Ataxia-telangiectasia: recommendations for multidisciplinary treatment.

Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.

ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia.

Ataxia telangiectasia (A-T) is a rare, progressive, multisystem disease that has a large number of complex and diverse manifestations which vary with age. Patients with A-T die prematurely with the leading causes of death being respiratory diseases and cancer. Respiratory manifestations include immune dysfunction leading to recurrent upper and lower respiratory infections; aspiration resulting from dysfunctional swallowing due to neurodegenerative deficits; inefficient cough; and interstitial lung disease/pulmonary fibrosis. Malnutrition is a significant comorbidity. The increased radiosensitivity and increased risk of cancer should be borne in mind when requesting radiological investigations. Aggressive proactive monitoring and treatment of these various aspects of lung disease under multidisciplinary expertise in the experience of national multidisciplinary clinics internationally forms the basis of this statement on the management of lung disease in A-T. Neurological management is outwith the scope of this document.

Real-time monitoring of hydrogen cyanide (HCN) and ammonia (NH3) emitted by Pseudomonas aeruginosa.

We present the real-time monitoring of hydrogen cyanide (HCN) production from Pseudomonas aeruginosa (P. aeruginosa) strains in vitro, using laser-based photoacoustic spectroscopy. Simultaneously, the production of ammonia (NH3) was measured, and the influence of different factors (e.g. the medium, temperature and antibiotics treatment) was assessed. Both reference strains and clinical isolates of patients with CF were studied, and compared to other pathogens commonly present in lungs/airways of CF patients. Hydrogen cyanide production starts to rise as soon as P. aeruginosa bacteria reach the stationary phase ((9.0-9.5) × 10(9) colony forming units, CFUs), up to concentrations of 14.5 microliters per hour (µl h(-1)). Different strains of P. aeruginosa produced HCN to varying degrees, and addition of tobramycin strongly reduced HCN production within 2 h from application. Burkholderia cepacia also produced HCN (up to 0.35µl h(-1) in 9.0 × 10(9) CFU) while other pathogens (Aspergillus fumigatus, Stenotrophomonas maltophilia, Mycobacterium abscessus) did not produce detectable levels. Our study reveals for the first time a broad overview of the dynamics of the HCN production in vitro.

Diagnosis of invasive pulmonary aspergillosis in children with bronchoalveolar lavage galactomannan.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in immunocompromised patients. Early diagnosis and therapy improves outcome. Assessment of galactomannan (GM) in bronchoalveolar lavage (BAL) fluid is a proposed tool to diagnose IPA. Little is known about the diagnostic value of BAL GM in children. MATERIALS AND METHODS: Retrospectively, 72 bronchoscopies were analyzed for GM in patients fulfilling the host factor criteria as defined by the EORTC/MSG. A cut-off index value GM of ≥0.5 was used. Clinical data, results of chest CT-scans and BAL cultures were collected. RESULTS: Sensitivity, specificity, PPV, and NPV of BAL GM for a diagnosis of proven and probable IPA (n = 41) were 82.4%, 87.5%, 82.4%, and 87.5% respectively. A significant relation was found for BAL GM and abnormal chest CT (P = 0.01). No significant relationship was observed between BAL Aspergillus sp. culture and chest CT (n = 47). BAL GM and serum GM correlated significantly. In 9 out of 12 patients classified as possible IPA, antifungal therapy was continued or started, despite a negative BAL GM. CONCLUSIONS: BAL GM test had good diagnostic value in children suspected of IPA. However, the decision to continue or start antifungal therapy was mainly determined by the clinical suspicion of IPA based on chest CT-outcome, serum GM index values and failure of antibiotic therapy.

Risk factors for pediatric intensive care admission in children with acute asthma.

INTRODUCTION: Severe acute asthma in children is associated with substantial morbidity and may require pediatric ICU (PICU) admission. The aim of the study was to determine risk factors for PICU admission. METHODS: The study used a retrospective multicenter case-control design. The cases included children admitted to the PICU because of severe acute asthma and a history of out-patient treatment by pediatricians or pediatric pulmonologists. Controls were children with asthma without a PICU admission for severe acute asthma. The children were matched for sex, age, hospital, and time elapsed since the diagnosis of asthma. Fourteen possible risk factors were analyzed. RESULTS: Sixty-six cases were matched to 164 controls. In univariate analysis, all but one of the analyzed variables were significantly associated with PICU-hospitalization. After multivariate conditional logistic regression analysis, 4 risk factors remained significant. These included active or passive smoking, allergies, earlier hospitalization for asthma, and non-sanitized home. CONCLUSIONS: Physicians and parents should be aware of these risk factors, and efforts should be made to counteract them.

How about your peers? Cystic fibrosis questionnaire data from healthy children and adolescents.

BACKGROUND: The Cystic Fibrosis Questionnaire (CFQ) is widely used in research as an instrument to measure quality of life in patients with cystic fibrosis (CF). In routine patient care however, measuring quality of life is still not implemented in guidelines. One of the reasons might be the lack of consensus on how to interpret CFQ scores of an individual patient, because appropriate reference data are lacking. The question which scores reflect normal functioning and which scores reflect clinically relevant problems is still unanswered. Moreover, there is no knowledge about how healthy children and adolescents report on their quality of life (on the CFQ). With regard to quality of life the effect of normal development should be taken into account, especially in childhood and adolescence. Therefore, it is important to gain more knowledge about how healthy children and adolescents report on their quality of life and if there are any difference in a healthy populations based on age or gender. Without these data we cannot adequately interpret the CFQ as a tool in clinical care to provide patient-tailored care. Therefore this study collected data of the CFQ in healthy children and adolescents with the aim to refer health status of CF youngsters to that of healthy peers. METHODS: The CFQ was completed by 478 healthy Dutch children and adolescents (aged 6-20) in a cross-sectional study. RESULTS: The majority of healthy children (over 65%) did not reach maximum scores on most domains of the CFQ. Median CFQ-scores of healthy children and adolescents ranged from 67 to 100 (on a scale of 0-100) on the different CFQ-domains. Significant differences in quality of life exist among healthy children and adolescents, and these depend on age and gender. CONCLUSIONS: Reference data of quality of life scores from a healthy population are essential for adequate interpretation of quality of life in young patients with CF. Clinicians should be aware that the perception of health-related quality of life is not as disease-specific as one might think and also relies on factors such as age, normal maturation and gender.

Prospective longitudinal evaluation of lung function during the first year of life after extracorporeal membrane oxygenation.

OBJECTIVE: To collect longitudinal data on lung function in the first year of life after extracorporeal membrane oxygenation and to evaluate relationships between lung function and perinatal factors. Longitudinal data on lung function in the first year of life after extracorporeal membrane oxygenation are lacking. DESIGN: Prospective longitudinal cohort study. SETTING: Outpatient clinic of a tertiary level pediatric hospital. PATIENTS: The cohort consisted of 64 infants; 33 received extracorporeal membrane oxygenation for meconium aspiration syndrome, 14 for congenital diaphragmatic hernia, four for sepsis, six for persistent pulmonary hypertension of the neonate, and seven for respiratory distress syndrome of infancy. Evaluation was at 6 mos and 12 mos; 39 infants were evaluated at both time points . INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Functional residual capacity and forced expiratory flow at functional residual capacity were measured and expressed as z score. Mean (sem) functional residual capacities in z score were 0.0 (0.2) and 0.2 (0.2) at 6 mos and 12 mos, respectively. Mean (sem) forced expiratory flow was significantly below average (z score = 0) (p < .001) at 6 mos and 12 mos: -1.1 (0.1) and -1.2 (0.1), respectively. At 12 mos, infants with diaphragmatic hernia had a functional residual capacity significantly above normal: mean (sem) z score = 1.2 (0.5). CONCLUSIONS: Infants treated with extracorporeal membrane oxygenation have normal lung volumes and stable forced expiratory flows within normal range, although below average, within the first year of life. There is reason to believe, therefore, that extracorporeal membrane oxygenation either ameliorates the harmful effects of mechanical ventilation or somehow preserves lung function in the very ill neonate.

Recombinant human DNase in children with airway malacia and lower respiratory tract infection.

BACKGROUND: Children with airway malacia often have protracted courses of airway infections, because dynamic airway collapse during coughing results in impaired mucociliary clearance. The aim of this study was to determine the effect of the mucolytic drug recombinant human deoxyribonuclease (rhDNase) on the recovery of respiratory symptoms in children with airway malacia and lower respiratory tract infection (LRTI). METHODS: In a randomized double-blind controlled clinical trial, 40 children with airway malacia and LRTI were randomly assigned to receive either 2.5 mg nebulized rhDNase or placebo twice daily for 2 weeks. The primary endpoint was the change in the cough diary score (CDS) (scale 0-5) from baseline to the second week of treatment. Secondary endpoints were VAS symptom scores for cough, dyspnea, and difficulty in expectorating sputum, need for an antibiotic course, and lung function data (FVC, FEV(1), FEF(75), R(int(e))). RESULTS: There was no significant difference in the mean change in CDSs from baseline between the rhDNase group and the placebo group (mean difference for daytime 0.19 (95% CI -0.53 to 0.90); for nighttime 0.38 (95% CI -0.30 to 1.05). Proportions of patients requiring antibiotics, and the mean changes in symptom scores and lung function from baseline did not significantly differ between both groups. CONCLUSION: Treatment with 2 weeks of nebulized rhDNase does not enhance recovery or reduce the need for antibiotics in children with airway malacia and LRTI. (Controlled-trials.com number, ISRCTN85366144).

Pharmacotherapy of impaired mucociliary clearance in non-CF pediatric lung disease. A review of the literature.

Mucoactive agents are used to treat a variety of lung diseases involving impaired mucociliary clearance or mucus hypersecretion. The mucoactive agents studied most frequently are N-acetylcysteine (NAC), recombinant human DNase (rhDNase), and hypertonic saline. Studies on the efficacy of these have been mainly conducted in adults, and in patients with cystic fibrosis (CF). The exact role of mucoactive agents in children with non-CF lung disease is not well established. We present an overview of the current literature reporting clinical outcome measures of treatment with NAC, rhDNase, and hypertonic saline in children.

Exhaled nitric oxide differentiates airway diseases in the first two years of life.

Fractional exhaled nitric oxide (FE(NO)) levels are increased in children and adults with asthma, whereas low levels have been found in cystic fibrosis and primary ciliary dyskinesia. The aim of this study was to investigate whether FE(NO) measurements could distinguish between children below the age of 2 with different airway diseases. FE(NO) measurements were performed in 118 infants aged between 4.6 and 25.2 mo: 74 infants with recurrent wheezing (RW), 24 with bronchopulmonary dysplasia (BPD), and 20 with cystic fibrosis (CF). FE(NO) was measured also in 100 healthy controls aged between 1.1 and 7.7 mo. Geometric mean (95% confidence interval) FE(NO) values were 10.4 (9.1-12.0) parts per billion (ppb) in healthy infants, 18.6 (15.6-22.2) ppb in wheezy infants, 11.7 (8.2-16.8) ppb in BPD infants and 5.9 (3.4-10.1) ppb in CF infants. FE(NO) in wheezers was higher than in controls, BPD, and CF (p = 0.009, p = 0.038, and p < 0.001, respectively). Atopic wheezers showed higher FE(NO) than nonatopic wheezers (p = 0.04). CF infants had lower FE(NO) than healthy controls and BPD infants (p = 0.003 and p = 0.043, respectively). FE(NO) values in BPD and control infants were not different. We conclude that FE(NO) is helpful to differentiate various airway diseases already in the first 2 y of life.

Tracheomalacia and bronchomalacia in children: incidence and patient characteristics.

OBJECTIVE: Congenital airway malacia is one of the few causes of irreversible airways obstruction in children, but the incidence in the general population is unknown. Severe airway malacia or malacia associated with specific syndromes is usually recognized and diagnosed early in infancy, but information about clinical features of children with primary malacia, often diagnosed only later in childhood, is scarce. METHODS: We analyzed all flexible bronchoscopies performed between 1997 and 2004 in the Sophia Children's Hospital, summarized clinical features of children with primary airway malacia, estimated the incidence of primary airway malacia, and calculated the predictive value of a clinical diagnosis of airway malacia by pediatric pulmonologists. RESULTS: In a total of 512 bronchoscopies, airway malacia was diagnosed in 160 children (94 males) at a median age of 4.0 years (range, 0 to 17 years). Airway malacia was classified as primary in 136 children and secondary in 24 children. The incidence of primary airway malacia was estimated to be at least 1 in 2,100. When pediatric pulmonologists expected to find airway malacia (based on symptoms, history, and lung function) prior to bronchoscopy, this was correct in 74% of the cases. In 52% of the airway malacia diagnoses, the diagnosis was not suspected prior to bronchoscopy. Presenting clinical features of children with airway malacia were variable and atypical, showing considerable overlap with features of allergic asthma. Peak expiratory flow was more reduced than FEV(1). CONCLUSION: Primary airway malacia is not rare in the general population, with an estimated incidence of at least 1 in 2,100 children. Airway malacia is difficult to recognize based on clinical features that show overlap with those of more common pulmonary diseases. We recommend bronchoscopy in patients with impaired exercise tolerance, recurrent lower airways infection, and therapy-resistant, irreversible, and/or atypical asthma to rule out airway malacia.

DNase and atelectasis in non-cystic fibrosis pediatric patients.

INTRODUCTION: No evidence based treatment is available for atelectasis. We aimed to evaluate the clinical and radiologic changes in pediatric patients who received DNase for persistent atelectasis that could not be attributed to cardiovascular causes, and who were unresponsive to treatment with inhaled bronchodilators and physiotherapy. METHODS: All non-cystic fibrosis pediatric patients who received nebulised or endotracheally instilled DNase for atelectasis between 1998 and 2002, with and without mechanical ventilation, were analysed in a retrospective descriptive study. The endpoints were the blood pCO2, the heart rate, the respiratory rate, the FiO2 and the chest X-ray scores before and after treatment. RESULTS: In 25 of 30 patients (median [range] age, 1.6 [0.1-11] years) who met inclusion criteria, paired data of at least three endpoints were available. All clinical parameters improved significantly within 2 hours (P < 0.01), except for the heart rate (P = 0.06). Chest X-ray scores improved significantly within 24 hours after DNase treatment (P < 0.001). Individual improvement was observed in 17 patients and no clinical change was observed in five patients. Temporary deterioration (n = 3) was associated with increased airway obstruction and desaturations. No other complications were observed. CONCLUSION: After treatment with DNase for atelectasis of presumably infectious origin in non-cystic fibrosis pediatric patients, rapid clinical improvement was observed within 2 hours and radiologic improvement was documented within 24 hours in the large majority of children, and increased airway obstruction and ventilation-perfusion mismatch occurred in three children, possibly due to rapid mobilisation of mucus. DNase may be an effective treatment for infectious atelectasis in non-cystic fibrosis pediatric patients.

Predictive value of infant lung function testing for airway malacia.

Airway malacia is present in a small proportion of wheezing infants. The usefulness of infant lung-function testing (ILFT) in ruling out malacia in wheezy infants is unknown. We assessed the predictive value of ILFT parameters for airway malacia diagnosed by flexible bronchoscopy. Thirty-two term infants (mean (SD) age, 11.0 (4.6) months) with chronic wheeze unresponsive to asthma treatment underwent ILFT prior to bronchoscopy. Functional residual capacity measured by plethysmograph (FRCp), maximal flow at FRC (V'max(FRC)), and tidal breathing parameters were obtained. Expiratory flow-volume curves were visually examined for tidal flow limitation. Malacia was observed during bronchoscopy in 20 infants. V'max(FRC) (Z-score) was significantly lower in the group with malacia as compared with the group without malacia. Lung-function measurements had a low negative predictive value and sensitivity. While flow limitation during tidal breathing was highly predictive and 100% specific for airway malacia, only half of the infants with malacia had tidal flow limitation. In this selected group of infants, routine lung function testing could not discriminate between infants with and without airway malacia. However, the presence of tidal flow limitation was 100% predictive and specific for airway malacia.

Bronchiectasis in children after renal or liver transplantation: a report of five cases.

More effective immunosuppressive treatment in children following organ transplantation has significantly improved the survival of the grafts. Therefore, quality of life, long-term prognosis and adverse drug reactions have become more important. One of the main complications of immunosuppressive drugs is infections of the respiratory tract, but irreversible damage to the airways has not been described after renal or liver transplantation. Five children following transplantation of kidney or liver were referred to the Paediatric Pulmonology department because of chronic respiratory complaints. Pulmonary function tests and HRCT scan were performed as routine patient care. Four children with a renal transplant and one with a liver transplant showed chronic bronchitis and moderate to severe airways obstruction. HRCT showed bronchiectasis in all of them. We speculate that the immunosuppressive treatment (in)directly contributes to irreversible airway damage. We recommend including follow-up of lung function in the post-transplantation protocol and considering bronchiectasis in case of respiratory symptoms, to try preventing further damage to the lung.

Preserved diffusion capacity in children with cystic fibrosis.

Early detection of progressive lung disease in cystic fibrosis (CF) may lead to better treatment and prognosis. Routine lung function indices may be relatively insensitive markers of peripheral airway obstruction and alveolar collapse. We hypothesized that the single-breath diffusion capacity of the lung for carbon monoxide (DLCO) would change before tests of airway function in patients with CF. We assessed lung function longitudinally in 53 children with CF during a mean period of 3.8 years to determine whether the diffusion capacity of the lung becomes abnormal before more conventional indices of lung function do. Within patients, DLCO was slightly elevated and remained stable, while forced expired volume in 1 sec (FEV1) and forced vital capacity (FVC) declined progressively (mean individual decline, -1.8% and -0.8% of predicted). Cross-sectionally, this decline was faster (mean group decline -3.8% and -2.8% of predicted), indicating an additional cohort effect. Normalized diffusion capacity at an early stage of CF is slightly elevated and is preserved in spite of progressive obstructive lung disease. This can be attributed to alterations in pulmonary and bronchial circulation due to loss of function and/or number of alveolar units. Diffusion capacity at rest does not appear to be a suitable early marker of progressive deterioration of CF lung disease.

DNase in stable cystic fibrosis infants: a pilot study.

OBJECTIVE: To assess the feasibility of measuring short-term effects of inhaled recombinant human deoxyribonuclease (rhDNase, Pulmozyme on lung function, pulse oximetry and symptom scores in infants and toddlers with stable cystic fibrosis. DESIGN: open-label randomized placebo controlled cross-over pilot study. PATIENTS AND METHODS: We treated nine CF patients (0.7-1.9 years) with nebulised rhDNase (2.5 mg) and NaCl 0.9% (10 ml) via jet nebulizer cross-over once daily during 2-week treatment blocks. Measurements were performed at baseline and after treatment blocks and consisted of lung function tests (plethysmography and tidal rapid thoraco-abdominal compression technique), overnight pulse oximetry, and daily symptom scores. RESULTS: DNase treatment and the different assessments were well tolerated by all children and their parents. Lung function showed increased airway patency after treatment with rhDNase (P < 0.001), but not after NaCl 0.9%. Overnight pulse oximetry and daily symptom scores did not change during the study period. CONCLUSIONS: This pilot study indicates that objective assessment of the effects of rhDNase is feasible in infants with CF who have little or no respiratory symptoms. Our results warrant a larger randomized placebo-controlled trial.