropriately.

Zhang Xiaolei: Consistent with Mr.
Tang's point of view, the therapeutic effect is judged according to the guidelines or the requirements of NDIP.

For patients who can cooperate with sputum examinations and have good compliance, if the symptoms and imaging findings are stable and the sputum bacteria continue to turn negative, the patient can be considered cured at the end of the treatment, and regular follow-up will be enough.

For patients with poor compliance, they often cannot cooperate with sputum examinations.
If the medication can be used regularly and the symptoms and imaging findings are stable, then the patient can be considered to have reached the stopping standard at the end of the treatment.

Fu Liang: As stated by two experts, for patients with multidrug-resistant tuberculosis, the activity of tuberculosis can be judged according to guidelines or NDIP standards.

However, this judgment is based on the comprehensive consideration of all inspection data, and there is no optimal indicator yet.

For example, when doing pathogenic testing, sputum culture takes a long time, the sensitivity of sputum smears is low, and the reliability of molecular biology is not strong, so pathogenic testing is not the most ideal indicator.

Furthermore, for patients who have failed multiple treatments, they will again meet the guideline discontinuation standards after treatment.
Whether the treatment should be discontinued is open to question.

Therefore, it is more meaningful to construct a set of ideal diagnostic criteria that can be quickly and accurately judged, and even quantified, to identify the activity of pulmonary tuberculosis.

For example, for diabetes and tuberculosis, how to judge the best course of treatment? Tang Zhigang: At present, it is only said that the course of treatment for diabetes and tuberculosis needs to be extended, but there is no fixed standard for the exact course of treatment.

Zhang Xiaolei: As Teacher Fu said, the current judgment of the curative effect of tuberculosis treatment is only based on the examination results and the comprehensive consideration of the doctor.

Fu Liang: Therefore, the efficacy of tuberculosis is mainly judged based on the doctor's experience.
Just like tuberculosis with diabetes, there is no fixed standard for the exact course of treatment, and there is a lack of high-quality evidence to support it.

One of the important reasons is that there is no ideal indicator to make judgments.

Do the two teachers have any new views on this? Tang Zhigang: Indeed, there is no fixed standard for judging the curative effect of diabetes combined with tuberculosis.
This is mainly related to the diabetes itself.
If diabetes is well controlled, the patient's treatment curative effect may be better, and the corresponding course of treatment may be shorter.
On the contrary, those with poor control may have better treatment effects.
The course of treatment may be longer.

Fu Liang: Director Deng National Defense led a consensus on diabetes and tuberculosis, which has been published in the "China National Defense Tuberculosis", but this consensus is still more empirical, and there is no research evidence to support a specific extension of the treatment course.

Zhang Xiaolei: Just like the formulation of a chemotherapy regimen, although an optimal standard plan is required, it is still necessary to formulate a personalized treatment plan based on the actual situation of the patient.
The same is true for the judgment of the effect of tuberculosis.
It is necessary to formulate a personality based on the patient's condition and financial ability.
Treatment plan.

If there is a quantitative standard, it can be timely and accurate to determine the timing of patients withdrawing medication, which will indeed help optimize the treatment of patients, but at present it still depends on guidelines and the judgment of doctors.

Fu Liang: Due to the lack of an idealized criterion, treatment is prone to two problems: undertreatment and overtreatment.
As mentioned above, diabetes and tuberculosis are prone to undertreatment. Therefore, an idealized standard is required for the judgment of curative effect, so are there any indicators that may be used as an idealized standard for judgment of curative effect at present or in the future? Tang Zhigang: As Teacher Fu said, the criteria for judging curative effects are indeed very important.
For example, MDR-TB has both standardized treatment plans and individualized treatment plans.
There are huge differences between individualized treatment plans, so in the end, one It is still worth thinking about what standard patients can discontinue the drug.

Because the standard is judged based on the patient’s symptoms, sputum pathology, and imaging examination results, but some patients in the clinic have reached the guideline withdrawal standard but still continue to take the drug, and some patients have reached the course of treatment but have not yet reached the guideline withdrawal standard.
The treatment needs to be prolonged, but there is no exact statement for how long it will be prolonged, and it is prone to undertreatment or overtreatment.

Zhang Xiaolei: If the curative effect is judged by sputum bacteria, although false negative results may occur when the amount of bacteria in the body is extremely low, if the sensitivity of the test can be improved, then the positive rate of the test can be increased.

Alternatively, the release of interferon-gamma can be detected, because the amount of interferon-gamma released during the acute or severe phase of the disease will increase accordingly, and the change in the level of interferon-gamma can be used as an auxiliary means to determine drug withdrawal.

Fu Liang: The release level of interferon gamma is indeed related to different stages of disease treatment.

Different from the result of sputum culture, which is either yin or yang, the expression of a new type of judgment marker such as gamma interferon is different in different periods of the disease, which can be quantified and may be used as an ideal judgment standard.

There is still a lack of other selectable candidate markers.

A study by Gao Qian, director of Henan Provincial Hospital of Infectious Diseases, showed that the treatment course of tuberculosis can be guided according to the high or low metabolism shown by CT.
Patients with low metabolism can take a relatively short course of treatment, and patients with high metabolism can take a relatively long course of treatment.
Medication, CT can be used as a criterion.

However, the shortcomings of CT detection are high cost and radiation problems, and high frequency detection is not possible.

From tuberculosis infection to the different stages of treatment, the body's bacterial load will gradually decrease, but tuberculosis infection is lifelong.
Even if the sputum bacteria are negative, dormant tuberculosis remains in the body after the drug is stopped. The lung tissue test results of animal models show that Bedaquiline can eliminate dormant tuberculosis bacteria, but the human body cannot achieve lung tissue testing.
Therefore, it cannot be explained that Bedaquiline can eliminate the dormant tuberculosis remaining in the human body and reduce the recurrence rate.
There is still a lack of one.
Quantifiable evaluation indicators.

If you rely on sputum culture to judge the therapeutic effect, it is obviously not an ideal indicator, so a quantifiable evaluation standard is indeed needed in the diagnosis and therapeutic effect of pulmonary tuberculosis.

Tang Zhigang: In the above situation, it is true that phlegmology testing cannot be used as a criterion for judgment.

Some patients are often encountered clinically, especially those with MDR-TB with lung damage.
Although the treatment course is completed, the sputum test is not negative, so how to evaluate the efficacy? Does the patient need to take medication for life? Since most of these patients cannot receive surgical treatment and can only be treated with drugs, some patients relapse after stopping the drug, and some patients are in stable condition.

So, how to judge the efficacy of patients with such lung damage? Zhang Xiaolei: There are many patients with lung damage in Heilongjiang, and many patients cannot receive surgery because of lung function or economic conditions.

In many patients, the mediastinum naturally shifted to the left during drug treatment, and the right lung developed compensatory emphysema.
Some patients were in stable condition after stopping the drug for more than two years.

Therefore, the efficacy evaluation criteria for such patients may consider the lung function after discontinuation of the drug.

Tang Zhigang: How long has it been treated? Zhang Xiaolei: The above two patients with lung lesions who were still in stable condition after drug withdrawal stopped the drug after two years of drug treatment, but their sputum bacteria test showed negative early.

At present, the two patients are in stable condition and show no signs of recurrence, and undergo regular imaging examinations.

In addition, there are two young male patients with lung damage in their 20s.
They have been treated with drugs for two years and have been stopped for 3 months for review.
Their condition is stable, but they cannot perform strenuous exercise due to impaired lung function.

However, the follow-up time for discontinuation of these patients is relatively short, and long-term follow-up observation is still needed.

Fu Liang: For refractory patients with lung damage, there are two problems in their treatment: one is the lack of good treatments; the second is that even if there are good treatments, there is no way to confirm that the treatment plan is really effective, that is, the lack of good curative effect Means of judgment.

For example, some people believe that BDQ-containing treatments can cure patients with damaged lungs, but apart from sputum culture, there is no other method to detect whether the damaged lungs carry bacteria, and it is not certain whether the damaged lungs will affect the healthy lungs.

At present, there is a lack of such ideal indicators that can evaluate the therapeutic effect of patients with damaged lungs.
Further exploration of basic and clinical research is needed to find an ideal indicator that can determine the disappearance time of live bacteria during the treatment process to determine the timing of drug withdrawal.

In this way, even for patients with diabetes and tuberculosis, in the case of diabetes control, the therapeutic effect can also be judged.

In addition, in addition to phlegmology, new ideal indicators can also be used to judge the efficacy of new drugs in the future.

At present, in addition to sputum disease, imaging is a more commonly used evaluation index.

Unlike sputum mycosis, which is either yin or yang, the imaging manifestations are diverse, including active images, intermediate stable images, and stable images.

If there is an ideal standard method rather than a doctor to accurately identify imaging manifestations, such as AI, it is feasible to judge the curative effect of tuberculosis.

Through data input, AI can recognize different pictures, so it is feasible as a detection standard for imaging.

If such an ideal activity criterion can be established, it can be used to evaluate the clinical efficacy of new drugs in the future, even preventive treatment of latent infections, and can be used to distinguish whether it is latent infection or the risk of patients developing tuberculosis.

There are many preventive treatment programs, such as 3HP program, 6 months isoniazid or rifampicin, 3 months isoniazid plus rifampicin.

In the process of preventive treatment, the amount of bacteria in the body will gradually decrease, and even reach the level of negative sputum bacteria, but there is also no ideal index to judge the curative effect, so it is very important to establish an ideal standard for curative effect evaluation, which is related to the patient's In the clinical diagnosis and treatment process, it is necessary to conduct research in this area.

What do you think? Tang Zhigang: For the two patients with lung damage mentioned by Teacher Tang who were in stable condition after stopping the drug, I suggest more follow-up observations.

After resection of many damaged lungs, it is found that there are more viable bacteria in the lungs.
Therefore, it is questionable whether such patients are cured. Because the amount of bacteria in such patients gradually decreases during the treatment process, reaching a very low level or confined to the damaged lung, but it is impossible to judge whether the bacteria in the damaged lung is completely eliminated at the end of the treatment, and the residual amount and the risk of recurrence cannot be determined.
Pay more attention.

As a rule of thumb, if the damaged lung can be completely shrunk and no oxygen enters, the patient's prognosis may be better.
However, if there is always a cavity or residual pus in the damaged lung, surgical resection of the damaged lung is required to ensure good health.
Prognosis.

Finally, as Teacher Fu said, a multi-dimensional or multi-index quantitative standard may be needed to evaluate the activity of the disease and the timing of drug withdrawal to reduce the false positive rate.

Fu Liang: In summary, the problems we are facing now: First, the indicators used in the efficacy judgment are not ideal, and there are shortcomings such as delay and poor accuracy.
Therefore, it is necessary to further optimize the existing efficacy judgment standards and optimize the direction.
I tend to develop a comprehensive evaluation and diagnosis package; the second is this comprehensive evaluation and diagnosis package.
At present, there is limited room for improvement in pathogenic detection, but the imaging performance is diverse.
You can consider quantification or the AI ​​technology mentioned above.
Make a judgment of curative effect.

The current technology has allowed the use of AI, and can improve the ability of AI to recognize pictures to the highest level of current experts, thereby reducing the error in imaging diagnosis; the third is to pay attention to the index problem of the efficacy judgment standard, in view of the current Tuberculosis treatment lacks new drugs and vaccines, and can only use existing treatment plans to prepare to judge the course of treatment and the timing of drug withdrawal.

Zhang Xiaolei: At present, the diagnosis and efficacy evaluation of tuberculosis are based on the comprehensive evaluation of clinical symptoms, sputum detection and imaging, and less consideration is given to the imperfections of this comprehensive evaluation standard.

After today’s discussion, a new research direction has emerged, that is, to find some other better indicators, to achieve personalized diagnosis and treatment of patients, and to accurately determine the timing of drug withdrawal to reduce the recurrence rate of patients.

I hope that in the future, I can continue to discuss and cooperate with the two teachers and conduct some research together.

Scan the QR code｜Add TB assistant to add friends, please note "TB" to receive more TB information, click on the "Read the original text" below to watch the replay of this issue of podcast↓↓↓