SARS-CoV-2 infection in pediatric population before and during the Delta (B.1.617.2) and Omicron (B.1.1.529) variants era

At the beginning of the COVID-19 epidemic, the available data during the period February 26, 2020, to June 10, 2020, suggested that the infection occurs more frequently in adults and seems to be unusual in infants (1.7–2% of the diagnosed cases of COVID-19) [29, 30]. On February 11, 2020, the Chinese Center for Disease Control and Prevention (China CDC) showed that among 72,314 cases less than 1% and 1% of the cases were in children younger than 10 years and 10 to 19 years, respectively [31]. In the United States, data concerning 149,760 laboratory-confirmed COVID-19 cases obtained between February 12 and April 2, 2020, showed that 1.7% were in children aged less than 18 years [32]. From March 5 to April 8, 2020, the Chicago Department of Public Health reported that among 6369 laboratory-confirmed cases, 1.0% were children aged 0–17 years [30].

Afterward, it appeared that the true incidence of infection in infants was underestimated [33]. A retrospective study based on Nationwide case series of 2135 COVID-19 pediatric patients (< 18 years) with COVID-19 reported to the China CDC, from January 16, 2020, to February 8, 2020, indicated that children of all ages appeared to be susceptible to COVID-19 [33]. In this study, 731 (34.1%) children had laboratory-confirmed COVID-19. The Center for Disease Control and Prevention (CDC) showed an increase in the rate of COVID-19 pediatric cases, from March to July 2020, in the USA: 7.3% of all COVID-19 cases compared to 1.7% of COVID-19 pediatric cases obtained during the period 12 February to 2 April [34, 35]. It seems that children and adults acquired infection at similar rates but develop different clinical manifestations [33]. In China, several studies including population varied from 731 to 1391 children showed only a few numbers of infants (1–2%) developed symptomatic forms [31‐36]. Also, a systematic review conducted by Bhuiyan et al. [37] showed that among 1214 confirmed COVID-19 pediatric cases younger than five years nearly half of the cases were asymptomatic.

Globally, the prevalence of COVID-19-positive infants was underreported. The number of COVID-19-positive infants was reported only in a few studies in which, it is indicated among other positive cases [38, 39]. Figure 2 shows the prevalence of COVID-19-positive infants in different regions of the world based on the reported data before the emergence of the delta and omicron variants. The prevalence of COVID-19 in infants varied from country to country (1.1–22.5%) (Fig. 2). The highest percentages of COVID-19 positive infants were from United States (22.5%), Saudi Arabia (13.2%), Spain (12.6%) and Nigeria (11.7%) [40‐43]. Lower percentages were found in Brazil (8.4%), Canada (7.3%), Korea (6.5%), India (5.9%), Norway (5.0%), Congo (4.5%), Germany (2.7%), Australia (2.6%), United Kingdom (2.2%), China (1.6–2.2%), Iran (1.7%), Italy (1.5%) and Netherland (1.1%) [37, 39, 44‐48]. These differences may be explained by the possible country-level influence on COVID-19 such as the testing strategy of suspected cases, the original population structure of each country, and whether the control measures (social distance, wearing masks, washing hands, etc.) were strictly followed by the public or not and also by the period of the state of the epidemic. However, it is necessary to point out that the true prevalence of COVID-19 in infants remains underestimated due to the lack of stated data and the high frequency of asymptomatic forms [49].

The need to understand the impact of children in the SARS-CoV-2 pandemic sighted researchers to study the transmission dynamics of SARS-CoV-2 between infant-infant and infant-adult. From February 2020 to January 2021, the obtained data were controversial. Many studies reported low transmissibility of SARS-CoV2 among children and also from children to adults [36, 38, 62, 63]. For instance, when investigating SARS-CoV-2 transmissibility in 23 clusters, Maltezou et al. showed that the transmission of infection within families including children occurs more frequently from adult to child [63]. Low transmissibility in children was also reported by other studies conducted in China and United States, which it has shown that young children often acquired infections through community sources [35, 37]. Bhuiyan et al. [37], found that among 1214 children younger than five years, the majority (> 95%) had a community source of infection. However, in the same period, other studies suggested an important role of children in the transmission dynamics of SARS-CoV-2 [30, 64]. A household transmission pattern study, in the United States, demonstrated that children were the potential source of further transmission in approximately 20% of households, with possible child-to-adult transmission in 20% and possible child-to-child transmission in 17% [64]. Also, Mannheim et al. suggested both child-to-child and child-to-adult transmission is estimated at 13% [30]. In India, based on the contact-tracing data from the Indian states of Tamil Nadu and Andhra Pradesh by 1 August 2020, Laxminarayan et al. [1] showed that the transmission occurs more frequently among children who contact cases from their own age. The enhanced infection risk among individuals exposed to similar-age cases was also apparent among adults [1]. The authors concluded that children may play a key role in the transmission dynamics of SARS-CoV-2 in middle and low incomes countries where social, cultural, and economic conditions favor close contact between children and also with adults [1, 65].

At the onset of the SARS-CoV-2 pandemic up to May 2021, compared to adults, children get less COVID-19 and had less severe cases [33, 48, 62‐64]. Unlike adults, infants develop more likely asymptomatic [33, 36, 72, 79‐83] or mild forms [16, 31, 33, 36, 64, 84, 85]. Symptomatic children reported fever and dry cough as the most common symptoms. They were reported at 36–73% and 19–54% of pediatric cases, respectively [32, 35, 48, 66, 67, 79, 86‐93]. The body temperature varied mainly between 37.5 and 38.5 [86]. These symptoms can be accompanied by headache, fatigue, myalgia, nasal congestion, sneezing, [28, 48, 64, 68, 69, 79, 86, 88, 89, 94]. Headache was reported in almost 25–79% of cases [48, 64, 70, 71].

Regarding nasal congestion, some studies, in the USA and China reported an important proportion of 50–68% of pediatric cases with rhinorrhea [64, 94]. In contrast, other studies based on a limited number of cases, reported fewer proportions ranging from 2.8 to 16% of cases with rhinorrhea and nose congestion [86, 87, 89, 91, 95].

While adult patients rarely developed intestinal signs, symptoms such as nausea, vomiting, abdominal pain, constipation, and diarrhea are frequent among pediatric populations [96, 97]. A wide variety of manifestations can appear before, with, or after the development of respiratory symptoms [67‐69, 79, 96, 98‐100]. Anorexia or poor appetite was frequent (34–67%), followed by diarrhea (2–32.5%), vomiting (1–28.3%), abdominal pain and discomfort (1–11.9%) and nausea (1–11.1%). [9, 79, 96, 99, 101‐110].

Compared with symptomatic adults, children were less likely to report loss of taste and loss of smell [48, 64] and more likely to report sore throat [64, 83, 86, 88, 89]. In Taiwan, up to April, 7, among 24 children, 12.5% had a loss of smell and/or taste [48]. Other studies reported also the development of sore throat. According to Laws RL and colleagues in a series of 19 children, 68% had presented sore throat [64]. However sore throat seems low in other studies: 1 case in a total of 20 [88], 2 cases of sore throat among 31 [89].

Before the emergence of the Delta variant, complications among positive COVID-19 children cases were less frequent. They were especially reported among patients with underlying medical conditions. Required hospitalization was in 11% to 60% of cases and admission to the Intensive Care Unit (ICU) in almost 10% of cases, the majority presented medical underlying conditions [32, 93, 112, 113].

Severe cases presented hypoxia, tachypnea and oxygen saturation less than 92% [33, 93]. Critical cases can rapidly progress into acute respiratory distress syndrome or respiratory failure and present shock, encephalopathy, myocardial injury, heart failure, coagulation dysfunction, acute kidney injury and Organ dysfunction [33, 87, 94].

As COVID-19 can trigger complications of an underlying disease, patients with immune deficits need to be monitored carefully during the COVID-19 pandemic [122]. Nevertheless, at the beginning of the pandemic, studies about COVID-19 among Primary Immunodeficiency (PID) patients were controversial. According to the Joint Forces of International Societies for Immunodeficiencies, most patients present a mild disease [122, 123]. For instance, In Iran, a case report of an eight-year-old boy who had Specific Antibody Deficiency (SAD), presented wet cough and rhinorrhea [124]. In general, patients with severe disease evolution, additionally, have comorbidities or complications of their immunodeficiency [122, 123].

Other studies considered that patients with immunodeficiency are at increased risk of developing severe COVID-19 [125‐127]. PID patients presented: shortness of breath, a drop in oxygen saturation, respiratory distress, tachypnea, seizure, cardiomegaly, cardiac, and pulmonary arrest, requiring hospitalization and admission to intensive care units [128‐130]. For instance, among an international series of 94 COVID-19 PID patients, 18 were admitted to intensive care units, and nine patients died [129]. Another study reported up to 50% hospitalization rate among PID requiring mechanical ventilation [130‐132]. Fatal outcomes were also reported among PID and Secondary Immunodeficiency (SID) patients. It was estimated up to 35.3% and 44% respectively [130].

It was expected that prolonged carriage of SARS-CoV-2 is possible such as in the case of viruses belonging to the family of Picornaviridae: poliovirus [133], non-polio enteroviruses [134, 135] and cosavirus [136]. Data reported shedding of infectious SARS-CoV-2 and genomic RNA by PID occurred for many months [137]. They excreted the virus up to 120 days after initial detection (70–120 days) [138]. In these cases, Primary Immunodeficient (PIDs) and Secondary Immunodeficient (SIDs) patients, may constitute an increased risk of transmission to the community with the persistence of a reservoir for the virus and the potential emergence of mutated strains.

The available data on immunocompromised patients infected with the delta variant is limited. According to the study of Hadjadj and colleagues, the emergence of SARS-CoV-2 strains like the Delta variant (B.1.617.2) with increased viral form and immune escape potential, raises concerns among immunocompromised patients [139, 140]. Recently, a new variant of concern (VOC) called Omicron was first identified on November 24, 2021, in an immunocompromised patient from Johannesburg, South Africa as a consequence of prolonged replication among PID patients [141‐145]. However, no more data has been published on the behavior of omicron in severely immunocompromised individuals [146].

There are many risk factors associated with the progression and severity of COVID19 in children such as age, male gender, ethnicity, comorbidity, coinfection and virus type [29].

In the United States, Bandi S and colleagues reported that the mean age of COVID-19–positive children was significantly higher than those testing negative (9.72 vs. 4.85 years) [188]. In another study, severe and critical cases were reported mainly in children aged less than 1 year [36]. However, DeBiasi RL and colleagues showed that adolescents and young adults were more commonly critically ill than younger children [189].

Ethnicity was examined in the study of Bandi et al. [188]. African American children had a significantly higher rate of positive tests for COVID-19: 6.8% versus 1.7% of white children. Among 58 children, in the United Kingdom, race (black or Asian) was described as a risk factor for COVID-19 [190].

Male gender is a risk factor for severe coronavirus disease in adults [191]. A predominance of boys was reported in all age subgroups among 2490 pediatric cases of COVID-19 in a series in the United States [32]. In a cross-sectional study of 48 children with COVID-19 admitted in the USA and Canadian intensive care units (ICUs), 52% were boys [192].

Underlying medical comorbidity may be a risk factor for severe disease in childhood [32, 80, 88, 92, 177, 192, 193].

The rate of patients with preexisting morbidity, developing severe COVID-19 manifestations, varied between 23 and 83% [193]. Among underlying diseases, chronic lung disease was the most common followed by cardiovascular disorder and immunosuppressive disease [32]. Malnutrition, cancers and kidney diseases were also implicated [178]. Respiratory syncytial virus and Enterobacter aerogenes were implicated [87, 194].