Is there a magic drug for tuberculosis? The British double-blind controlled trial is indispensable, but the devil has not gone far

Category：regimen

2020-12-15

this issue belongs to the series
author of "deadly epidemic": Zhu Liang

1946 in one day, 28-year-old Londoner John walked into the Brompton Hospital, which is the UK's largest lung disease specialist hospitals. Prior to this, John had had a low-grade fever for several days, night sweats at night, and coughing non-stop all day long. What's more terrifying was that there were bloodshot eyes in the sputum he coughed up.

After the examination is over, the doctor tells him with certainty: your disease is advanced tuberculosis . Before John could fully respond, the doctor handed him an envelope and told him: Please take this envelope to the inpatient department to complete the procedures. John took the envelope and coughed violently again. The late stage of tuberculosis was like a death notice. He stared at the envelope blankly and was silent. The envelope was succinctly written "Bronpton Hospital" and a string of numbers, which looked like a string of random numbers. Open the envelope, there is a card inside, marked with a letter "S" in bold.

Looking at this strange card, a glimmer of hope rose in John's heart, but the doctor asked him not to ask more and went directly to the inpatient department. John got up and left, his emotions were extremely complicated. Of course the most were fears and worries, but his strong desire to survive made him full of illusions about this card. He didn't know what the letter S on this card meant, so he could only guess. With various possibilities.

John's fear comes from the death rate of this terrible disease. Even in modern times, according to WHO data [1], tuberculosis is one of the top ten causes of death worldwide and the number one killer of a single infectious disease. It exists in all countries and all age groups. Moreover, this disease is highly contagious. When a patient with tuberculosis coughs, sneezes or spits, it is easy to spread the disease, and the risk of the infection for a lifetime is 5-15%. But once the disease occurs, if you don't get proper treatment, the mortality rate exceeds 45%. It is conceivable that in the 1940s, when there was no specific medicine, if you knew you had tuberculosis, you would feel the same as modern people knowing that you have advanced cancer.

Royal Brompton Hospital

White Plague

What kind of disease is tuberculosis? What is its pathogenesis? This is a very ancient disease, dating back to 2400 BC[2]. The mummy spine fragments of ancient Egypt at that time clearly confirmed tuberculous corrosive lesions. So counting, tuberculosis has at least 4000 years of history . Mrs. Xin Chai, who was unearthed in Mawangdui, Changsha, my country, confirmed that her left lung had calcified spots left by tuberculosis after her body was dissected. This at least proves that tuberculosis was introduced to our country more than two thousand years ago.

In ancient my country, tuberculosis was called "tuberculosis", and the incidence was extremely high, because there was a saying among the people that there were "nine out of ten tuberculosis", and even tuberculosis was called China's national disease. In the early days of the founding of New China, the infection rate of tuberculosis in large cities was as high as 80% to 90%, and the incidence rate was 4,000 per 100,000. That is to say, there was one tuberculosis patient in every 25 people [3]. It can be said that China is also the hardest hit area of tuberculosis.

Lin Daiyu in "A Dream of Red Mansions", from the perspective of symptoms, should be tuberculosis. Throughout the work, you can often read paragraphs about Daiyu waking up in the middle of the night, sweating, and coughing up blood. Yes, the typical symptoms of tuberculosis are severe cough, chest pain, coughing up blood or sputum, fever, night sweats, weakness, fatigue, loss of appetite, etc.

A Dream of Red Mansions 1987 version stills

Many Chinese and foreign writers died of tuberculosis, such as Keats, Chekhov, Kafka, Lu Xun and so on.

Readers who love science must know that the famous wave equation in quantum mechanics was completed by Schrödinger during the convalescence period after contracting tuberculosis. Although

has a long history and spreads all over the world, people have not always figured out how this disease happened, but only vaguely know that this disease seems to be an infectious disease. In ancient Greece BC, Hippocrates believed that tuberculosis was a widespreadFor the spread of the disease, he warned his students not to contact advanced patients. It was also mentioned in the Italian medical writings of the 17th century that it was an infectious disease.

However, these classics have some effect on preventing tuberculosis infection, but they are not helpful for treatment.

For more in-depth research, in 1679, a doctor named Franciscus Sylvius dissected the corpse of the deceased. He found that the patient’s lungs had granular lesions, some gray-white masses, which were called It is a nodule [4], but his gain is nothing more than that. Later in 1839, the German doctor Johann Lukas Schonlein named the disease Tuberculosis (Tuberculosis) based on the characteristics of the nodules. And because of this white nodules phenomenon, people also call this terrifying infectious disease the white plague.

White nodules

The pathogen

was discovered more than 20 years later. In 1865, French military doctor Jean-Antoine Villemin confirmed that tuberculosis can be transmitted from humans to cows and then to rabbits. He guessed that this might be from humans to cows and then to rabbits. Caused by microorganisms.

There are many scientists who have the same conjecture as him. At that time, many scientists were trying to find the culprit, but no one could find and prove the real pathogen.

Until 1881, the famous German bacteriologist Robert Koch also began research on the pathogen of tuberculosis. Koch became famous for his discovery of Bacillus anthracis. This time he passed countless staining tests and finally saw the elongated spindle-shaped bacteria in the sample No. 271, so Koch named it tuberculosis Bacillus . It was in the process of studying Mycobacterium tuberculosis that Koch gradually formed a basic law proving that a certain disease is caused by microorganisms. This is an extremely important achievement for modern medicine. This is the famous Koch law . Koch won the Nobel Prize in Medicine or Physiology in 1905 for his discovery of Mycobacterium tuberculosis.

Koch's discovery of tuberculosis commemorative stamps

The research has progressed here, and the medical community has finally found the cause of tuberculosis. It turns out that tuberculosis is at work. It is a gram-positive bacterium with a complex cell wall, showing a small size. The rod-like structure. It is most likely to affect the lungs and produce tuberculosis. Of course, it is not limited to the lungs. Mycobacterium tuberculosis can also be transported through the blood or lymphatic system and spread to any part of the body, such as the large intestine, meninges, kidneys and even bones.

Now that the cause has been found, you may think that what is left is to have a targeted, targeted elimination of this kind of bacteria. However, things are not as easy as imagined. Koch tried many methods to extract a tuberculin, but ultimately failed.

Baby’s first vaccine

If tuberculosis bacillus invades the human body and causes tuberculosis to be regarded as a defensive battle, to win, it is an idea to counterattack the enemy after the fall, but if it can resist the enemy before the fall A better way. This is the vaccine idea.

has a PhD in bacteriology from the famous Pasteur Institute, named Albert Calmette. He met veterinarian Dr. Camille Guerin at an academic conference and invited him to work together. Kalmay opened the first tuberculosis clinic in Europe in 1901 and embarked on the road of tuberculosis research.

Calmette (Albert Calmette, left) Camille Guerin (right)

We have told the story of smallpox before. Dr. Edward Jenner produces vaccinia from cowpox, which can be vaccinated against human smallpox. Inspired by this, KalmayHe Jielin also wants to start research on the bovine Mycobacterium tuberculosis. However, the bovine Mycobacterium tuberculosis is more toxic. This is the opposite of the smallpox vaccinia vaccine, which is less toxic, so it is safer as a vaccine. The bovine tuberculosis bacillus cannot be used as a vaccine because it is too toxic and the risk is too high. After all, these two people are Pasteur’s capable officers and have a wealth of research experience. Soon they thought of the method of attenuating the virus by passaging (in short, let the tuberculosis bacillus continue to reproduce and pass on), expecting them to reproduce. Change traits in the process. If a certain trait can reduce the toxicity, it will be retained and passed on.

In countless experiments, they found that 5% bovine bile glycerin potato is the most suitable medium, and as the number of passages increases, weaker strains can always be screened out. In 1921, they finally found a suitable strain, which has been passed down to the 231st generation. They proved the immune effect of the vaccine in guinea pigs and at the same time confirmed the safety of the vaccine. Pasteur used the first letters of their names to name the vaccine, which is BCG, and the Chinese name is BCG vaccine . After the advent of the

BCG vaccine, countless children have been saved. For those children born in tuberculosis families, the incidence of tuberculosis in the first year has been reduced from 25% to 2% [5], the effect is very significant.

In fact, BCG is familiar to all of us. Newborn babies are normally vaccinated with BCG on the first day of birth. If it is convenient for you at the moment, please raise your left arm. The circular scar on your upper arm is the proof of BCG vaccination.

Traces of BCG vaccination

The introduction of BCG in my country is also a tortuous process. After Pasteur announced the research results of BCG vaccine, a doctor named Wang Liang also noticed that paper [6]. When he returned to China from Hanoi to study medicine in the early years, he learned that a brother and a sister had died of tuberculosis, so he paid special attention to the progress of tuberculosis control. After he saw the paper, he went to France to find Dr. Calmay in the Pasteur Institute in 1931, and followed him to learn about the technology of BCG. More than two years later, he returned to his motherland with the vaccine and started vaccinating people in his own clinic in Chongqing. However, due to the turmoil of the year and the lack of official approval at the time, his BCG vaccine was ordered to ban in 1937.

Later, with the development of domestic biological products, Liu Yongchun from the Pasteur Institute in Shanghai Concession, Tang Feifan from the Central Epidemic Prevention Department and others gradually introduced BCG strains repeatedly. In any case, BCG has been spread in China.

However, just as people think that it can be cured like smallpox vaccine, more and more facts have proved that the protective effect of BCG is not perfect [7]. The protective effect on childhood meningitis and disseminated tuberculosis is very good, with an average protection rate of 86%, which has reached the protection rate of most vaccines [8]. However, the protective effect in adults is not obvious, and it cannot prevent the recurrence of primary infections and latent lung infections.

Finding specific drugs for tuberculosis treatment is still a medical problem to be overcome.

unveiled the curtain on antibiotics: Streptomycin

Selman Abraham Waksman of Rutgers University in the United States is a famous soil scientist. In 1915, when he was in college, he began to study soil microorganisms, and together with his classmates he extracted a kind of Actinomycetes Z17z.

Salman Waxman (Photo by Tarza Studio, New Brunswick, New Jersey)

At that time, people discovered that if Mycobacterium tuberculosis fell into the soil, it would be quickly killed, then is there something in the soil? Can a kind of microorganism or a certain substance resist Mycobacterium tuberculosis? In 1932, Professor Waxman was commissioned by the American Association against Tuberculosis and began to study this issue. He was inspired by Fleming’s penicillin extracted from Penicillium, and set out to search for antibiotics from Actinomycetes.Bacterial material. In 1939, he also received funding from Merck.

By 1941, Waxman and his team had studied more than 8,000 species of bacteria and also discovered various mycotoxins. In 1943, his student Albert Schatz extracted a new mycotin from Actinomyces griseus and named it streptomycin . The word antibiotic also appeared in this process. If Fleming's penicillin is the corner of the curtain, then Waxman is the person who really opened the curtain of antibiotics[9].

Streptomycin was extracted from Streptomyces griseus

In 1944 Waxman gave streptomycin to the Mayo Clinic for research. Living up to expectations, this streptomycin exhibits many excellent properties, can fight against many kinds of bacteria, including Mycobacterium tuberculosis, and complements the effects of penicillin. They used streptomycin in guinea pigs with tuberculosis. After 6 months of continuous treatment, they found that all 16 lesions had resolved. Thirty percent of guinea pigs could not detect Mycobacterium tuberculosis by histological and bacteriological methods, and the remaining 70% of their illnesses were also contained. In human trials, 21 pulmonary tuberculosis patients received streptomycin for 4 weeks, and at least 16 patients showed significant improvement. The appearance of

streptomycin is amazing. On the one hand, it shows a strong bactericidal ability. The killing effect of soil on Mycobacterium tuberculosis is precisely the contribution of this streptomycin. On the other hand, due to the huge economic benefits brought by streptomycin, Schatz and Waxman also went to court to fight for the right of discovery, which also confirmed from the side how important the discovery of streptomycin is.

In fact, the mechanism of streptomycin is to block the synthesis of proteins in infected cells, thereby inhibiting the reproduction of Mycobacterium tuberculosis.

Waxman won the Nobel Prize in Medicine or Physiology in 1952 for his contribution to the discovery of streptomycin.

Austin random double-blind experiment

When these news spread to the UK, it brought great excitement to the medical community. But according to Austin Bradford Hill, a professor of medical statistics, this is far from enough. Doctors at the time had discovered the body's self-healing and placebo effects. Some medical scientists with rigorous scientific thinking have realized that if a drug is to be proved to be effective, these interfering factors must be eliminated. The only way to eliminate these interfering factors is to conduct randomized double-blind controlled trial .

Austin Bradford Hill (Austin Bradford Hill) Austin Bradford Hill (Austin Bradford Hill)

In 1946, the British Medical Research Council (MRC) planned to conduct clinical trials of streptomycin [10][11]. They ordered 50 grams of streptomycin from the United States, and Austin became a member of the committee. This is also the first strict randomized double-blind controlled trial (RCT) in the history of medicine, which has great groundbreaking significance. [12]

Considering the limited amount of streptomycin, the trial he designed is arranged like this: select those pulmonary tuberculosis patients aged 15-30 years old, they must be newly infected with acute progressive bilateral pulmonary tuberculosis and are not suitable for wilting Depression therapy. (Collapse therapy is a method of artificially injecting clean air into the thoracic cavity or abdominal cavity, which can selectively shrink the diseased lung.) If there are patients who meet the conditions, they will be sent to the person in charge of the National Coordination Center. After determining that they meet the standards, A hospital bed will be arranged nearby, and a randomly numbered envelope will be assigned, and there will be a card marked "S" or "C" inside. S is actually the first letter of Streptomycin; and C means Control. If it is in the same hospital, the two groups cannot be arranged in the same ward to prevent communication with each other.

The John mentioned at the beginning of our story, he wasFortunately, I was randomly assigned to the S group. In fact, both groups S and C will receive standard medical treatment and bed rest arrangements. The only difference is that the S group additionally used streptomycin. A total of 55 patients were assigned to group S like him, while group C as a control had 52 patients.

John will take chest X-rays every month to assess his progress and regularly record physiological indicators such as fever, body weight and sedimentation rate. And the doctor who performed the chest X-ray examination was completely unaware of the grouping situation, which can prevent the examination results from showing predisposition.

was like this for half a year. When the results of the experiment were evaluated, there were only 4 deaths in group S and 15 deaths in group C. Streptomycin showed a significant effect. Soon, Merck began mass production of streptomycin, which played an important role in the treatment of tuberculosis.

In the 1940's, the streptomycin produced by Merck was used in the treatment of tuberculosis. The treatment they received was still the most standard treatment at the time, and for the patients in the control group, the coordination center gave them priority admission. And once the streptomycin is proved to be effective, they will be treated with the new drug after the drug supply is improved, and the unknown side effects of the new drug can be avoided. Therefore, there is no problem in medical ethics.

Unfortunately, streptomycin is not a magic drug. Although it has shown significant effects in the data, its side effects have gradually emerged. It can damage the vestibular nerve and the cochlear nerve, and can cause permanent hearing loss in severe cases. It is also toxic to the kidneys.

Of course, the two evils are the lesser one, and saving lives is the most important thing. However, there are still some patients who develop resistance to streptomycin . This makes streptomycin therapy, for some people, only harmful but not good.

Drug resistance and current status of tuberculosis

In the 1950s and 1960s, isoniazid, pyrazinyl, ethambutol, and rifampicin were successively developed successfully. Their alternating or combined use can greatly reduce the drug resistance of tuberculosis. Incidence rate. These drugs have been used until now and have become the first-line anti-tuberculosis drugs.

In the 1980s, the incidence of tuberculosis in industrialized countries began to decline steadily. Taking the United States as an example, the annual incidence fell from 280 0 cases in 1980 to 22,000 cases in 1984 [13]. Following this trend, it is generally believed that tuberculosis will no longer be a threat to public health.

However, when people saw the dawn of victory, many countries reduced their funding for tuberculosis control, and as a result, the situation began to deteriorate again. By 1992, the number of cases in the United States had risen to more than 26,000. A U-shaped curve appeared throughout the 1980s. From 1980 to 2000, the incidence in some sub-Saharan African countries increased from 50 per 100,000 to more than 200 per 100,000. Zimbabwe even reached 400 per 100,000, an increase of 8 times; The member states of the Soviet Union also increased from 40 per 100,000 in 1991 to about 70 per 100,000 in 2000. At the same time, drug resistance of Mycobacterium tuberculosis has become more and more common, and drug-resistant tuberculosis has emerged. A 1993 study showed that drug-resistant and multi-drug resistant cases in New York accounted for 23% and 7%, respectively. The multi-drug resistance here means resistance to isoniazid and rifampicin, two first-line drugs. In this case, second-line drugs are required for treatment.

WHO official website picture of tuberculosis patients

In 1993, in order to strengthen the control of the spread of tuberculosis, the WHO declared tuberculosis a "global emergency".

drug resistance has become the most important obstacle to eliminating tuberculosis. Following multidrug-resistant tuberculosis, there has also been widespread drug-resistant tuberculosis that is also resistant to second-line drugs, and even "completely resistant tuberculosis" that is ineffective in existing drug treatments.Drug-resistant tuberculosis". The earliest fully drug-resistant tuberculosis patients reported in the world were two Italian women who died in 2003 [14]. However, so far, due to the lack of drug resistance data of second-line drugs, and the in vitro test results cannot be compared with actual The clinical effect is equivalent, and the WHO has not yet recognized the term “complete drug resistance” [15].

Globally, India and China are the hardest hit areas of drug-resistant tuberculosis, and drug-resistant products in China account for 14%. India is 27%[16].

According to the data published in the Global Tuberculosis Report updated on October 14, 2020[17], 1.4 million people died of tuberculosis globally in 2019, and an estimated 10 million new tuberculosis cases were reported. The number of multi-drug cases is 10% higher than in 2018. However, the good news is that the incidence of tuberculosis has dropped by 2% every year, with a cumulative decrease of 9% between 2015 and 2019.

The situation in China has also improved considerably, from 2000 From year to 2019, the estimated number of cases has decreased year by year, from 1.4 million to 833,000[18], an average annual decline rate of 2.7%.

In May 2014, the 67th World Health Assembly issued a strategy to stop tuberculosis[19] Its vision is: A world without tuberculosis, tuberculosis will no longer cause death, disease and suffering . By 2035, the number of tuberculosis deaths will be reduced by 95% compared with 2015, and the number of incidences will be reduced by 90%, without the catastrophic impact of tuberculosis. Z2z

Global Stop Tuberculosis Strategy 2035 target

This strategy was reiterated at the 2018 UN meeting and won the support of all member states.

In this tortuous history of human fight tuberculosis, I think it is the most historic The significance is Austin’s randomized double-blind controlled trial.

In my opinion, the status of randomized double-blind controlled trials in the history of medicine cannot be overstated. has been hailed as the "track of new thinking in clinical medicine in the 21st century". "Syndrome medicine" is based on randomized double-blind controlled trials. I think that in the era when there is no randomized double-blind controlled trial, medicine always has a metaphysical taste. It is difficult to prove a definite causal relationship between medical treatment and disease recovery. However, when the randomized double-blind controlled trial gradually entered the research paradigm of modern medicine, the scientific nature of medicine became stronger and stronger, and medicine gradually began to get rid of the shadow of metaphysics. Z18z

I really hope that everyone can jump out of daily logic Trap, have more subjects Learn to think. Especially in medicine, we should stay away from the so-called folk remedies and the legends of one medicine for curing all diseases. I also hope that everyone can overcome their perceptual cognition of their bodies and believe in the rational conclusions verified by the scientific community.

Source:

https://www.who.int/en/news-room/fact-sheets/detail/tuberculosis
International Nurses Association, Tuberculosis Guide Third Edition, 2017: https://www.icn.ch/system/ files/documents/2020-06/Chinese%20ICN%20TB%20MDR%20TB%20guidelines%202017%20full.pdf
Jiang Yonghong, Centennial Documentary of Chinese Vaccine[M]Beijing: People's Publishing House, published in March 2020. Chapter 13
Li Liang, Li Qi, Xu Shaofa, etc., Therapeutics of Tuberculosis[M]Beijing: People's Medical Publishing House, May 2013. Chapter 1
[M] Han Ruifa, etc., Principles and Practice of BCG Immunotherapy for Bladder Cancer, People's Health Publishing. No. Chapter two
[J]Wang Liang, I got the BCG vaccine from France. Tuberculosis Health Education, 1994
https://www.who.int/immunization/BCG_Chinese.pdf
"Vaccination Science Knowledge" of the National Health and Construction Commission "The protection rate of most vaccines>80%" http://www.nhc.gov.cn/wjw/jbyfykz /201604/0fe932715ccd494e99b68c0fc9bda0c5.shtml
Zhang Qing, Wang Yufang, etc. History of Natural Medicine Chemistry: Streptomycin. Chinese Herbal Medicine vol 49,761 https://www.cnki.com.cn/Article/CJFDTotal-ZCYO201804001.htm
https://www.ncbi. nlm.nih.gov/pmc/articles/PMC1592068/
https://www.researchgate.net/profile/Roberto_Bucci/publication/286618742_Public_health_and_medical_humanities_history_corner_Austin_Bradford_Hill_Simply_nc_Bradford_Hill_Simply_nc_best4elinks/57065. articles/PMC3149409/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149409
https://www.sciencedirect.com/science/article/abs/pii/S1472979202000719
https://www.wired.com/ 2012/01/tdr-first-italy/ https://www.eurosurveillance.org/content/10.2807/esw.12.20.03194-en)
WHO: Frequently Asked Questions and Answers for Completely Drug-resistant Tuberculosis https://www.who.int/ tb/areas-of-work/drug-resistant-tb/totally-drug-resistant-tb-faq/zh/
https://www.who.int/en/news-room/fact-sheets/detail/ The tuberculosis
data comes from the TB report App provided by WHO. It can be downloaded at: https://www.who.int/teams/global-tuberculosis-programme/tb-reports
https://www.who.int/tb/strategy/end-tb/zh/