The dark side of the moon: severe therapy-resistant asthma in children.

Problematic severe asthma is the term used to describe children whose asthma is not responsive to standard therapy with high-dose inhaled corticosteroids and additional controllers. These children need to be assessed by a step-wise systematic protocol in order to confirm the diagnosis, evaluate co-morbidities, assess the adherence to treatment, and finally evaluate the basic management. More than half of these children have "difficult-to-treat asthma", which improves if the basic management is correct. Children whose asthma remains uncontrolled despite resolution of any reversible factors are termed "severe therapy-resistant" asthmatics; for them, an individualised treatment plan is developed after a detailed and invasive protocol of investigation. Therapeutic options for these patients can be divided into medications used in lower doses for children with less severe asthma, and those used in other pediatric diseases but not for asthma. Most treatments are unlicensed and there is a lack of high-quality evidence. Children with recurrent severe exacerbations, in particular in the context of good baseline asthma control, are particularly difficult to treat, and there is no evidence on which therapeutic option to recommend. International collaborations, using standard protocols of investigation, are needed to better understand mechanisms of severe therapy-resistant asthma and to deliver evidence-based treatments in the future.

Pharmacological treatment of severe, therapy-resistant asthma in children: what can we learn from where?

There is a lack of high-quality evidence on what treatment should be used in children with properly characterised severe, therapy-resistant asthma. Data have to be largely extrapolated from trials in children with mild asthma, and adults with severe asthma. Therapeutic options can be divided into medications used in lower doses for children with less severe asthma, and those used in other paediatric diseases but not for asthma (for example, methotrexate). In the first category are high-dose inhaled corticosteroids (ICS) (≤ 2,000 µg · day(-1) fluticasone equivalent), oral prednisolone, the anti-immunoglobulin (Ig)E antibody omalizumab, high-dose long-acting ß(2)-agonists, low-dose oral theophylline and intramuscular triamcinolone. If peripheral airway inflammation is thought to be a problem, the use of fine-particle ICS or low-dose oral corticosteroids may be considered. More experimental therapies include oral macrolides, cyclosporin, cytotoxic drugs such as methotrexate and azathioprine, gold salts, intravenous infusions of Ig, subcutaneous ß(2)-agonist treatment and, in those sensitised to fungi, oral antifungal therapy with itraconazole or voriconazole. Those with recurrent severe exacerbations, particularly in the context of good baseline asthma control, are particularly difficult to treat; baseline control and lung function must be optimised with the lowest possible dose of ICS, and allergen triggers and exposures minimised. The use of high-dose ICS, leukotriene receptor antagonists or both at the time of exacerbations can be considered. There is no evidence regarding which therapeutic option to recommend. Better evidence is required for all these treatment options, underscoring the need for the international and co-ordinated approach which we have previously advocated.

Assessment of problematic severe asthma in children.

Assessment of problematic severe asthma in children should be performed in a step-wise manner to ensure an optimal approach. A four-step assessment scheme is proposed. First, a full diagnostic work-up is performed to exclude other diseases which mimic asthma. Secondly, a multi-disciplinary assessment is performed to identify issues that may need attention, including comorbidities. Thirdly, the pattern of inflammation is assessed, and finally steroid responsiveness is documented. Based upon these four steps an optimal individualised treatment plan is developed. In this article the many gaps in our current knowledge in all these steps are highlighted, and recommendations for current clinical practice and future research are made. The lack of good data and the heterogeneity of problematic severe asthma still limit our ability to optimise the management on an individual basis in this small, but challenging group of patients.

Severe necrotizing pneumonia complicating influenza A (H1N1): the role of immunologic interaction.

This report describes the successful management of a documented necrotizing pneumonia due to Streptococcus pneumoniae in a child with pandemic influenza A (H1N1). The importance of early recognition of bacterial superinfection in patients with influenza and the immunologic interactive mechanisms between viruses and bacteria in determining respiratory diseases are highlighted. The role of modern molecular techniques in improving diagnostic microbiology sensitivity and informing consequent clinical care is emphasized.

Anesthesia in children with asthma and rhinitis.

The incidence of asthma is increasing worldwide, but morbidity and mortality are decreasing, because of improvements in medical care. Although the incidence of severe perioperative bronchospasm is relatively low in asthmatics undergoing anaesthesia, when it does occur it may be life-threatening. Preoperative assessment of asthma should include a specialized medical hystory and physical examination as well as pulmonary function testing. Potential trigger agents should be identified and avoided. In many asthmatic patients treatment with systemic corticosteroids and bronchodilators is indicated to prevent the inflammation and bronchocostriction associated with endotracheal intubation. Nonetheless, acute bronchospasm can still occur, especially at induction and emergence, and should be promptly and methodically managed.

Clinical modifications induced by drugs during the perioperative period.

Total intravenous anesthesia (TIVA) can be defined as a technique in which general anesthesia is induced and maintained using only intravenous agents. TIVA has become more popular in recent times because of the pharmacokinetic and pharmacodynamic properties of propofol, the availability of short acting synthetic opioids, and the development of delivery systems. Significant differences in anatomy and physiology in adults and children and special needs of younger patients have important consequences on many aspects of anesthesia. Airway and respiratory complications are the most common causes of morbidity during general anesthesia in children. Knowledge of the functional anatomy of airways in children forms the basis in the understanding of the pathological conditions that may occur.

Problematic severe asthma in children, not one problem but many: a GA2LEN initiative.

Although most children with asthma are easy to treat with low doses of safe medications, many remain symptomatic despite every therapeutic effort. The nomenclature regarding this group is confusing, and studies are difficult to compare due to the proliferation of terms describing poorly defined clinical entities. In this review of severe asthma in children, the term problematic severe asthma is used to describe children with any combination of chronic symptoms, acute severe exacerbations and persistent airflow limitation despite the prescription of multiple therapies. The approach to problematic severe asthma may vary with the age of the child, but, in general, three steps need to be taken in order to separate difficult-to-treat from severe therapy-resistant asthma. First, confirmation that the problem is really due to asthma requires a complete diagnostic re-evaluation. Secondly, the paediatrician needs to systematically exclude comorbidity, as well as personal or family psychosocial disorders. The third step is to re-evaluate medication adherence, inhaler technique and the child's environment. There is a clear need for a common international approach, since there is currently no uniform agreement regarding how best to approach children with problematic severe asthma. An essential first step is proper attention to basic care.

Medicines used in respiratory diseases only seen in children.

Detailed literature searches were carried out in seven respiratory disease areas. Therapeutic evidence for efficacy of medicinal products was assessed using the Grades of Recommendation, Assessment and Evaluation (GRADE) methodology, as well as an assessment of safety and side-effects. Systemic corticosteroids may reduce the development of bronchopulmonary dysplasia but have serious side-effects. Antioxidants need further study to demonstrate whether they have long-term benefits. Treatments for acute bronchiolitis have shown little benefit but new antiviral and monoclonal antibodies need further assessment. Well-constructed studies are needed to confirm the value of inhaled corticosteroids and/or montelukast in the management of viral-induced wheeze. Corticosteroids are the treatment of choice in croup. Minimal or no information is available for the treatment of congenital lung abnormalities, bronchiolitis obliterans and interstitial lung disease.

The allergic sensitization in infants with atopic eczema from different countries.

BACKGROUND: No study has compared allergic sensitization patterns in infants with atopic eczema from different countries. The aim of this study was to investigate the patterns of allergic sensitization in a cohort of infants with atopic eczema participating in a multicentre, international study. METHODS: Two thousand one hundred and eighty-four infants (mean age 17.6 months) with atopic eczema from allergic families were screened in 94 centres in 12 countries to participate in a randomized trial for the early prevention of asthma. Clinical history, Severity Scoring of Atopic Dermatitis Index, measurements for total serum IgE and specific IgE antibodies to eight food and inhalant allergens were entered into a database before randomization to treatment. A history of type of feeding in the first weeks of life and exposure to animals was recorded. RESULTS: A total of 52.9% of the infants had raised total IgE, and 55.5% were sensitized to at least one allergen. There was a wide difference in the total IgE values and in the sensitization rates to foods and aeroallergens among infants from different countries. The highest prevalence rates of allergen-sensitized infants were found in Australia (83%), the UK (79%) and Italy (76%). Infants from Belgium and Poland consistently had the lowest sensitization rates. In each country, a characteristic pattern of sensitization was found for aeroallergens (house dust mite > cat > grass pollen > Alternaria), but not for food allergens. CONCLUSIONS: In infants with atopic eczema, there is a wide variation in the pattern of allergic sensitization between countries, and data from one country are not necessarily generalizable to other countries.

Clinical evaluation and treatment of acute asthma exacerbations in children.

This update on treatment of asthma exacerbations in children is the result of an Italian Pediatric Society Task-force, made up of a panel of experts working in 2007-2008. The aim is to give clear indications on the use of the drugs most employed in children, grading the quality of evidence and the strength of recommendations. Suggestions on their limits due to unlicensed and off-label use are reported. The level of evidence and the strength of recommendations for different therapeutic approaches demonstrate that frequently the use of drugs in children is extrapolated from the experience in adults and that more studies are required to endorse the correct use of different drugs in asthmatic children.

Confirmation of the association between high levels of immunoglobulin E food sensitization and eczema in infancy: an international study.

BACKGROUND: Studies of Australian infants have reported that more than 80% of those with moderate atopic eczema (AE) have high levels of IgE food sensitization (IgE-FS) that are commonly associated with IgE food allergy. OBJECTIVES: To explore the relationship between high levels of IgE-FS and AE in a large cohort of young children with eczema participating in a multi-centre, international study. METHODS: Two thousand one hundred and eighty-four subjects (mean age 17.6 months, range 11.8-25.4; 1246 males) with active eczema from atopic families from 94 centres in 12 countries were studied. Clinical history, Scoring Atopic Dermatitis index as a measure of eczema severity and CAP-FEIA measurements for total IgE and IgE antibody levels to cow milk, egg and peanut were entered into a database. If CAP-FEIA levels exceeded previously reported age-specific cut-off levels for 95% positive predictive values (PPVs) for food allergy, subjects were defined as having high-risk IgE-FS (HR-IgE-FS). RESULTS: Serum was available from 2048 patients; 55.5% were atopic. The frequency of HR-IgE-FS to milk, egg and/or peanut was the greatest in patients whose eczema developed in the first 3 months of life and the least in those whose eczema developed after 12 months (P<0.0001). In a regression analysis to allow for potential confounding factors, children with HR-IgE-FS had the most severe eczema and the youngest age of onset (P<0.001); 64% of infants with severe eczema of onset-age <3 months had HR-IgE-FS. CONCLUSION: Early-onset severe eczema in infancy was associated with HR-IgE-FS. Clinical implications Food allergies should be routinely assessed in infants with moderate or severe eczema. Capsule summary In eczematous infants, the earlier the age of onset, and the greater the severity of eczema, the greater the frequency of associated high levels of IgE-FS.

New oral H1 antihistamines in children: facts and unmeet needs.

BACKGROUND: Second-generation antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1-receptors and because of their lower penetration to the central nervous system, having fewer sedative effects as a result. Over the last few years, new compounds with different pharmacokinetic properties have been synthesized. More recent improvements of the molecules, generally in the form of active metabolites, led to the synthesis of new-generation antihistamines. METHODS: Recommendations on the minimum criteria that would have to be met for compounds to be classified as new-generation antihistamines have been recently established by a consensus statement. In the past, the pharmacokinetics and pharmacodynamics of H1 antihistamines have not been optimally investigated in the pediatric population, especially in infants and young children. RESULTS: The pharmacology of second-generation H1 antihistamines has been investigated relatively deeper than old antihistamines in children. In the pediatric population, clinical studies with new-generation antihistamines are still limited in number and, with rare exceptions, of brief duration. Comparative trials on the efficacy and safety between different compounds are also lacking. CONCLUSIONS: Properly designed, long-term trials with new-generation H1 antihistamines need to be performed in single age groups, in order to better define the effects of these drugs in all pediatric population.

Complementary roles for lipid and protein allergens in triggering innate and adaptive immune systems.

BACKGROUND: Recent advances in allergy research mostly focussed on two major headings: improving protein allergen purification, which is aimed towards a better characterization of IgE- and T-cell reactive epitopes, and the potential new role for unconventional innate and regulatory T cells in controlling airway inflammation. These advancements could appear to be in conflict each other, as innate T cells have a poorly-defined antigen specificity that is often directed toward nonprotein substances, such as lipids. METHOD: To reconcile these contrasting findings, the model of cypress pollinosis as paradigmatic for studying allergic diseases in adults is suggested. RESULTS: The biochemical characterization of major native protein allergens from undenatured pollen grain demonstrated that the most relevant substance with IgE-binding activity is a glycohydrolase enzyme, which easily denaturizes in stored grains. Moreover, lipids from the pollen membrane are implicated in early pollen grain capture and recognition by CD1(+) dendritic cells (DC) and CD1-restricted T lymphocytes. These T cells display Th0/Th2 functional activity and are also able to produce regulatory cytokines, such as IL-10 and TGF-beta. CD1(+) immature DCs expand in the respiratory mucosa of allergic subjects and are able to process both proteins and lipids. CONCLUSION: A final scenario may suggest that expansion and functional activation of CD1(+) DCs is a key step for mounting a Th0/Th2-deviated immune response, and that such innate response does not confer long-lasting protective immunity.

Apoptosis, airway inflammation and anti-asthma therapy: from immunobiology to clinical application.

T lymphocyte apoptosis is essential for maintaining immune system homeostasis. Experimental evidence suggests apoptosis control mechanisms may be impaired in inflammatory conditions, particularly airway Th2-type allergic diseases. This review briefly examines the mucosal immune system homeostasis and common apoptotic pathways and discusses impaired apoptosis, allergy, airway inflammation, remodelling and fibrosis. Finally, the paper presents an update on pharmacological targeting of apoptosis to control airway inflammation in patients with allergic asthma.

IgE antibody responses in young children with atopic dermatitis.

In 2184 young children aged 13-24 months with atopic dermatitis (SCORAD 5-59) serum IgE antibodies to a standard panel of food and inhalant allergens were assayed. The frequency of positive IgE responses (>0.35 kU/l) increased with greater severity of skin disease. A significant minority of infants had levels of IgE antibody to foods to suggest they were at risk of acute reaction to those foods (7% to hen's egg, 3% to cow's milk, 4% to peanut). Our findings indicate that the frequency of positive IgE responses is related to disease severity and suggest that differences in the time course of the development of IgE responses to food, which are at maximum prevalence within the first year of life, while inhalant allergies, are still developing between 1 and 2 yr and beyond.

Haemothorax caused by isolated costal exostosis.

We report an unusual case of spontaneous haemothorax in a 13-year-old girl with isolated costal exostosis. Surgical excision of the exostosis was performed with complete resolution. Costal exostosis should be considered in the differential diagnosis of spontaneous haemothorax in children in order to avoid unnecessary investigation and to establish an adequate treatment plan.

Effects of 2 inhaled corticosteroids on growth: results of a randomized controlled trial.

OBJECTIVE: To compare the long-term effect of treatment with fluticasone propionate or beclomethasone dipropionate on growth in asthmatic children. DESIGN: Prospective, multicenter, randomized, double-blind, parallel-group study. SETTING: Children requiring regular treatment with inhaled corticosteroids and with a sexual maturity rating of Tanner stage 1 (prepubertal). PATIENTS: Three hundred forty-three children aged 4 to 11 years with asthma. The growth population (excluding patients with protocol violations likely to affect growth measurements) included 277 patients. INTERVENTIONS: Fluticasone propionate or beclomethasone dipropionate, both at a dosage of 200 microg administered twice daily via a dry powder inhaler (Diskhaler) for 12 months. MAIN OUTCOME MEASURES: Growth velocity, lung function, and serum and urinary cortisol levels. RESULTS: The adjusted mean growth velocity in the fluticasone group was significantly greater than that in the beclomethasone group (5.01 [SE, 0.14] vs 4.10 [SE, 0.15] cm/y; difference, 0.91 cm; 95% confidence interval, 0.63-1.20 cm; P<.001). Both treatments improved lung function, with significant differences in favor of fluticasone. Adverse events were similar in both groups, and there were no significant differences in effect on serum and urinary cortisol levels. CONCLUSIONS: The more favorable risk-benefit ratio of fluticasone indicates that this agent is preferable to beclomethasone for the long-term treatment of children with asthma, especially if moderate doses are required.

Viral and Mycoplasma pneumoniae pneumonias in school-age children: three-year follow-up of respiratory function.

We studied the evolution of respiratory function during and for 3 years after the acute onset of viral and Mycoplasma pneumoniae pneumonias in 13 school-age children. A mixed type transient ventilatory defect (restrictive and obstructive, but mainly restrictive) with large and small airway involvement was observed during the acute phase of the pneumonias. Residual small airway involvement was found over the next 12 months, but no pulmonary function abnormalities were present after 3 years. At that time, one of the 13 subjects displayed bronchial hyperreactivity to distilled water mist challenge. The authors concluded that viral and Mycoplasma pneumoniae pneumonia in previously healthy school-age children does not cause impaired lung function in later childhood.