On the evening of March 15, the National Health Commission issued the "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Trial Version 9)", which focused on revising the procedures for case detection and reporting, case admission and treatment, antiviral treatment, lifting isolation and discharge criteria. At the same time, the Pfizer antiviral drug PF-07321332/ritonavir tablets (Paxlovid) that were conditionally approved in China not long ago, the first self-developed anti-new coronavirus antibody drug in the mainland (amphavir monoclonal antibody/romimab injection), and the recently increased antigen detection supplementary means have been written into the diagnosis and treatment plan.
This latest treatment has received many positive reviews. At the 125th press conference on the prevention and control of the new crown pneumonia epidemic held in Shanghai on the morning of March 17, Zhang Wenhong, head of the Shanghai new crown pneumonia medical treatment expert group and director of the department of infectious diseases of Huashan Hospital, said that from the first edition to the ninth edition, so far, from nothing about the new crown virus, the earliest diagnosis and treatment plan has been based on medical experience, and with more and more scientific evidence, the final diagnosis and treatment plan must be based entirely on science to formulate a most reasonable plan.
He mentioned a detail that on the evening of March 16, it invited fifty or sixty experts in the field of infectious diseases to conduct a closed-door discussion on the Internet, "Everyone came to a conclusion that this diagnosis and treatment plan is the most scientific and best of all the current versions." ”
On the same day on March 16, Professor Lu Hongzhou, a well-known infectious disease expert and president of the Third People's Hospital of Shenzhen, also said in an interview with the surging news (www.thepaper.cn) reporter, "After more than 2 years of epidemic development, we have sufficient research results, have sufficient evidence, and scientifically carry out the diagnosis and treatment and management of new crown cases." ”
Dr. Zhang Qi, an associate researcher at tsinghua university's school of medicine who has been tracking the mutation of the new crown virus for a long time, also told the surging news (www.thepaper.cn) reporter that the Ami kerong variant strain is different from the previous epidemic strains and spreads rapidly, but the clinical symptoms as a whole are relatively mild, such as patients with asymptomatic infections and mild cases. "Therefore, I think the state has made relevant adjustments to the diagnosis and treatment plan in a very timely manner, showing rationality and scientificity."
What are the specific research and clinical data behind this most scientific and reasonable diagnosis and treatment plan so far?
"Predominantly asymptomatic infected and mild cases"
A major revision made in the ninth edition is that the implementation of centralized isolation management for mild cases, relevant centralized isolation places can not isolate people entering the country, close contacts and other groups at the same time. During the isolation and management period, symptomatic treatment and disease monitoring should be done, and if the condition worsens, it should be transferred to a designated hospital for treatment.
In addition, ordinary, severe, critical cases and cases with severe risk factors should be treated intensively in designated hospitals, of which severe and critical cases should be admitted to the ICU for treatment as soon as possible, and patients with high risk factors and severe disease tendencies should also be admitted to the ICU for treatment.
For the revision, the Medical Administration Bureau of the National Health commission pointed out that according to the opinions reflected in various places, "the patients of the Aomi Kerong mutant strain are mainly asymptomatic infected and mild cases, most of them do not need too much treatment, and all admission to designated hospitals will occupy a lot of medical resources", and further improved the classification and treatment measures for cases.
In fact, as early as January this year, when Tianjin and Anyang, Henan Province, faced the Battle of Aomi Kerong, Wu Zunyou, chief expert of epidemiology of the Chinese Center for Disease Control and Prevention, said at the first time that the symptoms of Aomi Kerong were mild, more difficult to find, more easy to spread, and a major challenge for group prevention.
The Omikejong variant was first detected in a case sample in South Africa on 9 November 2021. On January 7 of this year, the first report found that the team of Omicron, namely the South African Lancet Laboratory and the Botswana-Harvard AIDS Institute Partnership, published an article in the top academic journal Nature describing the identification of the new coronavirus variant in South Africa and the early rapid spread.
The research team mentioned that from mid-November 2021, the number of COVID-19 cases in Gauteng, the economic hub of South Africa, has increased rapidly. The rise in the number of cases and the rate of test positivity was first detected in Tswane (Pretoria), a city in the northern province of Gauteng. At the same time, the increase in cases was accompanied by an increase in the frequency of S gene target gene failure (SGTF) in Thermo Fisher's TaqPath assay. Since then, Omi kerong has led the fourth wave of the outbreak in South Africa.
Then, on January 19, The Lancet, a top medical journal, published an early assessment of the clinical severity of the SARS-CoV-2 Omiljung strain in South Africa. The study correlated data on COVID-19 cases in South Africa, SARS-CoV-2 laboratory test data, SARS-CoV-2 genomic data, and hospitalization data on COVID-19 cases.
The results of the study show that between 1 October 2021 (week 39) and 6 December 2021 (week 49), a total of 161328 cases of COVID-19 were reported in South Africa. 38,282 people were confirmed by the Above-mentioned TaqPath PCR test, of which 29,721 were SGTF infections and 1412 were non-SGTF infections. The proportion of SGTF infections increased from 2/63 (3.2%) in week 39 to 21,978/22,455 (97.9%) in week 48.
After controlling for hospitalization-related factors, the hospitalization rate of SGTF-infected people was significantly lower than that of non-SGTF-infected people (256/10,547, 2.4% vs 121/948, 12.8%); Adjust the ratio [aOR] to 0.2, 95% CI 0.1–0.3). After controlling for factors associated with disease severity, SGTF had a similar chance of severe illness with hospitalized patients who were not SGTF-infected (42/204, 21% vs 45/113, 40%; adjusted odds ratio [aOR] was 0.7, 95% CI 0.3–1.4). After controlling for factors associated with disease severity, the probability of severe illness in SGTF-infected patients was significantly reduced compared with those infected with the early Delta strain (496/793, 62.5% vs 57/244, 23.4%; adjusted odds ratio [aOR] was 0.3, 95% CI 0.2-0.5).
The team believes that this early analysis suggests that the hospitalization rate of SGTF-infected people is significantly lower compared with non-SGTF-infected people diagnosed at the same time. Compared with individuals infected with the Delta strain earlier, SGTF-infected people are significantly less likely to develop severe disease. They also analyzed that the reduction in the probability of severe illness may be due in part to previous immunity.
A similar conclusion was observed in Britain, another country that was swept by Aumikerron in the early days. A study released by the University of Edinburgh in December found that the risk of hospitalization caused by Omiqueron was 2/3 lower than that of Derta, and a study released by Imperial College London also pointed out that the rate of hospital admission to hospital treatment of people infected with Omikeron was 20%-25% lower than that of other strains, the rate of hospitalization more than one night was 45% lower than that of Delta, and the probability of hospitalization of people who had been infected with COVID-19 was 50-60% lower than that of patients who had not been infected before.
During the same period as the Lancet study was published, Professor Benjamin J Cowling, Co-Director of the School of Public Health of the University of Hong Kong and the WHO Collaborating Centre for epidemiology and control of Infectious Diseases, and others published an opinion piece in the journal. They wrote that in the early wave of epidemics, patients infected with the Omicron variant significantly reduced their chances of severe disease than those infected with the Delta variant. "These useful findings, from national COVID-19 hospital surveillance data, are reassuring confirmation of early indicators that the Ormi kerong strain could lead to less severe disease and social disruption and reduce the impact on hospital resources."
In terms of China's local data, at a press conference held by the joint prevention and control mechanism of the State Council on March 15, Lei Zhenglong, deputy director of the Disease Control Bureau of the National Health Commission and a first-level inspector, said that the current Aumicron variant has become the dominant strain imported from the world and the mainland and the local epidemic. The Omikeron variant is significantly more transmissible than other new coronavirus variants. In the past two months, the proportion of the sub-branch of the Omikejong BA.2 has also increased significantly, and the spread force has been further enhanced, and we have found that the clinical manifestations of infected people are mainly asymptomatic and mild, resulting in the hidden transmission of the epidemic, which is relatively late, resulting in the frequent occurrence of recent local epidemics, which increases the difficulty of our traceability and prevention and control.
Jiao Yahui, director of the Medical Administration Bureau of the National Health Commission, specifically talked about the case situation in Jilin Province, jilin province as of the morning of March 15, 8201 cases in the hospital, of which 2 cases of critical illness in Jilin City, 2 cases of heavy disease, 2 cases of heavy disease in Changchun City, the proportion of ordinary type is about 4%. This means that more than 95% of patients are asymptomatic infected and mild cases.
Of course, Professor Cowling also cautioned that it was important to understand the odds of a serious illness from Ami kerong. However, even if the overall clinical picture is mild, it may be offset by an increase in infection with the Omikejunn variant, which can cause considerable social confusion.
More effective in preventing the disease from progressing into severe disease
For patients with new crown admitted to designated hospitals, how to prevent the development of their diseases is an important task in the clinic.
For the antiviral treatment component, the ninth edition of the diagnosis and treatment plan has also been further regulated. One of the important revisions is to include two specific anti-coronavirus drugs approved by the State Food and Drug Administration into the diagnosis and treatment plan, namely: PF-07321332/ritonavir tablets (Paxlovid) and domestic monoclonal antibodies (amphavir monoclonal antibody/romimab injection).
Zhang Wenhong also mentioned at the press conference that in terms of therapeutic drugs, small molecule drugs and China's own antibody drugs are all in it, "All drugs that did not have a previous effect or whose effect was uncertain were all deleted." ”
Lu Hongzhou also told the surging news reporter, "With effective antiviral treatment drugs and neutralizing antibodies, we must use them as soon as possible." If it can be used in the early stages of the patient's disease, it can greatly reduce the load of the virus and inhibit the replication of the virus. He also mentioned that because the virus in the body is reduced, or the virus disappears quickly, then the damage caused by the virus to the patient's various organs will be prevented and will not develop into severe disease.
He believes that the early use of antiviral therapy drugs and neutralizing antibodies can effectively prevent patients from becoming critically ill. "The patient will not spend a long time detoxifying, reducing the contagiousness, and shortening his hospital stay."
Both Paxlovid and amphelumab/romimab injections are also currently well documented.
Previously, on February 11, the State Food and Drug Administration issued a news that according to the relevant provisions of the Drug Administration Law, in accordance with the special drug approval procedures, emergency review and approval were carried out, and the import registration of Pfizer's new coronavirus treatment drug nematvir tablets/ritonavir tablets combination packaging (Paxlovid) was conditionally approved. Paxlovid was approved in the United States on December 22, 2021 local time.
Paxlovid is an oral small molecule new coronavirus treatment. According to data previously published by Pfizer, Paxlovid, taken within 3 days of developing symptoms, reduced the probability of hospitalization or death in mild and moderate adult patients by 89% compared with placebo. The drug is used domestically to treat adult patients with mild to moderate novel coronavirus pneumonia (COVID-19) with high-risk factors for progression to severe disease, such as patients with high-risk factors for severe illness such as advanced age, chronic kidney disease, diabetes, cardiovascular disease, and chronic lung disease.
Ambavir maclizumab/romizumab injection is the first self-developed anti-new coronavirus antibody drug in mainland China. On the evening of December 8, 2021, the antibody drug jointly developed by the team of Professor Zhang Linqi of the School of Medicine of Tsinghua University, the team of Professor Wang Xinquan of the School of Life Sciences, the team of Professor Zhang Zheng of the Third People's Hospital of Shenzhen, and Tengsheng Huachuang Pharmaceutical Technology (Beijing) Co., Ltd. was officially approved for listing by the State Food and Drug Administration.
Ambavirzumab/romimab combination therapy is used to treat adults and adolescents (12-17 years, weighing ≥40 kg) with mild and ordinary types with a high risk factor for progression to severe (including hospitalization or death) with novel coronavirus infection (COVID-19). Among them, adolescents (12-17 years old, weight ≥40 kg) are conditionally approved. Its approval is based on a Phase 3 clinical trial of ACTIV-2 supported by the National Institutes of Health (NIH), which included positive interim and final outcomes in 847 enrolled patients. The final results showed that the combination of amphavir monoclonal/romizumab reduced the risk of hospitalization and death in COVID-19 outpatients at high risk of clinical progression by 80% (78% in the medium term) compared with placebo, which was statistically significant.
According to previously released data, although the activity of ambavirumab against the Omiljunn variant strain decreased significantly, romizumab was not affected by the Omiljung variant. Ultimately, the combination of ambavirumab/romizumab maintained neutral activity against the Omikejong variant strain. This is one of the few antibody therapies in the world that still maintains good neutralization activity against the Omikejong strain.
Luo Yongqing, CEO of Tengsheng Huachuang, previously told the surging news (www.thepaper.cn) reporter that compared with small molecule drugs, neutralizing antibodies have several different characteristics. "First of all, the mechanism of action of macromolecular neutralizing antibodies is not the same as that of small molecule drugs, macromolecular neutralizing antibodies take effect immediately through intravenous infusion, which is better for viruses that replicate very quickly, and from this level, neutralizing antibodies have an advantage, quickly reaching the highest blood concentration through intravenous injection to neutralize the virus." He believes that, taken together, neutralizing antibodies are drugs that are managed from preventing infection to blocking mild infection to severe infection and death.
Zhang Qi also told the surging news reporter that the ninth edition of the increase in the use of special drugs is a highlight, is the embodiment of the success of drug research and development in the mainland and the world, combined with the classification of treatment strategies, can greatly reduce the incidence of severe illness and death.
Specifically talking about amphavir maclizumab and romimab, she said, "This combination antibody drug is a drug independently developed in mainland China, with good safety, and the interaction with other drugs is small, the treatment window is up to 10 days after diagnosis, and only one-time injection is carried out, and patients can obtain long-term immunoprotective effects." ”
The first self-developed anti-new coronavirus antibody drug in mainland China, amphavir monoclonal antibody /romizumab combination therapy.
Look at the yin, or look at the contagious?
In addition, the ninth edition of the protocol is also seen as a "major adjustment" to the discharge criteria for patients and how to manage them after discharge.
Zhang Wenhong said, such as post-discharge management, isolation for 14 days or 21 days? Of course, it is generally believed that the longer the isolation, the safer it is, but to develop a plan for post-discharge management, we must formulate it scientifically. Second, how low is the virus so low that it is not contagious? Now seeing that viruses like to talk about CT values, they think that the lower the viral load, the better, but once the lower the better, it is unscientific. For example, some patients do not turn negative for 4 months, does it mean that we have to isolate this person in the designated hospital for 4 months? Definitely give a most scientific standard for nucleic acid discharge.
A key criterion introduced in the ninth edition is the nucleic acid Ct value ≥35. The criteria for the management of release from isolation and discharge were revised to "two consecutive nucleic acid detection N gene and ORF gene Ct values were ≥35 (fluorescence quantitative PCR method, the limit value is 40, the sampling time interval is at least 24 hours), or two consecutive negative nucleic acid tests for the new coronavirus (fluorescence quantitative PCR method, the limit value is less than 35, and the sampling time interval is at least 24 hours)". In addition, "14 days of isolation management and health monitoring after discharge" was revised to "7 days of home health monitoring after discharge from isolation management or after discharge".
The most widely used nucleic acid detection method in the field of pathogen detection, polymerase chain reaction PCR, is capable of rapidly replicating millions to billions of specific DNA fragments. The new coronavirus contains a very long single-stranded RNA genome, and when detected with PCR, the RNA molecules must first be converted into their complementary DNA sequences by reverse transcriptase, and then the newly synthesized DNA can be amplified by the PCR program, which is commonly known as RT-PCR. qRT-PCR (Quantitative Reverse Transcriptase-Polymerase Chain Reaction) for COVID-19 detection adds fluorescent chemicals (fluorescent dyes or fluorescent probes) to the PCR reaction system. The so-called Ct value, whose full name is Cycle Threshold Value, Chinese translated into the number of cycle thresholds, that is, the number of cycles of the PCR when the fluorescence signal is greater than the fluorescence threshold.
A domestic technician in the field of new crown testing told the surging news (www.thepaper.cn) reporter, "The lower the Ct value, the higher the virus concentration; the higher the Ct value, the lower the virus concentration." He mentioned that the adjustment of the new plan can be regarded as "not as strict as before for the release of isolation management or discharge standards." ”
Zhang Qi mentioned that relevant domestic studies have shown that when the nucleic acid Ct value of the infected person in the recovery period ≥ 35, the virus could not be isolated from the sample, and the close contacts were not found to be infected. Previous studies at the University of Hong Kong have also shown that if the Ct value is above 30, the virus can no longer be cultivated, and there is basically no risk of infection.
In fact, a team of researchers from India published a study last year titled "Ct values in RT-PCR are used to determine the viral load dynamics of SARS-CoV-2: a way to reduce the time to isolation of patients with COVID-19," in which they used RT-PCR to detect the clearance time of SARS-CoV-2 in respiratory samples from 207 infected cases. The results showed that a significant proportion of 31 COVID-19-positive cases with CT values greater than or equal to 45.7% turned negative within 7 days of the first detection of viral load. Among all patients with COVID-19, regardless of ct values, 60% turn negative within 14 days of the first test.
The research team believes that their results suggest that positive cases of COVID-19 with Ct values greater than or equal to 31 have a shorter time to clear the virus. They propose to consider shortening the isolation period for this group in order to provide sufficient space in COVID care centers and reduce the burden on medical infrastructure.
Jin Dongyan, a professor and virologist at the University of Hong Kong School of Medicine, also said in a recent interview with the media on antigen testing, "For people with Ct values of 30-45, the probability of antigen test results showing 'false negatives' is very high, but these patients are not infectious." For people with Ct values of 25-30, the infectivity is also relatively low. Many antigen detection reagents have a sensitivity of more than 95% or even 100% for the detection of infected people with a Ct value of less than 25. These are the very people we hope to identify in infection control who are highly contagious and have the potential to cause super-spread. ”
Lu Hongzhou also told the surging news reporter that there is clear evidence that after the infection has recovered, even if the virus detection has not turned negative, but the viral load is already very low, "when the Ct value is already very high, there is basically no infectivity, if you have to go to isolation, follow-up, and the so-called 'Fuyang', but also to pull back to follow up, isolation, so repeated, waste a lot of resources." He reminded that there was no need to talk about science.