Luuk N.A. Willems

Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids.

BACKGROUND: Current guidelines on the management of asthma advocate the use of anti-inflammatory treatment in all but mild disease. They define disease control in terms of clinical criteria such as lung function and symptoms. However, the relationship between the clinical control of the disease and inflammation of the airways is not clear. A cross sectional study was therefore undertaken to investigate the relationship between airways inflammation and measures of clinical control and bronchial hyperresponsiveness in asthmatic patients treated with inhaled steroids. METHODS: Twenty six atopic adults (19-45 years) with mild to moderate asthma (baseline forced expiratory volume in one second (FEV1) > or = 50% predicted, concentration of histamine causing a 20% fall in FEV1 (PC20) 0.02-7.6 mg/ml) on regular treatment with inhaled steroids entered the study. Diary card recordings during the two weeks before a methacholine challenge test and bronchoscopic examination were used to determine peak flow variability, symptom scores, and use of beta 2 agonists. Biopsy specimens were taken by fibreoptic bronchoscopy from the carina of the right lower and middle lobes, and from the main carina. Immunohistochemical staining was performed on cryostat sections with monoclonal antibodies against: eosinophil cationic protein (EG1, EG2), mast cell tryptase (AA1), CD45, CD22, CD3, CD4, CD8, CD25, and CD45RO. The number of positively stained cells in the lamina propria was counted twice by using an interactive display system. RESULTS: There were no differences in cell numbers between the three sites from which biopsy specimens were taken. The PC20 for methacholine was inversely related to the average number of total leucocytes, EG1+, and EG2+ cells, mast cells, CD8+, and CD45RO+ cells in the lamina propria. These relationships were similar for each of the biopsy sites. Symptom scores, beta 2 agonist usage, FEV1, and peak flow variability were not related to any of the cell counts. CONCLUSIONS: Infiltration of inflammatory cells in the lamina propria of the airways seems to persist in asthmatic outpatients despite regular treatment with inhaled steroids. The number of infiltrating leucocytes such as mast cells, (activated) eosinophils, CD8+, and CD45RO+ cells in bronchial biopsy specimens from these patients appears to be reflected by airway hyperresponsiveness to methacholine, but not by symptoms or lung function. These findings may have implications for the adjustment of anti-inflammatory treatment of patients with asthma.

Comparison of inflammatory cell counts in asthma: induced sputum vs bronchoalveolar lavage and bronchial biopsies

Background Induced sputum potentially allows monitoring of airway inflammation in patients with asthma in a non‐invasive way. However, the relationship between the cellular content in sputum and airway tissue has not been fully clarified.

Mediastinal restaging: EUS-FNA offers a new perspective

STUDY OBJECTIVEnWe hypothesized that transoesophageal endoscopic ultrasound guided fine needle aspiration (EUS-FNA) has the potential to be a valuable and accurate new diagnostic technique for mediastinal restaging in non-small cell lung cancer (NSCLC) after induction chemotherapy. The current restaging modalities either have a low diagnostic accuracy (computed tomography (CT) scan of the thorax) or they are invasive, can be technically difficult and are therefore not commonly performed (remediastinoscopy).nnnMETHODS AND PATIENTSnNineteen consecutive patients with NSCLC and proven ipsilateral or subcarinal lymph node metastases (N2 disease) who had been treated with induction chemotherapy underwent mediastinal restaging by EUS-FNA. Patients had either a partial response (n=14) or stable disease (n=5) based on sequential CT scans of the thorax.nnnINTERVENTIONSnEUS-FNA was performed in an ambulatory setting with biopsy of mediastinal lymph nodes (LN). No complications occurred. When EUS-FNA restaged the mediastinum as no regional lymph node metastasis (N0), surgical resection of the tumour with lymph node sampling or dissection was performed.nnnRESULTSnThe positive predictive value, negative predictive value, sensitivity, specificity and diagnostic accuracy of EUS-FNA in restaging mediastinal LN were 100, 67, 75, 100 and 83%, respectively.nnnCONCLUSIONS AND SIGNIFICANCEnEUS-FNA qualifies as an accurate, safe and minimally invasive diagnostic technique for the restaging of mediastinal lymph nodes after induction therapy in NSCLC. In the future EUS-FNA might play an important role in the mediastinal restaging in NSCLC, particularly to identify the subgroup of down staged patients who benefit most from further surgical treatment.

Morphological quantification of emphysema in small human lung specimens: Comparison of methods and relation with clinical data

Small human lung specimens are frequently used for cell biological studies of the pathogenesis of emphysema. In general, lung function and other clinical parameters are used to establish the presence and severity of emphysema/chronic obstructive pulmonary disease without morphological analysis of the specimens under investigation. In this study we compared three morphological methods to analyze emphysema, and evaluated whether clinical data correlate with the morphological data of individual lung samples. A total of 306 lung specimens from resected lung(lobes) from 221 patients were inflated and characterized using three morphological parameters: the Destructive Index, the Mean Linear Intercept, and Section Assessment. Morphological data were related to each other, to lung function data, and to smoking behavior. Significant correlations (P < .001) were observed between Section Assessment and Destructive Index (r = 0.92), Mean Linear Intercept with Destructive Index (r = 0.69) and Mean Linear Intercept with Section Assessment (r = 0.65). Section Assessment, being much less time consuming than Mean Linear Intercept and Destructive Index, is the parameter of choice for initial analysis. Destructive Index is the most sensitive parameter. There was a significant (P < .001), but weak correlation for all three parameters with the diffusion capacity for CO (KCO) (Destructive Index: r = −0.28; Mean Linear Intercept: r = −0.34; Section Assessment: r = −0.32), and with FEV1/IVC (Destructive Index: r = −0.29; Mean Linear Intercept: r = −0.33; Section Assessment: r = −0.28), but not with other lung function parameters. A significant difference (P < .05) between (ex-) smokers and never-smokers was observed for Destructive Index and Section Assessment. It is concluded that the application of the three morphological parameters represents a useful method to characterize emphysematous lesions in a (semi-)quantitative manner in small human lung specimens, and that Section Assessment is a suitable and fast method for initial screening. The extent of emphysema of individual lung specimens should be established by means of morphometry, rather than lung function data.

Screening for Small-Cell Lung Cancer: A Follow-Up Study of Patients With Lambert-Eaton Myasthenic Syndrome

PURPOSEnA small-cell lung carcinoma (SCLC) is found in 50% of patients with Lambert-Eaton myasthenic syndrome (LEMS). We evaluated screening to optimize screening strategy for SCLC. It is important to detect these tumors early in newly diagnosed patients with LEMS to offer optimal patient treatment.nnnPATIENTS AND METHODSnA large nationwide cohort study of consecutive patients in the Netherlands, seen between 1990 and 2007, were screened for the presence of a tumor using chest x-ray, computed tomography of the thorax (CT-thorax), [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET), bronchoscopy, and/or mediastinoscopy.nnnRESULTSnSCLC was found in 54 patients, and in 46 patients, no tumor was found during a median follow-up of 8 years (range, 3 to 26 years). All patients with SCLC had a positive smoking history and 86% were still smoking at diagnosis. SCLC was found in 92% of these patients within 3 months and in 96% within a year. At first screening, CT-thorax detected an SCLC in 45 patients (83%), whereas chest x-ray found the tumor in only 23 patients (51%). An SCLC was found during secondary screening in another nine patients (median, 3 months; range, 1 to 41 months). In six patients, a lung tumor was found by CT-thorax or FDG-PET, and in three patients, extrapulmonary metastases were found, initially without identifiable tumor mass on CT-thorax.nnnCONCLUSIONnIn almost all patients (96%), the SCLC was found within 1 year of diagnosis. CT-thorax scans detected most of the tumors (93%) and was far more sensitive than chest x-ray (51%). FDG-PET may have additive value in selected cases. We propose a screening protocol based on CT-thorax and FDG-PET.

IS THERE A SPECIFIC RELATIONSHIP BETWEEN ASTHMA AND PANIC DISORDER

The objective of the present study was three-fold: (1) to assess the prevalence of PD in asthmatic patients in comparison with non-asthmatic patients; (2) to investigate possible differences in pulmonary function and anxiety symptomatology between asthmatic patients with PD and those without; and (3) to evaluate possible differences in symptom perception during histamine-induced bronchoconstriction between asthmatic patients with PD versus asthmatic controls without PD matched for age, sex and bronchial responsiveness to histamine (PC20). The study was performed on 123 consecutive patients referred to the lung function laboratory of a university hospital for a histamine challenge test. Firstly, baseline measures for FEV1, anxiety (ADIS-R, ACQ, BSQ, and STAI) and depression (SDS) were collected. Subsequently, before and during induced bronchoconstriction FEV1, perceived breathlessness (Borg scale), subjective anxiety (SUDS), and somatic panic symptoms (PAQ) were assessed. The prevalence of PD in asthmatic patients, although higher than in the general population, was very similar to the rate observed in non-asthmatic patients. Baseline level of FEV1 and bronchial responsiveness to histamine (PC20) were also not significantly different between asthmatic patients with and without PD. Moreover, in comparison with matched controls, PD cases reported significantly higher levels of perceived breathlessness during induced bronchoconstriction, although their mean fall in FEV1 was very comparable. It is concluded that the higher prevalence of PD in asthma is non-specific and probably due to selection bias.

β-d-Glucan and S-adenosylmethionine serum levels for the diagnosis of Pneumocystis pneumonia in HIV-negative Patients: A prospective study

OBJECTIVEnTo prospectively assess the diagnostic utility of S-adenosylmethionine (AdoMet) and (1→3)-β-D-glucan (β-D-glucan) serum markers for Pneumocystis pneumonia (PCP) in HIV-negative patients.nnnMETHODSnHIV-negative, immunocompromised patients suspected of PCP based on clinical presentation and chest imaging were included. PCP was confirmed or rejected by results of direct microscopy and/or real-time PCR on broncho-alveolar lavage (BAL) fluid. Measurement of serum β-D-glucan and AdoMet was performed on serum samples collected at enrollment and during follow-up. Both serum β-D-glucan and AdoMet were assessed for diagnostic accuracy and correlation with clinical and laboratory parameters.nnnRESULTSnIn 31 patients enrolled (21 PCP-positive, 10 PCP-negative), AdoMet levels did not discriminate between patients with and without PCP. Elevated serum β-D-glucan was a reliable indicator for PCP with a sensitivity of 0.90 and specificity of 0.89 at the 60 pg/ml cut-off. In PCP-positive patients β-D-glucan serum levels decreased during treatment and inversely correlated with Pneumocystis PCR cycle threshold values in BAL fluid.nnnCONCLUSIONSnThe level of β-D-glucan--but not AdoMet--was diagnostic for PCP within the clinical context and may serve as marker for pulmonary fungal load and treatment monitoring.

Repeatability of measures of inflammatory cell number in bronchial biopsies in atopic asthma.

Airway pathology is increasingly considered to be a major outcome in asthma research. The aim of this study was to examine the intra-observer, within-section and between-biopsy repeatability, together with the implications for statistical power of a computerized quantitative analysis of inflammatory cell numbers in the lamina propria in bronchial biopsy specimens from atopic asthmatic subjects. Thirty six atopic adults (aged 19-40 yrs) with mild to moderate asthma (baseline forced expiratory volume in one second (FEV1) > or =50% of predicted value, methacholine (PC20) range 0.02-18.2 mg x mL[-1]) at various levels of treatment (25 subjects on inhaled steroids) entered the study. Biopsies were taken from the (sub)segmental carinae of the right lower and middle lobe and from the main carina. Specimens were snap-frozen and immunohistochemical staining was performed on cryostat sections with monoclonal antibodies against: (secreted) eosinophil cationic protein (EG1, EG2), mast cell tryptase (AA1), CD45, CD22, CD4, CD8, CD25, and CD45RO. Using a computerized system, the number of positively stained cells in the lamina propria was counted. When considering all cell types together, satisfactory intraclass correlation coefficients (ICC) values were obtained for intra-observer, within-section and between-biopsy repeatability, being 0.90, 0.80 and 0.81, respectively. The analysis of repeatability for individual cell types revealed ICC values ranging 0.47-0.82 for intra-observer, 0.44-0.76 for within-section and 0.37-0.67 for between-biopsy repeatability. The results imply that a sample-size between eight and 25 subjects is needed to detect at least one doubling difference in cell number per 0.1 mm2 for a particular inflammatory cell type in a study, using a within-group design with alpha=0.05 and power of 0.80. A sample-size of 13-48 subjects per group is required to detect the same difference between the groups in a parallel design.

Available treatment options for the management of Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome is a rare, but reasonably well-understood, antibody-mediated autoimmune disease that is caused by serum auto-antibodies and results in muscle weakness and autonomic dysfunction. One half of the patients have an idiopathic form, the other half a tumour-associated form of the disease. Three randomised trials and a large number of smaller clinical studies have resulted in a number of drugs becoming available for the treatment of Lambert-Eaton myasthenic syndrome. Several drugs are available for the symptomatic treatment of the disease, including guanidine, aminopyridines or acetylcholinesterase inhibitors. Other therapies aim to deplete the serum autoantibodies or to suppress the immune system. For this purpose, immunomodulating strategies, such as intravenous immunoglobulins or plasmapheresis, or several immunosuppressive agents are available. Chemotherapy has successfully ameliorated the course of disease in Lambert-Eaton myasthenic syndrome patients with an underlying tumour.

Illness perceptions and quality of life in Japanese and Dutch patients with non-small-cell lung cancer

This study examined quality of life (QOL) and illness perceptions in Dutch and Japanese patients with non-small-cell lung cancer, thereby extending the body of knowledge on cultural differences and psychosocial aspects of this illness. 24 Dutch and 22 Japanese patients with non-small-cell lung cancer filled out questionnaires on three occasions: immediately before chemotherapy, 1 week later, and 8 weeks after the initial chemotherapy. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed QOL, and the Brief Illness Perception Questionnaire (B-IPQ) illness perceptions. Scores on several QOL measures indicated (a) major impact of first chemotherapy sessions, and (b) some tendency to returning to baseline measures at 8 weeks. Differences between Japanese and Dutch samples were found on five EORTC QLQ-C30 dimensions: global health status, emotional functioning, social functioning, constipation, and financial difficulties, with the Dutch patients reporting more favorable scores. Regarding illness perceptions, Japanese patients had higher means on perceived treatment control and personal control, expressing a higher sense of belief in the success of medical treatment than Dutch patients. In both Japanese and Dutch patients, impact of chemotherapy on QOL was evident. Some differences in illness perceptions and QOL between the two samples were observed, with implications for integral medical management. Both samples reported illness perceptions that reflect the major consequences of non-small-cell lung cancer. Incorporating symptom reports, illness perceptions, and QOL into medical management may have positive consequences for patients with non-small-cell lung cancer.