Insight into the relationship between forced vital capacity and transfer of the lungs for carbon monoxide in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Forced vital capacity (FVC) is routinely used to quantify the severity and identify the progression of idiopathic pulmonary fibrosis (IPF). Although less commonly used, lung transfer of carbon monoxide (TLCO) correlates better with the severity of IPF than does FVC. METHODS: Aiming at studying how FVC behaves in relation to TLCO, we analysed cross-sectional data from 430 IPF patients, of which 221 had at least 2 assessments (performed 2.4 ± 1.9 years apart) available for longitudinal analyses. Thresholds for identifying "abnormal" FVC and TLCO values were the statistically-defined lower limits of normal (LLN). For patients with longitudinal data, mean annual absolute declines of FVC and TLCO were calculated. RESULTS: The correlation between FVC and TLCO (%predicted) was weak (R2=0.21). FVC was "abnormal" (i.e.,

Infections in autoimmune pulmonary alveolar proteinosis: a large retrospective cohort.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease, predisposing to an increased risk of infection. A complete picture of these infections is lacking. RESEARCH QUESTION: Describe the characteristics and clinical outcomes of patients diagnosed with aPAP, and to identify risk factors associated with opportunistic infections. METHODS: We conducted a retrospective cohort including all patients diagnosed with aPAP between 2008 and 2018 in France and Belgium. Data were collected using a standardised questionnaire including demographics, comorbidities, imaging features, outcomes and microbiological data. RESULTS: We included 104 patients, 2/3 were men and median age at diagnosis was 45 years. With a median follow-up of 3.4 years (IQR 1.7-6.6 years), 60 patients (58%), developed at least one infection, including 23 (22%) with opportunistic infections. Nocardia spp was the main pathogen identified (n=10). Thirty-five (34%) patients were hospitalised due to infection. In univariate analysis, male gender was associated with opportunistic infections (p=0.04, OR=3.88; 95% CI (1.02 to 22.06)). Anti-granulocyte macrophage colony-stimulating factor antibody titre at diagnosis was significantly higher among patients who developed nocardiosis (1058 (316-1591) vs 580 (200-1190), p=0.01). Nine patients had died (9%), but only one death was related to infection. INTERPRETATION: Patients with aPAP often presented with opportunistic infections, especially nocardiosis, which highlights the importance of systematic search for slow-growing bacteria in bronchoalveolar lavage or whole lung lavage.

French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis - 2021 update. Full-length version.

BACKGROUND: Since the latest 2017 French guidelines, knowledge about idiopathic pulmonary fibrosis has evolved considerably. METHODS: Practical guidelines were drafted on the initiative of the Coordinating Reference Center for Rare Pulmonary Diseases, led by the French Language Pulmonology Society (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of the entire OrphaLung network, pulmonologists practicing in various settings, radiologists, pathologists, a general practitioner, a health manager, and a patient association. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS), including an online vote using a Likert scale. RESULTS: After a literature review, 54 guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease: epidemiology, diagnostic procedures, quality criteria and interpretation of chest CT scans, lung biopsy indication and procedures, etiological workup, methods and indications for family screening and genetic testing, assessment of the functional impairment and prognosis, indication and use of antifibrotic agents, lung transplantation, management of symptoms, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are intended to guide the diagnosis and practical management of idiopathic pulmonary fibrosis.

Impact of Gender on the Characteristics of Patients with Idiopathic Pulmonary Fibrosis Included in the RaDiCo-ILD Cohort.

BACKGROUND: There is growing evidence of gender-specific phenotypic differences among patients with idiopathic pulmonary fibrosis (IPF), which may affect patient outcomes. OBJECTIVES: We present the characteristics of patients with IPF at inclusion in the French Rare Disease Cohort - Interstitial Lung Disease (RaDiCo-ILD) with the aim of characterizing gender-specific phenotypic differences. METHODS: Patients with IPF who were enrolled in the national, multicentre RaDiCo-ILD cohort were included. Demographic characteristics, comorbidities, health-related quality of life (HRQoL) scores, pulmonary function, chest imaging, and IPF treatment were collected at inclusion and described by gender. RESULTS: The cohort included 724 patients with IPF (54% of RaDiCo-ILD cohort), of whom 82.9% were male. The proportion of male and female patients with a prior history of smoking was 75.0% and 26.8%, respectively. Emphysema was present in 17.0% (95% confidence interval [CI]: 10.0, 24.0) of men and 5.4% (95% CI: 1.2, 9.6) of women. At inclusion, females had poorer HRQoL than males based on St. George's Respiratory Questionnaire scores (48.5 [95% CI: 43.9, 53.0] and 41.5 [39.4, 43.6], respectively). The mean forced vital capacity per cent predicted was 77.7% (95% CI: 76.2, 79.3) and 87.4% (83.4, 91.4) for males and females, respectively. Honeycombing on high-resolution computed tomography (HRCT) was present in 70.8% (95% CI: 61.0, 80.6) of males and 45.8% (95% CI: 35.1, 56.5) of females. CONCLUSIONS: This analysis of patients with IPF at inclusion in the RaDiCo-ILD cohort provides evidence that comorbid emphysema, lung volume reduction, and honeycombing on HRCT are more common characteristics of males than females.

Concurrence of 1- and 3-Min Sit-to-Stand Tests with the 6-Min Walk Test in Idiopathic Pulmonary Fibrosis.

BACKGROUND: In idiopathic pulmonary fibrosis (IPF), some physiological parameters measured during a 6-min walk test (6-MWT) impart reliable prognostic information. Sit-to-stand tests (STSTs) are field exercise tests that are easier to implement than the 6-MWT in daily practice. OBJECTIVES: The aims of the study were to test the reproducibility and compare 2 STSTs (the 1-min STST [1-STST] and the semi-paced 3-min chair rise test [3-CRT]) in IPF, and to determine if selected physiological parameters (speed of displacement and changes in pulse oxygen saturation [SpO2]) are interchangeable between the STSTs and the 6-MWT. METHODS: Thirty-three patients with stable IPF were studied in 3 French expert centers. To test reproducibility, intra-class correlations (ICCs) of parameters measured during tests performed 7-14 days apart were calculated. To test interchangeability, the agreement and correlation of physiological responses measured during STSTs and during 6-MWT were studied. RESULTS: Vertical displacements and changes in SpO2 during both STSTs were reproducible, with ICCs ranging from 0.78 [0.63-0.87] to 0.95 [0.92-0.97]. Vertical displacements during 1-STST and 3-CRT were correlated with 6-MWT distance (correlation coefficients (r) of 0.72 and 0.77, respectively; p < 0.001). Similarly, correlations were found between changes in SpO2 measured during the 2 STSTs and the 6-MWT, with coefficients ranging from 0.73 to 0.91 (p < 0.001). Distance walked and SpO2 during 6-MWT were well estimated from vertical displacement and SpO2 during the 2 STSTs, respectively. CONCLUSION: The correlations found between the 2 STSTs and the 6-MWT suggest that STSTs may be of interest to assess displacement and exercise-induced changes in SpO2 in IPF patients.

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.

Rheological analysis of sputum from patients with chronic bronchial diseases.

Bronchial diseases are characterised by the weak efficiency of mucus transport through the lower airways, leading in some cases to the muco-obstruction of bronchi. It has been hypothesised that this loss of clearance results from alterations in the mucus rheology, which are reflected in sputum samples collected from patients, making sputum rheology a possible biophysical marker of these diseases and their evolution. However, previous rheological studies have focused on quasi-static viscoelastic (linear storage and loss moduli) properties only, which are not representative of the mucus mobilisation within the respiratory tract. In this paper, we extend this approach further, by analysing both quasi-static and some dynamic (flow point) properties, to assess their usability and relative performance in characterising several chronic bronchial diseases (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) and distinguishing them from healthy subjects. We demonstrate that pathologies influence substantially the linear and flow properties. Linear moduli are weakly condition-specific and even though the corresponding ranges overlap, distinct levels can be identified. This directly relates to the specific mucus structure in each case. In contrast, the flow point is found to strongly increase in muco-obstructive diseases, which may reflect the complete failure of mucociliary clearance causing episodic obstructions. These results suggest that the analysis of quasi-static and dynamic regimes in sputum rheology is in fact useful as these regimes provide complementary markers of chronic bronchial diseases.

Favorable Evolution of Cryptococcal Meningitis in the Context of Flucytosine Resistance.

Cryptococcal meningitis is a critical illness affecting 0.2% to 5% solid-organ transplant recipients with a 40% to 50% mortality. We report the case of a 48-year-old lung transplant recipient, who, 15 months after a right lung graft, kept parakeets and developed meningitis due to Cryptococcus neoformans. Immunosuppressive treatment was based on a quadruple sequential immunosuppressive therapy that included induction therapy with thymoglobulin, followed by corticosteroids, calcineurin inhibitors, and mycophenolate mofetil. Antifungal susceptibility testing of Cryptococcus neoformans showed resistance to flucytosine and intermediate sensitivity to fluconazole. Initial treatment adhered to international guidelines; however, the patient could not tolerate an effective double-antifungal therapy during the first 2 months of treatment. Despite this delayed treatment for an aggressive infection in an immunocompromised patient, the patient survived without relapse and received maintenance treatment with fluconazole during the course of 3 years. Administration of calcineurin inhibitors as immunosuppressive treatment may partly explain this outcome, as this therapeutic class is known to protect from severe forms of cryptococcal meningitis.

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.

Skeletal muscle contractility and fatigability in adults with cystic fibrosis.

BACKGROUND: Recent discovery of cystic fibrosis transmembrane conductance regulator expression in human skeletal muscle suggests that CF patients may have intrinsic skeletal muscle abnormalities potentially leading to functional impairments. The aim of the present study was to determine whether CF patients with mild to moderate lung disease have altered skeletal muscle contractility and greater muscle fatigability compared to healthy controls. METHODS: Thirty adults (15 CF and 15 controls) performed a quadriceps neuromuscular evaluation using single and paired femoral nerve magnetic stimulations. Electromyographic and mechanical parameters during voluntary and magnetically-evoked contractions were recorded at rest, during and after a fatiguing isometric task. Quadriceps cross-sectional area was determined by magnetic resonance imaging. RESULTS: Some indexes of muscle contractility tended to be reduced at rest in CF compared to controls (e.g., mechanical response to doublets stimulation at 100 Hz: 74±30 Nm vs. 97±28 Nm, P=0.06) but all tendencies disappeared when expressed relative to quadriceps cross-sectional area (P>0.5 for all parameters). CF and controls had similar alterations in muscle contractility with fatigue, similar endurance and post exercise recovery. CONCLUSIONS: We found similar skeletal muscle endurance and fatigability in CF adults and controls and only trends for reduced muscle strength in CF which disappeared when normalized to muscle cross-sectional area. These results indicate small quantitative (reduced muscle mass) rather than qualitative (intrinsic skeletal muscle abnormalities) muscle alterations in CF with mild to moderate lung disease.

Use of intensive care in patients with nonresectable lung cancer.

BACKGROUND: Admission of patients with lung cancer to the ICU has been criticized. We evaluated whether ICU admission improved 3-month survival in patients with nonresectable lung cancer. Factors associated with survival were identified. METHODS: A retrospective study was conducted in consecutive nonsurgical patients with lung cancer admitted to three ICUs in France between 2000 and 2007, 2005 and 2007, and 2005 and 2006. RESULTS: We included 103 patients with a median (interquartile range) Simplified Acute Physiology Score II of 33 (25-46) and logistic organ dysfunction (LOD) score of 3 (1-4). Invasive mechanical ventilation was required in 41 (40%) patients. Sixty-three (61%) patients had metastasis and 26 (25%) an Eastern Cooperative Oncology Group performance status (ECOG-PS) > 2. The reason for ICU admission was acute respiratory failure in 58 (56%) patients. Three-month survival rate was 37% (95% CI, 28%-46%). By multivariate analysis, variables associated with mortality were ECOG-PS > 2 (hazard ratio [HR], 2.65; 95% CI, 1.43-4.88), metastasis at admission (HR, 1.90; 95% CI, 1.08-3.33), and worse LOD score (HR, 1.19; 95% CI, 1.08-1.32). An LOD score decrease over the first 72 h was associated with survival. CONCLUSIONS: Survival in nonsurgical patients with lung cancer requiring ICU admission was 37% after 90 days. Our results provide additional evidence that ICU management may be appropriate in patients with nonresectable lung cancer and organ failure.

Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases.

OBJECTIVE: We investigated SF and serum proteomic fingerprints of patients suffering from RA, OA and other miscellaneous inflammatory arthritides (MIAs) in order to identify RA-specific biomarkers. METHODS: SF profiles of 65 patients and serum profiles of 31 patients were studied by surface-enhanced laser desorption and ionization-time-of-flight-mass spectrometry technology. The most discriminating RA biomarkers were identified by matrix-assisted laser desorption ionization-time of flight and their overexpression was confirmed by western blotting and ELISA. RESULTS: Three biomarkers of 10 839, 10 445 and 13 338 Da, characterized as S100A8, S100A12 and S100A9 proteins, were the most up-regulated proteins in RA SF. Their expression was about 10-fold higher in RA SF vs OA SF. S100A8 exhibited a sensitivity of 82% and a specificity of 69% in discriminating RA from other MIAs, whereas S100A12 displayed a sensitivity of 79% and a specificity of 64%. Three peptides of 3351, 3423 and 3465 Da, corresponding to the alpha-defensins-1, -2 and -3, were also shown to differentiate RA from other MIAs with weaker sensitivity and specificity. Levels of S100A12, S100A8 and S100A9 were statistically correlated with the neutrophil count in MIA SF but not in the SF of RA patients. S100A8, S100A9, S100A12 and alpha-defensin expression in serum was not different in the three populations. CONCLUSION: The most enhanced proteins in RA SF, the S100A8, S100A9 and S00A12 proteins, distinguished RA from MIA with high accuracy. Possible implication of resident cells in this increase may play a role in RA physiopathology.

Lung transplantation for lymphangioleiomyomatosis: the French experience.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare disease, leading in some cases to end-stage respiratory failure. Lung transplantation (LT) represents a therapeutic option in advanced pulmonary LAM. METHODS: We conducted a retrospective multicenter study of 44 patients who underwent LT for LAM at 9 centers in France between 1988 and 2006. RESULTS: All patients were women with a mean age of 41+/-10 years at LT. There were 34 single-lung transplants and 11 bilateral transplants (one retransplantation). Prior clinical events related to LAM were present in 75% of the patients and previous thoracic surgical procedures were noted in 86.6% of cases. At the latest preoperative evaluation, 30 patients had an obstructive pattern (mean forced expiratory volume in 1 second: 26%+/-14% of predicted) and 15 had a combined restrictive and obstructive pattern, with a mean KCO=27%+/-8.8% of predicted, PaO2=52.8+/-10.4 and PaCO2=42.6+/-9.8 mm Hg. Intraoperative cardiopulmonary bypass was required in 13 cases. The length of mechanical ventilation was 7.5+/-12.8 days. The median duration of follow-up was 37 months. The 1, 2, 5, and 10 years survival rates were 79.6%, 74.4%, 64.7%, and 52.4%, respectively. Extensive pleural adhesions were found in 21 patients leading to severe intraoperative hemorrhage. Postoperative LAM-related complications were pneumothorax in the native lung in five patients, chylothorax in six, bronchial dehiscence or stenosis in seven. There were two cases of recurrence of LAM. CONCLUSION: Despite a high morbidity mainly caused by previous surgical interventions and disease-related complications, LT is a satisfactory therapeutic option for end-stage respiratory failure in LAM.