Rituximab in severe, treatment-refractory interstitial lung disease.

BACKGROUND AND OBJECTIVE: In patients with severe interstitial lung disease (ILD) progressing despite conventional immunosuppression, rituximab, a B-lymphocyte depleting monoclonal antibody, may offer an effective rescue therapy. METHODS: Retrospective assessment of 50 patients with severe, progressive ILD (of varying aetiologies, excluding idiopathic pulmonary fibrosis (IPF)) treated with rituximab between 2010 and 2012. Change in pulmonary function tests compared with pre-rituximab levels was assessed at 6-12 months post-treatment. RESULTS: ILD was associated with connective tissue disease in 33 patients, hypersensitivity pneumonitis in 6 patients and miscellaneous conditions in 11 patients. At the time of rituximab administration, patients had severe physiologic impairment with a median forced vital capacity (FVC) of 44.0% (24.0-99.0%) and diffusing capacity of carbon monoxide (DLCO ) of 24.5% (11.4-67.0%). In contrast with a median decline in FVC of 14.3% and DLCO of 18.8% in the 6-12 months prior to rituximab, analysis of paired pulmonary function data revealed a median improvement in FVC of 6.7% (P < 0.01) and stability of DLCO (0% change; P < 0.01) in the 6-12 months following rituximab treatment. Two patients developed serious infections (pneumonia) requiring hospitalization following rituximab, and 10 patients died from progression of underlying ILD, a median of 5.1 (1.2-24.5) months after treatment. CONCLUSIONS: In patients with severe, progressive non-IPF ILD unresponsive to conventional immunosuppression, rituximab may offer an effective therapeutic intervention. Future prospective, controlled trials are warranted to validate these findings, and to assess safety outcomes.

Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis.

OBJECTIVE: To evaluate C-reactive protein (CRP), globulin and white blood cell (WBC) count as predictors of treatment outcome in pulmonary tuberculosis (PTB). METHODS: An observational study of patients with active PTB was conducted at a tertiary centre. All patients had serum CRP, globulin and WBC measured at baseline and at 2 months following commencement of treatment. The outcome of interest was requirement for extension of treatment beyond 6 months. RESULTS: There were 226 patients included in the study. Serum globulin 45 g/l was the only baseline biomarker evaluated that independently predicted requirement for treatment extension (OR 3.42, 95%CI 1.597.32, P 0.001). An elevated globulin level that failed to normalise at 2 months was also associated with increased requirement for treatment extension (63.9% vs. 5.1%, P 0.001), and had a low negative likelihood ratio (0.07) for exclusion of requirement for treatment extension. On multivariable analysis, an elevated globulin that failed to normalise at 2 months was independently associated with requirement for treatment extension (OR 6.13, 95%CI 2.2316.80, P 0.001). CONCLUSIONS: Serum globulin independently predicts requirement for treatment extension in PTB and outperforms CRP and WBC as a predictive biomarker. Normalisation of globulin at 2 months following treatment commencement is associated with low risk of requirement for treatment extension.

The use of thoracic computed tomography scanning and EBUS-TBNA to diagnose tuberculosis of the central nervous system: two case reports.

Herein, we report two cases of tuberculosis (TB) of the central nervous system where accessing the cerebrospinal fluid for diagnostic purposes was relatively or absolutely contraindicated at presentation. The finding of mediastinal lymphadenopathy on thoracic computed tomography scans, which was not visible on plain chest radiography, allowed endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of these lymph nodes to support the diagnosis of TB in each patient and rule out other disease processes. EBUS-TBNA is a new bronchoscopic technique and in this case report appears to be a safe and useful option in the diagnosis of TB. Moreover, it proved to be so in cases where the main focus of disease was outside the thorax.

Paradoxical reactions in non-HIV tuberculosis presenting as endobronchial obstruction.

Paradoxical reaction (PR) in tuberculosis (TB) is common and may affect up to 25% of patients. PR has the potential to cause significant morbidity and, on occasion, death. Although PR has been recognised for some time, the pathophysiology, especially in HIV-negative patients, is not well understood. We present two cases of PR in HIV-negative patients with TB presenting as significant airway obstruction secondary to a florid endobronchial component. These cases demonstrate that PR should be considered in all patients presenting with airway symptoms who have started TB treatment. The outcomes of the cases illustrate the need for wider recognition of this condition and more research to characterise patients who may be at risk, in order to gain a greater understanding of the mechanisms involved and to make or predict this diagnosis earlier.

Nontuberculous mycobacterial disease and Aspergillus-related lung disease in bronchiectasis.

The aim of the present study was to determine whether patients with bronchiectasis and nontuberculous mycobacteria (NTM) have a higher prevalence of Aspergillus-related lung disease. A series of 30 consecutive patients with bronchiectasis and NTM (cases) were compared with 61 patients with bronchiectasis and no evidence of NTM (controls). Aspergillus serology and computerised tomography of the thorax were used to identify Aspergillus-related lung diseases, including aspergilloma, allergic bronchopulmonary aspergillosis and chronic necrotising pulmonary aspergillosis. The rate of positive Aspergillus serology was higher in cases with NTM disease compared with controls (10 out of 30 versus six out of 61). The radiological features of Aspergillus-related lung disease were also more common among patients with NTM disease than controls (six out of 30 versus none out of 61). This association between NTM disease and Aspergillus-related lung disease remained significant after adjustment for confounding effects of age and lung function (adjusted odds ratio 5.1, 95% confidence interval 1.5-17.0). Patients with bronchiectasis and nontuberculous mycobacterial disease have a higher prevalence of coexisting Aspergillus-related lung disease than patients with bronchiectasis and without nontuberculous mycobacteria. Identification of Aspergillus-related lung disease is important as prognosis amongst undetected cases is invariably poor.

Non-tuberculous mycobacteria in patients with bronchiectasis.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms. Patients with pre-existing lung damage are susceptible to NTM, but their prevalence in bronchiectasis is unknown. Distinguishing between lung colonisation and disease can be difficult. METHODS: A prospective study of 100 patients with bronchiectasis was undertaken to evaluate the prevalence of NTM in sputum, and a retrospective analysis of clinical, microbiological, lung function and radiology data of our clinic patients with NTM sputum isolates over 11 years was performed. RESULTS: The prevalence of NTM in this population of patients with bronchiectasis was 2%. Patients in the retrospective study were divided into three groups: bronchiectasis+multiple NTM isolates (n=25), bronchiectasis+single isolates (n=23), and non-bronchiectasis+multiple isolates (n=22). Mycobacterium avium complex (MAC) species predominated in patients with bronchiectasis compared with non-bronchiectasis lung disease (72% v 9%, p<0.0001). Single isolates were also frequently MAC (45.5%). Multiple isolates in bronchiectasis were more often smear positive on first sample than single isolates (p<0.0001). NTM were identified on routine screening samples or because of suggestive radiology. No particular bronchiectasis aetiology was associated with an NTM. Pseudomonas aeruginosa and Staphylococcus aureus were frequently co-cultured. Six (25%) of multiple NTM patients had cavities of which five were due to MAC. Half the patients with multiple isolates were treated, mostly due to progressive radiology. CONCLUSIONS: NTM are uncommon in non-cystic fibrosis bronchiectasis. Routine screening identifies otherwise unsuspected patients. MAC is the most frequent NTM isolated.

Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network.

Pulmonary epithelial cells, covering a 70-m2 surface area, have not previously been considered an important source of chemokines in pulmonary tuberculosis. We analyzed IL-8 secretion from A549 cells and primary normal human bronchial epithelial cells (NHBE) infected by Mycobacterium tuberculosis. Direct infection of A549 cells by M. tuberculosis caused IL-8 secretion of 7720 +/- 1610 pg/106 cells, but no IL-8 secretion from NHBE after 24 h. In contrast, conditioned media from M. tuberculosis-infected human monocytes (CoMTB) induced a much greater IL-8 secretion of 92,635 +/- 13,180 pg/106 A549 cells and 13,416 +/- 3,529 pg/106 NHBE after 24 h. CoMTB induced rapid IL-8 mRNA accumulation, which was stable over 24 h, compared with TNF-alpha-induced transcripts. CoMTB stimulated nuclear binding of p65, p50, and c-Rel subunits of NF-kappa B to IL-8 promoter sequences. Transient transfections with IL-8 promoter reporter constructs showed NF-kappa B binding-site mutations abolished IL-8 promoter activity while NF-IL-6 binding-site mutations decreased promoter activity to 50.2 +/- 6.3% of wild-type activity. IL-1R antagonist but not neutralizing anti-TNF-alpha inhibited epithelial cell IL-8 secretion, mRNA accumulation, and NF-kappa B binding. Recombinant IL-1 beta (2 ng/ml) induced similar levels of IL-8 secretion to CoMTB in both A549 cells and NHBE. Pulmonary epithelial cells are a major source of IL-8 in the initial host response to pulmonary tuberculosis. Such IL-8 secretion is NF-kappa B dependent, NF-IL-6 requiring, and activated by an IL-1-mediated pathway as a consequence of phagocytosis of M. tuberculosis by monocytes.

Attenuation of propranolol-induced bronchoconstriction by frusemide.

BACKGROUND: Inhaled propranolol causes bronchoconstriction in asthmatic subjects by an indirect mechanism which remains unclear. Inhaled frusemide has been shown to attenuate a number of indirectly acting bronchoconstrictor challenges. The aim of this study was to investigate whether frusemide could protect against propranolol-induced bronchoconstriction in patients with stable mild asthma. METHODS: Twelve asthmatic subjects were studied on three separate days. At the first visit subjects inhaled increasing doubling concentrations of propranolol (0.25-32 mg/ml), breathing tidally from a jet nebuliser. The provocative concentration of propranolol causing a 20% reduction in FEV1 (PC20FEV1 propranolol) was determined from the log concentration-response curve for each subject. At the following visits nebulised frusemide (4 ml x 10 mg/ml) or placebo (isotonic saline) was administered in a randomised, double blind, crossover fashion. FEV1 was measured immediately before and five minutes after drug administration. Individual PC20FEV1 propranolol was then administered and FEV1 was recorded at five minute intervals for 15 minutes. Residual bronchoconstriction was reversed with nebulised salbutamol. RESULTS: Frusemide had no acute bronchodilator effect but significantly reduced the maximum fall in FEV1 due to propranolol: mean fall 18.2% after placebo and 11.8% after frusemide. The median difference in maximum % fall in FEV1 within individuals between study days was 3.6% (95% CI 1.2 to 11.7). CONCLUSIONS: Frusemide attenuates propranolol-induced bronchoconstriction, a property shared with sodium cromoglycate. Both drugs block other indirect challenges and the present study lends further support to the suggestion that frusemide and cromoglycate share a similar mechanism of action in the airways.

Synergistic upregulation of interleukin-8 secretion from pulmonary epithelial cells by direct and monocyte-dependent effects of respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) infection is the major cause of severe bronchiolitis in infants. Pathology of this infection is partly due to excessive proinflammatory leukocyte influx mediated by chemokines. Although direct infection of the respiratory epithelium by RSV may induce chemokine secretion, little is known about the role of cytokine networks. We investigated the effects of conditioned medium (CM) from RSV-infected monocytes (RSV-CM) on respiratory epithelial (A549) cell chemokine release. RSV-CM, but not control CM (both at a 1:5 dilution), stimulated interleukin-8 (IL-8) secretion from A549 cells within 2 h, and secretion increased over 72 h to 11,360 +/- 1,090 pg/ml without affecting cell viability. In contrast, RSV-CM had only a small effect on RANTES secretion. RSV-CM interacted with direct RSV infection to synergistically amplify IL-8 secretion from respiratory epithelial cells (levels of secretion at 48 h were as follows: RSV-CM alone, 8,140 +/- 2,160 pg/ml; RSV alone, 12,170 +/- 300 pg/ml; RSV-CM plus RSV, 27,040 +/- 5,260 pg/ml; P < 0.05). RSV-CM induced degradation of IkappaBalpha within 5 min but did not affect IkappaBbeta. RSV-CM activated transient nuclear binding of NF-kappaB within 1 h, while activation of NF-IL6 was delayed until 8 h and was still detectable at 24 h. Promoter-reporter analysis demonstrated that NF-kappaB binding was essential and that NF-IL6 was important for IL-8 promoter activity in RSV-CM-activated cells. Blocking experiments revealed that the effects of RSV-CM depended on monocyte-derived IL-1 but that tumor necrosis factor alpha was not involved in this network. In summary, RSV infection of monocytes results in and amplifies direct RSV-mediated IL-8 secretion from respiratory epithelial cells by an NF-kappaB-dependent, NF-IL6-requiring mechanism.