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1.  Long-acting muscarinic antagonist use in adults with asthma: real-life prescribing and outcomes of add-on therapy with tiotropium bromide 
Randomized controlled trials indicate that addition of a long-acting muscarinic antagonist (LAMA) such as tiotropium may improve asthma control and reduce exacerbation risk in patients with poorly controlled asthma, but broader clinical studies are needed to investigate the effectiveness of LAMA in real-life asthma care.
Medical records of adults with asthma (aged ≥18 years) prescribed tiotropium were obtained from the UK Optimum Patient Care Research Database for the period 2001–2013. Patients diagnosed with chronic obstructive pulmonary disease were excluded, but no other clinical exclusions were applied. Two primary outcomes were compared in the year before (baseline) and the year after (outcome) addition of tiotropium: exacerbations (asthma-related hospital emergency department attendance or inpatient admission, or acute oral corticosteroid course) and acute respiratory events (exacerbation or antibiotic prescription with lower respiratory consultation). Secondary outcomes included lung function test results and short-acting β2 agonist usage. The Wilcoxon signed-rank test was used for variables measured on the interval scale, the marginal homogeneity test for categorized variables, and the paired t-test for lung function indices.
Of the 2,042 study patients, 83% were prescribed an inhaled corticosteroid and 68% a long-acting β2 agonist during the baseline year; 67% were prescribed both. Comparing baseline and outcome years, the percentage of patients having at least one exacerbation decreased from 37% to 27% (P<0.001) and the percentage having at least one acute respiratory event decreased from 58% to 47% (P<0.001). There were no significant changes in lung function, and usage of short-acting β2 agonists (in salbutamol/albuterol equivalents) increased from a median (interquartile range) of 274 (110, 548) to 329 (110, 603) μg/day (P=0.01).
In this real-life asthma population, addition of LAMA therapy was associated with significant decreases in the incidence of exacerbations and antibiotic prescriptions for lower respiratory tract infections in the following year.
PMCID: PMC4298307  PMID: 25609985
anticholinergic; bronchodilator; exacerbation; asthma control; oral corticosteroids
2.  Rituximab therapy in a patient with low grade B-cell lymphoproliferative disease and concomitant acquired angioedema 
Acquired angioedema is often associated with significant morbidity. An underlying lymphatic malignancy, autoimmune disorder, adenocarcinoma, or other malignancy may be present. Screening for these disorders should occur in all patients with acquired angioedema as treatment may result in resolution of angioedema.
PMCID: PMC4259552  PMID: 25506230
complement; C1-INH deficiency; ecallantide; hemopathy
3.  Diagnosis and management of food allergies: new and emerging options: a systematic review 
It is reported that 6% of children and 3% of adults have food allergies, with studies suggesting increased prevalence worldwide over the last few decades. Despite this, our diagnostic capabilities and techniques for managing patients with food allergies remain limited. We have conducted a systematic review of literature published within the last 5 years on the diagnosis and management of food allergies. While the gold standard for diagnosis remains the double-blind, placebo-controlled food challenge, this assessment is resource intensive and impractical in most clinical situations. In an effort to reduce the need for the double-blind, placebo-controlled food challenge, several risk-stratifying tests are employed, namely skin prick testing, measurement of serum-specific immunoglobulin E levels, component testing, and open food challenges. Management of food allergies typically involves allergen avoidance and carrying an epinephrine autoinjector. Clinical research trials of oral immunotherapy for some foods, including peanut, milk, egg, and peach, are under way. While oral immunotherapy is promising, its readiness for clinical application is controversial. In this review, we assess the latest studies published on the above diagnostic and management modalities, as well as novel strategies in the diagnosis and management of food allergy.
PMCID: PMC4216032  PMID: 25368525
skin prick testing; oral challenge; specific IgE; component testing; oral immunotherapy; epinephrine autoinjector
4.  The effects of concomitant GERD, dyspepsia, and rhinosinusitis on asthma symptoms and FeNO in asthmatic patients taking controller medications 
Losing the sense of smell, which suggests eosinophilic rhinosinusitis, is a subjective symptom, sometimes reported in asthmatic patients taking controller medication. Upper abdominal symptoms, suggesting gastroesophageal reflux disease (GERD) or functional dyspepsia, occur also in these patients. However, the relationship between these symptoms, concomitant with asthma, and the intensity of eosinophilic airway inflammation remains obscure.
To assess the symptoms of asthma and rhinosinusitis, and to examine the relationship between the symptoms and bronchial inflammation, a new questionnaire, the G scale, was developed. To investigate the effects of GERD, dyspepsia, and rhinosinusitis on asthma symptoms and bronchial inflammation, the symptoms of asthma and rhinosinusitis obtained by the G scale, upper abdominal symptoms obtained by the modified F scale, a questionnaire for GERD and dyspepsia, and fractional exhaled nitric oxide (FeNO) were analyzed.
A prospective, observational study was performed in four hospitals in Gunma prefecture, and a retrospective analysis was done using data obtained from five hospitals in Gunma prefecture and Fukui prefecture, Japan. A total of 252 patients diagnosed as having asthma participated in the prospective study.
The frequency of daytime phlegm or losing the sense of smell had a positive correlation with FeNO levels in asthmatic patients taking controller medication. Upper abdominal symptoms, as well as symptoms suggesting rhinitis, were well correlated with asthma symptoms. However, neither upper abdominal symptoms nor rhinitis symptoms increased FeNO levels, which reflect eosinophilic airway inflammation during treatment for asthma. On the other hand, the degree of upper abdominal symptoms or dyspepsia symptoms had a weak but significant negative correlation with FeNO levels.
Daytime phlegm and losing the sense of smell suggest that eosinophilic airway inflammation persists, despite anti-inflammatory therapy, in patients with asthma. Although rhinitis and GERD made the subjective symptoms of asthma worse, they did not seem to enhance eosinophilic airway inflammation.
PMCID: PMC4161609  PMID: 25228816
asthma symptoms; FeNO; rhinosinusitis; GERD; dyspepsia
5.  Dupilumab: a novel treatment for asthma 
Simultaneously with the steady progress towards a better knowledge of the pathobiology of asthma, the potential usefulness of anticytokine therapies is emerging as one of the key concepts in the newly developing treatments of this widespread airway disease. In particular, given the key role played by interleukin (IL)-4 and IL-13 in the pathophysiology of the most typical aspects of asthma, such as chronic airway inflammation, tissue remodeling, and bronchial hyperresponsiveness, these pleiotropic cytokines are now considered as suitable therapeutic targets. Among the recently developed antiasthma biologic drugs, the monoclonal antibody dupilumab is very promising because of its ability to inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. A recent trial showed that in patients with difficult-to-control asthma, dupilumab can markedly decrease asthma exacerbations and improve respiratory symptoms and lung function; these effects were paralleled by significant reductions in T-helper 2-associated inflammatory biomarkers. However, further larger and longer trials are required to extend and validate these preliminary results, and also to carefully study the safety and tolerability profile of dupilumab.
PMCID: PMC4159398  PMID: 25214796
Th2-high asthma; interleukin-4; interleukin-13; dupilumab
6.  Dietary pattern and asthma: a systematic review and meta-analysis 
The literature on the relationship between diet and asthma has largely focused on individual nutrients, with conflicting results. People consume a combination of foods from various groups that form a dietary pattern. Studying the role of dietary patterns in asthma is an emerging area of research. The purpose of this study was to systematically review dietary patterns and asthma outcomes in adults and children, to review maternal diet and child asthma, and to conduct a meta-analysis on the association between asthma prevalence and dietary patterns in adults.
We searched Medline, Scopus, and ISI Web of Knowledge up to January 2014. Two researchers independently reviewed studies meeting the inclusion criteria using the American Dietetic Association quality criteria. A linear mixed model was used to derive the pooled effect size (95% confidence interval) for each of three dietary pattern categories (healthy, unhealthy, and neutral).
Thirty-one studies were identified (16 cross-sectional, one case-control, 13 cohort, and one randomized controlled trial), including 12 in adults, 13 in children, five in pregnant woman–child pairs, and one in both children and pregnant woman–child pairs. Six of the 12 adult studies reported significant associations between dietary patterns and asthma outcomes (eg, ever asthma and forced expiratory volume in one second). Seven of ten studies examining the Mediterranean diet showed protective effects on child asthma and/or wheeze. Four of the six studies in mother-child pairs showed that maternal dietary patterns during pregnancy were not associated with child asthma or wheeze. The meta-analysis including six adult studies, the primary outcome of which was the prevalence of current or ever asthma, showed no association with healthy, unhealthy, or neutral dietary patterns.
The evidence suggests no association of dietary patterns with asthma prevalence in adults or of maternal diet with child asthma or wheeze. The Mediterranean diet in children may prevent asthma or wheeze, but randomized controlled trials are lacking.
Video abstract
PMCID: PMC4137988  PMID: 25143747
dietary pattern; asthma; systematic review; meta-analysis; adults; children
7.  Anaphylaxis avoidance and management: educating patients and their caregivers 
Anaphylaxis is an increasingly prevalent problem in westernized countries. Therefore, it is of utmost importance that the increasing numbers of patients at risk for anaphylaxis receive proper education on the etiology and risk factors as well as appropriate treatment of anaphylaxis with epinephrine. The physician’s role is crucial in order to educate the patients and care takers on effective measures to prevent anaphylaxis and empower them to take charge of early recognition and proper management of an anaphylactic reaction to prevent poor outcomes. This review summarizes the clinical presentation, triggers, avoidance, and management of anaphylaxis.
PMCID: PMC4096453  PMID: 25031541
food allergy; drug allergy; Hymenoptera; latex
8.  Elimination diets in the management of eosinophilic esophagitis 
Eosinophilic esophagitis, an increasingly recognized chronic inflammatory disorder isolated to the esophagus, is triggered by an abnormal allergic response to dietary antigens. Current treatment includes swallowed topical steroids and dietary modification, which aim to resolve symptoms and prevent long-term complications such as formation of strictures. The dietary approach has become more widely accepted because long-term steroid therapy is associated with potential risks. Dietary treatment includes elemental and elimination diets. An exclusive elemental diet, which requires replacement of all intact protein with amino acid-based formula, offers the best response of all available therapies, with remission in up to 96% of subjects proving it to be superior to all other available therapies including topical steroids. However, compliance with this approach is challenging because of poor taste and monotony. The high cost of formula and the associated psychosocial problems are additional drawbacks of this approach. Empiric and allergy test-directed elimination diets have gained popularity given that elimination of a limited number of foods is much easier and as such is more readily acceptable. There is a growing body of literature supporting this type of therapy in both children and adults. This paper reviews the evidence for all types of dietary therapy in eosinophilic esophagitis.
PMCID: PMC4043711  PMID: 24920928
eosinophilic esophagitis; dietary therapy; empiric elimination; elemental; allergy test-directed
9.  New combination treatments in the management of asthma: focus on fluticasone/vilanterol 
Despite the 2007 National Asthma Education and Prevention Program Expert Panel 3 guidelines for the treatment of uncontrolled asthma, many patients with poorly controlled asthma still continue to tax the health care system. Controlling asthma symptoms and preventing acute exacerbations have been the foundation of care. Using long-term controller treatments such as inhaled corticosteroids (ICS) and inhaled long-acting beta2-agonists (LABAs) is a common approach. While patient responses to recommended pharmacotherapy may vary, poor adherence to therapy also contributes to poor asthma control. A once-daily combination inhaler, such as fluticasone furoate, an ICS, in combination with vilanterol, a LABA, offers increased convenience and potential improved adherence, which should result in enhanced clinical outcomes and reduced exacerbations. The ICS/LABA combination inhaler of fluticasone furoate and vilanterol is currently approved in the United States for use in the maintenance of chronic obstructive pulmonary disease and to reduce exacerbations. This paper reviews the expanding literature on the efficacy of fluticasone furoate and vilanterol in treating asthma.
PMCID: PMC4014386  PMID: 24833910
inhaled corticosteroids (ICS); long-acting beta2-agonist (LABA); asthma treatments
10.  Differential serum protein markers and the clinical severity of asthma 
Asthma is a heterogeneous disease characterized by different clinical phenotypes and the involvement of multiple inflammatory pathways. During airway inflammation, many cytokines and chemokines are released and some are detectable in the sera.
Serum chemokines and cytokines, involved in airway inflammation in asthma patients, were investigated.
A total of 191 asthma patients were classified by hierarchical cluster analysis, including the following parameters: forced expiratory volume in 1 second (FEV1), eosinophil cationic protein (ECP) serum levels, blood eosinophils, Junipers asthma symptom score, and the change in FEV1, ECP serum levels, and blood eosinophils after 3 weeks of asthma therapy. Serum proteins were measured by multiplex analysis. Receiver operating characteristic (ROC) curves were used to evaluate the validity of serum proteins for discriminating between asthma clusters.
Classification of asthma patients identified one cluster with high ECP serum levels, increased blood eosinophils, low FEV1 values, and good FEV1 improvement in response to asthma therapy (n=60) and one cluster with low ECP serum levels, low numbers of blood eosinophils, higher FEV1 values, and no FEV1 improvement in response to asthma therapy (n=131). Serum interleukin (IL)-8, eotaxin, vascular endothelial growth factor (VEGF), cutaneous T-cell-attracting chemokine (CTACK), growth-related oncogene (GRO)-α, and hepatocyte growth factor (HGF) were significantly different between the two clusters of asthma patients. ROC analysis for serum proteins calculated a sensitivity of 55.9% and specificity of 75.8% for discriminating between them.
Serum cytokine and chemokine levels might be predictors for the severity of asthmatic inflammation, asthma control, and response to therapy, and therefore might be useful for treatment optimization.
PMCID: PMC4008293  PMID: 24851055
asthma; cluster; phenotype; serum cytokines
11.  Diagnosis and management of eosinophilic asthma: a US perspective 
Eosinophilic asthma is now recognized as an important subphenotype of asthma based on the pattern of inflammatory cellular infiltrate in the airway. Eosinophilic asthma can be associated with increased asthma severity, atopy, late-onset disease, and steroid refractoriness. Induced sputum cell count is the gold standard for identifying eosinophilic inflammation in asthma although several noninvasive biomarkers, including fractional exhaled nitric oxide and periostin, are emerging as potential surrogates. As novel therapies and biologic agents become increasingly available, there is an increased need for specific phenotype-directed treatment strategies. Greater recognition and understanding of the unique immunopathology of this asthma phenotype has important implications for management of the disease and the potential to improve patient outcomes. The present review provides a summary of the clinical features, pathogenesis, diagnosis, and management of eosinophilic asthma.
PMCID: PMC3990389  PMID: 24748808
asthma; eosinophil; allergy; Th2; IL-4; IL-13
12.  Switching patients from other inhaled corticosteroid devices to the Easyhaler®: historical, matched-cohort study of real-life asthma patients 
To investigate the clinical and cost effectiveness of switching real-life asthma patients from other types of inhalers to the Easyhaler® (EH) for the administration of inhaled corticosteroids (ICS).
Patients and methods
Historical, matched-cohort study of 1,958 asthma patients (children and adults) treated in UK primary-care practices, using data obtained from the Optimum Patient Care Research Database and Clinical Practice Research Datalink. Other inhalers (OH) included pressurized metered-dose inhalers, breath-actuated inhalers, and dry-powder inhalers, delivering beclomethasone, budesonide, fluticasone, or ciclesonide. Patients remaining on OH unchanged (same drug, dosage, and device; n=979) were matched 1:1 with those switched to the EH (beclomethasone or budesonide) at the same or lower ICS dosage (n=979), based on age, sex, year of index patient review/switch, most recent ICS drug, dosage, and device, and the number of severe exacerbations and average daily short-acting β2 agonist (SABA) dosage in the preceding year. Clinical outcomes and health care costs were compared between groups for 12 months before and after the switch. Co-primary clinical outcomes were: 1) risk domain asthma control (RDAC) – no asthma-related hospitalization, acute oral steroid use, or lower respiratory tract infection (LRTI); 2) exacerbation rate (American Thoracic Society [ATS] definition) – where exacerbation is asthma-related hospitalization or acute oral steroid use; 3) exacerbation rate (clinical definition) – where exacerbation is ATS exacerbation or LRTI; and 4) overall asthma control (OAC) – RDAC plus average salbutamol-equivalent SABA dosage ≤200 μg/day. Non-inferiority (at least equivalence) of EH was tested against OH for the four co-primary outcomes in order (hierarchical approach) by comparing the difference in proportions of patients [EH-OH] achieving asthma control or having no exacerbations in the outcome year, using a limit of 10% difference.
Non-inferiority was shown for the EH for all four co-primary outcomes. There were no significant differences between groups for RDAC or exacerbation rates, but EH patients were significantly more likely to achieve OAC (adjusted odds ratio [95% confidence interval]: 1.26 [1.05, 1.52]), as significantly more EH than OH patients had an average SABA dosage of ≤200 μg/day (52% versus 47%, respectively; P<0.001). Mean asthma-related health care costs increased from baseline to outcome years in both groups, but SABA costs increased significantly more in OH than EH patients (mean difference £5.5/patient/year) and consultation costs decreased significantly more in EH than OH patients (mean difference £13.5/patient/year).
Typical asthma patients may be switched from other ICS devices to the Easyhaler® with no reduction in clinical effectiveness or increase in cost.
PMCID: PMC3986277  PMID: 24748807
asthma; ICS; inhaler; Easyhaler; cost
13.  Link between vitamin D and airway remodeling 
In the last decade, many epidemiologic studies have investigated the link between vitamin D deficiency and asthma. Most studies have shown that vitamin D deficiency increases the risk of asthma and allergies. Low levels of vitamin D have been associated with asthma severity and loss of control, together with recurrent exacerbations. Remodeling is an early event in asthma described as a consequence of production of mediators and growth factors by inflammatory and resident bronchial cells. Consequently, lung function is altered, with a decrease in forced expiratory volume in one second and exacerbated airway hyperresponsiveness. Subepithelial fibrosis and airway smooth muscle cell hypertrophy are typical features of structural changes in the airways. In animal models, vitamin D deficiency enhances inflammation and bronchial anomalies. In severe asthma of childhood, major remodeling is observed in patients with low vitamin D levels. Conversely, the antifibrotic and antiproliferative effects of vitamin D in smooth muscle cells have been described in several experiments. In this review, we briefly summarize the current knowledge regarding the relationship between vitamin D and asthma, and focus on its effect on airway remodeling and its potential therapeutic impact for asthma.
PMCID: PMC3979801  PMID: 24729717
vitamin D; asthma; airway remodeling; airway smooth muscle; supplementation
14.  Tiotropium in asthma: a systematic review 
The objective of this paper is to systematically review the existing evidence of the effectiveness and safety profile of a long-acting inhaled muscarinic antagonist as add-on therapy in patients with asthma that is uncontrolled despite inhaled corticosteroid (ICS) use.
With the assistance of two experienced research librarians, we searched Ovid MEDLINE/PubMed (1946 to September 12, 2013), the Cochrane Library review, and the TRIP database. The key search terms were “tiotropium and asthma.” The search was limited to human data published in English. Included in the systematic review were all randomized controlled trials that evaluated the efficacy of tiotropium in patients with asthma. The clinical trials had to be at least 4 weeks in duration and to provide adequate information on clinically appropriate end points in asthma care (eg, change in lung function, exacerbation rates, and/or ICS dosing). Data on patient characteristics, study design, outcome measures, concomitant asthma medication, and adverse events were extracted from the full text of each included individual study. Marked heterogeneity of study design precluded statistical pooling of results for a meta-analysis. Consequently, only descriptive summaries of outcomes are provided.
Our database search retrieved 149 citations. We found five randomized controlled trials in humans that met our criteria for inclusion in the systematic review. We also found two open-label uncontrolled trials that were considered in the discussion. Each of the five included studies met the Consolidated Standards of Reporting Trials criteria for a well-designed randomized trial.
The five clinical studies included in this systematic review focused on evaluating the efficacy of tiotropium as add-on therapy to ICS or ICS in combination with a long-acting inhaled β2-agonist (LABA) in patients with uncontrolled moderate to severe persistent asthma. Tiotropium maintained lung function when ICSs were tapered and when an LABA was discontinued. Tiotropium improved lung function when added to ICS alone or ICS–LABA combination therapy. In the only trial to have compared the addition of tiotropium with doubling the dose of ICS, tiotropium provided significantly superior results. In trials in which the addition of tiotropium was compared with salmeterol, the beneficial effects of these two bronchodilators were similar. No safety concerns were found with use of tiotropium as add-on therapy.
Tiotropium may have a beneficial role in moderate to severe persistent asthma despite use of an ICS or ICS and LABA. Use of tiotropium as add-on therapy poses no safety concerns.
PMCID: PMC3942115  PMID: 24600237
tiotropium; asthma; lung; inflammation; inhaled corticosteroid; LABA; LAMA
15.  Implementing specific oral tolerance induction to milk into routine clinical practice: experience from first 50 patients 
Although the natural history of cow’s milk allergy is to resolve during childhood or adolescence, a small but significant proportion of children will remain allergic. Specific oral tolerance induction to cow’s milk (CM-SOTI) provides a treatment option in these children with continuing allergy with high success rates. However current sentiment limits widespread availability as existing reports advise that it is too soon to translate CM-SOTI into routine clinical practice.
In January 2007 we implemented a slow up-dosing CM-SOTI program. Eligible subjects were identified at routine visits to our children’s allergy clinic. Persisting cow’s milk allergy was confirmed from recent contact symptoms or a positive baked milk challenge. As allergic symptoms are common during CM-SOTI, families were provided with ready dietetic access for advice on dosing and symptom treatment. Subjects were continuously monitored at subsequent clinic visits or telephonically, where no longer followed, for a median of 49 months.
The first 50 subjects (35 males) treated ranged in age from 5.1 to 15.8 years (median 10.3 years). Full tolerance (250 mL) was achieved in 23 subjects, 9 without any symptoms, and a further 9 achieved partial tolerance with continued ingestion. Eighteen children failed to achieve any regular milk ingestion; 11 because of persistent or significant symptoms whilst 8 withdrew against medical advice. Allergic symptoms were predominantly mild to moderate in severity, although 2 cases needed treatment with inhaled salbutamol and a further 2 required intramuscular adrenaline. Clinical tolerance, both full and partial, persists beyond 5 years.
We have demonstrated that a CM-SOTI program can be successfully and safely implemented as routine clinical practice with acceptable compliance during prolonged home up-dosing, despite frequent allergic symptoms, and for up to 4 years after starting treatment. CM-SOTI can thus be put into practice more widely where there is appropriate support.
PMCID: PMC3913504  PMID: 24511241
cow’s milk allergy; specific oral tolerance induction; oral desensitization; compliance; safety
16.  5-grass pollen tablets achieve disease control in patients with seasonal allergic rhinitis unresponsive to drugs: a real-life study 
An important subpopulation in allergic rhinitis is represented by patients with severe form of disease that is not responsive to drug treatment. It has been reported that grass pollen subcutaneous immunotherapy is effective in drug-resistant patients. In a real-life study, we evaluated the efficacy of 5-grass pollen tablets in patients with grass pollen-induced allergic rhinitis not responsive to drug therapy.
We carried out this multicenter observational study in adults and adolescents with grass-induced allergic rhinitis not responsive to drug therapy who were treated for a year with 5-grass pollen tablets. Clinical data collected before and after sublingual immunotherapy (SLIT) included Allergic Rhinitis and its Impact on Asthma (ARIA) classification of allergic rhinitis, response to therapy, and patient satisfaction.
Forty-seven patients entered the study. By ARIA classification, three patients had moderate to severe intermittent allergic rhinitis, ten had mild persistent allergic rhinitis, and 34 had moderate to severe persistent allergic rhinitis. There were no cases of mild intermittent allergic rhinitis before SLIT. After SLIT, 33 patients had mild intermittent allergic rhinitis, none had moderate to severe intermittent allergic rhinitis, seven had mild persistent allergic rhinitis, and seven had moderate to severe persistent allergic rhinitis. The mean medication score decreased from 4.2±1.3 before to 2.4±2.0 after SLIT (P<0.01), representing a reduction of 42%. The response to treatment before SLIT was judged as poor by 70% of patients and very poor by 30%. Patient satisfaction was significantly increased after SLIT (P<0.01).
In real life, most patients with grass pollen-induced allergic rhinitis not responsive to drug treatment can achieve control of the condition with one season of treatment using 5-grass pollen tablets.
PMCID: PMC3862399  PMID: 24353432
grass pollen; rhinitis; drug resistance; allergen immunotherapy; effectiveness; patient satisfaction
17.  Safety of bronchodilators and corticosteroids for asthma during pregnancy: what we know and what we need to do better 
Asthma is a common medical condition complicating pregnancy with potentially serious effects on pregnancy outcome. The aim of this review is to provide an update on efficacy and safety of asthma medications, primarily bronchodilators and corticosteroids, used during pregnancy with focus on pregnancy outcome, and, furthermore, to discuss limitations of available studies and point to possible improvements in future studies. A planned series of systematic searches was conducted using the PubMed database. Use of short-acting β2-agonists has generally been established as safe, and the few studies stating otherwise appear to have, perhaps critical, methodological limitations. The safety of long-acting β2-agonists remains to be further investigated, and the few available studies have methodological limitations and, therefore, provide no definite answers, although a very recent study supports the safety of add-on long-acting β2-agonists to inhaled corticosteroids. Inhaled corticosteroids are generally found to be safe, although further research is needed to investigate both the efficacy and safety of high dose therapy with inhaled corticosteroids. Studies have reported associations between the use of systemic corticosteroids and adverse perinatal outcomes, such as preterm birth, low birth weight, and pre-eclampsia. This must, however, be weighed against the potential serious impact of severe, uncontrolled asthma itself on pregnancy outcome. The main obstacle to a valid interpretation of several of the available studies is the inadequate stratification for asthma severity and control. Overall, asthma in itself and not just poor asthma control poses a greater risk to pregnancy outcomes than asthma medication. Nonetheless, more studies focusing on disentangling the effects of asthma alone and asthma medications are needed. Increased use of stratified risk assessments, taking the concept of asthma severity into greater consideration, is much warranted in future studies.
PMCID: PMC3833838  PMID: 24259987
asthma; pregnancy; perinatal outcomes; asthma management; bronchodilators; inhaled corticosteroids; systemic corticosteroids
18.  Effects of two inhaled corticosteroid/long-acting beta-agonist combinations on small-airway dysfunction in mild asthmatics measured by impulse oscillometry 
We previously showed that the long-acting beta agonist (LABA) salmeterol as inhalation powder or metered-dose inhaler improves lung-function parameters assessed by impulse oscillometry (IOS) in 2- to 5-year-old children with reversible-airway disease within 15 minutes.
We studied 12- to 45-year-olds with mild persistent asthma in order to compare the onset and extent of peripheral airway effects following the first dose and after 4 weeks dosing with two inhaled corticosteroid (ICS)/LABA combinations: fluticasone propionate/salmeterol 115/21 and budesonide/formoterol 160/4.5.
Thirty subjects with mild persistent asthma using only an as-needed short-acting beta-agonist (albuterol) who had at least a 40% change in integrated low-frequency reactance postalbuterol were selected and randomized to receive either fluticasone propionate/salmeterol or budesonide/formoterol (15 subjects each). We collected three to six IOS replicates at baseline, at 5, 20, 40, 60, 120, and 240 minutes postdose at randomization, and after 4 weeks of twice-daily dosing. Blinded investigators calculated IOS frequency-dependent resistance and reactance (R5–R20 and AX), indicative of small-airway dysfunction, and also estimated the peripheral airway resistance (Rp) and peripheral airway compliance (Cp), using a respiratory-impedance model.
At randomization visits, onset of action was detected as early as 5 minutes (t-test, P < 0.05) after fluticasone propionate/salmeterol by Cp, and within 5 minutes after budesonide/formoterol by R5–R20, AX, Rp, and Cp. However, after 4 weeks of dosing, only Rp was significantly different (from 60 to 120 minutes) after fluticasone propionate/salmeterol, while R5–R20, AX, Rp, and Cp were not significantly different within 240 minutes after budesonide/formoterol.
These two ICS/LABA combinations initially improved the peripheral airway function of 12- to 45-year-old asthmatics significantly in about 5 minutes or less, as measured by R5–R20, AX, Rp, and/or Cp. After regular dosing for 4 weeks, pre- to postdose differences in these parameters had diminished significantly due to improved predose status of peripheral airways. Single dosing with ICS/LABA combinations in mild persistent asthma improves small-airway function, and the effect is maintained over a 12-hour interval by regular use for 4 weeks.
PMCID: PMC3743524  PMID: 23966795
asthma; ICS/LABA combination; impulse oscillometry parameters; lung-model parameters; peripheral airway resistance; peripheral airway compliance
19.  Infant anaphylaxis: the importance of early recognition 
Anaphylaxis is an acute severe reaction involving multiple systems that results from a rapid release of inflammatory mediators. Patients with asthma and prior allergic reactions are at risk for anaphylaxis. Infants can present a special challenge, as the hallmark symptoms and signs of anaphylaxis may be mistaken as normal findings. These include drooling, vomiting or diarrhea, scratching, and drowsiness. The clinical manifestations of anaphylaxis are broad, as a result of it being a systemic response to an external agent. Among infants and children, there are often respiratory and cutaneous findings. There also can be subtle signs and symptoms, which can often be missed or the findings misinterpreted as normal for developmental age. The incidence of anaphylaxis has increased globally among children presenting with allergic reactions. Early recognition of the signs and symptoms is crucial to effective diagnosis and treatment. This is particularly true among infants 13 months of age or younger who are nonverbal and may have subtle signs and symptoms of a life-threatening reaction to allergens. The purpose of this article is to highlight the differential clinical presentations of young children with anaphylaxis.
PMCID: PMC3706379  PMID: 23847427
anaphylaxis; infant; food allergy
20.  Factors influencing asthma control: results of a real-life prospective observational asthma inhaler treatment (ASIT) study 
Despite the availability of new pharmacological options and novel combinations of existing drug therapies, the rate of suboptimal asthma control is still high. Therefore, early identification of the clinical and behavioral factors responsible for poor asthma control, and interventions during routine outpatient visits to improve asthma trigger management, are strongly recommended. This study was designed to evaluate the profiles of asthmatic patients and their inhaler treatment devices in relation to asthma control in Turkey.
A total of 572 patients with persistent asthma (mean [standard deviation] age: 42.7 [12.1] years; 76% female) were included in this prospective observational study. A baseline visit (0 month, visit 1) and three follow-up visits (1, 3 and 6 months after enrolment) were conducted to collect data on demographics, past medical and asthma history, and inhaler device use.
Asthma control was identified in 61.5% of patients at visit 1 and increased to 87.3% at visit 4 (P < 0.001), regardless of sociodemographics, asthma duration, body mass index or smoking status. The presence of asthma-related comorbidity had a significantly negative effect on asthma control (P = 0.004). A significant decrease was determined, in the rate of uncontrolled asthma, upon follow-up among patients who were using a variety of fixed dose combination inhalers (P < 0.001 for each). Logistic regression analysis was used to show that the presence of asthma-related comorbidity (odds ratio [OR], 0.602; 95% confidence interval [CI], 0.419; 0.863, P = 0.006) and active smoking (OR, 0.522; 95% CI, 0.330; 0.825, P = 0.005) were significant predictors of asthma control.
Our findings indicate that, despite ongoing treatment, asthma control rate was 61.5% at visit 1 in adult outpatients with persistent asthma. However, by the final follow-up 6 months later, this had increased to 87.3%, independent of sociodemographic and clinical characteristics. Poor asthma control was associated with asthma-related comorbid diseases, while the efficacy of fixed dose combinations was evident in the achievement of asthma control.
PMCID: PMC3702275  PMID: 23843695
persistent asthma; patient profile; asthma control; inhaler treatment; adults; Turkey
21.  Racial differences in the association of CD14 polymorphisms with serum total IgE levels and allergen skin test reactivity 
The CD14 C-159T single nucleotide polymorphism (SNP) has been investigated widely as a candidate genetic locus in patients with allergic disease. There are conflicting results for the association of the CD14 C-159T SNP with total serum immunoglobulin E (IgE) levels and atopy. There are limited data regarding the association of the CD14 C-159T SNP in subjects of African ancestry. The aim of the study was to determine whether the C-159T SNP and other CD14 SNPs (C1188G, C1341T) were associated with total serum IgE levels and with allergy skin test results in nonatopic and atopic subjects; as well as in Caucasian and African American subjects.
A total of 291 participants, 18–40 years old, were screened to determine whether they were atopic and/or asthmatic. Analyses were performed to determine the association between CD14 C-159T, C1188G, or C1341T genotypes with serum IgE levels and with the number of positive skin tests among Caucasian or African American subjects.
We found no significant association of serum total IgE level with CD14 C-159T, C1188G, or C1341T genotypes within nonatopic or atopic subjects. Subjects with CD14-159 T alleles had significantly more positive allergen skin tests than subjects without CD14-159 T alleles (P = 0.0388). There was a significant association between the CD14 1188 G allele, but not the CD14 1341 T allele, with the number of positive skin-test results in Caucasians, but not in African Americans.
These results support a possible association between CD14 polymorphisms and atopy. CD14-159 T or CD14 1188 G alleles were associated with atopic disease. For subjects with CD14 1188 G alleles, the association with atopic disease was stronger in Caucasians compared to African Americans.
PMCID: PMC3699133  PMID: 23836995
total serum immunoglobulin E; IgE; skin prick test; SPT; CD14-159T; single nucleotide polymorphism; SNP; lipopolysaccharide; LPS; endotoxin
22.  Extrafine inhaled corticosteroid therapy in the control of asthma 
Small airways disease plays an important role in the pathogenesis of asthma, but assessment of small airways impairment is not easy in everyday clinical practice. The small airways can be examined by several invasive and noninvasive methods, most of which can at present be used only in the experimental setting. Inhalers providing extrafine inhaled corticosteroid particle sizes may achieve sufficient deposition in the peripheral airways. Many studies have reported the beneficial effects of extrafine inhaled corticosteroids on inflammation, ie, on dysfunction in both the central and distal airways in asthmatics, and there are some data on asthma phenotypes in which the small airways seem to be affected more than in other phenotypes, including nocturnal asthma, severe steroid-dependent or difficult-to-treat asthma, asthma complicated by smoking, elderly asthmatic patients and/or patients with fixed airflow obstruction, and asthmatic children. The relevant randomized controlled clinical trials indicate that the efficacy of extrafine and nonextrafine inhaled corticosteroid formulations is similar in terms of primary endpoints, but there are certain clinically important endpoints for which the extrafine formulations show additional benefits.
PMCID: PMC3681407  PMID: 23776339
small airways; inflammation; dysfunction; noninvasive evaluation methods; peripheral deposition
24.  Incidence and risk factors for exacerbations of asthma during pregnancy 
Asthma is one of the most common chronic diseases among pregnant women. Acute exacerbations of asthma during pregnancy have an unfavorable impact on pregnancy outcome. This review provides an overview of current knowledge of incidence, mechanisms, and risk factors for acute exacerbations of asthma during pregnancy.
A narrative literature review was carried out using the PubMed database.
During pregnancy, up to 6% of women with asthma are hospitalized for an acute exacerbation. The maternal immune system is characterized by a very high T-helper-2:T-helper-1 cytokine ratio during pregnancy and thereby provides an environment essential for fetal survival but one that may aggravate asthma. Cells of the innate immune system such as monocytes and neutrophils are also increased during pregnancy, and this too can exacerbate maternal asthma. Severe or difficult-to-control asthma appears to be the major risk factor for exacerbations during pregnancy, but studies also suggest that nonadherence with controller medication and viral infections are important triggers of exacerbations during pregnancy. So far, inconsistent findings have been reported regarding the effect of fetal sex on exacerbations during pregnancy. Other risk factors for exacerbation during pregnancy include obesity, ethnicity, and reflux, whereas atopy does not appear to be a risk factor.
The incidence of asthma exacerbations during pregnancy is disturbingly high. Severe asthma – better described as difficult-to-control asthma – nonadherence with controller therapy, viral infections, obesity, and ethnicity are likely to be important risk factors for exacerbations of asthma during pregnancy, whereas inconsistent findings have been reported with regard to the importance of sex of the fetus.
PMCID: PMC3650884  PMID: 23671393
acute exacerbations; pregnancy; asthma severity; incidence; risk factors
25.  Neonatal, atopic and infectious disease outcomes among children born to mothers with latent tuberculosis infection 
Exposure to microbes may result in maternal immune responses that can affect fetal immune development. Several lines of evidence have shown that mycobacterial antigens can change the onset of atopic disease. We hypothesized that infants born to mothers with a positive tuberculosis (TB) test and a negative chest radiograph, may exhibit differential development of atopic disease during early childhood. The study was designed as a case control study. Birth records for infants born to untreated mothers with a positive TB skin test (TST), as defined by ≥10 mm induration were reviewed (n = 145 cases) and compared to a randomly selected unmatched control cohort of 46 women with a negative TST who delivered during the same time period at Scripps Hospital in San Diego, CA, USA. Childhood outcome parameters reviewed were: (1) the onset of physician diagnosed asthma; (2) lower respiratory tract infection (LRTI) with wheezing, latent tuberculosis infection/wheezing diagnosed on physical examination; (3) nonsurgical hospitalization; (4) atopic disease (eye/skin/nasal-sinus disease); (5) infections: ear, LRTI, sinus. LRTI was defined as an infection of the lower airways, eg, pneumonia. Outcomes at the end of years 1, 2, and 3–5 years combined were analyzed. Fisher exact test, Chi-square analysis or Poisson regression analysis were used as appropriate and a P-value of <0.05 was defined as significant. The cases and controls had similar birth weights, gestational ages, maternal ages: 3.34 versus 3.35 kg; 38.3 versus 39.2 weeks, 27.4 versus 26 years (P = non-significant). The childhood outcome parameters of the new onset of asthma was significantly higher than controls by age 2 years, but not at other ages studied, based on available clinic follow up data (P = 0.02). There was a difference in the risk for lung infection at age 2 and 3–5 years (P < 0.0001). There were no differences in the other outcome parameters studied (P = ns). There were no cases of infants with a positive TST, maternal Bacille Calmette-Guerin vaccination or active maternal TB, based on our study findings. There was a higher occurrence of asthma and lung infections at age 2 years among controls (P = 0.02). Our study defines for the first time a possible influence of maternal latent TB infection on fetal and childhood illness.
PMCID: PMC3650890  PMID: 23671394
tuberculosis; fetal immune development; pediatric asthma

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