DOI: https://doi.org/10.21203/rs.3.rs-2962301/v1
In South Korea, COVID-19 vaccination has been recommended to children since October 2021, targeting all teenagers aged 12–15 years, with emphasis on high-risk group including chronic kidney disease (CKD) pediatric patients. In this study, we aimed to assess the rate of adverse events following COVID-19 vaccination in children with CKD in South Korea, using national cohort data.
We retrieved the Korea Disease Control and Prevention Agency-COVID19-National Health Insurance Service (K-COV-N) cohort data linked to the National Health Insurance System (NHIS) data, to calculate rate of purpura and other hemorrhagic conditions, Guillain-Barré syndrome (GBS), myocarditis and/or pericarditis, and anaphylaxis incidence in children with CKD, after BNT162b2 vaccination.
Among the 2,078 children with CKD, 69.2% (n = 1,437) had received BNT-162b2 vaccine. Guillain-Barré syndrome and anaphylaxis or anaphylactic shock did not occur during observed period. Purpura and hemorrhagic conditions were more frequent in the unvaccinated group (5/641 vs 1/1,437) while myocarditis/pericarditis was observed only in vaccinated group (0/641 vs 3/1437). The difference in the risk of any of these two events between vaccinated and unvaccinated groups was insignificant.
In this national cohort study of children with CKD in Korea, we found no evidence of increased risk of adverse events following BNT162b2 vaccination. Our results provide the safety profiles of COVID-19 vaccine for patients with CKD.
Children with underlying medical conditions are at risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its complications. The coronavirus disease-19 (COVID-19) vaccine therefore is particularly important for these children to prevent from severe illness or hospitalization. While the first COVID-19 mRNA vaccines were initially authorized for emergency use in adult population in December 2020, they were not available for children and adolescents under the age of 16 at the time due to the lack of safety data in this age group [1].
In South Korea, mass vaccination of BNT162b vaccine targeting adolescents aged 12–15 years started since November 2021. Despite of evidence indicating the protective effectiveness of COVID-19 vaccine in children, the parent’s willingness to vaccinate their children was low [2]. Parents of children with chronic kidney disease (CKD) may show more hesitancy to vaccinate their children [3]. Given the low COVID-19 vaccination coverage among children and the need for additional vaccination [4], reassurance of the vaccine safety in children and adolescents with CKD is important.
In this study, we aimed to assess the incidence of severe adverse events among children with CKD, using a national population data of South Korea.
We used the Korea Disease Control and Prevention Agency-COVID19-National Health Insurance Service (K-COV-N) cohort data established by linking the National Health Insurance System (NHIS) data to the information of COVID-19 infection and vaccination of the Korea Disease Control and Prevention Agency, as described in a previous study [5]. The NHIS database contains information on socio-demographics, including age, premium percentiles (proxy for income percentile), residential district, and clinical information on diagnoses, prescribed medications, procedures, and treatments covered by the NHIS for every visit to health institutions. Because the NHIS covers almost all the Korean population as a universal health insurance system, this database captures all the health care service use.
We constructed a cohort of children aged 12 − 15 years who were diagnosed with CKD (n = 2,127). We identified pediatric CKD patients using operational definition based on the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and prior treatment codes [6–8]: primary or first secondary diagnosis of chronic kidney disease or end stage kidney disease (ICD-10 codes E102, 'E112', 'E142', 'N08', 'N19', 'N18'), dependence on dialysis (Z992), transplant (Z940), D638 (anemia of renal failure), and either 1) undergoing regular dialysis (hemodialysis and/or peritoneal dialysis) treatment code or prescription code for longer than one month or 2) who had undergone kidney transplantation (R3280). We excluded those with SARS-CoV-2 infection between August 1 and December 31 in 2021 (n = 25) from the analysis due to the possible association between the serious adverse event and the infection. Furthe excluding death from other than COVID-19 infection (n = 24), the final study population was 2,078 adolescents.
Following the a priori knowledge, four adverse events: purpura and other hemorrhagic conditions, Guillain-Barré syndrome, myocarditis and/or pericarditis, and anaphylaxis, were analyzed. We identified these conditions based on hospital admission with the corresponding ICD-10 codes (Table 1). Adverse events that occurred between 0 and 60 days after BNT162b2 vaccination, within the observation period (between November 1 and December 31 in 2021), were counted as adverse events.
| Adverse events | ICD-10 codes |
|---|---|
| Purpura and other hemorrhagic conditions | D690, D691, D692, D693, D694, D695, D696, D698, D699 |
| Guillain-Barré syndrome | G610 |
| Myocarditis/pericarditis | I51.4, I30, I31.9, I32.8, I40, I41.8, I51.8 |
| Anaphylaxis or anaphylactic shock | T78.2, T88.6 |
In the final study population, we compared the baseline characteristics between vaccinated and unvaccinated CKD children in the pooled data. We matched vaccinated CKD children to unvaccinated control CKD children (who were not vaccinated or infected in the relevant exposure period). Matching was done based on the demographic and clinical risk factors including age, sex, medical aid, Seoul capital area residence, and pediatric comorbidity index (PCI). We calculated the PCI based on the methodology developed and validated in a prior study [9].
Using the Cox proportional hazard model, we estimated the safety of COVID-19 immunization by calculating hazard ratio (HR) of four adverse events in the vaccinated group with that of matched unvaccinated group. The protocol of this study was approved by the institutional review board of Korea University College of Medicine (KUIRB-2023-0030-01). This study was carried out in accordance with the REporting of studies Conducted using Observational Routinely-collected Data (RECORD) guidelines.
Between January 1, 2021, and October 31, 2021, a total of 2,078 pediatric CKD patients were identified. Among those, 69.2% (n = 1,437) had received BNT-162b2 vaccine between November 1 and December 31 in 2021 (Table 2). Mean age was 15 and 14 years in the vaccinated and unvaccinated patients. Twenty percent of pediatric CKD patients lived in Seoul capital area and 5–7% were medical aid beneficiaries. The PCI was higher in unvaccinated group (4.2 vs 4.0). After matching in accordance to the PCI, a total of 641 unvaccinated patients were matched to 1,282 vaccinees and the baseline characteristics were comparable between the two groups (Table 2).
| Variable | Before matching | After matching | |||
|---|---|---|---|---|---|
| Vaccinated N (%) | Unvaccinated N (%) | Vaccinated N (%) | Unvaccinated N (%) | ||
| Frequency | 1437 | 641 | 1282 | 641 | |
| Age (years), mean (SD) | 15.2 (1.6) | 14.2 (1.7) | 15.0 (1.6) | 14.2 (1.7) | |
| Male | 739 (51.4) | 361 (56.3) | 694 (54.1) | 361 (56.3) | |
| Seoul capital area | 300 (20.9) | 137 (21.4) | 260 (20.3) | 137 (21.4) | |
| Medical aid beneficiaries | 108 (7.5) | 32 (5.0) | 76 (5.9) | 32 (5.0) | |
| Comorbidities | |||||
| Any malignancy | 43 (3.0) | 58 (9.0) | 43 (3.4) | 58 (9.0) | |
| Depression | 77 (5.4) | 22 (3.4) | 76 (5.9) | 22 (3.4) | |
| Diabetes | 469 (32.6) | 124 (19.3) | 436 (34.0) | 124 (19.3) | |
| Epilepsy | 31 (2.2) | 31 (4.8) | 29 (2.3) | 31 (4.8) | |
| Drug abuse | 2 (0.1) | 0 (0.0) | 2 (0.2) | 0 (0.0) | |
| Psychotic disorders | 28 (1.9) | 10 (1.6) | 28 (2.2) | 10 (1.6) | |
| Anemia | 155 (10.8) | 93 (14.5) | 140 (10.9) | 93 (14.5) | |
| Cardiovascular conditions | 325 (22.6) | 232 (36.2) | 304 (23.7) | 232 (36.2) | |
| Chromosomal anomalies | 5 (0.3) | 5 (0.8) | 5 (0.4) | 5 (0.8) | |
| Congenital malformations | 107 (7.4) | 93 (14.5) | 96 (7.5) | 93 (14.5) | |
| Menstrual disorders | 57 (4.0) | 20 (3.1) | 50 (3.9) | 20 (3.1) | |
| Weight loss | 5 (0.3) | 7 (1.1) | 5 (0.4) | 7 (1.1) | |
| Anxiety | 52 (3.6) | 22 (3.4) | 48 (3.7) | 22 (3.4) | |
| Asthma | 51 (3.5) | 25 (3.9) | 47 (3.7) | 25 (3.9) | |
| Conduct disorder | 6 (0.4) | 1 (0.2) | 5 (0.4) | 1 (0.2) | |
| Developmental delays | 15 (1.0) | 14 (2.2) | 12 (0.9) | 14 (2.2) | |
| Eating disorders | 3 (0.2) | 2 (0.3) | 3 (0.2) | 2 (0.3) | |
| GI conditions | 944 (65.7) | 393 (61.3) | 846 (66.0) | 393 (61.3) | |
| Joint disorders | 23 (1.6) | 22 (3.4) | 22 (1.7) | 22 (3.4) | |
| Nausea and vomiting | 167 (11.6) | 78 (12.2) | 152 (11.9) | 78 (12.2) | |
| Pain conditions | 480 (33.4) | 199 (31.0) | 428 (33.4) | 199 (31.0) | |
| Sleep disorder | 14 (1.0) | 8 (1.2) | 13 (1.0) | 8 (1.2) | |
| Pediatric comorbidity index, mean (SD) | 4.0 (3.1) | 4.2 (3.1) | 4.1 (3.1) | 4.2 (3.1) | |
| CKD, chronic kidney disease; SD, standard deviation; GI, gastrointestinal. | |||||
Among the four adverse events of special interest, Guillain-Barré syndrome and anaphylaxis or anaphylactic shock did not occur in the study population, therefore were excluded from analysis. Purpura and hemorrhagic conditions were more frequent in the unvaccinated group compared to vaccinated group (5/641 vs 1/1,437) while three cases of myocarditis/pericarditis were observed in vaccinated group (0/641 vs 3/1437) (Table 3). The HR in vaccinated group in reference to unvaccinated group for purpura and hemorrhagic conditions was 0.19 (95% CI, 0.02–1.67, P = 0.135). Myocarditis and/or pericarditis occurred only in vaccinated adolescents with an odds ratio of infinity. Any of the two adverse events was 0.71 (95% CI, 0.18–2.70, P = 0.610).
| Adverse event | Vaccination status | N | Event | Person-year | HR (95% CI) | P |
|---|---|---|---|---|---|---|
| Before matching | ||||||
| Purpura and hemorrhagic conditions | Unvaccinated | 641 | 5 | 104 | 1.00 (Reference) | |
| Vaccinated | 1437 | 1 | 178 | 0.16 (0.02–1.40) | 0.098 | |
| Myocarditis or pericarditis | Unvaccinated | 641 | 0 | 105 | 1.00 (Reference) | |
| Vaccinated | 1437 | 3 | 177 | High (0-Inf) | 0.999 | |
| Any of the two | Unvaccinated | 641 | 5 | 104 | 1.00 (Reference) | |
| Vaccinated | 1437 | 4 | 177 | 0.60 (0.16–2.27) | 0.448 | |
| After matching | ||||||
| Purpura and hemorrhagic conditions | Unvaccinated | 641 | 5 | 104 | 1.00 (Reference) | |
| Vaccinated | 1282 | 1 | 150 | 0.19 (0.02–1.67) | 0.135 | |
| Myocarditis or pericarditis | Unvaccinated | 641 | 0 | 105 | 1.00 (Reference) | |
| Vaccinated | 1282 | 3 | 150 | High (0-Inf) | 0.999 | |
| Any of the two | Unvaccinated | 641 | 5 | 104 | 1.00 (Reference) | |
| Vaccinated | 1282 | 4 | 150 | 0.71 (0.18–2.70) | 0.610 | |
| HR, hazard ratio; CI, confidence interval. | ||||||
In this study, we found no increased risk of purpura and hemorrhagic disease, myocarditis/pericarditis in children with CKD who received BNT162b2 vaccine. The COVID-19 vaccine is the most important measure to prevent severe SARS-CoV-2 infection in children with risk factors [10]. A previous study showed that the children with CKD presenting with moderate-to-severe COVID-19 are at risk of severe complications, including severe acute kidney injury and mortality [11]. However, limited data on vaccine safety in children with CKD were available. Similar results were found in previous studies in Asia [12], in U.S. [13], and in European countries [14]. Children with CKD were reported to have a higher risk of serious COVID-19 compared to otherwise healthy persons [11]. In our data, among 1282 vaccinated children with CKD, 3 had a record of myocarditis and/or pericarditis during the observation period. However, when we compared the risk of occurrence of 2 myocarditis/pericarditis in 641 CKD patients without vaccination history, no increased risk was observed, suggesting that vaccination did not increase the risk of heart complication in children with CKD.
In the real-world setting, misinformation about the safety of COVID-19 vaccines can lead to vaccine hesitancy, causing low vaccination rates and increasing the risk of infection especially for children with underlying disease [2]. Because of this, there had been vaccine hesitance among parents of children with CKD. In a previous study, 64% of parents of children with CKD revealed that they were worried of COVID-19 vaccine's safety [3]. In sum, 30% of our children with CKD were not vaccinated likely due to various concerns about vaccines. As a previous survey showed a significant association between self-reported sufficiency and credibility of vaccine-related information [15], the findings of this study may aid in parental decision-making regarding COVID-19 vaccination for their children with CKD.
Despite evidence from clinical trials that focused on healthy adults, a real-world safety data is needed for children with underlying diseases. Although the children with CKD are at higher risk of complications if infected SARS-CoV-2, there is a public health gap to address this low vaccine coverage, likely due to vaccine hesitancy. Based on our result, vaccination is a safe intervention to prevent COVID-19 in children with CKD; hence the benefits of vaccination in this population must be emphasized. To the best of our knowledge, this is the largest safety data of BNT162b2 in children with CKD. This finding can contribute to pediatrician's and parent's understanding of the safety profile of BNT162b2 vaccine for children with CKD.
This study has number of limitations. First, our dataset does not have detailed clinical data, and we were unable to further stratify the analysis by the disease severity. Second, although the data we used covers all healthcare utilization records in Korea, we were unable to include data for prescriptions not reimbursed by the national health insurance. Third, our results of the risk period of 0–60 days might indicate a healthy vaccinee effect. Despite these limitations, the population-representativeness of data and important public health implications is a main strength of this study.
In this national cohort study among children with CKD in Korea, we found no evidence of increased risk of adverse events following BNT162b2 vaccination. Our results provide the safety profiles of COVID-19 vaccine for patients with CKD and highlight the importance of vaccination to prevent potential severe outcomes if infected.
Acknowledgment
This study used the KDCA and NHIS databases for policy and academic research (KDCA-NHIS-2022-1-587). The conclusions of this study are not related to this institution.
This research was supported by a grant (22183MFDS433) from the Ministry of Food and Drug Safety in 2022-2025