An open-label trial of rituximab therapy in pulmonary alveolar proteinosis.

Rituximab, a monoclonal antibody directed against the B-lymphocyte antigen CD20, has shown promise in several autoimmune disorders. Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterised by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF). An open-label, proof-of-concept phase II clinical trial was conducted in 10 PAP patients. The intervention consisted of two intravenous infusions of rituximab (1,000 mg) 15 days apart. Bronchoalveolar lavage (BAL) fluid and peripheral blood samples were collected. The primary outcome was improvement in arterial blood oxygenation. Both arterial oxygen tension and alveolar-arterial oxygen tension difference in room air improved in seven out of the nine patients completing the study. Lung function and high-resolution computed tomography scans, which were secondary outcomes, also improved. Peripheral blood CD19+ B-lymphocytes decreased from mean ± sem 15 ± 2% to <0.05% (n = 10) 15 days post-therapy. This decrease persisted for 3 months in all patients; at 6 months, CD19+ B-cells were detected in four out of seven patients (5 ± 2%). Total anti-GM-CSF immunoglobulin (Ig)G levels from baseline to 6 months were decreased in BAL fluids (n = 8) but unchanged in sera (n = 9). In this PAP cohort: 1) rituximab was well-tolerated and effectively ameliorated lung disease; and 2) reduction in anti-GM-CSF IgG levels in the lung correlated with disease changes, suggesting that disease pathogenesis is related to autoantibody levels in the target organ.

Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial.

The aim of the present study was to investigate the efficacy of infliximab for the treatment of extrapulmonary sarcoidosis. A prospective, randomised, double-blind, placebo-controlled trial was conducted, with infliximab at 3 and 5 mg x kg(-1) body weight administered over 24 weeks. Extrapulmonary organ severity was determined by a novel severity tool (extrapulmonary physician organ severity tool; ePOST) with an adjustment for the number of organs involved (ePOSTadj). In total, 138 patients enrolled in the trial of infliximab versus placebo for the treatment of chronic corticosteroid-dependent pulmonary sarcoidosis. The baseline severity of extrapulmonary organ involvement, as measured by ePOST, was similar across treatment groups. After 24 weeks of drug-therapy study, the change from baseline to week 24 in ePOST was greater for the combined infliximab group compared with the placebo group. After adjustment for the number of extrapulmonary organs involved, the improvement in ePOSTadj observed in the combined infliximab group was also greater than that observed in placebo-treated patients, after 24 weeks of therapy. The improvements in ePOST and ePOSTadj were not maintained during a subsequent 24-week washout period. Infliximab may be beneficial compared with placebo in the treatment of extrapulmonary sarcoidosis in patients already receiving corticosteroids, as assessed by the severity tool described in the present study.

Eosinophils generate brominating oxidants in allergen-induced asthma.

Eosinophils promote tissue injury and contribute to the pathogenesis of allergen-triggered diseases like asthma, but the chemical basis of damage to eosinophil targets is unknown. We now demonstrate that eosinophil activation in vivo results in oxidative damage of proteins through bromination of tyrosine residues, a heretofore unrecognized pathway for covalent modification of biologic targets in human tissues. Mass spectrometric studies demonstrated that 3-bromotyrosine serves as a specific "molecular fingerprint" for proteins modified through the eosinophil peroxidase-H(2)O(2) system in the presence of plasma levels of halides. We applied a localized allergen challenge to model the effects of eosinophils and brominating oxidants in human lung injury. Endobronchial biopsy specimens from allergen-challenged lung segments of asthmatic, but not healthy control, subjects demonstrated significant enrichments in eosinophils and eosinophil peroxidase. Baseline levels of 3-bromotyrosine in bronchoalveolar lavage (BAL) proteins from mildly allergic asthmatic individuals were modestly but not statistically significantly elevated over those in control subjects. After exposure to segmental allergen challenge, lung segments of asthmatics, but not healthy control subjects, exhibited a >10-fold increase in BAL 3-bromotyrosine content, but only two- to threefold increases in 3-chlorotyrosine, a specific oxidation product formed by neutrophil- and monocyte-derived myeloperoxidase. These results identify reactive brominating species produced by eosinophils as a distinct class of oxidants formed in vivo. They also reveal eosinophil peroxidase as a potential therapeutic target for allergen-triggered inflammatory tissue injury in humans.

Bilateral proximal pulmonary artery aneurysms simulating hilar adenopathy.

Proximal pulmonary artery aneurysms (PAAs) are rare. Most are associated with secondary pulmonary hypertension or a variety of rare systemic disorders. An asymptomatic adult patient presented with bilateral hilar enlargement on a routine chest roentgenogram. Computed tomography of the chest revealed 5 cm bilateral proximal PAAs with a normal pulmonary trunk. The clinician should consider proximal PAA in the differential diagnosis of hilar enlargement.

Transbronchial needle aspiration for histology specimens.

Fine-gauge (22-G) transbronchial needle aspiration (TBNA) has significantly added to the diagnostic yield of FOB, and in some institutions has become routine in staging bronchogenic carcinoma. Cytologic examination of the specimen obtained by n228G TBNA, however, has several limitations. The mediastinal aspirate can be contaminated by tumor cells from respiratory secretions, giving false positive diagnoses of unresectability. The diagnosis of benign conditions can seldom be made. Using 18-G TBNA, we can obtain specimens for histologic examination from paratracheal, peribronchial, and carinal areas by FOB. Both 18-G and 22-G TBNA were performed in 34 patients with radiographic abnormalities involving mediastinal or hilar areas. Tissue for histologic examination was obtained in 17 patients (50 percent) using 18-G TBNA and was diagnostic in 11 (32 percent), including three patients with benign conditions. The overall diagnostic yeild of 18-G TBNA was 41 percent (14/34 patients), increasing the yield of FOB from 50 percent to 58 percent. There were no false positive results and few minor complications. 18-G TBNA is effective in obtaining tissue for histologic examination and diagnosing benign conditions. In selected cases this technique increases the diagnostic yield of FOB.

Amyloidosis and pleural disease.

Pleural involvement with systemic amyloidosis has been reported rarely in the literature. Diagnosis of this entity by percutaneous needle biopsy of the pleura has been described only in two prior case reports. We describe five patients in whom the diagnosis of pleural amyloidosis was established by Cope needle biopsy during evaluation of pleural effusions of indeterminate cause. Three patients presented with a history suggestive of multiorgan disease and a pleural biopsy performed despite a transudative effusion demonstrated amyloid infiltration of the pleura, obviating the need for other organ biopsies. We conclude that in patients with pleural effusions, if history suggests multiorgan involvement and there is suspicion for amyloidosis, then a closed pleural biopsy with special stains for amyloid should be performed even if the effusions are transudative. This may be the diagnostic procedure of choice in such patients.

Pulmonary alveolar proteinosis: clinical features and outcomes.

INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare disease of unknown etiology and variable natural history. To date, the largest series from a single institution has consisted of 68 individuals. To extend the understanding of the clinical features and natural history of PAP, we present a series of 24 patients with PAP from a single institution. METHODS: Patients with PAP were identified by a review of The Cleveland Clinic Foundation discharge database from 1965 to 1995. After identification, a chart review of the 24 selected patients was conducted. Charts were abstracted for historical, diagnostic, and therapeutic features. Diagnosis was confirmed by a review of the lung biopsy, where it was available, by a lung pathologist. Follow-up by telephone was performed with 19 patients. RESULTS: Most patients (70%) were male, and smoking was common (75%; mean pack-years, 29) in the group. The mean age at initial evaluation was 43 years. Presenting symptoms were as follows: 19 patients (79%) reported dyspnea, 19 patients (79%) reported a cough, 4 patients (17%) reported hemoptysis, and 3 patients (13%) reported chest pain. The earliest available spirometry after presentation of symptoms showed a prediction of mean FEV1 of 74% (range, 45 to 99%) and a prediction of mean FVC of 76% (range, 41 to 99%). The diagnosis of PAP was established by transbronchial biopsy alone in 7 patients (29%) and by open-lung biopsy alone in 17 patients (71%). Whole lung lavage was deemed necessary in 13 patients (54%); 3 patients underwent lavage of one lung only, and 10 patients underwent bilateral whole lung lavage. Whole lung lavage was required only once in 46% of patients, and from two to four times in the remainder of patients. During the follow-up period (mean length of follow-up, 8.5 years; range, 5 months to 21 years), 25% of the patients died, but none as a result of sequelae of PAP. Half of the survivors reported persistent symptoms. CONCLUSIONS: In this series, which represents one of the largest single institutional experiences with PAP reported, the clinical features are largely consistent with previously reported cases. However, contrary to early reported experiences in which open-lung biopsy was frequently required to establish PAP and in which whole lung lavage was needed, transbronchial biopsy established the diagnosis in 29% of patients and whole lung lavage could be deferred in 46% of patients.

The impact of thoracoscopy on the management of pleural disease.

STUDY OBJECTIVE: To describe the diagnostic efficacy, morbidity, and patient outcome of thoracoscopy; to quantify the direct impact of thoracoscopy on clinical management; and to determine preoperative variables associated with finding malignancy at thoracoscopy to aid patient selection. DESIGN: Retrospective chart review of consecutive cases of thoracoscopy for pleural disease. SETTING: Single tertiary medical center. PATIENTS: One hundred eighty-two consecutive patients who underwent thoracoscopy for pleural disease over a 5-year period (from 1987 through 1992). MEASUREMENTS AND RESULTS: Final diagnoses were 98 (54%) malignant, 58 (32%) benign, and 26 (14%) idiopathic. Thoracoscopy had a diagnostic sensitivity of 95% for malignancy and 100% for benign disease. Malignancy was shown by thoracoscopy in 27 of 41 (66%) patients who had a preoperative nondiagnostic closed pleural biopsy, and in 24 of 35 (69%) patients who had at least 2 preoperative negative pleural cytologic specimens. Chart review by preestablished criteria showed information obtained from thoracoscopy directly influenced treatment in 155 (85%) patients. Thirty-seven (20%) patients, however, had at least one perioperative complication (15% major, 8% minor). Ten (6%) patients died during the same hospitalization in which a thoracoscopy was performed, although none died within 48 h. There was one thoracoscopy-related death. Sixty-two (34%) patients died within 6 months of thoracoscopy (death by all causes). Forty-seven (48%) patients who had intrathoracic malignancy present at thoracoscopy died within 6 months. Patients found to have malignant pleural disease by thoracoscopy were more likely to have a preoperative history of a malignancy (p = 0.001). Age more than 50 years was associated with finding malignancy at thoracoscopy (p = 0.04). A combined lymphocytic and hemorrhagic effusion was associated with malignancy (p = 0.004). Preoperative pleural data showed that idiopathic effusions had a significantly lower median lactate dehydrogenase (LDH) value (192, which was normal) compared with malignant or benign effusions. CONCLUSIONS: (1) Thoracoscopy increases yield for malignant and benign disease when thoracentesis and closed pleural biopsy are nondiagnostic. (2) Thoracoscopy directly affects clinical management in 85% of patients. (3) Significant complications can occur in patients receiving tertiary care. (4) For the evaluation of suspected malignant pleural disease, thoracoscopy has its greatest diagnostic yield in older patients who have a history of malignancy and who present with a lymphocytic, hemorrhagic, high LDH effusion.

Human alveolar macrophages and monocytes as a source and target for nitric oxide.

Nitric oxide (NO) is synthesized in the lung and this free radical participates in a wide array of regulatory, protective, and adverse interactions with cells. Both excess NO and its insufficiency have been implicated in the pathogenesis of numerous lung diseases with inflammatory components. Much of the available data concerning the source and regulation of NO production is derived from rodent systems. However, the requirements for NO production are more stringent in human monocytes/macrophages than in rodent systems. In contrast to rodent macrophages, human moncytes/macrophages generally do not respond to cytokine triggers with NO production [J. Leukocyte Biol. 58 (1995) 643, J. Exp. Med. 181 (1995) 735] and if NO is detected the levels are generally low [J. Leukocyte Biol. 58 (1995) 643]. The regulation of macrophage NO in the human appears to be a more selective and variable process than that seen in the rodent macrophages. In the human lung, the function of NO as toxic pro-inflammatory or protective anti-inflammatory agent is unresolved. While not a major source of NO in the human lung, the alveolar macrophage is an important producer of cytokines and this production may be modified by NO. Clear evidence of abnormalities in NO levels in the lungs of patients with asthma, bronchiectasis, viral infections, lung cancer and primary pulmonary hypertension (PPH) has been documented. Elevated inflammatory cytokines and oxidant production have been associated with all of these disease states. In terms of cytokine production, NO has been shown to decrease nuclear factor kappa B (NF-kappaB) activation. However, oxidants may interact with NO to form toxic compounds (e.g., NO combines with superoxide anion to form peroxynitrite). Furthermore, such reactions may decrease the availability of NO for blocking inflammatory cytokine production. Thus, available data suggests that a multiplicity of factors affect NO regulatory properties in inflammatory situations.

Role of bronchoscopy in asthma research.

Over the past 15 years, much has been learned about the presence of airway inflammation in asthma through the use of investigative bronchoscopy. It has become quite clear that inflammation is present even in mild asthma. In addition to the eosinophils, T-lymphocytes and a variety of cytokines have been identified to play a prominent role in asthmatic inflammation. The concept of delayed asthmatic response after allergen exposure and its relationship to cellular inflammation and airway hyper-reactivity has become more clearly established. Our understanding of asthmatic airway inflammation, however, is incomplete. As interesting as the database has been so far, investigative FB has not defined a unique profile for patients with asthma. Specifically, lavage or endobronchial biopsy has not identified parameters that help in the diagnosis, assessment of disease severity, prognosis, or likelihood to respond to specific therapies. Also, the exact relationship between parameters in lavage compared with mucosal biopsy and how these are related to airway hyper-reactivity and the clinical syndrome of asthma remains poorly understood. In this regard, it must be confessed that currently FB with lavage and biopsy in asthmatics needs to be considered as a research tool for specimen retrieval to help characterize and express inflammation. Although these techniques have contributed immensely to our understanding of asthma pathogenesis, presently these techniques do not have any practical role or clinical usefulness.

A practical guide for peak expiratory flow monitoring in asthma patients.

The peak expiratory flow rate is an objective measure of airflow obstruction that patients can learn with little difficulty, and which provides physicians objective information for assessing a patient's condition. We outline how to use peak flow monitoring as part of an asthma treatment plan.

Antileukotrienes and asthma: alternative or adjunct to inhaled steroids?

Antileukotriene agents may be reasonable and safe alternatives or adjuncts to inhaled steroid therapy in chronic asthma, as they act at sites further down in the inflammatory cascade. This article reviews the clinical experience with three antileukotriene agents and discusses their role in the management of asthma.

Asthma: current controversies and emerging therapies.

Despite advances in understanding the pathogenesis of asthma, a number of controversies regarding the optimal clinical management of asthma remain. This review of recent literature and current controversies, chosen mainly on the basis of relevance to clinical therapy, is directed toward nonspecialists caring for asthmatic patients.

Lung transplantation: the Cleveland Clinic experience.

BACKGROUND: Lung transplantation has been steadily developing as a therapeutic option for end-stage lung disease. METHODS: Retrospective analysis of all 26 patients who underwent lung transplantation at the Cleveland Clinic Foundation between February 1990 and February 1992. RESULTS: Nineteen single-lung transplantations and seven bilateral lung transplantations were performed. The 1-year actuarial survival for all recipients was 65%. A trend was noted towards better survival in recipients with emphysema (100%) and poorer survival in those with pulmonary hypertension (37.5%). Fungal sepsis and reimplantation lung injury were the most common causes of death, and most deaths (8 of 9) occurred within the first 4 weeks. Of 119 pulmonary complications, 82% occurred in the first 3 months, with infection (39%) and acute rejection (29%) being the most common. Bacterial and fungal infections occurred mainly in the first month, and cytomegalovirus infections occurred mainly in the second and third months. The majority of survivors have shown improvement in functional status. CONCLUSIONS: The early perioperative and 1-month post-transplantation period appears critical to long-term survival. Even though the complications are numerous, they are usually manageable, and, in general, do not result in long-term morbidity.

Spirometry for the primary care physician.

The clinician wishing to employ a spirometer in the office must be aware of the equipment available and the current standards for validating and maintaining such equipment. Indications for spirometry are fairly frequent in general medical practice for both diagnosis, response to therapy, and for risk assessment prior to surgery. The criteria for characterizing a spirogram as normal, obstructive or restrictive, are well defined. The information obtained may be very helpful to point to additional specific diagnostic studies or to outline a specific treatment plan.