key: cord-0834568-hdvj4d2o authors: Qiu, X.; Nergiz, A. I.; Maraolo, A. E.; Bogoch, I. I.; Low, N.; Cevik, M. title: Defining the role of asymptomatic SARS-CoV-2 transmission: a living systematic review date: 2020-09-03 journal: nan DOI: 10.1101/2020.09.01.20135194 sha: ec517ec7deec114e40cd1a5f538ea3565c0c400d doc_id: 834568 cord_uid: hdvj4d2o Background Reports suggest that asymptomatic individuals (those with no symptoms at all throughout the infection) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are infectious, but the extent of asymptomatic transmission requires further understanding. Purpose This living review aims to critically appraise available data about secondary attack rates from people with asymptomatic and pre-symptomatic SARS-CoV-2 infection. Data sources Medline, EMBASE, China Academic Journals full-text database (CNKI), and pre-print servers were searched from 30 December 2019 to 3 July 2020 using relevant MESH terms. Study selection Studies that report on contact tracing of index cases with asymptomatic or pre-symptomatic SARS-CoV-2 infection, in either English or Chinese were included. Data extraction Two authors independently extracted data and assessed study quality and risk of bias. We calculated the secondary attack rate as the number of contacts with SARS-CoV-2, divided by the number of contacts tested. Data synthesis Of 928 studies identified, 19 were included. Secondary attack rates from asymptomatic index cases ranged from 0% to 2.8% (9 studies). Pre-symptomatic secondary attack rates ranged from 0.7% to 31.8% (10 studies). The highest secondary attack rates were found in contacts who lived in the same household as the index case. Other activities associated with transmission were group activities such as sharing meals or playing board games with the index case. Limitations We excluded some studies because the index case or number of contacts were unclear. Owing to the anticipated heterogeneity, we did not produce a summary estimate of the included studies. Conclusion Asymptomatic patients can transmit SARS-CoV-2 to others, but our findings indicate that such individuals are responsible for fewer secondary infections than people with symptoms in the same studies. Systematic review registration PROSPERO CRD42020188168 Funding: No funding was received Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) demonstrates efficient 58 transmission in populations without effective public health interventions; basic reproduction 59 numbers (R 0 ) values range between 2-3 (1). While asymptomatic transmission has been 60 described as the "Achilles' heel" of control efforts during this pandemic, the extent to which 61 transmission of SARS-CoV-2 by people without symptoms drives this pandemic remains 62 uncertain (2). SARS-CoV-2 infection that is asymptomatic at the time of laboratory testing is 63 widely reported (3); however, studies that follow infected people over time suggest that many 64 infections are not asymptomatic throughout the entire disease course, and a large proportion of 65 these individuals ultimately develop a diverse range of symptoms (4-7). A living systematic 66 review of studies published up to 10 June 2020, estimated that 20% (95% CI 17 to 25%) of 67 people who become infected with SARS-CoV-2 remain asymptomatic throughout infection (7). 68 One of the barriers to understanding the role of asymptomatic transmission is the lack of 69 consistency in case definitions. While symptom severity exists on a spectrum, individuals 70 infected with SARS-CoV-2 can be miscategorized as asymptomatic, when they are 71 paucisymptomatic. For instance, Gudbjartsson et al. reported that approximately half of the 72 participants in their population screening in Iceland had symptoms despite asking symptomatic 73 patients not to participate (3). Additionally, studies that define symptomatic disease narrowly as 74 fever, cough, or shortness of breath might overestimate the proportion without symptoms (3, 8) . 75 It is increasingly clear that some individuals experience more diverse symptoms, including taste 76 and smell disturbance or myalgia, either for the entire course of illness or preceding respiratory 77 symptoms. These symptoms can be so mild and insidious that they do not limit patients' daily 78 activities (4, 9) . The situation is further complicated by subjective patient perception and 79 differences between studies in the elicitation and reporting of symptoms. 80 There are reports describing asymptomatic individuals with SARS-CoV-2 who are infectious (10) 81 and who have infected one or more contacts (11), but the extent and significance of 82 asymptomatic transmission requires further understanding. The aim of this review is to 83 . CC-BY-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 September 3, 2020. . https: //doi.org/10.1101 //doi.org/10. /2020 summarize the available evidence about secondary attack rates (defined as the probability that 84 an infected individual will transmit the disease to a susceptible individual) amongst the contacts 85 of asymptomatic or pre-symptomatic individuals with SARS-CoV-2 to provide information about 86 how contagious they are, and their role in driving the pandemic. 87 88 Methods: 89 Systematic review was registered in PROSPERO on 8 June 2020 (CRD42020188168) and will 90 be updated three times a year as a living systematic review (12). The larger review aims to 91 answer transmission dynamics of SARS-CoV-2. The analysis in this report addresses one of the 92 review questions; to identify asymptomatic and pre-symptomatic secondary attack rate. 93 94 Definitions 95 We defined "asymptomatic" as an individual with laboratory-confirmed SARS-CoV-2 infection 96 who does not demonstrate symptoms throughout their entire course of infection, or after 14 days 97 of follow up; "paucisymptomatic" as an individual with laboratory-confirmed SARS-CoV-2 98 infection with mild symptoms, and "pre-symptomatic" as an individual who reports no symptoms 99 at the time of the initial positive test result, but who goes on to develop recognised COVID-19 100 symptoms. We used these definitions to categorize the index cases. CC-BY-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 September 3, 2020. . https: //doi.org/10.1101 //doi.org/10. /2020 Studies were eligible if they met the inclusion criteria: (1) report on Coronavirus disease 2019 114 or SARS-CoV-2 infection and (2) report an outbreak investigation or contact tracing 115 study. Exclusion criteria were: (1) review articles; (2) observational studies providing only the 116 proportion of individuals infected; (3) studies that do not indicate the number of contacts or 117 secondary infections; and (4) reports in media sources. We also manually screened the 118 references of the included original studies and reviews to identify additional eligible studies. 119 120 Data Extraction 121 Two authors (XQ and AIN) independently reviewed reports by title and abstract for relevance, 122 with at least 20% of all reports being screened in duplicate to ensure consistency. Two authors 123 then independently read the full text report of all studies not excluded by title and abstract, to 124 consider eligibility for inclusion. Any disagreements regarding study inclusion were resolved 125 through discussion with a third author (MC). Data were extracted onto a standardized form. From 126 each study, the following variables were extracted: the name of the first author, year of 127 publication, country, sample size, details of index cases (categorised as asymptomatic, pre-128 symptomatic and symptomatic); event details such as environment, transmission details; number 129 of contacts, number of secondary cases. If these data were not reported, we contacted authors 130 to request them. The studies are summarized in text and table form, descriptive statistics were completed for key 140 outcome measures. Secondary attack rates were computed from raw data in each study, dividing 141 . CC-BY-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 September 3, 2020. . https://doi.org/10.1101/2020.09.01.20135194 doi: medRxiv preprint the number of infected contacts of primary cases by the total number of susceptible exposed 142 contacts. A 95% confidence interval [CI] was calculated by using the Clopper-Pearson method 143 (13, 14) . Secondary attack rates are presented as a proportion along with 95% CIs in forest 144 plots, stratified according to the features of index cases: truly asymptomatic or pre-symptomatic. 145 A 95% prediction interval is shown, but a pooled estimate was suppressed due to the expected 146 high methodological and clinical heterogeneity among the studies. A prediction interval is an 147 index of dispersion, providing information on how widely the true effect size varies. It is an 148 estimate of the range of values in which a future observation will fall (15) Of these 19 studies that indicated contact tracing of asymptomatic or pre-symptomatic index 162 cases, after reviewing the details and contacting the authors, we re-classified three studies from 163 asymptomatic to pre-symptomatic as the index cases developed symptoms later during the 164 disease course (16-18). 165 166 Of the 19 studies included, contact tracing of index patients who were identified as asymptomatic 168 cases, according to our definition, was reported in nine (Table 1, Figure 1 ) (6, 11, (19) (20) (21) (22) (23) (24) (25) . All 169 except one tested all close contacts for SARS-CoV-2, regardless of symptoms (23). Cheng et al. 170 . CC-BY-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 September 3, 2020. contacts of 8 asymptomatic cases were followed up, identifying one secondary case (secondary 182 attack rate 0.3% (95% CI 0.0, 1.8%) (25). In the same study, mild, moderate and severe attack 183 rates were 3.3%, 5.6% and 6.2%, respectively. Zhang et al. followed up 119 close contacts of 12 184 asymptomatic index cases and identified one secondary case, an asymptomatic secondary 185 attack rate of 0.8% (95% CI 0.0, 4.6). In the same study, the secondary attack rate was 3.5% 186 (95% CI 1.5-8.0) for those with mild, 5.7% (95% CI 2.5, 12.8%) for those with moderate, and 187 4.5% (95% CI 0.8, 21.8%) for those with severe symptoms (6). In this study, close contacts that 188 lived with an index case had 12 times the risk of infection as those who did not live with the index 189 case (RR 12.5 -95% CI 1.6, 100.8) and those who had frequent contact with an index case-190 patient, and those who had more than 5 contacts had 29 times the risk of infection as those with 191 fewer contacts (RR 29.0 -95% CI 3.6, 232.3). Two studies indicated an asymptomatic secondary 192 attack rate of 1% and 1. 9% (19, 20) . contacts together. The authors clarified that 3 asymptomatic index cases and their 106 close 194 contacts were followed up, leading to 3 secondary cases, a secondary attack rate of 2.8% (95% 195 CI 0.06, 8.0%). In this study, the overall secondary attack rate was 10.6% in the household 196 setting, which was higher for symptomatic cases (14.4%, 95% CI 8·8, 19·9%) than that of 197 asymptomatic cases and for non-household contacts 0.7 (95% CI 0.1, 1,3) (11). Zeng et al. 198 conducted the largest contact tracing study, following up 753 close contacts of asymptomatic 199 . CC-BY-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 September 3, 2020. . https://doi.org/10.1101/2020.09.01.20135194 doi: medRxiv preprint index cases and identified one secondary case, an asymptomatic secondary attack rate of 0.13% 200 (95% CI 0.0, 0.7%). In the same study, the secondary attack rate for all contacts was 2.0% (95% 201 CI 1.8, 2.3%) for confirmed symptomatic index cases (24). 202 203 Summary of pre-symptomatic secondary attack rates 204 Thirteen papers reported either outbreak investigations or contact tracing studies reporting 205 transmission from an index case during the pre-symptomatic period (11, 16, 18, 23, (26) (27) (28) (29) (30) (31) (32) (33) 206 (Table 2 ). Of those, ten studies followed up 22 to 585 close contacts whose initial exposure 207 occurred before symptom onset of the index case (Figure 3) . These studies reported secondary 208 attack rates ranging from 0% to 31.8%. Even in studies that followed up large numbers of 209 people, including community contacts, the majority of secondary cases identified were from the 210 same household or among friend gatherings. In these studies, having meals together, or playing 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 September 3, 2020. . This systematic review provides comprehensive data on secondary attack rates arising from 229 people with asymptomatic and pre-symptomatic SARS-CoV-2 infection. While asymptomatic 230 patients can transmit the virus to others (34), the findings from nine studies in this review found 231 secondary attack rates of zero to 2.8%, compared with secondary attack rates of 0.7% to 16.2% 232 in symptomatic cases in the same studies. These findings suggest that individuals who are 233 asymptomatic throughout the disease course are responsible for fewer secondary infections than 234 symptomatic and pre-symptomatic cases. For contacts whose exposure occurred before 235 symptom onset of the index case, transmission events were associated with living with the index 236 case or group activities such as sharing meals and playing board games. 237 The findings of our study raise the question about whether the low secondary attack rates from 239 asymptomatic individuals result from low infectiousness or a shorter duration of infectiousness. In 240 another living systematic review, of studies published up to 6 June 2020, we found that cases 241 with asymptomatic infection have a shorter duration of RNA shedding than symptomatic 242 individuals (35). Asymptomatic patients may therefore be contagious but for a shorter duration, 243 limiting the duration they could transmit to their contacts. However, there remain limited data on 244 the shedding of infectious virus in asymptomatic individuals to quantify their transmission 245 potential, which would be needed to inform policy on quarantine duration in the absence of 246 testing. Low likelihood of transmission from asymptomatic index cases combined with high 247 symptomatic secondary attack rates emphasises that, especially in the context of limited 248 resources, approaches should be targeted predominantly on identifying and immediately 249 isolating patients with prodromal or mild symptoms and their contacts, which may avert a 250 significant number of community transmission clusters (36). These findings are in line with 251 previous contact tracing and outbreak investigations suggesting that many SARS-CoV-2-infected 252 people either do not contribute to an onward transmission or have minimal potential to do so (37, 253 38), and a large number of cases are often caused by a small number of infected patients. 254 Clusters have become a prominent characteristic of SARS-CoV-2 which distinguishes it from 255 seasonal influenza, although a similar pattern was also observed in SARS-CoV and MERS-CoV. 256 257 . CC-BY-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 September 3, 2020. . https://doi.org/10.1101/2020.09.01.20135194 doi: medRxiv preprint The modelling studies suggest that it isn't possible to have epidemics of this size without 258 substantial pre-symptomatic transmission. Viral load dynamics of SARS-CoV-2 derived from 259 confirmed cases suggest that peak viral loads are detected at the start of symptom onset up to 260 day 5 of illness, suggesting highest infectiousness potential in just before or within the first few 261 days after symptom onset (35) CC-BY-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 September 3, 2020. . We identified two systematic reviews that investigated asymptomatic transmission, with different 287 research questions and search terms. One review included studies published up to 10 June 2020 288 and identified five studies that directly compared secondary attack rates between asymptomatic 289 and symptomatic index cases; all were included in our review (7). The summary risk ratios for 290 asymptomatic versus symptomatic (0.35, 95% CI 0.10, 1.27) and pre-symptomatic versus 291 symptomatic (0.63, 95% CI 0.18, 2.26) are consistent with our findings. The second review 292 estimated only household secondary attack rates and included studies published up to 29 July 293 2020 (42). Of three studies that included asymptomatic index cases, two were included in our 294 review. We excluded one of the studies because the number of contacts of asymptomatic index 295 cases was not specified; we have not yet received details of the study after contacting the 296 authors. Advantages of our review over these two studies are inclusion of studies published in 297 Chinese, search terms that aimed to capture studies specifically estimating secondary attack 298 rates in different settings and clarification about symptomatology of index cases through direct 299 contact with the authors. 300 301 Important barriers to more accurate quantification of the contribution of asymptomatic and pre-302 symptomatic SARS-CoV-2 transmission relate to the different definitions used to estimate the 303 asymptomatic fraction of infections, not taking into account mild or atypical symptoms, or the use 304 of estimates from cross-sectional studies without follow up (43). Therefore, in order to 305 understand the extend of asymptomatic infections and transmission, a clear and comprehensive 306 case definition, which assesses the presence or absence of a defined list of major and minor or 307 atypical symptoms is required in future studies. 308 309 In summary, whilst asymptomatic transmission is a major concern for SARS-CoV-2 community 310 spread, secondary attack rates from those who remain asymptomatic throughout their course of 311 infection are low suggesting limited infectiousness. Although it is difficult to estimate the 312 proportion of pre-symptomatic transmission, these patients are likely to be highly infectious 313 around the time of symptom onset and appear to transmit efficiently, especially within 314 households. Those with mild symptoms, who feel otherwise well, still carry large amounts of virus 315 . CC-BY-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 September 3, 2020 . . https://doi.org/10.1101 /2020 in the upper respiratory tract, which might contribute to easy and rapid spread of SARS-CoV-2 316 (20) . 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 September 3, 2020. . Transmission dynamics and secondary attack rates 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 September 3, 2020. Studies included in this report (n =19) . CC-BY-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 September 3, 2020. . https://doi.org/10.1101/2020.09.01.20135194 doi: medRxiv preprint For each study the SAR is reported with its 95% CI. 401 A prediction interval at the bottom of the forest is depicted . 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 . CC-BY-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 September 3, 2020. . https://doi.org/10.1101/2020.09.01.20135194 doi: medRxiv preprint For each study the SAR is reported with its 95% CI. 428 A prediction interval at the bottom of the forest is depicted. 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