Long-Term Effects of COVID-19 in Children and Young People: A 24-Month National Cohort Study

doi:10.21203/rs.3.rs-3750111/v1

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Long-Term Effects of COVID-19 in Children and Young People: A 24-Month National Cohort Study

https://doi.org/10.21203/rs.3.rs-3750111/v1

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Background

Most children and young people (CYP) in the United Kingdom have been infected with SARS-COV-2 and some continue to experience impairing symptoms after infection. Using data from a national cohort study, we report on symptoms and their impact 24 months post-infection for the first time.

Methods

The CloCk study is a national cohort in England, of CYP aged 11-to-17-years when they had a SARS-CoV-2 PCR test between September 2020 and March 2021. Of 31,012 CYP invited to complete a questionnaire 24-months post-PCR test, 12,632 CYP participated and were included in our analytic sample (response rate=40·7%). CYP were divided into four groups depending on their infection status: ‘initial test-negatives with no subsequent positive test’ (NN); ‘initial test-negatives with a subsequent positive test’ (NP); ‘initial test-positives with no report of subsequent re-infection’ (PN); and ‘initial test-positives with report of subsequent re-infection’ (PP). We examined whether symptom profiles 24-months post index-test differed by infection status using chi-squared or Mann-Whitney tests.

Findings

7.2% of CYP consistently fulfilled the definition of PCC at 3-, 6-, 12- and 24-months. These young people had a median of 5 or 6 symptoms at each time point. Between 20-25% of all four infection status groups reported 3 or more symptoms 24 months after testing and 10-25% of CYP experienced 5+ symptoms, with the reinfected (PP) group having more symptoms than the other two positive groups (NP and PN); the NN group had the lowest symptom burden (p<0.001). Symptoms or their impact did not vary by vaccination status.

PCC was more common in older (vs. younger) CYP and in the most (vs. least) deprived quintile. PCC was almost twice as common in females (vs. males) in both infection status groups.

Interpretation

The discrepancy in the proportion of CYP who fulfilled the Delphi consensus PCC definition at 24 months and those who consistently fulfilled the definition across time with multiple symptoms, highlights the importance of longitudinal studies and the need to consider clinical impairment and range of symptoms. Relatedly, further studies are needed to understand the pathophysiology, develop diagnostic tests and identify effective interventions for young people who continue to be significantly impaired by PCC.

Funding

This work is independent research jointly funded by The Department of Health and Social Care, in their capacity as the National Institute for Health Research (NIHR), and by UK Re-search & Innovation (UKRI) who have awarded funding grant number COV-LT-0022. The Department of Health and Social Care, as the NIHR, and UKRI were not involved in study design, data collection, analysis or interpretation of the data, nor the writing of the present study or the decision to submit the article for publication. All research at Great Ormond Street Hospital NHS Foundation Trust and UCL Great Ormond Street Institute of Child Health is made possible by the NIHR Great Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, UKRI or the Department of Health. SMPP is supported by a UK Medical Research Council Career Development Award (ref: MR/P020372/1).

Copyright

For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising.

Health sciences/Medical research/Paediatric research

Health sciences/Health care/Public health

Post Covid-19 condition

long COVID

young people

prospective

Post-COVID-19 condition (PCC), also called long COVID, in children and young people (CYP) under 18 years old is a difficult area of research, with many challenges compared to other classical epidemiological studies.^1,2. In the absence of a consistent surrogate outcome, proxy biomarker or specific imaging finding for PCC, early in the pandemic, Delphi consensus methodology provided a research definition of PCC.³ However, relatively few research studies on long COVID use any definition, further increasing the challenge of conducting research in this area.⁴ Additional complications are that many people were infected with SARS-CoV-2 before diagnostic tests were developed; most symptoms other than loss of taste and smell are not condition-specific; and there is variability in time and frequency of vaccinations in relation to SARS-CoV-2 infection. As the pandemic progressed, repeated waves of new SARS-CoV-2 variants and mass infection made it impossible to compare infected young people to an uninfected group. Finally, the general disruption to the lives of CYP due to the COVID-19 pandemic may contribute to somatic symptomatology as may a chronic post-viral syndrome.⁵

A recent systematic review emphasised that current evidence is dominated by smaller and often single site studies, frequently without using a recognised PCC definition and with short follow-up.^6,7 It is important to follow-up young people longitudinally to understand the natural course of symptoms after SARS-CoV-2 infection due to the impact on both public health and clinical care. One large scale, national study, that operationalises a published PCC Delphi research definition, is the CLoCk study. This study has reported findings on PCC in 20,202 CYP 12-months after their initial PCR test.^8,9

In previous CLoCk publications, test-positive CYP were compared to laboratory-confirmed SARS-CoV-2 test-negative CYP. However, by June 2022, 82-99% of CYP had SARS-CoV-2 antibodies, consistent with prior infection and/or COVID-19 vaccination.¹⁰ Therefore, it is no longer possible to compare test-positive with test-negative CYP from the CLoCk study. Instead, here we report on symptoms 24-months post-testing on four groups of CYP: ‘initial test-negatives with no subsequent positive test’ (negative-negative’ NN); ‘initial test-negatives with a subsequent positive test’ (negative-positive; NP); ‘initial test-positives with no report of subsequent re-infection’ (positive-negative; PN); and ‘initial test-positives with report of subsequent re-infection’ (positive-positive; PP). We report on over 12,600 CYP aged 11-17-years who underwent PCR testing between September 2020 and March 2021 with prospective data at 24-months after their initial PCR test. We operationalise the Delphi definition of PCC 24-months post PCR-testing to address questions about the profile, persistence and impact of symptoms post-infection.

Specifically, we hypothesised that:

(1) members of all four groups of CYP would have some symptoms 24-months after initial testing

(2) the most common symptoms would include some of tiredness, sleeping difficulties, shortness of breath, abdominal pain, concentration difficulties, muscle pain and headaches as identified in previous PCC studies ^6,11,12

(3) older CYP, females and CYP from ethnic minorities will have a higher PCC prevalence

(4) the PP group would have more symptoms and with greater impact than the two other positive groups (i.e., NP and PN)

(5) symptoms would not differ by vaccination status, as identified in our previous PCC studies⁸

The CLoCk study, described in detail elsewhere is a cohort study of SARS-CoV-2 PCR-positive CYP.¹³ Briefly, CYP who PCR-tested positive between September 2020 and March 2021 when they were aged 11-to-17-years, were matched at study invitation on month of test, age, sex, and geographical area to SARS-CoV-2 test-negative CYP using the SARS-CoV-2 testing dataset held by the United Kingdom Health Security Agency (UKHSA). After obtaining written informed consent, CYP completed an online questionnaire about their health at the time of their SARS-CoV-2 PCR test (“baseline”; retrospectively reported) and at approximately 3-, 6-, 12- and 24-months after their index-PCR test (with different numbers of respondents at each time point depending on the time of recruitment into the study, relative to their test date).

The dataset held by UKHSA can track repeated testing longitudinally within individuals. In addition, at each contact, we asked CYP if they ever tested positive for SARS-CoV-2 (by PCR or Lateral Flow Tests). Using both information on subsequent testing held by UKHSA and from self-report, we divided the CYP into the four groups: NN; NP; PN and PP (Figure 1).

Measures

The CLoCk questionnaire included demographics, elements of the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) Paediatric COVID-19 questionnaire, the recent Mental Health of Children and Young People in England surveys and originally included 21 symptoms (mostly assessed as present/absent).^6,11,12The validated health scales: the Strengths and Difficulties Questionnaire (SDQ),¹⁴ Short Warwick Edinburgh Mental Wellbeing Scale (SWEMWS),¹⁰Chalder Fatigue Scale,¹⁵and the EQ-5D-Y¹⁶ as a measure of quality of life and function, were also included. The CLoCk questionnaire was largely unchanged between study enrolment and subsequent follow-ups: redundant questions (e.g., demographics, symptoms at time of testing etc.) were removed at follow-ups, and a number of new questions were added (e.g., sleeping difficulties, a symptom severity scale, a symptom impact scale, and questions on the type of COVID-19 vaccination received and date each dose was administered) by the 24-month data collection sweep.¹³

The Delphi research definition of PCC in CYP³ was operationalised at the time of questionnaire completion (i.e., 24-months post-index test) as experiencing ≥1 symptom AND problems with mobility OR self-care OR doing usual activities OR having pain/discomfort OR feeling very worried/sad, based on the EQ-5D-Y scale. CYP meeting this operationalised research definition at 24-months post-index test were classified as having PCC at that time. Vaccination status (dosage: 0, 1, 2, 3+) was determined from information held at UKHSA; when information was missing (n=361), self-reported information from the 24-month post-index test questionnaire was used.

Statistical Methods

To assess representativeness of study participants, we compared their demographic characteristics (sex, age, ethnicity, region of residence, and Index of Multiple Deprivation) to the population invited to take part at 24-months, by infection status. To describe the symptom profiles in all four groups 24-months after initial testing, we tabulated the total number of symptoms (0,1, 2, 3, 4 and 5+) reported, prevalence of individual symptoms, self-rated health and symptom severity and impact 24-months post index-test. We examined the prevalence of individual symptoms visually. We assessed prevalence of meeting the PCC research definition 24-months post index-test by infection status. For the NN group the requirement of a positive test was excluded. We were unable to always confirm with certainty the last date of a positive test in the NP and PP groups because we used self-reported information on having a positive test (but date of positive test was not recorded). Hence, 24-months post index-test, for these two groups, we could not differentiate with confidence acute versus long-term COVID symptoms. Therefore, prevalence of PCC in the NP and PP groups was not determined. We examined study participant characteristics and 24-months post index-test health and wellbeing (via validated scales) stratified by infection status and PCC status at 24-months. We used chi-squared or Mann-Whitney tests to determine if symptom profiles at 24-months post index-test differed by infection status. Finally, study participant characteristics on validated scales 24-months post index-test, were stratified by infection status groups and vaccination status at 24-months. Most questions in the CLoCk questionnaire were compulsory, so missing data was minimal. However, questions on symptom severity and impact were added part way through 24-month data collection, so only available for a sub-sample. Questions regarding vaccination were optional and therefore had missing data. In this case, vaccination data was primarily used from UKHSA databases and supplemented with self-report: three CYP were excluded when examining vaccination status because their vaccination data was not available from UKHSA databases or self-report.

Data management and analysis were performed using STATA16.0.

Of the 31,012 CYP invited to fill in a questionnaire 24-months post-PCR test, 12,632 CYP participated and were included in our analytic sample (response rate=40·7%; Figure 1). Participating CYP were broadly representative of those invited (Table 1).

24-month follow-up questionnaires were returned at a median of 104.1 weeks [IQR:103·0, 105·6] after the index-PCR test. Prevalence of COVID-19 vaccination by 24-months varied from 90% (4,079/4,531) for the NN group to 78·2% (406/519) for the PP group (Supplementary Table 1). For the PP and NP groups, we are unable to determine the chronology of (re)infection and vaccination due to the self-report nature of the questionnaire.

At 24-months post index-test, all infection status groups reported symptoms, with tiredness, trouble sleeping, shortness of breath and headaches being most prevalent (Table 2, Figure 2). However, symptom profiles differed by infection status. In general, the NN group had the lowest prevalence of symptoms, with the NP and PN groups having a higher prevalence and the PP group having the highest prevalence. For example, for tiredness, the prevalence was 38% (1,736/4,534) in the NN group, ~45% (1,070/2,402) in the NP and PN (2,336/5,177) groups and 48% (249/519) in the PP group (p<0.001). Due to variation in prevalence of reported symptoms by infection status, the total number of reported symptoms also varied by infection status. For example, no symptoms ranged from 35·5% (184/519) in the PP group to 46·2% (2,093/4,534) in the NN group, while 5+ symptoms were reported by 14·2% (643/4,534) of NN to 20·8% (108/519) of PP CYP (p<0·001). Similarly, GP consultations over the 24-month period in relation to COVID-19 varied from 7·7% (348/4,534) in the NN group to 14·6% (76/519) in the PP group. In contrast, there was little difference in self-rated overall health, symptom severity or symptom impact at 24-months by infection status (p>0.10; Table 2).

Approximately one-quarter of CYP fulfilled the broad Delphi research definition of PCC 24-months after either a negative or positive PCR test (Table 3). PCC was more common in older than younger CYP and in the most, compared to the least, deprived quintile. Strikingly, PCC was almost twice as common in females compared to males in both infection status groups. There was little difference by ethnicity, with the exception of PCC in the PN group, but not the NN group, being reported in over one-third of CYP self-defining as ‘other’.

When examining the 943 index-test positive CYP with data at 3-, 6-, 12- and 24-months post index-test longitudinally, 233 (24.7% of 943) fulfilled the PCC Delphi research definition at 3-months follow-up, 135 (14.3%) continued to fulfil the PCC Delphi research definition at 6-months , and 94 (10.0%) continued to fulfil the PCC Delphi research definition at 12-months. Only 68 of these 943 CYP (7.2%) continued to fulfil the PCC Delphi research definition at the 24-month follow-up. Therefore, 7.2% consistently fulfilled the PCC Delphi research definition at 3-, 6-, 12- and 24-months (Figure 3). These 68 CYP reported a median of 5 symptoms (IQR 3,6) at 3-months, 5 symptoms (IQR 3,7) at 6-months, 6 symptoms (IQR 4, 8.75) at 12-months and 5 symptoms (IQR 3.25, 8) at 24-months post-index testing.

Table 3 shows that, at 24-months, for those fulfilling the PCC Delphi research definition after either a negative or positive PCR test, SDQ scores were higher indicating more difficulties, SWEMBS were lower indicating worse quality of life, and Chalder fatigue scale scores were higher indicating more tiredness compared to those not meeting the PCC Delphi research definition . Likewise, self-rated health was lower while symptom severity and symptom impact were higher in those fulfilling the PCC Delphi research definition, again irrespective of baseline PCR-test result.

Supplementary Table 1 shows that across all four infection status groups, vaccination uptake was lower for younger, compared to older CYP. In general, white CYP were more likely to be vaccinated compared to non-white CYP (especially Black African or Caribbean). However, much more striking is that across groups, CYP in the most deprived quintile were three times more likely to be unvaccinated compared to those in the least deprived quintile.

Supplementary Table 2 shows that irrespective of infection status, vaccinated versus unvaccinated, there were no obvious trends in numbers of symptoms reported, health, well-being or symptom impact or severity at 24-months.

Consistent with our hypotheses, a proportion of all four groups of CYP reported symptoms 24 months after initial testing, and the most common symptoms were tiredness, trouble sleeping, shortness of breath and headaches. While tiredness was the most prevalent symptom across all infection groups, the prevalence of abdominal pain, concentration difficulties (i.e., confusion, disorientation, or drowsiness) and muscle pain were relatively low. Although approximately one-quarter of all groups met the PCC Delphi research definition, only 7.2% met the criteria at all time points. This group consistently had a median of 5 or 6 symptoms and were therefore similar to the profile of young people seeking treatment for PCC from clinical services, the majority of whom had 5 or more symptoms at the time of seeking help.¹⁷

Older CYP and females were more likely to fulfil the PCC Delphi research definition 24-months post-testing. Although all ethnicities were equally likely to fulfil PCC, it was noticeable that non-white CYP were much less likely to be vaccinated. The reinfected (PP) group had more symptoms than the other two positive groups (i.e., NP, PN) as well as more GP consultations related to COVID-19 and hospital attendance, acknowledging the percentage of such consultations and attendances was small. We did not find that symptoms or their impact differed by vaccination status. Importantly, there was no significant difference in self-rated overall health, symptom severity or symptom impact at 24-months by infection status.

The symptoms reported are comparable with other studies in young people in terms of the prevalence and wide range of symptoms,^18,19 although, to our knowledge, no previous study has reported symptoms at 24 months post-infection. The most common symptoms in adults which have been reported at 24-month post-infection are shortness of breath, dizziness, heart racing, headaches, back pain, chest pain, fatigue and trouble sleeping.²⁰ These findings are similar to our current CYP study: at 24-month follow-up, the most common symptoms were tiredness, trouble sleeping, shortness of breath and headache with overall symptom prevalence generally higher in those with recurrent SARS-CoV-2 infection compare to those who never tested positive for the virus. In adults, the veterans’ study showed that the population that exhibited a second infection was different to the population that experienced a single infection. However, methodological concerns remain and thus we are cautious about overstating claims regarding re-infection in individual patients.²¹

We found that 5+ symptoms were reported by 14.2% of those who never had a confirmed SARS-CoV-2 infection and 20·8% of those with at least two proven infections. This is similar to other CYP studies of PCC reporting post-infection symptoms even after mild COVID-19.⁷ In a large, recent cross-sectional study of CYP,²² 13·3% of 12-to-17-year-olds with prior symptomatic SARS-CoV-2 infection had persistent symptoms for 3-months or more following COVID-19, mainly loss/change of sense of smell (52.2%) and taste (40.7%). Additionally, one in nine of these children reported a large impact in their ability to carry out day-to-day activities due to their symptoms which is broadly similar to the overall proportion in the CLoCk study seeking help from their GP, albeit, by 24-months follow-up.

Across all 4 sub-groups, self-reported symptoms and health at 24-months were of a similar prevalence to those reported by us at 12-months.⁸ For example, we previously reported that 10% of NN, 16-20% of PNs and NPs and 24% of PPs had 5+ symptoms 12-months post index-test; at 24-months corresponding values were 14% (NN), 17-18% (PN and NP) and 21% (PP).⁸ Essentially, the data show that at 12- and 24-months follow-up, between one-tenth and a quarter of CYP experience 5+ symptoms, depending on which infection-group they fall into. At 24-months, for those fulfilling the PCC Delphi research definition after either a negative or positive index-PCR test, SDQ and Chalder fatigue scores were higher indicating more difficulties and SWEMBS scores were lower indicating poorer well-being; and Chalder fatigue scale scores were higher. Self-rated health was poorer and symptom severity and symptom impact were higher in those fulfilling the PCC Delphi research definition, irrespective of baseline PCR-test result. Therefore, CYP experiencing symptoms at 24-months were more likely to have poorer concurrent physical and mental health compared to those reporting no symptoms, irrespective of their prior SARS-CoV-2 infection status. Importantly, too, the median global ratings of health, symptom impact and severity identified little difference by infection or vaccination status.

We found about one-quarter of CYP fulfilled the published PCC research definition at 24-months after either an initial negative or positive PCR test, perhaps reflecting that by 24-months all CYP are likely to have been infected at least once even if a proportion are asymptomatic and unaware that they have been infected.¹⁰ This could explain the relatively similar proportions meeting the definition in the two groups. It also speaks to the breadth of the PCC Delphi research definition which, in contrast to the WHO definition, does not require symptoms to have arisen within the first three months of infection.³ The types of symptoms reported are known to be prevalent in the general adolescent population, raising questions about the role of the initial SARS-CoV-2 infection in their aetiology.^23,24 In previous studies which have included control groups, using either children with no serologic evidence of previous SARS-CoV-2 infection or children that never received a positive molecular diagnosis of SARS-CoV-2, persisting symptoms were reported by many CYP, irrespective of SARS-CoV-2 infection or antibody status.^9,25–28Post-viral fatigue has also been described after the 1918 influenza pandemic, ‘swine flu’ epidemic of influenza A (H1N1), Ebolavirus, and tick-born encephalitis. After mononucleosis, Q-fever, and giardiasis, prospective cohort studies report that 10-15% of patients experience moderate to severe disability, meeting the diagnostic criteria for post-infective fatigue syndrome.²⁹ For SARS-CoV-2, adult studies have found a correlation between autoantibodies and acute SARS-CoV-2 infection severity^30–32 and between viral load and PCC prevalence.³³

Despite the growing volume of research on lasting symptoms after COVID-19, a definition of PCC has not been universally agreed. In addition to the Delphi Consensus Definition for PCC in CYP,³ the UK National Institute for Health and Care Excellence,³⁴ the World Health Organization,^2,35and the US Centers for Disease Control and Prevention³⁶ have published operational, clinical definitions of post–COVID-19 condition but all three are different and only the WHO definition applies to CYP. Of 295 studies reviewed in November 2022, almost two-thirds did not comply with any of the definitions,[NO_PRINTED_FORM] highlighting a problem in comparing outcomes between studies of PCC due to differences in definition. Judging by a more recent review from April 2023,³⁷ the Delphi consensus research definition is the only one currently being used for CYP. An important difference between the WHO and Delphi consensus research definition is that the WHO definition^2,35 requires symptoms of PCC to have arisen within three months of the initial infection. This means that new symptoms arising 6- or 12-months post-infection should not be considered as PCC. In our data, including only participants that completed questionnaires at every possible time point from 3-months post-index test, only 7% of CYP fulfilled the definition of PCC at 3-, 6-, 12- and 24-months.

It has been argued that, partly due to lack of testing, it is likely that current estimates are underestimating the true burden of those with PCC.¹ Moreover, cross-sectional studies provide only a static prevalence of symptoms of PCC and as these are likely to vary over time, such studies may underestimate the true burden of PCC within populations. That is why we have published CLoCk data as both ‘snap shots’ of the whole study cohort and longitudinal reports on smaller sub-sets with data at multiple timepoints.⁸These latter analyses show that in CYP, the prevalence of adverse symptoms reported at the time of a positive PCR-test declined over the first 12-months but some test-positives and test-negatives reported adverse symptoms for the first time at six- and 12-months post-test, particularly tiredness, shortness of breath, poor quality of life, poor well-being and fatigue.

Taking together all available data so far, our findings continue to raise important questions about the role of SARS-CoV-2 infection and ongoing symptoms reported by CYP as well as definitions of PCC in CYP. That some CYP will go on the develop persistent symptoms after acute SARS-CoV-2 infection is undeniable, consistent with other post-viral syndromes, and there is emerging evidence of viral persistence in children and immunological biomarkers in adults.⁸ It is, however, unlikely SARS-CoV-2 infection is responsible for all reported symptoms in 54-65% of CYP in our cohort. Whilst some symptoms such as loss of taste or smell are strongly associated with SARS-CoV-2 infection, these improve with time, while most of the other reported symptoms are non-specific and often commonly reported in adolescents, even before the current pandemic. Importantly, too, our findings clearly demonstrate no impact on self-rated health, symptom severity or symptom impact in CYP when assessed by infection or vaccination status.⁸ Nonetheless, CYP reporting symptoms at 24-months follow-up, irrespective of their SARS-CoV-2 infection status, were more likely to have poorer self-rated concurrent physical and mental health compared to those who did not report symptoms at 24-months, highlighting a wider need for assessment and interventions to support the physical and mental health of CYP in the community during critical developmental periods, irrespective of SARS-CoV-2 infection or pandemic effects.

With a response rate of 40·7% we have been able to retain CYP in our study over a long period. Moreover, previous analyses indicate that those taking part in the CLoCk study are broadly representative of CYP in England. Nonetheless, we have stated our study limitations previously, including those of potential selection bias and attrition over time.⁸ In this study, we additionally acknowledge issues around misclassification. For example, some CYP categorised as never having had previous SARS-CoV-2 infection may not be true ‘negatives’ (i.e., NN). False-negative serologic responses are possible after initial infection, negative molecular tests can be false-negative, lack of universal testing and lack of specific symptoms as well as asymptomatic infection may all lead to misclassification.^9,38 Similarly, infections may have gone undetected, especially after the cessation of free community testing in England from April 2022. Therefore, misclassification into the four infection status groups may have occurred, especially in the NN group. Additionally, we did not assess menstruation and some symptoms may be attributable to pre-menstrual syndrome given the high proportion of girls. Importantly, the study primarily focuses on CYP in England, and the findings may not be directly applicable to other populations or countries with different healthcare systems, vaccination rates, and demographics. Finally, the study primarily relied on self-reported symptoms and questionnaires, which may lack the precision of detailed, objective clinical assessments. However, it could be argued that this a strength of the study at this point given that there is no definitive diagnostic test to determine if a patient has PCC and we need to learn about new emerging symptoms, or re-emerging, chronic symptoms from those who are experiencing them.

In conclusion, we found that around one-quarter of CYP fulfilled the Delphi research PCC definition at 24-months after either a negative or positive PCR test but only 7.2% met the definition at all time points and those young people had multiple symptoms. However, there was no evidence that self-rated health, symptom severity or symptom impact varied by infection or vaccination status. Our study highlights the relatively high prevalence of non-specific symptoms in our cohort of CYP. Further studies are needed to understand the pathophysiology, develop diagnostic tests, and identify effective interventions for PCC in CYP.

Contributors

Conceptualization: TSte, SMPP, MDN, ED, AH, EW, IH, TF, TS, TC, RS; Methodology, SMPP, MDN, RS; Software: SMPP, MDN; Validation: SMPP, MDN; Formal Analysis: SMPP, MDN; Investigation: TSte, RS; Resources: LX, Data curation: SMPP, MDN; Writing (draft): TSte, SMPP, MDN, RS; Writing (review): TSte, SMPP, MDN, ED, AH, EW, IH, TF, TS, TC, LX, LFS, RS; Supervision: TSte, SMPP, RS; Funding: TSte, ED, AH, EW, IH, TF, TS, TC and RS.

All authors had full access to the data in the study and had the final responsibility for the decision to submit for publication. SMPP and MDN accessed and verified the data.

Declaration of interests

Terence Stephenson is Chair of the Health Research Authority and therefore recused himself from the Research Ethics Application. Trudie Chalder has been a member of the National Institute for Health and Care Excellence committee for long COVID-19. She has written self-help books on chronic fatigue and has done workshops on chronic fatigue and post-infectious syndromes. All remaining authors have no conflicts of interest.

Data sharing

Data is not publicly available. All requests for data will be reviewed by the Children & Young People with Long COVID-19 (CLoCk) study team to verify whether the request is subject to any intellectual property or confidentiality obligations. Requests for access to the participant-level data from this study can be submitted via email to [email protected] with detailed proposals for approval. A signed data access agreement with the CLoCk team is required before accessing shared data. Code is not made available as we have not used custom code or algorithms central to our conclusions.

Acknowledgments

This work is independent research jointly funded by the National Institute for Health and Care Research (NIHR) and UK Research & Innovation (UKRI), who have awarded funding grant number COVLT0022. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. SMPP is supported by a UK Medical Research Council Career Development Award (ref: MR/P020372/1). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, UKRI, or the Department of Health and Social Care.

Michael Lattimore, UKHSA, as Project Officer for the CLoCk study. Olivia Swann designed the elements of the ISARIC Paediatric COVID-19 follow-up questionnaire, which were incorporated into the online questionnaire used in this study to which all the CLoCk Consortium members contributed.

Ethics and registration details

Ethical approval was provided by the Health Research Authority Yorkshire and the Humber – South Yorkshire Research Ethics Committee (REC reference: 21/YH/0060; IRAS project ID: 293495). This study is registered with the ISRCTN registry (ISRCTN 34804192).

Additional Co-Applicants on the grant application and CLoCk Consortium members (alphabetical):

Marta Buszewicz, University College London, [email protected] (Orcid ID: 0000-0003-4016-5857)

Esther Crawley, University of Bristol, [email protected] (Orcid ID: 0000-0002-2521-0747)

Bianca De Stavola, University College London, [email protected] (Orcid ID: 0000-0001-7853-0528)

Shruti Garg, University of Manchester, [email protected] (Orcid ID: 0000-0002-4472-4583); Dougal Hargreaves, Imperial College London, [email protected] (Orcid ID: 0000-0003-0722-9847)

Shamez Ladhani, UKHSA, [email protected], (Orcid ID: 0000-0002-0856-2476)Michael Levin, Imperial College London, [email protected] (Orcid ID: 0000-0003-2767-6919)

Vanessa Poustie, University of Liverpool, [email protected] (Orcid ID: 0000-0003-2338-8768)

Malcolm Semple, University of Liverpool, [email protected], (Orcid ID: 0000-0001-9700-0418)

Kishan Sharma, Manchester University NHS Foundation Trust (sadly deceased)

Olivia Swann, University of Edinburgh, [email protected], (Orcid ID: 0000-0001-7386-2849)

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Table 1

Demographics of the target population and participants included in the 24-month sample
	Test-negatives invited to take part at 24-months (N = 17,322)	Participating initial-negatives (NN) (N = 4534)	Participating initial-negatives & infected (NP) (N = 2402)	Test-positives invited to take part at 24-months (N = 13,690)	Participating initial-positives (PN) (N = 5177)	Participating initial-positive & reinfected (PP) (N = 519)
		Response rate: 40.0%			Response rate: 41.6%
Sex
Female	10,666 (61.6%)	2974 (65.6%)	1580 (65.8%)	8,385 (61.3%)	3337 (64.5%)	339 (65.3%)
Male	6,656 (38.4%)	1560 (34.4%)	822 (34.2%)	5,305 (38.7%)	1840 (35.5%)	180 (34.7%)
Age at index test (years)
11–14	8,459 (48.8%)	1891 (41.7%)	1266 (52.7%)	6,398 (46.7%)	2342 (45.2%)	261 (50.3%)
15–17	8,863 (51.2%)	2643 (58.3%)	1136 (47.3%)	7,292 (53.3%)	2835 (54.8%)	258 (49.7%)
Ethnicity
White	13,043 (75.3%)	3333 (73.5%)	1947 (81.1%)	10,155 (74.2%)	3856 (74.5%)	399 (76.9%)
Asian, Asian British	2,441 (14.1%)	720 (15.9%)	238 (9.9%)	2,112 (15.4%)	789 (15.2%)	76 (14.6%)
Mixed	934 (5.4%)	241 (5.3%)	128 (5.3%)	681 (5.0%)	263 (5.1%)	28 (5.4%)
Black, African, Caribbean	543 (3.1%)	158 (3.5%)	57 (2.4%)		151 (2.9%)	9 (1.7%)
Other	260 (1.5%)	53 (1.2%)	27 (1.1%)	264 (1.9%)	87 (1.7%)	2 (0.4%)
Prefer not to say	101 (0.6%)	29 (0.6%)	5 (0.2%)	88 (0.6%)	31 (0.6%)	5 (1.0%)
Region
East Midlands	1,159 (6.7%)	315 (7.0%)	177 (7.4%)	1,051 (7.7%)	396 (7.6%)	42 (8.1%)
East of England	3,836 (22.2%)	989 (21.8%)	609 (25.4%)	2,211 (16.2%)	878 (17.0%)	73 (14.1%)
London	3,539 (20.4%)	961 (21.2%)	417 (17.4%)	2,618 (19.1%)	988 (19.1%)	93 (17.9%)
North East England	602 (3.5%)	160 (3.5%)	67 (2.8%)	596 (4.3%)	210 (4.1%)	18 (3.5%)
North West England	1,895 (10.9%)	495 (10.9%)	220 (9.2%)	1,711 (12.5%)	600 (11.6%)	67 (12.9%)
South East England	2,750 (15.9%)	735 (16.2%)	427 (17.8%)	2,167 (15.8%)	883 (17.1%)	83 (16.0%)
South West England	772 (4.5%)	192 (4.2%)	127 (5.3%)	742 (5.4%)	284 (5.5%)	44 (8.5%)
West Midlands	1,601 (9.2%)	403 (8.9%)	199 (8.3%)	1,431 (10.4%)	519 (10.0%)	50 (9.6%)
Yorkshire and the Humber	1,168 (6.7%)	284 (6.3%)	159 (6.6%)	1,163 (8.5%)	419 (8.0%)	49 (9.4%)
IMD quintile*
1 (most deprived)	2,929 (16.9%)	758 (16.7%)	335 (14.0%)	2,416 (17.6%)	825 (16.0%)	108 (20.8%)
2	3,071 (17.7%)	815 (18.0%)	383 (16.0%)	2,477 (18.1%)	928 (17.9%)	91 (17.6%)
3	3,283 (18.9%)	859 (19.0%)	460 (19.2%)	2,509 (18.3%)	941 (18.2%)	98 (18.9%)
4	3,739 (21.6%)	965 (21.3%)	526 (21.9%)	2,917 (21.3%)	1108 (21.4%)	105 (20.2%)
5 (least deprived)	4,300 (24.0%)	1137 (25.1%)	698 (29.1%)	3,371 (24.6%)	1375 (26.5%)	117 (22.5%)
Note: Data are rounded to 1 decimal point, percentages may sometimes add up to just above (100.1) or below (99.9) 100%.
*IMD: Index of Multiple Deprivation. The Index of Multiple Deprivation (IMD) was calculated from the CYP’s small local area level based geographic hierarchy (lower super output area) at the time of the first questionnaire and used as a proxy for socio-economic status. We report IMD quintiles from most (quintile 1) to least (quintile 5) deprived.

Table 2

Reported symptoms N(%),self-rated health^a, symptom severity^a and impact^a by SARS-CoV-2 status 24 months post-test
	24 months post-test
	Initial-negatives (NN) n = 4,534	Negative & infected (NP) n = 2,402	Initial-positives (PN) n = 5,177	Positive & re-infected (PP) n = 519	P value^d
Number of reported symptoms
0 symptom	2,093 (46.2%)	967 (40.3%)	1,969 (38.0%)	184 (35.5%)	< 0.001
1 symptom	724 (16.0%)	406 (16.9%)	886 (17.1%)	96 (18.5%)
2 symptoms	481 (10.6%)	272 (11.3%)	651 (12.6%)	50 (9.6%)
3 symptoms	332 (7.3%)	183 (7.6%)	456 (8.8%)	41 (7.9%)
4 symptoms	261 (5.8%)	149 (6.2%)	362 (7.0%)	40 (7.7%)
≥5 symptoms	643 (14.2%)	425 (17.7%)	853 (16.5%)	108 (20.8%)
Specific symptoms
Fever	156 (3.4%)	102 (4.2%)	201 (3.9%)	19 (3.7%)	0.386
Chills	475 (10.5%)	269 (11.2%)	620 (12.0%)	71 (13.8%)	0.040
Persistent cough	517 (11.4%)	294 (12.2%)	607 (11.7%)	64 (12.3%)	0.740
Tiredness	1,736 (38.3%)	1,070 (44.6%)	2,336 (45.1%)	249 (48.0%)	< 0.001
Shortness of breath	838 (18.5%)	526 (21.9%)	1,201 (23.2%)	128 (24.7%)	< 0.001
Loss of smell	112 (2.5%)	160 (6.7%)	274 (5.3%)	38 (7.3%)	< 0.001
Unusually hoarse voice	143 (3.2%)	97 (4.0%)	172 (3.3%)	13 (2.5%)	0.159
Unusual chest pain	246 (5.4%)	156 (6.5%)	366 (7.1%)	49 (9.4%)	< 0.001
Unusual abdominal pain	156 (3.4%)	101 (4.2%)	205 (4.0%)	25 (4.8%)	0.227
Diarrhoea	108 (2.4%)	53 (2.2%)	129 (2.5%)	17 (3.3%)	0.532
Headaches	652 (14.4%)	379 (15.8%)	832 (16.1%)	106 (20.4%)	0.002
Confusion, disorientation or drowsiness	191 (4.2%)	104 (4.3%)	276 (5.3%)	42 (8.1%)	< 0.001
Unusual eye-soreness	213 (4.7%)	109 (4.5%)	260 (5.0%)	26 (5.0%)	0.785
Skipping meals	342 (7.5%)	192 (8.0%)	434 (8.4%)	52 (10.0%)	0.168
Dizziness or light-headedness	416 (9.2%)	257 (10.7%)	602 (11.6%)	73 (14.1%)	< 0.001
Sore throat	495 (10.9%)	283 (11.8%)	579 (11.2%)	50 (9.63%)	0.489
Unusual strong muscle pains	119 (2.6%)	110 (4.6%)	225 (4.4%)	39 (7.5%)	< 0.001
Earache or ringing in ears	240 (5.3%)	150 (6.2%)	338 (6.5%)	44 (8.5%)	0.007
Raised welts on skin or swelling	44 (1.0%)	23 (1.0%)	62 (1.2%)	5 (1.0%)	0.667
Red/purple sores/blisters on feet	26 (0.6%)	24 (1.0%)	54 (1.0%)	3 (0.6%)	0.057
Sleeping difficulties	1,067 (23.5%)	654 (27.2%)	1,406 (27.2%)	172 (33.1%)	< 0.001
Other	175 (3.9%)	122 (5.1%)	234 (4.5%)	25 (4.8%)	0.104
Did you/your parent talk to the doctor about your Covid-19 symptoms?	348 (7.7%)	249 (10.4%)	468 (9.0%)	76 (14.6%)	< 0.001
Did you go to hospital about your Covid-19?	102 (2.3%)	73 (3.0%)	154 (3.0%)	23 (4.4%)	0.01
Self-rated health^a	85 (70,95)	85 (70, 90)	85 (70, 90)	85 (70, 90)	0.888
Symptom severity^a,b	50 (30,70)	50 (30,60)	50 (30, 70)	50 (30, 65)	0.645
Symptom impact^a,c	40 (20,70)	50 (20, 70)	40 (20, 70)	40 (20, 70)	0.104
^aReported as median(IQR), scored on a scale of 0 (worst) to 100 (best) for self-rated health; 0 (not severe at all) to 100 (extremely severe) for symptom severity; 0 (no impact) to 100 (extreme impact) for symptom impact; ^bbased on sub-sample N = 4,977; ^cbased on sub-sample N = 4,972 ^dp value from chi-squared test of association between SARS-CoV-2 status 24 months post index-test and number of symptoms/specific symptoms and from Mann-Whitney tests between SARS-CoV-2 status 24 months post index-test and self-rated health, symptom severity and symptom impact.

Table 3

Baseline characteristics (sex, age, ethnicity, region, IMD) and validated scales 24-months post index-test by SARS-CoV-2 status, stratified by PCC^a at 24 months (N(%), Mean (SD))
	SARS-CoV-2 Test Negatives (NN) N = 4,534		SARS-CoV-2 Test Positives (PN) N = 5,177
	Not meeting PCC definition at 24 months (n = 3,490)	Meeting PCC definition^a at 24 months (n = 1,044)	Not meeting PCC definition at 24 months (n = 3,893)	Meeting PCC definition^a at 24 months (n = 1,284)
Prevalence		23.0%		24.8%
Baseline characteristics: N(%)
Sex
Male	1,326 (85.0%)	234 (15.0%)	1,548 (84.1%)	292 (15.9%)
Female	2,164 (72.8%)	810 (27.2%)	2,345 (70.3%)	992 (29.7%)
Age at index-test (years)
11–14	1,528 (80.8%)	363 (19.2%)	1,802 (77.0%)	540 (23.1%)
15–17	1,962 (74.2%)	681 (25.8%)	2,091 (73.8%)	744 (26.2%)
Ethnicity
White	2,548 (76.5%)	785 (23.6%)	2,903 (75.3%)	953 (24.7%)
Asian or Asian British	569 (79.0%)	151 (21.0%)	598 (75.8%)	191 (24.2%)
Mixed	184 (76.4%)	57 (23.7%)	204 (77.6%)	59 (22.4%)
Black, African or Caribbean	123 (77.9%)	35 (22.2%)	109 (72.2%)	42 (27.8%)
Other	43 (81.1%)	10 (18.9%)	56 (64.4%)	31 (35.6%)
Prefer not to say	23 (79.3%)	6 (20.7%)	23 (74.2%)	8 (25.8%)
Region
East Midlands	237 (75.2%)	78 (24.8%)	288 (72.7%)	108 (27.3%)
East of England	758 (76.6%)	231 (23.4%)	663 (75.5%)	215 (24.5%)
London	766 (79.7%)	195 (20.3%)	743 (75.2%)	245 (24.8%)
North East	124 (77.5%)	36 (22.5)	166 (79.1%)	44 (21.0%)
North West	385 (77.8%)	110 (22.2%)	458 (76.3%)	142 (23.7%)
South East	578 (78.6%)	157 (21.4%)	666 (75.4%)	217 (24.6%)
South West	141 (73.4%)	51 (26.6%)	220 (77.5%)	64 (22.5%)
West Midlands	302 (74.9%)	101 (25.1%)	373 (71.9%)	146 (28.1%)
Yorkshire and the Humber	199 (70.1%)	85 (29.9%)	316 (75.5%)	103 (24.5%)
IMD quintile
1 (most deprived)	540 (71.2%)	218 (28.8%)	585 (70.9%)	240 (29.1%)
2	623 (76.4%)	192 (25.6%)	670 (72.2%)	258 (27.8%)
3	657 (76.5%)	202 (23.5%)	688 (73.1%)	253 (26.9%)
4	780 (80.8%)	185 (19.2%)	836 (75.5%)	272 (24.6%)
5 (least deprived)	890 (78.3%)	237 (21.7%)	1,114 (81.0%)	261 (19%)
Characteristics at 24-months post index-test: Mean(SD) or Median (IQR)
SDQ
Total Difficulties	10.9 (5.9)	17.1 (6.1)	10.5 (5.8)	16.4 (6.0)
Emotional symptoms	3.4 (2.4)	5.9 (2.5)	3.3 (2.4)	5.7 (2.4)
Conduct problems	1.5 (1.4)	2.2 (1.8)	1.4 (1.5)	2.2 (1.7)
Hyperactivity/inattention	3.9 (2.5)	5.7 (2.5)	3.8 (2.5)	5.5 (2.5)
Peer relationship problem	2.2 (1.8)	3.3 (2.2)	2.1 (1.7)	3.0 (2.0)
SWEMWBS	21.8 (4.0)	18.8 (3.4)	21.9 (3.9)	19.1 (3.5)
Chalder fatigue scale	12.7 (4.4)	18.1 (5.6)	12.8 (4.3)	18.5 (5.7)
Self-rated health^b	85 (80, 95)	70 (50, 80)	90 (80, 95)	70 (55, 80)
Symptom severity^bc	50 (30,60)	60 (40,70)	50 (30, 60)	60 (40, 70)
Symptom impact^bd	40 (10,60)	50 (30,80)	40 (10, 60)	50 (30, 80)
Note. SDQ = Strengths and Difficulties Questionnaire; SWEMBS = Short Warwick-Edinburgh Mental Wellbeing Scale.
A higher SDQ score indicates more problems; a higher SWEMWBS score indicates better mental well-being; a higher fatigue score is more severe.
^aUsing data from the questionnaire on symptoms and the EQ-5D-Y scale at the time of the questionnaire (i.e., approximately 24-months after the index PCR-test), PCC was operationalized as having at least 1 symptom and experiencing some/a lot of problems with respect to mobility, self-care, doing usual activities or having pain/discomfort or feeling very worried/sad. For test-negatives we excluded the need for a positive PCR test. Number of symptoms and the EQ-5D-Y scale at 24-months not shown in this table as they are part of the definition of PCC.
^bReported as median(IQR), scored on a scale of 0 (worst) to 100 (best) for self-rated health; 0 (not severe at all) to 100 (extremely severe) for symptom severity; 0 (no impact) to 100 (extreme impact) for symptom impact; ^cbased on sub-sample N = 4,977; ^dbased on sub-sample N = 4,972

Yes there is potential Competing Interest. Terence Stephenson is Chair of the Health Research Authority and therefore recused himself from the Research Ethics Application. Trudie Chalder has been a member of the National Institute for Health and Care Excellence committee for long COVID-19. She has written self-help books on chronic fatigue and has done workshops on chronic fatigue and post-infectious syndromes. All remaining authors have no conflicts of interest.

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Long-Term Effects of COVID-19 in Children and Young People: A 24-Month National Cohort Study

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