Analysis of Asymptomatic and Presymptomatic Transmission in SARS-CoV-2 Outbreak, Germany, 2020

We determined secondary attack rates (SAR) among close contacts of 59 asymptomatic and symptomatic coronavirus disease case-patients by presymptomatic and symptomatic exposure. We observed no transmission from asymptomatic case-patients and highest SAR through presymptomatic exposure. Rapid quarantine of close contacts with or without symptoms is needed to prevent presymptomatic transmission.

ID-19) pandemic, worldwide, >85 million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections had been reported as of January 7, 2021 (https://covid19.who.int). Although it was clear from the beginning of the pandemic that symptomatic transmission of SARS-CoV-2 occurs, presymptomatic transmission has also been described (1)(2)(3)(4)(5)(6). Furthermore, transmission from asymptomatic cases was deemed possible on the basis of fi ndings that viral load of asymptomatic cases was similar to that of symptomatic cases (7). Understanding how transmission occurs from asymptomatic cases and from symptomatic cases in their presymptomatic and symptomatic phase, as well as the frequency of transmission, is essential for public health management. We assessed asymptomatic, presymptomatic, and symptomatic transmission during an outbreak investigation of 59 COVID-19 cases by determining secondary attack rates (SAR) according to the respective exposure periods. In addition, we estimated key parameters such as serial interval and incubation period.

The Study
On February 29, 2020, a COVID-19 case was notifi ed to the local public health authority (LPHA) of a rural district in southern Germany without previously observed community transmission. During the infectious period, the case-patient had attended several carnival events in the district. The LPHA immediately initiated contact tracing, identifying all close contacts; they were quarantined and tested irrespective of symptoms. By the end of March 2020, a cluster of 59 cases had been identifi ed through successive contact tracing activities.
We interviewed the case-patients of the cluster by phone regarding symptoms developed during SARS-CoV-2 infection; potential source cases or events; and household contacts (HCs) and close nonhousehold or other contacts (OCs) in their infectious period (Appendix, https://wwwnc.cdc.gov/ EID/article/27/4/20-4576-App1.pdf). We obtained an empirical distribution of the serial interval from the average over all possible transmission trees of the cluster. We obtained generation time and incubation period by averaging over the estimates as described by Reich et al. (8) To estimate SAR and relative risks (RRs) we conducted a retrospective cohort study, including all HCs and OCs as recalled by the case-patients that met inclusion criteria (Appendix). We calculated pooled SAR of HCs and OCs for 2 outcomes, laboratory confi rmation (SAR lab ) and development of respiratory symptoms (SAR res ) in the following groups: HCs and OCs of asymptomatic case-patients who never experienced symptoms; HCs and OCs of We determined secondary attack rates (SAR) among close contacts of 59 asymptomatic and symptomatic coronavirus disease case-patients by presymptomatic and symptomatic exposure. We observed no transmission from asymptomatic case-patients and highest SAR through presymptomatic exposure. Rapid quarantine of close contacts with or without symptoms is needed to prevent presymptomatic transmission.

Analysis of Asymptomatic and Presymptomatic Transmission in SARS-
symptomatic case-patients in which the phase with contact could not be specified by the case-patient or with contact in both phases; OCs of symptomatic case-patients with contact only in the presymptomatic phase; and OCs of symptomatic case-patients with contact only in the symptomatic phase.
In total, 42 HCs and 212 OCs were included in the cohort study ( Table 1). The overall SAR lab was 13% (4/32) for HCs and 14% (20/148) for OCs. The overall SAR res was 29% (12/42) for HCs and 17% (29/170) for OCs (Table 2). We did not identify any HC who tested positive or experienced respiratory symptoms after contact with asymptomatic case-patients. Neither SAR lab nor SAR res of HCs of symptomatic casepatients were significantly higher compared with HCs of asymptomatic cases (SAR lab p = 1.0; SAR res p = 0.23). We observed no laboratory-confirmed SARS-CoV-2 transmission from asymptomatic case-patients to any of the 22 OCs (Table 2; Appendix Figure 2). SAR lab was highest for OCs with contact during the case-patients' presymptomatic phases (21%; 15/72) yielding a RR of 6.5 (95% CI 1.1-∞) when compared with contacts of asymptomatic case-patients. Adjusting for case-patients' age, sex, and number of contact persons showed no substantial changes in the magnitude of estimates (data not shown). Presymptomatic transmission accounted for >75% of all transmissions to OCs in the cohort (Appendix).

Conclusions
In this cluster of COVID-19 cases, little to no transmission occurred from asymptomatic case-patients. Presymptomatic transmission was more frequent than symptomatic transmission. The serial interval was short; very short intervals occurred. The fact that we did not detect any laboratory-confirmed SARS-CoV-2 transmission from asymptomatic case-patients is in line with multiple studies (9-11). However, Oran et al. have speculated that asymptomatic cases contribute to the rapid progression of the pandemic (12). Some studies may be prone to misclassify presymptomatic cases as asymptomatic, leading to heterogeneous reporting of SAR of asymptomatic cases, because of different case definitions or differential duration of follow-up. In our study we used a very sensitive case definition for symptomatic cases that did not require specific symptoms (e.g. fever) to be present. Also, timing of our study would have enabled detection of late onset of symptoms, which gives us confidence in our classification of exposure groups.
The 75% of SARS-CoV-2 transmissions in our cohort from case-patients in their presymptomatic phase exceeds reported transmission rates from other investigations (1,13,14). Possible reasons are the prior evidence that infectiousness peaks around the date of symptom onset, declining thereafter (15), and that case-patients probably reduced social contacts themselves once they experienced symptoms or when ordered to self-isolate. A large proportion of cases with presymptomatic transmission in our cluster is further supported by the median serial interval of 3 days.
Of note are the consequences for public health management: first, the need for early detection of CO-VID-19 cases and for initiation of contact tracing as soon as possible to quarantine close contacts, particularly because short serial intervals may lead to further transmission chains. Second, suspect case-patients or persons with any respiratory illness should immediately self-isolate and inform their contacts met in the presymptomatic and symptomatic phases.
A limitation of our study is that evidence was obtained from a single outbreak and might not be applicable to other settings. We used only information as recalled by the case-patients, which is imperfect and may introduce errors or bias. Because we used development of respiratory symptoms as a proxy for possible SARS-CoV-2 infections among contacts, and because incidence of respiratory illnesses was still high in this winter timeframe, SAR res may be overestimated. However, this possible source of misclassification should be nondifferential between groups. We excluded many HCs because of uncertainties about the potential simultaneous introduction of SARS-CoV-2 in the household, which may have led to an underestimation of SAR among HCs. In the transmission tree, we had to omit various source case-infectee pairs because case-patients' recalled symptom onset differed substantially from surveillance data and was not plausible (Appendix). Finally, although community transmission of SARS-CoV-2 was deemed unlikely in the affected district at the time, we cannot rule out that some cases acquired infections from other sources.
In conclusion, our study suggests that asymptomatic cases are unlikely to contribute substantially to the spread of SARS-CoV-2. COVID-19 cases should be detected and managed early to quarantine close contacts immediately and prevent presymptomatic transmissions.

Acknowledgments
As J.K.B. is a fellow of the European Public Health Microbiology Training at the European Centre for Disease Prevention and Control (ECDC) Fellowship Programme (and supported financially by this program) and M.B. is a fellow of the European Programme for Intervention Epidemiology Training at the ECDC and the Postgraduate Training for Applied Epidemiology at the Robert Koch Institute, we first acknowledge these programs. We also thank the local public health authority of the district for its continuous efforts fighting the COVID-19 pandemic as well as for providing us with information about the cluster and corresponding data for subsequent analysis. We thank the team of researchers assisting with the case interviews: Johannes Zeiher, Nora-Katharina Küpke, Sandra Niendorf, Sangeeta Banerji, and Susann Dupke. Furthermore, we especially thank all COVID-19 case-patients of this cluster for their participation in the study.

About the Author
Dr. Bender is a fellow of the European Public Health Microbiology Training Programme of the European Centre for Disease Prevention and Control. She is a microbiologist affiliated with the Nosocomial Pathogens and Antibiotic Resistances Unit, Department of Infectious Diseases of the Robert Koch Institute. Her research interest focuses on the emergence of multidrug-resistant nosocomial pathogens.