key: cord-0742834-zoe89706 authors: Bergia, María; Sanchez‐Marcos, Elena; Gonzalez‐Haba, Blanca; Hernaiz, Ana I.; de Ceano‐Vivas, María; García López‐Hortelano, Milagros; García‐García, Mª Luz; Jimenez‐García, Raquel; Calvo, Cristina title: Comparative study shows that 1 in 7 Spanish children with COVID‐19 symptoms were still experiencing issues after 12 weeks date: 2022-04-28 journal: Acta Paediatr DOI: 10.1111/apa.16368 sha: 4101232303d01dd3aff6e003205cbec44fa07489 doc_id: 742834 cord_uid: zoe89706 AIM: We investigated prolonged symptoms in children after COVID‐19, including the clinical characteristics and risk factors. METHODS: This multicentre retrospective study focused on 451 children under 18 years old who were diagnosed with symptomatic COVID‐19 between 14 March and 31 December 2020. Persistent symptoms were analysed with a telephone questionnaire by the attending physicians from 1 August to 30 September 2021. A control group of 98 with no history of COVID‐19, who were treated for other reasons, was also included. RESULTS: Most (82.0%) of the cases had mild infections that required outpatient care and 5.1% were admitted to the paediatric intensive care unit (PICU). We found that 18.4% had symptoms that lasted 4–12 weeks. There were also 14.6% who were symptomatic for longer than 12 weeks and the odds risks were higher for children aged 5 years or more (OR 3.0), hospitalised (OR 3.9), admitted to the PICU (OR 4.3) and with relatives who were symptomatic for 12 weeks or more (OR 2.8). The controls had similar percentages of prolonged symptoms, despite having no history of COVID‐19, especially those who were older than 5 years. CONCLUSION: This study confirmed that a worrying percentage of children had prolonged symptoms after COVID‐19. Children tend to have a relatively mild and less severe course of COVID-19 than adults and are less likely than them to require hospitalisation. 1, 2 However, a small percentage experience serious symptoms during the acute phase. These are mainly pneumonia, but can also include multisystem inflammatory syndrome in children (MIS-C). Many of these children need to be admitted to a paediatric intensive care unit (PICU). 3 Prolonged symptoms following the acute infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may last longer than 4 or even 12 weeks and have been widely described in both adult 4 and paediatric populations. [5] [6] [7] The UK National Institute for Health and Care Excellence (NICE) published guidelines in December 2020 on long COVID. These categorised symptoms that lasted for 4-12 weeks, after SARS-CoV-2 were confirmed with microbiological testing, as ongoing COVID-19. The guidelines further stated that if symptoms lasted more than 12 weeks they were considered to be prolonged COVID-19. 8 Updated NICE guidelines were published in November 2021 and these used different terminology. 9 They used ongoing symptomatic COVID-19 if the signs and symptoms of COVID-19 lasted for 4-12 weeks and post-COVID-19 syndrome if they lasted for more than 12 weeks and were not explained by an alternative diagnosis. The World Health Organization (WHO) used a Delphi process and also defined the term post-COVID-19 in adults as symptoms that lasted for more than 12 weeks, with other diagnoses excluded. 10 This study uses the latest 2021 NICE and WHO terms, as the actual time categories are identical to those in place when this study was carried out in 2021. There has been a lack of data regarding the prevalence of post-COVID-19 in childhood and its characteristics. 11 Cases have ranged from 2% to 20% of children affected by SARS-CoV-2, possibly due to the methodology used. [12] [13] [14] [15] [16] Data published by the UK Office for National Statistics on 1 April 2021 estimated that 9.8% of children between 2 and 11 years of age and 13% of children between 12 and 16 years had symptoms 5 weeks after their SARS-CoV-2 infection was confirmed. After 12 weeks, 7.4% of the children aged between 2 and 11 years and 8.2% between 12 and 16 years continued to have symptoms. 17 Children with post-COVID- 19 have reported that it has had a negative impact on their quality of life, similar to adults, and many have been unable to attend school. These symptoms may have initially gone unnoticed and not been attributed to the SARS-CoV-2 infection. 18, 19 That is why early diagnoses and adequate follow-up visits are important. 20 This is particularly crucial for paediatric patients, as they are at a sensitive stage of their emotional, physical and cognitive development. 11 The correct evaluation of the prevalence of post-COVID-19 in children is important when it comes to recommending vaccinations. The main aim of this study was to determine the prevalence of prolonged symptoms after acute COVID-19 at 4-12 weeks and more than 12 weeks in Spanish children with a confirmed SARS-CoV-2 infection. We also wanted to describe the clinical characteristics and identify possible risk factors in our population. A multicentre retrospective study was carried out at 3 university hospitals in Madrid. La Paz and Niño Jesús are the two largest hospitals in Madrid and during the first pandemic waves in 2020 they were responsible for any of the 1 million children in the region who needed to be admitted with COVID-19. The Severo Ochoa hospital served a population of 60,000 children during the first pandemic wave, but only provided outpatient treatment. Telephone calls were made to the parents of children who were diagnosed with confirmed symptomatic COVID-19 infections and were hospitalised, or attended any of the three hospitals, between 14 March and 31 December 2020. These calls were made by their attending physicians. The questionnaire on COVID-19 symptoms was specifically designed for the study and this was used for the telephone calls, which were made between 1 August and 30 September 2021. The study was approved by the Ethics Committee of La Paz Hospital (PI-4212) on the basis that we obtained consent from the parents during the telephone calls and that any data were incorporated into the patients' medical histories. The inclusion criteria were children under 18 years old with a diagnosis of SARS-CoV-2 infection confirmed by polymerase chain reaction, or an antigen test or serology, between 14 March and 31 December with any symptoms related to the SARS-CoV-2 infection. The parents or legal guardians needed to agree to participate in the telephone questionnaire. We excluded any children with asymptomatic SARS-CoV-2 infections. Post-COVID-19 was defined as when the subject had continuously presented symptoms, without recovering to their previous health status, for longer than 12 weeks. Ongoing symptomatic COVID-19 was defined as symptoms that were present for 4-12 weeks. Although we used the 2020 NICE guidelines 8 in force when the study was carried out, the latest terminology is used to • There has been a lack of research about post-COVID-19 in children, which is defined as ongoing symptoms for more than 12 weeks. • This multicentre questionnaire focused on 451 children under 18 years who had COVID-19 and found that 18.4% had symptoms that lasted 4-12 weeks and 14.6% had post-COVID-19. • The odds risks were higher for children aged 5 years and those who have been hospitalised and had relatives with post-COVID-19. reflect the 2021 NICE and WHO guidelines, which cover exactly the same timelines and definitions. 9, 10 A control group of inpatients and outpatients without a history of COVID-19, who were treated by any of the three hospitals during the same period, namely 14 March to 31 December 2020, were randomly selected from the medical records. Their parents were contacted between 1 August and 30 September 2021. The children were either treated in the emergency room without being admitted or were hospitalised for an issue not related to COVID-19. The children were chosen from patients with endocrinological, trauma or surgical pathology. The same questionnaire was used and carried out by telephone by the attending physicians who saw the controls. A number of variables were collected by the questionnaire. The demographic data comprised the subject's date of birth, sex, the date of any COVID-19 diagnosis and the onset of any symptoms. The variables related to those with a confirmed SARS-CoV-2 infection included the diagnostic method, clinical diagnosis, need for hospital admission and need for admission to the PICU. The parents were asked about the type of symptoms and how long they had lasted, the need for medical assistance and the type of assistance provided and any studies that were carried out. They were also asked about any comorbidities, the results of serology tests, whether any relatives also had COVID-19 and whether the patients had a subjective feeling of having had their symptoms misinterpreted. It was generally only possible to assess some symptoms in children who were over 5 years of age, such as anosmia, ageusia, sadness, apathy or anxiety. The main variable was the presence of at least one symptom lasting longer than 12 weeks. The statistical analysis was performed using SPSS, Version 21.0 (IBM Corp). Values were expressed as percentages for discrete and categorical variables and as medians and interquartile ranges (IQR) for continuous variables. The demographic, clinical and evolutionary characteristics were compared using the Mann-Whitney U test, and Fisher's exact test, as appropriate. Odds ratios (OR) were calculated, with their 95% confidence intervals (CI). A p-value of <0.05 was considered statistically significant. We identified 668 children with COVID-19 diagnoses and 150 controls treated for other reasons than COVID-19 during the same period and contacted their parents. Of these, 451 and 98, respectively, agreed to complete the questionnaire. Table 1 . We found that 18.4% had at least one or more symptoms at 4-12 weeks The clinical characteristics of the children with symptoms for more than 12 weeks were compared with the rest of the patients and are shown in Table 2 . A number of factors were significantly associated with post-COVID-19 and these were hospital admission (OR 3.9), need for PICU admission (OR 4.3) or a relative with symptoms for more than 12 weeks (OR 2.8). The post-COVID-19 group had longer hospital stays than those without this diagnosis (p = 0.047). Their symptoms were also different from other patients during acute COVID-19, with a higher proportion of pneumonia or MIS-C (p = 0.001). Comorbidities were not associated with symptoms lasting for more than 12 weeks, but symptoms such as dyspnoea, diarrhoea and abdominal pain were, even if they were short-lived. Symptoms that were significantly associated with post-COVID-19 were headache, anosmia and ageusia, myalgia, asthenia, concentration difficulties insomnia, apathy or feeling sad, anxiety, palpitations and dizziness. A variety of prolonged symptoms were described in 5.9% of the children and those that stood out included hair loss, memory loss or skin lesions. Post-COVID-19 symptoms for more than 12 weeks were more common in children aged 5 years of age or older (47.0%). They were compared with children under the age of 5 years. Any symptoms lasting 4-12 weeks were observed in 26.9% of the 212 children aged 5 years or older, compared to 10.9 of the 239 children under 5 years of age (p = 0.001). Symptoms that lasted longer than 12 weeks were observed in 22.6% and 7.5% of these age groups, respectively (p = 0.001). The diagnoses were slightly different, with more cases of MIS-C and pneumonia in the children aged 5 years or older. However, the hospitalisation and PICU admission rates were not significantly different. The prevalence of the symptoms in the 2 age groups, and their duration, is shown in Figure 2 . Table 4 and S2. Although none of the controls had tested positive for SAR-CoV-2 before they were included in the study, we noted that the parents of 20 children (20.4%) reported symptoms that could have been attributed to COVID-19 that lasted for 4-12 weeks. Another 19 children had symptoms that were characteristic of post-COVID-19 for longer than 12 weeks. These percentages were not significantly different from the children with confirmed COVID-19. Given that the children in the control group were significantly older, at a median of 7.8 vs. 4.0 years, we analysed the percentages with persistent symptoms who were 5 or more years of age in both groups. There were TA B L E 1 Symptoms and duration in the total cohort of children with COVID-19 To characterise the persistence of symptoms that indicated post-COVID-19, this specific sub-group was compared with the other cases and controls who were 5 years of age or older ( Table 5) . Post-COVID-19 in children, which lasts for more than 12 weeks after testing positive for SARS-CoV-2, is still being studied and debated. However, there is still insufficient data to provide a definitive statement about their frequency and characteristics. Our multicentre study of 451 children with a confirmed, symptomatic SARS-CoV-2 infection, found that 18.4% of cases were symptomatic for 4-12 weeks and 14.6% had at least 1 symptom that lasted longer than 12 weeks. These are very high figures and a considerable cause for concern. Up to 8.2% of the children had 2 or more symptoms lasting longer A similar percentage of prolonged symptoms was observed when children with COVID-19 were compared to a control group of children treated during the same period for problems other than COVID-19. These included vague symptoms, such as anxiety, insomnia, tachycardia or dizziness. These symptoms may be related to social distancing measures, including full lockdowns, and not to the SARS-CoV-2 infection. However, this group of children had fewer characteristic symptoms, such as anosmia, ageusia, myalgia or headaches. Our study had a number of strengths and limitations. One limitation was that most long-lasting symptoms, such as anosmia, ageusia, concentration difficulties, apathy and anxiety, could only be assessed in older children. This could be considered a bias when being 5 or more years of age was considered a risk factor for post- Our study had other limitations. The response rates were not as high as we would have liked because we were not able to contact all the parents. The retrospective nature of the study could also have led to memory errors and the data that was obtained may not have been precise. In addition, the fact that some of the children were hospitalised may have determined the duration of some symptoms, especially respiratory issues. We excluded children with asymptomatic SARS-CoV-2 infections and this meant that we were unable to rule out whether symptoms developed after initial as- Our study showed that children suffered prolonged symptoms after COVID-19 and that these significantly affected their lives and required specific clinical attention. In our series, post-COVID-19 particularly affected children over 5 years of age and was associated with symptoms such as asthenia, loss of appetite and myalgia. There is a clear need for further research on post-COVID-19 in children. The authors have no conflicts of interest to declare. 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