Gregory J. Keir

Rituximab in severe, treatment‐refractory interstitial lung disease

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.

Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy

In very severe interstitial lung disease associated with connective tissue disease (CTD-ILD), progressing despite maximal conventional immunosuppression, there is no effective medical rescue therapy. The aim of the present study was to test whether rituximab, a monoclonal antibody that depletes peripheral B lymphocytes, is effective as rescue therapy in very severe CTD-ILD, unresponsive to conventional immunosuppression. We performed a retrospective assessment of eight patients with severe and progressive CTD-ILD treated with rituximab. In six patients, change in pulmonary function tests (PFTs) compared with pre-rituximab levels, was assessed at 9–12 months post-treatment. In two patients, who were mechanically ventilated at the time of treatment, clinical and HRCT changes were assessed. Seven out of eight patients had a favourable treatment response to rituximab, while in one patient disease severity did not change. In contrast with previous progression, we observed a median significant improvement of 22% in diffusing capacity for carbon monoxide (from a median baseline of 25%; range 16–32%; p=0.04), and a median significant improvement of 18% in forced vital capacity (from a median baseline of 45%; range 37–59%; p=0.03), in the 9–12 months following treatment with rituximab. In very severe CTD-ILD unresponsive to conventional immunosuppression, rituximab may represent an effective, potentially life-saving, therapeutic intervention.

Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia.

RATIONALE Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality. OBJECTIVES To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group. METHODS In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks. MEASUREMENTS AND MAIN RESULTS Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m(2) and reduced cardiac index of 2.21 (± 0.5) L/min/m(2) were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group). CONCLUSIONS This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).

Connective tissue disease related fibrotic lung disease: high resolution computed tomographic and pulmonary function indices as prognostic determinants

Purpose To determine high resolution computed tomography (HRCT) patterns and pulmonary function indices which are associated with increased mortality in patients with connective tissue disease related fibrotic lung disease (CTD-FLD). Methods HRCTs from 168 patients with CTD-FLD were scored by 2 observers for a variety of HRCT patterns and traction bronchiectasis. A radiological diagnosis of usual interstitial pneumonia (UIP), fibrotic non-specific interstitial pneumonia (NSIP) or indeterminate was also assigned. Using Cox regression analysis, associations with mortality were identified. Honeycombing and traction bronchiectasis scores were converted to binary absence/presence scores and also tested. A subgroup analysis of patients with biopsy material (n=51) was performed by classifying patients according to radiological and histopathological diagnoses, as concordant UIP, discordant UIP and fibrotic NSIP. The prognostic separation of this classification was also evaluated. Results Severity of traction bronchiectasis (HR 1.10, p=0.001, 95% CIs 1.04 to 1.17), increasing extent of honeycombing (HR 1.08, p=0.021, 95% CI 1.03 to 1.13) and reduction in DLco (HR 0.97, p=0.013, 95% CI 0.95 to 0.99) were independently associated with increased mortality. Interobserver agreement and prognostic strength were higher for binary traction bronchiectasis scores (weighted κ (κw)=0.69, HR 4.00, p=0.001, 95%CI 1.19 to 13.38), than binary honeycombing scores (κw=0.50, HR 2.87, p=0.022, 95% CI 1.53 to 5.43). The radiological-histopathological classification was strongly associated with increased mortality (HR 2.74, p<0.001, 95% CI 1.57 to 4.77) and patients with discordant UIP had a better prognosis than concordant UIP but worse prognosis than fibrotic NSIP. Conclusions Severity of traction bronchiectasis, extent of honeycombing and DLco are strongly associated with mortality in CTD-FLD. Interobserver agreement for traction bronchiectasis is higher than for honeycombing. In CTD-FLD, radiological diagnosis has survival implications in biopsy proven UIP.

An integrated clinicoradiological staging system for pulmonary sarcoidosis: a case-cohort study

BACKGROUND Mortality in pulmonary sarcoidosis is highly variable and a reliable prognostic algorithm for disease staging and for guiding management decisions is needed. The objective of this study is to derive and test a staging system for determining prognosis in pulmonary sarcoidosis. METHODS We identified the prognostic value of high-resolution computed tomography (HRCT) patterns and pulmonary function tests, including the composite physiological index (CPI) in patients with pulmonary sarcoidosis. We integrated prognostic physiological and HRCT variables to form a clinical staging algorithm predictive of mortality in a test cohort. The staging system was externally validated in a separate cohort by the same methods of discrimination used in the primary analysis and tested for clinical applicability by four test observers. FINDINGS The test cohort included 251 patients with pulmonary sarcoidosis in the study referred to the Sarcoidosis clinic at the Royal Brompton Hospital, UK, between Jan 1, 2000, and June 30, 2010. The CPI was the strongest predictor of mortality (HR 1·04, 95% CI 1·02-1·06, p<0·0001) in the test cohort. An optimal CPI threshold of 40 units was identified (HR 4·24, 2·84-6·33, p<0·0001). The CPI40, main pulmonary artery diameter to ascending aorta diameter ratio (MPAD/AAD), and an extent of fibrosis threshold of 20% were combined to form a staging algorithm. When assessed in the validation cohort (n=252), this staging system was strikingly more predictive of mortality than any individual variable alone (HR 5·89, 2·68-10·08, p<0·0001). The staging system was successfully applied to the test and validation cohorts combined, by two radiologists and two physicians. INTERPRETATION A clear prognostic separation of patients with pulmonary sarcoidosis is provided by a simple staging system integrating the CPI and two HRCT variables.

Improving the detection of pulmonary hypertension in systemic sclerosis using pulmonary function tests

OBJECTIVE To construct a readily applicable formula for selecting patients with systemic sclerosis (SSc) for right-sided heart catheterization (RHC) based on the results of their pulmonary function tests (PFTs). METHODS The diagnostic value of PFT variables was quantified in 386 patients with SSc against data obtained from RHC. RESULTS We derived the following formula using data from 257 patients: predicted mPAP = 136 - SpO₂ - 0.25 × DLCO % predicted, where mPAP is the mean pulmonary artery pressure, SpO₂ is the oxygen saturation as measured by pulse oximetry, and DLCO is the diffusing capacity for carbon monoxide. We validated the formula in the remaining 129 SSc patients. The area under the curve was 0.75 (95% confidence interval [95% CI] 0.67, 0.84). Using a predicted threshold of 25 mm Hg, the sensitivity was 90.1% (95% CI 82, 96) and the specificity was 29.2% (95% CI 17, 44). When used as a screening procedure in a typical scleroderma patient population, it is projected that those with an mPAP below 25 mm Hg are unlikely to have pulmonary hypertension (PH; prevalence 4.4%), those with a predicted mPAP of 25-35 mm Hg are at average risk of having PH (prevalence of 11.3%), and those with a formula-predicted mPAP above 35 mm Hg are likely to have PH (prevalence of 62.9%), thus justifying RHC. In patients with equivocal findings on echocardiography, a high formula-predicted mPAP is strongly associated with the presence of PH. CONCLUSION We derived and validated an easily applied formula for determining pulmonary function in patients with SSc that identifies subgroups with a low, average, or high prevalence of PH. It provides information that is complementary to echocardiography and that should improve the selection of patients for RHC.

Novel use of rituximab in hypersensitivity pneumonitis refractory to conventional treatment

Hypersensitivity pneumonitis (HP) is treated by removal of the inciting antigen, if identified, and with corticosteroids and immunosuppressive agents in extensive or progressive disease. A minority of patients continue to decline and suffer outcomes comparable to idiopathic pulmonary fibrosis. Rituximab, a B cell depleting anti-CD20 antibody, has shown benefit in interstitial lung diseases (ILDs) associated with connective tissue diseases (CTDs).1–3 We report a novel use of rituximab in a case of HP refractory to conventional treatment. A 57-year-old female never-smoker, with no previous medical history, presented with a 6-month history of progressive breathlessness and dry cough. Pulmonary function tests (PFTs) were impaired, with 26% of diffusing capacity for carbon monoxide (DLco) and 44% of forced vital capacity (FVC). A high-resolution CT (HRCT) showed changes suggestive …

Cyclical caspofungin for chronic pulmonary aspergillosis in sarcoidosis

Abstract In sarcoidosis, chronic pulmonary aspergillosis (CPA) may be associated with significant morbidity, and treatment failure rates are often high, even with newer triazole antifungal agents. We report a treatment regimen of cyclical caspofungin infusions in 10 patients with sarcoidosis and worsening CPA despite oral triazoles.

Baseline characteristics of idiopathic pulmonary fibrosis: analysis from the Australian Idiopathic Pulmonary Fibrosis Registry

The prevalence of idiopathic pulmonary fibrosis (IPF), a fatal and progressive lung disease, is estimated at 1.25–63 out of 100 000, making large population studies difficult. Recently, the need for large longitudinal registries to study IPF has been recognised. The Australian IPF Registry (AIPFR) is a national registry collating comprehensive longitudinal data of IPF patients across Australia. We explored the characteristics of this IPF cohort and the effect of demographic and physiological parameters and specific management on mortality. Participants in the AIPFR (n=647, mean age 70.9±8.5 years, 67.7% male, median follow up 2 years, range 6 months–4.5 years) displayed a wide range of age, disease severity and co-morbidities that is not present in clinical trial cohorts. The cumulative mortality rate in year one, two, three and four was 5%, 24%, 37% and 44% respectively. Baseline lung function (forced vital capacity, diffusing capacity of the lung for carbon monoxide, composite physiological index) and GAP (gender, age, physiology) stage (hazard ratio 4.64, 95% CI 3.33–6.47, p<0.001) were strong predictors of mortality. Patients receiving anti-fibrotic medications had better survival (hazard ratio 0.56, 95% CI 0.34–0.92, p=0.022) than those not on anti-fibrotic medications, independent of underlying disease severity. The AIPFR provides important insights into the understanding of the natural history and clinical management of IPF. Data from the Australian IPF registry shows anti-fibrotic therapy and baseline physiology predict survival in IPF http://ow.ly/Ete2305OkU9

Treatment of idiopathic pulmonary fibrosis in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand and the Lung Foundation Australia

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease (ILD) of unknown aetiology with a median survival of only 2–5 years. It is characterized by progressive dyspnoea and worsening lung function, ultimately resulting in death.