R. Nove-Josserand

Late-Onset Combined Immune Deficiency: A Subset of Common Variable Immunodeficiency with Severe T Cell Defect

BACKGROUND Common variable immunodeficiency (CVID) is a primary immune deficiency defined by defective antibody production. In most series, a small proportion of patients present with opportunistic infections (OIs). METHODS The French DEFI study has enrolled patients with primary hypogammaglobulinemia and allows a detailed clinical and immunologic description of patients with previous OIs and/or at risk for OIs. RESULTS Among 313 patients with CVID, 28 patients (8.9%) presented with late-onset combined immune deficiency (LOCID), defined by the occurrence of an OI and/or a CD4(+) T cell count <200 x 10(6) cells/L, and were compared with the remaining 285 patients with CVID. The patients with LOCID more frequently belonged to consanguineous families (29% vs 8%; P = .004). They differed from patients with CVID with a higher prevalence of splenomegaly (64% vs 31%), granuloma (43% vs 10%), gastrointestinal disease (75% vs 42%), and lymphoma (29% vs 4%). Even on immunoglobulin substitution, they required more frequent antibiotics administration and hospitalization. Lymphocyte counts were lower, with a marked decrease in CD4(+) T cell counts (158 x 10(6) vs 604 x 10(6) cells/L; P < .001) and a severe defect in naive CD45RA(+)CCR7(+)CD4(+) T cell counts (<20% of total CD4(+) T cells in 71% of patients with LOCID vs 37% of patients with CVID; P = .001). The CD19(+) B cell compartment was also significantly decreased (20 x 10(6) vs 102 x 10(6) cells/L; P < .001). CONCLUSIONS LOCID differs from classic CVID in its clinical and immunologic characteristics. Systematic T cell phenotype may help to discriminate such patients from those with CVID. Identification of this phenotype should result in a more fitted diagnostic and therapeutic approach of infections and could provide insights for genetic diagnosis.

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.

Effectiveness of home treatment for patients with cystic fibrosis: The intravenous administration of antibiotics to treat respiratory infections†

Patients with cystic fibrosis (CF) experience repeated infectious respiratory exacerbations leading to a continuous decline in lung function. The exacerbations are treated in hospital or at home. Our aim was to compare the clinical outcome for patients undergoing intravenous antibiotic treatment either in hospital or at home. A retrospective 10‐year study was performed in four regional CF Centers. The outcome measures were percentage changes in forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC) and weight for age z‐score (WZS). FEV1, FVC, and WZS changes were calculated for the entire study period and for each course. A total of 1,164 courses were analyzed. For each course, the mean improvement in FEV1 and FVC was significantly higher when performed in hospital than when performed at home (P < 0.05). FEV1 and FVC values were 10.2%, 9.5% respectively in the hospital group and 7.3%, 6.8% in the home group. A total of 153 patients were analyzed (51 inpatients matched to 102 patients treated at home). The two groups had no significant differences in any outcome variable at baseline. The mean variation per year in FEV1 was greater in the hospital group versus the home group (−0.4% vs. −1.8%; P = 0.03). The mean variation per year in WZS was greater in the hospital group versus the home group (P < 0.01). Clinical outcome, as defined by spirometric parameters and body weight, was better after a course of treatment in hospital than after a home treatment. This benefit was maintained throughout of the study period. Pediatr Pulmonol. 2008; 43:908–915.

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.

Case series of omalizumab for allergic bronchopulmonary aspergillosis in cystic fibrosis patients

Allergic bronchopulmonary aspergillosis (ABPA) affects up to 15% of patients with cystic fibrosis (CF). Corticosteroids are used as first‐line therapy, but relapse and adverse effects commonly occur. Case reports have suggested the efficacy of the anti‐IgE recombinant humanized monoclonal antibody omalizumab. A retrospective multicenter observational French study retrieved 32 CF patients (11 children and 21 adults) who have received omalizumab for more than 3 months in the context of ABPA. Clinical characteristics, concomitant medications (inhaled and oral corticosteroids, antifungal drugs), lung function, body mass index (BMI), and serum IgE were compared at the start and during the first year of omalizumab therapy. Omalizumab‐related adverse effects and costs were also evaluated. No significant difference with omalizumab could be demonstrated with regard to lung function, BMI, or the number of patients receiving oral corticosteroids. At the time of initiation of omalizumab, 56% of patients were receiving oral corticosteroids. Five patients were able to discontinue corticosteroids during follow‐up and nine patients were able to reduce their daily dose. A total of 78% of the patients had received antifungal therapy at the time of the initiation of omalizumab. Treatment tolerance was good (12.5% of patients experienced side effects). The median cost of omalizumab treatment was €3,620 per patient per month. Omalizumab may represent a steroid‐sparing therapy in CF patients with ABPA. A randomized‐controlled trial is urgently required to provide higher level of evidence regarding the efficacy and cost‐effectiveness of omalizumab in CF patients with ABPA. Pediatr Pulmonol. 2017;52:190–197.

Outcome of Cystic Fibrosis-Related Diabetes Two Years after Lung Transplantation

Background: Although transplantation is known to impair glucose tolerance, evolution of pre-existing diabetes after lung transplantation (LT) in cystic fibrosis (CF) has never been described. Objectives: We aimed to assess the outcome of CF-related diabetes (CFRD) after LT, with the hypothesis that suppressing chronic inflammatory foci may improve glucose tolerance in some patients. Methods: In a retrospective study of 29 CF diabetic patients treated with insulin and undergoing LT, CFRD control was assessed 3 months before LT and 1 (n = 27) and 2 (n = 18) years after LT by measuring insulin dosage, fasting blood glucose and glycosylated hemoglobin (HbA1c) levels. Patients with HbA1c ≤7% and an insulin dose ≤1 UI/kg/day were defined as having controlled CFRD (group A). Other patients were assigned to group B. Results: Before LT, 19 (65.5%) patients were in group A. At 2 years, 6 of 10 (60%) patients who were in group B prior to LT had moved into group A, which then comprised 77.8% of all patients. Insulin could have been stopped in 5 patients. Uncontrolled CFRD before LT (OR = 16) and a long delay between the diagnosis of CFRD and LT (OR = 1.3) were significant predictors of uncontrolled CFRD at 1 year. Conclusions: LT does not seem to worsen CFRD in some patients, suggesting that in some cases, glucose tolerance may be improved by the suppression of chronic pulmonary infection.

Contraceptive practices and cervical screening in women with cystic fibrosis

STUDY QUESTION Is gynaecological management of women with cystic fibrosis (CF) adequate? SUMMARY ANSWER Gynaecological care (frequency of follow-up, cervical screening and contraceptive use among sexually active women) in women with CF fails to reach the recommended level. WHAT IS KNOWN ALREADY Little is known about gynaecological follow-up and cervical screening in CF. Only few studies have described contraceptive practices in cohorts of CF women. STUDY DESIGN, SIZE, DURATION We did a cross-sectional study in a cohort of 155 CF women attending the Lyon adult centre. Women attending the CF adult centre in 2014 completed a written questionnaire about their contraceptive choices, frequency of gynaecological follow-up and cervical screening. Other clinical data were collected from the CF adult centre registry. PARTICIPANTS/MATERIALS, SETTING, METHODS One hundred and twenty women (100%) answered the questionnaire, among whom two were post-menopausal (46 and 59 years of age), and five were pregnant. MAIN RESULTS AND THE ROLE OF CHANCE Seventy-four per cent of the women declared they had undergone gynaecological follow-up (89% of the women with transplantation), and only 55% reported having at least one previous Pap smear test. Among the transplanted patients, only 58% had had a Pap smear test, despite immunosuppressive treatment. The overall rate of contraception was only 64% and in diabetic women, it was 61%. Among contraception users; 65% used oral contraception, predominantly combined estrogen-progestagen (47%); among diabetic patients, 26% used progestin-only contraception. Intrauterine device accounted for 10% of patients using contraception, and tubal ligation only 4%. LIMITATIONS, REASONS FOR CAUTION This study is limited by its cross-sectional design. Despite an internal validation of the questionnaire showing an almost perfect agreement, the risk of recall bias has to be taken into account. WIDER IMPLICATIONS OF THE FINDINGS This study of practices highlights the importance of improved information regarding sexuality, fertility and reproductive health in young women with CF. A regular gynaecological follow-up and cervical screening is mandatory in this population. Better gynaecological care and contraceptive advice would help to avoid unplanned pregnancies, and optimize contraceptive selection in relationship to specific clinical conditions.

High incidence of non-tuberculous mycobacteria-positive cultures among adolescent with cystic fibrosis

BACKGROUND We evaluated the prevalence of non-tuberculous mycobacteria (NTM)-positive cultures among our cystic fibrosis (CF) center patients, reviewed risk factors for NTM positivity, and determined its impact on lung function evolution. METHODS From 2009 to 2014, CF adults and children attending the CF center of Lyon (France) and having at least one positive NTM isolate were included. Each case was matched by age and gender with two CF patients with no NTM isolate (controls). RESULTS 48 CF patients with NTM-positive isolates were matched to 96 controls. The age group for whom incident NTM was higher was young adolescents aged 13 to 17. A significant association for NTM positivity was found with Staphylococcusaureus in multivariate analysis and with allergic bronchopulmonary aspergillosis, corticosteroid and itraconazole in univariate analysis. Mean annual FEV1 decline was faster for NTM-positive patients compared to controls. CONCLUSION These data highlight the high incidence of NTM-positive cultures among young adolescents with CF.

Glucose trajectories in cystic fibrosis and their association with pulmonary function

BACKGROUND The prevalence of cystic fibrosis-related diabetes is increasing. This condition is potentially responsible for respiratory decline. METHODS At inclusion, then yearly (over three years), 111 children and 117 adults with cystic fibrosis had oral glucose tolerance and insulin tests at one (G1) and 2h (G2). KmL analysis identified homogeneous G1 and G2 glucose trajectories. A linear mixed model quantified the relationships between trajectories and FEV1 changes. RESULTS In children, there were three G1 and four G2 trajectories and FEV1 decrease was not significantly different between G1 or G2 trajectories. In adults, two G1 and four G2 trajectories were identified and FEV1 change was estimated at -0.85/year (95% CI: [-1.54; -0.17], p=0.01) whatever the G1 trajectory and found significantly faster in the high and increasing G2 trajectory (-2.1/year, [-3.9; -0.2], p=0.03). CONCLUSIONS In case of persistent G2 abnormality, physicians should be alert for clinical deterioration and intensify patient surveillance.

Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin-receptor agonists

Objectives The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP. Methods This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. Results We included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs. Conclusion Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy.