Wuhan pneumonia decoding

The Wuhan pneumonia has so far infected 300,000 people around the world, claimed more than 10,000 lives, shut down many countries, and put hundreds of millions of people under lockdown. At the same time, a "prime time" was created in the scientific community, with an estimated over 3,000 academic studies and articles related to the outbreak published in online journals or pre-print sites in just three months. This newspaper integrates the findings of scholars and tries to find out the true face of this deadly virus.

Since the outbreak of pneumonia in Wuhan, people have often compared the outbreak to the 2009 H1N1 influenza pandemic and the 2003 SARS that killed 299 people in Hong Kong. Although the spread of the Wuhan pneumonia temporarily is much lower than that of the influenza pandemic, and the death rate is not as high as that of SARS, the impact on society and the panic it caused are even greater. Combining relevant research from various places, the terrible thing about the Wuhan pneumonia is precisely because it combines the "superiority" of influenza and SARS in one, which is unavoidable and has the ability to cause a large number of casualties around the world.

Reporter: Guan Guanqi

Although the genetic sequence of Wuhan pneumonia virus and the way it invades cells are similar to those of SARS virus, multiple studies have shown that there are significant differences between the two in terms of disease development and transmission characteristics. In January this year, the University of Hong Kong and the Guangdong Center for Disease Control and Prevention conducted continuous virus tests for 18 patients with Wuhan pneumonia in Zhuhai . In the early stage of the disease, the Wuhan pneumonia virus is already highly infectious , and SARS generally does not reach its peak until the 10th day after the onset of the disease. The study, published in the New England Journal of Medicine, also found that asymptomatic patients had similar amounts of virus to those who had already become ill, suggesting that patients were likely to be infectious before the onset of symptoms . However, among the approximately 8,000 cases of SARS that year, there were almost no cases of asymptomatic infection, and the possibility of infecting others before the onset of the disease was extremely low.

General isolation measures are difficult to stop

Based on the statistics of multiple studies, the incubation period of Wuhan pneumonia (from being infected to the onset of the disease) is about 5 to 6 days on average, and the infection interval of patients (from being infected to infecting another person) is generally 4 to 7 days apart . Scholars from Imperial College London published an article in the medical journal "The Needle" earlier this month, saying that comparing these two figures and the related data on the amount of virus, patients infected with Wuhan pneumonia generally have the ability to transmit the virus about one to two days before the onset of the disease. Others, in disguise form a period of invisible transmission (asymptomatic but contagious) . Scholars pointed out that influenza also has similar characteristics, and it is precisely because of this characteristic that general isolation measures cannot completely stop the spread of influenza or Wuhan pneumonia virus, which allows the epidemic to spread on a large scale.

While the joint report of international experts in the WHO and China stated that asymptomatic transmission of the Wuhan pneumonia appears to be relatively rare and not the main driving force behind the spread of the virus, other studies have disclosed many cases of asymptomatic transmission. Taking an article published in the Journal of the American Medical Association by a scholar from Henan Provincial People's Hospital as an example, a 20-year-old woman arrived in Anyang, Henan Province from Wuhan on January 10. She had contact with five relatives, and the five people appeared one after another. She had symptoms and was tested positive for Wuhan pneumonia, but the woman has been without any abnormality . During the isolation period, the first test showed that she was negative for Wuhan pneumonia, and the diagnosis was only confirmed when she was re-examined.

The proportion of asymptomatic patients is difficult to estimate

Yuan Guoyong, chair professor of the Department of Microbiology at the University of Hong Kong, also disagrees with the WHO's view: "If asymptomatic is so rare, what will happen?" He took the nine confirmed cases of the Diamond Princess cruise ship after returning to Hong Kong as an example. One has obvious symptoms, and some people have never been sick. Yuan Xu pointed out that even if some patients have the disease, the symptoms can be so mild that it is difficult to detect. The Chinese medical treatment expert group led by Zhong Nanshan analyzed 1,099 cases and found that only 43.8% of them had fever when they sought medical treatment, but nearly 100% of SARS patients had fever symptoms.

Another JAMA study said nearly 900 (about 2%) of the more than 40,000 positive cases in China as of February 11 were asymptomatic, but the figures did not include patients lurking in the community. Yuan Guoyong pointed out that unless Hong Kong conducts a large-scale community virus screening at the same time in general outpatient clinics and private clinics in the 18 districts, it is impossible to estimate the overall proportion of asymptomatic patients. "So if everyone doesn't wear masks and rub hands with alcohol-based hand sanitizer, it's as if He Boliang said: One week becomes Daegu, and four weeks becomes Wuhan."

Although the transmission mode of Wuhan pneumonia is similar to that of influenza, the lethality of the two cannot be compared. Studies in recent months generally estimate that the death rate of Wuhan pneumonia is about 1% or more, while the current confirmed death rate is about 4.1%. Although this figure is far behind the SARS fatality rate of 9.6% in 2003, it is at least dozens of times higher than the fatality rate of the 2009 influenza pandemic (generally believed to be lower than 0.1%). If the current epidemic prevention measures fail , causing the Wuhan pneumonia to infect more than 10% of the world's population as it did in 2009, and the total death toll may be in the millions. The severe rate of pneumonia in Wuhan is closer to that of SARS, estimated to be as high as 15%, far exceeding the rate of influenza in 2009.

Yuan Guoyong compared the flu in winter every year, "My old man kills hundreds of people every year in winter. Your family has changed to three or four thousand. Are you talking about a big deal? It's not a joke. If you accept that there are So many people died, they were paralyzed by the hospital authority, the A&E department was drenched in the sun, and the ICU was out of the sun, not even a ventilator, you have to do everything...but can you accept it?"

Unlock Invasion Strongly Connected Human Cells

The transmission of Wuhan pneumonia is obviously stronger than that of SARS. In addition to the different transmission characteristics of the two, research also shows that the ability of the two viruses to invade cells is also very different.

Animal cells are covered with a variety of proteins called "receptors". For coronavirus to invade human cells, it often needs to use the "spike protein" on the surface of the virus to connect to a certain receptor in order to successfully enter through the cell membrane. The biological community regards receptors as "locks" and spike proteins as "keys". Generally, only a specific "key" can unlock a specific "lock" to open the door.

Earlier research published in the journal "Nature" has shown that the spike protein of Wuhan pneumonia virus, like SARS, can connect with ACE2 receptors present on the surface of human cells to invade cells. Scholars from the University of Texas in the United States followed up on the above results and published a research report in the journal "Science" and found that the strength of the Wuhan pneumonia virus to connect to the ACE2 receptor is 10 to 20 times higher than that of SARS. The researchers believe that the above findings are likely to be one of the reasons why Wuhan pneumonia can be easily transmitted from person to person.

The life cycle is similar to that of the Sars robbery, and the cell functions are replicated in large numbers

After Wuhan pneumonia uses the same receptors as SARS to invade cells, the life cycle in cells may be similar to SARS. Treatment options currently in use and to be clinically tested target different stages of the virus's life cycle, thereby inhibiting viral replication.

After the coronavirus invades human cells, it starts to replicate itself. The protein of the virus will be disassembled first, thereby releasing the viral RNA (equivalent to animal DNA) in the cell, and making the viral RNA replicase. Various functions and resources of the cell will be "hijacked", cooperate with the viral RNA replicase to continuously replicate the viral RNA, and produce a large number of new viral proteins. New viral proteins and new viral RNAs will recombine into new coronaviruses in cells and be released out of cells, invading other cells in the body and even infecting other people.

It is beneficial to produce antibodies in summer to relieve winter epidemics

Currently, Hong Kong mainly uses a combination of the anti-AIDS drug Lopinavir, the antiviral drug Ribavirin and interferon to treat Wuhan pneumonia. Among them, lopinavir can prevent the virus from making RNA replicase, and ribavirin can pretend to be Guanosine, the raw material of viral RNA, so that the RNA replicase cannot successfully replicate the RNA. However, the relevant treatment effect remains to be verified. According to the report of the Journal of the American Medical Association , Singapore has used lopinavir to treat five patients with severe pneumonia in Wuhan, and three of them improved within three days, reducing the need for oxygen therapy. Two of them Human nasal samples turned negative within two to five days. But the condition of the remaining two patients deteriorated.

The newly developed antiviral drug Remdesivir is seen as a new hope. Remdesivir is similar in function to ribavirin, and can pretend to be another raw material of viral RNA, Adenosine, thereby suppressing RNA replication. Research published in Nature by Chinese researchers shows that remdesivir can be "very effective" in controlling the invasion of the virus in a laboratory environment. The United States also treated the first confirmed patient locally with Remdesivir. The patient's fever subsided immediately the next day, and various symptoms were improved. Relevant clinical tests are still underway in various places.

In addition, researchers from Imperial College London, together with a British artificial intelligence company, claimed that using artificial intelligence technology, they found that the rheumatoid arthritis drug Baricitinib may prevent the virus from invading cells. The relevant results have been published in "The Needle" . But Yuan Guoyong expressed reservations about this finding, because rheumatoid arthritis is likely to suppress the immune system, "This is a great pot, because you need your immune system to fight a virus. 𠵱You can't fight it, As soon as the drug (virus) is stopped, I will go back.”

Experts expect that the Wuhan pneumonia epidemic is likely to last for many years. Therefore, in addition to treatment, it is also very important to develop vaccines to prevent infection with the virus. Multinational teams are developing their own vaccines against lung cancer, including the Department of Microbiology of the University of Hong Kong. Yuan Guoyong pointed out that the vaccine is still in the animal testing stage, and "the data from the pharmaceutical factory will have to wait at least a year to a year and a half."

Although research on drugs and vaccines is in full swing, Yuan Guoyong advised Hong Kong people not to have too much expectations, because the relevant supply cannot meet the global demand: "Even if you can only make the medicine work, do you get it first? You If you can’t even get a mask, will you get the medicine? Even if there is a vaccine, should you send Hong Kong first? Isn’t it the second country first?”

Yuan Guoyong believes that in order for most people to have antibodies to Wuhan pneumonia, we must always rely on natural immunity. He said that if there are no cases in the community after the summer, Hong Kong people take off their masks, which will spread the virus to each other. The infected people will have a relatively mild illness because their immune systems are better in the summer. Generate natural immunity, and eventually seven to eight adults will produce antibodies, so that the epidemic in winter will be alleviated, but the elderly with weakened immunity will still be at risk.

The intermediate host is hard to find, the Wuhan virus enters from the mouth

The initial outbreak of Wuhan pneumonia in the area of a market where game was sold is reminiscent of the SARS virus that originated in bats. Research results in the past two months show that bats are also likely to be the host of Wuhan pneumonia virus, but the exact source and the intermediate host of direct transmission to humans remain to be identified.

A study published in "Nature" in February showed that the genetic sequence of the Wuhan pneumonia virus is as high as 96.2% similar to the coronavirus RaTG13 found in the chrysanthemum-headed bat in Yunnan. The similarity between 2019-nCoV and 2019-nCoV is also 78.8% to 88.1%, indicating that the Wuhan pneumonia virus is likely to come from bats. But on the other hand, a report published by Chinese scientists in "The Needle" pointed out that since the outbreak of the epidemic in Wuhan was in the hibernation season of bats, and there were no bats in the species of game sold in the South China Seafood Market, it is very likely that there were bats among humans and bats. an intermediate host.

Pangolin spike protein resembles a lung

A Chinese study earlier pointed out that snakes are likely to play this role, but it was immediately opposed by experts from various countries and pointed out that the relevant research was flawed. Another study published in the "Journal of Medical Virology" found that although pangolins' coronaviruses are not as similar to the gene sequence of Wuhan pneumoviruses as the chrysanthemum bat, the "receptor-linked structure" of their spike proteins ( RBD) is more like the Wuhan virus than the chrysanthemum-headed bat. RBD is like the "pit pattern" on a key, which is the most important part in determining what receptors the spike protein can connect to and what cells the virus can infect. Therefore, it is inferred that pangolins may be the intermediate host for infecting humans. However , an analysis by China's National Science Review believes that the pangolin coronavirus and Wuhan pneumonia virus have similar receptor connection structures, which are likely to be formed by coincidence in their respective evolutionary processes, and the two may not be related, and the intermediate host of the virus is still unknown.

The initial outbreak point of Wuhan pneumonia is also debatable. According to official information, the earliest case of Wuhan pneumonia occurred on December 8 last year. However, according to the "New England Journal of Medicine" research on the early spread of Wuhan pneumonia, the earliest two cases of the disease on December 8 and 10 had not been to the South China Seafood Market or related history. The article "Acupuncture" written by a researcher from Jinyintan Hospital pushed the earliest case forward to December 1, and also never visited the Huanan Seafood Market.

However, Yuan Guoyong said that the current evidence still clearly points to the source of the virus being game from the Huanan Seafood Market, because the early cases were mainly distributed around the market, and the earliest cases reported above are probably not the first infected "patient zero". However, before the market was closed, the animals in the field had been removed and no further tests were conducted. Yuan believed that the intermediate host would be difficult to trace.

The Wuhan pneumonia spread from China to the world. The CCP has recently tried to whitewash itself and obscure the source of the virus. Yuan Guoyong believes that there is no point in arguing about the "source of the virus." "The bats fly around, hundreds to thousands of miles away, can you tell? ... But the outbreak (starting point) must be in Wuhan. The problem is the point. The solution will be launched in Wuhan first?"

Yuan Guoyong said that after the outbreak of SARS in the Pearl River Delta in 2003 and the H7N9 influenza outbreak in the Yangtze River Delta in Shanghai in 2013, he kept guessing the location of the next major epidemic in China. It happened in Wuhan in the middle, "Look back and turn your head, fasten your reasonable". He explained that Wuhan is an important transportation hub in China, the center of transit, high-speed rail and even water transportation, and the economy is developing at an extremely high speed. To the end, forgetful humans are the culprits of the plague .

The journal exploded and processed 150 submissions a day

The plague is spreading around the world. Scientists from all over the world have stepped out of the ivory tower and devoted a lot of resources and effort to study the Wuhan pneumonia in a short period of time to respond to this pressing social problem. According to the Google Scholar academic paper search engine, more than 3,000 papers related to Wuhan pneumonia have been published in journals or pre-print websites, and the growth rate has increased with the spread of the virus.

The highly influential American "New England Journal of Medicine" replied to reporters' inquiries that since the first article on Wuhan pneumonia was published on January 29, it has received 20 to 45 new submissions every day, and it has been tried in mid-March. Process over 150 submissions in one day. The editors of The New England stressed that they still insist that every result must go through peer-review and careful editing steps, while accelerating in response to the development of the epidemic, "The process that used to take weeks has been compressed to Complete within 48 hours."

In addition to traditional academic journals, many papers about the Wuhan pneumonia are also published on preprinted websites that are not peer-reviewed, such as medRxiv or bioRxiv. The results of these articles have not been reviewed by peer experts, and there is a greater chance of errors, but this channel allows new discoveries to be shared with the society for the first time.

Originally published in Hong Kong "Apple Daily" on March 23