Christopher Zappala

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.

Serum Interleukin 6 Is Predictive of Early Functional Decline and Mortality in Interstitial Lung Disease Associated with Systemic Sclerosis

Objective. Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD). Methods. A panel of 8 serum cytokines [interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1] was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline [forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15%] from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD. Results. In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC < 70%), serum IL-6 > 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4–7.2, p = 0.007), but not in those with severe ILD. Conclusion. In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.

Australian Idiopathic Pulmonary Fibrosis Registry : vital lessons from a national prospective collaborative project

There is little Australian epidemiologic data on idiopathic pulmonary fibrosis (IPF), a relatively uncommon but devastating disease. The vast geographic distances in Australia have been a major impediment for collaborative research into IPF. A collaborative national effort, the Australian IPF Registry, has been formed, launched and is recruiting successfully (n = 359, January 2014). Our experience provides unique insights for others wishing to set up IPF registries and in time for a global IPF registry.

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

Health-related quality of life in idiopathic pulmonary fibrosis: Data from the Australian IPF Registry

Studies analysing the effect of worsening pulmonary physiological impairment in idiopathic pulmonary fibrosis (IPF) with respect to quality of life have been limited to single centres or highly selected trial populations. The aim of this study was to determine the principal determinants of baseline and longitudinal health‐related quality of life (HRQoL) in a large unselected IPF population.

Determinants and outcomes of prolonged anxiety and depression in idiopathic pulmonary fibrosis

We have recently shown that anxiety and depression are common comorbidities for people with interstitial lung disease (ILD). In a cross-sectional single-centre study, the prevalence of anxiety was 31% and the prevalence of depression was 23% [1]. Anxiety and depression were not related to physiological parameters; however, dyspnoea and number of comorbidities were important contributors. The aims of this study were to determine the frequency of prolonged anxiety and depression among sufferers of idiopathic pulmonary fibrosis (IPF), and factors contributing to their persistence. Prolonged anxiety and depression occur frequently in IPF and strongly relate to dyspnoea and cough http://ow.ly/iWxV30cLCfl

Idiopathic pulmonary fibrosis: is all-cause mortality a practical and realistic end-point for clinical trials?

Dear Editor, We read with interest the article by Wells et al 1 in which the problematic selection of primary end-points for treatment studies in idiopathic pulmonary fibrosis (IPF) patients is addressed. In this document endorsed by respiratory physicians across Europe, the authors explore the implications of using all-cause mortality as a primary end-point in response to a recent statement by a working group on this topic.2 In a rather controversial statement by this working group, Raghu et al suggested that all-cause mortality and all-cause non-elective hospitalisation are the strongest and cleanest clinically meaningful end-points for use in Phase 3 clinical …

Aetiology and clinical phenotype still seem distant in sarcoidosis

The hypothesis that sarcoidosis results from a complex interaction between environment and immunogenetical susceptibility to the disease has been accepted for many years. Nonetheless, the exact nature of this susceptibility, and even if it is common across all patients, remains uncertain.The article byWilsher and colleagues in this issue probes this notion of immunobiological predisposition by examining the prevalence of atopy/asthma in sarcoidosis, and the degree of mutual exclusivity between T-helper 1 cells (TH1) and T-helper 2 cells (TH2) predominant cytokine patterns. Their finding of an absence of T-cell skewing is perhaps not surprising in the current era. Unifying statements regarding critical pathogenetical pathways in sarcoidosis, such as the role of TH1 predominant cytokine patterns, have been helpful to focus attention and debate. However, such statements also have the potential to mislead, or they represent an oversimplification of the true pathobiology. This problem applies equally to pathogenetical pathways and statements of clinical phenotype.Wilsher and colleagues have provided insight into the diverse immunopathogenesis of sarcoidosis, but it remains unclear as to whether hyperreactivity, coexistent asthma or the underpinning cytokine profiles provide greater clarity in regard to the nature of the disease, clinical phenotypes, and by extension, guide refinements in treatment strategy. The compartmentalization of CD4+ TH1 lymphocytes and activated macrophages in the lung and other involved organs is traditionally believed to be pathognomonic in sarcoidosis; however, it is possible that the complex network of cytokines and chemokines that orchestrate the disease evolve or change over time and between individuals. Patients may, thus, progress to a more TH2-dominant pattern which may be implicated in the genesis of fibrosis, or the more recently described TH17 phenotype, or another pathway yet to be defined. The additional role of T regulatory cells in autoimmune and chronic disease points us intuitively towards a complex model of pathogenesis consisting of multiple pathways producing lung injury that progresses well beyond a simple inverse relationship between TH1 and TH2 cytokine profiles. This immune phenotype complexity is well demonstrated in the variables response to therapy, specifically anti-tumour necrosis factor (TNF) agents. TNF is a key cytokine involved in granuloma formation. While infliximab and other anti-TNF agents have been shown to have a therapeutic benefit in some patients with sarcoidosis, there are now numerous case reports of patients developing a sarcoid-like illness while receiving these therapies (in the absence of mycobacterial infection), which then regresses when the anti-TNF agent is ceased. Decreased antigen clearance may be implicated. Similarly, the ‘immune paradox’ of extensive local inflammation coexistent with anergy, as indicated by suppression of the immune response to tuberculin, may relate to diminished dendritic cell function and/or expansion of regulatory T cells. Similar dangers lie in oversimplification of the definition of clinical phenotypes associated with certain T-cell profiles. Bronchial hypersensitivity is well described in sarcoidosis, and it may relate, among other variables, to the angiotensin-converting enzyme genotype. It has been found to exist in up to 20% of patients, and as a result, cough and wheeze may be prominent. Nonetheless, when the airway is involved, the reduced diameter of the diseased airway causing increased airway resistance may lead to a false-positive bronchoprovocation test or symptoms perceived as asthma. Wilsher and colleagues defined asthma in terms of a self-reported questionnaire, which therefore may have led to an inflation of asthma prevalence among patients with airway sarcoid. The differential diagnosis of patients with airway symptoms can obviously also include vasculitis and neoplasia in this context. The confounding effect of chronic obstructive airways disease was reduced in the current study by the lack of association of smoking status with atopy and observed lack of correlation with fixed obstruction on spirometry. It remains possible, therefore, that some patients labelled as asthma may, in fact, have only sarcoidosis. This confusion may delay definitive diagnosis in some cases, or lead to an erroneous diagnosis of both disorders in one individual. The negative relationship between asthma prevalence and chest radiographic stage is not surprising given the known lack of correlation between radiographic stage and sarcoid airway involvement. Similarly, on high-resolution computed tomography of the chest, CT features compatible with small airways disease contribute little to airflow obstruction, and paradoxically, a reticular pattern on CT, most frequently regarded as representative of pulmonary fibrosis, is the major morphological association of functional airflow obstruction. However, a history of wheezing is associated with the extent of groundglass opacification and reticular pattern on CT. Thus, the combination of airway involvement and interstitial involvement results in variable and complex pulmonary function abnormalities that do not correlate well with radiological appearances. This is underlined by the association of a lower gas transfer, which presumably reflects parenchymal abnormalities to a greater extent than airway pathology, with recent

Implications of the diagnostic criteria of idiopathic pulmonary fibrosis in clinical practice: Analysis from the Australian Idiopathic Pulmonary Fibrosis Registry: Implications of IPF diagnostic criteria

Current guidelines for the diagnosis of idiopathic pulmonary fibrosis (IPF) provide specific criteria for diagnosis in the setting of multidisciplinary discussion (MDD). We evaluate the utility and reproducibility of these diagnostic guidelines, using clinical data from the Australian IPF Registry.