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BACKGROUND AND OBJECTIVE: The importance of extracellular traps (ETs) in chronic respiratory conditions is increasingly recognized but their role in paediatric bronchiectasis is poorly understood. The specialized techniques currently required to study ETs preclude routine clinical use. A simple and cost-effective ETs detection method is needed to support diagnostic applications. We aimed to determine whether ETs could be detected using light microscopy-based assessment of Romanowsky-stained bronchoalveolar lavage (BAL) slides from children with bronchiectasis, and whether the ETs cellular origin could be determined. METHODS: Archived Romanowsky-stained BAL slides from a cross-sectional study of children with bronchiectasis were examined for ETs using light microscopy. The cellular origin of individual ETs was determined based on morphology and physical contact with surrounding cell(s). RESULTS: ETs were observed in 78.7% (70/89) of BAL slides with neutrophil (NETs), macrophage (METs), eosinophil (EETs) and lymphocyte (LETs) ETs observed in 32.6%, 51.7%, 4.5% and 9%, respectively. ETs of indeterminate cellular origin were present in 59.6% of slides. Identifiable and indeterminate ETs were co-detected in 43.8% of slides. CONCLUSION: BAL from children with bronchiectasis commonly contains multiple ET types that are detectable using Romanowsky-stained slides. While specialist techniques remain necessary to determining the cellular origin of all ETs, screening of Romanowsky-stained slides presents a cost-effective method that is well-suited to diagnostic settings. Our findings support further research to determine whether ETs can be used to define respiratory endotypes and to understand whether ETs-specific therapies may be required to resolve airway inflammation among children with bronchiectasis.
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Bronquiectasia , Armadilhas Extracelulares , Criança , Humanos , Líquido da Lavagem Broncoalveolar , Estudos Transversais , Lavagem Broncoalveolar , Bronquiectasia/diagnóstico , FibroseRESUMO
BACKGROUND AND OBJECTIVE: Long-term data on children with PBB has been identified as a research priority. We describe the 5-year outcomes for children with PBB to ascertain the presence of chronic respiratory disease (bronchiectasis, recurrent PBB and asthma) and identify the risk factors for these. METHODS: Prospective cohort study was undertaken at the Queensland Children's Hospital, Brisbane, Australia, of 166 children with PBB and 28 controls (undergoing bronchoscopy for symptoms other than chronic wet cough). Monitoring was by monthly contact via research staff. Clinical review, spirometry and CT chest were performed as clinically indicated. RESULTS: A total of 194 children were included in the analysis. Median duration of follow-up was 59 months (IQR: 50-71 months) post-index PBB episode, 67.5% had ongoing symptoms and 9.6% had bronchiectasis. Significant predictors of bronchiectasis were recurrent PBB in year 1 of follow-up (ORadj = 9.6, 95% CI: 1.8-50.1) and the presence of Haemophilus influenzae in the BAL (ORadj = 5.1, 95% CI: 1.4-19.1). Clinician-diagnosed asthma at final follow-up was present in 27.1% of children with PBB. A significant BDR (FEV1 improvement >12%) was obtained in 63.5% of the children who underwent reversibility testing. Positive allergen-specific IgE (ORadj = 14.8, 95% CI: 2.2-100.8) at baseline and bronchomalacia (ORadj = 5.9, 95% CI: 1.2-29.7) were significant predictors of asthma diagnosis. Spirometry parameters were in the normal range. CONCLUSION: As a significant proportion of children with PBB have ongoing symptoms at 5 years, and outcomes include bronchiectasis and asthma, they should be carefully followed up clinically. Defining biomarkers, endotypes and mechanistic studies elucidating the different outcomes are now required.
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Infecções Bacterianas , Bronquiectasia , Bronquite Crônica , Bronquite , Tosse/fisiopatologia , Bronquiectasia/epidemiologia , Bronquite/diagnóstico , Bronquite/epidemiologia , Criança , Humanos , Estudos ProspectivosRESUMO
BACKGROUND: Chronic neutrophilic inflammation, in both the presence and absence of infection, is a feature of bronchiectasis in adults and children. The anti-inflammatory properties of non-steroid anti-inflammatory drugs (NSAIDs) may be beneficial in reducing airway inflammation, thus potentially improving lung function and quality of life in patients with bronchiectasis. OBJECTIVES: To evaluate the efficacy of inhaled NSAIDs in the management of non-cystic fibrosis bronchiectasis in children and adults:⢠during stable bronchiectasis; and⢠for reduction of:∘ severity and frequency of acute respiratory exacerbations; and∘ long-term pulmonary decline. SEARCH METHODS: We searched the Cochrane Airways Group Trials Register, which includes reports identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched the trial registry ClinicalTrials.gov and the World Health Organization (WHO) trial portal. We carried out the latest searches on 22 September 2015. SELECTION CRITERIA: All randomised controlled trials comparing inhaled NSAIDs versus a control (placebo or usual treatment) in children or adults with bronchiectasis not related to cystic fibrosis. DATA COLLECTION AND ANALYSIS: We reviewed the results of searches against predetermined criteria for inclusion. MAIN RESULTS: One small, short-term trial was eligible for inclusion. We included this study of 25 adults with chronic lung disease (only 32% of people included in the trial had bronchiectasis), as the other conditions were linked to development of bronchiectasis, and all were characterised by chronic sputum production. We were not able to obtain separate data for people with a diagnosis of bronchiectasis. We judged that the study was at a high risk of selection bias.The primary outcome (mean difference in control of bronchiectasis severity, quality of life (Qol), cough scores) was not reported in the included study. The single trial in adults reported a significant reduction in sputum production over 14 days for the treatment group (inhaled indomethacin) compared with the placebo group (mean difference (MD) -75.00 g/day; 95% confidence interval (CI) -134.61 to -15.39) and a significant improvement in the Borg Dyspnoea Scale score (MD -1.90, 95% CI -3.15 to -0.65). We noted no significant differences between groups in lung function or blood indices and no reported adverse events. AUTHORS' CONCLUSIONS: No new studies of adults or children have been conducted since the last version of this review was published. Therefore, final conclusions have not changed. Current evidence is insufficient to support or refute the use of inhaled NSAIDs for the management of bronchiectasis in adults or children. One small trial reported a reduction in sputum production and improved dyspnoea among adults with chronic lung disease who were treated with inhaled indomethacin, indicating that additional studies on the efficacy of NSAIDs for treatment of patients with bronchiectasis are warranted.
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Anti-Inflamatórios não Esteroides/administração & dosagem , Bronquiectasia/tratamento farmacológico , Administração por Inalação , Adulto , Criança , Dispneia/tratamento farmacológico , Humanos , Escarro/metabolismoRESUMO
AIMS: The primary aim of this study was to determine the frequency of vitD deficiency/insufficiency in an opportunistic sample of Northern Territory (NT) children. The secondary aim was to evaluate whether: (i) 25(OH)vitD (25(OH)D) levels differ between Indigenous/non-Indigenous children; and (ii) VitD insufficiency is associated with increased acute/infective hospitalisations. METHODS: Twenty-five (OH)D levels were measured in 98 children <16 years between August 2011 and January 2012 (children hospitalised acutely/non-acutely and well children from other studies based in Darwin). VitD deficiency was defined as 25(OH)D < 50 nmol/L, and insufficiency was postulated to be <75 nmol/L. Demographic data were collected, and computer records were reviewed. RESULTS: Median age was 59 months (range 2-161); 3.1% were vitD deficient, 19.4% insufficient. There was no significant difference in mean 25(OH)D level between Indigenous (93.2, standard deviation (SD) 21.9, n = 42) and non-Indigenous (97.3, SD 27.9, n = 56) children (P = 0.32). Median number of hospitalisations/year were similar (P = 0.319) between vitD sufficient (0.34, range 0-12, n = 76) and insufficient (0.22, 0-6, n = 22) children. There was no significant difference between number of infective admissions per year between vitD sufficient/insufficient groups (P = 0.119). CONCLUSIONS: Compared with US data (19% deficient, 65% insufficient) fewer NT children are vitD deficient/insufficient. In our limited sample, being vitD insufficient was not associated with increased acute/infective hospitalisations, but a larger unbiased sample of NT children is needed. More information is needed about the optimum level of vitD for non-bone-related health in children.
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Deficiência de Vitamina D/epidemiologia , Adolescente , Peso Corporal , Criança , Pré-Escolar , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Masculino , Northern Territory/epidemiologia , Prevalência , Deficiência de Vitamina D/etnologiaRESUMO
BACKGROUND: Indigenous Australian children living in remote communities experience high rates of acute otitis media with tympanic membrane perforation (AOMwiP). Otitis media in this population is associated with dense nasopharyngeal colonization of three primary otopathogens; Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Little is known about the relative abundance of these pathogens during infection. The objective of this study was to estimate the abundance and concordance of otopathogens in ear discharge and paired nasopharyngeal swabs from children with AOMwiP (discharge of not more than 6 weeks' duration and perforation size <2%). METHODS: Culture and quantitative PCR (qPCR) estimation of H. influenzae, S. pneumoniae, M. catarrhalis and total bacterial load were performed on paired nasopharyngeal and ear discharge swabs from 55 Indigenous children with AOMwiP aged 3.5 - 45.6 months and resident in remote communities. RESULTS: By culture, H. influenzae, S. pneumoniae, and M. catarrhalis were detected in 80%, 84% and 91% of nasopharyngeal swabs, and 49%, 33% and 4% of ear discharge swabs, respectively. Using qPCR, H. influenzae, S. pneumoniae, and M. catarrhalis were detected in 82%, 82%, and 93% of nasopharyngeal swabs, and 89%, 41% and 18% of ear discharge swabs, respectively. Relative abundance of H. influenzae in ear discharge swabs was 0-68% of the total bacterial load (median 2.8%); whereas S. pneumoniae and M. catarrhalis relative abundances were consistently <2% of the total bacterial load. S. pneumoniae and M. catarrhalis abundances were significantly lower in ear discharge compared with nasopharyngeal swabs (p = 0.001, p < 0.001); no significant difference was observed in H. influenzae mean abundance at the two sites. CONCLUSIONS: H. influenzae was the dominant otopathogen detected in ear discharge swabs collected from children with AOMwiP. High prevalence and abundance of S. pneumoniae and M. catarrhalis in the nasopharynx did not predict ear discharge prevalence and abundances of these pathogens. PCR was substantially more sensitive than culture for ear discharge, and a necessary adjunct to standard microbiology. Quantitative methods are required to understand species abundance in polymicrobial infections and may be needed to measure accurately the microbiological impact of interventions and to provide a better understanding of clinical failure in these children.
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INTRODUCTION: Globally, acute respiratory infections (ARIs) are a leading cause of childhood morbidity and mortality. While ARI-related mortality is low in Australia, First Nations infants are hospitalised with ARIs up to nine times more often than their non-First Nations counterparts. The gap is widest in the Northern Territory (NT) where rates of both acute and chronic respiratory infection are among the highest reported in the world. Vitamin D deficiency is common among NT First Nations neonates and associated with an increased risk of ARI hospitalisation. We hypothesise that perinatal vitamin D supplementation will reduce the risk of ARI in the first year of life. METHODS AND ANALYSIS: 'D-Kids' is a parallel (1:1), double-blind (allocation concealed), randomised placebo-controlled trial conducted among NT First Nations mother-infant pairs. Pregnant women and their babies (n=314) receive either vitamin D or placebo. Women receive 14 000 IU/week or placebo from 28 to 34 weeks gestation until birth and babies receive 4200 IU/week or placebo from birth until age 4 months. The primary outcome is the incidence of ARI episodes receiving medical attention in the first year of life. Secondary outcomes include circulating vitamin D level and nasal pathogen prevalence. Tertiary outcomes include infant immune cell phenotypes and challenge responses. Blood, nasal swabs, breast milk and saliva are collected longitudinally across four study visits: enrolment, birth, infant age 4 and 12 months. The sample size provides 90% power to detect a 27.5% relative reduction in new ARI episodes between groups. ETHICS AND DISSEMINATION: This trial is approved by the NT Human Research Ethics Committee (2018-3160). Study outcomes will be disseminated to participant families, communities, local policy-makers, the broader research and clinical community via written and oral reports, education workshops, peer-reviewed journals, national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12618001174279.
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Deficiência de Vitamina D , Vitamina D , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Austrália/epidemiologia , Suplementos Nutricionais , Hospitalização , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/prevenção & controle , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Where conventional blood sampling is challenging, dried blood spots (DBS) provide a practical sample alternative for measuring vitamin D levels. Our study aimed to develop and evaluate a clinical pathology service-based assay suitable for measuring vitamin D in batches of DBS samples collected remote to the testing site. METHODS: A high throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with derivatisation was developed to measure 25-hydroxyvitamin D metabolites (25OHD3, 25OHD2 and 3-epi-25OHD3) in DBS samples. The assay was validated using paired DBS and plasma samples from 37 healthy adults. RESULTS: The assay reproducibly (<11.5% coefficient of variation) quantified 25OHD3 (range 1-300 nmol/L), 25OHD2 (range 2-300 nmol/L) and 3-epi-25OHD3 (range 1-200 nmol/L) in DBS samples. The 25OHD3 metabolite was detected in all DBS samples, 3-epi-25OHD3 in six plasma (range 2.1-6.3 nmol/L) and paired DBS samples, and 25OHD2 was not detected. Concentrations of 25OHD3 were highly correlated between paired samples: capillary DBS and venous plasma (r = 0.92), venous DBS and venous plasma (r = 0.93), and capillary DBS and venous DBS (r = 0.97). Ordinary least squares regression was used to characterise (ß = 0.81) and correct the systematic bias in DBS data (compared to paired plasma). Thereafter, Bland-Altman analysis demonstrated robust agreement between sample-methods. CONCLUSION: This simple and rapid DBS-based LC-MS/MS assay accurately quantified serum vitamin D metabolites using a paired-sample 'bridging strategy' to correct for the inherent sample-method bias.
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Calcifediol , Espectrometria de Massas em Tandem , Adulto , Cromatografia Líquida , Teste em Amostras de Sangue Seco , Humanos , Veias , Vitamina DRESUMO
Background: Preventing and/or reducing acute lower respiratory infections (ALRIs) in young children will lead to substantial short and long-term clinical benefits. While immunisation with pneumococcal conjugate vaccines (PCV) reduces paediatric ALRIs, its efficacy for reducing infant ALRIs following maternal immunisation has not been studied. Compared to other PCVs, the 10-valent pneumococcal-Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) is unique as it includes target antigens from two common lower airway pathogens, pneumococcal capsular polysaccharides and protein D, which is a conserved H. influenzae outer membrane lipoprotein. Aims: The primary aim of this randomised controlled trial (RCT) is to determine whether vaccinating pregnant women with PHiD-CV (compared to controls) reduces ALRIs in their infants' first year of life. Our secondary aims are to evaluate the impact of maternal PHiD-CV vaccination on different ALRI definitions and, in a subgroup, the infants' nasopharyngeal carriage of pneumococci and H. influenzae, and their immune responses to pneumococcal vaccine type serotypes and protein D. Methods: We are undertaking a parallel, multicentre, superiority RCT (1:1 allocation) at four sites across two countries (Australia, Malaysia). Healthy pregnant Australian First Nation or Malaysian women aged 17-40 years with singleton pregnancies between 27+6 and 34+6 weeks gestation are randomly assigned to receive either a single dose of PHiD-CV or usual care. Treatment allocation is concealed. Study outcome assessors are blinded to treatment arms. Our primary outcome is the rate of medically attended ALRIs by 12-months of age. Blood and nasopharyngeal swabs are collected from infants at birth, and at ages 6- and 12-months (in a subset). Our planned sample size (n = 292) provides 88% power (includes 10% anticipated loss to follow-up). Discussion: Results from this RCT potentially leads to prevention of early and recurrent ALRIs and thus preservation of lung health during the infant's vulnerable period when lung growth is maximum. The multicentre nature of our study increases the generalisability of its future findings and is complemented by assessing the microbiological and immunological outcomes in a subset of infants. Clinical Trial Registration: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374381, identifier: ACTRN12618000150246.
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BACKGROUND: Chronic neutrophilic inflammation, both in the presence and absence of infection, is a feature of bronchiectasis in adults and children. The anti-inflammatory properties of non-steroid anti-inflammatory drugs (NSAIDs) may be beneficial in reducing airway inflammation and thus potentially improve lung function and quality of life in patients with bronchiectasis. OBJECTIVES: To evaluate the efficacy of inhaled NSAIDs in the management of non-cystic fibrosis bronchiectasis in children and adults. SEARCH STRATEGY: We searched the Cochrane Airways Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 3), MEDLINE, OLDMEDLINE and EMBASE databases. The latest searches were carried out in October 2009 SELECTION CRITERIA: All randomised controlled trials comparing inhaled NSAIDs to a control group (placebo or usual treatment) in children or adults with bronchiectasis not related to cystic fibrosis. DATA COLLECTION AND ANALYSIS: We reviewed the results of the searches against pre-determined criteria for inclusion. MAIN RESULTS: One small, short-term trial was eligible for inclusion. We included this study of 25 adults with chronic lung disease (including bronchiectasis) as the other conditions were linked to development of bronchiectasis and all had chronic sputum production.The single trial in adults reported a significant reduction in sputum production over 14 days in the treatment group (inhaled indomethacin) compared to placebo (difference -75.00 g/day; 95% CI -134.61 to -15.39) and a significant improvement in a dyspnoea score (difference -1.90; 95% CI -3.15 to -0.65). There was no significant difference between groups in lung function or blood indices. No adverse events were reported. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to support or refute the use of inhaled NSAIDs in the management of bronchiectasis in adults or children. One small trial reported a reduction in sputum production and improved dyspnoea in adults with chronic lung disease who were treated with inhaled indomethacin, indicating that further studies on the efficacy of NSAIDs in treating patients with bronchiectasis are warranted.
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Anti-Inflamatórios não Esteroides/administração & dosagem , Bronquiectasia/tratamento farmacológico , Administração por Inalação , Adulto , Criança , Dispneia/tratamento farmacológico , Humanos , Escarro/metabolismoRESUMO
BACKGROUND: The burden of acute lower respiratory infection (ALRI) in Indigenous children of Australia's Northern Territory is among the highest globally. No published data exists on the effect of pneumococcal conjugate vaccine (PCV) introduction on ALRIs in this population beyond 2005. The aim of this study was to describe the rates of ALRI admissions to hospital in Indigenous infants in the Northern Territory from 2006 to 2015, across three periods of different PCV use. We hypothesised that broader valency PCVs would be more effective against hospitalisations for pneumonia. METHODS: We did a retrospective population-based cohort study of Indigenous infants born in the Northern Territory followed up until age 12 months. Data were from administrative hospital and perinatal datasets. International classification of diseases codes (tenth revision, Australian modification; ICD-10AM) were used to identify respiratory hospitalisations of interest: all-cause ALRI, all-cause pneumonia, bacterial pneumonia, viral pneumonia, influenza-like illness (ILI), respiratory syncytial virus ALRI (RSV-ALRI), and pneumococcal ALRI. Incidence rates were compared between PCV eras (7-valent PCV [PCV7], 2006-09; 10-valent PCV [PCV10], 2009-11; and 13-valent PCV [PCV13], 2011-15) using interrupted time trend analysis and negative binomial regression. FINDINGS: For children born between Jan 1, 2006, and Dec 31, 2015, 4138 ALRI episodes (31% of all hospitalisations) occurred among 2888 (20%) of the 14â594 infants. The overall ALRI hospitalisation rate was 29·7 episodes per 100 child-years. Prominent risk factors associated with ALRI hospitalisation were living in a remote community or the Central desert region, being born preterm or with low birthweight. ALRI rates were lowest in the PCV13 era, in association with a significant reduction in bacterial pneumonia hospitalisations in the PCV13 era compared with the PCV10 (incidence rate ratio 0·68, 95% CI 0·57-0·81) and PCV7 (0·70, 0·60-0·81) eras. In contrast, RSV-ALRI rates were 4·9 episodes per 100 child-years in each era. INTERPRETATION: A 30% reduction in bacterial-coded pneumonia hospitalisations in the Northern Territory during the era of PCV13 immunisation supports its ongoing use in the region. Despite the reduction, one in five Indigenous infants born in the region continue to be hospitalised with an ALRI in their first year of life. Future gains require multifaceted environmental and biomedical approaches. FUNDING: National Health and Medical Research Council of Australia.
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Hospitalização/estatística & dados numéricos , Vacinas Pneumocócicas/administração & dosagem , Pneumonia Pneumocócica/prevenção & controle , Infecções Respiratórias/epidemiologia , Doença Aguda , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Incidência , Povos Indígenas/estatística & dados numéricos , Lactente , Recém-Nascido , Masculino , Northern Territory/epidemiologia , Pneumonia Pneumocócica/epidemiologia , Infecções Respiratórias/prevenção & controle , Estudos Retrospectivos , Vacinação/estatística & dados numéricosRESUMO
AIM: Protracted bacterial bronchitis (PBB) is considered a potential precursor to bronchiectasis (BE) in some children. We previously showed that alveolar macrophages (AM) from children with PBB or BE have a similar significant defect in phagocytic capacity, with proinflammatory associations. We hypothesized that the mechanisms responsible for this defect involve dysregulation of the sphingosine-1-phosphate (S1P) signaling pathway, as we have found in adult inflammatory lung diseases. METHOD: We employed a Custom TaqMan OpenArray to investigate gene expression of S1P-generating enzymes: sphingosine kinases (SPHK) 1/2, S1P phosphatase 2 (SGPP2), S1P lyase 1 (SGPL1), S1P receptors (S1PR) 1/2/4/5; proinflammatory cytokines TNF-α (TNF) and IFNγ (IFNG), the cytotoxic mediator granzyme B (GZMB), and inflammasomes AIM2 and NLRP3, in bronchoalveolar lavage from 15 children with BE, 15 with PBB and 17 age-matched controls, and determined association with clinical/demographic variables and airway inflammation. RESULT: Significantly increased expression of S1PR1, S1PR2, and SPHK1 was noted in PBB and BE AM vs controls with increased SGPP2 only in PBB. TNF, IFNG, AIM2, and NLRP3 were significantly increased in both disease groups with increased GZMB only in PBB. There were no significant differences in the expression of any other S1P-related mediator between groups. There were significant positive associations between Haemophilus influenzae growth and expression of S1PR1 and NLRP3; between S1PR1 and S1PR2, NLRP3 and IFNG; between S1PR2 and AIM2, SPHK1, and SPHK2; and between SPHK1 and GZMB, IFNG, AIM2, and NLRP3. CONCLUSION: Children with PBB and BE share similar S1P-associated gene expression profiles. AM phagocytic dysfunction and inflammation in these children may occur due to dysregulated S1P signaling.
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Infecções Bacterianas/metabolismo , Bronquiectasia/metabolismo , Bronquite/metabolismo , Esfingosina/metabolismo , Animais , Infecções Bacterianas/complicações , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Bronquiectasia/etiologia , Bronquiectasia/genética , Bronquiectasia/microbiologia , Bronquite/complicações , Bronquite/genética , Bronquite/microbiologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Expressão Gênica , Granzimas/genética , Haemophilus influenzae , Humanos , Lactente , Interferon gama/genética , Masculino , Proteínas de Membrana/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Monoéster Fosfórico Hidrolases/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Transdução de Sinais , Receptores de Esfingosina-1-Fosfato/genéticaRESUMO
BACKGROUND: Effective management of protracted bacterial bronchitis (PBB) is needed to prevent chronic disease (eg, bronchiectasis). Understanding the contributions of ongoing airway infection and inflammation is important to achieving optimal PBB treatments. The aim of this study was to compare BAL microbiota, bacterial biomass, and inflammatory markers in children with PBB and age-matched control patients. METHODS: BAL was prospectively collected from 28 children with PBB (median age, 1.7 years; range, 0.6-7.4) and 8 control patients (median age, 1.9 years; range, 0.4-4.7). BAL microbiology was determined using culture, 16S ribosomal RNA gene sequencing and bacterial biomass quantification. BAL inflammatory cells, IL-8, and IL-1ß were used to assess lower airway inflammation. RESULTS: Bacterial biomass, neutrophil percentage, IL-8, and IL-1ß levels were significantly higher in children with PBB compared with control patients. BAL microbiota in children with PBB was significantly different to that of control patients (permutational multivariate analysis of variance P = .001) and clustered into four distinct profiles that were either dominated by a respiratory pathogen or contained a more diverse microbiota including Prevotella species. Alpha diversity was unrelated to bacterial biomass, culture of recognized respiratory pathogens, or inflammatory markers. CONCLUSIONS: Neutrophilic inflammation in children with PBB was associated with multiple BAL microbiota profiles. Significant associations between inflammatory markers and bacterial biomass, but not alpha diversity, suggest that inflammation in children with PBB is not driven by single pathogenic species. Understanding the role of the entire respiratory microbiota in PBB pathogenesis may be important to determining whether bacteria other than the recognized pathogens contribute to disease recurrence and progression to bronchiectasis.
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Bactérias/isolamento & purificação , Bronquite Crônica/microbiologia , Líquido da Lavagem Broncoalveolar/microbiologia , Microbiota/fisiologia , Bronquite Crônica/diagnóstico , Broncoscopia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Neutrófilos/patologia , Estudos ProspectivosRESUMO
BACKGROUND: Nontypeable Haemophilus influenzae (NTHi), the most common bacterial lower airway infection in children with protracted bacterial bronchitis, is associated with progression to bronchiectasis. We determined whether vaccination with 10-valent pneumococcal NTHi protein-D conjugate vaccine (PHiD-CV) reduced NTHi lower airway infection compared to children not PHiD-CV-vaccinated. Our unique childhood vaccination schedule and prospective 9-year bronchoalveolar lavage (BAL) collection provided an exclusive opportunity to examine this hypothesis. METHODS: Paired BAL fluids and nasopharyngeal (NP) swabs were collected from 543 children (2007-2016) undergoing bronchoscopy for chronic cough. Children who received a primary course of ≥2 doses of one pneumococcal conjugate vaccine (PCV) and <2 doses of another PCV were included in each vaccine group. Logistic regression determined associations between NTHi lower airway infection (≥104 colony-forming units/mL BAL) and age, sex, Indigenous status, antibiotic exposure, and PHiD-CV vaccination. RESULTS: Of 262 PCV7-vaccinated, 53 PHiD-CV-vaccinated and 166 PCV13-vaccinated children (62 had mixed schedules, <2 PCV doses or missing vaccination data), NTHi lower airway infection was detected in 89 (34%), 9 (17%) and 47 (28%), respectively. On multivariate regression, significant independent factors associated with reduced NTHi lower airway infection were PHiD-CV vaccination (ORadjustedâ¯=â¯0.42, 95%CI 0.19-0.93), macrolide use (ORadjustedâ¯=â¯0.57, 95%CI 0.35-0.93) and increasing age (ORadjustedâ¯=â¯0.88, 95%CI 0.80-0.96). PHiD-CV vaccination had no impact on NTHi NP carriage. CONCLUSIONS: PHiD-CV-vaccinated children were significantly less likely to have NTHi lower airway infection than children not PHiD-CV-vaccinated. PHiD-CV is likely an effective intervention for reducing NTHi endobronchial infection in children at risk of chronic suppurative lung diseases.
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Proteínas de Bactérias/imunologia , Proteínas de Transporte/imunologia , Infecções por Haemophilus/imunologia , Infecções por Haemophilus/prevenção & controle , Haemophilus influenzae/imunologia , Imunoglobulina D/imunologia , Lipoproteínas/imunologia , Vacinas Pneumocócicas/imunologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/prevenção & controle , Fatores Etários , Criança , Pré-Escolar , Feminino , Infecções por Haemophilus/diagnóstico , Infecções por Haemophilus/microbiologia , Humanos , Lactente , Masculino , Razão de Chances , Vacinas Pneumocócicas/administração & dosagem , Infecções Respiratórias/diagnóstico , Infecções Respiratórias/microbiologiaRESUMO
BACKGROUND: Differentiating lower airway bacterial infection from possible upper airway contamination in children with endobronchial disorders undergoing bronchoalveolar lavage (BAL) is important for guiding management. A diagnostic bacterial load threshold based on inflammatory markers has been determined to differentiate infection from upper airway contamination in infants with cystic fibrosis, but not for children with protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD), or bronchiectasis. METHODS: BAL samples from children undergoing bronchoscopy underwent quantitative bacterial culture, cytologic examination, and respiratory virus testing; a subset also had interleukin-8 examined. Geometric means (GMs) of total cell counts (TCCs) and neutrophil counts were plotted by respiratory pathogen bacterial load. Logistic regression determined associations between age, sex, Indigenous status, antibiotic exposure, virus detection and bacterial load, and elevated TCCs (>400 × 103 cells/mL) and airway neutrophilia (neutrophils >15% BAL leukocytes). RESULTS: From 2007 to 2016, 655 children with PBB, CSLD, or bronchiectasis were enrolled. In univariate analyses, Indigenous status and bacterial load ≥105 colony-forming units (CFU)/mL were positively associated with high TCCs. Viruses and bacterial load ≥104 CFU/mL were positively associated with neutrophilia; negative associations were seen for Indigenous status and macrolides. In children who had not received macrolide antibiotics, bacterial load was positively associated in multivariable analyses with high TCCs at ≥104 CFU/mL and with neutrophilia at ≥105 CFU/mL; GMs of TCCs and neutrophil counts were significantly elevated at 104 and 105 CFU/mL compared to negative cultures. CONCLUSIONS: Our findings support a BAL threshold ≥104 CFU/mL to define lower airway infection in children with chronic endobronchial disorders.
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Infecções Bacterianas/diagnóstico , Broncopatias/diagnóstico , Broncopatias/microbiologia , Lavagem Broncoalveolar , Fibrose Cística/complicações , Antibacterianos/uso terapêutico , Infecções Bacterianas/complicações , Infecções Bacterianas/tratamento farmacológico , Carga Bacteriana , Líquido da Lavagem Broncoalveolar/microbiologia , Broncoscopia , Criança , Pré-Escolar , Doença Crônica , Fibrose Cística/microbiologia , Feminino , Humanos , Lactente , Contagem de Leucócitos , Masculino , NeutrófilosRESUMO
AIM: Protracted bacterial bronchitis (PBB) is a common cause of prolonged cough in young children, and may be a precursor of bronchiectasis. Bacteria are often present in the lower airways in both PBB and bronchiectasis and may cause persistent infections. However, there is a paucity of information available on the pathogenesis of PBB and the factors associated with persistent bacterial infection and progression to bronchiectasis. This study hypothesised that lung immune cells in recurrent PBB and bronchiectasis differentially express genes related to immune cell dysfunction compared to lung immune cells from control subjects. METHOD: Cells isolated from bronchoalveolar lavage (adult-control and PBB BAL cells) were stimulated with nontypeable Haemophilus influenzae (NTHi), and expression of genes involved in various inflammatory pathways was assessed. RESULT: NTHi induced production of large amounts of IL-1ß, IL-6, and IL-8 in adult-control BAL cells, however BAL cells from PBB airways appeared refractory to NTHi stimulation. BAL cells from PBB and bronchiectasis showed differential expression of several genes relative to control cells, including CCL20, MARCO, CCL24, IL-10, PPAR-γ, CD200R, TREM2, RelB. Expression of genes involved in resolution of inflammation and anti-inflammation response, such as CD200R and IL-10, was associated with the number of pathogenic bacteria found in the airways. CONCLUSION: In summary, we have shown that the expression of genes related to macrophage function and resolution of inflammation are similar in PBB and bronchiectasis. Lung immune cell dysfunction in PBB and bronchiectasis may contribute to poor bacterial clearance and prolonged resolution of inflammation.
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Bronquiectasia/genética , Bronquiectasia/patologia , Bronquite/genética , Bronquite/patologia , Perfilação da Expressão Gênica , Líquido da Lavagem Broncoalveolar/citologia , Pré-Escolar , Tosse/etiologia , Progressão da Doença , Feminino , Humanos , Lactente , Interleucina-10/genética , MasculinoRESUMO
Protracted bacterial bronchitis (PBB) in young children is characterised by prolonged wet cough, prominent airway interleukin (IL)-1ß expression and infection, often with nontypeable Haemophilus influenzae (NTHi). The mechanisms responsible for IL-1-driven inflammation in PBB are poorly understood. We hypothesised that the inflammation in PBB involves the NLRP3 and/or AIM2 inflammasome/IL-1ß axis. Lung macrophages obtained from bronchoalveolar lavage (BAL), peripheral blood mononuclear cells (PBMCs), blood monocytes and monocyte-derived macrophages from patients with PBB and age-matched healthy controls were cultured in control medium or exposed to live NTHi. In healthy adult PBMCs, CD14+ monocytes contributed to 95% of total IL-1ß-producing cells upon NTHi stimulation. Stimulation of PBB PBMCs with NTHi significantly increased IL-1ß expression (p<0.001), but decreased NLRC4 expression (p<0.01). NTHi induced IL-1ß secretion in PBMCs from both healthy controls and patients with recurrent PBB. This was inhibited by Z-YVAD-FMK (a caspase-1 selective inhibitor) and by MCC950 (a NLRP3 selective inhibitor). In PBB BAL macrophages inflammasome complexes were visualised as fluorescence specks of NLRP3 or AIM2 colocalised with cleaved caspase-1 and cleaved IL-1ß. NTHi stimulation induced formation of specks of cleaved IL-1ß, NLRP3 and AIM2 in PBMCs, blood monocytes and monocyte-derived macrophages. We conclude that both the NLRP3 and AIM2 inflammasomes probably drive the IL-1ß-dominated inflammation in PBB.
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Bronchiectasis is a complex chronic respiratory condition traditionally characterized by chronic infection, airway inflammation, and progressive decline in lung function. Early diagnosis and intensive treatment protocols can stabilize or even improve the clinical prognosis of children with bronchiectasis. However, understanding the host immunologic mechanisms that contribute to recurrent infection and prolonged inflammation has been identified as an important area of research that would contribute substantially to effective prevention strategies for children at risk of bronchiectasis. This review will focus on the current understanding of the role of the host immune response and important pathogens in the pathogenesis of bronchiectasis (not associated with cystic fibrosis) in children.
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BACKGROUND: The high global burden of asthma and tobacco smoking among Indigenous people may potentially be reduced by appropriate interventions that target prevention of tobacco smoke uptake and improved asthma management. The latter includes targeted treatment based on airway inflammation. We undertook a feasibility study in two Darwin schools with a high proportion of Indigenous youth to determine the feasibility of an innovative, peer-led, school-based education program called the Asthma and Smoking Prevention Project (ASPP). A subset of children with reported persistent respiratory symptoms were also clinically evaluated to determine the lower airway inflammatory profile and optimize asthma management. METHODS: The ASPP is founded on an evidence-based three-step program and targets improving asthma management and preventing the uptake of tobacco smoking. The program uses a student-centered approach in which senior students (peer leaders) deliver the ASPP to Grade 7 students using activities, videos, and games. Students completed questionnaires related to asthma and smoking at baseline and 3 months after program delivery. Students with respiratory symptoms at 3 months were invited for a comprehensive clinical evaluation and tests including sputum induction. RESULTS: The ASPP was well received. Of the 203 students involved, 56 (28%) were Indigenous and 70% completed baseline and follow-up questionnaires. Self-reported asthma was high (19%), 10% of students reported smoking and 63% reported exposure to tobacco at home. Of the 22 students who were clinically evaluated, 41% were Indigenous. Clinically important airway inflammation was high; 23% had Fractional Exhaled Nitric Oxide Levels ≥35 ppb, 88% had airway neutrophilia (>15%), and 29% had airway eosinophilia (>2.5%). Optimization of medication and management was required in 59% of students. CONCLUSION: Our study has demonstrated the implementation of the ASPP was well received by the schools as well as by the students. The high prevalence of clinically important airway inflammation and suboptimal asthma management highlights the need for a community-based study on persistent respiratory symptoms in adolescents to reduce the burden of chronic lung disease particularly for Indigenous Australians.
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BACKGROUND: Chronic endobronchial infections in children are responsible for a high disease burden. Streptococcus pneumoniae is frequently isolated; however, few publications have described serotypes associated with non-invasive lower airway infection. METHODS: Paired nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) fluids were collected from children undergoing bronchoscopy for chronic cough. NP swabs were also collected from asymptomatic children in otitis media surveillance studies (controls). Specimens were processed and lower airway infection defined (⩾104 colony forming units/mL BAL) as previously described. Serotype-specific odds ratios (ORs) were calculated (as described for invasive pneumococcal disease) to indicate propensity for infection. RESULTS: From 2007-2015, paired specimens were processed from 435 children with protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) or bronchiectasis. S. pneumoniae lower airway infection was detected in 95 children: 27% with PBB and 20% with CSLD/bronchiectasis. Most (91%) children were vaccinated with ⩾2 doses of 7-valent, 10-valent or 13-valent pneumococcal conjugate vaccine. Paired NP and BAL serotype distributions were very similar; prevalent serotypes (>10 isolates) were 19A (9%), 19F, 6C, 35B, 15B, 16F, 15A, 15C, 23A, 23F and 11A. For 21 serotypes found in both NP and BAL specimens, ORs for infection were low; range 0.46 (serotype 23B) to 2.15 (serotype 6A). In the 2008-2013 surveillance studies, NP swabs were collected from 1565 asymptomatic children; 74% were pneumococcal carriers. For 21 of 22 serotypes found in both control NP swabs and BAL specimens, ORs for infection were similarly low; range 0.33 (serotype 23B) to 3.29 (serotype 22F); none was significantly different from 1. The exception was serotype 7B with OR 8.84 (95% CI 1.46, 38.1). CONCLUSIONS: Most NP carriage serotypes have a similar propensity to cause lower airway infection in children with suppurative lung diseases. Further development of pneumococcal vaccines is needed to prevent non-invasive disease caused by commonly carried serotypes.
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Bronquiectasia/microbiologia , Bronquite Crônica/microbiologia , Infecções Pneumocócicas/microbiologia , Pneumonia/microbiologia , Streptococcus pneumoniae/imunologia , Adolescente , Brônquios/imunologia , Brônquios/microbiologia , Brônquios/patologia , Bronquiectasia/complicações , Bronquiectasia/imunologia , Bronquiectasia/patologia , Bronquite Crônica/complicações , Bronquite Crônica/imunologia , Bronquite Crônica/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Broncoscopia , Criança , Pré-Escolar , Contagem de Colônia Microbiana , Feminino , Humanos , Lactente , Masculino , Nasofaringe/imunologia , Nasofaringe/microbiologia , Nasofaringe/patologia , Infecções Pneumocócicas/complicações , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Pneumonia/complicações , Pneumonia/imunologia , Pneumonia/patologia , Sorogrupo , Streptococcus pneumoniae/patogenicidade , SupuraçãoRESUMO
Protracted bacterial bronchitis (PBB) in young children is a common cause of prolonged wet cough and may be a precursor to bronchiectasis in some children. Although PBB and bronchiectasis are both characterised by neutrophilic airway inflammation and a prominent interleukin (IL)-1ß signature, the contribution of the IL-1ß pathway to host defence is not clear. This study aimed to compare systemic immune responses against common pathogens in children with PBB, bronchiectasis and control children and to determine the importance of the IL-1ß pathway. Non-typeable Haemophilus influenzae (NTHi) stimulation of peripheral blood mononuclear cells (PBMCs) from control subjects (n=20), those with recurrent PBB (n=20) and bronchiectasis (n=20) induced high concentrations of IL-1ß, IL-6, interferon (IFN)-γ and IL-10. Blocking with an IL-1 receptor antagonist (IL-1Ra) modified the cellular response to pathogens, inhibiting cytokine synthesis by NTHi-stimulated PBMCs and rhinovirus-stimulated PBMCs (in a separate PBB cohort). Inhibition of IFN-γ production by IL-1Ra was observed across multiple cell types, including CD3+ T cells and CD56+ NK cells. Our findings highlight the extent to which IL-1ß regulates the cellular immune response against two common respiratory pathogens. While blocking the IL-1ß pathway has the potential to reduce inflammation, this may come at the cost of protective immunity against NTHi and rhinovirus.