Early Lung Disease in Infants and Preschool Children with Cystic Fibrosis. What Have We Learned and What Should We Do about It?

Ranganathan, Sarath; Hall, Graham L.; Sly, Peter D.; Stick, Stephen M.; Douglas, T. A.

doi:10.1164/rccm.201606-1107ci

Cited by 106 publications

(90 citation statements)

References 87 publications

(113 reference statements)

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“…The number of exacerbations with advancing age may have a cumulative detrimental effect on pulmonary function . The relationship between an acute exacerbation in CF and PSG abnormalities such as significant hypoxemia has not been studied in detail before.…”

Section: Discussionmentioning

confidence: 99%

Predictors of sleep hypoxemia in children with cystic fibrosis

Isaiah¹,

Daher

Sharma

et al. 2019

Pediatric Pulmonology

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Objectives To identify the determinants of nocturnal hypoxemia in children with CF using clinical parameters, polysomnography (PSG), and lung function. Hypothesis Sleep hypoxemia in children with CF is predicted by both apnea hypopnea index (AHI) and percent predicted forced expiratory volume in one second (pFEV1). Design Retrospective case series. Methods Children aged 5‐18 years were included based on (i) a diagnosis of CF; and (ii) availability of concurrent PSG and pFEV1 data. The impact of (i) demographic and clinical parameters; and (ii) PSG and pFEV1, on the total sleep time spent with arterial oxygen saturation below 90% (TSpO2 < 90) was measured using regression analysis. P‐value <0.05 was considered significant. Results The mean age was 11.6 years (95% confidence interval: 9.5, 13.1). Twenty of 35 (57%) were boys and the mean body mass index percentile was 42.1 (31.5, 52.6). The most common ethnicity was white (66%). OSA was diagnosed in 50%. Neither demographic predictors nor clinical variables predicted the severity of hypoxemia (R2 = 0.23, P = 0.09). While pFEV1 and PSG variables accounted for significant proportion of the overall variance in TSpO2 < 90 (R2 = 0.53, P < 0.001), pFEV1 was identified as the single best predictor of sleep hypoxemia. A pFEV1 cut‐off of 53% indicated a sensitivity of 0.80 and a specificity of 0.87 in predicting sleep hypoxemia. Conclusions pFEV1 is the best predictor of sleep hypoxemia in children with CF and referred for PSG. No demographic or clinical predictors of hypoxemia were identified in this population.

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Section: Discussionmentioning

confidence: 99%

Predictors of sleep hypoxemia in children with cystic fibrosis

Isaiah¹,

Daher

Sharma

et al. 2019

Pediatric Pulmonology

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“…Morbidity and mortality in CF relate primarily to progressive lung damage, leading eventually to respiratory failure. Although some studies point to anomalies in prenatal development of large airways in CF (2), the first overt symptoms may be detected months to years after birth (3)(4)(5), primarily because of involvement of the small airways (6). Thanks to newborn screening, CF infants can be diagnosed within a few weeks of birth and monitored closely from a very young age, which has led to improved patient care and outcomes (7).…”

mentioning

confidence: 99%

“…Nearly 20 years have revealed that children with CF develop signs of lung disease early in life (5,11,12). Inflammation as evidenced by increased levels of proinflammatory mediators and downstream recruitment of blood neutrophils into the airway lumen occurs within a few weeks after birth (13).…”

mentioning

confidence: 99%

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis

Margaroli

Garratt

Horati

et al. 2019

Am J Respir Crit Care Med

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Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown.Objectives: To measure NE exocytosis by airway neutrophils in relation to free extracellular NE activity and lung damage in children with CF.Methods: We measured lung damage using chest computed tomography coupled with the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis scoring system. Concomitantly, we phenotyped blood and BAL fluid leukocytes by flow and image cytometry, and measured free extracellular NE activity using spectrophotometric and Förster resonance energy transfer assays. Children with airway inflammation linked to aerodigestive disorder were enrolled as control subjects.Measurements and Main Results: Children with CF but not disease control children harbored BAL fluid neutrophils with high exocytosis of primary granules, before the detection of bronchiectasis. This measure of NE exocytosis correlated with lung damage (R = 0.55; P = 0.0008), whereas the molecular measure of free extracellular NE activity did not. This discrepancy may be caused by the inhibition of extracellular NE by BAL fluid antiproteases and its binding to leukocytes.Conclusions: NE exocytosis by airway neutrophils occurs in all children with CF, and its cellular measure correlates with early lung damage. These findings implicate live airway neutrophils in early CF pathogenesis, which should instruct biomarker development and antiinflammatory therapy in children with CF.

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“…The low incidence of abnormal findings on CXR and lack of association between CXR score and growth suggests the need for a more sensitive indicator of lung disease in these infants. High-resolution chest computed tomography (CT) and bronchoalveolar lavage (BAL) are more effective at detecting early lung disease but are more invasive 3 . The multiple breath washout technique has been used to calculate Lung Clearance Index (LCI), a measure of ventilation inhomogeneity.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary findings in infants with cystic fibrosis during the first year of life: Results from the Baby Observational and Nutrition Study (BONUS) cohort study

Goetz

Kopp

Salvator

et al. 2019

Pediatric Pulmonology

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Importance Treatment recommendations for infants with CF standardize care, but most surveillance or treatment guidance of pulmonary manifestations are consensus-based due to sparse evidence. Objective To report observations about pulmonary correlates of growth and other clinical features in infants with CF. Methods We analyzed data from the prospective Baby Observational and Nutrition Study conducted in 28 centers across the US, including clinical features, medications, guardian diaries of respiratory symptoms, oropharyngeal swab cultures and chest radiographs (CXR) collected over the first year of life. Results Cough was reported in 84% of infants in the first year. Up to 30% had clinically important cough but only 6.3% had crackles; 16.5% had wheeze. Wisconsin CXR score was above 5 in 23% (normal=0; maximum score=100). Pseudomonas was recovered from at least one respiratory culture in 24% of infants and was associated with crackles/wheezes and use of proton pump inhibitors (PPI) (OR=5.47; 95% CI=1.36, 21.92; p=0.02) or PPI plus histamine-2 (H2) blocker (OR=8.2; 95% CI= 2.41, 27.93; p=0.001), but not H2 blocker alone. Hospitalization for respiratory indications occurred in 18% of infants and was associated with crackles/wheeze and abnormal CXR but not low weight, Pseudomonas or use of acid blockade. Conclusions Cough is common in infants with CF, but few present with crackles/wheeze or CXR changes. Pseudomonas is associated with use of PPI or PPI plus H2 blocker, but not with respiratory hospitalization. These observations cannot prove cause and effect but add to our understanding of pulmonary manifestations of CF in infants. Trial registration United Sttes ClinicalTrials.Gov registry (clinicaltrials.gov).

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Early Lung Disease in Infants and Preschool Children with Cystic Fibrosis. What Have We Learned and What Should We Do about It?

Cited by 106 publications

References 87 publications

Predictors of sleep hypoxemia in children with cystic fibrosis

Predictors of sleep hypoxemia in children with cystic fibrosis

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis

Pulmonary findings in infants with cystic fibrosis during the first year of life: Results from the Baby Observational and Nutrition Study (BONUS) cohort study

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