Optimizing care for children with difficult-to-treat and severe asthma through specialist paediatric asthma centres: expert practical experience and advice.

Severe asthma in children carries an unacceptable treatment burden, yet its rarity means clinical experience in treating it is limited, even among specialists. Practical guidance is needed to support clinical decision-making to optimize treatment for children with this condition.This modified Delphi convened 16 paediatric pulmonologists and allergologists from northern Europe, all experienced in treating children with severe asthma. Informed by interviews with stakeholders involved in the care of children with severe asthma (including paediatricians, nurses and carers), and an analysis of European guidelines, the experts built a consensus focused on the gaps in existing guidance. Explored were considerations for optimizing care for patients needing biologic treatment, and for selecting home or hospital delivery of biologics. This consensus is aimed at clinicians in specialist centres, as well as general paediatricians, paediatric allergologists and paediatric pulmonologists who refer children with the most severe asthma to specialist care. Consensus is based on expert opinion and is intended for use alongside published guidelines.Our discussions revealed three key facets to optimizing care. Firstly, early asthma detection in children presenting with wheezing and/or dyspnoea is vital, with a low threshold for referral from primary to specialist care. Secondly, children who may need biologics should be referred to and managed by specialist paediatric asthma centres; we define principles for the specialist team members, tests, and expertise necessary at such centres, as well as guidance on when homecare biologics delivery is and is not appropriate. Thirdly, shared decision-making is essential at all stages of the patient's journey: clear, concise treatment plans are vital for patient/carer self-management, and structured processes for transition from paediatric to adult services are valuable. The experts identified the potential for specialist paediatric asthma nurses to play a significant role in facilitating multidisciplinary working.Through this project is agreed a framework of practical advice to optimize the care of children with severe asthma. We encourage clinicians and policymakers to implement this practical advice to enhance patient care.

Invasive mucinous adenocarcinoma of the lung arising in a type 1 congenital pulmonary airway malformation in a 68-year-old patient: a case report.

INTRODUCTION: Congenital pulmonary airway malformation (CPAM), previously described as congenital cystic adenomatoid malformation (CCAM), is a congenital disorder of lung parenchyma. The association with the presence of a malignant transformation like rhabdomyosarcoma, pleuropulmonary blastoma, and most common invasive mucinous adenocarcinoma (IMA) is a rare development described in patients with CPAM. PATIENTS AND METHODS: Here, we report the case of a 68-year-old male patient who underwent a right lower lobectomy for a mass in the right pulmonary lobe. From his clinical history, we noted a recurrent pulmonary infection of a bullous malformation in the right lower lobe treated with antibiotics. RESULTS: The histopathological finding showed an invasive mucinous adenocarcinoma arising in a type 1 CPAM in the right lower lobe. A review of presentation, diagnosis, and treatment of this association is described in a case report. CONCLUSIONS: Surgical resection should be considered in adults with asymptomatic cysts to prevent malignant transformation. For further analysis, histopathological examination of specimen is essential for a proper diagnosis and eventually further postoperative treatment.

Effect of previous vaccination with pneumococcal conjugate vaccine on pneumococcal polysaccharide vaccine antibody responses.

During the past 10 years, pneumococcal conjugate vaccine (PCV) has become part of the standard childhood vaccination programme. This may impact upon the diagnosis of polysaccharide antibody deficiency by measurement of anti-polysaccharide immunoglobulin (Ig)G after immunization with unconjugated pneumococcal polysaccharide vaccine (PPV). Indeed, contrary to PPV, PCV induces a T-dependent, more pronounced memory response. The antibody response to PPV was studied retrospectively in patients referred for suspected humoral immunodeficiency. The study population was divided into four subgroups based on age (2-5 years versus ≥ 10 years) and time tested (1998-2005 versus 2010-12). Only 2-5-year-old children tested in 2010-12 had been vaccinated with PCV prior to PPV. The PCV primed group showed higher antibody responses for PCV-PPV shared serotypes 4 and 18C than the unprimed groups. To a lesser extent, this was also found for non-PCV serotype 9N, but not for non-PCV serotypes 19A and 8. Furthermore, PCV-priming elicited a higher IgG2 response. In conclusion, previous PCV vaccination affects antibody response to PPV for shared serotypes, but can also influence antibody response to some non-PCV serotypes (9N). With increasing number of serotypes included in PCV, the diagnostic assessment for polysaccharide antibody deficiency requires careful selection of serotypes that are not influenced by prior PCV (e.g. serotype 8). Further research is needed to identify more serotypes that are not influenced.

Respiratory morbidity in children with profound intellectual and multiple disability.

BACKGROUND: 'Profound intellectual and multiple disability' (PIMD) is defined as a profound cognitive disability with severe sensory and motor impairments. The aim of this study was to evaluate the respiratory morbidity in children with PIMD and investigate possible risk factors. METHODS: In 10 specialized facilities for daily care of patients with PIMD, children underwent a standardized clinical assessment evaluating respiratory and motor function. Additional medical information was obtained. RESULTS: One hundred and twenty seven children aged 2-21 years were tested (median age 12 years; IQR 8-16). 72% had epilepsy, 42% were gastrostomy fed. The median number of lower airway infection per years was four (IQR 1-4). While 68% of patient had no hospital admissions for respiratory disease, 12% of patients were admitted three times or more. Chronic antibiotic therapy was prescribed to nine patients (7%), and 19 patients (15%) were chronically treated with mucolytics, inhaled corticosteroids and/or bronchodilators. Chest physiotherapy was given daily to 26 patients (22%). Gastroesophageal reflux, swallowing problem and aspiration increased the risk for hospital admissions. Additionally risk factors were the severity of disability, axial hypotonia, presence of epilepsy, scoliosis, limited shoulder movement, paradoxical breathing and absence of a spontaneous cough reflex. CONCLUSION: The overall respiratory morbidity in our sample of children with PIMD was lower than anticipated. While a subgroup of children are prone to recurrent severe airway problems, the majority of children did not experience severe airway infections.

Value of allohaemagglutinins in the diagnosis of a polysaccharide antibody deficiency.

Polysaccharide antibody deficiency is characterized by a poor or absent antibody response after vaccination with an unconjugated pneumococcal polysaccharide vaccine. Allohaemagglutinins (AHA) are antibodies to A or B polysaccharide antigens on the red blood cells, and are often used as an additional or alternative measure to assess the polysaccharide antibody response. However, few studies have been conducted to establish the clinical significance of AHA. To investigate the value of AHA to diagnose a polysaccharide antibody deficiency, pneumococcal polysaccharide antibody titres and AHA were studied retrospectively in 180 subjects in whom both tests had been performed. Receiver operating characteristic curves for AHA versus the pneumococcal vaccine response as a marker for the anti-polysaccharide immune response revealed an area under the curve between 0·5 and 0·573. Sensitivity and specificity of AHA to detect a polysaccharide antibody deficiency, as diagnosed by vaccination response, were low (calculated for cut-off 1/4-1/32). In subjects with only low pneumococcal antibody response, the prevalence of bronchiectasis was significantly higher than in subjects with only low AHA (45·5 and 1·3%, respectively) or normal pneumococcal antibody response and AHA (2·4%). A logistic regression model showed that low pneumococcal antibody response but not AHA was associated with bronchiectasis (odds ratio 46·2). The results of this study do not support the routine use of AHA to assess the polysaccharide antibody response in patients with suspected immunodeficiency, but more studies are warranted to clarify the subject further.

CFTR biomarkers: time for promotion to surrogate end-point.

In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.

Comparison of two treatment regimens for eradication of Pseudomonas aeruginosa infection in children with cystic fibrosis.

UNLABELLED: In patients with cystic fibrosis (CF), treatment of new Pseudomonas aeruginosa (Pa) infection postpones the occurrence of chronic infection, but the best eradication regimen is unknown . AIM OF THE STUDY: Compare 2 Pa eradication regimens in children with new Pa infection. METHODS: Children with CF (0-18 years) and a new isolation of Pa from sputum, cough swab or BAL were randomized to treatment with tobramycin inhalation solution for 28 days (TIS) or inhaled sodiumcolistimethate (2×2millU/day) plus oral ciprofloxacin (30 mg/kg/day) for 3 months (CC). Airway cultures were taken for 6 consecutive months, then every 3 months. The primary outcome was Pa eradication at the end of treatment. Secondary outcome parameters were: time to Pa relapse from end of treatment, total and Pa specific IgG, FEV(1), BMI and Pa status at 2year follow-up. RESULTS: 58 patients with new Pa isolation were randomized. Their median age was 9 years (IQR 4.7-13.1) and their median FEV(1) 98% predicted (IQR 87-107). Eighteen treatments concerned the first Pa isolation 'ever' (TIS: 8; CC: 10). For the remaining, median time since previous Pa was 19 months (IQR 9-41). Eradication at end of treatment was similar for both treatments: 26/29 CC and 23/29 in TOBI treated patients (p=0.47). Median time to recurrence of Pa was 9 months (95% CI 0.0-19.0) for CC and 5 months (95% CI 1.7-8.3) for TIS (p=0.608). After 1 year, the 2 groups did not differ in change in total and Pa specific IgG, FEV(1) and BMI. After 2 years, 10% of patients had chronic Pa infection. CONCLUSION: In children with CF and new Pa infection, inhalation of TIS (28 days) or CC (3 months) resulted in similar eradication success at the end of treatment (80 and 90% respectively) and similar clinical evolution during the first 2 years of follow-up.

Pulmonary alveolar microlithiasis: a case report and review of the literature.

A 12-year-old girl of Turkish descent was referred 6 weeks after an influenza A infection because of persistent chest X-ray abnormalities compatible with interstitial lung disease. The clinically suspected diagnosis of pulmonary alveolar microlithiasis (PAM) supported by pathognomonic radiological abnormalities was confirmed by genetic analysis. The clinical presentation of PAM is illustrated by a case and review of the current literature on this subject: you only see what you know.

Hemoptysis after orthopedic surgery in an adolescent boy.

In children, post-obstructive pulmonary edema is a rare condition, caused by a sudden change in upper airway patency. It causes dyspnea, tachypnea, hypoxemia, and at times hemoptysis and respiratory insufficiency. It occurs as a complication in the immediate post-operative period. Pediatricians should be aware of this clinical entity.

Pulmonary exacerbation: towards a definition for use in clinical trials. Report from the EuroCareCF Working Group on outcome parameters in clinical trials.

Pulmonary exacerbations represent a key outcome variable in clinical trials of cystic fibrosis (CF). As there is variation in the trigger for use of intravenous antibiotics compared to the use of oral antibiotics or new nebulised therapy for treatment of exacerbations, the consensus view is that use of intravenous antibiotics cannot be regarded as the key defining character for an exacerbation on its own. The consensus view is that the clinical need for additional treatment as indicated by a recent change in clinical parameters provides the best definition of an exacerbation. Which parameters to include as well as the problems associated with the use of scoring systems and symptom clusters are being discussed.

Change in IgG and evolution of lung function in children with cystic fibrosis.

Reports from the seventies and eighties have shown that cystic fibrosis (CF) patients with severe lung disease have high levels of IgG and that this is associated with worse prognosis. We decided to explore IgG level as a possible outcome parameter for lung disease severity in a cohort of pediatric CF patients treated according to current standards of care. Seventy three CF children older than 5 years (and max 15 years old at the initial evaluation) attending the same CF center were followed during a period of 4 years. Data collection included spirometry, height, weight, sputum cultures and total IgG. Median age at the start was 10 years. IgG z scores<2 SD were seen in 2.7% of patients in 2004 and 2008. Twelve patients (16%) had an IgG>2 SD in 2004 and this number increased to 18 (25%) in 2008. IgG z-scores were inversely correlated with FEV(1)% predicted (r=-0.323 in 2004; p<.001). In longitudinal evaluation, changes in IgG z-score correlate inversely with changes in FEV(1)% predicted (r=-0.498; p<.001). We can conclude that even for CF patients treated according to current standards IgG z-score increases with age and is correlated with a decline in FEV(1).

Siblings of children with cystic fibrosis: quality of life and the impact of illness.

OBJECTIVE: To asses self-reported quality of life (QoL) and perception of impact of illness on siblings of children with cystic fibrosis (CF). METHODS: The Child Health Questionnaire was used to assess QoL. The Sibling Perception Questionnaire was used to assess impact of illness. RESULTS: Siblings of children with CF (n= 39) rated their QoL higher than siblings of healthy children on most QoL domains (e.g. Physical Functioning, Behavior, Mental Health). Siblings older than the child with CF reported a higher impact of CF than younger siblings. Perceived impact of illness was higher when the child with CF had been hospitalized or was intermittent or chronically infected with Pseudomonas aeruginosa. CONCLUSIONS: Siblings of children with CF reported a good QoL. QoL and impact of illness were related to indices of CF severity. Insight into sibling-issues helps CF teams to provide family-oriented care.

The fetal respiratory system as target for antenatal therapy.

The widespread use of prenatal ultrasound has made the fetus a patient. A number of conditions diagnosed as such may require therapy prior to birth. Herein we describe past, current and potential future procedures designed to treat pulmonary conditions in the antenatal period. When congenital cystic adenomatoid malformation (CCAM) is -associated with fetal hydrops, treatment is required. Prior to viability this may be in utero resection of the pathologic lung lobe or shunting of cystic lesions. More recently, fetuses with isolated congenital diaphragmatic hernia (CDH) with lethal lung hypoplasia have been offered percutaneous fetal tracheal occlusion to provoke lung growth. A very rare condition is laryngeal atresia, which requires peripartum re-establishment of the airways. As we get more -experience with access to the fetal airways, this may open the doors for novel therapies. One of these is gene delivery to treat fetuses with serious monogenic disorders or to induce transient overexpression of certain proteins. We review the individual hurdles that are being met by researchers when designing fetal gene therapeutic strategies, in particular for the fetal lung. Also the use of stem cells for pulmonary disorders is currently explored.

Use of nebulized amphotericin B in the treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis.

Background. Systemic steroids and adjunctive antifungal therapy are the cornerstone in treating allergic bronchopulmonary aspergillosis (ABPA) in the context of CF. Aim. Evaluate the use of inhaled amphotericin B (iAMB) as antifungal agent in this context. Methods. Report of 7 CF patients with recurrent or difficult to treat ABPA and failure to taper systemic corticosteroids treated with AMB deoxycholate (AMB-d) (Fungizone 25 mg 3× a week) or AMB lipid complex (ABLC) (Abelcet 50 mg twice weekly). Successful therapy was defined as steroid withdrawal without ABPA relapse within 12 months. Results. Therapy was successful in 6 of 7 patients treated with iAMB. In 5/6, lung function improved. The patient with treatment failure has concomitant MAC lung infection. Conclusion. Inhaled AMB may be an alternative to commonly used adjunctive antifungal therapy in the treatment of ABPA. More data are needed on safety and efficacy.

Characteristics of gastroesophageal reflux and potential risk of gastric content aspiration in children with cystic fibrosis.

OBJECTIVES: Increased gastroesophageal reflux (GER) is common in children with cystic fibrosis (CF). We studied the occurrence of acid, weakly acidic (WA), and weakly alkaline (WALK) reflux in children with CF and evaluated a possible surrogate marker for risk of gastric content aspiration. PATIENTS AND METHODS: Twenty-four children with CF underwent impedance-pH monitoring for detection of acid (pH < 4), WA (pH 4-7), and WALK-GER (pH > or = 7). In 11 children, cough was objectively recorded with esophageal manometry and the symptom association probability was calculated to determine the reflux-cough relation. Presence of bile acids (BA) was measured in the saliva of 65 patients with CF and 23 healthy children, respectively. RESULTS: Sixteen of the 24 children had increased GER (esophageal acid exposure). The majority of reflux events were acidic in nature. WA reflux was less common and WALK reflux was rare. The sequence reflux-cough was found in 8 of the 11 children and 1 of 11 children had a positive symptom association probability for reflux-cough. The sequence cough-reflux was found in only 3 of the 11 children. Only a small fraction of the total esophageal acid and volume exposure was secondary to cough. Twenty-three of the 65 children with CF had BA in saliva compared with none of the healthy controls. CONCLUSIONS: Although WA-GER is uncommon, acid GER is prevalent in children with CF. It is a primary phenomenon and is not secondary to cough. One third of the children with CF have BA in saliva, which may indicate an increased risk for aspiration. However, the impact of salivary BA and potential aspiration on CF pulmonary disease needs further investigation.

Montelukast does not prevent reactive airway disease in young children hospitalized for RSV bronchiolitis.

AIM: To evaluate the long-term effect of montelukast on symptoms of cough and wheeze following RSV bronchiolitis. METHODS: Fifty eight patients (aged < or = 24 months) hospitalized with a first episode of RSV bronchiolitis were enrolled in this double blind prospective randomized trial comparing montelukast (n = 31) vs placebo (n = 27). RESULTS: During the 3-month treatment period, there were no statistical significant differences between the two groups for symptom-free days and nights (48.5 [interquartile range 33.0.0-66.0] for montelukast vs 57.0 [29.0-71.0] for placebo p = 0.415) nor disease-free days and nights (44.5 days [26.0-54.0] vs 53.0 [22.3-71.0]; p = 0.266). During the 1 year follow-up, there were 41 exacerbations in the montelukast group vs 54 exacerbations in the placebo group (p = 0.57). Time to first exacerbation was not different. Number of unscheduled visits and need to start inhaled steroids were comparable in the two groups. CONCLUSION: Treatment with montelukast after hospital admission for RSV bronchiolitis in children younger than 2 years of age did not reduce symptoms of cough and wheeze. We cannot exclude that a subgroup of children may, however, benefit from this treatment.

'Difficult asthma': can symptoms be controlled in a structured environment?

OBJECTIVE: Difficult asthma implies persistent asthma symptoms despite therapy with high doses of inhaled corticosteroids. The objective was to evaluate children with difficult asthma in a setting that excludes aggravating factors such as poor treatment adherence and adverse environmental influences. PATIENTS AND METHODS: Sixty children (> or =6 years) had been referred because of difficult asthma to the rehabilitation centre over a period of 10 years. The diagnosis of poor asthma symptom control was confirmed if exacerbations continued during stay in the centre or if symptoms interfered with daily activities at least 3 times a week. RESULTS: The median stay at the centre was 5 months. In four patients a diagnosis other than asthma was made. In five patients symptom control remained difficult. In the remaining 51 children, asthma symptoms became well controlled. Many factors contributed to poor asthma control in the home setting: poor treatment adherence (n = 32), parental smoking (n = 22), allergen exposure (n = 10). Psychosocial problems occurred in 36 children. Contributing factors often co-existed. During stay at the centre, lung function improved in the group with well controlled asthma symptoms (P < 0.001) but not in the group with continued poor symptom control. In the majority of children who obtained good symptom control, this persisted in the years following discharge. CONCLUSION: Of 60 children referred with a diagnosis of difficult asthma, optimal medical management in a structured environment resulted in good symptom control in 51 patients; symptom control remained poor in 5 patients, a diagnosis other than asthma was made in 4 patients.