Our study represents one of the largest pediatric cohorts to date describing symptoms of SARS-CoV-2 infected patients in ambulatory settings. The study describes changes in the rate of symptoms in different time frames where different variants were dominant. Specifically, it demonstrates that fever was the most common symptom with different rates in different age groups and significantly more dominant during the fourth wave in Israel that was dominated by the Delta variant. The rate of febrile illness during the fourth wave was 33% among SARS-CoV-2 infected patients and 66% among COVID-19 patients (symptomatic patients).
Differences in symptoms during differing pandemic periods were described in smaller cohorts. Chua et al. described the clinical characteristics and transmission patterns among children and youths with COVID-19 in Hong kong in 2020. Their study found significant differences in the clinical presentations across the three waves of outbreaks (all before the Delta variant became dominant). The number of symptomatic children declined in the second and third waves compared to the first, but absolute numbers were low, and screening patterns might have changed over time. Somekh et al. described the increased spreading effectiveness of the Alpha variant in children compared to the first two waves of the pandemic in Israel; however, they did not report symptoms.
The difference in febrile illness among different age groups is intriguing and enhances some of the assumptions of why children have less severe diseases than adults. Preschool children had the lowest rate of febrile illness. Those children are post their toddler years where they were exposed to numerous viral illnesses that might enhance their innate and adapted immune response to coronaviruses in general.
Idyllo et al. followed patients hospitalized with COVID-19 and looked for preexisting immunity for seasonal coronavirus. They found evidence for preexisting immunity that affects the humoral response to SARS-CoV-2. Anderson et al. demonstrated that human serum samples before and after the onset of the COVID-19 pandemic with antibodies against common seasonal human coronaviruses are cross-reactive against SARS-CoV-2 but do not confer cross-protection against infection or hospitalization. In contrast, Guoma et al. suggest that recent seasonal coronavirus infections potentially limit the duration of symptoms following SARS-CoV-2 infections through mechanisms that do not involve cross-reactive antibodies and postulate that cellular immune responses are involved.
This assumption is strengthened by our findings of the steady increase of febrile illness as children advance in age after the age of six years. This population of preschool children should be the focus of further assessments in order to look for the complex mechanism behind this phenomenon. Interestingly – Infants had the highest level of febrile response. This finding is in line with descriptions of higher morbidity in infants compared to older children.
The proportion of fever and other symptoms in children was described in a few studies. The largest was an international network cohort described by Duarte-Salles et al. They described fever as the most common symptom ranging from 4.8 to 26.4% in different countries. This study took place before the emergence of the Delta variant. In another study from the united states, Parcha et al. described 12,306 COVID-19 patients. They have shown, similarly to our study, that fever was the most common symptom, although, in their study, there was a steady decline in the rate of fever from infants to adolescents. In another cohort from the beginning of the pandemic in the united states (data collection ended May 2020), Stokes et al. described fever as the most common symptom in children. The rate was high (46% percent in children aged 0-9 years and 35% percent in 10-19 years). The rate of febrile illness was the rate among patients with reported symptoms, which was low among the whole cohort making it challenging to describe the actual rate of febrile illness among all SARS-CoV-2 infected children.
The strength of our study relates to the structure of the healthcare system in Israel, which offers extensive medical care to the general public at no cost, allowing excellent access to care. Specifically, during the COVID-19 pandemic, PCR tests were offered at no cost for symptomatic patients and individuals exposed to verified SARS-CoV-2 patients, allowing us to present the full spectrum of the disease in children from asymptomatic patients to patients with a variety of symptoms.
The limitation of the study includes the type of interaction between the physician and the patient's parents, which was based mainly on a telephone interview and not on office appointments. In addition, the questionnaire was filled once in most of the cases – post-positive PCR results, limiting the opportunity to capture symptoms occurring later in the disease course. PCR results in the time period of the study did not undergo genomic sequencing; nevertheless, monitoring by the ministry of health showed that the third and fourth waves were dominated by the Alpha and Delta wave, respectively[10; 11]. This study was limited to children because symptoms comparison in adults between waves could not be made during the same time-period as most Israeli population was already vaccinated during the fourth wave.