Kaharu Sumino

Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.

IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065.

Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma

BACKGROUND Bronchial thermoplasty (BT) has previously been shown to improve asthma control out to 2 years in patients with severe persistent asthma. OBJECTIVE We sought to assess the effectiveness and safety of BT in asthmatic patients 5 years after therapy. METHODS BT-treated subjects from the Asthma Intervention Research 2 trial (ClinicalTrials.govNCT01350414) were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect. Outcomes assessed after BT included severe exacerbations, adverse events, health care use, spirometric data, and high-resolution computed tomographic scans. RESULTS One hundred sixty-two (85.3%) of 190 BT-treated subjects from the Asthma Intervention Research 2 trial completed 5 years of follow-up. The proportion of subjects experiencing severe exacerbations and emergency department (ED) visits and the rates of events in each of years 1 to 5 remained low and were less than those observed in the 12 months before BT treatment (average 5-year reduction in proportions: 44% for exacerbations and 78% for ED visits). Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Prebronchodilator FEV₁ values remained stable between years 1 and 5 after BT, despite a 18% reduction in average daily inhaled corticosteroid dose. High-resolution computed tomographic scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. CONCLUSIONS These data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety. BT has become an important addition to our treatment armamentarium and should be considered for patients with severe persistent asthma who remain symptomatic despite taking inhaled corticosteroids and long-acting β₂-agonists.

Genetic Variability of Human Metapneumovirus Infection: Evidence of a Shift in Viral Genotype without a Change in Illness

Human metapneumovirus (hMPV) was identified in 2001 as a cause of acute respiratory illness, but its characteristics are still being defined. We analyzed 3740 nasopharyngeal-wash specimens obtained during 2002-2004, using assays for common respiratory viruses and real-time polymerase chain reaction for hMPV. We detected hMPV in 5% of all specimens, compared with 28% for other respiratory viruses. Nucleotide sequence analysis of hMPV isolates revealed the predominant circulation of hMPV genotype A in the 2003 season but a switch to predominantly genotype B in 2004. Sequence analysis also revealed major differences in the hMPV G and SH genes but relative conservation of the F and N genes within each genotype. Phylogenetic analysis indicated a seasonal switch within hMPV genotype A subtypes as well. Despite genetic variability, we found no difference in the severity of illness caused by various hMPV isolates. These findings suggest that hMPV may vary in genetic structure, to allow for a seasonal shift in predominant genotype and the maintenance of infection rates.

Detection of Severe Human Metapneumovirus Infection by Real-Time Polymerase Chain Reaction and Histopathological Assessment

Abstract BackgroundInfections with common respiratory tract viruses can cause high mortality, especially in immunocompromised hosts, but the impact of human metapneumovirus (hMPV) in this setting was previously unknown MethodsWe evaluated consecutive bronchoalveolar lavage and bronchial wash fluid samples from 688 patients—72% were immunocompromised and were predominantly lung transplant recipients—for hMPV by use of quantitative real-time polymerase chain reaction (PCR), and positive results were correlated with clinical outcome and results of viral cultures, in situ hybridization, and lung histopathological assessment ResultsSix cases of hMPV infection were identified, and they had a similar frequency and occurred in a similar age range as other paramyxoviral infections. Four of 6 infections occurred in immunocompromised patients. Infection was confirmed by in situ hybridization for the viral nucleocapsid gene. Histopathological assessment of lung tissue samples showed acute and organizing injury, and smudge cell formation was distinct from findings in infections with other paramyxoviruses. Each patient with high titers of hMPV exhibited a complicated clinical course requiring prolonged hospitalization ConclusionsOur results provide in situ evidence of hMPV infection in humans and suggest that hMPV is a cause of clinically severe lower respiratory tract infection that can be detected during bronchoscopy by use of real-time PCR and routine histopathological assessment

Patient reminder systems and asthma medication adherence: a systematic review

Abstract Objective: One of the most common reasons for medication non-adherence for asthma patients is forgetfulness. Daily medication reminder system interventions in the form of text messages, automated phone calls and audiovisual reminder devices can potentially address this problem. The aim of this review was to assess the effectiveness of reminder systems on patient daily asthma medication adherence. Methods: We conducted a systematic review of the literature to identify randomized controlled trials (RCTs) which assessed the effect of reminder systems on daily asthma medication adherence. We searched all English-language articles in Pub Med (MEDLINE), CINAHL, EMBASE, PsychINFO and the Cochrane Library through May 2013. We abstracted data on the year of study publication, location, inclusion and exclusion criteria, patient characteristics, reminder system characteristics, effect on patient adherence rate and other outcomes measured. Descriptive statistics were used to summarize the characteristics and results of the studies. Results: Five RCTs and one pragmatic RCT were included in the analysis. Median follow-up time was 16 weeks. All of the six studies suggested that the reminder system intervention was associated with greater levels of participant asthma medication adherence compared to those participants in the control group. None of the studies documented a change in asthma-related quality of life or clinical asthma outcomes. Conclusion: All studies in our analysis suggest that reminder systems increase patient medication adherence, but none documented improved clinical outcomes. Further studies with longer intervention durations are needed to assess effects on clinical outcomes, as well as the sustainability of effects on patient adherence.

Methacholine challenge test: Diagnostic characteristics in asthmatic patients receiving controller medications

BACKGROUND The methacholine challenge test (MCT) is commonly used to assess airway hyperresponsiveness, but the diagnostic characteristics have not been well studied in asthmatic patients receiving controller medications after the use of high-potency inhaled corticosteroids became common. OBJECTIVES We investigated the ability of the MCT to differentiate participants with a physicians diagnosis of asthma from nonasthmatic participants. METHODS We conducted a cohort-control study in asthmatic participants (n= 126) who were receiving regular controller medications and nonasthmatic control participants (n= 93) to evaluate the sensitivity and specificity of the MCT. RESULTS The overall sensitivity was 77% and the specificity was 96% with a threshold PC(20) (the provocative concentration of methacholine that results in a 20% drop in FEV(1)) of 8 mg/mL. The sensitivity was significantly lower in white than in African American participants (69% vs 95%, P= .015) and higher in atopic compared with nonatopic (82% vs 52%, P= .005). Increasing the PC(20) threshold from 8 to 16 mg/mL did not noticeably improve the performance characteristics of the test. African American race, presence of atopy, and lower percent predicted FEV(1) were associated with a positive test result. CONCLUSIONS The utility of the MCT to rule out a diagnosis of asthma depends on racial and atopic characteristics. Clinicians should take into account the reduced sensitivity of the MCT in white and nonatopic asthmatic patients when using this test for the diagnosis of asthma.

Detection of respiratory viruses and the associated chemokine responses in serious acute respiratory illness

Background A specific diagnosis of a lower respiratory viral infection is often difficult despite frequent clinical suspicion. This low diagnostic yield may be improved by use of sensitive detection methods and biomarkers. Methods The prevalence, clinical predictors and inflammatory mediator profile of respiratory viral infection in serious acute respiratory illness were investigated. Sequential bronchoalveolar lavage (BAL) fluids from all patients hospitalised with acute respiratory illness over 12 months (n=283) were tested for the presence of 17 respiratory viruses by multiplex PCR assay and for newly discovered respiratory viruses (bocavirus, WU and KI polyomaviruses) by single-target PCR. BAL samples also underwent conventional testing (direct immunoflorescence and viral culture) for respiratory virus at the clinicians discretion. 27 inflammatory mediators were measured in a subset of the patients (n=64) using a multiplex immunoassay. Results 39 respiratory viruses were detected in 37 (13.1% of total) patients by molecular testing, including rhinovirus (n=13), influenza virus (n=8), respiratory syncytial virus (n=6), human metapneumovirus (n=3), coronavirus NL63 (n=2), parainfluenza virus (n=2), adenovirus (n=1) and newly discovered viruses (n=4). Molecular methods were 3.8-fold more sensitive than conventional methods. Clinical characteristics alone were insufficient to separate patients with and without respiratory virus. The presence of respiratory virus was associated with increased levels of interferon γ-inducible protein 10 (IP-10) (p<0.001) and eotaxin-1 (p=0.017) in BAL. Conclusions Respiratory viruses can be found in patients with serious acute respiratory illness by use of PCR assays more frequently than previously appreciated. IP-10 may be a useful biomarker for respiratory viral infection.

Vaccination of patients with mild and severe asthma with a 2009 pandemic H1N1 influenza virus vaccine

BACKGROUND Asthma was the most common comorbidity of patients hospitalized with 2009 H1N1 influenza. OBJECTIVE We sought to assess the immunogenicity and safety of an unadjuvanted, inactivated 2009 H1N1 vaccine in patients with severe versus mild-to-moderate asthma. METHODS We conducted an open-label study involving 390 participants (age, 12-79 years) enrolled in October-November 2009. Severe asthma was defined as need for 880 μg/d or more of inhaled fluticasone equivalent, systemic corticosteroids, or both. Within each severity group, participants were randomized to receive intramuscularly 15 or 30 μg of 2009 H1N1 vaccine twice 21 days apart. Immunogenicity end points were seroprotection (hemagglutination inhibition assay titer ≥40) and seroconversion (4-fold or greater titer increase). Safety was assessed through local and systemic reactogenicity, asthma exacerbations, and pulmonary function. RESULTS In patients with mild-to-moderate asthma (n = 217), the 2009 H1N1 vaccine provided equal seroprotection 21 days after the first immunization at the 15-μg (90.6%; 95% CI, 83.5% to 95.4%) and 30-μg (95.3%; 95% CI, 89.4% to 98.5%) doses. In patients with severe asthma (n = 173), seroprotection 21 days after the first immunization was 77.9% (95% CI, 67.7% to 86.1%) and 94.1% (95% CI, 86.8% to 98.1%) at the 15- and 30-μg doses, respectively (P = .004). The second vaccination did not provide further increases in seroprotection. Participants with severe asthma who are older than 60 years showed the lowest seroprotection (44.4% at day 21) with the 15-μg dose but had adequate seroprotection with 30 μg. The 2 dose groups did not differ in seroconversion rates. There were no safety concerns. CONCLUSION Monovalent inactivated 2009 H1N1 pandemic influenza vaccine was safe and provided overall seroprotection as a surrogate of efficacy. In patients older than 60 years with severe asthma, a 30-μg dose might be more appropriate.

Coexisting chronic conditions associated with mortality and morbidity in adult patients with asthma

Abstract Objective: Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma. Methods: In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n = 25 975, follow-up 3.0 ± 1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV and heart failure) and four conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates. Results: HIV followed by alcoholism and mental disorders among 18–45-years old, and heart failure, diabetes, IHD and cancer among those ≥65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18–45 years old, and chronic sinusitis, mental disorder and IHD among those ≥65-years old. GERD was associated with decreased risk for asthma exacerbation in all ages. Conclusions: Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.

Vitamin D Supplementation and the Risk of Colds in Patients with Asthma.

RATIONALE Restoration of vitamin D sufficiency may reduce asthma exacerbations, events that are often associated with respiratory tract infections and cold symptoms. OBJECTIVES To determine whether vitamin D supplementation reduces cold symptom occurrence and severity in adults with mild to moderate asthma and vitamin D insufficiency. METHODS Colds were assessed in the AsthmaNet VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness) trial, in which 408 adult patients were randomized to receive placebo or cholecalciferol (100,000 IU load plus 4,000 IU/d) for 28 weeks as add-on therapy. The primary outcome was cold symptom severity, which was assessed using daily scores on the 21-item Wisconsin Upper Respiratory Symptom Survey. MEASUREMENTS AND MAIN RESULTS A total of 203 participants experienced at least one cold. Despite achieving 25-hydroxyvitamin D levels of 41.9 ng/ml (95% confidence interval [CI], 40.1-43.7 ng/ml) by 12 weeks, vitamin D supplementation had no effect on the primary outcome: the average peak WURSS-21 scores (62.0 [95% CI, 55.1-68.9; placebo] and 58.7 [95% CI, 52.4-65.0; vitamin D]; P = 0.39). The rate of colds did not differ between groups (rate ratio [RR], 1.2; 95% CI, 0.9-1.5); however, among African Americans, those receiving vitamin D versus placebo had an increased rate of colds (RR, 1.7; 95% CI, 1.1-2.7; P = 0.02). This was also observed in a responder analysis of all subjects achieving vitamin D sufficiency, regardless of treatment assignment (RR, 1.4; 95% CI, 1.1-1.7; P = 0.009). CONCLUSIONS Our findings in patients with mild to moderate asthma undergoing an inhaled corticosteroid dose reduction do not support the use of vitamin D supplementation for the purpose of reducing cold severity or frequency.