AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland

Background

Narcolepsy is a chronic sleep disorder with strong genetic predisposition causing excessive daytime sleepiness and cataplexy. A sudden increase in childhood narcolepsy was observed in Finland soon after pandemic influenza epidemic and vaccination with ASO3-adjuvanted Pandemrix. No increase was observed in other age groups.

Methods

Retrospective cohort study. From January 1, 2009 to December 31, 2010 we retrospectively followed the cohort of all children living in Finland and born from January 1991 through December 2005. Vaccination data of the whole population was obtained from primary health care databases. All new cases with assigned ICD-10 code of narcolepsy were identified and the medical records reviewed by two experts to classify the diagnosis of narcolepsy according to the Brighton collaboration criteria. Onset of narcolepsy was defined as the first documented contact to health care because of excessive daytime sleepiness. The primary follow-up period was restricted to August 15, 2010, the day before media attention on post-vaccination narcolepsy started.

Findings

Vaccination coverage in the cohort was 75%. Of the 67 confirmed cases of narcolepsy, 46 vaccinated and 7 unvaccinated were included in the primary analysis. The incidence of narcolepsy was 9.0 in the vaccinated as compared to 0.7/100,000 person years in the unvaccinated individuals, the rate ratio being 12.7 (95% confidence interval 6.1–30.8). The vaccine-attributable risk of developing narcolepsy was 1∶16,000 vaccinated 4 to 19-year-olds (95% confidence interval 1∶13,000–1∶21,000).

Conclusions

Pandemrix vaccine contributed to the onset of narcolepsy among those 4 to 19 years old during the pandemic influenza in 2009–2010 in Finland. Further studies are needed to determine whether this observation exists in other populations and to elucidate potential underlying immunological mechanism. The role of the adjuvant in particular warrants further research before drawing conclusions about the use of adjuvanted pandemic vaccines in the future.     

No Serological Evidence of Influenza A H1N1pdm09 Virus Infection as a Contributing Factor in Childhood Narcolepsy after Pandemrix Vaccination Campaign in Finland

Background

Narcolepsy cataplexy syndrome, characterised by excessive daytime sleepiness and cataplexy, is strongly associated with a genetic marker, human leukocyte antigen (HLA) DQB1*06:02. A sudden increase in the incidence of childhood narcolepsy was observed after vaccination with AS03-adjuvanted Pandemrix influenza vaccine in Finland at the beginning of 2010. Here, we analysed whether the coinciding influenza A H1N1pdm pandemic contributed, together with the Pandemrix vaccination, to the increased incidence of childhood narcolepsy in 2010. The analysis was based on the presence or absence of antibody response against non-structural protein 1 (NS1) from H1N1pdm09 virus, which was not a component of Pandemrix vaccine.

Methods

Non-structural (NS) 1 proteins from recombinant influenza A/Udorn/72 (H3N2) and influenza A/Finland/554/09 (H1N1pdm09) viruses were purified and used in Western blot analysis to determine specific antibody responses in human sera. The sera were obtained from 45 patients who fell ill with narcolepsy after vaccination with AS03-adjuvanted Pandemrix at the end of 2009, and from controls.

Findings

Based on quantitative Western blot analysis, only two of the 45 (4.4%) Pandemrix-vaccinated narcoleptic patients showed specific antibody response against the NS1 protein from the H1N1pdm09 virus, indicating past infection with the H1N1pdm09 virus. Instead, paired serum samples from patients, who suffered from a laboratory confirmed H1N1pdm09 infection, showed high levels or diagnostic rises (96%) in H1N1pdm virus NS1-specific antibodies and very high cross-reactivity to H3N2 subtype influenza A virus NS1 protein.

Conclusion

Based on our findings, it is unlikely that H1N1pdm09 virus infection contributed to a sudden increase in the incidence of childhood narcolepsy observed in Finland in 2010 after AS03-adjuvanted Pandemrix vaccination.     

Antigenic Differences between AS03 Adjuvanted Influenza A (H1N1) Pandemic Vaccines: Implications for Pandemrix-Associated Narcolepsy Risk

Background

Narcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, however the triggers and disease mechanisms are poorly understood. Vaccine-attributable risk of narcolepsy reported so far with the AS03 adjuvanted H1N1 vaccination Pandemrix has been manifold compared to the AS03 adjuvanted Arepanrix, which contained differently produced H1N1 viral antigen preparation. Hence, antigenic differences and antibody response to these vaccines were investigated.

Methods and Findings

Increased circulating IgG-antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. H1N1 antigen of Arepanrix inhibited poorly these antibodies indicating antigenic difference between Arepanrix and Pandemrix. High-resolution gel electrophoresis quantitation and mass spectrometry identification analyses revealed higher amounts of structurally altered viral nucleoprotein (NP) in Pandemrix. Increased antibody levels to hemagglutinin (HA) and NP, particularly to detergent treated NP, was seen in narcolepsy. Higher levels of antibodies to NP were found in children with DQB1*06∶02 risk allele and in DQB1*06∶02 transgenic mice immunized with Pandemrix when compared to controls.

Conclusions

This work identified 1) higher amounts of structurally altered viral NP in Pandemrix than in Arepanrix, 2) detergent-induced antigenic changes of viral NP, that are recognized by antibodies from children with narcolepsy, and 3) increased antibody response to NP in association of DQB1*06∶02 risk allele of narcolepsy. These findings provide a link between Pandemrix and narcolepsy. Although detailed mechanisms of Pandemrix in narcolepsy remain elusive, our results move the focus from adjuvant(s) onto the H1N1 viral proteins.     

Risk of Narcolepsy Associated with Inactivated Adjuvanted (AS03) A/H1N1 (2009) Pandemic Influenza Vaccine in Quebec

Context

An association between an adjuvanted (AS03) A/H1N1 pandemic vaccine and narcolepsy has been reported in Europe.

Objective

To assess narcolepsy risk following administration of a similar vaccine in Quebec.

Design

Retrospective population-based study.

Setting

Neurologists and lung specialists in the province were invited to report narcolepsy cases to a single reference centre.

Population

Patients were interviewed by two sleep experts and standard diagnostic tests were performed. Immunization status was verified in the provincial pandemic influenza vaccination registry.

Main Outcome Measures

Confirmed narcolepsy with or without cataplexy with onset of excessive daytime sleepiness between January 1^st, 2009, and December 31^st, 2010. Relative risks (RRs) were calculated using a Poisson model in a cohort analysis, by a self-controlled case series (SCCS) and a case-control method.

Results

A total of 24 cases were included and overall incidence rate was 1.5 per million person-years. A cluster of 7 cases was observed among vaccinated persons in the winter 2009–2010. In the primary cohort analysis, 16-week post-vaccination RR was 4.32 (95% CI: 1.50–11.12). RR was 2.07 (0.70–6.17) in the SCCS, and 1.48 (0.37–7.03) using the case-control method. Estimates were lower when observation was restricted to the period of pandemic influenza circulation, and tended to be higher in persons <20 years old and for cataplexy cases.

Conclusions

Results are compatible with an excess risk of approximately one case per million vaccine doses, mainly in persons less than 20 years of age. However, a confounding effect of the influenza infection cannot be ruled out.     

Elevated peripheral visfatin levels in narcoleptic patients

Objective

Narcolepsy is a severe sleep disorder that is characterized by excessive daytime sleepiness, cataplexies and a tendency towards obesity. Recent discoveries indicate that the major pathophysiology is a loss of hypocretin (orexin) producing neurons due to immunologically mediated degeneration. Visfatin is a recently described proinflammatory adipokine. It is identical to the immune modulating pre-B-cell colony enhancing factor (PBEF). Our study examines the hypothesis that visfatin levels are altered in narcoleptic patients.

Methods

For the analysis, a total of n = 54 patients (n = 18 males and n = 36 females) with the diagnosis of narcolepsy according to DSM-IV and the International Classification of Sleep Disorders were examined (BMI mean 30.3±5.5, age mean 52.5±16.1 years). As a control group 39 unrelated (n = 12 males and n = 27 females) healthy volunteers with no sleep disorder according to DSM-IV were included (BMI mean 28.5±4.6, age mean 51.1±13.6 years). Peripheral visfatin levels were measured using a commercial enzyme immunoassay kit with a measurement range from 0.1–1000 ng/ml. Narcolepsy symptoms, severity and frequency of symptoms as well as the total duration of various aspects of the symptomatology were assessed by unstructured and structured clinical interviews in including the Stanford Center for Narcolepsy Sleep Inventory.

Results

Circulating visfatin was found to be significantly increased in HLA DR2 positive narcoleptic patients compared to controls.

Conclusion

Taken together, our results add to the evidence of disturbed immunological regulation in patients with narcolepsy.     

Symptoms associated with an abnormal echocardiogram in elderly primary care hypertension patients

Background

The prevalence and diagnostic value of heart failure symptoms in elderly primary care patients with hypertension is unknown.

Aim

To assess the prevalence, sensitivity, specificity, positive and negative predictive value of symptoms in association with an abnormal echocardiogram.

Design and setting

Cross-sectional screening study in five general practices in the south-east of the Netherlands.

Method

Between June 2010 and January 2013, 591 primary care hypertension patients aged between 60 and 85 years were included, without known heart failure and not treated by a cardiologist. All patients underwent an echocardiogram and a structured interview including assessment of heart failure symptoms: shortness of breath, fatigue, oedema, cold extremities, and restless sleep.

Results and conclusion

Restless sleep was reported by 25 %, cold extremities by 23 %, fatigue by 19 %, shortness of breath by 17 %, and oedema by 13 %. Oedema was the only symptom significantly associated with an abnormal echocardiogram (positive predictive value was 45 %, sensitivity 20 %, and specificity 90 %, OR 2.12; 95 % CI = 1.23–3.64), apart from higher age (OR 1.06; 95 % CI = 1.03–1.09), previous myocardial infarction (OR 3.00; 95 % CI = 1.28–7.03), and a systolic blood pressure of >160 mmHg (OR 1.62; 95 % CI = 1.08–2.41). Screening with echocardiography might be considered in patients with oedema.     

Post-pandemic seroprevalence of pandemic influenza A (H1N1) 2009 infection (swine flu) among children <18 years in Germany

Background

We determined antibodies to the pandemic influenza A (H1N1) 2009 virus in children to assess: the incidence of (H1N1) 2009 infections in the 2009/2010 season in Germany, the proportion of subclinical infections and to compare titers in vaccinated and infected children.

Methodology/Principal Findings

Eight pediatric hospitals distributed over Germany prospectively provided sera from in- or outpatients aged 1 to 17 years from April 1^st to July 31^st 2010. Vaccination history, recall of infections and sociodemographic factors were ascertained. Antibody titers were measured with a sensitive and specific in-house hemagglutination inhibition test (HIT) and compared to age-matched sera collected during 6 months before the onset of the pandemic in Germany. We analyzed 1420 post-pandemic and 300 pre-pandemic sera. Among unvaccinated children aged 1–4 and 5–17 years the prevalence of HI titers (≥1∶10) was 27.1% (95% CI: 23.5–31.3) and 53.5% (95% CI: 50.9–56.2) compared to 1.7% and 5.5%, respectively, for pre-pandemic sera, accounting for a serologically determined incidence of influenza A (H1N1) 2009 during the season 2009/2010 of 25,4% (95% CI : 19.3–30.5) in children aged 1–4 years and 48.0% (95% CI: 42.6–52.0) in 5–17 year old children. Of children with HI titers ≥1∶10, 25.5% (95% CI: 22.5–28.8) reported no history of any infectious disease since June 2009. Among vaccinated children, 92% (95%-CI: 87.0–96.6) of the 5–17 year old but only 47.8% (95%-CI: 33.5–66.5) of the 1–4 year old children exhibited HI titers against influenza A virus (H1N1) 2009.

Conclusion

Serologically determined incidence of influenza A (H1N1) 2009 infections in children indicates high infection rates with older children (5–17 years) infected twice as often as younger children. In about a quarter of the children with HI titers after the season 2009/2010 subclinical infections must be assumed. Low HI titers in young children after vaccination with the AS03_B-adjuvanted split virion vaccine need further scrutiny.     

Polymorphism Located between CPT1B and CHKB,and HLA-DRB1*1501-DQB1*0602 Haplotype Confer Susceptibility to CNS Hypersomnias (Essential Hypersomnia)

Background

SNP rs5770917 located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype were previously identified as susceptibility loci for narcolepsy with cataplexy. This study was conducted in order to investigate whether these genetic markers are associated with Japanese CNS hypersomnias (essential hypersomnia: EHS) other than narcolepsy with cataplexy.

Principal Findings

EHS was significantly associated with SNP rs5770917 (P_allele = 3.6×10⁻³; OR = 1.56; 95% c.i.: 1.12–2.15) and HLA-DRB1*1501-DQB1*0602 haplotype (P _positivity = 9.2×10⁻¹¹; OR = 3.97; 95% c.i.: 2.55–6.19). No interaction between the two markers (SNP rs5770917 and HLA-DRB1*1501-DQB1*0602 haplotype) was observed in EHS.

Conclusion

CPT1B, CHKB and HLA are candidates for susceptibility to CNS hypersomnias (EHS), as well as narcolepsy with cataplexy.     

Virosome-formulated Plasmodium falciparum AMA-1 & CSP derived peptides as malaria vaccine: randomized phase 1b trial in semi-immune adults & children

Background

This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children.

Methods

The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5–9 years) living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90.

Results

No serious or severe adverse events (AEs) related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014). In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR  = 0.50 [95%-CI: 0.29–0.88], p = 0.02).

Conclusion

These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00513669","term_id":"NCT00513669"}}NCT00513669     

Differences in Brain Morphological Findings between Narcolepsy with and without Cataplexy

Objective

Maps of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) obtained by diffusion tensor imaging (DTI) can detect microscopic axonal changes by estimating the diffusivity of water molecules using magnetic resonance imaging (MRI). We applied an MRI voxel-based statistical approach to FA and ADC maps to evaluate microstructural abnormalities in the brain in narcolepsy and to investigate differences between patients having narcolepsy with and without cataplexy.

Methods

Twelve patients with drug-naive narcolepsy with cataplexy (NA/CA), 12 with drug-naive narcolepsy without cataplexy (NA w/o CA) and 12 age-matched healthy normal controls (NC) were enrolled. FA and ADC maps for these 3 groups were statistically compared by using voxel-based one-way ANOVA. In addition, we investigated the correlation between FA and ADC values and clinical variables in the patient groups.

Results

Compared to the NC group, the NA/CA group showed higher ADC values in the left inferior frontal gyrus and left amygdala, and a lower ADC value in the left postcentral gyrus. The ADC value in the right inferior frontal gyrus and FA value in the right precuneus were higher for NA/CA group than for the NA w/o CA group. However, no significant differences were observed in FA and ADC values between the NA w/o CA and NC groups in any of the areas investigated. In addition, no correlation was found between the clinical variables and ADC and FA values of any brain areas in these patient groups.

Conclusions

Several microstructural changes were noted in the inferior frontal gyrus and amygdala in the NA/CA but not in the NA w/o CA group. These findings suggest that these 2 narcolepsy conditions have different pathological mechanisms: narcolepsy without cataplexy form appears to be a potentially broader condition without any significant brain imaging differences from normal controls.     

Temporal association of acute hepatitis A and Plasmodium falciparum malaria in children

Background

In sub-Saharan Africa, Plasmodium falciparum and hepatitis A (HAV) infections are common, especially in children. Co-infections with these two pathogens may therefore occur, but it is unknown if temporal clustering exists.

Materials and Methods

We studied the pattern of co-infection of P. falciparum malaria and acute HAV in Kenyan children under the age of 5 years in a cohort of children presenting with uncomplicated P. falciparum malaria. HAV status was determined during a 3-month follow-up period.

Discussion

Among 222 cases of uncomplicated malaria, 10 patients were anti-HAV IgM positive. The incidence of HAV infections during P. falciparum malaria was 1.7 (95% CI 0.81–3.1) infections/person-year while the cumulative incidence of HAV over the 3-month follow-up period was 0.27 (95% CI 0.14–0.50) infections/person-year. Children with or without HAV co-infections had similar mean P. falciparum asexual parasite densities at presentation (31,000/µL vs. 34,000/µL, respectively), largely exceeding the pyrogenic threshold of 2,500 parasites/µL in this population and minimizing risk of over-diagnosis of malaria as an explanation.

Conclusion

The observed temporal association between acute HAV and P. falciparum malaria suggests that co-infections of these two hepatotrophic human pathogens may result from changes in host susceptibility. Testing this hypothesis will require larger prospective studies.     

Hospitalized children with 2009 pandemic influenza A (H1N1): comparison to seasonal influenza and risk factors for admission to the ICU

Background

Limited data are available describing the clinical presentation and risk factors for admission to the intensive care unit for children with 2009 H1N1 infection.

Methods

We conducted a retrospective chart review of all hospitalized children with 2009 influenza A (H1N1) and 2008–09 seasonal influenza at The Children''s Hospital, Denver, Colorado.

Results

Of the 307 children identified with 2009 H1N1 infections, the median age was 6 years, 61% were male, and 66% had underlying medical conditions. Eighty children (26%) were admitted to the ICU. Thirty-two (40%) of the ICU patients required intubation and 17 (53%) of the intubated patients developed acute respiratory distress syndrome (ARDS). Four patients required extracorporeal membrane oxygenation. Eight (3%) of the hospitalized children died. Admission to the ICU was significantly associated with older age and underlying neurological condition. Compared to the 90 children admitted during the 2008–09 season, children admitted with 2009 H1N1 influenza were significantly older, had a shorter length of hospitalization, more use of antivirals, and a higher incidence of ARDS.

Conclusions

Compared to the 2008–09 season, hospitalized children with 2009 H1N1 influenza were much older and had more severe respiratory disease. Among children hospitalized with 2009 H1N1 influenza, risk factors for admission to the ICU included older age and having an underlying neurological condition. Children under the age of 2 hospitalized with 2009 H1N1 influenza were significantly less likely to require ICU care compared to older hospitalized children.     

Risk factors of household transmission of pandemic (H1N1) 2009 among patients treated with antivirals: a prospective study at a primary clinic in Japan

Background

Household transmission of influenza can affect the daily lives of patients and their families and be a trigger for community transmission, thus it is necessary to take precautions to prevent household transmission. We aimed to determine the risks of household transmission of pandemic (H1N1) 2009 influenza virus from an index patient who visited a primary clinic and was treated with antiviral drugs.

Methods

We followed up all the patients who were diagnosed with influenza A by rapid diagnostic test with a questionnaire or interview from July 2009 to April 2010. Secondary cases were defined as patients visiting the clinic or other clinics and being positive for influenza A by rapid diagnostic test within 7 days of onset of an index patient. Logistic regression analysis was used to explore the association between household transmission and the studied variables.

Results

We recruited 591 index patients and 1629 household contacts. The crude secondary attack rate was 7.3% [95% confidence interval (CI): 6.1–8.7]. Age of index patients (0–6 years old: odds ratio 2.56; 95% CI: 1.31–4.01; 7–12 years old: 2.44, 1.31–3.72; 30–39 years old 3.88; 2.09–5.21; 40 years old or more 2.76; 1.17–4.53) and number of household members with five or more (3.09, 2.11–4.07), medication started ≥48 hours from the onset of fever (2.38, 1.17–3.87) were significantly associated with household transmission.

Conclusions

Household transmission was associated with index patients aged ≤12 years old and adults ≥30 years with children, with more than five persons in the household, and medication initiated ≥48 hours from the onset of fever among the population, in which, antiviral treatment was given to all patients. We need to warn patients at high risk of household transmission to take additional precautions.     

Executive control of attention in narcolepsy

Background

Narcolepsy with cataplexy (NC) is a disabling sleep disorder characterized by early loss of hypocretin neurons that project to areas involved in the attention network. We characterized the executive control of attention in drug-free patients with NC to determine whether the executive deficits observed in patients with NC are specific to the disease itself or whether they reflect performance changes due to the severity of excessive daytime sleepiness.

Methodology

Twenty-two patients with NC compared to 22 patients with narcolepsy without cataplexy (NwC) matched for age, gender, intellectual level, objective daytime sleepiness and number of sleep onset REM periods (SOREMPs) were studied. Thirty-two matched healthy controls were included. All participants underwent a standardized interview, completed questionnaires, and neuropsychological tests. All patients underwent a polysomnography followed by multiple sleep latency tests (MSLT), with neuropsychological evaluation performed the same day between MSLT sessions.

Principal Findings

Irrespective of diagnosis, patients reported higher self-reported attentional complaints associated with the intensity of depressive symptoms. Patients with NC performed slower and more variably on simple reaction time tasks than patients with NwC, who did not differ from controls. Patients with NC and NwC generally performed slower, reacted more variably, and made more errors than controls on executive functioning tests. Individual profile analyses showed a clear heterogeneity of the severity of executive deficit. This severity was related to objective sleepiness, higher number of SOREMPs on the MSLT, and lower intelligence quotient. The nature and severity of the executive deficits were unrelated to NC and NwC diagnosis.

Conclusions

We demonstrated that drug-free patients with NC and NwC complained of attention deficit, with altered executive control of attention being explained by the severity of objective sleepiness and global intellectual level. Further studies are needed to explore whether medications that promote wakefulness can improve the executive functions in narcolepsy.     

Effective control of Schistosoma haematobium infection in a Ghanaian community following installation of a water recreation area

Background

Urogenital schistosomiasis caused by Schistosoma haematobium was endemic in Adasawase, Ghana in 2007. Transmission was reported to be primarily through recreational water contact.

Methods

We designed a water recreation area (WRA) to prevent transmission to school-aged children. The WRA features a concrete pool supplied by a borehole well and a gravity-driven rainwater collection system; it is 30 m² and is split into shallow and deep sections to accommodate a variety of age groups. The WRA opened in 2009 and children were encouraged to use it for recreation as opposed to the local river. We screened children annually for S. haematobium eggs in their urine in 2008, 2009, and 2010 and established differences in infection rates before (2008–09) and after (2009–10) installation of the WRA. After each annual screening, children were treated with praziquantel and rescreened to confirm parasite clearance.

Principal Findings

Initial baseline testing in 2008 established that 105 of 247 (42.5%) children were egg-positive. In 2009, with drug treatment alone, the pre-WRA annual cumulative incidence of infection was 29 of 216 (13.4%). In 2010, this incidence rate fell significantly (p<0.001, chi-squared) to 9 of 245 (3.7%) children after installation of the WRA. Logistic regression analysis was used to determine correlates of infection among the variables age, sex, distance between home and river, minutes observed at the river, low height-for-age, low weight-for-age, low Body Mass Index (BMI)-for-age, and previous infection status.

Conclusion/Significance

The installation and use of a WRA is a feasible and highly effective means to reduce the incidence of schistosomiasis in school-aged children in a rural Ghanaian community. In conjunction with drug treatment and education, such an intervention can represent a significant step towards the control of schistosomiasis. The WRA should be tested in other water-rich endemic areas to determine whether infection prevalence can be substantially reduced.     

Incidence rates of enterovirus 71 infections in young children during a nationwide epidemic in Taiwan, 2008-09

Objective

Enterovirus 71 (EV71) is causing life-threatening outbreaks in tropical Asia. In Taiwan and other tropical Asian countries, although nationwide EV71 epidemics occur cyclically, age-specific incidence rates of EV71 infections that are critical to estimate disease burden and design vaccine trials are not clear. A nationwide EV71 epidemic occurred in 2008–09 in Taiwan, which provided a unique opportunity to estimate age-specific incidence rates of EV71 infections.

Study Design

We prospectively recruited 749 healthy neonates and conducted follow-ups from June 2006 to December 2009. Sera were obtained from participants at 0, 6, 12, 24, and 36 months of age for measuring EV71 neutralizing antibody titers. If the participants developed suspected enterovirus illnesses, throat swabs were collected for virus isolation.

Results

We detected 28 EV71 infections including 20 symptomatic and 8 asymptomatic infections. Age-specific incidence rates of EV71 infection increased from 1.71 per 100 person-years at 0–6 months of age to 4.09, 5.74, and 4.97 per 100 person-years at 7–12, 13–24, and 25–36 months of age, respectively. Cumulative incidence rate was 15.15 per 100 persons by 36 months of age, respectively.

Conclusions

Risk of EV71 infections in Taiwan increased after 6 months of age during EV71 epidemics. The cumulative incidence rate was 15% by 36 months of age, and 29% of EV71 infections were asymptomatic in young children.     

Increasing incidence and age at diagnosis among children with type 1 diabetes mellitus over a 20-year period in Auckland (New Zealand)

Background

We aimed to evaluate the incidence of type 1 diabetes mellitus in children <15 years of age (yr) in the Auckland region (New Zealand) over 20 years (1990–2009).

Methods

We performed a retrospective review of all patients <15 yr diagnosed with type 1 diabetes, from an unselected complete regional cohort.

Results

There were 884 new cases of type 1 diabetes, and age at diagnosis rose from 7.6 yr in 1990/1 to 8.9 yr in 2008/9 (r² = 0.31, p = 0.009). There was a progressive increase in type 1 diabetes incidence among children <15 yr (p<0.0001), reaching 22.5 per 100,000 in 2009. However, the rise in incidence did not occur evenly among age groups, being 2.5-fold higher in older children (10–14 yr) than in the youngest group (0–4 yr). The incidence of new cases of type 1 diabetes was highest in New Zealand Europeans throughout the study period in all age groups (p<0.0001), but the rate of increase was similar in New Zealand Europeans and Non-Europeans. Type 1 diabetes incidence and average annual increase were similar in both sexes. There was no change in BMI SDS shortly after diagnosis, and no association between BMI SDS and age at diagnosis.

Conclusions

There has been a steady increase in type 1 diabetes incidence among children <15 yr in Auckland over 20 years. Contrary to other studies, age at diagnosis has increased and the greatest rise in incidence occurred in children 10–14 yr. There was little change in BMI SDS in this population, providing no support for the ‘accelerator hypothesis’.     

Association between insomnia symptoms and hemoglobin A1c level in Japanese men

Background

The evidence for an association between insomnia symptoms and blood hemoglobin A_1c (HbA_1c) level has been limited and inconclusive. The aim of this study was to assess whether each symptom of initial, middle, and terminal insomnia influences HbA_1c level in Japanese men.

Methods

This cross-sectional study examined 1,022 male workers aged 22–69 years with no history of diabetes at a Japanese company''s annual health check-up in April 2010. High HbA_1c was defined as a blood level of HbA_1c ≥6.0%. Three types of insomnia symptoms (i.e., difficulty in initiating sleep, difficulty in maintaining sleep, and early morning awakening) from the previous month were assessed by 3 responses (i.e., lasting more than 2 weeks, sometimes, and seldom or never [reference group]).

Results

The overall prevalence of high HbA_1c was 5.2%. High HbA_1c was positively and linearly associated with both difficulty in maintaining sleep (P for trend  = .002) and early morning awakening (P for trend  = .007). More specifically, after adjusting for potential confounding factors, high HbA_1c was significantly associated with difficulty in maintaining sleep lasting more than 2 weeks (adjusted odds ratio, 6.79 [95% confidence interval, 1.86–24.85]) or sometimes (2.33 [1.19–4.55]). High HbA_1c was also significantly associated with early morning awakening lasting more than 2 weeks (3.96 [1.24–12.59]).

Conclusion

Insomnia symptoms, particularly difficulty in maintaining sleep and early morning awakening, were found to have a close association with high HbA_1c in a dose-response relationship.