Current options in aerosolised drug therapy for children receiving respiratory support.

Inhalation of aerosolised medications are the mainstay of treatment for a number of chronic lung diseases and have several advantages over systemically-administered medications. These include more rapid onset of action for drugs such as ß-adrenergic agonists when compared with oral medication, high luminal doses for inhaled antibiotics when used to treat endobronchial infection, and an improved therapeutic index compared with systemic delivery for these and other classes of drugs such as corticosteroids. The use of aerosolised drugs to treat patients whose tracheas are intubated is less well established, in part because systemic delivery via the intravenous route can be a simpler alternative for many drugs. Consequently, research in this area is largely limited to a number of in vitro studies and very few clinical trials. Unfortunately, a lack of focus in this area has resulted in a number of practices which at best are ineffective, and at worst dangerous for the patient. Although there have been some attempts to re-invigorate research in order to improve delivery systems, current devices are, to a great extent, based on long-standing technology developed more than 50 years ago. In this review, we explore current knowledge and provide guidance as to when and how the inhaled route may be of value when treating patients whose tracheas are intubated, and we set out the challenges facing those attempting to advance the topic. We conclude by reviewing current areas of interest that may lead to more effective and widespread use of aerosols in the treatment of intubated patients.

Exhaled nitric oxide in the diagnosis of asthma in adults: a systematic review.

OBJECTIVES: To identify and synthesize evidence on the diagnostic accuracy of FE NO for asthma in adults. MATERIALS AND METHODS: Systematic searches (nine key biomedical databases and trial registers) were carried out on November 2014. Records were included if they recruited patients with the symptoms of asthma; used a single set of inclusion criteria; measured FE NO50 in accordance with American Thoracic Society guidelines, 2005 (off-line excluded); reported/allowed calculation of true-positive, true-negative, false-positive and false-negative patients as classified against any reference standard. Study quality was assessed using QUADAS II. Meta-analysis was planned where clinical study heterogeneity allowed. Rule-in and rule-out uses of FE NO were considered. RESULTS: A total of 4861 records were identified originally and 1312 in an update. Twenty-seven studies were included. Heterogeneity precluded meta-analysis. Results varied even within subgroups of studies. Cut-off values for the best sum of sensitivity and specificity varied from 12 to 55 p.p.b., but did not produce high accuracy. 100% sensitivity or 100% specificity was reported by some studies indicating potential use as a rule-in or rule-out strategy. CONCLUSIONS AND CLINICAL RELEVANCE: FE NO50 had variable diagnostic accuracy even within subgroups of studies with similar characteristics. Diagnostic accuracy, optimal cut-off values and best position for FE NO50 within a pathway remain poorly evidenced.

Investigation of gastrointestinal effects of organophosphate and carbamate pesticide residues on young children.

This prospective study was designed to investigate whether there is any association between gastrointestinal effects and pesticide residue exposure (as measured by metabolite levels in urine and faecal samples) in young children and to describe background levels of pesticide residues in samples from healthy children in the UK. Children (N=136) between the ages of 1.0 and 4.2 years were recruited. Of these, 107 provided background baseline samples and 26 provided samples when suffering from gastrointestinal symptoms. Urine samples (from all populations) were positive for (non-specific) carbaryl metabolite (urine 19/78, faeces 9/99), organophosphate metabolites (urine 103/135, faeces 47/111) and pirimicarb metabolite (urine 72/175, faeces 45/135). There were no statistically significant differences between samples from children when healthy or unwell. The urinary 95th percentile values for the healthy population of young children in this study were 31 nmol/l (carbaryl metabolite), 2156 nmol/l (total organophosphate metabolites) and 139 nmol/l (pirimicarb metabolite). In this study, samples from children suffering gastrointestinal symptoms were no more associated with anti-cholinergic pesticide metabolite levels or rotaviral infection than samples from healthy children. Background levels of anti-cholinergic pesticide metabolites in healthy UK children were in agreement with previously reported levels from the US and Germany.

The social organization of violence toward hostages: does violence in captivity indicate which kidnappers will kill?

It is questionable whether violence toward a hostage varies according to criminal or radical orientation of their kidnappers who hold them for ransom. This notion is important because it relates to the assumption that how the hostage is treated may indicate whether the victim may survive the ordeal. To investigate, 181 kidnappings cases were cross-tabulated with four previously identified violent tactics (inflicting pain, terror, psychological torture, and reward tactics) and three distinctive type of kidnappers (common criminal, organized criminal, and radical/terrorist groups). The results indicated that criminal groups tended to use a range of violent tactics to coerce a hostage in captivity, while radical groups more often specialized in psychological torture. Regardless of these observations, specific forms of violence, for example inflicting pain, provided a better indication of whether the hostage would be killed by his or her kidnappers. This suggests that the intensity of violence and not the type of group conducting the kidnapping indicates whether the hostage will be killed. The implications to the social organization of kidnapping groups are discussed further.

International consensus on (ICON) pediatric asthma.

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re-evaluate and fine-tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype-specific treatment choices; however, this goal has not yet been achieved.

Diagnosing and preventing chronic suppurative lung disease (CSLD) and bronchiectasis.

Current diagnostic labelling of childhood bronchiectasis by radiology has substantial limitations. These include the requirement for two high resolution computerised tomography [HRCT] scans (with associated adversity of radiation) if criteria is adhered to, adoption of radiological criteria for children from adult data, relatively high occurrence of false negative, and to a smaller extent false positive, in conventional HRCT scans when compared to multi-detector CT scans, determination of irreversible airway dilatation, and absence of normative data on broncho-arterial ratio in children. A paradigm presenting a spectrum related to airway bacteria, with associated degradation and inflammation products causing airway damage if untreated, entails protracted bacterial bronchitis (at the mild end) to irreversible airway dilatation with cystic formation as determined by HRCT (at the severe end of the spectrum). Increasing evidence suggests that progression of airway damage can be limited by intensive treatment, even in those predestined to have bronchiectasis (eg immune deficiency). Treatment is aimed at achieving a cure in those at the milder end of the spectrum to limiting further deterioration in those with severe 'irreversible' radiological bronchiectasis.

What the pulmonary specialist should know about the new inhalation therapies.

A collaboration of multidisciplinary experts on the delivery of pharmaceutical aerosols was facilitated by the European Respiratory Society (ERS) and the International Society for Aerosols in Medicine (ISAM), in order to draw up a consensus statement with clear, up-to-date recommendations that enable the pulmonary physician to choose the type of aerosol delivery device that is most suitable for their patient. The focus of the consensus statement is the patient-use aspect of the aerosol delivery devices that are currently available. The subject was divided into different topics, which were in turn assigned to at least two experts. The authors searched the literature according to their own strategies, with no central literature review being performed. To achieve consensus, draft reports and recommendations were reviewed and voted on by the entire panel. Specific recommendations for use of the devices can be found throughout the statement. Healthcare providers should ensure that their patients can and will use these devices correctly. This requires that the clinician: is aware of the devices that are currently available to deliver the prescribed drugs; knows the various techniques that are appropriate for each device; is able to evaluate the patient's inhalation technique to be sure they are using the devices properly; and ensures that the inhalation method is appropriate for each patient.

A feasibility study of sequential doublet chemotherapy comprising carboplatin-doxorubicin and carboplatin-paclitaxel for advanced endometrial adenocarcinoma and carcinosarcoma.

BACKGROUND: Platinum compounds, taxanes and anthracyclines provide the major effective drug classes in the treatment of advanced and recurrent endometrial cancer and carcinosarcoma. PATIENTS AND METHODS: A total of 52 women with advanced or recurrent endometrial cancer and carcinosarcoma were treated with four cycles of carboplatin area under the curve (AUC) 5 and doxorubicin (50 mg/m(2)) for four cycles before or after four cycles of carboplatin AUC5 and paclitaxel (175 mg/m(2)) with each cycle administered at 21-day intervals. RESULTS: Thirty-seven patients (71.2%) completed all planned treatment. Excluding six patients who did not complete treatment for non-drug-related causes, 80.4% completed all planned treatment. Three hundred and seventy-one treatment cycles were administered and 303 (81.7%) occurred on time. Common Toxicity Criteria grade 3/4 haematological toxic effects, particularly neutropenia and thrombocytopenia, were the predominant cause of treatment delays and dose reductions. A low incidence of grade 3 neurotoxicity and no cardiac toxicity were observed. The overall response rates for patients with evaluable disease were 82.1% and 66.7% for endometrial and carcinosarcoma, respectively. At a median follow-up of 21 months, the median progression-free survival for the endometrial adenocarcinoma and carcinosarcoma cohorts were 15.3 and 12.0 months, respectively. CONCLUSION: This regimen is generally well tolerated with encouraging efficacy.

Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach.

There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Chronic wet cough: Protracted bronchitis, chronic suppurative lung disease and bronchiectasis.

The role of persistent and recurrent bacterial infection of the conducting airways (endobronchial infection) in the causation of chronic respiratory symptoms, particularly chronic wet cough, has received very little attention over recent decades other than in the context of cystic fibrosis (CF). This is probably related (at least in part) to the (a) reduction in non-CF bronchiectasis in affluent countries and, (b) intense focus on asthma. In addition failure to characterize endobronchial infections has led to under-recognition and lack of research. The following article describes our current perspective of inter-related endobronchial infections causing chronic wet cough; persistent bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis. In all three conditions, impaired muco-ciliary clearance seems to be the common risk factor that provides organisms the opportunity to colonize the lower airway. Respiratory infections in early childhood would appear to be the most common initiating event but other conditions (e.g., tracheobronchomalacia, neuromuscular disease) increases the risk of bacterial colonization. Clinically these conditions overlap and the eventual diagnosis is evident only with further investigations and long term follow up. However whether these conditions are different conditions or reflect severity as part of a spectrum is yet to be determined. Also misdiagnosis of asthma is common and the diagnostic process is further complicated by the fact that the co-existence of asthma is not uncommon. The principles of managing PBB, CSLD and bronchiectasis are the same. Further work is required to improve recognition, diagnosis and management of these causes of chronic wet cough in children.

Persistent of respiratory syncytial virus in human dendritic cells and influence of nitric oxide.

The annual epidemics of respiratory syncytial virus (RSV) infection are probably explained by poor herd immunity and the existence of a dormant reservoir of virus that is activated by an unknown trigger. The virus causes particular problems in infants, the elderly and patients with chronic obstructive airways disease (COPD). During two consecutive winters, human monocyte-derived dendritic cells (DCs) were exposed on a single occasion to one of two forms of RSV labelled with a fluorescent expresser genes (rgRSV or rrRSV) during the epidemic season. The cultures were maintained for many months, with fresh DCs being added at monthly intervals. The cultures were variously exposed to 600 parts per billion (ppb) nitric oxide for 15 min, nitric oxide (NO) donors and NO inhibitors outside the RSV epidemic season. The pattern of productive infection of DCs in vitro appeared to parallel the natural epidemics, in that DCs exhibited evidence of viral replication and productive infection only as manifested by intracellular fluorescence and infection of HeLa cells during the RSV epidemic season. When the long-term cultures were exposed to the above agents outside the RSV epidemic season there was again evidence of vigorous replication and productive infection, as shown by the reappearance of fluorescence and productive infection of HeLa cells. The results indicate that RSV may remain dormant in dendritic cells for prolonged periods and that replication appears to be activated by suppression of endogenous NO production. These observations may be key to our understanding of the mechanisms contributing to the annual epidemics of RSV infection.

Omega-3 fatty acids (from fish oils) for cystic fibrosis.

BACKGROUND: Epidemiological and other studies suggest that a diet rich in omega-3 essential fatty acids (derived from fish oil) may have beneficial anti-inflammatory effects for chronic conditions such as cystic fibrosis (CF). OBJECTIVES: To determine whether there is evidence that omega-3 polyunsaturated fatty acid supplementation reduces morbidity and mortality. To identify any adverse events associated with omega-3 polyunsaturated fatty acid supplementation. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Authors and persons interested in the subject of the review were contacted. Most recent search: April 2007 SELECTION CRITERIA: Randomised controlled trials in people with CF comparing omega-3 fatty acid supplements with placebo. DATA COLLECTION AND ANALYSIS: Two authors independently selected the studies for inclusion in the review, independently extracted data and assessed the methodological quality of the studies. MAIN RESULTS: Searches identified seven studies; three of which, involving 48 participants, were eligible for inclusion in the review. Two studies compared omega-3 fatty acids to olive oil controls for a six-week treatment period. One study compared omega-3 fatty acids in the form of a liquid dietary supplement containing polyunsaturated fatty acids to a liquid dietary supplement control for six months. One short-term study (19 participants) comparing omega-3 to placebo reported a significant improvement in forced expiratory volume in one second, forced vital capacity and Shwachman score and a reduction in sputum volume in the omega-3 group. The longer-term study (17 participants) demonstrated a significant increase in essential fatty acid content in neutrophil membranes in study participants taking omega-3 supplements compared to placebo, weighted mean difference 0.90 (95% confidence interval 0.46 to 1.34). AUTHORS' CONCLUSIONS: This review found that regular omega-3 supplements may provide some benefits for people with CF with relatively few adverse effects, although the evidence is insufficient to draw firm conclusions or to recommend routine use of supplements of omega-3 fatty acids in people with CF. This review has highlighted the lack of data for many of the outcomes likely to be meaningful to people with or making treatment decisions about CF. A large, long-term, multicentre, randomised controlled study is needed in order to determine if there is a significant therapeutic effect and to assess the influence of disease severity, dosage and duration of treatment. Future researchers should note the need for additional pancreatic enzymes.

Phenotype of acute respiratory syncytial virus induced lower respiratory tract illness in infancy and subsequent morbidity.

UNLABELLED: The objective of this study was to investigate the association hypothesis that outcome following respiratory syncytial virus (RSV) induced bronchiolitis (RSVB) and RSV induced wheeze (RSVW) are different. At 3 years respiratory symptoms were more common in those with RSV infection than the control group but there was no increase in allergic sensitisation (11% vs 10%). Those with RSVW were more likely to have evidence of allergic sensitisation when compared with RSVB subjects (22% vs 7%), and have increased symptoms and increased use of inhaled steroids. CONCLUSION: The data argue that RSV infection during infancy does not induce allergic asthma and that host factors rather than the virus determine long-term outcomes.

Indoor air modification interventions for prolonged non-specific cough in children.

BACKGROUND: Non-specific cough has been defined as non-productive cough in the absence of identifiable respiratory disease or known aetiology and is common in childhood. These children are treated with a variety of therapies, including non-pharmacological treatments. There is a wide variety and a growing market for these non-pharmacological treatments that include air-modification modalities. OBJECTIVES: To determine the efficacy of air-modification modalities, (ionisers, vaporisers, humidifiers, air filters, regular vacuuming), in treating children with non-specific cough. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, OLDMEDLINE and EMBASE databases were searched by the Cochrane Airways Group. The latest searches were performed in November 2005. SELECTION CRITERIA: All randomised controlled trials comparing air-modification modalities with a placebo treatment, for any duration. DATA COLLECTION AND ANALYSIS: Results of searches were reviewed against pre-determined criteria for inclusion. Five papers were considered for inclusion but no eligible trials were identified and thus no data was available for analysis. MAIN RESULTS: No randomised controlled trials that examined the efficacy of air-modification modalities in the management of prolonged, non-specific cough in children were found. AUTHORS' CONCLUSIONS: Based on the evidence currently available, a recommendation can not be given for air-modification interventions in the treatment of prolonged, non-specific cough in children.

Differentiation and immune function of human dendritic cells following infection by respiratory syncytial virus.

RSV causes annual epidemics of bronchiolitis in winter months resulting in the hospitalization of many infants and the elderly. Dendritic cells (DCs) play a pivotal role in coordinating immune responses to infection and some viruses skew, or subvert, the immune functions of DCs. RSV infection of DCs could alter their function and this could explain why protection after natural RSV infection is incomplete and of short duration. In this study, this interaction between DCs and RSV was investigated using a human primary culture model. DCs were generated from purified healthy adult volunteer peripheral blood monocytes. Effects of RSV upon DC phenotype with RSV primed DCs was measured using flow cytometry. Changes to viability and proliferation of cocultured DCs and T-cells were determined using microscopy with fluorescent dyes (Hoechst 33342 and propidium iodide). DC maturation was not prevented by the RSV challenge. RSV infected a fraction of DCs (10-30%) but the virus replicated slowly in these cells with only small reduction to cell viability. DCs challenged with RSV stimulated T-cell proliferation less well than lipopolysaccharide. This is the first study to demonstrate RSV infection of human monocyte derived DCs and suggests that the virus does not significantly interfere with the function of these cells and potentially may promote cellular rather than humoral responses.

Pulmonary infection in mild variant cystic fibrosis: implications for care.

BACKGROUND: Disease phenotype in cystic fibrosis (CF) shows considerable heterogeneity. Atypical or mild mutations in the CFTR gene have been linked to late-onset pulmonary disease; however, few reports document the condition of the airway in infants and young children with apparent "mild" disease. Prognosis is uncertain in this group of patients and this, in turn, has led to inconsistency in management. Our initial experience of pulmonary infection in children with mild variant CF prompted a more detailed review of clinical outcome. METHODS: A retrospective cohort study was carried out comparing frequency of bacterial isolates and clinical outcomes in eleven compound heterozygotes for DeltaF508 and a second mild mutation, mainly R117H, with a matched group of DeltaF508 homozygotes. RESULTS: Staphylococcus aureus was isolated in 8 of the 11 patients with mild variant disease and Pseudomonas aeruginosa found in 7 (64%), although the frequency of positive cultures was significantly less (2.8/year) than the DeltaF508 homozygotes (6.1/year, p<0.05). Shwachman scores (median+range) were significantly higher in patients with mild mutations - 94, 74-92 vs. 88, 77-91; p<0.005); there was also a small but significant difference in chest radiograph (Chrispin-Norman) scores (median+range) (mild 5.1, 4-9, vs. severe 5.8, 3-10; p 0.04). There was little difference in lung function in terms of FEV1 (median+range) between the two groups (% predicted, mild 86.5, 68-87 vs. severe 76.0, 65-88; p 0.5). CONCLUSIONS: Most patients with mild variant CF will have bacterial isolates from airway cultures requiring antibiotic therapy three to four times a year. Infection with both S. aureus and P. aeruginosa is common. Anti-staphylococcal prophylaxis for the first two years should be considered.

Anticholinergic drugs for wheeze in children under the age of two years.

BACKGROUND: Wheeze in infancy and early childhood is common and appears to be increasing though the magnitude of any increase is unclear. Most wheezing episodes in infancy are precipitated by respiratory viral infections. Treatment of very young children with wheeze remains controversial. Anti-cholinergics are often prescribed but practice varies widely and the efficacy of this form of therapy remains the subject for debate. OBJECTIVES: Wheeze in infancy and early childhood is common and appears to be increasing. Most wheezing episodes in infancy are a result of viral infection. Bronchodilator medications such as beta2-agonists and anti-cholinergic agents are often used to relieve symptoms, but patterns of use vary. The objective of this review was to assess the effects of anti-cholinergic therapy in the treatment of wheezing infants. This is a second update of this review. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register of trials and the reference lists of articles. We contacted researchers in the field and industry sources. Searches were current as of June 2004. SELECTION CRITERIA: Randomised trials that compared anti-cholinergic therapy with placebo or beta2-agonists in wheezing children under two years of age. Children with acute bronchiolitis and chronic lung disease were excluded. DATA COLLECTION AND ANALYSIS: Eligibility for inclusion and quality of trials were assessed independently by two reviewers. MAIN RESULTS: Six trials involving 321 infants in three different settings were included. Compared with beta2-agonist alone, the combination of ipratropium bromide and beta2-agonist was associated with a reduced need for additional treatment, but no difference was seen in treatment response, respiratory rate or oxygen saturation improvement in the emergency department. There was no significant difference in length of hospital stay between ipratropium bromide and placebo; or between ipratropium bromide and beta2-agonist combined compared with beta2-agonist alone. However, combined ipratropium bromide and beta2-agonist compared to placebo showed significantly improved clinical scores at 24 hours. Parents preferred ipratropium bromide over nebulised water or placebo for relief of their children's symptoms at home. A further updated search conducted in June 2004 did not yield any new studies. AUTHORS' CONCLUSIONS: There is not enough evidence to support the uncritical use of anti-cholinergic therapy for wheezing infants, although parents using it at home were able to identify benefits.