Maria Kokosi

Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: a case-cohort study

BACKGROUND Diffuse parenchymal lung disease represents a diverse and challenging group of pulmonary disorders. A consistent diagnostic approach to diffuse parenchymal lung disease is crucial if clinical trial data are to be applied to individual patients. We aimed to evaluate inter-multidisciplinary team agreement for the diagnosis of diffuse parenchymal lung disease. METHODS We did a multicentre evaluation of clinical data of patients who presented to the interstitial lung disease unit of the Royal Brompton and Harefield NHS Foundation Trust (London, UK; host institution) and required multidisciplinary team meeting (MDTM) characterisation between March 1, 2010, and Aug 31, 2010. Only patients whose baseline clinical, radiological, and, if biopsy was taken, pathological data were undertaken at the host institution were included. Seven MDTMs, consisting of at least one clinician, radiologist, and pathologist, from seven countries (Denmark, France, Italy, Japan, Netherlands, Portugal, and the UK) evaluated cases of diffuse parenchymal lung disease in a two-stage process between Jan 1, and Oct 15, 2015. First, the clinician, radiologist, and pathologist (if lung biopsy was completed) independently evaluated each case, selected up to five differential diagnoses from a choice of diffuse lung diseases, and chose likelihoods (censored at 5% and summing to 100% in each case) for each of their differential diagnoses, without inter-disciplinary consultation. Second, these specialists convened at an MDTM and reviewed all data, selected up to five differential diagnoses, and chose diagnosis likelihoods. We compared inter-observer and inter-MDTM agreements on patient first-choice diagnoses using Cohens kappa coefficient (κ). We then estimated inter-observer and inter-MDTM agreement on the probability of diagnosis using weighted kappa coefficient (κw). We compared inter-observer and inter-MDTM confidence of patient first-choice diagnosis. Finally, we evaluated the prognostic significance of a first-choice diagnosis of idiopathic pulmonary fibrosis (IPF) versus not IPF for MDTMs, clinicians, and radiologists, using univariate Cox regression analysis. FINDINGS 70 patients were included in the final study cohort. Clinicians, radiologists, pathologists, and the MDTMs assigned their patient diagnoses between Jan 1, and Oct 15, 2015. IPF made up 88 (18%) of all 490 MDTM first-choice diagnoses. Inter-MDTM agreement for first-choice diagnoses overall was moderate (κ=0·50). Inter-MDTM agreement on diagnostic likelihoods was good for IPF (κw=0·71 [IQR 0·64-0·77]) and connective tissue disease-related interstitial lung disease (κw=0·73 [0·68-0·78]); moderate for non-specific interstitial pneumonia (NSIP; κw=0·42 [0·37-0·49]); and fair for hypersensitivity pneumonitis (κw=0·29 [0·24-0·40]). High-confidence diagnoses (>65% likelihood) of IPF were given in 68 (77%) of 88 cases by MDTMs, 62 (65%) of 96 cases by clinicians, and in 57 (66%) of 86 cases by radiologists. Greater prognostic separation was shown for an MDTM diagnosis of IPF than compared with individual clinicians diagnosis of this disease in five of seven MDTMs, and radiologists diagnosis of IPF in four of seven MDTMs. INTERPRETATION Agreement between MDTMs for diagnosis in diffuse lung disease is acceptable and good for a diagnosis of IPF, as validated by the non-significant greater prognostic separation of an IPF diagnosis made by MDTMs than the separation of a diagnosis made by individual clinicians or radiologists. Furthermore, MDTMs made the diagnosis of IPF with higher confidence and more frequently than did clinicians or radiologists. This difference is of particular importance, because accurate and consistent diagnoses of IPF are needed if clinical outcomes are to be optimised. Inter-multidisciplinary team agreement for a diagnosis of hypersensitivity pneumonitis is low, highlighting an urgent need for standardised diagnostic guidelines for this disease. FUNDING National Institute of Health Research, Imperial College London.

Prevalence and outcome of pulmonary fibrosis in microscopic polyangiitis

We sought to determine the type of pulmonary involvement in microscopic polyangiitis (MPA), primarily focusing on pulmonary fibrosis (PF), its prevalence, temporal relationship with other disease manifestations and outcome. 33 patients (16 males) with biopsy proven perinuclear anti-neutrophilic cytoplasmic antibody-positive MPA (age 63.5 yrs) participated in the study. Pulmonary involvement was assessed using standard methods, including radiographic imaging (chest radiographs and high-resolution computed tomography), pulmonary function testing, bronchoscopy and bronchoalveolar lavage, and, if indicated, lung biopsy. All-cause mortality was analysed by the Kaplan–Meier method and was compared between MPA patients with and without PF. At the time of diagnosis, renal involvement was detected in all patients, with renal biopsies being consistent with segmental necrotising glomerulonephritis in all patients. The most common respiratory symptom was haemoptysis, which was found in nine (27%) patients. PF was present in 12 (36%) patients at the time of diagnosis, whereas one patient developed PF while on therapy ∼10 yrs after disease diagnosis. In seven patients with PF, respiratory symptoms related to fibrosis preceded other disease manifestations by a median (range) period of 13 (5–120) months. Patients were followed up for a period of 38±30 months. Presence of PF was associated with increased mortality (p = 0.02), with six deaths occurring in the fibrotic group and one in the nonfibrotic group. In the fibrotic group most deaths were related to PF. PF occurs frequently in MPA, may precede other disease manifestations by a variable length of time and has a poor prognosis.

Mortality prediction in idiopathic pulmonary fibrosis: evaluation of computer-based CT analysis with conventional severity measures

Computer-based computed tomography (CT) analysis can provide objective quantitation of disease in idiopathic pulmonary fibrosis (IPF). A computer algorithm, CALIPER, was compared with conventional CT and pulmonary function measures of disease severity for mortality prediction. CT and pulmonary function variables (forced expiratory volume in 1 s, forced vital capacity, diffusion capacity of the lung for carbon monoxide, transfer coefficient of the lung for carbon monoxide and composite physiologic index (CPI)) of 283 consecutive patients with a multidisciplinary diagnosis of IPF were evaluated against mortality. Visual and CALIPER CT features included total extent of interstitial lung disease, honeycombing, reticular pattern, ground glass opacities and emphysema. In addition, CALIPER scored pulmonary vessel volume (PVV) while traction bronchiectasis and consolidation were only scored visually. A combination of mortality predictors was compared with the Gender, Age, Physiology model. On univariate analyses, all visual and CALIPER-derived interstitial features and functional indices were predictive of mortality to a 0.01 level of significance. On multivariate analysis, visual CT parameters were discarded. Independent predictors of mortality were CPI (hazard ratio (95% CI) 1.05 (1.02–1.07), p<0.001) and two CALIPER parameters: PVV (1.23 (1.08–1.40), p=0.001) and honeycombing (1.18 (1.06–1.32), p=0.002). A three-group staging system derived from this model was powerfully predictive of mortality (2.23 (1.85–2.69), p<0.0001). CALIPER-derived parameters, in particular PVV, are more accurate prognostically than traditional visual CT scores. Quantitative tools such as CALIPER have the potential to improve staging systems in IPF. CALIPER-derived parameters such as pulmonary vessel volume are more accurate prognostically than visual CT scores http://ow.ly/2b5G304exlA

Automated Quantitative Computed Tomography Versus Visual Computed Tomography Scoring in Idiopathic Pulmonary Fibrosis: Validation Against Pulmonary Function.

Purpose: The aim of the study was to determine whether a novel computed tomography (CT) postprocessing software technique (CALIPER) is superior to visual CT scoring as judged by functional correlations in idiopathic pulmonary fibrosis (IPF). Materials and Methods: A total of 283 consecutive patients with IPF had CT parenchymal patterns evaluated quantitatively with CALIPER and by visual scoring. These 2 techniques were evaluated against: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLco), carbon monoxide transfer coefficient (Kco), and a composite physiological index (CPI), with regard to extent of interstitial lung disease (ILD), extent of emphysema, and pulmonary vascular abnormalities. Results: CALIPER-derived estimates of ILD extent demonstrated stronger univariate correlations than visual scores for most pulmonary function tests (PFTs): (FEV1: CALIPER R2=0.29, visual R2=0.18; FVC: CALIPER R2=0.41, visual R2=0.27; DLco: CALIPER R2=0.31, visual R2=0.35; CPI: CALIPER R2=0.48, visual R2=0.44). Correlations between CT measures of emphysema extent and PFTs were weak and did not differ significantly between CALIPER and visual scoring. Intriguingly, the pulmonary vessel volume provided similar correlations to total ILD extent scored by CALIPER for FVC, DLco, and CPI (FVC: R2=0.45; DLco: R2=0.34; CPI: R2=0.53). Conclusions: CALIPER was superior to visual scoring as validated by functional correlations with PFTs. The pulmonary vessel volume, a novel CALIPER CT parameter with no visual scoring equivalent, has the potential to be a CT feature in the assessment of patients with IPF and requires further exploration.

Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: an international case–cohort study

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (κw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw=0.65, IQR 0.53–0.72, p<0.0001) than academic physicians (κw=0.56, IQR 0.45–0.65, p<0.0001) or physicians with access to multidisciplinary team (MDT) meetings (κw=0.54, IQR 0.45–0.64, p<0.0001). The prognostic accuracy of academic physicians with >20 years of experience (C-index=0.72, IQR 0.0–0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70–0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72–0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts. Academic status, access to MDT meetings and clinician experience predict accuracy of a clinical diagnosis of IPF http://ow.ly/k43W30cTMg1

Evaluation of computer-based computer tomography stratification against outcome models in connective tissue disease-related interstitial lung disease: a patient outcome study.

BackgroundTo evaluate computer-based computer tomography (CT) analysis (CALIPER) against visual CT scoring and pulmonary function tests (PFTs) when predicting mortality in patients with connective tissue disease-related interstitial lung disease (CTD-ILD). To identify outcome differences between distinct CTD-ILD groups derived following automated stratification of CALIPER variables.MethodsA total of 203 consecutive patients with assorted CTD-ILDs had CT parenchymal patterns evaluated by CALIPER and visual CT scoring: honeycombing, reticular pattern, ground glass opacities, pulmonary vessel volume, emphysema, and traction bronchiectasis. CT scores were evaluated against pulmonary function tests: forced vital capacity, diffusing capacity for carbon monoxide, carbon monoxide transfer coefficient, and composite physiologic index for mortality analysis. Automated stratification of CALIPER-CT variables was evaluated in place of and alongside forced vital capacity and diffusing capacity for carbon monoxide in the ILD gender, age physiology (ILD-GAP) model using receiver operating characteristic curve analysis.ResultsCox regression analyses identified four independent predictors of mortality: patient age (P < 0.0001), smoking history (P = 0.0003), carbon monoxide transfer coefficient (P = 0.003), and pulmonary vessel volume (P < 0.0001). Automated stratification of CALIPER variables identified three morphologically distinct groups which were stronger predictors of mortality than all CT and functional indices. The Stratified-CT model substituted automated stratified groups for functional indices in the ILD-GAP model and maintained model strength (area under curve (AUC) = 0.74, P < 0.0001), ILD-GAP (AUC = 0.72, P < 0.0001). Combining automated stratified groups with the ILD-GAP model (stratified CT-GAP model) strengthened predictions of 1- and 2-year mortality: ILD-GAP (AUC = 0.87 and 0.86, respectively); stratified CT-GAP (AUC = 0.89 and 0.88, respectively).ConclusionsCALIPER-derived pulmonary vessel volume is an independent predictor of mortality across all CTD-ILD patients. Furthermore, automated stratification of CALIPER CT variables represents a novel method of prognostication at least as robust as PFTs in CTD-ILD patients.

Rare idiopathic interstitial pneumonias: LIP and PPFE and rare histologic patterns of interstitial pneumonias: AFOP and BPIP

In the 2013 reclassification of the idiopathic interstitial pneumonias (IIPs), two rare IIPs (idiopathic lymphoid interstitial pneumonia (LIP), idiopathic pleuroparenchymal fibroelastosis (IPPFE)) and two rare histologic patterns (acute fibrinous and organizing pneumonia (AFOP), bronchiolocentric pattern of interstitial pneumonia (BPIP)) are described. All these entities are rare with small series published to date, mostly containing primary and secondary forms of disease. LIP is histologically characterized by diffuse polyclonal lymphoid cell infiltrate surrounding the airways and expanding the interstitium. Thin‐walled cysts and diffuse ground glass are considered the typical radiologic features. The clinical course is highly variable with corticosteroid responsiveness evident in approximately half of cases. IPPFE is defined histologically by coexisting upper lobe pleural and intra‐alveolar fibrosis with elastosis. Dense subpleural irregular fibrosis and consolidation are the cardinal radiologic features. A history of recurrent lower respiratory tract infection is frequent. Responses to immunomodulation have not been reported and the rate of progression appears to be highly variable. AFOP is a rare histologic pattern lying within the spectrum of acute/subacute lung injury, characterized by organizing pneumonia and intra‐alveolar fibrin deposition without hyaline membranes. BPIP is characterized histologically by fibrosis and/or inflammation confined to the alveolar interstitium around bronchovascular bundles, overlapping with peribronchial metaplasia and fibrosis in some series. Currently, AFOP and BPIP are both best viewed as histological entities rather than true clinical disorders, in the absence of characteristic associated imaging patterns and clinical features.

Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis

This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis. Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide (DLCO), transfer coefficient of the lung for carbon monoxide (KCO), composite physiologic index (CPI)) and mortality. The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using DLCO, and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p<0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p<0.0001) reduced gas transfer (DLCO). There is no prognostic impact of emphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema. Emphysema in IPF has no effect on outcome beyond that explained by combined fibrosis and emphysema extents http://ow.ly/BtU430bUnIg

Diffuse Pulmonary Ossification in Fibrosing Interstitial Lung Diseases: Prevalence and Associations

Purpose To investigate the prevalence of diffuse pulmonary ossification (DPO) in patients with fibrosing interstitial lung disease (ILD) and determine whether there are differences among the types of ILDs. Materials and Methods Institutional review board approval was given and patient consent was not required for this study. The study population comprised 892 consecutive patients with fibrosing ILD, including 456 patients with idiopathic pulmonary fibrosis (IPF) (men, 366; women, 90; median age, 72 years [range, 38-93 years]), 244 with nonspecific interstitial pneumonia (men, 79; women, 165; median age, 60.5 years [range, 23-86 years]), and 192 with chronic hypersensitivity pneumonitis (men, 76; women, 116; median age, 66 years [range, 35-88 years]). Pulmonary ossifications were recorded when nodules (<4 mm diameter) were identified on bone window images (width, 2500 HU; level, 500 HU). DPO was defined as 10 or more bilateral nodular ossifications (definition 1) or as one or more lobes with five or more bilateral nodular ossifications (definition 2). Relationships among pulmonary ossification and parenchymal patterns, clinical parameters, and multidisciplinary team diagnoses were examined. The prevalence of DPO was compared with the χ2 statistic or Fisher exact test, and multivariate analysis was performed with logistic regression. Results In the whole population, the prevalence of DPO was 166 (18.6%) and 106 (11.9%) of 892 patients according to definitions 1 and 2, respectively. The prevalence of DPO (definition 1) was significantly higher in patients with IPF (28.5%) than in those without IPF (8.3%, P < .001). Nine of 192 (4.7%) had chronic hypersensitivity pneumonitis (P < .001), and 27 of 244 (11.1%) had nonspecific interstitial pneumonia (P < .001). At multivariate analysis, DPO according to definition 1 was an independent predictor of IPF diagnosis (P < .001) and male sex (P = .003). Coarseness of fibrosing ILD (P = .011) and IPF diagnosis (P = .016) were independently associated with pulmonary ossification profusion. Conclusion DPO is common in patients with fibrosing ILD and is significantly more prevalent in patients with IPF than in those with other fibrosing ILDs, and thus, computed tomographic signs of DPO may be helpful for diagnosis of IPF.

Treatment strategies for idiopathic interstitial pneumonias.

Purpose of review With recent changes in diagnostic algorithms in idiopathic pulmonary fibrosis (IPF) guidelines and treatment advances in IPF, it is now necessary to reappraise the way in which clinicians should formulate treatment strategies in the idiopathic interstitial pneumonias. Recent findings The idiopathic interstitial pneumonias can usefully be subdivided into the following categories: first, definite IPF, second, probable IPF with major differential diagnoses of fibrotic nonspecific interstitial pneumonia and chronic hypersensitivity pneumonitis and third, apparently idiopathic interstitial pneumonias other than IPF. In definite IPF, the therapeutic landscape has irrevocably changed with the identification of robust treatment effects with pirfenidone and nintedanib, consisting of the prevention of approximately 50% of disease progression (as judged by serial forced vital capacity trends). In probable IPF, generally equating with high resolution computed tomography findings of ‘possible usual interstitial pneumonia’ and the nonperformance of a diagnostic surgical biopsy, management is based on multidisciplinary evaluation, integrating all available information, with a final ‘working diagnosis’ made for treatment purposes. In other idiopathic interstitial pneumonias and their major differentials, removal of potential triggers and immunomodulation remain the cornerstones of therapy, with treatment goals usefully designated using a disease behaviour classification. In mild disease, an initial policy of observation is often appropriate. Summary The striking recent treatment effects reported in IPF will have major management implications in the idiopathic interstitial pneumonia in general, whenever IPF is in the differential diagnosis.