Phenotypes and outcome of diffuse pulmonary non-amyloid light chain deposition disease.

BACKGROUND: Light chain deposition disease (LCDD) is a very rare entity. Clinical manifestations of LCDD vary according to the organs involved. Data on pulmonary LCDD are scarce and limited to small series or case reports. This study aimed to describe the characteristics and outcome of diffuse pulmonary non-amyloid LCDD localized to the lungs. STUDY DESIGN AND METHODS: A multicenter retrospective cohort study was conducted. Clinical characteristics were collected, and chest CTs were centrally reviewed. The diagnosis of pulmonary non-amyloid LCDD was confirmed by immunohistochemistry. RESULTS: Thirty-one cases were identified (68% female), with a median age at diagnosis of 50 years (IQR 20). Baseline FEV1/FVC was < 0.70 in 45% of patients. Mean (± SD) FEV1 and DLCO were 86% ± 26.2 and 52% ± 23.9, respectively. CT revealed peculiar patterns of thin-walled cysts (58%) and thin-walled cystic bronchiectases (27%). Increased serum kappa light chain was found in 87% of patients. Histological analysis showed kappa light chain deposits in all patients, except one with lambda chain deposits. Median annual FEV1 decline was 127 ml (IQR 178) and median DLCO decline was 4.3% (IQR 4.3). Sixteen patients received immunomodulatory treatment or chemotherapy; serum light chain levels decreased in 9 cases (75%), without significant improvement in FEV1 (p = 0.173). Overall, 48% of patients underwent bilateral lung transplantation. Transplant-free survival at 5 and 10 years were 70% and 30%, respectively. An annual FEV1 decline greater than 127 ml/year was associated with increased risk of death or transplantation (p = 0.005). CONCLUSIONS: Diffuse pulmonary LCDD is characterised by female predominance, a peculiar imaging pattern with bronchiectasis and/or cysts, progressive airway obstruction and severe DLCO impairment, and poor outcome. Lung transplantation is a treatment of choice.

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.

Impact of Lung Biopsy on Lung Function in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Video-assisted surgical lung biopsy (SLB) is performed in 10-30% of cases to establish the diagnosis of idiopathic pulmonary fibrosis (IPF). OBJECTIVES: The aim of the study was to analyze the impact of SLB on lung function in patients eventually diagnosed with IPF. METHODS: This is an observational, retrospective, monocentric study of all consecutive patients eventually diagnosed with IPF in multidisciplinary discussion who underwent SLB over 10 years in a specialized center. The primary end point was the variation in forced vital capacity (FVC) before and after the SLB. The secondary end points were the variations in forced expiratory volume in one second (FEV1), total lung capacity (TLC), carbon monoxide diffusion capacity (DLCO), and morbidity and mortality associated with the SLB. RESULTS: In 118 patients who underwent SLB and were diagnosed with IPF, a relative decrease in FVC of 4.8% (p < 0.001) was found between measurements performed before and after the procedure. The mean FVC decrease was 156 ± 386 mL in an average period of 185 days, representing an annualized decline of 363 ± 764 mL/year. A significant decrease was also observed after SLB in FEV1, TLC, and DLCO. Complications within 30 days of SLB occurred in 14.4% of patients. Two patients (1.7%) died within 30 days, where one of them had poor lung function. Survival at 1 year was significantly poorer in patients with FVC <50% at baseline. CONCLUSION: In this uncontrolled study in patients ultimately diagnosed with IPF, SLB was followed by a significant decline in FVC, which appears to be numerically greater than the average decline in the absence of treatment in the literature. Summary at a Glance: This study evaluated the change in lung function in 118 consecutive patients diagnosed with idiopathic pulmonary fibrosis by surgical lung biopsy. Forced vital capacity decreased by 156 ± 386 mL in a mean of 185 days between the last measurement before and first measurement after biopsy, representing an annualized decline of 363 ± 764 mL/year.

Prognostic value of right ventricular ejection fraction in pulmonary arterial hypertension.

Right ventricle ejection fraction (RVEF) evaluated with magnetic resonance imaging is a strong determinant of patient outcomes in pulmonary arterial hypertension. We evaluated the prognostic value of RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change 3-6 months after initiating pulmonary arterial hypertension-specific therapy. In a prospective cohort of newly diagnosed patients with idiopathic, heritable or anorexigen-associated pulmonary arterial hypertension, RVEF was measured at baseline (n=100) and 3-6 months after initiation of therapy (n=78). After a median follow-up of 4.1 years, 41 deaths occurred, including 35 from cardiovascular causes. Patients with a (median) baseline RVEF >25% had better survival than those with a RVEF <25% using Kaplan-Meier analysis (p=0.010). RVEF at baseline was an independent predictor of all-cause and cardiovascular mortality in adjusted Cox regression model (p=0.002 and p=0.007, respectively; HR 0.93 for both). Patients with stable or increased RVEF at 3-6 months had a trend for improved all-cause survival (HR 2.43, p=0.086) and had less cardiovascular mortality (HR 3.25, p=0.034) than those in whom RVEF decreased despite therapy. RVEF assessed with conventional planar equilibrium radionuclide angiography at baseline and change in RVEF 3-6 months after therapy initiation independently predict outcomes in patients with pulmonary arterial hypertension.

Pulmonary function test results are correlated with 6-minute walk distance, distance-saturation product, and 6-minute walk work in patients with lymphangioleiomyomatosis.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare multicystic lung disease. Although a correlation between pulmonary function test (PFT) results and exercise capacity appears probable, it has not yet been demonstrated. The aim of this study was to assess whether PFT results correlate with 6-minute walk test (6MWT) results in patients with LAM. METHODS: We conducted a retrospective study of all patients with a diagnosis of LAM followed in a French reference centre over a 13-year period. PFT and 6MWT data were collected. Distance-saturation product (DSP) and 6-minute walk work (6MWORK) were calculated. RESULTS: A total of 62 patients were included. Their median forced expiratory volume in 1 s (FEV1) was 82.7 % predicted and their median forced vital capacity (FVC) was 96.7 % predicted. The median diffusing capacity of the lungs for carbon monoxide (DLCO) was 58.5 % predicted and was decreased in 79 % of the patients. The median 6-minute walk distance was 535 m, which was 90.9 % of the 602 m predicted distance. The median DSP was 497.4 m % and the median 6MWORK was 32,910 kg.m. The distance walked during the 6MWT was significantly correlated with FVC%predicted (R = 0.435), FEV1 %predicted (R = 0.303), TLC%predicted (R = 0.345), FRC%predicted (R = 0.262), RV/TLC ratio (R = -0.271), and DLCO%predicted (R = 0.279). DSP and 6MWORK were each significantly correlated with different PFT results. CONCLUSION: The present study shows that PFT results are potential predictors of the exercise capacity in patients with LAM. Additional studies are required to evaluate the interest of DSP and 6MWORK in LAM.

Mepolizumab and benralizumab in patients with severe asthma and a history of eosinophilic granulomatosis with polyangiitis.

Introduction: Asthma associated with eosinophilic granulomatosis with polyangiitis (EGPA) is often severe and corticosteroid-dependent, leading to significant morbidity. Mepolizumab and benralizumab are humanized monoclonal antibodies targeting interleukin 5 (IL-5) and its receptor, respectively. They have been shown to be effective in steroid-sparing in patients with severe eosinophilic asthma. Objective: Our aim was to evaluate the efficacy and safety of mepolizumab and benralizumab prescribed for severe asthma in patients with EGPA under "real-world" conditions. Methods: This was a retrospective analysis of patients with EGPA and persistent asthma who received either mepolizumab 100 or 300 mg administered every 4 weeks, or benralizumab 30 mg administered every 4 weeks for the initial 3 injections and followed by an injection every 8 weeks thereafter, whilst combined with oral glucocorticoids. The follow-up every 6 ± 3 months included an assessment of clinical manifestations, pulmonary function tests and eosinophil cell count. The primary outcome was the proportion of patients at 12 months receiving a daily oral dose of prednisone or equivalent of 4 mg or less with a BVAS of 0. Results: Twenty-six patients were included. After 12 months of treatment with mepolizumab or benralizumab, 32% of patients met the primary outcome and were receiving less than 4 mg of prednisone per day with a BVAS of 0. The median dose of prednisone was 10 mg per day at baseline, 9 mg at 6 months, and 5 mg at 12 months (p ≤ 0.01). At 12 months, 23% of patients were weaned off corticosteroids, while an increase or no change in dose was observed in 27% of patients. The median eosinophil count was significantly reduced from 365 cells/mm3 to 55 cells/mm3 at 6 months and 70 cells/mm3 at 12 months, respectively. No significant change was observed in FEV1. After 12 months of treatment, 14% of patients had had an average of 1 exacerbation of asthma, compared with 52% of patients before baseline. The tolerability profile was favorable. Conclusion: In this real-world study in patients with severe asthma and a history of EGPA asthma, mepolizumab and benralizumab had a significant steroid-sparing effect and reduced asthma exacerbation, but no significant effect on lung function.

Hypereosinophilic obliterative bronchiolitis: a distinct, unrecognised syndrome.

Biopsy-proven cases of eosinophilic bronchiolitis have only been reported in isolation, and all come from Japan. We present six patients with hypereosinophilic obliterative bronchiolitis (HOB), defined by the following criteria: 1) blood eosinophil cell count >1 G·L(-1) and/or bronchoalveolar lavage eosinophil count >25%; 2) persistent airflow obstruction despite high-dose inhaled bronchodilators and corticosteroids; and 3) eosinophilic bronchiolitis at lung biopsy (n=1) and/or direct signs of bronchiolitis (centrilobular nodules and branching opacities) on computed tomography (n=6). Chronic dyspnoea and cough which was often severe, without the characteristic features of asthma, were the main clinical manifestations. Atopy and asthma were present in the history of three and two patients, respectively. One patient met biological criteria of the lymphoid variant of idiopathic hypereosinophilic syndrome. Mean blood eosinophil cell count was 2.7 G·L(-1) and mean eosinophil differential percentage at bronchoalveolar lavage was 63%. Mean initial forced expiratory volume in 1 s/forced vital capacity ratio was 50%, normalising with oral corticosteroid therapy in all patients. HOB manifestations recurred when oral prednisone was decreased to 10-20 mg·day(-1), but higher doses controlled the disease. HOB is a characteristic entity deserving to be individualised among the eosinophilic respiratory disorders. Thorough analysis is needed to determine whether unrecognised and/or smouldering HOB may further be a cause of irreversible airflow obstruction in chronic eosinophilic respiratory diseases.

Elaboration of a French version of the Duke Activity Status Index questionnaire and performance to predict functional capacity.

BACKGROUND: Guidelines recommend detecting poor functional capacity (VO2max < 14 ml.kg-1.min-1) to assess preoperative cardiac risk. This screening is performed via a cardiopulmonary exercise test (CPET), the self-reported inability to climb two flights of stairs, or the use of the Duke Activity Status Index (DASI) questionnaire, which has shown a significant correlation with VO2max and postoperative outcomes. The objectives of the present study were: 1) to create a French version of the DASI questionnaire (FDASI); 2) to assess its diagnostic performance in predicting functional capacity. METHODS: Consecutive adult patients undergoing CPET for medical or preoperative evaluation were prospectively included between May 2020 and March 2021. All patients were asked to complete FDASI as a self-questionnaire and report their inability to climb two flights of stairs. RESULTS: 122 patients were included. Test-retest reliability was 0.88 and 23 (19%) patients experienced a VO2max < 14 ml.kg-1.min-1. There was a significant positive relationship between FDASI and VO2max: r2 = 0.32; p < 0.001. ROCAUC was 0.81 [95%CI: 0.73-0.89]. The best FDASI score threshold was 36 points, leading to sensitivity and specificity values of 87% [74-100] and 68% [56-79], respectively. Besides, sensitivity and specificity were 35% [17-56] and 92% [86-97] for the self-reported inability to climb two flights of stairs. CONCLUSION: A FDASI score of 36 represents a reliable threshold the clinicians could routinely use to identify patients with a VO2max < 14 ml.kg-1.min-1. FDASI could advantageously replace the self-reported inability to climb two flights of stairs.

Right-to-left shunt with hypoxemia in pulmonary hypertension.

BACKGROUND: Hypoxemia is common in pulmonary hypertension (PH) and may be partly related to ventilation/perfusion mismatch, low diffusion capacity, low cardiac output, and/or right-to-left (RL) shunting. METHODS: To determine whether true RL shunting causing hypoxemia is caused by intracardiac shunting, as classically considered, a retrospective single center study was conducted in consecutive patients with precapillary PH, with hypoxemia at rest (PaO2 < 10 kPa), shunt fraction (Qs/Qt) greater than 5%, elevated alveolar-arterial difference of PO2 (AaPO2), and with transthoracic contrast echocardiography performed within 3 months. RESULTS: Among 263 patients with precapillary PH, 34 patients were included: pulmonary arterial hypertension, 21%; PH associated with lung disease, 47% (chronic obstructive pulmonary disease, 23%; interstitial lung disease, 9%; other, 15%); chronic thromboembolic PH, 26%; miscellaneous causes, 6%. Mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance were 45.8 +/- 10.8 mmHg, 2.2 +/- 0.6 L/min/m2, and 469 +/- 275 dyn.s.cm-5, respectively. PaO2 in room air was 6.8 +/- 1.3 kPa. Qs/Qt was 10.2 +/- 4.2%. AaPO2 under 100% oxygen was 32.5 +/- 12.4 kPa. Positive contrast was present at transthoracic contrast echocardiography in 6/34 (18%) of patients, including only 4/34 (12%) with intracardiac RL shunting. Qs/Qt did not correlate with hemodynamic parameters. Patients' characteristics did not differ according to the result of contrast echocardiography. CONCLUSION: When present in patients with precapillary PH, RL shunting is usually not related to reopening of patent foramen ovale, whatever the etiology of PH.

Safety of right heart catheterization for pulmonary hypertension in very elderly patients.

Right heart catheterization (RHC) is the reference test in diagnosing pulmonary hypertension (PH). The increasing age of patients at the time of diagnosis raises the issue of the morbidity of this invasive test in elderly individuals. We hypothesized that the morbidity associated with RHC would be increased in elderly patients and highlight differences in hemodynamic characteristics compared to younger patients. A retrospective study was conducted in a regional referral center for PH. Data for all consecutive RHCs performed during the study period were analyzed. Over a five-year period, 1060 RHCs were performed. Of the patients, 228 (21.5%) were aged ≥75 years and 832 (78.5%) were aged <75 years. Duration of the procedure and site of puncture did not differ according to age group (all P > 0.05). Nine procedures (0.9%) led to complications: three (1.3%) in patients aged >75 years and six (0.7%) in younger patients aged ( P = 0.5). Eight were local vascular injuries, directly related to a femoral vein puncture ( P < 0.001). Pulmonary arterial pressure and cardiac output were lower in patients aged >75 years than in younger patients ( P = 0.001). RHC may be performed regardless of patient age. The rate of RHC complications is not increased in individuals aged >75 years. As most complications were related to femoral vein puncture, this route should be avoided whenever possible.

Impact of comorbidities and delay in diagnosis in elderly patients with pulmonary hypertension.

Patient age at diagnosis of pulmonary hypertension is steadily increasing. The present study sought to analyse clinical characteristics, time to diagnosis and prognosis of pulmonary hypertension in elderly and very elderly patients. A study was conducted in a French regional referral centre for pulmonary hypertension. All consecutive patients diagnosed with pre-capillary pulmonary hypertension were included and categorised according to age: <65 years ("young"), 65-74 years ("elderly") and ≥75 years ("very elderly"). Over a 4-year period, 248 patients were included: 101 (40.7%) were young, 82 (33.1%) were elderly and 65 (26.2%) were very elderly. The median age at diagnosis among the total population was 68 years. Compared with young patients, elderly and very elderly patients had a longer time to diagnosis (7±48, 9±21 and 16±32 months, respectively; p<0.001). Patients ≥75 years also more often had group 4 pulmonary hypertension. The median overall survival was 46±1.4 months, but was only 37±4.9 months in elderly patients and 28±4.7 months in very elderly patients. Survival from the first symptoms and survival adjusted to comorbidity was similar across age groups. Patient age should be taken into account when diagnosing pulmonary hypertension as it is associated with a specific clinical profile and a worse prognosis. The difference in prognosis is likely to be related to a delay in diagnosis and a greater number of comorbidities.

Assist-control ventilation vs. low levels of pressure support ventilation on sleep quality in intubated ICU patients.

OBJECTIVE: To compare the impact of assist-control ventilation (ACV) and pressure support ventilation with 6 cmH2O inspiratory pressure (low PSV) on sleep quality. DESIGN: Prospective randomized cross-over study. PATIENTS: Twenty intubated and mechanically ventilated patients for acute on chronic respiratory failure. MEASUREMENTS: Patients were monitored by standard polysomnography at the end of their weaning period. Patients were assigned to receive either ACV from 10 p.m. to 2 a.m. and low PSV from 2 a.m. to 6 a.m. (ACV/low PSV group) or low PSV from 10 p.m. to 2 a.m. and ACV from 2 a.m. to 6 a.m. (low PSV/ACV group). RESULTS: There were significant increases in stages 1 and 2 non-rapid eye movement (NREM) sleep and reduction in wakefulness during the first part of the night and significant increases in stages 3 and 4 NREM sleep during the second part of the night were observed with ACV compared to low PSV. A significant negative correlation was observed between the perceived sleep quality and the amount of wakefulness while the amount of stage 2 NREM sleep was positively correlated with perceived sleep quality. CONCLUSIONS: ACV was significantly associated with a better sleep quality than those recorded during pressure support. The perception of sleep quality appeared to be better with ACV than with low PSV. On the basis of these results we recommend that intubated and mechanically ventilated patients for acute on chronic respiratory failure should be reventilated at night during their weaning period.

Effects of intermittent negative pressure ventilation on effective ventilation in normal awake subjects.

RATIONALE: Previous studies have shown that an increase in inspiratory pressure during nasal intermittent positive pressure ventilation (IPPV) does not result in increased effective minute ventilation (E) due to glottic interference. STUDY OBJECTIVES: To test the consequences of increases in negative pressure ventilation (NPV) on V(E). MATERIAL AND METHODS: Eight healthy awake subjects underwent NPV delivered by an iron lung. First, NPV was started at a respirator frequency (f) of 15 cycles per minute with an inspiratory negative pressure (INP) of - 15 cm H(2)O (F15-P15). Then, f was increased to 20 cycles per minute and INP was kept at - 15 cm H(2)O. Next, f was kept at 20 cycles per minute and INP was reduced to - 30 cm H(2)O (F20-P30). Finally, f was decreased to 15 cycles per minute and INP was kept at - 30 cm H(2)O. At each step and for each breath, effective tidal volume (VT), V(E), and end-tidal carbon dioxide pressure were measured. In three subjects, the glottis width was assessed using fiberoptic bronchoscopy. RESULTS: From spontaneous breathing to the first step of NPV (F15-P15), we observed an inhibition of the phasic inspiratory diaphragmatic electromyogram concomitant to a significant increase in V(E) (p < 0.0005). For the group as a whole, the increase in mechanical ventilation (from F15-P15 to F20-P30) resulted in significant increases in VT and V(E) leading to hypocapnia (p < 0.0005). Moreover, the glottis width did not decrease with the increase in mechanical ventilation. CONCLUSIONS: We conclude that in normal awake subjects, NPV allowed a significant increase in V(E). These results differ from those previously obtained with nasal IPPV in which the glottic width interferes with the delivered mechanical ventilation.

Conditions associated with severe carbon monoxide diffusion coefficient reduction.

OBJECTIVE: To identify conditions associated with severe carbon monoxide transfer coefficient reduction (Kco < 40% of predicted values). PATIENTS AND METHODS: We retrospectively reviewed pulmonary function tests, such as Kco measurement, in consecutive patients evaluated in the physiology unit of a University hospital over a 6-year period. Patients were included if they had at least 1 measure of severe Kco reduction, with further detailed pulmonary function tests, clinical data, and diagnostic procedures conducted within 6 months. RESULTS: 5576 patients underwent 9061 Kco measurements. 195 patients (3.5%) with Kco < 40% were investigated (156 males; mean age 62 ± 12 years). Mean Kco was 29 ± 9% of predicted values. The main conditions associated with severe Kco reduction were: emphysema (46%); interstitial lung disease (28%); combined pulmonary fibrosis and emphysema (16%); and pre-capillary pulmonary hypertension (8%). Systolic pulmonary artery pressure was ≥ 35 mmHg at echocardiography in 88% of patients. Right heart catheterization performed in 97 patients showed pre-capillary pulmonary hypertension in 86 of 195 patients (44%). Pulmonary hypertension was the most frequent condition associated with Kco severe reduction. Pulmonary hypertension was present in 29%, 53%, and 48% of patients with chronic obstructive pulmonary disease, interstitial lung disease, and combined pulmonary fibrosis and emphysema, respectively, and was disproportionate to the parenchymal lung disease (mean pulmonary artery pressure > 35 mmHg) in 63% of cases. CONCLUSION: Severe Kco reduction is frequently related to pulmonary hypertension, especially when associated with emphysema and/or interstitial lung disease. Systematic echocardiography is thus warranted in any patient with severe Kco diminution.

Comparison of 2 maintenance doses (100 microg vs 200 microg) in Hymenoptera venom immunotherapy: influence of the maintenance dose on the immunologic response.

BACKGROUND: In Hymenoptera venom immunotherapy, the maintenance dose is usually 100 microg. However, persistent systemic reactions to sting challenges could be treated by an increase in the maintenance dose to 200 microg with success, suggesting greater efficiency. OBJECTIVE: To compare the effects of 2 monthly maintenance doses (100 microg vs 200 microg) on skin test sensitivity and venom specific IgE antibody levels. METHODS: Twenty-two patients receiving Vespula venom immunotherapy were enrolled in this retrospective study. After rush therapy, the 100-microg maintenance dose initially administered was maintained (group 1, n = 13) or was increased to 200 microg (group 2, n = 9). RESULTS: Levels of venom specific IgE antibody and skin test results measured before the onset of immunotherapy were comparable in both groups. Unlike in group 1, a maintenance dose of 200 microg resulted in significant decreases in venom specific IgE antibody levels and skin test sensitivity. CONCLUSIONS: Increasing the monthly maintenance dose to 200 microg results in a greater degree of change in venom specific IgE antibody levels and skin test sensitivity than when maintaining a 100-microg dose. Our data strengthen those of previous clinical studies showing the usefulness of a 200-microg maintenance dose in the case of clinical failure of a 100-microg dose.