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monitoring or quarantine. Another analysis of 158 confirmed cases outside Wuhan estimated a similar median incubation period of 5,0 days (95 % CI, 4,4 to 5,6 days), with a range of 2 to 14 days (Linton 2020). In a detailed analysis of 36 cases linked to the first three clusters of circumscribed local transmission in Singapore, the median incubation period was 4 days with a range of 1-11 days (Pung 2020). Taken together, the incubation period of around 4-6 days is in line with that of other coronaviruses causing SARS or MERS (Virlogeux 2016). Of note, the time from exposure to onset of infectiousness (latent period) may be shorter. There is little doubt that transmission of SARS-CoV-2 during the late incubation period is possible (Li 2020). In a longitudinal study, the viral load was high 2-3 days before the onset of symptoms, and the peak was even reached 0.7 days before the onset of symptoms. The authors of this Nature Medicine paper estimated that approximately 44% (95% CI 25-69%) of all secondary infections are caused by such pre-symptomatic patients (He 2020).
Asymptomatic cases Understanding the frequency of asymptomatic patients and the temporal course of asymptomatic transmission will be crucial for assessing disease dynamics. It is important to distinguish those patients who will remain asymptomatic during the whole time of infection and those in which infection is still too early to cause symptoms (pre-symptomatic). While physicians need to be aware of asymptomatic cases, the true percentage is difficult to assess. To evaluate symptoms systematically is not trivial and the ascertainment process could lead to misclassification. If you do not ask precisely enough, you will get false negative answers. If questions are too specific, the interviewees may give false positive answers (confirmation bias). For example, in a large study, only two thirds of patients reporting olfactory symptoms had abnormal results in objective olfactory testing (see below). What is a symptom? And, is it possible to interview the demented residents of a nursing home? Sweet grandma will say she was fine over the last few weeks. A nice review addressed the three main methodological issues that hinder attempts to estimate the proportion of asymptomatic or pre-symptomatic individuals. First, incomplete symptom assessment may overestimate the asymptomatic fraction; second, studies with inadequate follow-up misclassify pre-symptomatic individuals; and third, serological studies might identify people with previously unrecognised infection, but reliance on poorly defined antibody responses and retrospective symptom assessment might result in misclassification (Meyerowitz 2020). In a living systematic review (through June 10, 2020, analyzing 79 studies in a range of different settings), 20% (95% CI 17%–25%) remained asymptomatic Kamps – Hoffmann
