A Hierarchical Framework for Assessing Transmission Causality of Respiratory Viruses<strong> </strong>

Abstract

We propose a hierarchical framework based on our experience of systematically reviewing and synthesizing 378 primary studies for an evidence-based update of the modes of transmission for SARS-CoV-2. These studies revealed significant methodological shortcomings with a lack of standardization in the design, conduct, testing and reporting of SARS-CoV-2 transmission. While this situation is in part excusable at the outset of a pandemic, evidence rules of proof for assessing the transmission of this virus are needed for this and future pandemics of viral respiratory pathogens. We review the history of causality assessment related to microbial etiologies with a focus on respiratory viruses and suggest a hierarchy of evidence to integrate clinical, epidemiologic, molecular and laboratory perspectives on transmission. The hierarchy, if applied to future studies, should narrow the uncertainty over the twin concepts of causality and transmission of human respiratory viruses. We attempt to address the translational gap between the current research evidence and the assessment of causality in the transmission of respiratory viruses with a focus on SARS-CoV-2. Experimentation, consistency and independent replication of research alongside our proposed framework provide a chain of evidence that can reduce the uncertainty over the transmission of respiratory viruses and increase the level of confidence in specific modes of transmission and the measures that should be undertaken to prevent transmission

Viral cultures for assessing fomite transmission of SARS-CoV-2: a systematic review and meta-analysis

“…The Ct values were lowest in fomite samples from two studies [12,19] that included participants receiving either high-flow oxygen or mechanical ventilation: 22.3 to 29.7, and 23 to 26, respectively. A third study [32], including participants on oxygen, reported higher Ct values (35)(36)(37)(38)(39)(40); however, the investigators noted that participants in the high-flow nasal oxygen (HFNO) group were sampled significantly later in their illness compared to those receiving only supplemental oxygen: mean 16-days vs mean 9 days, J o u r n a l P r e -p r o o f from symptom onset, respectively. The authors of one study of SARS-CoV-2 patients in acute care [23] reported that hypoxia on admission (P=0.003), Ct ≤30 on or after the sampling date (P=0.006), higher Charlson comorbidity index score (P=0.002), and shorter time from illness onset (<7 days) to sampling date (P=0.02) were significantly associated independent risk factors for positive SARS-CoV-2 PCR tests from fomite samples.…”

“…Evidence for a chain of transmission of SARS-CoV-2 from fomites to humans was not reported in the studies reviewed. Nonetheless, a chain of transmission was demonstrated by SARS-CoV-2 from respiratory tract specimens which can deposit on “fomites” that can survive for many hours and can readily cause invasive infection in the Syrian hamster model l[ 24 ] at very low infecting doses [ 37 ], fulfilling both the Gwaltney-Hendley postulates of viral causation and Koch’s postulates [ 38 ]. These very low infectious doses are consistent with the recently published human challenge experiments demonstrating infection in 53% using an inoculum of only 10 TCID50 (∼7PFU) in 0·1 mL of a wild-type virus (SARS-CoV-2/human/GBR/484861/2020) [ 39 ].…”

Viral cultures, Polymerase Chain Reaction Cycle Threshold Values and Viral Load Estimation for SARS-CoV-2 Infectious Potential Assessment in Hematopoietic Stem Cell and Solid Organ Transplant Patients: A Systematic Review

“…10 Although the dataset was limited, we observed an inverse relationship (Ct/Cq) or direct relationship (log copies): the viral burden indicated by these methods correlated with infectiousness, as shown by the ability to produce replication-competent virus in culture. The presence of replication-competent virus reflects one of the highest grades of evidence supporting the capability for forward transmission of SARS-CoV-2 16,17 .…”