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Background: There are limited data describing lung function changes in children after an asthma exacerbation. Our hypothesis was that lung function does not fully recover in children in the months following an asthma exacerbation. Methods: We used a data set of children with asthma where lung function (including FEV1, FEV1/FVC ratio and FEF25-75) was measured at 3-month intervals over a year. Mixed-level models compared spirometry measured on two occasions 3 months apart before a single exacerbation (assessments 1 and 2) with measurements made on two occasions after the exacerbation (assessments 3 and 4), with adjustment for covariates. Changes in spirometry over a year were also analysed across those with exacerbations in no, one or more than one 3-month periods. Results: For the 113 children who had a single exacerbation, spirometry measured at assessments 1 or 2 did not differ from measurements at assessments 3 or 4 when the whole population was considered. When stratified into tertiles by change in %FEV1 between assessments 2 and 3, those with the greater reduction were more likely to be treated with long-acting beta-agonist, but in this category, %FEV1 at assessment 4 had returned to the value at assessment 1. %FEV1 did not change over a 12-month period within and between the three exacerbation categories (n = 809). Conclusion: One or more asthma exacerbation was not associated with a fall in lung function for the whole population. In a subset of individuals, lung function does fall after an exacerbation but returns to pre-exacerbation values after a period of months.

Introduction: Fractional exhaled nitric oxide (F ENO) may be a useful objective measurement to guide asthma treatment. What remains uncertain is what change in F ENO is clinically significant. Methods: An individual patient data analysis was performed using data from seven randomized clinical trials which used F ENO to guide asthma treatment. The absolute and percentage intra-subject change in F ENO measurements over “stable” and also “unstable” 3-month periods were described. Results: Data were available in 1112 randomized controlled trial participants and ≥1 stable period was present for 665 individuals. The interquartile range (IQR) and limits of agreement (LoA) for change in absolute F ENO among individuals whose initial F ENO was ENO ≥50 ppb IQR was −29 to +17 ppb and LoA was −80 to +76 ppb. For percentage change in F ENO, the IQR and LoA for individuals whose initial F ENO was ENO ≥50 ppb were −33% to +35% and −159% to +192%. The variation in F ENO values for a stable period was similar irrespective of whether it was followed by a stable or unstable period. Conclusions: Over a 3-month period where F ENO is initially ENO is initially ≥50 ppb an percentage change of

Introduction: Repeated measurements of fractional exhaled nitric oxide (FeNO) may be useful objective measurements in the management of asthma. There is uncertainty in what merits a clinically-relevant change in FeNO. Methods: Individual participant data were obtained from seven randomised controlled trials where FeNO was used to guide asthma treatment. The FeNO values at the start and end of a period of stable asthma were analysed. The median absolute and percentage change in paired FeNO measurements at the start and end of a stable period were determined for individuals with a baseline FeNO of Results: Data were available in 665 children (mean age 13.1, 59%male). When the initial FeNO was Conclusions: These findings support current recommendations for interpretation of what may be a clinically relevant change in a FeNO value of ≤20ppb but for higher values, greater absolute and percentage change in FeNO values should be tolerated before any alteration in treatment is considered.

IntroductionExhaled nitric oxide fraction (FENO), a biomarker of eosinophilic airway inflammation, may be useful to guide asthma treatment. FENO-guided treatment may be more effective in certain subgroups for improving asthma outcomes compared to standard treatment.MethodsAn individual patient data analysis was performed using data from seven randomised clinical trials (RCTs) which used FENO to guide asthma treatment. The incidence of an asthma exacerbation and loss of control, and the time to first exacerbation and loss of control were described between five subgroups of RCT participants.ResultsData were available in 1112 RCT participants. Among those not treated with leukotriene receptor antagonists (LTRA), but not among those who were treated with LTRA, FENO-guided treatment was associated with reduced exacerbation risk (OR 0.68, 95% CI 0.49–0.94), longer time to first exacerbation (hazard ratio (HR) 0.76, 95% CI 0.57–0.99) and borderline reduced risk for loss of control (OR 0.70, 95% CI 0.49–1.00). Nonobese children, compared to obese children, were less likely to lose asthma control when treatment was guided by FENO (OR 0.69, 95% CI 0.48–0.99) and time to loss of control was longer (HR 0.77, 95% CI 0.61–0.99).ConclusionsAsthma treatment guided by FENO may be more effective in achieving better asthma outcomes for patients who are not treated with LTRA and who are not obese, compared to standard practice.

Background: repeated measurements of spirometry and fractional exhaled nitric oxide (FeNO) are recommended as part of the management of childhood asthma, but the evidence base for such recommendations is small. We tested the hypothesis that reducing spirometric indices or increasing FeNO will predict poor future asthma outcomes. Methods: a one-stage individual patient data meta-analysis used data from seven randomised controlled trials where FeNO was used to guide asthma treatment, and where spirometric indices were also measured. Change in %FEV1 and % change in FeNO between baseline and three months were related to having poor asthma control and to having an asthma exacerbation between three and six months after baseline. Results: data were available from 1112 children (mean age 12.6 years, mean %FEV1 94%). A 10% reduction in %FEV1 between baseline and three months was associated with 28% increased odds for asthma exacerbation [95% CI 3, 58] and with 21% increased odds for having poor asthma control [95% CI 1, 45] six months after baseline. A 50% increase in FeNO between baseline and three months was associated with 11% increase in odds for poor asthma control six months after baseline [95% CI 0, 16]. Baseline FeNO and %FEV1 were not related to asthma outcomes at three months. Conclusions: repeated measurements of %FEV1 which are typically within the “normal” range add to clinical risk assessment of future asthma outcomes in children. The role of repeated FeNO measurements is less certain since large changes were associated with small changes in outcome risk.

Introduction: Guidelines recommend spirometry and/or fractional exhaled nitric oxide (FeNO) as objective measurements to guide asthma management. Our hypothesis was that falling FEV1, FEV1/FVC ratio or FEF25-75 or rising FeNO measurements are associated with future adverse asthma outcomes. Methods: Data were obtained from 7 trials using FeNO to guide asthma treatment. Predictors were change in % FEV1, FEV1/FVC ratio or FEF25-75 and % change in FeNO between baseline and 3 months. Loss of asthma control and asthma attack between 3 and 6 months were the outcomes. A one-stage individual patient data meta-analysis was conducted using a mixed effects logistic model, including a random effect for study. Results: Data were available in 1112 children (58% male, mean age 12.6 years [SD 3.1]) from seven trials. A reduction of 10% FEV1 was associated with increased risk for future attack (OR 1.28 [1.02, 1.58]) and for loss of control (OR 1.21 [1, 1.45]), and a reduction of 10% FVC with increased risk for future attack (OR 1.40 [1.04, 1.88]). Changes in %FEF25-75 and %FEV1/FVC ratio were not linked to future outcomes. Each 20% increase in FeNO was associated with increased risk for future loss of control (OR 1.041 [1.000, 1.062]). Baseline %FEV1/FVC was associated with increased risk for attack over the next three months (OR per % predicted reduction 1.037 [1.007, 1.067]). Otherwise no measurement at baseline was associated with later outcome. Conclusions: Change in %FEV1 over a three month period may be useful as part of dynamic risk assessment. Whether a large change in FeNO may also be useful for dynamic risk assessment remains uncertain.

To the Editor: We thank Drs Yawn and Kaplan for their interest and comments on our article in which we describe a secondary analysis of data from seven published trials where fractional exhaled nitric oxide (Feno) was used to guide asthma treatment in children.1 We believe that our results offer relevance to clinicians attempting to interpret repeated measurements of spirometry and Feno. To the best of our knowledge, our analysis is the first to: (1) compare the clinical outcomes following a change in FEV1 and Feno over time; (2) compare clinical outcomes following absolute vs percent change in Feno; and (3) describe clinical outcomes following changes in FEV1 that fall within the range of “normal.”

Introduction Some guidelines advocate using FEV1 and/or fractional exhaled nitric oxide (FeNO) in the management of childhood asthma, but evidence supporting these recommendations is generally unsupportive. Our hypothesis was that reduced FEV1 and/or elevated FeNO measurements were associated with increased risk of future asthma attacks and loss of asthma control. Methods Data were obtained from six trials where FeNO was used to guide asthma treatment. Baseline% FEV1 and FeNO were linked to exacerbation and loss of control between baseline and three months. Change in% FEV1 and% change in FeNO between baseline and 3 months were also linked to exacerbation and loss of control between three and six months after baseline. A one-stage individual patient data meta-analysis was conducted using a random effect for study. Baseline confounders included in the model were age, sex, LABA, LTRA, ICS dose, trial arm, control and FeNO or FEV1 as appropriate. Results Data were available in 1049 children (58% male, mean age 12.7 years) from six trials. Each unit reduction in baseline% FEV1 was associated with increased risk for future exacerbation (OR 1.02 [1.00, 1.03] n=935, p=0.034) and with increased risk for loss of control (1.01 [1.00, 1.02], n=940, p=0.026) after three months. Similar associations were present between change in%FEV1 and outcomes after six months. Baseline FeNO was not related to asthma outcomes but each 10% increase in FeNO between baseline and three months was associated with increased risk for loss of asthma control by six months (OR 1.02 [1.01, 1.03], n=725, p=0.009) but not with asthma exacerbation. Falling% FEV1 and rising% FeNO between baseline and three months were independently associated with loss of control at six months. Conclusions Baseline% FEV1 is rather weakly associated with future asthma outcomes, and change in%FEV1 between visits does not strengthen this association. In contrast, baseline FeNO is not related to future outcomes but% change in FeNO has some precision for future asthma control. The utility of%FEV1 and FeNO in childhood asthma management needs to be rigorously evaluated in a clinical trial.

Background: Fractional exhaled nitric oxide (FeNO) may be a useful biomarker to guide asthma treatment. A study in children without asthma and with mild asthma suggested that FeNO may vary by up to 100% over 2 months. The aim of this study was to describe the change in FeNO over a 3 month period in children with moderate asthma who remained controlled and with stable inhaled corticosteroid (ICS) treatment. Methods: Data from 7 clinical trials were pooled. Each trial was broken down into three-month intervals. Individuals whose asthma was controlled and with stable ICS treatment over a particular 3-month interval were identified. The absolute and relative change in FeNO over this interval was described. Results: Data were available on 1115 children (58% male, mean age 12.6 years). FeNO values were similar in “FeNO” and “standard treatment” arms of the trials. There were 228 eligible children in the first three-month interval, 209 in the second, 294 in the third and 296 in the fourth interval. The median (interquartile range, IQR) change in FeNO during the first 3 months was +2 parts per billion, ppb (-6, +15) and values for the successive periods were +1 (-13, +10), 0 (-8, +10) and +1 (-6, +10). The median percentage change in FeNO (IQR) for the first 3 months was +10 (-28, 79) and for the next three periods were +2 (-35, 70), +1 (-24, 50) and +5 (-21, 46). Conclusions: FeNO values varied considerably in these eligible children. The 75th centile values suggest that absolute FeNO may rise by ≤15ppb and %FeNO by ≤80% without a change in the child’s clinical status. Similarly, the 25th centile values suggest that FeNO may fall by ≤15ppb or ≤40% without a change in clinical status.

Background: Meta-analysis shows FeNO guided treatment reduces the risk of asthma attacks compared to standard management. Here we test the hypothesis that there are sub groups of patients where FeNO guided treatment is associated with reduced risk for asthma attacks. Methods: Data from 7 clinical trials were pooled. Baseline characteristics included age, sex, ethnicity (white versus other), dose of inhaled corticosteroid (ICS), receipt of long acting beta agonist, receipt of leukotriene receptor antagonist (LTRA), %FEV1 and self-reported ICS adherence. The outcome was receipt of ≥1 course of oral corticosteroid (OCS) during the follow up period. Logistic regression related outcome to an interaction term between each characteristic and the trial arm (FeNO or standard treatment), including main effects and important covariates. Results: Data were available in 1115 children (58% male, mean age 12.6 years). The interaction term between LTRA treatment and trial group was significant (p=0.035): for those not treated with LTRA, 27% had ≥1 OCS course when treated by standard care and 20% with FeNO guided treatment; 38% treated with LTRA had ≥1 OCS course when treated by standard care and 43% when treated by FeNO guided management. There was a trend for outcomes to differ by ethnic group (p=0.070); for children other than white ≥1 OCS course was prescribed in 34% given standard treatment and 26% with FeNO guided treatment; and among white children the corresponding proportions were 19% and 23%. Conclusions: FeNO guided asthma treatment may be more effective in reducing the risk for asthma attacks among children who are non-white and not treated with LTRA.

To better understand vaccine-induced protection and its potential failure in light of recent whooping cough resurgence, we evaluated quantity as well as quality of memory T cell responses in B. pertussis-vaccinated preadolescent children. Using a technique based on flow cytometry to detect proliferation, cytokine production and phenotype of antigen-specific cells, we evaluated residual T cell memory in a cohort of preadolescents who received a whole-cell pertussis (wP; n=11) or an acellular pertussis vaccine (aP; n=13) during infancy, and with a median of 4 years elapsed from the last pertussis booster vaccine, which was aP for all children. We demonstrated that B. pertussis-specific memory T cells are detectable in the majority of preadolescent children several years after vaccination. CD4(+) and CD8(+) T cell proliferation in response to pertussis toxin and/or filamentous hemagglutinin was detected in 79% and 60% of the children respectively, and interferon-γ or tumor necrosis factor-α producing CD4(+) T cells were detected in 65% and 53% of the children respectively. Phenotyping of the responding cells showed that the majority of antigen-specific cells, whether defined by proliferation or cytokine production, were CD45RA(-)CCR7(-) effector memory T cells. Although the time since the last booster vaccine was significantly longer for wP-compared to aP-vaccinated children, their proliferation capacity in response to antigenic stimulation was comparable, and more children had a detectable cytokine response after wP- compared to aP-vaccination. This study supports at the immunological level recent epidemiological studies indicating that infant vaccination with wP induces longer lasting immunity than vaccination with aP-vaccines., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Due to their high risk of developing severe Bordetella pertussis (Bp) infections, it is recommended to immunize preterm infants at their chronological age. However, little is known about the persistence of their specific immune responses, especially of the cellular responses recognized to play a role in protection. We compared here the cellular immune responses to two major antigens of Bp between three groups of one year-old children born prematurely, who received for their primary vaccination respectively the whole cell vaccine Tetracoq(®) (TC), the acellular vaccine Tetravac(®) (TV), or the acellular vaccine Infanrix-hexa(®) (IR). Whereas most children had still detectable IFN-γ responses at one year of age, they were lower in the IR-vaccinated children compared to the two other groups. In contrast, both the TV- and the IR-vaccinated children displayed higher Th2-type immune responses, resulting in higher antigen-specific IFN-γ/IL-5 ratios in TC- than in TV- or IR-vaccinated children. The IFN-γ/IL-5 ratio of mitogen-induced cytokines was also lower in IR- compared to TC- or TV-vaccinated children. No major differences in the immune responses were noted after the booster compared to the pre-booster responses for each vaccine. The IR-vaccinated children had a persistently low specific Th1-type immune response associated with high specific Th2-type immune responses, resulting in lower antigen-specific IFN-γ/IL-5 ratios compared to the two other groups. We conclude that antigen-specific cellular immune responses persisted in one year-old children born prematurely and vaccinated during infancy at their chronological age, that a booster dose did not significantly boost the cellular immune responses, and that the Th1/Th2 balance of the immune responses is modulated by the different vaccines.

Objectives: We provide a narrative literature review on surveys used to assess the level of medication adherence in children and adolescents with asthma, the attitudes of these patients and their parents toward asthma therapy, and their expectations concerning asthma and available treatment. Methods: A PubMed search and manual selection of the retrieved papers was conducted to identify studies using surveys or interviews that addressed one of the three topics of interest. Results: Adherence to asthma medication varies across age groups and with the type of measurement used. Levels of 49–71% were observed in children and adolescents by objective measurements. Subjective measurements overestimate the level of adherence compared to objective measurements. A considerable percentage of parents expressed fear of side effects of inhaled corticosteroids, although the impact of these concerns on adherence is unclear. Many adolescents and parents adapt inhaled corticosteroids use according to the prevalence of asthma symptoms, by reducing or eliminating controller medication in the absence of symptoms. Pediatric asthma patients and their parents tend to overestimate the level of asthma control, either by underestimating asthma severity or by assuming that a better control is not possible. The knowledge of parents and adolescents concerning asthma management is suboptimal; moreover, insufficient knowledge about inhaled corticosteroids was linked to poor adherence. Conclusion: Medication adherence is crucial for a good control of asthma symptoms. Additional research concerning the triggers of non-adherence is still needed. Educating both the patients and their parents on proper asthma care might improve adherence.

Based on studies reporting specific antibody titers, it is recommended to vaccinate preterm infants against Bordetella pertussis according to their chronological age. However, as specific T-cell responses also are involved in the protection against B. pertussis, we have determined whether highly preterm infants (

Summary Specific anti-polysaccharide antibody deficiency (SPAD) is an immune disorder. Diagnostic criteria have not yet been defined clearly. One hundred and seventy-six children evaluated for recurrent respiratory tract infections were analysed retrospectively. For each subject, specific anti-pneumococcal antibodies had been measured with two enzyme-linked immunosorbent assays (ELISAs), one overall assay (OA) using the 23-valent pneumococcal polysaccharide vaccine (23-PPSV) as detecting antigen and the other purified pneumococcal polysaccharide serotypes (serotype-specific assay, SSA) (serotypes 14, 19F and 23F). Antibody levels were measured before (n = 176) and after (n = 93) immunization with the 23-PPSV. Before immunization, low titres were found for 138 of 176 patients (78%) with OA, compared to 20 of 176 patients (11%) with the SSA. We found a significant correlation between OA and SSA results. After immunization, 88% (71 of 81) of the patients considered as responders in the OA test were also responders in the SSA; 93% (71 of 76) of the patients classified as responders according to the SSA were also responders in the OA. SPAD was diagnosed in 8% (seven of 93) of patients on the basis of the absence of response in both tests. Thus, we propose to use OA as a screening test for SPAD before 23-PPSV immunization. After immunization, SSA should be used only in case of a low response in OA. Only the absence of or a very low antibody response detected by both tests should be used as a diagnostic criterion for SPAD.

Assessement of right ventricular (RV) contractility from end-systolic pressure-volume relationships (ESPVR) is difficult due to problems in measuring RV instantaneous volume and to effects of changes in RV preload or afterload. We therefore investigated in anesthetized dogs whether RV ESPVR and contractility can be determined without measuring RV volume and without changing RV preload or afterload. The maximal RV pressure of isovolumic beats (Pmax) was predicted from isovolumic portions of RV pressure during ejecting beats and compared with Pmaxmeasured during the first beat after pulmonary artery clamping. In RV pressure-volume loops obtained from RV pressure and integrated pulmonary arterial flow, end-systolic elastance ( E es) was assessed as the slope of Pmax-derived ESPVR, pulmonary artery effective elastance ( E a) as the slope of end-diastolic to end-systolic relation, and coupling efficiency as the E es-to- E a ratio ( E es/ E a). Predicted Pmax correlated with observed Pmax( r = 0.98 ± 0.02). Dobutamine increased E es from 1.07 to 2.00 mmHg/ml and E es/ E a from 1.64 to 2.49, and propranolol decreased E es/ E a from 1.64 to 0.91 (all P < 0.05). After adrenergic blockade, preload reduction did not affect E es, whereas hypoxia and arterial constriction markedly increased E aand somewhat increased E es due to the Anrep effect. Low preload did not affect E es/ E a and high afterload decreased E es/ E a. In conclusion, in the right ventricle 1) Pmax can be calculated from normal beats, 2) Pmax can be used to determine ESPVR without change in load, and 3) Pmax-derived ESPVR can be used to assess ventricular contractility and ventricular-arterial coupling efficiency.

Objective: Flow-pressure curves and vascular impedance are commonly used to investigate pulmonary circulation, but they may be affected at low flow by reflex neurohumoral activation. We therefore investigated the mechanical effects and the reflex effects of decreased flow on pulmonary vascular resistance and impedance. Methods: In ten anaesthetized dogs, we compared flow-pressure curves generated in less than 10 s to prevent sympathetic activation (fast curves), or generated over 20-30 min to allow neurohumoral equilibration (slow curves), in hyperoxia (inspired oxygen, 40%) and in hypoxia (inspired oxygen, 10%), before and after adrenergic blockade by phentolamine and propranolol. Resistance was assessed from the flow-pressure relationship. Impedance was computed from instantaneous flow and pressure obtained with an ultrasonic flowmeter and a micromanometer-tipped catheter. Results: At baseline, fast flow-pressure curves were steeper and had a lower pressure intercept. Transient low flow did not affect heart rate or pulmonary arterial elastance. Sustained low flow increased heart rate, resistance and elastance, suggesting baroreceptor-induced sympathetic stimulation. After adrenergic blockade, no difference persisted between effects of transient and sustained low flow. In hypoxia, slow and fast flow-pressure curves were similar. Hypoxia increased heart rate and resistance but did not decrease elastance, suggesting chemoreceptor-induced sympathetic stimulation. In hypoxia, differences between transient and sustained low flow were no longer significant, and were completely suppressed by adrenergic blockade. In two additional dogs, epinephrine infusion increased pulmonary vascular resistance and elastance. Conclusions: We conclude that (1) compared to transient low flow, sustained low flow is associated with increases in distal resistance and proximal elastance due to sympathetic stimulation and (2) these differences between the effects of transient and sustained low flow do not persist in hypoxia, because of an already present chemoreceptor-induced sympathetic stimulation.

The pig has been reported to present with a stronger hypoxic pulmonary vasoconstriction than many other species, including the dog, but it is not known whether this is associated with a different longitudinal partitioning of pulmonary vascular resistance (PVR). We investigated the relationships between cardiac output (Q) and mean pulmonary artery pressure (Ppa) minus occluded Ppa (Ppao), and effective pulmonary capillary pressure (Pc') minus Ppao, in seven minipigs and in seven dogs in hyperoxia (FI(O2) 0.4) and hypoxia (FI(O2) 0.1), first without, then with the inhalation of 80 ppm nitric oxide (NO) to inhibit any reversible component of PVR. Pc' was estimated from the Ppa decay curve following pulmonary artery balloon occlusion. In hyperoxia, minipigs compared to dogs had (Ppa - Ppao)/Q and (Pc' - Ppao)/Q plots shifted to higher pressures. Hypoxia at each level of Q increased Ppa - Ppao in minipigs more than in dogs, and Pc' - Ppao in minipigs only. Inhaled NO reversed hypoxia-induced changes in (Ppa - Ppao)/(Q and (Pc' - Ppao)/Q plots. We conclude that the minipig, compared to the dog, presents with higher PVR and reactivity including vessels downstream to the site of Pc' as determined by the arterial occlusion technique.

Lung Clearance Index (LCI) is a promising endpoint for use in CF clinical trials. Since correlation with validated clinical endpoints has not yet been established, we investigated the association between baseline LCI and risk of respiratory tract exacerbations (RTE) in children with CF. Methods: During a prospective observational study, baseline LCI (N2 washout), FEV1 and CFQR respiratory domain (CFQRres) were measured. RTE, defined as an increase in respiratory symptoms treated with IV antibiotics, were recorded during one year. Whether basline LCI predicted RTE was assessed with a Poisson regression model and Kaplan–Meier plots. LCI z-scores were calculated from values in 57 healthy children. Results: In 63 children with CF (median age 12.4 years, range 5−19), mean LCI z-score was 5.3 (SD 4.6) and mean FEV1 z-score −0.9 (SD 1.3). CFQRres correlated with LCI (R = −0.43, p< 0.001), but not with FEV1 (R=0.24, p = 0.051). In the 53 patients with a normal FEV1, CFQRres and LCI were still correlated (R = −0.44, p = 0.002). During the 12 months follow up, 25 patients (40%) experienced 47 RTE. LCI and FEV1 were predictors of RTE. Time to first RTE decreased with worsening LCI quartiles (Log Rank test, p< 0.001). Similarly, compared to the quartile with the lowest LCI, yearly RTE rate ratio in increasing LCI quartiles was 2.8 (95%CI 0.6–13.9, p = 0.205), 4.7 (95%CI 1.0–21.4, p = 0.046) and 13.6 (95%CI 3.2–57.0, p< 0.001). In the group with normal FEV1, LCI but not FEV1 z-score was still a predictor of RTE. Conclusion: Baseline LCI predicts the risk of RTE in children with CF, even in the subgroup with normal FEV1. These data further support the use of LCI as surrogate outcome in CF clinical trials.

To characterize the maturation of CD4(+) regulatory T lymphocytes (Treg) and of cytokine productions in preterm infants during their first 16 months of life.The proportions of CD4(+) Treg cells, their phenotypic characteristics, and the mitogen-induced cytokine productions by peripheral blood mononuclear cells (PBMC) were analysed in 26 very-preterm infants from 2 to 16 months of age, and compared to results obtained for 17 cord blood mononuclear cells (CBMC) from very-preterm infants, 12 from term infants and to blood samples from 40 adults.High proportion of CD25(+/high)CD4(+) Treg cells was found at birth in preterm CB with a gradual decreased afterwards. However, their percentage at 16 months of age was still higher than in term CB. In contrast to adults, preterm infants were characterized by excellent linear correlations between the proportions of CD25(+/high)CD4(+) and CD25(+/high)FoxP3(+) CD4(+) or CD25(+/high)CD127(low) CD4(+) or CD25(+/high)FoxP3(+)CD127(low) CD4(+)T lymphocytes. CD45RO(+) and HLA-DR(+) expressions were very low on preterm Treg and progressively increased with age. Functionally, preterm compared to term CBMC secreted in response to phytohaemagglutinin lower IFN-γ, higher IL-5 and similar IL-12p70, IL-10, IL-2 and IL-13 concentrations. IFN-γ, IL-12p70 and IL-10 productions were at 16 months still lower than those obtained for adultsPreterm differed from term CBMC both by their proportion and phenotype of CD4(+) Treg lymphocytes and by their cytokine secretions. Maturation occurred during infancy with similar IFN-γ secretion but with persistently higher proportion of CD4(+) Treg cells in 1 year preterm infants compared to term neonates.

Hypoxic pulmonary vasoconstriction (HPV) is inhibited in several models of acute lung injury. Whether HPV is preserved in pulmonary embolism is unknown. We investigated the effects of a reduction in the fraction of inspired O2 (FIO2) on pulmonary hemodynamics and gas exchange in anesthetized dogs before and after autologous blood clot pulmonary embolism. In a first group of 14 dogs, stimulus-response curves for HPV were constructed as pulmonary arterial pressure (Ppa) vs. FIO2 varied between 1.0 and 0.06 at a cardiac output (Q) kept constant at 3.5 l.min-1.m-2. Gas exchange was evaluated by using the multiple inert-gas elimination technique at FIO2 of 1.0, 0.4, and 0.1. Embolism decreased the relative magnitude of HPV, expressed as the gradient between Ppa and pulmonary arterial occluded pressure in hypoxia divided by (Ppa-pulmonary arterial occluded pressure) at FIO2 of 1.0, from 1.8 to 1.2 (P < 0.05). Retention minus excretion gradients for sulfur hexafluoride and ethane were increased by decreased FIO2 (P < 0.005 and P < 0.05, respectively) before but not after embolism. Hypoxia-induced deterioration in gas exchange before embolism was related to the amount of baseline very low ventilation-perfusion (VA/Q) ratios. Similar results were obtained in a second group of seven dogs with Q decreased to maintain Ppa at the same average value as before embolism. However, gas exchange was not affected by inspiratory hypoxia before as well as after embolism in this group, which presented with a lesser amount of baseline very low VA/Q. In both groups of dogs, increase in the FIO2 from 0.4 to 1.0 did not affect gas exchange. We conclude that 1) pulmonary embolism is associated with a partial inhibition of HPV, 2) HPV does not contribute to preserve gas exchange in pulmonary embolism, and 3) a strong HPV may deteriorate gas exchange in severe hypoxia in the presence of minor very low VA/Q inequality.

Plasmacytoid dendritic cells (pDCs) respond to unmethylated cytosine-phosphate-guanosine (CpG) motifs present in bacterial DNA or unmethylated synthetic oligodeoxynucleotides (CpG). In order to assess the function of pDCs in human newborns, interferon-α (IFN-α) production induced by CpG 2216 and phenotypic maturation of pDCs in response to CpG 2006 were compared in cord blood and adult blood. We first observed that neonatal pDCs displayed decreased up-regulation of CD80, CD83, CD86, and CD40, whereas HLA-DR and CD54 up-regulation did not differ significantly between adults and neonates. We then found that the production of IFN-α in response to CpG was dramatically impaired in cord blood. This neonatal defect was detected both at protein and mRNA levels and was still present in blood of 4-day-old babies. Further experiments on enriched pDCs confirmed that these cells are intrinsically deficient in CpG-induced IFN-α production at birth. These findings might be relevant to the increased susceptibility of human newborns to infections as well as to the use of CpG oligodeoxynucleotides as vaccine adjuvants in the neonatal period. (Blood. 2004;103:1030-1032)