Estimating infectiousness throughout SARS-CoV-2 infection course

Correlates of infectiousness The role that individuals with asymptomatic or mildly symptomatic severe acute respiratory syndrome coronavirus 2 have in transmission of the virus is not well understood. Jones et al. investigated viral load in patients, comparing those showing few, if any, symptoms with hospitalized cases. Approximately 400,000 individuals, mostly from Berlin, were tested from February 2020 to March 2021 and about 6% tested positive. Of the 25,381 positive subjects, about 8% showed very high viral loads. People became infectious within 2 days of infection, and in hospitalized individuals, about 4 days elapsed from the start of virus shedding to the time of peak viral load, which occurred 1 to 3 days before the onset of symptoms. Overall, viral load was highly variable, but was about 10-fold higher in persons infected with the B.1. 1.7 variant. Children had slightly lower viral loads than adults, although this difference may not be clinically significant. Science, abi5273, this issue p. eabi5273 Analysis of thousands of people who tested positive in Germany reveals that many were asymptomatic and a minority exhibited high viral loads. INTRODUCTION Although post facto studies have revealed the importance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission from presymptomatic, asymptomatic, and mildly symptomatic (PAMS) cases, the virological basis of their infectiousness remains largely unquantified. The reasons for the rapid spread of variant lineages of concern, such as B.1. 1.7, have yet to be fully determined. RATIONALE Viral load (viral RNA concentration) in patient samples and the rate of isolation success of virus from clinical specimens in cell culture are the clinical parameters most directly relevant to infectiousness and hence to transmission. To increase our understanding of the infectiousness of SARS-CoV-2, especially in PAMS cases and those infected with the B.1. 1.7 variant, we analyzed viral load data from 25,381 German cases, including 9519 hospitalized patients, 6110 PAMS cases from walk-in test centers, 1533 B.1. 1.7 variant infections, and the viral load time series of 4434 (mainly hospitalized) patients. Viral load results were then combined with estimated cell culture isolation probabilities, producing a clinical proxy estimate of infectiousness. RESULTS PAMS subjects had, at the first positive test, viral loads and estimated infectiousness only slightly less than hospitalized patients. Similarly, children were found to have mean viral loads only slightly lower (0.5 log10 units or less) than those of adults and ~78% of the adult peak cell culture isolation probability. Eight percent of first-positive viral loads were 109 copies per swab or higher, across a wide age range (mean 37.6 years, standard deviation 13.4 years), representing a likely highly infectious minority, one-third of whom were PAMS. Relative to non-B.1. 1.7 cases, patients with the B.1. 1.7 variant had viral loads that were higher by a factor of 10 and estimated cell culture infectivity that was higher by a factor of 2.6. Similar ranges of viral loads from B.1. 1.7 and B.1. 177 samples were shown to be capable of causing infection in Caco-2 cell culture. A time-course analysis estimates that a peak viral load of 108.1 copies per swab is reached 4.3 days after onset of shedding and shows that, across the course of infection, hospitalized patients have slightly higher viral loads than nonhospitalized cases, who in turn have viral loads slightly higher than PAMS cases. Higher viral loads are observed in first-positive tests of PAMS subjects, likely as a result of systematic earlier testing. Mean culture isolation probability declines to 0.5 at 5 days after peak viral load and to 0.3 at 10 days after peak viral load. We estimate a rate of viral load decline of 0.17 log10 units per day, which, combined with reported estimates of incubation time and time to loss of successful cell culture isolation, suggests that viral load peaks 1 to 3 days before onset of symptoms (in symptomatic cases). CONCLUSION PAMS subjects who test positive at walk-in test centers can be expected to be approximately as infectious as hospitalized patients. The level of expected infectious viral shedding of PAMS people is of high importance because they are circulating in the community at the time of detection of infection. Although viral load and cell culture infectivity cannot be translated directly to transmission probability, it is likely that the rapid spread of the B.1. 1.7 variant is partly attributable to higher viral load in these cases. Easily measured virological parameters can be used, for example, to estimate transmission risk from different groups (by age, gender, clinical status, etc.), to quantify variance, to show differences in virus variants, to highlight and quantify overdispersion, and to inform quarantine, containment, and elimination strategies. Viral load and cell culture infectivity in 25,381 SARS-CoV-2 infections. (A) Viral loads in presymptomatic, asymptomatic, and mildly symptomatic cases (PAMS; red), hospitalized patients (blue), and other subjects (black). (B) Expected first-positive viral load and cell culture isolation probability, colored as in (A). (C) Temporal estimation with lines representing patients, colored as in (A). (D) As in (C), but colored by age. Two elementary parameters for quantifying viral infection and shedding are viral load and whether samples yield a replicating virus isolate in cell culture. We examined 25,381 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Germany, including 6110 from test centers attended by presymptomatic, asymptomatic, and mildly symptomatic (PAMS) subjects, 9519 who were hospitalized, and 1533 B.1. 1.7 lineage infections. The viral load of the youngest subjects was lower than that of the older subjects by 0.5 (or fewer) log10 units, and they displayed an estimated ~78% of the peak cell culture replication probability; in part this was due to smaller swab sizes and unlikely to be clinically relevant. Viral loads above 109 copies per swab were found in 8% of subjects, one-third of whom were PAMS, with a mean age of 37.6 years. We estimate 4.3 days from onset of shedding to peak viral load (108.1 RNA copies per swab) and peak cell culture isolation probability (0.75). B.1. 1.7 subjects had mean log10 viral load 1.05 higher than that of non-B.1. 1.7 subjects, and the estimated cell culture replication probability of B.1. 1.7 subjects was higher by a factor of 2.6.