Tonsillectomies are associated with an increased risk of meningococcal carriage.

BACKGROUND: Neisseria meningitidis is a commensal organism with the potential to cause life-threatening disease. Colonisation is most common in adolescence and young adulthood. Various social factors have been associated with an increased risk of meningococcal carriage, but less is known about host factors that may influence the carriage status. Tonsillectomies have been shown to alter the pharyngeal microflora. This study assessed whether a history of tonsillectomy affects the risk of meningococcal colonisation. METHODS: Oropharyngeal swabs were collected from 15- to 16-year-old adolescents and 18- to 20-year-old young adults. Conventional culture methods and qPCR were used to detect meningococci. 16S qPCR was done to assess bacterial abundance in the samples. Data on history of tonsillectomies were collected from a central national database and the national university hospital. RESULTS: A total of 722 samples were collected; 197 from adolescents and 525 from young adults. Thirty-five participants were colonised with meningococci (4.8%). Eighty-eight participants had undergone a tonsillectomy, of which 10 (11.4%) carried meningococci, compared to 4% of those that had not. Prior tonsillectomy was associated with a threefold increased risk of meningococcal colonisation (OR 3.10, 95% CI 1.44-6.70, p = 0.004). Tonsillectomies remained a risk factor after adjusting for age, sex, recent antibiotic use and meningococcal vaccinations (aOR 2.49, 95% CI 1.13-5.48, p = 0.024). CONCLUSIONS: A history of tonsillectomy is associated with an increased risk of meningococcal colonisation. More studies are needed to shed light on the effects of tonsillectomies on the pharyngeal microbiome.

Genome-wide analyses identify 21 infertility loci and over 400 reproductive hormone loci across the allele frequency spectrum.

Genome-wide association studies (GWASs) may help inform treatments for infertility, whose causes remain unknown in many cases. Here we present GWAS meta-analyses across six cohorts for male and female infertility in up to 41,200 cases and 687,005 controls. We identified 21 genetic risk loci for infertility (P≤5E-08), of which 12 have not been reported for any reproductive condition. We found positive genetic correlations between endometriosis and all-cause female infertility (rg=0.585, P=8.98E-14), and between polycystic ovary syndrome and anovulatory infertility (rg=0.403, P=2.16E-03). The evolutionary persistence of female infertility-risk alleles in EBAG9 may be explained by recent directional selection. We additionally identified up to 269 genetic loci associated with follicle-stimulating hormone (FSH), luteinising hormone, oestradiol, and testosterone through sex-specific GWAS meta-analyses (N=6,095-246,862). While hormone-associated variants near FSHB and ARL14EP colocalised with signals for anovulatory infertility, we found no rg between female infertility and reproductive hormones (P>0.05). Exome sequencing analyses in the UK Biobank (N=197,340) revealed that women carrying testosterone-lowering rare variants in GPC2 were at higher risk of infertility (OR=2.63, P=1.25E-03). Taken together, our results suggest that while individual genes associated with hormone regulation may be relevant for fertility, there is limited genetic evidence for correlation between reproductive hormones and infertility at the population level. We provide the first comprehensive view of the genetic architecture of infertility across multiple diagnostic criteria in men and women, and characterise its relationship to other health conditions.

Influenza vaccination in pregnant women in Iceland 2010-2020 and the burden of influenza in pregnant women and their infants.

INTRODUCTION: Influenza vaccinations are recommended in pregnancy to protect both the pregnant woman and the unborn baby. The aim of this study was to assess the influenza vaccine uptake among pregnant women in Iceland in ten influenza seasons and to estimate the influenza disease burden on pregnant women and their infants. METHODS: This was a retrospective, descriptive study on influenza vaccine uptake among pregnant women and the burden of influenza and influenza-like illness (ILI) among pregnant women and their infants in ten influenza seasons. All women attending a 20-week ultrasound at Landspitali University Hospital in Reykjavik in August-April each influenza season 2010-2020 were included in the study. Data on influenza vaccinations and influenza/ILI diagnoses was collected from central national databases. RESULTS: The influenza vaccine uptake increased from 6.2 % in 2011-2012 to 37.5 % in 2019-2020. The incidence rate of influenza/ILI among pregnant women ranged from 5.5 to 22.1/1000 person-years. The estimated vaccine effectiveness in the ten influenza seasons was 34-100 %. The incidence rate of influenza/ILI among infants < 12 months of age was 0-13.4/1000 person-years. Influenza vaccinations in pregnancy are protective against influenza/ILI in pregnant women (IRR 0.36, 95 % CI 0.22-0.58), infants in the season of vaccination (IRR 0.40, 95 % CI 0.17-0.97) and probably for infants < 6 months of age (IRR 0.51, 95 % CI 0.22-1.21). CONCLUSIONS: Influenza vaccine coverage in pregnancy is suboptimal. Influenza vaccinations in pregnancy provide significant protection against influenza/ILI for pregnant women and infants in the season of vaccination. Initiatives to improve maternal vaccination coverage are needed.

Variant in the synaptonemal complex protein SYCE2 associates with pregnancy loss through effect on recombination.

Two-thirds of all human conceptions are lost, in most cases before clinical detection. The lack of detailed understanding of the causes of pregnancy losses constrains focused counseling for future pregnancies. We have previously shown that a missense variant in synaptonemal complex central element protein 2 (SYCE2), in a key residue for the assembly of the synaptonemal complex backbone, associates with recombination traits. Here we show that it also increases risk of pregnancy loss in a genome-wide association analysis on 114,761 women with reported pregnancy loss. We further show that the variant associates with more random placement of crossovers and lower recombination rate in longer chromosomes but higher in the shorter ones. These results support the hypothesis that some pregnancy losses are due to failures in recombination. They further demonstrate that variants with a substantial effect on the quality of recombination can be maintained in the population.

Early-onset group B streptococcal infections in five Nordic countries with different prevention policies, 1995 to 2019.

BackgroundNeonatal early-onset disease caused by group B Streptococcus (GBS) is a leading cause of infant morbidity. Intrapartum antibiotic prophylaxis (IAP) is effective in preventing early-onset GBS disease, but there is no agreement on the optimal strategy for identifying the pregnant women requiring this treatment, and both risk-based prophylaxis (RBP) and GBS screening-based prophylaxis (SBP) are used.AimThe aim of this study was to evaluate the effect of SBP as a public health intervention on the epidemiology of early-onset GBS infections.MethodsIn 2012, Finland started the universal SBP, while Denmark, Iceland, Norway and Sweden continued with RBP. We conducted an interrupted time series analysis taking 2012 as the intervention point to evaluate the impact of this intervention. The incidences of early- and late-onset GBS infections during Period I (1995-2011) and Period II (2012-2019) were collected from each national register, covering 6,605,564 live births.ResultsIn Finland, a reduction of 58% in the incidence of early-onset GBS disease, corresponding to an incidence rate ratio (IRR) of 0.42 (95% CI: 0.34-0.52), was observed after 2012. At the same time, the pooled IRR of other Nordic countries was 0.89 (95% CI: 0.80-1.0), specifically 0.89 (95% CI: 0.70-1.5) in Denmark, 0.34 (95% CI: 0.15-0.81) in Iceland, 0.72 (95% CI: 0.59-0.88) in Norway and 0.97 (95% CI: 0.85-1.1) in Sweden.ConclusionsIn this ecological study of five Nordic countries, early-onset GBS infections were approximately halved following introduction of the SBP approach as compared with RBP.

Long COVID in Icelandic Children: A Matched Cohort Study of Nonspecific Symptoms Following SARS-CoV-2 Infection.

PURPOSE: Pediatric severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections are usually mild and the mortality rates are low, but concerns have been raised about long-term symptoms that may resemble other postinfectious syndromes. Studies with robust control groups and high response rates have been few. METHODS: We obtained identifiers for all 837 Icelandic children diagnosed with SARS-CoV-2 by PCR between March 2020 and June 2021 and contacted them by telephone. We asked about 10 physical and mental symptoms being present at least twice weekly for at least 2 months. Participants who reported symptoms were contacted again a year later. For each subject who completed the questionnaire, an age- and sex-matched comparator without SARS-CoV-2 infection was asked to complete the same questionnaire, and the risk difference was calculated. RESULTS: Responses from 643 cases and 602 comparators were analyzed. Children who had been infected with SARS-CoV-2 were more likely to report one or more symptoms, except for anxiety/depression and sleep disturbances. Fatigue and loss of concentration were evidently more common in cases among teenagers (risk difference: 15%; 95% CI: 7-22% and 15%; 95% CI: 7-23%, respectively). At the second follow-up, close to a third of Long COVID cases had resolved but some participants had developed new persistent symptoms. CONCLUSION: Symptoms of Long COVID in children are common and impact their quality of life. The importance of further unraveling the pathophysiology of acute and long-term symptoms following SARS-CoV-2 infection in children is vital as well as potential preventive measures.

Adequate immune responses to vaccines after chemotherapy for leukaemia diagnosed in childhood.

AIM: The survival rate after treatment for childhood leukaemia has greatly improved, but could result in protracted immune deficiency. This study examined the immune status of children after chemotherapy and evaluated their responses to immunisation. METHODS: Subjects who had completed their treatment for acute lymphoblastic leukaemia at The Children's Hospital Reykjavík, Iceland, during 2011-2020 had blood drawn and were then immunised for influenza in October 2021. Blood was drawn again 4 weeks later and their humoral and cellular responses were measured with a haemagglutination inhibition assay and lymphocyte stimulation test. Antibodies to other immunisations were also evaluated. RESULTS: We studied 18 patients (10 male) who had completed their treatment at 3.7-20.3 years of age (mean 9.1), 11-84 months (mean 36.9) before enrolment. Conventional immunological evaluation did not reveal notable abnormalities. The responses to several childhood vaccinations, including the pneumococcal conjugate vaccination, were adequate in most patients. Humoral responses to the influenza vaccine confirmed adequate reactions in all but one patient. Considerable variations were observed in the lymphocyte stimulations tests. CONCLUSION: Most patients reacted adequately to immunisation, especially against annual influenza and Streptococcus pneumoniae, reiterating the usefulness of vaccinations. The most appropriate timing for vaccination after treatment still needs to be determined.

Meningococcal carriage in children and young adults: a cross-sectional and longitudinal study, Iceland, 2019 to 2021.

BackgroundNeisseria meningitidis is a commensal bacterium which can cause invasive disease. Colonisation studies are important to guide vaccination strategies.AimThe study's aim was to determine the prevalence of meningococcal colonisation, duration of carriage and distribution of genogroups in Iceland.MethodsWe collected samples from 1 to 6-year-old children, 15-16-year-old adolescents and 18-20-year-old young adults. Carriers were sampled at regular intervals until the first negative swab. Conventional culture methods and qPCR were applied to detect meningococci and determine the genogroup. Whole genome sequencing was done on groupable meningococci.ResultsNo meningococci were detected among 460 children, while one of 197 (0.5%) adolescents and 34 of 525 young adults (6.5 %) carried meningococci. Non-groupable meningococci were most common (62/77 isolates from 26/35 carriers), followed by genogroup B (MenB) (12/77 isolates from 6/35 carriers). Genogroup Y was detected in two individuals and genogroup W in one. None carried genogroup C (MenC). The longest duration of carriage was at least 21 months. Serial samples from persistent carriers were closely related in WGS.ConclusionsCarriage of pathogenic meningococci is rare in young Icelanders. Non-groupable meningococci were the most common colonising meningococci in Iceland, followed by MenB. No MenC were found. Whole genome sequencing suggests prolonged carriage of the same strains in persistent carriers.

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Obesity in adolescents does not influence early immune responses to influenza vaccination.

BACKGROUND: Obesity has been linked to reduced vaccine responses against tetanus, hepatitis B and influenza. Data on the influence of paediatric obesity on influenza vaccine response is still lacking and this study aims to fill the gap. METHODS: A total of 30 children with obesity and 30 children with normal weight, aged 12-18 years, were recruited. Participants were vaccinated with a tetravalent influenza vaccine. Blood was collected prior to the vaccination and again four weeks later. The humoral response was assessed with haemagglutinin inhibition assay. The cellular response was assessed with T-cell stimulation assays measuring TNF-α, IFN-γ, IL-2 and IL-13. RESULTS: Of the 29/30 from the study group and 30/30 from the control group finished both visits. Seroconversion occurred for > 90% of participants in both groups for the A/H1N1, A/H3N2 and B/Victoria strains, but the B/Yamagata strain had lower seroconversion rates (93% in the study group and 80% in the control group). 97-100% of participants from both groups had adequate serological responses following vaccination. Cellular responses were similar between the two groups post-vaccination. CONCLUSIONS: Early humoral and cellular immune responses to influenza vaccinations are similar among adolescents with obesity and normal weight.

Febrile Children with Pneumonia Have Higher Nasopharyngeal Bacterial Load Than Other Children with Fever.

Febrile episodes are common in children and the most frequent reason for attending emergency services. Although most infections have a benign and self-limiting course, severe and sometimes life-threatening infections occur. This prospective study describes a cohort of children presenting to a single-centre pediatric emergency department (ED) with suspected invasive bacterial infection, and explores the relationships between nasopharyngeal microbes and outcomes. All children attending the ED who had a blood culture taken were offered to participate over a two-year period. In addition to conventional medical care, a nasopharyngeal swab was obtained., which was analysed for respiratory viruses and three bacterial species using a quantitative PCR. Fisher's exact test, Wilcoxon rank sum, and multivariable models were used for statistical analyses of the 196 children (75% younger than four years) who were enrolled and had sufficient data for analysis; 92 had severe infections according to the study protocol, while five had bloodstream infections. Radiologically confirmed pneumonia was the most common severe infection found in 44/92 patients. The presence of respiratory viruses and the carriage of Streptococcus pneumoniae and Haemophilus influenzae were associated with a higher risk of pneumonia. Higher density colonisation with these bacteria were independent risk factors for pneumonia, whereas Moraxella catarrhalis carriage was associated with lower risk. Our data support the hypothesis that higher nasopharyngeal density of pneumococci and H. influenzae could play a role in the development of bacterial pneumonia in children. A preceding viral infection of the respiratory tract may be a trigger and play a role in the progression to severe lower respiratory tract infection.

Clinical and Socioeconomic Burden of Respiratory Syncytial Virus in Iceland.

INTRODUCTION: Respiratory syncytial virus (RSV), a very common pathogen, causes variable disease severity. In addition to considerable clinical burden on children, their families and healthcare facilities, RSV infections in children also carry significant direct and indirect socioeconomic burden. METHODS: We analyzed data from 5 consecutive RSV seasons (2015-2020) and used virologically confirmed RSV infections and age <5 years as case definition. Clinical information was retrieved from electronic patient records. Costs were estimated by assuming an annual 30% attack rate and a combination of direct medical costs and calculations of societal costs of lost productivity. RESULTS: A total of 716 children younger than 5 years of age had confirmed RSV infection of which 254 needed hospitalizations, most of whom were previously healthy. The median length of admission was 3.6 days and 13 patients needed intensive care. The hospital admission incidence rate was 2.5/1000 children/year, but 9.1 for children younger than 1 years of age. The total annual cost of RSV was estimated at €4.3 million, of which 10% was direct healthcare costs. DISCUSSION: The clinical and socioeconomic disease burden of RSV in Iceland is substantial despite slightly lower hospital admission rates than other high-income countries. The prevention of RSV in young children, either through maternal or infant vaccination, has the potential to decrease both clinical and financial impact of the annual epidemics.

Simplified antibiotic treatment for paediatric osteoarticular infections achieved good outcomes.

AIM: Early diagnosis of osteoarticular infections (OAI) in children and effective treatment prevents complications. The objective of this study was to evaluate effectiveness and safety of shortened intravenous antibiotic treatment of OAI. Incidence, diagnostics and pathogens of paediatric OAI were assessed. METHODS: This retrospective study included all paediatric OAI admissions to The Children's Hospital Iceland in 2006-2020. The treatment was evaluated by dividing the study cohort into two groups. The simplified treatment group received intravenous antibiotics for less than 7 days. The longer intravenous group received intravenous antibiotics for a minimum of 7 days. RESULTS: In total, 205 cases of OAI were included: 106 osteomyelitis, 83 septic arthritis and 16 with both. Age standardised incidence was 17 per 100,000 children and decreased over the study period (p = 0.004). A pathogen was identified in 37% (75/205) of cases of which 65% (49/75) were Staphylococcus aureus and 12% (9/75) Kingella kingae. Simplified treatment was not associated with increased risk of complications. CONCLUSION: This study supports claims that simplified treatment for OAI is safe and effective. Further simplification of treatment might be viable. For uncertain reasons the incidence of OAI was decreasing in Iceland, predominantly in young children.

The cerebrospinal fluid proteome of preterm infants predicts neurodevelopmental outcome.

Background: Survival rate increases for preterm infants, but long-term neurodevelopmental outcome predictors are lacking. Our primary aim was to determine whether a specific proteomic profile in cerebrospinal fluid (CSF) of preterm infants differs from that of term infants and to identify novel biomarkers of neurodevelopmental outcome in preterm infants. Methods: Twenty-seven preterm infants with median gestational age 27 w + 4 d and ten full-term infants were enrolled prospectively. Protein profiling of CSF were performed utilizing an antibody suspension bead array. The relative levels of 178 unique brain derived proteins and inflammatory mediators, selected from the Human Protein Atlas, were measured. Results: The CSF protein profile of preterm infants differed from that of term infants. Increased levels of brain specific proteins that are associated with neurodevelopment and neuroinflammatory pathways made up a distinct protein profile in the preterm infants. The most significant differences were seen in proteins involved in neurodevelopmental regulation and synaptic plasticity, as well as components of the innate immune system. Several proteins correlated with favorable outcome in preterm infants at 18-24 months corrected age. Among the proteins that provided strong predictors of outcome were vascular endothelial growth factor C, Neurocan core protein and seizure protein 6, all highly important in normal brain development. Conclusion: Our data suggest a vulnerability of the preterm brain to postnatal events and that alterations in protein levels may contribute to unfavorable neurodevelopmental outcome.

SARS-CoV-2 Infections in Icelandic Children: Close Follow-up of All Confirmed Cases in a Nationwide Study.

INTRODUCTION: Children are less likely to acquire SARS-CoV-2 infections than adults and when infected, usually have milder disease. True infection and complication rates are, however, difficult to ascertain. In Iceland, a strict test, trace and isolate policy was maintained from the start of the pandemic and offers more accurate information of the number of truly infected children in a nationwide study. MATERIAL AND METHODS: All children with positive PCR for SARS-CoV-2 infections from February 28, 2020 to August 31, 2021 were followed up through telephone consultations for at least 14 days and their symptoms were registered. Symptom severity and duration were categorized based on age groups and the source of infection was registered. RESULTS: A total of 1749 children were infected with SARS-CoV-2 in 3 waves of infections. All waves had similar disease severity whereas the incidence was 5-fold higher in the third wave (3.5 vs. 0.73/1000 children/month). No children had severe symptoms, 81 (4.6%) had moderate symptoms, 1287 (73.9%) had mild and 374 (21.5%) were asymptomatic. Symptoms from upper (n = 839, 48%) and lower respiratory tract (n = 744, 43%) were most common. Median duration of symptoms was 5 days and adolescents had a higher risk of prolonged duration [OR:1.84 (1.39-2.43)]. Nineteen (1.1%) children needed medical attention, but no child was hospitalized. The source of infection was a household member in 65% of cases. DISCUSSION: During the first 3 waves of the pandemic, SARS-CoV-2 infections in Icelandic children were mild and none were hospitalized. The most common symptoms were respiratory symptoms followed by fever, headache and tiredness. This study helps shed light on true complication rates of children with confirmed SARS-CoV-2 infection.

Longitudinal asthma and allergy study showed that childhood symptoms frequently persisted into adulthood.

AIMS: The prevalence of allergic diseases is high and increasing in many countries. The aim of this study was to describe the prevalence of allergic diseases and changes in clinical expression in a birth cohort followed for three decades. METHODS: We followed Icelandic citizens born in 1987 for allergic diseases when they were 2, 4, 8, 15, 21 and 29 years of age. These were diagnosed using standardised questionnaires, physical examinations and skin-prick tests. RESULTS: Just under half (46%) of the 112 who took part at 29 years of age had one or more allergic diseases, usually mild. Eczema was confirmed in 14% and was highest at the age of 2 years (31%). The prevalence of asthma was 23% and was highest at the age of 4 years (28%). Allergic rhinitis affected 30% at 29 years of age but was not found before the age of 2 years. In addition, 34% had a positive skin-prick test at 29 years of age. CONCLUSION: The results show that 46% of Icelandic adults diagnosed with allergic diseases during childhood still had symptoms at the age of 29, usually mild, developing from eczema in infancy to asthma and allergic rhinitis in adulthood.

Decreasing death rates and causes of death in Icelandic children-A longitudinal analysis.

BACKGROUND: Global death rate in children has been declining during the last decades worldwide, especially in high income countries. This has been attributed to several factors, including improved prenatal and perinatal care, immunisations, infection management as well as progress in diagnosis and treatment of most diseases. However, there is certainly room for further progress. The aim of the current study was to describe the changes in death rates and causes of death in Iceland, a high-income country during almost half a century. METHODS: The Causes of Death Register at The Directorate of Health was used to identify all children under the age of 18 years in Iceland that died during the study period from January 1st, 1971 until December 31st, 2018. Using Icelandic national identification numbers, individuals could be identified for further information. Hospital records, laboratory results and post-mortem diagnosis could be accessed if cause of death was unclear. FINDINGS: Results showed a distinct decrease in death rates in children during the study period that was continuous over the whole period. This was established for almost all causes of death and in all age groups. This reduction was primarily attributed to a decrease in fatal accidents and fewer deaths due to infections, perinatal or congenital disease as well as malignancies, the reduction in death rates from other causes was less distinct. Childhood suicide rates remained constant. INTERPRETATION: Our results are encouraging for further prevention of childhood deaths. In addition, our results emphasise the need to improve measures to detect and treat mental and behavioural disorders leading to childhood suicide.