Risk of long Covid in children infected with Omicron or <scp>pre‐Omicron SARS‐CoV</scp>‐2 variants

Abstract

Paediatric Long Covid has been reported globally,1 however, no previous analysis reported the different risk of persistence of symptoms in children infected with different SARS-CoV-2 variants. This is a prospective follow-up of children with a first microbiologically (through a Polymerase Chain Reaction nasopharyngeal swab) confirmed SARS-CoV-2 infection evaluated in-person at a referral paediatric post-covid clinic in Rome, Italy (Ethic approval ID4518, Prot0040139/21). Children were referred to our clinic by the inpatient ward, the paediatric emergency department or by family paediatricians. Children were assessed at 3–6–12 months following acute infection (up to 18 months for pre-Omicron infections). Long Covid was defined as persistence of symptoms for at least 3 months after initial infection, which had a negative impact on daily life and other possible diagnoses were excluded.2 Most probable infecting variant was defined according to prevalence provided by the Italian Minister of Health.3 At time of first assessment (3 months after infection), we collected information about the acute infection (signs and symptoms, need of admission and severity according to previous description4) and persisting symptoms. During each follow-up children were assessed to evaluate recovery (lack of persisting symptoms and return to pre-covid school, social and sport routine) or main persisting symptoms. A multivariate logistic regression was performed to evaluate the impact of SARS-COV-2 variant on the risk of persistence of symptoms at 3 and 6 months from the acute infection, considering the Omicron variant as the reference category. In patients still symptomatic at 3 months, a time-to-event analysis was conducted using the Kaplan–Meier method and curves were compared using the log-rank test. Cox-regression was used to estimate the hazard ratio and respective 95% confidence interval. One thousand two hundred and forty-three patients (47.6% females) were included. The median age was 7.25 years (4.00-10.25) and 164 patients (13.2%) had comorbidities. Two hundred and forty-two patients (19.5%) had received at least one dose of vaccine before infection. Regarding the acute phase, 109 patients (8.8%) were asymptomatic, 1111 patients (89.4%) had mild and 23 (1.8%) children had moderate infection. The variant most frequently reported in our sample was the omicron one with 880 cases (70.8%), followed by delta (247 cases, 19.9%), alfa (74 cases, 6%) and wild SARS-CoV-2(42 cases, 3.3%). In multivariate logistic regression, compared to the Omicron variant, all other variants were significantly associated with higher rate of persistence of symptoms at 3 and 6 months. The first variants were associated with the highest odds ratios: OR was 4.35 (2.68-7.07, p < 0.001) at 3 months and 9.88 [5.80-16.83] p < 0.001 at 6 months for the alfa variant and 4.12 (2.20-7.72, p < 0.001) at 3 months and 8.59 (4.31-17.11, p < 0.001) for wild-type SARS-CoV-2 (Table 1). One hundred and seventy patients were included in the Omicron arm and 124 in the non-Omicron arm for the time-to-event analysis. Overall, 71 events of symptoms regression occurred in the non-Omicron arm and 86 in the Omicron arm (HR 0.56, 95% CI 0.39–0.81, p = 0.002). In the landmark analysis, 67.2% of patients in the non-omicron arm and 41.7% in the Omicron arm were still symptomatic at 6 months and 39.3% and 0% at 12 months, respectively (Figure 1). In multivariate analysis, we found that children infected with Omicron had a significantly lower risk of experience persisting symptoms at 3 and 6 months after acute infection and in the survival analysis we found that the hazard of being still symptomatic remains higher in non-Omicron infected children at 6, 12 and 18 months. This is a relevant finding considering the high number of children that have been infected globally during Omicron waves. Interestingly, it has been demonstrated that children infected with Omicron also have a significantly reduced risk of developing Multisystem Inflammatory Syndrome.5 Reasons for reduced risk of negative post-acute outcomes may be related to differences in the viral spike protein or previous immunity from infection or vaccination, or both.6 Importantly, as a non-negligible number of children in our cohort developed Long Covid even when infected by Omicron and some children infected with pre-omicron virus were still symptomatic at 18 months follow-up, offering care to these families and studying this condition should remain a public health priority. Limitation of this study was the inability to exclude previous asymptomatic infections and the lack of a gold standard for the diagnosis of Long Covid, as well as the lack of inclusion of severe cases of acute Covid-19 and of genotyping confirmation of SARS-CoV-2 variants. We have not evaluated the effect of vaccination on the development of Long Covid in case of breakthrough infection, which will be assessed in a separate study. This is an important point of investigation, since adult studies have found reduced risk of symptom persistence in previously-vaccinated individuals with breakthrough infections.7 Dr Danilo Buonsenso conceptualised and designed the study, designed the data collection instruments, collected data, drafted the initial manuscript and critically reviewed and revised the manuscript. Drs Cristina De Rose, Rosa Morello, Piero Valentini and Giuseppe Zampino designed the data collection instruments, collected data, drafted the initial manuscript and critically reviewed and revised the manuscript. Drs Francesco Mariani and Luca Mastrantoni designed the data collection instruments, carried out the statistical analyses, drafted the initial manuscript and critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This study has been funded by Pfizer non-competitive grant, granted to Dr Buonsenso. The funder had no role in the development of the project nor in the interpretation of results. Dr Buonsenso was responsible for writing the project. DB has been granted by Pfizer a study on paediatric Long Covid and has participated in a peer-to-peer educational project on Long Covid funded by Pfizer. The other authors have nothing to declare.

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