A new coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China in late December 2019 and subsequently spread globally, requiring the declaration of a pandemic by the World Health Organization. Health on March 11, 2020.1 As of August 23, 2020, 23 million cases of the new respiratory disease coronavirus disease (COVID-19) and 800,000 deaths have been reported globally.1
Human-to-human transmission of SARS-CoV-2 was first reported by Chan et al2, when a family member with no travel history to Wuhan, China became infected several days after contact with family members. who returned from Wuhan.
As the potential of SARS-CoV-2 develops, it is becoming evident that asymptomatic infection and mild clinical disease are more prevalent in children than in adults.3,4 However, compared to adults, there are very few studies pediatric studies published to date.3,4
In the context of the ongoing COVID-19 pandemic, it is important to study the epidemiological characteristics, clinical manifestations, and chains of transmission in children to guide detection, containment, and prevention measures. Below, the authors present findings from clinical and epidemiological investigations and viral loads of children and adolescents with SARS-CoV-2 infection in Greece.
| Patients and Methods |
> Surveillance and contact tracing of SARS-CoV-2 infections
In Greece, cases of SARS-CoV-2 infection are reported to the National Public Health Organization. Laboratory-diagnosed cases are reported daily by doctors and laboratories testing for SARS-CoV-2 infection using real-time reverse transcriptase polymerase chain reaction (RT-PCR).
Data on hospitalized cases, admission to intensive care units (ICUs), complications and/or deaths associated with COVID-19 are also collected by the attending physicians through telephone interviews. Contact tracing of SARSCoV-2 infected cases is carried out and close contacts are instructed to remain isolated for 14 days after last exposure.
If symptoms appear, it is recommended that contacts be tested for SARS-CoV-2. In addition, mass and active laboratory testing and sampling by RT-PCR is also carried out, regardless of symptoms, for containment and in the context of cluster investigation in specific settings or populations such as the Gypsy population or those residing in camps. refugees.
> Data collection
The study period extended from February 26 (first case of COVID19 diagnosed in Greece) to June 30, 2020. The children were identified through the national registry of SARS-CoV-2 infections. Data were collected using a standardized questionnaire per case.
They contacted one parent (preferably the mother) of each child by telephone to collect data on any other household members who tested positive for SARS-CoV-2. If this was the case, information was collected on history of exposure to SARS-CoV-2 infection, date of diagnosis and onset of symptoms, and first case in the family.
Additionally, pediatricians from 9 hospitals across Greece were invited to contribute details about children with COVID-19 who had been hospitalized. Any data queries were reviewed by at least 2 investigators and were cleared with the reporting center. Data were analyzed by child unless otherwise stated.
> Virological research
Respiratory samples from patients were analyzed by real-time RT-PCR following commercial or in-house protocols. Children were categorized into 3 groups according to the PCR amplification cycle threshold value (Ct), such as high, moderate or low viral load (Ct <25, 25-30 or > 30, respectively). Samples with Ct > 38 were considered negative.
> Definitions
Asymptomatic SARS-CoV-2 cases were defined as those with positive PCR for SARS-CoV-2 in the absence of symptoms. COVID-19 cases were defined as those with a positive SARSCoV-2 PCR and compatible signs and symptoms. COVID-19 cases were classified as mild when patients were treated on an outpatient basis, moderate when patients were admitted to the hospital and had a favorable outcome, while those who were admitted to the ICU or were classified as severe. They had a fatal outcome.
Low-grade fever was defined as a temperature ≥37.5°C and <38.0°C twice in 24 hours, respectively. Fever was defined as a temperature ≥38.0°C twice within 24 hours, respectively.
The febrile episode was defined as fever alone. Acute respiratory infection was defined as the occurrence of at least one respiratory symptom (e.g., cough, sore throat, dyspnea). Influenza-like illness (ILI) was defined as the occurrence of fever, weakness, headache and/or myalgia in association with cough, dyspnea and/or pharyngeal pain.
Pneumonia was defined as a case of infection in a patient with computed tomography or radiographic findings consistent with pneumonia .
Children were defined as people under 19 years of age. A family cluster was defined as the detection of at least 2 cases of SARS-CoV-2 infection within a family. The first case was defined as the first case of COVID-19 in a family. Household members were defined as people living in the same residence. Close contact was defined as contact of >15 minutes within a distance of <2 m with a COVID-19 case.
> Statistical analysis
All items were coded and scored, and data were analyzed using IBM-SPSS 26 (IBM Corp. Released 2016). Categorical variables were compared using the chi-square test, while the t test was used for continuous variables. Logistic regression analysis was performed to evaluate characteristics predicting hospitalization in children.
Another logistic regression analysis was performed to evaluate characteristics predicting children’s viral load. P values <0.05 were considered statistically significant. The household attack rate of SARS-CoV-2 infection was estimated as follows: (number of household members with SARS-CoV-2 infection/number of household members) × 100. Notification rates were calculated using official data from the Hellenic Statistical Authority.5
> Ethical issues
The study was approved by the Board of Directors of the National Public Health Organization and the Ethics Committees of the hospitals where children with COVID-19 were hospitalized. Written consent was not required, as the data were pseudo-anonymized and collected in the context of epidemiological surveillance. The data was managed in accordance with national regulations and European Union laws.
| Results |
> Characteristics and viral loads of children with SARS-CoV-2 infection
A total of 203 children with SARS-CoV-2 infection were studied, corresponding to a cumulative notification rate of 9.74 cases per 100,000 children aged 0 to 19 years. Their average age was 11 years (range: 6 days to 18.4 years). Of the 203 children, 111 (54.7%) had an asymptomatic infection and 92 (45.3%) developed COVID-19.
Compared with other age groups, school-aged children aged 6 to 12 years were more likely to have an asymptomatic infection (being 34.2% of all asymptomatic infections), while infants <1 year were more likely to have an asymptomatic infection. of developing symptoms (representing 19.5% of all COVID-19 cases) (p value = 0.001).
Among 164 children for whom Ct values were available, 46 children (28.1%) had high viral load, 44 (26.8%) had moderate viral load, and 74 (45.1%) had low viral load.
There was no significant difference between children with asymptomatic infection and children with COVID-19 in terms of mean age, sex, underlying condition, and viral load. Furthermore, there was no significant difference between the 3 viral load groups in terms of mean age, age group distribution, sex, underlying condition, onset of fever, and hospitalization rate, even when children with moderate and high viral loads were grouped together. (data not revealed).
A logistic regression analysis performed to evaluate the association between age group, sex, having an underlying condition, infection category, hospitalization, and viral load found that none of these variables predicted viral load (data not shown).
Fever was the most prevalent symptom (42 children; 45.6%) followed by mild fever (26 children; 28.3%). Children had fever for a median of 2 days (range: 1-10 days). Regarding clinical syndromes, 45 children (48.9%) had an acute respiratory infection, 28 children (30.4%) had an ILI and 25 (27.2%) had a febrile episode.
> Children hospitalized with COVID-19
Twenty-four children with COVID-19 (26.1%) were hospitalized. The mean age was 12.2 months (range: 6 days to 18.4 years) and 12 hospitalized children (50%) were younger than 12 months. Pneumonia was diagnosed in 7 of 19 (29.2%) children who underwent chest x-ray, while one 18-year-old adolescent had findings suggestive of acute respiratory distress syndrome on chest x-ray.
Five children required supplemental oxygen. A child with chronic neurological disease (spinal muscular atrophy type II) was admitted to a pediatric ICU, required mechanical ventilation, underwent a tracheostomy, gradually improved but was still hospitalized at the end of the study period due to his underlying illness.
The median length of hospitalization for the remaining 23 children was 4.5 days (range: 1 to 13 days). Six children were treated with hydroxychloroquine, while lopinavir/ritonavir was used in 2 adolescents. The baby in the ICU was treated with hydroxychloroquine, azithromycin, oseltamivir, and systemic steroids. In all other children, all symptoms resolved without apparent sequelae. No fatal outcome was reported.
A logistic regression analysis found that the only variable that predicted hospitalization was being <5 years old (p value = 0.006). Sex, having an underlying condition, SARS-CoV-2 infection category, and viral load were not associated with a significant risk of hospitalization (data not shown).
> Epidemiological investigation
The epidemiological investigation revealed that transmission from a household member accounted for 132 of 178 (74.2%) pediatric cases with SARS-CoV-2 infection for which the source of infection was identified.
Two 18-year-old teenagers lived alone. The remaining 201 children corresponded to 133 families with a median of 5 household members (range: 1 to 16 members) per family and a median of 2 children (range: 1 to 6 children) per family.
In total there were 979 household members in the 133 families, of which 428 (43.7%) had laboratory-confirmed SARSCoV-2 infection, including 112 mothers, 97 fathers, 156 siblings, 39 grandparents, 11 uncles/aunts , 8 cousins, 3 nannies, 1 husband and 1 partner.
The median attack rate of SARS-CoV-2 infection was 40% (range: 11.1%-100%) per family. At least one additional household member tested positive for SARS-CoV-2 infection in 146 pediatric cases (71.9%), while a median of 2 household members (range: 0 to 8 members) tested positive in the family test.
An adult was the first case of SARS-CoV-2 infection in the families of 125 (66.8%) children with SARS-CoV-2 infection, while 62 children (33.2%) were identified as first or only case of SARS-CoV-2 infection in their families.
Of the 62 children mentioned above, 51 children did not have any other family members infected, 1 child had an unknown family history, and 10 children had at least one family member with SARS-CoV-2 infection.
Notably, there were 2 siblings who developed symptoms and tested positive for SARSCoV-2 33 days apart, while both parents tested negative; 2 siblings developed symptoms and tested positive concomitantly while both parents were negative; a family of 4 (2 siblings and both parents) and a family of 3 (the child and both parents) tested positive through mass screening in a highly endemic region (in both families the children were tested first, while the source of SARSCoV-2 infection remained unknown); 1 family of 4 (2 siblings and both parents) tested positive after community exposure (children were tested first); and an 18-year-old teenager whose mother and her 16-year-old sister tested positive for SARS-CoV-2, but it was unclear from whom he became infected.
In this latter family, there was evidence of transmission of SARS-CoV-2 from the 16-year-old girl to her mother. There was no other evidence of transmission from a child to an adult or from a child to another child. Overall, transmission occurred from an adult to a child in 133 families.
Finally, regarding the time of infection, 29 pediatric cases (14.3%) occurred before school closure (March 11), 19 cases (9.3%) after school closure, but before of confinement (March 23), 70 cases (34.5%) during the national confinement (March 23 to May 3) and 85 cases (41.9%) after the confinement was lifted (May 4 to May 30). June). Schools reopened gradually (depending on student grade) from May 11 to June 1 and closed for the summer on June 15. Students physically attended schools on other days.
| Discussion |
Understanding the characteristics of SARS-CoV-2 infection of children in a country and its role in the current COVID-19 pandemic is essential to guide public health interventions, including screening, school closures, use of masks and future vaccination guides. The authors studied 203 children and adolescents consecutively diagnosed with SARSCoV-2 infection in Greece. To our knowledge, this is one of the largest cohorts of children with SARS-CoV-2 infection and their viral loads published so far.
More than half of the children in this study had asymptomatic SARSCoV-2 infection, which is consistent with studies from China.3,4,6,7 However, it should be noted that the criteria for testing SARSCoV-2 have changed during the pandemic in Greece as elsewhere. As a result, it is difficult to make quantitative inferences about the distribution of asymptomatic versus COVID-19 infections.
In these series, infected school-aged children aged 6 to 12 years were more likely to be asymptomatic compared to other pediatric age groups, accounting for one-third of all asymptomatic infections. Furthermore, infants <1 year of age accounted for 19.5% of all COVID-19 cases and 50% of all hospitalized cases, which may be partially attributed to the increased awareness of pediatricians and parents and the search for medical care for sick babies.
Similarly, infants <1 year of age were 16.5% of the 406 children with COVID-19 in China, 4 and infants <2 years of age accounted for 40% of the 585 hospitalized pediatric cases in 77 healthcare facilities in Europe. 8
In this series, approximately one-third of children with COVID-19 had an ILI, pointing to the importance of influenza vaccination during the upcoming influenza season, to reduce the possibility of influenza and avoid diagnostic dilemmas and inappropriate management. in terms of antiviral therapy and infection control.9
As also reported by others, 4,10 children in this series had favorable outcomes and no deaths. No cases of pediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 were recorded in the participating hospitals most likely due to the rarity of SARS-CoV-2 transmission in the community and the small number of infected children.
A recent study conducted in the state of New York in the US estimated its rate at approximately 1:161 cases of COVID-19 among people under 21 years of age in the study population.11
According to studies from China and Switzerland and a family cluster study of SARS-CoV-2 infection by the authors, 4,10-12 in the current study, adults were the main source of SARS-CoV-2 infection in families, while their contribution to the spread of the virus within families was high. Notably, an adult household member was the source of infection in two-thirds of cases. This could be attributed to the fact that children are asymptomatic in a greater proportion than adults, and therefore less tested than the latter, unless they are secondary cases.
However, in this study, almost two-thirds of pediatric cases occurred outside the lockdown period, yet children were primarily infected by an adult family member and not the other way around.
Transmission of SARS-CoV-2 from children to adults has been occasionally reported.4 In this series, there was only one case of transmission of the infection from an adolescent with COVID-19 to his mother, while they found no evidence of transmission of child to child.
Similarly, investigation of a COVID-19 cluster in France found no case of transmission of the infection by a symptomatic infected child, even though the child had had many close contacts with classmates at 3 different schools. .13
The fact that children with SARS-CoV-2 infection are often asymptomatic or have mild illness (resulting in fewer opportunities to shed and spread the virus) compared to adults may explain this finding.12
However, in a large cohort of 59,073 contacts of 5706 COVID-19 cases across all age groups in South Korea, the highest rate of COVID-19 (18.6%) was found among household contacts of children. in school age and the lowest among children aged 0-9 years (5.3%). 14
The authors found a median attack rate of SARS-CoV-2 infection of 40% in families with an infected child, which ranged up to 100% in some families. Within families, attack rates as high as 75% have been reported in other studies.6,12,15,16
In the large cohort of 59,073 contacts in South Korea, 11.8% of household contacts were estimated to develop COVID-19 compared to 1.9% of non-household contacts, underscoring the dynamics of transmission of SARS-CoV-2 within homes.14
There is little data on the association between SARS-CoV-2 viral loads and infectivity, as well as the clinical manifestation and course of the disease. A recent study of 145 patients with mild or moderate COVID-19 found that children <5 years of age had significantly lower mean Ct values than children aged 5 to 17 years or adults, indicating that young children have a equivalent or higher viral load level in their upper respiratory tract compared to older children and adults.17
Significantly lower Cts have been found in mild COVID-19 cases at admission and on or after day 10 of illness, suggesting that higher and longer viral loads may be associated with severe clinical outcomes. .18 In this study, most children had moderate or high viral loads. However, they found no correlation between Ct values and age or severity of SARS-CoV-2 infection.
Symptomatic children had a higher burden in nasopharyngeal swab samples than asymptomatic children in one study, 19 however, no correlation between burdens and disease presentation has been found by others.20
Two recent studies found that children with SARS-CoV-2 infection have viral loads comparable to adults, making transmission plausible.20,21 Host or other factors could explain discrepancies between viral loads. in the upper respiratory tract of children and their contribution to virus transmission.
A limitation of the present study was the fact that the criteria for testing for SARS-CoV-2 infection and for hospitalization may have changed during the study period. The fact that Ct values correspond to the viral nucleic acid and not necessarily to the infecting virus must also be taken into account.
Recall bias regarding familial transmission events is also possible. An advantage of the current study is the large number of children and adolescents consecutively diagnosed with SARS-CoV-2 infection retrieved from the national surveillance database.
In conclusion, the large number of children with SARSCoV-2 infection collected throughout the country allowed the authors to study the epidemiological and clinical profiles of SARS-CoV-2 infections during infancy, childhood, and adolescence.
In this setting, adults appear to play a key role in introducing and spreading the virus in families, while there was only one case of transmission from a teenager to an adult family member. This contrasts with the fact that children manifest high and moderate viral loads regardless of age, appearance of symptoms or severity of infection.
Further studies are needed to elucidate the role of young patients in the ongoing pandemic and particularly in light of the reopening of schools and the need to prioritize groups for future COVID-19 vaccination.
