[Markers of severity and predictors of response to treatment in severe asthma]. / Marqueurs de sévérité et marqueurs prédictifs de réponse au traitement dans l'asthme sévère.

Asthma is a multifactorial disease with complex pathophysiology. Knowledge of its immunopathology and inflammatory mechanisms is progressing and has led to the development over recent years of increasingly targeted therapeutic strategies. The objective of this review is to pinpoint the different predictive markers of asthma severity and therapeutic response. Obesity, nasal polyposis, gastroesophageal reflux disease and intolerance to aspirin have all been considered as clinical markers associated with asthma severity, as have functional markers such as bronchial obstruction, low FEV1, small daily variations in FEV1, and high FeNO. While sinonasal polyposis and allergic comorbidities are associated with better response to omalizumab, nasal polyposis or long-term systemic steroid use are associated with better response to antibodies targeting the IL5 pathway. Elevated total IgE concentrations and eosinophil counts are classic biological markers regularly found in severe asthma. Blood eosinophils are predictive biomarkers of response to anti-IgE, anti-IL5, anti-IL5R and anti-IL4R biotherapies. Dupilumab is particularly effective in a subgroup of patients with marked type 2 inflammation (long-term systemic corticosteroid therapy, eosinophilia≥150/µl or FENO>20 ppb). Chest imaging may help to identify severe patients by seeking out bronchial wall thickening and bronchial dilation. Study of the patient's environment is crucial insofar as exposure to tobacco, dust mites and molds, as well as outdoor and indoor air pollutants (cleaning products), can trigger asthma exacerbation. Wider and more systematic use of markers of severity or response to treatment could foster increasingly targeted and tailored approaches to severe asthma.

Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury.

Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)-dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.

Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. RESULTS: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. CONCLUSIONS: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

[Pulmonary intravascular talcosis: A case report]. / Talcose intravasculaire pulmonaire : à propos d'un cas.

INTRODUCTION: Pulmonary intravascular talcosis is a rare condition occurring in intravenous drug users injecting oral medications. Talc results in a foreign-body granulomatous reaction giving a radiological haematogenic miliary appearance mimicking miliary tuberculosis. Drug users represent a population at risk for both these conditions and their distinction may be challenging. CASE REPORT: We reported the case of a man, 33 year-old, intravenous drug addict, detected by the health services because he was the partner of a person who died of contagious and multi-resistant tuberculosis. Chest X-ray and CT scan showed a typical miliary appearance. Despite negative microbiology, clinical diagnosis of miliary tuberculosis was retained. Due to the lack of radiological improvement despite appropriate antibiotic treatment, re-evaluation and trans-bronchial biopsy were undertaken. The presence of granulomas centered by birefringent foreign bodies in polarized light led to a diagnosis of pulmonary intravascular talcosis. CONCLUSION: In the presence of pulmonary miliary in an intravenous drug addict, intravascular talcosis should be suspected.

[The biological rationale for immunotherapy in cancer]. / Rationnel biologique de l'immunothérapie des cancers.

INTRODUCTION: Immunotherapy aims to promote the immune system's activity against malignant cells by stimulating the response to several tumor antigens. STATE OF THE ART: Immunosurveillance may adjust the immunogenicity of tumors. To be effective, immunity must induce the specific activation of CD4+ and CD8+ T lymphocytes, as well as activation of innate immunity. Activator and inhibitory costimulatory molecules regulate T lymphocyte activation at immunity checkpoints such as PD-1/PD-L1 and CTLA-4. Adaptive immune resistance confers tumour resistance to immunosurveillance through these immune checkpoints. PERSPECTIVES: Approaches involving the combination of several immunotherapies with each other or with chemotherapy and radiotherapy and antibodies against other molecules of costimulation are under development. The development of biomarkers, which can select a targeted population and predict therapeutic response, represents a major challenge. Tumour high-throughput sequencing could refine "immunoscore". Intratumoral T cell receptor seems to represent a promising biomarker. CONCLUSIONS: Numerous challenges still remain in developing research approaches for the development of immunotherapies.

[Emphysema, did you say emphysema?] / Emphysème, vous avez dit emphysème ?

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a common condition that may initially look simple but may conceal other diseases capable of accelerating its natural history or even simulating it. We describe four cases presenting as COPD with emphysema that were reclassified on the basis of certain clinical characteristics and the radiological pattern. CASE REPORTS: A 52 year old never smoking woman presenting with emphysema was eventually diagnosed as having lymphangioleiomyomatosis on the basis of an abdominal CT scan showing kidney angiomyolipomas. A 44 years old smoker presenting with rapidly evolving emphysema was eventually diagnosed as having Langerhans cell histiocytosis on the basis of a previous chest CT (four years earlier) showing cavitating nodules. An airport refueler, 73 years old, with severe emphysema despite never having smoked, was eventually diagnosed as suffering from alpha-1 antitrypsin deficiency. The last patient was a 54 year old man, a never smoker, who presented with severe airflow limitation and multilobar hyperlucency, with bronchiectasis in the same areas. He was eventually diagnosed as having a severe form of the Swyer-James-MacLeod syndrome. CONCLUSION: These four case reports underline the importance of questioning the diagnosis of COPD when certain particular phenotypic characteristics are identified.

Detection of PD-L1 in circulating tumor cells and white blood cells from patients with advanced non-small-cell lung cancer.

Background: Expression of PD-L1 in tumor cells and tumor-infiltrating immune cells has been associated with improved efficacy to anti-PD-1/PD-L1 inhibitors in patients with advanced-stage non-small-cell lung cancer (NSCLC) and emerged as a potential biomarker for the selection of patients to cancer immunotherapies. We investigated the utility of circulating tumor cells (CTCs) and circulating white blood cells (WBCs) as a noninvasive method to evaluate PD-L1 status in advanced NSCLC patients. Patients and methods: CTCs and circulating WBCs were enriched from peripheral blood samples (ISET® platform; Rarecells) from 106 NSCLC patients. PD-L1 expression on ISET filters and matched-tumor tissue was evaluated by automated immunostaining (SP142 antibody; Ventana), and quantified in tumor cells and WBCs. Results: CTCs were detected in 80 (75%) patients, with levels ranging from 2 to 256 CTCs/4 ml, and median of 60 CTCs/4 ml. Among 71 evaluable samples with matched-tissue and CTCs, 6 patients (8%) showed ≥1 PD-L1-positive CTCs and 11 patients (15%) showed ≥1% PD-L1-positive tumor cells in tumor tissue with 93% concordance between tissue and CTCs (sensitivity = 55%; specificity = 100%). From 74 samples with matched-tissue and circulating WBCs, 40 patients (54%) showed ≥1% PD-L1-positive immune infiltrates in tumor tissue and 39 patients (53%) showed ≥1% PD-L1 positive in circulating WBCs, with 80% concordance between blood and tissue (sensitivity = 82%; specificity = 79%). We found a trend for worse survival in patients receiving first-line cisplatin-based chemotherapy treatments, whose tumors express PD-L1 in CTCs or immune cells (progression-free and overall survival), similar to the effects of PD-L1 expression in matched-patient tumors. Conclusions: These results demonstrated that PD-L1 status in CTCs and circulating WBCs correlate with PD-L1 status in tumor tissue, revealing the potential of CTCs assessment as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with advanced-stage NSCLC.

Pulmonary sarcoid-like granulomatosis induced by nivolumab.

The use of antibodies against programmed death (PD)1, such as nivolumab and pembrolizumab, has dramatically improved the prognosis of patients with advanced melanoma. Nivolumab is also approved in advanced squamous cell nonsmall-cell lung cancer. These immunotherapies are associated with a unique set of toxicities termed immune-related adverse events, which are different from toxicities observed with conventional cytotoxic chemotherapy. We report the case of a 56-year-old man who was diagnosed with metastatic melanoma and who received nivolumab. One week after the second infusion, he developed pulmonary symptoms, dry eye syndrome and a bilateral swelling of the parotid glands. Investigations were negative for infection. The bronchoalveolar lavage differential cell count showed 32% lymphocytes with an increased CD4 : CD8 ratio, and bronchial biopsies revealed noncaseating epithelioid granulomas, without malignant cells. The clinical and radiological courses were rapidly favourable with oral corticosteroid. This case illustrates that sarcoidosis can be induced by nivolumab treatment. With the increasing use of anti-PD1 inhibitors in patients with advanced melanoma and squamous cell nonsmall-cell lung cancer, clinicians should be aware of this potential associated immune-related adverse event.

Immunotherapy in Non-Small Cell Lung Cancer: Biological Principles and Future Opportunities.

Immunotherapy aims to amplify the anticancer immune response through reactivation of the lymphocytic response raised against several tumor neo-antigens. To obtain an effective immune response, this therapeutic approach requires that a number of immunological checkpoints be passed, such as the activation of excitatory costimulatory signals or the avoidance of coinhibitory molecules. Among the immune checkpoints, the interaction of the membrane-bound ligand PD-1 and its receptor PD-L1 has received much attention because of remarkable efficacy in numerous clinical trials for various cancer types, including non-small cell lung cancer (NSCLC). However, several limitations exist with these therapeutic agents when used as monotherapy, with objective responses observed in only 30-40% of patients, with the majority of patients demonstrating innate resistance, and approximately 25% of responders later demonstrating disease progression. Recent developments in the understanding of cancer immunology have the potential to identify mechanisms of innate and acquired resistance to immune checkpoint inhibitors through translational research in human samples. This review focuses on the biological basic principles for immunological checkpoint blockade, and highlights the current status and the perspectives of this therapeutic approach in NSCLC patients.

[Recurrent pericarditis as an initial manifestation of Wegener's granulomatosis]. / Péricardites récidivantes révélatrices d'une maladie de Wegener.

Recurrent pericarditis occur in around a quarter of patients after a first episode of acute pericarditis. Most of the cases are idiopathic or viral pericarditis or post-pericardial injury syndromes. Recurrent pericarditis are most likely to occur in patients with known systemic lupus erythematosus or rheumatoid arthritis but are rare in other systemic auto-immune diseases. We report here an unusual case of a patient with a 5-year history of four acute myopericarditis revealing Wegener's granulomatosis. Clinicians should consider the possibility of Wegener's granulomatosis in case of recurrent pericarditis and look for features suggestive of granulomatous disease affecting the upper and lower respiratory tract. In this setting, antineutrophil cytoplasmic autoantibodies (ANCA) testing and/or biopsy of involved organs appear of particular interest to confirm the diagnosis.

Multiple lung parenchymal abnormalities: Don't panic, let's be pragmatic! The 6 question rule - a checklist strategy.

Analysis of multiple lung parenchymal abnormalities on HRCT is a real diagnostic challenge. These abnormalities may be due to a disease of the pulmonary interstitial tissue, the bronchial tree, the cardiovascular system or to abnormal alveolar filling with fluid, blood, cells or tumor, several of these etiologies possibly being concomitant. Systematic pathophysiological reasoning, in the form of a logical checklist, guides reflection and covers many of the most frequent diagnoses and potentially treatable emergencies that can be identified by the non-specialist radiologist. This approach also provides a basis for deepening knowledge of each area. The use of the mnemonic FIBROVAKIM (fibrosis-bronchi-vascular-cancer-infection-medication) is easy to apply and summarizes this strategy.

[Daily physical activity in adult patients with cystic fibrosis]. / Activité physique quotidienne de patients adultes atteints de mucoviscidose.

Assessment of daily physical activity (DPA) is a major element in the development of respiratory rehabilitation. The aim of this study was to evaluate the DPA and the daily energy expenditure (DEE) in adult patients with cystic fibrosis. Thirty adult patients (16 women, 14 men, mean age 27.1±8.4 years) with cystic fibrosis (FVC: 69.2±19%, FEV1: 55.1±24%, BMI: 20.5±3.6kg/m(2)), in stable condition were included in the study. The questionnaire allowed DPA to estimate DEE from the intensity and type of activity. This tool divides the DEE into four intensity levels: less than 1 Metabolic Equivalent Task (MET), greater than 1 and less than 3 METs, 3-5 METs, and greater than 5 METs. A shuttle test for estimating VO(2) peak was performed in all patients. The DEE reached 9478.4±3224.3kJ24h(-1) and was significantly and highly correlated with calculated peak VO(2) (l/min) (r=0.876, P=<0.001); 22% DEE was less than 3 METs, 10% between 3 and 5 METs et 2,5% greater than 5 METs; 65% DEE was less than 1 MET. There was a strong correlation between DEE and BMI (r=0.860, P=<0.001), a low correlation with FVC (r=0.423, P=0.02). This questionnaire is relevant for estimating DPA and DEE in patients with cystic fibrosis and is an interesting test to be used to evaluate changes in patients after pulmonary rehabilitation.

[Procalcitonin, a useful biomarker in pediatric urinary tract infection]. / La procalcitonine : un marqueur utile pour l'enfant présentant une infection urinaire.

Urinary tract infections (UTIs) are one of the most common sources of bacterial infections among young febrile children. Accurate diagnosis of acute pyelonephritis (APN) and vesico-ureteral reflux (VUR) are important because of their association with renal scarring, sometimes leading to long-term complications. However, the gold standard examinations are either a DMSA scan for APN and scarring, or cystography for VUR, but both present limitations (feasibility, pain, cost, etc.). Procalcitonin, a reliable marker of bacterial infections, was demonstrated to be a good predictor of renal parenchymal involvement in the acute phase and in late renal scars, as well as of high-grade VUR. These findings need further broad validations and impact studies before being implemented into daily practice. However, procalcitonin may play a role in the complex and still debated picture of which examination should be performed after UTI in children.

Infectious risk of endovaginal and transrectal ultrasonography: systematic review and meta-analysis.

BACKGROUND: Appropriate endovaginal/rectal ultrasound transducer disinfection has been an ongoing and vexed question in gynaecology, obstetrics and urology. However, the routine use of probe covers followed by low-level disinfection (wipes/spray) is usually applied between patients in some countries (e.g. France). AIM: To perform a systematic review and meta-analysis of the scientific literature in order to identify case reports of contamination following endovaginal/rectal probe use, and to estimate the infection prevalence related to the use of these probes in common daily practice. METHODS: Systematic review and meta-analysis. RESULTS: From the 867 potentially eligible references, 32 articles were finally included. Very few cases with an established route of contamination had been reported. Indeed, apart from occurrence of outbreaks, it is difficult if not impossible to detect viral contamination through the use of endovaginal/rectal ultrasound probes. However, there was a pooled prevalence of 12.9% (95% confidence interval: 1.7-24.3) for pathogenic bacteria, and 1.0% (0.0-10.0) for frequently occurring virus (human papillomavirus, herpes simplex virus, and cytomegalovirus) for endovaginal/rectal probes, both after low-level disinfection. The pooled prevalence of infected patients after transrectal ultrasound and guided biopsies was estimated to be 3.1% (1.6-4.3). CONCLUSIONS: There appears to be a risk of transmitting bacterial or viral infections via endovaginal/rectal ultrasound transducer, and the present meta-analysis provides an estimate of this risk. Further research with sophisticated modelling is warranted to quantify the risk.

Home-based pulmonary rehabilitation in idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a severe chronic lung disease. Pulmonary rehabilitation could improve the quality of life of patients with this condition. METHODS: We prospectively evaluated the impact of an 8-week home-based pulmonary rehabilitation programme over 10 months in stable patients suffering from IPF. Exercise capacity, pulmonary function, dyspnoea and quality of life were analyzed before and after the rehabilitation programme. RESULTS: Seventeen patients were included and 13 completed the study. Mean functional vital capacity (FVC) was 2.15±0.79L and mean diffusing capacity for carbon monoxide (DLCO) was 7.81±3.99mL/min/mmHg. Six patients were treated with low dose oral steroids (20mg/day of prednisone) with or without immunosuppressive treatments; six were taking part in therapeutic trials. Mean endurance time (7.4±9.1 min vs. 14.1±12.1 min; P=0.01), number of steps per minute on a stepper (322±97 vs. 456±163; P=0.026), six-minute walk distance relative to heart rate (HR) (11±6 vs. 17±12; P=0.006), exercise dyspnoea (P=0.026), sensation of physical limitation on the SF-36 (25%±26 vs. 49%±38; P=0.047) and four out of seven visual analogue scales were significantly improved after rehabilitation. In contrast, no significant difference was observed in resting pulmonary function or in other items on quality of life questionnaires. CONCLUSION: A home-based programme of pulmonary rehabilitation is feasible in IPF patients. It significantly improved endurance parameters and physical limitation in this patient group without changing pulmonary function.

Selective strategy for urethral catheterization in febrile young girls to confirm urinary tract infection diagnosis.

BACKGROUND: Urinary tract infections (UTIs) are a common source of bacterial infections in childhood. Making a proper diagnosis is important but requires invasive urine collection techniques. We aimed to derive a clinical decision rule to identify non-toilet-trained febrile girls at high risk for UTIs to restrict urethral catheterizations (UCs) to this high-risk group of patients. METHODS: We included all non-toilet-trained girls with a positive microscopic urinalysis from urine collected by sterile bag in a prospective cohort study to derive a model to predict UTI assessed by urine culture from UC. RESULTS: Thirty-seven patients were included. Absence of another source of fever on examination and the child's unusual behaviour were found to be independent predictors of UTI. The corresponding model offered an 85% sensitivity [95% confidence interval (CI): 56-96], with a 59% specificity (95% CI: 30-83) for UTI. The internal cross-validation by bootstrap led to an 85% sensitivity (95% CI: 68-100), and a 59% specificity (95% CI: 35-83). CONCLUSION: We derived a clinical decision model to selectively identify young febrile girls at high risk for UTI with a positive microscopic analysis and propose UC with an 85% sensitivity, which would avoid approximately 60% of unnecessary UCs; although further validation is necessary before daily clinical use.

[Tolerance and efficacy of ceftazidime in combination with aztreonam for exacerbations of cystic fibrosis]. / Intérêt de l'association ceftazidime et aztréonam dans les exacerbations de mucoviscidose à Pseudomonas aeruginosa multirésistant.

BACKGROUND: Antibiotic therapy for acute pulmonary exacerbations in patients with cystic fibrosis is usually chosen based on the results of antimicrobial susceptibility. This can be difficult when bacteria are multiresistant. The objective of this retrospective study was to evaluate the tolerance and efficiency of ceftazidime and aztreonam combination (+/-tobramycin, +/-ciprofloxacin) in the treatment of acute exacerbations in cystic fibrosis patients who were chronically colonized with multiresistant P. aeruginosa. PATIENTS: Seventeen severe patients, with FEV(1)=1070+/-66 mL and BMI=18+/-0.6 kg/m(2), who had chronic colonisation with P. aeruginosa with intermediate sensitivity or resistance to ceftazidime and aztreonam, were studied between June 2003 and March 2007. Oxygen saturation, dyspnoea, weight, FEV(1), FVC, and tolerance were evaluated before and after antibiotic courses. RESULTS: Forty-two courses of treatment, administered between June 2003 and March 2007 were studied: Patients increased their FEV(1) and FVC (p=0.01). One antibiotic course was stopped after four days because of cutaneous side effects. The median delay until the next exacerbation was 101+/-10 days. These courses were compared with other combinations of antibiotics that the patients had received before. The combination of ceftazidime and aztreonam was more effective in patients receiving less than four courses per year for acute pulmonary exacerbation. CONCLUSION: In chronically P. aeruginosa colonised cystic fibrosis patients, ceftazidime and aztreonam combination (+/-tobramycin, +/-ciprofloxacin) is well tolerated and efficient. This treatment suggests a clinical and functional benefit is possible, even in patients with severe disease.

[Prognostic value of clinical exercise testing in adult patients with cystic fibrosis]. / Intérêt pronostique de l'épreuve fonctionnelle d'exercice au cours de la mucoviscidose de l'adulte.

BACKGROUND: Current guidelines for referring cystic fibrosis (CF) patients for lung transplantation, based on resting parameters, are insufficient to predict 3-year mortality. The aim of this study was to determine the prognostic value of cardiopulmonary exercise testing (CPET) in adult CF patients. METHODS: A multicenter retrospective study on 3-year outcomes was made on 51 adult CF patients who underwent CPET with blood gas analysis. Demographic data, resting pulmonary function and CPET parameters were collected to perform a univariate survival analysis by Kaplan-Meier curves and log-rank tests. To estimate prognosis, a multivariate logistic regression analysis was performed. RESULTS: The survival log-rank analysis indicated that lower FEV(1), lower body mass index (BMI), diabetes mellitus, lower work rate and higher alveolar-arterial gradient for oxygen (P[A-a]O(2)) at peak exercise were associated with a significantly higher risk of death. The logistic regression analysis showed that BMI (<19.8) and P(A-a)O(2) peak (>43 mmHg) were independently associated with a lower chance of survival. CONCLUSION: CPET with blood gas analysis may have a prognostic value in adult CF patients. Further larger prospective clinical studies are warranted to confirm these preliminary results.

The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening.

BACKGROUND: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. METHODS: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p(R117H)), on either intron 8 T5 or T7 background, and F508del (p(F508del)) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. RESULTS: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p(F508del) was 1.06%, p(R117H;T7) 0.27% and p(R117H;T5)<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. CONCLUSIONS: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.