Showing papers by "Joseph M. Pilewski published in 2019"

Impaired Cytomegalovirus Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short Telomeres.

Abstract: Rationale: Cytomegalovirus (CMV)-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predi...

Intracellular Heat Shock Protein 70 Deficiency in Pulmonary Fibrosis.

Abstract: Idiopathic pulmonary fibrosis (IPF) pathogenesis has been postulated to involve a variety of mechanisms associated with the aging process, including loss of protein homeostasis (proteostasis). Heat shock proteins are cellular chaperones that serve a number of vital maintenance and repair functions, including the regulation of proteostasis. Previously published data have implicated heat shock protein 70 (Hsp70) in the development of pulmonary fibrosis in animal models. We sought to identify alterations in Hsp70 expression in IPF lung. Hsp70 mRNA and protein were decreased in primary fibroblasts cultured from IPF versus normal donor lung tissue. In addition to cultured fibroblasts, Hsp70 expression was decreased in intact IPF lung, a stressed environment in which upregulation of protective heat shock proteins would be anticipated. In support of a mechanistic association between decreased Hsp70 and fibrosis, cultured primary lung fibroblasts deficient in Hsp70 secreted increased extracellular matrix proteins. Treatment of primary normal human lung fibroblasts in vitro with either of the profibrotic molecules IGFBP5 (insulin-like growth factor-binding protein 5) or transforming growth factor-β1 downregulated Hsp70, suggesting Hsp70 is a downstream target in the fibrotic cascade. Hsp70-knockout mice subjected to an inhalational bleomycin model of pulmonary fibrosis demonstrated accelerated fibrosis versus wild-type control animals. We therefore conclude that reduced Hsp70 protein contributes to fibrosis and that interventions aimed at restoring normal expression of Hsp70 represent a novel therapeutic strategy for pulmonary fibrosis.

Transcriptomic Responses to Ivacaftor and Prediction of Ivacaftor Clinical Responsiveness.

Abstract: Ivacaftor is a drug that was recently approved by the U.S. Food and Drug Administration for the treatment of patients with cystic fibrosis (CF) and at least one copy of the G511D mutation in the CFTR (CF transmembrane conductance regulator) gene. The transcriptomic effect of ivacaftor in patients with CF remains unclear. Here, we sought to examine whether and how the transcriptome of patients is influenced by ivacaftor treatment, and to determine whether these data allow prediction of ivacaftor responsiveness. Our data originated from the G551D Observational Study (GOAL). We performed RNA sequencing (RNA-seq) on peripheral blood mononuclear cells (PBMCs) from 56 patients and compared the transcriptomic changes that occurred before and after ivacaftor treatment. We used consensus clustering to stratify patients into subgroups based on their clinical responses after treatment, and we determined differences between subgroups in baseline gene expression. A random forest model was built to predict ivacaftor responsiveness. We identified 239 genes (false discovery rate < 0.1) that were significantly influenced by ivacaftor in PBMCs. The functions of these genes relate to cell differentiation, microbial infection, inflammation, Toll-like receptor signaling, and metabolism. We classified patients into "good" and "moderate" responder groups based on their clinical response to ivacaftor. We identified a panel of signature genes and built a statistical model for predicting CFTR modulator responsiveness. Despite a limited sample size, adequate prediction performance was achieved with an accuracy of 0.92. In conclusion, for the first time, the present study demonstrates profound transcriptomic impacts of ivacaftor in PBMCs from patients with CF, and provides a pilot statistical model for predicting clinical responsiveness to ivacaftor before treatment.

Clinical predictors of cystic fibrosis chronic rhinosinusitis severity.

Abstract: Background Chronic rhinosinusitis (CRS) is a significant manifestation of cystic fibrosis (CF) with wide-ranging symptom and disease severity. The goal of the study was to determine clinical variables that correlate with outcome measures of disease severity. Methods A prospective, longitudinal, observational study of 33 adults with symptomatic CRS treated in a CF-focused otolaryngology clinic was performed. Symptom severity, the presence of rhinosinusitis exacerbations, and endoscopic appearance were assessed, and regression analysis was used to determine clinical predictors of disease outcome. Results Thirty-three adults with CF-CRS were included in the study and followed for a mean of 15 months. Rhinosinusitis exacerbations occurred in 61% of participants during the study, and female sex increased the odds of presenting with an exacerbation visit. Sinus disease exacerbations were associated with an odds ratio of 2.07 for presenting with a pulmonary exacerbation at the next visit. CF-related diabetes was found to be associated with worse symptoms and endoscopic appearance. Infection with Staphylococcus aureus predicted worsening of symptoms, whereas infections with Pseudomonas aeruginosa improved over time. Allergic rhinitis was associated with worse endoscopic appearance, and nasal steroid use was associated with improved endoscopic appearance. Conclusion Sex, CF-related diabetes, sinonasal infection status, allergic rhinitis, and nasal steroid use may all modulate severity of CF-CRS in adults. Sinusitis exacerbation may be a precursor to pulmonary exacerbation.

Insulin-like growth factor (IGF)-II- mediated fibrosis in pathogenic lung conditions.

Abstract: Type 2 insulin-like growth factor (IGF-II) levels are increased in fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF) and scleroderma/systemic sclerosis-associated pulmonary fibrosis (SSc). Our goal was to investigate the contribution of IGF receptors to IGF-II-mediated fibrosis in these diseases and identify other potential mechanisms key to the fibrotic process. Cognate receptor gene and protein expression were analyzed with qRT-PCR and immunoblot in primary fibroblasts derived from lung tissues of normal donors (NL) and patients with IPF or SSc. Compared to NL, steady-state receptor gene expression was decreased in SSc but not in IPF. IGF-II stimulation differentially decreased receptor mRNA and protein levels in NL, IPF, and SSc fibroblasts. Neutralizing antibody, siRNA, and receptor inhibition targeting endogenous IGF-II and its primary receptors, type 1 IGF receptor (IGF1R), IGF2R, and insulin receptor (IR) resulted in loss of the IGF-II response. IGF-II tipped the TIMP:MMP balance, promoting a fibrotic environment both intracellularly and extracellularly. Differentiation of fibroblasts into myofibroblasts by IGF-II was blocked with a TGFβ1 receptor inhibitor. IGF-II also increased TGFβ2 and TGFβ3 expression, with subsequent activation of canonical SMAD2/3 signaling. Therefore, IGF-II promoted fibrosis through IGF1R, IR, and IGF1R/IR, differentiated fibroblasts into myofibroblasts, decreased protease production and extracellular matrix degradation, and stimulated expression of two TGFβ isoforms, suggesting that IGF-II exerts pro-fibrotic effects via multiple mechanisms.

Organ Transplantation for Cystic Fibrosis.

Abstract: Cystic fibrosis (CF) remains the most common indication for lung transplantation in children and the third most common in adults and has the highest median survival posttransplant for all pretransplant diagnoses. Criteria for transplant in patients with CF vary widely among transplant centers and early referral to multiple centers may be needed to maximize opportunities for lung transplantation. Comorbidities unique to CF such as resistant and atypical pathogens like Burkholderia and Mycobacterium abscessus, and cirrhosis require special consideration for lung transplantation but should not be considered as absolute contraindications. For those patients who are listed for lung transplantation, mechanical support with extracorporeal membrane oxygenation and mechanical ventilation can be efficacious as bridges to lung transplantation in experienced centers with adequate resources. Liver and pancreas transplantations are also acceptable options for end-organ disease related to CF and can provide improvements in both quantity and quality of life.

Symptom Burden and Unmet Existential Needs in Adults With Cystic Fibrosis.

Abstract: Although patients with cystic fibrosis (CF) experience many symptoms and impaired quality of life, little is known about existential distress. This multivariable logistic regression evaluated the relationship between symptom burden and five existential needs representing existential distress in 164 adults with CF. Eleven percent of participants reported no symptom burden, 61% mild burden, and 28% moderate/severe burden. The most prevalent existential needs were fears about CF worsening (50%) and uncertainty about the future (39%). Participants with moderate/severe symptom burden were likelier to report needing support with all five needs than participants with no or mild burden. For each six-point increase in burden, there was an increased odds of reporting need for support with learning to feel in control, feelings about death and dying, fears about CF worsening, uncertainty about the future, and concerns about worries of others. CF-specific palliative care support based on these prevalent unmet existential needs should be developed and provided.

Outcomes in Lung Transplant Recipients With Mycobacterium abscessus Infection: A 15-Year Experience From a Large Tertiary Care Center.

Abstract: Background Mycobacterium abscessus (M abscessus) infection is a serious complication post–lung transplant (LTx). We examined determinants of outcomes in LTx recipients infected with M abscessus. Methods Electronic records of all patients who underwent LTx in a single transplant center between 2000 and 2015 were screened for isolation of M abscessus before or after LTx. Results Twenty-six cases of M abscessus isolation were identified. Twenty-four had M abscessus isolation post-LTx. Two had M abscessus isolated from a surgical site, while the others were pulmonary isolates. Out of these 22 with pulmonary isolates, 12 had clinical disease. In 73% of patients, treatment had to be temporarily held or switched due to intolerance and toxicity. There was a statistically significant worsening in survival in those who developed clinical disease compared to matched controls. Among the 12 patients with clinical pulmonary disease, use of clofazimine was significantly associated with a favorable outcome. Six patients had M abscessus isolation pretransplant. Four developed M abscessus recurrence at a median of 2 months post-LTx. Two recurrences were surgical site infections, and 2 were pulmonary infections. Conclusion M abscessus infection is difficult to treat as tolerance to medications used is poor. M abscessus pneumonia is associated with worse survival post-LTx. Use of clofazimine is associated with 1-year infection-free survival.

Insulin-like growth factor binding protein-4 exerts antifibrotic activity by reducing levels of connective tissue growth factor and the C-X-C chemokine receptor 4

Abstract: The Insulin-like growth factor (IGF) system plays an important role in variety cellular biological functions; we previously reported levels of IGF binding proteins (IGFBP) -3 and -5 are increased in dermal and pulmonary fibrosis associated with the prototypic fibrosing disease systemic sclerosis (SSc), induce extracellular matrix (ECM) production, and promote fibrosis. We sought to examine the effects of another member of the family, IGFBP-4, on ECM production and fibrosis using cell-based, ex vivo organ culture and in vivo mouse lung fibrosis models. IGFBP-4 mRNA levels were significantly decreased in pulmonary fibroblasts of patients with SSc. ECM components were significantly reduced by endogenous and exogenous IGFBP-4. IGFBP-4 also blocked TGFβ-induced ECM production, and inhibited ECM production ex vivo in human lung and skin in organ culture. In vivo, IGFBP-4 reduced bleomycin-induced collagen production and histologic evidence of fibrosis. Silencing IGFBP-4 expression to mimic levels observed in SSc lung fibroblasts resulted in increased ECM production. IGFBP-4 reduced mRNA and protein levels of the chemokine receptor CXCR4 and the pro-fibrotic factor CTGF. Further, CTGF silencing potentiated the anti-fibrotic effects of IGFBP-4. Reduced IGFBP-4 levels in SSc lung fibroblasts may contribute to the fibrotic phenotype via loss of IGFBP-4 anti-fibrotic activity.

Multiprobe Nuclear Imaging of the Cystic Fibrosis Lung as a Biomarker of Therapeutic Effect.

Abstract: Background: Nuclear imaging biomarkers illustrate unique aspects of lung physiology and are useful for assessing therapeutic effects in cystic fibrosis (CF) lung disease. We have developed a multiprobe method to simultaneously measure mucociliary clearance (MCC) and paracellular absorption (ABS). MCC is a direct measure of mucus clearance. ABS has been related to airway surface liquid (ASL) absorption through previous in vitro studies. Methods: We describe baseline factors affecting MCC and ABS using data from a retrospective baseline group (n = 22) and the response of the measures to inhaled 7% hypertonic saline (HS) and dry powder mannitol using data from a prospective response group (n = 7). A retrospective healthy control group (n = 15) is also described. The baseline and control groups performed single measurements of MCC/ABS. The response group performed baseline measurements of MCC/ABS and measurements after each intervention. Results: ABS was correlated (Spearman's ρ = 0.51, p = 0.06) to sweat chloride, a systemic measure of cystic fibrosis transmembrane conductance regulator (CFTR) function, whereas MCC was not. Baseline MCC was depressed after Pseudomonas aeruginosa infection as we have previously described. MCC provided a more sensitive indication of therapeutic effect and indicated improved clearance with mannitol compared with HS. Conclusion: MCC provides a useful and well-established means of testing therapies directed at improving mucus clearance in the lung. ABS may provide a means of detecting local changes in ASL absorption and CFTR function in the lung. Both are useful tools for studying the key aspects of CF lung pathophysiology (ASL hyperabsorption and MCC depression) that link the basic genetic defects of CF to disease manifestations in the lung.

Associations between demographic characteristics and unmet supportive care needs in adults with cystic fibrosis.

Abstract: Context Patients living with cystic fibrosis (CF) report impaired quality of life. Little is known about unmet supportive care needs among adults living with CF and how they are associated with demographic characteristics. Objectives The primary objective of this study was to identify associations between demographic variables and unmet supportive care needs regarding anxiety, sadness, pain and uncertainty about the future of living with CF. Methods We recruited 165 adults with CF from a single academic medical centre to complete a brief demographic survey and the Supportive Care Needs Survey (SCNS-34), a validated self-reported needs assessment that measures the prevalence of and preferences for support for 34 needs that commonly occur in patients with serious illness. Results Approximately half of the participant sample was male, with a median age of 29 years, varying income levels and a range of lung disease severity. We found statistically significant associations between insufficient income and increased odds of reporting need for support regarding anxiety (OR: 6.48; 95% CI 2.08 to 20.2), sadness (OR: 6.15; 95% CI 2.04 to 18.5), pain (OR: 7.06; 95% CI 2.22 to 22.4) and worries surrounding uncertainty about the future (OR: 3.43; 95% CI 1.18 to 9.99). Conclusion Adults with CF report significant unmet needs for support in several physical and emotional domains. Many of these domains were associated with demographic characteristics, most notably, income. Our findings underscore the importance of developing treatment approaches that are sensitive to patient demographics when addressing unmet supportive care needs among adults with CF.

Call for changes in lung allocation to reduce transplant wait-list mortality for cystic fibrosis

Abstract: and cheap: extracorporeal membrane oxygenation versus prone position in acute respiratory distress syndrome. Am J Respir Crit Care Med 2018;197:991–993. 4. Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015;372:747–755. 5. Cressoni M, Gotti M, Chiurazzi C, Massari D, Algieri I, Amini M, et al. Mechanical power and development of ventilator-induced lung injury. Anesthesiology 2016;124:1100–1108. 6. Serpa Neto A, Deliberato RO, Johnson AEW, Bos LD, Amorim P, Pereira SM, et al.; PROVE Network Investigators. Mechanical power of ventilation is associated with mortality in critically ill patients: an analysis of patients in two observational cohorts. Intensive Care Med 2018;44:1914–1922. 7. Zhang Z, Zheng B, Liu N, Ge H, Hong Y. Mechanical power normalized to predicted body weight as a predictor of mortality in patients with acute respiratory distress syndrome. Intensive Care Med 2019;45:856–864. 8. Combes A, Hajage D, Capellier G, Demoule A, Lavoué S, Guervilly C, et al.; EOLIA Trial Group, REVA, and ECMONet. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med 2018;378:1965–1975. 9. Araos J, Alegria L, Garcia P, Cruces P, Soto D, Erranz B, et al. Nearapneic ventilation decreases lung injury and fibroproliferation in an acute respiratory distress syndrome model with extracorporeal membrane oxygenation. Am J Respir Crit Care Med 2019;199: 603–612.

Successful Lung Transplantation in a Patient with Chronic Granulomatous Disease

Abstract: Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder caused by defective NADPH oxidase and impaired production of superoxide that is necessary for effective intracellular killing of pathogens. Patients with CGD are prone to severe, recurrent bacterial and invasive fungal infections of the lungs, skin, GI tract, and liver. Pulmonary complications are common and include pneumonia, abscess, granulomatous disease, and chronic inflammation that can lead to fibrosis and bronchiectasis [1]. For those patients with CGD who develop end-stage lung disease, lung transplantation is a potential life-saving treatment, but necessitates life-long therapy with immunosuppressive medications. We present the first case of a successful double-lung transplant in a CGD patient with severe bronchiectasis and end-stage lung disease. This case report was previously presented as an abstract [2].

Lung Transplant Referral Consensus Guidelines for Individuals with Cystic Fibrosis: An Opportunity for Partnerships between CF and Lung Transplant Centers

Abstract: Purpose Nearly 40% of individuals with cystic fibrosis (CF) and decreased FEV1 die without lung transplantation (LTx) in the United States, with an annual mortality rate of 10%. In addition, a substantial proportion of CF individuals with rapidly declining FEV1 (baseline FEV1 >30% predicted) die without being referred for LTx evaluation. The objective of these guidelines is to provide recommendations to the CF community to enhance identification and timely referral of individuals with CF who could benefit from LTx, as well as to encourage partnerships between CF Centers and LTx Centers to improve the referral process. Methods The CF Foundation invited a multidisciplinary team to participate in development of consensus guidelines. Three work groups performed literature searches and developed recommendations related to: understanding the timing for transplant referral; early referral and modifiable barriers; and transition to transplant. The committee voted on draft recommendations with an a priori voting threshold of 80% consensus. As part of the consensus guidelines, a focus group of seven CF transplant recipients and two spouses provided qualitative data on transplant transition to supplement objective criteria. Draft recommendation statements were released for public comment Sept 19, 2018. Results The committee reached 100% consensus on all draft recommendation statements. Key elements include: 1) Earlier introduction of LTx as a potential therapeutic option; 2) Employing overall clinical trajectory to determine the timing of referral in lieu of reliance on FEV1; 3) Early referral for individuals with potentially reversible barriers to LTx; 4) Referral for 2nd opinions for patients declined for transplant; and 5) Improving communication between CF and LTx Centers. Conclusion These guidelines will provide guidance to CF Programs, LTx Centers, and individuals with CF and their families to ensure that potentially eligible individuals receive timely LTx referral. They emphasize the important role that Transplant Centers play in patient education. While these recommendations will inevitably lead to the referral of some individuals who will be “too early” to list, earlier referral is intended to ensure that everyone with CF who has the potential to benefit is given the opportunity to consider LTx.

Lung Transplantation for Patients with Cystic Fibrosis and Achromobacter xylosoxidans in the Lung Allocation Score Era

Abstract: Purpose Lung transplantation is an accepted therapy for patients with end stage lung disease due to Cystic Fibrosis (CF). Up to ten percent of patients with CF are colonized with Achromobacter xylosoxidans, a gram negative organism that due to its intrinsic resistance to many antibiotics may affect negatively impact post-transplant outcomes. Methods We conducted a retrospective cohort analysis of all patients receiving lung transplantation for CF from 6/2005-2015 at the University of Pittsburgh Medical Center. Patients with Burkholderia species were excluded. General and transplant related demographics, pre and post-transplant respiratory cultures, and cause of death were examined. Graft survival was measured through February 2018 or last follow-up. Descriptive statistics were used to compare baseline demographics using parametric and non-parametric tests. Survival was estimated and compared by Kaplan Meier analysis. Results Twenty-nine percent (26/89) of patients had a history of Achromobacter infection prior to transplantation. Pre-transplantation, patients with Achromobacter had a slightly higher FEV1 (25.8 +/- 2.1 vs 22.3 +/- 0.07, p=0.031) but trended towards requiring more mechanical ventilation (42 vs 24%, p=0.081). Compared to patients without Achromobacter, there was not a statistically significant difference in 1 year (0.84 vs 0.94%) and 3 year survival (0.68 vs 0.84%) (Figure 1, p=0.291). Of the Achromobacter patients, forty-two percent (11/26) had positive explant bronchial cultures and forty-six percent (12/26) had Achromobacter isolated after transplantation. Of the 12 patients with recurrent Achromobacter, only 4 had positive explant cultures. Only 1 of 11 deaths was attributable to Achromobacter. Conclusion Lung transplantation is a viable treatment option for patients with end stage CF and a history of infection with Achromobacter and these patients should be considered candidates for transplantation.

Detrimental Association of Hypogammaglobulinemia With Chronic Lung Allograft Dysfunction and Death Is Not Mitigated by On-Demand Immunoglobulin G Replacement After Lung Transplantation.

Abstract: Background:Hypogammaglobulinemia (HGG), immunoglobulin G (IgG) <700 mg/dL, is associated with infections, chronic lung allograft dysfunction, and death following lung transplantation. This study ev...