Approximately 9 months of the SARS-CoV-2 virus spreading across the globe has led to widespread COVID-19 acute hospitalizations and death. The rapidity and highly communicable nature of the SARS-CoV-2 outbreak has hampered the design and execution of definitive randomized, controlled trials of therapy outside of the clinic or hospital. In the absence of clinical trial results, physicians must use what has been learned about the pathophysiology of SARS-CoV-2 infection in determining early outpatient treatment of the illness with the aim of preventing hospitalization or death. This paper outlines key pathophysiological principles that relate to the patient with early infection treated at home. Therapeutic approaches based on these principles include: 1) reduction of reinoculation, 2) combination antiviral therapy, 3) immunomodulation, 4) antiplatelet/antithrombotic therapy 5) administration of oxygen, monitoring, and telemedicine. Future randomized trials testing the principles and agents discussed in this paper will undoubtedly refine and clarify their individual roles, however we emphasize the immediate need for management guidance in the setting of widespread hospital resource consumption, morbidity, and mortality.
Most patients who arrive to the hospital by emergency medical services with COVID-19 do not initially require forms of advanced medical care.
Once hospitalized, ∼25% require mechanical ventilation, advanced circulatory support, or renal replacement therapy. Hence, it is conceivable that some if not a majority of hospitalizations could be avoided with a treat-at-home first approach with appropriate telemedicine monitoring and access to oxygen and therapeutics.
Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 18 March 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6912e2
One could argue the results of definitive trials were needed at the outset of the pandemic, and certainly are needed now with over 1 million cases and 500,000 deaths worldwide. Because COVID-19 is highly communicable, many ambulatory clinics do not care for patients in face-to-face visits and these patients are commonly declined by pharmacies, laboratories, and imaging centers. On May 14, 2020, after about 1 million cases and 90,000 deaths in the US had already occurred, the National Institutes of Health announced it was launching an outpatient trial of hydroxychloroquine (HCQ) and azithromycin in COVID-19. A month later the agency announced it was closing the trial due to lack of enrollment with only 20 of 2000 patients recruited. No safety concerns were associated with the trial. This effort serves as the best current working example of the lack of feasibility of outpatient trials for COVID-19. It is also a strong signal that future ambulatory trial results are not imminent or likely to report soon enough to have a significant public health impact on clinical outcomes.
It is beyond the scope of this paper to review every preclinical and retrospective study of proposed COVID-19 therapy. Hence the agents proposed are those that have appreciable clinical support and are feasible for administration in the ambulatory setting. SARS-CoV-2 as with many infections, may be amenable to therapy early in its course but is probably not responsive to the same treatments very late in the hospitalized and terminal stages of illness.
Control of Contagion
Many sources of information suggest the main place of viral transmission occurs in the home.
Facial covering for all contacts within the home as well as frequent use of hand sanitizer and hand washing is mandatory. Sterilizing surfaces such as countertops, door handles, phones, and other devices is advised. When possible, other close contacts can move out of the domicile and temporary stay with others not ill with SARS-CoV-2. Findings from multiple studies indicate that policies concerning control of the spread SARS-CoV-2 are effective and extension into the home as the most frequent site of viral transfer is paramount.
Reduction of Self-Reinoculation
In hospitalized patients, negative pressure is applied to the room air largely to reduce spread outside of the room. We propose that fresh air could reduce reinoculation and potentially reduce the severity of illness and possibly reduce household spread during quarantine. This calls for open windows, fans for aeration, or spending long periods of time outdoors away from others with no face covering in order to disperse and not re-inhale the viral bioaerosol.
Combination Antiviral Therapy
Additionally, secondary processes that depend on viral stimulation including activation of inflammatory cells, cytokines, and coagulation could potentially be lessened if viral replication is attenuated. Because no form of readily available medication has been designed specifically to inhibit SARS-CoV-2 replication, two or more of the nonspecific agents listed below can be entertained. None of the approaches listed below have specific regulatory approved advertising labels for their manufacturers, thus all would be appropriately considered acceptable “off-label” use.
Zinc Lozenges and Zinc Sulfate
By extension, this readily available nontoxic therapy could be deployed at the first signs of COVID-19.
Zinc lozenges can be administered five times a day for up to five days and extended if needed if symptoms persist. The amount of elemental zinc lozenges is
The currently completed retrospective studies and randomized trials have generally shown these findings: 1) when started late in the hospital course and for short durations of time, antimalarials appear to be ineffective, 2) when started earlier in the hospital course, for progressively longer durations and in outpatients, antimalarials may reduce the progression of disease, prevent hospitalization, and are associated with reduced mortality.
In a retrospective inpatient study of 2541 patients hospitalized with COVID-19, therapy associated with an adjusted reduction in mortality was HCQ alone, HR=0.34 (95% CI 0.25-0.46), p HCQ was approved by the U.S. Food and Drug Administration in 1955, has been used by hundreds of millions of people worldwide since then, is sold over the counter in many countries and has a well characterized safety profile that should not raise undue alarm.
, While asymptomatic QT prolongation is a well-recognized and infrequent (
It has been commonly utilized in COVID-19 studies initially based upon a French reports demonstrating markedly reduced durations of viral shedding, fewer hospitalizations, and reduced mortality combination with HCQ as compared to those untreated.
In the large inpatient study (n=2451) discussed above, those who received azithromycin alone had an adjusted hazard ratio for mortality of 1.05, 95% CI 0.68-1.62, p=0.83. The combination of HCQ and azithromycin has been used as standard-of-care in other contexts as a standard of care in more than 300,000 older adults with multiple comorbidities.
This agent is well tolerated and like HCQ can prolong the QTc in
The same safety precautions for HCQ listed above could be extended to azithromycin with or without HCQ. Because both HCQ and AZ have small but potentially additive risks of QTc prolongation, patients with known or suspected arrhythmias or taking contraindicated medications or should have more thorough workup (review of baseline electrocardiogram, imaging studies, etc) before receiving these two together. One of many dosing schemes is 250 mg po bid for 5 days and may extend to 30 days for persistent symptoms or evidence of bacterial superinfection.
This drug has no effect on cardiac conduction and has the main caveat of gastrointestinal upset and esophagitis. As with azithromycin, doxycycline has the advantage of offering antibacterial coverage for superimposed bacterial infection in the upper respiratory tract. Doxycycline has a high degree of activity against many common respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, anaerobes such as Bacteroides and anaerobic/microaerophilic streptococci and atypical agents like Legionella, Mycoplasma pneumoniae, and Chlamydia pneumoniae.
One of many dosing schemes is 200 mg po followed by 100 mg po bid for 5 days and may extend to 30 days for persistent symptoms or evidence of bacterial superinfection. Doxycycline may be useful with HCQ for patients in whom the HCQ-AZ combination is not desired.
It has been previously used for treatment of some life-threatening infections such as Ebola virus, Lassa virus and rabies. Its therapeutic efficacy has been proven in these diseases.
Like, the antimalarials and antibiotics, favipiravir has no large-scale randomized trials completed at this time, given the short time frame of the pandemic. A dose administration could be 1600 mg po bid on day 1, following by 600 mg po bid for 14 days.
As with any acute inflammatory state, early treatment with immunomodulators is expected to impart greater benefit. In COVID-19, some of the first respiratory findings are nasal congestion, cough, and wheezing. These features are due to excess inflammation and cytokine activation. Early use of corticosteroids is a rational intervention for COVID-19 patients with these features as they would be in acute asthma or reactive airways disease.
The RECOVERY trial randomized 6425 hospitalized patients with COVID-19 in a 2:1 ratio to dexamethasone 6 mg po/IV qd for up to 10 days and found dexamethasone reduced mortality, HR=0.65, 95% CI 0.51-0.82, p One potential dosing scheme for outpatients starting on day five or the onset of respiratory symptoms is prednisone 1 mg/kg given daily for five days with or without a subsequent taper.
The clinical primary end point (2-point change in World Health Organization ordinal scale) occurred in 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Because the short-term safety profile is well understood, it is reasonable to consider this agent along with corticosteroids in an attempt to reduce the effects of cytokine storm. A dosing scheme of 1.2 mg po, followed by 0.6 mg po bid for three weeks can be considered.
Antiplatelet Agents and Antithrombotics
COVID-19 patients have described chest heaviness associated with desaturation that suggests the possibility of pulmonary thrombosis.
Multiple reports have described elevated D-dimer levels in acutely ill COVID-19 patients which has been consistently associated with increased risk of deep venous thrombosis and pulmonary embolism.
Necropsy studies have described pulmonary microthrombosis in COVID-19.
These observations support the notion that endothelial injury and thrombosis are playing a role oxygen desaturation, a cardinal reason for hospitalization and supportive care.
Based on this pathophysiologic rationale, aspirin 81 mg per day can be administered as an initial antiplatelet and anti-inflammatory agent.
Ambulatory patients can be additionally treated with subcutaneous low-molecular weight heparin or with short-acting novel anticoagulant drugs in dosing schemes similar to those use in outpatient thromboprophylaxis. In a retrospective study of 2773 COVID-19 inpatients, 28% received anticoagulant therapy within 2 days of admission, and despite being used in more severe cases, anticoagulant administration was associated with a reduction in mortality, HR =0.86 per day of therapy, 95% CI: 0.82-0.89; p
Many acutely ill outpatients also have general indications for VTE prophylaxis applicable to COVID-19.
Delivery of Oxygen and Monitoring
Many of the measures discussed in this paper could be extended to seniors in COVID-19 treatment units in nursing homes and other non-hospital settings. This would leave the purposes of hospitalization being administration of intravenous fluid and parenteral medication, assisted pressure or mechanical ventilation, and advanced mechanical circulatory support.
Acute COVID-19 has a great range of clinical severity from asymptomatic to fatal. In the absence of clinical trials and guidelines, with hospitalizations and mortality mounting, it is prudent to deploy treatment for COVID-19 based upon pathophysiological principles. We have proposed an algorithm based on age and comorbidities that allows for a large proportion to be monitored and treated at home during self-isolation with the aim of reducing the risks of hospitalization and death.
Urgent need for individual mobile phone and institutional reporting of at home, hospitalized, and intensive care unit cases of SARS-CoV-2 (COVID-19) infection.
Rev Cardiovasc Med. 2020; 21: 1-7https://doi.org/10.31083/j.rcm.2020.01.42
Clinical Characteristics of Patients With Coronavirus Disease 2019 (COVID-19) Receiving Emergency Medical Services in King County, Washington.
JAMA Netw Open. 2020; 3 ()e2014549https://doi.org/10.1001/jamanetworkopen.2020.14549
Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
BMJ. 2020; 369 (): m1996https://doi.org/10.1136/bmj.m1996
Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 18 March 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6912e2
https://www.worldometers.info/coronavirus/accessed July 3, 2020
https://clinicaltrials.gov/ct2/who_tableaccessed July 3, 2020
Fulminant Acute Kidney Injury in a Young Patient with Novel Coronavirus 2019.
Cardiorenal Med. 2020; (): 1-6https://doi.org/10.1159/000508179
Prescription Fill Patterns for Commonly Used Drugs During the COVID-19 Pandemic in the United States.
JAMA. 2020; 323 (): 2524-2526https://doi.org/10.1001/jama.2020.9184
Quarantine alone or in combination with other public health measures to control COVID-19: a rapid review.
Cochrane Database Syst Rev. 2020; 4 ()CD013574https://doi.org/10.1002/14651858.CD013574
Reconstruction of Transmission Pairs for novel Coronavirus Disease 2019 (COVID-19) in mainland China: Estimation of Super-spreading Events, Serial Interval, and Hazard of Infection.
Clin Infect Dis. 2020; (): ciaa790https://doi.org/10.1093/cid/ciaa790
The effect of large-scale anti-contagion policies on the COVID-19 pandemic.
Nature. 2020; ()https://doi.org/10.1038/s41586-020-2404-8
Effects of ambient temperature and humidity on droplet lifetime – A perspective of exhalation sneeze droplets with COVID-19 virus transmission.
Int J Hyg Environ Health. 2020; 229 ()113568https://doi.org/10.1016/j.ijheh.2020.113568
COVID-19 therapeutic options for patients with kidney disease.
Kidney Int. 2020 Jun; 97 (): 1297-1298https://doi.org/10.1016/j.kint.2020.03.015
COVID-19 and off label use of drugs: an ethical viewpoint.
Daru. 2020; (): 1-5https://doi.org/10.1007/s40199-020-00351-y
Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial.
Ann Intern Med. 2000; 133: 245-252https://doi.org/10.7326/0003-4819-133-4-200008150-00006
Can Zn Be a Critical Element in COVID-19 Treatment?.
Biol Trace Elem Res. 2020; (): 1-9https://doi.org/10.1007/s12011-020-02194-9
https://docs.google.com/document/d/1pjgHlqI-ZuKOziN3txQsN5zz62v3K043pR3DdhEmcos/editaccessed July 3, 2020
Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture.
PLoS Pathog. 2010; 6 ()e1001176https://doi.org/10.1371/journal.ppat.1001176
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State.
JAMA. 2020 May 11; 323 (): 2493-2502https://doi.org/10.1001/jama.2020.8630
Arshad S et al, Treatment with Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized with COVID-19, Published:July 01, 2020DOI:https://doi.org/10.1016/j.ijid.2020.06.099
Risk Factors for Mortality in Patients with COVID-19 in New York City.
J Gen Intern Med. 2020; (): 1-10https://doi.org/10.1007/s11606-020-05983-z
Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.
Nat Rev Rheumatol. 2020; 16: 155-166https://doi.org/10.1038/s41584-020-0372-x
Macrolides and viral infections: focus on azithromycin in COVID-19 pathology.
Int J Antimicrobial Agents. June 2020; ()https://doi.org/10.1016/j.ijantimicag.2020.106053
Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis.
Travel Med Infect Dis. 2020; ()101791https://doi.org/10.1016/j.tmaid.2020.101791
Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France.
Travel Med Infect Dis. 2020; 35101738https://doi.org/10.1016/j.tmaid.2020.101738
Early Outpatient Treatment of Symptomatic, High-Risk Covid-19 Patients that Should be Ramped-Up Immediately as Key to the Pandemic Crisis.
Am J Epidemiol. 2020; (): kwaa093https://doi.org/10.1093/aje/kwaa093
Clinical failure with and without empiric atypical bacteria coverage in hospitalized adults with community-acquired pneumonia: a systematic review and meta-analysis.
BMC Infect Dis. 2017; 17 (): 385https://doi.org/10.1186/s12879-017-2495-5
Doxycycline as a potential partner of COVID-19 therapies.
IDCases. 2020; 21 (): e00864https://doi.org/10.1016/j.idcr.2020.e00864
Sodhi M, Etminan M. Therapeutic Potential for Tetracyclines in the Treatment of COVID-19 Pharmacotherapy2020;40(5):487–488 doi: 10.1002/phar.2395
Doxycycline Is a Cost-effective Therapy for Hospitalized Patients With Community-Acquired Pneumonia.
Arch Intern Med. 1999; 159: 266-270https://doi.org/10.1001/archinte.159.3.266
Favipiravir, an antiviral for COVID-19?.
J Antimicrob Chemother. 2020; 75: 2013-2014https://doi.org/10.1093/jac/dkaa171
A review of the safety of favipiravir – a potential treatment in the COVID-19 pandemic?.
J Virus Erad. 2020; 6 (): 45-51
The Mechanism and Clinical Outcome of patients with Corona Virus Disease 2019 Whose Nucleic Acid Test has changed from negative to positive, and the therapeutic efficacy of Favipiravir: A structured summary of a study protocol for a randomised controlled trial.
Trials. 2020; 21 (): 488https://doi.org/10.1186/s13063-020-04430-y
Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors.
Emerg Microbes Infect. 2020; 9: 1123-1130https://doi.org/10.1080/22221751.2020.1770129
Can steroids reverse the severe COVID-19 induced “cytokine storm”?.
J Med Virol. 2020; ()https://doi.org/10.1002/jmv.26165
Role of corticosteroid in the management of COVID-19: A systemic review and a Clinician’s perspective.
Diabetes Metab Syndr. 2020; 14 (): 971-978https://doi.org/10.1016/j.dsx.2020.06.054
Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.
JAMA Netw Open. 2020; 3 ()e2013136https://doi.org/10.1001/jamanetworkopen.2020.13136
World Health Organization R&D blueprint and COVID-19. Accessed March 25, 2020. https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus/en/
The evolution of pulmonary pathology in fatal COVID-19 disease: an autopsy study with clinical correlation.
Virchows Arch. 2020; (): 1-9https://doi.org/10.1007/s00428-020-02881-x
The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications.
Circ Res. 2020; ()https://doi.org/10.1161/CIRCRESAHA.120.317447
Clinico-Radiological Evaluation and Correlation of CT Chest Images with Progress of Disease in COVID-19 Patients.
J Assoc Physicians India. 2020; 68: 34-42
Pulmonary Embolism and Increased Levels of d-Dimer in Patients with Coronavirus Disease.
Emerg Infect Dis. 2020; 26 ()https://doi.org/10.3201/eid2610.202127
Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors.
J Thromb Thrombolysis. 2020; 50: 211-216https://doi.org/10.1007/s11239-020-02146-z
Incidence of pulmonary embolism in non-critically ill COVID-19 patients. Predicting factors for a challenging diagnosis.
J Thromb Thrombolysis. 2020; ()https://doi.org/10.1007/s11239-020-02190-9
Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.
N Engl J Med. 2020; ()https://doi.org/10.1056/NEJMoa2015432
Anticoagulation Options for Coronavirus Disease 2019 (COVID-19)-Induced Coagulopathy.
Cureus. 2020; 12 (): e8150https://doi.org/10.7759/cureus.8150
Antiviral activity of aspirin against RNA viruses of the respiratory tract-an in vitro study.
Influenza Other Respir Viruses. 2017; 11: 85-92https://doi.org/10.1111/irv.12421
Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.
J Thromb Haem. March 2020; https://doi.org/10.1111/jth.14817
Prevention, Diagnosis, and Treatment of VTE in Patients With COVID-19: CHEST Guideline and Expert Panel Report.
Chest. 2020; () ()https://doi.org/10.1016/j.chest.2020.05.559
A Transdisciplinary COVID-19 Early Respiratory Intervention Protocol: An Implementation Story.
J Hosp Med. 2020; 15: 372-374https://doi.org/10.12788/jhm.3456
In Press Journal Pre-Proof
Funding source(s): none related
Conflict of interest statement for all authors: nothing to disclose
All authors had access to the data and a role in writing the manuscript
© 2020 Published by Elsevier Inc.
For non-commercial purposes:
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article (private use only, not for distribution)
- Reuse portions or extracts from the article in other works
- Sell or re-use for commercial purposes
- Distribute translations or adaptations of the article