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ABSTRACT: Cardiac asthma has been defined as wheezing, coughing and orthopnea due to congestive heart failure. The clinical distinction between bronchial asthma and cardiac asthma can be straight forward, except in patients with chronic lung disease coexisting with left heart disease. Pulmonary edema and pulmonary vascular congestion have been thought to be the primary causes of cardiac asthma but most patients have a poor response to diuretics. There appears to be limited effectiveness of classical asthma medications like bronchodilators or corticosteroids in treating cardiac asthma. Evidence suggests that circulating inflammatory factors and tissue growth factors also lead to airway obstruction suggesting the possibility of developing novel therapies.
Expert Review of Respiratory Medicine 12/2012; 6(6):705-14.
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ABSTRACT: Abstract BACKGROUND:Cardiac asthma describes symptoms of airflow obstruction due to heart failure. Chronic heart failure is associated with decreased forced expiratory volume in one second (FEV1) and FEV1 improves after heart transplantation. Fibrotic remodeling of the heart and airways is mediated in part, through transforming growth factor (TGF)-β. Blood TGF-β1 concentration correlates with ventricular remodeling in cardiac disease and TGF-β decreases after repair. METHODS:We established a co-culture of normal human bronchial epithelial (NHBE) cells differentiated at air-liquid interface with submerged basal cardiomyoblasts. Airway cells were immunostained with cytokeratin, actin, and involucrin. TGF-β synthesis was assayed using enzyme-linked immunosorbent assay (ELISA). Phosphorylation of Smad in NHBE cells was determined by western blotting. Mice given doxorubicin developed cardiac failure and their airways were histologically examined. RESULTS:Co-culture induced involucrin-positive, squamous metaplasia of NHBE cells and this was attenuated by TGF-β antibody. Total TGF-β1 was increased in co-culture conditioned medium (p<0.001). After 14 days exposure to recombinant TGF-β1 there was squamous transformation of NHBE cells. One week after removing cardiomyoblasts from culture, squamous metaplasia resolved into normal ciliated epithelia. Smad was phosphorylated in NHBE cells with cardiomyoblasts or with recombinant TGF-β1 exposure. The airways of mice with heart failure also demonstrated involucrin-positive squamous transformation CONCLUSIONS:TGF-β from cardiomyoblasts or from the failing heart can cause airway squamous metaplasia via Smad signaling and this is blocked by TGF-β and reversed when cardiac cells are removed from culture. This appears to be an important mechanism for airflow obstruction with heart failure; sometimes described as cardiac asthma.
Chest 04/2012; · 5.25 Impact Factor
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ABSTRACT: The clinically significant actions of oral azithromycin in modifying progressive cystic fibrosis (CF) lung disease have been well documented. In vitro and clinical data suggests that clarithromycin has immunomodulatory properties similar to other 14-member macrolides, however two previously reported short term, open label trials of clairthromycin in small numbers of patients with CF failed to show significant benefits in modifying lung function or inflammation. We performed an international double blind, cross-over trial in which 63 subjects with CF were studied while receiving either placeo or 500 mg oral clarithromycin twice daily for 5 months, with a 1-month wash-out. The primary efficacy end point was the change in lung function (FEV(1) and FVC) during the clarithromycin treatment period compared to placebo treatment. Secondary efficacy end points included; quality of life, number of pulmonary exacerbations, height and weight, sputum inflammatory mediator content, sputum transportability and surface properties, bacterial flora, nasal potential difference, and breath condensate. No significant difference in either the primary efficacy end point or any secondary end point was seen during the period of clarithromycin treatment compared to those seen during placebo administration. We conclude that clarithromycin is not effective in treating CF lung disease.
Pediatric Pulmonology 01/2012; 47(6):551-7. · 2.53 Impact Factor
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Bruce K Rubin
Chest 09/2011; 140(3):567. · 5.25 Impact Factor
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Bruce K Rubin
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ABSTRACT: The lung and conducting airways are ideal portals for drug delivery. The airways are easily accessible by oral or nasal inhalation; the airway and alveolar surface is large, allowing for drug dispersion; and many drugs do not cross the airway-blood barrier, permitting the use of higher topical drug doses for airway disease than would be practical with systemic administration. On the other hand, alveolar deposition of drugs allows rapid absorption into the pulmonary circulation and back to the left heart and systemic distribution, bypassing the intestinal tract and liver inactivation. Recently, there has been a feast of new aerosol devices and drug formulations that promise the effective delivery of an amazing array of medications far beyond pressurized metered-dose inhalers and nebulizers and asthma medicines.
Respiratory care 09/2011; 56(9):1411-21; discussion 1421-3. · 2.01 Impact Factor
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Bruce K Rubin
Chest 08/2011; 140(2):278-9. · 5.25 Impact Factor
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ABSTRACT: ABSTRACT As part of the innate and adaptive immune system, airway epithelial cells secrete proinflammatory cytokines after activation of Toll-like receptors (TLRs) by pathogens. Nevertheless, cystic fibrosis (CF) airways are chronically infected with Pseudomonas aeruginosa, suggesting a modified immune response in CF. The authors have shown that in CF bronchial epithelial cells, a reduced surface expression of TLR-4 causes a diminished interleukin (IL)-8 and IL-6 response upon lipopolysaccharide (LPS) stimulation. However, there is no information regarding activation of the MyD88 (myeloid differentiation primary response gene 88)-independent TLR-4 signaling pathway by LPS, which results in the activation of adaptive immune responses by secretion of the T cell-recruiting chemokine interferon-γ-inducible protein (IP)-10. Therefore, the authors investigated the induction of IP-10 in CF bronchial epithelial cell line CFBE41o- and its CFTR-corrected isotype under well-differentiating conditions. TLR-4 surface expression was significantly reduced in CFBE41o- by a factor of 2, compared to the CFTR-corrected cells. In CFTR-corrected cells, stimulation with LPS increased IP-10 secretion. Incubating cells with siRNA directed against TLR-4 inhibited the LPS stimulated increase of IP-10 in CFTR-corrected cells. The reduced TLR-4 surface expression in CF cells causes the loss of induction of IP-10 by LPS. This could compromise adaptive immune responses in CF due to a reduced T-cell recruitment.
Experimental Lung Research 06/2011; 37(6):319-26. · 1.22 Impact Factor
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ABSTRACT: Airway mucins are the major molecular constituents of mucus. Mucus forms the first barrier to invading organisms in the airways and is an important defense mechanism of the lung. We confirm that mucin concentrations are significantly decreased in airway secretions of subjects with cystic fibrosis (CF) who have chronic Pseudomonas aeruginosa infection. In sputum from CF subjects without a history of P. aeruginosa, we found no significant difference in the mucin concentration compared to mucus from normal controls. We demonstrate that mucins can be degraded by synthetic human neutrophil elastase (HNE) and P. aeruginosa elastase B (pseudolysin) and that degradation was inhibited by serine proteases inhibitors (diisopropyl fluorophosphates [DFP], phenylmethylsulfonyl fluoride [PMSF], and 1-chloro-3-tosylamido-7-amino-2-heptanone HCl [TLCK]). The mucin concentration in airway secretions from CF subjects is similar to that for normal subjects until there is infection by P. aeruginosa, and after that, the mucin concentration decreases dramatically. This is most likely due to degradation by serine proteases. The loss of this mucin barrier may contribute to chronic airway infection in the CF airway.
Infection and immunity 06/2011; 79(8):3438-44. · 4.21 Impact Factor
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ABSTRACT: IL-13 is a T-helper class 2 cytokine that induces goblet cell hyperplasia and mucus production in airway epithelial cells. Because macrolide antibiotics are known to have immunomodulatory and mucoregulatory properties, the aim of this study was to examine the effect of clarithromycin on IL-13-induced goblet cell hyperplasia and mucin hypersecretion in normal human bronchial epithelial (NHBE) cells. NHBE cells were cultured to differentiation at an air-liquid interface with IL-13 plus clarithromycin or vehicle. Histochemical analysis was performed using H&E staining, periodic acid-Schiff (PAS) staining, and MUC5AC immunostaining. MUC5AC synthesis was assayed using RT-PCR and ELISA. Western blotting was used to evaluate signaling pathways. IL-13 significantly increased the number of PAS-positive, MUC5AC-positive goblet cells, and this was significantly attenuated by clarithromycin at concentrations greater than 8 μg/ml (P < 0.01). Clarithromycin also dose-dependently decreased MUC5AC mRNA expression induced by IL-13 (P < 0.001), and, at 24 μg/ml, clarithromycin significantly attenuated the amount of MUC5AC protein in cell supernatants (P < 0.01). Western blotting showed that clarithromycin affected IL-13 receptor janus kinase signal transducers, activators of transcription6 (STAT6), and epidermal growth factor receptor mitogen-activated protein kinase signaling and that inhibition of these pathways by clarithromycin decreased goblet cell hyperplasia via nuclear factor-κB inactivation. We conclude that clarithromycin inhibits goblet cell hyperplasia and may directly regulate mucus secretion by IL-13 in NHBE cells.
American Journal of Respiratory Cell and Molecular Biology 06/2011; 45(5):1075-83. · 5.13 Impact Factor
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ABSTRACT: The purpose of this paper is to review the recent literature related to asthma, COPD, pulmonary function testing, and ventilator-associated pneumonia. Topics covered related to asthma include genetics and epigenetics; exposures; viruses; diet, obesity and exercise; exhaled nitric oxide; and drug therapy (β agonists, macrolides, tiotropium and monteleukast). Topics covered related to COPD include childhood disadvantage factors and COPD; vitamin D deficiency and COPD; β-blockers and COPD; corticosteroid therapy during COPD exacerbations; oxygen administration during pre-hospital transport of patients with COPD exacerbation; and prognosis of patients admitted to the hospital for COPD exacerbation. Topics related to pulmonary function testing include methods and techniques; predicted values; natural history, pulmonary function in health and disease; and the COPD controversy. Finally, the paper includes the following topics related to ventilator-associated pneumonia: the tube, the intubation route, and the cuff; mechanical ventilation; the bundle; and cost. These topics were chosen and reviewed in a manner that is most likely to have interest to the readers of Respiratory Care.
Respiratory care 04/2011; 56(4):488-502. · 2.01 Impact Factor
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ABSTRACT: IL-8 is an important activator and chemoattractant for neutrophils that is produced by normal human bronchial epithelial (NHBE) cells through mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 pathways. Dapsone, a synthetic sulfone, is widely used to treat chronic neutrophil dermatoses. We investigated the effects of dapsone on polarized IL-8 secretion from lipopolysaccharide (LPS)-stimulated NHBE cells and further evaluated its ability to decrease LPS-induced inflammation in the ferret airway.
NHBE cells were grown at air-liquid interface (ALI) to ciliated differentiation. Baseline and endotoxin (LPS)-stimulated IL-8 secretion was measured by enzyme-linked immunosorbent assay at air and basal sides with and without dapsone. Western blotting was used to determine signaling pathways. In vivo, ferrets were exposed to intratracheal LPS over a period of 5 days. Once inflammation was established, oral or nebulized dapsone was administered for 5 days. Intraepithelial neutrophil accumulation was analyzed histologically, and mucociliary transport was measured on the excised trachea.
Dapsone, 1 μg/mL, did not influence unstimulated (basal) IL-8 secretion. Apical LPS stimulation induced both apical and basolateral IL-8, but basolateral LPS increased only basolateral IL-8. Dapsone inhibited polarized IL-8 secretion from ALI-conditioned cells. Dapsone also decreased LPS-induced IL-8 mRNA level. LPS led to phosphorylation of extracellular signal-regulated kinase 1/2, but not p38 MAPK or c-Jun NH(2)-terminal kinase. LPS also induced NF-κB p65 phosphorylation, an effect that was inhibited by dapsone. Both oral and aerosol dapsone decreased LPS-induced intraepithelial neutrophil accumulation, but only treatment with aerosol dapsone restored mucociliary transport to normal.
Dapsone, given either systemically or as an aerosol, may be useful in treating neutrophilic airway inflammation.
Chest 03/2011; 140(4):980-90. · 5.25 Impact Factor
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ABSTRACT: Plastic bronchitis is an uncommon disorder generally associated with congenital heart disease or sickle cell acute chest syndrome. During the winter outbreak of 2009 influenza A(H1N1) [influenza A(H1N1)] virus infection, we cared for three children who developed plastic bronchitis without the typical underlying conditions. The diagnosis of plastic bronchitis was made using flexible bronchoscopy and was confirmed by histopathology. These children had influenza-like illness, and the assay for influenza A(H1N1) virus was positive in their nasopharyngeal swab and BAL fluid. The chest imaging showed consolidation or atelectasis. After bronchoscopic extraction of casts and antiviral treatment, all of the patients recovered, and there has been no recurrence of the plastic bronchitis. Infection with influenza A(H1N1) is known to cause inflammation and decreased mucociliary clearance, and this may place some patients, especially children, at risk for airway obstruction.
Chest 12/2010; 138(6):1486-8. · 5.25 Impact Factor
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ABSTRACT: The authors were given the charge of providing a vision of the future in paediatric respirology. Themes selected for being ripe for this visionary analysis include bronchopulmonary dysplasia (BPD), asthma, cystic fibrosis (CF), lung infections, obstructive sleep disordered breathing (OSDB) and pulmonary diagnostics and monitoring. A profound reduction or elimination of BPD is seen. Given the strong genetic component of this disease, genetic biomarkers will likely be identified that will permit much earlier recognition of BPD susceptibility and potentially the ability to modify disease course by altering gene expression. The ultimate prevention of BPD will be to prevent prematurity, but recognition of both the genetic basis of BPD and the inflammatory background should lead to improved prevention and therapy. A clear understanding and definition of asthma phenotypes will lead to more specific and targeted therapy, earlier detection and prevention, better monitoring of severity and adherence to therapy, lower mortality and decreased inappropriate diagnosis of asthma. The greatest opportunities in asthma care will likely come through tools to improve adherence to effective therapy. Also, areas are identified where better therapies are needed such as in patients with severe mucus hypersecretion (secretory hyperresponsiveness) especially in those with life-threatening asthma. The future of CF is easier to foresee with early successes seen in clinical trials. After the expected ability to correct the CF transmembrane regulator, care will need to change and additional research will be needed. Additionally, the face of CF is changing with more adults than children presently having the disease. This will necessitate changes to our approach to treating this disease in a fortunately aging population. If we are going to affect the worldwide lung health of children, we will need to address respiratory infections particularly pneumonia, tuberculosis and HIV-associated infections. Preventive, diagnostic and treatment strategies will shape the future face of these problems. The availability of inexpensive, readily available, and rapid molecular techniques to identify true infection (including HIV and tuberculosis) may permit earlier use of effective therapy while preventing the inappropriate use of antibiotics for common viral diseases. Sleep medicine will continue to be an important aspect of paediatric pulmonology. The evaluation of OSDB cannot rely on full-night attended polysomnography due to limited access. Identifying reliable markers of end organ dysfunction in children with OSDB may permit more rapid identification of patients in need of intervention like CPAP and assisted breathing. In addition, management options, as an alternative to adenotonsilectomy, are listed with a call for further research. Pulmonary diagnostics and monitoring will see the development and refinement of tools like the lung clearance index and the analysis of exhaled gases, volatiles and dissolved biomarkers of inflammation as techniques that might help clinicians identify both the initiation of inflammation while it is more amenable to therapy, and to identify more readily the early changes associated with chronic lung diseases in children. The authors hope that these visionary articles will generate comments, arguments, inspiration, and perhaps even motivate funding agencies.
Respirology 07/2010; 15(5):733-41. · 2.42 Impact Factor
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ABSTRACT: Macrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-kappaB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.
Clinical microbiology reviews 07/2010; 23(3):590-615. · 14.69 Impact Factor
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Bruce K Rubin
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ABSTRACT: This paper reviews the history of aerosol therapy; discusses patient, drug, and device factors that can influence the success of aerosol therapy; and identifies trends that will drive the science of aerosol therapy in the future. Aerosol medication is generally less expensive, works more rapidly, and produces fewer side effects than the same drug given systemically. Aerosol therapy has been used for thousands of years by steaming and burning plant material. In the 50 years since the invention of the pressurized metered-dose inhaler, advances in drugs and devices have made aerosols the most commonly used way to deliver therapy for asthma and COPD. The requirements for aerosol therapy depend on the target site of action and the underlying disease. Medication to treat airways disease should deposit on the conducting airways. Effective deposition of airway particles generally requires particle size between 0.5 and 5 microm mass median aerodynamic diameter; however, a smaller particle size neither equates to greater side effects nor greater effectiveness. However, medications like peptides intended for systemic absorption, need to deposit on the alveolar capillary bed. Thus ultrafine particles, a slow inhalation, and relatively normal airways that do not hinder aerosol penetration will optimize systemic delivery. Aerosolized antimicrobials are often used for the treatment of cystic fibrosis or bronchiectasis, and mucoactive agents to promote mucus clearance have been delivered by aerosol. As technology improves, a greater variety of novel medications are being developed for aerosol delivery, including for therapy of pulmonary hypertension, as vaccines, for decreasing dyspnea, to treat airway inflammation, for migraine headache, for nicotine and drug addiction, and ultimately for gene therapy. Common reasons for therapeutic failure of aerosol medications include the use of inactive or depleted medications, inappropriate use of the aerosol device, and, most importantly, poor adherence to prescribed therapy. The respiratory therapist plays a key role in patient education, device selection, and outcomes assessment.
Respiratory care 07/2010; 55(7):911-21. · 2.01 Impact Factor
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ABSTRACT: Endotracheal tube (ETT) intubation impairs mucus clearance, which can lead to respiratory compromise. We compared three ETTs that have intrinsic capacity to aspirate secretions pooling above the cuff.
We evaluated the ability of three ETTs with suction, Hi-Lo Evac, Teleflex ISIS, and Portex Blue Line SACETT, to aspirate saliva and mucus simulants at continuous or intermittent vacuum pressures. We also evaluated the potential for a flexible tracheal membrane to obstruct the ETT suction port with applied vacuum. We measured the dimensions of the suction tubing at critical points to calculate differences in flow.
In a rigid tracheal model, the ISIS aspirated saliva simulant more quickly with continuous low pressure suction than Evac (P = .0006) and SACETT (P < .0001) as well as with intermittent high pressure suction (P < .0001). For mucus simulant, the ISIS aspirated stimulant better than the other ETTs at high intermittent suction (P < .0001); the Evac was more effective than the SACETT (P = .0019). For low and continuous suction, suction ports in all ETTs occluded with mucus, except for ISIS, at the highest continuous suction tested. In a trachea model with a flexible posterior membrane, this membrane either partially or completely occluded the suction port of all tubes at high continuous or intermittent suction. The ISIS was more prone to obstruction by the flexible membrane than the Evac. We found large differences in suction tubing cross-sectional area between the ISIS and the other tubes, and flow calculations using the Hagen-Poiseuille equation can explain the observed differences in volumes aspirated and tendency toward lumen obstruction.
The ISIS transmits suction pressure to the tube orifice more powerfully than the Evac and SACETT. This feature makes the ISIS less prone to obstruction by mucus but more likely to obstruct by tissue suction.
Chest 04/2010; 138(4):863-9. · 5.25 Impact Factor
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Bruce K Rubin
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ABSTRACT: A variety of mucoactive medications are used to treat chronic lung disease. When evaluating the role of the cough, it must be considered as an important protective mechanism. Therefore, it may be more important to improve the effectiveness of cough than to suppress or eliminate a chronic cough in patients with chronic lung disease. This article discusses the composition of mucus and phlegm, the process of mucin secretion and mucus clearance, and reviews current therapy and mucolytics in use or being studied for mucus clearance disorders.
Otolaryngologic Clinics of North America 02/2010; 43(1):27-34, vii-viii. · 1.65 Impact Factor
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ABSTRACT: Topical delivery of medications to the airway as medical aerosols is the first line treatment of asthma. Medical aerosols
are produced by a range of devices and each device has its own characteristics, method of operation, and target patient population.
Aerosol delivery can be a challenge as the structure of the airways is designed to minimize lung penetration of many aerosols
found in the air around us; from dust and pollen to airborne pathogens. The smaller the airway, the greater the flow turbulence
and therefore, the greater the volume of particles filtered. Thus, delivery of medical aerosols to children is often an order
of magnitude less than adults [1]. This challenge is greater in asthma when there is airflow limitation, inflammation, excess
mucus secretion, and airway remodeling [2]. Patient education for proper device use is as critical as proper device selection
for effective therapy [3, 4]. In this chapter, we discuss the characteristics of aerosol devices and the best techniques for
aerosol delivery in patients with asthma.
12/2009: pages 245-258;
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Bruce K Rubin
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ABSTRACT: Although some clinicians still believe that cystic fibrosis (CF) lung disease is largely due to hypersecretion of very viscous mucus, it has never been demonstrated that there is mucus hypersecretion in CF and it is clear that there is almost no intact mucin (the principal polymeric component of normal mucus) in CF sputum. CF sputum has lower viscosity when compared to asthma or bronchitis sputa, but is highly tenacious and biochemically most closely resembles pus. Tenacity and lower viscosity lead to decreased cough clearance of infected phlegm, which is thought to induce a persistent inflammatory state in the airway, leading to bronchiectasis. There are many medications and devices either in use or under development that are meant to improve airway hygiene in CF by assisting with sputum expectoration. This paper discusses the scientific basis and potential mechanism of action for many of these interventions and briefly reviews the clinical evidence of their safety and effectiveness.
Respiratory care 07/2009; 54(6):726-32; discussion 732. · 2.01 Impact Factor
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ABSTRACT: The 43rd Respiratory Care Journal Conference brought together experts from the United States, Canada, and the United Kingdom to review the art and science of cystic fibrosis (CF). This is the first time that CF was the topic for the Journal Conference, and it came about 6 decades after the disease was named, and 20 years after the gene was discovered on chromosome 7. Though CF is a multisystem disease, it is the chronic and progressive lung disease that causes most of the morbidity and mortality. The participants at the conference reviewed the epidemiology, pathophysiology, treatment, and novel therapies in the pipeline for CF lung disease. They also emphasized the many crucial roles that the respiratory therapist plays in CF, including diagnostic testing, aerosol therapies, airway clearance, infection control, patient and peer education, and patient advocacy. The May and June 2009 issues of the Journal reflect how diligently the participants worked to provide up-to-date reviews and lively discussions of these topics.
Respiratory care 07/2009; 54(6):796-800. · 2.01 Impact Factor
