Implementation of Model-Based Dose Adjustment of Tobramycin in Adult Patients with Cystic Fibrosis.

Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with CF. We analyzed data from adult patients with CF who received IV tobramycin and had model-guided TDM during the first year of implementation of MIPD. The predictive performance of a pharmacokinetic (PK) model was assessed. Observed maximal (Cmax) and minimal (Cmin) concentrations after initial dosing were compared with target values. We compared the initial doses and adjusted doses after model-based TDM, as well as renal function at the beginning and end of therapy. A total of 78 tobramycin courses were administered in 61 patients. After initial dosing set by physicians (mean, 9.2 ± 1.4 mg/kg), 68.8% of patients did not achieve the target Cmax ≥ 30 mg/L. The PK model fit the data very well, with a median absolute percentage error of 4.9%. MIPD was associated with a significant increase in tobramycin doses (p < 0.001) without significant change in renal function. Model-based dose suggestions were wellaccepted by the physicians and the expected target attainment for Cmax was 83%. To conclude, the implementation of MIPD was effective in changing prescribing practice and was not associated with nephrotoxic events in adult patients with CF.

Iron Deficiency in Cystic Fibrosis: A Cross-Sectional Single-Centre Study in a Referral Adult Centre.

Iron deficiency (ID) diagnosis in cystic fibrosis (CF) is challenging because of frequent systemic inflammation. We aimed to determine the prevalence and risk factors of ID in adult patients with CF. We conducted a single-centre prospective study in a referral centre. ID was defined by transferrin saturation ≤16% or ferritin ≤20 (women) or 30 (men) µg/L, or ≤100 µg/L in the case of systemic inflammation. Apparent exacerbation was an exclusion criterion. We included 165 patients (78 women), mean age­31.1 ± 8.9 years. ID prevalence was 44.2%. ID was significantly associated with female gender (58.9% vs. 38%), lower age (29.4 ± 8.5 vs. 32.5 ± 9.1), lower body mass index (20.5 ± 2.2 vs. 21.3 ± 2.5), and Pseudomonas aeruginosa colonization (70.8% vs. 55.1%). Diabetes mellitus, antiacid drug use and low pulmonary function were more frequent in patients with ID with no statistical significance. The use of CFTR correctors was not associated with ID. In the multivariate analysis, ID was associated with female gender (OR 2.64, CI95% 1.31−5.31), age < 30 years (OR 2.30, CI95% 1.16−4.56), and P. aeruginosa (OR 2.09, CI95% 1.04−4.19).

A formalized transition program for cystic fibrosis: A 10-year retrospective analysis of 97 patients in Lyon.

INTRODUCTION: The prognosis of people diagnosed with cystic fibrosis (CF) has dramatically improved over the past decade in France, largely due to advances in CF care management, including an emphasis on chronic maintenance medications. Currently, the majority of French CF patients are adults, which means that they went through a transition process from receiving care at a pediatric CF center to receiving care at an adult CF center. To determine the impact of the transfer on clinical evolution, we report the transition procedure of our CF center in Lyon. MATERIALS AND METHODS: From January 2006 to December 2016, 97 CF patients underwent a standardized process of transitioning from the pediatric to the adult CF center in Lyon. We compared the clinical evolution of these patients during three periods, starting the year before transition and ending the year after transition. Clinical data taken into account were forced expiratory volume in 1 s (FEV1 in liters), body mass index (BMI in kg/m2 ), pulmonary colonization, number of antibiotic courses, number of days of hospitalization per year, and outpatient visits per year. RESULTS: No significant differences were observed between respiratory and nutritional status, respiratory microbiome, number of antibiotic courses, or number of hospitalizations or visits when comparing the threeperiods of observation around transition (the year before, the first year after, and the second year after transfer). CONCLUSION: The standardized transition procedure used in Lyon is associated with the clinical stability of our CF patients.

Inflammation of Unknown Origin: Evaluation and Prognosis of 57 Cases.

(1) Background: there are few studies on the inflammation of unknown origin (IUO). We sought to determine the etiologies and prognosis of IUO, as well as the contribution of complementary examinations. (2) Methods: this retrospective study analyzed patients meeting the Vanderschueren's criteria in the Hospices Civils de Lyon from 2005 to 2020. (3) Results: a total of 57 patients (mean age: 67 years; interquartile range: 55-79) were included. Final diagnoses were made for 26 (46%) patients. Non-infectious inflammatory diseases were the most common diagnoses (13/26, 50%), followed by neoplasms (10/26, 38%; 8/10 hematological malignancies), infections (2/26, 8%), and miscellaneous causes (1/26, 4%). Moreover, 18-FDG-PET/CT was contributory in 12/42 cases. Anti-neutrophil cytoplasmic antibodies, serology, temporal biopsies, and bone marrow aspirates were contributory in 3/41, 1/57, 5/23, and 3/19 cases, respectively. At last follow-up (mean follow-up duration: 48 months), 8/31 undiagnosed patients were cured (five received an empirical treatment), and 5/31 died (one death was related to the empirical treatment). (4) Conclusion: more than half of the IUO remained undiagnosed. Non-infectious inflammatory diseases and hematological malignancies were the most common etiologies. Moreover, 18-FDG-PET/CT had the highest diagnostic value. Most IUO without final diagnosis persisted. The role of empirical treatments remains to be explored.

Risk factors for nontuberculous mycobacterial isolation in patients with cystic fibrosis: A meta-analysis.

BACKGROUND: To better understand the mechanisms of infection with nontuberculous mycobacteria (NTM) in patients with cystic fibrosis (CF), we explore different risk factors associated with NTM positivity in a meta-analysis. METHODS: Studies published before 31 July 2019 were selected from MEDLINE. Combined odds ratios (ORs) were calculated by pooling the ORs of each study. The weighted mean difference (WMD) was used for continuous numerical measurements. Summary data were pooled using fixed- or random-effects models according to the presence of heterogeneity (P < .1 or I2 > 50%). RESULTS: Nineteen studies with a total of 23 418 patients, of whom 1421 (6%) were diagnosed as NTM positive, were included. Older age was significantly associated with NTM positivity (WMD = 2.12, 95% confidence interval [CI]: 1.11-3.13; P < .01, fixed-effects model). The OR for Staphylococcus aureus colonization was 1.66 (95% CI: 1.21-2.26; P = .001) in 11 studies (8091 patients), the OR for Aspergillus fumigatus colonization was 3.59 (95% CI: 3.05-4.23; P < .001) in 11 studies (20 480 patients), and the OR for Stenotrophomonas maltophilia colonization was 3.41 (95% CI: 2.66-4.39; P < .01) in seven studies (14 935 patients). Oral corticosteroids were significantly associated with NTM positivity (OR = 1.98, 95% CI: 1.24-3.16; P < .01, 6 studies, 1936 patients). No other factor showed a significant association. CONCLUSION: Older age, S. aureus, S. maltophilia, and A. fumigatus chronic colonization, and oral corticosteroids were significantly associated with an increased risk of NTM positivity. CF patients with more severe conditions should be closely monitored for NTM.

Pregnancy outcome in women with cystic fibrosis and poor pulmonary function.

BACKGROUND: To investigate how poor pre-gestational pulmonary function influenced pregnancy outcome and clinical status evolution in women with cystic fibrosis. METHODS: Pregnancies in women without lung transplantation with a first delivery reported to the French cystic fibrosis registry between 2000 and 2012 were identified. Pregnancy outcomes and clinical trends (body mass index - BMI, and pulmonary function) over a 4-year follow-up in women with poor pre-gestational pulmonary function, defined as forced expiratory volume (FEV1) ≤ 50%, were compared to those in women with FEV1 ˃ 50%. RESULTS: A total of 149 women had a first delivery and 36 (24.2%) of these had pre-gestational FEV1 ≤ 50%. There was no significant difference in age or frequency of assisted conception between the 2 groups. The rate of cesarean section was significantly higher in women with FEV1 ≤ 50% (43.7% vs. 21.1%, p = .01). The frequency of preterm birth did not differ significantly between the two groups, but median infant birthweight was significantly lower in women with FEV1 ≤ 50% (2705 g; range: 650-3700 vs. 3044 g; range: 1590-3860, p = .003). Despite significantly lower FEV1 and BMI the year before pregnancy for women with poor pulmonary function, the decline in these parameters during the study period did not differ significantly between the two groups. CONCLUSION: Poor pre-gestational pulmonary function in women with cystic fibrosis was associated with a higher rate of cesarean section and a clinically significant impact on fetal growth, but was not associated with more important pulmonary and nutritional decline over the study period.

The diagnosis of hypersensitivity to antibiotics is rarely confirmed by allergy work-up in cystic fibrosis patients.

Cystic fibrosis (CF) patients receive many antibiotic treatments for recurrent respiratory infections and frequently report antibiotic hypersensitivity reactions (HSRs). In this retrospective study, medical records of CF patients were reviewed to clarify the clinical features, the culprit antibiotics, and the prevalence of antibiotic HSRs in the CF population. From 601 CF patients, 95 suspected antibiotic HSRs occurred in 60 patients (prevalence of 10.0%). ß-Lactams were the most common inducers, but cotrimoxazole was also frequently involved. Seventy-six of 95 suspected HSRs were assessed by allergy workup including skin tests (43/76 reactions) and/or drug reintroduction as a full course of the culprit antibiotic (73 of 76 reactions). From the 43 suspected HSRs that were skin-tested, only three had positive skin tests and were not subjected to drug readministration. All the other 73 suspected HSRs received a full course of the culprit antibiotic: HSR symptoms recurred in 10 of 73 cases and therefore were considered as confirmed antibiotic HSRs; for the remaining 63 suspected HSRs that did not relapse after drug readministration, the diagnosis of antibiotic HSRs was excluded. In summary, 13 of 76 suspected HSRs were confirmed as antibiotic HSRs. The prevalence of suspected and confirmed antibiotic HSRs in CF patients appears similar to that reported in the general population. Of note, most of the antibiotic suspected HSRs are not confirmed after allergology workup. A complete allergy workup appears therefore crucial to make a correct diagnosis and to avoid unnecessary contraindication of major antibiotics.

Cystic fibrosis-related diabetes before lung transplantation is associated with lower survival but does not affect long-term renal function.

OBJECTIVE: To describe the prevalence of cystic fibrosis-related diabetes (CFRD) before and after lung transplantation (LT); to analyse the survival and renal function after LT according to the CFRD status before LT. METHODS: Sixty cystic fibrosis (CF) patients transplanted at the Lyon University Hospital between 2004 and 2014 were included. Genotype, pancreatic status, age at LT, survival were recorded. Glucose tolerance status, daily insulin dose requirement, glomerular filtration rate (GFR), and daily glucocorticoid (GC) dose were recorded before LT and until December 2016. RESULTS: The median follow-up was 5.6 (3.8-8.2) years, and nine patients died. Survival was poorest for patients with CFRD before LT compared with those without CFRD (P = 0.03) but was not correlated with the GFR before LT, with sex, age at LT, or CF genotype. The prevalence of CFRD was 68% at 2 years and 54% at 5 years. For persistent insulin-treated CFRD, the insulin requirement decreased (-2.1 IU/d/y; P < 0.01) and was correlated with the daily GC dose (+0.4 IU/d for one additional milligram, P = 0.012). Seven (11%) patients who had insulin-treated CFRD before LT became nondiabetic after LT, with a median time of 2 (1-4) years. After LT, the GFR decreased (-5.3 ml/min/1.73 m 2 /y; P < 0.001) and was not correlated with the CFRD status before LT. CONCLUSIONS: CFRD before LT is associated with poor survival after LT, which should lead to better management of diabetes. Some patients with pre-LT CFRD became nondiabetic after LT. CFRD is not associated with renal insufficiency after LT.

Aminoglycoside exposure and renal function before lung transplantation in adult cystic fibrosis patients.

Background: Patients with cystic fibrosis (CF) are at risk of kidney injury even before undergoing lung transplantation, because of prolonged exposure to aminoglycosides (AGs), chronic dehydration and complications of diabetes mellitus. The usual equations estimating the glomerular filtration rate (GFR), such as Cockcroft-Gault and Modification of Diet in Renal Disease, are not adapted to the CF population due to patients' low body weight and reduced muscle mass. The aim of this study was to precisely measure GFR in adult CF patients and to see whether repeated AG treatment would impair renal function before lung transplantation. Methods: Inulin or iohexol clearances were performed in 25 adult CF patients when they entered the lung transplant waiting list. No patient was treated with AGs at the time of GFR measurement. Body mass index (BMI), history of diabetes mellitus and blood pressure were recorded. Exposure to intravenous (IV) AGs within 5 years prior to the GFR measurement was obtained from the patient's medical files. Urine samples were collected to check for albuminuria and proteinuria. Results: The population was predominantly female (67%). The mean age was 32 years, the mean BMI was 19 kg/m2 and 28% had CF-related diabetes. Median exposure to IV AG within 5 years before GFR measurement was 155 days with a mean dosage of 7.7mg/kg/day. The mean measured GFR was 106 mL/min/1.73 m2 and the mean estimated GFR according to the Chronic Kidney Disease Epidemiology Collaboration formula was 124 mL/min/1.73 m2. Conclusion: Despite prolonged exposure to high-dose IV AG, no decline in GFR was observed in these patients.

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.

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.

Rare and unusual presentation of Cladophialophora infection in a pulmonary transplant cystic fibrosis patient.

A 35-year-old woman with severe cystic fibrosis was admitted for sudden loss of strength in both legs, revealing a myelitis. The medullary lesion biopsy revealed phaeohyphomycosis caused by Cladophialophora species. Myelitis caused by Cladophialophora bantiana is a rare disease associated with high mortality.

Elevated IgG4 serum levels in patients with cystic fibrosis.

OBJECTIVE: Serum immunoglobulin (Ig) G4 elevation has been associated with several pathological conditions other than IgG4-related disease (IgG4-RD). In cystic fibrosis (CF), an elevation of specific IgG4 has been associated with colonization and infection by Pseudomonas aeruginosa. IgG4 elevation may be a marker of chronic infection or inflammatory stimulation. The aim of this study was to explore the prevalence of elevated IgG4 levels in CF and its correlation with the major clinical and microbiological features found in CF patients. METHODS: In a cross-sectional study, we analyzed data from a large cohort of adult CF patients attending the CF center of Lyon University Hospital. An elevated IgG4 level was defined as being above the cut-off value of 135 mg/dL. RESULTS: One hundred and sixty-five CF patients were analyzed. An IgG4 elevation was detected in 43 patients (26%). Compared with the control group (≤ 135 mg/dL), high IgG4 patients exhibited a greater prevalence of Staphylococcus aureus colonization and higher IgG, IgG1, IgG2 and IgE levels. No significant differences were observed in terms of pulmonary function, colonization with Pseudomonas aeruginosa, or the annual rate of bronchial exacerbations. CONCLUSION: An elevated IgG4 serum level was frequently detected in adult CF patients and did not appear to be associated with poor lung function. We suggest that IgG4 elevation is a marker of the activation of tolerance. Its clinical significance remains to be demonstrated.

Neutropenia in Patients with Common Variable Immunodeficiency: a Rare Event Associated with Severe Outcome.

BACKGROUND: Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID. METHODS: The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed. RESULTS: Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0-1400]*106/L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P < 0.05). Neutropenia was diagnosed for 10 patients before 22 years old. The most frequent symptoms, except infections, were autoimmune cytopenia, i.e., thrombopenia or anemia (11/16). Ten patients were affected with lymphoproliferative diseases. Two patients were in the infection only group and the others belonged to one or several other CVID groups. The median level of IgG was 2.6 g/L [0.35-4.4]. Most patients presented increased numbers of CD21low CD38low B cell, as already described in CVID autoimmune cytopenia group. Neutropenia was considered autoimmune in 11 cases. NGS for 52 genes of interest was performed on 8 patients. No deleterious mutations were found in LRBA, CTLA4, and PIK3. More than one potentially damaging variant in other genes associated with CVID were present in most patients arguing for a multigene process. CONCLUSION: Neutropenia is generally associated with another cytopenia and presumably of autoimmune origin during CVID. In the DEFI study, neutropenia is coupled with more severe clinical outcomes. It appears as an "alarm bell" considering patients' presentation and the high rate of deaths. Whole exome sequencing diagnosis should improve management.

Pregnancy outcome in women with cystic fibrosis-related diabetes.

INTRODUCTION: With increasing life expectancy, more women with cystic fibrosis and diabetes mellitus become pregnant. We investigated how pre-gestational diabetes (cystic fibrosis-related diabetes) influenced pregnancy outcome and the clinical status of these women. MATERIAL AND METHODS: We analyzed all pregnancies reported to the French cystic fibrosis registry between 2001 and 2012, and compared forced expiratory volume (FEV1 ) and body mass index before and after pregnancy in women with and without pre-gestational diabetes having a first delivery. RESULTS: A total 249 women delivered 314 infants. Among these, 189 women had a first delivery and 29 of these had pre-gestational diabetes. There was a trend towards a higher rate of assisted conception among diabetic women (53.8%) than non-diabetic women (34.5%, p = 0.06), and the rate of cesarean section was significantly higher in diabetic women (48% vs. 21.4%, p = 0.005). The rate of preterm birth and mean infant birthweight did not differ significantly between diabetic and non-diabetic women. Forced expiratory volume before pregnancy was significantly lower in the diabetic group. The decline in forced expiratory volume and body mass index following pregnancy did not differ between the women with and those without pre-gestational diabetes. CONCLUSION: Pre-gestational diabetes in women with cystic fibrosis is associated with a higher rate of cesarean section but does not seem to have a clinically significant impact on fetal growth or preterm delivery. The changes in maternal pulmonary and nutritional status following pregnancy in women with cystic fibrosis were not influenced by pre-gestational diabetes.

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.

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. © 2016 Wiley Periodicals, Inc.

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.