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1.  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
vitamin D; asthma; airway remodeling; airway smooth muscle; supplementation
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
12.  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
13.  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
14.  A multicenter evaluation of the efficacy and duration of action of alcaftadine 0.25% and olopatadine 0.2% in the conjunctival allergen challenge model 
The purpose of this study was to evaluate the efficacy and duration of action of once-daily dosing with alcaftadine 0.25% ophthalmic solution and olopatadine 0.2% ophthalmic solution as compared with placebo in the prevention of ocular itching, and to directly compare the efficacy of alcaftadine 0.25% with olopatadine 0.2% in the prevention of ocular itching associated with allergic conjunctivitis using the conjunctival allergen challenge model.
Subjects with allergic conjunctivitis (n = 127) were enrolled in a multicenter, double-masked, randomized, active-controlled and placebo-controlled clinical trial. Using the conjunctival allergen challenge model, this study was conducted over the course of approximately 5 weeks. Subjects were randomized into one of three treatment arms: alcaftadine 0.25% ophthalmic solution, olopatadine 0.2% ophthalmic solution, or placebo. Study medications were administered twice over the course of the trial. The primary efficacy measure for the study was ocular itching evaluated by the subject at 3, 5, and 7 minutes post challenge. Secondary endpoints, measured at 7, 15, and 20 minutes post challenge, included conjunctival, ciliary, and episcleral redness, lid swelling, chemosis, and tearing. Duration of action was measured at 16 and 24 hours post-instillation of the study medication at visits 3 and 4, respectively.
For the primary measure of ocular itching, both actives, alcaftadine 0.25% and olopatadine 0.2%, were statistically superior to placebo at all three measured time points for both the 16-hour and 24-hour measures (P < 0.0001). Eyes treated with alcaftadine 0.25% had numerically lower mean ocular itching scores than eyes treated with olopatadine 0.2% at every time point, and this difference was statistically significant at the 3-minute time point 16 hours post instillation (P = 0.026). Eyes treated with alcaftadine 0.25% and with olopatadine 0.2% displayed significantly less lid swelling relative to placebo at every time point for the 16-hour and 24-hour post-instillation visits (P < 0.005). Alcaftadine 0.25% was the only active treatment that provided statistically significant relief of chemosis at every time point of the 24-hour post-instillation visit.
Both the alcaftadine 0.25% and olopatadine 0.2% ophthalmic solutions provided highly effective relief of ocular itching at both 16 and 24 hours post-instillation. Treatment differences between the actives were most pronounced at the earliest time point (3 minutes post-challenge) following conjunctival allergen challenge (16 hours), when alcaftadine 0.25% ophthalmic solution was statistically superior to olopatadine 0.2% ophthalmic solution. Alcaftadine 0.25% was the only treatment to provide significant relief from chemosis at both 16 and 24 hours post-instillation. Both active treatments and placebo were generally safe and well tolerated.
PMCID: PMC3792834  PMID: 24109191
alcaftadine 0.25%; olopatadine 0.2%; conjunctival allergen challenge model
16.  A direct comparison of efficacy between desloratadine and rupatadine in seasonal allergic rhinoconjunctivitis: a randomized, double-blind, placebo-controlled study 
H1-antihistamines are recommended as the first-line symptomatic treatment of allergic rhinitis. The objective of this study was to evaluate the effects of rupatadine (RUP) versus desloratadine (DES) in subjects with seasonal allergic rhinitis (SAR).
To assess the efficacy and safety of RUP in SAR in comparison with placebo (PL) and DES. A randomized, double-blind, multicenter, international, and PL-controlled study was carried out. The main selection criteria included SAR patients over 12 years old with a positive prick test to a relevant seasonal allergen for the geographic area. Symptomatic patients at screening with a nasal symptom sum score of ≥6 points (nasal discharge, nasal obstruction, sneezing, and nasal pruritus), a non-nasal score of ≥3 points (ocular pruritus, ocular redness, and tearing eyes), and a rhinorrhea score of ≥2 points with laboratory test results and electrocardiography within acceptable limits were included in the study. Change from baseline in the total symptom-score (T7SS) over the 4-week treatment period (reflective evaluation) was considered the primary efficacy variable. Secondary efficacy measures included total nasal symptom score (T4NSS) and conjunctival symptom score (T3NNSS), both of which are reflective and instantaneous evaluations. Furthermore questions related to quality of life (eg, sleep disturbances or impairment of daily activities) have also been evaluated. Safety was assessed according to adverse events reported, as well as laboratory and electrocardiography controls.
A total of 379 patients were randomized, of which 356 were included and allocated to PL (n = 122), RUP (n = 117), or DES (n = 117). Mean change of T7SS over the 4-week treatment period was significantly reduced in the RUP (–46.1%, P = 0.03) and DES (–48.9%, P = 0.01) groups, compared with PL. Similarly, RUP and DES were comparable and significantly superior to PL for all secondary endpoints, including nasal and conjunctival symptoms and patients’ and investigator’s overall clinical opinions. Symptom score evaluation (both reflective and instantaneous evaluations) throughout the treatment period showed a progressive and maintained significant improvement with both treatments at day 7 (P = 0.01), day 14 (P = 0.007), and day 21 (P = 0.01) in comparison with PL. Adverse events were scarce and were similar in both treatment groups. Electrocardiography (QTc) and lab test results did not show any relevant findings
RUP is a very good choice for SAR due to its contribution to the improvement of nasal (including obstruction) and non-nasal symptoms to a similar degree as DES.
PMCID: PMC3582315  PMID: 23459334
allergic rhinitis; seasonal; H1-antihistamines; rupatadine; desloratadine
17.  Utility of adjunctive macrolide therapy in treatment of children with asthma: a systematic review and meta-analysis 
The purpose of this study was to investigate macrolides as an adjunct to an asthma controller regimen in children with asthma.
Prospective clinical trials of macrolide therapy in children with asthma using outcome measures of change in forced expiratory volume in one second (FEV1) and/or oral corticosteroid requirement were searched for in PubMed up to December 2009. The reference lists of studies were also included in the analysis, as well as those listed in published meta-analyses.
The literature search yielded 116 studies, six of which were included in this meta-analysis. The change in FEV1 from baseline with adjunctive use of macrolide therapy in all children was not significant (0.25% predicted; 95% confidence interval [CI] −0.37, 0.86 predicted, P = 0.43); however, the change in FEV1 among children receiving daily oral corticosteroids was significant (3.89% predicted; 95% CI −0.01, 7.79, P = 0.05). Addition of macrolide therapy to the treatment of children with oral corticosteroid-dependent asthma resulted in a statistically significant decrease in daily corticosteroid dosage (−3.45 mg/day; 95% CI −5.79, −1.09 mg/day, P = 0.004). This reduction in daily corticosteroid dosage was directly proportional to the duration of macrolide therapy (−0.17 mg methylprednisolone per week of macrolide therapy; 95% CI −0.33, −0.021, P = 0.025).
Addition of macrolides to the treatment regimen of children with oral corticosteroid-dependent asthma improves FEV1 and decreases the daily dosage of corticosteroids required for control in these children. The degree of dose reduction is directly related to the duration of macrolide therapy. Additional large, randomized, placebo-controlled trials of adjunctive macrolide use in children with oral corticosteroid-dependent asthma are required to verify this observation.
PMCID: PMC3549681  PMID: 23345983
chronic asthma; macrolides; corticosteroid sparing
18.  Lung penetration and patient adherence considerations in the management of asthma: role of extra-fine formulations 
The mainstay of management in asthma is inhalation therapy at the target site, with direct delivery of the aerosolized drug into the airways to treat inflammation and relieve obstruction. Abundant evidence is available to support the concept that inflammatory and functional changes at the level of the most peripheral airways strongly contribute to the complexity and heterogeneous manifestations of asthma. It is now largely accepted that there is a wide range of clinical phenotypes of the disease, characterized primarily by small airways involvement. Thus, an appropriate diagnostic algorithm cannot exclude biological and functional assessment of the peripheral airways. Similarly, achievement of optimal control of the disease and appropriate management of specific phenotypes of asthma should be based on drugs (and delivery options) able to distribute uniformly along the bronchial tree and to reach the most peripheral airways. Products developed with the Modulite® technology platform have been demonstrated to meet these aims. Recent real-life studies have shown clearly that extra-fine fixed-combination inhaled therapy provides better asthma control than non-extra-fine formulations, thus translating the activity of the drugs into greater effectiveness in clinical practice. We suggest that in patients with incomplete asthma control despite good lung function, involvement of the peripheral airways should always be suspected. When this is the case, treatments targeting both the large and small airways should be used to improve asthma control. Above all, it is emphasized that patient adherence with prescribed medications can contribute to clinical success, and clinicians should always be aware of the role played by patients themselves in determining the success or failure of treatment.
PMCID: PMC3559081  PMID: 23378776
asthma; small airways; inflammation; quality of life; device
19.  Fluticasone propionate-salmeterol versus inhaled corticosteroids plus montelukast: outcomes study in pediatric patients with asthma 
The purpose of this study (GSK ADA111194) was to compare asthma-related health care utilization and costs associated with fluticasone propionate (an inhaled corticosteroid [ICS]) and salmeterol (a long-acting beta-agonist) in a single inhalation device (fluticasone propionate-salmeterol) versus the combination of ICS + montelukast in the treatment of pediatric patients with asthma.
This was a retrospective, observational cohort study using a large health insurance claims database spanning January 1, 2000 to January 31, 2008. The target population was patients aged 4–11 years with at least one pharmacy claim for fluticasone propionate-salmeterol, any ICS, or montelukast during the study period. The date of first claim for the medication of interest was deemed the index date. Patients were required to be continuously eligible to receive health care services one year prior to and 30 days after the index date, and have at least one claim with an ICD-9-CM code for asthma (493.xx) in the one-year pre-index period. Patients with prescriptions for fluticasone propionate-salmeterol, ICS + montelukast, or long-acting beta-agonists during the pre-index period were excluded. Patients were matched on a 1:1 basis according to three variables, ie, pre-index use of oral corticosteroids, ICS, and presence of pre-index respiratory-related hospitalizations/emergency department visits. The risk of asthma-related hospitalization, combined hospitalization/emergency department visit, and monthly asthma-related costs were assessed using multivariate methods.
Of the 3001 patients identified, 2231 patients were on fluticasone propionate-salmeterol and 770 were on ICS + montelukast. After matching, there were 747 pairs of fluticasone propionate-salmeterol and ICS + montelukast patients, which were well matched for baseline characteristics. Patients who started fluticasone propionate-salmeterol compared with patients on ICS + montelukast had a significantly (P < 0.02) lower rate of asthma-related hospitalizations (0.3% versus 3.5%) and asthma-related hospitalizations/emergency department visits (3.5% versus 5.7%). After controlling for baseline and patient characteristics, fluticasone propionate-salmeterol users were associated with a significantly lower risk of an asthma-related hospitalization (adjusted hazard ratio 0.039; 95% confidence interval 0.004–0.408) or hospitalization/emergency department visit (hazard ratio 0.441; 95% confidence interval 0.225–0.864), and $151 (95% confidence interval 67–346) lower asthma-related monthly costs compared with ICS + montelukast.
In patients aged 4–11 years with asthma, use of fluticasone propionate-salmeterol was associated with lower asthma-related health care utilization and costs compared with use of ICS + montelukast.
PMCID: PMC3536350  PMID: 23300347
fluticasone propionate; salmeterol; montelukast; inhaled corticosteroids; asthma; pediatric; outcomes; asthma
20.  Single systemic administration of Ag85B of mycobacteria DNA inhibits allergic airway inflammation in a mouse model of asthma 
The immune responses of T-helper (Th) and T-regulatory cells are thought to play a crucial role in the pathogenesis of allergic airway inflammation observed in asthma. The correction of immune response by these cells should be considered in the prevention and treatment of asthma. Native antigen 85B (Ag85B) of mycobacteria, which cross-reacts among mycobacteria species, may play an important biological role in host–pathogen interaction since it elicits various immune responses by activation of Th cells. The current study investigated the antiallergic inflammatory effects of DNA administration of Ag85B from Mycobacterium kansasii in a mouse model of asthma. Immunization of BALB/c mice with alum-adsorbed ovalbumin followed by aspiration with aerosolized ovalbumin resulted in the development of allergic airway inflammation. Administration of Ag85B DNA before the aerosolized ovalbumin challenge protected the mice from subsequent induction of allergic airway inflammation. Serum and bronchoalveolar lavage immunoglobulin E levels, extent of eosinophil infiltration, and levels of Th2-type cytokines in Ag85B DNA-administered mice were significantly lower than those in control plasmid-immunized mice, and levels of Th1-and T-regulatory-type cytokines were enhanced by Ag85B administration. The results of this study provide evidence for the potential utility of Ag85B DNA inoculation as a novel approach for the treatment of asthma.
PMCID: PMC3526857  PMID: 23271916
immunotherapy; asthma; Ag85B; mycobacteria; allergy
21.  Allergic bronchopulmonary aspergillosis treated successfully for one year with omalizumab 
Current therapy for allergic bronchopulmonary aspergillosis (ABPA) uses oral corticosteroids, exposing patients to the adverse effects of these agents. There are reports of the steroid-sparing effect of anti-IgE therapy with omalizumab for ABPA in patients with cystic fibrosis (CF), but there is little information on its efficacy against ABPA in patients with bronchial asthma without CF.
To examine the effects of omalizumab, measured by asthma control, blood eosinophilia, total serum immunoglobulin E (IgE), oral corticosteroid requirements, and forced expiratory volume spirometry in patients with ABPA and bronchial asthma.
A retrospective review of charts from 2004–2006 of patients treated with omalizumab at an academic allergy and immunology practice in the Bronx, New York were examined for systemic steroid and rescue inhaler usage, serum immunoglobulin E levels, blood eosinophil counts, and asthma symptoms, as measured by the Asthma Control Test (ACT).
A total of 21 charts were screened for the diagnosis of ABPA and bronchial asthma. Four patients with ABPA were identified; two of these patients were male. The median monthly systemic corticosteroid use at 6 months and 12 months decreased from baseline usage. Total serum IgE decreased in all patients at 12 months of therapy. Pre-bronchodilator forced expiratory vital capacity at one second (FEV1) was variable at 1 year of treatment. There was an improvement in Asthma Control Test (ACT) symptom scores for both daytime and nighttime symptoms.
Treatment with omalizumab creates a steroid-sparing effect, reduces systemic inflammatory markers, and results in improvement in ACT scores in patients with ABPA.
PMCID: PMC3508546  PMID: 23204847
allergic bronchopulmonary aspergillosis; omalizumab; asthma
22.  Acute bronchospasm and resolution captured on dynamic CT 
Computed tomography (CT) imaging provides a noninvasive window beneath the skin, defines lung pathology, and facilitates virtual and multimodality fusion interventions. A CT scan of acute bronchospasm is shown during a CT-guided lung intervention. Dynamic or sequential CT imaging can depict and perhaps even quantify acute reversible bronchospasm, and could potentially play a role in better understanding pharmacologic interventions for reactive airways and the resulting effects.
PMCID: PMC3496962  PMID: 23152689
acute bronchospasm; dynamic CT; albuterol; physiological response; noninvasive
23.  Potential role of histamine releasing factor (HRF) as a therapeutic target for treating asthma and allergy 
Histamine releasing factor (HRF), also known as translationally controlled tumor protein (TCTP), is a highly conserved, ubiquitous protein that has both intracellular and extracellular functions. Here, we will highlight the history of the molecule, its clinical implications with a focus on its extracellular functioning, and its potential role as a therapeutic target in asthma and allergy. The cells and cytokines produced when stimulated or primed by HRF/TCTP are detailed as well as the downstream signaling pathway that HRF/TCTP elicits. While it was originally thought that HRF/TCTP interacted with IgE, the finding that cells not binding IgE also respond to HRF/TCTP called this interaction into question. HRF/TCTP, or at least its mouse counterpart, appears to interact with some, but not all IgE and IgG molecules. HRF/TCTP has been shown to activate multiple human cells including basophils, eosinophils, T cells, and B cells. Since many of the cells activated by HRF/TCTP participate in the allergic response, extracellular functions of HRF/TCTP may exacerbate the allergic, inflammatory cascade. Particularly exciting is that small molecule agonists of Src homology 2-containing inositol phosphatase-1 have been shown to modulate the phosphoinositide 3-kinase/AKT pathway and may control inflammatory disorders. This review discusses this possibility in light of HRF/TCTP.
PMCID: PMC3461606  PMID: 23055753
human basophils; human eosinophils; inducible transgenic mouse; interleukin 4; interleukin 13; translationally controlled tumor protein (TCTP)
24.  Comparison of the robustness and functionality of three adrenaline auto-injectors 
Anaphylaxis is a medical emergency that requires the intramuscular injection of adrenaline using an adrenaline auto-injector (AAI). This study compared the robustness and performance characteristics of three AAIs available in Europe.
Three AAIs (Jext®, EpiPen®, and Anapen®) were tested in terms of the force needed to activate the AAIs, exposed needle length, injection volume, and injection time. Three conditions were used to assess robustness: base conditions, after three successive free-fall drops from 1.5 m, and after a 40 kg static load challenge. The injection depth and estimated volume of solution delivered into ballistic gelatin were also assessed.
Less force was required to remove the safety cap from Jext and EpiPen than from Anapen under base conditions. The required force was unaffected by free-fall drop tests, whereas the static load test significantly increased the force required to remove the safety cap from Jext (difference from base value 7.7 N; P < 0.001) and from EpiPen ( difference from base value 30.3 N; P < 0.001). Two Anapens could not be activated after the free-fall and static load tests. The mean exposed needle length was 15.36 mm (standard error [SE] 0.04) for Jext, 15.02 mm (SE 0.05) for EpiPen, and 7.49 mm (SE 0.15) for Anapen. The mean maximum injection depth in gelatin within 10 seconds was 28.87 mm (standard deviation [SD] 0.73) for Jext, 29.68 mm (SD 2.08) for EpiPen, and 18.74 mm (SD 1.25) for Anapen.
A comparison of the robustness and performance characteristics of the three AAIs showed that cartridge-based devices (Jext and EpiPen) appeared to be significantly more robust and capable of rapidly and consistently delivering the correct dose of adrenaline to the correct tissue compartment than the syringe-based Anapen. Overall, Jext performed better than EpiPen or Anapen following mechanical stress designed to mimic real-world use.
PMCID: PMC3430083  PMID: 22952410
anaphylaxis; adrenaline auto-injector; Anapen; EpiPen; Jext; injection depth; reliability
25.  Long-term use of doxycycline can improve chronic asthma and possibly remodeling: the result of a pilot observation 
Progressive loss of lung function and reversibility characterize chronic asthma. The conventional therapy is targeted to control the disease without targeting the loss of lung function or reversibility. In a prospective real-world observation of long-term use of add-on doxycycline as a matrix-metalloproteinase inhibitor, we documented significant improvement in lung function with possible reversal of remodeling.
Chronic asthma shows progressive decline in lung function with reduction or even loss of reversibility secondary to remodeling. A set of endopeptidase enzymes known as matrix metalloproteinases are intimately related to the pathogenesis of asthma and remodeling. The inhibition of matrix metalloproteinases is recognized as a prospective way of treating asthma and its corresponding structural remodeling.
In a randomized, prospective, real-world study, we have observed the change in lung function (spirometry) with an add-on of long-term doxycycline to standard asthma therapy as per the Global Initiative for Asthma guidelines in a small asthmatic population. The change in terms of forced expiratory volume (FEV1), forced vital capacity (FVC), percent of FEV1 (FEV1%), and forced expiratory flow (FEF25–75) were noted following variable duration of doxycycline therapy.
There has been a global improvement in all the parameters in all the six patients suggesting improvement in obstruction, and reduction in air trapping following a treatment of add-on doxycycline for a mean duration of 162.83 ± 83.07 days. Of the changes seen, the post bronchodilator FEV1, the FVC, and the FEF25–75 showed significant improvements with the P-value set at 0.004, 0.054, and 0.031, respectively. There was also evidence of the reversal of remodeling from the improvement in the FEV1/FVC ratio. Moreover there was a greater than expected improvement of pre-bronchodilator FEV1 after treatment that far surpassed the initial post-bronchodialator FEV1 value. Even after such a change, there were presences of some reversibility suggesting room for further improvement.
The results suggest significant improvements in the obstructive parameters used to evaluate asthma, with possible reversal of remodeling evident in chronic asthmatics when treated with doxycycline in addition to standard therapies. This observation needs further scientific validation.
PMCID: PMC3422814  PMID: 22923997
chronic asthma; doxycycline; FEV1; FEV1/FVC; matrix metalliproteinase

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