The clinical manifestations and transmission of coronavirus disease 2019 (COVID-19) differed significantly between children and adults when the ancestral strain predominated: children presented with mild disease and were sometimes asymptomatic, whereas adults were more likely to be symptomatic.1 SARS-CoV-2 ) was lower among children than among adults,1 SARS-CoV-2 variants of concerns (VOC) were recently reported to have increased transmissibility.2 , 3 SARS-CoV-2 continues to undergo genetic changes, and new VOCs are likely to be identified. As of October 2022, 5 VOCs (alpha through delta and omicron) were classified due to their higher virulence or transmissibility by the World Health Organization.4 children ,2 , 5 , 6 children were rarely observed in Japan .7 8 Japan .9 Japan , the number of pediatric COVID-19 cases requiring hospitalization has significantly increased, as compared with the period of alpha and delta predominance.10
Phylogenetic analysis indicates that the omicron variant has multiple subvariants. Subvariants BA.1 and BA.2 were the first identified, followed by subvariants BA.4 and BA.5 , which circulated worldwide and caused large outbreaks.11 10 , 12–14 BA.5 infection are poorly understood.
COVID-19 mRNA vaccines have been helpful to prevent infection, symptomatic infection and hospitalization.15–17 BA.5 ) infection does not persist for a long time with a decrease within a few months; however, VE against hospitalization due to BA.1/BA.2 infection remains high (68%–83%).15 , 16 , 18–20 children had been encouraged as a strategy to prevent hospitalization by omicron. Although VE against hospitalization in children during BA.1/BA.2 predominance was reported previously, to our knowledge, VE against hospitalization during BA.5 predominance was not reported.
In Japan , COVID-19 mRNA vaccines were approved for children 12 years old or older (BNT162b2 and mRNA-1273) in May 2021, and for children 5–11 years of age (BNT162b2) in January 20229 Japan during the study period were monovalent mRNA vaccines. Bivalent mRNA vaccines were not approved for children when the study was performed. However, as of October 11, 2022, vaccination rates were estimated at 40.9% for the 3rd dose in children 12 years or older21 children 5–11 years old.22 children 5–11 years of age; however, this effort has been unsuccessful because of fear of vaccines, and vaccine hesitancy reinforced by television programs, websites and social networking sites.
Located in the north of the Japanese mainland, Niigata Prefecture has 258,769 children 15 years of age or younger.23 children accurately represent the clinical profile for Niigata Prefecture. To clarify changes in the clinical characteristics of children infected with SARS-CoV-2 variants, this epidemiologic study analyzed the profile of COVID-19 infection in children from the beginning of the COVID-19 outbreak (January 2020) through the outbreak of BA.5 (July/August 2022) in Niigata, Japan . In addition, we estimated the effectiveness of vaccines in preventing hospitalization in children .
METHODS
Data Collection
This study was a retrospective observational population-based study conducted in Niigata, Japan . We collected clinical data on COVID-19 among children (age 15 years or younger) admitted to 1 of 13 hospitals (Niigata University Medical and Dental Hospital and affiliated hospitals) in Niigata, Japan , between January 1, 2020, and August 31, 2022. Electronic health records of each hospital were collected to analyze the monthly number of pediatric COVID-19 admissions and clinical characteristics [month of admission, age, gender, symptoms, underlying diseases related to the risk of severe COVID-19,24 9 children from the Niigata Prefecture office.
Definitions
A COVID-19 case was defined as a person with a positive result on a SARS-CoV-2 polymerase chain reaction or antigen test under national surveillance. Additionally, symptomatic individuals who had contact with SARS-CoV-2 –positive family members living in the same household were considered to have COVID-19. Among hospitalized patients, a positive SARS-CoV-2 test result was considered a confirmation of COVID-19 infection. Because the detection rate of BA.1/BA.2 was approximately 0% in late December 2021 and 100% in early January 2022, and the rate of BA.5 exceeded 67% in early July 2022 (Figure Supplemental Digital Content 1, https://links.lww.com/INF/E970 BA.5 -predominant, in accordance with detection rates for each lineage of SARS-CoV-2 in Niigata Prefecture (Text, Supplemental Digital Content 2, https://links.lww.com/INF/E971 children 5–11 years old, and receipt of a 2nd or 3rd dose for children 12 years old or older. The febrile seizure was classified as simple or complex, in accordance with a previous report.25 febrile seizures were defined as primary generalized seizures that lasted for less than 15 minutes and did not recur within 24 hours. Complex febrile seizures were defined as focal, prolonged (≥15 minutes) and/or recurrent within 24 hours.25
Evaluation of Vaccine Effectiveness Against Hospitalization for BA.5 Infection
We collected data on monthly COVID-19 vaccination rates for children in Niigata Prefecture. To determine vaccine effectiveness against pediatric hospitalization for BA.5 infection, we estimated the number, age and vaccination history of pediatric COVID-19 patients, using data collected by Niigata Prefecture under the Infectious Disease Control Law of Japan . We analyzed admission rates during BA.5 predominance in relation to COVID-19 vaccination status among children 5–15 years of age.
Ethical Considerations
Because we retrospectively collected clinical data from medical charts, informed consent was obtained by the opt-out method, in accordance with the ethical guidelines for human research in Japan . The present epidemiologic study was approved by the Ethics Committee of Niigata University (2022-0153).
Statistical Analyses
We compared clinical characteristics of pediatric COVID-19 during the periods of BA.1/BA.2 predominance and BA.5 predominance. The χ 2 test was used to compare differences in gender, underlying diseases related to the risk of severe COVID-19, COVID-19 vaccine completion, symptoms, diagnosis, treatment, ICU management and outcomes. The Mann–Whitney U test was used to compare differences in age and LOS. To compare the admission rates of children by febrile seizure divided by total pediatric COVID-19 hospitalized children between BA.1/BA.2 and BA.5 predominance, we used the χ 2 test. To evaluate VE against hospitalization among children 5–15 years of age, we calculated VE by using the χ 2 test. All statistical analyses were performed with Stata version 16.1 (Stata Corp., College Station, TX). A P value of <0.05 was considered to indicate statistical significance.
RESULTS
Monthly Number of Pediatric Admissions
Between January 1, 2020, and August 31, 2022, 49,387 children (19,085 children /100,000 population) were newly diagnosed as having COVID-19, and 393 were hospitalized for COVID-19 (Fig. 1 children were included in the analysis. Before omicron predominance (ie, January 2020 through December 2021), only 10 patients were hospitalized, as compared with 226 patients (96%) in the period of omicron predominance (January 2022 through August 2022), 140 (59%) of whom were hospitalized during the period of BA.5 predominance (July 2022 through August 2022) (Fig. 1
FIGURE 1.: Monthly number of admissions of children with coronavirus disease 2019 in Niigata, Japan , from January 2020 through August 2022. In total, 49,387 children (19,085 children /100,000 population) were newly diagnosed as having coronavirus disease 2019 (COVID-19) (dotted line). Among them, 393 were hospitalized with COVID-19 between January 1st, 2020, and August 31st, 2022. After excluding patients admitted for isolation or observation (yellow), data from 236 patients were analyzed (dark blue). Before the omicron surge (until December 2021), only 10 patients who required hospitalization for medical care. Notably, 59% (140/236) of pediatric COVID-19 patients were admitted (*) during the period of BA.5 predominance (July through August 2022).
Clinical Characteristics of Patients During BA.1/BA.2 Predominance and BA.5 Predominance
The clinical characteristics of pediatric COVID-19 were compared between the 86 cases (0.48 cases/day) recorded during BA.1/BA.2 predominance and the 140 cases (2.26 cases/day) recorded during BA.5 predominance (Table 1 BA.5 predominance (96.4%) than during BA.1/BA.2 predominance (88.4%) (P = 0.02) (Table 2 BA.5 predominance (55.8% vs. 37.9%, P < 0.01). Notably, hospitalization for febrile seizure was more frequent during BA.5 predominance than during BA.1/BA2 predominance (27.9% vs. 7.0%, P < 0.01). The admission rates of children by febrile seizure divided by total pediatric COVID-19 hospitalization in Niigata, Japan showed that the rate of BA.5 predominance (0.14%, 39/27,305) was higher than that in BA.1/BA.2 predominance (0.03%, 6/21,099) (P < 0.01). Patients with simple seizure were admitted to the hospital if they had poor medical access, were of atypical age (older than 5 years) or had a post-ictal status longer than 60 minutes (thus requiring exclusion of encephalopathy/encephalitis). During the BA.5 predominance, more hospitalized patients had complex febrile seizures (15.0%, 21/140), and seizure clusters (71.4%, 15/21) were common than status epilepticus (19.0%, 4/21) among children with complex seizure. Both simple and complex febrile seizures occurred in a broad age range (age 6 months to 10 years) and 35% (14/39) of patients with febrile seizure were 6 years of age or older during the BA.5 -predominant period (Fig. 2 BA.5 predominance, there were 17 patients (44%) who were older than 5 years old and were eligible for the COVID-19 vaccine during the study period. Three patients (18%) completed 2 doses of the COVID-19 vaccine, while the COVID-19 vaccination rate for 5–11 years old was approximately 31% in Niigata, Japan (Table, Supplemental Digital Content 3, https://links.lww.com/INF/E972
TABLE 1. -
Characteristics of
Children With Coronavirus Disease 2019 During BA.1/BA.2 Predominance and
BA.5 Predominance
Total
BA.1/BA.2 Predominance*
BA.5 Predominance†
P Values‡
No. of cases
226
86
140
NA
Age, median years (IQR)
5.6 (1.5–8.9)
6.1 (1.4–9.0)
5.2 (1.4–8.4)
0.34
<6 months, no. (%)
33 (14.6%)
9 (10.5%)
24 (17.1%)
0.17
6 months to 4 years, no. (%)
70 (31.0%)
26 (30.2%)
44 (31.4%)
0.85
5–11 years, no. (%)
111 (49.1%)
46 (53.5%)
65 (46.4%)
0.30
12–15 years, no. (%)
12 (5.3%)
5 (5.8%)
7 (5.0%)
0.79
Female, no. (%)
100 (44.2%)
32 (37.2%)
68 (48.6%)
0.08
Underlying disease related to the risk of severe COVID-19§ , no. (%)
24 (10.6%)
10 (11.6%)
14 (10.0%)
0.70
Completed COVID-19 vaccination, no. (%)
12 (5.3%)
4 (4.7%)
8 (5.7%)
0.73
* Period of BA.1/BA.2 predominance: January through June 2022.
† Period of BA.5 predominance: July through August 2022.
‡ Characteristics were compared for patients during BA.1/BA.2 predominance and BA.5 predominance. The Mann-Whitney U test was used to compare age; the χ 2 test was used to compare the other variables.
§ Underlying diseases related to the risk of severe COVID-19 were including chronic respiratory diseases, chronic cardiac diseases, chronic kidney diseases, neurological and neuromuscular diseases, hematologic diseases, diabetes, metabolic diseases, malignancy, rheumatoid and collagen diseases, endocrine diseases, chronic gastrointestinal and hepatic diseases, immunodeficiency, and other chronic conditions defined by
Japan Pediatric Society.
24 COVID-19 indicates coronavirus disease 2019; IQR, interquartile range; NA, not applicable.
TABLE 2. -
Clinical Profile of
Children Hospitalized with COVID-19 During BA.1/BA.2 Predominance and
BA.5 predominance
Total
BA.1/BA.2 Predominance*
BA.5 Predominance†
P Values‡
No. of cases
226
86
140
NA
Symptoms
Fever, no. (%)
211 (93.4%)
76 (88.4%)
135 (96.4%)
0.02
Nasal discharge, no. (%)
31 (13.7%)
5 (5.8%)
26 (18.6%)
< 0.01
Cough, no. (%)
68 (30.1%)
25 (29.1%)
43 (30.7%)
0.79
Nausea and vomiting, no. (%)
101 (44.7%)
48 (55.8%)
53 (37.9%)
< 0.01
Diarrhea, no. (%)
22 (9.7%)
7 (8.1%)
15 (10.7%)
0.53
Seizure, no. (%)
47 (20.8%)
6 (7.0%)
41 (29.3%)
< 0.01
Reason for admission
Febrile seizure, no. (%)
45 (19.9%)
6 (7.0%)
39 (27.9%)
< 0.01
Simple, no. (%)
20 (8.8%)
2 (2.3%)
18 (12.9%)
< 0.01
Complex, no. (%)
25 (11.1%)
4 (4.7%)
21 (15.0%)
0.02
Status epilepticus, no. (%)
6 (2.7%)
2 (2.3%)
4 (2.9%)
0.81
Cluster, no. (%)
17 (7.5%)
2 (2.3%)
15 (10.7%)
0.02
Encephalopathy, no. (%)
1 (0.4%)
0 (0%)
1 (0.7%)
0.43
Croup, no. (%)
6 (2.7%)
4 (4.7%)
2 (1.4%)
0.14
Dehydration/Oral intake failure, no. (%)
105 (46.5%)
45 (52.3%)
60 (42.9%)
0.18
Management and outcomes
Length of hospital stay, median days (IQR)
2 (2–3)
3 (2–4)
2 (1–3)
< 0.01
ICU admissions, no. (%)
11 (4.9%)
1 (1.2%)
10 (7.1%)
0.04
Mechanical ventilation, no. (%)
2 (0.9%)
1 (1.2%)
1 (0.7%)
0.73
Death, no. (%)
1 (0.4%)
0 (0%)
1 (0.7%)
0.43
ICU indicates intensive.
* Period of BA.1/BA.2 predominance: January through June 2022.
† Period of BA.5 predominance: July through August 2022.
‡ Characteristics were compared for patients during BA.1/BA.2 predominance and BA.5 predominance. The Mann-Whitney U test was used to compare age; the χ 2 test was used to compare the other variables.
Care unit; NA, not applicable
FIGURE 2.: Age distribution of patients with a febrile seizure during BA.5 predominance. The age range was wide (6 months to 10 years) for hospitalized children with a febrile seizures . Simple seizure (n = 20, light blue) and complex seizure (n = 25, dark purple) were observed at all ages.
Notably, 8 years old male with encephalopathy died during BA.5 predominance. The child had no underlying disease and no COVID-19 vaccination. Because the case showed fever and cluster of seizures without altered mental status, he was admitted to the hospital under the diagnosis of complex febrile seizures . However, he was in the status epilepticus and subsequently became cardiopulmonary arrest due to significant cerebral edema after several hours of admission. He passed away on hospital day 14th despite treatment such as immunoglobulin and corticosteroid for acute encephalopathy. During the periods of BA.1/BA.2 predominance and BA.5 predominance, 1 patient developed viral pneumonia associated with COVID-19 infection, and no patient developed myocarditis/pericarditis or multisystem inflammatory syndrome in children (MIS-C). Before omicron predominance, there was 1 case of myocarditis/pericarditis, febrile seizure with status epilepticus, and viral pneumonia caused by COVID-19. These 3 cases had no underlying disease and the COVID-19 vaccine was not available in Japan at the time.
VE Against Hospitalization for BA.5 Infection
In Niigata, Japan , 31% of children 5–11 years and 76% of children 12–14 years of age had received 2 doses of a COVID-19 vaccine by August 31, 2022 (Table, Supplemental Digital Content 3, https://links.lww.com/INF/E972 children 5–15 years old tested positive for SARS-CoV-2 on a polymerase chain reaction or antigen test. In an analysis of the rate of COVID-19 hospitalization in relation to vaccination status, the effectiveness of COVID-19 vaccination for preventing hospitalization was estimated at 75% (95% confidence interval 48–88%, P < 0.01).
DISCUSSION
This study compared the effects of the BA.5 variant with those of the BA.1/BA.2 variants in Japanese children . Although the number of hospital admissions was higher during BA.1/BA.2 omicron predominance than during alpha and delta predominance, BA.5 infection resulted in higher infection and hospitalization rates, because of dehydration/oral intake failure and febrile seizure. Fortunately, COVID-19 vaccination of children reduced the risk of hospitalization in those infected with the BA.5 variant.
Previous studies of the characteristics of omicron BA.1/BA.2 lineage infection revealed that BA.1/BA.2 infection was more likely to cause upper respiratory infections than lower respiratory infections; croup, in particular, was an important clinical feature of the presentation.3 , 26 , 27 BA.5 predominance periods (4.7% vs. 1.4%, P = 0.14). Besides, nausea/vomiting was more frequent during BA.1/BA.2 predominance than during BA.5 predominance (55.8% vs. 37.9%, P < 0.01) (Table 2 BA.5 predominance, the policy recommending hospitalization of patients with only gastrointestinal symptoms was changed after COVID-19 wards reached maximum capacity because of the increased number of patients with neurological complications. The decrease in hospitalizations of patients with gastrointestinal symptoms may also have been related to the fact that the local medical association promoted the use of oral rehydration solutions and behavioral changes of patients’ family members, in an attempt to reduce the number of clinic visits and hospitalizations during that period. Besides, the governmental infection control strategies including the restriction of human flow had not changed significantly in Japan throughout 2022 when BA.1/BA.2 and BA.5 were predominant strains. Japanese tried to keep avoiding closed spaces, crowded places and close-contact settings (3 C’s) and were very strict to wear face masks in different settings. In addition, daycare centers kept opening throughout 2022. There was no remarkable change in Japanese behavior toward COVID-19; however, there was a sharp increase in newly diagnosed COVID-19 patients during BA.5 predominance.
As compared with delta variant infections among children , BA.1/BA.2 resulted in lower rates of hospitalization [hazard ratio (HR) 0.66)] admission to ICU (HR 0.35), and need for mechanical ventilation (HR 0.15); however, the incidence rate of BA.1/BA.2 infection was 6–8 times that of delta variant infection.3 12 children in Japan , the omicron variant outbreak was associated with a substantial number of pediatric hospitalizations. The rapid increase in the number of infections strained healthcare resources. Patients with omicron infection filled the beds of COVID-19 wards, and some patients with severe diseases other than COVID-19 could not be hospitalized because of the lack of hospital beds.
The increase in neurological complications due to the omicron variant was an important concern. The spread of BA.1/BA.2 increased the incidence of neurological complications, including febrile and nonfebrile seizures and encephalopathy, in the US.13 Japan . Emergency visits and hospitalizations for febrile seizure were more frequent in the omicron era than before it.10 Japan ,28 29 29 BA.5 predominance, the incidence was significantly higher during the latter period. An increase in neurological complications was also observed nationwide in Japan . The Japanese Society of Intensive Care Medicine reported that seizures and encephalopathy accounted for 37% of moderate to severe cases of pediatric COVID-19 in Japan during BA.5 predominance.30 children 6 months to 5 years of age and is more common in Japanese children than in those of other races/ethnicities31 , 32 Fig. 2 febrile seizures , such as meningitis, encephalitis and brain abscess. During BA.5 predominance, the febrile seizure must be included in the differential diagnosis when older children present with fever and seizure.
The emergence of BA.5 significantly affected children in Japan . Because the prevalence of febrile seizure in East Asia is higher than in the US and European countries (8%–11% vs. 2%–5%),32 BA.5 outbreak has a greater impact than BA.1/BA.2 as a risk of febrile seizure in countries in East Asia. Besides, the seroprevalence of anti-SARS-CoV-2 antibodies in the US and Europe was reaching 70%–90% before BA.5 predominance,33 , 34 Japan was only 8.5%. Therefore, the wide spread of BA.5 might affect more children in Japan than in the US and European countries. Because clinical characteristics of BA.5 infection among children has not been reported in other countries, the accumulation of evidence is definitely needed to see a similar trend is observed or not.
Analysis of fatal pediatric COVID-19 cases in Japan showed that 44% (18/41) of patients had underlying diseases; however, the other patients either had no underlying disease or their disease status was unknown.35 children without underlying disease are at risk of severe disease or death. In addition, no standard treatment has been established for some severe pediatric diseases, such as encephalopathy. Therefore, COVID-19 vaccines are critical in reducing the risk of severe disease. In this study, COVID-19 vaccination of children had a VE of 75% against hospitalization during BA.5 predominance. This result is consistent with previously reported values for VE against hospitalization in children infected with BA.1/BA.2 (68%–83%).16 , 18 children 5–11 years old (19.1% had received 2 doses),21 children younger than 5 years To prevent dire outcomes in children with COVID-19, vaccine rates among children must be increased.
This study has some limitations. First, we were unable to ascertain the date of the last vaccination and assess VE in relation to the time since the last vaccination. Because no study has reported VE in relation to time since last vaccination against BA.5 , VE must be assessed as part of any attempt to formulate a vaccine strategy against BA.5 infection. Second, we were unable to analyze data from all patients with neurological complications caused by COVID-19, because most patients with febrile seizure did not require hospitalization, and collection of outpatient data for such patients was not possible. Third, we were unable to perform detailed microbiological analyses for the SARS-CoV-2 positive patients; however, the routine infectious diseases surveillance in Niigata Prefecture revealed that no significant changes in the incidence of other viral infections such as human herpes viruses 6/7 were observed.36 SARS-CoV-2 -positive family members living in the same household were considered to have COVID-19. Unfortunately, we were not able to identify the rate of such patients in this category in the dataset. Finally, we were unable to perform viral genetic analysis of all patients. Therefore, we compared symptoms, diagnoses and management of COVID-19 during the periods of BA.1/BA2 predominance and BA.5 predominance, as did simultaneous epidemiologic reports of COVID-19 (14, 26, 27).
CONCLUSIONS
Compared to the omicron variant BA.1/BA.2, the emergence of BA.5 had more significant impact, and the incidence of neurologic complications requiring hospitalization increased. To prevent severe disease and death, COVID-19 vaccination of children must be vigorously promoted to manage BA.5 and future variant outbreaks.
ACKNOWLEDGMENTS
We are grateful to the staff members of local health centers who assisted with this study. The hospitals that participated in this study were the Niigata University Medical and Dental Hospital, Niigata City General Hospital, Niigata Prefectural Central Hospital, Niigata Prefectural Shibata Hospital, Uonuma Kikan Hospital, Nagaoka Red Cross Hospital, Tachikawa General Hospital, Nagaoka Chuo General Hospital, Joetsu General Hospital, National Hospital Organization Niigata Hospital, Saiseikai Niigata Hospital, Kashiwazaki General Hospital, and Medical Center, and the National Hospital Organization Nishi-Niigata Chuo Hospital. We acknowledge David Kipler for editing the article.
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