Tuberculosis has been around for almost as long as humans began documenting their lives. In the ruins of Neolithic cemeteries in Northern Europe, the Middle East, and ancient Egyptian cemeteries, we can find evidence of this chronic disease.
The human eye cannot see the pathogenic bacteria, but it can see the terrible consequences of them - high fever, sudden weight loss, long-term hemoptysis. More importantly, this pathogen spreads extremely quickly, and each time the tuberculosis bacteria continue to form new mechanisms, evade the attack of the immune system, survive in the new host, and continue to spread.
It wasn't until the 1940s, when antibiotics came along, that humans were able to truly control TB bacteria. In China, from the 1950s to the 1970s, the chemotherapy regimen composed of streptomycin, aminosalicylic acid and isoniazid was the most classic and effective combination of anti-tuberculosis at that time, known as the "old three modernizations". The anti-TUBERCULO drug Rifabian, and for a long time, was one of the main anti-TUBERCULO drugs in China.
However, anti-TB drugs are a double-edged sword, killing TB bacteria at the same time, but also lead to pathogens appear natural resistance to drugs, strains in this way successively develop resistance to many types of drugs.
Today, drug-resistant TB has become an urgent public health problem around the world.
In China, the number of drug-resistant TB patients is much higher than the global average due to the abuse of antibiotics, the irregular use of drugs by some tuberculosis patients, the large population base, and the overall lack of wealth.
At the same time, the level of primary medical institutions is insufficient, the medical service system is fragmented, the prevention and treatment is separated, the treatment cycle of drug-resistant tuberculosis is long, the side effects of drugs are large, the rapid detection instrument reagents, second-line drugs are relatively expensive, etc., which have repeatedly trapped Drug-resistant tuberculosis patients and doctors in China.
According to the World Health Organization, there are 842,000 new cases of TB on the mainland each year, of which about 65,000 are MDR/rifampicin resistant, ranking second in the world, after India.
The "White Plague" is not an ancient legend, and today it is still torturing our public health system.
24 March 2022 marks the 27th World TB Day.
Drug-resistant tuberculosis in China
In the hospital clinic, a diagnosed tuberculosis patient did not have time to put on a mask, violently covered his mouth with a tissue, and coughed out a mouthful of phlegm, with blood.
She carefully wrapped the tissue, put it in a bottle, sealed it, and quickly pulled up the mask. She realized that in her infectious state, every cough could release millions of TB bacteria, which, if not taken, would float in the air and could infect anyone who was breathing.
Humans have been fighting TB for thousands of years, and there were many ways to deal with TB in the old days, including taking body fluids from insects, bleeding patients, keeping them at high altitudes, traveling to sea, abstaining from alcohol, and so on.
Mycobacterium tuberculosis Source: Continuing Education Course on MDR-TB Control
At the end of the 19th century, after tuberculosis entered the era of bacteriology, Western medical scientists and biologists have been trying to develop effective drugs against tuberculosis bacteria.
Until 1944, the special drug of tuberculosis " streptomycin " was invented , as an antibiotic , it can effectively inhibit the proliferation of tuberculosis bacteria. In the years that followed, amsalicylic acid and isoniazid appeared in combination with streptomycin to effectively treat tuberculosis. Subsequently, other drugs of Rifampicin were introduced.
New problems arise.
Today, some mycobacterium tuberculosis is resistant to existing anti-tuberculosis drugs. Antibiotics, once the ultimate weapon, have become less useful.
This is not incomprehensible. The individual lineage of pathogens is constantly evolving, forming new mechanisms. Artificial application of antibiotics to fight it, the bacteria will mutate in the direction of dominant survival, under the induction of continuous administration, more and more resistant strains will be used, and fewer and fewer strains can be treated. Tuberculosis is very representative of this.
Fu Liang, attending physician of the Second Department of Pulmonary Diseases of the Third People's Hospital of Shenzhen, said that there are two main types of drug-resistant patients in the outpatient clinic:
One is long-term transmission of patients, that is, infected with tuberculosis bacteria very early, but not cured, and later became resistant bacteria. The other is recent transmission, in which patients who have just been diagnosed for the first time are drug-resistant patients. "In the past, many patients were thought to be resistant because they were not well treated, but now we find that probably nearly half of the patients are recently transmitted."
Among the drug-resistant TB classifications, MDR-TB is a major focus in China and globally.
"In drug-resistant TB, our main concerns are isoniazid resistance alone, rifampicin alone or isoniazid and carifofopine resistance."
Fu Liang explained, "The standard definition of multidrug resistance that we often refer to isoniazid and rifampicin is both resistant. However, in practice, we found that the disposal of mono-nefab is treated in the same way as multi-drug resistance, because at the same time as mono-resistant rifampicin, the proportion of isoniazid resistance is also very high, about 80%."
The data shows that in 2019, 18% to 21% of patients worldwide who have been treated for TB were MDR/rifampicin. Among them, there are about 65,000 MDR-tb/rifampicin-resistant patients in mainland China, accounting for 14% of global cases, ranking second in the world.
Why is the problem of MDR-TB so prominent in China?
Several doctors have told "occasional cures" for several reasons:
The first is the misuse of antibiotics. The data shows that about 40% of patients in China have the misuse of antibiotics, resulting in more drug-resistant patients and more resistant patients in China than in other countries.
"In particular, quinolone antibiotics, in some general hospitals, are widely used in ordinary pneumonia, therefore, China's quinolone resistance rate is higher than that of foreign countries, but quinolone drugs are the main drugs for anti-tuberculosis treatment, so the use of quinolones alone to cause drug resistance is very common in China," explains Jin Wu, deputy chief physician of the Tuberculosis Department of Wuhan Pulmonary Hospital.
Source: Social Education Publishing House
Irregular medication is a problem. A doctor at a third-tier hospital in a first-tier city told "occasional cures" that some of the patients she treated were treated repeatedly locally, using second-line anti-tuberculosis drugs prematurely, or even single drugs. "When anti-TUBERCULO treatment is carried out with a single drug, TB bacteria are easily resistant to this drug, and the treatment effect is significantly reduced, so we follow the principle of using at least four drugs in combination. And when a single drug resistance occurs, you can't just consider replacing one drug."
Self-medication in TB patients can also develop resistance. Through medication, some patients' symptoms will be significantly improved, such as no longer coughing, sputum, some patients mistakenly think that they have healed, self-medication, which can easily lead to the suppression of tuberculosis bacteria re-multiply and drug resistance.
Patient management is always a headache for doctors. Compared with ordinary TB, the treatment course of MDR-TB is longer, "the initial course of treatment is 18 months, depending on the size of the drug resistance and the number of drug resistance types, it may even be extended to two years or even more than 30 months," Jin said. During this time, some patients will lose due to a long course of treatment or serious side effects. More data show that only 60% of MDR-TB patients are detected, and there are still a large number of patients who are hidden and undetected, which means that when patients become a potential source of infection in the process of disease, they will spread.
MDR-TB is not just a medical problem.
In the doctors' offices, they have seen many poor patients who have to give up treatment because they cannot afford expensive anti-TUBERCULO drugs such as beidaquinoline, linezolid, and clofazimine. "Some people are even poorer and poorer, unable to work because of illness, and face high drug costs."
One patient told "Occasional Cure" that of the five drugs she took, bedaquinoline was the most expensive, at $8,400 a box and needed to be taken one box a month. "Here, this drug is not enrolled in medical insurance, all at your own expense."
Difficulties in diagnosing multidrug-resistant TB
In March 2021, after receiving a diagnosis of tuberculosis, Charing began hospitalization. During her hospitalization, doctors told her that there might be resistance. Two days later, resistance genetic testing showed that she was resistant to rifampicin and isoniazid.
"I asked the doctor, and I said that I had read the data that many multidrug-resistant patients were resistant after repeated treatment. The doctor explained that because when I was infected, I was a drug-resistant tuberculosis bacterium, and I felt very unlucky."
But after questioning some patients, Xia Lin was somewhat glad that she did not take too many detours on the road to diagnosing multi-drug resistance.
Compared with Xia Lin, Su Qi's medical experience is full of twists and turns.
He developed symptoms a little earlier than Charing, in the summer of 2020. Because he had been coughing and back pain, he went to the designated tuberculosis hospital in the city. He worked in a third- and fourth-tier city in the south, sweltering in the summer, and shared a room of fifty square meters with three or four friends. He always recalled later that it was the harsh living environment that caused him to be infected. But no one could give him an answer.
On the first examination at the hospital, the chest x-ray showed that the right lung had a great shadow and hollowness. The doctor told him that tuberculosis was suspected. Doctors diagnosed him with tuberculosis by making DNA fragments, but he could not find a live tuberculosis bacillus.
He began more than three months of medication, at first the cough disappeared, "thinking that victory was ahead", but not long after, the symptoms appeared again, and the re-examination found that the hole in the right lung did not improve at all, and even "the hole increased".
Xia Lin went to the provincial tuberculosis designated hospital, did a lot of tests, and within a few days, the doctor concluded, "Nilifaping and isoniazid."
"At that time, the feeling was that people were willing to live in big cities, and the level of doctors in hospitals in big cities was different, and the equipment was different."
In patients with MDR-TB, the diagnostic and treatment dilemma spreads out layer by layer.
At present, the common means of domestic detection are still sputum smears and sputum cultures, but the disadvantage is that the diagnosis is very slow, it takes about 2 to 3 months, and the technical sensitivity is not high. Doctors say that while waiting for the test results, there is a loss of patients or some irregular medications.
Diagnosis of MDR-TB is based on sputum culture and medication. Source: Continuing Education Course on MDR-TB Control
Fu Liang introduced that in fact, the industry's recommended preferred method is the detection of the molecular diagnostic instrument Xpert, which can detect whether TB DNA and rifampicin are resistant at the same time, and the results can be produced in two hours.
"But this instrument in the grassroots promotion is not very good, when it first came out, the World Health Organization gave away a lot of instruments for free to China's grassroots institutions, but a very real problem is that reagents need to be purchased separately, a reagent may be five or six hundred pieces, many places can not afford." And not only at the grassroots level, but even in the tuberculosis specialties of some tertiary hospitals, this instrument is only placed here, and the high cost is on the one hand, on the other hand, because Xpert's test is not in medical insurance, so it is difficult to promote."
At the same time, Fu Liang added that there are many links in the diagnosis of suspicious cases, taking his Shenzhen Third Hospital as an example, it will do smear culture, Xpert testing, if the patient does not have sputum, it will be recommended to do tracheoscopy, and ordinary tuberculosis DNA testing can be selected - this will be much cheaper than Xpert. If the DNA is positive, it will be tested by the dissolution curve method to determine whether it is resistant to isoniazid, rifampicin, streptomycin, fluoroquinolones and so on. "The problem of drug resistance can be detected in the first week or two of the basic admission, and we will definitely track the sputum culture behind us."
However, "free tuberculosis treatment" in mainland China is limited. In the diagnostic process, only two free chest x-ray and sputum smear tests are provided. In treatment, only free first-line anti-TUBERCULO drugs are provided for ordinary tuberculosis patients and sputum smears and chest x-rays during treatment.
The dilemma of diagnosis and treatment under the new crown epidemic
Diagnosis is only the first step, and subsequent treatment is a constant test for patients and doctors.
The Wuhan Pulmonary Hospital, where Jin Wu is located, holds business training and study for grass-roots hospitals every year, and he will still notice that in addition to improving the awareness of doctors' business training, he also faces other problems.
For example, some effective drugs for the treatment of anti-MDR-TB are not available in primary medical institutions, and the accessibility of drugs is very poor. At the same time, there are no corresponding supporting reimbursement measures, and some places even have reimbursement in place. "This has caused many patients to not get medicine in the local area, but they cannot travel back and forth to the provincial capital city, and some patients are troublesome and can only give up taking medicine."
Jin Wu's clinic Image source: Courtesy of the interviewee
At present, the mainland's tuberculosis prevention and control model is a "trinity" model, with the CDC, tuberculosis designated hospitals, and grass-roots health institutions.
According to the idea of the top-level design, it is relatively perfect, but in the specific implementation, patients and doctors will find many problems with poor connection.
Taking Fu Liang's Shenzhen Municipality as an example, the designated tuberculosis hospital and the chronic disease prevention and control hospital belong to the Health Commission and the CDC. Therefore, when specifically transporting patients, it is easy to have problems such as poor communication of patient information. But in the Wuhan Pulmonary Hospital, where Jin Wu is located, it is a hospital-institute integration, a designated hospital, and a prevention and treatment institution, and "communication is relatively smooth".
In addition, medical institutions and chronic disease prevention and treatment hospitals have different "specific coping methods and concepts." Fu Liang added, "Chronic hospitals may guarantee basic medical care, and in the face of some difficult or difficult problems, they will recommend that patients be referred to a specialized designated hospital."
Many times, behind the "poor compliance of MDR-TB patients" that doctors refer to is partly the challenge of side effects of MDR-TB treatment drugs.
"In the core protocol, the adverse reactions of some drugs can cause problems with hematopoietic inhibition in the patient's blood system, and platelets, red blood cells, and white blood cells are very significantly reduced, which is much higher than ordinary tuberculosis. In addition, there are common cases such as skin pigmentation darkening due to taking some drugs, which is difficult for some young people, especially female patients, to accept. There are some medications that can trigger mood and personality changes in patients. In addition, some drugs can have an effect on heart function."
When asked about the most impressive cases, Jin Wu thought for a long time, almost every day, he was facing the side effects of patients and constantly giving solutions.
"Now there is a lack of a standard set of procedures to guide doctors how to deal with it, and it cannot be said that in addition to the side effects, stop the drug." Every time we have a meeting, we are asked, what should I do if this side effect occurs? How to solve that side effect?"
One of Fu Liang's work in the department is to manage the side effects of patients with MDR-TB, and he has compiled a side effect management manual according to the medical guidelines and circulated it in the department.
MDR-TB Patient Management Table Source: Courtesy of respondents
The advent of the COVID-19 pandemic has brought new challenges to China's anti-TB work, which is still in trouble.
In 2021, doctors in Shanghai, Jiangsu, Beijing, Xinjiang and other places have reported that in the early stage of the new crown epidemic, tuberculosis work faced difficulties, and the number of tuberculosis reports dropped significantly.
Taking Beijing as an example, from January to August 2020, the number of reported cases of tuberculosis in Beijing decreased compared with the same period in 2019, of which the decline from January to May was the most significant, with a decline of 35. 99%、29. 90%、 56.65%、27. 12% and 33. 03%。
Doctors analyzed that mainly due to the fact that after the outbreak of the epidemic, various medical institutions concentrated a large number of people, money and materials to deal with the new crown pneumonia epidemic, some medical staff (especially inspectors) were redistributed to give priority to fighting the new crown pneumonia epidemic, and the tuberculosis service system was not functioning smoothly.
Some hospitals have implemented a non-fever diagnosis appointment system, non-essential non-hospitalization, and outpatients and inpatients have been greatly reduced. But for some drug-resistant TB patients, reimbursement for some drugs can only be achieved through hospitalization.
At the same time, patients were affected by epidemic control measures and could not go to the hospital to get medicine.
At the beginning of 2020, the new crown epidemic in Wuhan was the most serious, and the Wuhan Pulmonary Hospital where Jin Wu was located took emergency measures to send drugs to patients through various channels and remotely guide patients for treatment.
"During the epidemic, the proportion of patients in our hospitals, because we have taken a lot of emergency measures, is relatively small due to the epidemic and the treatment is interrupted."
At this time, Fu Liang's Shenzhen is fighting the new crown epidemic in an all-round way, including the Third People's Hospital where he is located, "but our tuberculosis outpatient clinic and inpatient department are operating normally, but some patients from other places can't get the medicine, so they stop the drug."
Explorers
Industry insiders clearly show the main plight of MDR-RESISTANT patients in China: long treatment cycles, heavy economic burdens, and poor compliance.
These are seen and need to be addressed.
In the past, the trajectory of multidrug-resistant treatment was that the more drugs were used, the longer the course of the disease, but the cure rate was only about 50%. In recent years, Chinese and foreign doctors have changed their thinking and tried to explore the "short-term solution to multi-drug resistant treatment".
In the past few years, Jin Wu and Fu Liang have also launched the "short-term plan" project in the hospital, and the data are still considerable, with good outcome rates of 90% and 95% respectively, but the sample size is relatively small.
Fu Liang said, "We hope to be able to make a plan that conforms to China's national conditions," a grounded plan."
The first patient in South China (bedaquinoline was listed in China on 1 January 2020) on bedaquinoline is receiving medication. Image source: Courtesy of respondents
"For example, our MDR-TB testing could do better to detect drug resistance, because the burden of our TB is heavy, but there is not much research on this aspect." In addition, for example, the drug of clofazimin, because the side effect is coloring and blackening, is used in Chinese groups, there will be obvious problems, we should study it more thoroughly, how to manage this drug. There is also the problem of drug accessibility, many new drugs in the world, to china marketing or need time, and even the level of reimbursement is different, such as bedaquinoline, so our plan, to take into account whether there is a situation is not used bedaquinoline."
Jin Wu has been working on TUBERCULO for more than 20 years, and he has figured out his own way of managing patients.
"Diagnosis and treatment doesn't just happen in the outpatient clinic, there is not enough time in the clinic."
He has a patient population of nearly 500 people. "Drug-resistant patients are mainly home therapy, and they will encounter discomfort at any time and throw problems in the group."
Therefore, Jin Wu developed a habit of spending time every night to see the problems raised by patients and give solutions.
Jin Wu conducts patient management in the WeChat group. Image source: Courtesy of respondents
"The patient will feel that the doctor is standing with him, which will enhance his confidence in treatment, the patient has something to rely on, which requires the doctor to spend a lot of personal time, but for me, these patients can get some therapeutic promotion, so I will have a sense of professional footwork." 」 Of course, we also take some peer education, such as having experienced patients communicate with new patients to help each other build confidence."
But the dilemma is not just solved by doctors and patients working together, it is a system problem.
From the perspective of public policies, the central government has begun to propose some policies and plans from all localities. For example, in the Healthy China 2030 Planning Outline, the Healthy China Action Plan and the Notice of the Action Plan to Stop Tuberculosis, all put forward requirements for tuberculosis and comprehensive prevention and control, and to reduce the social burden of the disease and the burden on the individual family of patients. This includes the inclusion of a large number of anti-TB drugs in the national essential medicines list to ensure the production, availability and accessibility of anti-TB drugs.
At the local level, taking Jiangsu Province as an example, in 2020, the full-time funding for drug-resistant tuberculosis in the area will be about 40 million yuan, of which half of the subsidized drugs will be subsidized, and the finance will successively purchase second-line drugs such as linezolid, cycloserine, clofacidamine, bedaquinoline, etc., provide patients free of charge, and incorporate some high-value special drugs into the "dual channel" management, pay alone, and improve the accessibility of out-of-hospital drugs for patients.
"We are not doing clinical research to publish an article, we hope to change the management strategy of MDR-TB treatment in China."
Fu Liang said, "We hope to provide some evidence to the Medical Insurance Bureau and the Health Commission that China can have a plan that suits its own national conditions, which requires some clinical research evidence." At present, in addition to efficacy, we are also evaluating the content of health economics, hoping to give some support to the policy, what is effective, what needs to be negotiated for drugs or to solve the reimbursement problem."
"We are all talking about encouraging new drug research and development, but the fact is that China's new drug research and development level will not be able to catch up with foreign countries in the short term." Moreover, no matter how many new drugs there are, there will be a day of resistance, so we need to cure as many MDR-TB patients as possible in a limited time, which is what we can do now."
(In order to protect personal privacy, Xia Lin and Su Qi are pseudonyms in the text)
Author: Su Weichu
Producer: Li Chen
First image source: Visual China