Saturday, June 6, 2020

Hydroxychloroquine and azithromycin as a treatment of COVID-19 3

The Lancet, one of the world’s top medical journals, on Thursday retracted an influential study that raised alarms about the safety of the experimental Covid-19 treatments chloroquine and hydroxychloroquine amid scrutiny of the data underlying the paper.

Just over an hour later, the New England Journal of Medicine retracted a separate study, focused on blood pressure medications in Covid-19, that relied on data from the same company.

The retractions came at the request of the authors of the studies, published last month, who were not directly involved with the data collection and sources, the journals said.

“We can no longer vouch for the veracity of the primary data sources,” Mandeep Mehra of Brigham and Women’s Hospital, Frank Ruschitzka of University Hospital Zurich, and Amit Patel of University of Utah said in a statement issued by the Lancet. “Due to this unfortunate development, the authors request that the paper be retracted.”

Meanwhile, on Wednesday, researchers reported the results of the first gold-standard clinical trial of hydroxycholoroquine in Covid-19, concluding that it did not prevent infections any better than placebo. Other clinical trials, including some looking at the drugs as treatments, are ongoing.

The Lancet study gained so much attention because it went further than other observational studies that had similarly found the drugs were not associated with improved outcomes for patients. The study, which was purportedly based on patient data from 671 hospitals on six continents, reported the drugs also corresponded to higher mortality.

The findings led to the pause of some global clinical trials studying hydroxychloroquine so researchers could check for any safety concerns. Outside experts, however, quickly raised concerns after noticing inconsistencies in the data. They asked the company that compiled and analyzed the data, Surgisphere, to explain how it sourced its data.

As scrutiny grew, the authors on the paper not affiliated with Surgisphere called for an independent audit. In their Lancet statement Thursday, they said that Surgisphere was not cooperating with the independent reviewers and would not provide the data.

“As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process,” the researchers wrote.

The retraction of the Lancet paper is sure to add fuel to contentious arguments about the potential of chloroquine and hydroxychloroquine, two old malaria drugs, in Covid-19, the disease caused by the novel coronavirus. President Trump has touted them as valuable treatments, despite a lack of rigorous data showing they have a benefit.

RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis
Prof Mandeep R Mehra, MD
Sapan S Desai, MD
Prof Frank Ruschitzka, MD
Amit N Patel, MD
Published:May 22, 2020DOI:



  1. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Retraction: Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621 [published online ahead of print, 2020 Jun 4] [retraction of: N Engl J Med. 2020 May 1;:]. N Engl J Med. 2020;10.1056/NEJMc2021225. doi:10.1056/NEJMc2021225

    Rubin EJ. Expression of Concern: Mehra MR et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621 [published online ahead of print, 2020 Jun 2]. N Engl J Med. 2020;NEJMe2020822. doi:10.1056/NEJMe2020822

  2. One of the more disturbing aspects of the Coronavirus pandemic is the politicization of medical matters, most notably seen in the conflict surrounding hydroxychloroquine. A media storm followed President Trump’s suggestion that the drug showed promise and a victory declared after a study claimed the drug was harmful. But tests of hydroxychloroquine have been resumed since it was discovered that the research slamming the drug could not possibly have been more bogus.

    On 17 March, the AIFA Scientific-Technical Commission of the Italian Medicines Agency expressed a favorable opinion on including the off-label use of chloroquine and hydroxychloroquine for the treatment of COVID‑19. At a press conference held two days later, President Trump suggested that the drugs were being investigated as a potential treatment. The FDA later said they had not given approval for the drug to be used in the treatment of COVID‑19but was now allowing chloroquine under compassionate-use guidelines. The drug then became the focus of a media battle.

    Based on the results of a study published in The Lancet, the World Health Organization (WHO) suspended hydroxychloroquine from its global drug trials for COVID‑19 treatments on 26 May due to safety concerns raised in that study. The study based on the conclusions from three of four authors said neither chloroquine nor hydroxychloroquine (HCQ) with antibiotics hold any significant promise as a treatment for Covid-19 and stated that patients were at greater risk of death. The authors based their study on data provided by the US company Surgisphere, a healthcare analytics company.

    On Thursday, the Lancet retracted the article after an investigation by The Guardian revealed errors in the data that was provided for the research by Surgisphere. The authors stated they were unable to complete an independent audit of the data underpinning their analysis. As a result, they have concluded that they ‘can no longer vouch for the veracity of the primary data sources.’

    The journal’s editor, Richard Horton, said he was appalled by developments. “This is a shocking example of research misconduct in the middle of a global health emergency,” he told the Guardian.

    The New England Journal of Medicine also retracted a paper based on the Surgisphere database, also co-authored by Mehra and Desai.

    In a statement, published by the journal, the authors said: “Because all the authors were not granted access to the raw data and the raw data could not be made available to a third-party auditor, we are unable to validate the primary data sources underlying our article, ‘Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19’. We therefore request that the article be retracted.”

    The Guardian reported that some of the employees of Surgisphere involved in the research that led to the WHO and governments changing their policies concerning the use of hydroxychloroquine included a science fiction writer who, for the purposes of the hydroxychloroquine study, was listed by the company as a science editor and an adult-content model who was listed as a marketing executive. Several of Surgisphere’s employees were found to have little or no data or scientific background.

    Sapan Desai, one of the co-authors of the paper delegitimizing hydroxychloroquine, was discovered to be the target of three malpractice suits.

    The Guardian also found many questionable aspects of Surgisphere’s online presence, which was almost nonexistent despite its claim to “run one of the largest and fastest hospital databases in the world.” Several of hospitals whose input would have been essential in any investigation into the treatment of coronavirus with hydroxychloroquine claimed never to have been contacted by Surgisphere.(continued)

  3. (continued)But the damage is not limited to the exclusion of the potentially life-saving benefits of hydroxychloroquine. Another study using the Surgisphere database, again co-authored by Desai, found the anti-parasite drug ivermectin reduced death rates in severely ill Covid-19 patients. It was published online in the Social Science Research Network e-library, before peer-review or publication in a medical journal, and prompted the Peruvian government to add ivermectin to its national Covid-19 therapeutic guidelines.

    Under the scrutiny concerning its results, Surgisphere has so far failed to adequately explain its data or methodology.

    The WHO recently announced that trials on hydroxychloroquine’s efficacy in treating COVID-19 would now resume. There are currently 48 or more trials underway in the US including at least 17 that are testing whether it could still play a role as a prophylactic preventing COVID-19 infection, even if it may not help treat patients who are already infected with the coronavirus.

  4. Samia Arshad, Paul Kilgore, Zohra S. Chaudhry, Gordon Jacobsen, Dee Dee Wang, Kylie Huitsing, Indira Brar, George J. Alangaden, Mayur S. Ramesh, John E. McKinnon, William O’Neill, Marcus Zervos, Varidhi Nauriyal, Asif Abdul Hamed, Owais Nadeem, Jennifer Swiderek, Amanda Godfrey, Jeffrey Jennings, Jayna Gardner-Gray, Adam M Ackerman, Jonathan Lezotte, Joseph Ruhala, Raef Fadel, Amit Vahia, Smitha Gudipati, Tommy Parraga, Anita Shallal, Gina Maki, Zain Tariq, Geehan Suleyman, Nicholas Yared, Erica Herc, Johnathan Williams, Odaliz Abreu Lanfranco,
    Pallavi Bhargava, Katherine Reyes, Anne Chen. Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19 International Journal of Infectious Diseases. Published:July 01, 2020 DOI:


    As of May27, 2020 there are over 1,678,843 confirmed cases of COVID-19 claiming more than 100,000 lives in the Unites States. Currently there is no known effective therapy or vaccine.

    According to a protocol-based treatment algorithm, among hospitalized patients, use of hydroxychloroquine alone and in combination with azithromycin was associated with a significant reduction in-hospital mortality compared to not receiving hydroxychloroquine.

    -Findings of this observational study provide crucial data on experience with hydroxychloroquine therapy, providing necessary interim guidance for COVID-19 therapeutic practice. (continued)

  5. (continued)Abstract

    The United States is in an acceleration phase of the COVID-19 pandemic. Currently there is no known effective therapy or vaccine for treatment of SARS-CoV-2, highlighting urgency around identifying effective therapies.

    The purpose of this study was to evaluate the role of hydroxychloroquine therapy alone and in combination with azithromycin in hospitalized patients positive for COVID-19.

    Multi-center retrospective observational study

    The Henry Ford Health System (HFHS) in Southeast Michigan: large six hospital integrated health system; the largest of hospitals is an 802-bed quaternary academic teaching hospital in urban Detroit, Michigan.

    Consecutive patients hospitalized with a COVID-related admission in the health system from March 10,2020 to May 2,2020 were included. Only the first admission was included for patients with multiple admissions. All patients evaluated were 18 years of age and older and were treated as inpatients for at least 48 hours unless expired within 24 hours.

    Receipt of hydroxychloroquine alone, hydroxychloroquine in combination with azithromycin, azithromycin alone, or neither.

    Main Outcome
    The primary outcome was in-hospital mortality.

    Of 2,541 patients, with a median total hospitalization time of 6 days (IQR: 4-10 days), median age was 64 years (IQR:53-76 years), 51% male, 56% African American, with median time to follow-up of 28.5 days (IQR:3-53). Overall in-hospital mortality was 18.1% (95% CI:16.6%-19.7%); by treatment: hydroxychloroquine + azithromycin, 157/783 (20.1% [95% CI: 17.3%-23.0%]), hydroxychloroquine alone, 162/1202 (13.5% [95% CI: 11.6%-15.5%]), azithromycin alone, 33/147 (22.4% [95% CI: 16.0%-30.1%]), and neither drug, 108/409 (26.4% [95% CI: 22.2%-31.0%])​. Primary cause of mortality was respiratory failure (88%); no patient had documented torsades de pointes. From Cox regression modeling, predictors of mortality were age>65 years (HR:2.6 [95% CI:1.9-3.3]), white race (HR:1.7 [95% CI:1.4-2.1]), CKD (HR:1.7 [95%CI:1.4-2.1]), reduced O2 saturation level on admission (HR:1.5 [95%CI:1.1-2.1]), and ventilator use during admission (HR: 2.2 [95%CI:1.4-3.3]). Hydroxychloroquine provided a 66% hazard ratio reduction, and hydroxychloroquine + azithromycin 71% compared to neither treatment (p < 0.001).

    Conclusions and Relevance
    In this multi-hospital assessment, when controlling for COVID-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in COVID-19 associated mortality. Prospective trials are needed to examine this impact.

  6. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 [published online ahead of print, 2020 Jul 23]. N Engl J Med. 2020;10.1056/NEJMoa2019014. doi:10.1056/NEJMoa2019014


    Background: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.

    Methods: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.

    Results: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.

    Conclusions: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; number, NCT04322123.).

  7. As professor of epidemiology at Yale School of Public Health, I have authored over 300 peer-reviewed publications and currently hold senior positions on the editorial boards of several leading journals. I am usually accustomed to advocating for positions within the mainstream of medicine, so have been flummoxed to find that, in the midst of a crisis, I am fighting for a treatment that the data fully support but which, for reasons having nothing to do with a correct understanding of the science, has been pushed to the sidelines. As a result, tens of thousands of patients with COVID-19 are dying unnecessarily. Fortunately, the situation can be reversed easily and quickly.

    I am referring, of course, to the medication hydroxychloroquine. When this inexpensive oral medication is given very early in the course of illness, before the virus has had time to multiply beyond control, it has shown to be highly effective, especially when given in combination with the antibiotics azithromycin or doxycycline and the nutritional supplement zinc.

    On May 27, I published an article in the American Journal of Epidemiology (AJE) entitled, "Early Outpatient Treatment of Symptomatic, High-Risk COVID-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis." That article, published in the world's leading epidemiology journal, analyzed five studies, demonstrating clear-cut and significant benefits to treated patients, plus other very large studies that showed the medication safety.

    Physicians who have been using these medications in the face of widespread skepticism have been truly heroic. They have done what the science shows is best for their patients, often at great personal risk. I myself know of two doctors who have saved the lives of hundreds of patients with these medications, but are now fighting state medical boards to save their licenses and reputations. The cases against them are completely without scientific merit.

    Since publication of my May 27 article, seven more studies have demonstrated similar benefit. In a lengthy follow-up letter, also published by AJE, I discuss these seven studies and renew my call for the immediate early use of hydroxychloroquine in high-risk patients. These seven studies include: an additional 400 high-risk patients treated by Dr. Vladimir Zelenko, with zero deaths; four studies totaling almost 500 high-risk patients treated in nursing homes and clinics across the U.S., with no deaths; a controlled trial of more than 700 high-risk patients in Brazil, with significantly reduced risk of hospitalization and two deaths among 334 patients treated with hydroxychloroquine; and another study of 398 matched patients in France, also with significantly reduced hospitalization risk. Since my letter was published, even more doctors have reported to me their completely successful use.

    Yes, I know that another Yale professor is saying that HCQ can save lives.

    And to those of you who have pointed out that he is a full professor while I am a mere associate professor, you really know how to hurt a guy. I have no idea why he wrote that article and didn't mention any of the randomized trials. But I embrace the academic freedom that he and I both have to present our best interpretation of the data.

    Science is ever-learning, ever-developing. More trials will come out and we need to integrate those results into these results to make decisions. We need to let new, high-quality evidence change our beliefs. I am willing to do that. I hope that you are too. But I want randomized trials. Because — if I didn't say it enough — randomization ensures that the treatment and control groups are well balanced, and that makes all the difference.

  8. A new meta-analysis of published studies into the drug hydroxychloroquine shows that it does not lower mortality in COVID-19 patients, and using it combined with the antibiotic azithromycin is associated with a 27% increased mortality. The study is published in Clinical Microbiology and Infection, the official journal of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).

    “This meta-analysis shows that hydroxychloroquine alone is not effective for the treatment of COVID-19 patients and that the combination of hydroxychloroquine and azithromycin increases the risk of mortality,” say the authors who include Thibault Fiolet, Center for Research in Epidemiology and Population Health, INSERM, Institut Gustave Roussy and Paris-Sud 11 University/Paris-Saclay University, Paris, France. “These data support current clinical recommendations such as those of the US National Institutes of Health (NIH) which do not recommend the use of hydroxychloroquine alone or in combination with azithromycin for COVID-19 patients.”

    Chloroquine is used to prevent and treat malaria, while hydroxychloroquine is a less toxic metabolite of chloroquine and is used to treat rheumatic diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and Sjogren’s syndrome. Hydroxychloroquine in particular has received extensive media coverage since the outbreak of the SARS-CoV-2 pandemic as a potential treatment for COVID-19. Azithromycin is used to treat a wide range of bacterial infections, but has also been promoted as a potential treatment for COVID-19 due to its alleged antiviral or anti-inflammatory properties.

    In this new analysis, the authors searched for studies that assessed chloroquine or hydroxychloroquine with or without the antibiotic azithromycin. The authors found 29 articles that met their criteria, all except one of which were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with or without azithromycin.

    Among the 29 articles, 3 were randomized controlled trials, one was a non-randomized trial and 25 were observational studies, including 11 with a ‘critical’ risk of bias and 14 with a ‘serious or moderate’ risk of bias*. After excluding studies with a critical risk of bias, the meta-analysis included 11,932 patients in the hydroxychloroquine group, 8,081 in the hydroxychloroquine with azithromycin group and 12,930 in the control group (who received neither drug).

    The results showed that hydroxychloroquine was not associated with mortality, either in all trials combined, or in separate analyses of randomized controlled trials or observational studies. The relative risk of death for use of hydroxychloroquine was 17% lower than controls for all studies combined, but 9% higher in randomized controlled trials. In both cases, these results were not statistically significant. (continued)

  9. (continued)However, the combination of hydroxychloroquine and azithromycin in patients with COVID-19 was associated with a statistically significant 27% increase in mortality compared with controls. The authors say: “These results confirm the preliminary findings of several observational studies which have shown that the combination of hydroxychloroquine and azithromycin might increase the risk of acute, life-threatening cardiovascular events.”

    The authors discuss limitations of their work which include the differing levels of COVID-19 disease severity across patients and also the actual definition of severity. Furthermore, most of the studies included were observational studies (not designed to find a causal relationship). Finally, this meta-analysis did not include results from the European DisCoVeRy trial and the WHO Solidarity trial that are not yet published or communicated (but both have already discontinued their hydroxychloroquine arms).

    The authors conclude: “There is already a great number of studies that have evaluated hydroxychloroquine alone or in combination and it seems unlikely at this stage that any efficacy will ever emerge. Our results suggest that there is no need for further studies evaluating these molecules, and the European DisCoveRy and WHO international Solidarity clinical trials have already discontinued treatment arms using hydroxychloroquine.”

  10. On April 30, OANN reported that Dr. Vladimir Zelenko is among a group of doctors nominated for the Nobel Peace Prize for adopting hydroxychloroquine (HCQ) treatment for the Chinese Communist Party virus (Covid-19).

    Since last year, Dr. Zelenko is one of the first medical doctors to recommend a cocktail treatment involving both HCQ and Zinc. The two chemicals are indispensable because they enhance each other’s antiviral properties. According to Dr. Zelenko, HCQ brings Zinc ions into cells so that Zinc can attack the virus.

    Dr. Zelenko said he doesn’t think much of the award, but it gives credibility to the message that there are effective prophylactics or early treatment for the CCP virus. Since March last year, Dr. Zelenko has been one of the first doctors to treat the CCP virus successfully in an outpatient setting. In fact, he will publish an upcoming research article discussing that early HCQ treatment reduces hospitalization and death by 84% among the high-risk population. And other studies reproduced similar results.

    When asked to comment on the current administration’s handling of the pandemic, Dr. Zelenko suggested that we shouldn’t give in to fears, because effective treatment is available, including over-the-counter drugs. There are two risk factors: “one is the state you live in, and two is the doctor you choose.” A patient’s survival depends on whether his doctor chooses effective medicine. Dr. Zelenko said, “You don’t need to fear this if you can get good care.”

    Dr. Zelenko finished his undergraduate studies at Hofstra University. He later attended S.U.N.Y at Buffalo School of Medicine. After having completed his hospital residency, he has been a family medicine physician in New York’s Hudson Valley since 2004.

    He graduated summa cum laude with a B.A. degree with high honors in Chemistry from Hofstra University. After receiving an academic scholarship to attend S.U.N.Y. at Buffalo School of Medicine, he earned his M.D. degree in May 2000. Dr. Zelenko completed his family medicine residency at South Nassau Communities Hospital in Oceanside, N.Y. in May 2004. Since then, Dr. Zelenko has practiced family medicine in New York’s Hudson Valley. He has been described by his patients as like a family member to thousands of families, and is a medical adviser to the volunteer ambulance corps in Kiryas Joel, New York.

  11. Derwand R, Scholz M, Zelenko V. COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study. Int J Antimicrob Agents. 2020 Dec;56(6):106214. doi: 10.1016/j.ijantimicag.2020.106214. Epub 2020 Oct 26. PMID: 33122096; PMCID: PMC7587171.

    The aim of this study was to describe the outcomes of patients with coronavirus disease 2019 (COVID-19) in the outpatient setting after early treatment with zinc, low-dose hydroxychloroquine and azithromycin (triple therapy) dependent on risk stratification. This was a retrospective case series study in the general practice setting. A total of 141 COVID-19 patients with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the year 2020 were included. The main outcome measures were risk-stratified treatment decision and rates of hospitalisation and all-cause death. A median of 4 days [interquartile range (IQR) 3-6 days; available for n = 66/141 patients] after the onset of symptoms, 141 patients (median age 58 years, IQR 40-67 years; 73.0% male) received a prescription for triple therapy for 5 days. Independent public reference data from 377 confirmed COVID-19 patients in the same community were used as untreated controls. Of 141 treated patients, 4 (2.8%) were hospitalised, which was significantly fewer (P < 0.001) compared with 58 (15.4%) of 377 untreated patients [odds ratio (OR) = 0.16, 95% confidence interval (CI) 0.06-0.5]. One patient (0.7%) in the treatment group died versus 13 patients (3.4%) in the untreated group (OR = 0.2, 95% CI 0.03-1.5; P = 0.12). No cardiac side effects were observed. Risk stratification-based treatment of COVID-19 outpatients as early as possible after symptom onset using triple therapy, including the combination of zinc with low-dose hydroxychloroquine, was associated with significantly fewer hospitalisations.

  12. McCullough PA, Alexander PE, Armstrong R, Arvinte C, Bain AF, Bartlett RP, Berkowitz RL, Berry AC, Borody TJ, Brewer JH, Brufsky AM, Clarke T, Derwand R, Eck A, Eck J, Eisner RA, Fareed GC, Farella A, Fonseca SNS, Geyer CE Jr, Gonnering RS, Graves KE, Gross KBV, Hazan S, Held KS, Hight HT, Immanuel S, Jacobs MM, Ladapo JA, Lee LH, Littell J, Lozano I, Mangat HS, Marble B, McKinnon JE, Merritt LD, Orient JM, Oskoui R, Pompan DC, Procter BC, Prodromos C, Rajter JC, Rajter JJ, Ram CVS, Rios SS, Risch HA, Robb MJA, Rutherford M, Scholz M, Singleton MM, Tumlin JA, Tyson BM, Urso RG, Victory K, Vliet EL, Wax CM, Wolkoff AG, Wooll V, Zelenko V. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Rev Cardiovasc Med. 2020 Dec 30;21(4):517-530. doi: 10.31083/j.rcm.2020.04.264. PMID: 33387997.

    The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.