Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life. METHODS: We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations). RESULTS: The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash. CONCLUSIONS: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244).

Inhaled treprostinil in pulmonary hypertension associated with COPD: PERFECT study results.

BACKGROUND: Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study (ClinicalTrials.gov: NCT03496623) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. METHODS: Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12. RESULTS: In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. CONCLUSIONS: The risk-benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.

Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is a rare angiogenic disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Pazopanib is an oral multi-kinase angiogenesis inhibitor with promise to treat bleeding in HHT. We analyzed outcomes of HHT patients with the most severe bleeding causing RBC transfusion dependence treated on a predefined institutional pazopanib treatment pathway (with data collected retrospectively). The primary endpoint was achievement of transfusion independence. Secondary endpoints included hemoglobin, epistaxis severity score, RBC transfusion and iron infusion requirements, number of local hemostatic procedures, ferritin and transferrin saturation, compared using paired and repeated measures mean tests. Thirteen transfusion-dependent HHT patients received pazopanib [median (range) dose 150 (25-300) mg daily)] for a median of 22 months. All patients achieved transfusion independence. Compared with pretreatment, pazopanib increased mean hemoglobin by 4.8 (95% CI, 3.6-5.9) g/dL (7.8 vs. 12.7 g/dL, P < 0.0001) and decreased mean epistaxis severity score by 4.77 (3.11-6.44) points (7.20 vs. 2.43 points, P < 0.0001) after 12 months of treatment. Compared with 3 months of pretreatment, RBC transfusions decreased by 93% (median of 16.0 vs. 0.0 units, P < 0.0001) and elemental iron infusion decreased by 92% (median of 4500 vs. 0 mg, P = 0.005) during the first 3 months of treatment; improvements were maintained over time. Pazopanib was well-tolerated: hypertension, lymphocytopenia, and fatigue were the most common TEAEs. In conclusion, pazopanib was safe and effective to manage severe bleeding in HHT, liberating all patients from transfusion dependence and normalizing hematologic parameters at doses lower than used to treat malignancies. These findings require confirmation in a randomized trial.

Prospective cohort of cryobiopsy in interstitial lung diseases: a single center experience.

RATIONALE: Transbronchial cryobiopsy has been increasingly used to diagnose interstitial lung diseases. However, there is uncertainty regarding its accuracy and risks, mainly due to a paucity of prospective or randomized trials comparing cryobiopsy to surgical biopsy. OBJECTIVES: To evaluate the diagnostic yield and complications of cryobiopsy in patients selected by multidisciplinary discussion. METHODS: This was a prospective cohort from 2017 to 2019. We included consecutive patients with suspected interstitial lung diseases being considered for lung biopsy presented at our multidisciplinary meeting. MEASUREMENTS AND MAIN RESULTS: Of 112 patients, we recommended no biopsy in 31, transbronchial forceps biopsy in 16, cryobiopsy in 54 and surgical biopsy in 11. By the end of the study, 34 patients had had cryobiopsy and 24 patients, surgical biopsy. Overall pathologic and multidisciplinary diagnostic yield of cryobiopsy was 47.1% and 61.8%, respectively. The yield increased over time for both pathologic (year 1: 28.6%, year 2: 54.5%, year 3: 66.7%, p = 0.161) and multidisciplinary (year 1: 50%, year 2: 63.6%, year 3: 77.8%, p = 0.412) diagnosis. Overall rate of grade 4 bleeding after cryobiopsy was 11.8%. Cryobiopsy required less chest tube placement (11.8% vs 100%, p < 0.001) and less hospitalizations compared to surgical biopsy (26.5% vs 95.7%, p < 0.001), but hospitalized patients had a longer median hospital stay (2 days vs 1 day, p = 0.004). CONCLUSIONS: Diagnostic yield of cryobiopsy increased over time but the overall grade 4 bleeding rate was 11.8%.

An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study.

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHT-associated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, epistaxis severity score, red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. 238 HHT patients received bevacizumab for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% CI, 2.9-3.5 g/dL) [mean hemoglobin 8.6 (8.5, 8.8) g/dL versus 11.8 (11.5, 12.1) g/dL, p<0.0001)] and decreased the epistaxis severity score (ESS) by 3.4 (3.2-3.7) points [mean ESS 6.8 (6.6-7.1) versus 3.4 (3.2-3.7), P<0.0001] during the first year of treatment. Compared with 6 months pretreatment, RBC units transfused decreased by 82% [median of 6.0 (IQR 0.0-13.0) units versus 0 (IQR, 0.0-1.0) units, P<0.0001] and iron infusions decreased by 70% [median of 6.0 (1.0-18.0) infusions versus 1.0 (0.0-4.0) infusions, P<0.0001] during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective to manage chronic bleeding and anemia in HHT.

Temporarily switching from oral to intravenous selexipag in patients with pulmonary arterial hypertension: safety, tolerability, and pharmacokinetic results from an open-label, phase III study.

BACKGROUND: The oral IP receptor agonist selexipag is approved for the long-term treatment of pulmonary arterial hypertension (PAH). Treatment interruptions should be avoided due to the progressive nature of the disease. An intravenous (IV) formulation of selexipag was developed to provide a treatment option for short-term interruptions to oral selexipag. In this prospective, multicenter, open-label study, the safety, tolerability, and pharmacokinetics of temporarily switching between oral and IV selexipag were investigated (NCT03187678, ClinicalTrials.gov). METHODS: PAH patients receiving stable oral selexipag doses were enrolled. Following three consecutive IV selexipag infusions patients resumed oral selexipag. Corresponding IV and oral doses were selected to achieve comparable exposure to the active metabolite of selexipag. Safety outcomes were monitored throughout, and pharmacokinetic samples were obtained after oral and IV administration. RESULTS: All 20 patients completed the study. Fifteen patients had adverse events (AEs), most were mild, and none resulted in discontinuation. Headache was the most common AE throughout the study (four patients). Three serious AEs occurred in two patients with underlying comorbidities when oral dosing had resumed. There were no changes in WHO functional class for any patient and no clinically symptomatic changes in blood pressure were observed. Comparable exposure to the active metabolite of selexipag was demonstrated following corresponding oral and IV selexipag doses. CONCLUSIONS: Temporarily switching between corresponding doses of oral and IV selexipag was well-tolerated with no unexpected safety findings and comparable exposure to the active metabolite. Treatment with IV selexipag is a feasible option to bridge temporary oral selexipag treatment interruptions.

Performance of diagnostic criteria in patients clinically judged to have cardiac sarcoidosis: Is it time to regroup?

BACKGROUND: The diagnosis of cardiac sarcoidosis (CS) is challenging. Because of the current limitations of endomyocardial biopsy as a reference standard, physicians rely on advanced cardiac imaging, multidisciplinary evaluation, and diagnostic criteria to diagnose CS. AIMS: To compare the 3 main available diagnostic criteria in patients clinically judged to have CS. METHODS: We prospectively included patients clinically judged to have CS by a multidisciplinary sarcoidosis team from November 2016 to October 2017. We included only incident cases (diagnosis of CS within 1 year of inclusion). We applied retrospectively the following diagnostic criteria: the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG), the Heart Rhythm Society (HRS), and the Japanese Circulation Society (JCS) 2016 criteria. RESULTS: We identified 69 patients. Diagnostic criteria classified patients as follows: WASOG as highly probable (1.4%), probable (52.2%), possible (0%), some criteria (40.6%), and no criteria (5.8%); HRS as histological diagnosis (1.4%), probable (52.2%), some criteria (40.6%), and no criteria (5.8%); JCS as histological diagnosis (1.4%), clinical diagnosis (58%), some criteria (39.1%), and no criteria (1.4%). Concordance was high between WASOG and HRS (κ = 1) but low between JCS and the others (κ = 0.326). CONCLUSIONS: A high proportion of patients clinically judged to have CS are unable to be classified according to the 3 main diagnostic criteria. There is low concordance between JCS criteria and the other 2 criteria (WASOG and HRS).

Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia.

Pazopanib (Votrient) is an orally administered tyrosine kinase inhibitor that blocks VEGF receptors potentially serving as anti-angiogenic treatment for hereditary hemorrhagic telangiectasia (HHT). We report a prospective, multi-center, open-label, dose-escalating study [50 mg, 100 mg, 200 mg, and 400 mg], designed as a proof-of-concept study to demonstrate efficacy of pazopanib on HHT-related bleeding, and to measure safety. Patients, recruited at 5 HHT Centers, required ≥ 2 Curacao criteria AND [anemia OR severe epistaxis with iron deficiency]. Co-primary outcomes, hemoglobin (Hgb) and epistaxis severity, were measured during and after treatment, and compared to baseline. Safety monitoring occurred every 1.5 weeks. Seven patients were treated with 50 mg pazopanib daily. Six/seven showed at least 50% decrease in epistaxis duration relative to baseline at some point during study; 3 showed at least 50% decrease in duration during Weeks 11 and 12. Six patients showed a decrease in ESS of > 0.71 (MID) relative to baseline at some point during study; 3/6 showed a sustained improvement. Four patients showed > 2 gm improvement in Hgb relative to baseline at one or more points during study. Health-related QOL scores improved on all SF-36 domains at Week 6 and/or Week 12, except general health (unchanged). There were 19 adverse events (AE) including one severe AE (elevated LFTs, withdrawn from dosing at 43 days); with no serious AE. In conclusion, we observed an improvement in Hgb and/or epistaxis in all treated patients. This occurred at a dose much lower than typically used for oncologic indications, with no serious AE. Further studies of pazopanib efficacy are warranted.

The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome.

BACKGROUND: Juvenile polyposis syndrome is a dominant GI polyposis syndrome defined by ≥ 5 GI juvenile polyps or ≥ 1 juvenile polyps with a family history of juvenile polyposis. Mutations in BMPR1A or SMAD4 are found in 50% of individuals. Hereditary hemorrhagic telangiectasia is a dominant disorder characterized by epistaxis, visceral arteriovenous malformations, and telangiectasias. Hereditary hemorrhagic telangiectasia is diagnosed when ≥ 3 criteria including clinical manifestations or a family history, are present. A juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome has previously been reported in 22% of patients with juvenile polyposis due to a SMAD4 mutation. OBJECTIVE: Our objective was to determine the prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia by Curacao criteria in our juvenile polyposis SMAD4 patients. DESIGN, PATIENTS, AND SETTING: This was a cohort study of juvenile polyposis patients in our inherited colon cancer registries. Hereditary hemorrhagic telangiectasia manifestations were obtained from medical records, patient contact, and/or prospective hereditary hemorrhagic telangiectasia screening. The Curacao criteria was used for diagnosis of hereditary hemorrhagic telangiectasia (≥ 3 criteria diagnostic; 2 criteria suspect of). MAIN OUTCOME MEASURES: Prevalence and clinical manifestations of hereditary hemorrhagic telangiectasia in juvenile polyposis SMAD4 patients. RESULTS: Forty-one juvenile polyposis families were identified. Genetic testing was available for individuals within 18 families. SMAD4 mutations were found in 21 relatives in 9 families. Eighty-one percent of SMAD4 patients had hereditary hemorrhagic telangiectasia and 14% were suspected of having hereditary hemorrhagic telangiectasia. Epistaxis and asthma are the most common symptoms in our overlap patients. Symptomatic and subclinical arteriovenous malformations were noted near universally. LIMITATIONS: There was a single, tertiary referral center. CONCLUSIONS: Nearly all juvenile polyposis SMAD4 patients have the overlap syndrome. The clinical implications and need for hereditary hemorrhagic telangiectasia screening are important factors for genetic testing in juvenile polyposis. Health care providers must be cognizant of the juvenile polyposis-hereditary hemorrhagic telangiectasia overlap syndrome and the implications for management of these patients.

Acute interstitial pneumonia (AIP): relationship to Hamman-Rich syndrome, diffuse alveolar damage (DAD), and acute respiratory distress syndrome (ARDS).

Acute interstitial pneumonia (AIP) is a term used for an idiopathic form of acute lung injury characterized clinically by acute respiratory failure with bilateral lung infiltrates and histologically by diffuse alveolar damage (DAD), a combination of findings previously known as the Hamman-Rich syndrome. This review aims to clarify the diagnostic criteria of AIP, its relationship with DAD and acute respiratory distress syndrome (ARDS), key etiologies that need to be excluded before making the diagnosis, and the salient clinical features. Cases that meet clinical and pathologic criteria for AIP overlap substantially with those that fulfill clinical criteria for ARDS. The main differences between AIP and ARDS are that AIP requires a histologic diagnosis of DAD and exclusion of known etiologies. AIP should also be distinguished from "acute exacerbation of IPF," a condition in which acute lung injury (usually DAD) supervenes on underlying usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF).

Sclerotherapy Versus Cautery/Laser Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia.

OBJECTIVES/HYPOTHESIS: Surgical interventions for epistaxis management in hereditary hemorrhagic telangiectasia (HHT) demonstrate short-term success and require repeated procedures for disease control. Although electrocautery and/or laser photocoagulation (C ± L) are most frequently performed, sodium tetradecyl sclerotherapy (STS) is emerging as a promising newer treatment. We hypothesized that in a 24-month time period, STS would require fewer treatments than C ± L to maintain epistaxis severity within the mild range. STUDY DESIGN: Retrospective study. METHODS: We retrospectively assessed 67 patients with HHT with moderate and severe epistaxis that were treated periodically with C ± L (34 patients) versus STS (33 patients). The primary outcome was the number of procedures needed to maintain the epistaxis severity score (ESS) as mild. Secondary outcomes assessed for differences in postoperative complications, hemoglobin levels, iron stores, hematologic support, and quality-of-life (QoL) scores. RESULTS: To maintain ESS in the mild range, 1.6 STS procedures (range, 1-4) were performed versus 3.6 C ± L procedures (range, 1-8) (P = .003). Significant postoperative differences included reduction in nasal crusting (3% vs. 32%, P = .001), foul odor (3% vs. 35%, P < .001), and septal perforation (3% vs. 29%, P = .006) after STS. There were no significant differences between the two treatments in hemoglobin levels, iron stores, hematologic support, or QoL scores. CONCLUSION: STS is able to attain satisfactory epistaxis control with significantly fewer procedures and lower postoperative complications than C ± L. STS should be considered as the initial surgical intervention for epistaxis in patients with HHT. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:920-925, 2022.

Roflumilast (Daliresp®) to reduce acute pulmonary events in fibrotic sarcoidosis: a multi-center, double blind, placebo controlled, randomized clinical trial.

BACKGROUND: Fibrotic sarcoidosis patients often have acute events of increased cough and sputum production. We evaluated the impact of roflumilast in fibrotic sarcoidosis patients with repeated episodes of increased cough and sputum. METHODS: Sarcoidosis patients with pulmonary fibrosis and at least two acute episodes in the previous year were randomized to receive either roflumilast (ROF) or placebo (PLA) in a double blind, placebo controlled multi-center trial. Subjects were assessed initially and every three months for 12 months. At each visit, spirometry and health related quality of life questionnaires were completed. For each subject, the best forced expiratory volume at 1 second (FEV-1) was noted. RESULTS: Of the 38 subjects who enrolled in the study, 28 subjects (14 in each group) received at least three months of treatment and 10 in each arm completing all 12 months of study. During the treatment, patients treated with ROF were less likely to have visits in which the FEV-1 was less than 90% of the best FEV-1 (Odds ratio=0.34 (0.16 to 0.76 95% confidence interval, p=0.0073). At the end of treatment with ROF, patients had a significant improvement in their KSQ LUNG (Initial visit: 45.3 ± 6.89 (Mean ± S.D.); Last visit: 52.6± 7.91, p<0.05) with no change for PLA treated patients. CONCLUSION: Patients treated with at least three months of roflumilast had fewer follow-up visits with an FEV-1 of less than 90% of best value. At the end of treatment, ROF treated patients had a better quality of life as assessed by KSQ LUNG. CLINICAL TRIAL REGISTRATION: NCT01830959.

SMAD4 mutation and the combined syndrome of juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia.

Juvenile polyposis syndrome (JPS) and hereditary haemorrhagic telangiectasia (HHT) are autosomal dominant disorders with characteristic clinical phenotypes. Recently, reports of the combined syndrome of JPS and HHT have been described in individuals with mutations in the SMAD4 gene, whose product-SMAD4-is a critical intracellular effector in the signalling pathway of transforming growth factor beta (TGFbeta). This report describes a 24-year-old man who presented to the Respiratory Institute after colectomy for JPS with a SMAD4 mutation and who was subsequently diagnosed to have HHT with asymptomatic cerebral and pulmonary arteriovenous malformations (AVMs). Patients with JPS due to a SMAD4 mutation should be screened for the vascular lesions associated with HHT, especially occult AVMs in visceral organs, which may potentially present catastrophically with serious medical consequences.

Echocardiography, 6-minute walk distance, and distance-saturation product as predictors of pulmonary arterial hypertension in idiopathic pulmonary fibrosis.

BACKGROUND: Pulmonary arterial hypertension (PAH) is frequently seen in patients with idiopathic pulmonary fibrosis (IPF). We sought to examine the performance of echocardiography, 6-min walk test (6MWT) distance, distance-saturation product (DSP), and pulse oximetry (SpO2) in detecting underlying PAH in IPF. METHODS: 626 lung transplanted patients from February 1990 to December 2007 were considered. Subjects with pre-transplant diagnosis of IPF were evaluated. Based on findings in pre-transplant right heart catheterization, the presence or absence of PAH was recorded. Right-ventricle systolic pressure, 6MWT distance, DSP, and lowest SpO2 during 6MWT were compared in PAH and non-PAH groups. Receiver operating characteristic curves for each variable to assess prediction of PAH were constructed. RESULTS: 131 patients were transplanted due to IPF. Of these 131 patients, 58 (44%) were eligible. PAH was diagnosed by right heart catheterization in 25 (43%) of 58 eligible patients. The mean pulmonary arterial pressure in PAH patients was 33 mm Hg, and 19 mm Hg in non-PAH patients (P = .001). 6MWT distance was 321 m in the PAH group, and 346 m in the non-PAH one (P = .38). DSP in PAH subjects was 272 meters% and 286 meters% in those with no PAH (P = .57). The lowest SpO2 in the PAH and non-PAH groups were 84% and 82%, respectively (P = .38). The diagnostic accuracy of the echocardiography exceeded that of the other variables (area under the curve 0.72). CONCLUSIONS: Right-ventricle systolic pressure measured by echocardiography, by 6MWT distance, by DSP, or by SpO2 performs poorly in detecting PAH in IPF. Measured by right heart catheterization, right-ventricle systolic pressure performs better to predict PAH in IPF.

Desquamative interstitial pneumonia as the initial manifestation of systemic sclerosis.

Interstitial lung disease (ILD) is a frequent pulmonary complication of systemic sclerosis (SSc), and nonspecific interstitial pneumonia is the most commonly recognized pattern of lung injury in these patients. In this report, we describe a never-smoker female presenting with Raynaud phenomenon and ILD that demonstrated desquamative interstitial pneumonia (DIP) on surgical lung biopsy. After 8 months, she was diagnosed with pulmonary hypertension at which time clinical examinations and serologic findings established the diagnosis of SSc. This case report expands the spectrum of patterns of ILD seen in association with SSc to include DIP.

Obstructive bronchiolar disease identified by CT in the non-transplant population: analysis of 29 consecutive cases.

BACKGROUND AND OBJECTIVE: Obstructive bronchiolar disease or constrictive bronchiolitis, particularly in non-transplant patients, is poorly understood. This study identified the associated diseases, presenting features, and clinical course of obstructive bronchiolar disease identified by CT in the non-transplant adult population. METHODS: Retrospective single-centre study of 29 consecutive patients clinically diagnosed to have an obstructive bronchiolar disease based on the presence of respiratory symptoms and abnormal CT findings consisting of mosaic perfusion pattern with air trapping. RESULTS: The median age was 54 years (range, 25-80 years); 20 were women (69%) and four patients (14%) had a smoking history. All 29 patients presented with respiratory symptoms, predominantly dyspnoea. The most common cause of obstructive bronchiolar disease was rheumatoid arthritis (34%). Other causes included hypersensitivity pneumonitis, multiple carcinoid tumorlets, Sjögren's syndrome, paraneoplastic pemphigus, inflammatory bowel disease and Swyer-James syndrome. The underlying cause was not identifiable in nine patients (31%), that is, cryptogenic constrictive bronchiolitis. An obstructive pattern was seen on pulmonary function testing in most patients (86%) with the exception of those with hypersensitivity pneumonitis and extreme obesity. Management usually included corticosteroid therapy, inhaled and oral, and bronchodilator therapy. Additional medications included macrolides, cytotoxic agents and other immunomodulator therapy. Pharmacologic therapy did not provide improvement in pulmonary function in the majority of patients but the follow-up data were limited. CONCLUSIONS: Diverse causes and underlying diseases are associated with obstructive bronchiolar disease diagnosed radiologically in the non-transplant adult population. Rheumatoid arthritis-associated and cryptogenic constrictive bronchiolitis are found in over one-half of these patients. Most patients with obstructive bronchiolar disease do not appear to improve with currently available therapy.

Nicotine and oxidative cigarette smoke constituents induce immune-modulatory and pro-inflammatory dendritic cell responses.

Chronic airway inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD), a destructive cigarette smoke-induced lung disease. Although it is apparent that dendritic cells (DCs) are an important constituent of the chronic inflammatory cell influx found in airways of COPD patients, the functional roles of DCs in the pathogenesis of smoking-induced emphysema are unknown. We postulated that DCs activated by cigarette smoke constituents directly participate in the chronic inflammation that characterizes COPD airways. Concordant with this hypothesis, we observed that incubation of DCs with cigarette smoke extract (CSE), and chronic exposure of mice to cigarette smoke, both augmented the generation of neutrophilic chemokines by immature and lipopolysaccharide (LPS) or CD40L-matured DCs. The generation of interleukin-8 (CXCL8/IL-8) by human DCs conditioned with CSE was suppressed by the anti-oxidant n-acetyl cysteine (NAC), implying the involvement of oxidant sensitive pathways as a primary mechanism involved in the enhanced CXCL8/IL-8 generation. Cigarette smoke extract and nicotine also augment the production of secreted prostaglandin-E2 and intra-cellular cyclo-oxygenase-2 (COX-2) in maturing DCs. Whereas NAC suppressed production of CXCL8 by CSE-conditioned DCs, it augmented production of PGE2 and cellular COX-2 levels in maturing DCs. These studies indicate that the stimulation of DCs by cigarette smoke-induced oxidative stress and nicotine promote the generation of pro-inflammatory responses that promote chronic inflammation in smokers. Certain pharmacologic strategies such as anti-oxidant therapy may be only partially effective in mitigating cigarette smoke-induced pro-inflammatory DC-mediated responses in smokers.

Pulmonary hypertension caused by sarcoidosis.

Pulmonary hypertension is an uncommon complication of sarcoidosis, but in severe pulmonary disease it occurs frequently. It is an important cause of cryptogenic dyspnea in sarcoidosis patients and can occur despite the absence of pulmonary fibrosis. The true prevalence is unknown. With the advent of specific therapies for pulmonary hypertension, there has been a resurgence of interest in the pathophysiology, diagnosis, and treatment of sarcoidosis-associated pulmonary hypertension. This article reviews the status of the current epidemiologic, pathophysiologic, and therapeutic knowledge regarding this entity.