Although SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is generally mild in children and adolescents, the disease has been associated with serious illness and increased mortality in individuals with severe comorbidities. Data regarding the immunogenicity of the BNT162b2 mRNA COVID-19 (coronavirus disease of 2019) vaccine in adolescents with severe comorbidities are limited. A recent study found a normal humoral vaccine response in patients with chronic diseases and poor response in patients with impaired immunity such as post-transplantation recipients and adolescents with cancer.1 In Denmark, the BNT162b2 mRNA COVID-19 vaccine was offered to individuals aged 16–17 years with chronic diseases from 27 December 2020, 5 months before the national vaccine recommendation for healthy adolescents. Due to low vaccine availability at that time of the pandemic, only adolescents with the most severe chronic diseases were offered vaccination. We aimed to investigate the immunogenicity of SARS-CoV-2 mRNA vaccination in these adolescents to identify individuals with poor vaccine response. This prospective observational cohort study included adolescents with severe chronic diseases receiving treatment at the tertiary referral centre, Copenhagen University Hospital, Rigshospitalet. Patients were invited to participate if offered a COVID vaccine from ultimo December 2020. Infection with SARS-CoV-2 prior to vaccination was not an exclusion criterion. Antibody response was measured using the Shenzhen Yhlo Biotech (Shenzhen, China) assays iFlash-SARS-CoV-2 IgG (nucleoprotein IgG) and IgG iFlash-SARS-CoV-2 IgG-S (S1 spike protein IgG). Three consecutive blood samples were planned to be collected from day 0 to day 180 following vaccination. Time points for collection of blood samples differed for each patient as they were collected at the time of scheduled outpatient clinical consultations due to the complete lockdown during the first part of the study period. The threshold for positivity was defined as values ≥8.0 AU/mL for both assays. The study was approved by the Ethics Committee of the Capital Region of Denmark (H-20028631) and the Danish Data Protection Agency (P-2019-29). Informed consent was obtained before participation. A total of 23 patients aged 15–18 years participated, including 12 (52%) with severe chronic lung diseases, 6 (26%) with chronic neurological disorders, 2 (9%) with heart diseases, and 3 (13%) following transplantation (details are provided in Table S1). Two patients received T-cell suppressive therapy after heart transplantation (case 1; tacrolimus, mycophenolate, and azathioprine) and 6 months post-haematopoietic stem cell transplantation (case 2; tacrolimus), respectively, and one patient with cystic fibrosis received abatacept (case 3), a biological immune inhibitor of T-cell co-stimulation (Figure 1, Table S1). The remainder did not receive immunosuppressive therapy. SARS-CoV-2 serology was investigated a median of 2 times (range 1–5) in each patient. All patients received two doses of the BNT162b2 mRNA COVID-19 vaccine with a median interval of 22 days (range 21–47). After the first vaccine, and before the second dose, the median anti-spike IgG for patients not receiving immunosuppressive therapy was 115 AU/mL (range 0.4–547; positivity ≥8.0 AU/mL). Following the second vaccine, the median anti-spike IgG was 2765 AU/mL (range 387–4732) day 7–75, 1070 AU/mL (range 452–2385) day 76–150 and 416 AU/mL (38–1785) day 151–236. The median values for different disease categories are given in Figure 1. The two patients who received T-cell suppressive therapy had anti-spike IgG <8 AU/mL on days 41, 109, and 207 (case 1) and 19 AU/mL, 9 AU/mL, and <8 AU/mL on days 37, 80 and 164 (case 2), after the second vaccine. Case 3 who received abatacept had a spike IgG of 2451 AU/mL and 145 IE/mL on days 44 and 156 after the second vaccine, similar to the levels of the patients not receiving immunosuppressive therapy. One patient had SARS-CoV-2 infection during the study period proven by PCR and seroconversion of nucleocapsid IgG, in addition to increasing S1 spike protein IgG day 258 (case 4; Figure 1). The remaining patients had no signs of SARS-CoV-2 infection before or during the study, based on clinical suspicion, PCR results and negative nucleocapsid IgG antibodies (Table S1). In this prospective case series, we found high levels of anti-spike IgG antibodies following the mRNA COVID-19 vaccine, compared with the levels before vaccination, in adolescents with severe chronic diseases who did not receive immunosuppressive therapy. Although the antibodies decreased with time, the patients still had high levels of antibodies at follow-up after 5–9 months. Our findings are in line with high vaccine immunogenicity 3 months after the second vaccine, determined by a surrogate virus neutralisation test, in a larger study including adolescents with chronic diseases.1 We found very low levels of anti-spike IgG antibodies in the two adolescents receiving T-cell suppressive therapy, which has also been observed previously in adolescents and adults receiving immunosuppressive treatment.1, 2 Thus, close monitoring of such patients is warranted to guide their risk of infection. High levels of anti-spike IgG antibodies were observed in one adolescent who received abatacept. This contrasts with the reduced immunogenicity found in adults receiving abatacept, reflecting the inhibition of B- to T cell co-stimulation.3 One fully vaccinated patient with protective levels of spike antibodies had confirmed SARS-CoV-2 infection which significantly boosted the immune response. Such a hybrid immunity has also been observed in adults.4 The limitations of this study include few participants, lack of a control group with healthy adolescents as well as lack of conventional virus-based neutralisation tests and measurements of cellular responses. In conclusion, adolescents with severe chronic disease not receiving immunosuppressive treatment all had high levels of antibodies, also at follow-up after 6 months. The study was funded by a COVID-19 grant from the National Ministry of Higher Education and Science (grant no. 0237-00004B) and Innovation Fund Denmark (0176-00020B). The authors have no conflicts of interests. Table S1. 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Abstract Aim Our aim was to investigate whether risk factors, including selected genetic variants, appeared with the same frequency in preterm‐born and term‐born children with respiratory symptoms. Methods We conducted an observational study on a cohort at Copenhagen University Hospital Hillerød, Denmark, consisting of 63 preterm‐born and 86 term‐born children who were included at birth and followed to 6 years of age. Odd ratios (OR) and 95% CIs were calculated. Results Valid genotyping data were obtained from 135 children and 126 and 64 parents completed questionnaires at the 1‐year and 6‐year follows‐ups, respectively. The C allele of rs3751972 was associated with an increased wheezing risk at 6 years of age in term‐born children, but not in preterm‐born children (OR 8.84, 95% CI 1.02–76.72, p = 0.05 versus OR 2.33, 95% CI 0.59–9.20, p = 0.23, respectively). At 1 year of age, preterm‐born children with respiratory symptoms were three times as likely to have parents who smoked than those without such symptoms (65% and 21%, respectively, p = 0.005). Conclusion Genetic variants known to affect the risk of respiratory symptoms did not seem to affect the risk of wheezing in preterm children. Parental smoking was a significant risk factor for respiratory symptoms.
Background— Extracellular superoxide dismutase (EC-SOD) is an antioxidative enzyme found in high concentrations in the arterial wall. Two to three percent of all people in Denmark carry an R213G substitution, which increases plasma concentration 10-fold. This may reduce arterial wall EC-SOD concentrations, increase intimal LDL oxidation, and therefore may accelerate atherogenesis. Our primary hypothesis was that EC-SOD-R213G predisposes to ischemic heart disease (IHD). The secondary hypothesis was that EC-SOD-R213G offers predictive ability with respect to IHD beyond that offered by measurements of plasma EC-SOD and autoantibodies against oxidized LDL (oxLDL). Methods and Results— The primary hypothesis was tested in a prospective, population-based study of 9188 participants from The Copenhagen City Heart Study with 956 incident IHD events during 23 years of follow-up and retested cross-sectionally with independent case populations of patients with IHD (n=943) or ischemic cerebrovascular disease (ICVD) (n=617). Case populations were compared with unmatched IHD/ICVD-free control subjects from The Copenhagen City Heart Study (n=7992). The secondary hypothesis was tested by using a nested case-control study comparing patients with IHD (n=956) with age- and gender-matched control subjects (n=956). Age- and gender-adjusted relative risk for IHD in heterozygotes (n=221, 2.4%) versus noncarriers (n=8965, 97.6%) was 1.5 (95% CI, 1.1 to 2.1). Retesting confirmed this: Age- and gender-adjusted odds ratios for IHD was 1.4 (1.0 to 2.0) and for ICVD 1.7 (1.1 to 2.7). Additional adjustment for plasma EC-SOD produced an odds ratio for IHD in heterozygotes versus noncarriers of 9.2 (1.2 to 72), whereas adjustment for autoantibodies against oxLDL produced an odds ratio of 2.5 (1.2 to 5.3). Conclusions— Heterozygosity for EC-SOD-R213G is associated with increased IHD risk. Genotyping offers predictive ability with respect to IHD beyond that offered by plasma EC-SOD and autoantibodies against oxLDL.
Fontan-type operations in patients with functionally univentricular hearts have been performed for almost 40 years. Since the first description of the Fontan operation, short- and medium-term operative survival has been good in the current era due to careful patient selection, modifications in surgical techniques, and advances in postoperative care. However, a number of serious long-term complications affect most patients. Nonetheless, the prevalence of univentriucular patients is increasing as the number of late survivors increases. Caregivers will therefore be evermore faced with the challenge of recognizing and managing the Fontan related complications and patients with failing Fontan physiology. This review discusses the current surgical management of patients with functionally univentricular heart (UVH) and long-term sequelae of the univentricular circulation based on literature on outcome after the Fontan procedure.
Abstract The care for patients with serious conditions is increasingly guided by genomic medicine, and genomic medicine may equally transform care for healthy individual if genomic population screening is implemented. This study examines the medical impact of opportunistic genomic screening (OGS) in a cohort of patients undergoing comprehensive genomic germline DNA testing for childhood cancer, including the impact on their relatives. Medical actionability and uptake after cascade testing in the period following disclosure of OGS results was quantified. A secondary finding was reported to 19/595 (3.2%) probands primarily in genes related to cardiovascular and lipid disorders. After a mean follow up time of 1.6 years (Interquartile range (IQR): 0.57-1.92 yrs.) only 12 (63%) of these variants were found to be medically actionable. Clinical follow up or treatment was planned in 16 relatives, and as in the probands, the prescribed treatment was primarily betablockers or cholesterol lowering therapy. No invasive procedures or implantation of medical devices were performed in probands or relatives, and no reproductive counseling was requested. After an average of 1.6 years of follow-up 2.25 relatives per family with an actionable finding had been tested. This real-world experience of OGS grants new insight into the practical implementation effects and derived health care demands of genotype-first screening. The resulting health care effect and impact on demand for genetic counseling and workup in relatives extends beyond the effect in the probands.
Rationale: Increased oxidative stress is involved in chronic obstructive pulmonary disease (COPD); however, plasma and bronchial lining fluid contains the antioxidant extracellular superoxide dismutase. Approximately 2% of white individuals carry the R213G polymorphism in the gene encoding extracellular superoxide dismutase, which increases plasma extracellular superoxide dismutase 10-fold and presumably also renders bronchial lining fluid high in extracellular superoxide dismutase.Objective: We tested the hypothesis that R213G reduces the risk of COPD.Methods: We studied cross-sectionally and prospectively (during 24 yr) 9,258 individuals from the Danish general population genotyped for R213G.Measurements: We determined plasma extracellular superoxide dismutase concentration, pulmonary function and COPD diagnosed by means of spirometry or through national hospitalization and death registers.Main Results: In the general population, 97.5% were noncarriers, 2.4% were heterozygotes, and 0.02% were homozygotes. Among R213G noncarriers, extracellular superoxide dismutase plasma concentration was 148 ± 52 and 142 ± 43 ng/ml (mean ± SD) in individuals with and without COPD (Student's t test, p = 0.02). Among heterozygotes, corresponding concentrations were 1,665 ± 498 ng/ml and 1,256 ± 379 (p < 0.001). The adjusted odds ratio for spirometrically diagnosed COPD in heterozygotes versus noncarriers was 0.5 (95% confidence interval: 0.3–0.9). After stratification, the equivalent adjusted odds ratio was 1.5 (0.3–6.6) among nonsmokers and 0.4 (0.2–0.8) among smokers (p value for interaction = 0.10). The adjusted hazard ratio for COPD hospitalization or death during follow-up in heterozygotes versus noncarriers was 0.3 (0.1–0.8).Conclusions: Extracellular superoxide dismutase R213G heterozygosity protects against development of COPD in the Danish general population. This was observed in smokers, but not in nonsmokers.
