Discussion
After widespread distribution of COVID 19 in pediatric patients, one of the most important issues was long-lasting complications in our next generation. Current evidences have mentioned increased risk of diabetes mellitus type I and severe diabetes ketoacidosis in children infected by SARS-CoV-2 (20). Autoimmune disorders might be more expected in coming years due to impact of COVID 19 on immune system (21). One of the most prevalent symptoms in children infected by SARS-CoV-2 is respiratory manifestation (22). There are increasing evidences of pulmonary sequel especially in adult population after infection (23). To the best of our knowledge present study is the first systematic review and meta-analysis evaluating the impact of COVID 19 on respiratory system of younger generation in long-term. In six eligible studies, 272 pediatric patients (143 females and 129 males) were evaluated with the mean age of 12.68 years. The mean of recovery time after SARS-CoV-2 infection was 3.94 months.
Infection generally was mild and most of patients had no or only mild symptoms. All spirometry parameters were in normal range. Two studies were evaluated post bronchodilator parameters. Their results showed no reversible obstructive changes in airways of children with history of COVID 19. Fortunately, all studies reported FEF 25-75%. It is one of the most sensitive measures of obstructive diseases in peripheral airways (24-27). The meta-mean of FEF25-75% was 105.05%, which was in normal range. According to our meta-results, no obstructive disease in studied population was detected.
One of the most expected involved areas in respiratory system during COVID 19 is alveolar epithelial cells (28, 29). It seems that peripheral airways with an internal diameter less than 2 millimeters are more prone to impair after SARS-CoV-2 infection. While these parts of respiratory system represent 90% of total lung capacity but only have role in less than 20% of airflow (30, 31). So, simple spirometry which measuring FEV1 and FVC hardly might detect early stages of pulmonary involvement after COVID 19. Measuring diffusion capacity is more sensitive in detection of pulmonary diseases especially in early stages (32). Unfortunately, only 177 out of 238 participants had DLCO values. However, according to meta-results the mean of DLCO was within normal range (108.97 %, 95%CI: (86.15, 131.79)). A meta-analysis in adults was evaluated pulmonary function post-COVID 19 infection. Results showed decreased DLCO in nearly 40% of survivors (33, 34). Decreased DLCO might be an early indicator of interstitial lung diseases even before change in lung volumes (35, 36). Chronic interstitial pneumonia and diffuse alveolar hemorrhage are demonstrated in few studies, which have reported histological finding in autopsy (37-39). Patients with SARS-CoV-2 may had pulmonary fibrosis, which is considered as defined sequel of barotrauma. All of these pathologies can impair carbon monoxide diffusion capacity (40). In present study, one explanation for normal DLCO may be none-severe infection in most of studied children. We have tried to evaluate impact of disease severity in spirometry parameters. However, there were not significant difference between the result in symptomatic and asymptomatic patients. Future studies with longer period of follow-up and evaluating patients with more severe respiratory presentation are needed. We had also heterogeneity in atopy and asthma background of our included studies. However, according to meta-regression chronic pulmonary disease (such as asthma) had not a significant effect on pooled mean of major outcomes.
Less severity of respiratory system involvement in children infected by SARS-CoV-2 comparing with adult, might be possible explanation for different outcome between them (3). In addition, preexisting diseases in adults like chronic respiratory diseases, cardiac diseases and diabetes mellitus may induce impairment in pulmonary function. On the other hand, children during infancy and preschool age usually have more severe course during infection (41, 42). Because majority of our included participants were teenage, more studies which can evaluate pulmonary sequel in infants and young toddlers, should be designed. In addition, different variants of SARS-CoV-2 like Delta or Omicron had resulted to different presentation and probably different outcomes. Therefore, studies, which determine type of variants, may be useful. It is possible that pulmonary sequel of survived children is so tiny and routine pulmonary function test cannot detect abnormalities. It is useful to design exercise-challenging studies in survived children after COVID 19 to detect subtle or mild changes in pulmonary function.