Neutrophil-to-lymphocyte ratio as a biomarker of acute pulmonary exacerbations in children with cystic fibrosis: a retrospective cohort study.

BACKGROUND: Neutrophils are key contributors to chronic airway inflammation in cystic fibrosis (CF) lung disease, although airway and blood-based neutrophil markers are seldom used. The neutrophil-to-lymphocyte ratio (NLR) is an accessible biomarker, the clinical utility of which has not been adequately studied. OBJECTIVE: This study aimed to investigate the characteristics of the NLR in children with CF and its correlations with acute pulmonary exacerbations and spirometry. DESIGN: A previous study had collected clinical data from children with CF for a 3-year period between 2016 and 2021. Retrospectively, NLR values were categorised according to patients' clinical status during blood sample collection as 'stable', 'acute pulmonary exacerbation' or 'elective admission for chronic clinical concern'. MAIN OUTCOME MEASURES: Demographic characteristics associated with the NLR; changes in NLR values in relation to clinical status; relationship between NLR and lung function. RESULTS: 141 children with CF were included. NLR values during clinical stability were higher in females and increased with age. For children admitted for intravenous antibiotics, NLR values significantly increased from clinical stability (median (IQR)=1.13 (0.75-1.51)) to acute pulmonary exacerbations (median (IQR)=1.50 (0.96-2.65), p=0.001), but similar changes were not observed in elective admissions. The NLR was not associated with lung function. CONCLUSIONS: The NLR demonstrated associations with clinical status in children with CF with significant elevations during acute pulmonary exacerbations. While its utility as a single-marker measure is limited, monitoring the NLR over time may help identify periods of increased inflammation.

Detection of Bronchiolitis Obliterans Syndrome Using Nitrogen Multiple Breath Washout in Children Posthemopoietic Stem Cell Transplant.

Bronchiolitis obliterans syndrome (BOS) is a severe complication following hemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI2.5) derived from the nitrogen multiple breath washout (N2MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. We aimed to examine the feasibility of performing surveillance N2MBW in children post-HSCT, and in an exploratory analysis, determine if LCI2.5 led to earlier detection of BOS when compared to spirometric indices. Participants aged 5 to 17 years were recruited prior to receiving HSCT into a prospective, single-center, feasibility study at the Royal Children's Hospital, Melbourne. N2MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9, and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. Twenty-one (12 male) children with a mean age of 13.4 (range 9.2 to 17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI2.5, while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV1). Ninety-nine percent of N2MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while 2 participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI2.5 ranging from 3 to 5 units and mean reductions in FEV1 % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI2.5 values were significantly worse when compared with the no BOS group (P < .001). Relative changes in LCI2.5 and FEV1 were both predictive of BOS at 6 months post HSCT. This study demonstrates that N2MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI2.5 did not lead to earlier detection of BOS, when compared to spirometry.

Unsupervised home spirometry is not equivalent to supervised clinic spirometry in children and young people with cystic fibrosis: Results from the CLIMB-CF study.

BACKGROUND: Handheld spirometry allows monitoring of lung function at home, of particular importance during the COVID-19 pandemic. Pediatric studies are unclear on whether values are interchangeable with traditional, clinic-based spirometry. We aimed to assess differences between contemporaneous, home (unsupervised) and clinic (supervised) spirometry and the variability of the former. The accuracy of the commercially available spirometer used in the study was also tested. METHODS: Data from participants in the Clinical Monitoring and Biomarkers to stratify severity and predict outcomes in children with cystic fibrosisc (CLIMB-CF) Study aged ≥ 6 years who had paired (±1 day) clinic and home forced expiratory volume in 1 s (FEV1 ) readings were analyzed. Variability during clinical stability over 6-months was assessed. Four devices from Vitalograph were tested using 1 and 3 L calibration syringes. RESULTS: Sixty-seven participants (median [interquartile range] age 10.7 [7.6-13.9] years) provided home and clinic FEV1 data pairs. The mean (SD) FEV1 % bias was 6.5% [±8.2%]) with wide limits of agreement (-9.6% to +22.7%); 76.2% of participants recorded lower results at home. Coefficient of variation of home FEV1 % during stable periods was 9.9%. Data from the testing of the handheld device used in CLIMB-CF showed a potential underread. CONCLUSION: In children and adolescents, home spirometry using hand-held equipment cannot be used interchangeably with clinic spirometry. Home spirometry is moderately variable during clinical stability. New handheld devices underread, particularly at lower volumes of potential clinical significance for smaller patients; this suggests that supervision does not account fully for the discrepancy. Opportunities should be taken to obtain dual device measurements in clinic, so that trend data from home can be utilized more accurately.

Validation of the 25 level modified shuttle test in children with cystic fibrosis.

OBJECTIVE: To evaluate the validity and reliability of the modified shuttle 25-level test (MST-25) in children with cystic fibrosis (CF). METHODS: A prospective single center study in clinically stable children with CF. Participants undertook two testing conditions on different days: (1) 2xMST-25 tests; (2) cardiopulmonary exercise test (CPET). Test order was randomized. Nadir oxygen saturation (SpO2 ), peak heart rate (HR), breathlessness (modified Borg), rate of perceived exertion (RPE), energy expenditure (EE) and metabolic equivalents (MET) from the MST-25 and CPET were compared to assess validity, while outcomes from 2xMST-25 tests were compared for reliability. CPET was performed using breath-by-breath analysis and EE from the MST-25 obtained using the SenseWear Armband. RESULTS: Strong correlations were found between MST-25 distance and peak oxygen uptake, peak work and minute ventilation on CPET (all r > 0.7, p < 0.01). Moderate correlations were found between MST-25 distance and CPET for METs (r = 0.5) and HR (r = 0.6). Weak associations between tests were evident for nadir SpO2 (r = 0.1), modified Borg (rs = 0.2) and RPE (rs = 0.2). Test-retest reliability was excellent for MST-25 distance (ICC 0.91), peak EE (ICC 0.99) and peak METs (ICC 0.90). Good reliability was achieved for HR (ICC 0.84) and modified Borg score (ICC 0.77), while moderate reliability for nadir SpO2 (ICC 0.64) and RPE (ICC 0.68) was observed. CONCLUSION: The MST-25 is a valid and reliable field test for the assessment of exercise capacity in children with CF. The MST-25 can be used to accurately monitor exercise capacity and prescribe exercise training, particularly when CPET is not available.

Associations between peak oxygen uptake, lung function, and bronchiectasis in children with cystic fibrosis in the era of CFTR modulators.

BACKGROUND: With the emergence of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, forced expiratory volume in 1 s (FEV1 ) may become a less sensitive measure of pulmonary disease progression in children with cystic fibrosis (CF). Increasing evidence shows that peak oxygen uptake (VO2peak ) is a strong predictor of prognosis in CF. The primary aim of this study was to describe the associations between peak oxygen uptake, lung function, and bronchiectasis in children with CF in the era of CFTR modulators. METHODS: Spirometry and a maximal cardiopulmonary exercise test (CPET) were performed on the same day and compared to markers of disease severity. Markers of disease severity included a number of pulmonary exacerbations resulting in hospital admission within the preceding 12 months, body mass index, Pseudomonas aeruginosa (PsA) infection, and bronchiectasis. RESULTS: Fifty-two subjects (24 female) with CF participated in the study with a mean (SD) age of 13.8 (2.4) years, range 8-18 years. Forty-nine participants met satisfactory criteria for a maximal CPET. A significant correlation was found between relative VO2peak %predicted and FEV1 %predicted (r = .546, p < .001). A total of 4/49 children demonstrated an impaired aerobic capacity despite normal spirometry. Participants who had experienced one or more pulmonary exacerbations in the previous 12 months had a significantly lower relative VO2peak %predicted (p = .02). CONCLUSIONS: In children with CF who have mild pulmonary disease, there is significant correlation between FEV1 and VO2peak . In all, 8.2% of participants had an abnormal CPET result despite normal spirometry, and preceding pulmonary exacerbations were associated with poorer CPET outcomes. CPET may offer important prognostic information for clinical decision making in this new era of CFTR modulators.

The effectiveness of a high-intensity games intervention on improving indices of health in young children.

This study assessed the effectiveness of a 6-week, high-intensity, games-based intervention on physiological and anthropometric indices of health, in normal weight (n = 26; 32.5 ± 8.9 kg) and obese (n = 29; 49.3 ± 8.9 kg) children (n = 32 boys, 23 girls), aged 8-10 years. Children were randomised into an exercise or control group. The exercise group participated in a twice-weekly, 40 min active games intervention, alongside their usual school physical education classes. The control group did not take part in the intervention. Before and after the intervention, participants completed both a maximal and submaximal graded exercise test. The submaximal exercise test comprised of a 6 min, moderate- and 6 min heavy-intensity bout, interspersed with a 5 min recovery. The exercise group demonstrated improvements in maximal oxygen uptake (51.4 ± 8.5 vs 54.3 ± 9.6 ml · kg(-1) · min(-1)) and peak running speed (11.3 ± 1.6 vs 11.9 ± 1.6 km · h(-1)), and a reduction in the oxygen cost of submaximal exercise between assessments (P < .05). A decrease in waist circumference and increase in muscle mass were observed between assessments for the obese participants randomised to the intervention (both P < .05). This study demonstrates that a short-term, high-intensity games intervention may elicit positive changes in physiological and anthropometric indices of health in normal weight and obese children.

The influence of a six-week, high-intensity games intervention on the pulmonary oxygen uptake kinetics in prepubertal obese and normal-weight children.

The pulmonary oxygen uptake response is deleteriously influenced by obesity in prepubertal children, as evidenced by a slower phase II response. To date, no studies have investigated the ability of an exercise intervention to ameliorate this. The objective of the study was to investigate the influence of a 6-week, high-intensity, games-orientated intervention on the oxygen uptake kinetic response of prepubertal obese and normal-weight children during heavy-intensity exercise. Thirteen normal-weight and 15 obese children participated in a twice-weekly exercise intervention involving repeated bouts of 6-min high-intensity, games-orientated exercises followed by 2 min of recovery. Sixteen normal-weight and 11 obese children served as a control group. At baseline and post-intervention, each participant completed a graded-exercise test to volitional exhaustion and constant work-rate, heavy-intensity exercise. Post-intervention, obese children demonstrated a reduced phase II τ (pre-intervention: 30 ± 8 cf. post-intervention: 24 ± 7 s), mean response time (pre-intervention: 50 ± 10 cf. post-intervention: 38 ± 9 s) and phase II amplitude (pre-intervention: 1.51 ± 0.30 cf. post-intervention: 1.34 ± 0.27 L·min(-1)). No changes were evident in the normal-weight children. In conclusion, the present findings demonstrate that a 6-week, high-intensity intervention can have a significant positive impact on the dynamic oxygen uptake response of obese prepubertal children.

Sexual differences in central arterial wave reflection are evident in prepubescent children.

OBJECTIVE: The objective of this study was to examine the influence of sex on central arterial wave reflection in healthy prepubescent children matched for body size and cardiorespiratory fitness. METHODS: Fifty-five healthy children (9.8 ±â€Š1.0 years, 44% girls) were recruited. Cardiorespiratory fitness was assessed using a treadmill-based graded exercise test to volitional exhaustion. Pulse wave analysis was used to measure augmentation index (AIx) and central blood pressures. RESULTS: The girls and boys were matched for age, body size and cardiorespiratory fitness. There were no significant differences between sexes for heart rate or central blood pressure parameters. Girls demonstrated a significantly greater AIx than the boys (8.9 ±â€Š9.3 vs. 1.9 ±â€Š10.8%, P = 0.015, d = 0.69). CONCLUSION: Sexual differences in central arterial wave reflection exist prepubescence, independent of stature or cardiorespiratory fitness. Further study is required to elucidate the mechanism(s) explaining this phenomenon and to determine the influence of wave reflections on left ventricular mass during childhood.

Validation of oscillometric pulse wave analysis measurements in children.

BACKGROUND: Pulse wave analysis (PWA) has emerged as a noninvasive, valid, reliable, and widely used technique to investigate central blood pressures and systemic arterial wave reflection (augmentation index). The gold-standard technique is tonometry, but this technique can be challenging, especially when used on children. The purpose of this study was to validate oscillometric PWA for use in children. METHODS: Fifty-seven healthy children were recruited for participation. Central blood pressures and peripheral augmentation index (pAIx) were measured objectively using oscillometric (Pulsecor R7) and tonometric (SphygmaCor) devices. All measurements were made during the same visit under standardized conditions between the hours of 8 am and 10 am in the fasted state. RESULTS: Tonometric measurements were unsuccessful on 1 child. Comparisons were made on 56 children (mean age = 9.8±1.0 y; 57% male). A very strong relationship was found between devices for central systolic (r = 0.94; P < 0.001), diastolic (r = 0.99; P < 0.001) and mean (r = 0.96; P < 0.001) blood pressures. However, Bland-Altman analysis indicated a bias toward greater systolic blood pressures with the oscillometric monitor (mean difference = 4.5mm Hg; 95% confidence interval (CI) = -5.16 to -3.89). A good relationship was found for pAIx (r = 0.71; P < 0.001); the mean difference between devices was -1.70% (95% CI = -4.47% to 1.08%), which is not significantly different from zero. CONCLUSIONS: Findings from this study suggest that oscillometric PWA provides valid measures of central blood pressure and arterial wave reflection in children aged 8-10 years.

A randomized controlled trial to assess the effect of self-paced walking on task-specific anxiety in cardiac rehabilitation patients.

PURPOSE: Cardiac rehabilitation can reduce overall anxiety. However, task-specific anxiety is yet to be investigated in the cardiac patient. This study investigates the effect of an outdoor walking intervention (WI) in alleviating the high degree of task-specific anxiety in cardiac patients. METHODS: Participants (N = 22, mean age ± SD = 62.0 ± 10.8 years, 9 women), who had experienced a cardiac event and exhibited a moderate to high level of anxiety for outdoor walking (anxiety score ≥ 7 on a modified version of the Hospital Anxiety and Depression Scale), were initially assessed during an incremental shuttle walk test and a self-paced 1-mile walk. Heart rate and the ratings of perceived exertion were monitored during both tests. Participants also completed an exercise self-efficacy (ESE) questionnaire. Following this, participants were randomized to either a 3 sessions per week, 4 weeks, self-paced WI on a predetermined variable topographic course, or to a control group (CG; 30-minute stationary cycling, 3 sessions per week for 4 weeks). Identical assessments (Incremental Shuttle Walk Test, Self-Paced 1-Mile Walk, Hospital Anxiety and Depression Scale, ESE) were used postintervention. The 2 groups were compared for anxiety, ESE, and fitness by analysis of variance. RESULT: The WI group exhibited a significantly greater decrease in task-specific anxiety (51%; P < .01), increased self-efficacy (6.6%; P < .001) and improved fitness (P < .05) in comparison with CG. CONCLUSION: This study demonstrated that task familiarization reduced the task-specific anxiety associated with outdoor walking in cardiac patients and, as such, may help in changing exercise behavior patterns in patients undergoing cardiac rehabilitation.

The influence of body weight on the pulmonary oxygen uptake kinetics in pre-pubertal children during moderate- and heavy intensity treadmill exercise.

To assess the influence of obesity on the oxygen uptake VO2 kinetics of pre-pubertal children during moderate- and heavy intensity treadmill exercise. We hypothesised that obese (OB) children would demonstrate significantly slower VO2 kinetics than their normal weight (NW) counterparts during moderate- and heavy intensity exercise. 18 OB (9.8 ± 0.5 years; 24.1 ± 2.0 kg m(2)) and 19 NW (9.7 ± 0.5 years; 17.6 ± 1.0 kg m(2)) children completed a graded-exercise test to volitional exhaustion and two submaximal constant work rate treadmill tests at moderate (90 % gas exchange threshold) and heavy (∆ 40 %) exercise intensities. Bodyweight significantly influenced the VO2 kinetics during both moderate- and heavy exercise intensities (P < 0.05). During moderate intensity exercise, the phase II τ (OB: 30 ± 13 cf. NW: 22 ± 7 s), mean response time (MRT; OB: 35 ± 16 cf. NW: 25 ± 10 s), phase II gain (OB: 156 ± 21 cf. NW: 111 ± 18 mL O2 kg(-1) km(-1)) and oxygen deficit (OB: 0.36 ± 0.11 cf. NW: 0.20 ± 0.06 L) were significantly higher in the OB children (all P < 0.05). During heavy intensity exercise, the τ (OB: 33 ± 9 cf. NW: 27 ± 6 s; P < 0.05) and phase II gain (OB: 212 ± 61 cf. NW: 163 ± 23 mL O2 kg(-1) km(-1); P < 0.05) were similarly higher in the OB children. A slow component was observed in all participants during heavy intensity exercise, but was not influenced by weight status. In conclusion, this study demonstrates that weight status significantly influences the dynamic VO2 response at the onset of treadmill exercise in children and highlights that the deleterious effects of being obese are already manifest pre-puberty.