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Introduction to COVID-19, history, impact, symptoms and prevention

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COVID-19: Disease, management, treatment, and social impact

a Department of Chemistry, College of Sciences, Taibah University, Al-Medina Al-Munawara 41477, Saudi Arabia

b Department of Chemistry, Jamia Millia Islamia, (Central University), New Delhi 11025, India

Omar M.L. Alharbi

c Department of Biology, College of Sciences, Taibah University, Al-Medina Al-Munawara 41477, Saudi Arabia

COVID-19 was originated from Wuhan city of Hubei Province in China in December 2019. Since then it has spread in more than 210 countries and territories. It is a viral disease due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus. The patients show flu-like symptoms with a dry cough, sore throat, high fever, and breathing problems. The disease due to SARS-CoV-2 was named as COVID-19. About 2.2 million people have been infected with more than 0.15 million deaths globally. The United States of America is the most affected country with the highest patients of about 0.7 million. Despite great efforts, there is no treatment of this disease. However, prevention and management are the best options. This article describes SARS-CoV-2, disease, prevention and management, treatment and social impact on society. It was analyzed that a combination of antiviral drugs with hydroxyl-chloroquine and azithromycin (with the consultation of a medical practitioner) may be the best option to treat the patients, depending on the patient's conditions and symptoms. However, Unani therapy may be useful along with allopathic treatment. It is urgently advised and requested that all the persons should follow the preventive measures, managements and quarantine strictly without any religious discrepancy otherwise the situation may be the worst. Also, there is an urgent requirement to educate our new generation for science and technology to fight against any such disaster in future; if any. There is no need to be panic and proper prevention and management are essential to combat this disease. This article may be useful to create awareness among the public, to prevent, manage and treat COVID-19.

Graphical abstract

1. Introduction

Coronaviruses belong to the Coronaviridae family and appear just like spiked rings when observed through an electron microscope. The surface looks with various spikes, which are helpful to attack and bind living cells. These are the viruses causing the simple common cold disease to severe illnesses like Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome (SARS-CoV). The source of these viruses is some animals including bats. The word coronavirus is a derivative of the Latin corona, which means crown or halo, that states to the typical look indicative of a crown or a solar corona around the virions. These viruses are having a positive-sense single-stranded RNA genome (27 to 34 kilobases) and helical symmetry nucleocapsid ( Su et al., 2016 ; Sexton et al., 2016 ). Typically, the coronaviruses are of ~20 nm size draped with a large petal or club-shaped surface appearance. The first coronavirus was discovered in 1937 in the birds and later on in the 1960s in humans ( Coronavirus: Common Symptoms, Preventive Measures, and how to Diagnose it. Caringly Yours, 2020 ). The various types of viruses, capable to infect human beings are 229E, OC43, HCoV-NL63, SARS-CoV, MERS-CoV, HKU1 and SARS-CoV-2. There are several outbreaks from time to time due to these viruses. The most notorious outbreaks were in 2003, 2012, 2015 and 2018 with 774, 400, 36 and 42 deaths, respectively. It is important to mention that the 2019–2020 outbreak is started in Wuhan, Hubei Province, China in December 2019 ( The Editorial Board, 2020 ) when a new strain of coronavirus was detected on 31st December 2019 ( WHO, 2020 ). World Health Organization (WHO) has given name to this virus as 2019-nCoV ( Novel Coronavirus 2019, 2020 ) which was later renamed as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses. The diseases caused by this virus is called as coronavirus disease 2019 and abbreviated as COVID-19 [CO: corona, VI: virus, D: disease and 19: 2019 year]. This virus was found to have 86.9% resemblance to a bat coronavirus, and, hence, is suspected to develop from bats ( Lu et al., 2020 ; Wan et al., 2020 ; Zhu et al., 2020 ). This virus is out broken in pneumonia type of disease with respiratory problems, leading to death due to respiratory failure. About 210 countries and territories have been reported to be infected with major outbreaks in the USA, China, South Korea, Italy, Iran, Japan, etc. tolling about 2.2 million patients with more than 0.15 million deaths globally. The United States of America is the most affected country with the highest patients of about 0.7 million and about 35,000 deaths. This article is dedicated to the recent outbreak of 2019–2020 describing the diseases, symptoms, spread, prevention, and treatment. This article may be useful to control the present outbreak and future spread.

2. Disease and symptoms

Coronaviruses infect the upper gastrointestinal and respiratory tract of the mammals (including humans) and the birds. These viruses cause many diseases in animals and human beings but we are limited in this article with SARS-CoV-2, leading to COVID-19 disease. The whole clinical picture of COVID-19 is not completely known. The occurrence of the illness ranged from mild to severe. SARS-CoV-2 propagate through RNA replication using RNA-dependent RNA polymerases enzyme. This virus can mutate slowly, posing a challenge for its treatment and control. The symptoms of COVID-19 may arise within 2 to 14 days after the infection. Besides, in some cases, the diseases prevail after 27 days. However, Chinese researchers mentioned 5.2 days as an average incubation period ( Li et al., 2020 ). The duration of the survival of death is 6 to 41 days after infection of the coronavirus. It depends on the age, health and clinical conditions of the patients ( Wan et al., 2020 ).

The common signs of infection are fatigue, muscle pain, sneezing, sore throat, dry cough, high fever, respiratory problems, etc. with some severe cases having pneumonia, serious respiratory syndrome, kidney failure and even death ( Huang et al., 2020 ; Hui et al., 2020 ; Ren et al., 2020 ). The COVID-19 risk is greater in older people, kids and the patients having other health problems like lung diseases, heart diseases, diabetes, and cancer. It is important to mention that it is not necessary to have COVID-19 if these symptoms are seen because such types of symptoms are also seen in the case of other virus infections, except breathing and diarrhea problems. The pathological conditions of coronavirus include greater counts of chemokines, cytokines, and leukocytes, and high levels of plasma pro-inflammatory cytokines and C-reactive protein. The chances are greater of COVID-19 if there is shortness of breath, dry cough, and a person comes in the contact with a COVID-19 patient or traveled with COVID-19 effected area. Under such a situation, the clinical test for COVID-19 is a must. However, some persons recover easily while others may take some time depending on the health conditions and the age of the patients. WHO categorized the COVID-19 virus as of β-CoV of group 2B ( Carlos et al., 2020 ). The genome of this virus is identified and it resembles the SARS-CoV (80% similarity) and MERS-CoV (50% similarity) ( Lu et al., 2020 ; Ren et al., 2020 ). It is interesting to note that both MERS-CoV and SARS-CoV have their origin in the bats ( Cui et al., 2019 ).

3. Modes of transmission

During the last few decades, it was observed that coronaviruses can infect rats, mice, cats, dogs, horses, turkeys, cattle and pigs. Occasionally, these animals may communicate coronaviruses to humans. The coronavirus is spread by the sneezing, cough droplets and contact. Normally, this virus enters the body through the mouth, nose, and eyes ( Transmission of Novel Coronavirus (2019-nCoV), 2020 ). It has been reported that the virus may infect a person at a distance of about a 6 ft (1.8 m) radius. The virus can survive for 2 h to few days in cough and sneezing droplets lying on the surface or ground. An infection may be by touching an object or surface which has already a virus but it is not the major course of the infection. This virus has been detected in stools of the patients but no infection via stool has been reported.

The cellular infection model is very similar to SARS-CoV. The main target of this virus is lungs and the virus spikes (binding domains) get attached to the cell receptors of the lungs. These are known as angiotensin-converting enzyme 2 (ACE2) receptors ( Jaimes et al., 2020 ; Wan et al., 2020 ). Belouzard et al. (2009) reported that a proteolytic cleavage occurs at SARS-CoV S protein at position (S2') interceded the membrane fusion and viral infectivity. The chances of the infection may arise if a person comes in contact with the infected person. Now, COVID-19 has become pandemic as per the WHO report. The data of the patients in the different countries at a different time was analyzed and the efforts are made to find out the routes of transmission globally. Consequently, the routes of COVID-19 pandemic in most of the effected countries are shown in flow chart ( Fig. 1 ).

COVID-19 routs of transmission to the most effected countries.

4. Prevention and the management

The prevention and management are very important issues to control COVID-19. Therefore, there is a great need for the collective efforts of the public and the government. The regular and the proper care of the homes and hospitals are very important to control this calamity. The regular recommendations to minimize the infection are cleaning of your area. The most important is to avoid sneezing and cough at the public place. The hand cleaning with soap and sanitizer, mouth and nose coverage with mask during sneezing and coughing are essential. Thoroughly washing foodstuff before cocking may help in this regard. The simple house-keeping disinfectants may kill the virus on the surfaces. Regularly cleaning of the surface by the disinfectants may control the virus outbreak. It is always better to avoid the interactions with anyone; suspecting respiratory problems symptoms like sneezing, coughing, breathing problem, etc. It is also advisable to stay at home if anyone has flue and common cold-like symptoms. It is also better not to go to school, work and public places, not use public means of transport (aircraft, train, metro, bus, taxi, etc.). Some important suggestions may include avoiding travel, and collection at a particular place. The drinking of hot water after every hour may be helpful. Plenty of lukewarm water (~ 5 L per day) may help in this regard. The governments should provide facilities for the decontamination of the hands at the public places. The guidelines are available for healthcare providers, medical staff, researchers and public health individuals ( Jin et al., 2020 ). They can use to control COVID-19 globally. During the entire period of COVID-19, it was realized that this disease is spreading among those who are not taking it seriously and are not following the directions of WHO and the local government. Some people are trying to target one community for the spreading COVID-19 while this virus does not recognize and race, creed, sex, age, and religion. Therefore, it is urgently advised and requested that all the persons should follow the preventive measures, managements and quarantine strictly without any religious discrepancy otherwise the situation may be the worst.

5. Treatment

There is no precise treatment for coronavirus but prevention, management and supporting healthcare may provide relief in the outbreak of COVID-19. However, some approaches have been or may be used to control this disease. These approaches may be categorized in Allopathic, Unani and Homeopathic treatments. But before all this treatment, plenty of testing facilities should be available to the health care sectors.

5.1. Allopathic medicines

Allopathic treatment and management include oxygen therapy, intravenous fluid infusion with life support in dangerous cases. It is also advisable to contact a medicinal practitioner if the flue like symptoms prevails. Coronavirus may show comparable proteins for virus replication to human immunodeficiency virus (HIV). Therefore, HIV protease inhibitors and nucleoside analogs may be operative to treat COVID-19 ( Lu, 2020 ). A combination of lopinavir and ritonavir, previously used for SARS-Cov and MERS-Cov, may be useful ( Chu et al., 2004 ; Momattin et al., 2019 ). China is doing clinical trials of remdesivir, which was developed for the Ebola virus. Besides, other anti-viral medicines like oseltamivir, ganciclovir, ribavirin, favipiravir, nelfinavir, arbidol, remdesivir and galidesivir are being examined for COVID-19 treatment ( Agostini et al., 2018 ; Chen et al., 2020 ; Guangdi and Clercq, 2020 ; Sheahan et al., 2020 ; Xu et al., 2020 ). Wang et al. (2020) reported that a combination of remdesivir and chloroquine may be effective to treat COVID-19 disease. Besides, the peptide (EK1), neuraminidase inhibitors, DNA synthesis inhibitors (tenofovir disoproxil and lamivudine) may be useful to control COVID-19. Also, 2 (ACE2)-based peptides (an angiotensin-converting enzyme), 3CLpro-1 (3CLpro inhibitor) and vinylsulfone protease inhibitors are known to show antiviral activities ( Morse et al., 2020 ). Recently, an Italian patient of COVID-19 is treated in Sawai Man Singh (SMS) Hospital, Jaipur India by giving a combination of lopinavir (200 mg) and ritonavir (50 mg) twice a day. Besides, the patient was also given a combination of oseltamivir and chloroquine medicine. The patient test was found negative for COVID-19. Cheng et al. (2006) extracted some saikosaponins (a group of oleanane derivatives, usually as glucosides) and tested against the proliferation of some viruses. The authors reported that saikosaponin B2 (6 μM) inhibited human coronavirus 229E effectively. In this way, the saikosaponin B2 along with other glucosides may be tested for COVID-19. The broad range of spectrum antibiotics may be used to control the additional bacterial infection after a virus attack. Some drugs are under clinical trial and results are still awaited. The best approach to fight with viruses is vaccination. Therefore, scientists are trying to develop a vaccine for this virus and probably may be available after some time.

5.2. Unani medicines

Generally, the Unani medicines (plant-based medicines) are non-toxic and without any side effects. Unani and Ayurvedic methods of the treatment are based on the plant materials. The different parts of the various plants are well known for a long time for their anti-viral activities ( Li et al., 2005 ; Lin et al., 2014 ; Kim et al., 2010 ). The most important plants are Glycyrrhiza glabra , Allium cepa, Allium sativum, Ocimum sanctum, Ocimum tenuiflorum, Piper nigrum, Cinnamomum verum, Daucus maritimus , Curcuma longa , etc. An aqueous extract of these plants along with lemon juice and honey was found to be effective for flu and common cold virus infections. The ingredients present in this recipe have ant-viral properties ( Bano et al., 2017 ; Chang et al., 2013 ; Bayan et al., 2014 ; Fatima et al., 2016 ; Ghoke et al., 2018 ; Hashemipour et al., 2014 ; Jiang et al., 2013 ; Konowalchuk and Speirs, 1978 ; Lee et al., 2012 ; Miladi et al., 2012 ; Omer et al., 2014 ; Praditya et al., 2019 ; Weber et al., 1992 ). The root of Licorice ( Glycyrrhiza glabra ) is known to have a good antiviral potential ( Wang et al., 2015a ). This plant is native of Asia and Europe and recognized as a weed. Fiore et al. (2008) carried out an in vitro study of Glycyrrhiza glabra plant and reported that this plant showed antiviral activities of several viruses including SARS related coronavirus, HIV-1, and respiratory syncytial virus. Asl and Hosseinzadeh (2007) presented a review of the antiviral activity of Glycyrrhiza glabra . The authors reported this plant active against SARS, HIV, varicella zoster, hepatitis A, B, C, cytomegalo virus herpes simplex type-1. Another review was from Anagha et al. (2014) on the antiviral activity of Glycyrrhiza glabra plant. The authors described the activity of this plant against various viruses like H1N1, H5N1, Influenza A virus (IAV), Hepatitis C virus, Rotavirus, HIV and SARS-associated coronavirus. Similarly, Wang et al. (2015b) also presented a review of the antiviral and antimicrobial activities of Glycyrrhiza glabra . The authors described the presence of more than 300 flavonoids and 20 triterpenoids in this plant. The authors summarized the active components and the most probable mechanisms of these constituents. Therefore, an aqueous extract of this plant along with other plants as mentioned above may be useful to control COVID-19. On January 29, 2020, the Government of India issued an advisory based on Indian traditional medicine practices Ayurveda, Homeopathy and Unani, New Delhi. The advisory includes the ways of preventive management and described a list of some Unani medicines. The interested persons may find these medicines at https://pib.gov.in/PressReleasePage.aspx?PRID=1600895# and can use after proper consultation with the Unani medical practitioners.

5.3. Homeopathy

In homeopathy, arsenic at very low concentration is considered beneficial for several diseases including viral infections. Recently, Directorate of AYUSH, New Delhi, India issued an order dater on January 30, 2020, to take prophylactic medicine to avoid coronavirus infection. The directorate suggested taking 4 pills of Arsenic Album-30 medicine once daily in empty stomach for 3 days. Arsenic Album-30 is highly diluted arsenic trioxide and work as homeopathic prophylaxis. It is important to mention here that there is no clinical evidence for Arsenic Album-30 medicine as an effective medicine. After that, a criticism for homeopathy came into existence and it was called as pseudoscience. An article is published in Taiwan Medical News on February 18, 2020 ( https://www.thailandmedical.news/news/india-slammed-for-proposing-usage-of-homeopathy-to-prevent-coronavirus ) and some people criticized homeopathy to manage COVID-19 infection. The persons who criticized are Dr. David Robert Grimes (Irish science write) and Dr. Edzard Ernst (an emeritus professor, University of Exeter, UK and a critic of homeopathy). However, Dr. Mitchell Fleisher (second vice president, American Institute of Homeopathy) advised to carry out a comparative clinical study on the acute coronavirus infection by giving to homeopathic medicines to an individual and experimental group, and allopathic medicines to another, for 250 patients in each group. It was stated to confirm the scientific truth. But after this statement again Dr. David Robert Grimes criticized it as completely unethical and according to him, Homeopathy has no reasonable mechanism of action. Furthermore, he added that it is irresponsible to propose a trial for a serious pandemic. He also mentioned that many studies on homeopathy have indicated that it does not work. Also, the news director of Thailand Medical News Jakkapong Watcharachaijunta criticized the use of homeopathic medicine in controlling COVID-19. At this point, it is very important to mention the work of Dr. Robert T. Mathie et al. (2013) whose research work described that Arsenicum album medicine as effective to reduce fever, runny nose, headache, sore throat in the patients with swine flu symptoms. During writing this article under this section, it was realized that the subject matter is debatable and needs the scientific study to support the working of Homeopathic medicine for COVID-19. It is suggested that some research work should be funded by the government and the research should be carried out to make the situation clear. It is significant to add here that personally I (Prof. Imran Ali) used some homeopathic medicine when living in India for some diseases and found them effective. Besides, I also observed that some homeopathic medicines are effective to treat a variety of diseases.

6. Immune system boosters

It is observed that early deaths were in older people, probably because of the poor immunity, which fosters faster progress of COVID-19 ( Li et al., 2020 ; Wang et al., 2020 ). Therefore, it is significant to boost our immune system. It is important to suggest that people should use some supplements to boost their immune systems. Healthy people should take plenty of citrus fruits having various vitamins. Some dry fruits (almonds, walnuts, and dates) are also useful to improve the immune system. However, older people and the patients may take vitamins and zinc supplements with the consultation of medical practitioners. The important vitamins are A, C, D and E. It is also advisable to take zinc and iodine intakes. It is too wise not to smoke and take other narcotic products. Always an adequate sleep is essential to boost up the immune system. Avoid any stress and do proper and regular exercises.

7. Social impact

In the present scenario, COVID-19 has affected all the sectors of society. There is a big loss globally, and it cannot be estimated exactly. However, some aspects are discussed herein. Nowadays, the whole world is just like a family where everyone has to contribute to run the family. Similarly, the production of various items including medicines, machines, motor vehicles, computers, mobiles, etc. are controlled by many countries. Generally, the different components are being manufactured in various countries while these are assembled in other countries – Globalization. It is just like a chain process where the progress is stopped if even a single chain-link gets collapsed. It is a well-known fact that China is the biggest manufacturer of the various components, APIs and other raw materials while China is the most affected country due to COVID-19. And that is why the whole world is affected economically very badly due to a decrease in industrial production. The travel ban has been imposed by some countries resulting in millions of dollars loss to the airlines and tourism industry. There is a shortage of medicines, sanitizers, masks, and other commodities, which has hiked the prices of these items many times. The various functions, especially scientific conferences, business meetings, sports events, fashion shows, and the marriage parties are suggested to avoid, which is a big social impact on society. The Kingdom of Saudi Arabia has provisionally banned Umrah (pilgrimage) for the pilgrims to Mecca and Medina (the two holiest cities of the Islam religion). All these factors affected the local and global share markets badly. The USA big stock indexes such as S & P 500 Index, NASDAQ-100, Dow Jones Industrial Average, etc. have shown sharp fall since 2008. Many countries have banned to attend the classes in schools, colleges, and the Universities and millions of the student are not getting a good quality of education. It is very difficult to assess this loss in terms of money but has a big disadvantage to the students and their families. Briefly, there is a big loss to the worldwide economy and the expert assessed a loss of about 2.7 trillion US dollars ( https://www.bloomberg.com/graphics/2020-coronavirus-pandemic-global-economic-risk/ ).

8. Future perspectives

As expected SARS-CoV is zoonotic and originated from the bats. It is observed that many people are consuming various animals as food-stuffs. Some animals like bats, snakes, cats, mice, rats, dogs, pigs, etc. should not be consumed as these may have dangerous microbes while the only safe animals should be consumed. Moreover, it is also advisable that we should consume vegetables and fruits as maximum as possible in our food. There is an urgent need to educate our new generation for science and technology to fight against any such disaster in future; if any. Of course, the world is progressing towards advancement and even then We don't have highly specialized research centers. Therefore, there should be highly specialized research centers under the umbrella of WHO and funded by all the countries of the world. These centers should be located in the various parts of the world and be efficient, capable and specialized to control any calamity in the world in the future. The most important required research centers are for viral diseases, bacterial illnesses, mosquito, and insect-based diseases, cancer, etc. These centers are essential to combat any future calamity in the world if any. A paper was published by Casanova et al. (2010) and the authors studied the effect of temperature and humidity on the survival of gastroenteritis virus (TGEV) and mouse hepatitis virus (MHV) on the surface. The authors reported that the chances of the virus's survival are poor at 40 °C or high temperature with low humidity. Furthermore, the authors reported that TGEV and MHV could be used as conservative surrogates for modeling experience, transmission risk and control measurements for enveloped viruses like influenza virus and SARS-CoV virus on the surfaces. Therefore, it may be expected that the propagation of SARS-CoV-2 will decrease at high temperatures and low humidity. Now, we are at the end of April 2020 and progressing towards the summer. Therefore, it is expected that the coronavirus cases will decrease in the coming time; especially in the Middle East countries.

9. Conclusion

COVID-19 disease is originated from Wuhan city of Hubei Province in China in December 2019 and has become pandemic as per WHO. The disease has spread in 210 countries and territories with about 2.2 million patients and more than 0.15 million deaths globally. The United States of America is the most affected country with the highest patients of about 0.7 million. It is a viral disease due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus. The patients show flu-like symptoms with high fever and breathing problems. The disease due to SARS-CoV-2 was named as COVID-19. Still, there is no treatment of this disease. However, prevention and management are the best options. A combination of antiviral drugs with hydroxyl-chloroquine and azithromycin (with the consultation of a medical practitioner) may be the best option to treat the patients, depending on the patient's conditions and symptoms. However, Unani therapy may be useful along with allopathic treatment. Probably, the number of COVID-19 cases may decrease in the coming time as the summer is approaching and the rate of virus transmission may be low at high temperature and low humidity. It was realized that this disease is spreading among those who are not taking it seriously and are not following the directions of WHO and the local governments. Therefore, it is urgently advised and requested that all the persons should follow the preventive measures, managements and quarantine strictly without any religious discrepancy otherwise the situation may be the worst. Also, there is an urgent requirement to educate our new generation for science and technology to fight against any such disaster in future; if any. There is no need to be panic and proper prevention and management are essential to combat this disease. Briefly, there is a need for collective efforts globally without any religious discrepancy to fight against such diseases in the future.

CRediT authorship contribution statement

Imran Ali: Conceptualization, Methodology. Omar M.L. Alharbi: Investigation, Writing - original draft.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

The authors are thankful to the administration of Taibah University, Al-Madinah Al-Munawarah and Government of Saudi Arabia for providing facilities and the encouragement to write this article.

Funding source

No funding source for this work.

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Introduction to COVID-19: methods for detection, prevention, response and control

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Coronaviruses are a large family of viruses that are known to cause illness ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS).

A novel coronavirus (COVID-19) was identified in 2019 in Wuhan, China. This is a new coronavirus that has not been previously identified in humans.

This course provides a general introduction to COVID-19 and emerging respiratory viruses and is intended for public health professionals, incident managers and personnel working for the United Nations, international organizations and NGOs.

As the official disease name was established after material creation, any mention of nCoV refers to COVID-19, the infectious disease caused by the most recently discovered coronavirus.

Please note that the content of this course is currently being revised to reflect the most recent guidance. You can find updated information on certain COVID-19-related topics in the following courses: Vaccination: COVID-19 vaccines channel IPC measures: IPC for COVID-19 Antigen rapid diagnostic testing: 1) SARS-CoV-2 antigen rapid diagnostic testing ; 2) Key considerations for SARS-CoV-2 antigen RDT implementation

Please note: These materials were last updated on 16/12/2020.

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Emerging respiratory viruses, including covid-19: introduction:, module 1: introduction to emerging respiratory viruses, including covid-19:, module 2: detecting emerging respiratory viruses, including covid-19: surveillance:, module 3: detecting emerging respiratory viruses, including covid-19: laboratory investigations:, module 4: risk communication :, module 5 : community engagement:, module 6: preventing and responding to an emerging respiratory virus, including covid-19:, enroll me for this course, certificate requirements.

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Conclusions, supplementary data.

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Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19

D. R. B. and J. D. H. contributed equally to this work.

Potential conflicts of interest. J. B. B. reports contracted fees and travel support for contracted activities for consulting work paid to the University of North Carolina by Novo Nordisk; grant support by NIH, PCORI, Bayer, Boehringer-Ingelheim, Carmot, Corcept, Dexcom, Eli Lilly, Insulet, MannKind, Novo Nordisk, and vTv Therapeutics; personal compensation for consultation from Alkahest, Altimmune, Anji, Aqua Medical Inc, AstraZeneca, Boehringer-Ingelheim, CeQur, Corcept Therapeutics, Eli Lilly, embecta, GentiBio, Glyscend, Insulet, Mellitus Health, Metsera, Moderna, Novo Nordisk, Pendulum Therapeutics, Praetego, Stability Health, Tandem, Terns Inc, and Vertex.; personal compensation for expert testimony from Medtronic MiniMed; participation on advisory boards for Altimmune, AstraZeneca, and Insulet; a leadership role for the Association of Clinical and Translational Science; and stock/options in Glyscend, Mellitus Health, Pendulum Therapeutics, Praetego, and Stability Health. M. A. P. receives consulting fees from Opticyte and Cytovale. A. B. K. has served as an external consultant for Roche Diagnostics; received speaker honoraria from Siemens Healthcare Diagnostics, the American Kidney Fund, the National Kidney Foundation, the American Society of Nephrology, and Yale University Department of Laboratory Medicine; research support unrelated to this work from Siemens Healthcare Diagnostics, Kyowa Kirin Pharmaceutical Development, the Juvenile Diabetes Research Foundation, and the NIH; support for travel from College of American Pathologists Point-Of-Care Testing Committee; participation on an advisory board for the Minnesota Newborn Screening Advisory Committee; grants from NIH and JDRF for multiple unrelated clinical research projects and Kyowa Kirin Pharmaceutical Development and Siemens Healthcare Diagnostics for unrelated clinical research studies; and leadership roles for the American Board of Clinical Chemistry, Association for Diagnostics and Laboratory Medicine (ADLM) Evidence-Based Laboratory Medicine Subcommittee, and ADLM Academy Test Utilization Committee. M. R. R. reports consulting fees from 20/20 Gene Systems for coronavirus disease 2019 testing. D. B. R. reports grants from the NIH NCATS ACTIV-6 Steering Committee Chair. K. C. reports stock or stock options for United Health Group. C. T. B. reports consulting fees from NCATS/DCRI and the ACTIV-6 Executive Committee and support for travel from Academic Medical Education. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Carolyn T Bramante, Kenneth B Beckman, Tanvi Mehta, Amy B Karger, David J Odde, Christopher J Tignanelli, John B Buse, Darrell M Johnson, Ray H B Watson, Jerry J Daniel, David M Liebovitz, Jacinda M Nicklas, Ken Cohen, Michael A Puskarich, Hrishikesh K Belani, Lianne K Siegel, Nichole R Klatt, Blake Anderson, Katrina M Hartman, Via Rao, Aubrey A Hagen, Barkha Patel, Sarah L Fenno, Nandini Avula, Neha V Reddy, Spencer M Erickson, Regina D Fricton, Samuel Lee, Gwendolyn Griffiths, Matthew F Pullen, Jennifer L Thompson, Nancy E Sherwood, Thomas A Murray, Michael R Rose, David R Boulware, Jared D Huling, COVID-OUT Study Team , Favorable Antiviral Effect of Metformin on SARS-CoV-2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of COVID-19, Clinical Infectious Diseases , Volume 79, Issue 2, 15 August 2024, Pages 354–363, https://doi.org/10.1093/cid/ciae159

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Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%.

COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction.

The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log 10 copies/mL; 95% confidence interval [CI], −1.05 to −.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo.

In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology.

NCT04510194.

(See the Invited Commentary by Siedner and Sax on pages 292–4.)

COVID-OUT was a multisite, phase 3, quadruple-blinded, placebo-controlled, randomized clinical trial to test whether outpatient treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevented severe coronavirus disease 2019 (COVID-19) [ 1 ].

The selection of metformin was motivated by in silico modeling, in vitro data, and human lung tissue data that showed that metformin decreased SARS-CoV-2 viral growth and improved cell viability [ 2–4 ]. The in silico modeling identified protein translation as a key process in SARS-CoV-2 replication, similar to protein mapping of SARS-CoV-2 [ 3 ]. Metformin inhibits the mechanistic target of rapamycin (mTOR) [ 5 ], which controls protein translation [ 6 , 7 ]. Metformin has shown in vitro antiviral actions against the Zika virus and against hepatitis C via mTOR inhibition [ 8–11 ].

Severe COVID-19 was defined using a binary, 4-part composite outcome (1 reading <94% SpO 2 on a home oximeter/emergency department visit/hospitalization/death) through 14 days and was not significant. After removing the 1 oxygen reading <94% component per the prespecified statistical analysis plan (SAP), metformin reduced the odds of emergency department visits/hospitalizations/death by day 14 by 42%, of hospitalization/death by day 28 by 58%, and of long COVID diagnoses by day 300 by 42% [ 1 , 12 ].

Here, we present the viral load quantification from samples obtained during the COVID-OUT trial. The trial used a 2 × 3 factorial design of parallel treatments to efficiently assess 3 medications: immediate-release metformin, ivermectin, and fluvoxamine at doses not previously studied in COVID-19 trials.

Study Design, Sample, and Oversight

COVID-OUT was an investigator-initiated, multisite, phase 3, quadruple-blinded, placebo-controlled randomized clinical trial ( Supplementary Tables 1 and 2 ) [ 1 ] that enrolled from 30 December 2020 to 28 January 2022. COVID-OUT was decentralized to prevent SARS-CoV-2 spread. The participants, care providers, investigators, and outcomes assessors remained blinded to treatment allocation.

Institutional review boards (IRBs) at each site and the Advarra Central IRB approved the protocol. An independent data and safety monitoring board (DSMB) monitored safety and efficacy. All analyses and covariates were prespecified in the SAP, which was submitted to the DSMB before enrollment ended and submitted in February 2022 with the primary outcome manuscript and then published [ 1 ]. An independent monitor oversaw study conduct per the Declaration of Helsinki, Good Clinical Practice Guidelines, and local requirements.

COVID-OUT excluded low-risk individuals, limiting enrollment to standard-risk adults aged 30 to 85 years with a body mass index (BMI) in the overweight or obesity categories, documented + SARS-CoV-2 within 3 days, and no prior confirmed SARS-CoV-2 infection. Pregnant women were randomized to metformin or placebo and not to ivermectin or fluvoxamine. Exclusion criteria included hospitalized, symptom onset >7 days prior, and unstable heart, liver, or kidney failure [ 1 ].

Metformin dosing was as follows: 500 mg on day 1, 500 mg twice daily on days 2–5, and 500 mg in the morning and 1000 mg in the evening on days 6–14. Fluvoxamine dosing was as follows: 50 mg on day 1 and 50 mg twice daily on days 2–14. Ivermectin dosing was as follows: a median of 430  µg/kg/day (range, 390 to 470  µg/kg/day) for 3 days.

Clinical and Virologic End Points

The primary end point was severe COVID-19 by day 14, defined using a binary, 4-part composite end point: 1 reading <94% SpO 2 on home oximeter/emergency department visit/hospitalization/death due to COVID-19. Secondary end points included hospitalization or death by day 28 and long COVID over the 10-month follow-up. The virologic secondary end point was overall viral load in follow-up, adjusted for baseline viral load as prespecified in the SAP.

Self-collection of anterior nares samples was an optional component of the randomized trial. Supply chain shortages caused administrative censoring of 78 participants who did not receive materials for collecting day 1, day 5, or day 10 samples; 3 did not receive materials for day 5 or day 10 samples ( Supplementary Figure 1, Supplementary Tables 3–6 ).

Laboratory Procedures

Participants received written instructions with pictures on self-collecting from the anterior mid-turbinate, which has excellent concordance with professionally collected nasal swabs [ 13 ]. Viral load was measured via reverse-transcription quantitative polymerase chain reaction using N1 and N2 targets in the SARS-CoV-2 nucleocapsid protein, with relative cycle threshold values converted to absolute copy number via calibration to droplet digital polymerase chain reaction. Detailed methods can be found in Supplementary Table 7 .

While participant self-collection may vary between participants, self-collection of samples is done by the same individual at baseline and follow-up. Thus, participant self-collection may have less variability between baseline and follow-up than when study or clinical staff obtain samples.

Statistical Analyses

We evaluated randomized study drug assignment on the impact of log 10 -transformed viral load on day 5 and day 10 with a linear Tobit regression model where the effect of study drugs was allowed to differ on day 5 and day 10. This was decided a priori as a rigorous analytic approach to account for left censoring due to the viral load limit of quantification. Repeated measures were accounted for using clustered standard errors within participants. Analyses of viral loads estimated the adjusted mean reduction averaged over time and the adjusted mean reduction at day 5 and day 10. We evaluated impact over time on the probability of viral load being undetectable using generalized estimating equations with a logistic link; estimates are reported as adjusted odds ratios (ORs) and 95% confidence intervals (CIs).

The COVID-OUT trial was a 2 × 3 factorial design of parallel distinct treatments ( Supplementary Table 2 ). All analyses were adjusted for baseline viral load, vaccination status, time since last vaccination for those vaccinated before enrollment, receipt of other study medications within factorial trial, laboratory that processed the nasal swabs, and exact time and date of specimen collection. Additional details and the results of the analyses with dropping of adjustment variables are presented in Supplementary Tables 8 and 9 .

To handle missing values, we used multiple imputation with chained equations to multiply impute missing viral load outcomes and vaccination status. Missing covariate information was jointly imputed along with missing outcomes using random forests for the univariate imputation models. Along with outcome and vaccination status information, imputation models were informed by sex, BMI, symptom duration, race/ethnicity, baseline comorbidities, clinical outcomes, and enrollment time categorized by the dominant pandemic variant. Complete case analysis without imputation of missing data is presented in Supplementary Figures 2–4 . Heterogeneity of effect was assessed across a priori subgroups of baseline characteristics. Starting metformin in <4 days of symptom onset is a subgroup that aligns with antiviral trials and reflects real-world use, as metformin is widely available.

Among 1323 randomized participants in the COVID-OUT trial, 999 (76%) chose to participate in the optional substudy and provided at least 1 nasal swab sample ( Table 1 , Supplementary Figure 1 ). The demographics of the participants who submitted swabs were similar to those who did not submit nasal swabs ( Supplementary Tables 3–5 ). Day 1 samples were provided by 945 participants, 871 provided day 5 samples, and 775 provided day 10 samples ( Supplementary Table 6 ). The overall viral load was a median of 4.88 log 10 copies/mL (interquartile range [IQR], 2.99 to 6.18) on day 1, 1.90 (IQR, 0 to 3.93) on day 5, and 0 (IQR, 0 to 1.90 with 0 representing the limit of quantification) on day 10.

Baseline Characteristics of Participants Who Submitted Any Nasal Swab

Values are percent (n) or median (interquartile range) unless specified. Cardiovascular disease defined as hypertension, hyperlipidemia, coronary artery disease, past myocardial infarction, congestive heart failure, pacemaker, arrhythmias, or pulmonary hypertension.

Abbreviation: BMI, body mass index.

a Unknown n = 22.

The overall mean SARS-CoV-2 viral load reduction with metformin was −0.56 log 10 copies/mL (95% CI, −1.05 to −0.06) greater than placebo across all follow-up ( P = .027). The antiviral effect of metformin compared with placebo was −0.47 log 10 copies/mL (95% CI, −0.93 to −0.014) on day 5 and −0.64 log 10 copies/mL (95% CI, −1.42 to 0.13) on day 10 ( Figure 1 ). Neither ivermectin nor fluvoxamine had virologic effect ( Figure 2 , Supplementary Figure 2 , Supplementary Tables 8–10 ).

Effect of metformin versus placebo on viral load over time, detectable viral load, and rebound viral load. A , Adjusted mean change in log10 copies per milliliter (viral load) from baseline (day 1) to day 5 and day 10 for metformin (lower line) and placebo (upper line). Mean change estimates are based on the adjusted, multiply imputed Tobit analysis (the primary analytic approach) that corresponds to the overall metformin analysis presented in Figure 2 . B , Adjusted percent of viral load samples that were detectable at day 1, day 5, and day 10. The percent viral load detected estimates were based on the adjusted, multiply imputed logistic generalized estimating equations (GEE) analysis corresponding to the overall metformin analysis depicted in Figure 3 . Odds ratios correspond to adjusted effects on the odds ratio scale. C , Bar chart depicting the percent of participants whose day 10 viral load was greater than the day 5 viral load and the odds ratio for having viral load rebound using the multiply imputed logistic GEE. Abbreviation: CI, confidence interval.

Overall results for metformin, ivermectin, and fluvoxamine on viral load; heterogeneity of treatment effect of metformin versus placebo. This is a forest plot that depicts the effect of active medication compared with control on log10 copies per milliliter (viral load), overall, and at day 5 and day 10. Viral Effect* denotes the adjusted mean change in viral load in log10 copies per milliliter with 95% confidence intervals for the adjusted mean change. Analyses were conducted using the primary analytic approach, a multiply imputed Tobit model. The vertical dashed line indicates the value for a null effect. The top 3 rows show ivermectin, the next 3 rows show fluvoxamine, and the following 3 rows show metformin. Below these, the effect of metformin compared with placebo is shown by a priori subgroups of baseline characteristics. Abbreviation: CI, confidence interval.

When the adjustment covariates were dropped one at a time—baseline viral load, vaccination status, time since last vaccination, other study medications within the factorial trial, and the laboratory processing the nasal swabs—in addition to dropping all adjustment covariates, the results were similar. The range in the estimated average effect was −0.51 log 10 copies/mL (95% CI, −1.04 to 0.01; P = .056) to −0.66 log 10 copies/mL (95% CI, −1.215 to −0.097; P = .021) with the latter arising from the unadjusted model ( Supplementary Table 9 ).

Those in the metformin group were less likely to have a detectable viral load than those in the placebo group (OR, 0.72; 95% CI, .55 to .94; Figure 1) . This effect was higher at day 10 (OR, 0.65; 95% CI, .43 to .98) when 1500 mg/d of metformin was being prescribed than at day 5 (OR, 0.79; 95% CI, .60 to 1.05) when 1000 mg/d was prescribed. Viral rebound was defined as having a higher viral load at day 10 than day 5. In the placebo group, 5.95% (22 of 370) of participants had viral rebound compared with 3.28% (12 of 366) in the metformin group (adjusted OR, .68; 95% CI, .36 to 1.29) for metformin compared with placebo ( Figure 1) .

Metformin's effect on continuous viral load and conversion to undetectable viral load was consistent across a priori identified subgroups of baseline characteristics ( Figures 2 and 3 ). Subgroups should be interpreted with caution because of low power, risk of making multiple comparisons without correction, and sparse data bias. One subgroup warrants additional detail for interpretation. The antiviral effect on geometric log 10 scale was greater among those with baseline viral loads <100 000 copies/mL (mean −1.17 log 10 copies/mL reduction) than among those with >100 000 copies/mL (mean −0.49 log 10 copies/mL reduction); although the reduction in absolute copies per milliliter would be greater among those with higher viral loads ( Figures 2 and 3 ). Mean, median viral load levels are presented in Supplementary Table 11 ; sensitivity analyses are presented in Supplementary Figures 5–7 and Supplementary Table 12 .

Overall results for metformin, ivermectin, and fluvoxamine on detectability of viral load; heterogeneity of treatment effect of metformin versus placebo. This is a forest plot that depicts the effect of active medication compared with control on the proportion of participants with a detectable viral load, overall and at days 5 and 10. Estimate* denotes the adjusted mean risk difference in the percent of samples with detected viral load with 95% confidence intervals for the adjusted risk difference. The vertical dashed line indicates the value for a null effect. The estimated risk differences are derived from the adjusted, multiply imputed logistic generalized estimating equations (GEE) analytic approach. The top 3 rows show ivermectin, the next 3 rows show fluvoxamine, and the following 3 rows show metformin. Below these, the effect of metformin compared with placebo is shown by a priori subgroups of baseline characteristics. Abbreviation: CI, confidence interval.

In the virologic end point of the COVID-OUT phase 3, randomized trial, metformin significantly reduced SARS-CoV-2 viral load over 10 days [ 1 ]. The mean reduction was −0.56 log 10 copies/mL greater than placebo. The antiviral response is consistent with the statistically significant and clinically relevant effects of metformin in preventing clinical outcomes: severe COVID-19 (emergency department visit, hospitalization, or death) through day 14, hospitalization or death by day 28, and the diagnosis of long COVID [ 1 , 12 ]. The magnitude of effect on clinical outcomes was larger when metformin was started earlier in the course of infection at <4 days from symptom onset, with metformin reducing the odds of severe COVID-19 by 55% (OR, 0.45; 95% CI, .22 to .93) and of long COVID by 65% (hazard ratio = 0.35; 95% CI, .15 to .95; Figure 4) . An improved effect size for clinical outcomes when therapies are started earlier in the course of infection is consistent with an antiviral action [ 14 ].

Overview of results from the COVID-OUT trial. This is a forest plot that combines the severe, acute coronavirus disease 2019 outcome as well as the long-term follow-up outcome from the COVID-OUT trial [ 1 , 12 ]. Two a priori subgroups from the COVID-OUT trial are also presented: pregnant individuals and those who started the study drug within 4 days of symptom onset, to match the primary analytic sample of other antivirals. Abbreviations: COVID-19, coronavirus disease 2019; ITT, intention to treat; mITT, modified intention to treat; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

The objective of the COVID-OUT trial was to determine whether metformin prevented severe COVID-19. Severe COVID-19 was defined with a binary, 4-part composite outcome (<94% SpO 2 on a home oximeter/emergency department visit/hospitalization/death) at a time when the implications of “silent hypoxia” were unknown and fears of overwhelmed emergency services caused concern that deaths would occur at home before patients reached the emergency department. As a scientific community, we now understand that 1 reading below 94% is not severe COVID-19. An accurate definition of severe COVID-19 (emergency department visit/hospitalization/death) was ascertained within the same data-generation process. In such situations, recommendations are sometimes made based on the totality of evidence from a single randomized trial [ 15–17 ].

The antiviral effect in this phase 3, randomized trial is also consistent with emerging data from other trials. In a phase 2, randomized trial with 20 participants, the metformin group had better clinical outcomes, achieved an undetectable viral load 2.3 days faster than placebo ( P = .03), and had a larger proportion of patients with an undetectable viral load at 3.3 days in the metformin group ( P = .04) [ 18 ]. A recent in vitro study showed that metformin decreased infectious SARS-CoV-2 titers and viral RNA in 2 cell lines, Caco2 and Calu3, at a clinically appropriate concentration [ 19 ].

Conversely, an abandoned randomized trial testing extended-release metformin 1500 mg/d without a dose titration did not report improved SARS-CoV-2 viral clearance at day 7 [ 20 ]. Several differences between the Together Trial and the COVID-OUT trial are important for understanding the data. First, the Together Trial allowed individuals already taking metformin to enroll and be randomized to placebo or more metformin [ 20 , 21 ]. To compare starting metformin versus placebo, the authors excluded those already taking metformin at baseline and reported that emergency department visit or hospitalization occurred in 9.2% (17 of 185) randomized to metformin compared with 14.8% (27 of 183) randomized to placebo (relative risk, 0.63; 95% confidence interval, .35 to 1.10, Probability of superiority = 0.949) [ 22 ]. Thus, the Together Trial results for starting metformin versus placebo are similar. Second, 1500 mg/day without escalating the dose over 6 days would cause side effects, especially if the study participant was already taking metformin [ 23 ]. Third, extended-release and immediate-release metformin have different pharmacokinetic properties. Immediate-release metformin has higher systemic exposure than extended-release metformin, which may improve antiviral actions, but this is not known [ 24 , 25 ]. Given the similar clinical outcomes between immediate and extended-release, a direct comparison of the 2 may be important for understanding pharmacokinetics against SARS-CoV-2.

In comparison with other SARS-CoV-2 antivirals, when considering all enrolled participants, at day 5, the antiviral effect over placebo was 0.47 log 10 copies/mL for metformin, 0.30 log 10 copies/mL for molnupiravir, and 0.80 log 10 copies/mL for nirmatrelvir/ritonavir [ 26 , 27 ]. At day 10, the viral load reduction over blinded placebo was 0.64 log 10 copies/mL for metformin, 0.35 log 10 copies/mL for nirmatrelvir, and 0.19 log 10 copies/mL for molnupiravir [ 26 , 27 ]. We note that the 3 trials enrolled different populations and at different times and locations during the pandemic. In the COVID-OUT metformin trial, half were vaccinated [ 1 , 12 ].

The magnitude of metformin's antiviral effect was larger at day 10 than at day 5 overall and across subgroups, which correlates with the dose titration from 1000 mg on days 2–5 to 1500 mg on days 6–14. The dose titration to 1500 mg over 6 days used in the COVID-OUT trial was faster than typical use. When used chronically, that is, for diabetes, prediabetes, or weight loss, metformin is slowly titrated to 2000 mg daily over 4–8 weeks. While metformin's effect on diabetes control is not consistently dose-dependent, metformin's gastrointestinal side effects are known to be dose-dependent [ 25 ]. Thus, despite what appears to be dose-dependent antiviral effects, a faster dose titration should likely only be considered in individuals with no gastrointestinal side effects from metformin.

When assessing for heterogeneity of effect, metformin was consistent across subgroups. Metformin's antiviral effect in vaccinated versus unvaccinated of −0.48 versus −0.86 log 10 copies/mL at day 10 mirrors nirmatrelvir, for which the effect in seropositive participants was smaller than in the overall trial population, −0.13 versus −0.35 log 10 copies/mL at day 10 [ 26 ]. Effective primed memory B- and T-cell anamnestic immunity prompting effective response by day 5 in vaccinated persons may account for this trend in both trials. Subgroups should be interpreted with caution because of low power and multiple comparisons [ 28 ].

Both nirmatrelvir and molnupiravir are pathogen-directed antiviral agents. Therapeutics may have an important role in targeting host factors rather than viral factors, as targeting the host may be less likely to induce drug-resistant viral variants through mutation–selection [ 11 , 29 ]. We did not study the mechanism for the antiviral activity or an antiinflammatory action in this trial. Previous work has shown that metformin's inhibition of mTOR complex 1 may depend on AMP-activated protein kinase (AMPK) at low doses but not high doses [ 5 ]. An AMPK-independent inhibition of mTOR may be more efficient. Additionally, metformin demonstrates a dose-dependent ability to inhibit interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha in the presence of lipopolysaccharide, inflammatory products that correlate with COVID-19 severity [ 30 , 31 ].

In addition to antiviral activity, metformin appears to have relevant antiinflammatory actions. In mice without diabetes, metformin inhibited mitochondrial ATP and DNA synthesis to evade NLRP3 inflammasome activation [ 32 ]. In macrophages of mice without diabetes infected with SARS-CoV-2, metformin inhibited inflammasome activation, IL-1 production, and IL-6 secretion and also increased the IL-10 antiinflammatory response to lipopolysaccharide, thereby attenuating lipopolysaccharide-induced lung injury [ 32 ]. In a recent assay of human lung epithelial cell lines, metformin inhibited the cleavage of caspase-1 by NSP6, inhibiting the maturation and release of IL-1, a key factor that mediates inflammatory responses [ 7 ]. The idea of pleiotropic effects is being embraced in novel therapeutics being developed for both antiviral and anti-inflammatory actions [ 33 ].

Strengths of our study include the large sample size and detailed participant information collected, including the exact time and date of specimen collection. One limitation was the sampling time frame of only day 1, day 5, and day 10 due to limited resources. By day 10 post-randomization, 77% of participants in the placebo group and 86% in the metformin group had an undetectable viral load. As viral load is lower in vaccinated persons [ 34 ], this degree of undetectable viral loads differs from findings from earlier clinical trials conducted in unvaccinated participants without known prior infection [ 26 , 27 ]. Sampling earlier and more frequently, that is, day 1, day 3, day 6, and day 9 in future trials, may better characterize differences in viral shedding earlier in the infection and over time, dependent on the duration of therapy and timing of enrollment.

Future work could assess whether synergy exists between metformin and direct SARS-CoV-2 antivirals, as previous work showed that metformin improved sustained virologic clearance of hepatitis C virus and improved outcomes in other respiratory infections [ 35–37 ]. The biophysical modeling that motivated this trial predicts additive/cooperative effects in combination with transcription inhibitors. Combination therapy might decrease selective pressure, and metformin has few medication interactions, so treatment with metformin could continue beyond 5 days while home medications are restarted. Additionally, continuing metformin could reduce symptom rebound, given its effects on T-cell immunity [ 38 , 39 ]. Further data are needed to understand whether decreased viral load and faster viral clearance decrease onward transmission of SARS-CoV-2.

Metformin is safe in children and pregnant individuals with and without preexisting diabetes [ 40–42 ]. Individuals with or without diabetes do not need to check blood sugar when taking metformin. Historical concerns about lactic acidosis were driven by other biguanides; metformin does not increase risk of lactic acidosis [ 43 ]. Metformin improves outcomes in patients with heart, liver, and kidney failure, as well as during hospitalizations and perioperatively [ 44–48 ].

In a large randomized, controlled trial conducted in nonhospitalized, standard-risk adults, metformin reduced the incidence of severe COVID-19 by day 14, of hospitalizations by day 28, and of long COVID diagnosis by day 300. In this virologic analysis, we found a corresponding significant reduction in viral load with metformin compared with placebo and a lower likelihood of viral load rebound. While 22% of participants in the trial were enrolled during the Omicron era, metformin has not been assessed in individuals with a history of prior infection and thus should be trialed in the current state of the pandemic. Metformin is currently being trialed in low-risk adults [ 49 ].

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Disclaimer. The funders had no influence on the design or conduct of the trial and were not involved in data collection or analysis, writing of the manuscript, or decision to submit for publication. The authors assume responsibility for trial fidelity and the accuracy and completeness of the data and analyses.

Financial support . The fluvoxamine placebo tablets were donated by the Apotex Pharmacy. The ivermectin placebo and active tablets were donated by the Edenbridge Pharmacy. The trial was funded by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and the UnitedHealth Group Foundation. C. T. B. was supported by grants (KL2TR002492 and UL1TR002494) from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) and by a grant (K23 DK124654) from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH. J. B. B. was supported by a grant (UL1TR002489) from NCATS. J. M. N. was supported by a grant (K23HL133604) from the National Heart, Lung, and Blood Institute (NHLBI) of the NIH. D. J. O. was supported by the Institute for Engineering in Medicine, University of Minnesota Office of Academic and Clinical Affairs COVID-19 Rapid Response Grant, the Earl E. Bakken Professorship for Engineering in Medicine, and by grants (U54 CA210190 and P01 CA254849) from the National Cancer Institute of the NIH. D. M. L. receives funding from NIH RECOVER (OT2HL161847). L. K. S. was supported by NIH grants (18X107CF6 and 18X107CF5) through a contract with Leidos Biomedical and by grants from the HLBI of the NIH (T32HL129956) and the NIH (R01LM012982 and R21LM012744). M. A. P. receives grants from the Bill and Melinda Gates Foundation (INV-017069), Minnesota Partnership for Biotechnology and Medical Genomics (00086722) and NHLBI (OT2HL156812).

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• outpatients
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• severe acute respiratory syndrome
• post-acute covid-19 syndrome

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Gop-led committees release biden impeachment report without formally recommending the house move forward with impeachment.

The trio of Republican-led committees leading the impeachment inquiry into President Joe Biden on Monday released a report arguing that the president has “engaged in impeachable conduct” without making a formal recommendation for the House of Representatives to move forward with impeachment.

Instead, the 291-page report recycles previous unsupported claims to argue that Biden “knowingly participated” in a conspiracy to leverage his office while as vice president and beyond to financially benefit his family, and leaves it up to the House of Representatives to evaluate.

Republicans unveiled the report on the day the Democratic National Convention begins in Chicago, hours before Biden is expected to address the event in a keynote speech.

In a statement Monday, White House spokeswoman Sharon Yang slammed congressional Republicans for their “failed” impeachment endeavor.

“After wasting nearly two years and millions of taxpayer dollars, House Republicans have finally given up on their wild goose chase,” Yang said. “This failed stunt will only be remembered for how it became an embarrassment that their own members distanced themselves from as they only managed to turn up evidence that refuted their false and baseless conspiracy theories.”

The report’s release also comes at a precarious moment for House Republicans. Since Republicans launched their impeachment inquiry into Biden 11 months ago, they have failed to convince their narrow majority to move forward with articles of impeachment. With Biden no longer seeking reelection, and attention on Capitol Hill shifting to the 2024 presidential election, the GOP momentum to continue to use investigative muscle to scrutinize Biden and his family has also dissipated.

It will all come down to House Speaker Mike Johnson and whether he decides to try to push through articles of impeachment during the three weeks the House returns to Washington in September while simultaneously addressing the crucial September 30 government funding deadline.

“I think it’s kind of a moot point now,” GOP Rep. Lisa McClain of Michigan, who serves on the House Oversight Committee, one of the trio of committees leading the inquiry, told CNN last month.

Another GOP lawmaker serving on the House Judiciary Committee, also part of the inquiry effort, acknowledged that Biden stepping aside takes the political undertones out of the report.

“I think the American people have a right to know what was going on with the family enterprises,” GOP Rep. Tom McClintock of California said ahead of the report’s release. “I think it has the advantage of being less politically charged now because Biden is no longer facing voters.”

GOP Rep. Doug LaMalfa, also of California, who has said he thought it would be unproductive for Republicans to try to impeach Biden given that it would go nowhere in the Democratic-controlled Senate, said in July of the prospect of a final report, “If they need to tidy up something to put a bow on it, fine, but putting a lot of effort into it wouldn’t really be too productive either.”

This was not how Republicans wanted their prized investigation into Biden to end after pouring over subpoenaed bank records and conducting key interviews with the president’s son, Hunter, and brother, James, as well as a slew of family business associates.

GOP Rep. Matt Gaetz of Florida, who has long called for Biden to be impeached, told CNN, “No,” this is not how he wanted the investigation to end.

But other Republicans said regardless of the political moment, the report needed to be released. In the wake of Biden’s disastrous debate performance in June that led to the unraveling of his reelection bid, Republicans sat on their final report and let the Democratic infighting play out. But with Biden’s decision to step aside and the final stretch before the November elections closing in, Republicans acknowledged that their window was closing.

House Judiciary Chairman Jim Jordan of Ohio, who is co-leading the inquiry, told CNN ahead of the report’s release, “We have a constitutional duty to do oversight. We’ve done oversight. It’s important that I think we put the findings out there and issue a report. So, I do think it’s important to come out.”

House Oversight Chairman James Comer of Kentucky, another co-lead on the inquiry, has long maintained that his goal is to pursue legislation banning influence peddling and that it is not his job to impeach, even if he believes the evidence supports impeachment.

Another Judiciary Committee member, Rep. Harriet Hageman of Wyoming told CNN in July Biden’s decision to bow out of the presidential race has no bearings on the inquiry’s final report.

“I wanted this investigation to end with the truth,” Hageman said. “Whatever decision they make doesn’t make any difference to me. The way I wanted this to end is for the American people to understand the magnitude of the Biden crime family.”

Democratic Rep. Jamie Raskin, the ranking member of the House Committee on Oversight and Accountability, said in a statement that the impeachment report continues “debunking and refuting the same old lies and propaganda that have defined the Oversight Republicans’ embarrassing work in the wasted 118th Congress.”

“I would call it a complete exoneration of the target of their pathetic attacks—President Joe Biden,” Raskin said.

GOP claims of ‘influence peddling and grift’

The Republican-led report claims to “expose a years-long pattern of influence peddling and grift centered around and facilitated by Joe Biden.” However, it is largely a retread of  previous GOP theories  that exaggerate Biden’s connections to his brother’s and son’s highly lucrative foreign business dealings, which the report claimed totaled “over $18 million from foreign sources.”

Perhaps the claim investigators said was most damning is the allegation that Hunter Biden, James Biden and their business partners knowingly sold “the brand” — or potential access to Joe Biden.

But one of these business partners  testified  that they were only offering an “illusion” of access.

That partner, Devon Archer, who was  convicted  in a separate fraud scheme unrelated to the Bidens, told investigators that Hunter Biden put his father on speakerphone “maybe 20 times” during meetings with foreign partners, and that they saw this as “access and influence,” according to the report, which highlighted these details from Archer’s testimony that were already made public months ago.

“The people to whom this ‘illusion’ of access was sold by Biden family members did, in fact, obtain access to Joe Biden in private, non-disclosed settings,” the report says.

However, Archer  also testified  that “nothing” material to the business was discussed when Joe Biden was on the phone or at a  handful of dinners  with business partners where Joe Biden stopped by. And the Republican report doesn’t appear to contain any new examples of substantive business interactions between Joe Biden and his family’s business associates in Ukraine, China, Russia or elsewhere.

Still, the report asserts that it was known “the Biden family business model centered on Joe Biden’s influence and positions of power,” citing Archer’s testimony. But that isn’t necessarily a new revelation: Even Hunter Biden has publicly  acknowledged  that he would “probably not” have been tapped to serve on the highly paid board of Ukrainian energy firm Burisma if he weren’t Joe Biden’s son.

Former Biden family business associate recycles unproven allegations

The report features a series of  unproven allegations from former Biden family business associate Tony Bobulinski, including claims that have been disputed by other witnesses.

It states that Bobulinski testified that “Joe Biden was more than a participant in and a beneficiary of his family’s business; he was an enabler, despite being buffered by a complex scheme to maintain plausible deniability.”

The claims, however, stand in stark contrast to a list of other Biden family business associates who have stated that Joe Biden, as a private citizen and as vice president, was never involved in his any of his family’s foreign business dealings.

While congressional Republicans have seized on the claims, Democrats have argued that Bobulinski is not a credible witness.

The committees highlight a 2017 email sent by James Gilliar, whom the committee describes as another Biden family associate, to Bobulinski that, according to the report, was about “remuneration packages” for a venture involving Chinese energy interests. The email outlines a “provisional agreement” for equity distribution with a breakdown of numbers alongside a series of initials. One-line states, “10 held by H for the big guy ?”

Bobulinski testified to the committees that the H referred to Hunter Biden and the “big guy” was a reference to Joe Biden.

Hunter Biden’s lawyers  have countered  that the proposed equity breakdown from the email was “never included in any agreement” and that the breakdown was actually proposed by Bobulinski, and never even garnered any response from Hunter Biden.

According to the report, Bobulinski disputed that, saying, “Hunter Biden responded to this email I think three-plus times.”

Separately, the report states that in a different exchange Hunter Biden sent a message to an official with a Chinese energy conglomerate in which he invoked his father a way that was “threatening.”

“I am sitting here with my father and we would like to understand why the commitment made has not been fulfilled,” the message reads, according to the report.

The message states that “if I get a call or text from anyone involved in this other than you” or a select few other individuals, “I will make certain that between the man sitting next to me and every person he knows and my ability to forever hold a grudge that you will regret not following my direction.”

Biden has fired back against claims from House Republicans that he was involved in business dealings with his son and brother, telling reporters last year that the GOP claims are “a bunch of lies.”

Report accuses White House of hampering Congress’ access to key documents and witnesses

The report also accused the White House and others in the Biden administration of hampering Congress’ efforts to obtain key documents and witnesses related to probes of the president’s handling of classified materials and his son’s business dealings.

In the aftermath of the February release of the report on Special Counsel Robert Hur’s investigation into Biden’s handling of classified documents, the committees sought an audio recording of the two-day interview Biden sat for with Hur in October. Hur’s  report did not lead to charges against Biden , but it contained politically and personally damaging judgments about the president’s age and mental fitness.

The transcript of Biden’s interview with Hur  was released weeks later , but Republicans have demanded the DOJ turn over the recording because they say it would provide greater insight into Biden’s cognition. They also accused the White House of editing verbal miscues from previous official transcripts of Biden.

The president asserted his executive privilege over the audio files, and the DOJ has  defended its decision  to not release them by saying doing so raises privacy concerns and could dissuade cooperation from witnesses in future investigations. It also strongly implied the Republican committees sought the audio for political purposes.

The report said the White House also prevented the National Archives and Records Administration from releasing the bulk of emails requested by the committee that Joe Biden sent and received from a pseudonymous email account during his time as vice president.

It also claimed the Biden administration obstructed federal investigations into Hunter Biden’s taxes and business — though many of the committee’s allegations were nonspecific or stemmed from before Biden was president.

The committee said both the FBI and IRS investigations into Hunter Biden were hampered by red tape or required additional layers of approval and oversight before parts of the investigation could proceed — a result that the committee said was due to his father’s then-position as a former vice president, and a likely future candidate for the top of the ticket. The tax investigation into Hunter Biden began in 2018, before Biden announced his 2020 candidacy. The FBI, with the assistance of the US Attorney’s Office for the District of Delaware, opened a separate probe into his business dealings in 2019.

“From the outset, the FBI, the Justice Department, and IRS all recognized the sensitivity of investigation the former Vice President’s son, particularly in the state in which the Bidens are a prominent family,” the report said. “As a result, Hunter Biden was afforded extra protection, and investigators were forced to jump through additional hoops they would not normally experience in a typical case.”

While witnesses acknowledged the Bidens’ prominence in Delaware added to the sensitivity surrounding the home-state investigation into Hunter Biden, examples provided in the report seemed to reflect on the anxieties of the agents involved in the investigation rather than any influence from Biden.

An IRS agent involved in the Biden probe, who later became a whistleblower alleging political interference in the investigation, testified that an FBI agent in Wilmington “was concerned about the consequences for him and his family” if he had to be involved in a Biden case in Delaware. Top IRS officials  have disputed  the whistleblower’s claims.

This story has been updated with additional information.

CNN’s Haley Talbot and Asher Moskowitz contributed to this report.

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