Elizabeth Renzoni

Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis

In therapeutic studies in idiopathic pulmonary fibrosis (IPF), the low prevalence of significant change in pulmonary functional tests (PFTs) has been a major constraint. The prognostic value of “marginal” changes in PFTs in IPF and fibrotic non-specific interstitial pneumonia (NSIP) was evaluated. In patients with biopsy-proven IPF (n = 84) and NSIP (n = 72), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DL,CO) trends at 6 months were categorised as “significant” (FVC >10%; DL,CO >15%) or “marginal” (FVC 5–10%; DL,CO 7.5–15%). Proportional hazards analysis and time-dependent receiver operating characteristic methodology were used to examine PFT trends against mortality. In IPF, reductions in FVC were significant in 22 cases (26%) and marginal in 19 cases (23%). Mortality was higher in patients with a significant decline in FVC (hazard ratio (HR) 2.80, 95% CI 1.54–5.06; p<0.001) and those with a marginal decline in FVC (HR 2.31, 95% CI 1.19–4.50; p = 0.01) than in those with stable disease. Progression-free survival was lower when the decline in FVC was marginal than in stable disease (HR 2.34, 95% CI 1.19–4.60; p = 0.01). Marginal changes in DL,CO in IPF and marginal changes in FVC and DL,CO in fibrotic NSIP did not provide useful prognostic information. Marginal change in FVC in IPF denotes a poor outcome. These findings are applicable to clinical practice and to the selection of patients with more progressive disease for therapeutic studies.

Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF

Background: While idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, the aetiology of IPF is poorly understood. Familial cases of pulmonary fibrosis suggest a genetic basis for some forms of the disease. Recent reports have linked genetic mutations in surfactant protein C (SFTPC) with familial forms of pulmonary fibrosis, including one large family in which a number of family members were diagnosed with usual interstitial pneumonitis (UIP), the pathological correlate to IPF. Because of this finding in familial cases of pulmonary fibrosis, we searched for SFTPC mutations in a cohort of sporadic cases of UIP and non-specific interstitial pneumonitis (NSIP). Methods: The gene for SFTPC was sequenced in 89 patients diagnosed with UIP, 46 patients with NSIP, and 104 normal controls. Results: Ten single nucleotide polymorphisms in the SFTPC sequence were found in IPF patients and not in controls. Only one of these created an exonic change resulting in a change in amino acid sequence. In this case, a T to C substitution resulted in a change in amino acid 73 of the precursor protein from isoleucine to threonine. Of the remaining polymorphisms, one was in the 5′ UTR, two were exonic without predicted amino acid sequence changes, and six were intronic. One intronic mutation suggested a potential enhancement of a splicing site. Conclusions: Mutations in SFTPC are identified infrequently in this patient population. These findings indicate that SFTPC mutations do not contribute to the pathogenesis of IPF in the majority of sporadic cases.

Significance of connective tissue disease features in idiopathic interstitial pneumonia

In idiopathic interstitial pneumonia (IIP), the significance of connective tissue disease (CTD) features in the absence of a specific CTD diagnosis remains unclear. We studied the clinical and prognostic utility of a diagnosis of undifferentiated CTD (UCTD) in patients with biopsy-proven IIP. IIP patients undergoing surgical lung biopsy (1979–2005) were studied (nonspecific interstitial pneumonia (NSIP), n=45; idiopathic pulmonary fibrosis, n=56). UCTD was considered present when serum autoantibodies were present and symptoms or signs suggested CTD. The relationship between UCTD and NSIP histology was evaluated. A clinical algorithm that best predicted NSIP histology was constructed using a priori variables. The prognostic utility of UCTD, and of this algorithm, was evaluated. UCTD was present in 14 (31%) NSIP and seven (13%) IPF patients. UCTD was not associated with a survival benefit. The algorithm predictive of NSIP (OR 10.4, 95% CI 3.21–33.67; p<0.0001) consisted of the absence of typical high-resolution computed tomography (HRCT) features for IPF and 1) a compatible demographic profile (females aged <50 yrs) or 2) Raynaud’s phenomenon. In patients with an HRCT scan not typical for IPF, this algorithm predicted improved survival (hazard ratio 0.35, 95% CI 0.14–0.85; p=0.02) independent of IIP severity. UCTD is associated with NSIP histology. However, the diagnostic and prognostic significance of UCTD in IIP patients remains unclear.

BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia.

Idiopathic pulmonary fibrosis (IPF), which has the histological pattern of usual interstitial pneumonia (UIP), is a progressive interstitial lung disease with a poor prognosis. Idiopathic interstitial pneumonias with a histological pattern of nonspecific interstitial pneumonia (NSIP) have a better prognosis than UIP, and may present with a clinical picture identical to IPF. The authors hypothesised that bronchoalveolar lavage (BAL) findings may distinguish between UIP and NSIP, and have prognostic value within disease subgroups. BAL findings were studied retrospectively in 54 patients with histologically proven (surgical biopsy) idiopathic UIP (n=35) or fibrotic NSIP (n=19), all presenting clinically as IPF. These findings were also compared with the BAL profile of patients with other categories of idiopathic interstitial pneumonias. BAL total and differential cell counts did not differ between the two groups. Survival was better in NSIP. In neither group were BAL findings predictive of survival or changes in lung function at 1 yr, even after adjustment for disease severity, smoking andtreatment. BAL differential counts in fibrotic NSIP differed from respiratory bronchiolitis-associated interstitial lung disease, but not from desquamative interstitial pneumonia or cellular NSIP. The authors conclude that bronchoalveolar lavage findings do not discriminate between usual interstitial pneumonia and nonspecific interstitial pneumonia in patients presenting with clinical features of idiopathic pulmonary fibrosis, and have no prognostic value, once the distinction between the two has been made histologically.

The impact of parental smoking on asthma and wheezing. SIDRIA Collaborative Group. Studi Italiani sui Disturbi Respiratori nell'Infanzia e l'Ambiente.

To evaluate the impact of parental smoking on childhood asthma and wheezing, we studied two random samples of subjects ages 6–7 and 13–14 years in ten areas of northern and central Italy. Standardized questionnaires were completed by parents of 18,737 children and 21,068 adolescents (response rates, 92.8% and 96.3%, respectively) about their smoking habits and the respiratory health of their children. Adolescents were asked about their respiratory health and personal smoking. We compared two groups of cases with healthy subjects: “current asthma” (children, 5.2%; adolescents, 6.2%) and “current wheezing” not labeled as asthma (children = 4.5%, adolescents = 8.5%). Exposure to smoke of at least one parent increased the relative risk of current asthma among children [odds ratio (OR) =.34; 95% confidence interval (CI) = 1.11–1.62] and of current wheezing among adolescents OR = 1.24; 95% CI = 1.07–1.44). Maternal smoking had a stronger effect than paternal smoking. Maternal smoking during pregnancy was associated with current asthma (OR = 1.62; 95% CI = 1.34–1.96) and current wheezing in children (OR = 1.31; 95% CI = 1.06–1.62); the effects were lower among adolescents. Among subjects with a negative history of parental asthma, maternal smoking was associated with current wheezing in both age groups, whereas among those with a positive history of parental asthma it was associated with current asthma in children, but not in adolescents. We estimated that 15% (95% CI = 12–19) of the current asthma cases among children and 11% (95% CI = 8.3–14) of the current wheezing cases among adolescents are attributable to parental smoking in Italy. (Epidemiology 1999;10:692–698)

A polymorphism in the promoter region of the CD86 (B7.2) gene is associated with systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disease of unknown aetiology characterized by fibrosis of the skin and internal organs, vascular abnormalities and humoral autoimmunity. Strong T‐cell‐dependent autoantibody and HLA associations are found in SSc subsets. The co‐stimulatory molecule, CD86, expressed by antigen‐presenting cells, plays a crucial role in priming naïve lymphocytes. We hypothesized that SSc, or one of the disease subsets, could be associated with single‐nucleotide polymorphisms of the CD86 gene. Using sequence specific primer‐polymerase chain reaction (SSP‐PCR) methodology, we assessed four CD86 polymorphisms in 221 patients with SSc and 227 healthy control subjects from the UK. Haplotypes were constructed by inference and confirmed using PHASE algorithm. We found a strong association between SSc and a specific haplotype (haplotype 5), which was more prevalent in patients than in controls (29% vs 15%, OR = 2.3, χ2 = 12, P = 0.0005). This association could be attributed to the novel −3479 promoter polymorphism; a significant difference was observed in the distribution of the CD86 −3479 G allele in patients with SSc compared to controls (43.7% vs. 32.4%, OR = 1.7, χ2 = 12.1, P = 0.0005). TRANSFAC analyses suggest that the CD86‐3479T allele contains putative GATA and TBP sites, whereas G allele does not. We assessed the relative DNA protein‐binding activity of the −3479 polymorphism in vitro using electromobility gel shift assays (EMSA), which showed that the −3479G allele has less binding affinity compared to the T allele for nuclear proteins. These findings highlight the importance of co‐stimulatory pathways in SSc pathogenesis.

Alveolar proteinosis with hypersensitivity pneumonitis: A new clinical phenotype

Background and objective:  The aim of the present study was to report the features of five patients with concurrent histopathological features of pulmonary alveolar proteinosis (PAP) and hypersensitivity pneumonitis (HP) and their high‐resolution CT (HRCT) appearances.

A7.14 IRF5 Polymorphisms in Systemic Sclerosis

Introduction The transcription factor interferon regulatory factor 5 (IRF-5) plays a key role in the Toll-like receptor signalling pathway, and activation of the type I interferon response. As well as being associated with a number of other rheumatological diseases, including systemic lupus erythematosus and rheumatoid arthritis, IRF5 has been identified as a candidate gene for systemic sclerosis (SSc) in a number of genome wide association studies. Although this finding has been replicated in several different studies, there has been variation in the single nucleotide polymorphisms (SNPs) tested, thereby making it difficult to determine which IRF5 SNP(s) may be playing a role in susceptibility to SSc. We therefore tested a number of IRF5 SNPs in a UK based population with the aim of elucidating the true causal variant(s). Materials and Methods To investigate involvement of this gene in susceptibility to SSc, UK Caucasian patients and controls (SSc n = 465, controls n = 416) were genotyped using commercially available TaqMan assays. The IRF5 SNPs Rs4728142, Rs2004640, Rs10954213, and Rs10488631, previously reported to be associated with SSc, were selected for investigation. The presence of pulmonary fibrosis was defined as a forced vital capacity <75% and/or the presence of fibrosis on chest imaging. Results The allele frequencies of each of the four IRF5 SNPs were not significantly different (using Bonferroni correction for multiple testing) in the healthy controls and patients with SSc (Rs4728142: 0.52/0.50, Rs2004640: 0.56/0.60, Rs10954213: 0.37/0.35, Rs10488631: 0.12/0.14). There was also no significant difference found for any of the SNPs when the SSc patients were subdivided according to disease type (limited/diffuse), presence of pulmonary fibrosis, or auto-antibody type. Conclusions In contrast to previously published studies we did not detect a significant difference in allele frequency between patients with SSc and healthy control individuals for any of the four IRF5 SNPs tested. However, due to the modest cohort sizes available, this study has limited power and therefore may have been unable to detect allele frequency differences with small effects. This study therefore will be repeated with larger cohorts in order to validate these results.

Safety and tolerability of nintedanib for the treatment of idiopathic pulmonary fibrosis in routine UK clinical practice

Nintedanib, a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF), reduces annual forced vital capacity (FVC) decline in these patients by ∼50% with combined analysis of data from clinical trials showing a trend towards reduction in mortality [1–3]. Nintedanib prescription criteria for the treatment of IPF vary between countries and in 2016, the National Institute for Health and Care Excellence approved nintedanib in England and Wales for patients with an FVC between 50% and 80% predicted [4]. Prior to this approval, nintedanib was available through a manufacturer-funded programme with varying prescribing criteria. We investigated the safety and tolerability of nintedanib in UK clinical practice during this period in which FVC prescription criteria differed from those now available in routine practice. In IPF, commencement of antifibrotic therapy in patients with preserved lung volume may increase the duration of therapy http://ow.ly/4HeM30lFS67

P248 Patient eligibility for anti-fibrotic therapy in idiopathic pulmonary fibrosis can be altered by use of different sets of reference values for calculation of fvc percent predicted

Introduction Antifibrotic drugs for idiopathic pulmonary fibrosis (IPF) patients in England and Scotland are only available to those with FVC percent predicted (FVC%pred) less than or equal to 80%. The prescribing guidance does not state which reference values should be used. Aims To find out if the use of different sets of reference values affects the numbers of patients with FVC%pred greater than and less than 80%. To find out which reference equations were in use at UK centres prescribing antifibrotics for IPF in April 2016. Methods We searched databases for patients diagnosed with IPF at our interstitial lung disease (ILD) unit from 1/1/2010 to 31/12/2015. We calculated FVC%pred using three different sets of reference values (ECSC, GLI or NHANES). The chief respiratory physiologist in each ILD centre in England was contacted and asked which reference values they used to calculate FVC%pred. In Scotland, four hospitals with an ILD MDT were contacted and asked the same. McNemar tests were used to compare the proportion of patients eligible for antifibrotic prescription when FVC%pred was calculated by ECSC or either NHANES or GLI. Results See Table 1. We identified 671 unique patients: after exclusions, 528 had complete data. There was a higher proportion of patients calculated to have an FVC%pred >80% (ineligible for antifibrotics) using ECSC than GLI: Chi-square 22.0, 1df, P<0.0001. The difference in proportions was greater when ECSC was compared to NHANES: Chi square 33.03, 1df, P < 0.0001. Of 30 patients with ECSC FVC%pred 80–85%, 27 [90%: 95% CI: 79–100%) had their FVC%pred fall to <80% when recalculated with NHANES. 18 of 20 ILD centres in England were using ECSC to calculate FVC%pred; others used GLI (n = 1) and Falaschetti (n = 1). All four Scottish centres were using ECSC. Discussion Many patients with ECSC FVC%pred too high for antifibrotics fall into the eligible range when NHANES, the set of reference values used in the ASCEND pirfenidone trial, or GLI, as recommended by the UK Association for Respiratory Technology and Physiology(ARTP) are used. Conclusions We urge physicians and physiologists to ensure that reference values used to calculate FVC%pred are cited in lung function reports. Those choosing reference values must be aware of implications for patients. Abstract P248 Table 1 Results for all IPF patients: Demographics and Disease Severity by FVC percent predicted Total IPF patients n = 528 Sex Male Female Row total Number of patients (proportion) 431 (82%) 97 (18%) 528 Ethnicity Caucasian Non-Caucasian Number of patients (proportion) 453 (86%) 75 (14%) 528 Characteristic Unit Median IQ range Age years 72 68–78 FVC litres 2.175 1.700–2.780 Reference equations used ECSC FVC%pred 64.9 52.2–75.9 GLI FVC%pred 60.6 49.3–72.4 NHANES FVC%pred 58.9 49.4–70.0 FVC percent predicted range >80% <80% Row total Reference equations used ECSC Number of patients 98 430 528 GLI 73 455 528 NHANES 64 464 528 Key for Table 1: FVC = forced vital capacity; ECSC = European Community for Steel and Coal; GLI = Global Lung Index; NHANES = National Health and Nutrition Examination Survey; %pred = percent predicted; IQ = interquartile