Immunoglobulin in COVID-19 has not been listed yet. What are you snapping up?

After Lianhua Qingwen, imported antiviral drugs, montmorillonite powder and other drugs, intravenous immunoglobulin is becoming another target of COVID-19 epidemic in recent days. According to media reports, its price has risen from the normal several hundred yuan to more than two thousand yuan.

Intravenous injection of human immunoglobulin, referred to as "intravenous immunoglobulin" or "intravenous immunoglobulin", is used to treat primary immunoglobulin deficiency, secondary immunoglobulin deficiency, autoimmune diseases and so on.

65438+10.4, a pediatrician posted on social media, saying that "Kawasaki patients can't find immunoglobulin now." Kawasaki disease is an acute febrile and eruptive childhood disease with systemic vasculitis as the main damage, which needs immunoglobulin treatment after onset.

A respiratory doctor at Japan-China Friendship Hospital bluntly said in an interview with a reporter from Newsweek, "At present, there is no evidence-based medical evidence that immunoglobulin can treat Japanese infected people. So we don't recommend it. "

65438+1On October 5th, it was mentioned in the 10th edition of COVID-19 Infection Diagnosis and Treatment Plan issued by National Health Commission and state administration of traditional chinese medicine that intravenous injection of coronavirus pneumonia-19 human immunoglobulin can be used for patients with serious risk factors, high viral load and rapid progress in early stage. But this immunoglobulin is not a common intravenous immunoglobulin that people have bought at present.

Immunoglobulin Atlas/vision china

The robbed gamma globulin was not aimed at COVID-19.

Xu Peihong and others in the pharmacy department of Ruijin Hospital affiliated to Shanghai Jiaotong University School of Medicine pointed out in the paper "Analysis of the Production, Use and Development Trend of Blood Products in China" published in 2020 that human immunoglobulin accounts for 14.53% in the domestic blood products market, and other blood products drugs also include human albumin and recombinant human thrombopoietin.

Intravenous injection of human immunoglobulin is an immune substance produced by antigen stimulating immune system. Immunoglobulin can be divided into IgA, IgG, IgM and other subclasses, and IgG is the main immunoglobulin used as medicine.

Gamma globulin is mainly used to enhance immunity and treat primary immunoglobulin deficiency, secondary immunoglobulin deficiency and autoimmune diseases. When treating hypogammaglobulinemia, antibody deficiency or other immunodeficiency states, Jinping can play an anti-inflammatory role by providing passive immunity, that is, providing antibodies with sufficient concentration to resist various pathogens.

"Gamma globulin is rarely used in the clinical treatment of COVID-19's patients. It is only when treating a pediatric disease called multiple system inflammatory syndrome that this drug is supported by clinical data and included in the corresponding guidelines. " Gao Lei, chairman of the North American Chinese Medical Association and expert member of the American Heart Association, said in an interview with China Newsweek.

In the ninth edition and the latest updated tenth edition of the diagnosis and treatment plan released in March 2022, COVID-19's "antiviral therapy" includes five therapies: antiviral drugs, monoclonal antibodies, intravenous coronavirus pneumonia-19 human immunoglobulin and plasma of convalescent patients.

In terms of intravenous injection of coronavirus pneumonia-19 human immunoglobulin, both versions of the scheme are written to be applicable to patients with high risk factors, high viral load and rapid disease progression in the early stage. According to the tenth edition of the diagnosis and treatment plan, the dose is light 100mg/kg, medium 200mg/kg and heavy 400mg/kg, and it can be infused again the next day according to the improvement of the patient's condition, with a total number of times not exceeding 5.

"At present, the intravenous immunoglobulin that everyone snapped up is not a specific drug for COVID-19 patients; Coronavirus pneumonia-19 human immunoglobulin is a specific therapeutic drug for COVID-19. " Li Meng, the pharmacist in charge of tongji hospital Pharmacy Department of Huazhong University of Science and Technology, pointed out. In addition to intravenous injection of coronavirus pneumonia-19 human immunoglobulin, there are many immunoglobulins that are specific, such as hepatitis B immunoglobulin, rabies immunoglobulin and tetanus immunoglobulin. In other words, coronavirus pneumonia-19 human immunoglobulin is just one of "static propylene".

At the beginning of September, 20021,Sinopharm China Bio announced that the coronavirus pneumonia-19 human immunoglobulin intravenous injection developed by Tiantan Bio, a blood products company of Sinopharm Group, had been approved by the State Administration of Medical Supplies to carry out clinical trials. According to the biological introduction of the Temple of Heaven, intravenous injection of coronavirus pneumonia-19 human immunoglobulin is a new kind of therapeutic biological product, and it is the first COVID-19-specific therapeutic drug prepared by plasma immunization of inactivated COVID-19 vaccine in the world. In other words, coronavirus pneumonia-19 human immunoglobulin is a globulin containing antibodies of rehabilitation personnel obtained by purifying the plasma of rehabilitation personnel in COVID-19.

According to reports, Tiantan Bio is the only specialized company of blood products under China Bio. At that time, the company announced that coronavirus pneumonia-19 human immunoglobulin for intravenous injection was an original product of Tiantan Bio-products, and no similar products were listed at home and abroad. At present, the product has invested 29.7729 million yuan in research and development.

In February, 2022, Tiantan Bio announced that its coronavirus pneumonia-19 human immunoglobulin for intravenous injection had completed the preparations for clinical ethics review, clinical drug release and pre-clinical enrollment according to the requirements of drug clinical trials, and recently launched a phase II clinical trial in the United Arab Emirates. However, according to the reporter's inquiry, as of now, there is no news that the drug has completed clinical trials or listed.

China Newsweek consulted the directors of intensive care units and infectious diseases departments of several hospitals in Beijing and Guangzhou, and they all said that the immunoglobulin for COVID-19 was not on the market and had never been used by themselves.

Gamma globulin in the treatment of severe cases in COVID-19: lack of evidence.

Gao Lei, chairman of the North American Chinese Medical Association and an expert member of the American Heart Association, told China Newsweek that the North American Chinese Medical Association has recently organized many online meetings with American doctors and China doctors. The theme of the conference is the experience and latest progress of anti-epidemic treatment in the United States. "A very important experience is that the regimen used in treatment must be supported by clinical data. For example, regarding the controversial hormone therapy, it has accumulated more and more effective evidence in the treatment of COVID-19. " He said.

However, intravenous immunoglobulin is a drug for COVID-19's disease, and there is no evidence to support it. The transition of COVID-19 patients from severe to critical illness may be related to excessive immune response. Therefore, anti-inflammatory drugs, including corticosteroids, have been re-used to treat patients with severe COVID-19 infection. However, in the treatment of COVID-19, the clinical efficacy and safety of these two anti-inflammatory drugs are controversial.

Recently, different hospitals have different attitudes towards immunoglobulin in the Reference Guide to Diagnosis and Treatment. For example, gamma globulin is recommended in the guidelines for diagnosis and treatment in Huaxi Hospital. The Department of Respiratory Medicine of Tsinghua Chang Gung suggests that gamma globulin and glucocorticoid should be used in combination or alone for patients with severe or severe COVID-19 viral pneumonia. In addition, COVID-19-specific immunoglobulin or monoclonal immunoglobulin can also be used for treatment.

At present, the World Health Organization, the US Centers for Disease Control and Prevention and other institutions have not included gamma globulin in COVID-19's treatment plan. Zhan Qingyuan, chief physician of the Department of Respiratory and Critical Care Medicine of the Respiratory Center of China-Japan Friendship Hospital, and others recently published the "Expert Opinions on Clinical Treatment of Severe Infection Caused by Omicron-induced New Crown Pneumonia", which clearly pointed out that gamma globulin and plasma treatment are not recommended during the recovery period.

In July, 2022, Dr. Lai Zheng Zhi and others from Taiwan Province Province, China published a study in the Review of Experts on Antiviral Therapy. This meta-analysis of 472 patients and 6 randomized controlled trials of intravenous immunoglobulin showed that the use of gamma globulin could not improve the clinical outcome of hospitalized patients with pneumonia in COVID-19 in terms of mortality, mechanical ventilation, the need to stay in ICU and the length of stay.

Similarly, in February, 2022, a paper published in The Lancet-Breath reported a multicenter, double-blind, placebo-controlled phase III clinical trial in France. The results showed that intravenous immunoglobulin could not improve the clinical outcome of moderate and severe COVID-19 patients who needed invasive mechanical ventilation due to ARDS on the 28th day of evaluation. In addition, the results of the study also showed that the probability of serious adverse events increased in the study group using gamma globulin, mainly including deep vein thrombosis and pulmonary embolism.

On June 27th, 2022, Du Bin, director of the ICU of Peking Union Medical College Hospital, Qiu Haibo, director of the Department of Critical Care Medicine of Zhong Da Hospital affiliated to Southeast University School of Medicine, and many other serious experts published papers in the Frontier of Immunology. The situation of 754 ICU inpatients in 19 hospital during the Wuhan epidemic in 2020 was analyzed, among which 392 patients received intravenous immunoglobulin treatment. Results There was no obvious correlation between the use of gamma globulin and the reduction of mortality, and no survival benefit was found.

Wang Guiqiang, director of the Department of Infectious Diseases of the First Hospital of Peking University, said in an interview with CCTV at the beginning of June 5438+ 10 that intravenous gamma globulin can reduce the inflammatory reaction, but it is only recommended for the treatment of severe patients. He said, "Basically, it is only needed by patients entering ICU, and it is only effective when inflammatory factors storm. It is not suitable for home use, nor can it prevent COVID-19 infection. It is not recommended to stay at home. "

Li Meng, the pharmacist in charge of tongji hospital Pharmacy Department of Huazhong University of Science and Technology, stressed that gamma globulin belongs to blood products, and improper use will bring many side effects; Moreover, the drug can't expand production capacity like antipyretics. In the special period when demand exceeds supply, it is necessary to strictly control the use and leave it to patients who really need it.

Hualan Bio is a domestic enterprise engaged in the research, development, production and sales of biological products such as blood products, vaccines and recombinant proteins. In its official website, the company pointed out that the raw material of intravenous immunoglobulin comes from human blood. Although the raw plasma has been screened for related pathogens, and measures to remove and inactivate viruses have been added in the production process, there are still potential risks of spreading some known and unknown pathogens in theory, and the advantages and disadvantages should be weighed in clinical use.

If the drug is used without authorization, an infectious doctor told China Newsweek that it may have side effects on the nervous system, blood system and kidneys. In addition, human immunoglobulin, as a blood product, is also prone to allergic reactions during infusion, which may be life-threatening in severe cases.

The National Institutes of Health of the United States wrote in the "Guidelines for Diagnosis and Treatment of COVID-19" updated on June 5438+February 1 2022 that adults and children should not use gamma globulin to treat acute coronavirus pneumonia-19; It is suggested that gamma globulin combined with low to moderate doses of glucocorticoid should be used to treat children with multiple system inflammatory syndrome, but routine gamma globulin alone is not recommended to treat MIS-C.

In the United States, officials regularly update the guidelines every six months based on the results of clinical trials, Gao Lei pointed out, because the evidence of drugs is constantly changing. For example, during the Delta epidemic, the United States also used monoclonal antibodies to treat COVID-19, but after the Omicron mutant appeared, plasma therapy and monoclonal antibodies in the recovery period were ineffective.

He suggested that related clinical trials can also be conducted in China to determine the efficacy of gamma globulin. "In fact, there are enough COVID-19 patients in China now, and the results can be observed in clinical trials for 30-50 days."

An infectious disease doctor in a 3A hospital also pointed out to China Newsweek that the diagnosis and treatment plan of the National Health and Family Planning Commission should clearly point out its effectiveness in Omicron, and give evidence-based evidence for some treatment plans with no evidence or insufficient evidence, such as plasma and monoclonal antibodies in convalescence.

Regarding COVID-19-specific immunoglobulin, Gao Lei said that in principle or in theory, many drugs can be tried, but in the end they all need clinical data to support them. If it fails, they will stop using it without wasting medical resources. At the same time, drugs in clinical trials should not enter the guidelines.

Reporter: Peng

Intern: Li