key: cord-310753-sv88b0dt
authors: Marks, M.; Millat, P.; Ouchi, D.; Roberts, C. h.; Alemany, A.; Corbacho-Monne, M.; Ubals, M.; Vall-Mayans, M.; Gonzalez Beiras, C.; Prat, N.; Ara, J.; Clotet, B.; Mitja, O.
title: Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study
date: 2020-10-27
journal: nan
DOI: 10.1101/2020.10.27.20220277
sha: 
doc_id: 310753
cord_uid: sv88b0dt

Background There remains limited data on what variables affect the risk of transmission of SARS-CoV-2 and developing symptomatic Covid-19 and in particular the relationship to viral load (VL). Methods We analysed data collected in a trial of hydroxychloroquine post-exposure prophylaxis. Covid-19 cases and their contacts were identified through the local epidemiological surveillance system. VL, estimated by quantitative PCR, was assessed at enrollment, at day 14, and whenever the participant reported Covid-19-like symptoms. Risk of transmission, risk of developing symptomatic disease and incubation dynamics were evaluated using random-effects regression analysis. Findings We identified 314 cases, 282 of which had at least one contact (753 contacts in total). Ninety (33%) of 282 clusters had at least one transmission event. The secondary attack rate was 16% (125/753), with a variation from 12% to 24% for VL of the index case of <106, and >109 copies/mL, respectively (OR per log10 increase in VL 1.3 95%CI 1.1 to 1.6). Increased risk of transmission was also associated with household contact (OR 2.7; 1.4 to 5.06) and age of the contact (OR 1.02; 1.01 to 1.04). The proportion of PCR positive contacts who developed symptomatic Covid-19 was 40.3% (181/449), with a variation from 25% to 60% for VL of the contact <107, and >109 copies/mL (HR log10 increase in VL 1.12; 95% CI 1.05 to 1.2). Time to onset of symptomatic disease decreased from a median of 7 days (IQR 5 to 10) for individuals with an initial viral load <107 to 6 days (4 to 8) and 5 days (3 to 8) for individuals with an initial viral load of 107 to 109 and >109, respectively. Interpretation We show that the viral load of the index case is a leading driver of SARS-CoV-2 transmission. The risk of symptomatic Covid-19 is strongly associated with viral load of the contact at baseline, which shortens the incubation time in a dose-dependent manner.

Evidence before this study 54

In September 2020, we searched PubMed database for articles reporting on factors influencing transmission 55 and the risk of developing symptomatic disease. Search terms included "Covid-19", "transmission", 56 "incubation time", and "risk", with no language restrictions. By the time of performing this search, various 57 authors had reported on retrospective analyses of clusters of index cases and their corresponding contacts, 58 as well as series of patients who developed symptomatic Covid-19 disease after PCR positive result. 59

Besides describing the secondary attack rate, various authors identified risk factors for transmission 60 associated with the place and duration of exposure and the lack of use of personal protective equipment. 61

However, we found no clear evidence regarding the influence of the characteristics of the index case on 62 transmission risk. Similarly, although various retrospective series of patients with positive PCR results had 63 reported incubation times elsewhere, the characteristics of index case and contacts that may influence the 64 risk of developing symptomatic Covid-19 and the time to this event had been barely addressed. 65

We analyzed data from a large cluster-randomized clinical trial on post-exposure therapy for Covid-19 that 67 provide new information on SARS-CoV-2 transmission dynamics. Several design components add value 68 to this dataset. Notably, quantitative PCR was available for the index cases to estimate risk of transmission. 69 Furthermore, quantitative PCR was also performed on asymptomatic contacts at the time of enrollment 70 allowing to investigate the dynamics of symptomatic disease onset among them. We found that the viral 71 load of the index case was the leading determinant of the risk of SARS-CoV-2 PCR positivity among 72 contacts. Among contacts who were SARS-CoV-2 PCR positive at baseline, viral load significantly 73 influenced the risk of developing the symptomatic disease in a dose-dependent manner. This influence also 74 became apparent in the incubation time, which shortened with increasing baseline viral loads. 75

Our results provide important insights into the knowledge regarding the risk of SARS-CoV-2 transmission 77 and Covid-19 development. The fact that the transmission risk is primarily driven by the viral load of index 78 cases, more than other factors such as their symptoms or age, suggests that all cases should be considered 79 potential transmitters irrespective of their presentation and encourages assessing viral load in cases with a 80 larger number of close contacts. Similarly, our results regarding the risk and expected time to developing 81 symptomatic Covid-19 encourage risk stratification of newly diagnosed SARS-CoV-2 infections based on 82 the initial viral load. 83 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 27, 2020. ; https://doi.org/10.1101/2020.10.27.20220277 doi: medRxiv preprint 84 85 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 27, 2020. The availability of data regarding the factors that may enhance transmission is essential for designing 93 interventions to control SARS-CoV-2 spread. Currently available data provide information on the risk of 94 transmission related to the place and duration of exposure, and the use of respiratory and eye protection 1,3-95 5,8 but not on other factors related to the characteristics of index cases and their contacts. Over the course 96 of infection, the virus has been identified in respiratory tract specimens 1-2 days before the onset of 97 symptoms, and it can persist for up to 13 days after the onset of symptoms in mild cases. 9 However, the 98 detection of viral RNA by PCR does not necessarily equate with infectivity, and the exact relationship 99 between viral load and risk of transmission from a case is still not clear. 10,11 100

Another challenge for public health interventions is the risk stratification of infected individuals for 101 developing symptomatic illness. Studies investigating case-contact pairs have reported highly variable 102 secondary attack rates (i.e., range 0.7% to 75%), depending on the type of exposure-duration, place, pre-103 or post-symptomatic. 12-15 On the other hand, the proportion of PCR-positive infected contacts that progress 104 to symptomatic disease has been typically around 40% -60%. 16 Estimates of mean or median incubation 105 period have been consistently between 5-7 days. 17-19 Nonetheless, little is known about factors that may 106 contribute to variation on the risk of developing Covid-19 symptoms or the incubation periods among 107 infected individuals. 108

The objective of this study was to evaluate transmission dynamics of SARS-CoV-2 in the context of a trial 109 of post-exposure prophylaxis and evaluate the influence of baseline variables-including viral load of the 110 index cases and exposed contacts-to transmission, development of symptomatic disease, and the 111 incubation period. 112 113 114 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 27, 2020. SARS-CoV-2 PCR positive case during more than 15 minutes within two meters. 128

All Covid-19 cases included in the present analysis were non-hospitalized adults (i.e., ≥ 18 years of age) 129 with quantitative PCR result available at baseline, mild symptom onset within five days before enrollment, 130 and no evidence of SARS-CoV-2 infections in their accommodation (i.e., household or nursing home) or 131 workplace within the 14 days before enrollment. Contacts selected for the analysis were adults with a recent 132 history of exposure and absence of Covid-19-like symptoms within the seven days preceding enrolment. 133 Contacts were exposed to the index case as either a healthcare worker, a household contact, a nursing home 134 worker, or a nursing home resident. 135

A dedicated outbreak field team visited cases and contacts at home or nursing home on days 1 (enrollment) 137 and 14. At the first clinical assessment on day 1 they conducted a baseline assessment, including a 138 questionnaire for symptoms of Covid-19 and collected relevant epidemiological information using a 139 structured interview: time of first exposure to the index case, place of contact (hospital, home, nursing care 140 facility), routine use of a mask of both, the case and the contact, and sleep location concerning the index 141 case (e.g., same room, same house). Symptoms surveillance consisted of active monitoring by phone on 142 days 3, and 7, a home visit on day 14, and passive monitoring whenever the participants developed 143 symptoms. Participants who developed symptoms were visited the same day they notified symptom onset 144 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 27, 2020. ; https://doi.org/10.1101/2020.10.27.20220277 doi: medRxiv preprint (unscheduled visits) by the field team, which recorded the date of symptom onset, type of symptoms from 145 a pre-specified checklist, and symptom severity, graded on a 1-to-4 scale. The analysis regarding the determinants of transmission was performed using clusters of an index case (i.e., 170 a Covid-19 case with at least one close contact) and their corresponding contacts. To identify risk factors 171 for transmission, we fitted a random-effects logistic regression model for the risk of transmission within a 172 cluster. Factors with potential influence on the risk of transmission included characteristics of the potential 173 transmitter (i.e., age, sex, viral load, and the presence or absence of respiratory symptoms) and contacts 174 (i.e., age, sex, and the type of contact they had with the index case). Finally, the analysis regarding the risk 175 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 27, 2020. (Table 1) . 192

At the first study visit, the median viral load amongst Covid-19 cases was 10 8 (IQR 10 6 -10 9 ). In 194 multivariable linear regression the viral load amongst cases was higher in individuals who reported cough, 195 fever, or rhinitis (Table 2 ). There was no association between the age or sex of the Covid-19 case nor the 196 presence of reported dyspnea or anosmia with viral load. copies/mL to 24% where the index case had a viral load >10 9 copies/mL ( Figure 1B) . According to the 205 multivariate analysis, the viral load of the index case was strongly associated with the risk of onward 206 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 27, 2020. ; https://doi.org/10.1101/2020.10.27.20220277 doi: medRxiv preprint transmission (OR per log10 increase in VL 1.3; 95% CI 1.1-1.6) ( Table 3) . Ninety percent (114/125) of 207 transmission events had an index case viral load of 5.1 log10 copies/ml or more, and 50% (61/125) had a 208 viral load of 8.8 log10 copies/ml or more. Other factors associated with an increased risk of transmission 209 were household contact (OR 2.7, 95% 1.4-5.06) and age of the contact (OR 1.02, 95% 1.01-1.04). There 210 was no association of risk of transmission with reported mask usage by contacts, with the age or gender of 211 the index case nor with the presence of respiratory symptoms in the index case at the initial study visit 212 (Table 3) . 213

We did not find any evidence of an association between the viral load of the index cases and the first viral 214 load of incident positive results amongst contacts (p = 0.1, Supplementary Figure 1) . Also, after excluding 215 contacts who were PCR positive at the first study visit, we found no association between the viral load of 216 the index case and the time to onset of incident SARS-CoV-2 infection (HR 1.01 95% CI 0.83-1.23). 217

Overall, 449 contacts had a positive PCR result at first visit regardless of availability on viral load data of 219 their index case (n=125) or not (n=324). Twenty-eight (6.3%) of 449 contacts had symptoms at the first 220 visit and 181 (40.3%) developed symptomatic Covid-19 within the follow-up period. The multivariable 221 cox-regression analysis, after adjusting for age and sex, revealed that increasing viral load levels of the 222 contact at day 1 were associated with an increased risk of developing symptomatic disease. The risk of 223 symptomatic disease was approximately 25% amongst individuals with an initial viral load of <10 7 224 copies/mL compared to a more than 60% amongst those with an initial viral load of >10 9 (HR per log10 225 increase in VL 1.12; 95% CI 1.05 -1.2; p = 0.0006) (Figure 2A ). There was no association between with 226 sex or age of individuals and the risk of developing symptomatic Covid-19. 227

The median time from exposure to symptom onset was 7 days (IQR 5 -9). The time to onset of symptomatic 228 disease decreased from a median of 7 days (IQR 5 -10) for individuals with an initial viral load <10 7 229 copies/mL to 6 days (IQR 4 -8) and 5 days (IQR 3 -8) for individuals with an initial viral load of 10 7 -10 9 230 and >10 9 copies/mL, respectively ( Figure 2B) In our study, we found that increasing viral load values in nasopharyngeal swabs of Covid-19 cases were 235 associated with the greatest risk of transmission measured by SARS-CoV-2 PCR positivity among contacts 236 and also a higher risk of transmission in household environment compared to other indoor situations. In 237 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 27, 2020. ; https://doi.org/10.1101/2020.10.27.20220277 doi: medRxiv preprint addition, we found that higher viral loads in swabs of asymptomatic contacts were associated to higher risk 238 of developing symptomatic Covid-19 and have shorter incubation periods than those with a lower viral 239 load. 240

To our knowledge this is the largest study that evaluates the relationship of viral load in Covid-19 cases 241 and risk of transmission. In our cohort, a high proportion (67%) of index cases did not cause secondary 242

infections. However, we identified 90 (33%) clusters with transmission events and the multivariate analysis 243 revealed that clusters centered on index cases with high viral load were significantly more likely to result 244 in transmission. Secondary attack rate was under 12% when the index case viral load was <10 6 copies/ml 245 compared to more than 20% amongst clusters with the highest viral loads. In line with previous analyses of 246 case-contact clusters, 9,12,14 we also found that household exposure to an index case was associated with a 247 higher risk of transmission that other types of contact, presumably reflecting duration and proximity of 248 exposure. Age of the contact was also identified in our multivariate analysis as a significant-albeit 249 modest-determinant of transmission. This factor has shown uneven influence across results reported 250 elsewhere, but seems to play a secondary role among adults. 13,14 Finally, unlike previous analyses that 251 reported a relationship between coughing and transmission, 13 we did not find any association. This finding 252

suggests that the absence of cough does not preclude significant onward transmission, particularly if the 253 viral load is high. Taken together, our results indicate that the viral load, rather than symptoms, may be the 254 predominant driver of transmission. 255 Importantly, we report that high viral short after exposure in asymptomatic contacts was strongly associated 256 with the risk of developing symptomatic Covid-19 disease. We found an approximately 25% chance of 257 developing symptomatic disease amongst individuals with an initial viral load <10 7 copies/mL compared 258 to a more than 60% chance amongst individuals with a viral load >10 9 . These data may provide rationale 259 for risk stratification for developing illness. Moreover, the initial viral load significantly shifted the 260 incubation time, which ranged from 5 days in participants with a high viral load to 7 days in participants 261 with a low viral load. Our study is the first analysis of prospective data that investigates the association 262 between initial viral load and the incubation time. 263

The study has several limitations. First, asymptomatic people were not enrolled as index cases, affecting 264 our ability to fully characterize all types of transmission chain. Second, we did not find any evidence of 265 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 27, 2020. confirmation of infection) rather than time to positive PCR test based on serial testing. Nonetheless, 270 accurate calculation of the incubation period was feasible because of the prospective nature of the study, 271 accurate identification of exposure by face-to-face interview, and intensive active and passive monitoring 272 of exposed contacts. Also, we followed participants over 14-day periods, thus incubation periods beyond 273 14 days may not have been detected. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 27, 2020. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 27, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 27, 2020. ; https://doi.org/10.1101/2020.10.27.20220277 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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