New Dominant-Negative IL6ST Variants Expand the Immunological and Clinical Spectrum of GP130-Dependent Hyper-IgE Syndrome.

Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) suffer from a constellation of manifestations including recurrent bacterial and fungal infections, severe atopy, and skeletal abnormalities. This condition is typically caused by monoallelic dominant-negative (DN) STAT3 variants. In 2020, we described 12 patients from eight kindreds with DN IL6ST variants resulting in a new form of AD HIES. These variants encoded truncated GP130 receptors, with intact extracellular and transmembrane domains, but lacking the intracellular recycling motif and the four STAT3-binding residues, resulting in an inability to recycle and activate STAT3. We report here two new DN variants of IL6ST in three unrelated families with HIES-AD. The biochemical and clinical impacts of these variants are different from those of the previously reported variants. The p.(Ser731Valfs*8) variant, identified in seven patients from two families, lacks the recycling motif and all the STAT3-binding residues, but its levels on the cell surface are only slightly increased and it underlies mild biological phenotypes with variable clinical expressivity. The p.(Arg768*) variant, identified in a single patient, lacks the recycling motif and the three most distal STAT3-binding residues. This variant accumulates at the cell surface and underlies severe biological and clinical phenotypes. The p.(Ser731Valfs*8) variant shows that a DN GP130 expressed at near normal levels on the cell surface can underlie heterogeneous clinical presentations, ranging from mild to severe. The p.(Arg768*) variant demonstrates that a truncated GP130 protein retaining one STAT3-binding residue can underlie severe HIES.

Determinants of lung function changes in athletic swimmers. A review.

AIM: To summarise lung function characteristics of athletic swimmers and discuss mechanisms explaining these changes while putting forward the lack of a clear understanding of the precise physiological factors implicated. METHODS: Literature search until 07.2021 on Medline and EMBASE using keywords swimming, athletes, respiratory physiology, lung development, lung function tests. Relevant articles in French and English were reviewed. RESULTS: We found insufficient data to perform a meta-analysis. However, there is evidence that swimmers have better expiratory flows and increased baseline lung volumes than non-athletes or non-swimmers. Although these features can result from changes in lung development following intense training over the years, the contribution of a genetic predisposition and positive selection cannot be totally excluded. CONCLUSION: Disentangling the participation of constitutional factors and years of hard training to explain the larger lung volumes of athletic swimmers is in favour of an adaptative response of the lungs to early swim training through modification of the pathway of lung development. There seems to be an optimal window of opportunity before the end of growth for these adaptational changes to occur. Precise mechanisms, and contribution of adaptative change on lung physiology, remain to be further studied.

[Exercise induced dyspnea in adolescents]. / Dyspnée d'effort chez l'adolescent.

Exercise induced dyspnea is a common complaint among adolescents, whether sedentary or competitive athletes. This complaint may be associated with reduced athletic performance and general fatigue. It can be caused by various etiologies, sometimes concomitant. It is important for clinicians to obtain a specific history and then perform the appropriate additional tests. The three most common diagnostic entities are exercise-induced asthma/bronchoconstriction, exercise-induced laryngeal obstruction, and physical deconditioning, each with distinctive characteristics. Therapeutic management, including environmental measures and appropriate drug treatment, must be individualized and depends on the etiology.

La dyspnée d'effort est une plainte fréquente chez l'adolescent, qu'il soit sédentaire ou sportif de compétition. Cette plainte peut être associée à une baisse des performances sportives et à une fatigue générale. Elle peut être causée par diverses étiologies, parfois concomitantes. Il est important pour les cliniciens d'obtenir une anamnèse spécifique pour ensuite réaliser les examens complémentaires appropriés. Les trois entités diagnostiques les plus fréquentes sont l'asthme/bronchoconstriction induite par l'effort, l'obstruction laryngée induite par l'exercice, et le déconditionnement physique, présentant chacune des caractéristiques distinctives. La prise en charge thérapeutique doit être individualisée et dépend de l'étiologie retrouvée, incluant des mesures environnementales et un traitement médicamenteux approprié.

[« Doctor, my child swallowed water, can he die from dry drowning ? ¼ An update on drowning in 2018]. / «Docteur, mon enfant a bu la tasse, peut-il mourir d'une noyade sèche ? ¼.

Drowning is a significant and neglected public health problem mostly affecting young children. The definition of drowning has recently been modified and the notions of « dry drowning ¼, « secondary drowning ¼ and « near drowning ¼ are no longer accepted or used. However, recent articles in the media describing dry drowning of children have been reported. This entity seems to be absent of the actual scientific literature and worried parents can be reassured. Increased vigilance is the key as prevention is the most efficient intervention to reduce drowning mortality. To provide more guidance to the pediatrician and the general practitioner we are reviewing the most recent literature on the subject, as well as facts in the mater of drowning prevention.

La noyade est un problème de santé publique grave et négligé touchant principalement les enfants en bas âge. La définition de la noyade a été revue récemment et les notions de noyade « sèche ¼, « secondaire ¼ ou « presque-noyade ¼ ne sont plus reconnues ou utilisées. On observe néanmoins la mention récente dans les médias de noyades sèches d'enfants. L'entité décrite semble absente de la littérature médicale actuelle et les parents inquiets peuvent être rassurés. La vigilance reste toutefois de mise, car la prévention est l'intervention la plus efficace pour réduire la mortalité par noyade. Pour guider au mieux le pédiatre et le médecin de premier recours, nous revoyons les connaissances actuelles sur le sujet ainsi que les preuves en matière de prévention de la noyade.

Elevated lung clearance index in infants with cystic fibrosis shortly after birth.

It is not known at what age lung function impairment may arise in children with cystic fibrosis (CF). We assessed lung function shortly after birth in infants with CF diagnosed by newborn screening.We performed infant lung function measurements in a prospective cohort of infants with CF and healthy controls. We assessed lung clearance index (LCI), functional residual capacity (FRC) and tidal breathing parameters. The primary outcome was prevalence and severity of abnormal lung function (±1.64 z-scores) in CF.We enrolled 53 infants with CF (mean age 7.8 weeks) and 57 controls (mean age 5.2 weeks). Compared to controls, LCI and FRC were elevated (mean difference 0.30, 95% CI 0.02-0.60; p=0.034 and 14.5 mL, 95% CI 7.7-21.3 mL; p<0.001, respectively), while ratio of time to peak tidal expiratory flow to expiratory time was decreased in infants with CF. In 22 (41.5%) infants with CF, either LCI or FRC exceeded 1.64 z-scores; three infants had both elevated LCI and FRC.Shortly after birth, abnormal lung function is prevalent in CF infants. Ventilation inhomogeneity or hyperinflation may serve as noninvasive markers to monitor CF lung disease and specific treatment effects, and could thus be used as outcome parameters for future intervention studies in this age group.

Death after cessation of treatment by cystic fibrosis patients: An international survey of clinicians.

BACKGROUND: Little is known about cystic fibrosis patients, who are not considered to be terminally ill, and who die after voluntary cessation of treatment. AIM: This study was undertaken to provide an international snapshot of this issue. DESIGN: An online survey was distributed across three continents. SETTING: Distribution to the medical directors of the cystic fibrosis centres affiliated with the US Cystic Fibrosis Foundation, Cystic Fibrosis Australia (inclusion of New Zealand) and to every clinician member of the European Cystic Fibrosis Society. RESULTS: More than 200 cystic fibrosis patients not considered to be terminally ill and, who voluntarily ceased treatment, were reported by the clinicians surveyed. Detailed data were reported in 102 patients (4 children, 25 adolescents and 73 adults). Only one child, six adolescents and one adult were judged by clinicians not to be competent to make the decision to stop treatment. Time-consuming and low immediate-impact therapies, such as respiratory physiotherapy, were most frequently discontinued. Resignation was the main reported reason for discontinuing treatment, followed by reactive depression and lack of familial support. A total of 69% of the patients received palliative care and 72% died in the 6 months following cessation of treatment. CONCLUSION: Death of cystic fibrosis patients, not considered to be terminally ill, is reported in Europe, the United States and Australia due to voluntary cessation of treatment.

Case Report: When cystic fibrosis, elexacaftor/tezacaftor/ivacaftor therapy, and alpha1 antitrypsin deficiency get together.

In the last 10 years, the care of patients with cystic fibrosis (CF) has been revolutionized with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs, with a major impact on symptoms and life expectancy, especially considering the newest and highly effective elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) therapy. Conversely, adverse effects are relatively frequent, with some being life-threatening, such as severe hepatitis. Clinical trials on children starting CFTR modulators have reported transaminase elevations >3× upper limit of the norm in 10%-20% of patients, whereas real-life studies have reported discontinuation rates three times higher than those observed in phase 3 trials. We report the case of a 10-year-old boy with CF who developed severe acute hepatitis 2 weeks after starting ELX/TEZ/IVA therapy. An extensive screening for potential causes led to the identification of heterozygous alpha1-antitrypsin (AAT) deficiency with genotype MZ. The Z allele of SERPINA1 gene, encoding AAT, is known as a risk factor for CF liver disease. We hypothesized that it may act as a risk factor for drug-induced liver injury from CFTR modulators, notably ELX/TEZ/IVA. Therefore, checking AAT before starting CFTR modulator therapy can be suggested, in particular for children with previous, even transient, liver disease.

Lung structural and functional impairments in young children with cystic fibrosis diagnosed following newborn screening - A nationwide observational study.

BACKGROUND: Non-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV1, functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening. METHODS: Lung function (LCI, FEV1) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 - 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood. RESULTS: LCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV1. Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes. CONCLUSIONS: The LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood.

Data accuracy, consistency and completeness of the national Swiss cystic fibrosis patient registry: Lessons from an ECFSPR data quality project.

BACKGROUND: Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research. METHODS: All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed. RESULTS: The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with <5 % for almost all variables. A considerable number of missing source data occurred for CFTR variants. Availability of ICs varied largely between centers (10 centers had >5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved. CONCLUSIONS: Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research.

Chest physiotherapy using passive expiratory techniques does not reduce bronchiolitis severity: a randomised controlled trial.

Chest physiotherapy (CP) using passive expiratory manoeuvres is widely used in Western Europe for the treatment of bronchiolitis, despite lacking evidence for its efficacy. We undertook an open randomised trial to evaluate the effectiveness of CP in infants hospitalised for bronchiolitis by comparing the time to clinical stability, the daily improvement of a severity score and the occurrence of complications between patients with and without CP. Children <1 year admitted for bronchiolitis in a tertiary hospital during two consecutive respiratory syncytial virus seasons were randomised to group 1 with CP (prolonged slow expiratory technique, slow accelerated expiratory flow, rarely induced cough) or group 2 without CP. All children received standard care (rhinopharyngeal suctioning, minimal handling, oxygen for saturation ≥92%, fractionated meals). Ninety-nine eligible children (mean age, 3.9 months), 50 in group 1 and 49 in group 2, with similar baseline variables and clinical severity at admission. Time to clinical stability, assessed as primary outcome, was similar for both groups (2.9 ± 2.1 vs. 3.2 ± 2.8 days, P = 0.45). The rate of improvement of a clinical and respiratory score, defined as secondary outcome, only showed a slightly faster improvement of the respiratory score in the intervention group when including stethoacoustic properties (P = 0.044). Complications were rare but occurred more frequently, although not significantly (P = 0.21), in the control arm. In conclusion, this study shows the absence of effectiveness of CP using passive expiratory techniques in infants hospitalised for bronchiolitis. It seems justified to recommend against the routine use of CP in these patients.

Early blood exchange transfusion in malignant pertussis: a case report.

OBJECTIVE: To report early blood exchange transfusion in malignant pertussis and a favorable clinical outcome. SETTING: A pediatric intensive care unit in a tertiary hospital in Geneva, Switzerland. DESIGN: A descriptive case report. PATIENT: An 8-wk-old girl was diagnosed with malignant pertussis (extreme leukocytosis, seizures, pneumonia, and secondary severe hypoxic respiratory failure associated with pulmonary hypertension). After administration of a one-volume blood exchange transfusion, a rapid decrease in white blood cell count (from 119,000/mm(3) to 36,500/mm(3)) was observed and followed by clinical improvement and favorable outcome despite the initial presence of all described risk factors associated with a high mortality. CONCLUSION: The use of exchange blood transfusion early in the course of the disease might help to prevent a fatal outcome of malignant pertussis.

CFTR-function and ventilation inhomogeneity in individuals with cystic fibrosis.

BACKGROUND: Increased (abnormal) ventilation inhomogeneity in individuals with mild Cystic Fibrosis (CF) lung disease may become a treatable trait for small-molecule therapeutics improving Cystic Fibrosis Transmembrane Regulator (CFTR) function. The relationship between CFTR function and ventilation inhomogeneity is unknown. We aimed to identify and quantify increased ventilation inhomogeneity in relation to CFTR function. METHODS: This was an international, multi-center, cross-sectional study. We collated data from individuals aged 3-25 years with minimal (CFTR-MF) or residual (CFTR-RF) function of a variety of CFTR genotypes and FEV1 ≥ 70% predicted. We measured lung function using nitrogen multiple-breath washout and spirometry. We compared lung clearance index (LCI) and FEV1 between individuals with CFTR-MF vs CFTR-RF using a mixed effects multi-variable linear regression model to account for study differences and a logistic model based on propensity-score matching to adjust for possible confounding. RESULTS: We included 141 with CFTR-MF and 35 with CFTR-RF. LCI (> 1.96 z-score) was elevated in 71.6% individuals with CFTR-MF and in 40.0% with CFTR-RF. FEV1 (< -1.96 z-score) was reduced in 11.3% individuals with CFTR-MF and in 5.7% with CFTR-RF. The mean difference (95% CI) of LCI and FEV1 between CFTR-MF and CFTR-RF was 3.71 (1.63 to 5.79) and -0.40 (-0.83 to 0.02) z-score. The LCI differences were similar after adjustment for confounders and in individuals with normal FEV1. CONCLUSION: Increased ventilation inhomogeneity is associated with less CFTR function. In individuals with mild CF lung disease, LCI can identify and quantify increased ventilation inhomogeneity, a candidate treatable trait.

Respiratory symptoms do not reflect functional impairment in early CF lung disease.

BACKGROUND: Lung disease can develop within the first year of life in infants with cystic fibrosis (CF). However, the frequency and severity of respiratory symptoms in infancy are not known. METHODS: We assessed respiratory symptoms in 50 infants with CF and 50 healthy matched controls from two prospective birth cohort studies. Respiratory symptoms and respiratory rate were documented by standardized weekly interviews throughout the first year. Infants performed multiple breath washout in the first weeks of life. RESULTS: We analyzed 4552 data points (2217 in CF). Respiratory symptoms (either mild or severe) were not more frequent in infants with CF (OR:1.1;95% CI:[0.76, 1.59]; p=0.6). Higher lung clearance index and higher respiratory rate in infants with CF were not associated with respiratory symptoms. CONCLUSIONS: We found no difference in respiratory symptoms between healthy and CF infants. These data indicate that early CF lung disease may not be captured by clinical presentation alone.

Chlamydia pneumoniae and Mycoplasma pneumoniae in children with cystic fibrosis: impact on bacterial respiratory microbiota diversity.

OBJECTIVES: The contribution of intracellular and fastidious bacteria in Cystic fibrosis (CF) pulmonary exacerbations, and progressive lung function decline remains unknown. This project aimed to explore their impact on bacterial microbiota diversity over time in CF children. METHODS: Sixty-one children enrolled in the MUCOVIB multicentre prospective cohort provided 746 samples, mostly nasopharyngeal swabs, throat swabs and sputa which were analysed using culture, specific real-time qPCRs and 16S rRNA amplicon metagenomics. RESULTS: Chlamydia pneumoniae (n = 3) and Mycoplasma pneumoniae (n = 1) were prospectively documented in 6.6% of CF children. Microbiota alpha-diversity in children with a documented C. pneumoniae was highly variable, similarly to children infected with Staphylococcus aureus or Pseudomonas aeruginosa. The transition from routine follow-up visits to pulmonary exacerbation (n = 17) yielded variable changes in diversity indexes with some extreme loss of diversity. CONCLUSIONS: The high rate of C. pneumoniae detection supports the need for regular screenings in CF patients. A minor impact of C. pneumoniae on the microbial community structure was documented. Although detected in a single patient, M. pneumoniae should also be considered as a possible aetiology of lung infection in CF subjects.

Prevalence of tuberculosis in migrant children in Switzerland and relevance of current screening guidelines.

AIMS: Since 2016, Swiss guidelines recommend screening of all migrant children <5 years of age for tuberculosis (TB) and to screen older children only if they have risk factors for TB. Our goals were to describe the epidemiology of latent tuberculosis (LTBI) in migrant children at the Lausanne University Hospital, to identify determinants of LTBI and tuberculosis disease (TBD), and to evaluate the risk of a false-positive tuberculin skin test (TST) when using a positivity limit of 5 mm. METHODS: Newly arrived migrant children 0–18 years of age were prospectively enrolled from 31 August 2015 to 31 August 2017. Every migrant child was assessed for the risk of TB exposure and TBD and was administered a TST. A TB-spot test was performed in children ≥5 years of age when the TST was positive. Children with clinical and/or radiological signs of TBD were further investigated. Children ≥5 years of age with a positive TB-spot test and children <5 years of age with a positive TST, without clinico-radiological signs of TBD received a diagnosis of LTBI. A false-positive TST result was diagnosed in children ≥5 years of age when the TB-spot test was negative. Potential determinants of TB (LTBI and TBD) and of false-positive TSTs were identified. Student’s t-test or the Kruskal-Wallis test were used for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. All variables with a p-value <0.05 were included in a multivariate logistic regression model. RESULTS: Two hundred and fifty-three patients were eligible for the study. The median age of the patients was 8.1 years (interquartile range [IQR] 4.5–12.8) and 104 (41%) were female. Twenty-four percent of the patients (62/253) came from a country with a moderate–high incidence of TBD (≥80 cases per 100,000 individuals). Twenty-eight patients (11%) had positive TSTs, and TB was confirmed in 17 (6.7%) of these patients (16 with LTBI and 1 with TBD). On multivariate analysis, moderate–high incidence of TBD in the country of origin (adjusted odds ratio [aOR] 18.8, 95% confidence interval [CI] 5.1–68.6; p <0.001), older age (aOR 1.1, 95% CI 1.0–1.3; p = 0.025), and contact with a TBD patient (aOR 8, 95% CI 1.8–36.2; p = 0.007) were associated with a diagnosis of TB. Among the 23 children over 5 years of age who had a positive TST with measurement available, a measure between 5–9 mm was more frequent in case of a false-positive TST (5/9, 56% vs 0/14, 0%, p = 0.002). BCG vaccination was the only predictor of a false-positive TST (p = 0.03). CONCLUSION: Screening migrant children ≥5 years of age for TB could confer a public health benefit even in the absence of other risk factors. The limit of TST positivity could be raised from ≥5 mm to ≥10 mm to decrease the rate of false-positive results. A national assessment of migrant children between the ages of 5 and 15 should be carried out to confirm our findings.

Monoacylglycerol Form of Omega-3s Improves Its Bioavailability in Humans Compared to Other Forms.

Numerous benefits are attributed to omega-3 fatty acids (OM3) especially in cardiovascular health. However, bioavailability and clinical efficacy depend on numerous factors, including OM3 form, food matrix effects (especially the lipid content of the diet), and metabolic capacity. Here, we show in humans that a "pre-digested" OM3-sn-1(3)-monoacylglycerol lipid structure (OM3-MAG) has a significantly greater absorption at high therapeutic doses (2.9 g/day) than the most commonly OM3-ethyl ester (3.1 g/day) form (used for the treatment of hypertriglyceridemia), and a comparable profile to other pre-digested OM3 free fatty acids (OM3-FFA) structure (3.2 g/day). Nutritional supplement doses of MAG resulted in similar increases in OM3 blood level, compared to OM3 triacylglycerols (OM3-TAG) supplements in obese subjects (1.2 g/day) under low fat diet, and in children with cystic fibrosis (1.0 g/day). These results suggest that both forms of pre-digested OM3-MAG and OM3-FFA are effectively absorbed and re-incorporated effectively into triacylglycerols inside the enterocytes, before being exported into the chylomicrons lipid transport system. The pre-digested OM3-MAG might provide a more effective therapy in severe cardiovascular conditions where high doses of OM3 are required and a low-fat diet is indicated, which limited digestive lipase activity.

Feeding a diet containing a fructooligosaccharide mix can enhance Salmonella vaccine efficacy in mice.

Fructooligosaccharides (FOS) are considered prebiotics because of their ability to promote growth of specific beneficial gut bacteria, such as bifidobacteria. Some studies reported potential immune-modulating properties. The aim of this study was to investigate the effect of FOS:inulin mix on murine response to Salmonella vaccine and evaluate the relevance toward protection against Salmonella infection. Balb/c mice were fed a diet containing 5% FOS:inulin mix or a control diet 1 wk before oral immunization with a suboptimal dose of live attenuated Salmonella typhimurium vaccine. Four weeks after vaccination, mice were infected with LD100 of virulent S. typhimurium. Specific blood Salmonella immunoglobulin G and fecal immunoglobulin A significantly increased in mice fed the diet containing prebiotics compared with control mice 4 wk postimmunization. Peritoneal macrophage phagocytic activity also significantly increased in FOS:inulin-fed mice at 1 wk postimmunization compared with control mice. No detectable effects were observed on the percentage of lymphoid cell subsets in the spleen. However, production of cytokines, interferon-gamma, interleukin-12, and tumor necrosis factor alpha, was numerically increased in spleen cell cultures stimulated with mitogens from FOS:inulin-fed mice 1 and 4 wk postimmunization. Salmonella translocation to lymphoid organs was not affected by feeding FOS:inulin. However, the improved response to Salmonella vaccine was concomitant with an increase in the survival rate of FOS:inulin-fed mice upon challenge with virulent Salmonella. No detectable effects were observed on the composition or the metabolic activity of the microbiota. Overall, the data suggest that a diet supplemented with FOS:inulin mix stimulates mucosal immunity and seems to improve efficacy of an oral vaccine.

Lower exhaled nitric oxide in infants with Cystic Fibrosis compared to healthy controls.

Exhaled nitric oxide (FENO) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FENO is decreased. To understand if reduced FENO is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FENO in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FENO was lower in CF compared to controls (p=0.0006) and the effect was more pronounced in CF infants without residual CFTR function (p<0.0001). This suggests that FENO is reduced in CF early in life, possibly associated with underlying CFTR dysfunction.