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Review 1: "Is Higher Viral Load in SARS-CoV-2 Associated With Death?"

This study is potentially informative but the results should be approached with caution. The claim that high viral load indicates higher mortality is not fully supported. Multiple confounding variables have not been taken into account.

Published onSep 03, 2020
Review 1: "Is Higher Viral Load in SARS-CoV-2 Associated With Death?"

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

This retrospective study by Faíco-Filho, et al. aimed to find associations between SARS-CoV-2 viral load [expressed as cycle threshold (Ct) values from a RT-PCR assay], disease severity and death. The authors used a one-time measurement, upon admission to hospital, in rhino-pharyngeal swabs from a relatively large number of symptomatic patients. The patients were roughly categorized as having mild (did not need hospitalization), moderate (hospitalized) or severe (hospitalized in ICU) disease.


Data in literature regarding the viral load and shedding kinetics between mild and severe COVID-19 and link to clinical outcomes, are conflicting. This study confirmed findings of others, that admission SARS-CoV-2 viral load among hospitalized patients with COVID-19 correlated with in-hospital mortality (Magleby et al., Clin Infect Dis 2020), however, it has several limitations and drawbacks.


Apart from the limitations recognized by the authors (“focus on virologic aspects and not including the effects of comorbidities, clinical symptoms, date of admission, date of sample collection, use of antivirals and antibiotics and duration of symptoms before testing”), several other confounders have not been taken into account in the analysis. For example, no adjustment has been made for age. As seen in Fig. 1, 43% of patients (n=374) belonged to age groups 15-44 years and had a Ct lower than 25. Also, patients in the age group 45-54 had a median Ct value of 25. As younger persons have usually milder symptoms for undefined yet reasons, this could at least partly explain the finding that patients with milder symptoms had higher viral loads (lower Ct values) than those with moderate symptoms. This finding could further be discussed and explained after a detailed analysis of the time of onset of symptoms and time of hospital visit or admission. As shown in Asian studies early on in the pandemic, it seems that viral load peaks during the pre-symptomatic stage of the disease and slowly declines to become undetectable by day 18 to 21 (He X, et al., Nat Med 2020). Therefore, higher viral loads are seen in mild disease rather than severe disease, as they reflect the time from onset of infection, as commented by Argyropoulos et al., (The American journal of pathology, 2020), who also found that viral loads were inversely correlated with disease severity. This is just to mention a couple of confounders in this complex issue.


Furthermore, the individual’s immune system, and how it reacts to this virus is another factor to impact morbidity, as studies have shown that over-reactive immune response to virus rather than virus titer itself is responsible for major morbidity (Ye Q et al., J Infect 2020). It has been shown in many studies that the immune reaction following SARS-COV-2 infection is complex and considered responsible for high morbidity and even death also among younger, previously healthy patients, with no apparent risk factors.
The authors of this preprint conclude that “admission SARS-CoV-2 viral load is an important surrogate biomarker of Infectivity”. This statement is not accurate, as: (a) the term “infectivity” is about transmission of the infection, which is not the subject of the study and (b) even if the authors mean “biomarker for disease severity, or morbidity” by this term, this is not accurate either, as patients with moderate disease had higher RT-PCR assay Ct values than patients with mild symptoms. In fact, this finding is the weak point of the study, and not only because it is poorly discussed in the preprint, but also for the reasons mentioned above.


In short, the conclusion that “the findings of this study suggest that Ct values can be used to assist clinicians to identify patients at a high risk for severe outcome”, is a strong statement and should be interpreted with caution. Viral load kinetics is a complex issue depending on multiple interacting factors, addressed in a rather simplistic way in this study, which seems rather incomplete.

References


1. Magleby R, Westblade LF, Trzebucki A, et al. Impact of SARS-CoV-2 Viral Load on Risk of Intubation and Mortality Among Hospitalized Patients with Coronavirus Disease 2019. Clin Infect Dis. 2020 Jun 30: ciaa851. doi: 10.1093/cid/ciaa851.
2. He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med 2020, 26:672e675.
3. Argyropoulos KV, Serrano A, Hu J, et al. Association of Initial Viral Load in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Patients with Outcome and Symptoms. Am J Pathol. 2020;190(9):1881-1887. doi:10.1016/j.ajpath.2020.07.001.
4. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine Storm' in COVID-19. J Infect. 2020;80(6):607-613. doi:10.1016/j.jinf.2020.03.037.

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