Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

BACKGROUND: Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA. METHODS: Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12 months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline. RESULTS: 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6 months, 83% improved with remission in 34% and partial response in 49%, and by 12 months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12 months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12 months. Adverse events included 15 infections (6 were severe). CONCLUSIONS: The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.

Aspiration and development of subglottic stenosis in patients with Wegener's granulomatosis.

OBJECTIVE: In patients with Wegener's granulomatosis, subglottic stenosis can develop due to active disease; however, some patients develop subglottic stenosis with no clear evidence of airway inflammation. In some cases of idiopathic subglottic stenosis, an association with gastroesophageal reflux disease has been found. Our study assessed the potential role of gastroesophageal reflux as an aetiological factor in the development of subglottic stenosis in patients with Wegener's granulomatosis. DESIGN: We assessed evidence of active reflux disease, using 24-hour pH monitoring and assessment of bile salts in bronchoalveolar lavage fluid. SUBJECTS: Ten Wegener's granulomatosis patients with subglottic stenosis underwent 24-hour pH monitoring and bronchoscopy and lavage of the right middle lobe. A similar number of control patients were included. RESULTS: There was no statistically significant difference in the occurrence of bronchoalveolar bile salts in patients with subglottic stenosis (n = 2) versus control patients (zero) (p = 0.457). There was good correlation between the detection of reflux by 24-hour pH monitoring and the detection of bronchoalveolar bile salts (kappa = 0.769). CONCLUSION: In this small study of patients with Wegener's granulomatosis, there was no evidence of an association between the development of subglottic stenosis and gastroesophageal reflux.

B-cell depletion with rituximab for refractory head and neck Wegener's granulomatosis: a cohort study.

OBJECTIVES: This study aimed to evaluate the response of refractory Wegener's granulomatosis affecting the ear, nose and throat and granulomatous eye disease to B-cell depletion with rituximab. DESIGN: A retrospective case note review. SETTING: Tertiary Centre. PARTICIPANTS: All patients who received rituximab for refractory Wegener's granulomatosis affecting the head and neck were included. MAIN OUTCOME MEASURES: Demographic and follow-up data at five time points were recorded. Response was measured using change in the Birmingham Vasculitis Activity Score and prednisolone dose. Secondary outcomes included changes in additional immunomodulators and anti-neutrophil cytoplasm antibodies serology. Adverse events were recorded for the duration of follow-up. RESULTS: Thirty-four patients were included in the analysis. The median age was 47, the male to female ratio was 3 : 2 and the overall median follow-up was 25.5 months. At six months, nine (26%) patients had a partial response, twenty-one (62%) were in remission and four (12%) did not respond. All four non-responders went into remission after a second course of rituximab. Total Birmingham Vasculitis Assessment score decreased after rituximab at all time points (P < 0.001). Four of five patients with retro-orbital involvement responded well to treatment. Two patients were considered secondary failures requiring alternative therapy after an initial response. Adverse events included four major chest infections, two cancers and six infusion reactions. CONCLUSIONS: Our cohort derived considerable benefit from rituximab permitting a reduction in immunosuppressive exposure and prednisolone dose with few major adverse effects. There was an 80% (4/5) response in patients with retro-orbital granulomas. The effect of rituximab was most noticeable in the first 6 months (88% response).

Vasculitis of the upper and lower airway.

The pulmonary vasculitides are a heterogeneous group of rare disorders that result from an inflammatory process damaging the vessel wall and consequent impaired blood flow, ischaemia and tissue necrosis. The clinical manifestation of these vasculitides depends on the site, size, type and severity of the inflammatory process. Vasculitis involving the airways is a common feature of the anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides (AASVs) and can predate the diagnosis by years. Secondary causes of vasculitis associated with connective tissue disorders are also capable of presenting with pulmonary features. Recognition of involvement, investigation and treatment are important to ameliorate symptoms for patients. This article concentrates on the assessment and specific management of upper and lower airway problems of AASV.

Single-lung transplant complicated by unexpected explant carcinoma: a management dilemma.

Interstitial pneumonia is well known to increase the risk of lung cancer. We describe a young man who underwent single-lung transplantation for confirmed usual interstitial pneumonia and who was unexpectedly found to have multifocal adenocarcinoma in the explanted lung. Induction immunosuppression therapy was decreased and full screening for further tumor development was undertaken. Post-operatively further consolidative changes developed in the remaining native lung and, after diagnosis and staging, a native pneumonectomy was performed for adenocarcinoma. The good early outcome and management dilemmas are discussed, together with a review of the literature.

Aortic valve replacement for late infective endocarditis after heart-lung transplantation.

Infective endocarditis is a rare but life-threatening complication of heart and heart-lung transplantation. We describe a 32-year-old woman who developed aortic valvular endocarditis following heart-lung transplantation. Enterococcus was the infective organism. The patient's condition was successfully managed using prolonged intravenous antibiotic therapy and aortic valve replacement.

Effect of manually assisted cough and mechanical insufflation on cough flow of normal subjects, patients with chronic obstructive pulmonary disease (COPD), and patients with respiratory muscle weakness.

BACKGROUND: It has been suggested that cough effectiveness can be improved by assisted techniques. The effects of manually assisted cough and mechanical insufflation on cough flow physiology are reported in this study. METHODS: The physiological actions and patient self-assessment of manually assisted cough and mechanical insufflation were investigated in 29 subjects (nine normal subjects, eight patients with chronic obstructive pulmonary disease (COPD), four subjects with respiratory muscle weakness (RMW) with scoliosis, and eight subjects with RMW without scoliosis). RESULTS: The peak cough expiratory flow rate and cough expiratory volume were not improved by manually assisted cough and mechanical insufflation alone or in combination in normal subjects. The median increase in peak cough expiratory flow in subjects with RMW without scoliosis with manually assisted cough alone or in combination with mechanical insufflation of 84 l/min (95% confidence interval (CI) 19 to 122) and 144 l/min (95% CI 14 to 195), respectively, reflects improvement in the expulsive phase of coughing by these techniques. Manually assisted cough and mechanical insufflation in combination raised peak expiratory flow rate more than either technique alone in this group. The abnormal chest shape in scoliotic subjects and the fixed inspiratory pressure used made effective manually assisted cough and mechanical insufflation difficult in this group and no improvements were found. In patients with COPD manually assisted cough alone and in combination with mechanical insufflation decreased peak expiratory flow rate by 144 l/min (95% CI 25 to 259) and 135 l/min (95% CI 30 to 312), respectively. CONCLUSIONS: Manually assisted cough and mechanical insufflation should be considered to assist expectoration of secretions in patients with RMW without scoliosis but not in those with scoliosis.

Pathogenic alpha 1-antitrypsin polymers are formed by reactive loop-beta-sheet A linkage.

alpha(1)-Antitrypsin is the most abundant circulating protease inhibitor and the archetype of the serine protease inhibitor or serpin superfamily. Members of this family may be inactivated by point mutations that favor transition to a polymeric conformation. This polymeric conformation underlies diseases as diverse as alpha(1)-antitrypsin deficiency-related cirrhosis, thrombosis, angio-edema, and dementia. The precise structural linkage within a polymer has been the subject of much debate with evidence for reactive loop insertion into beta-sheet A or C or as strand 7A. We have used site directed cysteine mutants and fluorescence resonance energy transfer (FRET) to measure a number of distances between monomeric units in polymeric alpha(1)-antitrypsin. We have then used a combinatorial approach to compare distances determined from FRET with distances obtained from 2.9 x 10(6) different possible orientations of the alpha(1)-antitrypsin polymer. The closest matches between experimental FRET measurements and theoretical structures show conclusively that polymers of alpha(1)-antitrypsin form by insertion of the reactive loop into beta-sheet A.

A kinetic mechanism for the polymerization of alpha1-antitrypsin.

The mutation in the Z deficiency variant of alpha1-antitrypsin perturbs the structure of the protein to allow a unique intermolecular linkage. These loop-sheet polymers are retained within the endoplasmic reticulum of hepatocytes to form inclusions that are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. The process of polymer formation has been investigated here by intrinsic tryptophan fluorescence, fluorescence polarization, circular dichroic spectra and extrinsic fluorescence with 8-anilino-1-naphthalenesulfonic acid and tetramethylrhodamine-5-iodoacetamide. These biophysical techniques have demonstrated that alpha1-antitrypsin polymerization is a two-stage process and have allowed the calculation of rates for both of these steps. The initial fast phase is unimolecular and likely to represent temperature-induced protein unfolding, while the slow phase is bimolecular and associated with loop-sheet interaction and polymer formation. The naturally occurring Z, S, and I variants and recombinant site-directed reactive loop and shutter domain mutants of alpha1-antitrypsin were used to demonstrate the close association between protein stability and rate of alpha1-antitrypsin polymerization. Taken together, these data allow us to propose a kinetic mechanism for alpha1-antitrypsin polymer formation that involves the generation of an unstable intermediate, which can form polymers or generate latent protein.

Tracheal involvement in Wegener's granulomatosis: evaluation using spiral CT.

OBJECTIVE: To describe the computed tomography (CT) appearances of tracheal stenosis in Wegener's granulomatosis (WG) and to assess the additional value of reformatted images. PATIENTS AND METHODS: Ten patients with tracheal involvement by WG were assessed with spiral CT and both coronal and three-dimensional surface shaded images were generated. Fibreoptic bronchoscopy was also performed in all patients. RESULTS: Ninety per cent of lesions were situated in the subglottic region. In all cases there was circumferential mucosal thickening, in nine cases extending over a relatively short distance (mean 2.4 cm). The degree of narrowing of the axial luminal diameter ranged from 23% to 100%. In three patients there was contiguous involvement of the vocal cords evident on CT, two further cases with mild vocal cord inflammation were identified bronchoscopically. Other CT findings included mucosal irregularity and ulceration (50%), and involvement of the tracheal cartilages (20%). CONCLUSION: Wegener's granulomatosis may involve the trachea with resultant stenosis. Spiral CT is an easily performed, non-invasive technique which provides accurate assessment of tracheal lesions and is complementary to bronchoscopy. The main additional advantage of coronal reformatted images was our added confidence in defining the upper and lower limits of lesions and in the evaluation of vocal cord involvement.

Mask intermittent positive pressure ventilation in chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease.

Noninvasive ventilation in chronic obstructive pulmonary disease (COPD) has been shown to improve arterial blood gases but its long-term role has not been established. We retrospectively studied 26 consecutive patients with hypercapnic ventilatory failure due to COPD in whom oxygen therapy caused worsening hypercapnia (defined as a rise in the daytime arterial carbon dioxide tension (Pa,CO2) to >8.0 kPa or nocturnal transcutaneous carbon dioxide tension (Ptc,CO2) to >9 kPa). All were treated with mask ventilation (15 with nasal and 11 face masks) at night and during daytime naps. Additional oxygen therapy was required in 15 patients. The mean annualized death rate was 10.8% with a 1 and 3 yr survival of 92 and 68%, respectively. After 1 yr the median daytime Pa,CO2 had fallen by 1.35 kPa and the arterial oxygen tension (Pa,O2) had risen by 2.4 kPa. In subjects not using additional oxygen the median overnight Sa,O2 rose by 12% and the Ptc,CO2 fell by 2.8 kPa after 1 yr. The haematocrit was significantly less than pretreatment at 6 months and 1 yr. Quality of life in the domain of role limitation by physical health (measured using the SF-36 questionnaire) improved significantly at 6 months. Survival in this selected group with clinically stable airflow obstruction unable to tolerate oxygen therapy and treated with noninvasive mask ventilation is better than historical controls and is comparable to those able to tolerate oxygen therapy. Poor survival was associated with a low forced expiratory volume in one second, a low body mass index and a high nocturnal transcutaneous carbon dioxide tension. No difference in survival was found between those treated with mask intermittent positive pressure ventilation alone or with mask intermittent positive pressure and supplementary oxygen therapy.