Discussion

This meta-analysis showed approximately one-quarter of children were asymptomatic, which is very alarming as these children could be asymptomatic spreaders. Studies reveal comparable or prolonged spread of virus by asymptomatic carriers compared to symptomatic patients11,12 ,however this theory is debatable in recent literature13. It could be an important factor to consider in public health policy-making regarding re-opening of schools and play areas. The proportion of asymptomatic patients in China and outside China were similar in our study, 28% and 21% respectively. However, these numbers are likely an underestimation due to the small number of data-rich studies published outside China and the sampling bias towards hospitalized and more ill children.
Fever and cough were the most reported symptoms in this meta-analysis, which is consistent with findings reported by two other meta-analyses14. This study shows that children present with more upper respiratory findings such as sore throat, nasal congestion and rhinorrhea, whereas dyspnea is less frequently seen in children compared to their adult counterparts15. An array of gastrointestinal symptoms such as nausea, vomiting, abdominal pain and diarrhea are reported in pediatric patients with COVID-19, however, it is difficult to discern the proportion of these symptoms attributable to the disease process or part of the side-effects of therapeutic agents used for treatment or a combination of both. Our study showed approximately one out of seven children had some associated co-morbidity. This was unlike other meta-analyses in the literature which under or infrequently reported comorbidities in pediatric patients13,14. We further dissected the comorbidities and found the most common being history of congenital heart disease and obesity. The other co-morbidities associated with COVID-19 presentation in children in our study included history of prematurity, neurological diseases (epilepsy, febrile seizures), asthma, cancer and diabetes, which is distinctive from what was found in most adult studies16.
This meta-analysis’ findings revealed neutropenia, lymphocytosis and leukopenia as the most common white cell abnormalities. Interestingly, neutropenia was not analyzed in other meta-analyses and hence was not reported14,17. This study also showed elevated CRP, LFTs and Lactate Dehydrogenase (LDH) similar to the studies by Ding et al and Zhang el al14,17. Our study also showed elevated procalcitonin which was mirrored by Ding et al, but dissimilar from Zhang et al. Co-infections were found in close to one-fourth of patients, which is again a peculiar finding of pediatric COVID-19 and the most common co-infections were due to Mycoplasma pneumoniaeand Influenza A/B. Ground glass opacities on CT-scan were the most common radiological finding present in more than a third of patients, resembling previous literature on pediatric COVID-1914. Another interesting radiological finding of this meta-analysis was the equal proportion of unilateral and bilateral lesions in CT-scans in children with COVID-19. In contrast, Mantovani et al reported a higher proportion of unilateral involvement than bilateral, while most other meta-analyses have not described other radio findings other than GGOs13,14,17. It is important to note that this study’s confidence intervals were narrower and hence more precise than other meta-analyses due to the higher sample size from data-rich articles.
95.9% of patients were hospitalized and 93.9% of patients received some form of treatment based on our findings. This observation could be skewed, as most studies with sufficient data to synthesize the clinical findings and outcomes would consist of more symptomatic, sick and hospitalized patients. Anti-virals were the most used therapeutic agents, apart from analgesics and herbal medicines, followed by antibiotics. It is important to note that there was an expected therapeutic variability due to different protocols across the world as well as the changing trends of the pandemic. Intravenous immunoglobulin (IVIG) and glucocorticoids were unique treatment options for pediatric patients with SARS-CoV-2, especially with the emergence of MIS-C18. This analysis did not show frequent use of hydroxychloroquine treatment (5.7%) as expected and one of the reasons for that could be the evolving therapeutic trends over the course of the pandemic.
Of the hospitalized patients, a small proportion required intensive care admission and even fewer required mechanical ventilation. These important outcomes are under-reported in meta-analysis literature13,14,17. Shock was one of the striking complications of the disease course present in about 13% of patients, as highlighted by our meta-analysis. 83.3% of patients were discharged and this value could be confounded by the time span of the studies and different protocols for patient discharge. Our meta-analysis reports higher than expected death rate (4.2%) compared to surveillance data19, but this may be due to sampling and reporting bias within studies.
It is possible that our results were confounded by the lack of data outside of China, heterogeneity of a few variables and potential bias within the articles selected. In addition, the variations of diagnostic and therapeutic protocols in different parts of the world and its transformation with the evolving pandemic affects the outcomes reported. Despite the lack of data-rich MIS-C literature published until early July 2020, three MIS-C studies were included in our meta-analysis with 26 patients presenting with prolonged fever and a combination of signs and symptoms such as gastrointestinal manifestations, rash, conjunctivitis, shock with or without multiorgan failure20-22. More data on MIS-C is needed to better equip clinicians and epidemiologists in navigating the rough seas of this global pandemic.