Dominic A. Fitzgerald

The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses.

Objectives To evaluate current processes by which young children presenting with a febrile illness but suspected of having serious bacterial infection are diagnosed and treated, and to develop and test a multivariable model to distinguish serious bacterial infections from self limiting non-bacterial illnesses. Design Two year prospective cohort study. Setting The emergency department of The Children’s Hospital at Westmead, Westmead, Australia. Participants Children aged less than 5 years presenting with a febrile illness between 1 July 2004 and 30 June 2006. Intervention A standardised clinical evaluation that included mandatory entry of 40 clinical features into the hospital’s electronic record keeping system was performed by physicians. Serious bacterial infections were confirmed or excluded using standard radiological and microbiological tests and follow-up. Main outcome measures Diagnosis of one of three key types of serious bacterial infection (urinary tract infection, pneumonia, and bacteraemia), and the accuracy of both our clinical decision making model and clinician judgment in making these diagnoses. Results We had follow-up data for 93% of the 15 781 instances of febrile illnesses recorded during the study period. The combined prevalence of any of the three infections of interest (urinary tract infection, pneumonia, or bacteraemia) was 7.2% (1120/15 781, 95% confidence interval (CI) 6.7% to 7.5%), with urinary tract infection the diagnosis in 543 (3.4%) cases of febrile illness (95% CI 3.2% to 3.7%), pneumonia in 533 (3.4%) cases (95% CI 3.1% to 3.7%), and bacteraemia in 64 (0.4%) cases (95% CI 0.3% to 0.5%). Almost all (>94%) of the children with serious bacterial infections had the appropriate test (urine culture, chest radiograph, or blood culture). Antibiotics were prescribed acutely in 66% (359/543) of children with urinary tract infection, 69% (366/533) with pneumonia, and 81% (52/64) with bacteraemia. However, 20% (2686/13 557) of children without bacterial infection were also prescribed antibiotics. On the basis of the data from the clinical evaluations and the confirmed diagnosis, a diagnostic model was developed using multinomial logistic regression methods. Physicians’ diagnoses of bacterial infection had low sensitivity (10-50%) and high specificity (90-100%), whereas the clinical diagnostic model provided a broad range of values for sensitivity and specificity. Conclusions Emergency department physicians tend to underestimate the likelihood of serious bacterial infection in young children with fever, leading to undertreatment with antibiotics. A clinical diagnostic model could improve decision making by increasing sensitivity for detecting serious bacterial infection, thereby improving early treatment.

Lipid peroxidation as determined by plasma isoprostanes is related to disease severity in mild asthma.

Oxidative stress is believed to play an important role in the pathophysiology of asthma. Recently discovered F2-isoprostanes, of which 8-iso-PGF2α is the most well-known isomer, have emerged as the most reliable marker of in vivo oxidative stress. The aim of this study was to examine 8-iso-PGF2α as a biomarker of oxidative stress in mild asthma in relation to endogenous and dietary antioxidant protection. Total (free and esterified) plasma 8-iso-PGF2α, plasma dietary antioxidants (vitamins E and C,β-carotene, Zn, and Se), and erythrocyte antioxidant enzyme activities (glutathione peroxidase and superoxide dismutase) were measured in 15 mild asthmatics and 15 age-and sex-matched controls. Total plasma 8-iso-PGF2α levels [median (quartile 1-quartile 3)] were significantly increased in the sthmatics [213 pg/mL (122–455) vs. 139 pg/mL (109–174), P=0.042]. The 8-iso-PGF2α levels were found to be associated with clinical asthma severity (P=0.044) and inhaled corticosteroid use (P=0.027) in asthmatics. No differences were observed in the plasma dietary antioxidant vitamins. The asthmatics had significantly lower plasma levels of Zn (P=0.027) and Se (P=0.006). Plasma Se correlated negatively with 8-iso-PGF2α (r=−0.725, P=0.002). No differences between the groups were observed for glutathione peroxidase or superoxide dismutase, however, superoxide dismutase activity was negatively associated with asthma severity (P=0.042). In conclusion, oxidative stress is increased in mild asthmatics, as reflected by increased plasma levels of 8-iso-PGF2α and a deficiency in plasma Zn and Se. The isoprostane 8-iso-PGF2α may provide a useful tool in intervention studies aimed at improving clinical status in asthma.

Respiratory morbidity of hospitalized children with Trisomy 21.

Objective: To review the respiratory morbidity in children with Trisomy 21 admitted to a teaching hospital.

Oxidative Stress in Cystic Fibrosis: Dietary and Metabolic Factors

Objective: To examine oxidative stress in CF by measuring 8-iso-PGF2α and antioxidant defenses, in relation to dietary intake, immune function and clinical status. Methods: We measured total plasma concentrations of 8-iso-PGF2α and dietary antioxidants (vitamin E, vitamin C, β-carotene), erythrocyte antioxidant enzyme activities (glutathione peroxidase and superoxide dismutase), lung function and dietary intake in 21 CF subjects and 21 healthy age- and gender-matched controls. Results: Total plasma 8-iso-PGF2α concentration (median [quartile 1–quartile 3]) was significantly higher in CF subjects compared to controls (214 pg/mL (155–331) vs. 135 pg/mL (101–168), p=0.001). Neutrophil, monocyte and total white cell counts were elevated in the CF group and these correlated with 8-iso-PGF2α concentration. Despite similar dietary intake, lower plasma antioxidant concentrations were observed in the CF group (vitamin E, p < 0.001, vitamin C, p=0.004, β-carotene, p=0.001). 8-iso-PGF2α correlated negatively with plasma vitamin E, C and β-carotene concentrations. Conclusion: Oxidative stress is increased in CF patients, despite normal dietary antioxidant intake. The immune response appears to be a key factor causing oxidative stress. Antioxidant intervention aimed at reducing oxidative stress in CF needs to be assessed.

Normal Development of the Lung and Premature Birth

The following review focuses on the normal development of the lung from conception to birth. The defined periods of lung development-Embryonic, Pseudoglandular, Canalicular, Saccular and Alveolar-will be explored in detail in relation to gestational age. Cellular differentiation, formation of the conducting airways and respiratory zone and development of the alveoli will be reviewed. Pulmonary vascular development will also be examined within these periods to relate the formation of the blood-air barrier to the lungs for their essential function of gas exchange after birth. The development of the surfactant and cortisol systems will also be discussed as these need to be mature before the lungs are able to take on their role of respiration following birth. It is clear that premature birth interrupts normal lung development so the effect of preterm birth on lung development will be examined and the respiratory consequences of very preterm birth will be briefly explored.

Outcome of noninvasive ventilation in children with neuromuscular disease

Objective: To assess the effect of institution of noninvasive ventilation (NIV) on clinical outcome and quality of life (QOL) in a cohort of children with severe neuromuscular disorders. Methods: We reviewed records and obtained clinical data from the year prior to commencing NIV and annually thereafter. Data obtained included diagnosis, patient symptoms, mortality, NIV adverse effects, pulmonary function tests, polysomnographic data, length of hospitalizations, and health care costs. Patients and parents completed questionnaires assessing QOL with NIV and recalling QOL before NIV. Results: Fourteen of 17 (82%) suitable patients were enrolled. Follow-up ranged from 6 to 84 months (median 30). Symptoms of daytime sleepiness (p = 0.003) and headache (p = 0.046) improved after initiation of NIV. Sleep quality assessed by polysomnography also improved. Hospitalization rates (p = 0.002) and health care costs (p = 0.003) decreased. QOL remained stable after NIV, despite disease progression. Conclusion: Treatment of respiratory failure, in children with neuromuscular disease, with noninvasive ventilation results in a reduction in symptoms, hospitalizations, and health care costs without adverse effects on quality of life.

Consensus statement on standard of care for congenital myopathies.

Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee’s recommendations for symptom assessments and therapeutic interventions. It is the committee’s goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome.

Severity of obstructive apnoea in children with Down syndrome who snore

Diagnostic overnight polysomnograms of 33 children with Down syndrome who snored were reviewed. Mean age was 4.9 years, none had had adenotonsillectomy, 91% were non-obese (Down syndrome specific body mass index standard deviation score (BMI SDS) <+2.0) and yet 97% demonstrated obstructive sleep apnoea, with an average apnoea hypopnoea index (AHI) of 12.9 episodes per hour (normal <1) and an average oxygen desaturation of 4%. A higher AHI was associated with lower minimum Spo2, higher Tcco2 and higher number of arousals from sleep per hour (p<0.001). Polysomnography should be a routine investigation for children with Down syndrome who snore regardless of body habitus.

Improved survival in cystic fibrosis patients diagnosed by newborn screening compared to a historical cohort from the same centre

Background Newborn screening (NBS) for cystic fibrosis (CF) is associated with improved early nutritional outcomes and improved spirometry in children. The aim of this study was to determine whether early diagnosis and treatment of CF with NBS in New South Wales in 1981 led to better clinical outcomes and survival into early adulthood. Methods Retrospective observational study comprising two original cohorts born in the 3 years before (‘non-screened cohort’, n=57) and after (‘screened’; n=60) the introduction of NBS. Patient records were assessed at transfer from paediatric to adult care by age 19 years and survival was documented to age 25 years. Results Non-screened patients (n=38) when compared with screened patients (n=41) had a higher rate and lower age of Pseudomonas aeruginosa acquisition at age 18 years (p≤0.01). Height, weight and body mass index (BMI) z scores (all p<0.01) and forced expiratory volume in 1 s (FEV1)% were better in the screened group (n=41) (difference: 16.7±6.4%; p=0.01) compared to non-screened (n=38) subjects on transfer to adult care. Each 1% increase in FEV1% was associated with a 3% (95% CI 1% to 5%; p=0.001) decrease in risk of death and each 1.0 kg/m2 increase in BMI contributed to a 44% (95% CI 31% to 55%; p<0.001) decrease in risk of death. This accumulated in a significant survival difference at age 25 years (25 vs 13 deaths or lung transplants; p=0.01). Conclusion NBS for CF leads to better lung function, nutritional status and improved survival in screened patients in early adulthood.

Safety of the Newer Inhaled Corticosteroids in Childhood Asthma

Inhaled corticosteroids (ICS) remain a vital part of the management of persistent asthma, but concerns have been raised about their potential adverse effects in children. This review examines the safety data on three new ICS — fluticasone propionate, mometasone, and extrafine beclomethasone in hydrofluoroalkane (HFA-134a) propellant (QVAR®1 formulation) in relation to the older corticosteroids.Topical adverse effects such as thrush and dysphonia are rare, but dental erosion is a possibility with powder forms of ICS because of their low pH. Thus, it is important to stress mouth rinsing after administration and maintaining good dental hygiene to minimize this risk.Biochemical adrenal suppression can be readily demonstrated, particularly with high doses of all ICS. The clinical relevance of this was uncertain in the past, but there have now been >50 reported cases of acute adrenal crises in children receiving ICS, most of whom were on fluticasone propionate. In order to minimize the risk of symptomatic adrenal suppression, it is important to back-titrate the ICS dose and alert families of children receiving high-dose ICS of this potential adverse effect. A pediatric endocrine opinion should be sought if adrenal suppression is suspected. The older ICS cause temporary slowing of growth velocity, but the limited data available do not show any significant compromise of final adult height. The effect on growth of fluticasone propionate may not be as great as with the older ICS, but the studies have been short term and only used low doses of fluticasone propionate. There have been case reports of growth suppression in children receiving high doses of fluticasone propionate. The limited studies performed on the effect of ICS on bone mineral density in children did not show any adverse effects, but there may be an increased risk of fractures.Hydrofluoroalkane beclomethasone (QVAR) is essentially the same drug as chlorofluorocarbon beclomethasone, but with double the lung deposition owing to the smaller particle size. Thus, it could be expected that any adverse effects seen with chlorofluorocarbon beclomethasone would be the same with hydrofluoroalkane beclomethasone. However, some of the published data, particularly in adults, suggest that hydrofluoroalkane beclomethasone may be less systemically active than chlorofluorocarbon beclomethasone, even at equipotent doses. As yet, there are no long-term data on mometasone, but initial studies in adults suggest there may be less suppression of the hypothalamic-pituitary-adrenal axis, although further studies are required, particularly in children.ICS will remain a cornerstone in the management of persistent pediatric asthma, provided that the diagnosis of asthma is secure. It is very important to use ICS appropriately and to ensure the lowest possible doses are used to achieve symptom control, thus minimizing the risk of serious adverse effects.