Infection

Incubation period

(Last update 21 September 2021)

The incubation period is the time between exposure to a virus and the development of symptoms (referred to as symptom onset). Based on data available from studies investigating infections with ancestral strains of SARS-CoV-2, the incubation period of COVID-19 is five to six days on average (range: two to 14 days). Some studies, including modelling studies, have suggested that most symptomatic cases are expected to have an incubation period of between two and 12 days [1-6]. This information is important for determining when testing should be done. However, some evidence suggests that the incubation period of more recent SARS-CoV-2 variants could be shorter than that of ancestral strains [7-10].

Infectivity, viral shedding, and viral load

(Last update 21 September 2021)

Infectivity

The exact duration of infectivity of COVID-19 patients (the period during which they can transmit the virus to others) may vary between variants and by vaccination status. However, isolation of live virus from clinical samples, which is used as a surrogate in measuring infectivity, is rarely performed. In studies of non-severe cases, the virus was successfully isolated up to 10 days from the onset of symptoms [11-16]. Limited data indicate that immunocompromised patients have a prolonged infectivity period, e.g. >20 days after symptom onset [17-19].

Viral shedding

Viral shedding, defined as ‘a qualitative description of disease status determined by a positive SARS-CoV-2 RT-PCR test result’ [20], indicates the presence of viral genetic material but does not always indicate infectivity. Viral shedding also occurs in asymptomatic infections and can begin before symptom onset and clinical diagnosis [21].

A pre-print study of individual patient data including 7 340 observations of viral shedding analyses estimated a median duration of viral shedding in respiratory samples of 4.76 days (95% confidence interval (CI): 3.44–5.11) and in gastrointestinal samples of 4.94 days (95% CI: 4.09–5.8) [20]. A systematic review and metanalysis estimated a duration of viral shedding of 17.0 days (maximum shedding duration: 83 days) in upper respiratory tract samples, 14.6 days (maximum: 59 days) in lower respiratory tract samples, 17.2 days (maximum: 35 days) in stool samples, and 16.6 days (maximum: 60 days) in serum samples [22].

However, some COVID-19 patients have positive RT-PCR results long after (e.g. 60 to >100 days) initial diagnosis and clinical diagnosis [22-26]. Studies in hospitalised COVID-19 patients have found that the RT-PCR test for SARS-CoV-2 could remain positive in respiratory samples for up to six weeks from illness onset [27,28]. Some evidence is emerging that these cases were not linked with secondary transmission [29,30]. Prolonged shedding of SARS-CoV-2 RNA has been shown even after seroconversion [29-31].

Several factors have been associated with prolonged viral shedding, such as symptomatic infection [32], severe disease [17,23,33], advanced age (>60 years) [32], delayed diagnosis, some chronic diseases (e.g. cancer), immunodeficiency disorders and corticosteroid treatment [17,32]. Available evidence indicates that there is no association between sex and duration of viral shedding [17].

Viral load

Viral load, defined as a ‘quantitative viral titre (e.g. copy number)’ [20], is a useful marker for assessing viral kinetics, disease severity and prognosis.

A pooled analysis of individual patient data including 5 328 observations of viral load estimated that SARS-CoV-2 viral load peaked prior to symptom onset [20]. Similar results have been reported from a mathematical model, which predicted that viral load peaks, on average, one day before symptom onset [34]. SARS-CoV-2 viral load in respiratory samples peaks during the prodromal phase and then decreases steadily afterwards [20].

Patients with severe disease have significantly higher viral loads than patients with mild disease [20]. Advanced age (>60 years) has also been associated with higher viral loads [20,34,35]. However, it has been shown that children have viral loads similar to that of adults [36]. Prolonged viral shedding with high viral load have been associated with poor outcomes in hospitalised patients [34].

Impact of the Delta variant of concern (VOC) on transmission, viral load and viral shedding

There is epidemiological evidence that the Delta VOC is more transmissible than the ancestral and Alpha strains, with transmissibility nearly double that of the wild-type SARS-CoV-2 virus that circulated during autumn 2020 [10,37-40]. This increased transmissibility was a key factor in the rapid dominance of the Delta VOC. Only a few studies have assessed the virological characteristics of the Delta VOC and showed heterogenic results. Current evidence suggests that the Delta variant has a reduced incubation period, as well as higher viral loads and prolonged duration of viral shedding (up to 18 days) [8,41,42]. Two pre-prints estimated that infected individuals are most infectious during the early stages of infection, with peak infectiousness at 2.1 days before symptom onset, and observed that they maintained high viral loads for up to seven days after symptom onset [8,10].

Impact of prior infection and vaccination on viral load and viral shedding

At present, there is limited evidence on viral load or duration of viral shedding after reinfection or a breakthrough infection (i.e. an infection in a fully vaccinated individual). Studies of viral load in SARS-CoV-2-positive individuals conducted from late 2020 to early 2021 indicated that viral load was reduced in those who had received a COVID-19 vaccine. Very recent results indicate that vaccination may have less effect in initially reducing viral load in infections caused by the Delta VOC [43,44]. However, a reduced duration and lower probability of infectivity in vaccinated individuals has been suggested by two recently published pre-prints that compared vaccinated individuals to unvaccinated individuals: a multicentre, retrospective cohort study from Singapore reported a faster decline in viral loads and a study on healthcare workers from the Netherlands showed a lower probability of infectious virus detection in respiratory samples [45,46].

Reinfection

(Last update 21 September 2021)

In September 2020, ECDC published a threat assessment brief in response to a small number of published case reports documenting suspected or possible reinfections in individuals that had recovered from prior episodes of SARS-CoV-2 infection [43]. This brief highlighted the challenges in determining whether such reports represent true reinfections, persistent viral shedding, or recurrence of positive (re-positive) PCR diagnostic tests [47]. Additional lines of investigation to support a diagnosis of reinfection were also highlighted and included genetic sequencing to compare virus isolates from the initial infection with those from the suspected reinfection episode.

A diagnosis of true reinfection with SARS-CoV-2 can only be established when viral clearance is complete for the first episode of infection, and sufficient time has elapsed to allow for immune responses to be mounted. Re-positive PCR tests have been widely reported in convalescent patients. However, in the absence of a documented symptom-free period and supportive diagnostic sequencing, it is difficult to exclude fluctuations in viral shedding or false-negative results when viral loads are low [48-51].

Reinfection incidence and surveillance in the EU/EEA

While reinfection events appear to be rare (studies from Denmark, Czechia and the United Kingdom suggest they amount to less than 1% of documented SARS-CoV-2-positive cases [52-54]), there is currently limited population-level data available that captures the burden of reinfection cases at the national level and over time. A survey of EU/EEA countries conducted by ECDC in January 2021 revealed that the majority of the 17 countries that responded reported having a working case definition and a national reporting system to capture reinfection cases. These definitions, although similar, were not standardised [55]. In order to better ascertain the burden and impact of SARS-CoV-2 reinfection across the EU/EEA, particularly in the context of emerging variants with immune escape potential, ECDC has established a surveillance case definition for suspected reinfection and has introduced new case-based and aggregate variables to improve systematic reporting via The European Surveillance System (TESSy) [56]. A suspected COVID-19 reinfection case is defined as:

Positive polymerase chain reaction (PCR) or rapid antigen detection test (RADT) sample ≥60 days following:

  • previous positive PCR,
  • previous positive RADT, or
  • previous positive serology (anti-spike IgG Ab).

This case definition takes into account the time required to mount a neutralising antibody response and the variability of neutralising antibody dynamics following infection with SARS-CoV-2, the potential risk of early immune escape posed by emerging VOCs, as well as existing surveillance practices and reporting capabilities among EU/EEA countries. To collect data on suspected reinfection cases via TESSy, an update to the metadata was implemented on 12 March 2021; more information can be found in the latest reporting protocol [55]. Standardised surveillance reporting protocols for suspected reinfection cases within the EU/EEA will facilitate the assessment of:

  • the total number and incidence of suspected reinfection cases,
  • the risk of suspected reinfection by VOCs, and
  • the severity of suspected reinfection cases, as compared to first episodes of infection.

Depending on the quality of data submitted to TESSy on suspected reinfection cases, these outputs will be considered for inclusion in ECDC’s COVID-19 country overview reports [56].

 

References

Supporting document: List of references