Anne-Marie Russell

The Role of Bacteria in the Pathogenesis and Progression of Idiopathic Pulmonary Fibrosis

RATIONALE Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown cause that leads to respiratory failure and death within 5 years of diagnosis. Overt respiratory infection and immunosuppression carry a high morbidity and mortality, and polymorphisms in genes related to epithelial integrity and host defense predispose to IPF. OBJECTIVES To investigate the role of bacteria in the pathogenesis and progression of IPF. METHODS We prospectively enrolled patients diagnosed with IPF according to international criteria together with healthy smokers, nonsmokers, and subjects with moderate chronic obstructive pulmonary disease as control subjects. Subjects underwent bronchoalveolar lavage (BAL), from which genomic DNA was isolated. The V3-V5 region of the bacterial 16S rRNA gene was amplified, allowing quantification of bacterial load and identification of communities by 16S rRNA quantitative polymerase chain reaction and pyrosequencing. MEASUREMENTS AND MAIN RESULTS Sixty-five patients with IPF had double the burden of bacteria in BAL fluid compared with 44 control subjects. Baseline bacterial burden predicted the rate of decline in lung volume and risk of death and associated independently with the rs35705950 polymorphism of the MUC5B mucin gene, a proven host susceptibility factor for IPF. Sequencing yielded 912,883 high-quality reads from all subjects. We identified Haemophilus, Streptococcus, Neisseria, and Veillonella spp. to be more abundant in cases than control subjects. Regression analyses indicated that these specific operational taxonomic units as well as bacterial burden associated independently with IPF. CONCLUSIONS IPF is characterized by an increased bacterial burden in BAL that predicts decline in lung function and death. Trials of antimicrobial therapy are needed to determine if microbial burden is pathogenic in the disease.

Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study

BACKGROUND Idiopathic pulmonary fibrosis, a progressive and inevitably fatal disorder, has a highly variable clinical course. Biomarkers that reflect disease activity are urgently needed to inform patient management and for use as biomarkers of therapeutic response (theragnostic biomarkers) in clinical trials. We aimed to determine whether dynamic change in markers of extracellular matrix (ECM) turnover predicts progression of idiopathic pulmonary fibrosis as determined by change in forced vital capacity and death. METHODS In this ongoing prospective, multicentre, observational cohort study (PROFILE), participants with idiopathic pulmonary fibrosis or idiopathic non-specific interstitial pneumonia diagnosed within the preceding 6 months were recruited from two coordinating centres (Nottingham, UK, and, Royal Brompton Hospital, London, UK). Serum samples were prospectively collected at baseline, 1 month, 3 months, and 6 months and were analysed for a panel of novel matrix metalloprotease (MMP)-degraded ECM proteins, by ELISA-based, neoepitope assay. 11 neoepitopes were tested in a discovery cohort of 55 patients to identify biomarkers of sufficient rigour for more detailed analyses. Eight were then further assessed in a validation cohort of 134 patients with 50 age-matched and sex-matched controls. Changes in biomarker concentrations were related to subsequent progression of idiopathic pulmonary fibrosis (defined as death or decline in forced vital capacity >10% at 12 months after study enrolment) using a repeated measures model. The PROFILE study is registered on ClinicalTrials.gov, numbers NCT01134822 and NCT01110694. FINDINGS Of 214 eligible participants recruited between Sept 1, 2010, and March 31, 2012, 189 had a confirmed diagnosis of idiopathic pulmonary fibrosis and were included in subsequent analyses. In the discovery cohort, mean concentrations of seven neoepitopes (BGM, p=0·009; C1M, p=0·009; C3M, p=0·046; C6M, p=0·032; CRPM, p=0·008; ELM2, p=0·02; and VICM, p=0·0007) differed significantly between healthy controls and participants with idiopathic pulmonary fibrosis. Baseline concentrations of six neoepitopes (C1M, p=0·012; C3A, p=0·012; C3M, p=0·0005; C6M, p=0·0003; CRPM, p=0·021; and VICM, p=0·046) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=32) than in those with stable disease (n=23). In the validation cohort, mean concentrations of C1M (p=0·001), C3M (p=0·044), C6M (p=0·003), and CRPM (p=0·024) at baseline were higher in patients with idiopathic pulmonary fibrosis than in healthy controls. When assessed longitudinally, concentrations of six neoepitopes (BGM, C1M, C3A, C3M, C6M, and CRPM) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=71) than in patients with stable idiopathic pulmonary fibrosis (n=60) by 6 months. Baseline concentrations of two neoepitopes were associated with increased mortality (C1M: HR 1·62 [95% CI 1·14-2·31], p=0·0069; C3A: 1·91 [1·06-3·46], p=0·032). The rate of change between baseline and 3 months of six neoepitopes (BGM: HR 1·084 [95% CI 1·03-1·14], p=0·0019; C1M: 1·01 [1·003-1·017], p=0·0039; C3M: 1·106 [1·045-1·170], p=0·0005; C5M: 1·003 [1·001-1·005], p=0·0011; C6M: 1·042 [1·007-1·078], p=0·017; and CRPM: 1·38 [1·16-1·63], p=0·0002) was strongly predictive of overall survival, and the increased risk was proportional to the magnitude of change in neoepitope concentrations. The strongest association with 3-month rate of biomarker change was recorded for CRPM; greater than 0 ng/mL per month conferred a HR of 2·16 (95% CI 1·15-4·07), whereas a rate greater than 1 ng/mL per month resulted in an HR 4·08 (2·14-7·8), and a rate greater than 1·7 ng/mL per month was associated with an HR 6·61 (2·74-15·94). INTERPRETATION Concentrations of protein fragments generated by MMP activity are increased in the serum of individuals with idiopathic pulmonary fibrosis compared with healthy controls. Increased neoepitope concentrations were associated with disease progression, and the rate of this increase predicted survival. Serial measurements of neoepitopes have potential to be used as theragnostic biomarkers in clinical trials and to guide management of idiopathic pulmonary fibrosis. FUNDING GlaxoSmithKline R&D and the Medical Research Council.

Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis

Background A polymorphism (rs35705950) 3 kb upstream of MUC5B, the gene encoding Mucin 5 subtype B, has been shown to be associated with familial and sporadic idiopathic pulmonary fibrosis (IPF). We set out to verify whether this variant is also a risk factor for fibrotic lung disease in other settings and to confirm the published findings in a UK Caucasian IPF population. Methods Caucasian UK healthy controls (n=416) and patients with IPF (n=110), sarcoidosis (n=180) and systemic sclerosis (SSc) (n=440) were genotyped to test for association. The SSc and sarcoidosis cohorts were subdivided according to the presence or absence of fibrotic lung disease. To assess correlation with disease progression, time to decline in forced vital capacity and/or lung carbon monoxide transfer factor was used in the IPF and SSc groups, while a persistent decline at 4 years since baseline was evaluated in patients with sarcoidosis. Results A significant association of the MUC5B promoter single nucleotide polymorphism with IPF (p=2.04×10–17; OR 4.90, 95% CI 3.42 to 7.03) was confirmed in this UK population. The MUC5B variant was not a risk factor for lung fibrosis in patients with SSc or sarcoidosis and did not predict more rapidly progressive lung disease in any of the groups. Rather, a trend for a longer time to decline in forced vital capacity was observed in patients with IPF. Conclusions We confirm the MUC5B variant association with IPF. We did not observe an association with lung fibrosis in the context of SSc or sarcoidosis, potentially highlighting fundamental differences in genetic susceptibility, although the limited subgroup numbers do not allow a definitive exclusion of an association.

Cough in idiopathic pulmonary fibrosis

Many patients with idiopathic pulmonary fibrosis (IPF) complain of chronic refractory cough. Chronic cough is a distressing and disabling symptom with a major impact on quality of life. During recent years, progress has been made in gaining insight into the pathogenesis of cough in IPF, which is most probably “multifactorial” and influenced by mechanical, biochemical and neurosensory changes, with an important role for comorbidities as well. Clinical trials of cough treatment in IPF are emerging, and cough is increasingly included as a secondary end-point in trials assessing new compounds for IPF. It is important that such studies include adequate end-points to assess cough both objectively and subjectively. This article summarises the latest insights into chronic cough in IPF. It describes the different theories regarding the pathophysiology of cough, reviews the different methods to assess cough and deals with recent and future developments in the treatment of cough in IPF. Latest insights into pathophysiology of cough, methods to assess cough and developments in treatment of cough in IPF http://ow.ly/YfVAH

The need for patient-centred clinical research in idiopathic pulmonary fibrosis

Patient-centredness is an accepted term and is perceived by healthcare professionals to be morally and ethically desirable. We are motivated by the belief that this approach will improve the patient-professional experience of the decision-making process and improve health outcomes. We acknowledge that patients, either as participants or as co-investigators, have positive contributions to make to research. As the idiopathic pulmonary fibrosis (IPF) community enters a new era of clinical research activity we consider that there is greater capacity for patient involvement and partnership.Patient involvement in research can be optimised through collaborations in the research design, study conduct, and dissemination. There is increasing interest in using patient- reported outcomes (PROs), such as health-related quality of life, and symptoms measures to inform decision-making and ensure patient perspectives are taken into account. PROs are an essential component of specialist IPF services, to monitor and improve care delivery and to measure and benchmark performance. In clinical trials, PROs can additionally be used to define entry criteria, evaluate efficacy of an intervention, and evaluate adverse events. We suggest that there is a much wider scope for including patient-centred PROs in clinical research and for creative thought in developing patient co-investigator roles.Participation in research activity requires highly refined decision-making processes, particularly in a condition such as IPF, which has an often unpredictable trajectory. The IPF research landscape has changed and the design and conduct of clinical trials in IPF requires some radical rethinking. It is accepted that involving patients in the role of co-investigators will impact the research questions we ask and result in study designs that are patient-centred. IPF clinical trials have been hindered by the lack of availability of validated, disease-specific questionnaires. A conservative approach appears to have been taken to the inclusion of generic symptom or quality of life measures as PRO endpoints. Thus, the impact of new drugs on the quality of life of research participants demonstrates only minimal benefit. It is time to refocus on a patient-centred approach with regards to the co-investigator role, PRO development, and research participants.

Palliative care in interstitial lung disease: living well

Progressive fibrotic interstitial lung diseases (ILDs) are characterised by major reductions in quality of life and survival and have similarities to certain malignancies. However, palliative care expertise is conspicuously inaccessible to many patients with ILD. Unmet patient and caregiver needs include effective pharmacological and psychosocial interventions to improve quality of life throughout the disease course, sensitive advanced care planning, and timely patient-centred end-of-life care. The incorrect perception that palliative care is synonymous with end-of-life care, with no role earlier in the course of ILD, has created a culture of neglect. Interventions that aim to improve life expectancy are often prioritised without rigorous assessment of the individuals health and psychosocial needs, thereby inadvertently reducing quality of life. As in malignant disorders, radical interventions to slow disease progression and palliative measures to improve quality of life should both be prioritised. Efficient patient-centred models of palliative care must be validated, taking into account religious and cultural differences, as well as variability of resources. Effective implementation of palliative care for ILD will require multidisciplinary participation from clinicians, specialist nurses, psychologists, social workers, and, in some countries, non-governmental faith and community-based organisations with access to palliative care expertise.

Effect of pirfenidone on cough in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease. In patients with IPF, cough is one of the most disabling symptoms and is an independent predictor of disease progression [1–3]. Cough in IPF is often non-responsive to antitussive therapy [4], and studies on cough are scarce and have unfortunately not yet resulted in effective treatments. Several observations suggest that pirfenidone, an anti-fibrotic drug, might decrease cough [5, 6]. We aimed to measure objectively the effect of pirfenidone on cough in patients with IPF and substantial cough. In addition, we assessed the effect of pirfenidone on subjective cough and quality of life (QoL) measures. In patients with IPF, pirfenidone reduces objective 24-h cough counts and improves subjective measures of cough http://ow.ly/iiGu30f7Pea

Non-pharmacological treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fatal disorder that remains difficult to treat. In this review, we examine non-pharmacological treatment modalities, including lung transplantation, pulmonary rehabilitation and palliation. Lung transplantation, the only therapeutic intervention that offers survival benefit, should be considered in all IPF patients with progressive disease who meet the International Society for Heart and Lung transplantation guidelines. Pulmonary rehabilitation improves exercise capacity, reduces dyspnoea and improves quality of life in IPF patients, and should be made available to patients. For those patients with advanced disease, palliative services offer symptom management, improved quality of life and psychological support for patients and their caregivers.

P276 Development of patient reported experience measure (PREM) for idiopathic pulmonary fibrosis (IPF)

Background Research into patient experiences of living with IPF has increased. A key challenge is how to use this data intelligently to enable commissioners and providers to improve the quality of services delivered to this group of patients. This project aims to develop an IPF-PREM informed by patients’ perceptions of their healthcare experiences. The IPF-PREM is underpinned by the NHS Patient Experience Framework (NPEF);1 National Institute for Health and Care Excellence (NICE) Quality Standards (QS15 and 79) and aligned to national initiatives integrating Patient Reported Outcome Measures (PROMs) and PREMs into NHS care. Methods A scoping exercise was undertaken with patients diagnosed with IPF on their journey through the healthcare system covering eight areas corresponding to the NPEF.1 Twenty patients representing all stages of the disease trajectory participated in one of three focus groups. Transcripts underwent content and thematic analysis. Patient preferences were also sought on questionnaire design. Results A number of key themes emerged. See Table 1. Of particular importance were issues concerning access: to specialist centres, medication and primary care services; consistency of care to prevent confusion; coordination of care especially for patients with multi-morbidities and getting the right information at the right time in the right way. Information enabling practical self-management was highly valued. Overarching was the need for continuity of care close to home. Participants valued having a nurse to co-ordinate care and to talk to at all stages of the care pathway. The response categories patients were keen to avoid were visual images such as smiley faces. Conclusions The IPF-PREM will provide a valuable quality indicator for IPF service delivery at all stages of the disease trajectory complementing IPF PROMs. Implementation of the PREM will enable commissioners and providers to improve the quality of the services and the patient experience of care delivered across the wider inter-disciplinary team. Reference DH 2011 NHS Patient Experience Framework. Abstract P276 Table 1 NPEF domain Focus group themes Respect for patient-centred values Recalibrating quality of life and wanting feedback on PROMs data; impact of breathlessness on independence; the need to talk and the need not to talk to be respected Coordination and integration of care Challenges of managing other health issues and lack of social/fiscal support – administrative processes often a barrier Information, communication and education The need to talk to others affected with IPF; more information at the beginning; to understand choices in healthcare; information customised to specific needs Physical comfort Impact on activities of daily life and how to physically manage these – support with transitions to oxygen therapy; need for effective symptom relief Emotional support Better access to psychological/counselling services for self and caregivers. Value having telephone support; healthcare professionals responding promptly to requests for advice. Wanting and not wanting to know prognosis Involvement of family and friends Family may have different information needs – respecting patient’s wishes – support for wives’; husband’s; partners often lacking – guilt associated with burden of caring Transition and continuity Do not want to be abandoned at end of life – feel better supported by clinicians known at diagnosis. Value copies of correspondence. Value having a key contact – particularly specialist nurse Access to care Having a progressive condition makes waiting to be seen by a specialist centre or for transplant assessment stressful. Travel presents challenges: dichotomy of wanting care close to home but with specialist input; too many health care appointments

What's it like to live with idiopathic pulmonary fibrosis? Ask the experts.

Over the last 5–7 years, an enlightened paradigm has emerged for clinical research. In it, patients are not simply “subjects” to be studied or numbers to be analysed; more than “key stakeholders”, patients are increasingly (and justly) recognised as the soul and substance of clinical investigation [1]. Patient advocacy organisations have added significant momentum to this movement by promoting patient-centred healthcare and helping to give a global voice to those who suffer from a range of conditions or impairments. Recent discussion on stratified medicine advocates the inclusion of patient perspectives and experience to inform the often complex decision-making processes regarding treatment [2]. Governing bodies and funding organisations have developed policies, programmes and agendas that have largely shaped the paradigm by fostering patient-centred investigations and advocating that studies be designed to ask and answer questions deemed important to patients, and include outcomes that are meaningful to patients [3]. Sharing and informing IPF healthcare decisions through partnerships with patients and their caregivers http://ow.ly/YHp3X