Background: Diagnosis of sarcoidosis often involves endobronchial biopsy (EBB), but studies have shown varying yields for EBB in suspected sarcoidosis, partly due to differences in identifying abnormal mucosa under white light (WL). Narrow band imaging (NBI) may assist in the visualization of abnormal mucosa, but its role in sarcoidosis remains to be characterized. Methods: Individuals referred for suspected sarcoidosis were considered for enrollment. Bronchoscopy with both WL and NBI was conducted, followed by EBB. The main objectives were to characterize NBI abnormalities in this patient population and determine the incremental yield of NBI-directed EBB. Results: In our cohort of 100 suspected sarcoidosis patients (66% male, median age 42), 88 were diagnosed with sarcoidosis, through cytopathology (n=78) or clinical evaluation (n=10). NBI high-grade lesions were more common than WL high-grade lesions (58% vs. 27%, difference 31%, 95% CI 18.3-42.5% P<0.001). High-grade WL EBB were more likely to be positive than low-grade WL biopsies [20/31 (65%) vs. 20/91 (22%), odds ratio (OR) 6.5, 95% CI 2.7-15.6, P<0.01]). Conversely, high-grade NBI lesions were no more likely to be positive than low-grade NBI lesions [23/63 (37%) vs. 17/59, (29%), OR 1.42, 95% CI 0.66-3.0, P=0.366]. EBB positivity and false-negative EBUS-TBNA were more common in patients with Scadding stage 2 or greater, suggesting that the chest radiography stage may help select patients more likely to benefit from adjunctive EBB. Conclusion: NBI abnormalities are common in patients with sarcoidosis, but unlike WL abnormalities, do not predict the finding of granulomatous inflammation on EBB. The chest radiography stage may be useful to identify patients more likely to benefit from EBB in addition to EBUS-TBNA.

ABSTRACTObjectiveOnset and exacerbation of autoimmune, inflammatory or steroid‐responsive conditions have been reported following the remission of Cushing syndrome, leading to challenges in distinguishing a new condition versus expected symptomatology following remission. We describe a case of a 42‐year‐old man presenting with new‐onset sarcoidosis diagnosed 12 months following the surgical cure of Cushing syndrome and synthesise existing literature reporting on de novo conditions presenting after Cushing syndrome remission.MethodsA scoping review was conducted in Medline, Epub, Ovid and PubMed. Case reports and case series detailing adult patients presenting with new‐onset conditions following Cushing syndrome remission were included.ResultsIn total, 1641 articles were screened, 138 full‐text studies were assessed for eligibility, and 43 studies were included, of which 84 cases (including our case) were identified. Most patients were female (85.7%), and the median reported age was 39.5 years old (IQR = 13). Thyroid diseases were the most commonly reported conditions (48.8%), followed by sarcoidosis (15.5%). Psoriasis, lymphocytic hypophysitis, idiopathic intracranial hypertension, multiple sclerosis, rheumatoid arthritis, lupus and seronegative arthritis were reported in more than one case. The median duration between Cushing remission and de novo condition diagnosis was 4.1 months (IQR = 3.75). Of those patients, 59.5% were receiving corticosteroid therapy at the time of onset.ConclusionOur scoping review identified several cases of de novo conditions emerging following the remission of Cushing syndrome. They occurred mostly in women and within the year following remission. Clinicians should remain aware that new symptoms, particularly in the first year following the treatment of Cushing syndrome, may be manifestations of a wide range of conditions aside from adrenal insufficiency or glucocorticoid withdrawal syndrome.

RATIONALE: Tumor necrosis factor-alpha (TNF-alpha) inhibitors have been implicated in the development of sarcoid-like granulomatous inflammation when used for treatment of a variety of immune-related diseases. The mechanisms are not completely understood, and the clinical, radiographic and histologic findings of this condition require further description. The literature surrounding this is largely limited to single case reports. OBJECTIVES: The objective of this study was to describe pulmonary sarcoid-like granulomatosis in 5 patients receiving etanercept therapy prescribed for inflammatory arthritis. METHODS: We retrospectively reviewed the medical records of 5 patients who developed granulomatous sarcoid-like manifestations while on treatment with etanercept for inflammatory arthritis. Data surrounding clinical features and radiographic and histologic findings, as well as clinical outcomes, were described. RESULTS: Median time from initiation of treatment to development of symptoms was 36 months (range 7-60 months). All patients had radiographic abnormalities on chest imaging, with 4 patients having adenopathy on thoracic imaging, and 2 of the 5 patients having parenchymal involvement. Biopsy evidence of granulomatous inflammation was seen in all patients. Three of 5 patients had discontinuation of etanercept when the diagnosis was made, and all experienced improvement. Of the 2 patients that were continued on etanercept, 1 had spontaneous improvement and the other had stable, asymptomatic radiographic abnormalities. Only 1 patient was treated with corticosteroids. CONCLUSION: Pulmonary sarcoid-like granulomatosis is incompletely understood and establishing the causal role of these drugs in sarcoid-like lung disease is difficult. We hope that the addition of these 5 cases of etanercept-related pulmonary sarcoid-like granulomatosis will add to our future understanding of this response to etanercept and other anti-TNF-alpha agents.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disorder characterized by alveolar accumulation of surfactant composed of lipids and proteins resulting in hypoxemic respiratory failure. Although spontaneous remission has been noted, whole lung lavage (WLL) is the standard of care in those requiring treatment. Pharmacologic treatments have been tried, most notably inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF). Case series have shown improved gas exchange or pulmonary function parameters, and less need for WLL after therapy with inhaled GM-CSF.1–3 A more recent randomized trial however only showed minimal improvement in A-a gradient and no other significant benefits.4 Currently there are no Food and Drug Administraton approved pharmacologic treatments for aPAP. Peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to play an important role in alveolar macrophage (AM) phospholipid and cholesterol efflux. PPARγ is present in the macrophages of healthy humans, and has been shown to be deficient in patients with aPAP and in an animal model of this disease which employs GM-CSF knockout (KO) mice.5–8 Upregulation of PPARγ leads to increased cholesterol efflux from AMs and decreased amounts of intracellular and extracellular phospholipids resulting in a decreased size of the AM compared with untreated mice.5 Administering PPARγ agonists to GM-CSF KO mice can reduce bronchoalveolar lavage (BAL) fluid turbidity and cholesterol levels,9 markers of disease severity in the mouse model. Although it is not known whether administering PPARγ agonists to humans with aPAP would lead to similar findings, PPARγ agonists, such as pioglitazone, may have potential in the clinical management of aPAP.5 We hypothesized that treatment of aPAP patients with pioglitazone would increase cholesterol efflux from AMs leading to a decrease in their size. We sought to measure the effect of pioglitazone on AMs in a patient treated with pioglitazone off-label for aPAP. CASE BACKGROUND A 52-year-old otherwise healthy male was diagnosed with aPAP in 2006 after presenting with hypoxic respiratory failure. A computed tomography scan showed a crazy paving pattern and BAL fluid demonstrated the typical milky appearance with Periodic-acid Schiff (PAS)-positive proteinaceous material on cytologic examination. Serum and BAL fluid were both positive for anti-GM-CSF antibodies (Mitogen Lab, Calgary, AB, Canada) confirming aPAP. He was treated with a WLL but was subsequently lost to follow-up until he returned with hypoxic respiratory failure again in 2009. He underwent several subsequent WLL in 2009 but continued to have refractory symptoms and hypoxemia and by January 2017 had undergone 42 unilateral WLL procedures using a technique similar to that described by Adbelmalak et al.10 Additional therapies included an 8-week course (24 sessions) of plasmapheresis as well as 8 months of inhaled GM-CSF. Neither produced any significant clinical improvement in pulmonary function testing or oxygen requirements. Despite the multiple WLLs by January 2017 the patient had gradually deteriorated and become oxygen dependent requiring 2 to 5 L via nasal prongs. There was diminishing benefit with subsequent WLLs as less proteinaceous material was removed compared with prior WLLs and improvement in oxygenation postprocedure was no longer noted. In addition, high resolution computed tomography scan of the lungs demonstrated progressive fibrosis (worsening reticulation with architectural distortion) with reduced ground glass and crazy paving. In view of limited options, progressive disease, and prior research showing the potential for reducing disease severity, a decision was made to treat with pioglitazone 30 mg daily. Institutional ethics were not obtained as it was a clinical decision to administer pioglitazone on an off-label, compassionate basis. Decision to pursue objective measurements pertaining to AMs was made after commencement of treatment to evaluate the effect of the medication. Patient consent was obtained for the off-label use of the medication as well as for the publication of this report. No adverse effects of the medication were noted while on treatment. METHODS BAL fluid was collected before initiation of pioglitazone therapy (January 2017) and after 9 months of treatment with no additional WLL performed in between. The fluid was centrifuged in a Shandon CytoSpin 3 cytocentrifuge (Thermo Fisher Scientific, Waltham, MA) at 1000 RPM for 3 minutes and cytospins prepared. The slides were stained with Wright-Giemsa stain and consisted mainly of AMs (∼99%). For assessment of mean AM diameter, a total of 75 AMs randomly selected in each cytospin were photographed ×200 magnification and then measured with ImageJ 1.51s software (https://imagej.nih.gov/ij/), blinded as to whether it was collected before or after treatment with pioglitazone. The longest diameter of the AM and the diameter orthogonal to this was measured. The average of these 2 measurements was considered the cell diameter. In addition, qualitative assessment of PAS-positive material and neutral lipids within the cell were performed. For these assessments, at least 100 AMs were assessed before and after pioglitazone treatment. Oil Red O was used to determine lipid content,5 and AMs were designated either positive or negative for stain. With respect to PAS, AMs were designated as having no/minimal, moderate, or strong positivity. A semiquantitative Histochemical score (H-score) was calculated for the PAS stain using methods previously described.11 A t test was performed on the mean diameters of the AMs before and after pioglitazone therapy, as well as the H-score before and after treatment (IBM SPSS Statistics 24.0.0.0). χ2 analysis was performed on the results of the Oil Red O staining. RESULTS The mean AM diameter decreased from 25.64 to 22.38 μm after therapy, representing a 12.7% decrease (P=0.002) (Fig. 1). There was a reduction in number of strongly PAS-positive AMs from 31.8% to 22.2% and increase in number of AMs with no/minimal PAS-positive material from 38.2% to 41.7%, but this did not meet statistical significance (Fig. 2). H-score for the PAS stain was 193.6 before pioglitazone, and decreased to 180.5 after treatment, however, this did not meet statistical significance (P=0.234) (Fig. 2). There was a nonsignificant reduction in proportion of AMs staining Oil Red O positive from 9.9% to 7.5% (P=0.427).FIGURE 1: Graphical representation of cell diameter prepioglitazone and postpioglitazone therapy. Each circle in the scatter plot signifies an individual cell size measurement. The horizontal line demonstrates the mean for the respective sample. AM indicates alveolar macrophage.FIGURE 2: Assessments of AM intracellular glycoprotein content. Clustered bar chart demonstrating fraction of AMs prepioglitazone and postpioglitazone therapy of different PAS stain grade. No statistical difference by H-score. AM indicates alveolar macrophage; H-score, Histochemical score; PAS, Periodic-acid Schiff.DISCUSSION AM size is a simple, although imperfect, marker of the total lipoproteinaceous material that has accumulated in patients with aPAP. We inferred that a significant decrease in the size of AMs may correlate with decrease in accumulation of lipid material within the cells and might therefore represent a decrease in disease severity. In this patient with refractory aPAP, a reduction in AM size was shown after 9 months of treatment with a PPARγ agonist. We believe the decreased AM size was due to improved cholesterol efflux from the cell as this would be consistent with previously published data of PPARγ agonist therapy in a mouse model of PAP.9 It should be noted that both prepioglitazone and postpioglitazone AM size was larger than the previously reported mean size for never-smokers (17.1 µm),12 consistent with aPAP. Despite the decrease in mean cell diameter, no significant change was seen in degree of intracellular PAS-positive material, or lipids seen with Oil Red O stain between samples. Previously rates of Oil Red O positivity of >90% in aPAP has been reported.5 The low proportion of cells staining positive for Oil Red O both pretreatment and posttreatment raises the possibility that the lipoproteinaceous material accumulation was not severe and therefore the fibrosis was the more clinically significant factor. There was neither clinical improvement nor deterioration in the patient’s oxygenation, pulmonary function testing, or subjective reporting of symptoms during this time frame. Starting therapy late after development of significant fibrosis may have minimized the potential for clinical improvement. Whether treatment earlier in his disease course would have led to clinical improvement is unknown. Similarly, it is unknown if pioglitazone prevented this patient from deteriorating further although this remains a possibility. Our paper has several limitations. Only one subject was evaluated and therefore we do not know if this could be reproduced in others. In addition, we do not know the expected changes in mean AM diameter on serial bronchoscopy and the decrease may have been due to normal intertest variability, although we feel this is less likely due to the number of AMs examined. The optimal dose of pioglitazone is not known for this situation, nor if a different dose would have yielded different results. Whether pioglitazone would lead to clinical improvement if used in other patients or at earlier stages of disease is not known. This medication’s use was off-label and no recommendations regarding routine use in aPAP can be made from this data. This report is the first to describe a reduction in AM size in a human patient with aPAP following the administration of a PPARγ agonist. Findings are consistent with prior laboratory and animal research and support the hypothesis that pioglitazone could potentially reduce disease severity in humans with aPAP. A phase 1 study of this drug in humans is underway (ClinicalTrials.gov Identifier: NCT03231033) and should give even more information about this drug as a potential therapy.

Pulmonary hypertension (PH) is a well described and clinically important complication in sarcoidosis. The epidemiology of sarcoidosis-associated pulmonary hypertension (SaPH) varies depending on the characteristics of the population analysed, but ranges from 3–75%, depending on method of diagnosis (i.e. echocardiography versus right heart catheterisation (RHC)) and severity of underlying sarcoidosis [1–4]. Elevation of pulmonary arterial pressure in sarcoidosis can occur via a number of mechanisms (figure 1) [5, 6] and, as such, SaPH has remained under group 5 (PH with unclear and/or multifactorial mechanisms) in the recent 6th World Symposium on Pulmonary Hypertension [7]. The breadth of pathophysiologic mechanisms that lead to PH is fairly unique to sarcoidosis, which makes SaPH an interesting but complicated entity. Pre-capillary pulmonary hypertension is a rare and heterogenous complication in sarcoidosis. 6-min walking distance is a robust and consistent prognostic factor, but the role of pulmonary arterial hypertension-targeted treatments remains controversial. http://bit.ly/2J27Yps

Background: Sarcoidosis is characterized by non-necrotizing epithelioid granulomatous inflammation. Sarcoid-like granulomatous disease has been associated with tumor necrosis factor-α (TNF-α) inhibitor therapy. Methods: We conducted a systematic search of MEDLINE, EMBASE, Scopus, and Web of Science. Two investigators screened all abstracts and selected articles for full-text review. Disagreements were resolved by a 3rd investigator. Results: Our search generated 825 titles and 146 full text articles and conference abstracts were reviewed. Sixty-four published reports describing 86 cases were included. Articles were limited to single case reports or small case series describing biopsy-confirmed sarcoid-like pulmonary granulomatous disease following TNF-α inhibition. The most frequent underlying indications for TNF-α use were rheumatoid arthritis (n=43, 50%), ankylosing spondylitis (n=12, 14%), and Crohn’s disease (n=11, 13%). The implicated TNF-α inhibitor was etanercept in 36 (41%), adalimumab in 26 (30%), infliximab in 22 (25%), and golimumab in 2 cases (2%). Seventeen cases (20%) had isolated bilateral hilar adenopathy and 69 (80%) had parenchymal involvement. Thirty-eight cases (44%) resolved after discontinuation of the TNF-α inhibitor. However, corticosteroids were used in 40 cases (47%) either empirically or due to persistent symptoms. Conclusions: This is the first scoping review to compile and summarize sarcoid-like pulmonary disease related to TNF-α inhibition. Increased awareness could aid in more prompt recognition and appropriate drug withdrawal for those who experience pulmonary sarcoid-like granulomatosis during TNF-α inhibitor therapy.

Pre-capillary pulmonary hypertension is a rare and heterogenous complication in sarcoidosis. 6-min walking distance is a robust and consistent prognostic factor, but the role of pulmonary arterial hypertension-targeted treatments remains controversial.http://bit.ly/2J27Yps

Background and Objective: Little is known about the utility of physical examination (PE) findings in patients with suspected pulmonary hypertension (PH) in the modern era. We aimed to determine the diagnostic utility of commonly referenced PE findings for PH when compared to the gold standard, right heart catheterization (RHC) Methods: Sequential patients undergoing RHC at the PH clinic in Calgary, Canada were prospectively enrolled and examined by a respirologist within 60 minutes of RHC. Examiners were blinded to indication and diagnosis. Examiners determined presence or absence of: high jugular venous pressure (JVP)>3cm, palpable P2, parasternal heave, abdominal-jugular reflex (AJR), loud P2, P2 louder than A2 (P2>A2), right-sided S3, and extra-physiologic splitting of S2. PE findings were compared to RHC to determine the sensitivity (Sn), specificity (Sp), positive (+LR) and negative likelihood ratio (-LR) values for identifying PH (mPAP≥25mmHg). Results: 105 patients were enrolled. 66% were female with a median age of 61 (Interquartile Range 28-85). 13 patients (12%) did not have PH (mPAP <25 mmHg). The diagnostic performances of PE findings are displayed in Table 1. Conclusions: The physical examination has inadequate diagnostic utility in detecting or excluding the presence of PH.

Inflammatory myofibroblastic tumour (IMT) is a rare form of inflammatory pseudotumour of the lung. Complete surgical resection is the treatment of choice, with corticosteroid-based medical therapy reserved for cases where complete resection is not possible.1 To date, the majority of recurrent cases have occurred subsequent to incomplete resection or after discontinuation of steroids when used as primary therapy.1 2 There is a paucity of data guiding the follow-up of patients who undergo complete resection. In addition, the efficacy of oral steroids in the treatment of IMT remains poorly characterised and the optimal duration of therapy is unknown. A 46-year-old lifetime non-smoker presented in December 2015 with dyspnoea, fatigue, night sweats and weight loss. A chest X-ray demonstrated a new left lower lobe mass. His history was significant only for a right pneumonectomy in June 2005 for a large inflammatory pseudotumour. This pneumonectomy was performed for definitive surgical management, as the mass was adjacent to …

SESSION TITLE: Pulmonary Vascular Disease I SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 26, 2016 at 01:30 PM - 02:30 PM PURPOSE: Little is known about the utility of physical examination (PE) findings in evaluating patients with suspected moderate or severe pulmonary hypertension (PH) in the modern era. Our previous work has shown that PE is not adequate for excluding or confirming PH using the threshold of mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg. We aimed to determine the diagnostic utility of commonly referenced physical exam findings for detecting moderate-severe PH (mPAP ≥ 35 mmHg). METHODS: Sequential patients undergoing right heart catheterization (RHC) at the PH clinic in Calgary, Canada were prospectively enrolled. A respirologist with PH experience examined each patient within 1 hour of RHC. Examiners were blinded to indication for RHC and diagnosis. Examiners determined presence or absence of physical examination signs: high jugular venous pressure (JVP) > 4cm, cV wave, palpable P2, parasternal heave, abdominal-jugular reflex (AJR), loud P2, P2 louder than A2 (P2>A2), right-sided S3, right-sided S4, pitting edema, tricuspid regurgitation and extra-physiologic splitting of S2. Examiner findings were compared to RHC to determine the sensitivity (Sn), specificity (Sp), positive (+LR) and negative likelihood ratio (-LR) with a threshold mPAP ≥ 35 to define moderate-to-severe PH. RESULTS: 105 patients were enrolled. 66 were female with a median age of 61 (Interquartile Range 53-71). Median BMI 29.2 (Interquartile range 24.1-35.7). 69 patients (65.7 %) had moderate or severe PH (mPAP ≥ 35 mmHg). The diagnostic performances of PE findings are shown below. Examination Finding Sn (95%CI) Sp (95%CI) +LR(95%CI) -LR(95%CI) JVP>4cm 76 (64-85) 55 (38-72) 1.7 (1.2-2.6) 0.4 (0.2-0.7) cV wave 53 (40-66) 74 (56-87) 2.1 (1.1-3.8) 0.6 (0.5-0.9) Palpable P2 32 (22-46) 68 (51-83) 1.0 (0.6-1.9) 1.0 (0.7-1.3) Parasternal heave 45 (33-58) 74 (56-87) 1.8 (0.9-3.3) 0.7 (0.5-1.0) AJR 54 (41-67) 54 (37-71) 1.2 (0.8-1.8) 0.8 (0.6-1.3) Loud P2 86 (74-93) 31 (17-49) 1.3 (1.0-1.6) 0.4 (0.2-1.0) P2>A2 67 (54-78) 42 (27-60) 1.2 (0.8-1.6) 0.8 (0.5-1.3) R-sided S3 17 (9-29) 91 (75-98) 2.0 (0.6-6.7) 0.9 (0.8-1.1) R-sided S4 23 (14-36) 85 (69-95) 1.6 (0.7-4.1) 0.9 (0.7-1.1) Extra-physiologic Split S2 18 (10-31) 80 (63-91) 0.9 (0.4-2.2) 1.0 (0.8-1.2) Pitting Edema 47 (34-60) 77 (59-89) 2.1 (1.1-4.0) 0.7 (0.5-0.9) Tricuspid Regurgitation 51 (38-64) 63 (45-78) 1.4 (0.85-2.3) 0.8 (0.5-1.1). CONCLUSIONS: A JVP of greater than or equal to 4 cm above the sternal angle, and a loud P2 appear to have reasonable sensitivity to detect the condition. Right-sided S3 and S4 appear to have reasonable specificity. However, overall the physical exam has limited diagnostic utility in detecting the presence of moderate-severe pulmonary hypertension. These results are in keeping with our prior work. CLINICAL IMPLICATIONS: The physical exam for pulmonary hypertension alone, even when performed by respirologists with training in PH, has limited ability to identify patients with significantly elevated mean pulmonary artery pressures. This stresses the importance of alternative radiographic, biochemical and potentially invasive methods in combination with the physical exam in the work up and diagnosis of pulmonary hypertension. DISCLOSURE: The following authors have nothing to disclose: Daniel Vis, Kevin Solverson, Doug Helmersen, Jason Weatherald, Mitesh Thakrar, Rhea Varughese, Jeffrey Shaw, Michael Braganza, Naushad Hirani, Luke Rannelli No Product/Research Disclosure Information