Colds as predictors of the onset and severity of COPD exacerbations.

RATIONALE: Common colds are associated with acute respiratory symptom exacerbations in COPD patients. OBJECTIVE: To determine exacerbation risk and severity in COPD patients with/without coincident self-reported colds. METHODS: Global initiative for chronic Obstructive Lung Disease stage I-IV COPD patients electronically transmitted respiratory symptom diaries to research staff daily between December 2006 and April 2009. Respiratory symptom worsening prompted contact by a study nurse and patient assessment to determine if a cold was present or an exacerbation underway. A composite daily symptom score was derived for each subject from diarized symptom data. The exacerbation/cold/virus relation was examined using a Poisson regression model, the relation of colds to respiratory symptom severity using generalized estimating equation models. RESULTS: Daily diary transmission compliance of >97% enabled detection of all possible exacerbations. Among 262 exacerbations meeting Anthonisen criteria, 218 (83%) had cold-like symptoms present at their inception, but respiratory viruses were detected in only 106 (40%). Within-subject exacerbation risk was 30 times (95% confidence interval [CI]: 20, 47; P<0.001) greater with colds present. Compared to cold- and virus-negative exacerbations (n=57), the mean increase in composite symptom score in those cold and virus positive (n=79) was 0.93 (95% CI: 0.61, 1.25; P<0.001), cold-positive and virus-negative exacerbations (n=100) 0.51 (95% CI: 0.21, 0.81; P<0.001), cold-negative and virus-positive exacerbations (n=26) 0.58 (95% CI: 0.23, 0.94; P<0.001). CONCLUSION: This study emphasizes the importance of colds in COPD exacerbation risk and severity, even in the absence of virus detection. COPD patients should act promptly when cold symptoms appear to facilitate early intervention for exacerbation prevention or management.

Detection of COPD Exacerbations and compliance with patient-reported daily symptom diaries using a smart phone-based information system [corrected].

BACKGROUND: Paper-based diaries and self-report of symptom worsening in COPD may lead to underdetection of exacerbations. Epidemiologically, COPD exacerbations exhibit seasonal patterns peaking at year-end. We examined whether the use of a BlackBerry-based daily symptom diary would detect 95% or more of exacerbations and enable characterization of seasonal differences among them. METHODS: Fifty participants with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage I to IV COPD began a community-based study in December 2007. Another 30 began in December 2008. Participants transmitted daily symptom diaries using a BlackBerry. Alerts were triggered when symptom changes, missed diary transmissions, or medical care for a respiratory problem occurred. Participant encounters were initiated if COPD exacerbations were suspected. Participants used their BlackBerrys to report returns to normal breathing. RESULTS: Participants transmitted 99.9% of 28,514 possible daily diaries. All 191 (2.5/participant-year) COPD exacerbations meeting Anthonisen criteria were detected. During 148 of the 191 exacerbations (78%, 1.97/participant-year), patients were hospitalized and/or ordered prednisone, an antibiotic, or both. Respiratory viruses were detected in 78 of the 191 exacerbations (41%). Those coinciding with a respiratory viral infection averaged 12.0 days, and those without averaged 8.9 days (P < .04), with no difference in Anthonisen score. Respiratory symptom scores before exacerbations and after normal breathing return showed no differences. Exacerbations were more frequent during the Christmas period than the rest of the year but were not more frequent than in the rest of winter alone. CONCLUSIONS: Smartphone-based collection of COPD symptom diaries enables near-complete identification of exacerbations at inception. Exacerbation rates in the Christmas season do not reach levels that necessitate changes in disease management.

The Christmas season as a risk factor for chronic obstructive pulmonary disease exacerbations.

BACKGROUND: Epidemics of hospitalization for chronic obstructive pulmonary disease (COPD) occur annually during the Christmas holidays, and COPD exacerbations commonly coincide with respiratory viral infections. OBJECTIVE: To compare the incidence and determinants of COPD exacerbations occurring between the Christmas holiday period and the remainder of the winter season. METHODS: Seventy-one subjects with COPD of mixed severity faxed daily symptom diaries to a computer monitoring system from December 1, 2006, to April 30, 2007. Possible exacerbations prompted a home visit for assessment, spirometry and specimen collection for virological testing. RESULTS: Study subjects submitted a total of 95.4% of possible daily symptom diary sheets by fax. Of 114 possible COPD exacerbations detected using the faxed diaries, 110 met the Anthonisen criteria for true exacerbations. A total of 47 exacerbations (mean 6.7/week) occurred during the Christmas holiday period, while 63 exacerbations (mean 4.3/week) occurred during the remainder of winter. Of the Christmas period exacerbations and of those in the balance of winter, 21 (44%) and 20 (32%), respectively, coincided with respiratory viral infections. CONCLUSIONS: The incidence of COPD exacerbations during the Christmas period was greater than during the rest of winter in 2006/2007 and peaked immediately before Christmas - in contrast to hospital presentation for COPD, which peaked during the Christmas week. No clear role of respiratory viral infections in the increased rate of exacerbations during the Christmas period was established in the present study. COPD patients were highly compliant with daily symptom reporting using faxed daily diaries, which permitted nearly complete detection of all exacerbations that occurred at incidence.

The Back to School asthma study: the effect of montelukast on asthma burden when initiated prophylactically at the start of the school year.

BACKGROUND: Pediatric asthma hospitalizations peak in early autumn. OBJECTIVE: To determine the effectiveness of montelukast therapy in reducing the asthma burden in children when initiated prophylactically on school return. METHODS: This was a randomized, multicenter, double-blind, placebo-controlled study of children with asthma aged 6 to 14 years. No minimum asthma symptoms were required, and patients could continue inhaled corticosteroid (ICS) use. Montelukast, 5 mg, chewable tablet (n = 580) or matching placebo (n = 582) was taken the night before the first day of school and nightly thereafter for 8 weeks. The primary end point was the percentage of days with worsening asthma, defined by one of the following: (1) increased beta-agonist use, (2) increased daytime symptoms, (3) awake "all night," (4) oral corticosteroid rescue or increased ICS use for worsening asthma, or (5) unanticipated health care utilization. RESULTS: The reduction in the percentage of days with worsening asthma with montelukast use versus placebo use was not significant (24.3% vs 27.2%, P = .07). Prespecified subgroup analyses demonstrated nonsignificant trends favoring montelukast therapy in boys and older children but no effect by baseline ICS use or history of cold symptoms. Post hoc analysis showed a nonsignificant trend favoring montelukast therapy in reducing worsening asthma days for children commencing school after August 15 compared with earlier commencement. CONCLUSIONS: Montelukast use was not significantly more effective than was placebo use in reducing the percentage of days with worsening asthma when initiated at the start of the school year. The effect of montelukast treatment on the fall peak in asthma burden may depend on sex, age, and the date of school return.

A probit- log- skew-normal mixture model for repeated measures data with excess zeros, with application to a cohort study of paediatric respiratory symptoms.

BACKGROUND: A zero-inflated continuous outcome is characterized by occurrence of "excess" zeros that more than a single distribution can explain, with the positive observations forming a skewed distribution. Mixture models are employed for regression analysis of zero-inflated data. Moreover, for repeated measures zero-inflated data the clustering structure should also be modeled for an adequate analysis. METHODS: Diary of Asthma and Viral Infections Study (DAVIS) was a one year (2004) cohort study conducted at McMaster University to monitor viral infection and respiratory symptoms in children aged 5-11 years with and without asthma. Respiratory symptoms were recorded daily using either an Internet or paper-based diary. Changes in symptoms were assessed by study staff and led to collection of nasal fluid specimens for virological testing. The study objectives included investigating the response of respiratory symptoms to respiratory viral infection in children with and without asthma over a one year period. Due to sparse data daily respiratory symptom scores were aggregated into weekly average scores. More than 70% of the weekly average scores were zero, with the positive scores forming a skewed distribution. We propose a random effects probit/log-skew-normal mixture model to analyze the DAVIS data. The model parameters were estimated using a maximum marginal likelihood approach. A simulation study was conducted to assess the performance of the proposed mixture model if the underlying distribution of the positive response is different from log-skew normal. RESULTS: Viral infection status was highly significant in both probit and log-skew normal model components respectively. The probability of being symptom free was much lower for the week a child was viral positive relative to the week she/he was viral negative. The severity of the symptoms was also greater for the week a child was viral positive. The probability of being symptom free was smaller for asthmatics relative to non-asthmatics throughout the year, whereas there was no difference in the severity of the symptoms between the two groups. CONCLUSIONS: A positive association was observed between viral infection status and both the probability of experiencing any respiratory symptoms, and their severity during the year. For DAVIS data the random effects probit -log skew normal model fits significantly better than the random effects probit -log normal model, endorsing our parametric choice for the model. The simulation study indicates that our proposed model seems to be robust to misspecification of the distribution of the positive skewed response.

A review of select recent patents on novel nanocarriers.

Nanocarriers offer several advantages in drug delivery including increased retention time in the body, the ability to solubilize hydrophobic cargo, and the ability to target specific tissues. These attributes have led to a large volume of research being dedicated to the development of novel nanocarriers and their use in treating disease. Many advances have been made in the synthesis and formulation of nanocarriers. For instance, flash precipitation and the use of rotary evaporator provide new methods for nanocarrier synthesis. Biomolecules like heparin and sarcosine have been successfully utilized for the synthesis of unique copolymers for use in nanocarrier systems. Also, the efficacy of nanocarrier targeting has been increased by taking advantage of unique microenvironments present in specific pathologies, utilization of phage properties, and scaffold systems for multiple targeting moieties. Finally, nanocarriers have been shown to provide immunomodulatory effects. This article provides a focused review of several recent patents covering the synthesis, composition and the use of novel nanocarriers.

The similarities and differences of epidemic cycles of chronic obstructive pulmonary disease and asthma exacerbations.

The majority of chronic obstructive pulmonary disease (COPD) and asthma exacerbations in both children and adults are associated with respiratory viral infections and are cyclic in nature. Some variation in these cycles is associated with the timing of the appearance of respiratory viruses, particularly influenza and respiratory syncytial virus. Much more, however, is associated with signal events that are of either fixed or predictable timing. In children, asthma exacerbations reach epidemic levels following school return after the summer vacation and these are predominantly associated with rhinovirus infections. Although younger adults experience a rise in asthma exacerbations at this time, these are secondary to the epidemic in children. Older adults with either COPD or asthma experience only a slightly elevated risk of exacerbations after school return, and hospital presentations for pneumonia in any age group show only marginal increases at that time. Exacerbations of both COPD and adult asthma, with increasing risk with age, are at their highest average annual levels during the Christmas period. This effect appears to be independent of the timing of above average levels of influenza, RSV, parainfluenza, or adenovirus detections; however, hospitalization for respiratory tract infections in all age groups reaches high levels at the same time. Both the post-summer vacation asthma epidemic and the Christmas epidemic of COPD, asthma, and pneumonia are synchronous with the timing of signal events, the day of school return for the former and Christmas Day for the latter, and have been for several years. The agents responsible for the Christmas epidemic of respiratory diseases have not yet been identified. The differences between age and disease exacerbation patterns after school return and at Christmas suggest that either different agents are involved or that the response to a common agent is different between the two signal events.

Attenuation of the September epidemic of asthma exacerbations in children: a randomized, controlled trial of montelukast added to usual therapy.

BACKGROUND: A recurring epidemic of asthma exacerbations in children occurs annually in September in North America when school resumes after summer vacation. OBJECTIVE: Our goal was to determine whether montelukast, added to usual asthma therapy, would reduce days with worse asthma symptoms and unscheduled physician visits of children during the September epidemic. PATIENTS AND METHODS: A total of 194 asthmatic children aged 2 to 14 years, stratified according to age group (2-5, 6-9, and 10-14 years) and gender, participated in a double-blind, randomized, placebo-controlled trial of the addition of montelukast to usual asthma therapy between September 1 and October 15, 2005. RESULTS: Children randomly assigned to receive montelukast experienced a 53% reduction in days with worse asthma symptoms compared with placebo (3.9% vs 8.3%) and a 78% reduction in unscheduled physician visits for asthma (4 [montelukast] vs 18 [placebo] visits). The benefit of montelukast was seen both in those using and not using regular inhaled corticosteroids and among those reporting and not reporting colds during the trial. There were differences in efficacy according to age and gender. Boys aged 2 to 5 years showed greater benefit from montelukast (0.4% vs 8.8% days with worse asthma symptoms) than did older boys, whereas among girls the treatment effect was most evident in 10- to 14-year-olds (4.6% [montelukast] vs 17.0% [placebo]), with nonsignificant effects in younger girls. CONCLUSIONS: Montelukast added to usual treatment reduced the risk of worsened asthma symptoms and unscheduled physician visits during the predictable annual September asthma epidemic. Treatment-effect differences observed between age and gender groups require additional investigation.

Understanding the September asthma epidemic.

The highly predictable increase in emergency department visits, hospital admissions, and unscheduled physician consultations for childhood asthma in North America every September is uniquely related to school return. Rhinovirus infection is likely the major trigger, initially affecting asthma in school-age children, followed by similar but lesser increases in asthma morbidity in younger children and in adults. Low use of asthma medications during summer may fuel the epidemic, which may be attenuated by the short-term addition of an effective controller therapy.

The September epidemic of asthma hospitalization: school children as disease vectors.

BACKGROUND: Viral infections are associated with the majority of asthma exacerbations in children and adults. Increased asthma hospitalization rates of children and adults, particularly in the early fall, have been observed to follow school vacations. OBJECTIVE: We sought to determine the sequence of timing of September asthma hospitalization epidemics in children and adults and to determine whether school-age children are the primary source of transmission of agents that cause them. METHODS: By using Canadian asthma hospital admission data from 1990 to 2002, we examined geographic variation in the timing of fall asthma epidemics and applied mathematical modeling to estimate their exact timing and magnitude in school-age children, preschool children, and adults, and relation to school return. RESULTS: The September asthma hospitalization epidemic peak occurred in school-age children each year on average 17.7 (95% CI, 16.8-18.5) days after Labor Day. Similar epidemics of lesser magnitude were observed in preschool children peaking 1.7 (95% CI, 0.9-2.5; P<.001) days later, and in adults 6.3 (95% CI, 4.7-7.9; P<.001) days later than in school-age children. The epidemics peaked 4.2 (95% CI, 1.2-7.1; P<.001) days earlier in school-age children in northernmost compared with southernmost latitudes. CONCLUSION: September epidemics of asthma hospitalizations in Canada have a precise relationship to school return after the summer vacation. It may be speculated that school-age children transmit the agents responsible for the epidemic to adults. Measures to improve asthma control and reduce transmission of infections should be directed at children with asthma before school return.

The September epidemic of asthma exacerbations in children: a search for etiology.

BACKGROUND: Predictable peaks of asthma exacerbation requiring hospital treatment, of greatest magnitude in children and of uncertain etiology, occur globally after school returns. OBJECTIVE: We wished to determine whether asthmatic children requiring emergency department treatment for exacerbations after school return in September were more likely to have respiratory viruses present and less likely to have prescriptions for control medications than children with equally severe asthma not requiring emergent treatment. METHODS: Rates of viral detection and characteristics of asthma management in 57 (of 60) children age 5 to 15 years presenting to emergency departments with asthma in 2 communities in Canada between September 10 and 30, 2001, (cases) were compared with those in 157 age-matched volunteer children with asthma of comparable severity studied simultaneously (controls). RESULTS: Human picornaviruses were detected in 52% of cases and 29% of controls ( P = .002) and viruses of any type in 62% of cases and 41% of controls ( P = .011). Cases were less likely to have been prescribed controller medication (inhaled corticosteroid, 49% vs 85%; P < .0001; leukotriene receptor antagonist, 9% vs 21%; P = .04). CONCLUSION: Respiratory viruses were detected in the majority of children presenting to emergency departments with asthma during the September epidemic of the disease and in a significant minority of children with asthma in the community. The latter were more likely to have anti-inflammatory medication prescriptions than children requiring emergent treatment. Such medication may reduce the risk of emergency department treatment for asthma during the September epidemic.