Studies summarizing the clinical picture of COVID-19 in children are lacking. This review characterizes clinical symptoms, laboratory, and imaging findings, as well as therapies provided to confirmed pediatric cases of COVID-19.
Methods
Adhering to PRISMA guidelines, we searched four medical databases (PubMed, LitCovid, Scopus, WHO COVID-19 database) between December 1, 2019 to May 14, 2020 using the keywords “novel coronavirus”, “COVID-19” or “SARS-CoV-2”. We included published or in press peer-reviewed cross-sectional, case series, and case reports providing clinical signs, imaging findings, and/or laboratory results of pediatric patients who were positive for COVID-19. Risk of bias was appraised through the quality assessment tool published by the National Institutes of Health
Findings
We identified 131 studies across 26 countries comprising 7780 pediatric patients. Although fever (59·1%) and cough (55·9%) were the most frequent symptoms 19·3% of children were asymptomatic. Patchy lesions (21·0%) and ground-glass opacities (32·9%) depicted lung radiograph and computed tomography findings, respectively. Immunocompromised children or those with respiratory/cardiac disease comprised the largest subset of COVID-19 children with underlying medical conditions (152 of 233 individuals). Coinfections were observed in 5.6% of children and abnormal laboratory markers included serum D-dimer, procalcitonin, creatine kinase, and interleukin-6. Seven deaths were reported (0·09%) and 11 children (0·14%) met inclusion for multisystem inflammatory syndrome in children.
Interpretation
This review provides evidence that children diagnosed with COVID-19 have an overall excellent prognosis. Future longitudinal studies are needed to confirm our findings and better understand which patients are at increased risk for developing severe inflammation and multiorgan failure.
Over the last 6 months, there have been over 6·4 million worldwide cases of SARS-CoV-2 infection and our knowledge of the disease and its epidemiologic and clinical characteristics continue to evolve.However, since it was first reported in Wuhan city in December 2019, most studies have focused on symptomatic adults. In the presence of this rapidly emerging, novel infection, identification of clinical and laboratory characteristics in the pediatric population is essential to guide clinical care, predict disease severity, and determine prognosis. In this context, we performed the largest and most comprehensive systematic review of published studies involving pediatric patients with known COVID-19. Our systematic review summarized the clinical, laboratory and radiologic features of COVID-19 in neonates, children, and adolescents.
Our review also supports the findings by a recent systematic review by Castagnoli et al. [17] Their study included a total of 1,065 COVID-19 infected children and concluded that, by and large, the prognosis for children was excellent, demonstrated by only one death. Compared to that review and other COVID-19 pediatric systematic reviews, this manuscript has several key advantages: (1) we summarize 131 studies that includes 7780 children from 26 different countries, (2) this report synthesizes underlying pediatric medical conditions and delineates bacterial and viral coinfections, (3) we quantitatively describe clinical symptoms and imaging findings, (4) herein, we conglomerate the mean and standard deviation of frequently used laboratory analytes in COVID-19 positive children, (5) our report presents antiviral therapies by specific agents, and (6) our systematic review offers a preliminary comparison of patients with/without MIS-C.
Although SARS-CoV-2 infection was first identified in China, the United States has now amassed the highest number of confirmed cases. Calculations made on June 4th, 2020 from the COVID-19 Dashboard by the Center for Systems Science and Engineering at Johns Hopkins University indicate that China has 4·5% of total confirmed COVID-19 cases compared to the United States. As expected, the most common vector for childhood infection is close contact to an affected family member or residing in an area with a high population of cases. Our findings align with the results of an April 2020 report by Dong et al, in which there was a clear trend that the disease spread rapidly from a Chinese province to surrounding provinces and cities in children from December to February. Furthermore, Qiu and colleagues studied 36 pediatric COVID-19 positive patients in which ten patients (28%) were asymptomatic latent cases identified secondary to an adult family member who was infected, symptomatic, or traveled to an endemic area. This lends concern that children, who may be asymptomatic, may play a role in community transmission of the virus.Results from this systematic review echo findings describing milder symptoms in pediatric cases of SARS-CoV-2 infection. For instance, the most common clinical manifestations we found were fever (59·1%), cough (55·9%), rhinorrhea (20·0%) and myalgia/fatigue (18·7%). Unlike adults, children rarely progressed to severe upper respiratory symptoms requiring intensive care unit admission. Although transmission rates for SARS-CoV-2 are high, symptoms are less severe than SARS/Middle East Respiratory Syndrome (MERS) infection.Serum inflammatory markers, specifically D-dimer, procalcitonin, creatine kinase, and interleukin-6, were consistently abnormal in the studies included in this review. Alterations to acute-phase infection-related biomarkers are corroborated in adult case series and meta-analyses. However, we must take caution when interpreting these outcomes and await more robust, longitudinal laboratory analyses. Again, these blood analyses are non-specific and may merely represent a pro-inflammatory state induced by the virus.In terms of imaging findings, we found that most patients had normal chest x-rays, a finding that is not surprising as most pediatric patients did not present with respiratory symptoms. Paralleling this review, a meta-analysis of CT features for COVID-19, showed that diffuse bilateral ground-glass opacities were the most common finding at all stages of disease. Despite these promising associations, it is important to consider that radiologic manifestations from various pathogens may have a similar impression and should be ruled out. Co-infections with other respiratory illnesses including influenza and mycoplasma were described in 72 patients. As elegantly described by Cox and colleagues, most fatalities from the 1918 influenza outbreak were secondary to bacterial infection. Thus, future reports should not only describe coinfections but also detail pertinent negatives. At present, our study had a low rate of reporting the infectious workup (26·7) of patients. Illustrating the importance, one of two patients that died in the study by Shekerdemian et al was due to gram negative sepsis in a child with comorbidities who developed end organ failure.Although most children have an uneventful course, a present concern is an inflammatory cascade in pediatric patients with COVID-19. Clinical presentation includes an unremitting high fever, and includes systemic signs such as rash, conjunctivitis, and/or gastrointestinal symptoms. The case series of eight children from London required respiratory assistance, whether it was oxygen support (n=1), noninvasive ventilation (n=2) or intubation and mechanical ventilation (n=4). One patient was so ill that he required mechanical ventilation and extracorporeal membrane oxygenation. In addition, all required vasopressor support and demonstrated elevated levels of ferritin, D-dimers, troponin, procalcitonin, and C-reactive protein (CRP). Additionally, cardiac imaging showed ventricular dysfunction in five children. In another article, Italian investigators describe ten patients with MIS-C. Correspondingly, they describe patients manifesting with fever, diarrhea (n=6), and abnormal echocardiograms (n=6). Laboratory specifics showed elevated CRP, lymphopenia, thrombocytopenia, and elevated ferritin levels.We found evidence of MIS-C features in 11 children who also presented with fever (n=11), dyspnea (n=8), and diarrhea (n=6). According to Riphagen and Verdoni, lymphopenia was marked in our cohort of patients, as well as increased levels of lactate dehydrogenase, CRP and D-dimer. Despite low numbers we did observe an interesting lower level of CD16+CD56+ natural killer (NK) cells in patients with MIS-C. Both lymphopenia and a reduced number/activity of NK cells in adults has correlated with a more severe COVID-19 disease progression.Little is known about the perinatal aspects of COVID-19, and there have been several reported cases of neonatal infection, suggesting a possible perinatal or vertical transmission during pregnancy. However, in a report by Chen et al., all nine neonates born to COVID-19 positive mothers tested negative for the virus after cesarean delivery. In another study by Zhang et al., 10 neonates from COVID-19 positive mother all tested negative for the infection. Moreover, this is further supported by analysis of breast milk and placental pathologic specimens from COVID-19 positive mothers, which have returned negative for the virus. Lastly, vertical transmission was not observed with either SARS-CoV-1 or in MERS-CoV; therefore, it is unlikely that maternal vertical transmission during third trimester occurs, or is likely very rare. However, from the limited data published, we cannot determine the consequences of SARS-CoV-2 infection in early pregnancy and if it can be transmitted to the fetus and hinder organ development, malformations, growth abnormalities, or even lead to premature labor or spontaneous abortions. Also, Dong et al communicated an alarming finding in which the proportion of severe and critical cases were higher in neonates when compared to the >16-year-old age group (10·6% vs. 3·0%). As a community, we must stay vigilant, practice social distancing, hand wash frequently, and be especially careful with our children who are at potentially higher risk for critical disease (e.g. multiple comorbidities, weakened immune systems, etc.).
There are several limitations to this review. First, many of the included studies were case reports or cases with low patient numbers. Second, the level of evidence for all the studies was low. Next, we unified the laboratory data to mean and standard deviation. There are inherent issues when using averages including the impact of outliers. We did not include suspected cases, which would allow for a direct comparison of symptoms, labs, imaging, and outcome data. Of concern, many of the studies were incomplete and did not include a comprehensive picture of the patients. Future studies should not generalize data (“CBC was normal”), or categorize laboratory values (i.e., number of patients with elevated CRP), or group therapies (i.e., patient received “antiviral therapy”), or display aggregate data between adults and children. If feasible, divide the symptoms, laboratory markers, and imaging characteristics by children vs. adults. A better understanding of COVID-19 requires access to data, even if it is provided in the appendix or supplementary section of the article. In this way, we will be able to identify the best biomarkers that can stratify disease severity and potential short- and long-term outcomes. Another limitation, is that we had a small number of patients that fit the criteria for MIS-C. Reasons for the small number of patients includes a lack of reporting all of the signs, symptoms, and laboratory markers necessary to make the diagnosis (especially duration of fever). Missing information for laboratory markers (D-dimer, interleukins, and CD%) hinders our preliminary findings. Lastly, the literature focusing on COVID-19 is very dynamic and growing rapidly and we expect the rates, especially for MIS-C, of our outcomes to change
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