Almost from the beginning of human beings recording their own lives, Tuberculosis is like a shadow. We can find evidence of this chronic disease in the ruins of Nordic, Neolithic Age, and ancient Egyptian cemeteries.
Humans cannot see pathogenic bacteria in the naked eye, but they can see the terrifying consequences of it - high fever does not subside, weight loss, and long-term hemoptysis. More importantly, this bacteria spreads extremely quickly. Every time, tuberculosis continues to form a new mechanism to avoid the attack of the immune system, survive in the new host, and continue to spread.
It was not until the 1940s that antibiotic appeared that humans truly effectively controlled tuberculosis. In China, from the 1950s to the 1970s, the chemotherapy regimen composed of streptomycin , aminosalicylic acid, and isoniazid was the most classic and best-efficient combination of anti-tuberculosis at that time, and was called "Lao Sanhua". The anti-tuberculosis drug rifampin has been released, and for a long time, it has been one of the main anti-tuberculosis drugs in China.
However, anti-tuberculosis drugs are a double-edged sword. While killing tuberculosis bacillus, they also cause pathogens to have natural resistance to drugs. The strains have successively become resistant to many types of drugs in this way.
Today, drug-resistant tuberculosis has become a public health problem that needs to be solved urgently in the world.
In China, the number of drug-resistant tuberculosis patients is far higher than the global average due to the abuse of antibiotics, irregular medication use of some tuberculosis patients, large population base, and overall lack of wealth.
At the same time, the level of primary medical institutions is insufficient, the medical service system is fragmented, prevention and treatment is isolated, the treatment cycle of drug-resistant tuberculosis is long, the side effects of drugs are great, rapid detection instruments and reagents, second-line drugs are relatively expensive, etc., which have repeatedly trapped China's drug-resistant tuberculosis patients and doctors.
According to WHO estimates, there are 842,000 new tuberculosis patients in my country every year, of which about 65,000 patients with multidrug-resistant/rifampicine-resistant patients, ranking second in the world, second only to India.
"White Plague" is not an ancient legend. Today, we are still questioning our public health system.
March 24, 2022 is the 27th "World Tuberculosis Day".
Drug-resistant tuberculosis In China
In the outpatient clinic, a confirmed Tuberculosis patient did not have time to wear a mask, and suddenly covered his mouth with a tissue, burst out a mouthful of phlegm, with blood.
She carefully wrapped the tissue, put it in a bottle, sealed it, and quickly pulled the mask on. She realized that she, who was in the contagious period, could release millions of tuberculosis bacteria with every cough, and if no action was taken, these bacteria would float in the air and could infect anyone who was breathing.
Humans have been fighting against tuberculosis for thousands of years. In the past, there were many treatments for tuberculosis, including taking insect body fluids, bleeding patients, allowing patients to live in high-altitude areas, traveling at sea, quitting alcohol, etc.
Mycobacterium tuberculosis Source: "Continuing Education Course for Control of Multidrug-resistant Tuberculosis"
9 At the end of the century, after tuberculosis entered the bacteriology era, Western medical scientists and biologists have been trying to develop effective drugs for tuberculosis bacteria.
Until 1944, the special drug for tuberculosis, "Streptomycin", was invented as an antibiotic, which can effectively inhibit the reproduction of tuberculosis bacteria. In the following years, ammonia salicylic acid and isoniazid appeared one after another, and were used in combination with streptomycin to effectively treat tuberculosis. Subsequently, other drugs such as rifampin were released one after another.
New problem has emerged.
Nowadays, some Mycobacterium tuberculosis have developed resistance to existing anti-tuberculosis drugs. Antibiotics that once served as the ultimate weapon have become less useful.
This is not incomprehensible. The individual lineage of bacteria continues to evolve and form new mechanisms.If antibiotics are used artificially 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.
Fu Liang, attending physician of the Department of Pulmonary Diseases, Shenzhen Third People's Hospital, said that there are mainly two types of drug-resistant patients in the outpatient clinic:
The first type is a long-term transmission patient, that is, tuberculosis bacteria were infected very early, but it was not cured, and later it became drug-resistant bacteria. Another type is recent transmission, that is, patients who have just been diagnosed and come for the first time for diagnosis and treatment are drug-resistant patients. "In the past, it was believed that many patients developed drug resistance because they were not well treated, but now we have found that nearly half of the patients may have been recently transmitted."
In the drug-resistant tuberculosis classification, multidrug-resistant tuberculosis has been paid special attention in China and the world.
"In drug-resistant tuberculosis, we mainly focus on isoniazid alone, rifampin alone, or isoniazid alone, or isoniazid Californian resistance."
Fu Liang explained, "The standard definition of multidrug resistance we often mention isoniazid and rifampicine is at the same time. But in actual operation, when we found that single-rifampicine resistance, the treatment was treated as multidrug resistance, because while single-rifampic resistance, the proportion of isoniazid resistance is also very high, about 80%.
data show that in 2019, 18% to 21% of patients worldwide who have received tuberculosis treatment were multidrug-resistant/rifampicine. Among them, there are about 65,000 patients with multidrug/rifampic resistance in my country, accounting for 14% of the global cases, ranking second in the world.
In China, why is the problem of multidrug-resistant tuberculosis so prominent?
Several doctors told "occasional cure", mainly based on several reasons:
is the abuse of antibiotics first. data shows that about 40% of patients in China have abuse of antibiotics, resulting in more drug-resistant patients and drug-resistant types in China than in other countries.
"Especially antibiotics of quinolones are widely used in common pneumonia in some general hospitals. Therefore, the drug resistance rate of quinolones in China is higher than that in foreign countries, but quinolones are the main drug for anti-tuberculosis treatment. Therefore, the situation of drug resistance caused by quinolones alone is very common in China," said Jin Wu, deputy chief physician of the Department of Tuberculosis at Wuhan Pulmonary Hospital.
Image source: Social Education Press Popular Science
Improper use of medicine is a problem. A doctor from a first-tier city tertiary hospital told "occasionally cured". Some of the patients she admitted were treated repeatedly in the local area, using second-line anti-tuberculosis drugs prematurely, or even single drugs. "When a single drug is used for anti-tuberculosis treatment, tuberculosis bacteria are easily resistant to this drug, and the treatment effect is significantly reduced. Therefore, the principle we follow is to use at least four drugs in combination. Moreover, when a single drug resistance occurs, we cannot only consider replacing one drug."
Tubber patients will also develop drug resistance by themselves. treatment with medication, some patients' symptoms will be significantly improved, such as no longer coughing or sputum, and some patients mistakenly think that they have recovered and stop the medication on their own. This can easily lead to the already inhibited tuberculosis bacteria reproducing in large quantities and developing drug resistance. The management of patients with
has always been a headache for doctors. Compared with ordinary tuberculosis, the treatment course of multidrug-resistant tuberculosis is longer. "The initial course is 18 months. It will even be extended to two years or even more than 30 months depending on the area of drug resistance and the type of drug resistance," said Jin Wu. During this period, some patients will lose due to long courses of treatment or serious side effects. There are also data that only 60% of multidrug-resistant patients are detected, and a large number of patients are still hidden and undetected, which means that when patients become sick, they will become a potential source of infection for transmission.
Multiple-resistant tuberculosis is not just a medical problem.
In the doctors' clinic, they have seen many poor patients who have to give up treatment because they cannot afford the treatment plan such as expensive antituberculosis drugs such as bedaquiline, linezolid, and clofazimin. "Some people are even more poor, because they are unable to work due to illness and face high medical expenses."
A patient told "occasional cure" that among the five drugs she took, bedaquiline was the highest price, with a box of 8,400 yuan, and one box needed to be taken a month. "We have no medical insurance here, and we have to pay for it at all."
Disorder diagnosis of multidrug-resistant tuberculosis
021, after obtaining the diagnosis of tuberculosis, Xia Lin began to be hospitalized for treatment. During her hospitalization, the doctor told her that she might have drug resistance. Two days later, drug resistance genetic tests showed that she was resistant to rifampin and isoniazid.
"I asked the doctor, I said I had read the information. Many patients with multidrug resistant are resistant after repeated treatment. How could I do this when I first started the treatment? The doctor explained that because when I was infected, I felt that I was resistant to drug-resistant tuberculosis bacteria, and I felt quite unlucky."
But after asking some patients, Xia Lin was a little lucky that she did not take many detours on the road to confirming multidrug resistance.
Compared with Xia Lin, Su Qi's medical experience can be said to be ups and downs.
He had symptoms earlier than Xia Lin, in the summer of 2020. Because of his constant cough and back pain, he went to the designated hospital for tuberculosis in the city. He works in a third- and fourth-tier city in the south. It is hot in summer and shares a room of 50 square meters with three or four friends. Later he always recalled whether the harsh living environment caused him to be infected. But no one can answer him.
The first time I went to the hospital for examination, the chest radiograph showed that there was a huge shadow and hole in the right lung. The doctor told him that it was suspected of tuberculosis. The doctor diagnosed him with tuberculosis infection by doing tuberculosis, but he could not find the living tuberculosis bacillus.
He started to treat the medication for more than three months. At first, the cough disappeared and "thinked that victory was ahead", but not long after, the symptoms appeared again. Re-examination found that the hollow in the right lung had not improved at all, and even "enlarged the hollow."
Xia Lin went to the designated hospital for tuberculosis in the provincial capital and underwent many examinations. After a few days, the doctor concluded, "Nerrifampin and isoniazid."
"I felt at that time, I was not blamed for people who were willing to live in big cities. The doctor level in hospitals in big cities was different, and the equipment and other equipment were also different."
In patients with multidrug-resistant tuberculosis, the diagnosis and treatment difficulties are spread out layer by layer.
At present, the common methods of domestic testing are still sputum smears and sputum culture , but the disadvantage is that the diagnosis is very slow, which takes about 2 to 3 months, and the technical sensitivity is not high. Doctors say that while waiting for the test results, patients will lose their patients or start taking some irregular medication. The diagnosis of
MDR-TB needs to be based on sputum culture and medicine. Source: "Continuing Education Course for Multidrug-resistant Tuberculosis Control"
Fu Liang introduced that in fact, the preferred method recommended in the industry is the detection of the molecular diagnostic instrument Xpert, which can detect whether tuberculosis DNA and rifampin are resistant to drugs at the same time, and the results can be obtained in two hours.
"But this instrument is not very well promoted at the grassroots level. When it first came out, the World Health Organization gave away many instruments for free to China's grassroots institutions. However, a very realistic problem is that reagents need to be purchased separately. A reagent may cost five or six hundred yuan, which cannot be afforded in many places. And not only at the grassroots level, but even in the tuberculosis specialties of some tertiary hospitals, this instrument is only placed here. The high cost is one. On the other hand, because Xpert's testing is not in medical insurance, it is difficult to promote."
At the same time, Fu Liang added that there are many links in the diagnosis of suspicious cases. Taking the Third Hospital of Shenzhen where he is, he will do smear culture and Xpert testing. If the patient has no sputum, it will be recommended to do bronchoscopy , and there are ordinary tuberculosis DNA testing to choose--this is comparable Xpert will be much cheaper.If DNA is positive, it will be determined by dissolution curve method whether it is resistant to isoniazid, rifampin, streptomycin, fluoroquinolones, etc. "Basically, drug resistance can be found one to two weeks before admission, and we will definitely track the sputum culture later."
However, my country's "free tuberculosis treatment" is limited. In the diagnosis stage, there are only two free items: chest X-ray and sputum smear. During treatment, free first-line anti-tuberculosis drugs are provided for ordinary tuberculosis patients, as well as sputum smears and chest X-rays during treatment.
Diagnosis under the COVID-19 pandemic
Diagnosis is only the first step, and subsequent treatment continues to test patients and doctors.
Wuhan Pulmonary Hospital where Jin Wu is located will hold business training and study for grassroots hospital every year. He will still notice that in addition to improving doctors' awareness of business training, he also faces other problems.
For example, some effective drugs for the treatment of anti-multiple-resistant tuberculosis are not available in primary medical institutions, and the accessibility of drugs is very poor. At the same time, there are no corresponding reimbursement measures, and some places even fail to reimburse. "This causes many patients to not get the medicine locally, but they cannot travel back and forth in provincial capitals. Some patients find it troublesome and have to give up taking the medicine."
Jinwu's Clinic Source: Respondents provide
Currently, my country's tuberculosis prevention and control model is a "trinity" model, Central for Disease Control and Prevention, , designated hospitals for tuberculosis, and grassroots health institutions.
is relatively perfect according to the top-level design idea, but during the specific implementation, patients and doctors will find many problems of poor connection.
Take Fu Liang's Shenzhen City as an example. The designated hospital for tuberculosis and the Chronic Disease Prevention and Control Hospital are divided into the Health Commission and the Center for Disease Control and Prevention. Therefore, when transporting patients in detail, problems such as poor communication of patient information are prone to occur. But at the Wuhan Pulmonary Hospital where Jin Wu is located, it is a unified hospital, a designated hospital and a prevention and treatment institution, and "communication is relatively smooth."
In addition, the "specific response methods and concepts" of medical institutions and chronic disease prevention and control hospitals are also different. Fu Liang added, "Chronic hospitals may guarantee basic medical care. In the face of some difficult to diagnose or difficult problems, patients will be recommended to refer to a designated hospital for specialized hospitals."
Many times, behind the "poor compliance of multidrug-resistant patients" mentioned by doctors is partly the challenge caused by the side effects of multidrug-resistant tuberculosis treatment drugs.
"In the core plan, the adverse reactions of some drugs will cause the patient's blood system hematopoiesis inhibition. platelet , red blood cells , white blood cells are reduced very significantly, which is much higher than ordinary tuberculosis. In addition, there are common situations such as taking some drugs to cause darkening of skin pigmentation, which is difficult for some young people, especially female patients. Some drugs can cause changes in the patient's mood and personality. In addition, some drugs will have some impact on heart function."
When asked about the most impressive case, Jin Wu thought for a long time. Almost every day, he was facing the side effects of the patient and constantly gave solutions.
"Now there is a lack of a standard process to guide doctors on how to deal with it. We can't say that apart from side effects, we can stop the medicine at once. Every time we have a meeting, we will be asked, what should we do if this side effect occurs? How to solve that side effect?"
Fu Liang's work in the department is to manage the side effects of patients with multidrug-resistant tuberculosis. He compiled a side effect management manual for circulating it in the department according to medical guidelines.
Anti-multiple-resistant tuberculosis patient management table Source: Respondents provide
The arrival of the new crown epidemic has brought new challenges to China's anti-tuberculosis work, which is still in trouble.
021, doctors from Shanghai, Jiangsu, Beijing, Xinjiang and other places reported that in the early stages of the outbreak of the new crown epidemic, tuberculosis work was facing difficulties, and the number of reports on tuberculosis decreased significantly.
Take Beijing as an example. From January to August 2020, the incidence of tuberculosis in Beijing decreased compared with the same period in 2019, with the declines most significantly in January to May, with the declines of 35.99%, 29.90%, 56.65%, 27.12% and 33.03% respectively.
Doctors analyzed that it was mainly because 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, and some medical personnel (especially testers) were reassigned to fight the new crown pneumonia epidemic first, and the tuberculosis service system was not functioning smoothly.
. Some hospitals have implemented a non-fever clinic appointment system and no hospitalization unless necessary. The outpatient and inpatient patients have been significantly reduced. But for some patients with drug-resistant tuberculosis, reimbursement of some drugs can only be achieved through hospitalization.
At the same time, the patient was affected by epidemic control measures and was unable to go to the hospital for medicine.
020, the COVID-19 epidemic in Wuhan was the most serious. The Wuhan Pulmonary Hospital where Jin Wu was located took emergency measures, sending medicine to patients through various channels and remotely guiding patients for treatment.
"During the epidemic, the proportion of patients in our hospital, because we have taken many emergency measures, is relatively small.
At this time, Shenzhen where Fu Liang is in full swing against the COVID-19 epidemic, including the Third People's Hospital where he is. "But our tuberculosis clinic and inpatient department are operating normally, but some patients from other places can't get the medicine and stopped the medicine."
Explorer
Industry insiders clearly demonstrated the main difficulties of Chinese multidrug-resistant patients: long treatment cycle, heavy economic burden, and poor compliance.
and these are seen and need to be solved.
In the past, the treatment trajectory of multidrug resistance was that the more medicine was used, the course of the disease was getting longer and longer, but the cure rate was only about 50%. In recent years, Chinese and foreign doctors have changed their thinking and tried to explore "short-range multidrug-resistant treatment plans".
In the past few years, Jin Wu and Fu Liang have also launched "short-range plan" projects in the hospital. The current data is quite considerable, with good outcome rates of 90% and 95% respectively, but the sample size is relatively small.
Fu Liang said, "We hope to make a plan that conforms to the "national conditions of China"" and a down-to-earth plan. ”
The first case of patients in South China (bedaquiline was launched in China on January 1, 2020) were taking the medicine. Source: The interviewee provides
"For example, our multidrug-resistant tuberculosis test can be done better to discover drug resistance, because our dosage of drug-resistant tuberculosis is very heavy, but there are not many studies in this regard. In addition, for example, the drug clofazimin, because the side effect is that the coloring becomes dark, will have obvious problems in Chinese people. We should study it more thoroughly and how to manage this drug. There are also issues with drug accessibility. Many new drugs in the international market still take time to go to China, and even the reimbursement levels are different in different places, such as bedaquiline. Therefore, in our plan, we must consider whether there is a situation that cannot be used bedaquiline."
Jinwu has been engaged in the fight against tuberculosis for more than 20 years. He has also figured out his own way of how to manage patients.
"Diagnosis and treatment not only happen in the outpatient clinic, but the time in the clinic is far from enough."
He has a patient group with nearly 500 people. "Drug-resistant patients are mainly treated at home. If you encounter discomfort at any time, you will raise problems in the group."
Therefore, Jin Wu has developed a habit of spending time seeing the problems raised by the patients every night and solving them.
Jinwu conducts patient management in WeChat group. Source: Respondent provided
"Patients will feel that the doctor is standing with him, which will enhance his confidence in treatment and the patient has something to rely on. This requires the doctor to spend a lot of private time, but for me, these patients can get some therapeutic promotion, and I will have a sense of professional footing.Of course, we will also adopt some peer education, such as allowing experienced patients to communicate with new patients to help each other build confidence. ”
But the dilemma cannot be solved by the cooperation between doctors and patients. This is a systematic problem.
From the perspective of public policy, the central government has begun to propose some policies and plans to various places. For example, in the " Healthy China 2030 Outline ", "Healthy China Action Plan" and the "Notice on the Action Plan to Curb the Tuberculosis", both of which put forward requirements for tuberculosis and comprehensive prevention and control, reducing the social burden of the disease and the personal family burden of patients. It includes inclusion of a large number of anti-tuberculosis drugs in the national basic medicine directory to ensure the production, supply and access of anti-tuberculosis drugs.
At the local level, taking Jiangsu Province as an example, the full-time funding for drug-resistant tuberculosis in the area in 2020 was about 40 million yuan, of which half of the subsidized drugs were purchased. The finance department successively purchased second-line drugs such as linezolid, cycloserine , clofazimin, bedaquiline and other second-line drugs, providing patients with free of charge, and included some high-value special drugs in the "dual channel" management, and paid in a single line to improve the accessibility of patients' out-of-hospital drugs.
"We do clinical research not to post an article. We hope to change China's multidrug-resistant tuberculosis treatment management strategy."
Fu Liang said, "We hope to provide some evidence to the Medical Insurance Bureau and the Health Commission. China can have plans that meet its national conditions, which requires some clinical research evidence. At present, in addition to the efficacy, we are also evaluating the content of health economics , hoping to give some policy support. What plan is effective is that it requires drug negotiation or reimbursement problems."
"We are all talking about encouraging new drug development, but one fact is that China's new drug 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 drug resistance, so we must cure as many patients with multidrug-resistant tuberculosis as possible in a limited time. This is what we can do now."
(To protect personal privacy, Xia Lin and Su Qi are pseudonyms in the article)
Written by: Su Weichu
Producer: Li Chen
First picture source: Visual China
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