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Cavaillon JM, Chaudry IH. Facing stress and inflammation: From the cell to the planet. World J Exp Med 2024; 14:96422. [PMID: 39713080 PMCID: PMC11551703 DOI: 10.5493/wjem.v14.i4.96422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/27/2024] [Accepted: 09/19/2024] [Indexed: 10/31/2024] Open
Abstract
As identified in 1936 by Hans Selye, stress is shaping diseases through the induction of inflammation. But inflammation display some yin yang properties. On one hand inflammation is merging with the innate immune response aimed to fight infectious or sterile insults, on the other hand inflammation favors chronic physical or psychological disorders. Nature has equipped the cells, the organs, and the individuals with mediators and mechanisms that allow them to deal with stress, and even a good stress (eustress) has been associated with homeostasis. Likewise, societies and the planet are exposed to stressful settings, but wars and global warming suggest that the regulatory mechanisms are poorly efficient. In this review we list some inducers of the physiological stress, psychologic stress, societal stress, and planetary stress, and mention some of the great number of parameters which affect and modulate the response to stress and render it different from an individual to another, from the cellular level to the societal one. The cell, the organ, the individual, the society, and the planet share many stressors of which the consequences are extremely interconnected ending in the domino effect and the butterfly effect.
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Affiliation(s)
| | - Irshad H Chaudry
- Department of Surgery, University of Alabama Birmingham, Birmingham, AL 35294, United States
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2
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Britto CJ, Taylor-Cousar JL. Until it's done for everyone: the role of CFTR modulator label expansion. Eur Respir J 2024; 64:2401898. [PMID: 39542511 DOI: 10.1183/13993003.01898-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 11/17/2024]
Affiliation(s)
- Clemente J Britto
- Division of Pulmonary, Critical Care, and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jennifer L Taylor-Cousar
- Division of Pulmonary and Sleep Medicine, Department of Pediatrics, University of Alabama at National Jewish Health, Denver, CO, USA
- Divisions of Pulmonary, Critical Care and Sleep Medicine, and Pediatric Pulmonary Medicine, University of Colorado, Aurora, CO, USA
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3
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Holtrop M, Cosmich S, Lee M, Keller A, Jain R. Sex Differences After Treatment With Ivacaftor in People With Cystic Fibrosis. Chest 2024; 166:951-962. [PMID: 38871282 DOI: 10.1016/j.chest.2024.05.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/15/2024] Open
Abstract
BACKGROUND Historically, studies show that female patients with cystic fibrosis (CF) have worse pulmonary outcomes than male patients, including decreased life expectancy. It is unknown whether this disparity persists in the new era of highly effective modulator therapies. Ivacaftor has been available in the United States for > 10 years, allowing for the opportunity to understand the impact this therapy may have on sex disparities in CF. We hypothesized that female patients will continue to show worse outcomes because we suspect that the disparity is not driven solely by ion channel dysfunction. RESEARCH QUESTION Does a difference in outcomes between male and female patients persist after the initiation of ivacaftor in people with CF? STUDY DESIGN AND METHODS We conducted a retrospective cohort study using the CF Foundation Patient Registry comparing changes in pulmonary exacerbation rate, lung function (FEV1 % predicted), and presence of Pseudomonas aeruginosa among male patients vs female patients before and after initiation of treatment with the highly effective modulator ivacaftor. RESULTS The cohort comprised 1,900 people with CF who were treated with ivacaftor between 2010 and 2017; 928 patients (48.84%) were male and 972 patients (51.16%) were female with a mean age of 33.09 years. Male patients showed a significant decrease in pulmonary exacerbations after ivacaftor treatment (from 0.38 to 0.34; adjusted rate ratio, 0.89; P = .028), whereas female patients did not (from 0.48 to 0.45; adjusted rate ratio, 0.95; P = .174). FEV1 % predicted similarly decreased in both male and female patients before vs after ivacaftor treatment. P aeruginosa prevalence decreased to a similar extent in both male and female patients after ivacaftor treatment. INTERPRETATION Our findings demonstrate that sex disparities in CF persist in those treated with ivacaftor because of differences in pulmonary exacerbations. More research is needed to determine the specific pathophysiologic drivers of this disparity.
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Affiliation(s)
- Melanie Holtrop
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Sophia Cosmich
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - MinJae Lee
- Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX
| | - Ashley Keller
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Raksha Jain
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
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4
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Agarwal R, Muthu V, Sehgal IS, Prasad KT, Dhooria S, Garg M, Aggarwal AN, Rudramurthy SM, Chakrabarti A. Sex Differences in Allergic Bronchopulmonary Aspergillosis and its Impact on Exacerbations. Mycopathologia 2024; 189:90. [PMID: 39361087 DOI: 10.1007/s11046-024-00893-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 09/08/2024] [Indexed: 12/02/2024]
Abstract
The impact of sex on allergic bronchopulmonary aspergillosis (ABPA) outcomes remains uncertain. We retrospectively included ABPA subjects per the revised International Society for Human and Animal Mycology ABPA working group criteria over 13 years. We compared the clinical features, lung function, immunological tests, imaging, and ABPA exacerbation rates between men and women. Our primary objective was to assess whether women experience higher ABPA exacerbations than men. We included 731 ABPA subjects (mean age, 34.5 years; 49.5% women). Women with ABPA were older and had underlying asthma more frequently than men. There was no difference in lung function, immunological investigations, and imaging between men and women. ABPA exacerbations occurred in a slightly higher proportion of women than men (44.5% vs. 38.2%) but did not reach statistical significance (p = 0.09). We did not find a significant sex difference in ABPA exacerbation rates. Prospective studies should confirm our findings.
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Affiliation(s)
- Ritesh Agarwal
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
| | - Valliappan Muthu
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Inderpaul Singh Sehgal
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Kuruswamy Thurai Prasad
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Sahajal Dhooria
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Mandeep Garg
- Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research (PGIMER), Sector-12, Chandigarh, 160012, India
| | - Ashutosh N Aggarwal
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Shivaprakash M Rudramurthy
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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5
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Harvey BJ, McElvaney NG. Sex differences in airway disease: estrogen and airway surface liquid dynamics. Biol Sex Differ 2024; 15:56. [PMID: 39026347 PMCID: PMC11264786 DOI: 10.1186/s13293-024-00633-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 07/03/2024] [Indexed: 07/20/2024] Open
Abstract
Biological sex differences exist for many airway diseases in which females have either worse or better health outcomes. Inflammatory airway diseases such as cystic fibrosis (CF) and asthma display a clear male advantage in post-puberty while a female benefit is observed in asthma during the pre-puberty years. The influence of menstrual cycle stage and pregnancy on the frequency and severity of pulmonary exacerbations in CF and asthma point to a role for sex steroid hormones, particularly estrogen, in underpinning biological sex differences in these diseases. There are many ways by which estrogen may aggravate asthma and CF involving disturbances in airway surface liquid (ASL) dynamics, inappropriate hyper-immune and allergenic responses, as well as exacerbation of pathogen virulence. The deleterious effect of estrogen on pulmonary function in CF and asthma contrasts with the female advantage observed in airway diseases characterised by pulmonary edema such as pneumonia, acute respiratory distress syndrome (ARDS) and COVID-19. Airway surface liquid hypersecretion and alveolar flooding are hallmarks of ARDS and COVID-19, and contribute to the morbidity and mortality of severe forms of these diseases. ASL dynamics encompasses the intrinsic features of the thin lining of fluid covering the airway epithelium which regulate mucociliary clearance (ciliary beat, ASL height, volume, pH, viscosity, mucins, and channel activating proteases) in addition to innate defence mechanisms (pathogen virulence, cytokines, defensins, specialised pro-resolution lipid mediators, and metabolism). Estrogen regulation of ASL dynamics contributing to biological sex differences in CF, asthma and COVID-19 is a major focus of this review.
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Affiliation(s)
- Brian J Harvey
- Faculty of Medicine and Health Sciences, Royal College of Surgeons in Ireland, 126 St Stephens Green, Dublin 2, Ireland.
- Department of Medicine, RCSI ERC, Beaumont Hospital, Dublin 2, Ireland.
| | - Noel G McElvaney
- Faculty of Medicine and Health Sciences, Royal College of Surgeons in Ireland, 126 St Stephens Green, Dublin 2, Ireland
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6
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Singh H, Jani C, Marshall DC, Franco R, Bhatt P, Podder S, Shalhoub J, Kurman JS, Nanchal R, Uluer AZ, Salciccioli JD. Cystic fibrosis-related mortality in the United States from 1999 to 2020: an observational analysis of time trends and disparities. Sci Rep 2023; 13:15030. [PMID: 37699961 PMCID: PMC10497589 DOI: 10.1038/s41598-023-41868-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 09/01/2023] [Indexed: 09/14/2023] Open
Abstract
Cystic fibrosis transmembrane conductance regulator modulators have revolutionized cystic fibrosis (CF) care in the past decade. This study explores the CF-related mortality trends in the US from 1999 to 2020. We extracted CF-related mortality data from the CDC WONDER database. CF age-standardized mortality rates (ASMRs) were identified by ICD-10 code E84 and were stratified by demographic and geographical variables. Temporal trends were analyzed using Joinpoint modeling. CF-related ASMRs decreased from 1.9 to 1.04 per million population (p = 0.013), with a greater reduction in recent years. This trend was replicated in both sexes. The median age of death increased from 24 to 37 years. CF mortality rates decreased across sex, white race, non-Hispanic ethnicity, census regions, and urbanization status. Incongruent trends were reported in non-white races and Hispanic ethnicity. A lower median age of death was observed in women, non-white races, and Hispanic ethnicity. SARS-CoV-2 infection was the primary cause of death in 1.7% of CF decedents in 2020. The national CF-related mortality rates declined and the median age of death among CF decedents increased significantly indicating better survival in the recent years. The changes were relatively slow during the earlier period of the study, followed by a greater decline lately. We observed patterns of sex, ethnic, racial, and geographical disparities associated with the worsening of the gap between ethnicities, narrowing of the gap between races and rural vs. urban counties, and closing of the gap between sexes over the study period.
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Affiliation(s)
- Harpreet Singh
- Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA.
- Medical Data Research Collaborative, London, UK.
| | - Chinmay Jani
- Department of Medicine, Mount Auburn Hospital/Beth Israel Lahey Health, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Medical Data Research Collaborative, London, UK
| | - Dominic C Marshall
- National Heart and Lung Institute, Imperial College London, London, UK
- Medical Data Research Collaborative, London, UK
| | - Rose Franco
- Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Padmanabh Bhatt
- Department of Medicine, Mount Auburn Hospital/Beth Israel Lahey Health, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Medical Data Research Collaborative, London, UK
| | - Shreya Podder
- Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Joseph Shalhoub
- Imperial College Healthcare NHS Trust, London, UK
- Medical Data Research Collaborative, London, UK
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Jonathan S Kurman
- Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Rahul Nanchal
- Division of Pulmonary and Critical Care Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA
| | - Ahmet Z Uluer
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Justin D Salciccioli
- Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Medical Data Research Collaborative, London, UK
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7
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Deny M, Popotas A, Hanssens L, Lefèvre N, Arroba Nuñez LA, Ouafo GS, Corazza F, Casimir G, Chamekh M. Sex-biased expression of selected chromosome x-linked microRNAs with potent regulatory effect on the inflammatory response in children with cystic fibrosis: A preliminary pilot investigation. Front Immunol 2023; 14:1114239. [PMID: 37077918 PMCID: PMC10106689 DOI: 10.3389/fimmu.2023.1114239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/22/2023] [Indexed: 04/05/2023] Open
Abstract
Previous studies have reported sex disparity in cystic fibrosis (CF) disease, with females experiencing more pulmonary exacerbations and frequent microbial infections resulting in shorter survival expectancy. This concerns both pubertal and prepubertal females, which is in support to the prominent role of gene dosage rather than the hormonal status. The underlying mechanisms are still poorly understood. The X chromosome codes for a large number of micro-RNAs (miRNAs) that play a crucial role in the post-transcriptional regulation of several genes involved in various biological processes, including inflammation. However, their level of expression in CF males and females has not been sufficiently explored. In this study, we compared in male and female CF patients the expression of selected X-linked miRNAs involved in inflammatory processes. Cytokine and chemokine profiles were also evaluated at both protein and transcript levels and cross-analyzed with the miRNA expression levels. We observed increased expression of miR-223-3p, miR-106a-5p, miR-221-3p and miR-502-5p in CF patients compared to healthy controls. Interestingly, the overexpression of miR-221-3p was found to be significantly higher in CF girls than in CF boys and this correlates positively with IL-1β. Moreover, we found a trend toward lower expression in CF girls than in CF boys of suppressor of cytokine signaling 1 (SOCS1) and the ubiquitin-editing enzyme PDLIM2, two mRNA targets of miR-221-3p that are known to inhibit the NF-κB pathway. Collectively, this clinical study highlights a sex-bias in X-linked miR-221-3p expression in blood cells and its potential contribution to sustaining a higher inflammatory response in CF girls.
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Affiliation(s)
- Maud Deny
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Université Libre de Bruxelles (ULB) Center for Research in Immunology (U-CRI), Brussels, Belgium
| | - Alexandros Popotas
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Laurence Hanssens
- Institut de Mucoviscidose – Unité Pédiatrique, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Nicolas Lefèvre
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Institut de Mucoviscidose – Unité Pédiatrique, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Luis Alexis Arroba Nuñez
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Université Libre de Bruxelles (ULB) Center for Research in Immunology (U-CRI), Brussels, Belgium
| | - Ghislaine Simo Ouafo
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Université Libre de Bruxelles (ULB) Center for Research in Immunology (U-CRI), Brussels, Belgium
| | - Francis Corazza
- Laboratoire de Médecine Translationnelle, Centre Hospitalier Universitaire Brugmann, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Georges Casimir
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Institut de Mucoviscidose – Unité Pédiatrique, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Mustapha Chamekh
- Inflammation Unit, Laboratory of Pediatric Research, Faculty of Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium
- Université Libre de Bruxelles (ULB) Center for Research in Immunology (U-CRI), Brussels, Belgium
- *Correspondence: Mustapha Chamekh,
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8
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Thornton CS, Parkins MD. Microbial Epidemiology of the Cystic Fibrosis Airways: Past, Present, and Future. Semin Respir Crit Care Med 2023; 44:269-286. [PMID: 36623820 DOI: 10.1055/s-0042-1758732] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Progressive obstructive lung disease secondary to chronic airway infection, coupled with impaired host immunity, is the leading cause of morbidity and mortality in cystic fibrosis (CF). Classical pathogens found in the airways of persons with CF (pwCF) include Pseudomonas aeruginosa, Staphylococcus aureus, the Burkholderia cepacia complex, Achromobacter species, and Haemophilus influenzae. While traditional respiratory-tract surveillance culturing has focused on this limited range of pathogens, the use of both comprehensive culture and culture-independent molecular approaches have demonstrated complex highly personalized microbial communities. Loss of bacterial community diversity and richness, counteracted with relative increases in dominant taxa by traditional CF pathogens such as Burkholderia or Pseudomonas, have long been considered the hallmark of disease progression. Acquisition of these classic pathogens is viewed as a harbinger of advanced disease and postulated to be driven in part by recurrent and frequent antibiotic exposure driven by frequent acute pulmonary exacerbations. Recently, CF transmembrane conductance regulator (CFTR) modulators, small molecules designed to potentiate or restore diminished protein levels/function, have been successfully developed and have profoundly influenced disease course. Despite the multitude of clinical benefits, structural lung damage and consequent chronic airway infection persist in pwCF. In this article, we review the microbial epidemiology of pwCF, focus on our evolving understanding of these infections in the era of modulators, and identify future challenges in infection surveillance and clinical management.
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Affiliation(s)
- Christina S Thornton
- Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Michael D Parkins
- Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Canada.,Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Alberta, Canada
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9
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Britto CJ, Ratjen F, Clancy JP. Emerging Approaches to Monitor and Modify Care in the Era of Cystic Fibrosis Transmembrane Conductance Regulators. Clin Chest Med 2022; 43:631-646. [PMID: 36344071 DOI: 10.1016/j.ccm.2022.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
As we characterize the clinical benefits of highly effective modulator therapy (HEMT) in the cystic fibrosis (CF) population, our paradigm for treating and monitoring disease continues to evolve. More sensitive approaches are necessary to detect early disease and clinical progression. This article reviews evolving strategies to assess disease control and progression in the HEMT era. This article also explores developments in pulmonary function monitoring, advanced respiratory imaging, tools for the collection of patient-reported outcomes, and their application to profile individual responses, guide therapeutic decisions, and improve the quality of life of people with CF.
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Affiliation(s)
- Clemente J Britto
- Yale Adult Cystic Fibrosis Program, Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine.
| | - Felix Ratjen
- Division of Respiratory Medicine, Translational Medicine, University of Toronto Hospital for Sick Children, 555 University Avenue, Toronto Ontario M5G 1X8, Canada
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Montemayor K, Jain R. Cystic Fibrosis: Highly Effective Targeted Therapeutics and the Impact on Sex and Racial Disparities. Med Clin North Am 2022; 106:1001-1012. [PMID: 36280328 DOI: 10.1016/j.mcna.2022.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
People with Cystic Fibrosis (CF) are living longer and healthier lives due in part to new therapies, called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators. However, disparities in outcomes still exist, with females demonstrating a shorter life expectancy than males; this is opposed to the typical female versus male life expectancy in the general United States population. In addition, minority populations such as those of Hispanic ethnicity and African Americans are less frequently eligible for these new CFTR modulators. The mechanisms driving this difference and the relative contribution of CFTR to the etiology are not yet elucidated.
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Affiliation(s)
- Kristina Montemayor
- Department of Medicine, Johns Hopkins University, 1830 E. Monument Street 5th Floor, Baltimore, MD 21205, USA
| | - Raksha Jain
- Department of Medicine, University of Texas Southwestern, 5323 Harry Hines Boulevard, Dallas, TX 75390-8558, USA.
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11
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Holban AM, Gregoire CM, Gestal MC. Conquering the host: Bordetella spp. and Pseudomonas aeruginosa molecular regulators in lung infection. Front Microbiol 2022; 13:983149. [PMID: 36225372 PMCID: PMC9549215 DOI: 10.3389/fmicb.2022.983149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/17/2022] [Indexed: 11/27/2022] Open
Abstract
When bacteria sense cues from the host environment, stress responses are activated. Two component systems, sigma factors, small RNAs, ppGpp stringent response, and chaperones start coordinate the expression of virulence factors or immunomodulators to allow bacteria to respond. Although, some of these are well studied, such as the two-component systems, the contribution of other regulators, such as sigma factors or ppGpp, is increasingly gaining attention. Pseudomonas aeruginosa is the gold standard pathogen for studying the molecular mechanisms to sense and respond to environmental cues. Bordetella spp., on the other hand, is a microbial model for studying host-pathogen interactions at the molecular level. These two pathogens have the ability to colonize the lungs of patients with chronic diseases, suggesting that they have the potential to share a niche and interact. However, the molecular networks that facilitate adaptation of Bordetella spp. to cues are unclear. Here, we offer a side-by-side comparison of what is known about these diverse molecular mechanisms that bacteria utilize to counteract host immune responses, while highlighting the relatively unexplored interactions between them.
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Affiliation(s)
- Alina M. Holban
- Research Institute of the University of Bucharest (ICUB), Bucharest, Romania
- Department of Microbiology and Immunology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Courtney M. Gregoire
- Department of Microbiology and Immunology, Louisiana State University Health Science Center, Shreveport, LA, United States
| | - Monica C. Gestal
- Department of Microbiology and Immunology, Louisiana State University Health Science Center, Shreveport, LA, United States
- *Correspondence: Monica C. Gestal, ;
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12
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Arrazuria R, Kerscher B, Huber KE, Hoover JL, Lundberg CV, Hansen JU, Sordello S, Renard S, Aranzana-Climent V, Hughes D, Gribbon P, Friberg LE, Bekeredjian-Ding I. Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents. Front Microbiol 2022; 13:988728. [PMID: 36160241 PMCID: PMC9493352 DOI: 10.3389/fmicb.2022.988728] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/15/2022] [Indexed: 11/20/2022] Open
Abstract
Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of in vivo models that mimic clinical infection, translational challenges remain high. Standardization of in vivo models is deemed necessary to improve the robustness and reproducibility of preclinical studies and thus translational research. The European Innovative Medicines Initiative (IMI)-funded “Collaboration for prevention and treatment of MDR bacterial infections” (COMBINE) consortium, aims to develop a standardized, quality-controlled murine pneumonia model for preclinical efficacy testing of novel anti-infective candidates and to improve tools for the translation of preclinical data to the clinic. In this review of murine pneumonia model data published in the last 10 years, we present our findings of considerable variability in the protocols employed for testing the efficacy of antimicrobial compounds using this in vivo model. Based on specific inclusion criteria, fifty-three studies focusing on antimicrobial assessment against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii were reviewed in detail. The data revealed marked differences in the experimental design of the murine pneumonia models employed in the literature. Notably, several differences were observed in variables that are expected to impact the obtained results, such as the immune status of the animals, the age, infection route and sample processing, highlighting the necessity of a standardized model.
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Affiliation(s)
- Rakel Arrazuria
- Division of Microbiology, Paul-Ehrlich-Institut, Langen, Germany
| | | | - Karen E. Huber
- Division of Microbiology, Paul-Ehrlich-Institut, Langen, Germany
| | - Jennifer L. Hoover
- Infectious Diseases Research Unit, GlaxoSmithKline Pharmaceuticals, Collegeville, PA, United States
| | | | - Jon Ulf Hansen
- Department of Bacteria, Parasites & Fungi, Statens Serum Institut, Copenhagen, Denmark
| | | | | | | | - Diarmaid Hughes
- Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
| | - Philip Gribbon
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort, Hamburg, Germany
| | | | - Isabelle Bekeredjian-Ding
- Division of Microbiology, Paul-Ehrlich-Institut, Langen, Germany
- Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
- *Correspondence: Isabelle Bekeredjian-Ding,
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13
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Planet PJ. Adaptation and Evolution of Pathogens in the Cystic Fibrosis Lung. J Pediatric Infect Dis Soc 2022; 11:S23-S31. [PMID: 36069898 PMCID: PMC9451014 DOI: 10.1093/jpids/piac073] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 02/05/2023]
Abstract
As opposed to acute respiratory infections, the persistent bacterial infections of the lung that characterize cystic fibrosis (CF) provide ample time for bacteria to evolve and adapt. The process of adaptation is recorded in mutations that accumulate over time in the genomes of the infecting bacteria. Some of these mutations lead to obvious phenotypic differences such as antibiotic resistance or the well-known mucoid phenotype of Pseudomonas aeruginosa. Other mutations may be just as important but harder to detect such as increased mutation rates, cell surface changes, and shifts in metabolism and nutrient acquisition. Remarkably, many of the adaptations occur again and again in different patients, signaling that bacteria are adapting to solve specific challenges in the CF respiratory tract. This parallel evolution even extends across distinct bacterial species. This review addresses the bacterial systems that are known to change in long-term CF infections with a special emphasis on cross-species comparisons. Consideration is given to how adaptation may impact health in CF, and the possible evolutionary mechanisms that lead to the repeated parallel adaptations.
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Affiliation(s)
- Paul J Planet
- Corresponding Author: Paul J. Planet, MD, PhD, 3615 Civic Center Blvd, Philadelphia, PA 19104. E-mail:
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14
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Al-Zawity J, Afzal F, Awan A, Nordhoff D, Kleimann A, Wesner D, Montier T, Le Gall T, Müller M. Effects of the Sex Steroid Hormone Estradiol on Biofilm Growth of Cystic Fibrosis Pseudomonas aeruginosa Isolates. Front Cell Infect Microbiol 2022; 12:941014. [PMID: 35909974 PMCID: PMC9326073 DOI: 10.3389/fcimb.2022.941014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/08/2022] [Indexed: 11/23/2022] Open
Abstract
Women with cystic fibrosis (CF) have a significantly lower life expectancy compared to men, which is indicated by an earlier impairment of lung function due to chronic colonization with biofilm formed by Pseudomonas aeruginosa. There is growing evidence that blood serum concentrations of the steroid sex hormone estradiol (E2) correlate with the occurrence of pulmonary exacerbations in CF but also play a role in the mucoid switch of P. aeruginosa. This study aims to shed light on possible microbiological reasons for sexual dimorphism in CF by investigating the influence of E2 on biofilm formation of P. aeruginosa CF isolates. For this purpose, 10 CF isolates of the respiratory tract derived from different CF patients have been treated with E2 in a microtiter plate biofilm model. Biofilms have been examined by crystal violet assays, field emission scanning electron microscopy (FE-SEM), 3D laser scanning microscopy (LSM), and quorum sensing (QS) reporter assays of the supernatants taken from biofilms. This allowed us to simultaneously investigate the effects of E2 on attached biofilm mass, biofilm ultrastructure, and QS activity. Upon E2 treatment, six out of 10 investigated CF isolates showed an increase of attached biofilm mass, whereas biofilms from two tested non-CF laboratory strains (PAO1 and ATCC19660) did not. Moreover, FE-SEM and 3D LSM analyses of the E2 responsive CF biofilms revealed ultrastructural remodeling of biofilm structure at different scales with increased formation of prominent biofilm spots, enhanced coverage with extracellular polymeric substance (EPS), and extended average surface roughness. QS activity measurements performed in biofilm supernatants via luminescence acyl homoserine lactone (AHL) reporter assays further showed that E2 treatment may also modulate QS signaling, as shown in an E2 sensitive CF isolate. Together, our results suggest the biofilm modulating effects of E2 on various clinical CF isolates that are documented by both biomass and ultrastructural changes of biofilms. The gained new insight into the influence of steroid hormones on P. aeruginosa biofilm phenotypes might pave the way for novel future approaches in personalized medicine based on the patients’ sex and hormonal status.
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Affiliation(s)
- Jiwar Al-Zawity
- Physical Chemistry I and Research Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), Department of Chemistry and Biology, University of Siegen, Siegen, Germany
| | - Faria Afzal
- Physical Chemistry I and Research Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), Department of Chemistry and Biology, University of Siegen, Siegen, Germany
| | - Aysha Awan
- Physical Chemistry I and Research Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), Department of Chemistry and Biology, University of Siegen, Siegen, Germany
| | - Daniela Nordhoff
- Physical Chemistry I and Research Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), Department of Chemistry and Biology, University of Siegen, Siegen, Germany
| | - Alexander Kleimann
- Physical Chemistry I and Research Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), Department of Chemistry and Biology, University of Siegen, Siegen, Germany
| | - Daniel Wesner
- Physical Chemistry I and Research Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), Department of Chemistry and Biology, University of Siegen, Siegen, Germany
| | - Tristan Montier
- INSERM, Univ Brest, EFS, UMR 1078, GGB-GTCA, Brest, France
- CHRU de Brest, Service de Génétique Médicale et de Biologie de la Reproduction, Centre de Référence des Maladies Rares “Maladies Neuromusculaires”, Brest, France
| | - Tony Le Gall
- INSERM, Univ Brest, EFS, UMR 1078, GGB-GTCA, Brest, France
| | - Mareike Müller
- Physical Chemistry I and Research Center of Micro- and Nanochemistry and (Bio)Technology (Cμ), Department of Chemistry and Biology, University of Siegen, Siegen, Germany
- *Correspondence: Mareike Müller,
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15
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Somayaji R, Chalmers JD. Just breathe: a review of sex and gender in chronic lung disease. Eur Respir Rev 2022; 31:31/163/210111. [PMID: 35022256 DOI: 10.1183/16000617.0111-2021] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 08/20/2021] [Indexed: 01/08/2023] Open
Abstract
Chronic lung diseases are the third leading cause of death worldwide and are increasing in prevalence over time. Although much of our traditional understanding of health and disease is derived from study of the male of the species - be it animal or human - there is increasing evidence that sex and gender contribute to differences in disease risk, prevalence, presentation, severity, treatment approach, response and outcomes. Chronic obstructive pulmonary disease, asthma and bronchiectasis represent the most prevalent and studied chronic lung diseases and have key sex- and gender-based differences which are critical to consider and incorporate into clinical and research approaches. Mechanistic differences present opportunities for therapeutic development whereas behavioural and clinical differences on the part of patients and providers present opportunities for greater education and understanding at multiple levels. In this review, we seek to summarise the sex- and gender-based differences in key chronic lung diseases and outline the clinical and research implications for stakeholders.
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Affiliation(s)
- Ranjani Somayaji
- Dept of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada .,Dept of Microbiology, Immunology and Infectious Disease, University of Calgary, Calgary, Canada.,Dept of Community Health Sciences, University of Calgary, Calgary, Canada
| | - James D Chalmers
- Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
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16
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Espinosa J, Raja S. Social Disparities in Benign Lung Diseases. Thorac Surg Clin 2022; 32:43-49. [PMID: 34801194 PMCID: PMC9760325 DOI: 10.1016/j.thorsurg.2021.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The many socioeconomic disparities in the myriad of diagnoses that make up benign lung diseases are unfortunately a global issue that was most recently highlighted by the COVID-19 pandemic of 2020. In this chapter, we will be reviewing the socioeconomic disparities in benign lung disease from both a United States perspective as well as a global perspective. We will cover the spectrum of infectious, obstructive, and restrictive lung disease and review the evidence on how social disparities affect these populations and their access to medical care.
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Affiliation(s)
- Jairo Espinosa
- Department of Thoracic Surgery, Temple University Hospital, 3401 N. Broad Street, Suite C501, Parkinson Pavilion, Philadelphia, PA 19140, USA.
| | - Siva Raja
- Department of Thoracic Surgery, Cleveland Clinic 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
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17
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McKiernan PJ, Molloy KP, Glasgow AMA, McElvaney NG, Greene CM. miR-224-5p and miR-545-5p Levels Relate to Exacerbations and Lung Function in a Pilot Study of X-Linked MicroRNA Expression in Cystic Fibrosis Monocytes. Front Genet 2021; 12:739311. [PMID: 34868211 PMCID: PMC8633565 DOI: 10.3389/fgene.2021.739311] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 10/18/2021] [Indexed: 01/10/2023] Open
Abstract
Altered microRNA expression patterns in bronchial brushings from people with versus without cystic fibrosis (CF) relate to functional changes and disease pathophysiology. The expression of microRNAs encoded on the X chromosome is also altered in peripheral blood monocytes of p. Phe508del homozygous versus non-CF individuals. Here we investigate whether levels of the top seven X-linked microRNAs (miR-224-5p, miR-452-5p, miR-450b-5p, miR-542-3p, miR-450a-5p, miR-424-5p, and miR-545-5p) that are significantly increased over 1.5 fold in CF versus non-CF monocytes correlate with lung function. CD14+ monocytes were isolated from males and females with (n = 12) and without cystic fibrosis (n = 12) and examined for the expression of X-linked microRNAs by qRT-PCR array. MicroRNA target mRNA levels were quantified using qRT-PCR. Clinical correlations with lung function data were analysed in the CF cohort. Increasing levels of miR-545-5p correlated moderately with FEV1% predicted (r = -0.4553, p > 0.05) and strongly with exacerbation rate (r = 0.5858, p = 0.0483). miR-224-5p levels were significantly higher in the severe (FEV1 <40%) versus mild (FEV1 ≥80%, p = 0.0377) or moderate (FEV1 40-79%, p = 0.0350) groups. MiR-224-5p expression inversely correlated with lung function (FEV1%: r = -0.5944, p = 0.0457) and positively correlated with exacerbation rates (r = 0.6139, p = 0.0370). These data show that peripheral blood monocyte miR-545-5p and miR-224-5p levels correlate with exacerbation rate, whilst miR-224-5p levels also correlate with lung function in cystic fibrosis.
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Affiliation(s)
- Paul J McKiernan
- Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Kevin P Molloy
- Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Arlene M A Glasgow
- Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Noel G McElvaney
- Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Catherine M Greene
- Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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18
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Cation complexation by mucoid Pseudomonas aeruginosa extracellular polysaccharide. PLoS One 2021; 16:e0257026. [PMID: 34473773 PMCID: PMC8412252 DOI: 10.1371/journal.pone.0257026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/23/2021] [Indexed: 11/25/2022] Open
Abstract
Mucoid Pseudomonas aeruginosa is a prevalent cystic fibrosis (CF) lung colonizer, producing an extracellular matrix (ECM) composed predominantly of the extracellular polysaccharide (EPS) alginate. The ECM limits antimicrobial penetration and, consequently, CF sufferers are prone to chronic mucoid P. aeruginosa lung infections. Interactions between cations with elevated concentrations in the CF lung and the anionic EPS, enhance the structural rigidity of the biofilm and exacerbates virulence. In this work, two large mucoid P. aeruginosa EPS models, based on β-D-mannuronate (M) and β-D-mannuronate-α-L-guluronate systems (M-G), and encompassing thermodynamically stable acetylation configurations–a structural motif unique to mucoid P. aeruginosa–were created. Using highly accurate first principles calculations, stable coordination environments adopted by the cations have been identified and thermodynamic stability quantified. These models show the weak cross-linking capability of Na+ and Mg2+ ions relative to Ca2+ ions and indicate a preference for cation binding within M-G blocks due to the smaller torsional rearrangements needed to reveal stable binding sites. The geometry of the chelation site influences the stability of the resulting complexes more than electrostatic interactions, and the results show nuanced chemical insight into previous experimental observations.
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19
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Understanding the Intersection between Gender Transition and Health Outcomes in Cystic Fibrosis. Ann Am Thorac Soc 2021; 19:504-506. [PMID: 34469707 DOI: 10.1513/annalsats.202105-535rl] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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20
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Abstract
Women with cystic fibrosis (CF) face several unaddressed concerns related to their health. These areas of concern include explanations and guidance on a sex disparity in outcomes, timing of puberty, effects of contraception, prevalence of infertility and impact of pregnancy, and prevention of urinary incontinence and osteoporosis. These understudied topics leave women with numerous unanswered questions about how to manage sexual and reproductive health in the setting of CF. Because people with CF are living longer and healthier lives, there is an increasing awareness of these important aspects of care and multiple ongoing studies to address these understudied topics.
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21
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Differences in Nutritional Status and Inflammatory Biomarkers between Female and Male Patients with Bronchiectasis: A Large-Cohort Study. Biomedicines 2021; 9:biomedicines9080905. [PMID: 34440109 PMCID: PMC8389575 DOI: 10.3390/biomedicines9080905] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/23/2021] [Accepted: 07/24/2021] [Indexed: 01/11/2023] Open
Abstract
We hypothesized that systemic inflammatory and nutritional parameters may differ between male and female patients with non-CF bronchiectasis. In a large patient cohort from the Spanish Online Bronchiectasis Registry (RIBRON), clinical features, systemic inflammatory and nutritional parameters were analyzed in male and female patients with bronchiectasis. Lung function, disease severity using several scores, nutritional status, systemic inflammatory parameters, and multivariate regression analyses were performed to identify differences between male and female patients in the target variables. The number of female patients included in the registry was greater than male patients and they had a less severe disease as measured by all three indices of disease severity, a lower degree of airway obstruction, worse diffusion capacity and airway trapping, better nutritional parameters, and lower levels of inflammatory biomarkers. Multivariate regression analysis evidenced that strong relationships were found between female gender and the following variables: total numbers of leukocytes and neutrophils, hemoglobin, hematocrit, creatinine, and body mass index (BMI). Multivariate regression analyses evidenced that nutritional parameters and inflammatory biomarkers may be reliable indicators of gender-related differences in patients with non-CF bronchiectasis. These findings deserve further attention in follow-up investigations in which the potential predictive value of those biomarkers should be thoroughly explored.
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22
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Sex differences in treatment patterns in cystic fibrosis pulmonary exacerbations. J Cyst Fibros 2021; 20:920-925. [PMID: 34090802 DOI: 10.1016/j.jcf.2021.05.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 03/03/2021] [Accepted: 05/17/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Females with cystic fibrosis (CF) have been shown to have worse pulmonary exacerbation (PEx) related outcomes compared to males. However, it is unknown if sex differences in treatment patterns are contributing to these outcomes. Thus, we sought to explore sex differences in treatment patterns in the Standardized Treatment of Pulmonary Exacerbations (STOP) cohort. METHODS Data for 220 participants from the STOP cohort were analyzed. Multivariable regression models were used to assess if female sex was associated with duration of treatment with IV antibiotics and inpatient length of stay. Secondary outcomes included antibiotic selection, adjunctive therapies, mean FEV1pp and CFRSD-CRISS respiratory symptom scores at the four study assessments. RESULTS In our adjusted model, the average number of IV antibiotic treatment days was 13% higher in females compared to males (IRR 1.13, 95% CI=1.02,1.25; p=0.02). We found no sex differences in inpatient length of stay, number of IV antibiotics, antibiotic selection or initiation of adjunctive therapies. Overall, females had higher CFRSD-CRISS scores at the end of IV therapy indicating worse symptom severity (23.6 for females vs. 18.5 for males, p=0.03). CONCLUSIONS Despite females having a longer treatment duration, our findings demonstrate that males and females are receiving similar treatments which suggest that the outcome disparities in females with CF may not be due to failure to provide the same level of care. Further research dedicated to sex differences in CF is necessary to understand why clinical outcomes differ between males and females.
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23
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Sex and Gender Differences in Lung Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1304:227-258. [PMID: 34019273 DOI: 10.1007/978-3-030-68748-9_14] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Sex differences in the anatomy and physiology of the respiratory system have been widely reported. These intrinsic sex differences have also been shown to modulate the pathophysiology, incidence, morbidity, and mortality of several lung diseases across the life span. In this chapter, we describe the epidemiology of sex differences in respiratory diseases including neonatal lung disease (respiratory distress syndrome, bronchopulmonary dysplasia) and pediatric and adult disease (including asthma, cystic fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, lymphangioleiomyomatosis, obstructive sleep apnea, pulmonary arterial hypertension, and respiratory viral infections such as respiratory syncytial virus, influenza, and SARS-CoV-2). We also discuss the current state of research on the mechanisms underlying the observed sex differences in lung disease susceptibility and severity and the importance of considering both sex and gender variables in research studies' design and analysis.
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24
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Kim D, Liao J, Scales NB, Martini C, Luan X, Abu-Arish A, Robert R, Luo Y, McKay GA, Nguyen D, Tewfik MA, Poirier CD, Matouk E, Ianowski JP, Frenkiel S, Hanrahan JW. Large pH oscillations promote host defense against human airways infection. J Exp Med 2021; 218:e20201831. [PMID: 33533914 PMCID: PMC7845918 DOI: 10.1084/jem.20201831] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/01/2020] [Accepted: 11/18/2020] [Indexed: 12/19/2022] Open
Abstract
The airway mucosal microenvironment is crucial for host defense against inhaled pathogens but remains poorly understood. We report here that the airway surface normally undergoes surprisingly large excursions in pH during breathing that can reach pH 9.0 during inhalation, making it the most alkaline fluid in the body. Transient alkalinization requires luminal bicarbonate and membrane-bound carbonic anhydrase 12 (CA12) and is antimicrobial. Luminal bicarbonate concentration and CA12 expression are both reduced in cystic fibrosis (CF), and mucus accumulation both buffers the pH and obstructs airflow, further suppressing the oscillations and bacterial-killing efficacy. Defective pH oscillations may compromise airway host defense in other respiratory diseases and explain CF-like airway infections in people with CA12 mutations.
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Affiliation(s)
- Dusik Kim
- Department of Physiology, McGill University, Montréal, Québec, Canada
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
| | - Jie Liao
- Department of Physiology, McGill University, Montréal, Québec, Canada
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
| | - Nathan B. Scales
- Department of Physiology, McGill University, Montréal, Québec, Canada
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
| | - Carolina Martini
- Department of Physiology, McGill University, Montréal, Québec, Canada
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
| | - Xiaojie Luan
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Asmahan Abu-Arish
- Department of Physiology, McGill University, Montréal, Québec, Canada
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
| | - Renaud Robert
- Department of Physiology, McGill University, Montréal, Québec, Canada
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
| | - Yishan Luo
- Department of Physiology, McGill University, Montréal, Québec, Canada
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
| | - Geoffrey A. McKay
- Department of Medicine, McGill University, Research Institute–McGill University Health Centre, Montréal, Québec, Canada
| | - Dao Nguyen
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
- Department of Medicine, McGill University, Research Institute–McGill University Health Centre, Montréal, Québec, Canada
| | - Marc A. Tewfik
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
- Department of Medicine, McGill University, Research Institute–McGill University Health Centre, Montréal, Québec, Canada
- Department of Otolaryngology–Head and Neck Surgery, McGill University Health Centre, Montréal, Québec, Canada
| | - Charles D. Poirier
- Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada
| | - Elias Matouk
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
- Adult Cystic Fibrosis Clinic, Montreal Chest Institute, McGill University Health Centre, Montréal, Québec, Canada
| | - Juan P. Ianowski
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Saul Frenkiel
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
- Department of Medicine, McGill University, Research Institute–McGill University Health Centre, Montréal, Québec, Canada
- Department of Otolaryngology–Head and Neck Surgery, McGill University Health Centre, Montréal, Québec, Canada
| | - John W. Hanrahan
- Department of Physiology, McGill University, Montréal, Québec, Canada
- Cystic Fibrosis Translational Research Center, McGill University, Montréal, Québec, Canada
- Department of Medicine, McGill University, Research Institute–McGill University Health Centre, Montréal, Québec, Canada
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25
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Shaffer L, Bozkanat K, Lau M, Sharma P, Sathe M, Lopez X, Jain R. Gender-affirming hormone therapy in cystic fibrosis - A case of new Pseudomonas infection. Respir Med Case Rep 2021; 32:101353. [PMID: 33537203 PMCID: PMC7841348 DOI: 10.1016/j.rmcr.2021.101353] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/28/2020] [Accepted: 01/17/2021] [Indexed: 11/17/2022] Open
Abstract
Background Little is known about the impact of hormone therapy on transgender youth with Cystic Fibrosis (CF). This case report describes an 18-year-old affirmed female with CF who was treated with hormone therapy associated in timing with new growth of Pseudomonas aeruginosa in her sputum culture. Discussion We highlight important considerations, including the impact of gender-affirming hormone therapy on overall CF disease course. Evidence supports that females with CF have worse outcomes than males, which are partly attributed to estrogen effects. Pseudomonas aeruginosa is one of the most prevalent pathogens in people with CF. Here, we highlight a transfemale who grows Pseudomonas aeruginosa for the first time since her youth, nearly 1 year after starting estrogen therapy. This is consistent with previous literature of an association between high estrogen levels and Pseudomonas aeruginosa prevalence, but has never been evaluated in a transgender population. Conclusion Through this case, we demonstrate the need for additional research to understand the relationship between gender-affirmative hormone transition and CF care and management.
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Affiliation(s)
- L Shaffer
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - K Bozkanat
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - M Lau
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - P Sharma
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - M Sathe
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - X Lopez
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - R Jain
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Hughan KS, Daley T, Rayas MS, Kelly A, Roe A. Female reproductive health in cystic fibrosis. J Cyst Fibros 2020; 18 Suppl 2:S95-S104. [PMID: 31679735 DOI: 10.1016/j.jcf.2019.08.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/21/2019] [Accepted: 08/22/2019] [Indexed: 02/06/2023]
Abstract
Women with cystic fibrosis (CF) are living longer and healthier lives, and opportunities for childbearing are increasingly promising. However, this population can also face sexual and reproductive health concerns, including menstrual irregularities, unplanned pregnancies, infertility and pregnancy complications. Additionally, more women are entering menopause and are at risk for the consequences of estrogen deficiency. The exact mechanisms involved in female reproductive health conditions in CF are not clearly understood, but are thought to include cystic fibrosis transmembrane regulator (CFTR)-mediated abnormalities, changes in female sex hormones, and other CF health-related factors. In the era of CFTR modulator therapy, new data are necessary to understand the impact of CFTR modulation on contraceptive effectiveness, fertility, and pregnancy outcomes to help guide future clinical care. This article reviews the current scientific knowledge of major reproductive health issues for women with CF.
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Affiliation(s)
- Kara S Hughan
- Division of Pediatric Endocrinology and Diabetes, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA, USA.
| | - Tanicia Daley
- Division of Pediatric Endocrinology and Metabolism, Emory Children's Pediatric Institute, Emory University School of Medicine, 1400 Tullie Road, Atlanta, GA, USA
| | - Maria Socorro Rayas
- Division of Pediatric Endocrinology and Diabetes, University of Texas Health San Antonio, 7703 Floyd Curl, San Antonio, TX, USA
| | - Andrea Kelly
- Division of Pediatric Endocrinology and Diabetes, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, 2716 South Street, Philadelphia, PA, USA
| | - Andrea Roe
- Division of Family Planning, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, 1000 Courtyard, 3400 Spruce Street, Philadelphia, PA, USA
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27
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Garcia-Clemente M, de la Rosa D, Máiz L, Girón R, Blanco M, Olveira C, Canton R, Martinez-García MA. Impact of Pseudomonas aeruginosa Infection on Patients with Chronic Inflammatory Airway Diseases. J Clin Med 2020; 9:jcm9123800. [PMID: 33255354 PMCID: PMC7760986 DOI: 10.3390/jcm9123800] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 11/20/2020] [Accepted: 11/22/2020] [Indexed: 12/12/2022] Open
Abstract
Pseudomonas aeruginosa (P. aeruginosa) is a ubiquitous and opportunistic microorganism and is considered one of the most significant pathogens that produce chronic colonization and infection of the lower respiratory tract, especially in people with chronic inflammatory airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis. From a microbiological viewpoint, the presence and persistence of P. aeruginosa over time are characterized by adaptation within the host that precludes any rapid, devastating injury to the host. Moreover, this microorganism usually develops antibiotic resistance, which is accelerated in chronic infections especially in those situations where the frequent use of antimicrobials facilitates the selection of “hypermutator P. aeruginosa strain”. This phenomenon has been observed in people with bronchiectasis, CF, and the “exacerbator” COPD phenotype. From a clinical point of view, a chronic bronchial infection of P. aeruginosa has been related to more severity and poor prognosis in people with CF, bronchiectasis, and probably in COPD, but little is known on the effect of this microorganism infection in people with asthma. The relationship between the impact and treatment of P. aeruginosa infection in people with airway diseases emerges as an important future challenge and it is the most important objective of this review.
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Affiliation(s)
- Marta Garcia-Clemente
- Pneumology Department, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain;
| | - David de la Rosa
- Pneumology Department, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain;
| | - Luis Máiz
- Servicio de Neumología, Unidad de Fibrosis Quística, Bronquiectasias e Infección Bronquial Crónica, Hospital Ramón y Cajal, 28034 Madrid, Spain;
| | - Rosa Girón
- Pneumology Department, Hospital Univesitario la Princesa, 28006 Madrid, Spain;
| | - Marina Blanco
- Servicio de Neumología, Hospital Universitario A Coruña, 15006 A Coruña, Spain;
| | - Casilda Olveira
- Servicio de Neumología, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain;
| | - Rafael Canton
- Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain;
| | - Miguel Angel Martinez-García
- Pneumology Department, Universitary and Polytechnic La Fe Hospital, 46012 Valencia, Spain
- Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28034 Madrid, Spain
- Correspondence: ; Tel.: +34-609865934
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Early acquisition and conversion of Pseudomonas aeruginosa in Hispanic youth with cystic fibrosis in the United States. J Cyst Fibros 2020; 20:424-431. [PMID: 33162303 DOI: 10.1016/j.jcf.2020.10.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/17/2020] [Accepted: 10/23/2020] [Indexed: 11/21/2022]
Abstract
BACKGROUND For unknown reasons, Hispanic patients with cystic fibrosis (CF) have more severe pulmonary disease than non-Hispanic white patients. In CF, the pulmonary pathogen Pseudomonas aeruginosa is associated with worse outcomes. We sought to determine if Hispanic patients with CF are at an increased risk of acquiring P. aeruginosa or acquire it earlier than non-Hispanic white patients. METHODS This is a longitudinal study comparing the timing and risk of acquisition of different forms of P. aeruginosa between Hispanic and non-Hispanic white patients aged 0-21 years old with CF in the CF Foundation Patient Registry (CFFPR) in 2008-2013. The age at the initial acquisition of P. aeruginosa (initial acquisition, mucoid, chronic, multidrug-resistant) was summarized using Kaplan-Meier survival curves and analyzed using Cox proportional hazards regression models. RESULTS Of 10,464 patients, 788 (7.5%) were Hispanic and 9,676 (92.5%) were non-Hispanic white. Hispanic patients acquired all forms of P. aeruginosa at a younger age than non-Hispanic white patients. Hispanic patients had a higher risk of acquiring P. aeruginosa than non-Hispanic white patients: the hazard ratio (HR) was 1.26 (95% CI 1.16-1.38, p<0.001) for initial P. aeruginosa, 1.59 (95% CI 1.43-1.77, p<0.001) for mucoid P. aeruginosa, 1.91 (95% CI 1.64-2.23, p<0.001) for multidrug-resistant P. aeruginosa, and 1.39 (95% CI 1.25-1.55, p<0.001) for chronic P. aeruginosa. CONCLUSIONS Hispanic patients have an increased risk of acquiring P. aeruginosa and acquire it at an earlier age than non-Hispanic white patients in the United States. This may contribute to increased morbidity and mortality in Hispanic patients with CF.
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Bradbury NA. Cystic Fibrosis and Genotype-Dependent Therapy: Is There a Need for a Sex-Specific Therapy? GENDER AND THE GENOME 2020. [DOI: 10.1177/2470289720937025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulation (CFTR) anion channel. Loss of CFTR protein and/or function disrupts chloride, bicarbonate, and fluid transport and also impacts epithelial sodium transport. Such altered ion and fluid transport produces mucus obstruction, inflammation, pulmonary infection, and damage to multiple organs. Although an autosomal disease, it is apparent that gender differences in life expectancy and quality of life do exist. Conventionally established therapies have treated the downstream sequelae of CFTR dysfunction and have led to a steady increase in life expectancy. Physicians now have access to medications that treat the basic defect in CF, in the form of CFTR modulators. These drugs target the trafficking and/or function of CFTR to improve clinical outcomes for patients. This review summarizes the science behind CFTR modulators and shows how these drugs have dramatically changed how patients with CF are treated. Surprisingly, although the drug target(s) are identical in males and females, CF females seem to display a greater improvement than their male counterparts.
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Affiliation(s)
- Neil A. Bradbury
- Department of Physiology and Biophysics and Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
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30
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Douafer H, Andrieu V, Brunel JM. Scope and limitations on aerosol drug delivery for the treatment of infectious respiratory diseases. J Control Release 2020; 325:276-292. [PMID: 32652109 DOI: 10.1016/j.jconrel.2020.07.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 07/03/2020] [Accepted: 07/04/2020] [Indexed: 01/24/2023]
Abstract
The rise of antimicrobial resistance has created an urgent need for the development of new methods for antibiotics delivery to patients with pulmonary infections in order to mainly increase the effectiveness of the drugs administration, to minimize the risk of emergence of resistant strains, and to prevent patients reinfection. Since bacterial resistance is often related to antibiotic concentration, their pulmonary administration could eradicate strains resistant to the same drug at the concentration achieved through the systemic circulation. Pulmonary administration offers several advantages; it directly targets the site of the infection which allows the inhaled dose of the drug to be reduced compared to that administered orally or parenterally while keeping the same local effect. The review article is made with an objective to compile information about various existing modern technologies developed to provide greater patient compliance and reduce the undesirable side effect of the drugs. In conclusion, aerosol antibiotic delivery appears as one of the best technologies for the treatment of pulmonary infectious diseases and able to limit the systemic adverse effects related to the high drug dose and to make life easier for the patients.
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Affiliation(s)
- Hana Douafer
- Aix Marseille Univ, INSERM, SSA, MCT, 13385 Marseille, France
| | - Véronique Andrieu
- Aix Marseille Univ, IRD, APHM, MEPHI, IHU Méditerranée Infection, Faculté de Médecine et de Pharmacie, 13385 Marseille, France
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31
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Christian F, Thierman A, Shirley E, Allen K, Cross C, Jones K. Sustained Glycemic Control With Ivacaftor in Cystic Fibrosis-Related Diabetes. J Investig Med High Impact Case Rep 2020; 7:2324709619842898. [PMID: 31010313 PMCID: PMC6480995 DOI: 10.1177/2324709619842898] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Cystic fibrosis-related diabetes (CFRD) is a common comorbidity in cystic fibrosis with pancreatic insufficiency occurring early in the disease process. Current treatment is exogenous insulin therapy as CFRD is due to impaired insulin secretion. Recent small studies have shown improvement in endogenous insulin secretion with a short period of ivacaftor therapy in primarily pediatric patients with cystic fibrosis transmembrane conductance regulator mutations amenable to potentiation. In this article, we present the case of an adult patient with long-standing CFRD who developed sustained improvement in glycemic control after initiation of ivacaftor.
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Affiliation(s)
- Francis Christian
- 1 University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | | | - Erin Shirley
- 2 University of Oklahoma, Oklahoma City, OK, USA
| | - Karen Allen
- 1 University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Cory Cross
- 1 University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kellie Jones
- 1 University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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32
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Diab Cáceres L, Girón Moreno RM, García Castillo E, Pastor Sanz MT, Olveira C, García Clemente M, Nieto Royo R, Prados Sánchez C, Caballero Sánchez P, Olivera Serrano MJ, Padilla Galo A, Nava Tomas E, Esteban Peris A, Fernández Velilla M, Torres MI, Ancochea Bermúdez J. Effect of Sex Differences on Computed Tomography Findings in Adults With Cystic Fibrosis: A Multicenter Study. Arch Bronconeumol 2020; 57:256-263. [PMID: 32107115 DOI: 10.1016/j.arbres.2019.12.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 12/28/2019] [Accepted: 12/30/2019] [Indexed: 01/20/2023]
Abstract
BACKGROUND The survival of women with cystic fibrosis (CF) is lower than that of men by approximately 5 years. While various factors have been put forward to account for this discrepancy, no specific reasons have been established. Our hypothesis was that anatomical-structural involvement is more pronounced in women with CF than in men and that this is reflected in thoracic HRCT findings. MATERIAL AND METHODS We performed a prospective multicentre study, in which adult patients were consecutively included over 18 months. Chest HRCT was performed, and findings were scored by 2 thoracic radiologists using the modified Bhalla system. We also studied respiratory function, applied the CFQR 14+ questionnaire, and collected clinical variables. RESULTS Of the 360 patients followed up in the participating units, 160 were eventually included. Mean age was 28 years, and 47.5% were women. The mean±SD global score on the modified Bhalla score was 13.7±3.8 in women and 15.2±3.8 in men (p=0.024). The highest scores were observed for sacculations, bronchial generations, and air trapping in women. Women had lower BMI, %FEV1, %FVC, and %DLCO. Similarly, the results for the respiratory domain in CFQR 14+ were worse in women, who also had more annual exacerbations. CONCLUSIONS This is the first study to provide evidence of the implication of sex differences in HRCT findings in patients with CF. Women with CF present a more severe form of the disease that results in more frequent exacerbations, poorer functional and nutritional outcomes, deterioration of quality of life, and greater structural damage.
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Affiliation(s)
| | | | | | | | - Casilda Olveira
- Pulmonology Service, Hospital Regional Universitario de Málaga, Málaga, Spain
| | | | - Rosa Nieto Royo
- Pulmonology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain
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33
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Mooney C, McKiernan PJ, Raoof R, Henshall DC, Linnane B, McNally P, Glasgow AMA, Greene CM. Plasma microRNA levels in male and female children with cystic fibrosis. Sci Rep 2020; 10:1141. [PMID: 31980676 PMCID: PMC6981182 DOI: 10.1038/s41598-020-57964-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/21/2019] [Indexed: 12/16/2022] Open
Abstract
A gender gap exists in cystic fibrosis (CF). Here we investigate whether plasma microRNA expression profiles differ between the sexes in CF children. MicroRNA expression was quantified in paediatric CF plasma (n = 12; six females; Age range:1-6; Median Age: 3; 9 p.Phe508del homo- or heterozygotes) using TaqMan OpenArray Human miRNA Panels. Principal component analysis indicated differences in male versus female miRNA profiles. The miRNA array analysis revealed two miRNAs which were significantly increased in the female samples (miR-885-5p; fold change (FC):5.07, adjusted p value: 0.026 and miR-193a-5p; FC:2.6, adjusted p value: 0.031), although only miR-885-5p was validated as increased in females using specific qPCR assay (p < 0.0001). Gene ontology analysis of miR-885-5p validated targets identified cell migration, motility and fibrosis as processes potentially affected, with RAC1-mediated signalling featuring significantly. There is a significant increase in miR-885-5p in plasma of females versus males with CF under six years of age.
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Affiliation(s)
- C Mooney
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- School of Computer Science, University College Dublin, Dublin, Ireland
| | - P J McKiernan
- Lung Biology Group, Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - R Raoof
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- Department of Anatomy, College of Medicine, University of Mosul, Mosul, Iraq
| | - D C Henshall
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland
- FutureNeuro Research Centre, RCSI, Dublin, Ireland
| | - B Linnane
- Study for Host Infection in Early Lung Disease in CF (SHIELD CF), National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland
- Graduate Entry Medical School and Centre for Interventions in Infection, Inflammation & Immunity (4i), University of Limerick, Limerick, Ireland
| | - P McNally
- Study for Host Infection in Early Lung Disease in CF (SHIELD CF), National Children's Research Centre, Children's Health Ireland at Crumlin, Dublin, Ireland
- Department of Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - A M A Glasgow
- Lung Biology Group, Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland.
| | - C M Greene
- Lung Biology Group, Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Dublin, Ireland
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McGarry ME, Williams WA, McColley SA. The demographics of adverse outcomes in cystic fibrosis. Pediatr Pulmonol 2019; 54 Suppl 3:S74-S83. [PMID: 31715087 PMCID: PMC6857719 DOI: 10.1002/ppul.24434] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 06/16/2019] [Indexed: 01/08/2023]
Abstract
Understanding variability in cystic fibrosis (CF) health outcomes requires an understanding of factors that go far beyond Cystic Fibrosis Transmembrane Receptor (CFTR) function caused by different gene mutations. Social and environmental factors that influence health have a significant influence on the trajectory of health in CF and in other chronic diseases. In this article, we review demographic factors associated with poorer health outcomes in CF, known and postulated biological mechanisms of these outcomes, and interventions that healthcare teams can implement that may reduce outcome disparities.
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Affiliation(s)
- Meghan E McGarry
- Department of Pediatrics, University of California San Francisco, San Francisco, California
| | - Wadsworth A Williams
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Susanna A McColley
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.,Division of Pulmonary and Sleep Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.,Stanley Manne Children's Research Institute, Chicago, Illinois
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35
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Han MK, Arteaga-Solis E, Blenis J, Bourjeily G, Clegg DJ, DeMeo D, Duffy J, Gaston B, Heller NM, Hemnes A, Henske EP, Jain R, Lahm T, Lancaster LH, Lee J, Legato MJ, McKee S, Mehra R, Morris A, Prakash YS, Stampfli MR, Gopal-Srivastava R, Laposky AD, Punturieri A, Reineck L, Tigno X, Clayton J. Female Sex and Gender in Lung/Sleep Health and Disease. Increased Understanding of Basic Biological, Pathophysiological, and Behavioral Mechanisms Leading to Better Health for Female Patients with Lung Disease. Am J Respir Crit Care Med 2019; 198:850-858. [PMID: 29746147 DOI: 10.1164/rccm.201801-0168ws] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Female sex/gender is an undercharacterized variable in studies related to lung development and disease. Notwithstanding, many aspects of lung and sleep biology and pathobiology are impacted by female sex and female reproductive transitions. These may manifest as differential gene expression or peculiar organ development. Some conditions are more prevalent in women, such as asthma and insomnia, or, in the case of lymphangioleiomyomatosis, are seen almost exclusively in women. In other diseases, presentation differs, such as the higher frequency of exacerbations experienced by women with chronic obstructive pulmonary disease or greater cardiac morbidity among women with sleep-disordered breathing. Recent advances in -omics and behavioral science provide an opportunity to specifically address sex-based differences and explore research needs and opportunities that will elucidate biochemical pathways, thus enabling more targeted/personalized therapies. To explore the status of and opportunities for research in this area, the NHLBI, in partnership with the NIH Office of Research on Women's Health and the Office of Rare Diseases Research, convened a workshop of investigators in Bethesda, Maryland on September 18 and 19, 2017. At the workshop, the participants reviewed the current understanding of the biological, behavioral, and clinical implications of female sex and gender on lung and sleep health and disease, and formulated recommendations that address research gaps, with a view to achieving better health outcomes through more precise management of female patients with nonneoplastic lung disease. This report summarizes those discussions.
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Affiliation(s)
- MeiLan K Han
- 1 Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, Michigan
| | - Emilio Arteaga-Solis
- 2 Division of Pediatric Pulmonology, Columbia University Medical Center, New York, New York
| | - John Blenis
- 3 Pharmacology Ph.D. Program, Sandra and Edward Meyer Cancer Center, New York, New York
| | - Ghada Bourjeily
- 4 Department of Medicine, Brown University, Providence, Rhode Island
| | - Deborah J Clegg
- 5 Department of Medicine, University of California Los Angeles, Los Angeles, California
| | - Dawn DeMeo
- 6 Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Jeanne Duffy
- 7 Department of Medicine and.,8 Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Ben Gaston
- 9 Pediatric Pulmonology, Case Western Reserve University, Cleveland, Ohio
| | - Nicola M Heller
- 10 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Anna Hemnes
- 11 Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Elizabeth Petri Henske
- 12 Division of Pulmonary and Critical Care, Brigham and Women's Hospital, Boston, Massachusetts
| | - Raksha Jain
- 13 Division of Pulmonary and Critical Care, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tim Lahm
- 14 Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Lisa H Lancaster
- 15 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Joyce Lee
- 16 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado
| | | | - Sherry McKee
- 18 Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut
| | - Reena Mehra
- 19 Neurologic Institute, Cleveland Clinic, Cleveland, Ohio
| | - Alison Morris
- 20 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Y S Prakash
- 21 Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Martin R Stampfli
- 22 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Rashmi Gopal-Srivastava
- 23 Office of Rare Diseases Research, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland
| | - Aaron D Laposky
- 24 Division of Lung Diseases, NHLBI/NIH, Bethesda, Maryland; and
| | | | - Lora Reineck
- 24 Division of Lung Diseases, NHLBI/NIH, Bethesda, Maryland; and
| | - Xenia Tigno
- 24 Division of Lung Diseases, NHLBI/NIH, Bethesda, Maryland; and
| | - Janine Clayton
- 25 Office of Research on Women's Health, NIH-Office of the Director, Bethesda, Maryland
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36
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Abbott L, Plummer A, Hoo ZH, Wildman M. Duration of intravenous antibiotic therapy in people with cystic fibrosis. Cochrane Database Syst Rev 2019; 9:CD006682. [PMID: 31487382 PMCID: PMC6728060 DOI: 10.1002/14651858.cd006682.pub6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Progressive lung damage from recurrent exacerbations is the major cause of mortality and morbidity in cystic fibrosis. Life expectancy of people with cystic fibrosis has increased dramatically in the last 40 years. One of the major reasons for this increase is the mounting use of antibiotics to treat chest exacerbations caused by bacterial infections. The optimal duration of intravenous antibiotic therapy is not clearly defined. Individuals usually receive intravenous antibiotics for 14 days, but treatment may range from 10 to 21 days. A shorter duration of antibiotic treatment risks inadequate clearance of infection which could lead to further lung damage. Prolonged courses of intravenous antibiotics are expensive and inconvenient. The risk of systemic side effects such as allergic reactions to antibiotics also increases with prolonged courses and the use of aminoglycosides requires frequent monitoring to minimise some of their side effects. However, some organisms which infect people with cystic fibrosis are known to be multi-resistant to antibiotics, and may require a longer course of treatment. This is an update of previously published reviews. OBJECTIVES To assess the optimal duration of intravenous antibiotic therapy for treating chest exacerbations in people with cystic fibrosis. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings. Most recent search of the Group's Cystic Fibrosis Trials Register: 30 May 2019.We also searched online trials registries. Most recent search of the ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) portal: 06 January 2019. SELECTION CRITERIA Randomised and quasi-randomised controlled trials comparing different durations of intravenous antibiotic courses for acute respiratory exacerbations in people with CF, either with the same drugs at the same dosage, the same drugs at a different dosage or frequency or different antibiotics altogether, including studies with additional therapeutic agents. DATA COLLECTION AND ANALYSIS No eligible trials were identified for inclusion. A trial looking at the standardised treatment of pulmonary exacerbations is currently ongoing and will be included when the results are published. MAIN RESULTS: No eligible trials were included. AUTHORS' CONCLUSIONS There are no clear guidelines on the optimum duration of intravenous antibiotic treatment. Duration of treatment is currently based on unit policies and response to treatment. Shorter duration of treatment should improve quality of life and adherence, result in a reduced incidence of drug reactions and be less costly. However, the shorter duration may not be sufficient to clear a chest infection and may result in an early recurrence of an exacerbation. This systematic review identifies the need for a multicentre, randomised controlled trial comparing different durations of intravenous antibiotic treatment as it has important clinical and financial implications. The currently ongoing STOP2 trial is expected to provide some guidance on these questions when published.
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Affiliation(s)
- Linsey Abbott
- Pharmacy Department, Northern General Hospital, Herries Road, Sheffield, UK, S5 7AU
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37
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McKiernan PJ, Smith SGJ, Durham AL, Adcock IM, McElvaney NG, Greene CM. The Estrogen-Induced miR-19 Downregulates Secretory Leucoprotease Inhibitor Expression in Monocytes. J Innate Immun 2019; 12:90-102. [PMID: 31266011 DOI: 10.1159/000500419] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 04/16/2019] [Indexed: 12/11/2022] Open
Abstract
Compared to females, males are more susceptible to acute viral and other respiratory tract infections that display greater severity and higher mortality. In contrast, females tend to fare worse with chronic inflammatory diseases. Circulating 17β-estradiol (E2) is a female-specific factor that may influence the progression of human lung diseases. Here we hypothesize that E2 modulates the inflammatory response of monocytes through microRNA (miRNA)-based modulation of secretory leucoprotease inhibitor (SLPI), an antiprotease with immunomodulatory effects. Monocytic cells were treated ± E2, and differentially expressed miRNAs were identified using PCR profiling. Cells were transfected with miRNA mimics or antimiRs and SLPI mRNA and protein levels were quantified. Luciferase activity assay using wildtype and ΔmiR-19a/b-SLPI3'UTR reporter constructs and chromatin immunoprecipitation on E2-treated monocytes were performed. E2 downregulated SLPI and upregulated miR-19 expression in monocytes. Transfection with premiR-19b reduced SLPI mRNA and protein levels and this effect was abrogated using antimiRs against miR-19b. miR-19b directly binds the SLPI 3'UTR. The mechanism responsible for E2-mediated upregulation of miR-19 occurs via increased MIR17HG promoter activity mediated by c-MYC. Overall E2 decreases SLPI expression in human monocytic cells, via changes in miRNA expression and highlights the potential for estrogen to modulate the innate immune system.
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Affiliation(s)
- Paul J McKiernan
- Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Stephen G J Smith
- Department of Clinical Microbiology, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Andrew L Durham
- Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Ian M Adcock
- Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Noel G McElvaney
- Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Catherine M Greene
- Department of Clinical Microbiology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland,
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Malhotra S, Hayes D, Wozniak DJ. Cystic Fibrosis and Pseudomonas aeruginosa: the Host-Microbe Interface. Clin Microbiol Rev 2019; 32:e00138-18. [PMID: 31142499 PMCID: PMC6589863 DOI: 10.1128/cmr.00138-18] [Citation(s) in RCA: 287] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
In human pathophysiology, the clash between microbial infection and host immunity contributes to multiple diseases. Cystic fibrosis (CF) is a classical example of this phenomenon, wherein a dysfunctional, hyperinflammatory immune response combined with chronic pulmonary infections wreak havoc upon the airway, leading to a disease course of substantial morbidity and shortened life span. Pseudomonas aeruginosa is an opportunistic pathogen that commonly infects the CF lung, promoting an accelerated decline of pulmonary function. Importantly, P. aeruginosa exhibits significant resistance to innate immune effectors and to antibiotics, in part, by expressing specific virulence factors (e.g., antioxidants and exopolysaccharides) and by acquiring adaptive mutations during chronic infection. In an effort to review our current understanding of the host-pathogen interface driving CF pulmonary disease, we discuss (i) the progression of disease within the primitive CF lung, specifically focusing on the role of host versus bacterial factors; (ii) critical, neutrophil-derived innate immune effectors that are implicated in CF pulmonary disease, including reactive oxygen species (ROS) and antimicrobial peptides (e.g., LL-37); (iii) P. aeruginosa virulence factors and adaptive mutations that enable evasion of the host response; and (iv) ongoing work examining the distribution and colocalization of host and bacterial factors within distinct anatomical niches of the CF lung.
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Affiliation(s)
- Sankalp Malhotra
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, Ohio, USA
- The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Don Hayes
- The Ohio State University College of Medicine, Columbus, Ohio, USA
- Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA
- Section of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Daniel J Wozniak
- The Ohio State University College of Medicine, Columbus, Ohio, USA
- Section of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Microbiology, The Ohio State University, Columbus, Ohio, USA
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Malhotra S, Hayes D, Wozniak DJ. Mucoid Pseudomonas aeruginosa and regional inflammation in the cystic fibrosis lung. J Cyst Fibros 2019; 18:796-803. [PMID: 31036488 DOI: 10.1016/j.jcf.2019.04.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/05/2019] [Accepted: 04/08/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND Pseudomonas aeruginosa is the prominent bacterial pathogen in the cystic fibrosis (CF) lung and contributes to significant morbidity and mortality. Though P. aeruginosa strains initially colonizing the CF lung have a nonmucoid colony morphology, they often mutate into mucoid variants that are associated with clinical deterioration. Both nonmucoid and mucoid P. aeruginosa variants are often co-isolated on microbiological cultures of sputum collected from CF patients. With regional variation in bronchiectasis, tissue damage, inflammation, and microbial colonization, lobar distribution of nonmucoid and mucoid P. aeruginosa variants may impact local microenvironments in the CF lung, but this has not been well-studied. METHODS We prospectively collected lobe-specific bronchoalveolar lavage (BAL) fluid from a CF patient cohort (n = 14) using a standardized bronchoscopic protocol where collection was performed in 6 lobar regions. The lobar BAL specimens were plated on P. aeruginosa-selective media and proinflammatory cytokines (IL-1, TNF, IL-6 and IL-8) were measured via cytokine array. Correlations between infecting P. aeruginosa variants (nonmucoid, mucoid, or mixed-variant populations), the lobar regions in which these variants were found, and regional proinflammatory cytokine concentrations were measured. RESULTS P. aeruginosa mucoid and nonmucoid variants were homogenously distributed throughout the CF lung. However, infection with mucoid variants (found within single- or mixed-variant populations) was associated with significantly greater regional inflammation. The upper and lower lobes of the CF lung did not exhibit differences in inflammatory cytokine concentrations. CONCLUSIONS Mucoid P. aeruginosa infection is a microbial determinant of regional inflammation within the CF lung.
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Affiliation(s)
- Sankalp Malhotra
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; The Ohio State University College of Medicine, Columbus, OH, USA
| | - Don Hayes
- The Ohio State University College of Medicine, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA; Section. of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA
| | - Daniel J Wozniak
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA; The Ohio State University College of Medicine, Columbus, OH, USA; Department of Microbiology, The Ohio State University, Columbus, OH, USA.
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Parkins MD, Somayaji R, Waters VJ. Epidemiology, Biology, and Impact of Clonal Pseudomonas aeruginosa Infections in Cystic Fibrosis. Clin Microbiol Rev 2018; 31:e00019-18. [PMID: 30158299 PMCID: PMC6148191 DOI: 10.1128/cmr.00019-18] [Citation(s) in RCA: 166] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Chronic lower airway infection with Pseudomonas aeruginosa is a major contributor to morbidity and mortality in individuals suffering from the genetic disease cystic fibrosis (CF). Whereas it was long presumed that each patient independently acquired unique strains of P. aeruginosa present in their living environment, multiple studies have since demonstrated that shared strains of P. aeruginosa exist among individuals with CF. Many of these shared strains, often referred to as clonal or epidemic strains, can be transmitted from one CF individual to another, potentially reaching epidemic status. Numerous epidemic P. aeruginosa strains have been described from different parts of the world and are often associated with an antibiotic-resistant phenotype. Importantly, infection with these strains often portends a worse prognosis than for infection with nonclonal strains, including an increased pulmonary exacerbation rate, exaggerated lung function decline, and progression to end-stage lung disease. This review describes the global epidemiology of clonal P. aeruginosa strains in CF and summarizes the current literature regarding the underlying biology and clinical impact of globally important CF clones. Mechanisms associated with patient-to-patient transmission are discussed, and best-evidence practices to prevent infections are highlighted. Preventing new infections with epidemic P. aeruginosa strains is of paramount importance in mitigating CF disease progression.
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Affiliation(s)
- Michael D Parkins
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Ranjani Somayaji
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Valerie J Waters
- Translational Medicine, Research Institute, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Department of Pediatrics, Division of Infectious Diseases, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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41
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Drumm M. Giants in Chest Medicine: Professor Pamela B. Davis, MD, PhD. Chest 2018; 154:240-241. [PMID: 30080499 DOI: 10.1016/j.chest.2018.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 03/12/2018] [Indexed: 10/28/2022] Open
Affiliation(s)
- Mitchell Drumm
- Departments of Pediatrics, and Genetics and Genome Sciences, The Research Institute for Children's Health, Connie and Jim Brown Professor in Cystic Fibrosis Research, Case Western Reserve University, Cleveland, Ohio.
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42
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Vidaillac C, Yong VFL, Jaggi TK, Soh MM, Chotirmall SH. Gender differences in bronchiectasis: a real issue? Breathe (Sheff) 2018; 14:108-121. [PMID: 29875830 PMCID: PMC5980467 DOI: 10.1183/20734735.000218] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Gender differences in chronic respiratory disease, including cystic fibrosis and non-cystic fibrosis bronchiectasis are clinically apparent and of increasing importance. Differences in disease prevalence, severity and outcome are all described, however, the precise cause of the gender dichotomy and their associated underlying mechanisms have been poorly characterised. A lack of dedicated clinical and epidemiological research focused in this area has led to a paucity of data and therefore a lack of understanding of its key drivers. Diagnosis, disease pathogenesis and treatment response are all complex but important aspects of bronchiectasis with an evident gender bias. Broadening our understanding of the interplay between microbiology, host physiology and the environment in the context of chronic lung diseases, such as bronchiectasis, is critical to unravelling mechanisms driving the observed gender differences. In this review, epidemiological, biological and environmental evidence related to gender in bronchiectasis is summarised. This illustrates gender differences as a “real issue” with the objective of mapping out a future framework upon which a gender-tailored medical approach may be incorporated into the diagnosis, monitoring and treatment of bronchiectasis. CF and non-CF bronchiectasis are complex multifactorial chronic pulmonary diseases demonstrating gender differences in their prevalence, severity and infections, some of which are attributable to sex hormoneshttp://ow.ly/beDf30jseK4
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Affiliation(s)
- Celine Vidaillac
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Valerie F L Yong
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Tavleen K Jaggi
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Min-Min Soh
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Sanjay H Chotirmall
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
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43
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KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa. J Cyst Fibros 2017; 17:484-491. [PMID: 29292092 DOI: 10.1016/j.jcf.2017.12.006] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 12/13/2017] [Accepted: 12/14/2017] [Indexed: 12/27/2022]
Abstract
BACKGROUND Chronic Pseudomonas aeruginosa (Pa) airways infection, exuberant local inflammation, and progressive lung function loss are hallmarks of cystic fibrosis (CF). KB001-A is an anti-PcrV PEGylated monoclonal antibody fragment to the Type III secretion system of Pa. This 16-week study evaluated KB001-A associated effect on time-to-need for antibiotics for worsening respiratory signs and symptoms, as well as safety, and treatment-associated changes in symptom scores, inflammatory markers, and spirometry. METHODS This was a randomized, double-blind, placebo-controlled, repeat-dose study in CF subjects with Pa. Intravenous 10mg/kg KB001-A or placebo infusions were administered at baseline and weeks 2, 4, 8, and 16, with a 4-week follow-up. Sputum inflammatory markers were assessed in a sub-study. Time-to-need for antibiotics was compared between groups by Kaplan Meier analysis and Cox proportional hazards modeling adjusting for randomization strata. RESULTS Of 182 subjects, 169 received at least one infusion of KB001-A (n=83) or placebo (n=86). KB001-A was generally safe and well-tolerated as compared to placebo, with no significant emergent adverse effects other than one serious adverse event of elevated hepatic enzymes of unclear etiology. Time to need for antibiotics did not differ between groups (HR: 1.00; 95% CI: 0.69, 1.45, p=0.995). A 3.2 increase in ppFEV1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p=0.003). Mean changes from baseline in log10 sputum neutrophil elastase (NE) had a non-significant decrease (-0.27, 95% CI: -0.58,0.04, p=0.084) while IL-8 concentrations at week 16 were significantly lower (-0.27, 95% CI: -0.55,0.00, p=0.048) among KB001-A subjects (n=16) relative to placebo (n=13). CONCLUSIONS KB001-A was safe and well-tolerated and associated with a modest FEV1 benefit and reduction in select sputum inflammatory markers (IL-8). KB001-A was not associated with an increased time to need for antibiotics. The lack of efficacy seen with KB001-A may be due, in part, to the low levels of the type III secretion proteins previously reported in sputum of CF patients chronically infected with Pa.
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17β-Estradiol Dysregulates Innate Immune Responses to Pseudomonas aeruginosa Respiratory Infection and Is Modulated by Estrogen Receptor Antagonism. Infect Immun 2017; 85:IAI.00422-17. [PMID: 28784925 DOI: 10.1128/iai.00422-17] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 07/11/2017] [Indexed: 01/22/2023] Open
Abstract
Females have a more severe clinical course than males in terms of several inflammatory lung conditions. Notably, females with cystic fibrosis (CF) suffer worse outcomes, particularly in the setting of Pseudomonas aeruginosa infection. Sex hormones have been implicated in experimental and clinical studies; however, immune mechanisms responsible for this sex-based disparity are unknown and the specific sex hormone target for therapeutic manipulation has not been identified. The objective of this study was to assess mechanisms behind the impact of female sex hormones on host immune responses to P. aeruginosa We used wild-type and CF mice, which we hormone manipulated, inoculated with P. aeruginosa, and then examined for outcomes and inflammatory responses. Neutrophils isolated from mice and human subjects were tested for responses to P. aeruginosa We found that female mice inoculated with P. aeruginosa died earlier and showed slower bacterial clearance than males (P < 0.0001). Ovariectomized females supplemented with 17β-estradiol succumbed to P. aeruginosa challenge earlier than progesterone- or vehicle-supplemented mice (P = 0.0003). 17β-Estradiol-treated ovariectomized female mice demonstrated increased lung levels of inflammatory cytokines, and when rendered neutropenic the mortality difference was abrogated. Neutrophils treated with 17β-estradiol demonstrated an enhanced oxidative burst but decreased P. aeruginosa killing and earlier cell necrosis. The estrogen receptor (ER) antagonist ICI 182,780 improved survival in female mice infected with P. aeruginosa and restored neutrophil function. We concluded that ER antagonism rescues estrogen-mediated neutrophil dysfunction and improves survival in response to P. aeruginosa ER-mediated processes may explain the sex-based mortality gap in CF and other inflammatory lung illnesses, and the ER blockade represents a rational therapeutic strategy.
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Russell CJ, Simon TD, Mamey MR, Newth CJL, Neely MN. Pseudomonas aeruginosa and post-tracheotomy bacterial respiratory tract infection readmissions. Pediatr Pulmonol 2017; 52:1212-1218. [PMID: 28440922 PMCID: PMC5561001 DOI: 10.1002/ppul.23716] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Accepted: 03/31/2017] [Indexed: 11/05/2022]
Abstract
OBJECTIVE Identify risk factors for readmission due to a bacterial tracheostomy-associated respiratory tract infection (bTARTI) within 12 months of discharge after tracheotomy. DESIGN/METHODS We performed a retrospective cohort study of 240 children who underwent tracheotomy and were discharged with tracheotsomy in place between January 1, 2005 and June 30, 2013. Children with prolonged total or post-tracheotomy length of stay (LOS), less than 12 months of follow-up, or who died during the index hospitalization were excluded. Readmission for a bTARTI (eg, pneumonia, tracheitis) treated with antibiotics, as ascertained by manual chart review, was the outcome variable. We used multivariate logistic regression to identify the independent association between risk factors and hospital readmission for bTARTI within 12 months. RESULTS At index hospitalizations for tracheotomy, the median admission age was 5 months (interquartile range [IQR] 2-43 months) and median LOS was 73 days (IQR 43-121 days). Most patients were of Hispanic ethnicity (n = 162, 68%) and were publicly insured (n = 213, 89%). Nearly half (n = 112, 47%) were discharged on positive pressure mechanical ventilation. Many (n = 103, 43%) were admitted for bTARTI within 12 months of discharge. Only Hispanic ethnicity (adjusted odds ratio [AOR] 2.0; 95% confidence interval [CI]: 1.1-3.9; P = 0.03) and acquisition of Pseudomonas aeruginosa between tracheotomy and discharge from index hospitalization (AOR 3.2; 95%CI: 1.2-8.3; P = 0.02) were independently associated with increased odds of bTARTI readmission, while discharge on gastrointestinal pro-motility agents was associated with decreased risk (AOR = 0.4; 95%CI: 0.2-0.8; P = 0.01). CONCLUSIONS Hispanic ethnicity and post-tracheotomy acquisition of P. aeruginosa during initial hospitalization are associated with bTARTI readmission.
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Affiliation(s)
- Christopher J Russell
- Divisions of Hospital Medicine, Children's Hospital Los Angeles, Los Angeles, California.,Department of Pediatrics, Keck School of Medicine, University of Southern California
| | - Tamara D Simon
- Department of Pediatrics, University of Washington/Seattle Children's Hospital, Seattle, Washington.,Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, Washington
| | - Mary R Mamey
- Divisions of Hospital Medicine, Children's Hospital Los Angeles, Los Angeles, California
| | - Christopher J L Newth
- Department of Pediatrics, Keck School of Medicine, University of Southern California.,Division of Critical Care, Children's Hospital Los Angeles, Los Angeles, California
| | - Michael N Neely
- Department of Pediatrics, Keck School of Medicine, University of Southern California.,Division of Infectious Diseases, Children's Hospital Los Angeles, Los Angeles, California
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46
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Ewing J, McCaughan J, Moore J, Fairley D, Sutherland B, Reid A, Downey D. Relative resistance index (RRI) – a scoring system for antibiotic resistance in Pseudomonas aeruginosa. Br J Biomed Sci 2017; 74:198-202. [DOI: 10.1080/09674845.2017.1338500] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- J Ewing
- Regional Adult Cystic Fibrosis Centre, Belfast City Hospital, Belfast Health & Social Care Trust, Belfast, UK
| | - J McCaughan
- Regional Adult Cystic Fibrosis Centre, Belfast City Hospital, Belfast Health & Social Care Trust, Belfast, UK
- Regional Paediatric Cystic Fibrosis Centre, Royal Belfast Hospital for Sick Children, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK
- Department of Microbiology, Belfast Health & Social Care Trust, Belfast, UK
| | - J Moore
- Regional Adult Cystic Fibrosis Centre, Belfast City Hospital, Belfast Health & Social Care Trust, Belfast, UK
- Department of Microbiology, Belfast Health & Social Care Trust, Belfast, UK
- Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK
| | - D Fairley
- Department of Microbiology, Belfast Health & Social Care Trust, Belfast, UK
| | - B Sutherland
- Regional Adult Cystic Fibrosis Centre, Belfast City Hospital, Belfast Health & Social Care Trust, Belfast, UK
- Department of Microbiology, Belfast Health & Social Care Trust, Belfast, UK
| | - A Reid
- Regional Paediatric Cystic Fibrosis Centre, Royal Belfast Hospital for Sick Children, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast, UK
| | - D Downey
- Regional Adult Cystic Fibrosis Centre, Belfast City Hospital, Belfast Health & Social Care Trust, Belfast, UK
- Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK
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47
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Stephenson AL, Stanojevic S, Sykes J, Burgel PR. The changing epidemiology and demography of cystic fibrosis. Presse Med 2017; 46:e87-e95. [PMID: 28554720 DOI: 10.1016/j.lpm.2017.04.012] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 04/05/2017] [Indexed: 01/26/2023] Open
Abstract
Once considered a pediatric disease with a poor prognosis, individuals born with cystic fibrosis (CF) today can expect to live well into adulthood. The implementation of multidisciplinary care, novel treatments and newborn screening has resulted in the rapid evolution in the demographics of the CF population. The purpose of this review is to highlight the evolving epidemiology and demographics of the CF population internationally.
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Affiliation(s)
- Anne L Stephenson
- University of Toronto, St-Michael's hospital, Li Ka Shing knowledge institute, Keenan research centre, department of medicine, adult CF program, 30, Bond street, 6th floor, Bond Wing, M5B 1W8 Toronto, ON, Canada; University of Toronto, institute of health policy, management and evaluation, Toronto, ON, Canada.
| | - Sanja Stanojevic
- The hospital for sick children, division of respiratory medicine, Toronto, ON, Canada; University of Toronto, institute of health policy, management and evaluation, Toronto, ON, Canada
| | - Jenna Sykes
- University of Toronto, St-Michael's hospital, Li Ka Shing knowledge institute, Keenan research centre, department of medicine, adult CF program, 30, Bond street, 6th floor, Bond Wing, M5B 1W8 Toronto, ON, Canada
| | - Pierre-Regis Burgel
- Sorbonne Paris Cité, université Paris Descartes, 75014 Paris, France; Assistance publique-Hôpitaux de Paris, hôpital Cochin, 75014 Paris, France
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48
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Heirali AA, Workentine ML, Acosta N, Poonja A, Storey DG, Somayaji R, Rabin HR, Whelan FJ, Surette MG, Parkins MD. The effects of inhaled aztreonam on the cystic fibrosis lung microbiome. MICROBIOME 2017; 5:51. [PMID: 28476135 PMCID: PMC5420135 DOI: 10.1186/s40168-017-0265-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 04/12/2017] [Indexed: 05/28/2023]
Abstract
BACKGROUND Aztreonam lysine for inhalation (AZLI) is an inhaled antibiotic used to treat chronic Pseudomonas aeruginosa infection in CF. AZLI improves lung function and quality of life, and reduces exacerbations-improvements attributed to its antipseudomonal activity. Given the extremely high aztreonam concentrations achieved in the lower airways by nebulization, we speculate this may extend its spectrum of activity to other organisms. As such, we sought to determine if AZLI affects the CF lung microbiome and whether community constituents can be used to predict treatment responsiveness. METHODS Patients were included if they had chronic P. aeruginosa infection and repeated sputum samples collected before and after AZLI. Sputum DNA was extracted, and the V3-hypervariable region of the 16S ribosomal RNA (rRNA) gene amplified and sequenced. RESULTS Twenty-four patients naïve to AZLI contributed 162 samples. The cohort had a median age of 37.1 years, and a median FEV1 of 44% predicted. Fourteen patients were a priori defined as responders for achieving ≥3% FEV1 improvement following initiation. No significant changes in alpha diversity were noted following AZLI. Furthermore, beta diversity demonstrated clustering with respect to patients, but had no association with AZLI use. However, we did observe a decline in the relative abundance of several individual operational taxonomic units (OTUs) following AZLI initiation suggesting that specific sub-populations of organisms may be impacted. Patients with higher abundance of Staphylococcus and anaerobic organisms including Prevotella and Fusobacterium were less likely to respond to therapy. CONCLUSIONS Results from our study suggest potential alternate/additional mechanisms by which AZLI functions. Moreover, our study suggests that the CF microbiota may be used as a biomarker to predict patient responsiveness to therapy suggesting the microbiome may be harnessed for the personalization of therapies.
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Affiliation(s)
- Alya A Heirali
- Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, AB, Canada
| | | | - Nicole Acosta
- Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, AB, Canada
| | - Ali Poonja
- Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, AB, Canada
| | - Douglas G Storey
- Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, AB, Canada
- Department of Biological Sciences, The University of Calgary, Calgary, AB, Canada
| | - Ranjani Somayaji
- Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, AB, Canada
- Department of Medicine, The University of Calgary, 3330 Hospital Drive, NW, Calgary, AB, Canada
| | - Harvey R Rabin
- Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, AB, Canada
- Department of Medicine, The University of Calgary, 3330 Hospital Drive, NW, Calgary, AB, Canada
| | - Fiona J Whelan
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Michael G Surette
- Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, AB, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada
| | - Michael D Parkins
- Department of Microbiology, Immunology and Infectious Diseases, The University of Calgary, Calgary, AB, Canada.
- Department of Medicine, The University of Calgary, 3330 Hospital Drive, NW, Calgary, AB, Canada.
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Zacharasiewicz A, Renner S, Haderer F, Weber M, Dehlink E, Szepfalusi Z, Frischer T. Early detection of lung function decrements in children and adolescents with cystic fibrosis using new reference values. Wien Klin Wochenschr 2017; 129:533-539. [PMID: 28281010 DOI: 10.1007/s00508-017-1184-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 02/15/2017] [Indexed: 12/01/2022]
Abstract
Interpretation of lung function values in children with cystic fibrosis (CF) depends on the applied reference values. We hypothesize that differences between the new global lung function initiative (GLI) values and the formerly used Zapletal et al. values produce significantly different clinical results. We analyzed 3719 lung function measurements of 108 children and adolescents (n = 54 male; aged 6-18 years) with CF treated between September 1991 and July 2009. Data were analyzed in milliliters (ml) and % predicted (pred.) and interpreted using Zapletal and GLI reference values. Applying GLI compared to Zapletal resulted in significantly lower mean forced expiratory volume in 1s (FEV1)% pred. VALUES Zapletal 86.6% (SD 20.6), GLI 79.9% (SD 20.3) and 32% (n = 497/1543) were misclassified as normal when using Zapletal. Despite showing no overall differences in FEV1 and forced vital capacity (FVC) between concomitant Pseudomonas detection (PA+) in n = 938 and Pseudomonas negative (PA-) (n = 2781) using either reference PA+ resulted in lower FEV1 and FVC values with increasing age; however, measurement of small airway obstruction with forced expiratory flow at 75% of FVC (FEF75) values - available for Zapletal -showed significant differences. Reassurance regarding lung function when using old reference values may occur with potential clinical significance. Discrepancies in lung function interpretation underline the importance of using uniform and best available reference values.
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Affiliation(s)
- Angela Zacharasiewicz
- Department of Pediatrics and Adolescent Medicine, Wilhelminenspital Vienna, Montleartstrasse 37, 1160, Vienna, Austria.
| | - Sabine Renner
- Department of Pediatrics, Medical University Hospital Vienna, Vienna, Austria
| | - Flora Haderer
- Department of Pediatrics, Medical University Hospital Vienna, Vienna, Austria
| | - Michael Weber
- Department of Biomedical Imaging and Image Guided Therapy, Medical University Vienna, Vienna, Austria
| | - Eleonore Dehlink
- Department of Pediatrics, Medical University Hospital Vienna, Vienna, Austria.,Department of Pediatrics, The Royal Brompton Hospital, Sydney Street, SW3 6NP, London, UK
| | - Zsolt Szepfalusi
- Department of Pediatrics, Medical University Hospital Vienna, Vienna, Austria
| | - Thomas Frischer
- Department of Pediatrics and Adolescent Medicine, Wilhelminenspital Vienna, Montleartstrasse 37, 1160, Vienna, Austria.,Department of Pediatrics, Medical University Hospital Vienna, Vienna, Austria
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50
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Wijers CD, Chmiel JF, Gaston BM. Bacterial infections in patients with primary ciliary dyskinesia: Comparison with cystic fibrosis. Chron Respir Dis 2017; 14:392-406. [PMID: 29081265 PMCID: PMC5729729 DOI: 10.1177/1479972317694621] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder associated with severely impaired mucociliary clearance caused by defects in ciliary structure and function. Although recurrent bacterial infection of the respiratory tract is one of the major clinical features of this disease, PCD airway microbiology is understudied. Despite the differences in pathophysiology, assumptions about respiratory tract infections in patients with PCD are often extrapolated from cystic fibrosis (CF) airway microbiology. This review aims to summarize the current understanding of bacterial infections in patients with PCD, including infections with Pseudomonas aeruginosa, Staphylococcus aureus, and Moraxella catarrhalis, as it relates to bacterial infections in patients with CF. Further, we will discuss current and potential future treatment strategies aimed at improving the care of patients with PCD suffering from recurring bacterial infections.
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Affiliation(s)
- Christiaan Dm Wijers
- 1 Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - James F Chmiel
- 1 Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Benjamin M Gaston
- 1 Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, OH, USA
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