Symptom experience before vs. after confirmed SARS-CoV-2 infection: a population and case control study using prospectively recorded symptom data. (preprint)

Background: Some individuals experience prolonged illness after acute COVID-19. We assessed whether pre-infection symptoms affected post-COVID illness duration. Methods Survival analysis was performed in adults (n=23,452) with community-managed SARC-CoV-2 infection prospectively self-logging data through the ZOE COVID Symptom Study app, at least weekly, from 8 weeks before to 12 weeks after COVID-19 onset, conditioned on presence vs. absence of baseline symptoms (4-8 weeks before COVID-19). A case-control study was performed in 1350 individuals with long illness ([≥]8 weeks, 906 [67.1%] with illness [≥]12 weeks), matched 1:1 (for age, sex, body mass index, testing week, prior infection, vaccination, smoking, index of multiple deprivation) with 1350 individuals with short illness (<4 weeks). Baseline symptoms were compared between the two groups; and against post-COVID symptoms. Findings: Individuals reporting baseline symptoms had longer post-COVID symptom duration (from 10 to 15 days) with baseline fatigue nearly doubling duration. Two-thirds (910 of 1350 [67.4%]) of individuals with long illness were asymptomatic beforehand. However, 440 (32.6%) had baseline symptoms, vs. 255 (18.9%) of 1350 individuals with short illness (p<0.0001). Baseline symptoms increased the odds ratio for long illness (2.14 [CI: 1.78; 2.57]). Prior comorbidities were more common in individuals with long vs. short illness. In individuals with long illness, baseline symptomatic (vs. asymptomatic) individuals were more likely to be female, younger, and have prior comorbidities; and baseline and post-acute symptoms and symptom burden correlated strongly. Interpretation: Individuals experiencing symptoms before COVID-19 have longer illness duration and increased odds of long illness. However, many individuals with long illness are well before SARS-CoV-2 infection.

Vaccination against SARS-CoV-2 in UK school-aged children and young people decreases infection rates and reduces COVID-19 symptoms (preprint)

Background We aim to explore the effectiveness of one-dose BNT162b2 vaccination upon SARS-CoV-2 infection rates in children and young people (CYP) during Delta and Omicron variant predominance in the UK, and study its effect on COVID-19 presentation and post-vaccination symptoms. Methods In this prospective longitudinal cohort study, we analysed data from 115,775 CYP aged 12-17 years, proxy-reported through the Covid Symptom Study (CSS) smartphone application. We calculated post-vaccination infection risk after one dose of BNT162b2. We described the illness profile of CYP with post-vaccination SARS-CoV-2 infection, compared to unvaccinated CYP. Findings Between August 5, 2021 and February 14, 2022, 25,971 UK CYP aged 12-17 years received one dose of BNT162b2 vaccine. Vaccination reduced infection (reporting) risk (-80.4% and -53.7% at 14-30 days with Delta and Omicron variants respectively, and -61.5% and -63.7% after 61-90 days). The probability of remaining infection-free diverged after vaccination, and was more robust with prior infection. Vaccinated CYP who contracted SARS-CoV-2 during the Delta period had milder disease than unvaccinated CYP; however, during the Omicron period this was only evident in children aged 12-15 years, and overall disease profile was similar in both vaccinated and unvaccinated CYP. Post-vaccination local side-effects were common, systemic side-effects were uncommon, and both resolved quickly. Interpretation One dose of BNT162b2 vaccine reduced risk of SARS-CoV-2 infection for at least 90 days in CYP aged 12-17 years. Vaccine protection was modulated by SARS-CoV-2 variant type (lower for Omicron than Delta variant), and was enhanced by pre-vaccination SARS-CoV-2 infection. Severity of COVID-19 presentation after vaccination is generally milder, although unvaccinated CYP also have an uncomplicated course. Overall, vaccination was well-tolerated.

Illness characteristics of COVID-19 in children infected with the SARS-CoV-2 Delta variant (preprint)

Background The Delta (B.1.617.2) SARSCoV2 variant became the predominant UK circulating strain in May 2021. Whether COVID19 from Delta infection differs to infection with other variants in children is unknown. Methods Through the prospective COVID Symptom Study, 109,626 UK school-aged children were proxy-reported between December 28, 2020 and July 8, 2021. We selected all symptomatic children who tested positive for SARS-CoV-2 and were proxy-reported at least weekly, within two timeframes: December 28, 2020 to May 6, 2021 (Alpha (B.1.1.7) the main UK circulating variant); and May 26 to July 8, 2021 (Delta the main UK circulating variant). We assessed illness profiles (symptom prevalence, duration, and burden), hospital presentation, and presence of long (>28 day) illness; and calculated odds ratios for symptoms presenting within the first 28 days of illness. Findings 694 (276 younger [5 11 years], 418 older [12 17 years]) symptomatic children tested positive for SARS-CoV-2 with Alpha infection and 706 (227 younger and 479 older) children with Delta infection. Median illness duration was short with either variant (overall cohort: 5 days (IQR 2 9.75) with Alpha, 5 days (IQR 2 9) with Delta). The seven most prevalent symptoms were common to both variants. Symptom burden over the first 28 days was slightly greater with Delta compared with Alpha infection (in younger children, 3 (IQR 2 5) with Alpha, 4 (IQR 2 7) with Delta; in older children 5 (IQR 3 8) with Alpha and 6 (IQR 3 9) with Delta infection in older children). The odds of several symptoms were higher with Delta than Alpha infection, including headache and fever. Few children presented to hospital, and long illness duration was uncommon, with either variant. Interpretation COVID-19 in UK school-aged children due to SARSCoV2 Delta strain B.1.617.2 resembles illness due to the Alpha variant B.1.1.7., with short duration and similar symptom burden.

Illness duration and symptom profile in a large cohort of symptomatic UK school-aged children tested for SARS-CoV-2 (preprint)

Background In children, SARS-CoV-2 is usually asymptomatic or causes a mild illness of short duration. Persistent illness has been reported; however, its prevalence and characteristics are unclear. We aimed to determine illness duration and characteristics in symptomatic UK school-aged children tested for SARS-CoV-2 using data from the COVID Symptom Study, the largest citizen participatory epidemiological study to date. Methods Data from 258,790 children aged 5-17 years were reported by an adult proxy between 24 March 2020 and 22 February 2021. Illness duration and symptom profiles were analysed for all children testing positive for SARS-CoV-2 for whom illness duration could be determined, considered overall and within younger (5-11 years) and older (12-17 years) age groups. Data from symptomatic children testing negative for SARS-CoV-2, matched 1:1 for age, gender, and week of testing, were also assessed. Findings 1,734 children (588 younger children, 1,146 older children) had a positive SARS-CoV-2 test result and calculable duration of illness with the study time frame. The commonest symptoms were headache (62.2%) and fatigue (55.0%). Median illness duration was six days (vs. three days in children testing negative); and was positively associated with age (rs 0.19, p<1.e-4) with median duration seven days in older vs. five days in younger children. Seventy-seven (4.4%) children had illness duration =>28 days (LC28); LC28 was more common in older compared with younger children (59 (5.1%) vs. 18 (3.1%), p=0.046). The commonest symptoms experienced by children with LC28 were fatigue (84.4%), headache and anosmia (both 77.9%); however, by day 28 the median symptom burden was two. Only 25 (1.8%) of 1,379 children experienced symptoms for [≥]56 days. Few children (15 children, 0.9%) in the negatively-tested cohort experienced prolonged symptom duration; however, these children experienced greater symptom burden (both throughout their illness and at day 28) than children positive for SARS-CoV-2. Interpretation Some children with COVID-19 experience prolonged illness duration; reassuringly, symptom burden in these children did not increase with time, and most recovered by day 56. Some children who tested negative for SARS-CoV-2 also had persistent and burdensome illness. Thus, a holistic approach for all children with persistent illness during the pandemic is required.

Anosmia and other SARS-CoV-2 positive test-associated symptoms, across three national, digital surveillance platforms as the COVID-19 pandemic and response unfolded: an observation study (preprint)

Background: Multiple participatory surveillance platforms were developed across the world in response to the COVID-19 pandemic, providing a real-time understanding of community-wide COVID-19 epidemiology. During this time, testing criteria broadened and healthcare policies matured. We sought to test whether there were consistent associations of symptoms with SARS-CoV-2 test status across three national surveillance platforms, during periods of testing and policy changes, and whether inconsistencies could better inform our understanding and future studies as the COVID-19 pandemic progresses. Methods: Four months (1st April 2020 to 31st July 2020) of observation through three volunteer COVID-19 digital surveillance platforms targeting communities in three countries (Israel, United Kingdom, and United States). Logistic regression of self-reported symptom on self-reported SARS-CoV-2 test status (or test access), adjusted for age and sex, in each of the study cohorts. Odds ratios over time were compared to known changes in testing policies and fluctuations in COVID-19 incidence. Findings: Anosmia/ageusia was the strongest, most consistent symptom associated with a positive COVID-19 test, based on 658325 tests (5% positive) from over 10 million respondents in three digital surveillance platforms using longitudinal and cross-sectional survey methodologies. During higher-incidence periods with broader testing criteria, core COVID-19 symptoms were more strongly associated with test status. Lower incidence periods had, overall, larger confidence intervals. Interpretation: The strong association of anosmia/ageusia with self-reported SARS-CoV-2 test positivity is omnipresent, supporting its validity as a reliable COVID-19 signal, regardless of the participatory surveillance platform or testing policy. This analysis highlights that precise effect estimates, as well as an understanding of test access patterns to interpret differences, are best done only when incidence is high. These findings strongly support the need for testing access to be as open as possible both for real-time epidemiologic investigation and public health utility.

SARS-CoV-2 (COVID-19) infection in pregnant women: characterization of symptoms and syndromes predictive of disease and severity through real-time, remote participatory epidemiology. (preprint)

Background: From the beginning of COVID-19 pandemic, pregnant women have been considered at greater risk of severe morbidity and mortality. However, data on hospitalized pregnant women show that the symptom profile and risk factors for severe disease are similar to those among women who are not pregnant, although preterm birth, Cesarean delivery, and stillbirth may be more frequent and vertical transmission is possible. Limited data are available for the cohort of pregnant women that gave rise to these hospitalized cases, hindering our ability to quantify risk of COVID-19 sequelae for pregnant women in the community. Objective: To test the hypothesis that pregnant women in community differ in their COVID-19 symptoms profile and disease severity compared to non-pregnant women. This was assessed in two community-based cohorts of women aged 18-44 years in the United Kingdom, Sweden and the United States of America. Study design: This observational study used prospectively collected longitudinal (smartphone application interface) and cross-sectional (web-based survey) data. Participants in the discovery cohort were drawn from 400,750 UK, Sweden and US women (79 pregnant who tested positive) who self-reported symptoms and events longitudinally via their smartphone, and a replication cohort drawn from 1,344,966 USA women (162 pregnant who tested positive) cross-sectional self-reports samples from the social media active user base. The study compared frequencies of symptoms and events, including self-reported SARS-CoV-2 testing and differences between pregnant and non-pregnant women who were hospitalized and those who recovered in the community. Multivariable regression was used to investigate disease severity and comorbidity effects. Results: Pregnant and non-pregnant women positive for SARS-CoV-2 infection drawn from these community cohorts were not different with respect to COVID-19-related severity. Pregnant women were more likely to have received SARS-CoV-2 testing than non-pregnant, despite reporting fewer clinical symptoms. Pre-existing lung disease was most closely associated with the severity of symptoms in pregnant hospitalized women. Heart and kidney diseases and diabetes were additional factors of increased risk. The most frequent symptoms among all non-hospitalized women were anosmia [63% in pregnant, 92% in non-pregnant] and headache [72%, 62%]. Cardiopulmonary symptoms, including persistent cough [80%] and chest pain [73%], were more frequent among pregnant women who were hospitalized. Gastrointestinal symptoms, including nausea and vomiting, were different among pregnant and non-pregnant women who developed severe outcomes. Conclusions: Although pregnancy is widely considered a risk factor for SARS-CoV-2 infection and outcomes, and was associated with higher propensity for testing, the profile of symptom characteristics and severity in our community-based cohorts were comparable to those observed among non-pregnant women, except for the gastrointestinal symptoms. Consistent with observations in non-pregnant populations, comorbidities such as lung disease and diabetes were associated with an increased risk of more severe SARS-CoV-2 infection during pregnancy. Pregnant women with pre-existing conditions require careful monitoring for the evolution of their symptoms during SARS-CoV-2 infection.

Effects of environmental factors on severity and mortality of COVID-19 (preprint)

BackgroundMost respiratory viruses show pronounced seasonality, but for SARS-CoV-2 this still needs to be documented. MethodsWe examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. FindingsMeta-analysis of the mortality risk in eight European hospitals estimated odds ratios per one day increase in the admission date to be 0.981 (0.973-0.988, p<0.001) and per increase in ambient temperature of one degree Celsius to be 0.854 (0.773-0.944, p=0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to Intensive Care Unit and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. InterpretationSeverity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation. Mucosal barrier and mucociliary clearance can significantly decrease viral load and disease progression, and their inactivation by low relative humidity of indoor air might significantly contribute to severity of the disease.