The epidemic of new coronaviruses has continued to spread, but there is currently no specific cure for this disease. However, for severe and critically ill patients, the use of convalescent plasma therapy in China has shown certain results.
Why can the plasma of rehabilitated patients treat severe patients with new type of coronavirus pneumonia? Pan Leiting, a professor at the School of Physical Sciences of Nankai University, wrote an explanation.
What role does the plasma of rehabilitation patients play in the treatment of new coronaviruses?
Plasma is the whole blood leaving the blood vessel after anticoagulation treatment, and then centrifuged to precipitate. The obtained cell-free liquid is rich in plasma proteins and various antibodies.
An important mechanism for the body to deal with the virus is to produce antibodies, bind to the virus, and then kill the virus.
The essence of the vaccine is to stimulate the body to produce antibodies after the inactivated virus is injected into the body. As a result, most patients with new-type coronavirus pneumonia will have specific antibodies against the new-type coronavirus in their blood after recovery.
The plasma of the recovered person was extracted and introduced into the patient's body, and foreign aid antibodies were introduced to help the patient's body kill and neutralize the virus.
Antibodies can be divided into two categories according to their mechanism of action: neutralizing antibodies and non-neutralizing antibodies.
The antibody against the spike protein of the new coronavirus is a neutralizing antibody. It binds spike protein on the surface of the virus and blocks the binding of spike protein to ACE2, thus blocking the virus from entering cells. It can be seen that neutralizing antibodies directly exert antiviral effects through physical obstacles.
Non-neutralizing antibodies are antibodies against viral envelope proteins or membrane proteins. After binding to the corresponding proteins on the surface of the virus, they do not affect spike protein to mediate the virus into lung epithelial cells but rely on immune mechanisms to mediate the body's phagocytic immune cells. -Macrophage phagocytosis of the virus.
Therefore, non-neutralizing antibodies act indirectly to clear the virus. Neutralizing antibodies are the main force for antibodies to exert antiviral effects. It should be pointed out that non-neutralizing antibodies are sometimes "abducted" by the virus to "help".
After the virus is normally phagocytosed, it is encapsulated in the vesicles of the endosome, and then the endosome moves away from the cell surface and moves into the cell. In the process, it fuses with the lysosome vesicles, and the lysosome contains various A variety of hydrolases can hydrolyze viruses.
However, the virus is constantly evolving, using all means to escape phagocytosis. For example, after the virus is swallowed, it will try to remove the outer envelope, expose the viral nucleic acid, and then transfer the nucleic acid from the endosome to macrophages. In the cytoplasm.
In the cytoplasm, viral nucleic acids replicate and assemble into new viral particles and are released outside the cell.
In this way, the virus uses such non-neutralizing antibodies to turn immune cells into host of the virus, turning the enemy into friends, escaping immune killing and achieving self-amplification. The virus's intracellular expansion in macrophages may not be the worst thing. Worse still, the virus may promote the inflammatory storm through macrophages.
In the early stages of viral infection, macrophages function well in all aspects, phagocytosing and hydrolyzing antibody-mediated viruses.
In the later period, macrophages not only sensed the signals of the virus, but also the signals of various cytokines. The functions of the macrophages changed, and the virus took advantage of the opportunity to escape lysosomal killing and a large number of macrophages were amplified. And a large number of amplified viruses in turn strongly activate macrophages, which in turn releases excessive amounts of pro-inflammatory factors, causing damage to lung tissue.
It is not difficult to see that the non-neutralizing antibodies in the plasma may have adverse effects, especially in the later stages of the disease, exacerbating the inflammatory storm. Neutralizing antibodies in plasma are the most needed antibodies for treatment.
How to prevent the risks caused by plasma treatment?
In the absence of a vaccine, plasma is an option for the treatment of new coronavirus pneumonia, but it is a niche treatment method. Currently, the number of cured patients is much smaller than that of patients, and not everyone can use the plasma. The amount of plasma available is therefore very limited.
In addition, due to the complexity of the immune system, there is a series of uncertain factors (such as non-neutralizing antibodies) in the plasma of others imported, which may exacerbate the body damage of patients in the later stages of the disease.
At present, plasma therapy is mainly effective for critically ill patients, and its effect on critically ill patients is very limited.
In the absence of better treatment methods, borrowing the plasma of recovered patients can be said to be the last line of defense. "There is no way", not life-saving straw. Plasma therapy must be used dialectically, choosing the right time and the right people.
There are two aspects to safety risk: patients and recoverees.
For patients: 1) The patient population must be selective, such as those who are too old, have severe underlying diseases, or are not suitable for patients with plasma allergy; 2) This method should be used during the appropriate duration of the patient's body. If an "inflammatory storm" occurs, then the patient's heart, liver, kidney and other organs are damaged and fail. If antibodies are re-input at this time, the inflammation storm may be accelerated, and the organs may be damaged.
The symptoms of patients in the later stages are not caused directly by the virus, but the damage caused by the body's immune system. It is too late to clear the virus by plasma antibodies.
For rehabilitated patients: 1) Whether the plasma virus in the rehabilitated patients is discharged. Rehabilitated patients generally cannot detect the new coronavirus, but it does not mean that they are completely free of the virus, especially the false negative result of the current nucleic acid kit test; 2) Whether the recovered patients have infectious diseases such as hepatitis B, syphilis, AIDS, etc., to avoid cross infection.
In principle, two weeks after discharge, it was confirmed that no new coronavirus in the body could donate about 400mL of plasma for clinical treatment. Ideally, the rehabilitation is required to be 18-55 years of age, without basic diseases such as hypertension and diabetes, without infectious diseases such as hepatitis B, and normal indicators of blood glucose and lipids. However, even if all the indicators of the recovered person are healthy, their plasma may not be suitable.
Because the plasma used to treat new coronavirus pneumonia must contain high titers of antibodies, especially "neutralizing" antibodies (this test cost, sensitivity is also a problem).
Not all patients with new type of coronavirus pneumonia will produce high titer antibodies. Due to different diagnosis and recovery time, antibody titers will also be different. The longer the patient cures, the lower the antibody concentration will be. In summary, the cost of searching and identifying the available plasma for rehabilitators is high, which also determines that it can only be a niche therapy.
In addition, the plasma of patients recovering from the new coronavirus pneumonia cannot be applied to every patient:
1) The patient population must be selective, such as those who are too old, have severe underlying diseases, or are not suitable for patients with plasma allergies;
2) Plasma input by patients in the later stages of the disease is meaningless. Once an "inflammatory storm" occurs in the patient's body, the patient's heart, liver, kidney and other organs are damaged and fail. If antibodies are input again at this time, the inflammation storm will be accelerated and the organs Damage. The symptoms of patients in the later stages are not directly caused by the virus, but the damage caused by the body's immune system;
3) The blood type must match.
What is the difference between plasma transfusion and traditional blood transfusion
Plasma transfusion is different from traditional blood transfusion. Traditional blood transfusion is used to collect whole blood. When transfusion is performed, blood cells (such as red blood cells and platelets) are mainly used for rescue functions.
The new type of coronavirus pneumonia treatment only needs to remove the plasma of various blood cells, and rely on the antibodies in it to play a rescue function. Plasma transfusion should also pay attention to blood type matching, although plasma has no red blood cells.
For example, red blood cells in blood type A have A antigen on the surface, and anti-B antibodies are present in plasma; B blood red blood cells have B antigen on the surface, and anti-A antibodies are present in plasma.
Once type A blood is mistakenly input into type B plasma, a large amount of anti-A antibodies will be brought into the type B plasma. In addition, the anti-A antibodies will bind to the recipient's type A red blood cells, which will make the recipient's red blood cells Dissolution occurs causing hemolysis.
Is integrated Chinese and western medicine the most effective way?
Some time ago, in vitro tests conducted by the Joint Discovery Laboratory of Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Wuhan Institute of Virology proved that Shuanghuanglian inhibited the new coronavirus, causing everyone to snatch.
Later, this also caused many scholars to be dissatisfied, thinking that this conclusion was too hasty. In fact, there is no problem with the experiment itself and its description, but the general public has limited professional literacy. It is believed that in vitro experiments can be useful to the human body, which causes misunderstanding.
I personally admire Chinese medicine very much, but the development of Chinese medicine so far is often misunderstood and ridiculed, which really makes people feel sad. I think there are two biggest problems with traditional Chinese medicine, which leads to repetitive curative effects and poor stability, making people afraid to use it on a large scale:
1) There are too few people who really understand Chinese medicine. Traditional Chinese medicine places great emphasis on dialectics. There is no magic medicine. If you have to take medicine because of the cause, you can dialectically adjust the usage. A good Chinese medicine practitioner is definitely a philosopher and requires a high level of comprehensive literacy. In a sense, cultivating a good Chinese medicine is much more difficult than Western medicine.
2) Lack of good traditional Chinese medicine. Due to the large-scale cultivation of many traditional Chinese medicines, the efficacy is not as good as before. A typical example is ginseng;
3) The scientific discussion of the pharmacology of Chinese medicine is relatively lagging behind. In order to develop Chinese medicine, it is still necessary to be as scientific as possible. What is the effective ingredient in the compound medicine? What is the mechanism.
I think people of insight in Chinese medicine should seize this opportunity to summarize a set of reasonable and experience-based treatment methods for the new type of coronavirus pneumonia to correct the name of Chinese medicine.
The combination of TCM and Western medicine is personally considered a "false proposition". The reason is very simple. Take the new type of coronavirus pneumonia, for example, we all have different opinions on the treatment methods of TCM, and the methods of TCM are also different.
What is the combination of the two companies who have not figured it out? I think it is still down-to-earth, whether Western medicine or Chinese medicine, it is important to be able to rationally treat the new type of coronavirus pneumonia with your own method in the field, and then summarize them separately, and discuss the combination in the future.
How can a vaccine be developed quickly?
The general process of vaccine development includes: 1) obtaining the immune source, ie the virus, and obtaining the subunits related to the isolation of live virus, etc .; 2) conducting the immune response test and animal protection test, and doing the preclinical toxicology research; Optimize production processes; 4) Conduct clinical declarations to achieve vaccine market.
As of February 6, the China Vaccine Industry Association announced that a total of 17 member units are developing the new coronavirus pneumonia vaccine.
There are also scientific research teams abroad who are working hard to develop new coronavirus pneumonia vaccines. Research groups have claimed to strive to develop a vaccine against the new coronavirus within six months.
However, experience has shown that it may take more than two years to develop a truly effective vaccine. A vaccine developed against a "rapid epidemic and rapid disappearance" is usually laborious and has little long-tail benefits, so many organizations are not active.
History tells us that we should not have too high expectations of vaccines in the face of epidemics. Wearing masks, washing hands, and protecting ourselves may be more pragmatic.
So far, the epidemic situation has developed, and the understanding of the new coronavirus itself and its diseases has been deepened. It has benefited from two aspects, one is basic scientific research, and the other is clinical observation and pathological research.
Basic research:
1) Fudan Zhang Yongzhen's team Nature published the genome sequence of the new coronavirus to lock the "kinship" between the new coronavirus and SARS;
2) Shi Zhengli Nature article of Wuhan Institute of Virology indicates that the new coronavirus, like SARS virus, also enters human cells through the Spike protein (spike protein) on the surface of the virus in combination with human angiotensin-converting enzyme II (ACE2) protein. ACE2 is a "new corona "Virus" guide;
3) The research team at the University of Texas at Austin used cryo-electron microscopy to analyze the near-atom structure of the Spike protein (spike protein) on the surface of the new coronavirus and found that the virus uses a highly glycosylated homotrimeric S protein to enter the host At the same time, it was found that the affinity of the new coronavirus S protein to ACE2 is much higher than that of SARS (> 10-20 times), which can explain why the virus can be passed from person to person. This result provides an important structural biological basis for vaccine design and discovery of antiviral drugs;
4) Zhou Qiang's team at West Lake University successfully analyzed the three-dimensional structure of ACE2 using a cryo-electron microscope platform, and found that ACE2 exists as a dimer and has two conformational changes, open and closed, but both conformations contain a mutual recognition interface with the corona virus. It helps to understand the structural basis and functional characteristics of coronavirus entering target cells, and plays an important role in discovering and optimizing inhibitors that block entry into cells. It is not difficult to see the importance of basic research, let us deeply understand the structure and invasion mechanism of new coronaviruses.
Clinical observation and pathological research:
1) In terms of the use of the drug, we have explored a variety of available drugs, and found that the AIDS treatment drug Kelizhi (a protease inhibitor) and the anti-Ebola drug redecive (RNA-dependent RNA polymerase inhibitor) are effective The old drug immunosuppressant chloroquine phosphate is also not recommended. Large dose of poor health C, interleukin 6 receptor antibody "touzumab" has also been found to have a good effect;
2) On February 17, The Lancet published the first anatomy and pathology report of the academician Wang Fusheng's team of the Fifth Medical Center of the General Hospital of the Chinese People's Liberation Army. It was found that the main cause of patient death was diffuse pulmonary alveolar damage and transparent lung membrane formation in the lungs, which was consistent with acute ARDS manifestations of respiratory distress syndrome.
It has also been found that the important cause of lung injury is indeed the excessive activation of immune cells.
The lung performance of patients with this new type of coronavirus pneumonia is not the same as SARS. There is no severe fibrosis, alveoli are still present, but the inflammation is very strong, and there is a large amount of mucus, which is very viscous, which will cause the patient's ventilation to be unsmooth;
3) Scientists from the Guangdong Provincial Center for Disease Control and Prevention published a newsletter in the New England Journal of Medicine, saying that compared with SARS, the transmission of the new coronavirus is closer to influenza.
Soon after the patient's first symptoms, the virus level rises, and the virus level in the nasal cavity is higher than the virus level in the throat. This transmission is more similar to the flu. It has also been found that there are asymptomatic virus spreaders.
These findings suggest that detection and isolation of new cases of coronavirus pneumonia may require a different prevention and control strategy than SARS;
4) Zhang Dingyu, director of Wuhan Jinyintan Hospital, said in an interview that currently, for critically ill patients, as long as tracheal intubation is performed, patients are rarely successfully extubated. The treatment of critically ill patients is currently a major problem and has a bottleneck.
He had only one patient who was successfully rescued by ECMO.
On February 19, a press conference of three medical treatment experts from the Central Guidance Group of Beijing Chaoyang Hospital Tong Zhaohui, Beijing Ditan Hospital Jiang Rongmeng, and Central South University Xiangya Hospital Wu Anhua agreed that the new type of coronavirus pneumonia is extremely infectious, and patients with severe illness must be over 50 years old. Elderly-oriented (SARS is young and middle-aged), severe illness is more difficult to treat than SARS, and the disease progresses rapidly, especially the rapid development of hypoxia, which can easily lead to respiratory failure and heart, kidney, and intestinal failure (SARS disease organs are mainly the lungs ), So move the treatment port forward as much as possible.
Overall, the mortality rate of new coronavirus pneumonia is lower than SARS. The above clinical observations and pathological studies also provide new evidence and strategies for subsequent treatment.
According to media reports, the trend of the epidemic is improving. But the task is still difficult
