Biomed Res Int. 2021 Jul 8;2021:6647734. doi: 10.1155/2021/6647734. eCollection 2021.

ABSTRACT

Pancreatic enzyme replacement therapy (PERT) and fat predigestion are key in ensuring the optimal growth of patients with cystic fibrosis. Our study attempted to highlight differences between fat predigestion and conventional PERT on body composition of young pigs with exocrine pancreatic insufficiency (EPI). EPI and healthy pigs were fed with high-fat diet for six weeks. During the last two weeks of the study, all pigs received additional nocturnal alimentation with Peptamen AF (PAF) and were divided into three groups: H-healthy pigs receiving PAF; P-EPI pigs receiving PAF+PERT; and L-EPI pigs receiving PAF predigested with an immobilized microbial lipase. Additional nocturnal alimentation increased the body weight gain of EPI pigs with better efficacy in P pigs. Humerus length and area in pigs in groups L and P were lower than that observed in pigs in group H (p value 0.005-0.088). However, bone mineral density and strength were significantly higher in P and L as compared to that of H pigs (p value 0.0026-0.0739). The gut structure was improved in P pigs. The levels of neurospecific proteins measured in the brain were mainly affected in P and less in L pigs as compared to H pigs. The beneficial effects of the nocturnal feeding with the semielemental diet in the prevention of EPI pigs' growth/development retardation are differently modified by PERT or fat predigestion in terms of growth, bone properties, neurospecific protein distribution, and gut structure.

PMID:34307664 | PMC:PMC8282365 | DOI:10.1155/2021/6647734

Int J Chronic Dis. 2021 Jul 7;2021:6708865. doi: 10.1155/2021/6708865. eCollection 2021.

ABSTRACT

AIMS: This systemic review and meta-analysis were aimed at determining the level of anxiety and depression among cystic fibrosis patients in the world.

METHODS: We conducted a systematic search of published studies from PubMed, EMBASE, MEDLINE, Cochrane, Scopus, Web of Science, CINAHL, and manually on Google Scholar. This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of studies was assessed by the modified Newcastle-Ottawa Scale (NOS). Meta-analysis was carried out using a random-effects method using the STATA™ Version 14 software. Trim and fill analysis was done to correct the presence of significant publication bias.

RESULT: From 419,820 obtained studies, 26 studies from 2 different parts of the world including 9766. The overall global pooled prevalence of anxiety and depression after correction for publication bias by trim and fill analysis was found to be 24.91(95% CI: 20.8-28.9) for anxiety. The subgroup analyses revealed with the lowest prevalence, 23.59%, (95% CI: 8.08, 39.09)) in North America and the highest, 26.77%, (95% CI: 22.5, 31.04) seen in Europe for anxiety and with the highest prevalence, 18.67%, (95% CI: 9.82, 27.5) in North America and the lowest, 13.27%, (95% CI: -10.05, 16.5) seen in Europe for depression.

CONCLUSION: The global prevalence of anxiety and depression among cystic fibrosis patients is common. Therefore, close monitoring of the patient, regularly screening for anxiety and depression, and appropriate prevention techniques is recommended.

PMID:34307644 | PMC:PMC8282398 | DOI:10.1155/2021/6708865

Front Pediatr. 2021 Jul 9;9:659728. doi: 10.3389/fped.2021.659728. eCollection 2021.

ABSTRACT

Aims: We evaluated the impact of cystic fibrosis-related diabetes (CFRD) on lung disease and nutritional status. Study Design: The retrospective cohort study evaluated the subjects' medical records from 2004 to 2019. All participants older than 10 years diagnosed by a 30-minutely sampled OGTT formed OGTT-CFRD subgroup. The participants diagnosed with continuous glucose monitoring (CGM) (at least two peaks above 11.1 mmol/l and more than 10% of recorded time above 7.8 mmol/l) formed a CFRD-CGM subgroup. The participants without CFRD formed a non-CFRD group. The longitudinal follow-up was made 2 years before and 3 years after insulin therapy initiation. Results: Of 144 participants included, aged 10-55 years (44% males), 28 (19.4%) had CFRD. The HbA1c was significantly lower in the CGM-CFRD in comparison to the OGTT-CFRD subgroup (5.9 ± 0.62 and 7.3 ± 1.7% respectfully; p = 0.04). Subjects with CFRD were malnourished in comparison to non-CFRD, with significant improvements with insulin replacement therapy in regard to BMI Z-score (-1.4 ± 1.3 vs. -0.5 ± 1.2%, p = 0.04) and pulmonary exacerbation score (p = 0.02). In OGTT-CFRD subgroup there is an increase in FEV1 (62.7 ± 26.3 to 65.1 ± 21.7%, p = 0.7) and decrease in FVC (from 76.4 ± 24.2 to 71.2 ± 20%, p = 0.003) from diagnosis to second year of follow-up. In CGM-CFRD subgroup there was a decrease in FEV1 (from 58.2 ± 28.2 to 52.8 ± 25.9%, p = 0.2) and FVC-values (from 72.4 ± 26.5 to 67.4 ± 29.1%, p = 0.08).Chronic Pseudomonas aeruginosa infection was more prevalent in the CFRD group (p = 0.003). Conclusion: Continuous glucose monitoring is a useful tool for insight of glucose impairment and diagnosis of CFRD. Early recognition of CFRD and therapeutic intervention has favorable effects on clinical course of the disease.

PMID:34307249 | PMC:PMC8298893 | DOI:10.3389/fped.2021.659728

Dig Liver Dis. 2021 Jul 22:S1590-8658(21)00370-4. doi: 10.1016/j.dld.2021.06.034. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) and CF-related liver disease can lead to disturbances in bile acid metabolism.

AIM: This study determined serum bile acid concentrations in CF to define their usefulness in liver disease assessment.

METHODS: Primary, secondary and conjugated bile acid levels were measured in three CF groups (25 patients each) exhibiting: liver cirrhosis, other liver disease, no liver disease, and in 25 healthy subjects (HS).

RESULTS: Bile acid levels were higher in CF patients than in HS, except for glycodeoxycholic acid (GDCA). However, bile acid concentrations did not differ between patients with cirrhosis and other liver involvement. GDCA and deoxycholic acid (DCA) differentiated CF patients with non-cirrhotic liver disease from those without liver disease (GDCA-AUC: 0.924, 95%CI 0.822-1.000, p<0.001; DCA-AUC: 0.867, 95%CI: 0.731-1.000, p<0.001). Principal component analysis revealed that in CF liver disease was related to GDCA, GGTP activity, severe genotype and pancreatic insufficiency.

CONCLUSIONS: A CF-specific bile acid profile was defined and shown to relate to liver disease. GDCA differentiates patients with non-cirrhotic liver involvement from those with no detectable liver disease. Hence, GDCA is a candidate for validation as a biomarker of non-cirrhotic progression of liver disease in CF.

PMID:34305015 | DOI:10.1016/j.dld.2021.06.034

J Cyst Fibros. 2021 Jul 22:S1569-1993(21)01299-6. doi: 10.1016/j.jcf.2021.07.002. Online ahead of print.

ABSTRACT

BACKGROUND: The Food and Drug Administration considers patient-reported outcome measures (PROMs) an essential part of clinical research studies for approval of new drugs and new indications for existing drugs. GALAXY evaluated the feasibility of electronic PROMs (ePROMS) to conduct a comprehensive evaluation of gastrointestinal (GI) symptoms in persons with cystic fibrosis (pwCF).

METHODS: Three validated GI ePROMs (PAC-SYM, PAGI-SYM and PAC-QOL) were combined with a Stool-Specific questionnaire to make up the GALAXY ePROMs and administered prospectively across 26 CF centers in the United States. The ePROMs were completed at enrollment visit and then electronically at weeks 1, 2 and 4. PwCF at least 2 years and older were eligible for the study. Reminders were only provided by the mobile application during the study window.

RESULTS: There were 402 participants enrolled in GALAXY. Of those, 169 (42%) were under 18 years old and 193 (48%) were female. The proportion of all follow-up weeks with at least 1 ePROM fully completed was 80%, slightly higher in those ≥18 years of age (82.5%) compared to those <18 years of age (76.5%). When assessing the completion for all 4 ePROMs, the percentage was 77.6%, also higher among those ≥18 year of age (81.5% versus 72.2% for < 18 years of age).

CONCLUSION: Using ePROMs, our study demonstrated that GI symptoms can be feasibly collected with good reproducibility and with minimal involvement of research coordinator time. This mechanism of symptom collection may provide an efficient tool for future CF trials.

PMID:34305007 | DOI:10.1016/j.jcf.2021.07.002

Front Med. 2021 Jul 24. doi: 10.1007/s11684-021-0846-5. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a rare autosomal recessive disease with only one pathogenic gene cystic fibrosis transmembrane conductance regulator (CFTR). To identify the potential pathogenic mutations in a Chinese patient with CF, we conducted Sanger sequencing on the genomic DNA of the patient and his parents and detected all 27 coding exons of CFTR and their flanking intronic regions. The patient is a compound heterozygote of c.2909G > A, p.Gly970Asp in exon 18 and c.1210-3C > G in cis with a poly-T of 5T (T5) sequence, 3 bp upstream in intron 9. The splicing effect of c.1210-3C > G was verified via minigene assay in vitro, indicating that wild-type plasmid containing c.1210-3C together with T7 sequence produced a normal transcript and partial exon 10-skipping-transcript, whereas mutant plasmid containing c.1210-3G in cis with T5 sequence caused almost all mRNA to skip exon 10. Overall, c.1210-3C > G, the newly identified pathogenic mutation in our patient, in combination with T5 sequence in cis, affects the CFTR gene splicing and produces nearly no normal transcript in vitro. Moreover, this patient carries a p.Gly970Asp mutation, thus confirming the high-frequency of this mutation in Chinese patients with CF.

PMID:34302615 | DOI:10.1007/s11684-021-0846-5

Thorax. 2021 Jul 22:thoraxjnl-2021-216928. doi: 10.1136/thoraxjnl-2021-216928. Online ahead of print.

ABSTRACT

BACKGROUND: Lung clearance index (LCI) is a valuable research tool in cystic fibrosis (CF) but clinical application has been limited by technical challenges and uncertainty about how to interpret longitudinal change. In order to help inform clinical practice, this study aimed to assess feasibility, repeatability and longitudinal LCI change in children and adults with CF with predominantly mild baseline disease.

METHODS: Prospective, 3-year, multicentre, observational study of repeated LCI measurement at time of clinical review in patients with CF >5 years, delivered using a rapid wash-in system.

RESULTS: 112 patients completed at least one LCI assessment and 98 (90%) were still under follow-up at study end. The median (IQR) age was 14.7 (8.6-22.2) years and the mean (SD) FEV1 z-score was -1.2 (1.3). Of 81 subjects with normal FEV1 (>-2 z-scores), 63% had raised LCI (indicating worse lung function). For repeat stable measurements within 6 months, the mean (limits of agreement) change in LCI was 0.9% (-18.8% to 20.7%). A latent class growth model analysis identified four discrete clusters with high accuracy, differentiated by baseline LCI and FEV1. Baseline LCI was the strongest factor associated with longitudinal change. The median total test time was under 19 min.

CONCLUSIONS: Most patients with CF with well-preserved lung function show stable LCI over time. Cluster behaviours can be identified and baseline LCI is a risk factor for future progression. These results support the use of LCI in clinical practice in identifying patients at risk of lung function decline.

PMID:34301741 | DOI:10.1136/thoraxjnl-2021-216928

Cell Biosci. 2021 Jul 23;11(1):145. doi: 10.1186/s13578-021-00662-w.

ABSTRACT

Since CRISPR/Cas9 was harnessed to edit DNA, the field of gene therapy has witnessed great advances in gene editing. New avenues were created for the treatment of diseases such as Cystic Fibrosis (CF). CF is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Despite the success of gene editing with the CRISPR/Cas9 in vitro, challenges still exist when using CRISPR/Cas9 in vivo to cure CF lung disease. The delivery of CRISPR/Cas9 into lungs, as well as the difficulty to achieve the efficiency required for clinical efficacy, has brought forth new challenges. Viral and non-viral vectors have been shown to deliver DNA successfully in vivo, but the sustained expression of CFTR was not adequate. Before the introduction of Helper-Dependent Adenoviral vectors (HD-Ad), clinical trials of treating pulmonary genetic diseases with first-generation viral vectors have shown limited efficacy. With the advantages of larger capacity and lower immunogenicity of HD-Ad, together with the versatility of the CRISPR/Cas9 system, delivering CRISPR/Cas9 to the airway with HD-Ad for lung gene therapy shows great potential. In this review, we discuss the status of the application of CRISPR/Cas9 in CF gene therapy, the existing challenges in the field, as well as new hurdles introduced by the presence of CRISPR/Cas9 in the lungs. Through the analysis of these challenges, we present the potential of CRISPR/Cas9-mediated lung gene therapy using HD-Ad vectors with Cystic Fibrosis lung disease as a model of therapy.

PMID:34301308 | DOI:10.1186/s13578-021-00662-w

Sensors (Basel). 2021 Jul 20;21(14):4931. doi: 10.3390/s21144931.

ABSTRACT

Conventional lung auscultation is essential in the management of respiratory diseases. However, detecting adventitious sounds outside medical facilities remains challenging. We assessed the feasibility of lung auscultation using the smartphone built-in microphone in real-world clinical practice. We recruited 134 patients (median[interquartile range] 16[11-22.25]y; 54% male; 31% cystic fibrosis, 29% other respiratory diseases, 28% asthma; 12% no respiratory diseases) at the Pediatrics and Pulmonology departments of a tertiary hospital. First, clinicians performed conventional auscultation with analog stethoscopes at 4 locations (trachea, right anterior chest, right and left lung bases), and documented any adventitious sounds. Then, smartphone auscultation was recorded twice in the same four locations. The recordings (n = 1060) were classified by two annotators. Seventy-three percent of recordings had quality (obtained in 92% of the participants), with the quality proportion being higher at the trachea (82%) and in the children's group (75%). Adventitious sounds were present in only 35% of the participants and 14% of the recordings, which may have contributed to the fair agreement between conventional and smartphone auscultation (85%; k = 0.35(95% CI 0.26-0.44)). Our results show that smartphone auscultation was feasible, but further investigation is required to improve its agreement with conventional auscultation.

PMID:34300670 | DOI:10.3390/s21144931

Int J Mol Sci. 2021 Jul 16;22(14):7606. doi: 10.3390/ijms22147606.

ABSTRACT

Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) which instigates a myriad of respiratory complications including increased vulnerability to lung infections and lung inflammation. The extensive influx of pro-inflammatory cells and production of mediators into the CF lung leading to lung tissue damage and increased susceptibility to microbial infections, creates a highly inflammatory environment. The CF inflammation is particularly driven by neutrophil infiltration, through the IL-23/17 pathway, and function, through NE, NETosis, and NLRP3-inflammasome formation. Better understanding of these pathways may uncover untapped therapeutic targets, potentially reducing disease burden experienced by CF patients. This review outlines the dysregulated lung inflammatory response in CF, explores the current understanding of CFTR modulators on lung inflammation, and provides context for their potential use as therapeutics for CF. Finally, we discuss the determinants that need to be taken into consideration to understand the exaggerated inflammatory response in the CF lung.

PMID:34299226 | DOI:10.3390/ijms22147606

Int J Mol Sci. 2021 Jul 15;22(14):7590. doi: 10.3390/ijms22147590.

ABSTRACT

Different causative therapeutics for CF patients have been developed. There are still no mutation-specific therapeutics for some patients, especially those with rare CFTR mutations. For this purpose, high-throughput screens have been performed which result in various candidate compounds, with mostly unclear modes of action. In order to elucidate the mechanism of action for promising candidate substances and to be able to predict possible synergistic effects of substance combinations, we used a systems biology approach to create a model of the CFTR maturation pathway in cells in a standardized, human- and machine-readable format. It is composed of a core map, manually curated from small-scale experiments in human cells, and a coarse map including interactors identified in large-scale efforts. The manually curated core map includes 170 different molecular entities and 156 reactions from 221 publications. The coarse map encompasses 1384 unique proteins from four publications. The overlap between the two data sources amounts to 46 proteins. The CFTR Lifecycle Map can be used to support the identification of potential targets inside the cell and elucidate the mode of action for candidate substances. It thereby provides a backbone to structure available data as well as a tool to develop hypotheses regarding novel therapeutics.

PMID:34299207 | DOI:10.3390/ijms22147590

FEBS J. 2021 Jul 23. doi: 10.1111/febs.16135. Online ahead of print.

ABSTRACT

Cyanide is traditionally viewed as a cytotoxic agent, with its primary mode of action being the inhibition of mitochondrial Complex IV (cytochrome c oxidase). However, recent studies demonstrate that the effect of cyanide on Complex IV in various mammalian cells is biphasic: in lower concentrations (nanomolar to low micromolar) cyanide stimulates Complex IV activity, increases ATP production and accelerates cell proliferation, while at higher concentrations (high micromolar to low millimolar) it produces the previously known ("classic") toxic effects. The first part of the article describes the cytotoxic actions of cyanide in the context of environmental toxicology, and highlights pathophysiological conditions (e.g. cystic fibrosis with Pseudomonas colonization) where bacterially-produced cyanide exerts deleterious effects to the host. The second part of the article summarizes the mammalian sources of cyanide production and overviews the emerging concept that mammalian cells may produce cyanide, in low concentrations, to serve biological regulatory roles. Cyanide fulfills many of the general criteria as a 'classical' mammalian gasotransmitter and shares some common features with the current members of this class: nitric oxide, carbon monoxide and hydrogen sulfide.

PMID:34297873 | DOI:10.1111/febs.16135

Vet Rec. 2021 Jul;189(2):78-79. doi: 10.1002/vetr.756.

NO ABSTRACT

PMID:34297394 | DOI:10.1002/vetr.756

J Vasc Access. 2021 Jul 23:11297298211035310. doi: 10.1177/11297298211035310. Online ahead of print.

ABSTRACT

OBJECTIVE: Short midline catheter use in paediatric populations appears to be increasing, however data on success rates and efficacy are sparse. This study aims to describe the success rate when midline venous catheters are employed as a single device for intravenous antibiotic therapy in paediatric patients with cystic fibrosis.

METHODS: A retrospective cohort study was performed in a single institution, retrieving electronic medical record data from July 2017 through March 2020. The primary outcome was device success, defined as a catheter that remained functional until the end of antibiotic therapy. Reasons for device failure were categorized in a standard fashion.

RESULTS: Primary outcome data were available for 116 catheter insertions, involving 49 patients and 55 proceduralists. The success rate was 84% (n = 98). Median age at insertion was 15 years (range 4-19) and median weight 52 kg (13-81). Soft, polyether block amide, Arrow® Seldinger Arterial Catheters were employed. Only 16 patients (14%) required general anaesthesia. Median time to failure was 6 days, and median time to successful completion of treatment was 13 days. Six of 18 failures occurred within 48 h and were likely insertion complications. The most common reasons for device failure were occlusion, extravasation, phlebitis and dislodgement. More than half of patients (56%) received antibiotic therapy at home.

CONCLUSION: There is a high single device success rate when inserting short midlines for 13-day intravenous pulmonary antibiotic therapy in children with cystic fibrosis. These results should be confirmed with a prospective study.

PMID:34296638 | DOI:10.1177/11297298211035310

Eur Arch Otorhinolaryngol. 2021 Jul 22. doi: 10.1007/s00405-021-06875-6. Online ahead of print.

ABSTRACT

PURPOSE: Chronic rhinosinusitis (CRS) is observed in almost 100% of patients with cystic fibrosis (CF). CF-related CRS treatment is extremely challenging because of the underlying genetic defect leading to its development. CRS in CF is often refractory to standard therapy, while recurrences after surgical treatment are inevitable in the majority of patients. This study provides a precise review of the current knowledge regarding possible therapeutic options for CF-related CRS.

METHODS: The Medline and Web of Science databases were searched without a time limit using the terms "cystic fibrosis" in conjunction with "otorhinolaryngological manifestation", "rhinology" and "sinusitis".

RESULTS: Precise guidelines for CF-induced CRS therapy are lacking due to the lack of large cohort randomized controlled trials. None of the existing therapeutic agents has already been recommended for CRS in CF. Therapy targeting the underlying genetic defect, intranasal dornase alfa administration, and topical delivery of colistin and tobramycin showed promising results in CF-related CRS therapy. Besides the potential effectiveness of nasal steroids, strong recommendations for their usage in CF have not been provided yet. Systemic corticosteroid usage is controversial due to its potential negative influence on pulmonary disease. Ibuprofen revealed some positive effects on CF-related CRS in molecular and small cohort studies. Intranasal irrigation with saline solutions could relieve sinonasal symptoms. Nasal decongestants are not recommended. Endoscopic sinus surgery is the first-line surgical option for refractory CRS. Extensive surgical approaches should be considered as they could improve long-term outcomes in CRS.

CONCLUSION: Further studies are warranted to establish consensus for CF-related CRS therapy.

PMID:34296343 | DOI:10.1007/s00405-021-06875-6

Front Pediatr. 2021 Jul 6;9:645063. doi: 10.3389/fped.2021.645063. eCollection 2021.

ABSTRACT

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, data registered in the European countries revealed increasing cases of infection in cystic fibrosis (CF) patients. In the course of this pandemic, we enrolled 17 CF patients for a study evaluating inflammatory markers. One of them developed COVID-19, giving us the possibility to analyze inflammatory markers in the acute phase as compared to levels detected before and after the infectious episode and to levels measured in the other CF patients enrolled to the study who did not experience COVID-19 and 23 patients referred to our center for SARS-CoV-2 infection.

PMID:34295857 | PMC:PMC8291286 | DOI:10.3389/fped.2021.645063

Breathe (Sheff). 2021 Mar;17(1):210013. doi: 10.1183/20734735.0013-2021.

ABSTRACT

Treatment for cystic fibrosis interweaves with daily life and can be burdensome, but hope is ever present with the continuing advancement of treatment. https://bit.ly/36PZnSL.

PMID:34295412 | PMC:PMC8291944 | DOI:10.1183/20734735.0013-2021

Breathe (Sheff). 2021 Mar;17(1):210005. doi: 10.1183/20734735.0005-2021.

ABSTRACT

Advances in therapies and management of conditions encountered by paediatric respiratory specialists have led to improved outcomes and improved survival rates dramatically in chronic diseases such as cystic fibrosis. However, this has also meant an increase in treatment burden. A variety of inhaled treatments are crucial in managing paediatric respiratory diseases, but these patients also have to take many oral medications. It is widely recognised that developing oral formulations appropriate for the paediatric population can affect how well a product is received by patients and their families. Consideration should be given to palatability and the number of medicines to be administered as these can all contribute to treatment adherence. Polypharmacy specifically in the context of management of patients with cystic fibrosis is not a new concept, but the recently introduced cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies and their potential for interactions and adverse reactions create novel challenges. There are some strategies that families and healthcare professionals can implement to reduce treatment burden. This review will also provide some insight into the life of a teenager with cystic fibrosis and the relative complexities of her treatment and the impacts on daily life.

EDUCATIONAL AIMS: To describe the difficulties faced by children with long-term respiratory conditions having to take oral medication.To discuss oral drug interactions that may exist within paediatric respiratory medicine and to consider issues with polypharmacy.To highlight strategies that may be used to reduce the burden of care for children on oral medication.

PMID:34295409 | PMC:PMC8291910 | DOI:10.1183/20734735.0005-2021

Int J Chron Obstruct Pulmon Dis. 2021 Jul 16;16:2119-2127. doi: 10.2147/COPD.S311236. eCollection 2021.

ABSTRACT

BACKGROUND AND OBJECTIVE: Prescribing inhaled corticosteroids (ICS) for bronchiectasis (BE) in the absence of obstructive lung disease is controversial. Studies investigating ICS therapy and impact on morbidity and mortality in BE are sparse.

METHODS: This study comprises all patients with BE managed at respiratory outpatient clinics at two university hospitals in the Capital Region of Denmark 2014-2015. Baseline data were obtained from patient medical records, and patients were followed until April 2020.

RESULTS: Out of 264 patients, 122 (46%) were prescribed ICS with no demographic differences between users/non-users of ICS. Among patients prescribed ICS, 21% did not have a concomitant diagnosis of asthma or COPD. Patients prescribed ICS had lower lung function (median FEV1 65.2 vs 80.9%pred, p<0.001) and a higher symptom burden in terms of cough (p 0.028), sputum production (p <0.001) and dyspnea (p <0.001). Pseudomonas-positive sputum cultures were more common in ICS-treated patients (6.5 vs 20%, p 0.010), as were previous severe exacerbations (41% vs 21%, p <0.001). In terms of mortality, high-dose ICS use was associated with increased mortality in multivariable Cox regression adjusted for age, sex, FEV1 and concomitant asthma/COPD (HR 4.93 [95% CI 1.73-14.0], p 0.003).

CONCLUSION: In this cohort, close to one out of five patients with BE were prescribed ICS despite having no concomitant diagnosis of asthma or COPD. Overall, ICS treatment was associated with higher morbidity and mortality, though causation is difficult to establish.

PMID:34295156 | PMC:PMC8291380 | DOI:10.2147/COPD.S311236

Pulm Pharmacol Ther. 2021 Jul 19:102058. doi: 10.1016/j.pupt.2021.102058. Online ahead of print.

ABSTRACT

BACKGROUND: /Question: Nontuberculous mycobacteria (NTM) infections are increasingly detected but difficult to cure given complex drug-resistance patterns. Select U.S. centers have incorporated clofazimine in the treatment of NTM but experience is limited as procurement restrictions hamper widespread use.

METHODS: A prospective cohort study was performed in patients diagnosed with pulmonary or extrapulmonary NTM infection and treated with clofazimine between February 2015 and April 2019 at a tertiary referral hospital. Treatment success was defined by a combined outcome of clinical stabilization, microbiologic cure and radiologic improvement. Secondary outcomes included all-cause mortality and time to sputum culture conversion. Uni/multi-variate regression were used to define associations between pre-determined predictor variables and overall treatment outcome.

RESULTS: Of 44 patients enrolled, 39 (89%) received clofazimine along with a median of 3 concomitant antibiotics. Thirty-one (80%) of patients had pulmonary NTM infection, with Mycobacterium abscessus group and Mycobacterium avium complex being the most common species groups identified. Of 36 people with evaluable outcomes, 35 (97%) survived and 22 (58%) had treatment success, including 12 of 19 (63%) with Mycobacterium abscessus group. In multivariate analysis, patients with Mycobacterium abscessus group were more likely to experience treatment success (OR 18.22, 95%CI 0.972-341.43, p=0.052), while macrolide resistance predicted a lack of treatment success (OR 0.053, 95%CI 0.003-0.841, p= 0.037). Clofazimine was well-tolerated.

CONCLUSION: Adding clofazimine to multi-class antibiotic regimens for drug-resistant NTM infection led to treatment success in the majority treated. Randomized controlled studies are needed to determine the individual impact of clofazimine within an otherwise optimized drug regimen.

PMID:34293446 | DOI:10.1016/j.pupt.2021.102058