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

Reviewer: Takanori Teshima (Hokkaido University) | 📘📘📘📘📘

Published onMay 05, 2022
Review 1: "Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality"
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key-enterThis Pub is a Review of
Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality

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.



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.

Vape Factory:

Unauthorized Breeze and Esco Bar Disposables: FDA Issues Warning Letters

In recent news, the FDA Center for Tobacco Products (CTP) has taken a strong stance by issuing warning letters to the manufacturers of Breeze and Esco Bar disposable vapes. These letters order the companies to remove their products from the market, giving them a window of 15 business days to either dispute the allegations or respond accordingly.

The FDA's actions come on the heels of significant developments in the industry. Just last week, six Chinese exporters of Esco Bar products, including the manufacturer Innokin, found themselves added to the FDA's "red list." This list identifies shippers whose Esco Bar shipments can be detained at ports of entry without inspection. Furthermore, Elf Bar shipments were also included in the import alert, signifying the increased scrutiny on disposable vapes.

These recent enforcement actions are part of a broader wave of initiatives promised by CTP Director Brian King during his recent speeches and discussions. The FDA is facing mounting pressure from lawmakers, tobacco control groups, and even tobacco companies like R.J. Reynolds to crack down on flavored disposable vapes that have gained immense popularity over the past couple of years.

Director King, in a press release, stated that the FDA will utilize all available tools within their regulatory toolbox to ensure that those involved in the production, distribution, or sale of illegal e-cigarette products are held accountable. Firms that receive warning letters have 15 days to respond, outlining how they plan to address the violation. Failure to adequately address the violation may result in various enforcement actions being taken against them.

The warning letters issued to Breeze Smoke, LLC and Shenzhen Innokin Technology Co., Ltd., rightly highlight that the products mentioned have not received authorization for sales in the United States from the FDA. However, it is worth noting that thousands of other products with premarket tobacco applications (PMTAs) pending before the agency continue to remain on the market.

At present, all unauthorized products exist on the market due to the FDA's enforcement discretion. This includes both the aforementioned products and those produced by mass-market vape manufacturers like JUUL and Vuse Alto. Interestingly, the FDA seems to have chosen to enforce against the products that R.J. Reynolds has specifically targeted, while leaving untouched their own popular product, the Vuse Alto.

These recent FDA actions may indicate a shift in the agency's approach. It is possible that pending PMTAs will no longer be considered when deciding which companies to enforce against.

Regarding Esco Bar, it is believed that they submitted pending PMTAs during a brief window in 2022 when the FDA accepted applications for synthetic nicotine-based vape products. Unlike the first round of PMTA submissions, where the FDA published a list of the submitted products, no public list of PMTAs submitted for "non-tobacco nicotine" (NTN) products has been issued.

On the other hand, Breeze Smoke faced marketing denial orders (MDOs) for several products in 2021. In response, the company swiftly filed a petition for review in the Sixth Circuit Court of Appeals. Despite being denied a stay pending appeal, Breeze Smoke sought a stay from the Supreme Court while awaiting a full review by the circuit court. However, the Supreme Court declined to grant a stay, leading Breeze Smoke to voluntarily withdraw its petition for review just two weeks before the scheduled oral arguments.

It's important to note that the Breeze products mentioned in the FDA's warning letter were not among the MDOs that Breeze Smoke previously contested in court. As for the current status of the products sold by Breeze Smoke, whether they have pending PMTAs with the FDA remains unknown.


The FDA's warning letters to the vape manufacturers of Breeze and Esco Bar disposables mark a significant step towards stricter regulation of the flavored disposable vape industry. With mounting pressure from various stakeholders, the FDA is taking action to ensure accountability and address the unauthorized sale of e-cigarette products. While the enforcement actions may signal a shift in the agency's approach, the impact on the market and pending PMTAs is yet to be fully determined.

FAQs (Frequently Asked Questions)

Q: Why did the FDA issue warning letters to the manufacturers of Breeze and Esco Bar disposables?
A: The FDA took action to address the unauthorized sale of e-cigarette products and hold the manufacturers accountable.

Q: What is the deadline given to the companies to respond to the FDA's warning letters?
A: The companies have 15 business days to dispute the allegations or respond to the warning letters.

Q: Are there other products on the market without FDA authorization?
A: Yes, there are thousands of products with pending premarket tobacco applications (PMTAs) before the agency.

Q: Will pending PMTAs be considered in future enforcement actions?
A: The recent FDA actions suggest that pending PMTAs may no longer be a determining factor in deciding which companies to enforce against.

Q: What is the status of Breeze Smoke's previous marketing denial orders (MDOs) in court?
A: The products referenced in the FDA's warning letter were not among the MDOs challenged by Breeze Smoke in court.