Early Outpatient Treatment of Symptomatic, High-risk COVID-19 Patients That Should Be Ramped Up Immediately as Key to the Pandemic Crisis

Harvey A. Risch


Am J Epidemiol. 2020;189(11):1218-1226. 

In This Article

Abstract and Introduction


More than 1.6 million Americans have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than 10 times that number carry antibodies to it. High-risk patients with progressing symptomatic disease currently have only hospitalization treatment, with its high mortality, available to them. An outpatient treatment that prevents hospitalization is desperately needed. Two candidate medications have been widely discussed: remdesivir and hydroxychloroquine (HCQ) + azithromycin (AZ). Remdesivir has shown mild effectiveness in hospitalized inpatients, but no trials in outpatients have been registered. HCQ + AZ has been widely misrepresented in both clinical reports and public media, and results of outpatient trials are not expected until September. Early outpatient illness is very different from later florid disease requiring hospitalization, and the treatments differ. Evidence about use of HCQ alone, or of HCQ + AZ in inpatients, is irrelevant with regard to the efficacy of HCQ + AZ in early high-risk outpatient disease. Five studies, including 2 controlled clinical trials, have demonstrated significant major outpatient treatment efficacy. HCQ + AZ has been used as the standard of care in more than 300,000 older adults with multiple comorbid conditions; the estimated proportion of such patients diagnosed with cardiac arrhythmia attributable to the medications is 47 per 100,000 users, among whom estimated mortality is less than 20% (9/100,000 users), as compared with the 10,000 Americans now dying each week. These medications need to be made widely available and promoted immediately for physicians to prescribe.


Aside from the now more than 1.6 million Americans found through testing and public-health reporting to be infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), seropositivity studies in California,[1,2] Colorado,[3] and New York City and State[4] suggest that some 10- to 50-fold larger numbers of people carry antibodies to the virus. The workforce and effort required to carry out contact tracing on these tens of millions of Americans is not practical. While these studies have generated some media criticism, recent similar studies of blood donor samples in the Netherlands found 3% with SARS-CoV-2 antibodies,[5] and 5% of household volunteers in Spain were found to have antibodies.[6] Even allowing for some degree of false-positivity of these antibody tests, they still indicate that appreciably larger fractions of the population have been infected than have been characterized by identified reported cases. "Flattening the curve" by means of social distancing, mask-wearing, and staying at home serves to reduce hospital loads and spread them out over time, but to date it has pushed the infection reproduction number at time t (Rt ) down only to about 1.0;[7] thus, even if maintained, over time very large numbers of people in the United States may eventually get the infection. The great majority of infected people are at low risk for progression or will manifest the infection asymptomatically. For the rest, outpatient treatment that prevents disease progression and hospitalization is required. Exposures will occur as isolation policies are lifted and people begin to mix, even with various degrees of public isolation such as mask usage and physical separation still in place. Thus, the key to returning society toward normal functioning and to preventing huge loss of life, especially among older individuals, people with comorbidity, and African Americans and Hispanics/Latinos, is a safe, effective, and proactive outpatient treatment that prevents hospitalization in the first place.

All medical treatments have costs and benefits. In an ideal world, randomized double-blinded controlled clinical trials establish evidence for the relative degree of benefit, and if they are large enough, for estimates of the frequencies of adverse events. These trials take time to conduct: to get formal approval, to get funding, to enroll enough eligible patients, to wait for the outcomes to occur, and to analyze the data. In the context of the coronavirus disease 2019 (COVID-19) pandemic, we are presently averaging about 10,000 deaths per week in the United States, under moderately strong isolation policies that have put more than 36 million people out of work. Results of currently ongoing or planned randomized trials for use of a number of outpatient medications are many weeks or months off, and there are no guarantees that the results for these agents, even if statistically significant, will show sufficient magnitudes of effectiveness to be useful clinically. We are rapidly reaching a breaking point in the ability to maintain the status quo; states have begun the process of lifting their restrictions, and we thus need to evaluate what evidence we do have for promising outpatient treatments.