Cerebrospinal Fluid Diagnostics of Alzheimer's Disease in Patients with Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide and a frequent comorbidity in idiopathic normal pressure hydrocephalus (iNPH). The presence of AD pathology is associated with worse outcomes after a shunt procedure in iNPH. Preoperative diagnosis of AD is challenging in patients with iNPH, which involves reduced concentrations of the cerebrospinal fluid (CSF) AD biomarkers. OBJECTIVE: Our aim was to estimate the effect size of iNPH as a factor in CSF levels of AD biomarkers and to test if correction could be used to improve diagnostic value. METHODS: Our cohort included 222 iNPH patients with data in the Kuopio NPH registry and brain biopsy and CSF samples available. We divided the patients into groups according to AD pathology per brain biopsy. For control cohorts, we had CSF samples from cognitively healthy individuals (n = 33) and patients with diagnosed AD and no iNPH (n = 39).*-31ptResults:Levels of all investigated biomarkers differed significantly between groups, with the exception of t-Tau levels between healthy individuals and iNPH patients with AD pathology. Applying a correction factor for each biomarker (0.842*Aß1 - 42, 0.779*t-Tau, and 0.610*P-Tau181) for the effect of iNPH yielded a sensitivity of 2.4% and specificity of 100%. The ratio of P-Tau181 to Aß1 - 42 was moderately effective in aiding recognition of AD pathology in iNPH patients (sensitivity 0.79, specificity 0.76, area under the curve 0.824). CONCLUSION: Correcting for iNPH as a factor failed to improve diagnostic effectiveness, but the P-Tau181/Aß1 - 42 ratio showed some utility in the diagnosis of AD in iNPH patients.

Early-life environment and the risk of eczema at 2 years-Meta-analyses of six Finnish birth cohorts.

BACKGROUND: Urban-related nature exposures are suggested to contribute to the rising prevalence of allergic diseases despite little supporting evidence. Our aim was to evaluate the impact of 12 land cover classes and two greenness indices around homes at birth on the development of doctor-diagnosed eczema by the age of 2 years, and the influence of birth season. METHODS: Data from 5085 children were obtained from six Finnish birth cohorts. Exposures were provided by the Coordination of Information on the Environment in three predefined grid sizes. Adjusted logistic regression was run in each cohort, and pooled effects across cohorts were estimated using fixed or random effect meta-analyses. RESULTS: In meta-analyses, neither greenness indices (NDVI or VCDI, 250 m × 250 m grid size) nor residential or industrial/commercial areas were associated with eczema by age of 2 years. Coniferous forest (adjusted odds ratio 1.19; 95% confidence interval 1.01-1.39 for the middle and 1.16; 0.98-1.28 for the highest vs. lowest tertile) and mixed forest (1.21; 1.02-1.42 middle vs. lowest tertile) were associated with elevated eczema risk. Higher coverage with agricultural areas tended to associate with elevated eczema risk (1.20; 0.98-1.48 vs. none). In contrast, transport infrastructure was inversely associated with eczema (0.77; 0.65-0.91 highest vs. lowest tertile). CONCLUSION: Greenness around the home during early childhood does not seem to protect from eczema. In contrast, nearby coniferous and mixed forests may increase eczema risk, as well as being born in spring close to forest or high-green areas.

Concordance of Alzheimer's Disease-Related Biomarkers Between Intraventricular and Lumbar Cerebrospinal Fluid in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Alzheimer's disease cerebrospinal fluid (CSF) biomarkers amyloid-ß 1-42 (Aß42), total tau (T-tau), and phosphorylated tau 181 (P-tau181) are widely used. However, concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar CSF (L-CSF) has been demonstrated in idiopathic normal pressure hydrocephalus (iNPH), potentially affecting clinical utility. OBJECTIVE: Here we aim to provide conversion factors for clinical and research use between V-CSF and L-CSF. METHODS: Altogether 138 iNPH patients participated. L-CSF samples were obtained prior to shunt surgery. Intraoperative V-CSF samples were obtained from 97 patients. Post-operative follow-up L- and V-CSF (shunt reservoir) samples of 41 patients were obtained 1-73 months after surgery and then after 3, 6, and 18 months. CSF concentrations of Aß42, T-tau, and P-tau181 were analyzed using commercial ELISA assays. RESULTS: Preoperative L-CSF Aß42, T-tau, and P-tau181 correlated to intraoperative V-CSF (ρ= 0.34-0.55, p < 0.001). Strong correlations were seen between postoperative L- and V-CSF for all biomarkers in every follow-up sampling point (ρs Aß42: 0.77-0.88, T-tau: 0.91-0.94, P-tau181: 0.94-0.96, p < 0.0001). Regression equations were determined for intraoperative V- and preoperative L-CSF (Aß42: V-CSF = 185+0.34*L-CSF, T-tau: Ln(V-CSF) = 3.11+0.49*Ln(L-CSF), P-tau181: V-CSF = 8.2+0.51*L-CSF), and for postoperative V- and L-CSF (Aß42: V-CSF = 86.7+0.75*L-CSF, T-tau: V-CSF = 86.9+0.62*L-CSF, P-tau181: V-CSF = 2.6+0.74*L-CSF). CONCLUSION: Aß42, T-tau, and P-tau181 correlate linearly in-between V- and L-CSF, even stronger after CSF shunt surgery. Equations presented here, provide a novel tool to use V-CSF for diagnostic and prognostic entities relying on the L-CSF concentrations and can be applicable to clinical use when L-CSF samples are not available or less invasively obtained shunt reservoir samples should be interpreted.

Effect of Haemophilus influenzae, Streptococcus pneumoniae and influenza vaccinations on infections, immune response and asthma control in preschool children with asthma.

BACKGROUND: Haemophilus influenzae (H. influenzae), Streptococcus pneumoniae (pneumococcus) and influenza vaccines are administered in children to prevent infections caused by these pathogens. The benefits of vaccination for asthma control in children and the elicited immune response are not fully understood. This study aimed to investigate the impact of these vaccinations on respiratory infections, asthma symptoms, asthma severity and control status, pathogen colonization and in vitro immune responses to different stimulants mimicking infections in asthmatic children. METHODS: Children aged 4-6 years were recruited into the multicentre prospective PreDicta study conducted across five European countries. Information about vaccination history, infections, antibiotic use, inhaled corticosteroid (ICS) use and asthma symptoms in the last 12 months were obtained from questionnaires of the study. Nasopharyngeal samples were collected at the first visit to assess bacterial and viral colonization, and venous blood for isolation of peripheral blood mononuclear cells (PBMCs). The PBMCs were stimulated with phytohemagglutinin, R848, Poly I:C and zymosan. The levels of 22 cytokines and chemokines were measured in cell culture supernatants using a luminometric multiplex assay. RESULTS: One-hundred and forty asthmatic preschool children (5.3 ± 0.7 years) and 53 healthy children (5.0 ± 0.8 years) from the PreDicta cohort were included in the current study. Asthmatic children were associated with more frequent upper and lower respiratory infections, and more frequent and longer duration of antibiotic use compared with healthy children. In asthmatic children, sufficient H. influenzae vaccination was associated with a shorter duration of upper respiratory infection (URI) and overall use and average dose of ICS. The airway colonization was characterized by less pneumococcus and more rhinovirus. Pneumococcal vaccination was associated with a reduction in the use rate and average dose of ICS, improved asthma control, and less human enterovirus and more H. influenzae and rhinovirus (RV) airway colonization. Influenza vaccination in the last 12 months was associated with a longer duration of URI, but with a decrease in the occurrence of lower respiratory infection (LRI) and the duration of gastrointestinal (GI) infection and antibiotic use. Asthmatic preschoolers vaccinated with H. influenzae, pneumococcus or influenza presented higher levels of Th1-, Th2-, Th17- and regulatory T cells (Treg)-related cytokines in unstimulated PBMCs. Under stimulation, PBMCs from asthmatic preschoolers with pneumococcal vaccination displayed a predominant anti-inflammatory immune response, whereas PBMCs from asthmatic children with sufficient H. influenzae or influenza vaccination were associated with both pro- and anti-inflammatory immune responses. CONCLUSION: In asthmatic preschoolers, the standard childhood vaccinations to common respiratory pathogens have beneficial effects on asthma control and may modulate immune responses relevant to asthma pathogenesis.

High-speed Video Microscopy Analysis for First-line Diagnosis of Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a congenital disorder predominantly inherited in an autosomal recessive trait. The disorder causes disturbance in the motion of cilia, leading to severe impairment of mucociliary clearance (MCC). If undiagnosed or diagnosed too late, the condition leads to the development of bronchiectasis and serious damage to the lungs in later life. Most of the methods for diagnosing PCD are time-consuming and demand extensive economic resources to establish them. High-speed video microscopy analysis (HSVMA) is the only diagnostic tool to visualize and analyze living respiratory cells with beating cilia in vitro. It is fast, cost-effective, and, in experienced hands, very reliable as a diagnostic tool for PCD. In addition, classical diagnostic measures such as transmission electron microscopy (TEM) are not applicable for some mutations as morphological changes are absent. This paper describes the process of collecting respiratory epithelial cells, the further preparation of the specimen, and the process of HSVMA. We also describe how brushed cells can be successfully kept unharmed and beating by keeping them in a nourishing medium for storage and transport to the investigation site in cases where a clinic does not possess the equipment to perform HSVMA. Also shown are videos with pathologic beating patterns from patients with a mutation in the dynein arm heavy chain 11 gene (DNAH11), which cannot be diagnosed with TEM; the result of an inconclusive HSVMA due to infection of the upper airways, as well as an unsuccessful brushing with superimposition of red blood cells. With this article, we would like to encourage every unit dealing with pulmonology patients and rare lung diseases to perform HSVMA as part of their daily routine diagnostics for PCD or send the specimens over to a center specializing in performing HSVMA.

Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients.

BACKGROUND: The relationship between cerebrospinal fluid (CSF) biomarkers and the clinical features of idiopathic normal pressure hydrocephalus (iNPH) has been inconclusive. We aimed to evaluate CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid ß (Aß) aggregation, tau pathology, neuroinflammation and axonal degeneration in relation to the clinical features of pre- and post-shunt surgery in iNPH patients. METHODS: Mini Mental State Examination (MMSE) scores and gait velocity were evaluated pre- and postoperatively in cohorts of 65 Finnish (FIN) and 82 Swedish (SWE) iNPH patients. Lumbar CSF samples were obtained prior to shunt surgery and analysed for soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPß); amyloid-ß isoforms of 42, 40 and 38 (Aß42, Aß40, Aß38); total tau (T-tau); phosphorylated tau (P-tau181); neurofilament light (NfL) and monocyte chemoattractant protein 1 (MCP1). RESULTS: Preoperative patient characteristics showed no significant differences between patients in the FIN and SWE cohorts. Patients in both cohorts had significantly improved gait velocity after shunt surgery (p < 0.0001). Low CSF T-tau and absence of apolipoprotein E ε4 predicted over 20% gait improvement postoperatively (p = 0.043 and p = 0.008). Preoperative CSF T-tau, P-tau181 and NfL correlated negatively with MMSE scores both pre- (p < 0.01) and post-surgery (p < 0.01). Furthermore, T-tau, NfL and Aß42 correlated with MMSE outcomes (p < 0.05). Low preoperative CSF P-tau181 (p = 0.001) and T-tau with NfL (p < 0.001 and p = 0.049) best predicted pre- and postoperative MMSE scores greater than or equal to 26. CONCLUSIONS: CSF biomarkers of neurodegeneration appeared to correlate with pre- and postoperative cognition, providing a window into neuropathological processes. In addition, preoperative CSF neurodegeneration biomarkers may have potential in the prediction of gait and cognitive outcomes after shunt surgery.

Physical activity in asthma control and its immune modulatory effect in asthmatic preschoolers.

BACKGROUND: The impact of physical activity on immune response is a hot topic in exercise immunology, but studies involving asthmatic children are scarce. Our aims were to examine whether there were any differences in the level of physical activity and daily TV attendance, to assess its role on asthma control and immune responses to various immune stimulants. METHODS: Weekly physical activity and daily television attendance were obtained from questionnaires at inclusion of the PreDicta study. PBMC cultures were stimulated with phytohemagglutinin (PHA), R848, poly I:C, and zymosan. A panel of cytokines was measured and quantified in cell culture supernatants using luminometric multiplex immunofluorescence beads-based assay. RESULTS: Asthmatic preschoolers showed significantly more TV attendance than their healthy peers (58.6% vs. 41.5% 1-3 h daily and only 25.7% vs. 47.2% ≤1 h daily) and poor asthma control was associated with less frequent physical activity (PA) (75% no or occasional activity in uncontrolled vs. 20% in controlled asthma; 25% ≥3 times weekly vs. 62%). Asthmatics with increased PA exhibited elevated cytokine levels in response to polyclonal stimulants, suggesting a readiness of circulating immune cells for type 1, 2, and 17 cytokine release compared to subjects with low PA and high TV attendance. This may also represent a proinflammatory state in high PA asthmatic children. Low physical activity and high TV attendance were associated with a decrease in proinflammatory cytokines. Proinflammatory cytokines were correlating with each other in in vitro immune responses of asthmatic children, but not healthy controls, this correlation was more pronounced in children with sedentary behavior. CONCLUSION: Asthmatic children show more sedentary behavior than healthy subjects, while poor asthma control is associated with a substantial decrease in physical activity. Our results suggest that asthmatic children may profit from regular exercise, as elevated cytokine levels in stimulated conditions indicate an immune system prepared for responding strongly in case of different types of infections. However, it has to be considered that a hyperinflammatory state in high PA may not be beneficial in asthmatic children.

Maternal prenatal psychological distress associates with offspring early-life wheezing - FinnBrain Birth Cohort.

BACKGROUND: Exposure to prenatal maternal psychological distress may contribute to the development of childhood atopic disorders. Little is known about the importance of distress severity and its duration for the risk. Our aim was to investigate how chronic maternal depressive and anxiety symptoms across gestation influence the risk of wheezing and eczema at child age 24 months. METHODS: The study population was drawn from the FinnBrain Birth Cohort Study, including 1305 mother-infant dyads followed across gestation until the child age of 24 months when the outcomes were mother-reported wheezing ever and doctor-diagnosed eczema. To investigate the risk of wheezing phenotypes, wheezing with and without eczema was separated. Maternal distress was assessed with the Edinburgh Postnatal Depression Scale for depressive and the Symptom Checklist-90 for anxiety symptoms three times during pregnancy, and the chronicity was demonstrated using symptom trajectories composed by latent growth mixture modeling. RESULTS: Of the children, 219/1305 (17%) had wheezing ever and 285/1276 (22%) had eczema. Risk of wheezing ever was elevated with maternal consistently high depressive symptoms (adjusted odds ratio 2.74; 95% confidence interval 1.37-5.50) or moderate and increasing anxiety symptoms (1.94; 1.06-3.54, respectively). Similarly, wheezing without eczema was associated with consistently high depressive (3.60; 1.63-7.94, respectively) and moderate and increasing anxiety symptoms (2.43; 1.21-4.91, respectively). CONCLUSIONS: Maternal chronic psychological distress across gestation was associated with toddler wheezing and especially wheezing without other atopic features (eczema). This finding supports the theory of intrauterine programming effect by maternal psychological distress on offspring immune system and respiratory morbidity.

Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) drives the resolution of allergic asthma.

RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses like Rhinovirus cause induction of RANTES production by epithelial cells. Here, we studied the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma and validated and extended this study to the airways of adults with and without asthma. We further translated these studies to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Here we show an unpredicted therapeutic role of RANTES in the resolution of allergen-induced asthma by orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung.

Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. OBJECTIVE: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-ß (Aß) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. METHODS: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aß plaques in frontal cortical brain biopsy and 13 iNPH patients without Aß pathology. CSF Amyloid-ß42 (Aß42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. RESULTS: All biomarkers but Aß42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aß42 instead showed divergent longitudinal decrease between Aß-positive and -negative patients in L-CSF, and thereafter increase in Aß-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aß42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aß42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aß42 showed higher concentration in non-carriers of allele ɛ4. CONCLUSION: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aß pathology, while NFL normalized toward its pre-shunt levels. Aß42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

Clinical correlates of rhinovirus infection in preschool asthma.

BACKGROUND: Investigation of preschool asthma is important since not all children outgrow their illness during this age. Data are scarce on the role of rhinovirus (RV) infections in this patient group. OBJECTIVES: To investigate the role of RV infections in preschool asthma: (i) susceptibility factors, (ii) clinical course, and (iii) medium-term outcome. METHODS: A total of 130 asthmatic children aged 4-6 years from the multinational PreDicta cohort were prospectively followed for a 12-month period. Allergy tests and a standard health questionnaire were carried out at study entry. Respiratory virus presence in nasopharyngeal washes was studied at illness visits and at 3 scheduled visits. RESULTS: At study entry, mean age of the children was 5.3 years. Of 571 visits, 54% were positive for any virus and 39% for RV. Patient characteristics were only assessed with RV infection due to low number of other viruses. The use of supplementary vitamin D was inversely associated with RV infection (P < .05). RV infection was associated with more severe course of acute illness in terms of more severe nighttime coughing, more sleep disturbances, and more days with runny nose (all P < .05). RV infection was also associated with more severe disease course during the 12-month follow-up in terms of more nights with awakenings and more days of exercise-related symptoms (both P < .05). CONCLUSIONS: Vitamin D supplementation may have an anti-rhinovirus effect. Both short- and medium-term outcomes suggest RV infection to be an important clinical marker of instable preschool asthma.

Eucapnic voluntary hyperventilation test decreases exhaled nitric oxide level in children.

BACKGROUND: Exhaled nitric oxide (FeNO) measurements and eucapnic voluntary hyperventilation (EVH) tests have been used as diagnostic tools for asthma. Data on the impact of hyperventilation on the level of FeNO are limited. AIM: We aimed to evaluate whether EVH tests affect the level of FeNO in children aged 10-16 years. METHODS: A total of 234 children aged 10-16 years had a 6-min EVH test performed. In total, FeNO values for 153 of 234 children were measured before the test and within 15 min after the test. According to a baseline FeNO level of 20 ppb, children were divided into two groups: those with low values (FeNO < 20 ppb) and those with high values (FeNO ≥ 20 ppb). RESULTS: The median age of the children was 13.4 years (interquartile range 12.3-15.3 years); 58% were boys and 42% were girls. Of these children, 51% were sensitized to aeroallergens. In 101 of 153 children (66%), the FeNO values decreased after the EVH test. In children with low and high baseline levels, the median level of FeNO decreased after the EVH test: 10.5 ppb before versus 9.5 ppb after (p < .011), and 31.0 ppb before versus 28.0 ppb after (p < .011), respectively. The decrease in FeNO after EVH test was not associated with induced bronchoconstriction expressed as a change in FEV1 (Rs  = .19). CONCLUSIONS: The EVH test decreases FeNO levels. Therefore, FeNO should be measured before an EVH test is performed.

Two novel mutations in the DNAH11 gene in primary ciliary dyskinesia (CILD7) with considerable variety in the clinical and beating cilia phenotype.

BACKGROUND: Diagnosis of primary ciliary dyskinesia (PCD) still remains a challenge, especially with mutations in the Dynein Arm Heavy Chain 11 (DNAH11) gene. Classical diagnostic measures like Transmission Electron Microscopy (TEM) are not applicable for mutations in the DNAH11 gene since ultrastructural defects of the ciliary apparatus are absent. Novel mutations encoding for PCD appear all the time with considerable variation in the clinical picture, making it necessary to update data bases and guidelines for PCD diagnostics. METHODS: In this study we examined two unrelated, Finnish families with symptoms of PCD applying the clinical scoring system: Primary ciliary dyskinesia Rule (PICADAR), high speed video microscopy analysis (HSVMA) for ciliary movement, a commercially available gene panel analysis and nasal Nitric Oxide (nNO) measurements if applicable. RESULTS: Two, likely pathogenic variants in the DNAH11 gene (c.2341G > A, p. (Glu781Lys) ja c.7645 + 5G > A) were detected. In the first family, compound heterozygous mutations led to disease manifestation in two of 4 children, which showed a similar phenotype of cilia beating pattern but marked differences in disease severity. In the second family, all three children were homozygotes for the c.2341G > A p.(Glu781Lys) mutation and showed a similar degree of disease severity. However, the phenotype of cilia beating pattern was different ranging from stiff, static cilia to a hyperkinetic movement in one of these children. CONCLUSIONS: In this study we describe two Finnish families with PCD, revealing two novel mutations in the DNAH11 gene which show considerable variety in the clinical and beating cilia phenotype. The results of this study show the clinician that PCD can be much milder than generally expected and diagnosis demands a combination of measures which are only successful in experienced hands. Chronic and repeatedly treated wet cough should raise suspicion of PCD, referring the patient for further diagnostics to a specialised PCD centre.

Cut-off values to evaluate exercise-induced asthma in eucapnic voluntary hyperventilation test for children.

BACKGROUND AND AIM: The eucapnic voluntary hyperventilation (EVH) testing is a diagnostic tool for diagnostics of exercise-induced bronchoconstriction; while the testing has become more common among children, data on the test's feasibility among children remain limited. Our aim was to investigate EVH testing feasibility among children, diagnostic testing cut-off values, and which factors affect testing outcomes. METHODS: We recruited 134 patients aged 10-16 years with a history of exercise-induced dyspnoea and 100 healthy control children to undergo 6-min EVH testing. Testing feasibility was assessed by the children's ability to achieve ≥70% of the target minute ventilation of 30 times forced expiratory volume in 1 s (FEV1). Bronchoconstriction was assessed as a minimum of 8%, 10%, 12%, 15% or 20% fall in FEV1. Patient characteristics were correlated with EVH outcomes. RESULTS: Overall, 98% of the children reached ≥70%, 88% reached ≥80%, 79% reached ≥90% and 62% reached ≥100% of target ventilation in EVH testing; of children with a history of exercise-induced dyspnoea, the decline percentages were as follows: 24% (≥8% fall), 17% (≥10% fall), 10% (≥12% fall), 6% (≥15% fall) and 5% (≥20% fall) in FEV1, compared to 11%, 4%, 3%, 1% and 0% among the healthy controls, respectively. Healthy controls and boys performed testing at higher ventilation rates (p < .05). CONCLUSION: Eucapnic voluntary hyperventilation testing is feasible among children aged 10-16 years and has diagnostic value in evaluating exercise-induced dyspnoea among children. A minimum 10% fall in FEV1 is a good diagnostic cut-off value. Disease status appears to be important covariates.

Evolution of Airway Inflammation in Preschoolers with Asthma-Results of a Two-Year Longitudinal Study.

Fractional exhaled nitric oxide (FeNO) is a non-invasive marker for eosinophilic airway inflammation and has been used for monitoring asthma. Here, we assess the characteristics of FeNO from preschool to school age, in parallel with asthma activity. A total of 167 asthmatic children and 66 healthy, age-matched controls were included in the 2-year prospective PreDicta study evaluating wheeze/asthma persistence in preschool-aged children. Information on asthma/rhinitis activity, infections and atopy was recorded at baseline. Follow-up visits were performed at 6-month intervals, as well as upon exacerbation/cold and 4-6 weeks later in the asthmatic group. We obtained 539 FeNO measurements from asthmatics and 42 from controls. At baseline, FeNO values did not differ between the two groups (median: 3.0 ppb vs. 2.0 ppb, respectively). FeNO values at 6, 12, 18 and 24 months (4.0, CI: 0.0-8.6; 6.0, CI: 2.8-12.0; 8.0, CI: 4.0-14.0; 8.5, CI: 4.4-14.5 ppb, respectively) increased with age (correlation p ≤ 0.001) and atopy (p = 0.03). FeNO was non-significantly increased from baseline to the symptomatic visit, while it decreased after convalescence (p = 0.007). Markers of disease activity, such as wheezing episodes and days with asthma were associated with increased FeNO values during the study (p < 0.05 for all). Age, atopy and disease activity were found to be important FeNO determinants in preschool children. Longitudinal and individualized FeNO assessment may be valuable in monitoring asthmatic children with recurrent wheezing or mild asthma.

Prenatal maternal distress associates with a blunted cortisol response in rhinovirus-positive infants.

INTRODUCTION: Prenatal exposure to maternal psychological distress (PD) may have programming effects on the fetus/infant hypothalamic-pituitary-adrenal (HPA) axis and subsequently on the development of the fetus' immune function. Therefore, our aim was to study whether prenatal exposure to PD is related to early infant HPA axis reactivity in the context of a subclinical rhinovirus infection that challenges infants HPA axis postnatally. METHODS: This study included 336 10-week-old infants from the nested case control Focus Cohort of the FinnBrain Birth Cohort Study. The outcome was infant HPA axis reactivity in a stress test. The acute stressor comprised of pediatric examination with venipuncture and nasal swabs for virus assessment. Saliva cortisol samples were collected at 5 time points: baseline, 0, 15, 25 and 35 min after the stressor. HPA axis reactivity was defined by the cumulative post-stressor cortisol concentration. RESULTS: HPA axis reactivity was blunted in the PD/rhinovirus + group compared to the average of control/rhinovirus+, PD/rhinovirus-, and control/rhinovirus- groups (difference: 14.7 ln [nmol/L] × min, 95% confidence interval 3.8-25.6, p = .008). HPA axis reactivity was significantly blunted only in boys with rhinovirus detected when separately tested for boys and girls (p = .04). CONCLUSION: Our finding of PD-exposed rhinovirus-positive infants having blunted cortisol secretion gives rise to a hypothesis that maternal PD during pregnancy influences infant HPA axis functioning and the functioning of the immune system. Future studies are needed to test whether this suppression of the HPA axis that co-occurs with rhinovirus infection associates with later disease development (e.g., asthma).

Rhinovirus Species-Specific Antibodies Differentially Reflect Clinical Outcomes in Health and Asthma.

Rationale: Rhinoviruses (RVs) are major triggers of common cold and acute asthma exacerbations. RV species A, B, and C may have distinct clinical impact; however, little is known regarding RV species-specific antibody responses in health and asthma.Objectives: To describe and compare total and RV species-specific antibody levels in healthy children and children with asthma, away from an acute event.Methods: Serum samples from 163 preschool children with mild to moderate asthma and 72 healthy control subjects from the multinational Predicta cohort were analyzed using the recently developed PreDicta RV antibody chip.Measurements and Main Results: RV antibody levels varied, with RV-C and RV-A being higher than RV-B in both groups. Compared with control subjects, asthma was characterized by significantly higher levels of antibodies to RV-A and RV-C, but not RV-B. RV antibody levels positively correlated with the number of common colds over the previous year in healthy children, and wheeze episodes in children with asthma. Antibody levels also positively correlated with asthma severity but not with current asthma control.Conclusions: The variable humoral response to RV species in both groups suggests a differential infectivity pattern between RV species. In healthy preschoolers, RV antibodies accumulate with colds. In asthma, RV-A and RV-C antibodies are much higher and further increase with disease severity and wheeze episodes. Higher antibody levels in asthma may be caused by a compromised innate immune response, leading to increased exposure of the adaptive immune response to the virus. Importantly, there is no apparent protection with increasing levels of antibodies.

Contribution of repeated infections in asthma persistence from preschool to school age: Design and characteristics of the PreDicta cohort.

BACKGROUND: The PreDicta cohort was designed to prospectively evaluate wheeze/asthma persistence in preschoolers in association with viral/microbial exposures and immunological responses. We present the cohort design and demographic/disease characteristics and evaluate unsupervised and predefined phenotypic subgroups at inclusion. METHODS: PreDicta is a 2-year prospective study conducted in five European regions, including children 4-6 years with a diagnosis of asthma as cases and healthy age-matched controls. At baseline, detailed information on demographics, asthma and allergy-related disease activity, exposures, and lifestyle were recorded. Lung function, airway inflammation, and immune responses were also assessed. Power analysis confirmed that the cohort is adequate to answer the initial hypothesis. RESULTS: A total of 167 asthmatic children (102 males) and 66 healthy controls (30 males) were included. Groups were homogeneous in respect to most baseline characteristics, with the exception of male gender in cases (61%) and exposure to tobacco smoke. Comorbidities and number and duration of infections were significantly higher in asthmatics than controls. 55.7% of asthmatic children had at least one positive skin prick test to aeroallergens (controls: 33.3%, P = .002). Spirometric and exhaled nitric oxide values were within normal limits; only baseline FEV0.5 and FEV1 reversibility values were significantly different between groups. Viral infections were the most common triggers (89.2%) independent of severity, control, or atopy; however, overlapping phenotypes were also common. Severity and control clustered together in an unsupervised analysis, separating moderate from mild disease. CONCLUSIONS: The PreDicta cohort presented no differences in non-asthma related measures; however, it is well balanced regarding key phenotypic characteristics representative of "preschool asthma".

Eucapnic voluntary hyperventilation test in children.

BACKGROUND: In children, exercise-induced dyspnea is a common symptom that can be due to dysfunctional breathing. EVH test has bee used especially in elite athletes as bronchoprovocation test. Currently, there are only few studies on the EVH test. New research methods are required alongside the traditionally used tests especially due to dysfunctional breathing disorder. PURPOSE: The purpose of the "pilot study" was to study the usability of the EVH test with real time biofeedback in children of 10-16 years of age in the diagnostics of exercise-induced dyspnea. METHODS: Six 10-16-year-old teenagers with history of exercise-induced dyspnea and three healthy control subjects were selected for the study. A 6-minute EVH test with realtime biofeedback was performed on the patients and the diagnosis was confirmed on the basis of clinical findings and spirometry follow-up either as normal, asthma or dysfunctional breathing. RESULTS: The study was successful in the patients. In the spirometry follow-up, three patients had bronchoconstriction (FEV1 decline over 10%), dysfunctional breathing condition was observed in three patients and three control patients experienced no symptoms. Only two DFB-patients didn't reach the target level of minute ventilation due to a clinical symptom (inspiratory stridor). CONCLUSION: The EVH test was successful in the 10-16-year-old children having participated in the study and the test was well tolerated. Through the study, it was possible to provoke both dysfunctional breathing disorder and bronchoconstriction in the symptomatic patients. Based on the pilot study, EVH test seems to be usable in the diagnostics of pediatric exercise-induced dyspnea but larger studies are warranted to confirm our preliminary findings.