Rob Janssen

TIMP-3 promoter gene polymorphisms in BFL.

Bird fanciers’ lung (BFL) is a form of hypersensitivity pneumonitis induced by inhalation of antigens from birds.1 Only a small percentage of bird fanciers will develop BFL, so it is likely that these patients have a certain genetic predisposition to the disease.1 Matrix metalloproteinases (MMP) are zinc enzymes responsible for the degradation of the extracellular matrix. The proteolytic activities of MMP are counter-regulated by tissue inhibitors of MMP (TIMP). Hill found a decreased carriership of the rare TIMP-3 −1296C and −915G promoter alleles in Mexican patients with pigeon induced BFL, suggesting a protective effect of these alleles against the development of this disease.2 Only two previously published genetic association studies to date have focused on the susceptibility to BFL and both were performed in Mexican pigeon breeders.2,3 We have undertaken a study to …

Strongyloides stercoralis hyperinfection mimicking accelerated form of idiopathic pulmonary fibrosis

Rapidly progressive disease has recently been recognised as a common cause of death in patients with idiopathic pulmonary fi brosis (IPF). IPF is the most prevalent form of idiopathic interstitial pneumonia, and also has the worst prognosis. A 57-year-old man from Suriname with Indian ancestry presented to our hospital with dyspnoea and was diagnosed with IPF after surgical lung biopsy. Leucocyte diff erential count of the blood showed a modest eosinophilia of 15%. Since the patient’s total IgE levels were raised (6·24 g/L; normal range 0–0·24 g/L) and specifi c IgE antibodies were found against house dust mites and pollens, the eosinophilia was explained by concomitant atopy. Because of an assumed rapidly progressive disease, he was treated with methyl prednisolone (1000 mg per day for 3 days) after exclusion of common alternative diagnoses such as opportunistic respiratory infections. During his stay in hospital, the patient had diarrhoea. Strongyloides stercoralis larvae were seen in a stool specimen. Hyperinfection syndrome was suspected and treatment with ivermectin (15 μg/kg) started. 1 day after initiation of ivermectin, our patient died due to respiratory failure. Autopsy results excluded IPF exacerbation as the cause of death. A lung specimen obtained post-mortem showed diff use alveolar damage in the exudative phase with focal organisation (fi gure A). There were areas with chronic infl ammation and marked eosinophilia. Furthermore, S stercoralis larvae were present in these areas of infl ammation and in the lumen of bronchi (fi gure B; arrows). The presence of S stercoralis in our patient’s lung tissue was indicative of hyperinfection syndrome. In the absence of early diagnosis and treatment, the prognosis of complicated strongyloidiasis is very poor. Retrospectively, we undertook an ELISA on serum that was obtained from our patient at disease presentation. S stercoralis antibodies were already detectable in this sample. This case underlines the importance of screening for S stercoralis in patients from endemic regions before starting immunosuppressive therapy. Many doctors trained in the developed world are not very familiar with tropical diseases. However, knowledge is very important since more patients in the Netherlands, and other highincome countries, have immigrated from tropical countries.

Increased circulating desmosine and age-dependent elastinolysis in idiopathic pulmonary fibrosis

Although chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) seem to be opposite entities from a clinical perspective, common initial pathogenic steps have been suggested in both lung diseases. Emphysema is caused by an elastase/anti-elastase imbalance leading to accelerated elastin degradation. Elastinolysis is however, also accelerated in the IPF patients’ lungs. The amino acids desmosine and isodesmosine (DES) are unique to elastin. During the degradation process, elastases liberate DES from elastin fibers. Blood DES levels consequently reflect the rate of systemic elastinolysis and are increased in COPD. This is the first report describing elevated DES levels in IPF patients. We also demonstrated that the age-related increment of DES concentrations is enhanced in IPF. Our current study suggests that elastinolysis is a shared pathogenic step in both COPD and IPF. Further investigation is required to establish the relevance of accelerated elastin degradation in IPF and to determine whether decelerating this process leads to slower progression of lung fibrosis and better survival for patients with IPF.

Lysyl Oxidase Inhibition by Heparin in Idiopathic Pulmonary Fibrosis: Is There Still Hope?

Lasky JA, Loyd JE, Noth I, Olman MA, et al.; Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2007;176: 636–643. 4. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307: 2526–2533. 5. Guerin C, Bayle F, Leray V, Debord S, Stoian A, Yonis H, Roudaut JB, Bourdin G, Devouassoux-Shisheboran M, Bucher E, et al. Open lung biopsy in nonresolving ARDS frequently identifies diffuse alveolar damage regardless of the severity stage and may have implications for patient management. Intensive Care Med 2015;41: 222–230. 6. Putman RK, Hunninghake GM, Barragan-Bradford D, Dieffenbach PB, Serhan K, Adams U, McKeon A, Hatabu H, Nishino M, Padera RF, et al. Interstitial lung abnormalities and the acute respiratory distress syndrome [abstract]. Am J Respir Crit Care Med 2016;193: A1855. 7. Dolinay T, Kim YS, Howrylak J, Hunninghake GM, An CH, Fredenburgh L, Massaro AF, Rogers A, Gazourian L, Nakahira K, et al. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med 2012;185: 1225–1234. 8. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American–European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818–824. 9. Gibelin A, Parrot A, Maitre B, Brun-Buisson C, Mekontso Dessap A, Fartoukh M, de Prost N. Acute respiratory distress syndrome mimickers lacking common risk factors of the Berlin definition. Intensive Care Med 2016;42:164–172. 10. Schwarz MI, Albert RK. “Imitators” of the ARDS: implications for diagnosis and treatment. Chest 2004;125:1530–1535.

Copper as the most likely pathogenic divergence factor between lung fibrosis and emphysema

Although fibrosis and emphysema are in many ways on opposite ends of the pulmonary parenchymal disease spectrum, they seem to share common pathomechanistic steps. This is illustrated by the coexistence of both entities in lungs of individuals with combined pulmonary fibrosis and emphysema. Macroproteins elastin and collagen are major constituents of the pulmonary extracellular matrix. The prevailing paradigm states that emphysema is caused by an imbalance between destructive proteolytic and protective antiproteolytic enzymes leading to accelerated degradation of elastin fibers in the lungs. Rates of elastin breakdown, however, are equally enhanced in patients with idiopathic pulmonary fibrosis (IPF) and emphysema. Excessive accumulation of collagen is a hallmark of IPF. Surprisingly, collagen levels in the lung parenchyma of patients with emphysema are also higher than in controls. The concentration of elastin fibers is elevated in fibrotic lungs, despite accelerated elastinolysis, suggesting that elastin repair is also enhanced in IPF. Since elastin concentrations are reduced in emphysematous lungs, the factor of divergence between emphysema and fibrosis seems to be the degree of elastin repair. Multiple elastin repair steps can be deduced of which tropoelastin synthesis and crosslinking of tropoelastin polymers by the copper dependent enzyme lysyl oxidase seem to be the most important ones. We suspect that the distinction in the pathogeneses of lung fibrosis and emphysema depends on the local availability of copper to activate sufficient lysyl oxidase for elastin crosslinking, and suggest assessing the effects of inhalation therapy with copper plus heparin in emphysema and heparin monotherapy in IPF.

Inhalation therapy for repairing damaged elastin fibers and decelerating elastinolysis in chronic obstructive pulmonary disease

ABSTRACT Introduction: Current pharmacologic therapy of chronic obstructive pulmonary disease (COPD) can reduce respiratory symptoms and exacerbation frequency. However, no single COPD intervention except for lung transplantation has proven effective in recovering lung function. Lung elasticity is reduced in COPD lungs, which is for a large part due to chronically enhanced elastin degradation. Elastin calcification and formation of advanced glycation end products (AGEs) may also contribute to this. Areas covered: We propose inhalation therapy to induce repair of damaged pulmonary elastin fibers by stimulating tropoelastin synthesis, assembly and crosslinking in order to improve lung function in patients with COPD. Decelerating elastinolysis is another treatment objective, as well as decalcification and deglycation of the extracellular matrix. Expert commentary: Studies should be conducted to test whether it is feasible to restore pulmonary elastin fibers with inhalation therapy. We expect that the optimal formulation will turn out to be a combination of copper, epigallocatechin-(3-)gallate or pentagalloyl glucose, vitamin A/D/K, magnesium, heparin or heparan sulfate, minoxidil and one or more AGEs inhibitors. Establishing a treatment that has the proven ability to facilitate regain of lost lung function in COPD patients would cause a major paradigm shift in this debilitating disease.

Inter-hospital variation in resource utilization of diagnostic and follow-up biomarkers in adult community-acquired pneumonia

Introduction: In value-based healthcare, optimal patient outcomes are pursued with optimal use of care. Aims and objectives: Our aim was to assess the inter-hospital variation in resource utilization of diagnostic and follow-up biomarkers in adult community-acquired pneumonia, to fuel discussions about achieving optimal outcomes for the lowest cost. Methods: This study was conducted in the mid-trial population of a Dutch multicenter placebo-controlled trial, investigating dexamethasone as adjunctive treatment for community-acquired pneumonia. All charged care items were captured, filtered on diagnostic and follow-up biomarkers and subsequently categorized. Average numbers of items and costs were calculated. Analyses were limited to the top 5 items per category that were utilized >10% of the patients. Results: Mean costs for clinical chemistry testing ranged from 25 to 49 euros per patient between hospitals. For radiology exams the range was from 87 to 118 euros. The costs for microbiology testing showed the most inter-hospital variation with a mean difference of 531 euros per patient. The cost-driver behind this difference was the amount of PCR testing. Conclusions: Our findings suggests that cost savings may be achieved through standardization of microbiology testing. Further investigation is needed to explore the optimal set of diagnostic testing in relation to clinical outcomes.

CorrespondenceSecondhand Smoke Exposure Effect on Elastin Degradation Markers: Which Factors Should Be Taken Into Account?

Affi liations: From the Section of Pulmonary and Critical Care Medicine, Asthma Clinical Research Center (Dr Hanania), Baylor College of Medicine; Division of Pulmonary and Critical Care Medicine (Dr Celli), Brigham and Women’s Hospital, Harvard University; Division of Pulmonary Disease and Critical Care Medicine (Dr Donohue), University of North Carolina at Chapel Hill; and Clinical Research, Respiratory and Infl ammation Therapeutic Area (Dr Martin), AstraZeneca LP. Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Hanania has received research grant support from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Novartis, and Pfi zer and has served as a consultant for GlaxoSmithKline, Novartis, and Pfi zer and on the Speakers Bureaus of GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca. Dr Celli has received grants from GlaxoSmithKline, Boehringer Ingelheim, Forrest Medical, and AstraZeneca to the division he heads to complete research studies. He has received advisory board payments from GlaxoSmithKline, Boehringer Ingelheim, Almirall, and AstraZeneca. Dr Donohue has received grant monies from Boehringer Ingelheim, Novartis, Johnson & Johnson, National Institutes of Health, and Alpha-1 Foundation, has served as a consultant for Novartis, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Pfi zer, and Merck, and has participated in speaking activities for Boehringer Ingelheim, Pfi zer, GlaxoSmithKline, and AstraZeneca. Dr Martin is a salaried employee at AstraZeneca LP holding company and receives shares/stock as part of a compensation package . Correspondence to: Nicola A. Hanania, MD, FCCP, Baylor College of Medicine, 1504 Taub Loop, Houston, TX 77030; e-mail: hanania@bcm.tmc.edu

Secondhand Smoke Exposure Effect on Elastin Degradation Markers:Which Factors Should Be Taken Into Account?

Affi liations: From the Section of Pulmonary and Critical Care Medicine, Asthma Clinical Research Center (Dr Hanania), Baylor College of Medicine; Division of Pulmonary and Critical Care Medicine (Dr Celli), Brigham and Women’s Hospital, Harvard University; Division of Pulmonary Disease and Critical Care Medicine (Dr Donohue), University of North Carolina at Chapel Hill; and Clinical Research, Respiratory and Infl ammation Therapeutic Area (Dr Martin), AstraZeneca LP. Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Hanania has received research grant support from Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Novartis, and Pfi zer and has served as a consultant for GlaxoSmithKline, Novartis, and Pfi zer and on the Speakers Bureaus of GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca. Dr Celli has received grants from GlaxoSmithKline, Boehringer Ingelheim, Forrest Medical, and AstraZeneca to the division he heads to complete research studies. He has received advisory board payments from GlaxoSmithKline, Boehringer Ingelheim, Almirall, and AstraZeneca. Dr Donohue has received grant monies from Boehringer Ingelheim, Novartis, Johnson & Johnson, National Institutes of Health, and Alpha-1 Foundation, has served as a consultant for Novartis, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Pfi zer, and Merck, and has participated in speaking activities for Boehringer Ingelheim, Pfi zer, GlaxoSmithKline, and AstraZeneca. Dr Martin is a salaried employee at AstraZeneca LP holding company and receives shares/stock as part of a compensation package . Correspondence to: Nicola A. Hanania, MD, FCCP, Baylor College of Medicine, 1504 Taub Loop, Houston, TX 77030; e-mail: hanania@bcm.tmc.edu