Biomarkers in Systemic Sclerosis: An Overview.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by significant fibrosis of the skin and internal organs, with the main involvement of the lungs, kidneys, heart, esophagus, and intestines. SSc is also characterized by macro- and microvascular damage with reduced peripheral blood perfusion. Several studies have reported more than 240 pathways and numerous dysregulation proteins, giving insight into how the field of biomarkers in SSc is still extremely complex and evolving. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, and anti-centromere and anti-topoisomerase I antibodies are considered classic biomarkers with precise clinical features. Recent studies have reported that trans-forming growth factor ß (TGF-ß) plays a central role in the fibrotic process. In addition, interferon regulatory factor 5 (IRF5), interleukin receptor-associated kinase-1 (IRAK-1), connective tissue growth factor (CTGF), transducer and activator of transcription signal 4 (STAT4), pyrin-containing domain 1 (NLRP1), as well as genetic factors, including DRB1 alleles, are implicated in SSc damage. Several interleukins (e.g., IL-1, IL-6, IL-10, IL-17, IL-22, and IL-35) and chemokines (e.g., CCL 2, 5, 23, and CXC 9, 10, 16) are elevated in SSc. While adiponectin and maresin 1 are reduced in patients with SSc, biomarkers are important in research but will be increasingly so in the diagnosis and therapeutic approach to SSc. This review aims to present and highlight the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

Chronic Thromboembolic Pulmonary Hypertension: An Observational Study.

Background and Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH) has a high mortality. The treatment of CTEPH could be balloon pulmonary angioplasty (BPA), medical (MT) or pulmonary endarterectomy (PEA). This study aims to assess the clinical characteristics of CTEPH patients, surgically or medically treated, in a pulmonology referral center. Materials and Methods: A total of 124 patients with PH with suspected CTEPH (53 male subjects and 71 female subjects; mean age at diagnosis 67 ± 6) were asked to give informed consent and then were evaluated. The presence of CTEPH was ascertained by medical evaluations, radiology and laboratory tests. Results: After the evaluation of all clinical data, 65 patients met the inclusion criteria for CTEPH and they were therefore enrolled (22 males and 43 females; mean age at diagnosis was 69 ± 8). 26 CTEPH patients were treated with PEA, 32 with MT and 7 with BPA. There was a statistically significant age difference between the PEA and MT groups, at the time of diagnosis, the PEA patients were younger than the MT patients, whereas there was no statistically significant difference in other clinical characteristics (e.g., smoking habit, thrombophilia predisposition), as well as functional and hemodynamic parameters (e.g., 6-min walk test, right heart catheterization). During three years of follow-up, no patients in the PEA groups died; conversely, eleven patients in the MT group died during the same period (p < 0.05). Furthermore, a significant decrease in plasma BNP values and an increase in a meter at the six-minute walk test, 1 and 3 years after surgery, were observed in the PEA group (p < 0.05). Conclusions: This study seems to confirm that pulmonary endarterectomy (PEA) can provide an improvement in functional tests in CTEPH.

Pirfenidone and Nintedanib in Pulmonary Fibrosis: Lights and Shadows.

Pirfenidone and Nintedanib are specific drugs used against idiopathic pulmonary fibrosis (IPF) that showed efficacy in non-IPF fibrosing interstitial lung diseases (ILD). Both drugs have side effects that affect patients in different ways and have different levels of severity, making treatment even more challenging for patients and clinicians. The present review aims to assess the effectiveness and potential complications of Pirfenidone and Nintedanib treatment regimens across various ILD diseases. A detailed search was performed in relevant articles published between 2018 and 2023 listed in PubMed, UpToDate, Google Scholar, and ResearchGate, supplemented with manual research. The following keywords were searched in the databases in all possible combinations: Nintedanib; Pirfenidone, interstitial lung disease, and idiopathic pulmonary fibrosis. The most widely accepted method for evaluating the progression of ILD is through the decline in forced vital capacity (FVC), as determined by respiratory function tests. Specifically, a decrease in FVC over a 6-12-month period correlates directly with increased mortality rates. Antifibrotic drugs Pirfenidone and Nintedanib have been extensively validated; however, some patients reported several side effects, predominantly gastrointestinal symptoms (such as diarrhea, dyspepsia, and vomiting), as well as photosensitivity and skin rashes, particularly associated with Pirfenidone. In cases where the side effects are extremely severe and are more threatening than the disease itself, the treatment has to be discontinued. However, further research is needed to optimize the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality. Finally, other studies are requested to establish the treatments that can stop ILD progression.

Transbronchial lung cryobiopsy and pulmonary fibrosis: A never-ending story?

Background: The diagnostic process of pulmonary fibrosis (PF) is often challenging, requires a collaborative effort of several experts, and often requires bioptic material, which can be difficult to obtain, both in terms of quality and technique. The main procedures available to obtain such samples are transbronchial lung cryobiopsy (TBLC) and surgical lung biopsy (SLB). Objective: The purpose of this paper is to review the evidence for the role of TBLC in the diagnostic-therapeutic process of PF. Methods: A comprehensive review was performed to identify articles to date that addressed the role of TBLC in the diagnostic-therapeutic process of PF using the PubMed® database. Results: The reasoned search identified 206 papers, including 21 manuscripts (three reviews, one systematic review, two guidelines, two prospective studies, three retrospective studies, one cross-sectional study, one original article, three editorials, three clinical trials, and two unclassifiable studies), which were included in the final review. Conclusions: TBLC is gaining increasing efficacy and improving safety profile; however, there are currently no clear data demonstrating its superiority over SLB. Therefore, the two techniques should be considered with careful rationalization on a case-by-case basis. Further research is needed to further optimize and standardize the procedure and to thoroughly study the histological and molecular characteristics of PF.

An Overview of Different Techniques for Improving the Treatment of Pulmonary Hypertension Secondary in Systemic Sclerosis Patients.

In systemic sclerosis (SSc) mortality is mainly linked to lung involvement which is characterized by interstitial lung disease (ILD) and pulmonary hypertension (PH). In SSc, PH may be due to different etiologies, including ILD, chronic thromboembolic disease, pulmonary veno-occlusive disease, and pulmonary arterial hypertension (PAH). The main tool to screen PAH is transthoracic echocardiography (TTE), which has a sensitivity of 90%, even if definitive diagnosis should be confirmed by right heart catheterization (RHC). The radiological evaluation (i.e., HRTC) plays an important role in defining the possible causes and in monitoring the evolution of lung damage. For PAH, identifying individuals who have borderline elevation of pulmonary arterial pressure needs to be appropriately managed and followed. In the past few years, the strategy for the management of PAH has significantly evolved and new trials are underway to test other therapies. This review provides an overview of the tools to evaluate PAH in SSc patients and on treatment options for these patients.

Severe COVID-19 ARDS Treated by Bronchoalveolar Lavage with Diluted Exogenous Pulmonary Surfactant as Salvage Therapy: In Pursuit of the Holy Grail?

BACKGROUND: Severe pneumonia caused by coronavirus disease 2019 (COVID-19) is characterized by inflammatory lung injury, progressive parenchymal stiffening and consolidation, alveolar and airway collapse, altered vascular permeability, diffuse alveolar damage, and surfactant deficiency. COVID-19 causes both pneumonia and acute respiratory distress syndrome (COVID-19 ARDS). COVID-19 ARDS is characterized by severe refractory hypoxemia and high mortality. Despite extensive research, the treatment of COVID-19 ARDS is far from satisfactory. Some treatments are recommended for exhibiting some clinically positive impacts on COVID-19 patients although there are already several drugs in clinical trials, some of which are already demonstrating promising results in addressing COVID-19. Few studies have demonstrated beneficial effects in non-COVID-19 ARDS treatment of exogenous surfactant, and there is no evidence-based, proven method for the procedure of surfactant administration. AIM: The aim of this work is to underline the key role of ATII cells and reduced surfactant levels in COVID-19 ARDS and to emphasize the rational basis for exogenous surfactant therapy in COVID-19 ARDS, providing insights for future research. METHODS: In this article, we describe and support via the literature the decision to administer large volumes of surfactant to two patients via bronchoalveolar lavage to maximize its distribution in the respiratory tract. RESULTS: In this study, we report on two cases of COVID-19 ARDS in patients who have been successfully treated with diluted surfactants by bronchoalveolar lavage, followed by a low-dose bolus of surfactant. CONCLUSION: Combining the administration of diluted, exogenous pulmonary surfactant via bronchoalveolar lavage along with the standard therapy for SARS-CoV-2-induced ARDS may be a promising way of improving the management of ARDS.

Chronic Thromboembolic Pulmonary Hypertension: An Update.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease observed in a small proportion of patients after acute pulmonary embolism (PE). CTEPH has a high morbidity and mortality rate, related to the PH severity, and a poor prognosis, which mirrors the right ventricular dysfunction involvement. Pulmonary endarterectomy (PEA) reduces pulmonary vascular resistance, making it the treatment of choice and should be offered to operable CTEPH patients, as significant symptomatic and prognostic improvement has been observed. Moreover, these patients may also benefit from the advances made in surgical techniques and pulmonary hypertension-specific medication. However, not all patients are eligible for PEA surgery, as some have either distal pulmonary vascular obstruction and/or significant comorbidities. Therefore, surgical candidates should be carefully selected by an interprofessional team in expert centers. This review aims at making an overview of the risk factors and latest developments in diagnostic tools and treatment options for CTEPH.

Gastroesophageal Reflux Disease in Idiopathic Pulmonary Fibrosis: Viewer or Actor? To Treat or Not to Treat?

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare and severe disease with a median survival of ∼3 years. Several risk factors have been identified, such as age, genetic predisposition, tobacco exposure, and gastro-oesophageal reflux disease (GERD). Prevalence of GERD in IPF is high and may affect 87% of patients, of whom only half (47%) report symptoms. Objective: The aim of this study is to review current evidence regarding the correlation between GERD and IPF and to evaluate the current studies regarding treatments for GERD-IPF. Methods: A review to identify research papers documenting an association between GERD and IPF was performed. Results: We identified several studies that have confirmed the association between GERD and IPF, with an increased acid exposure, risk of gastric aspiration and bile acids levels in these patients. Few studies focused their attention on GERD treatment, showing how antiacid therapy was not able to change IPF evolution. Conclusions: This review investigating the correlation between GERD and IPF has confirmed the hypothesized association. However, further large prospective studies are needed to corroborate and elucidate these findings with a focus on preventative and treatment strategies.

Laser Speckle Contrast Analysis: Functional Evaluation of Microvascular Damage in Connective Tissue Diseases. Is There Evidence of Correlations With Organ Involvement, Such as Pulmonary Damage?

Laser speckle contrast analysis (LASCA) is a non-contact technique able to quantify peripheral blood perfusion (PBP) over large skin areas. LASCA has been used to study hand PBP in several clinical conditions. These include systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) and LASCA showed that PBP was significantly lower in these conditions than in healthy subjects (HS). Moreover, it has been demonstrated that LASCA is a safe technique also able to monitor digital ulcer perfusion and their evolution in SSc patients, during systemic and local treatment. The use of LASCA, coupled with reactivity tests is commonplace in the field of microvascular function research. Post-occlusive hyperemia reactivity (POHR) and local thermal hyperemia, associated with laser techniques are reliable tests in the evaluation of perfusion in SSc patients. Other studies used laser speckled techniques, together with acetylcholine and sodium nitroprusside iontophoresis, as specific tests of endothelium function. In conclusion, LASCA is a safe, non-contact reliable instrument for the quantification of PBP at skin level and can also be associated with reactivity tests to monitor disease progression and response to treatment in different connective tissue diseases.

The Relationship between Pulmonary Damage and Peripheral Vascular Manifestations in Systemic Sclerosis Patients.

Systemic sclerosis (SSc) is an autoimmune disease, characterized by the presence of generalized vasculopathy and tissue fibrosis. Collagen vascular disorder in SSc is due to fibroblast and endothelial cell dysfunctions. This leads to collagen overproduction, vascular impairment and immune system abnormalities and, in the last stage, multi-organ damage. Thus, to avoid organ damage, which has a poor prognosis, all patients should be carefully evaluated and followed. This is particularly important in the initial disease phase, so as to facilitate early identification of any organ involvement and to allow for appropriate therapy. Pulmonary disease in SSc mainly involves interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). High-resolution computed tomography (HRCT) and pulmonary function tests (PFT) have been proposed to monitor parenchymal damage. Although transthoracic echocardiography is the most commonly used screening tool for PAH in SSc patients, definitive diagnosis necessitates confirmation by right heart catheterization (RHC). Moreover, some studies have demonstrated that nailfold videocapillaroscopy (NVC) provides an accurate evaluation of the microvascular damage in SSc and is able to predict internal organ involvement, such as lung impairment. This review provides an overview of the correlation between lung damage and microvascular involvement in SSc patients.

High-Resolution Computed Tomography and Lung Ultrasound in Patients with Systemic Sclerosis: Which One to Choose?

Imaging plays a pivotal role in systemic sclerosis for both diagnosis management of pulmonary complications, and high-resolution computed tomography (HRCT) is the most sensitive technique for the evaluation of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Indeed, several studies have demonstrated that HRCT helps radiologists and clinicians to make a correct diagnosis on the basis of recognised typical patterns for SSc-ILD. Most SSc patients affected by ILD have a non-specific interstitial pneumonia pattern (NISP) on HRCT scan, whilst a minority of cases fulfil the criteria for usual interstitial pneumonia (UIP). Moreover, several recent studies have demonstrated that lung ultrasound (LUS) is an emergent tool in SSc diagnosis and follow-up, although its role is still to be confirmed. Therefore, this article aims at evaluating the role of LUS in SSc screening, aimed at limiting the use of CT to selected cases.

High-Resolution Computed Tomography: Lights and Shadows in Improving Care for SSc-ILD Patients.

The diagnosis and classification of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is essential to improve the prognosis of systemic sclerosis (SSc) patients. The risk-stratification of disease severity and follow-up requires a multidisciplinary approach, integrating high-resolution computed tomography (HRTC) of the lung, pulmonary function tests (PFT), along with clinical and symptomatic evaluations. The use of HRCT in detecting SSc-ILD is not so much based on a definitive validation, but rather reflects the widespread clinician recognition of dissatisfaction with other modalities. However, due to the heterogeneity of SSc-ILD and the potential absence of symptoms in early or mild disease, it is prudent to consider as many parameters as possible in the assessment and monitoring of newly diagnosed patients. An early diagnosis meets the primary goal, i.e., the prevention of disease progression. The current first line treatment regimens are mainly centered on immunosuppressive therapy. This review assesses the role HRCT plays in optimizing care and improving clinical outcomes in SSc-ILD patients.

Accuracy of right atrial pressure estimation using a multi-parameter approach derived from inferior vena cava semi-automated edge-tracking echocardiography: a pilot study in patients with cardiovascular disorders.

The echocardiographic estimation of right atrial pressure (RAP) is based on the size and inspiratory collapse of the inferior vena cava (IVC). However, this method has proven to have limits of reliability. The aim of this study is to assess feasibility and accuracy of a new semi-automated approach to estimate RAP. Standard acquired echocardiographic images were processed with a semi-automated technique. Indexes related to the collapsibility of the vessel during inspiration (Caval Index, CI) and new indexes of pulsatility, obtained considering only the stimulation due to either respiration (Respiratory Caval Index, RCI) or heartbeats (Cardiac Caval Index, CCI) were derived. Binary Tree Models (BTM) were then developed to estimate either 3 or 5 RAP classes (BTM3 and BTM5) using indexes estimated by the semi-automated technique. These BTMs were compared with two standard estimation (SE) echocardiographic methods, indicated as A and B, distinguishing among 3 and 5 RAP classes, respectively. Direct RAP measurements obtained during a right heart catheterization (RHC) were used as reference. 62 consecutive 'all-comers' patients that had a RHC were enrolled; 13 patients were excluded for technical reasons. Therefore 49 patients were included in this study (mean age 62.2 ± 15.2 years, 75.5% pulmonary hypertension, 34.7% severe left ventricular dysfunction and 51% right ventricular dysfunction). The SE methods showed poor accuracy for RAP estimation (method A: misclassification error, ME = 51%, R2 = 0.22; method B: ME = 69%, R2 = 0.26). Instead, the new semi-automated methods BTM3 and BTM5 have higher accuracy (ME = 14%, R2 = 0.47 and ME = 22%, R2 = 0.61, respectively). In conclusion, a multi-parametric approach using IVC indexes extracted by the semi-automated approach is a promising tool for a more accurate estimation of RAP.

Reliability of noninvasive hemodynamic assessment with Doppler echocardiography: comparison with the invasive evaluation.

AIMS: The study aimed at evaluating the reliability and reproducibility of various noninvasive echocardiographic techniques for the estimation of the main hemodynamic parameters in clinical practice. METHODS: A total of 84 patients with a generic indication of right heart catheterization (RHC) executed a transthoracic echocardiography shortly before or after the RHC. All the parameters necessary for a noninvasive hemodynamic evaluation of right atrial pressure, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure, pulmonary vascular resistance and cardiac output were acquired and the agreement with the invasive measures was evaluated by a Bland-Altman analysis. RESULTS: Noninvasive evaluation of right atrial pressure showed a moderate and low correlation with RHC using inferior vena cava parameters (r = 0.517) and tricuspid E/E' ratio (sensitivity 0.23, specificity 0.72), respectively. PAPs estimation from the tricuspid regurgitation peak velocity had a good correlation (r = 0.836) and feasibility (82.1%), as well as PAPm from tricuspid regurgitation mean gradient (r = 0.78, applicability 72.6%) and from pulmonary acceleration time (sensitivity 0.85, specificity 0.5, applicability 92.9%). Pulmonary capillary wedge pressure multiparametric evaluation, as suggested by the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations, showed a good correlation (sensitivity 0.96, specificity 0.59). The noninvasive evaluation of pulmonary vascular resistance and cardiac output did not prove to be clinically accurate. CONCLUSION: Various hemodynamic parameters can be adequately estimated with noninvasive methods. In particular, a multiparametric approach for the evaluation of left ventricle filling pressures is advisable and the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations are reliable even in a heterogeneous population with a significant quota of precapillary pulmonary hypertension.

Cough and ventilatory adjustments evoked by aerosolised capsaicin and distilled water (fog) in man.

Airway receptors mediate cough and ventilatory adjustments. Simultaneous assessment of cough sensory-motor components and changes in breathing pattern may provide insights into the receptor(s) prevailingly stimulated by inhaled irritants. Nineteen subjects inhaled capsaicin and fog up to threshold concentrations for cough. Cough intensity, respiratory sensations and changes in breathing pattern induced by the two irritants were compared. Capsaicin and fog cough threshold values did not correlate. Coughing induced by both agents was preceded by qualitatively similar sensations and by significant increases in minute ventilation and respiratory drive due to selective increases in tidal volume (P<0.01). Cough intensity was similar with both agents. Cough frequency and the intensity of the urge to cough were higher with capsaicin (P<0.01). The lack of correlation between fog and capsaicin cough threshold values suggests differences in the neural mechanisms activated. The selective increase in tidal volume suggests prevailing involvement of rapidly adapting receptors. The stronger sensations evoked by capsaicin may contribute to the higher cough frequency observed with this agent.

Complement Protein C1q Binds to Hyaluronic Acid in the Malignant Pleural Mesothelioma Microenvironment and Promotes Tumor Growth.

C1q is the first recognition subcomponent of the complement classical pathway, which acts toward the clearance of pathogens and apoptotic cells. C1q is also known to modulate a range of functions of immune and non-immune cells, and has been shown to be involved in placental development and sensorial synaptic pruning. We have recently shown that C1q can promote tumor by encouraging their adhesion, migration, and proliferation in addition to angiogenesis and metastasis. In this study, we have examined the role of human C1q in the microenvironment of malignant pleural mesothelioma (MPM), a rare form of cancer commonly associated with exposure to asbestos. We found that C1q was highly expressed in all MPM histotypes, particularly in epithelioid rather than in sarcomatoid histotype. C1q avidly bound high and low molecular weight hyaluronic acid (HA) via its globular domain. C1q bound to HA was able to induce adhesion and proliferation of mesothelioma cells (MES) via enhancement of ERK1/2, SAPK/JNK, and p38 phosphorylation; however, it did not activate the complement cascade. Consistent with the modular organization of the globular domain, we demonstrated that C1q may bind to HA through ghA module, whereas it may interact with human MES through the ghC. In conclusion, C1q highly expressed in MPM binds to HA and enhances the tumor growth promoting cell adhesion and proliferation. These data can help develop novel diagnostic markers and molecular targets for MPM.

Sildenafil in severe pulmonary hypertension associated with chronic obstructive pulmonary disease: A randomized controlled multicenter clinical trial.

BACKGROUND: Pulmonary hypertension (PH) is a well-known independent prognostic factor in chronic obstructive pulmonary disease (COPD) and a sufficient criterion for lung transplant candidacy. Limited data are currently available on the hemodynamic and clinical effect of phosphodiesterase 5 inhibitors in patients with severe PH associated with COPD. This study assessed the effect of sildenafil on pulmonary hemodynamics and gas exchange in severe PH associated with COPD. METHODS: After screening, this multicenter, randomized, placebo-controlled double-blind trial randomized patients to receive 20 mg sildenafil or placebo 3 times a day (ratio 2:1) for 16 weeks. The primary end point was the reduction in pulmonary vascular resistance. Secondary end points included BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, 6-minute walk test, and quality of life questionnaire. Changes in the partial pressure of arterial oxygen were evaluated as a safety parameter. RESULTS: The final population included 28 patients, 18 in the sildenafil group and 10 in the placebo group. At 16 week, patients treated with sildenafil had a decrease in pulmonary vascular resistance (mean difference with placebo -1.4 WU; 95% confidence interval, ≤ -0.05; p = 0.04). Sildenafil also improved the BODE index, diffusion capacity of the lung for carbon monoxide percentage, and quality of life. Change from baseline in the partial pressure of arterial oxygen was not significantly different between the sildenafil and placebo groups. CONCLUSIONS: This pilot study found that treatment with sildenafil reduced pulmonary vascular resistance and improved the BODE index and quality of life, without a significant effect on gas exchange.

Agreement between two methods for assessing bioequivalence of inhaled salbutamol.

For inhaled medications, bioequivalence testing is becoming increasingly important owing to the availability of many inhalation devices. We evaluated agreement between the Finney bioassay and the Emax model in the assessment of bioequivalence of salbutamol administered via a metered-dose inhaler with a spacer (pMDI+ Volumatic) or via a dry-powder inhaler (Diskus) in asthmatic patients with methacholine-induced bronchoconstriction. Eighteen patients inhaled methacholine until FEV 1 decreased by approximately 35% of control. Following inhalation of placebo, 200 and 400 mcg salbutamol through the pMDI+ Volumatic or the Diskus, changes in FEV 1 were repeatedly measured over a 60-min observation period. Bioequivalence of salbutamol administered via the two inhalation devices was assessed by calculating the relative potency of each device by using the Finney 2-by-2 parallel regression analysis and the non-linear, Emax model. Agreement between these methods in calculating relative potency was evaluated by using the Bland-Altman method. After salbutamol FEV 1 values were similar irrespective of the device employed, and greater (P<0.01) than those after placebo. However, assessment of relative potencies obtained with both the Finney (1.97, 90% CI 1.62-2.32) and the Emax (2.25, 90% CI 1.90-2.60) methods revealed that twice the salbutamol dose was needed to reverse methacholine-induced bronchoconstriction when the drug was inhaled via the Diskus than via the pMDI+ Volumatic. The mean difference in relative potency (-0.28, 90% CI -0.001 to -0.56) calculated with both methods did not significantly differ from zero, and none of the individual differences exceeded the limits of agreement. The Finney and the Emax methods provide comparable results in the evaluation of bioequivalence of different salbutamol formulations. The pMDI+ Volumatic is twice as efficient as the Diskus in lung delivery of salbutamol in asthma patients.