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BACKGROUND: In patients with interstitial lung disease (ILD), exercise-induced desaturation during the 6-min walk test (6MWT), specifically nadir oxygen saturation (nSpO2) of ≤88 % is a negative prognostic marker. As the 6MWT is often impractical for ILD patients, the aim of this study is to compare the 1-min sit-to-stand test (1minSTS) with the 6MWT to detect exercise-induced desaturation. METHODS: Participants were recruited from a tertiary referral clinic with both tests performed on the same day. Utilising Bland-Altman analysis, the relationship between nSpO2 on 1minSTS and 6MWT was determined. An area under the receiver operating characteristic curve (AUC) determined the ability of nSpO2 on 1minSTS test to predict SpO2 ≤88 % on 6MWT. RESULTS: Fifty participants completed the study (idiopathic pulmonary fibrosis n = 24, 48 %; connective tissue disease associated ILD n = 20, 40 %; other ILD n = 6, 12 %). Mean (SD) FVC%pred was 73 ± 16 %, mean DLCO%pred 57 ± 16 % and resting SpO2 99 ± 1 %. The 1minSTS resulted in less exercise-induced oxygen desaturation, with a median IQR nSpO2 of 95 % (89-98) and 93 % (85-96) respectively (p < 0.001). Moderate agreement was determined between the nSpO2 on both tests, with a mean difference of 3.2 % [-14 to +3.0 %]. The 1minSTS test accurately identified participants with nSpO2 ≤88 % on 6MWT (AUC 0.96). Oxygen desaturation ≤94 % during the 1minSTS test provided 100 % sensitivity and 87 % specificity for oxygen desaturation ≤88 % at 6MWT. CONCLUSION: This study demonstrates that exercise-induced oxygen desaturation during the 1minSTS test correlates with oxygen desaturation on 6MWT. The 1minSTS may be a practical screening tool for ILD patients who would benefit from further exercise testing.
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BACKGROUND AND AIMS: The experience of outpatient care may differ for select patient groups. This prospective study evaluates the adult patient experience of multidisciplinary outpatient cystic fibrosis (CF) care with videoconferencing through telehealth compared with face-to-face care the year prior. METHODS: People with CF without a lung transplant were recruited. Patient-reported outcomes were obtained at commencement and 12 months into the study, reflecting both their face-to-face and telehealth through videoconferencing experience, respectively. Three patient cohorts were analysed: (i) participants with a regional residence, (ii) participants with a nonregional including metropolitan residence and (iii) participants with colonised multiresistant microbiota. RESULTS: Seventy-four patients were enrolled in the study (mean age, 37 ± 11 years; 50% male; mean forced expiratory volume in the first second of expiration, 60% [standard deviation, 23]) between February 2020 and May 2021. No differences between models were observed in the participants' rating of the health care team, general and mental health rating, and their confidence in handling treatment plans at home. No between-group differences in the Cystic Fibrosis Questionnaire - Revised (CFQ-R) were observed. Travel duration and the cost of attending a clinic was significantly reduced, particularly for the regional group (4 h, AU$108 per clinic; P < 0.05). A total of 93% respondents preferred to continue with a hybrid approach. CONCLUSION: In this pilot study, participants' experience of care and quality of life were no different with face-to-face and virtual care between the groups. Time and cost-savings, particularly for patients living in regional areas, were observed. Most participants preferred to continue with a hybrid model for outpatient care.
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Background: Cystic fibrosis (CF) is caused by a wide spectrum of mutations in the CF transmembrane conductance regulator (CFTR) gene, with some leading to non-classical clinical presentations. We present an integrated in vivo, in silico and in vitro investigation of an individual with CF carrying the rare Q1291H-CFTR allele and the common F508del allele. At age 56 years, the participant had obstructive lung disease and bronchiectasis, qualifying for Elexacaftor/Tezacaftor/Ivacaftor (ETI) CFTR modulator treatment due to their F508del allele. Q1291H CFTR incurs a splicing defect, producing both a normally spliced but mutant mRNA isoform and a misspliced isoform with a premature termination codon, causing nonsense mediated decay. The effectiveness of ETI in restoring Q1291H-CFTR is largely unknown. Methods: We collected clinical endpoint measurements, including forced expiratory volume in 1 s percent predicted (FEV1pp) and body mass index (BMI), and examined medical history. In silico simulations of the Q1291H-CFTR were compared to Q1291R, G551D, and wild-type (WT)-CFTR. We quantified relative Q1291H CFTR mRNA isoform abundance in patient-derived nasal epithelial cells. Differentiated pseudostratified airway epithelial cell models at air liquid interface were created and ETI treatment impact on CFTR was assessed by electrophysiology assays and Western blot. Results: The participant ceased ETI treatment after 3 months due to adverse events and no improvement in FEV1pp or BMI. In silico simulations of Q1291H-CFTR identified impairment of ATP binding similar to known gating mutants Q1291R and G551D-CFTR. Q1291H and F508del mRNA transcripts composed 32.91% and 67.09% of total mRNA respectively, indicating 50.94% of Q1291H mRNA was misspliced and degraded. Mature Q1291H-CFTR protein expression was reduced (3.18% ± 0.60% of WT/WT) and remained unchanged with ETI. Baseline CFTR activity was minimal (3.45 ± 0.25 µA/cm2) and not enhanced with ETI (5.73 ± 0.48 µA/cm2), aligning with the individual's clinical evaluation as a non-responder to ETI. Conclusion: The combination of in silico simulations and in vitro theratyping in patient-derived cell models can effectively assess CFTR modulator efficacy for individuals with non-classical CF manifestations or rare CFTR mutations, guiding personalized treatment strategies and optimizing clinical outcomes.
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BACKGROUND: Sleep is paramount for optimal brain development in infants admitted to the neonatal intensive care unit. Besides (minimally) invasive technical approaches to study sleep in infants, there is currently a large variety of behavioral sleep stage classification methods (BSSCs) that can be used to identify sleep stages in preterm infants born <37 weeks gestational age. However, they operate different criteria to define sleep stages, which limits the comparability and reproducibility of research on preterm sleep. This scoping review aims to: 1) identify and elaborate on existing neonatal BSSCs used for preterm infants, 2) examine the reliability and validity of these BSSCs, and 3) identify which criteria are most used for different ages, ranging from 23 to 37 weeks postmenstrual age at observation. METHODS: To map the existing BSSCs, PubMed, EMBASE and Cochrane were searched for studies using a BSSC to identify sleep stages in preterm infants. RESULTS: In total, 36 BSSCs were identified with on average five item categories assessed per BSSC, most frequently: eyes, body movements, facial movements, sounds, and respiratory pattern. Furthermore, validity and reliability of the BSSCs were tested in less than half of the included studies. Finally, BSSCs were used in infants of all ages, regardless the age for which the BSSC was originally developed. CONCLUSIONS: Items used for scoring in the different BSSCs were relatively consistent. The age ranges, reliability, and validity of the BSSCs were not consistently reported in most studies. Either validation studies of existing BSSCs or new BSSCs are necessary to improve the comparability and reproducibility of previous and future preterm behavioral sleep studies.
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Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Humanos , Lactente , Recém-Nascido , Reprodutibilidade dos Testes , Sono , Fases do SonoRESUMO
Spirometry is usually performed under the supervision of a trained respiratory scientist to ensure acceptability and repeatability of results. To evaluate the quality of spirometry performance by adult cystic fibrosis (CF) patients with and without observation by a trained respiratory scientist, an observational, single centre study was conducted between February to December 2020. 74 adults were recruited and instructed to perform spirometry without supervision within 24 h of their remote CF clinic consultation. Spirometry was repeated at their consultation, supervised by a respiratory scientist using video conferencing. The majority of patients achieved grade A (excellent) or B (very good) spirometry quality with (95%) and without supervision (93%) independent of lung function severity. Similarly, forced expiratory volume in 1 second demonstrated no significant differences with paired spirometry performed within a 24 hour period. For a large proportion of adult CF patients, unsupervised portable spirometry produces acceptable and repeatable results.
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Fibrose Cística/terapia , Qualidade da Assistência à Saúde , Espirometria/métodos , Telemedicina/métodos , Adulto , Feminino , Serviços de Assistência Domiciliar , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Cystic fibrosis (CF) is a genetic disorder causing dysfunctional ion transport resulting in accumulation of viscous mucus that fosters chronic bacterial biofilm-associated infection in the airways. Achromobacter xylosoxidans and Stenotrophomonas maltophilia are increasingly prevalent CF pathogens and while Burkholderia cencocepacia is slowly decreasing; all are complicated by multidrug resistance that is enhanced by biofilm formation. This study investigates potential synergy between the antibiotics ciprofloxacin (0.5-128 µg/mL), colistin (0.5-128 µg/mL) and tobramycin (0.5-128 µg/mL) when combined with the neutral pH form of N-Acetylcysteine (NACneutral) (0.5-16.3 mg/mL) against 11 cystic fibrosis strains of Burkholderia, Stenotrophomonas and Achromobacter sp. in planktonic and biofilm cultures. We screened for potential synergism using checkerboard assays from which fraction inhibitory concentration indices (FICI) were calculated. Synergistic (FICI ≤ 0.5) and additive (0.5 > FICI ≥ 1) combinations were tested on irreversibly attached bacteria and 48 h mature biofilms via time-course and colony forming units (CFU/mL) assays. This study suggests that planktonic FICI analysis does not necessarily translate to reduction in bacterial loads in a biofilm model. Future directions include refining synergy testing and determining further mechanisms of action of NAC to understand how it may interact with antibiotics to better predict synergy.
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Premature birth (before 37 weeks of gestation) has been linked to a variety of adverse neurological outcomes. Sleep problems are associated with decreased neurocognitive functioning, which is especially common in children born preterm. The exact relationship between prematurity and sleep at school age is unknown. A systematic review is performed with the aim to assess the relationship between prematurity and sleep at school age (5th to 18th year of life), in comparison to sleep of their peers born full-term. Of 347 possibly eligible studies, nine were included. The overall conclusion is that prematurity is associated with earlier bedtimes and a lower sleep quality, in particular more nocturnal awakenings and more non-rapid eye movement stage 2 sleep. Interpretations and limitations of the review are discussed. Moreover, suggestions for future research are brought forward, including the need for a systematic approach with consistent outcome measures in this field of research. A better understanding of the mechanisms that influence sleep in the vulnerable group of children born preterm could help optimize these children's behavioral and intellectual development.
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Nascimento Prematuro , Criança , Cognição , Feminino , Humanos , Recém-Nascido , Gravidez , Instituições Acadêmicas , SonoRESUMO
BACKGROUND: Lumacaftor/ivacaftor (LUM/IVA) improves outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with ppFEV1 > 40%. There is limited safety or efficacy data in patients with ppFEV1 < 40%. We determined whether LUM/IVA in patients with ppFEV1 < 40 would reduce the rate of pulmonary exacerbations. METHODS: This was a case control study performed on patients > 12 years, homozygous for Phe508del CFTR mutation and with ppFEV1 < 40%. Control subjects were matched for age, sex and ppFEV1, and had mutations ineligible for LUM/IVA. We assessed the rate of pulmonary exacerbations requiring intravenous antibiotics, the mean rate of change in ppFEV1 over 12 months and all adverse events. RESULTS: Data was collected from 7 Australian CF centres on 105 patients; 72 on LUM/IVA and 33 controls. LUM/IVA demonstrated a large reduction in exacerbations with an incident rate ratio of 0.455 (95%CI; 0.306 - 0.676), p < 0.001 after adjusting for the number of exacerbations in the previous 12 months. LUM/IVA prolonged the time to first exacerbation and reduced the rate of decline in ppFEV1 over 12 months. Adverse events were common; chest tightness or dyspnoea was experienced by 55% and resulted in cessation of treatment in 32%. CONCLUSIONS: Treatment with LUM/IVA resulted in a substantially lower rate of pulmonary exacerbations, prolonged time to first exacerbation and slowed the rate of decline of ppFEV1 in participants with severe lung disease. Adverse reactions to LUM/IVA however were unacceptably frequent, and resulted in a very high discontinuation rate.
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Antibacterianos/administração & dosagem , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística , Infecções Respiratórias , Administração Intravenosa , Adulto , Aminofenóis/administração & dosagem , Aminofenóis/efeitos adversos , Aminopiridinas/administração & dosagem , Aminopiridinas/efeitos adversos , Austrália/epidemiologia , Benzodioxóis/administração & dosagem , Benzodioxóis/efeitos adversos , Estudos de Casos e Controles , Agonistas dos Canais de Cloreto/administração & dosagem , Agonistas dos Canais de Cloreto/efeitos adversos , Fibrose Cística/complicações , Fibrose Cística/diagnóstico , Fibrose Cística/genética , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Mutação , Quinolonas/administração & dosagem , Quinolonas/efeitos adversos , Testes de Função Respiratória/métodos , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/etiologia , Exacerbação dos SintomasRESUMO
PURPOSE: Australian data regarding the management of patients with bronchiectasis is scarce. We sought to compare the management of adults with bronchiectasis attending tertiary Australian centres with recent national and international guidelines. METHODS: The Australian Bronchiectasis Registry is a centralised database of patients with radiologically confirmed bronchiectasis unrelated to cystic fibrosis recruited from 14 tertiary Australian hospitals. We excluded children (<18 years) and those with incomplete data, leaving 589 adults for cross-sectional analyses. We compared the proportion of patients receiving certain therapies, as compared to the proportion eligible for those treatments according to the current guidelines and baseline clinical information available from the registry. RESULTS: Pulmonary rehabilitation was attended by 22%, although it was indicated in 67% of the cohort. Airway clearance was undertaken in 52% of patients, although 71% reported chronic productive cough. Sputum bacterial culture results were available for 59%, and mycobacterial culture results were available for 29% of the cohort. Inhaled antibiotics were used in half of potentially eligible patients. Despite guideline recommendations against routine use, inhaled corticosteroids were used in 48% of patients. Long-term macrolides were used in 28% of participants. CONCLUSIONS: Discrepancies exist between guideline recommendations and real-world treatment of bronchiectasis in Australia, even in tertiary centres. These findings suggest the need for increased patient referral to pulmonary rehabilitation, increased attention to airway clearance, increased collection of sputum samples (especially for mycobacterial culture) and rationalisation of inhaled corticosteroid use. These findings encourage a review of treatment access and will inform ongoing education to promote evidence-based care for people living with bronchiectasis.
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Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Bronquiectasia/terapia , Medicina Baseada em Evidências , Fidelidade a Diretrizes/estatística & dados numéricos , Modalidades de Fisioterapia/estatística & dados numéricos , Terapia Respiratória/estatística & dados numéricos , Centros de Atenção Terciária , Administração por Inalação , Idoso , Austrália , Bronquiectasia/complicações , Broncodilatadores/uso terapêutico , Feminino , Infecções por Haemophilus/complicações , Infecções por Haemophilus/tratamento farmacológico , Acessibilidade aos Serviços de Saúde , Humanos , Macrolídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Guias de Prática Clínica como Assunto , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológicoRESUMO
BACKGROUND: /objective: There are no large, multi-centre studies of Australians with bronchiectasis. The Australian Bronchiectasis Registry (ABR) was established in 2015 to create a longitudinal research platform. We aimed to describe the baseline characteristics of adult ABR participants and assess the impact of disease severity and exacerbation phenotype on quality of life (QoL). METHODS: The ABR is a centralised database of patients with radiologically confirmed bronchiectasis unrelated to cystic fibrosis. We analysed the baseline data of adult patients (≥18 years). RESULTS: From March 2016-August 2018, 799 adults were enrolled from 14 Australian sites. Baseline data were available for 589 adults predominantly from six tertiary centres (420 female, median age 71 years (interquartile range 64-77), 14% with chronic Pseudomonas aeruginosa infection). Most patients had moderate or severe disease based on the Bronchiectasis Severity Index (BSI) (84%) and FACED (59%) composite scores. Using Global Lung function Initiative-2012 reference equations, the majority of patients (48%) had normal spirometry; only 34% had airflow obstruction (FEV1/FVCâ¯<â¯LLN). Disease severity scores (BSI and FACED) were negatively correlated with QoL-Bronchiectasis domain scores (rs between -0.09 and -0.58). The frequent exacerbator phenotype (≥3 in the preceding year) was identified in 23%; this group had lower scores in all QoL-B domains (pâ¯≤â¯0.001) and more hospitalisations (pâ¯<â¯0.001) than those with <3 exacerbations. CONCLUSIONS: The largest cohort of Australian adults with bronchiectasis has been described. Using contemporary criteria, most patients with bronchiectasis did not have airflow obstruction. The frequent exacerbation trait connotes poorer QoL and greater health-care utilisation.
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Bronquiectasia , Progressão da Doença , Qualidade de Vida , Sistema de Registros , Índice de Gravidade de Doença , Idoso , Austrália , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Once neglected in research and underappreciated in practice, there is renewed interest in bronchiectasis unrelated to cystic fibrosis. Bronchiectasis is a chronic lung disease characterised by chronic cough, sputum production and recurrent pulmonary exacerbations. It is diagnosed radiologically on high resolution computed tomography chest scan by bronchial dilatation (wider than the accompanying artery). The causes of bronchiectasis are diverse and include previous respiratory tract infections, chronic obstructive pulmonary disease, asthma, immunodeficiency and connective tissue diseases. A large proportion of cases are idiopathic, reflecting our incomplete understanding of disease pathogenesis. Progress in the evidence base is reflected in the 2017 European management guidelines and the 2015 update to the Australian guidelines. Effective airway clearance remains the cornerstone of bronchiectasis management. This should be personalised and reviewed regularly by a respiratory physiotherapist. There is now robust evidence for the long term use of oral macrolide antibiotics in selected patients to reduce exacerbation frequency. The routine use of long term inhaled corticosteroids and/or long-acting bronchodilators should be avoided, unless concomitant chronic obstructive pulmonary disease or asthma exists. The evidence for nebulised agents including hypertonic saline, mannitol and antibiotics is evolving; however, access is challenging outside tertiary clinics, and nebulising equipment is required. Smokers should be supported to quit. All patients should receive influenza and pneumococcal vaccination. Patients with impaired exercise capacity should attend pulmonary rehabilitation. There is an important minority of patients for whom aetiology-specific treatment exists. The prevalence of bronchiectasis is increasing worldwide; however, the burden of disease within Australia is not well defined. To this end, the Australian Bronchiectasis Registry began recruitment in 2016 and is interoperable with the European and United States bronchiectasis registries to enable collaborative research. The recent addition of a bronchiectasis diagnosis-related group to the Australian Refined Diagnostic Related Group classification system will allow definition of the disease burden within the Australian hospital system.