Oran and Topol reply to Cevik, Bogoch, Carson et al.
Creators: name: Oran, Daniel P.
name: Topol, Eric J.
Publisher: name: Zenodo
Year: 2020

description: <strong>Oran and Topol reply to Cevik, Bogoch, Carson et al.</strong> We would like to re-emphasize the points made in the opening paragraphs of our review: Most data from the 16 cohorts in this narrative review are not the output of large, carefully designed studies with randomly selected, representative samples. They do not generally purport to depict anything more than certain circumscribed cohorts at specific moments in time. We have not attempted to pool them for the purposes of statistical analysis. When viewed as a collection, though—as a kind of mosaic or patchwork—these data may offer potentially valuable insights into SARS-CoV-2 incidence and the highly variable effect of infection. The difficulty of distinguishing asymptomatic persons from those who are merely presymptomatic is a stumbling block. To be clear, the asymptomatic individual is infected with SARS-CoV-2 but will never develop symptoms of COVID-19. In contrast, the presymptomatic individual is similarly infected but eventually will develop symptoms. The simple solution to this conundrum is longitudinal testing—that is, repeated observations of the individual over time. Unfortunately, only 5 of our cohorts include longitudinal data. We must therefore acknowledge the possibility that some of the proportions of asymptomatic persons are lower than reported. So we are puzzled by your critique. We clearly state that most of these studies are cross-sectional in nature, taking care to label in our table the minority of longitudinal studies. We clearly explain the ambiguity surrounding asymptomatic versus presymptomatic status. As for your contention that “recent studies assessing longitudinal characteristics of viral load and transmission have found truly asymptomatic patients have significantly lower viral loads than those who develop symptoms and transmit to fewer secondary cases,” it has been reported [1] that at least four other studies [2,3,4,5] found “the presence of SARS-CoV-2 RNA with lower Ct values in samples collected from persons in whom symptoms of COVID-19 never developed.” The authors note that “lower [Ct] values indicate higher viral load and imply higher infectiousness.” [1] In our opinion, the unpublished “systematic review” preprint that you refer to, which appeared after our article was published and has not been subject to peer review, fails to adequately address the compelling data that it includes (as did we) from Vo, Italy. Not only is that a unique, large representative sample with longitudinal assessment, but its findings are supported by other cohorts that we included. In the study, completed over 14 days, the researchers concluded that the proportion of asymptomatic individuals was 43%. In addition, none of the subjects who were asymptomatic at the beginning of the study had developed symptoms by the end. In the midst of a global pandemic, we believed that it would be valuable to collect all the currently available data on an ill-defined phenotype and address an important issue: whether a sizable proportion of those infected with SARS-CoV-2 will have no symptoms. As of late May 2020, when we completed our review, which was just five months after the appearance of the first cases of COVID-19, much of that data was in rough and fragmentary form. We think that we faithfully and accurately reported what we found. Journalism has been described as a first draft of history. In a similar way, our narrative review, which has collected the earliest available evidence, is a first draft of science. In the months and years ahead, new evidence — ideally, from well-designed, large-scale studies with representative samples — will appear, adding greater detail and clarity to our knowledge. We share your perspective that significant gaps remain in what we know about crucial aspects of COVID-19, including the details and frequency of SARS-CoV-2 transmission by infected individuals who have no symptoms, and the harm to the lungs and possibly other parts of the body that might be associated with asymptomatic infection. We are unaware of any other pathogen that can cause asymptomatic infection in a significant minority of patients (whether that is 20% or 40%) and also have lethality potential. A larger question that remains is the extent to which asymptomatic individuals can infect others, which has not yet been determined. We look forward to collaborating with all interested investigators to pursue that important objective. Daniel P. Oran and Eric J. Topol June 10, 2020 REFERENCES [1] Furukawa NW, Brooks JT, Sobel J. Evidence supporting transmission of severe acute respiratory syndrome coronavirus 2 while presymptomatic or asymptomatic. Emerg Infect Dis. 2020 Jul. [2] Hoehl S, Rabenau H, Berger A, Kortenbusch M, Cinatl J, Bojkova D, et al. Evidence of SARS-CoV-2 infection in returning travelers from Wuhan, China. N Engl J Med. 2020;382:1278–80. [3] Kam KQ, Yung CF, Cui L, Lin Tzer Pin R, Mak TM, Maiwald M, et al. A well infant with coronavirus disease 2019 with high viral load. Clin Infect Dis. 2020;ciaa201; Epub ahead of print. [4] Le TQM, Takemura T, Moi ML, Nabeshima T, Nguyen LKH, Hoang VMP, et al. Severe acute respiratory syndrome coronavirus 2 shedding by travelers, Vietnam, 2020. Emerg Infect Dis. 2020;26. [5] Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper respiratory specimens of infected patients. N Engl J Med. 2020;382:1177–9.