Control of Confounding and Reporting of Results in Causal Inference Studies. Guidance for Authors from Editors of Respiratory, Sleep, and Critical Care Journals.

Ann Am Thorac Soc. 2019 01;16(1):22-28

Authors: Lederer DJ, Bell SC, Branson RD, Chalmers JD, Marshall R, Maslove DM, Ost DE, Punjabi NM, Schatz M, Smyth AR, Stewart PW, Suissa S, Adjei AA, Akdis CA, Azoulay É, Bakker J, Ballas ZK, Bardin PG, Barreiro E, Bellomo R, Bernstein JA, Brusasco V, Buchman TG, Chokroverty S, Collop NA, Crapo JD, Fitzgerald DA, Hale L, Hart N, Herth FJ, Iwashyna TJ, Jenkins G, Kolb M, Marks GB, Mazzone P, Moorman JR, Murphy TM, Noah TL, Reynolds P, Riemann D, Russell RE, Sheikh A, Sotgiu G, Swenson ER, Szczesniak R, Szymusiak R, Teboul JL, Vincent JL

PMID: 30230362 [PubMed - indexed for MEDLINE]

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"Cystic Fibrosis"

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Middle ear disease in CF? It's not just about the sinuses anymore!

Int J Pediatr Otorhinolaryngol. 2020 Apr 01;134:110032

Authors: McCoy JL, Kaffenberger TM, Yang TS, Shaffer AD, Dohar JE

Abstract
INTRODUCTION: Historically cystic fibrosis (CF), in contrast to primary ciliary dyskinesia (PCD), has been considered protective of the middle ear from otitis media and rarely were such patients "severely affected" to require tympanostomy tube placement (BMT). Previously the Pittsburgh Otitis Media Research group reported a 10% prevalence of otitis media in the pediatric CF population which is significantly lower than age matched non-CF children. We studied the prevalence of OM in pediatric CF patients to assess if the otologic phenotype has changed in parallel with changes in the diagnosis itself.
METHODS: The medical records of 133 CF patients seen either inpatient or outpatient from one of the largest tertiary pediatric CF centers in the world from 2010 to 2019 were reviewed for demographics, acute otitis media (AOM) episodes, risk factors for AOM, placement of myringotomy tubes, genotype, BMI, pancreatic status, respiratory culture results, and pulmonary exacerbations.
RESULTS: Just over half (52.6%) the patients were male. A median age for CF diagnosis was 11 days old (range 0 days-16 years). The most common genotype (49.6%) was homozygous for ΔF508 mutation. Fifty-five (41.4%) patients had 1-2 episodes of AOM, and 15 (11.3%) were severely affected (i.e. ≥3 episodes/6 months or ≥4 episodes/year). COME was diagnosed in 4 (3.0%) of the patients. Twelve (9.0%) patients had tympanostomy tubes at least once, including 3 patients with multiple sets of tubes. Having at least one AOM episode was not predicted by genetic mutation groups, BMI, age at diagnosis, or comorbidities, p > .05.
CONCLUSIONS: The time-honored adage of CF protecting against otitis media is no longer true and pediatric otolaryngologists must now prioritize the management of middle ear disease as highly as sino-nasal and pulmonary disease. Future study into mechanisms explaining the change is needed.

PMID: 32259649 [PubMed - as supplied by publisher]

Exploring the relationship between FEV1 loss and recovery and aminoglycoside pharmacokinetics in adult patients with cystic fibrosis: implications for clinical dosing strategies.

Pharmacotherapy. 2020 Apr 07;:

Authors: Hoff BM, Scheetz MH, Jain M, Cullina JF, Rhodes NJ

Abstract
OBJECTIVE: Systemic aminoglycosides remain a cornerstone of treatment for Cystic Fibrosis (CF) pulmonary exacerbations (PEx); however, the impact of aminoglycoside pharmacokinetics (PK) on outcomes is not well defined in adult CF patients. Our objective was to assess the impact of increasing PK exposures on the clinical outcomes of PEx treatment in adult CF patients receiving high-dose and standard-dose extended-interval aminoglycosides.
METHODS: We conducted a retrospective study of adult CF patients treated with an intravenous aminoglycoside for a PEx. Serum amikacin, gentamicin, and tobramycin levels and FEV1 data were used to evaluate exposure-response relationships. PK parameters were estimated using a Bayesian approach to obtain AUC0-24hr , Cmax0-24hr , Cmin0-24hr estimates. The primary efficacy endpoint was a 90% recovery of baseline FEV1 by 30 days post-treatment. Toxicity included signs or symptoms of ototoxicity, vestibular, or renal toxicity. Multivariate linear mixed-effects models of FEV1 were used for exposure-response analysis.
RESULTS: The study included 51 patients who contributed 188 FEV1 observations. There were 3.0±1.7 (mean±SD) aminoglycoside concentrations per patient. The mean AUC0-24hr , Cmax0-24hr , and Cmin0-24hr across all agents and patients were 156±96 mg*hr/L, 29.9±12.7 mg/L, and 0.35±0.66 mg/L, respectively. A total of 42 amikacin-, gentamicin-, or tobramycin-treated patients contributed to the efficacy analysis, of whom 85.7% experienced recovery post-treatment. Of the 51 included patients, six (11.8%) experienced seven toxicity events. In exploratory exposure-response analyses, neither AUC0-24hr nor Cmax0-24hr were associated with FEV1 values after adjusting for clinical covariates and baseline FEV1 .
CONCLUSIONS: Increasing aminoglycoside AUC0-24hr and Cmax0-24hr were not associated with FEV1 during PEx treatment. While individualizing aminoglycoside dosing in adult CF patients is necessary to minimize toxicity risk, more work is needed to define optimally safe and effective dosing strategies for this population.

PMID: 32259317 [PubMed - as supplied by publisher]

Emerging Cystic Fibrosis Transmembrane Conductance Regulator Modulators as New Drugs for Cystic Fibrosis: A Portrait of in Vitro Pharmacology and Clinical Translation.

ACS Pharmacol Transl Sci. 2020 Feb 14;3(1):4-10

Authors: Ghelani DP, Schneider-Futschik EK

Abstract
Pharmacological correction of the defective ion channel with cystic fibrosis transmembrane conductance regulator (CFTR) has become an attractive approach to therapy directed at the root cause of the life-limiting disease cystic fibrosis (CF). CFTR defects range from absence, misfolding, and resulting degradation to functional defects of the CFTR protein. The discovery and development of the CFTR potentiator ivacaftor was a major break-through in CF therapy and has triggered an enormous incentive for seeking effective modulators such as lumacaftor, tezacaftor or elexacaftor for all patients with CF. A number of emerging CFTR modulators are currently in the development pipeline, and rescue levels of CFTR protein approach a cure for cystic fibrosis. In this review, we identify and characterize all preclinical and clinical emerging CFTR modulators and discuss the in vitro pharmacology, looking at CFTR protein expression and chloride transport and the translation to the clinic. The new emerging CFTR modulators could offer new therapeutic solutions for CF patients.

PMID: 32259083 [PubMed - as supplied by publisher]

Oral ethinyl estradiol treatment in women with cystic fibrosis is associated with lower bone mineral density.

J Clin Transl Endocrinol. 2020 Jun;20:100223

Authors: Wu M, Hunt WR, Putman MS, Tangpricha V

Abstract
Objective: The purpose of this study was to determine whether estrogen supplementation primarily from oral contraceptive pills compared to no estrogen supplementation is associated with differences in mean bone mineral density (BMD) measured by DXA in a cross-sectional study of women with cystic fibrosis (CF).
Methods: In this cross-sectional study of women with CF followed at a single center, we analyzed 49 women with CF ages 18-50 years with a documented DXA. BMD of women with CF taking estrogen supplementation was compared to BMD of women with CF not taking estrogen supplementation.
Results: Twelve women with CF were taking estrogen supplementation with mean dose of 23.3 mcg/day (SD 6.9 mcg/day) of ethinyl estradiol. There were no statistically significant differences between demographics of the 12 women with CF taking estrogen supplementation compared to the 37 women with CF not taking estrogen supplementation. Women taking estrogen had lower mean lumbar spine Z-score: -0.7 ± 0.7, compared to women not taking estrogen, Z-score: -0.04 ± 1.0 (p-value 0.046). Women taking estrogen had lower mean BMD at the lumbar spine: 0.952 ± 0.086 g/cm2, compared to women not taking estrogen: 1.023 ± 0.105 g/cm2 (p-value 0.038). Similar trends were seen at the total hip and femoral neck.
Conclusion: Low-dose estrogen supplementation in premenopausal women with CF was associated with lower BMD compared to no estrogen supplementation in a similar group of premenopausal young women with CF. Future studies are needed to investigate the optimal formulation, route of administration, and dose to accrue and preserve bone mass in premenopausal women with CF.

PMID: 32257821 [PubMed - as supplied by publisher]

Effects of high intensity interval training on exercise capacity in people with chronic pulmonary conditions: a narrative review.

BMC Sports Sci Med Rehabil. 2020;12:22

Authors: Sawyer A, Cavalheri V, Hill K

Abstract
Background: Exercise training is important in the management of adults with chronic pulmonary conditions. However, achieving high intensity exercise may be challenging for this clinical population. There has been clinical interest in applying interval-based training as a strategy to optimise the load that can be tolerated during exercise training. Evidence for such an approach is limited in most chronic pulmonary populations.
Main body: In this narrative review, we provide an appraisal of studies investigating whole-body high intensity interval training (HIIT) in adults with chronic obstructive pulmonary disease (COPD). This is the first review to also include studies investigating HIIT in people with conditions other than COPD. Studies undertaken in adults with a chronic pulmonary condition were reviewed when participants were randomised to receive; (i) HIIT or no exercise or, (ii) HIIT or moderate intensity continuous exercise. Data were extracted on peak rate of oxygen uptake (VO2peak; 'cardiorespiratory fitness') and maximal work rate (Wmax; 'exercise capacity').In people with COPD, two studies demonstrated between-group differences favouring HIIT compared with no exercise. There appears to be no advantage for HIIT compared to continuous exercise on these outcomes. In people with cystic fibrosis (CF), no studies have compared HIIT to no exercise and the two studies that compared HIIT to continuous exercise reported similar benefits. In people prior to resection for non-small cell lung cancer, one study demonstrated a between-group difference in favour of HIIT compared with no exercise on VO2peak. In people with asthma, one study demonstrated a between-group difference in favour of HIIT compared with no exercise on VO2peak and one that compared HIIT to continuous exercise reported similar benefits. No studies were identified non-CF bronchiectasis or interstitial lung diseases.
Conclusions: High intensity interval training increases cardiorespiratory fitness and exercise capacity when compared with no exercise and produces a similar magnitude of change as continuous exercise in people with COPD. There is a paucity of studies exploring the effects of HIIT in other chronic pulmonary conditions.

PMID: 32257221 [PubMed - as supplied by publisher]

Recent progress in structural studies on TMEM16A channel.

Comput Struct Biotechnol J. 2020;18:714-722

Authors: Shi S, Pang C, Guo S, Chen Y, Ma B, Qu C, Ji Q, An H

Abstract
The calcium-activated chloride channel, also known as TMEM16A, shows both calcium and membrane potential dependent activation. The channel is expressed broadly and contributes to a variety of physiological processes, and it is expected to be a target for the treatment of diseases such as hypertension, pain, cystic fibrosis and lung cancer. A thorough understanding of the structural characteristics of TMEM16A is important to reveal its physiological and pathological roles. Recent studies have released several Cryo-EM structures of the channel, revealed the structural basis and mechanism of the gating of the channel. This review focused on the understandings of the structural basis and molecular mechanism of the gating and permeation of TMEM16A channel, which will provide important basis for the development of drugs targeting TMEM16A.

PMID: 32257055 [PubMed - as supplied by publisher]

Functional and Pharmacological Characterization of the Rare CFTR Mutation W361R.

Front Pharmacol. 2020;11:295

Authors: Billet A, Elbahnsi A, Jollivet-Souchet M, Hoffmann B, Mornon JP, Callebaut I, Becq F

Abstract
Understanding the functional consequence of rare cystic fibrosis (CF) mutations is mandatory for the adoption of precision therapeutic approaches for CF. Here we studied the effect of the very rare CF mutation, W361R, on CFTR processing and function. We applied western blot, patch clamp and pharmacological modulators of CFTR to study the maturation and ion transport properties of pEGFP-WT and mutant CFTR constructs, W361R, F508del and L69H-CFTR, expressed in HEK293 cells. Structural analyses were also performed to study the molecular environment of the W361 residue. Western blot showed that W361R-CFTR was not efficiently processed to a mature band C, similar to F508del CFTR, but unlike F508del CFTR, it did exhibit significant transport activity at the cell surface in response to cAMP agonists. Importantly, W361R-CFTR also responded well to CFTR modulators: its maturation defect was efficiently corrected by VX-809 treatment and its channel activity further potentiated by VX-770. Based on these results, we postulate that W361R is a novel class-2 CF mutation that causes abnormal protein maturation which can be corrected by VX-809, and additionally potentiated by VX-770, two FDA-approved small molecules. At the structural level, W361 is located within a class-2 CF mutation hotspot that includes other mutations that induce variable disease severity. Analysis of the 3D structure of CFTR within a lipid environment indicated that W361, together with other mutations located in this hotspot, is at the edge of a groove which stably accommodates lipid acyl chains. We suggest this lipid environment impacts CFTR folding, maturation and response to CFTR modulators.

PMID: 32256364 [PubMed - as supplied by publisher]

Responsible use of organoids in precision medicine: the need for active participant involvement.

Development. 2020 Apr 06;147(7):

Authors: Lensink MA, Jongsma KR, Boers SN, Noordhoek JJ, Beekman JM, Bredenoord AL

Abstract
Organoids are three-dimensional multicellular structures grown in vitro from stem cells and which recapitulate some organ function. They are derivatives of living tissue that can be stored in biobanks for a multitude of research purposes. Biobank research on organoids derived from patients is highly promising for precision medicine, which aims to target treatment to individual patients. The dominant approach for protecting the interests of biobank participants emphasizes broad consent in combination with privacy protection and ex ante (predictive) ethics review. In this paradigm, participants are positioned as passive donors; however, organoid biobanking for precision medicine purposes raises challenges that we believe cannot be adequately addressed without more ongoing involvement of patient-participants. In this Spotlight, we argue why a shift from passive donation towards more active involvement is particularly crucial for biobank research on organoids aimed at precision medicine, and suggest some approaches appropriate to this context.

PMID: 32253255 [PubMed - in process]

Functional constipation masked as irritable bowel syndrome.

BMC Gastroenterol. 2020 Apr 06;20(1):86

Authors: Tosto M, D'Andrea P, Salamone I, Pellegrino S, Costa S, Lucanto MC, Pallio S, Magazzu' G, Guandalini S

Abstract
BACKGROUND: Rome IV criteria for functional gastrointestinal disorders state that children suspected of having Irritable Bowel Syndrome (IBS) with Constipation (IBS-C) should be preliminarily treated for constipation. We aimed at verifying if functional constipation may indeed lead to an erroneous diagnosis of IBS with diarrhea (IBS-D) or IBS with mixed pattern of diarrhea and constipation (IBS-M).
METHODS: We prospectively enrolled in an unblinded fashion 10 and 16 consecutive children referred to our center who met Rome IV criteria for a diagnosis of IBS-D and IBS-M, respectively. Patients who fulfilled criteria for suspect "occult constipation" were then given a bowel cleaning regimen with Polyethylene glycol 3350, re-evaluated at 2 months and followed up for at least 6 months. Sixteen additional patients with IBS with Constipation (IBS-C) referred in the same period served as control. The endpoints were: 1) a decrease of more than 50% in abdominal pain intensity and frequency scores; and 2) for patients with IBS-D and IBS-M: resolution of diarrhea.
RESULTS: The endpoints were met by 8 (80%) and 14 (87%) of the patients with IBS-D and IBS-M, respectively, with decrease of abdominal pain and resolution of "diarrhea". The response was not significantly different from that observed in 15 (93%) of the IBS-C control group.
CONCLUSION: Acknowledging the limitations of the small number of patients and of the uncontrolled nature of the study, we suggest that a possibly large number of patients labeled as IBS-D or IBS-M may actually simply present functional constipation and should be managed as such.

PMID: 32252644 [PubMed - in process]

Impact of Bacterial Toxins in the Lungs.

Toxins (Basel). 2020 Apr 02;12(4):

Authors: Lucas R, Hadizamani Y, Gonzales J, Gorshkov B, Bodmer T, Berthiaume Y, Moehrlen U, Lode H, Huwer H, Hudel M, Mraheil MA, Toque HAF, Chakraborty T, Hamacher J

Abstract
Bacterial toxins play a key role in the pathogenesis of lung disease. Based on their structural and functional properties, they employ various strategies to modulate lung barrier function and to impair host defense in order to promote infection. Although in general, these toxins target common cellular signaling pathways and host compartments, toxin- and cell-specific effects have also been reported. Toxins can affect resident pulmonary cells involved in alveolar fluid clearance (AFC) and barrier function through impairing vectorial Na+ transport and through cytoskeletal collapse, as such, destroying cell-cell adhesions. The resulting loss of alveolar-capillary barrier integrity and fluid clearance capacity will induce capillary leak and foster edema formation, which will in turn impair gas exchange and endanger the survival of the host. Toxins modulate or neutralize protective host cell mechanisms of both the innate and adaptive immunity response during chronic infection. In particular, toxins can either recruit or kill central players of the lung's innate immune responses to pathogenic attacks, i.e., alveolar macrophages (AMs) and neutrophils. Pulmonary disorders resulting from these toxin actions include, e.g., acute lung injury (ALI), the acute respiratory syndrome (ARDS), and severe pneumonia. When acute infection converts to persistence, i.e., colonization and chronic infection, lung diseases, such as bronchitis, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) can arise. The aim of this review is to discuss the impact of bacterial toxins in the lungs and the resulting outcomes for pathogenesis, their roles in promoting bacterial dissemination, and bacterial survival in disease progression.

PMID: 32252376 [PubMed - in process]

Updates on bone health in children with gastrointestinal diseases.

Ann Pediatr Endocrinol Metab. 2020 Mar;25(1):10-14

Authors: Yang HR

Abstract
Chronic gastrointestinal diseases such as inflammatory bowel disease, malabsorption syndromes (e.g., intestinal lymphangiectasia, celiac disease, congenital chloride diarrhea, cystic fibrosis), and postsubtotal gastrectomy state or short-bowel syndrome after extensive bowel resection are related to poor bone health in pediatric patients due to increased risks of low bone mineral density, osteoporosis, and fractures. The pathophysiology of abnormal bone health in pediatric gastrointestinal diseases may present from inflammation to malabsorption. In children with chronic gastrointestinal diseases at high risk of poor bone health, routine evaluation using dual-energy X-ray absorptiometry and appropriate prevention or treatment strategies are needed.

PMID: 32252211 [PubMed]

Treatments for priapism in boys and men with sickle cell disease.

Cochrane Database Syst Rev. 2020 Apr 06;4:CD004198

Authors: Chinegwundoh FI, Smith S, Anie KA

Abstract
BACKGROUND: Sickle cell disease comprises a group of genetic haemoglobin disorders. The predominant symptom associated with sickle cell disease is pain resulting from the occlusion of small blood vessels by abnormally 'sickle-shaped' red blood cells. There are other complications, including chronic organ damage and prolonged painful erection of the penis, known as priapism. Severity of sickle cell disease is variable, and treatment is usually symptomatic. Priapism affects up to half of all men with sickle cell disease, however, there is no consistency in treatment. We therefore need to know the best way of treating this complication in order to offer an effective interventional approach to all affected individuals. This is an update of a previously published review.
OBJECTIVES: To assess the benefits and risks of different treatments for stuttering (repeated short episodes) and fulminant (lasting for six hours or more) priapism in sickle cell disease.
SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched trial registries. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 September 2019. Date of most recent search of trial registries and of Embase: 01 October 2019.
SELECTION CRITERIA: All randomised or quasi-randomised controlled trials comparing non-surgical or surgical treatment with placebo or no treatment, or with another intervention for stuttering or fulminant priapism.
DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed the risk of bias of the trials.
MAIN RESULTS: Three trials with 102 participants were identified and met the criteria for inclusion in this review. These trials compared stilboestrol to placebo, sildenafil to placebo and a four-arm trial which compared ephedrine or etilefrine to placebo and ranged in duration from two weeks to six months. All of the trials were conducted in an outpatient setting in Jamaica, Nigeria and the UK. None of the trials measured our first primary outcome, detumescence. However, all three trials reported on the reduction in frequency of stuttering priapism, our second primary outcome; and from the evidence included in this review, we are uncertain whether stilboestrol, etilefrine or ephedrine reduce the frequency of stuttering priapism as the certainty of the evidence has been assessed as very low. Additionally, we conclude that sildenafil may make little or no difference (low-certainty evidence). Two trials reported on immediate side effects and we are uncertain whether etilefrine or ephedrine reduce the occurrence of these (very low-certainty of evidence) and also conclude that sildenafil may make little or no difference in side effects (low-quality evidence). Given that all of the trials were at risk of bias and all had low participant numbers, we considered the certainty of the evidence to be low to very low.
AUTHORS' CONCLUSIONS: There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease.

PMID: 32251534 [PubMed - as supplied by publisher]

Chronic rhinosinusitis with nasal polyps impact in severe asthma patients: Evidences from the Severe Asthma Network Italy (SANI) registry.

Respir Med. 2020 Apr 02;166:105947

Authors: Canonica GW, Malvezzi L, Blasi F, Paggiaro P, Mantero M, Senna G, Heffler E, Severe Asthma Network Italy (SANI)

Abstract
BACKGROUND: The clinical and laboratory features of patients enrolled in the Severe Asthma Network in Italy (SANI) registry, a web-based observatory collecting demographic, clinical, functional and inflammatory data of patients with severe asthma were evaluated, with a special emphasis to chronic rhinosinusitis with nasal polyposis (CRSwNP).
METHODS: For each eligible patients the following information has been collected: demographic data, clinical features, asthma control in the previous month according to the GINA (Global INitiative for Asthma) Guidelines and standardized questionnaires, concomitant regular and on demand treatments and inflammatory markers.
RESULTS: 695 patients with severe asthma enrolled in 66 SANI centers were analyzed. The prevalence of chronic rhinosinusitis with nasal polyposis was 40.6%. Atopic dermatitis and bronchiectasis was significantly more frequent in patients with CRSwNP than in subjects without nasal polyposis; similarly, FeNO values are significantly higher in subject with CRSwNP than in patients without nasal polyposis. Finally, patients with CRSwNP had a significantly higher number of asthma exacerbations per year, more days on oral corticosteroids and were more likely to be OCS long term users.
CONCLUSION: OCS sparing is needed in patients with severe asthma, mainly in subjects with CRSwNP, adopting adequate strategies such as a better adherence to the treatment with inhaled therapy according to the GINA recommendations, the use of biologic agents and a multidisciplinary approach of the patient.

PMID: 32250875 [PubMed - as supplied by publisher]

Non-CF bronchiectasis: Orphan disease no longer.

Respir Med. 2020 Mar 27;166:105940

Authors: Imam JS, Duarte AG

Abstract
Bronchiectasis is a complex, chronic respiratory condition, characterized by frequent cough and exertional dyspnea due to a range of conditions that include inherited mucociliary defects, inhalational airway injury, immunodeficiency states and prior respiratory infections. For years, bronchiectasis was classified as either being caused by cystic fibrosis or non-cystic fibrosis. Non-cystic fibrosis bronchiectasis, once considered an orphan disease, is more prevalent worldwide in part due to greater availability of chest computed tomographic imaging. Identification of the cause of non-cystic fibrosis bronchiectasis with the use of chest imaging, laboratory testing, and microbiologic assessment of airway secretions can lead to initiation of specific therapies aimed at slowing disease progression. Nonpharmacologic therapies such as airway clearance techniques and pulmonary rehabilitation improve patient symptoms. Inhaled corticosteroids should not be routinely prescribed unless concomitant asthma or COPD is present. Inhaled antibiotics prescribed to individuals with >3 exacerbations per year are well tolerated, reduce airway bacteria load and may reduce the frequency of exacerbations. Likewise, chronic macrolide therapy reduces the frequency of exacerbations. Medical therapies for cystic fibrosis bronchiectasis may not be effective in treatment of non-cystic fibrosis bronchiectasis.

PMID: 32250872 [PubMed - as supplied by publisher]

What drives inhaler prescription for asthma patients? Results from a real-life retrospective analysis.

Respir Med. 2020 Mar 20;166:105937

Authors: Lavorini F, Bianco A, Blasi F, Braido F, Corsico AG, Di Marco F, Gentile A, Paggiaro PL, Pegoraro V, Pelaia G, Rogliani P, Santus P, Scichilone N, Soldi A, Canonica GW

Abstract
BACKGROUND: The choice of inhaler device for asthma patients depends upon multiple attributes. We investigated factors that may drive general practitioners (GPs) and respiratory specialists in the prescription of inhaler devices for asthma patients who initiated inhalation therapy.
METHODS: We retrospectively analysed prescriptions by GPs and respiratory specialists to asthma patients commencing inhaled corticosteroid/long-acting β2-agonist combination therapy available as both pressurised metered-dose inhalers (pMDIs) and dry powder inhalers (DPIs). Patient characteristics were compared by device and multivariate analysis was used to model the likelihood of receiving a pMDI as opposed to a DPI in order to identify drivers for prescription. A sample of the respiratory specialists completed an ad-hoc survey of their perceived success in achieving asthma control in their patients and barriers to attaining full control.
RESULTS: Prescription of a particular inhaler device was unrelated to the characteristics of the patients. Multivariate analysis revealed that the main driver for the choice of inhaler device choice was the medication (Odds Ratio and 95% Confidence Interval, respectively for GPs and specialists: 0.19 [0.16-0.23]; 0.17 [0.08-0.37]). Specialists perceived asthma as being inadequately controlled in 41% of their patients, and considered patients' difficulties in using DPIs and pMDIs as instrumental in this, citing a need for a novel, more effective inhaler technology.
CONCLUSION: Physicians choose inhaler devices according to the prescribed drugs and not to the characteristics of the individual patient. This may reflect a lack of confidence in existing inhaler devices and underlines the need for technologies, which are more reliable and easier to use by patients.

PMID: 32250870 [PubMed - as supplied by publisher]

Immunoactive preparations and regulatory responses in the respiratory tract: potential for clinical application in chronic inflammatory airway diseases.

Expert Rev Respir Med. 2020 Apr 06;:

Authors: Feleszko W, Rossi GA, Krenke R, Canonica GW, van Gerven L, Kalyuzhin O

Abstract
Introduction: The prevalence of chronic inflammatory airway diseases is rising. Their treatment with corticosteroids increases infection risk, while overuse of antimicrobial agents may increase morbidity and antimicrobial resistance. Non-specific immunomodulatory compounds alter immune responses to both infectious and atopic challenges. These compounds may offer an alternative approach for symptom reduction and prophylaxis against both infections and exacerbations in chronic inflammatory airway disease.Areas covered: We assessed the available data on the efficacy of non-specific immunomodulators including bacterial lysates, synthetic compounds, and vaccines in chronic rhinosinusitis (CRS); allergic and non-allergic rhinitis; chronic obstructive pulmonary disease (COPD), and asthma. A search of PubMed was carried out using the 'Clinical Trials' filter for each condition and immunomodulatory product detailed below, where available, data from meta-analyses were reported.Expert opinion: Pre-clinical data has revealed a coherent mechanistic path of action for oral immunomodulators on the respiratory immune system, principally via the gut-lung immune axis. In patients with asthma, allergic rhinitis, CRS, and COPD immunomodulatory therapy reduces symptoms, exacerbations, hospitalizations, and drug consumption. However, data are heterogeneous, and study quality remains limited. A lack of high-quality recent trials remains the major unmet research need in the field.

PMID: 32250709 [PubMed - as supplied by publisher]

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Cochrane Database Syst Rev. 2020 Apr 06;4:CD012389

Authors: Estcourt LJ, Kimber C, Hopewell S, Trivella M, Doree C, Abboud MR

Abstract
BACKGROUND: Sickle cell disease (SCD) is one of the commonest severe monogenic disorders in the world, due to the inheritance of two abnormal haemoglobin (beta globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Silent cerebral infarcts are the commonest neurological complication in children and probably adults with SCD. Silent cerebral infarcts also affect academic performance, increase cognitive deficits and may lower intelligence quotient.
OBJECTIVES: To assess the effectiveness of interventions to reduce or prevent silent cerebral infarcts in people with SCD.
SEARCH METHODS: We searched for relevant trials in the Cochrane Library, MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1980), and ongoing trial databases; all searches current to 14 November 2019. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register: 07 October 2019.
SELECTION CRITERIA: Randomised controlled trials comparing interventions to prevent silent cerebral infarcts in people with SCD. There were no restrictions by outcomes examined, language or publication status.
DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures.
MAIN RESULTS: We included five trials (660 children or adolescents) published between 1998 and 2016. Four of the five trials were terminated early. The vast majority of participants had the haemoglobin (Hb)SS form of SCD. One trial focused on preventing silent cerebral infarcts or stroke; three trials were for primary stroke prevention and one trial dealt with secondary stroke prevention. Three trials compared the use of regular long-term red blood cell transfusions to standard care. Two of these trials included children with no previous long-term transfusions: one in children with normal transcranial doppler (TCD) velocities; and one in children with abnormal TCD velocities. The third trial included children and adolescents on long-term transfusion. Two trials compared the drug hydroxyurea and phlebotomy to long-term transfusions and iron chelation therapy: one in primary prevention (children), and one in secondary prevention (children and adolescents). The quality of the evidence was moderate to very low across different outcomes according to GRADE methodology. This was due to trials being at high risk of bias because they were unblinded; indirectness (available evidence was only for children with HbSS); and imprecise outcome estimates. Long-term red blood cell transfusions versus standard care Children with no previous long-term transfusions and higher risk of stroke (abnormal TCD velocities or previous history of silent cerebral infarcts) Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, risk ratio (RR) 0.11 (95% confidence interval (CI) 0.02 to 0.86) (one trial, 124 participants, low-quality evidence); but make little or no difference to the incidence of silent cerebral infarcts in children with previous silent cerebral infarcts on magnetic resonance imaging and normal or conditional TCDs, RR 0.70 (95% CI 0.23 to 2.13) (one trial, 196 participants, low-quality evidence). No deaths were reported in either trial. Long-term red blood cell transfusions may reduce the incidence of: acute chest syndrome, RR 0.24 (95% CI 0.12 to 0.49) (two trials, 326 participants, low-quality evidence); and painful crisis, RR 0.63 (95% CI 0.42 to 0.95) (two trials, 326 participants, low-quality evidence); and probably reduces the incidence of clinical stroke, RR 0.12 (95% CI 0.03 to 0.49) (two trials, 326 participants, moderate-quality evidence). Long-term red blood cell transfusions may improve quality of life in children with previous silent cerebral infarcts (difference estimate -0.54; 95% confidence interval -0.92 to -0.17; one trial; 166 participants), but may have no effect on cognitive function (least squares means: 1.7, 95% CI -1.1 to 4.4) (one trial, 166 participants, low-quality evidence). Transfusions continued versus transfusions halted: children and adolescents with normalised TCD velocities (79 participants; one trial) Continuing red blood cell transfusions may reduce the incidence of silent cerebral infarcts, RR 0.29 (95% CI 0.09 to 0.97 (low-quality evidence). We are very uncertain whether continuing red blood cell transfusions has any effect on all-cause mortality, Peto odds ratio (OR) 8.00 (95% CI 0.16 to 404.12); or clinical stroke, RR 0.22 (95% CI 0.01 to 4.35) (very low-quality evidence). The trial did not report: comparative numbers for SCD-related adverse events; quality of life; or cognitive function. Hydroxyurea and phlebotomy versus transfusions and chelation Primary prevention, children (121 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts (no infarcts); all-cause mortality (no deaths); risk of stroke (no strokes); or SCD-related complications, RR 1.52 (95% CI 0.58 to 4.02) (very low-quality evidence). Secondary prevention, children and adolescents with a history of stroke (133 participants; one trial) We are very uncertain whether switching to hydroxyurea and phlebotomy has any effect on: silent cerebral infarcts, Peto OR 7.28 (95% CI 0.14 to 366.91); all-cause mortality, Peto OR 1.02 (95%CI 0.06 to 16.41); or clinical stroke, RR 14.78 (95% CI 0.86 to 253.66) (very low-quality evidence). Switching to hydroxyurea and phlebotomy may increase the risk of SCD-related complications, RR 3.10 (95% CI 1.42 to 6.75) (low-quality evidence). Neither trial reported on quality of life or cognitive function.
AUTHORS' CONCLUSIONS: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD. Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises). In children and adolescents at high risk of stroke whose TCD velocities have normalised, continuing red blood cell transfusions may reduce the risk of silent cerebral infarcts. No treatment duration threshold has been established for stopping transfusions. Switching to hydroxyurea with phlebotomy may increase the risk of silent cerebral infarcts and SCD-related serious adverse events in secondary stroke prevention. All other evidence in this review is of very low-quality.

PMID: 32250453 [PubMed - as supplied by publisher]

The anti-inflammatory potential of selected plant-derived compounds in respiratory diseases.

Curr Pharm Des. 2020 Apr 05;:

Authors: Wieczfinska J, Sitarek P, Kowalczyk T, Skała E, Pawliczak R

Abstract
Inflammation plays a major role in chronic airway diseases like asthma, COPD and cystic fibrosis. Inflammation plays a crucial role in the worsening of the lung function resulting in worsening symptoms. The inflammatory process is very complexed, therefore the strategies for developing effective treatment for inflammatory airway diseases, would benefit from the use of natural substances. Plant products have demonstrated anti-inflammatory properties on various lung disease models and numerous natural plant agents have successfully been used to treat inflammation. Naturally occurring substances may exert some anti-inflammatory effects by modulating some of the inflammatory pathways. These agents have been used in different cultures for thousands of years and have proven to be relatively safe. Parthenolide, apocynin, proanthocyanidins and boswellic acid present different mechanisms of actions - among others, through NF-κB or NADPH oxidase inhibition, therefore showing a wide range of applications in various inflammatory diseases. Moreover, some of them have also antioxidant properties. This review provides an overview of the anti-inflammatory effects of some of the natural agents and illustrates their great potential as sources of drugs to cover an extensive range of pharmacological effects.

PMID: 32250214 [PubMed - as supplied by publisher]