Persistent symptoms after COVID-19 in children and adolescents from Argentina.

OBJECTIVES: Although long COVID-19 is widely recognized in adults, less information is available about this condition in children, especially in developing countries. Here, we studied the long-term symptoms of SARS-CoV-2 infection beyond 3 months and the associated risk factors in a pediatric population. METHODS: This observational study included 639 Argentinian children and adolescents with previously confirmed COVID-19 from June 2020-June 2021 and 577 children without previous COVID-19. Parents completed a survey about symptoms that their child had for >3 months after the diagnosis of SARS-CoV-2 infection. RESULTS: At least one persistent symptom was observed more frequently in children with previous COVID-19 than in the non-COVID-19 group (34% vs 13%, P <0.0001). SARS-CoV-2 infection increased the risk of headache, dizziness, loss of taste, dyspnea, cough, fatigue, muscle pain, and loss of weight by three- to seven-fold. The loss of smell was only reported in infected children. After controlling for the other variables, older age, symptomatic COVID-19, and comorbidities were independent predictors of long-term symptoms. CONCLUSIONS: One-third of children experienced persistent symptoms after COVID-19. Older age, symptomatic infection, and comorbidities were shown to be risk factors for long COVID-19. Pediatric long COVID-19 is a new condition that requires further investigation.

Extracellular ATP and Imbalance of CD4+ T Cell Compartment in Pediatric COVID-19.

Severe COVID-19 in children is rare, but the reasons underlying are unclear. Profound alterations in T cell responses have been well characterized in the course of adult severe COVID-19, but little is known about the T cell function in children with COVID-19. Here, we made three major observations in a cohort of symptomatic children with acute COVID-19: 1) a reduced frequency of circulating FoxP3+ regulatory T cells, 2) the prevalence of a TH17 polarizing microenvironment characterized by high plasma levels of IL-6, IL-23, and IL17A, and an increased frequency of CD4+ T cells expressing ROR-γt, the master regulator of TH17 development, and 3) high plasma levels of ATP together with an increased expression of the P2X7 receptor. Moreover, that plasma levels of ATP displayed an inverse correlation with the frequency of regulatory T cells but a positive correlation with the frequency of CD4+ T cells positive for the expression of ROR-γt. Collectively, our data indicate an imbalance in CD4+ T cell profiles during pediatric COVID-19 that might favor the course of inflammatory processes. This finding also suggests a possible role for the extracellular ATP in the acquisition of an inflammatory signature by the T cell compartment offering a novel understanding of the involved mechanisms.

Antibody response against SARS-CoV-2 variants of concern in children infected with pre-Omicron variants: An observational cohort study.

BACKGROUND: Despite that pediatric COVID-19 is usually asymptomatic or mild, SARS-CoV-2 infection typically results in the development of an antibody response. Contradictory observations have been reported when the antibody response of children and adults were compared in terms of strength, specificity and perdurability. METHODS: This observational study includes three cohorts infected with SARS-CoV-2 between March 2020-July 2021: unvaccinated infected children (n=115), unvaccinated infected adults (n=62), and vaccinated infected children (n=76). Plasma anti-spike IgG antibodies and neutralising activity against Wuhan, Delta and Omicron variants after 7-17 months post-infection were analysed. FINDINGS: More than 95% of unvaccinated infected children and adults remained seropositive when evaluated at 382-491 and 386-420 days after infection, respectively. Anti-spike IgG titers and plasma neutralising activity against Wuhan, Delta and Omicron variants were higher in children compared to adults. No differences were found when unvaccinated infected children were stratified by age, gender or presence/absence of symptoms in the acute phase of SARS-CoV-2 infection, but a slight decrease in the antibody response was observed in those with comorbidities. Vaccination of previously infected children with two doses of the inactivated BBIBP-CorV or the mRNA vaccines, BNT162b2 and/or mRNA-1273, further increased anti-spike IgG titers and neutralising activity against Wuhan, Delta and Omicron variants. INTERPRETATION: Unvaccinated infected children mount a more potent and sustained antibody response compared with adults, which is significantly increased after vaccination. Further studies including not only the analysis of the immune response but also the effectiveness to prevent reinfections by the different Omicron lineages are required to optimise vaccination strategy in children. FUNDING: National Agency for Scientific and Technological Promotion from Argentina (PICTO-COVID-SECUELAS-00007 and PMO-BID-PICT2018-2548).

Blood neutrophils from children with COVID-19 exhibit both inflammatory and anti-inflammatory markers.

BACKGROUND: Perhaps reflecting that children with COVID-19 rarely exhibit severe respiratory symptoms and often remain asymptomatic, little attention has been paid to explore the immune response in pediatric COVID-19. Here, we analyzed the phenotype and function of circulating neutrophils from children with COVID-19. METHODS: An observational study including 182 children with COVID-19, 21 children with multisystem inflammatory syndrome (MIS-C), and 40 healthy children was performed in Buenos Aires, Argentina. Neutrophil phenotype was analyzed by flow cytometry in blood samples. Cytokine production, plasma levels of IgG antibodies directed to the spike protein of SARS-CoV-2 and citrullinated histone H3 were measured by ELISA. Cell-free DNA was quantified by fluorometry. FINDINGS: Compared with healthy controls, neutrophils from children with COVID-19 showed a lower expression of CD11b, CD66b, and L-selectin but a higher expression of the activation markers HLA-DR, CD64 and PECAM-1 and the inhibitory receptors LAIR-1 and PD-L1. No differences in the production of cytokines and NETs were observed. Interestingly, the expression of CD64 in neutrophils and the serum concentration of IgG antibodies directed to the spike protein of SARS-CoV-2 distinguished asymptomatic from mild and moderate COVID-19. INTERPRETATION: Acute lung injury is a prominent feature of severe COVID-19 in adults. A low expression of adhesion molecules together with a high expression of inhibitory receptors in neutrophils from children with COVID-19 might prevent tissue infiltration by neutrophils preserving lung function. FUNDING: This study was supported by the Ministry of Science and Technology (National Agency for Scientific and Technological Promotion, IP-COVID-19-0277 and PMO BID PICT 2018-2548), and University of Buenos Aires from Argentina (20020170100573BA).

A poor and delayed anti-SARS-CoV2 IgG response is associated to severe COVID-19 in children.

BACKGROUND: Most children and youth develop mild or asymptomatic disease during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, a very small number of patients suffer severe Coronavirus induced disease 2019 (COVID-19). The reasons underlying these different outcomes remain unknown. METHODS: We analyzed three different cohorts: children with acute infection (n=550), convalescent children (n=138), and MIS-C (multisystem inflammatory syndrome in children, n=42). IgG and IgM antibodies to the spike protein of SARS-CoV-2, serum-neutralizing activity, plasma cytokine levels, and the frequency of circulating Follicular T helper cells (cTfh) and plasmablasts were analyzed by conventional methods. FINDINGS: Fifty-eight percent of the children in the acute phase of infection had no detectable antibodies at the time of sampling while a seronegative status was found in 25% and 12% of convalescent and MIS-C children, respectively. When children in the acute phase of the infection were stratified according disease severity, we found that contrasting with the response of children with asymptomatic, mild and moderate disease, children with severe COVID-19 did not develop any detectable response. A defective antibody response was also observed in the convalescent cohort for children with severe disease at the time of admission. This poor antibody response was associated to both, a low frequency of cTfh and a high plasma concentration of inflammatory cytokines. INTERPRETATION: A weak and delayed kinetic of antibody response to SARS-CoV-2 together with a systemic pro-inflammatory profile characterize pediatric severe COVID-19. Because comorbidities are highly prevalent in children with severe COVID-19, further studies are needed to clarify their contribution in the weak antibody response observed in severe disease. FUNDING: National Agency for Scientific and Technological Promotion from Argentina (IP-COVID-19-0277 and PMO-BID-PICT2018-2548).

[Validation of a simplified prediction rule to identify etiology in children with pneumonia]. / Validación de una regla de predicción simplificada para la presunción de etiología en niños con neumonía.

INTRODUCTION: Identifying on admission those children with bacterial pneumonia could reduce inappropriate antibiotic use. The BPS (Bacterial Pneumonia Score) is a clinical prediction rule that accurately identifies children with bacterial pneumonia. Because the interpretation of chest X-ray included in this model could be considered difficult, a simplified version was developed, but this version has not yet been validated in a different population. OBJECTIVE: To validate a simplified clinical prediction rule to identify children with an increased risk of having bacterial pneumonia. METHODS: Children aged under 5 years, hospitalized for pneumonia (viral or bacterial) were included. On admission, axillary temperature, age, absolute neutrophil count, bands, and chest radiograph were evaluated. RESULTS: We included 168 patients (23 with bacterial pneumonia and 145 with viral pneumonia). Those with bacterial pneumonia showed a score higher than those with viral pneumonia (5.3 ± 2.5 vs. 2.6 ± 2.02; p <0.001). A score =3 points was identified as the optimum cutoff value to predict bacterial pneumonia (aucROC= 0.79; 95% IC: 0.68-0.90), and was more frequent among patients with bacterial than viral pneumonia (19/23 vs. 42/145, p= 0.003; OR: 4.8; CI95%: 1.4-17.6), achieving 82.6% sensitivity, 50.3% specificity, 20.9% positive predictive value, 94.8% negative predictive value, 1.66 positive likelihood ratio and 0.35 negative likelihood ratio. CONCLUSIONS: The evaluated simplified prediction rule showed a limited diagnostic accuracy on identifying children with bacterial pneumonia, being less accurate than the BPS.

Validación de una regla de predicción simplificada para la presunción de etiología en niños con neumonía / Validation of a simplified prediction rule to identify etiology in children with pneumonia

Introducción. Identifcar inicialmente los niños con neumonía bacteriana puede reducir el uso inadecuado de antibióticos. El puntaje BPS (Bacterial Pneumonia Score) es un modelo de predicción clínica que alcanzó adecuada precisión diagnóstica en la predicción de niños con neumonía bacteriana. Sin embargo, como la interpretación de la radiografía de tórax que incluye este modelo es algo compleja, se desarrolló una versión simplifcada, cuya validación en otra población aún no se ha realizado. Objetivo. Validar una regla de predicción clínica simplifcada para identifcar niños con riesgo de presentar neumonía bacteriana. Métodos. Se estudiaron niños <5 años internados por neumonía con etiología confirmada (viral o bacteriana), y se registraron componentes de la regla de predicción clínica simplifcada (temperatura axilar, edad, neutróflos totales, neutróflos inmaduros y radiografía de tórax). Resultados. Se incorporaron 168 pacientes (23 presentaron neumonía bacteriana y 145 viral). Aquellos con neumonía bacteriana presentaron un valor de la escala mayor que los de etiología viral (5,3 ± 2,5 contra 2,6 ± 2,02; p <0,001). Un puntaje =3 fue identifcado como el mejor punto de corte para predecir neumonía bacteriana (área bajo la curva de predicción relativa [aucROC]= 0,79; IC95%: 0,68-0,90), y fue signifcativamente más frecuente en pacientes con neumonía bacteriana que viral (19/23 contra 72/145, p= 0,003; OR= 4,8; IC95%: 1,4-17,6). La predicción de neumonía bacteriana mostró una sensibilidad de 82,6%, especifcidad 50,3%, valor predictivo positivo 20,9%, valor predictivo negativo 94,8%, razón de verosimilitud positiva 1,66 y razón de verosimilitud negativa 0,35. Conclusiones. La regla de predicción clínica simplifcada evaluada mostró una limitada capacidad diagnóstica para identifcar a niños con neumonía bacteriana y resultó inferior al BPS.

Introduction. Identifying on admission those children with bacterial pneumonia could reduce inappropriate antibiotic use. The BPS (Bacterial Pneumonia Score) is a clinical prediction rule that accurately identifes children with bacterial pneumonia. Because the interpretation of chest X-ray included in this model could be considered diffcult, a simplifed version was developed, but this version has not yet been validated in a different population. Objective. To validate a simplifed clinical prediction rule to identify children with an increased risk of having bacterial pneumonia. Methods. Children aged under 5 years, hospitalized for pneumonia (viral or bacterial) were included. On admission, axillary temperature, age, absolute neutrophil count, bands, and chest radiograph were evaluated. Results. We included 168 patients (23 with bacte­rial pneumonia and 145 with viral pneumonia). Those with bacterial pneumonia showed a score higher than those with viral pneumonia (5.3 ± 2.5 vs. 2.6 ± 2.02; p <0.001). A score =3 points was identifed as the optimum cutoff value to predict bacterial pneumonia (aucROC= 0.79; 95% IC: 0.68-0.90), and was more frequent among patients with bacterial than viral pneumonia (19/23 vs. 42/145, p= 0.003; OR: 4.8; CI95%: 1.4-17.6), achieving 82.6% sensitivity, 50.3% specifcity, 20.9% positive predictive value, 94.8% negative predictive value, 1.66 positive likelihood ratio and 0.35 negative likelihood ratio. Conclusions. The evaluated simplifed prediction rule showed a limited diagnostic accuracy on identifying children with bacterial pneumonia, being less accurate than the BPS.