Ashutosh N. Aggarwal

Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis

The aetiology of sarcoidosis is currently unknown. Due to the clinical and histological similarities between sarcoidosis and tuberculosis, the role of mycobacteria has been repeatedly investigated as an aetiological agent for sarcoidosis. The current meta-analysis aimed to evaluate the available molecular evidence on the possible role of mycobacteria in the development of sarcoidosis. The MEDLINE, EMBASE, CINAHL, DARE and CENTRAL databases were searched for relevant studies published from 1980 to 2006, and studies evaluating the presence of mycobacteria using molecular techniques in biological samples of patients with sarcoidosis were included in the current analysis. The 95% confidence intervals (CI) were calculated for the expected proportion (of individual studies); the data was then pooled to obtain a summary success rate with 95% CI. The odds ratio (95% CI) was also calculated in order to assess the presence of mycobacteria in samples of patients with sarcoidosis versus those from nonsarcoidosis control samples. The database search yielded 31 studies. All studies used polymerase chain reaction for nucleic acid amplification followed by identification of nucleic acid sequences specific for different types of mycobacteria. Overall, 231 out of the 874 patients were positive for mycobacteria with a positive signal rate of 26.4 (23.6–29.5%), and the odds of finding mycobacteria in samples of patients with sarcoidosis versus controls were 9.67 (4.56–20.5%) using the random effects model and 19.49 (11.21–35.54%) using the exact method. There was methodological and statistical heterogeneity and evidence of publication bias. The results of the current study illustrate a demonstrable mycobacterial presence in sarcoidosis lesions suggesting an association between mycobacteria and some cases of sarcoidosis. To avoid methodological diversity, larger multicentre trials with a central laboratory for sample testing should be designed.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration vs Conventional Transbronchial Needle Aspiration in the Diagnosis of Sarcoidosis

BACKGROUND Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is superior to conventional transbronchial needle aspiration (cTBNA) in the staging of lung cancer. However, its efficiency in diagnosis of sarcoidosis when combined with endobronchial biopsy (EBB) and transbronchial lung biopsy (TBLB) has not been studied. This randomized controlled trial compares diagnostic yield of EBUS-TBNA vs cTBNA in combination with EBB and TBLB. METHODS Patients with clinical diagnosis of sarcoidosis were randomized 1:1 to EBUS-TBNA or cTBNA. All patients underwent TBLB and EBB. The primary outcome was detection of granulomas. The secondary end points were the individual and cumulative yields of various procedures, serious adverse events, and procedure time. RESULTS Of the 130 patients, sarcoidosis was diagnosed in 117 (62 cTBNA, 55 EBUS-TBNA). The two groups were similar at baseline. Granulomas were demonstrated in 104 (53 cTBNA, 51 EBUS-TBNA) patients and were similar in two groups (85.5% vs 92.7%, P = .34). Individually, EBUS-TBNA had the highest yield (41 of 55, 74.5%), which was better than cTBNA (30 of 62, 48.4%, P = .004) or EBB (40 of 111, 36.3%, P < .0001) but not TBLB (78 of 112, 69.6%, P = .54). Adding EBB/TBLB to cTBNA led to an increase in granuloma detection, whereas the addition of TBLB (but not EBB) significantly enhanced the yield of EBUS-TBNA. The procedure time was significantly longer with EBUS-TBNA. No major adverse events occurred. CONCLUSIONS Individually, EBUS-TBNA has the highest diagnostic yield in sarcoidosis, but it should be combined with TBLB for the optimal yield. The diagnostic yield of cTBNA (plus EBB and TBLB) is similar to EBUS-TBNA plus TBLB. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01908868; URL: www.clinicaltrials.gov.

Do glucocorticoids decrease mortality in acute respiratory distress syndrome? A meta-analysis

Background and objectives:  Glucocorticoids have been shown to improve survival when used in patients with septic shock. The aim of this study was to analyse the role of glucocorticoids in decreasing mortality in acute respiratory distress syndrome (ARDS) both in the acute and the fibroproliferative phases.

Diagnostic Performance of Various Tests and Criteria Employed in Allergic Bronchopulmonary Aspergillosis: A Latent Class Analysis

Aim The efficiency of various investigations and diagnostic criteria used in diagnosis of allergic bronchopulmonary aspergillosis (ABPA) remain unknown, primarily because of the lack of a gold standard. Latent class analysis (LCA) can provide estimates of sensitivity and specificity in absence of gold standard. Herein, we report the performance of various investigations and criteria employed in diagnosis of ABPA. Methods Consecutive subjects with asthma underwent all the following investigations Aspergillus skin test, IgE levels (total and A.fumigatus specific), Aspergillus precipitins, eosinophil count, chest radiograph, and high-resolution computed tomography (HRCT) of the chest. We used LCA to estimate the performance of various diagnostic tests and criteria in identification of ABPA. Results There were 372 asthmatics with a mean age of 35.9 years. The prevalence of Aspergillus sensitization was 53.2%. The sensitivity and specificity of various tests were Aspergillus skin test positivity (94.7%, 79.7%); IgE levels>1000 IU/mL (97.1%, 37.7%); A.fumigatus specific IgE levels>0.35 kUA/L (100%, 69.3%); Aspergillus precipitins (42.7%, 97.1%); eosinophil count>1000 cells/µL (29.5%, 93.1%); chest radiographic opacities (36.1%, 92.5%); bronchiectasis (91.9%, 80.9%); and, high-attenuation mucus (39.7%, 100%). The most accurate criteria was the Patterson criteria using six components followed by the Agarwal criteria. However, there was substantial decline in accuracy of the Patterson criteria if components of the criteria were either increased or decreased from six. Conclusions A.fumigatus specific IgE levels and high-attenuation mucus were found to be the most sensitive and specific test respectively in diagnosis of ABPA. The Patterson criteria remain the best diagnostic criteria however they have good veridicality only if six criteria are used.

An alternate method of classifying allergic bronchopulmonary aspergillosis based on high-attenuation mucus.

Background and Aim Allergic bronchopulmonary aspergillosis (ABPA) is classified radiologically based on the findings of central bronchiectasis (CB) and other radiologic features (ORF). However, the long-term clinical significance of these classifications remains unknown. We hypothesized that the immunological activity and outcomes of ABPA could be predicted on HRCT chest finding of high-attenuation mucus (HAM), a marker of inflammatory activity. In this study, we evaluate the severity and clinical outcomes of ABPA with different radiological classifications. Methods Patients were classified based on CT chest findings as: (a) serologic ABPA (ABPA-S) and ABPA-CB; (b) ABPA-S, ABPA-CB, and ABPA-CB-ORF; and, (c) ABPA-S, ABPA-CB and ABPA-CB-HAM. The clinical, spirometric and serological (total and A fumigatus specific IgE levels, eosinophil count) severity of the disease and clinical outcomes in various classifications were analyzed. Results Of the 234 (123 males, 111 females; mean age, 34.1 years) patients, 55 (23.5%) had normal HRCT, 179 (76.5%) had CB, 49 (20.9%) had HAM, and 27 (11.5%) had ORF. All immunological markers were consistently higher in the HAM classification, while in other classifications these findings were inconsistent. On multivariate analysis, the factors predicting frequent relapses were presence of HAM (OR 7.38; 95% CI, 3.21–17.0) and CB (OR 3.93; 95% CI, 1.63–9.48) after adjusting for ORF. Conclusions The classification scheme based on HAM most consistently predicts immunological severity in ABPA. Central bronchiectasis and HAM are independent predictors of recurrent relapses in ABPA. Hence, HAM should be employed in the radiological classification of ABPA.

Inhaled Corticosteroids vs Placebo for Preventing COPD Exacerbations: A Systematic Review and Metaregression of Randomized Controlled Trials

BACKGROUND Inhaled corticosteroids (ICS) have been shown to decrease the occurrence of COPD exacerbations. However, the relationship of baseline lung function and reduction of exacerbations with the use of ICS remains unknown. Herein, we perform a metaregression to evaluate the efficacy of ICS in preventing COPD exacerbations. METHODS We searched the PubMed, EmBase, and Cochrane Central Database of Controlled Trials databases (1988-2008) for studies that have reported the efficacy of ICS vs placebo in preventing COPD exacerbations. We pooled the risk ratio (RR) and 95% CIs from individual studies using a random-effects model to assess the exacerbations in the two groups. We also performed a weighted random effects metaregression using baseline FEV(1) values. RESULTS Our search yielded 11 studies (8,164 patients). The use of ICS was associated with reduction in the occurrence of exacerbations (RR, 0.82; 95% CI, 0.73-0.92). There was the presence of significant statistical heterogeneity but no evidence of publication bias. Sensitivity analysis revealed benefit of ICS only in patients with FEV(1) < 50% (RR, 0.79; 95% CI, 0.69-0.89) with persistence of statistical heterogeneity. Metaregression showed that the percentage risk reduction in exacerbations with the use of ICS is invariant across the severity of COPD (assessed by FEV(1)). CONCLUSION There is only a modest benefit of ICS in preventing COPD exacerbations, which is not related to the level of baseline lung function on metaregression analysis. The benefits of ICS in preventing COPD exacerbations thus seem to be overstated.

Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature.

Patients with aspergilloma can be safely managed with supportive therapy in absence of massive haemoptysis. We hypothesised that chronic cavitary pulmonary aspergillosis (CCPA) could also be managed on similar grounds. The aim of this prospective, randomised controlled trial was to evaluate the efficacy and safety of itraconazole in CCPA. Consecutive patients of CCPA with presence of chronic pulmonary/systemic symptoms; and pulmonary cavities; and presence of Aspergillus (immunological or microbiological) were randomised to receive either supportive treatment alone or itraconazole 400 mg daily for 6 months plus supportive therapy. Response was assessed clinically, radiologically and overall after 6 months therapy. A total of 31 patients (mean age, 37 years) were randomised to itraconazole (n = 17) or the control (n = 14) group. The number of patients showing overall response was significantly higher in the itraconazole group (76.5%) vs. the control (35.7%) group (P = 0.02). The numbers of patients demonstrating clinical or radiological response were also significantly higher in the itraconazole group (P = 0.016 and 0.01 respectively). Adverse events were noted in eight patients in the itraconazole group, however, none was serious or led to discontinuation of the study drug. Itraconazole was found to be superior to standard supportive treatment alone in stabilising cases of CCPA. (clinicaltrials.gov; NCT01259336).

Clinical significance of decline in serum IgE levels in allergic bronchopulmonary aspergillosis

BACKGROUND AND AIMS The total serum IgE level is a marker of immunological activity in allergic bronchopulmonary aspergillosis (ABPA), and a 35% decline beyond six weeks is traditionally taken as criteria for remission. The aim of this study was to evaluate the magnitude and clinical significance of decline in serum IgE levels at six weeks in patients with ABPA. METHODS All consecutive patients with ABPA presenting to the Chest Clinic were followed up with clinical evaluation, total IgE levels and chest x-ray every six weeks for three months. We analyzed the percentage decline in IgE levels and correlated it with clinical outcomes of relapse and complete remission. RESULTS Of the 242 asthmatics, 54 were diagnosed with ABPA (29 males, 25 females; mean age-34 years). There was clinical and radiological improvement at six weeks in all patients receiving glucocorticoid therapy. The IgE levels fell by a mean of 38.8%, and the decline was significantly higher in patients with baseline IgE levels >2500IU/mL than with levels <or=2500IU/mL (44% vs. 26%). Twenty-two patients did not attain a 35% decline in IgE levels, and this number was significantly higher in patients with IgE levels <2500IU/mL. On multivariate analysis, the decline in IgE levels at six weeks did not predict clinical outcomes. CONCLUSIONS A 35% decline in serum IgE levels at six weeks is not seen in all patients with ABPA, and the decline is slower in patients with baseline IgE levels <2500IU/mL. The quantum decline in serum IgE levels does not predict clinical outcomes.

Aspergillus hypersensitivity and allergic bronchopulmonary aspergillosis in patients with acute severe asthma in a respiratory intensive care unit in North India

The prevalence of allergic bronchopulmonary aspergillosis (ABPA) in chronic asthma has been reported in various studies. However, no study has systematically evaluated the occurrence of Aspergillus hypersensitivity (AH) and ABPA in acute severe asthma (ASA). The aim of this study was to investigate the occurrence of AH and ABPA in patients with ASA. All patients with ASA admitted to the respiratory intensive care unit (ICU) of this institute underwent a prospective evaluation for ABPA using Aspergillus skin test (AST) as a screening tool. Patients with positive AST were labelled as AH and were further investigated for ABPA. Patients with ASA were compared with historical control group of 755 outpatient bronchial asthma patients previously reported. Of the 357 ICU admissions, 57 (43 females, 14 males; mean age 43.5 years) patients were admitted with a diagnosis of ASA. The occurrence of AH was 50.9% [95% confidence interval (CI) 38.3–63.4; 29/57 patients] whereas the prevalence of ABPA was 38.6% (95% CI 27.1–51.6; 22/57 patients) in patients with ASA. The occurrence of AH and ABPA was significantly higher in the ASA group compared with the outpatient bronchial asthma group (38.5% and 20.5%, respectively). The prevalence of serological ABPA (ABPA without central bronchiectasis) was also higher in the ASA group compared with the outpatient bronchial asthma group (45.4% vs. 23.9%). The occurrence of AH and ABPA is very high in patients with acute asthma admitted to a respiratory ICU. Furthermore, the occurrence of high percentage of serological ABPA calls for the use of AST as a routine screening tool for ABPA in all patients with acute asthma at discharge.

Aspergillus hypersensitivity in patients with chronic obstructive pulmonary disease: COPD as a risk factor for ABPA?

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus which primarily complicates the course of asthma and cystic fibrosis. There is a theoretical possibility that patients with chronic obstructive pulmonary disease (COPD) can also develop Aspergillus hypersensitivity (AH) and/or ABPA. The aim of this prospective case-control study conducted in the Chest Clinic was to evaluate the prevalence of AH/ABPA in patients with COPD. Two hundred subjects with COPD (17, 62, 74, 47; GOLD guidelines stages I–IV respectively) and 100 healthy volunteers were screened with an Aspergillus skin test. Patients were said to have AH if they demonstrated immediate cutaneous hyperreactivity to A. fumigatus antigen and those with positive responses were further investigated for ABPA. Of this patient population there were 179 (89.5%) males and 21 (10.5%) females with a mean age of 57.1 in the COPD arm and 88 males and 12 females with a mean age of 52.3 in the control arm. AH was found in 17 (8.5%) patients with COPD as compared to none in the control group. Two (1.0%) COPD patients fulfilled the serologic criteria for the diagnosis of ABPA. On univariate analysis, age of the patient, duration of COPD, smoking index and the COPD severity did not predict the occurrence of AH. On the basis of this study we concluded that AH/ABPA can occur in patients with COPD, and it is probable that COPD could be a predisposing factor for AH/ABPA. The clinical significance of AH and ABPA in COPD remains unclear.