Trajectories of cough without a cold in early childhood and associations with atopic diseases.

BACKGROUND: Although children can frequently experience a cough that affects their quality of life, few epidemiological studies have explored cough without a cold during childhood. OBJECTIVES: The objective of the study was to describe the latent class trajectories of cough from one to 10 years old and analyse their association with wheezing, atopy and allergic diseases. METHODS: Questions about cough, wheeze and allergic diseases were asked at 1, 1.5, 2, 3, 4, 5, 6 and 10 years of age in the European prospective cohort of Protection against Allergy: STUdy in Rural Environment (PASTURE). Specific IgE assays were performed at 10 years of age. Questions regarding a cough without a cold were used to build a latent class model of cough over time. RESULTS: Among the 961 children included in the study, apart from the never/infrequent trajectory (59.9%), eight trajectories of cough without a cold were identified: five grouped acute transient classes (24.1%), moderate transient (6.8%), late persistent (4.8%) and early persistent (4.4%). Compared with the never/infrequent trajectory, the other trajectories were significantly associated with wheezing, asthma and allergic rhinitis. For asthma, the strongest association was with the early persistent trajectory (ORa  = 31.00 [14.03-68.51]), which was inversely associated with farm environment (ORa  = 0.39 [0.19-0.77]) and had a high prevalence of cough triggers and unremitting wheeze. Late and early persistent trajectories were also associated with food allergy. Atopic sensitization was only associated with the late persistent trajectory. CONCLUSION: Late and early persistent coughs without a cold are positively associated with atopic respiratory diseases and food allergy. Children having recurrent cough without a cold with night cough and triggers would benefit from an asthma and allergy assessment. Growing up on a farm is associated with reduced early persistent cough.

Chest physiotherapy enhances detection of Pseudomonas aeruginosa in nonexpectorating children with cystic fibrosis.

Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.

First Wave of COVID-19 in French Patients with Cystic Fibrosis.

Viral infections are known to lead to serious respiratory complications in cystic fibrosis (CF) patients. Hypothesizing that CF patients were a population at high risk for severe respiratory complications from SARS-CoV-2 infection, we conducted a national study to describe the clinical expression of COVID-19 in French CF patients. This prospective observational study involves all 47 French CF centers caring for approximately 7500 CF patients. Between March 1st and June 30th 2020, 31 patients were diagnosed with COVID-19: 19 had positive SARS-CoV-2 RT-PCR in nasopharyngeal swabs; 1 had negative RT-PCR but typical COVID-19 signs on a CT scan; and 11 had positive SARS-CoV-2 serology. Fifteen were males, median (range) age was 31 (9-60) years, and 12 patients were living with a lung transplant. The majority of the patients had CF-related diabetes (n = 19, 61.3%), and a mild lung disease (n = 19, 65%, with percent-predicted forced expiratory volume in 1 s (ppFEV1) > 70). Three (10%) patients remained asymptomatic. For the 28 (90%) patients who displayed symptoms, most common symptoms at admission were fever (n = 22, 78.6%), fatigue (n = 14, 50%), and increased cough (n = 14, 50%). Nineteen were hospitalized (including 11 out of the 12 post-lung transplant patients), seven required oxygen therapy, and four (3 post-lung transplant patients) were admitted to an Intensive Care Unit (ICU). Ten developed complications (including acute respiratory distress syndrome in two post-lung transplant patients), but all recovered and were discharged home without noticeable short-term sequelae. Overall, French CF patients were rarely diagnosed with COVID-19. Further research should establish whether they were not infected or remained asymptomatic upon infection. In diagnosed cases, the short-term evolution was favorable with rare acute respiratory distress syndrome and no death. Post-lung transplant patients had more severe outcomes and should be monitored more closely.

Health-related quality of life in infants and children with interstitial lung disease.

INTRODUCTION: Interstitial lung disease in children (chILD) is a highly heterogeneous group of rare and severe respiratory disorders. The disease by itself, the burden of the treatments (oxygen therapy, corticosteroid pulses, nutritional support) and recurrent hospitalizations may impair the quality of life (QoL) of these children. The aim of the study was to compare the health-related QoL (HR-QoL) in chILD compared to a healthy population and to find out the predictive factors of an altered QoL. METHODS: Patients aged 1 month to 18 years with ILD of known or unknown etiology were prospectively included. Parents and children over 8 years old were asked to fill the PedsQL 4.0 Generic Core Scale ranging from 0 to 100 points. RESULTS: A total of 78 children were recruited in 13 French pediatric centers. Total scores were 11.94 points (P = 0.0003) less for child self-report and 14.08 points ( P < 0.0001) less for parent proxy-report with respect to the healthy population. The clinical factors associated with a lower total score were: extrapulmonary expression of the disease, higher Fan severity score, long-term oxygen therapy, nutritional support, and a number of oral treatments. CONCLUSION: Using a validated quality of life (QoL) scale, we showed that health-related-QoL is significantly impaired in chILD compared with a healthy population. Factors altering QoL score are easy to recognize and could help identify children at a heightened risk of low QoL.

Clinical and microbiological characteristics of cystic fibrosis adults never colonized by Pseudomonas aeruginosa: Analysis of the French CF registry.

Pseudomonas aeruginosa is the main cause of chronic airway infection in cystic fibrosis (CF). However, for unclear reasons some patients are never colonized by P. aeruginosa. The objectives of this study were to better define the clinical, genetic, and microbiological characteristics of such a subpopulation and to identify predictive factors of non-colonization with P. aeruginosa. The French CF patient registry 2013-2014 was used to identify CF patients aged ≥ 20 years. The clinical outcomes, CF Transmembrane conductance Regulator (CFTR) genotypes, and microbiological data of patients reported positive at least once for P. aeruginosa ("Pyo" group, n = 1,827) were compared to those of patients with no history of P. aeruginosa isolation ("Never" group, n = 303). Predictive factors of non-colonization by P. aeruginosa were identified by multivariate logistic regression model with backward selection. Absence of aspergillosis (odds ratio (OR) [95% CI] = 1.64 [1.01-2.66]), absence of diabetes (2.25 [1.21-4.18]), pancreatic sufficiency (1.81 [1.30-2.52]), forced expiratory volume 1 (FEV1) ≥ 80% (3.03 [2.28-4.03]), older age at CF diagnosis (1.03 [1.02-1.04]), and absence of F508del/F508del genotype (2.17 [1.48-3.19]) were predictive clinical factors associated with absence of infection ("Never" group). Microbiologically, this same group was associated with more frequent detection of Haemophilus influenzae and lower rates of Stenotrophomonas maltophilia, Achromobacter xylosoxidans and Aspergillus spp. (all p<0.01) in sputum. This study strongly suggests that the absence of pulmonary colonization by P. aeruginosa in a minority of CF adults (14.2%) is associated with a milder form of the disease. Recent progress in the development of drugs to correct CFTR deficiency thus may be decisive in the control of P. aeruginosa lung infection.

The protective effect of cheese consumption at 18 months on allergic diseases in the first 6 years.

BACKGROUND: The effect of exposure to microorganisms on allergic diseases has been well studied. The protective effect of early food diversity against allergic diseases was previously shown in the PASTURE cohort study. The consumption of cheese, a food potentially rich in microbial diversity, deserves further examination. We aimed to evaluate whether cheese consumption is associated with allergic diseases. METHODS: In the PASTURE study (birth cohort in 5 European countries), data on feeding practices, environmental factors, and allergic diseases were collected by questionnaires from birth to 6 years (N = 931). Cheese consumption at 18 months of age was quantified in terms of frequency and diversity (ie, number of consumed types among 6 types: hard pressed, semipressed, soft, blue, fresh cheese, and cheese from the farm). Multiple logistic regressions were performed to evaluate the effect of cheese consumption on atopic dermatitis (AD), food allergy (FA), allergic rhinitis, asthma, and atopic sensitization at 6 years after adjustment for confounders of atopy. RESULTS: Cheese consumption (vs. nonconsumption) had a significant protective effect on AD (OR = 0.51 [0.29-0.90], P = 0.02) and FA (OR = 0.32, [0.15-0.71], P = 0.004), but no effect on atopic sensitization, allergic rhinitis, and asthma at 6 years. This effect on AD and FA may be related to the diversity of consumed cheeses (OR = 0.64 [0.48-0.85] per cheese type, P = 0.002; OR = 0.55 [0.33-0.92], P = 0.02, respectively). CONCLUSION: Although reverse causality cannot totally be ruled out, cheese diversity at 18 months had a protective effect against AD and FA at 6 years in addition to the protective effect of diversity of other foods.

Palivizumab prophylaxis in infants with cystic fibrosis does not delay first isolation of Pseudomonas aeruginosa or Staphylococcus aureus.

Respiratory syncytial virus (RSV) infections may worsen cystic fibrosis (CF) lung disease and favor Pseudomonas aeruginosa (Pa) or Staphylococcus aureus (Sa) acquisition, which is of particular importance in the youngest patients. We aimed to determine the effectiveness of PVZ on microbiological outcomes in young children with CF. We conducted a retrospective case-control study to compare these outcomes in children who systematically received PVZ (PVZ+; n = 40) or not (PVZ-; n = 140). One case was matched with at least three same-gender controls born the same year and month. Median (range) age at first Pa isolation was not statistically different between PVZ- (12.3 [3.8-32.6] months) and PVZ+ (10.4 [1.2-33.0] months; p = 0.953) patients. A similar trend was found for Sa (PVZ+: 6.4 [2.0-59.0] months; PVZ-: 3.8 [0.1-74.1] months; p = 0.191). The proportion of Pa isolations by 3 years of age did not differ between groups (PVZ+ 40% vs. PVZ- 41.4%), but this proportion was higher for Sa in the PVZ+ group (97%) than in the PVZ- group (85%; p = 0.001). Healthcare consumption and growth outcomes did not significantly differ between groups. CONCLUSION: Systematic PVZ use did not delay key pathogen acquisition in young children with CF. What is known: • Palivizumab is the only available monoclonal antibody against respiratory syncytial virus infection. • Whether or not it is useful in infants with cystic fibrosis remains controversial. What is new: • Palivizumab does not delay key pathogens (Pseudomonas aeruginosa, Staphylococcus aureus) first isolation in young children with cystic fibrosis. • Palivizumab does not reduce healthcare consumption or improve growth during the first 3 years of life of young children with cystic fibrosis.

Phenotypes of Atopic Dermatitis Depending on the Timing of Onset and Progression in Childhood.

Importance: Atopic dermatitis is an inflammatory, pruritic skin disease that often occurs in early infancy with a chronic course. However, a specific description of subtypes of atopic dermatitis depending on the timing of onset and progression of the disease in childhood is lacking. Objective: To identify different phenotypes of atopic dermatitis using a definition based on symptoms before age 6 years and to determine whether some subtypes are more at risk for developing other allergic diseases. Design, Setting, and Participants: The Protection Against Allergy Study in Rural Environments (PASTURE) is a European birth cohort where pregnant women were recruited between August 2002 and March 2005 and divided in 2 groups dependent on whether they lived on a farm. Children from this cohort with data on atopic dermatitis from birth to 6 years of age were included. Exposures: Atopic dermatitis, defined as an itchy rash on typical locations from birth to 6 years. Main Outcomes and Measures: The latent class analysis was used to identify subtypes of atopic dermatitis in childhood based on the course of symptoms. Multivariable logistic regressions were used to analyze the association between atopic dermatitis phenotypes and other allergic diseases. Results: We included 1038 children; of these, 506 were girls. The latent class analysis model with the best fit to PASTURE data separated 4 phenotypes of atopic dermatitis in childhood: 2 early phenotypes with onset before age 2 years (early transient [n = 96; 9.2%] and early persistent [n = 67; 6.5%]), the late phenotype with onset at age 2 years or older (n = 50; 4.8%), and the never/infrequent phenotype (n = 825; 79.5%), defined as children with no atopic dermatitis. Children with both parents with history of allergies were 5 times more at risk to develop atopic dermatitis with an early-persistent phenotype compared with children with parents with no history of allergies. Both early phenotypes were strongly associated with food allergy. The risk of developing asthma was significantly increased among the early-persistent phenotype (adjusted odds ratio, 2.87; 95% CI, 1.31-6.31). The late phenotype was only positively associated with allergic rhinitis. Conclusions and Relevance: Using latent class analysis, 4 phenotypes of atopic dermatitis were identified depending on the onset and course of the disease. The prevalence of asthma and food allergy by 6 years of age was strongly increased among children with early phenotypes (within age 2 years), especially with persistent symptoms. These findings are important for the development of strategies in allergy prevention.

Disagreement between Skin Prick Tests and Specific IgE in Early Childhood.

BACKGROUND: Accurate diagnosis of allergic sensitization is essential in clinical practice and allergy research, and the choice of assessment method may have an important impact. The PASTURE study (Protection against Allergy: Study of Rural Environment) examines the influence of exposure to a dairy farm environment on the occurrence of allergy in a cohort of rural European children from birth to 10 years. The aim of our study was to analyze agreement between skin prick tests (SPTs), to aeroallergens and food allergens, and specific IgE and to evaluate the association of SPT with atopic dermatitis in the 204 French children of the PASTURE study. METHODS: SPT, atopic dermatitis assessment, and specific IgE measurements were performed at 1, 4.5, and 6 years. RESULTS: A total of 137 children attended all three visits. The agreement between SPTs and specific IgE was poor except for perennial aeroallergens at 6 years and for an IgE cutoff greater than 0.7 IU/ml (κ = 0.69, 0.5202 - 0.8621). The prevalence of positive SPTs increased with age. Positive SPTs were transient at 1 year, whereas they were persistent between 4.5 and 6 years. Positive SPTs at 1 year were predictive of the occurrence of atopic dermatitis during follow-up. CONCLUSION: SPTs did not have good agreement with serum-specific IgE in early childhood. Both tests (SPT and specific IgE) should be used. Skin allergenic reactivity increased with age and was transient at 1 year but associated with the occurrence of atopic dermatitis.

Central venous thrombosis and thrombophilia in cystic fibrosis: A prospective study.

BACKGROUND AND AIMS: Catheter venous thrombosis may result in life-threatening embolic complications. Recently, a thrombophilic tendency was described in cystic fibrosis (CF), the significance of which remains unclear. The aims of this study were to (1) document the frequency of catheter venous thrombosis detected by colour-Doppler-ultrasound (Doppler-US), (2) assess genetic and acquired thrombophilia risk factors for catheter venous thrombosis and hypercoagulability status and (3) provide recommendations on laboratory screening when considering insertion of a totally implantable vascular access device (TIVAD) in CF patients. METHODS: We designed a multicentre prospective study in patients selected at the time of catheter insertion. Doppler-US was scheduled at 1 and 6months after insertion and before insertion in case of a previous central line. Blood samplings were drawn at insertion and at 1 and 6months later. RESULTS: One-hundred patients received a TIVAD and 90 completed the 6-month study. Prevalence of thrombophilia abnormalities and hypercoagulability was found in 50% of the cohorts. Conversely, catheter venous thrombosis frequency was low (6.6%). CONCLUSION: Our data do not support biological screening at the time of a TIVAD insertion. We emphasise the contribution of a medical history of venous thromboembolism and prospective Doppler-US for identifying asymptomatic catheter venous thrombosis to select patients who may benefit from biological screening and possible anticoagulant therapy.

Prenatal and early-life exposures alter expression of innate immunity genes: the PASTURE cohort study.

BACKGROUND: There is evidence that gene expression of innate immunity receptors is upregulated by farming-related exposures. OBJECTIVE: We sought to determine environmental and nutritional exposures associated with the gene expression of innate immunity receptors during pregnancy and the first year of a child's life. METHODS: For the Protection Against Allergy: Study in Rural Environments (PASTURE) birth cohort study, 1133 pregnant women were recruited in rural areas of Austria, Finland, France, Germany, and Switzerland. mRNA expression of the Toll-like receptor (TLR) 1 through TLR9 and CD14 was assessed in blood samples at birth (n= 938) and year 1 (n= 752). Environmental exposures, as assessed by using questionnaires and a diary kept during year 1, and polymorphisms in innate receptor genes were related to gene expression of innate immunity receptors by using ANOVA and multivariate regression analysis. RESULTS: Gene expression of innate immunity receptors in cord blood was overall higher in neonates of farmers (P for multifactorial multivariate ANOVA= .041), significantly so for TLR7 (adjusted geometric means ratio [aGMR], 1.15; 95% CI, 1.02-1.30) and TLR8 (aGMR, 1.15; 95% CI, 1.04-1.26). Unboiled farm milk consumption during the first year of life showed the strongest association with mRNA expression at year 1, taking the diversity of other foods introduced during that period into account: TLR4 (aGMR, 1.22; 95% CI, 1.03-1.45), TLR5 (aGMR, 1.19; 95% CI, 1.01-1.41), and TLR6 (aGMR, 1.20; 95% CI, 1.04-1.38). A previously described modification of the association between farm milk consumption and CD14 gene expression by the single nucleotide polymorphism CD14/C-1721T was not found. CONCLUSION: Farming-related exposures, such as raw farm milk consumption, that were previously reported to decrease the risk for allergic outcomes were associated with a change in gene expression of innate immunity receptors in early life.

A national internet-linked based database for pediatric interstitial lung diseases: the French network.

BACKGROUND: Interstitial lung diseases (ILDs) in children represent a heterogeneous group of rare respiratory disorders that affect the lung parenchyma. After the launch of the French Reference Centre for Rare Lung Diseases (RespiRare®), we created a national network and a web-linked database to collect data on pediatric ILD. METHODS: Since 2008, the database has been set up in all RespiRare® centres. After patient's parents' oral consent is obtained, physicians enter the data of children with ILD: identity, social data and environmental data; specific aetiological diagnosis of the ILD if known, genetics, patient visits to the centre, and all medical examinations and tests done for the diagnosis and/or during follow up. Each participating centre has a free access to his own patients' data only, and cross-centre studies require mutual agreement. Physicians may use the system as a daily aid for patient care through a web-linked medical file, backed on this database. RESULTS: Data was collected for 205 cases of ILD. The M/F sex ratio was 0.9. Median age at diagnosis was 1.5 years old [0-16.9]. A specific aetiology was identified in 149 (72.7%) patients while 56 (27.3%) cases remain undiagnosed. Surfactant deficiencies and alveolar proteinosis, haemosiderosis, and sarcoidosis represent almost half of the diagnoses. Median length of follow-up is 2.9 years [0-17.2]. CONCLUSIONS: We introduce here the French network and the largest national database in pediatric ILDs. The diagnosis spectrum and the estimated incidence are consistent with other European databases. An important challenge will be to reduce the proportion of unclassified ILDs by a standardized diagnosis work-up. This database is a great opportunity to improve patient care and disease pathogenesis knowledge. A European network including physicians and European foundations is now emerging with the initial aim of devising a simplified European database/register as a first step to larger European studies.

Development of atopic dermatitis according to age of onset and association with early-life exposures.

BACKGROUND: Environmental factors can affect the development of atopic dermatitis, and this was described to be already effective during pregnancy and in early life. An important early postnatal exposure is nutrition, although its association with allergic disease remains unclear. OBJECTIVE: We sought to determine prospectively whether early postnatal exposures, such as the introduction to complementary food in the first year of life, are associated with the development of atopic dermatitis, taking into account the reverse causality. METHODS: One thousand forty-one children who participated in the Protection Against Allergy-Study in Rural Environments birth cohort study were included in the current study. Atopic dermatitis was defined by a doctor's diagnosis reported by the parents of children up to 4 years of age, by questionnaires, and/or by positive SCORAD scores from 1 year of age and according to the age of onset within or after the first year of life. Feeding practices were reported by parents in monthly diaries between the 3rd and 12th months of life. RESULTS: The diversity of introduction of complementary food in the first year of life was associated with a reduction in the risk of having atopic dermatitis with onset after the first year of life (adjusted odds ratio for atopic dermatitis with each additional major food item introduced, 0.76; 95% CI, 0.65-0.88). The introduction of yogurt in the first year of life also reduced the risk for atopic dermatitis (adjusted odds ratio, 0.41; 95% CI, 0.23-0.73). CONCLUSION: As early-life exposure, the introduction of yogurt and the diversity of food introduced in the first year of life might have a protective effect against atopic dermatitis.