Why is Mycoplasma pneumoniae Epidemic Only Spreading in China?

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Why is Mycoplasma pneumoniae Epidemic Only Spreading in China?

Why is Mycoplasma pneumoniae Epidemic Only Spreading in China?

The vanguard of respiratory diseases in the autumn and winter of 2023 was an ancient pathogen – Mycoplasma pneumoniae.

At that time, pediatric outpatient clinics were filled with children infected with Mycoplasma pneumoniae, and the World Health Organization also expressed concerns about this drug-resistant pathogen.

In a paper published in Nature at the time, the epidemic of respiratory diseases was referred to as the “mysterious wave of childhood pneumonia in China.”

Recently, an article from Suzhou University published in The Lancet Microbe detailed the “mysterious” Mycoplasma pneumoniae epidemic.

Why is Mycoplasma pneumoniae Epidemic Only Spreading in China?

In East Asia, there already exists a unique family of drug-resistant Mycoplasma pneumoniae. In 2019, a drug-resistant mutation closely related to this epidemic was first discovered in samples from Taiwan, China. In 2020, this mutation was detected in Beijing for the first time.

Subsequently, after nearly three years of covert and low-profile transmission during the pandemic, this Mycoplasma pneumoniae mutant strain, which was estimated to have already begun spreading across China before 2020, finally experienced a long-awaited widespread transmission in the first year after the pandemic was opened.

Last year’s Mycoplasma pneumoniae epidemic did not suddenly erupt out of nowhere. “For a long time, Mycoplasma pneumoniae had little presence, and few people paid attention to them, but their transmission has always been ongoing in the population,” explained Professor Zhou Zhemin, the corresponding author of the article from Suzhou University’s Suzhou Medical College, to The Intellectual. And Zhou Zhemin’s attention to Mycoplasma pneumoniae stems from a small incident in life.

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With little presence and a low mortality rate but a high hospitalization rate

Two years ago, the child of this microbiology professor was infected with Mycoplasma pneumoniae.

“It was in October 2021 when my 9-year-old child was infected with Mycoplasma pneumoniae. Took him to Suzhou Children’s Hospital, received injections and infusions, lasted for three weeks.” It wasn’t a severe illness, didn’t require hospitalization, but had to shuttle back and forth between the hospital and school. Interacting with a large group of parents in similar situations at the hospital, this father realized that Mycoplasma pneumoniae, which he had studied on animals over 20 years ago, was quietly spreading among children. He decided to do something about it.

Mycoplasma pneumoniae infection is more common in children aged 5 and above, and it is a respiratory infection disease with a rare mortality rate but prolonged difficulty in treatment.

The difficulty in treating a disease is almost synonymous with the severity of a pathogen in the eyes of medical personnel. Because difficulty in treatment means occupying medical resources, and the prolonged resistance of Mycoplasma pneumoniae to treatment makes pediatricians abhor this pathogen. Zhou Zhemin quickly found Dr. Chen Zhengrong, director of the Respiratory Department of Suzhou University Affiliated Children’s Hospital, who also hoped to study Mycoplasma pneumoniae. The two decided to find a breakthrough to see where this epidemic of Mycoplasma pneumoniae came from and how it came about.

To study this pathogen, which has long lacked presence, these researchers face many obstacles.

Firstly, currently, there is a lack of overall data on Mycoplasma pneumoniae infection in China. However, what we know for sure is that Mycoplasma pneumoniae is the main cause of community-acquired pneumonia in adolescents.

Secondly, culturing Mycoplasma pneumoniae is also a very tricky problem. Suzhou University young teacher Li Heng explained, “Mycoplasma lacks a cell wall, which makes it insensitive to many antibiotics. In addition, during clinical culture, due to differences in osmotic pressure of the culture medium, Mycoplasma, which lacks cell wall protection, is difficult to culture outside the body.”

This is a situation where the epidemic is unclear and almost impossible to culture artificially, and then study it.

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Analysis result: A mysterious mutation only prevalent in East Asia

For a pathogen with high isolation difficulty and long culture period, “being able to study its evolution and variation benefits entirely from recent breakthroughs in technical methods,” explained Zhou Zhemin.

Using metagenomics methods, they not only can analyze the presence of microorganisms in a large number of clinical samples but also can outline the evolution and mutation of target microorganisms—this is like detecting whether several fish in a big pot of fish soup come from the same family and even which piece of meat comes from the son and which piece comes from the father.

In 448 samples of bronchoalveolar lavage fluid or swabs from infected children, they identified 179 samples infected with Mycoplasma pneumoniae, and then used the data from these samples to construct a phylogenetic tree of Mycoplasma pneumoniae in China. By comparing this tree with data from East Asia, Asia, and even globally, they revealed the unique transmission situation of Mycoplasma pneumoniae in China.

Zhou Zhemin explained, “An important mutation is the EC1 mutation, which appeared around 2010. Around 2012, it caused a major outbreak in Japan. At that time, in the Japanese region, (Mycoplasma pneumoniae) resistance was already very high.”

Afterwards, EC1 did not spread to other parts of the world, and it was almost isolated in the small region of East Asia.

“The important feature of East Asian strains is that they have a higher resistance, with overall resistance to macrolides exceeding 80%, while other regions are relatively lower. Even in Singapore, which is also in Asia, their Mycoplasma pneumoniae resistance is not high.” Zhou Zhemin added.

Evolution continues in a corner of the world.

Currently, it is speculated that a key node was between 2017 and 2019, during which a more resistant strain, EC2, was born. A point mutation was found on the 23S rRNA sequence of EC2, which would lead to macrolide resistance, meaning the new mutation made Mycoplasma pneumoniae resistant to the most commonly used drugs.

In 2019, EC2 was first detected in a sample from Taiwan, China. “This new strain, in addition to being more resistant, is basically similar to the prevalent strain in Japan. Essentially, this may also be a long-standing strain in our East Asian region, and at some moment, it suddenly gained a stronger resistance.”

Around 2020, EC2 also appeared in Beijing. Then came the COVID-19 pandemic, which delayed the spread of this mutant strain. In the first year after the pandemic, it had the opportunity to spread.

“Our research this time, looking at the evolution and transmission of Mycoplasma pneumoniae from a genomic perspective, suggests possible evolutionary and transmission paths of Mycoplasma pneumoniae-resistant mutant strains, from Japan and Korea (2016), to Taiwan, China (2019), sporadic occurrences nationwide (2020), and finally to the pattern of outbreak in autumn and winter (2023).” Zhou Zhemin explained.

So, the discussion last year: although antibiotic use has become more standardized recently, Mycoplasma pneumoniae resistance remains at a high level. Are there other reasons?

Li Heng explained, “According to data from the National Clinical

Application Monitoring Network for Antibacterial Drugs in China, the clinical use of antibiotics in recent years has indeed been well controlled. In addition, according to our time tree estimation, the occurrence of resistance gene mutations occurred long before the large outbreak in autumn and winter 2023. Meanwhile, in the process of bacterial transmission, besides resistance, environmental adaptability is also a very important factor, which together leads to the spread of bacteria. Therefore, the occurrence and spread of Mycoplasma pneumoniae resistance cannot be simply attributed to improper use of antibiotics.”

Why do we still need to pay attention to these niche pathogens?

And what is the significance of tracing such a pathogen that has a history of hundreds of years, has long coexisted with humans, and has brought a huge disease burden?

Niche, however, is not unimportant, Li Heng explained, “Understanding a pathogen can better deal with it. Mycoplasma, essentially bacteria rather than viruses, has biological characteristics different from those we often hear about such as SARS, COVID-19, and avian flu. Therefore, there will be differences in treatment and prevention measures against bacteria and viruses. Therefore, for this type of pathogen, although the scientific research investment is relatively small, they are closely related to our healthy life at all times. The transmission process and research methods of this Mycoplasma may also provide important inspiration for the study of other pathogens.

As for Mycoplasma pneumoniae itself, Zhou Zhemin said, “We speculate that after last year’s outbreak ended, the prevalence of Mycoplasma pneumoniae will return to the usual level of previous years.”

However, evolution continues, and no one knows when a niche pathogen with little presence will bring about a big trouble and become a hot topic overnight.