[Show abstract][Hide abstract] ABSTRACT: Background Idiopathic Pulmonary Fibrosis (IPF) is an increasingly important respiratory illness in the UK. Rising prevalence of disease, emerging treatments, development of clinical guidelines for diagnosis and management and a NHS England service specification1 increase demands on healthcare providers who are required to enhance capacity or reconfigure services to manage patients.
Aims Estimate the patient care pathways across service providers in England compared with pathways recommended by NICE guidelines2 and the NHS England Service Specification; in terms of time and cost per patient by ‘diagnosis’, ‘management’ and ‘monitoring’, and then levels of reimbursement to providers for current levels of care and those recommended.
Methods Structured interviews with clinicians and coders ascertained current levels of service provision, excluding drug costs, by 14 NHS specialist ILD providers. Data were analysed utilising a bottom-up costing approach to estimate the total pathway costs. Comparison with services and costs as recommended by NICE guidelines and service specification allowed estimation of NHS providers’ profit or loss.
Results The estimated mean cost per patient for the first year of diagnosis, management and monitoring was £1,414, which is approximately £418 (42%) more than is reimbursed by the PBR tariff.3 By comparison, the equivalent cost of the NICE/service specification pathway is approximately £477 (41%) more than reimbursed by the tariff. In particular, it was noted that significant staff time is required for MDT discussion, but that this is not reimbursed.
Conclusions Results suggest that current NHS tariffs for ILD are insufficient to support current service provision. This is true for current levels of care as well as for the levels of care recommended by NICE. The risks of failure to amend the NHS tariff are:
[Show abstract][Hide abstract] ABSTRACT: Introduction and objectives From September 2011 to May 2013, pirfenidone was available in the UK in a named patient programme (NPP). We present results from an extension to a previous real-world study (Parfrey et al. Abstract S98, BTS Winter Conference 2012) now including longer follow-up and all patients enrolled in the pirfenidone NPP from 4 centres.
Methods Four centre, retrospective, cohort review of patient outcomes in the 24 months following pirfenidone initiation in the NPP. Discontinuation data were separately collected for all patients prescribed pirfenidone at the Brompton between Sept 2011 and May 2014.
Results Two hundred and eighteen eligible patients have been identified. Demographic data have been collected for 124 patients (78% male) and outcome data at 12 months from 58 patients. Mean (±S. D.) age at diagnosis was 67.1(± 8.1) years. Mean time from diagnosis to pirfenidone initiation was 27.7(± 30.6) months. At pirfenidone initiation, mean FVC was 69.3(±18.9)% predicted (with 27 (22.0%) patients having FVC >80% predicted); DLco was 40.3(± 13.8)% predicted. Following a 14-day titration period, 53 (93%) patients were receiving the recommended dose of 2403 mg/day pirfenidone. At 6 and 12 months; 47 (81%) and 44 (76%) patients continued to receive pirfenidone.
187 patients have been prescribed pirfenidone at the Brompton since Sept 2011. At 10 months following initiation 18.5% of these have discontinued pirfenidone with no further discontinuations beyond this time. For patients in the NPP with available paired baseline and 6 or 12 month FVC, mean decline in FVC% predicted over first 6 months of pirfenidone treatment was 3.2(± 7.9)%; over first 12 months 1.6(±12.0)%. One patient’s FVC% predicted declined >10% in the first 12 months of treatment. Mean decline in DLco% predicted over first 6 months from pirfenidone initiation was 9.1(± 14.7)%; over first 12 months’ treatment, 7.0(± 17.2)%.
Conclusions The high proportion of patients remaining on pirfenidone at 12 months suggests it is well tolerated and any tolerability issues tend to occur early in treatment. Lung function is largely preserved at 12 months following pirfenidone initiation. Longer-term observation of lung function and clinical outcomes will continue to determine the real-world benefits of pirfenidone.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic pulmonary fibrosis (IPF) and non-specific interstitial pneumonia (NSIP) are forms of idiopathic interstitial pneumonias that have distinct histopathological features and outcomes. It is unknown if these idiopathic interstitial pneumonias have common mechanisms of fibrosis. Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of sporadic and familial idiopathic pulmonary fibrosis. In response to endoplasmic reticulum (ER) stress, cells trigger the unfolded protein response (UPR) with upregulation of chaperones, such as BiP, and the phosphatase growth arrest and DNA damage 34 (GADD34). However, this may have profound effects on cell proliferation and survival. We hypothesised that ER stress may also be involved in the pathogenesis of NSIP.
Paraffin embedded lung biopsy sections from 4 patients with sporadic idiopathic pulmonary fibrosis (IPF) (UIP histopathology) and 4 non-specific interstitial pneumonia (NSIP) (NSIP histopathology) were evaluated for the ER stress markers BiP and GADD34 using immunohistochemistry. For each biopsy sample, six high power fields (x 200 magnification) were scored for fibrosis and inflammation as well as BiP and GADD34 using semi-quantitative analysis by 2 blinded, independent investigators.
BiP and GADD34 were expressed in areas of fibrosis, localised to reactive type II pneumocytes and endothelial cells. No staining was detected in fibroblasts or fibroblastic foci. In sporadic IPF (UIP), levels of BiP within the epithelium correlated with fibrosis (r2 0.56, p = 0.0001, Figure 1a) more than inflammation (r2 0.38, p = 0.0013). In contrast, epithelial GADD34 was more strongly associated with NSIP fibrosis (r2 0.56, p < 0.0001, Figure 1b). There was no association between the ER stress markers and inflammation in NSIP.
These data suggest that ER stress and the unfolded protein response are features of NSIP as well as IPF and may play a role in determining the severity of the fibrotic response.
[Show abstract][Hide abstract] ABSTRACT: Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.
Full-text · Article · Feb 2014 · The Journal of Rheumatology
[Show abstract][Hide abstract] ABSTRACT: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities.
The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF).
A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed.
Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.
[Show abstract][Hide abstract] ABSTRACT: Introduction and Objectives There are limited data on the healthcare resource use that arises as a consequence of idiopathic pulmonary fibrosis (IPF). Navaratnam et al 1 have recently reported rising hospital admissions due to IPF but utilisation of other health related services by individuals with IPF is unknown. As part of a real world assessment of the clinical experience of pirfenidone via the UK Named Patient Program data were collected to determine the burden placed on healthcare resources as a consequence of IPF.
Methods A multi-centre, retrospective, cohort review was undertaken across 4 NHS Trusts. Hospital resource use data were collected from the clinical records of individuals starting pirfenidone for IPF through the NPP before June 2012.
Results Data were available from 100 patients (76% male) at baseline and 67 through to nine months from baseline. At baseline, the mean ± S.D. age was 69.3 ± 7.5 years, mean ± S.D. FVC% predicted was 70% ± 19% and 62 patients were on oxygen therapy. In the first 6 months from baseline, 11 patients had 15 IPF-related hospitalisations of which 6 were for an acute exacerbation. One patient was hospitalised in the 6–9 months period. The mean ± S.D. and median (IQR) hospital bed days in the first 6 months were 11.0 ± 7.5 and 11.0 (6.0–13.5) days respectively for hospitalised patients and mean ± S.D. 1.2 ± 4.2 days for all patients. One patient was admitted to the Intensive Care Unit, for 5 days. Eighteen patients had IPF-related Accident and Emergency department visits, 3 had an IPF-related day-case and 67 outpatient clinic visits, with a mean of 2.1 ± 2.0 outpatient clinic visits per patient in the first 6 months of the observation period.
Conclusion IPF is a terminal disease associated with significant morbidity and mortality. This is reflected in the high level of resource use and frequent accessing of health care services by this severely ill cohort of patients. Whether resource use has been positively impacted by the introduction of pirfenidone is unknown but merits prospective assessment.
Reference Navaratnam V, Fogarty AW, McKeever T, Hubbard RB. The Increasing Secondary Care Burden of Idiopathic Pulmonary Fibrosis Hospital Admission Trends in England >From 1998 to 2010. CHEST 2013; 143(4):1078–1084
[Show abstract][Hide abstract] ABSTRACT: Pulmonary fibrosis is the end stage of many diffuse parenchymal lung diseases. It is characterised by excessive matrix formation leading to destruction of the normal lung architecture and finally death. Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the delineation of primary pathways has proven to be elusive.
In this review susceptibility and injurious agents, such as viruses and gastro-oesophageal reflux, and their probable role in initiating disease will be discussed. Further topics that are elaborated are candidate ancillary pathways, including immune mechanisms, oxidative and endoplasmic reticulum stress, activation of the coagulation cascade and the potential role of stem cells. This review will try to provide the reader with an integrated view on the current knowledge and attempts to provide a road map for future research.
It is important to explore robust models of overall pathogenesis, reconciling a large number of clinical and scientific observations. We believe that the integration of current data into a "big picture" overview of fibrogenesis is essential for the development of effective antifibrotic strategies. The latter will probably consist of a combination of agents targeting a number of key pathways.
Full-text · Article · May 2013 · European Respiratory Journal
[Show abstract][Hide abstract] ABSTRACT: Neutrophils are critical effector cells of the innate immune response and are recruited to sites of tissue injury in response to locally generated chemoattractants. Neutrophil recruitment is a highly regulated process involving complex interactions with the vascular endothelium and underlying tissue stroma. In addition to adhering to the endothelium, neutrophils can also self-associate, (a process known as homotypic aggregation - HA), which has been proposed to play a key role in disease states such as sepsis. Aminopepetidase N or CD13 is a widely expressed membrane-bound metallopeptidase involved in the migration and invasion of cancer and endothelial cells. Neutrophils express CD13 on their cell surface, which is upregulated by TNF-α, IL-8 and fMLP We have shown that inhibition of aminopeptidase activity enhances the efficacy of TNF-α-induced neutrophil apoptosis (Cowburn et al. J Biol Chem 2006; 281:12458). Cross-linking anti-CD13 monoclonal antibodies (mAb) have been shown to induce HA of monocytic cells through PI3K activation (Mina-Osorio et al. J Leuk Biol 2006; 79:719). We hypothesised that CD13 may be involved in neutrophil migration and HA. Using plasma-Percoll purified human neutrophils and a modified Boyden filtre assay we showed that IL-8 mediated neutrophil chemotaxis was not affected by either the CD13 mAb WM-15 or the aminopeptidase enzymatic inhibitor bestatin. In contrast, IL-8-mediated neutrophil migration through type 1 collagen gels was significantly impaired by WM-15 and MY7 mAbs, which both inhibit enzymatic activity and induce clustering of CD13. The non-clustering CD13 antibody WM-47 and bestatin had no effect. WM-15 and MY7 also promoted neutrophil aggregation as assessed by light microscopy. Phase-contrast video-microscopy demonstrated that in WM-15 treated neutrophils, where HA was evident, the percentage of cells entering collagen 1 gels in response to IL-8 was significantly reduced (26.9% vs 71.8% in non-HA cells). WM-15 does not prime neutrophils, as assessed by superoxide production and shape change, and the cell surface expression of CD11b, CD18 and CD66b were not altered. These data suggest a novel role for CD13 in the homotypic aggregation of neutrophils, which reduces chemoattractant-induced migration through collagen 1 matrix and may predispose to neutrophil micro-aggregation within the circulation.
[Show abstract][Hide abstract] ABSTRACT: Background:
Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of the lungs of unknown origin with a poor prognosis. A small trial of co-trimoxazole demonstrated improvements in symptoms and functional parameters over a 3-month period. We therefore conducted a larger trial with a concurrent economic evaluation to investigate this antibiotic further.
We report an economic evaluation alongside a multi-centre, randomised, placebo-controlled, double-blind trial of 12 months therapy with 960 mg co-trimoxazole daily in 181 patients with fibrotic idiopathic interstitial pneumonia (IIP). Patients were recruited from 28 university and district hospitals in the UK and were aged over 40 years with fibrotic IIP. We report costs to the National Health Service (NHS) and society, change in forced vital capacity (primary endpoint) and quality-adjusted life-years (QALYs) gained, incremental cost effectiveness and cost utility ratios over 12 months.
From the perspective of society, mean cost per patient in the co-trimoxazole arm was approximately £1177 higher than in the placebo arm, but mean QALYs were 0.053 higher yielding an incremental cost-effectiveness ratio of £22,012 per QALY gained with a 54.44 % probability of being below £30,000. The cost of IPF to UK society in 2011 is tentatively estimated at £124 million, of which 13 % is NHS costs, 1 % social services, 2 % patient out-of-pocket costs and 84 % lost productivity.
Given commonly employed thresholds in the UK NHS, on balance co-trimoxazole may be a cost-effective treatment for IPF, although there is substantial decision uncertainty. However, recent guidance on the use of immunosuppressive therapy in IPF patients should be taken into account prior to any policy decision.
[Show abstract][Hide abstract] ABSTRACT: Lung biopsy is the last option to obtain lung tissue for a precise diagnosis in patients with interstitial lung disease (ILD). Several surgical techniques have been reported. The successful application of a hybrid approach is herein reported. The procedure utilizes a single-trocar video-assisted thoracoscopic surgery technique to localize and withdraw the tip of the lingula outside the chest to perform a biopsy in the diagnosis of ILDs. The advantages of this technique over other commonly used methods have also been discussed.
[Show abstract][Hide abstract] ABSTRACT: Pleuroparenchymal fibroelastosis (PPFE) is a rare condition characterised by predominantly upper lobe pleural and subjacent parenchymal fibrosis, the latter being intra-alveolar with accompanying elastosis of the alveolar walls. The aim of this study was to review cases fulfilling published imaging and histological criteria, and identify any common clinical features that may suggest an underlying aetiology for a condition that has previously been regarded as idiopathic. Of 12 patients (seven females, median age 57 yrs), the presenting symptoms were shortness of breath (11 out of 12 patients) and dry cough (six out of 12 patients). Seven patients reported recurrent infections during the course of their disease. Five demonstrated nonspecific autoantibody positivity. Two patients had a family history of interstitial lung disease (ILD). High-resolution computed tomography features of lung disease remote from the pleuroparenchymal changes were present in six out of 12 patients (coexistent fibrosis, n=5; bronchiectasis, n=1). Of seven patients with tissue sampled from the lower lobes, four patients showed less intense PPFE changes (one with additional features of hypersensitivity pneumonitis) and three showed usual interstitial pneumonia. PPFE is a distinct clinicopathological entity, with clinical data suggesting a link to recurrent pulmonary infection. Genetic and autoimmune mechanisms may also contribute to the development of these changes. PPFE may also present with more diffuse involvement than previously reported, and coexist with different patterns of ILD.
Preview · Article · Mar 2012 · European Respiratory Journal
[Show abstract][Hide abstract] ABSTRACT: The serpinopathies result from point mutations in members of the serine protease inhibitor or serpin superfamily. They are characterized by the formation of ordered polymers that are retained within the cell of synthesis. This causes disease by a "toxic gain of function" from the accumulated protein and a "loss of function" as a result of the deficiency of inhibitors that control important proteolytic cascades. The serpinopathies are exemplified by the Z (Glu342Lys) mutant of α₁-antitrypsin that results in the retention of ordered polymers within the endoplasmic reticulum of hepatocytes. These polymers form the intracellular inclusions that are associated with neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. A second example results from mutations in the neurone-specific serpin-neuroserpin to form ordered polymers that are retained as inclusions within subcortical neurones as Collins' bodies. These inclusions underlie the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. There are different pathways to polymer formation in vitro but not all form polymers that are relevant in vivo. It is therefore essential that protein-based structural studies are interpreted in the context of human samples and cell and animal models of disease. We describe here the biochemical techniques, monoclonal antibodies, cell biology, animal models, and stem cell technology that are useful to characterize the serpin polymers that form in vivo.
Full-text · Article · Dec 2011 · Methods in enzymology
[Show abstract][Hide abstract] ABSTRACT: Rituximab (RTX), a B-cell depleting mAb, has been reported to cause pulmonary toxicity in many patients. As the use of this biologic is increasing, we have undertaken a systematic review of the literature to gauge the nature and extent of non-infection-related RTX-induced lung disease.
A systematic literature review was undertaken to document all reported cases of RTX-associated interstitial lung disease (RTX-ILD), evaluating the epidemiological, clinical, radiological, histopathological, laboratory and management data from the available primary sources. The search was conducted using PubMed, the Cochrane Library and EMBASE up to June 2010 using the terms RTX in the advanced search option without limitations and all relevant publications reviewed manually. In addition, unpublished data from the Food and Drug Administration, the European Medicines Agency and the manufacturer (Roche) were evaluated to complement this search. Identified articles were included if they displayed a potential relationship between the administration of RTX and ILD following exclusion of other likely causes.
A total of 121 cases of potential RTX-ILD were identified from 21 clinical studies/trials, 30 case reports and 10 case series. The most common indication for RTX was diffuse large B-cell lymphoma. RTX-ILD occurred more frequently in male patients and was most common during the fifth and sixth decades of life. In most cases, RTX was part of combination chemotherapy, but in 30 (24.7%) cases it was given as monotherapy. The mean and median number of cycles of RTX before disease onset was four, but cases following the first cycle or as late as the 12th cycle were also identified. The mean time of onset, from the last RTX infusion until symptom development or relevant abnormal radiological change was 30 days (range 0-158 days). Abnormal radiological findings were similar in all patients, with diffuse bilateral lung infiltrates apparent on chest radiographs and/or thoracic CT. Hypoxaemia was seen in all cases and pulmonary function tests were uniformly abnormal with a characteristic diffusion capacity deficit and restrictive ventilatory pattern. RTX-ILD was fatal in 18 cases.
ILD is a rare but potentially fatal complication of RTX therapy. This diagnosis should be considered in any patient who develops respiratory symptoms or new radiographic changes while receiving this biologic agent.
Full-text · Article · Dec 2011 · Rheumatology (Oxford, England)
[Show abstract][Hide abstract] ABSTRACT: The serpinopathies result from point mutations in members of the serine protease inhibitor or serpin superfamily. They are characterized by the formation of ordered polymers that are retained within the cell of synthesis. This causes disease by a “toxic gain of function” from the accumulated protein and a “loss of function” as a result of the deficiency of inhibitors that control important proteolytic cascades. The serpinopathies are exemplified by the Z (Glu342Lys) mutant of α1-antitrypsin that results in the retention of ordered polymers within the endoplasmic reticulum of hepatocytes. These polymers form the intracellular inclusions that are associated with neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. A second example results from mutations in the neurone-specific serpin–neuroserpin to form ordered polymers that are retained as inclusions within subcortical neurones as Collins’ bodies. These inclusions underlie the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. There are different pathways to polymer formation in vitro but not all form polymers that are relevant in vivo. It is therefore essential that protein-based structural studies are interpreted in the context of human samples and cell and animal models of disease. We describe here the biochemical techniques, monoclonal antibodies, cell biology, animal models, and stem cell technology that are useful to characterize the serpin polymers that form in vivo.