RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
The search of prognostic factors for the SARS-CoV-2 infection is still open, and several surveys in the whole world have examined various elements.
The work by El Zein et al.  proposes an analysis of the initial SARS-CoV-2 viral load-measured as cycle threshold (Ct) - as a factor which correlates which the number of death in Detroit, Michigan, during the first wave of the epidemic. The authors observed that between April 4 and June 5, 2020 there was a declining trend in the Ct of RT-PCR specific for SARS-CoV-2 and that this phenomenon correlated with a decrease in mortality of hospitalized patients.
An unexplained phenomenon, which must be further analyzed, is that the infected and hospitalized subjects in Detroit were already decreasing when the rest of the United States, and possibly in the world, still presented a rampant number of cases with COVID-19. Apart from this epidemiological observation, the study is well conducted and illustrates in convincing manner the relationship between being dead or alive and a different range in Ct values. A further data that could be analyzed is the number of death among all 3 categories of hospitalized subjects with high, intermediate, and low viral load.
A recent review and meta-analysis on viral load dynamics, viral shedding and infectiousness of new Coronaviruses  points out the positive correlation with Ct values and age and the evidence of the highest viral load values in the upper respiratory tract during the first week of illness, which could possibly correlate with an higher infectivity and mortality in hospitalized patients.
Other than the quantitative analysis of the viral replication, another factor which could determine a different burden of infectivity is the genotypic variation on viral proteins. Authors from Houston, Texas, have reported a Gly614 amino acid substitution in the spike protein in the majority of local cases during the second wave of the SARS-CoV-2 pandemic . This amino acid change has been linked with higher viral loads in the nasopharynx at the initial diagnosis, thus potentially associated with an higher transmission and infectivity.
The essential issue when considering viral burden, morbidity and mortality is how to put in place other pivotal information, such as clinical (i.e. course of illness, duration of illness, and co-morbidities) and demographic questions, as acknowledged by El Zein and colleagues. In a recent retrospective analysis on the 30-day mortality in the Infectious Diseases and Intensive Care units at Luigi Sacco Hospital, University of Milan, Italy , we found that older age and obesity were independently associated with an increased risk of 30-day death, which was also associated with critical disease, higher C-reactive protein levels and creatinine kinase levels above 185 U/L upon admission.
Our results, among others, underline a combined value of clinical and virological assessments and molecular biology evaluations to determine and analyze the course of COVID-19 diseases. The challenge remains to condensate all these data in a useful tool for Infectious Diseases physicians who are still in the front-line for fighting this awful pandemic.
References 1. El Zein S, El-Hor N, Chehab O, Alkassis S, Mishra T, Trivedi V, Salimnia H, Chandrasekar P. Declining Trend in the Initial SARS-CoV-2 Viral Load During the Pandemic: Preliminary Observations from Detroit, Michigan. doi: https://doi.org/10.1101/2020.11.16.20231597.
2. Muge C, Tate M, Lloyd O, Maraolo AE, Schafers J, Ho A. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and metaanalysis. The Lancet Microbe 2020, doi.org/10.1016/S2666-5247(20)30172-5.
3. Long SW, Olsen RJ, Christensen PA, Bernard DW, Davis JJ, Shukla M, Nguyen M, Saavedra MO, Yerramilli P, Pruitt L, Subedi S, Kuo HC, Hendrickson H, Eskandari G, Nguyen HAT, Long JH, Kumaraswami M, Goike J, Boutz D, Gollihar J, McLellan JS, Chou CW, Javanmardi K, Finkelstein IJ, Musser JM. Molecular Architecture of Early Dissemination and Massive Second Wave of the SARSCoV-2 Virus in a Major Metropolitan Area mBio. 2020 Oct 30;11(6):e02707-20. doi: 10.1128/mBio.02707-20.
4. Giacomelli A, Ridolfo AL, Milazzo L, Oreni L, Bernacchia D, Siano M, Bonazzetti C, Covizzi A, Schiuma M, Passerini M, Piscaglia M, Coen M, Gubertini G, Rizzardini G, Cogliati C, Brambilla AM, Colombo R, Castelli A, Rech R, Riva A, Torre A, Meroni L, Rusconi S, Antinori S, Galli M. 30-day mortality in patients hospitalized with COVID-19 during the first wave of the Italian epidemic: A prospective cohort study. Pharmacol Res. 2020 Aug;158:104931. doi: 10.1016/j.phrs.2020.104931. Epub 2020 May 22.