Nebulised liposomal amphotericin-B as maintenance therapy in allergic bronchopulmonary aspergillosis: a randomised, multicentre trial.

BACKGROUND: In allergic bronchopulmonary aspergillosis (ABPA), prolonged nebulised antifungal treatment may be a strategy for maintaining remission. METHODS: We performed a randomised, single-blind, clinical trial in 30 centres. Patients with controlled ABPA after 4-month attack treatment (corticosteroids and itraconazole) were randomly assigned to nebulised liposomal amphotericin-B or placebo for 6 months. The primary outcome was occurrence of a first severe clinical exacerbation within 24 months following randomisation. Secondary outcomes included the median time to first severe clinical exacerbation, number of severe clinical exacerbations per patient, ABPA-related biological parameters. RESULTS: Among 174 enrolled patients with ABPA from March 2015 through July 2017, 139 were controlled after 4-month attack treatment and were randomised. The primary outcome occurred in 33 (50.8%) out of 65 patients in the nebulised liposomal amphotericin-B group and 38 (51.3%) out of 74 in the placebo group (absolute difference -0.6%, 95% CI -16.8- +15.6%; OR 0.98, 95% CI 0.50-1.90; p=0.95). The median (interquartile range) time to first severe clinical exacerbation was longer in the liposomal amphotericin-B group: 337 days (168-476 days) versus 177 days (64-288 days). At the end of maintenance therapy, total immunoglobulin-E and Aspergillus precipitins were significantly decreased in the nebulised liposomal amphotericin-B group. CONCLUSIONS: In ABPA, maintenance therapy using nebulised liposomal amphotericin-B did not reduce the risk of severe clinical exacerbation. The presence of some positive secondary outcomes creates clinical equipoise for further research.

Hiatal hernia on thoracic computed tomography in pulmonary fibrosis.

Gastro-oesophageal reflux has long been suspected of implication in the genesis and progression of idiopathic pulmonary fibrosis (IPF). We hypothesised that hiatal hernia may be more frequent in IPF than in other interstitial lung disease (ILD), and that hiatal hernia may be associated with more severe clinical characteristics in IPF.We retrospectively compared the prevalence of hiatal hernia on computed tomographic (CT) scans in 79 patients with IPF and 103 patients with other ILD (17 scleroderma, 54 other connective tissue diseases and 32 chronic hypersensitivity pneumonitis). In the IPF group, we compared the clinical, biological, functional, CT scan characteristics and mortality of patients with hiatal hernia (n=42) and without hiatal hernia (n=37).The prevalence of hiatal hernia on CT scan at IPF diagnosis was 53%, similar to ILD associated with scleroderma, but significantly higher than in the two other ILD groups. The size of the hiatal hernia was not linked to either fibrosis CT scan scores, or reduction in lung function in any group. Mortality from respiratory causes was significantly higher among IPF patients with hiatal hernia than among those without hiatal hernia (p=0.009).Hiatal hernia might have a specific role in IPF genesis, possibly due to pathological gastro-oesophageal reflux.

High Prevalence of the Lung Ultrasound Interstitial Syndrome in Systemic Sclerosis Patients with Normal HRCT and Lung Function-A Pilot Study.

Objective: High-resolution computed tomography (HRCT) may lack sensitivity for the early detection of interstitial lung disease associated with systemic sclerosis (SSc-ILD). Lung ultrasound is an emerging technique for the diagnosis of SSc-ILD. This cross-sectional study aimed to describe the prevalence of ultrasound interstitial syndrome in SSc patients with normal HRCT and pulmonary function tests (PFT). Methods: Thirty SSc patients with normal HRCT, FVC > 80% predicted and DLCO > 70% predicted were included. Echocardiography and PFT including impulse oscillometry and cardiopulmonary exercise testing were performed. Lung ultrasound was analyzed by two blinded operators. Patients were classified into two groups, according to the presence or absence of ultrasound interstitial syndrome, defined as the sum of B-lines in all thoracic areas ≥10 and/or pleural line thickness >3 mm on at least one thoracic area and/or a pleural line irregularity score >16%. Results: Ultrasound interstitial syndrome was present in 12 patients (40%). Inter-reader agreement for the diagnosis of ultrasound interstitial syndrome defined by the Kappa coefficient was 0.93 (95%CI 0.79-1.00). Patients with ultrasound interstitial syndrome were younger (37 years vs. 53 years, p = 0.009), more often had pitting scars (n = 7/12 vs. 3/18, p = 0.045) and had lower FVC (102 vs. 110% pred, p = 0.009), TLC (114 vs. 122% pred, p = 0.042) and low-frequency respiratory system reactance (Xrs5 Z-score 0.16 vs. 1.02, p = 0.018), while pulmonary gas exchange was similar. Conclusions: Ultrasound interstitial syndrome was detected in 12/30 SSc patients with normal HRCT and PFT. Patients with ultrasound interstitial syndrome had differences in lung function consistent with reduced respiratory compliance, suggesting minimal and/or early suspected SSc-ILD.

CT Imaging Assessment of Response to Treatment in Allergic Bronchopulmonary Aspergillosis in Adults With Bronchial Asthma.

BACKGROUND: One of the major challenges in managing allergic bronchopulmonary aspergillosis remains consistent and reproducible assessment of response to treatment. RESEARCH QUESTION: What are the most relevant changes in CT scan parameters over time for assessing response to treatment? STUDY DESIGN AND METHODS: In this ancillary study of a randomized clinical trial (NebuLamB), patients with asthma with available CT scan and without exacerbation during a 4-month allergic bronchopulmonary aspergillosis exacerbation treatment period (corticosteroids and itraconazole) were included. Changed CT scan parameters were assessed by systematic analyses of CT scan findings at initiation and end of treatment. CT scans were assessed by two radiologists anonymized to the clinical data. Radiologic parameters were determined by selecting those showing significant changes over time. Improvement of at least one, without worsening of the others, defined the radiologic response. Agreement between radiologic changes and clinical and immunologic responses was likewise investigated. RESULTS: Among the 139 originally randomized patients, 132 were included. We identified five CT scan parameters showing significant changes at end of treatment: mucoid impaction extent, mucoid impaction density, centrilobular micronodules, consolidation/ground-glass opacities, and bronchial wall thickening (P < .05). These changes were only weakly associated with one another, except for mucoid impaction extent and density. No agreement was observed between clinical, immunologic, and radiologic responses, assessed as an overall response, or considering each of the parameters (Cohen κ, -0.01 to 0.24). INTERPRETATION: Changes in extent and density of mucoid impaction, centrilobular micronodules, consolidation/ground-glass opacities, and thickening of the bronchial walls were found to be the most relevant CT scan parameters to assess radiologic response to treatment. A clinical, immunologic, and radiologic multidimensional approach should be adopted to assess outcomes, probably with a composite definition of response to treatment. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02273661; URL: www. CLINICALTRIALS: gov).

Point-of-care ultrasonography for risk stratification of non-critical suspected COVID-19 patients on admission (POCUSCO): A prospective binational study.

BACKGROUND: Lung point-of-care ultrasonography (L-POCUS) is highly effective in detecting pulmonary peripheral patterns and may allow early identification of patients who are likely to develop an acute respiratory distress syndrome (ARDS). We hypothesized that L-POCUS performed within the first 48 hours of non-critical patients with suspected COVID-19 would identify those with a high-risk of worsening. METHODS: POCUSCO was a prospective, multicenter study. Non-critical adult patients who presented to the emergency department (ED) for suspected or confirmed COVID-19 were included and had L-POCUS performed within 48 hours following ED presentation. The lung damage severity was assessed using a previously developed score reflecting both the extension and the intensity of lung damage. The primary outcome was the rate of patients requiring intubation or who died within 14 days following inclusion. RESULTS: Among 296 patients, 8 (2.7%) met the primary outcome. The area under the curve (AUC) of L-POCUS was 0.80 [95%CI:0.60-0.94]. The score values which achieved a sensibility >95% in defining low-risk patients and a specificity >95% in defining high-risk patients were <1 and ≥16, respectively. The rate of patients with an unfavorable outcome was 0/95 (0%[95%CI:0-3.9]) for low-risk patients (score = 0), 4/184 (2.17%[95%CI:0.8-5.5]) for intermediate-risk patients (score 1-15) and 4/17 (23.5%[95%CI:11.4-42.4]) for high-risk patients (score ≥16). In confirmed COVID-19 patients (n = 58), the AUC of L-POCUS was 0.97 [95%CI:0.92-1.00]. CONCLUSION: L-POCUS performed within the first 48 hours following ED presentation allows risk-stratification of patients with non-severe COVID-19.

Impulse oscillometry and spirometry measurements relative to personal best values at the time of acute exacerbations of cystic fibrosis in adults.

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.

ThOracic Ultrasound in Idiopathic Pulmonary Fibrosis Evolution (TOUPIE): research protocol of a multicentric prospective study.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is the most common and severe interstitial lung disease (ILD). It is a progressive disease that requires a regular follow-up: clinical examination, pulmonary function testing (PFT) and CT scan, which is performed yearly in France. These exams have two major disadvantages: patients with severe dyspnoea have difficulties to perform PFT and repeated CT scans expose to high dose of radiations. Considering these limits, it would be relevant to develop new tools to monitor the progression of IPF lesions. Three main signs have been described in ILD with lung ultrasound (LUS): the number of B lines, the irregularity and the thickening of the pleural line. Cross-sectional studies already correlated the intensity of these signs with the severity of fibrosis lesions on CT scan in patients with IPF, but no prospective study described the evolution of the three main LUS signs, nor the correlation between clinical evaluation, PFT and CT scan. Our hypothesis is that LUS is a relevant tool to highlight the evolution of pulmonary lesions in IPF. The main objective of our study is to show an increase in one or more of the three main LUS signs (total number of B lines, pleural line irregularity score and pleural line thickness) during the follow-up. METHODS: ThOracic Ultrasound in Idiopathic Pulmonary Fibrosis Evolution is a French prospective, multicentric and non-interventional study. Every 3 months, patients with IPF will have a clinical examination, PFT and LUS. CT data will be collected if the CT scan is performed within 3 months before the inclusion; the second CT scan will be performed from 9 to 12 months after the inclusion. The presence, location and severity of LUS signs will be recorded for each patient, and their correlation with clinical, functional and CT scan evolution will be evaluated. 30 patients will be enrolled. ETHICS AND DISSEMINATION: The protocol was approved by the French Research Ethics Committee (Comité de Protection des Personnes SUD OUEST ET OUTRE MER II, reference RIPH3-RNI19-TOUPIE) on 11 April 2019. Results will be disseminated via peer-reviewed publication and presentation at international conferences. TRIAL REGISTRATION NUMBER: NCT03944928;Pre-results.

Follow-up of adults with noncritical COVID-19 two months after symptom onset.

OBJECTIVES: To describe the clinical evolution and predictors of symptom persistence during 2 months' follow-up in adults with noncritical coronavirus disease 2019 (COVID-19). METHODS: We performed descriptive clinical follow-up (day (D) 7, D30 and D60) of 150 patients with noncritical COVID-19 confirmed by real-time reverse transcriptase PCR at Tours University Hospital from 17 March to 3 June 2020, including demographic, clinical and laboratory data collected from the electronic medical records and by phone call. Persisting symptoms were defined by the presence at D30 or D60 of at least one of the following: weight loss ≥5%, severe dyspnoea or asthenia, chest pain, palpitations, anosmia/ageusia, headache, cutaneous signs, arthralgia, myalgia, digestive disorders, fever or sick leave. RESULTS: At D30, 68% (103/150) of patients had at least one symptom; and at D60, 66% (86/130) had symptoms, mainly anosmia/ageusia: 59% (89/150) at symptom onset, 28% (40/150) at D30 and 23% (29/130) at D60. Dyspnoea concerned 36.7% (55/150) patients at D30 and 30% (39/130) at D60. Half of the patients (74/150) at D30 and 40% (52/130) at D60 reported asthenia. Persistent symptoms at D60 were significantly associated with age 40 to 60 years old, hospital admission and abnormal auscultation at symptom onset. At D30, severe COVID-19 and/or dyspnoea at symptom onset were additional factors associated with persistent symptoms. CONCLUSIONS: Up to 2 months after symptom onset, two thirds of adults with noncritical COVID-19 had complaints, mainly anosmia/ageusia, dyspnoea or asthenia. A prolonged medical follow-up of patients with COVID-19 seems essential, whatever the initial clinical presentation.

Pharmacokinetics of colistin after nebulization or intravenous administration of colistin methanesulphonate (Colimycin®) to cystic fibrosis patients.

OBJECTIVES: Colistin, administered as the prodrug colistin methanesulphonate (CMS), is an antibiotic frequently administered as aerosol in cystic fibrosis (CF) patient. Our aim was to assess the plasma PK of colistin in CF patients treated with CMS administered intravenously or as aerosol and to compare these results with those previously reported in healthy volunteers. METHODS: Six CF patients were included, CMS and colistin concentrations were measured in plasma, urine and sputum. Either after single intravenous administration of 2 Million International Unit (MIU) or after repeated nebulizations of 2 MIU of CMS. PK of CMS and colistin were assessed by a mixed effect modeling approach. RESULTS: Renal clearance of CMS was lower in CF patients compared to that previously reported in healthy volunteers (64.3 mL/min (RSE = 15%) vs. 103 mL/min (RSE = 8%)). However, apparent clearance of colistin was higher in CF patients compared to healthy volunteers (124 mL/min (RSE = 13%) vs. 48.7 mL/min (RSE = 15%)), resulting in reduced systemic exposure to colistin (dose normalized AUC (2 MIU) of 7.4 h.mg/L/MIU vs. 11.2 h.mg/L/MIU). After repeated nebulizations, colistin concentrations were very low in plasma (<0.21 mg/L). CONCLUSIONS: Although our study suggests a lower median dose normalized colistin plasma concentrations in CF patients compared with healthy controls, this difference was not significant and a larger study is needed to substantiate this.

Identification of Patient Profiles with High Risk of Hospital Re-Admissions for Acute COPD Exacerbations (AECOPD) in France Using a Machine Learning Model.

Purpose: To characterise patients with chronic obstructive pulmonary disease (COPD) who are rehospitalised for an acute exacerbation, to estimate the cost of these hospitalisations, to characterise high risk patient sub groups and to identify factors potentially associated with the risk of rehospitalisation. Patients and Methods: This was a retrospective study using the French National Hospital Discharge Database. All patients aged ≥40 years hospitalised for an acute exacerbation of COPD between 2015 and 2016 were identified and followed for six months. Patients with at least one rehospitalisation for acute exacerbation of COPD constituted the rehospitalisation analysis population. A machine learning model was built to study the factors associated with the risk of rehospitalisation using decision tree analysis. A direct cost analysis was performed from the perspective of national health insurance. Results: A total of 143,006 eligible patients were hospitalised for an acute exacerbation of COPD (AECOPD) in 2015-2016 (mean age: 74 years; 62.1% men). 25,090 (18.8%) were rehospitalised for another exacerbation within six months. In this study, 8.5% of patients died during or immediately following the index hospitalisation and 10.5% died during or immediately after rehospitalisation (p <0.001). The specific cost of these rehospitalisations was € 5304. The overall total cost per patient of all AECOPD-related stays was € 9623, being significantly higher in patients who were rehospitalised (€ 16,275) compared to those who were not (€ 8208). In decision tree analysis, the most important driver of rehospitalisation was hospitalisation in the previous two years (contributing 85% of the information). Conclusion: Rehospitalisations for acute exacerbations of COPD carry a high epidemiological and economic burden. Since hospitalisation for an acute exacerbation is the most important determinant of future rehospitalisations, management of COPD needs to focus on interventions aimed at decreasing the rehospitalisation risk of in order to lower the burden of disease.

Cross-Cultural Adaptation and Psychometric Validation of the French Version of the FAMCARE-Patient (FFP-16) Questionnaire for Outpatients With Advanced-Stage Cancer.

CONTEXT: Satisfaction is known to be correlated with the quality of care; it indicates the adequacy of the caregivers' responses in meeting the needs and expectations of patients. The FAMCARE-Patient questionnaire has been used to quantify satisfaction level in outpatients with advanced-stage cancers. OBJECTIVES: To translate and cross-culturally adapt the FAMCARE-Patient questionnaire for French patients and to evaluate the psychometric properties of this version. METHODS: The original questionnaire was translated into French and adapted to French cultural context by an expert committee. The French FAMCARE-Patient Version 16 (FFP-16) was then pilot tested among 51 patients. Subsequently, psychometric properties were evaluated in a cross-sectional study by administrating the new tool to 176 adult outpatients with advanced-stage cancer who underwent oncological care at our university hospital. RESULTS: We performed a confirmatory factor analysis and assessed the reliability and validity of the questionnaire. The one-factor structure was confirmed, and it had an acceptable fit with a comparative fit index and root mean square error of approximation of 0.93 and 0.07, respectively. Internal reliability was high as shown by Cronbach's alpha (α = 0.95). Reproducibility was very good (intraclass correlation coefficient 0.91). The FFP-16 score was independent of the Eastern Cooperative Oncology Group and the overall Edmonton Symptom Assessment Scale distress scores. It was significantly but weakly correlated with anxiety, well-being, and overall quality of life (Spearman's correlation coefficient = -0.18, -0.20, and 0.30, respectively; P < 0.05). CONCLUSION: We found the FFP-16 questionnaire to be a reliable and valid instrument for the assessment of satisfaction in French outpatients with advanced-stage cancer.

Serum IgG Concentrations in Adult Patients Experiencing Virus-Induced Severe Asthma Exacerbations.

BACKGROUND: Patients experiencing severe asthma exacerbations have a poorer quality of life and an increase in morbidity and mortality. Viruses are frequently involved in asthma exacerbations. OBJECTIVE: To determine the value of measuring serum IgG concentrations in asthma exacerbations and assess their link with viral infections in patients hospitalized for asthma. METHODS: Patients hospitalized for asthma exacerbation were included in an observational study from January 1, 2015, to December 31, 2015. Serum IgG concentrations on admission were compared between patients with a positive upper airway viral sample and those with a negative viral sample. RESULTS: Among the 82 patients included, those with positive viral nasopharyngeal samples (n = 40) presented with lower serum IgG concentrations during exacerbation than those with a negative viral sample (n = 42) (10.1 ± 2.3 g/L vs 11.5 ± 3.6 g/L; P < .05). The median concentration of serum IgG was lower in patients hospitalized for more than 3 days compared with those hospitalized for less than 3 days (10.0 g/L [8.2-12.4] vs 11.4 g/L [10.1-12.8]; P < .05) and in patients who received oral corticosteroid therapy for more than 5 days compared with those treated with oral steroids for less than 5 days (10.1 g/L [8.3-12.2] vs 11.6 g/L [10.0-13.8]; P < .05). CONCLUSIONS: Serum IgG level was significantly lower when asthma exacerbations were associated with positive viral samples. The patients with lower serum IgG concentrations required longer hospitalizations and longer courses of steroids.

Predictive factors for lumacaftor/ivacaftor clinical response.

BACKGROUND: Ivacaftor-lumacaftor combination therapy corrects the F508 del-CFTR mutated protein which causes Cystic Fibrosis. The clinical response of the patients treated with the combination therapy is highly variable. This study aimed to determine factors involved in the individual's response to lumacaftor-ivacaftor therapy. METHODS: Sweat test was assessed at baseline and after 6 months of ivacaftor-lumacaftor treatment in 41 homozygous F508del children and young adults. ß-adrenergic peak sweat secretion, nasal potential difference (NPD) and intestinal current measurements (ICM) were performed in patients accepting these tests. Seric level of lumacaftor and ivacaftor were determined and additional CFTR variant were searched. RESULTS: Sweat chloride concentration significantly decreased after treatment, whereas the ß-adrenergic peak sweat response did not vary in 9 patients who underwent these tests. The average level of F508del-CFTR activity rescue reached up to 15% of the normal level in intestinal epithelium, as studied by ICM in 12 patients (p = .03) and 20% of normal in the nasal epithelium in NPD tests performed in 21 patients (NS). There was no significant correlation between these changes and improvements in FEV1 at 6 months. Serum drug levels did not correlate with changes in FEV1, BMI-Zscore or other CFTR activity biomarkers. Additional exonic variants were identified in 4 patients. The F87L-I1027T-F508del-CFTR complex allele abolished the lumacaftor corrector effect. CONCLUSION: This observational study investigates a number of potential factors linked to the clinical response of F508del homozygous patients treated with lumacaftor-ivacaftor combination therapy. Lumacaftor and ivacaftor blood levels are not associated with the clinical response. Additional exonic variants may influence protein correction.

Immunotherapy for cancer in people living with HIV: safety with an efficacy signal from the series in real life experience.

OBJECTIVE: To report efficacy and tolerance of nivolumab or pembrolizumab, PD-1 inhibitors, in people living with HIV (PLWHIV) and cancer. DESIGN: Series of PLWHIV cancer patients treated with anti-PD1 agents in real-life clinical practice. METHODS: From May 2014 to January 2019, 575 HIV-infected patients have been discussed in the French CANCERVIH national multidisciplinary board and included in the network database. Twenty-three patients were treated with immune checkpoint inhibitors in daily practice. We report the demographic characteristics, CD4 T-cell counts, HIV viral loads, safety and efficacy data of these 23 PLWHIV treated in routine practice with nivolumab or pembrolizumab for nonsmall cell lung cancer (n = 21), melanoma (n = 1) and head and neck cancer (n = 1) retrospectively collected from the database CANCERVIH network. The median CD4 T-cell count at treatment initiation was 370 cells/µl (IQR: 125-1485). HIV viral load was undetectable in all patients. RESULTS: As of 29 April 2019, with a median follow-up of 10.8 months (2.0-27.7), the median number of injections was 6 (IQR: 4-18). Only two grade 3 adverse reactions were reported (no toxic deaths or immune-related deaths). Among the 23 patients, a partial response was observed in five patients (22%), a stabilization for five (22%) and a progression in 13 (57%). Only one patient experienced a positive HIV viral load, but this occurred following ART interruption. CONCLUSION: Treatment with PD-1 inhibitors seems to have an efficacy signal and be well tolerated in PLWHIV, including impact on CD4 lymphocyte count and HIV load, that should be monitored during treatment course (regarding real-life experience).

Pulmonary manifestations of Sjögren's syndrome.

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.

Spatial and temporal Antarctic Ice Sheet mass trends, glacio-isostatic adjustment, and surface processes from a joint inversion of satellite altimeter, gravity, and GPS data.

We present spatiotemporal mass balance trends for the Antarctic Ice Sheet from a statistical inversion of satellite altimetry, gravimetry, and elastic-corrected GPS data for the period 2003-2013. Our method simultaneously determines annual trends in ice dynamics, surface mass balance anomalies, and a time-invariant solution for glacio-isostatic adjustment while remaining largely independent of forward models. We establish that over the period 2003-2013, Antarctica has been losing mass at a rate of -84 ± 22 Gt yr-1, with a sustained negative mean trend of dynamic imbalance of -111 ± 13 Gt yr-1. West Antarctica is the largest contributor with -112 ± 10 Gt yr-1, mainly triggered by high thinning rates of glaciers draining into the Amundsen Sea Embayment. The Antarctic Peninsula has experienced a dramatic increase in mass loss in the last decade, with a mean rate of -28 ± 7 Gt yr-1 and significantly higher values for the most recent years following the destabilization of the Southern Antarctic Peninsula around 2010. The total mass loss is partly compensated by a significant mass gain of 56 ± 18 Gt yr-1 in East Antarctica due to a positive trend of surface mass balance anomalies.