sample of the study population was not associated with changes in T scores or FRAX scores. Moreover, as FRAX may be an easy method for assessing osteoporosis in a systemic disease like COPD, our results suggest that pa- tients with COPD should routinely have their BMD eval- uated by DXA or FRAX, even in the absence of severe disease or glucocorticoid use. This approach can reduce risk of fracture and could allow adequate treatment of osteoporosis. As we also show that vitamin D levels were lower in osteoporotic patients and that low vitamin D levels are related to number of exacerbations and hospi- talizations in the last year, vitamin D supplementation may be needed in all patients with COPD, and especially in those with high FRAX scores. Moreover, vitamin D supplementation significantly reduces the episodes of exacerbation and, therefore, hospitalization, thus influecing favourably the costs of pulmonary disease. Nevertheless, future studies are needed to evaluate the relationship between vitamin D supplementation and the long-term risk of fractures in patients with COPD.
during follow-up experienced an improvement in the St George’s Respiratory Questionnaire (SGRQ) of 11.8 units at 1 month and 17 units after 5 months of the onset of the exacerbation. These results indicate that the recovery of health status after an exacerbation may take longer than previously expected. In contrast, median recovery time for lung function after an exacerbation is 6 days and for symptoms is 7 days . However, this recovery may be influenced by the severity of the exacerbation. The more severe the exacerbation, the longer it takes to recover. S EEMUNGAL et al.  showed that only 75% of patients return to their baseline peak flow values 35 days after the episode. The SGRQ and Medical Research Council questionnaire were completed by patients at the end of the study. Exacerbations were more frequent in patients with frequent previous exacerbations (OR 5.5, p 5 0.001). Using the median number of exacerbations, patients were classified as infrequent exacerbators (0–2) or frequent exacerbators (3–8). SGRQ total score was significantly worse in frequent exacer- bators (mean difference 14.8; p , 0.001) (fig. 1).
of inhaled anticholinergic therapy might cause similar problems to those they described related to withdrawal of inhaled corticosteroids. However, our results clearly refute that suggestion. Furthermore, we have demonstrated a similar reduction in the number of exacerbations per patient year in those who continued and those who discontinued inhaled anticholinergic therapy upon randomization into these tiotropium clinical trials. This significant benefit argues that the clinical trial results, in terms of the difference between tiotropium and placebo, favor a positive effect from tiotropium rather than a negative effect from inhaled anticholinergic withdrawal in the placebo group.
Results: Participants had a median age of 68.0 years, 71.3% were males, and 71.8% suffered from comorbidities. The median disease duration was 10.0 years. Of the patients, 45.3% were classified as having GOLD (Global initiative for chronic Obstructive Lung Disease) stage III or IV COPD. Patients with four or more comorbidities had 78.5% and threefold-higher than expected number of exacerbations and hospitalizations, respectively, as well as fivefold-higher risk of admission to the ICU compared to those with no comorbidities. Obese patients had 6.2% fewer expected exacerbations compared to those with a normal body mass index. Patients with GOLD stage IV had 74.5% and fivefold-higher expected number of exacerbations and hospi- talizations, respectively, and nearly threefold-higher risk of admission to the ICU compared to stage I patients. An additional risk factor for exacerbations and hospitalizations was low compliance with treatment: 45% of patients reported forgetting to take their medication, and 81% reported a preference for a treatment with a lower dosing frequency.
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Although the mean number of exacerbations, the mean number of ICU admissions, and the number of intubations were similar in both sexes in the previous year, more females than men previously exacerbated and hospitalized for two times than men. The prolonged length of hospitalization occurred more in women than males in the previous year. This can be interpreted as women having more severe exac- erbations or more instances of hospitalization due to either severity or a different presentation of exacerbation that leads doctors to hospitalize them. Hurst et al showed that the main trigger that predicts the future exacerbation was previous exacerbation history. 36 Our results led to the question if sex
with the natural logarithm of the total time at risk in years as offset variable and the number of exacerbations as out- come. The time at risk was defined as total time in the study, which was shorter than the duration of the study for patients who dropped out or died before the end of the study. The estimated regression coefficients for the predictors were transformed into incidence rate ratio (IRR) by taking the exponent of the estimated coefficient. All variables included as predictors were measured at baseline. The five different prediction models varied in the number of predictors and the type of model used. The first two prediction models were pre-specified and included the same predictors for all data sources. For the first model, groups were asked to estimate a model including the predictors FEV 1 % predicted at baseline and treatment for the two trials, that is, RECODE and UPLIFT. For the second model, groups were asked to include the same patient and clinical parameters as in a previously published prediction model by Briggs et al, 16
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This report highlights a number of points that will be important for future clinical studies of the relationship between stress and asthma. Firstly, there is a need for prospective studies of sufficient size and duration to allow more detailed investigation of both the short term effects of stress on asthma and airway function, evident within days, and the longer term effects evident weeks to months later. Such studies should be analysed using statistical techniques that can allow detailed investigation of the time course of measured outcomes. Future studies will also need to distinguish between stimuli or events that cause stress and those more likely to be temporarily increasing physiological arousal, and to consider factors such as duration of the stress and levels of chronic adversity.
The initial approach to COPD therapy (Table 1) is bronchodilation, achieved through the use of short- or long-acting muscarinic (anticholinergic) antagonists or b-agonists. Short-acting agents can relieve dyspnea symptoms and improve quality of life. They are usu- ally used first in mild COPD. Long-acting agents relieve dyspnea symptoms and improve quality of life, and also reduce the risk of exacerbations and hospitalizations (eg, tiotropium reduces exacerbations by 29% versus placebo, and reduces the odds of hospitalization by 66% versus ipratropium). 6,7 As COPD severity and functional
Methods: LifeLink™ Health Plan Claims Database was used to identify patients diagnosed with COPD who initiated roflumilast (roflumilast group) or $3 other COPD maintenance drugs (non-roflumilast group) from May 1, 2011 to December 31, 2012. Patients must have been enrolled for 12 months before (baseline) and 3 months after (postindex) the initiation date, $40 years old, not systemic corticosteroid dependent, and without asthma diagnosis at baseline. Difference-in-difference models compared change from baseline in exacerbations, HCRU (office, emergency visits, and hospitalizations), and total costs between groups, adjust- ing for baseline differences.
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the present study to observe moderate and severe exacer- bations 1 year before and after baseline to investigate the characteristics of Japanese COPD patients who were frequent exacerbators. Based on exacerbations during the previous year, we found that frequent exacerbators were more likely to be female, have a lower body mass index, have a signifi- cantly lower FEV 1 predicted, have a higher mMRC-scale grade (lower exercise tolerance), and have a lower total CAT score (lower HRQoL). We also found that the char- acteristics of frequent exacerbators were similar between Japanese and Westerners, except for body mass index, as reported previously. 12,16,32 Interestingly, univariate analysis
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exacerbations/year based on one single study. However, this comparison was reported as non-significant by the original authors and may be significant in our analyses because of the approximations we had to use. In addi- tion, a second study reporting a non-significant differ- ence but not detailing the results could not be included in the analyses. For these reasons, this result should be treated with great caution.
The importance of RV infections in acute asthma has been seen in other studies where it was associated with 71%– 85% [5,7] of exacerbations, and was also a recognized pathogen for the lower airway . It may be worthwhile to investigate children who wheeze below 3 years for the presence of RV infection. Children with RV-induced wheeze in infancy were 4 times more likely to develop asthma by the age of 6 years than those in whom wheez- ing was associated with other viruses . Researchers at the University of Wisconsin followed high-risk children (with either one or both parents having had allergies or asthma) from birth to six years in the Childhood Origins of Asthma (COAST) study and evaluated them for the presence of specific viruses during wheezing illnesses. Children who had RV and wheezed during the first year of life were nearly three times as likely to have asthma at six years of age, whereas those children with RSV who wheezed did not have an increased asthma risk. The authors concluded that 'wheezing RV illnesses occurring at any time during the first three years of life were associ- ated with a nearly 10-fold increase in asthma risk at six years', making this viral trigger a significant predictor of asthma development in high risk children. . Accord- ing to Johnston and co-workers  viral infection of the upper airways by common cold viruses frequently triggers a response in the lower airways leading to prolonged mor- bidity, particularly in those subjects who have significant pre-existing airway disease. Early detection of RV-induced wheeze in very young children assumes clinical impor- tance and encourages close monitoring because of the increased risk of developing early childhood wheeze. The major viral trigger for paediatric asthma in Trinidad was RV which was not associated with seasonality, sug- gesting that the virus presents a year round risk factor for asthmatic children in Trinidad. In an earlier study we found children with asthma exacerbations reported symp- toms of cold, fever and sore throat that they attributed to a 'cold' in the seven days before visiting the emergency room . These symptoms may have been due to an allergic response mistaken for an infection, or may have been manifestations of a true viral infection. We did not examine children for associated allergic rhinitis which
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Chronic obstructive pulmonary disease (COPD) is a chronic progressive disease which is characterized by an inexorable decline in respiratory function, exercise capacity, and health status. This chronic clinical course of COPD is punctuated by periods of increased symptoms that are termed “acute exacerbations”. Acute exacerbations are significant events in the course of the disease as they accelerate disease progression, impair quality of life, and are the major contributor to morbidity and mortality in COPD. In addition they are the major cause of excess health care costs as they often result in unscheduled health care visits, treatment costs, and hospitalizations. Therefore, preventing exacerbations is a major therapeutic goal that has not been achieved with currently available treatments. The major causes of exacerbations are respiratory infections with both viruses and bacteria. Although a role for infection in both stable COPD and COPD exacerbations has long been established, controversy remains regarding a number of issues including the effect of bacterial infection in stable COPD, the relative contributions of viruses and bacteria in COPD exacerbations, mechanisms of susceptibility to infection, and the role of antibiotics.
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From a functional point of view, patients with bronchiectasis might show a variety of patterns ranging from normal lung function to pathophysiological abnormalities, including obstructive, restrictive, isolated air trapping or mixed patterns [6, 7]. From a clinical point of view, some patients might be paucisymptomatic. In other patients, bronchiectasis may be detected unexpectedly through haemoptysis or pneumonia, whereas others again may have daily symptoms of cough and sputum production with periodic exacerbations . From a microbiological point of view, Pseudomonas aeruginosa and Haemophilus influenzae are the most common bacteria detected in bronchiectatic airways but other pathogens including fungi, mycobacteria and viruses can colonise and/or infect patients with bronchiectasis [9 – 11]. Detected microorganisms and the balance between different microorganisms may vary among different continents and nations as pointed out in a recent paper by C HANDRASEKARAN et al. . Geographic variations in the airway microbiology of
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The non-pleuritic chest pain often came on early in the exacerbation, with 19 subjects (51%) reporting the pain as being present before change in cough, sputum characteristics, or dyspnea. The chest pain tended to persist throughout the exacerbations with some mild fluctuations and it subsided as the patient recovered. There were no clear associated aggravating or relieving factors. Five subjects described non-pleuritic chest pain occurring without an exacerbation; this lasted from 1 to 8 days and settled spontaneously.
Mechanisms involved in infectious COPD exacerbations are not entirely clear. Various cellular types and molecules are involved in its pathogenesis. Importantly, the Th17 profile has been linked as one of the main participants, which involves a complex system of proinflammatory cells and molecules. For these reasons, it is essential to conduct clinical and basic studies to have a broader perspective of the molecular and cellular mechanisms that take place during COPD exacerba- tions, which can compromise the life of patients.
To the best of our knowledge, this is the ﬁ rst study that shows that elderly patients with frequent exacerbations of advanced COPD demand much more health care than elderly patients with frequent exacerbations of CHF do. During the study period, COPD subjects exacerbated sig- ni ﬁ cantly more often than the CHF subjects did and exhib- ited signi ﬁ cantly more hospitalizations and home care due to the urgent need to treat COPD exacerbations. Overall, the intervention supplied – a combination of telemonitoring and HBHC – signi ﬁ cantly reduced hospitalization frequency for both COPD and CHF subjects compared to the status prior inclusion. Considering that COPD subjects were signi ﬁ - cantly younger than CHF subjects were and had signi ﬁ - cantly less comorbidity, the differences described are probably best explained by different disease characteristics and different exacerbation pattern. It might be that most exacerbations of CHF are earlier and easier detected, and further, that deterioration is more easily prevented, and treatment is more ef ﬁ cient compared to exacerbations of COPD. The method of reporting with a digital pen and a Health Diary form were well accepted and easy to handle by patients, and the health care personnel found the web- based telemonitoring system easy to use.
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Other secondary endpoints included: peak FEV 1 and forced vital capacity (FVC); trough FVC; Transitional Dyspnea Index (TDI) focal score; and St George’s Respira- tory Questionnaire (SGRQ) total score at weeks 12 and 26. At all sites, patients used an electronic diary (e-diary) to capture the use of rescue medication, exacerbations, and other symptoms experienced during the study. Exploratory objec- tives included the assessment of health-related quality of life using the COPD assessment test (CAT) score at weeks 12 and 26 and COPD exacerbations that occurred over 26 weeks. The definition of exacerbations and safety assessments are provided in the online Supplementary materials.
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COPD patients may have evidence of chronic lower respiratory tract colonisation with bacteria, but the detection of bacteria in the sputum of patients with COPD does not mean that in general these patients have a higher risk of exacerbations. Older studies did not find differences between the rates of isolation of bacteria from sputum during stable disease and exacerbation . More recent studies found an association between exacerbation and the isolation of a new strain of a bacterial pathogen . In addition, the reported efficacy of long-term antibiotic treatment with macrolides in reducing exacerbation frequency may suggest that bacteria are relevant for the induction of exacerbations, although this is a matter of debate . Viral infections are an even more important risk factor for exacerbations of COPD. A case – control study found viral respiratory pathogens more often in respiratory specimens of hospitalised patients with exacerbated COPD than in control patients (56% versus 19%) . The most common viruses detected were picornaviruses (36%), followed by influenza A (25%), respiratory syncytial virus (22%) and parainfluenza (10%). A review of 24 studies of viral infections in COPD exacerbations (from 2001 to 2015) showed virus detection rates in respiratory specimens of 22–64% . The investigation of the impact of seasonality on COPD exacerbation frequency in the TORCH (Towards a Revolution in COPD Health) study showed an almost two-fold increase in the winter months in both the northern and southern regions, while no seasonal pattern occurred in the tropics . The authors suspected increased exposure to viral infections to be a potentially contributing factor.
Overall, the outcome among omalizumab-treated patients was better than the placebo group as evalu- ated by reduction in BDP dosage, percentage of pa- tients who discontinued BDP, incidence and fre- quency of asthma exacerbations, participants’ and investigators’ global evaluations of treatment effec- tiveness, dosage of rescue medication, missed school days, and unscheduled medical contacts attributable to asthma-related medical problems. The frequency and types of all adverse events, judged treatment related or not, were similar in the omalizumab group and the placebo group. The majority of adverse events were mild to moderate in severity. Study- drug–related adverse events occurred more fre- quently in the omalizumab group than in the placebo group, but were relatively infrequent in both groups. The several cases of urticaria were nearly all mild or moderate.
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