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 CONCLUSIONS: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes.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.

[Pulmonary arterial hypertension related to systemic sclerosis in 2008]. / L'hypertension artérielle pulmonaire de la sclérodermie systémique en 2008.

Systemic sclerosis-related pulmonary arterial hypertension (PAH) is a severe disease affecting about 1000 patients in France. In 2008, all scleroderma patients are screened for PAH by a yearly cardiac Doppler ultrasonography. The pathogenesis of systemic sclerosis-related PAH is poorly known but it seems that besides common arteriolar remodeling (media hypertrophy, intimal thickening, endothelial proliferation), venular lesions suggesting obstructive venous disease and inflammatory lesions may be also be involved. Prostacyclin and analogues, phosphodiesterase-5 inhibitors (sildenafil) and endothelin-1 receptor antagonists are proposed as specific treatments for systemic sclerosis-related PAH. Unlike bosentan, which is non-selective, inhibiting both ETA and ETB receptors, sodium sitaxentan is highly selective for ETA receptors; this could favor pulmonary vasodilation.

[Heart and heart-lung transplants thorax complications: major radiologic forms]. / Complications thoraciques des greffes pulmonaires et cardiopulmonaires: principaux aspects radiologiques.

Bipulmonary and cardiopulmonary transplantations are among the most difficult to perform, with a 10-year survival rate estimated at 33%. This low rate can be attributed to thoracic complications that can be classified into three distinct groups: 1) early complications, occurring in the first 30 days after transplantation (hemothorax, diaphragmatic paralysis, reperfusion edema, hydric overloading, acute rejection); 2) late complications that occur beyond the first month (bronchiolitis obliterans syndrome, bronchic stenosis, sirolimus-induced lung disorders, initial disease recurrence); and 3) infections classed separately because of their high morbidity and mortality (thoracic wall abscess, bacterial and viral pneumonia, CMV, pneumocystosis, Aspergillus necrotizing bronchitis). Imaging is essential in screening and diagnosing these complications as part of the clinician's monitoring throughout the rest of the transplant recipient's life. In diagnosis, combined with clinical and biological data, imaging has its place in delaying the onset of these diseases.

Evaluation of quantitative PCR for early diagnosis of Pseudomonas aeruginosa infection in cystic fibrosis: a prospective cohort study.

OBJECTIVES: Early detection of Pseudomonas aeruginosa lung positivity is a key element in cystic fibrosis (CF) management. PCR has increased the accuracy of detection of many microorganisms. Clinical relevance of P. aeruginosa quantitative PCR (qPCR) in this context is unclear. Our aim was to determine P. aeruginosa qPCR sensitivity and specificity, and to assess the possible time saved by qPCR in comparison with standard practice (culture). METHODS: A multicentre cohort study was conducted over a 3-year period in 96 patients with CF without chronic P. aeruginosa colonization. Sputum samples were collected at each visit. Conventional culture and two-step qPCR (oprL qPCR and gyrB/ecfX qPCR) were performed for 707 samples. The positivity criteria were based on the qPCR results, defined in a previous study as follow: oprL qPCR positivity alone if bacterial density was <730 CFU/mL or oprL qPCR combined with gyrB/ecfX qPCR if bacterial density was ≥730 CFU/mL. RESULTS: During follow up, 36 of the 96 patients with CF were diagnosed on culture as colonized with P. aeruginosa. This two-step qPCR displayed a sensitivity of 94.3% (95% CI 79.7%-98.6%), and a specificity of 86.3% (95% CI 83.4%-88.7%). It enabled P. aeruginosa acquisition to be diagnosed earlier in 20 patients, providing a median detection time gain of 8 months (interquartile range 3.7-17.6) for them. CONCLUSIONS: Implementing oprL and gyrB/ecfX qPCR in the management of patients with CF allowed earlier detection of first P. aeruginosa lung positivity than culture alone.

Retrospective clinical comparison of Celsior solution to modified blood Wallwork solution in lung transplantation for cystic fibrosis.

OBJECTIVE: To compare the preservative effects of Celsior solution and modified blood Wallwork solution in lung transplantation. METHODS: From 1989 to 2000, 44 lung transplantations for cystic fibrosis were performed: 26 grafts were preserved with modified blood Wallwork solution and 18 with Celsior solution. RESULTS: Preoperative status of the 2 groups was similar. The ratio of arterial oxygen to fraction of inspired oxygen and the pulmonary vascular resistance on the first postoperative day did not differ significantly between the 2 groups. Early death was 4% (SD, 20%) in the Wallwork group versus 11% (SD, 32%) in the Celsior group (not significant). No death was related to graft failure. The forced expiratory volume in 1 second during the first month after transplantation was 63% (SD, 19%) in the Wallwork group versus 63% (SD, 16%) in the Celsior group (not significant). CONCLUSION: Because the solution does not need to be prepared on site and does not require blood from the donor, Celsior seems better than Wallwork solution for preserving lung grafts.

[Heart-lung transplantation and cystic fibrosis. Indications and results]. / Transplantation cardiopulmonaire et mucoviscidose. Indications et résultats.

BACKGROUND: Heart lung transplantation for++ cystic fibrosis is now performed in patients with severe lung disease but the experience is still scarce with the exception of some specialized centers. PATIENTS AND METHODS: Twenty-one patients underwent heart-lung transplantation between September 1989 and November 1994 in our institution, with a high standard of reliability in tracheal anastomosis and with a low incidence of hospital mortality (5%). RESULTS: The actuarial patient survival is 90.2% (95% confidence interval, 70 to 97%) at 1 year and 75.7% (95% confidence interval, 51 to 90%) at 3 and 4 years. The mean forced expiratory volume in 1 second (FEV1) increases from 20.1% predicted preoperatively to 76.1%. CONCLUSION: Despite the presence of airway pathogens, these results confirm that heart-lung transplantation for cystic fibrosis leads to a pronounced improvement in lung function and good rehabilitation after surgery. The two main obstacles are the shortage of donor organs and the possibility of late deterioration in lung function with a progressive airflow obstruction.

[Lung transplantation in cystic fibrosis in adults. Patient selection criteria]. / Transplantation pulmonaire dans la mucoviscidose de l'adulte. Recommandations pour la sélection des candidats.

Lung transplantation (LT) became during the ten past years an important therapeutic option for cystic fibrosis adult patients with end-stage chronic lung disease. LT clearly improves both survival and long term quality of life. A rigorous selection of the candidates is of paramount importance to improve the results of LT because of the lack of shortage of organs. This selection requires a multidisciplinary assessment to refuse patients with absolute exclusion criteria or general medical conditions that impact negatively on short- and long-term outcome. One of the major difficulties is to determine the best time to refer patients to transplantation, arguing the comparison between the predicted survival time of the candidate, under optimal medical therapy, with or without LT. The selection period is also an active process to prepare the patients to the postoperative follow-up and includes a nutritional and rehabilitation program with an educational and psychological preparation. The aim of the present work is to gather the worldwide principles of the selection of the CF patients for LT, commonly used by the LT centers. These recommendations should provide the CF center practitioners with the main elements to prepare their patients to an LT project before a relentless end-stage clinical condition.

[Mucoviscidosis: lung transplantation is always in order]. / Mucoviscidose: la transplantation pulmonaire toujours d'actualité.

THE ONLY SOLUTION: Despite significant progress in the management of patients with multiple sclerosis, lung transplantation remains the only chance for survival in those with severe respiratory failure. WAITING LIST INCLUSION CRITERIA: Lung function tests, the patientís general states and psychological and familial factors all contribute to determining inscription on lung transplantation waiting lists. TECHNICAL ASPECTS: Heart-lung, monoblock two-lung and sequential two-lung transplantations are detailed according to the respective advantages and disadvantages. RESULTS: Hospital mortality is about 5% and 5-year survival about 50%. However, only 10% of the patients on waiting lists due to the lack of organs survive for 2 years. PERSPECTIVES: The number of grafts must be increased by developing lobular grafts from live donors using the bipartition technique. Nevertheless, xenografts remain the most promising perspective for increasing the number of patients who can benefit from this therapy.

[Invasive nosocomial pulmonary aspergillosis]. / Aspergilloses pulmonaires invasives d'origine nosocomiale.

Immunodepressed patients, particularly those with neutropenia or bone marrow or organ grafts, are at risk of developing nosocomial invasive pulmonary aspergilosis. The favoring factors, early diagnostic criteria and curative treatment protocols are well known. Prognosis remains however quite severe with a death rate above 50%. Preventive measures are required for the treatment of these high-risk patients and epidemiology surveillance is needed in case of aspergillosis acquired in the hospital.

[Association of sarcoidosis and autoimmune thyroiditis]. / Association sarcoïdose et thyroïdite auto-immune.

The thyroid gland involvement in sarcoidosis is rare but not exceptional. Usually there is little or no clinical expression although hyperthyroidism may be present. The granulomatous infiltration of the thyroid gland cannot be responsible for all the abnormalities observed. In certain cases, there is undoubtedly an autoimmune disease. We report a case of concomitant discovery of sarcoidosis and Hashimoto's thyroiditis. Despite their relative frequency, there could be a relationship between these two pathologies, especially in light of their similar pathophysiology.

[Pulmonary and cardiopulmonary transplantation in mucoviscidosis]. / Transplantation pulmonaire et cardiopulmonaire au cours de la mucoviscidose.

As early as 1987, several teams in France began lung transplantation for patients with cystic fibrosis. Most of these teams propose transplantation when the life expectancy is under 2 years. The major functional criteria are VEMS < 30%, PaC02 > 50 mmHg and PaO2 < 55 mmHg. This contribution focuses on psychologic, nutritional and infectious aspects required in preparing the patients for transplantation and on graft selection. Surgical techniques and patient care after transplantation are also reported. The overall probability of survival after transplantation for cystic fibrosis is 48, 35 and 29% at 1, 2 and 3 years respectively with wide intercentre variation. The lack of sufficient graft supply and the risk of post-transplantation degradation remain the two principal problems for transplantation in cystic fibrosis.

Familial extensive idiopathic bilateral pleural fibrosis.

The authors report three sisters with bilateral isolated apical pleural fibrosis of unknown origin, which did not respond to empirical antituberculosis therapy and oral corticosteroids. The disease evolved in an unrelenting fashion producing pleural fibrosis at the lung bases and leading to the death of two sisters and to lung transplantation in the other one. There was no history of other familial disease or consanguinity. The particular features of these cases and the differences from other reports of apparently cryptogenic pleural fibrosis are outlined.