The expanded French compassionate programme for elexacaftor-tezacaftor-ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response. METHODS: The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France's 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses. FINDINGS: The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV1 (ppFEV1) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV1 was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor. INTERPRETATION: In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population. FUNDING: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.

Intimacy and sexual life of females with cystic fibrosis.

INTRODUCTION: The effects of cystic fibrosis (CF) on females' sexuality have not been described. The aims of the present study were to describe and characterize sexual issues in females with CF. METHODS: We included adult (≥18 years) females with CF currently or previously in a sexual relationship from 11 adult CF centres in France. We collected quantitative data using a modified version of the self-administered Pelvic Incontinence Sexual Questionnaire IUGA-Revised (PISQ-IR). We performed one-to-one interviews using a semi-directive framework in volunteer females to further characterize the effects of CF on sexual life. We summarized answers to questionnaire as percentages and analysed interviews by theme according to discourse analysis method. RESULTS: Between November 2019 and July 2021, 212 females completed the PISQR-IR, of whom 15 were interviewed. Of the females who completed the questionnaire, 93.4% were concerned about the discomfort, pain, or unpleasantness they experienced during sexual intercourse. The most frequent cause of sexual difficulties was a lack of vaginal lubrication (78.8%), followed by pain (74.1%) and discomfort. Interviews revealed sexual lives that were uncomfortable or painful, unsatisfying or avoided for most females, with a strong impression of being sexually different, incompetent, and betrayed by their bodies in terms of sexual desire. CONCLUSION: Sexual difficulties faced by females with CF are highly prevalent. Increasing awareness regarding sex life issues in females with CF appears necessary to improve their management by CF multidisciplinary teams.

Detection of Specific IgE against Molds Involved in Allergic Bronchopulmonary Mycoses in Patients with Cystic Fibrosis.

CONTEXT: Allergic bronchopulmonary mycoses (ABPM) can be due to molds other than Aspergillus fumigatus in patients with cystic fibrosis (pwCF). We aimed to develop immunoassays for the detection of specific IgE (sIgE) directed against five fungal species involved in ABPM: Aspergillus terreus, Scedosporium apiospermum, Lomentospora prolificans, Rasamsonia argillacea, and Exophiala dermatitidis. MATERIALS AND METHODS: Serum samples (n = 356) from 238 pwCF, collected in eight CF care centers in France, Germany, and Italy, were analyzed by dissociated enhanced lanthanide fluorescent immunoassay (DELFIA®) to assess levels of sIgE directed against antigenic extracts of each fungus. Clinical, biological, and radiological data were collected for each episode. One hundred serum samples from healthy blood donors were used as controls. Sera were classified into four groups depending on the level of sIgE according to the quartile repartition calculated for the pwCF population. A score of 4 for values above the 3rd quartile corresponds to an elevated level of sIgE. RESULTS: PwCF showed higher levels of sIgE than controls. Based on criteria from the ABPA-ISHAM working group, with an additional criterion of "a sIgE score of 4 for at least one non-A. fumigatus mold", we were able to diagnose six cases of ABPM. CONCLUSIONS: Using 417 IU/mL as the threshold for total IgE and the same additional criterion, we identified seven additional pwCF with "putative ABPM". Detection of sIgE by DELFIA® showed good analytical performance and supports the role played by non-A. fumigatus molds in ABPM. However, commercially available kits usable in routine practice are needed to improve the diagnosis of ABPM.

Sexual dysfunction in cystic fibrosis.

BACKGROUND: Sexual dysfunction (erectile dysfunction in males, sexual dissatisfaction, sexual interest/arousal disorders, and dyspareunia in females) has not been the subject of indepth research in people with cystic fibrosis (CF). This study aimed to determine the prevalence of sexual dysfunction in adults with CF, factors associated with sexual dysfunction, and the impact of sexual dysfunction on quality of life. METHOD: We conducted a multicentre study in adults with cystic fibrosis followed in specialist centres in Western France. We assessed erectile dysfunction and its severity using the IIEF5 self-questionnaire (International Index of Erectile Function); the FSFI (Female Sexual Function Index) was used to assess sexual function in females, and we evaluated quality of life in both sexes using the CFQ-R14+ questionnaire. RESULTS: In total, 77 males and 74 females completed the sexual function questionnaire (mean age 32+/- 10 and 25+/- 8,5 years respectively). Among them, 21 % of males and 30 % of females reported sexual dysfunction. CFQ-R14+ score was significantly lower in males with erectile dysfunction than those without (p < 0.001). Faecal incontinence was associated with more frequent sexual dysfunction in females and higher severity of erectile dysfunction in males. CONCLUSION: The prevalence of sexual disorders is relatively high in males and females with cystic fibrosis. Therefore, it seems important to train specialist teams to address the issue of sexuality without embarrassment, and to encourage them to seek out and treat faecal incontinence, which is associated with greater severity or frequency of these symptoms.

Multisystemic Effects of Elexacaftor-Tezacaftor-Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease.

Rationale: Limited data exist on the safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. Objectives: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. Methods: A prospective observational study, including all adults aged 18 years and older with percentage predicted forced expiratory volume in 1 second (ppFEV1) ⩽ 40 who initiated ETI from December 2019 to June 2021 in France, was conducted. PwCF were followed until August 8, 2022. Results: ETI was initiated in 434 pwCF with a median ppFEV1 of 30 (interquartile range, 25-35), including 27 with severe cystic fibrosis liver disease and 183 with diabetes. PwCF were followed for a median of 587 (interquartile range, 396-728) days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was due mostly to lung transplantation (n = 5) or death (n = 4). Absolute increase in ppFEV1 by a mean of +14.2% (95% confidence interval, 13.1-15.4%) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the youngest age quartile was almost twice that of the oldest quartile (P < 0.001); body mass index < 18.5 kg/m2 was found in 38.6% at initiation versus 11.3% at 12 months (P = 0.0001). Increases in serum concentrations of vitamins A and E, but not 25-hydroxy vitamin D3, were observed. Significant reductions in the percentages of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, and inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of patients with diabetes. Conclusions: ETI is safe in pwCF and advanced lung disease, with multisystem pulmonary and extrapulmonary benefits.

Physical activity promotion in French cystic fibrosis centers: capitalizing on experience.

BACKGROUND: Physical activity (PA) provides physical and psychosocial benefits for people with cystic fibrosis (pwCF). However, practice levels remain below recommendations and strategies for promoting PA in specialist centers need to be better identified. The socio-ecological model of health emphasizes the central role of policies and environment in influencing individuals' health behaviors. This model provides a basis for understanding how health professionals perceive the promotion of PA in their centers. OBJECTIVE: The aim of this study was to explore intervention components of PA promotion in specialized CF centers in France that are "experienced" in PA promotion, to identify elements that can be transferable to other centers. METHODS: A descriptive qualitative study was conducted with 16 healthcare professionals and pwCF. Semi-structured interviews were conducted and analyzed using inductive and deductive methods classically used in psychology. RESULTS: Five themes were extracted: the action and its context, the partnerships established around this action to promote physical activity, the evaluation of the action, its reproducibility, and the changes induced by COVID-19. CONCLUSIONS: Some factors emerged as essential for promoting PA among pwCF, notably the dialogue between the health professionals and patients, the presence of adapted PA instructors, and the involvement of partners.

Prevalence and severity of functional urinary and anorectal disorders and their impact on quality of life in cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), coughing is associated with a risk of pelvic floor dysfunction. However, data on the prevalence of symptoms (stress urinary incontinence, bladder overactivity, dysuria, and faecal incontinence) are lacking in males and females with CF. The impact of incontinence on adherence to respiratory care has not been studied. METHODS: We conducted a multicentre study in adults with CF followed in the North-West French CF network. Urinary disorders and their severity were assessed using the Urinary Symptom Profile (USP) self-report questionnaire; the impact of urinary disorders on general quality of life was measured using the SF-Qualiveen questionnaire; faecal incontinence was assessed using the Wexner self-report questionnaire; and the CFQ-R14+ questionnaire was used to assess quality of life. A self-administered questionnaire developed for the study assessed the impact of symptoms on respiratory care. RESULTS: Of the 178 people with CF included, 34 % reported stress urinary incontinence, with a large female predominance (63.5 % of females vs. 7.5 % of males), 65 % bladder overactivity (including 16 % urge incontinence) and 50 % faecal incontinence, also with a female predominance. Neither urinary nor faecal incontinence were related to the severity of the respiratory impairment (FEV1). Quality of life was particularly affected in women. Stress urinary Incontinence symptoms affected respiratory care in both sexes. CONCLUSION: The prevalence of functional urinary and faecal disorders was high in adults with CF and impacted on quality of life and respiratory care. Therefore, multidisciplinary teams must have knowledge of symptoms, the diagnostic tools and management strategies to provide specific treatment.

Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates. METHODS: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021. RESULTS: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV1) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation. CONCLUSION: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

In Vitro Activity of 22 Antibiotics against Achromobacter Isolates from People with Cystic Fibrosis. Are There New Therapeutic Options?

Bacteria belonging to the genus Achromobacter are increasingly isolated from respiratory samples of people with cystic fibrosis (PWCF). The management of this multidrug-resistant genus is challenging and characterised by a lack of international recommendations, therapeutic guidelines and data concerning antibiotic susceptibility, especially concerning the newer antibiotics. The objective of this study was to describe the antibiotic susceptibility of Achromobacter isolates from PWCF, including susceptibility to new antibiotics. The minimum inhibitory concentrations (MICs) of 22 antibiotics were determined for a panel of 23 Achromobacter isolates from 19 respiratory samples of PWCF. Two microdilution MIC plates were used: EUMDROXF® plate (Sensititre) and Micronaut-S Pseudomonas MIC® plate (Merlin) and completed by a third method if necessary (E-test® or UMIC®). Among usual antimicrobial agents, the most active was imipenem (70% susceptibility). Trimethoprim-sulfamethoxazole, piperacillin and tigecycline (65%, 56% and 52% susceptibility, respectively) were still useful for the treatment of Achromobacter infections. Among new therapeutic options, ß-lactams combined with a ß-lactamase-inhibitor did not bring benefits compared to ß-lactam alone. On the other hand, cefiderocol appeared as a promising therapeutic alternative for managing Achromobacter infections in PWCF. This study provides the first results on the susceptibility of clinical Achromobacter isolates concerning new antibiotics. More microbiological and clinical data are required to establish the optimal treatment of Achromobacter infections.

Apparent Yield Stress of Sputum as a Relevant Biomarker in Cystic Fibrosis.

The mucus obstructing the airways of Cystic Fibrosis (CF) patients is a yield stress fluid. Linear and non-linear rheological analyses of CF sputa can provide relevant biophysical markers, which could be used for the management of this disease. Sputa were collected from CF patients either without any induction or following an aerosol treatment with the recombinant human DNAse (rhDNAse, Pulmozyme®). Several sample preparations were considered and multiple measurements were performed in order to assess both the repeatability and the robustness of the rheological measurements. The linear and non-linear rheological properties of all CF sputa were characterized. While no correlation between oscillatory shear linear viscoelastic properties and clinical data was observed, the steady shear flow data showed that the apparent yield stress of sputum from CF patients previously treated with rhDNAse was approximately one decade lower than that of non-treated CF patients. Similar results were obtained with sputa from non-induced CF patients subjected ex vivo to a Pulmozyme® aerosol treatment. The results demonstrate that the apparent yield stress of patient sputa is a relevant predictive/prognostic biomarker in CF patients and could help in the development of new mucolytic agents.

Development and validation of the Cystic Fibrosis Decisional Balance for Physical Activity scale (CF-DB-PA).

BACKGROUND: People with cystic fibrosis (pwCF) derive several physiological and psychological benefits from regular physical activity (PA), but the practice is lower than recommended. Knowledge about the facilitators of and barriers to PA at the individual level is important to act positively on PA behaviors. This study validated the Cystic Fibrosis Decisional Balance for Physical Activity scale (CF-DB-PA) for adults with CF. METHODS: French adults with CF were recruited in several specialist centres in France. The CF-DB-PA scale was validated following a quantitative study protocol comprising four stages: (1) tests of the clarity and relevance of a preliminary 44-item version and reduction analysis, (2) confirmatory factor analysis and tests of dimensionality through equation modelling analysis, (3) tests of reliability with Cronbach alphas for the internal consistency and a test-retest with a 2-to-3 week interval for temporal stability, and 4) tests of construct validity with Spearman correlations to measure the associations between each subscale and the theoretically related constructs (i.e., quality of life, PA and exercise tolerance). RESULTS: A total of 201 French adults with CF participated in the validation study. The CF-DB-PA comprises 23 items divided into two factors: facilitators of and barriers to PA. Each factor is divided into three subscales: physical, psychological and environmental. The factors (facilitators and barriers) can be used independently or combined as a whole. A general score of decisional balance for PA can also be calculated. The bi-factor model presented satisfactory adjustment indexes: χ2 (194) = 362.33; p < .001; TLI = .87; CFI = .90; RMSEA = .067. The scale showed satisfactory internal consistency (Cronbach's α = .77). The test-retest reliability was not significant for either subscale, indicating stability over time. The facilitators subscale correlated significantly with the self-reported score of PA (r = .33, p < .01) and quality of life (r = .24, p < .05). The barriers subscale correlated significantly with the self-reported scores of PA (r = - .42, p > .01), quality of life (r = - .44, p < .01), exercise tolerance (r = - .34, p < .01) and spirometry tests (r = - .30, p < .05). CONCLUSIONS: The CF-DB-PA is a reliable and valid questionnaire assessing the decisional balance for PA, the facilitators of and the barriers to PA for adults with CF in French-speaking samples.

Chest physiotherapy enhances detection of Pseudomonas aeruginosa in nonexpectorating children with cystic fibrosis.

Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.

An observational study of anaerobic bacteria in cystic fibrosis lung using culture dependant and independent approaches.

Strict anaerobes are undeniably important residents of the cystic fibrosis (CF) lung but are still unknowns. The main objectives of this study were to describe anaerobic bacteria diversity in CF airway microbiota and to evaluate the association with lung function. An observational study was conducted during eight months. A hundred and one patients were enrolled in the study, and 150 sputum samples were collected using a sterile sample kit designed to preserve anaerobic conditions. An extended-culture approach on 112 sputa and a molecular approach (quantitative PCR targeting three of the main anaerobic genera in CF lung: Prevotella, Veillonella, and Fusobacterium) on 141 sputa were developed. On culture, 91.1% of sputa were positive for at least one anaerobic bacterial species, with an average of six anaerobic species detected per sputum. Thirty-one anaerobic genera and 69 species were found, which is the largest anaerobe diversity ever reported in CF lungs. Better lung function (defined as Forced Expiratory Volume in one second > 70%) was significantly associated with higher quantification of Veillonella. These results raise the question of the potential impact of anaerobes on lung function.

Rapid Improvement after Starting Elexacaftor-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease.

Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV1 = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV1 was +15.1 (+13.8 to +16.4; P < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively (P < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended.

Sputum versus nasopharyngeal samples for the molecular diagnosis of respiratory viral infection in cystic fibrosis: A pilot study.

Viruses are important agents in lung function deterioration in Cystic Fibrosis (CF). To date, no standard operating procedures (SOPs) have been established to determine which sampling method is the most effective for an optimal virological diagnosis of respiratory viral infections in CF. Here we investigated the performances of two sampling sites, sputum samples versus nasopharyngeal (NP) swabs, for thirty participants from three CF centres presenting an acute respiratory infection. Sputum and NP samples were simultaneously collected and multiplex PCR targeting 16 to 18 viruses were performed. Viruses were detected for 18/30 patients (60%). A high concordance between the sputum and NP samples was observed in 25 (83%) paired samples of which 13 tested positive and 12 tested negative. These results highlighted the relevance of sputum sampling for diagnostic of respiratory viruses in CF, which is less invasive and better accepted by CF patients than NP, and allows accurate bacterial detection.

First Wave of COVID-19 in French Patients with Cystic Fibrosis.

Viral infections are known to lead to serious respiratory complications in cystic fibrosis (CF) patients. Hypothesizing that CF patients were a population at high risk for severe respiratory complications from SARS-CoV-2 infection, we conducted a national study to describe the clinical expression of COVID-19 in French CF patients. This prospective observational study involves all 47 French CF centers caring for approximately 7500 CF patients. Between March 1st and June 30th 2020, 31 patients were diagnosed with COVID-19: 19 had positive SARS-CoV-2 RT-PCR in nasopharyngeal swabs; 1 had negative RT-PCR but typical COVID-19 signs on a CT scan; and 11 had positive SARS-CoV-2 serology. Fifteen were males, median (range) age was 31 (9-60) years, and 12 patients were living with a lung transplant. The majority of the patients had CF-related diabetes (n = 19, 61.3%), and a mild lung disease (n = 19, 65%, with percent-predicted forced expiratory volume in 1 s (ppFEV1) > 70). Three (10%) patients remained asymptomatic. For the 28 (90%) patients who displayed symptoms, most common symptoms at admission were fever (n = 22, 78.6%), fatigue (n = 14, 50%), and increased cough (n = 14, 50%). Nineteen were hospitalized (including 11 out of the 12 post-lung transplant patients), seven required oxygen therapy, and four (3 post-lung transplant patients) were admitted to an Intensive Care Unit (ICU). Ten developed complications (including acute respiratory distress syndrome in two post-lung transplant patients), but all recovered and were discharged home without noticeable short-term sequelae. Overall, French CF patients were rarely diagnosed with COVID-19. Further research should establish whether they were not infected or remained asymptomatic upon infection. In diagnosed cases, the short-term evolution was favorable with rare acute respiratory distress syndrome and no death. Post-lung transplant patients had more severe outcomes and should be monitored more closely.

Pneumocystis jirovecii in Patients With Cystic Fibrosis: A Review.

Pneumocystis pneumonia (PCP) remains the most frequent AIDS-defining illness in developed countries. This infection also occurs in non-AIDS immunosuppressed patients, e.g., those who have undergone an organ transplantation. Moreover, mild Pneumocystis jirovecii infections related to low pulmonary fungal burden, frequently designated as pulmonary colonization, occurs in patients with chronic pulmonary diseases, e.g., cystic fibrosis (CF). Indeed, this autosomal recessive disorder alters mucociliary clearance leading to bacterial and fungal colonization of the airways. This mini-review compiles and discusses available information on P. jirovecii and CF. It highlights significant differences in the prevalence of P. jirovecii pulmonary colonization in European and Brazilian CF patients. It also describes the microbiota associated with P. jirovecii in CF patients colonized by P. jirovecii. Furthermore, we have described P. jirovecii genomic diversity in colonized CF patients. In addition of pulmonary colonization, it appears that PCP can occur in CF patients specifically after lung transplantation, thus requiring preventive strategies. In other respects, Pneumocystis primary infection is a worldwide phenomenon occurring in non-immunosuppressed infants within their first months. The primary infection is mostly asymptomatic but it can also present as a benign self-limiting infection. It probably occurs in the same manner in CF infants. Nonetheless, two cases of severe Pneumocystis primary infection mimicking PCP in CF infants have been reported, the genetic disease appearing in these circumstances as a risk factor of PCP while the host-pathogen interaction in older children and adults with pulmonary colonization remains to be clarified.

Optimizations of In Vitro Mucus and Cell Culture Models to Better Predict In Vivo Gene Transfer in Pathological Lung Respiratory Airways: Cystic Fibrosis as an Example.

The respiratory epithelium can be affected by many diseases that could be treated using aerosol gene therapy. Among these, cystic fibrosis (CF) is a lethal inherited disease characterized by airways complications, which determine the life expectancy and the effectiveness of aerosolized treatments. Beside evaluations performed under in vivo settings, cell culture models mimicking in vivo pathophysiological conditions can provide complementary insights into the potential of gene transfer strategies. Such models must consider multiple parameters, following the rationale that proper gene transfer evaluations depend on whether they are performed under experimental conditions close to pathophysiological settings. In addition, the mucus layer, which covers the epithelial cells, constitutes a physical barrier for gene delivery, especially in diseases such as CF. Artificial mucus models featuring physical and biological properties similar to CF mucus allow determining the ability of gene transfer systems to effectively reach the underlying epithelium. In this review, we describe mucus and cellular models relevant for CF aerosol gene therapy, with a particular emphasis on mucus rheology. We strongly believe that combining multiple pathophysiological features in single complex cell culture models could help bridge the gaps between in vitro and in vivo settings, as well as viral and non-viral gene delivery strategies.

Prevalence and dynamics of Lactobacillus sp. in the lower respiratory tract of patients with cystic fibrosis.

No prevalence or dynamics analysis of Lactobacilli in the lung of cystic fibrosis (CF) patients has yet been conducted. In order to use them as probiotics in the treatment of Pseudomonas aeruginosa infection, we describe their lung epidemiology. Over a period of 8 months, we analyzed 279 sputum samples from 124 CF patients classified according to their P. aeruginosa Leeds status of colonization. A total of 137 strains belonging to 11 species were isolated. The prevalence of carriage was 61%. No difference in species diversity or frequency was observed according to Leeds criteria. The next step will be to focus on the strain level.