Impact of liquid sublingual immunotherapy on asthma onset and progression in patients with allergic rhinitis: a nationwide population-based study (EfficAPSI study).

Background: The only disease-modifying treatment currently available for allergic rhinitis (AR) is allergen immunotherapy (AIT). The main objective of the EfficAPSI real-world study (RWS) was to evaluate the impact of liquid sublingual immunotherapy (SLIT-liquid) on asthma onset and evolution in AR patients. Methods: An analysis with propensity score weighting was performed using the EfficAPSI cohort, comparing patients dispensed SLIT-liquid with patients dispensed AR symptomatic medication with no history of AIT (controls). Index date corresponded to the first dispensation of either treatment. The sensitive definition of asthma event considered the first asthma drug dispensation, hospitalisation or long-term disease (LTD) for asthma, the specific one omitted drug dispensation and the combined one considered omalizumab or three ICS ± LABA dispensation, hospitalisation or LTD. In patients with pre-existing asthma, the GINA treatment step-up evolution was analysed. Findings: In this cohort including 112,492 SLIT-liquid and 333,082 controls, SLIT-liquid exposure was associated with a significant lower risk of asthma onset vs. control, according to all definitions (combined: HR [95% CI] = 0.62 [0.60-0.63], sensitive: 0.77 [0.76-0.78], and specific: 0.67 [0.61-0.72]). Exposure to SLIT was associated with a one-third reduction in GINA step-up regardless baseline steps. Interpretation: In this national RWS with the largest number of person-years of follow-up to date in the field of AIT, SLIT-liquid was associated with a significant reduction in the risk of asthma onset or worsening. The use of three definitions (sensitive or specific) and GINA step-up reinforced the rigorous methodology, substantiating SLIT-liquid evidence as a causal treatment option for patients with respiratory allergies. Funding: Stallergenes Greer.

A successful linkage of a named patient products of sublingual immunotherapy-dispensing registry to French healthcare insurance database (SNDS): methodological constitution of the EfficAPSI cohort.

BACKGROUND: The only causal treatment for allergic rhinitis (AR) is allergen immunotherapy (AIT) including personalized liquid sublingual AIT (SLIT). We present the methodology for establishing the EfficAPSI cohort to further evaluate the real-life effectiveness and use of SLIT liquid. RESEARCH DESIGN AND METHODS: The EfficAPSI cohort was constituted by deterministic linkage of Stallergenes Greer dispensing and nationwide French healthcare insurance system (SNDS) databases. Data from 2006 to 2018 were extracted. All patients who initiated Stallergenes Greer SLIT liquid between 2010 and 2013 were considered as exposed and those dispensed with AR symptomatic treatment only as control. To limit the impact of confounding, the models will be weighted using the inverse probability of treatment weighting (IPTW). RESULTS: A total of 445,574 patients were included; median age was 38 years; 59.1% were female. Exposed patients (n = 112,492) were significantly younger, more frequently males, and less likely to have comorbidities than controls (n = 333,082). After IPTW, patients' characteristics from both groups were similar. CONCLUSIONS: To date, the EfficAPSI cohort has the largest number of person-years of follow-up in the field of AIT. The completeness of the data allows to evaluate SLIT liquid effectiveness with rigorous methodology, leading to important insights on personalized medicine in real-life.

[Obstructive Sleep Apnea in Children: A Team effort!] / Syndrome d'apnées obstructives du sommeil de l'enfant : une affaire d'équipe !

Obstructive Sleep Apnea (OSA) in children, which has a multifactorial origin, can lead, if not treated, to severe medical complications, growth disturbances, behavioural changes and reduced quality of life. Nowadays, it is underdiagnosed whereas early screening, diagnosis and interdisciplinary treatment are essential. Furthermore, many families and health professionals do not often know where to go when there is suspicion of OSA for a child. Orthodontists are uniquely positioned to screen, to refer to the appropriate specialist and to treat, if needed, patients who may be at high risk for OSA. The authors describe the synergistic means to screen, diagnose and treat paediatric OSA in a collaborative and interactive approach between ENT, orthodontists, pneumo-allergologists, sleep physicians, endocrinologists, orofacial myo-functional therapists and speech therapists. These means which are clinically illustrated in this paper fit the guidelines which have been recently published as white papers by official professional specialists organisations involved in paediatric OSA treatment (AAPD, AAO, FFO, SFORL, SFRMS…). The development of multidisciplinary teams gathering specialists who are conscious about the mutual benefits of the specialties involved in paediatric OSA should contribute to optimize the child treatment care pathway and the short, mid and long term outcomes.

Vibrating-mesh nebulizer maintenance by CF patients: Results from a French survey.

PURPOSE OF THE STUDY: Vibrating-mesh nebulizers are widely used at home for cystic fibrosis (CF) treatment, with a therapeutic efficiency closely linked to the mesh performance. This national study looks at the maintenance at home by CF patients and their families of the mesh of the eFlow®rapid nebulizer. Ninety-two patients from 34 French CF centers, treated at home with inhaled drugs delivered with a vibrating-mesh nebulizer, answered to a phone standardized questionnaire specifying the different techniques of maintenance of the nebulizer. PRINCIPAL RESULTS: Patients were aged from 2 to 68 years (58.7% of children). They inhaled a mean of 1.8 nebulizations per day. Maintenance was assumed by patients in 36% of the cases. All steps of the theoretical maintenance of a nebulizer were respected in 66% of the cases. The mesh was not cleaned in 45.6%, not disinfected or not thermically disinfected in 32.5%, and not rinsed after chemical disinfection in 45.5% of the case. Only 49% of the patients knew the role of the MeshCare® system in the mesh maintenance, and only 39% had already used it when the nebulization duration reached 10 min. CONCLUSIONS: Efforts about education, particularly for the maintenance of the mesh, are needed for CF patients using a vibrating-mesh nebulizer at home.

Lessons from a French collaborative case-control study in cystic fibrosis patients during the 2009 A/H1N1 influenza pandemy.

BACKGROUND: Viral infections such as influenza are thought to impact respiratory parameters and to promote infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF). However, the real morbidity of the influenza virus in CF needs to be further investigated because previous studies were only observational. METHODS: CF patients were included in a case-control study (n = 44 cases and n = 371 controls) during the 2009 pandemic A/H1N1 influenza. Cases were patients with polymerase reaction chain-confirmed influenza A/H1N1 infection. Controls did not report any influenza symptoms during the same period. Sputum colonization and lung function were monitored during 1 year after inclusion. RESULTS: Cases were significantly younger than controls (mean(SD) 14.9 years(11) versus 20.1 years (13.2) and significantly less frequently colonized with P. aeruginosa (34 % versus 53 %). During influenza infection, 74 % of cases had pulmonary exacerbation, 92 % had antibiotics adapted to their usual sputum colonization and 82 % were treated with oseltamivir. Two cases required lung transplantation after A/H1N1 infection (one had not received oseltamivir and the other one had been treated late). The cases received a mean number of antibiotic treatments significantly higher during the year after the influenza infection (mean(SD) 2.8 (2.4) for cases versus 1.8(2.1) for controls; p = 0.002). An age-matched comparison did not demonstrate any significant modification of bronchopulmonary bacterial colonization during the year after influenza infection nor any significant change in FEV1 at months 1, 3 and 12 after A/H1N1 infection. CONCLUSIONS: Our results do not demonstrate any change in sputum colonization nor significant lung disease progression after pandemic A/H1N1 influenza. TRIAL REGISTRATION: Clinical Trials.gov registration number: NCT01499914.

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.

Assessment of disease control in allergic rhinitis.

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative has had a significant impact, by raising awareness of allergic rhinitis (AR) and improving the diagnosis and treatment of AR sufferers. ARIA classifies the severity of AR as "mild" or "moderate/severe" on the basis of "yes"/"no" answers to four questions. This two-point classification has been criticized as providing little guidance on patient management; patients with "mild" AR are unlikely to consult a physician, whereas the group of patients with "moderate/severe" seen by specialists is heterogeneous. These perceived shortcomings have prompted attempts to improve the ARIA classification or, by analogy with the Global Initiative for Asthma (GINA), adopt approaches based on "disease control" in AR. Even though "disease severity", "disease control" and "responsiveness to treatment" are different (albeit related) metrics, they are not mutually exclusive. Currently, there is no single, accepted definition, but we propose that "disease control" in AR can combine (i) measurements of the severity and/or frequency of daily or nocturnal symptoms, (ii) impairments in social, physical, professional and educational activities, (iii) respiratory function monitoring and (iv) exacerbations (e.g. unscheduled medical consultations and rescue medication use). Although control-based classifications have a number of limitations (e.g. their dependence on treatment compliance and the patient's psychological status), these instruments could be used as an adjunct to the ARIA severity classification and regional practice parameters. Here, we assess the strengths and weaknesses of the current two-level ARIA classification, analyze published proposals for its modification and review the literature on instruments that measure AR control. We conclude that there is a need for research in which severity is compared with control in terms of their effects on patient management.

Recurrent abdominal pain in children with cystic fibrosis: a pilot prospective longitudinal evaluation of characteristics and management.

Children with cystic fibrosis commonly experience abdominal pain; however this remains poorly characterised. This prospective cross-sectional study with a longitudinal design, examined the prevalence, causes and effect of pain management via daily diaries, validated questionnaires for pain characteristics, anxiety status and quality of life. One hundred and thirty CF patients aged 8 to 18 years, regularly followed at our centre, were questioned on recurrent abdominal pain. Eight patients fulfilled the criteria; all wished to enter the study. Pain management included behavioural intervention with effective pain relief, and had a positive impact on anxiety and quality of life. This study is the first one to prospectively assess recurrent abdominal pain in CF. We documented a very low prevalence of 6%. We suggest that, ruling out abdominal discomfort, only a minority of CF children presented recurrent abdominal pain with a true negative impact on daily life. We emphasise the need for further studies including larger cohorts.

Pharmacokinetics and safety of tobramycin administered by the PARI eFlow rapid nebulizer in cystic fibrosis.

BACKGROUND: Nebulization times have been identified as an issue in patient compliance with tobramycin solution for inhalation (TSI) therapy in cystic fibrosis (CF). METHODS: In this randomized, open-label, multicentre, two-period, crossover study, patients (n=25) with CF and chronic pulmonary pseudomonal infection received TSI for 15 days via eFlow rapid or LC PLUS nebulizer. Nebulization times and sputum/serum tobramycin concentrations were determined, and safety evaluated. RESULTS: Nebulization times were significantly shorter for eFlow rapid versus LC PLUS on Day 1 (least squares mean estimate of the difference -10.5 min, 95% confidence intervals [CI] -12.6, -8.3, p<0.0001) and Day 15 (difference -7.7 min, 95% CI -9.0, -6.5, p<0.0001). Broadly comparable sputum/systemic exposure to tobramycin was observed and the incidence of adverse events was similar for both nebulizers. CONCLUSION: Use of the eFlow rapid nebulizer reduced TSI nebulization time. The systemic exposure to tobramycin appeared to be broadly similar in this exploratory study.

Influence of interleukin-10 on Aspergillus fumigatus infection in patients with cystic fibrosis.

Recent evidence suggests that genetic polymorphisms that affect the production of interleukin (IL)-10 may play a role in the response to pathogens in cystic fibrosis (CF). The present study was designed to investigate a possible association between alleles carried at position -1082 in the promoter region of the IL-10 gene and clinical data on 378 patients with CF. After adjustment for potential confounding variables, a significant relationship was found between the -1082GG genotype and both colonization with Aspergillus fumigatus and allergic bronchopulmonary aspergillosis. In addition, higher serum levels of IL-10 were observed in patients colonized with A. fumigatus. These results suggest that polymorphisms in the promoter region of the IL-10 gene may influence the host response to A. fumigatus in the context of CF.

Glutathione-S-transferase M1, M3, P1 and T1 polymorphisms and severity of lung disease in children with cystic fibrosis.

OBJECTIVES: Progression and severity of lung disease differs markedly and early between patients with cystic fibrosis (CF). We investigated the hypothesis that polymorphisms in the detoxifying enzymes glutathione-S-transferase (GST) could influence phenotypic presentation of lung disease in CF. METHODS: Genotypes for GSTM1, GSTM3, GSTP1 and GSTT1 were determined in a cohort of 146 children with CF by PCR-based methods. Pulmonary function, assessed by spirometric measures of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), was analysed in children at the age of 9. RESULTS: No association between spirometric measurements, and GSTM1, GSTP1 or GSTT1 genotypes was found. As compared with patients homozygous for GSTM3*A allele, CF children carrying the GSTM3*B allele displayed a significant better lung function, assessed by both mean values of FEV1 and of FVC (respectively P = 0.01 and P = 0.002). These correlations remained significant after adjustment for potential confounding factors (respectively adjusted P = 0.008 and P = 0.002) and also in subgroups of CF patients who carry the deltaF508 CFTR mutation. Haplotype analysis of GSTM3 in combination with GSTM1 indicated that the positive impact of GSTM3*B allele on pulmonary performances was barely influenced by the GSTM1 genotypes of CF children. CONCLUSIONS: These data provide the first evidence suggesting that polymorphism of the GSTM3 gene contributes to clinical severity in CF, which may have prognostic significance and could prompt to start a more targeted therapy in young patients with CF.

Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB.

We have analyzed surfactant protein B (SP-B) and its encoding gene (SFTPB, MIM 178640) in 40 unrelated pediatric patients with unexplained respiratory distress (URD). There was high consanguinity (eight kindreds) and an underlying autosomal recessive trait could be inferred in most cases, with overall high sex ratio (32/17) suggesting proband's gender to impact on penetrance. The clinical/biological presentations fitted into three major nosologic frameworks. I: SP-B deficiency (nine probands), complete or incomplete, with homozygous/compoundly heterozygous mutations identified (six probands), including one from the population isolate of Réunion Island (496delG). In addition, there was a consanguineous kindred in which incomplete deficiency was unambiguously unlinked to SFTPB. II: pulmonary alveolar proteinosis (PAP, 19 probands), with typical storage of PAS-positive material within the alveoli with foamy macrophages and variable interstitial reaction, which was diagnosed in most patients from Réunion Island. In contrast to previously published findings, mutation and/or segregation analyses excluded SFTPB as a disease locus, although slight metabolic derangement related to SP-B and/or mild SFTPB changes could somehow contribute to disease. III: URD without evidence for SP-B deficiency or PAP (12 probands), equally unlinked to SFTPB, although a single patient had a possibly causal, maternally-derived, heterozygous genetic change (G4521A). The population frequency of five known and four novel SNPs was studied, providing as many potential markers for pulmonary disease related to SFTPB. Overall, URD was found to be heterogeneous, both phenotypically and genetically, even in population isolates where a founder effect might have been expected. When disease loci are identified, patient genotyping will be crucial as a diagnostic aid, for devising proper treatment, and as a basis for genetic counseling.