Review 1: "Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality"

Takanori Teshima

doi:doi:10.1162/2e3983f5.0c9a0ff7

Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality

by Julio Silva, Carolina Lucas, Maria Sundaram, Benjamin Israelow, Patrick Wong, Jon Klein, Maria Tokuyama, Peiwen Lu, Arvind Venkataraman, Feimei Liu, Tianyang Mao, Ji Eun Oh, Annsea Park, Arnau Casanovas-Massana, Chantal B. F. Vogels, M. Catherine Muenker, Joseph Zell, John B. Fournier, Melissa Campbell, Michael Chiorazzi, Edwin Ruiz Fuentes, Mary E Petrone, Chaney C. Kalinich, Isabel M. Ott, Annie Watkins, Adam J. Moore, Maura Nakahata, Nathan D. Grubaugh, Shelli Farhadian, Charles Dela Cruz, Albert I. Ko, Wade L. Schulz, Aaron Ring, Shuangge Ma, Saad Omer, Anne L Wyllie, Akiko Iwasaki, and undefined undefined

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dx.doi.org

Description

While several clinical and immunological parameters correlate with disease severity and mortality in SARS-CoV-2 infection, work remains in identifying unifying correlates of coronavirus disease 2019 (COVID-19) that can be used to guide clinical practice. Here, we examine saliva and nasopharyngeal (NP) viral load over time and correlate them with patient demographics, and cellular and immune profiling. We found that saliva viral load was significantly higher in those with COVID-19 risk factors; that it correlated with increasing levels of disease severity and showed a superior ability over nasopharyngeal viral load as a predictor of mortality over time (AUC=0.90). A comprehensive analysis of immune factors and cell subsets revealed strong predictors of high and low saliva viral load, which were associated with increased disease severity or better overall outcomes, respectively. Saliva viral load was positively associated with many known COVID-19 inflammatory markers such as IL-6, IL-18, IL-10, and CXCL10, as well as type 1 immune response cytokines. Higher saliva viral loads strongly correlated with the progressive depletion of platelets, lymphocytes, and effector T cell subsets including circulating follicular CD4 T cells (cTfh). Anti-spike (S) and anti-receptor binding domain (RBD) IgG levels were negatively correlated with saliva viral load showing a strong temporal association that could help distinguish severity and mortality in COVID-19. Finally, patients with fatal COVID-19 exhibited higher viral loads, which correlated with the depletion of cTfh cells, and lower production of anti-RBD and anti-S IgG levels. Together these results demonstrated that viral load – as measured by saliva but not nasopharyngeal — is a dynamic unifying correlate of disease presentation, severity, and mortality over time.

RR:C19 Evidence Scale rating by reviewer:

Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

Recent studies clearly demonstrate that saliva is a viable alternative to nasopharyngeal swab samples (NPS) for the detection of SARS-CoV-2. However, prognostic impacts of the viral load by saliva vs. NPS remain to be determined. This study by Silva et al. evaluated the association of the viral load (saliva vs. NPS) with COVID-19 risk factors, immune profiles, and clinical outcomes. Saliva viral load, not NPS viral load, was significantly higher in high-risk patients. Interestingly, saliva viral load was associated with laboratory data abnormalities such as thrombocytopenia and lymphopenia, and high blood levels of inflammatory cytokines/chemokines. Most importantly, high saliva viral load was predictive of increased disease severity and poor survival. These results highlight that saliva and NPS samples are not equivalent measures of the disease process and clinical outcomes; differences in sensitivity and specificity for the detection of SARS-CoV-2 between collection sites are no longer of importance. This study suggests that saliva viral load may reflect the viral replicative and invasive process in the patient's body more than nasopharyngeal viral load; however, precise mechanisms remain to be elucidated. Nevertheless, this study indicates that saliva testing should be the standard of care for the diagnosis of COVID-19 with prognostic implications with additional logistic advantages over NPS. Methods are well described and might be easily reproduced by an expert in the field. My opinion is that this preprint article can be classified as “strong,” since the study is well-conceived, competently performed and conclusions are correctly drawn.