Asymptomatic cases

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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).

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

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during follow-up, but biases in study designs limit the certainty of this estimate (Buitrago-Garcia 2020). In seven studies of defined populations screened for SARS-CoV-2 and then followed, 31% (95% CI 26%–37%) remained asymptomatic. Another review found that asymptomatic persons seem to account for approximately 40-45% of infections, and that they can transmit the virus to others for an extended period, perhaps longer than 14 days. The absence of COVID-19 symptoms might not necessarily imply an absence of harm as subclinical lung abnormalities are frequent (Oran 2020). The probable best data come from 3,600 people on board the cruise ship Diamond Princess (Mizumoto 2020) who became involuntary actors in a “wellcontrolled experiment” where passengers and crew comprised an environmentally homogeneous cohort. Due to insufficient hygienic conditions, > 700 people became infected while the ship was quarantined in the port of Yokohama, Japan. After systematic testing, 328 (51,7%) of the first 634 confirmed cases were found to be asymptomatic. Considering incubation periods between 5,5 and 9,5 days, the authors calculated the true asymptomatic proportion at 17,9% (Mizumoto 2020). The outbreak at the aircraft carrier USS Theodore Roosevelt revealed that 146/736 infected sailors (19,8%) remained asymptomatic for the duration of the study period.

Table 1. Larger studies with defined populations; proportion of asymptomatic patients (LTF = long-term facilities)

Population, n Asymptomatic

Kasper 2020 US Aircraft carrier, mainly young sailors and crew members (n=1.271) 43%

Borras-Bermejo 2020 Nursing Homes Spain, residents (n=768) and staff (n = 403) 68% of residents, 56% of staff (including pre-symptomatic)

Feaster 2020 LTFs California, residents and staff (n = 631) 19-86% of residents, 17-31% of staff

Gudbjartsson 2020 Icelandic Population (n = 1,221) 43% (including presymptomatic)

Hoxha 2020 LTFs Belgium, residents (n = 4059) and staff (n = 2185) Lavezzo 2020 (Small town) Vo, Italy, all residents (n = 2812) Marossy 2020 LTFs London (n = 2455) 75% of residents, 74% of staff (including pre-symptomatic)

43%

51% of residents, 69% of staff

There is no doubt that asymptomatic patients may transmit the virus (Bai 2020, Rothe 2020). In several studies from Northern Italy or Korea, viral loads in nasal swabs did not differ significantly between asymptomatic and symptomatic subjects, suggesting the same potential for transmitting the virus