This fatal sore throat was cured thanks to his “fighting poison with poison” a hundred years ago!

Sore throat is the first symptom of about one-third of people with respiratory tract infections and may be one of the most common discomforts we feel. Especially in the past one or two years, many people have experienced the torture of sore throat in a short period of time. Although this symptom can sometimes be very painful, most people are not in danger of death.

In the not too distant history, there was a fatal sore throat with a very high mortality rate . During the course of the disease, a layer of white exudate would appear in the patient's throat, so this sore throat was named "diphtheria". More than a hundred years ago, it was the main cause of death in children.

Diphtheria is a human disease caused by Corynebacterium diphtheriae, and the mortality rate of pediatric infections caused by its virulent strains is as high as 30% to 50% . Before the advent of effective treatments, tens of thousands of children in the United States and Europe died of diphtheria every year.

Ancient Greek medical literature described diseases with symptoms similar to diphtheria (but we cannot determine whether these descriptions refer to diphtheria). The total number of people who died from this disease in history has long been a confusing matter.

Diphtheria can cause a swollen neck, sometimes called cow neck. Image source: Wikipedia

Today, we seem to rarely hear of people around us having diphtheria. In the occasional mention of diphtheria, it seems to be only when the DTP vaccine (made of pertussis vaccine, refined diphtheria and tetanus toxoids in appropriate proportions, used to prevent pertussis, diphtheria and tetanus) is administered.

However, diphtheria has not completely disappeared . The latest data from the WHO shows that in 2020, a total of 10,107 cases of diphtheria were reported worldwide, with the least cases in Europe, at 6, followed by America, at 79. More than 90% of the world's reported diphtheria cases are concentrated in Africa and Southeast Asian countries, with 5,387 and 4,002 cases respectively. In China, there were no diphtheria cases reported for more than 10 years from 2010 to 2020, but two cases of diphtheria appeared in the country.

It should be said that the world we live in today is much safer than it was more than a hundred years ago. For a peaceful and prosperous country, as long as its public health measures can still function well and the planned immunization for the population does not go wrong, then diphtheria is no longer a major health threat. But we should also know that today's peaceful life is not something that comes naturally .

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The story of mankind's conquest of diphtheria has a very special significance in the history of medicine. It is the first ray of light in the dawn of modern medicine. At that time, the microbial theory had just replaced the classical theory in the medical system. Some scholars pointed out that diphtheria was in a sense the " darling of the germ revolution ." Before the beginning of the 20th century, diphtheria provided the best single model to prove the germ theory of disease.

The protagonist of this story is Emil von Behring (1854-1917). Unlike many children of medical families who have been influenced by the environment since childhood, his journey into medicine seems somewhat incredible.

When Belin was young, his family was poor and had to support more than ten children. However, Pastor Leibz of his parish found that the child was very intelligent, so he provided him with financial help and sent him to the high school of arts and sciences in Hohenstein, East Prussia.

Emil von Behring (1854-1917) Image source: Wikipedia

Because of his later achievements, Belin was called the " savior of children ". I wonder if Pastor Rebolds realized at the time that his good deed actually changed the fate of tens of millions of families, just like a butterfly flapping its wings in South America could cause a tornado in Texas, USA.

When he was in high school, Behring had already developed an interest in medicine. However, due to his poor family, his family did not want him to go to medical school, but wanted him to become a pastor. So Behring had no choice but to go to Königsberg to study theology. Just when his life was about to deviate, Pastor Leibolds changed his course again, which made people wonder if he had traveled back from the later world.

Perhaps geniuses are really different from ordinary people since childhood, and their brilliance cannot be covered by poverty. To test jade, it takes three days to burn it, and to identify materials, it takes seven years. Pastor Leibolds, who has a keen eye for talent, has supported not only the future of a young man, but also the hope of modern medicine.

It turned out that Reverend Leibolds' nephew was a senior military doctor. Through this relationship, Leibolds sent Behring to study medicine at Deresi William College in 1874. Behring would be trained as a military doctor here and would serve the army for ten years. During his service, in addition to completing his daily medical work, Behring also did some medical research, which made his superiors realize that he was a promising talent.

In 1885, Behring passed the examination for district medical officer, and in 1889 he became an assistant to Robert Koch (1843-1910) at the Department of Hygiene at the University of Berlin.

In the history of medicine, Koch is a founder of the field of microbiology who is as famous as Pasteur (Louis Pasteur, 1822-1895). With the efforts of the two of them and their disciples, the four humors theory of disease-causing in classical medicine is on the decline, and the microbial theory of disease-causing is becoming more and more popular. This time, science and rationality have penetrated into the medical camp and spread in all directions.

Such exploration continued to bear fruit during the exciting final decades of the 19th century: new pathogens were discovered every few months. The infectious diseases that had been identified at the time included tuberculosis, cholera, diphtheria, plague, dysentery, gonorrhea, and tetanus.

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Why did people abandon the theory of four humors, or why did people unanimously believe that a certain microorganism was the cause of a specific disease?

This is where Koch's postulates come in. This series of steps was first outlined by Koch's student Friedirich Loffler (1852-1915) in 1883 in conjunction with his identification of the microorganism that causes diphtheria:

If diphtheria is a disease caused by a microorganism, then the following three assumptions must be fulfilled:

1. The suspected bacteria must have been associated with the disease.

2. Suspected bacteria can be separated from the patient and cultured in the laboratory.

3. The bacteria inoculated in the experiment must be able to cause the symptoms.

(In 1905, a fourth requirement was added: the bacterium must be capable of being reisolated from the experimental infection.)

Note*: Koch's postulates were developed in the 19th century and are general technical rules that could be used to identify pathogens based on the technology at that time. However, at that time, many diseases were clearly related to certain substances, and many diseases were confirmed to be caused by certain pathogens, but they could not fully meet Koch's postulates. Therefore, although Koch's postulates have a place in medical history and continue to help with microbial diagnosis, modern biological research no longer requires full compliance with the four postulates. As a research method, Koch's postulates may have been impacted by modern research methods to some extent and no longer seem to be so significant, but as a research idea, it is still extremely valuable for people to establish rigorous thinking habits.

As the saying goes, heroes are made by the times, and Behring's most important research is closely related to the epoch-making contributions of other scientists during this period. In 1889, Behring began to study diphtheria and tetanus bacteria and their toxins. He tried to infect guinea pigs with the amount of diphtheria bacteria that most animals could survive after infection. He found that if these surviving guinea pigs were given a lethal dose of diphtheria bacteria, they would still remain healthy.

Behring realized that this resistance to diphtheria came from certain substances (antitoxins) in the serum of immunized animals that did not directly kill or inhibit the growth of bacteria, but they could neutralize the bacterial toxins.

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In December 1890, Behring published "The Origin of Immunity to Diphtheria and Tetanus in Animals" (co-authored with Kitasato Shibasaburo). Soon after, he published "The Origin of Immunity to Diphtheria in Animals", which made it possible to use antitoxin serum to treat diphtheria based on such immunological principles.

On Christmas Eve in 1891, a girl who unfortunately suffered from diphtheria had a tracheotomy in the clinic (to prevent suffocation caused by diphtheria membrane), but her condition continued to worsen. The doctor was at a loss, but later a mysterious captain medical officer injected a tube of yellowish liquid into the little girl's body. As a result, the little girl miraculously recovered on Christmas morning.

This once widely acclaimed story of the first successful use of antitoxin serum to treat diphtheria is likely to be fictitious, because in 1891 no one could provide enough diphtheria antitoxin serum for clinical treatment, and there were sometimes many trivial obstacles between theory and practice.

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At that time, there were thousands of cases of diphtheria in Berlin alone every year. People were of course in urgent need of effective treatment, but how could all patients receive serum treatment?

The initial animal tests were conducted on guinea pigs. If clinical practice is taken into consideration, larger animals must be used. During this period, people at the Pasteur Institute began to try to obtain diphtheria antitoxin by immunizing horses, and Behring immediately followed up and adopted this method to prepare diphtheria antitoxin serum.

A poster promoting diphtheria immunization in the UK. Image source: Wikipedia

In 1893, under Behring's leadership, several German pediatric clinics began clinical trials of diphtheria antitoxin. Researchers gradually found that if treatment was started within two days of the first symptoms of the child, 97% of the children would survive (if by our standards today, a 3% mortality rate for a disease after treatment is still unacceptable, but don't forget that without this serum therapy, the mortality rate of diphtheria was as high as 30% to 50%).

If treatment is delayed until 6 days after onset, the mortality rate is probably similar to that of not giving serum therapy.

In the long-term situation where humans have no real cure, suddenly there is such a method with such remarkable efficacy, so the speed of spread of this treatment method must be extremely fast.

Therefore, serum therapy soon spread to the other side of the ocean. In 1895, the American company Mulford produced the first batch of diphtheria antitoxin. If everything went well, American children would no longer be threatened by diphtheria.

But progress in medicine is rarely smooth sailing . In October 1901, more than a dozen children died suddenly after receiving antitoxin serum treatment. The cause of death was not diphtheria, but tetanus. Why did such a tragedy happen?

The investigation results showed that a horse named Jim had been providing serum to the company for three years. However, during this process, the researchers found that the horse was accidentally infected with tetanus, so it was killed. Unfortunately, the contaminated serum samples were sent to doctors by mistake and then used on children with diphtheria...

Even more unfortunately, similar tragedies happened several times in a row. This series of accidents forced the U.S. Congress to respond quickly, and the consideration of government regulation of biological drug legislation immediately turned into action. After months of discussion on the bill, on July 1, 1902, the first U.S. law on drug regulation, the Biological Preparation Control Act, was passed without objection.

If the history of medicine is the history of human struggle against disease, then the history of human control of drugs is, to a greater extent, the history of human struggle against the dark side of itself. This is another turbulent legend, and we will not go into it for now, and return to the story of Behring and diphtheria.

Thanks to Behring’s contribution, diphtheria has been transformed from a dangerous killer of children to a curable disease. It should be said that in the pre-antibiotic era, serum therapy was already quite remarkable.

But Behring soon realized that if serum therapy could be applied early, the therapeutic effect would be good, but such treatment would still not affect the incidence of diphtheria. This was a hindsight treatment (passive immunity). Could it directly prevent people from getting sick?

So Behring started researching diphtheria vaccines. In 1914, Behring's diphtheria vaccine showed encouraging results. During the diphtheria epidemic, only two children among 633 children who received diphtheria vaccines became ill, while a considerable number of cases occurred among children in neighboring areas who had not been vaccinated.

This shows that active immunization can prevent diphtheria outbreaks in children, and we can live without the threat of diphtheria today, thanks to the research of Behring and other pioneers.

Copyright images in the gallery. Reprinting and using them may lead to copyright disputes.

In the last years of Behring's life, a young doctor listed his great medical achievements in front of him. Behring said disapprovingly that when a person enters old age, no matter how outstanding his life's work is, it should not be mentioned as capital, because those things are already a long time ago.

I don't know why, but this scene always reminds me of the movie "The Lord of the Rings": the elderly Bilbo Baggins may not care much about his contribution to Middle-earth when he was young, but the elves remember, so Bilbo Baggins has the honor of going to the land of immortality with the elves.

Humanity also dedicated immortal honor to this "child savior" Emil von Behring, and his name was forever engraved in the first position of the Nobel Prize in Physiology or Medicine - 1901.

Author: Li Qingchen, deputy chief physician of thoracic surgery, Harbin Children's Hospital

Review丨Sun Yifei Director of the Medical Education History Research Office of Hebei Medical University