Carriers of germline telomerase‐related gene (TRG) mutations can show poor prognosis, with an increase in common hematological complications after lung transplantation (LT) for pulmonary fibrosis. ...The aim of this study was to describe the outcomes after LT in recipients carrying a germline TRG mutation and to identify the predictors of survival. In a multicenter cohort of LT patients, we retrospectively reviewed those carrying pathogenic TRG variations (n = 38; TERT, n = 23, TERC, n = 9, RTEL1, n = 6) between 2009 and 2018. The median age at LT was 54 years (interquartile range IQR 46–59); 68% were male and 71% had idiopathic pulmonary fibrosis. During the diagnosis of pulmonary fibrosis, 28 (74%) had a hematological disease, including eight with myelodysplasia. After a median follow‐up of 26 months (IQR 15–46), 38 patients received LT. The overall post‐LT median survival was 3.75 years (IQR 1.8‐NA). The risk of death after LT was increased for patients with myelodysplasia (HR 4.1 95% CI 1.5–11.5) or short telomere (HR 2.2 1.0–5.0) before LT. After LT, all patients had anemia, 66% had thrombocytopenia, and 39% had neutropenia. Chronic lung allograft dysfunction frequency was 29% at 4 years. The present findings support the use of LT in TRG mutation carriers without myelodysplasia. Hematological evaluation should be systematically performed before LT.
Among patients with telomerase‐related gene mutations who undergo lung transplantation for idiopathic pulmonary fibrosis, pre‐transplant myelodysolasia is associated with reduced post‐transplant survival.
Background and Purpose
The Arp2/3 multiprotein complex regulates branched polymerisation of the actin cytoskeleton and may contribute to collagen synthesis and fibrogenesis in the lung.
Experimental ...Approach
Expression of Arp2/3 components was assessed in human lung fibroblasts and in the bleomycin‐induced pulmonary fibrosis model in mice. The Arp2/3 complex was repressed with the allosteric inhibitor CK666 and with interfering RNAs targeting the ARP2, ARP3 and ARPC2 subunits (siARP2, siARP3 and siARPC2) in CCD‐16Lu human lung fibroblasts in vitro. Mice received daily intraperitoneal injections of CK666 from the 7th to the 14th day after tracheal bleomycin instillation.
Key Results
Expression of Arp2/3 complex subunits mRNAs was increased in fibroblasts treated with TGF‐β1 and in the lungs of bleomycin‐treated mice compared with controls. In vitro, CK666 and siARPC2 inhibited cell growth and TGF‐β1‐induced α‐smooth muscle actin (ACTA2) and collagen‐1 (COL1) expression. CK666 also decreased ACTA2 and COL1 expression in unstimulated cells. CK666 reduced Akt phosphorylation and repressed phospho‐GSK3β, β‐catenin and MRTF‐A levels in unstimulated fibroblasts. In vivo, CK666 reduced levels of both procollagen‐1 and insoluble collagen in bleomycin‐treated mice.
Conclusion and Implications
Expression of the Arp2/3 complex was increased in profibrotic environments in vitro and in vivo. Inhibition of the Arp2/3 complex repressed ACTA2 and COL1 expression and repressed an Akt/phospho‐GSK3β/β‐catenin/MRTF‐A pathway in lung fibroblasts. CK666 exerted antifibrotic properties in the lung in vivo. Inhibition of the Arp2/3 complex could represent an interesting new therapy for idiopathic pulmonary fibrosis and other fibrotic interstitial lung diseases.
Background
Increased physiological dead space ventilation (VD/VT) at exercise reflects pulmonary gas exchange impairment and is a sensitive marker of cardio‐respiratory disease.
VD/VT is typically ...not measured during routine cardiopulmonary exercise testing (CPET) because its calculation requires arterial blood gas analysis for determination of PaCO2. Instead, dead space ventilation is indirectly evaluated as a determinant of the ventilation (VE)/VCO2 relationship, which also depends on the PaCO2 set point. We hypothesized that VD/VT calculations based on non‐invasive transcutaneous PCO2 (PtcCO2) measurement had better diagnostic characteristics than the VE/VCO2 slope for the discrimination of healthy subjects from patients with COPD, a common disease associated with impaired pulmonary gas exchange.
Methods
Retrospective study of 19 healthy controls and 24 COPD patients who underwent CPET with continuous PtcCO2 monitoring. Areas under receiver operating characteristics curves (AUC) were calculated to assess diagnostic accuracy of CPET measurement for the discrimination of COPD and Controls.
Results
The AUC for PtcCO2‐based VD/VT at VT1 (0.977) was significantly higher than for the VE/VCO2 slope (0.660), SpO2 at peak exercise (0.913), decrease in inspiratory capacity (0.719), and ventilatory reserve (0.708). At a threshold of 0.24, the sensitivity and specificity of PtcCO2‐based VD/VT for the discrimination of COPD patients and healthy Controls were 100% and 84%, respectively. All Control subjects had PtcCO2‐based VD/VT ≤ 0.25.
Conclusions
PtcCO2‐based VD/VT was the most accurate measurement to discriminate healthy controls from subjects with COPD, a chronic lung disease associated with altered pulmonary gas exchange. Non‐invasive monitoring of PtcCO2 may be useful for routine CPET.
•The sensitivity of evaluated SARS-CoV-2 immunoassays ranged from 95.6% to 97.8%.•The specificity was 92.1% for Euroimmun IgG and ≥ 98.9% for Abbott IgG, Wantai Ab and DiaPro confirmation IgG ...assays.•A lack of specificity was observed for low positive Euroimmun IgG results (ratio<5) and inconclusive RT-PCR results.•A lack of sensitivity was observed for early serology (<14 days) or late RT-PCR testing (>30 days).
The aim of the present study was to evaluate the clinical performance of four SARS-CoV-2 immunoassays and their contribution in routine care for the diagnosis of COVID-19, in order to benefit of robust data before their extensive use.
The clinical performance of Euroimmun ELISA SARS-CoV-2 IgG, Abbott SARS-CoV-2 IgG, Wantai SARS-CoV-2 Ab ELISA, and DiaPro COVID-19 IgG confirmation were evaluated in the context of both a retrospective and a prospective analysis of COVID-19 patients. The retrospective analysis included plasma samples from 63 COVID-19 patients and 89 control (pre-pandemic) patients. The prospective study included 203 patients who tested either negative (n = 181) or positive (n = 22) by RT-PCR before serology sampling.
The specificity was 92.1 %, 98.9 %, 100 % and 98.9 % and the sensitivity 14 days after onset of symptoms was 95.6 %, 95.6 %, 97.8 % and 95.6 % for Euroimmun IgG, Abbott IgG, Wantai Ab, and DiaPro IgG confirmation SARS-CoV-2 immunoassays, respectively. The low specificity of Euroimmun IgG (for ratio <5) was not confirmed in routine care setting (98.5 % negative agreement). Serology was complementary to RT-PCR in routine care and lead to identification of false positive (Ct>38, <2 targets detected) and false negative RT-PCR results (>1 month post onset of symptoms).
Serology was complementary to RT-PCR for the diagnosis of COVID-19 at least 14 days after onset of symptoms. First line serology testing can be performed with Wantai Ab or Abbott IgG assays, while DiaPro IgG confirmation assay can be used as an efficient confirmation assay.
Background
Diagnosis of acute exacerbation (AE) of cystic fibrosis (CF) must be precise because both under‐ and over‐prescription of antibiotics may be detrimental. How lung function tests contribute ...to diagnose AE is unclear. We aimed to describe variation of spirometry and oscillometry measurements, at Stable state and at AE in adults with CF.
Methods
Patients were included in a retrospective single‐centre study when both spirometry (FEV1, FVC) and oscillometry (X5, R5, R5−R20 and AX) data were available for at least one Stable and one AE visit between December 2016 and July 2019. For each visit, we calculated variation (Δ) in spirometry and oscillometry indices in comparison with personal best values. Measurements were expressed as % of predicted values and Z‐scores when applicable. Areas under ROC curves (AUC) were computed.
Results
Forty‐two patients (28 ± 9 years, FEV1 64 ± 21%) were included; 80 AE and 104 Stable visits were analysed. FEV1 (L, %pred and Z‐score) and FVC (%pred and Z‐score) varied significantly between AE and Stable visits (p < .05), although differences were small (80 ml/2.7%pred for FEV1). Among oscillometry indices, X5 (kPa.s.L−1), R5–R20 (kPa.s.L−1) and AX (kPa/L) varied significantly. The AUCs for the variation in spirometry indices ranged from 0.601 (ΔFVC L) to 0.635 (ΔFEV1%pred). They were not significantly different from the AUCs for ΔX5 (0.589), ΔR5−R20 (0.649) and ΔAX (0.598).
Conclusions
Performance of both spirometry and oscillometry to discriminate AE from Stable state was poor. Variation of oscillometry indices (X5, R5−R20, AX) may be helpful when spirometry is unreliable or uncomfortable.
In 9-20% of cases, Sjögren's syndrome is associated with various respiratory symptoms. The most typical manifestations are chronic interstitial lung disease (ILD) and tracheobronchial disease. The ...most common manifestation of ILD is nonspecific interstitial pneumonia in its fibrosing variant. Other types of ILD, such as organising pneumonia, usual interstitial pneumonia and lymphocytic interstitial pneumonitis, are rare. Their radiological presentation is less distinctive, and definitive diagnosis may require the use of transbronchial or surgical lung biopsy. Corticosteroid therapy is the mainstay of ILD treatment in Sjögren's syndrome, but the use of other immunosuppressive drugs needs to be determined. ILD is a significant cause of death in Sjögren's syndrome. Tracheobronchial disease is common in Sjögren's syndrome, characterised by diffuse lymphocytic infiltration of the airway. It is sometimes responsible for a crippling chronic cough. It can also present in the form of bronchial hyperresponsiveness, bronchiectasis, bronchiolitis or recurrent respiratory infections. The management of these manifestations may require treatment for dryness and/or inflammation of the airways. Airway disease has little effect on respiratory function and is rarely the cause of death in Sjögren's syndrome patients. Rare respiratory complications such as amyloidosis, lymphoma or pulmonary hypertension should not be disregarded in Sjögren's syndrome patients.
Increased physiological dead space ventilation (V
/V
) at exercise reflects pulmonary gas exchange impairment and is a sensitive marker of cardio-respiratory disease. V
/V
is typically not measured ...during routine cardiopulmonary exercise testing (CPET) because its calculation requires arterial blood gas analysis for determination of PaCO
. Instead, dead space ventilation is indirectly evaluated as a determinant of the ventilation (VE)/VCO
relationship, which also depends on the PaCO
set point. We hypothesized that V
/V
calculations based on non-invasive transcutaneous PCO
(PtcCO
) measurement had better diagnostic characteristics than the VE/VCO
slope for the discrimination of healthy subjects from patients with COPD, a common disease associated with impaired pulmonary gas exchange.
Retrospective study of 19 healthy controls and 24 COPD patients who underwent CPET with continuous PtcCO
monitoring. Areas under receiver operating characteristics curves (AUC) were calculated to assess diagnostic accuracy of CPET measurement for the discrimination of COPD and Controls.
The AUC for PtcCO
-based V
/V
at VT1 (0.977) was significantly higher than for the VE/VCO
slope (0.660), SpO
at peak exercise (0.913), decrease in inspiratory capacity (0.719), and ventilatory reserve (0.708). At a threshold of 0.24, the sensitivity and specificity of PtcCO
-based V
/V
for the discrimination of COPD patients and healthy Controls were 100% and 84%, respectively. All Control subjects had PtcCO
-based V
/V
≤ 0.25.
PtcCO
-based V
/V
was the most accurate measurement to discriminate healthy controls from subjects with COPD, a chronic lung disease associated with altered pulmonary gas exchange. Non-invasive monitoring of PtcCO
may be useful for routine CPET.
Abstract Background Mycophenolate mofetil (MMF) has been used to treat interstitial lung disease (ILD), but mycophenolate (MPA) pharmacokinetics was not reported for this use. This ancillary study of ...the EVER‐ILD protocol aimed at describing the pharmacokinetic variability of MPA using population modelling in ILD. Methods Concentrations of MPA were measured during an 8‐h course for 27 ILD patients treated with 1000 mg MMF b.i.d. Absorption, distribution and elimination of MPA were described using population compartment models with first‐order transfer and elimination rate constants, while accounting for both absorption peaks using gamma absorption models. Results The pharmacokinetics of MPA was best described using a two‐compartment model and two gamma absorption models, model performances of this model were still similar to those of a one gamma absorption model. This pharmacokinetics seemed to be notably influenced by body weight, renal function and inflammatory status. The distribubtion value area under the concentration curve between two administrations of MMF was AUC 12 = 52.5 mg.h/L in median (interquartile range: 42.2–58.0 mg.h/L). Conclusion This is the first study reporting MPA pharmacokinetics in ILD. This pharmacokinetics appears to be similar to other indications and should be further investigated in future studies.
Background and Objective
Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults.
Methods
We conducted a ...multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed.
Results
We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% (52–72) and DLco was 44% (35–50). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground‐glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DLCO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DLCO, p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow‐up in the ABCA3 group.
Conclusion
SFTPC and ABCA3‐associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground‐glass opacities and/or cysts is frequently found in these rare conditions.
We report the characteristics and follow‐up data of 36 adult patients in France with ILD associated variant(s) in SFTPC or ABCA3. SFTPC and ABCA3‐associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground‐glass opacities and/or cysts is frequently found in these rare conditions.
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