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Early Outpatient Treatment of SARS-CoV-2 (COVID-19): A Comment

  • Tony M. Korman
    Correspondence
    Requests for reprints should be addressed to Tony M. Korman, MBBS, FRACP, FRACPA, Monash Infectious Diseases, 246 Clayton Rd, Clayton, Victoria, 3168, Australia.
    Affiliations
    Adjunct Clinical Professor, Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia

    Director, Monash Infectious Diseases, Director, Microbiology, Monash Pathology, Monash Health, Clayton Australia
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  • James H. McMahon
    Affiliations
    Head of Clinical Research Unit and Infectious Diseases Physician, Department of Infectious Diseases, The Alfred and Central Clinical School, Monash University, Melbourne, Australia

    Level 2, Burnet Institute, Melbourne, Australia

    Infectious Diseases Physician, Monash Infectious Diseases, Monash Health, Clayton, Australia
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      To the Editor:
      McCullough et al propose a treatment algorithm for early outpatient treatment of coronavirus disease 2019 (COVID-19), which is not supported by evidence.

      McCullough P, Kelly R, Ruocco G, et al. Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection. Am J Med. Accessed August 30, 2020. doi: https://dx.doi.org/10.1016/j.amjmed.2020.07.003

      Early intervention is desperately needed, but unfortunately, no effective treatment is available.

      Korman TM. Early outpatient treatment of symptomatic, high-risk COVID-19 patients [e-pub ahead of print]. Am J Epidemiol. Accessed August 30, 2020. doi: https://doi.org/10.1093/aje/kwaa154

      Neither zinc (Zn) nor doxycycline have demonstrated inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro or in animal or human studies. Favipiravir has antiviral activity against SARS-CoV-2 but does not have “proven” therapeutic efficacy in Ebola, Lassa fever, or rabies as claimed. Favipiravir should only be administered as part of clinical trials assessing efficacy and safety.
      The Randomized Evaluation of COVID-19 therapy (RECOVERY) trial proved that large clinical trials can be completed rapidly during a pandemic. Dexamethasone was associated with reduced mortality for patients receiving invasive mechanical ventilation or supplemental oxygen but not for patients receiving no respiratory support at randomization.

      The RECOVERY Collaboration Group. Dexamethasone in hospitalized patients with COVID-19 - preliminary report [e-pub ahead of print]. N Eng J Med. Accessed August 30, 2020. doi: https://doi.org/10.1056/NEJMoa2021436

      Possible efficacy of prednisone in early disease is unproven speculation that cannot be recommended without further study.
      McCullough et al recommended “antivirals” hydroxychloroquine (HCQ) and azithromycin (AZ) “immediately” for high-risk patients, but HCQ did not show antiviral activity in human airway epithelium, and neither HCQ nor HCQ with AZ showed a significant effect on SARS-CoV-2 viral load in macaques.
      • Maisonnasse P
      • Guedj J
      • Contreras V
      • et al.
      Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates.
      In a meta-analysis (total participants n = 32,943), HCQ was not associated with reduced mortality in hospitalized patients, but HCQ with AZ significantly increased mortality.

      Fiolet T, Guihur A, Rebeaud M, et al. Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis [e-pub ahead of print]. Clin Microbiol Infect. Accessed August 30, 2020. doi: https://dx.doi.org/10.1016/j.cmi.2020.08.022

      Observational studies in which HCQ with or without AZ was associated with reduced mortality include important confounders (concomitant corticosteroid use in the HCQ group, more than double the nontreated group).
      • Lee T
      • MacKenzie L
      • McDonald E
      • et al.
      An observational cohort study of hydroxychloroquine and azithromycin for COVID-19: (can't get no) satisfaction.
      Early treatment of outpatients with mild disease with HCQ with or without AZ has not demonstrated clinical or virological benefit, and no significant reduction of risk of hospitalization.

      Fox MP, D'Agostino McGowan L, James BD, et al. Concerns about the special article on hydroxychloroquine and azithromycin in high risk outpatients with COVID-19 by Dr. Harvey Risch [e-pub ahead of print]. Am J Epidemiol. Accessed August 30, 2020. doi: https://doi.org/10.1093/aje/kwaa189

      Facing mounting contrary evidence, the proponents of HCQ with AZ resemble the deluded Black Knight from Monty Python and the Holy Grail whose limbs are progressively cut off but continues to confidently proclaim triumph in the battle.

      References

      1. McCullough P, Kelly R, Ruocco G, et al. Pathophysiological basis and rationale for early outpatient treatment of SARS-CoV-2 (COVID-19) infection. Am J Med. Accessed August 30, 2020. doi: https://dx.doi.org/10.1016/j.amjmed.2020.07.003

      2. Korman TM. Early outpatient treatment of symptomatic, high-risk COVID-19 patients [e-pub ahead of print]. Am J Epidemiol. Accessed August 30, 2020. doi: https://doi.org/10.1093/aje/kwaa154

      3. The RECOVERY Collaboration Group. Dexamethasone in hospitalized patients with COVID-19 - preliminary report [e-pub ahead of print]. N Eng J Med. Accessed August 30, 2020. doi: https://doi.org/10.1056/NEJMoa2021436

        • Maisonnasse P
        • Guedj J
        • Contreras V
        • et al.
        Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates.
        Nature. 2020; : 584-587
      4. Fiolet T, Guihur A, Rebeaud M, et al. Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis [e-pub ahead of print]. Clin Microbiol Infect. Accessed August 30, 2020. doi: https://dx.doi.org/10.1016/j.cmi.2020.08.022

        • Lee T
        • MacKenzie L
        • McDonald E
        • et al.
        An observational cohort study of hydroxychloroquine and azithromycin for COVID-19: (can't get no) satisfaction.
        Int J Infect Dis. 2020; 98: 216-217
      5. Fox MP, D'Agostino McGowan L, James BD, et al. Concerns about the special article on hydroxychloroquine and azithromycin in high risk outpatients with COVID-19 by Dr. Harvey Risch [e-pub ahead of print]. Am J Epidemiol. Accessed August 30, 2020. doi: https://doi.org/10.1093/aje/kwaa189

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      • The Reply
        The American Journal of MedicineVol. 134Issue 3
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          We recognize the attempts by Korman and McMahon to appraise and dismiss evidence with respect to individual medical therapies as the human suffering, hospitalizations, and deaths continue to mount in the coronavirus disease 2019 (COVID-19) pandemic. In an emergency response to the COVID worldwide pandemic, we believe it is more prudent to act now based on clinical judgment with the early use of therapies based on the pathophysiology of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness as disclosed.
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