Jure Manfreda

Antibiotic Therapy in Exacerbations of Chronic Obstructive Pulmonary Disease

The effects of broad-spectrum antibiotic and placebo therapy in patients with chronic obstructive pulmonary disease in exacerbation were compared in a randomized, double-blinded, crossover trial. Exacerbations were defined in terms of increased dyspnea, sputum production, and sputum purulence. Exacerbations were followed at 3-day intervals by home visits, and those that resolved in 21 days were designated treatment successes. Treatment failures included exacerbations in which symptoms did not resolve but no intervention was necessary, and those in which the patients condition deteriorated so that intervention was necessary. Over 3.5 years in 173 patients, 362 exacerbations were treated, 180 with placebo and 182 with antibiotic. The success rate with placebo was 55% and with antibiotic 68%. The rate of failure with deterioration was 19% with placebo and 10% with antibiotic. There was a significant benefit associated with antibiotic. Peak flow recovered more rapidly with antibiotic treatment than with placebo. Side effects were uncommon and did not differ between antibiotic and placebo.

The Effects of a Smoking Cessation Intervention on 14.5-Year Mortality: A Randomized Clinical Trial

Context Although there are many health benefits for smokers who stop smoking, we still lack evidence from randomized, controlled trials that smoking cessation programs reduce mortality. Contribution In this randomized, controlled trial of a 10-week-long smoking cessation intervention in 5887 smokers with asymptomatic airway obstruction, 14-year mortality rates were higher in the usual care group than in the smoking cessation group (hazard ratio, 1.18 [95% CI, 1.02 to 1.37]). The mortality benefit was greatest among the 21.7% of the intervention group who actually managed to quit smoking. Implications Smoking cessation programs substantially reduce mortality even when only a minority of patients stop smoking. The Editors Smoking cessation almost certainly has beneficial effects on subsequent mortality (1). However, the strongest support for this assertion comes from cohort studies, where smokers and quitters were self-selected. Results from randomized trials, which avoid the selection issue, have largely been disappointing because mortality benefits have not been clear or have not been clearly attributable to smoking cessation (1). The Lung Health Study (LHS) was a randomized clinical trial of smoking cessation and inhaled bronchodilator (ipratropium) therapy in smokers 35 to 60 years of age who did not consider themselves ill but had evidence of mild to moderate airway obstruction (2). Individuals with serious disease, hypertension, obesity, or excessive alcohol intake were excluded. The primary research questions were whether a smoking cessation program and use of inhaled ipratropium would decrease the rate of decline of lung function and would affect mortality and morbidity over 5 years. These results have been reported elsewhere (3, 4). The smoking cessation program was associated with cumulative reduced decline in lung function (FEV1) that was largest in participants who stopped smoking early in the study; inhaled ipratropium produced a small noncumulative increase in FEV1 that disappeared when the drug was withdrawn (3). Intention-to-treat analysis after 5 years did not reveal differences in morbidity or mortality among treatment groups (4), although subgroup analysis showed that smoking cessation was associated with significant reductions in fatal or nonfatal cardiovascular disease and coronary heart disease. This paper reports the effects of the study intervention on mortality in LHS participants 14.5 years after randomization. Methods The design of the LHS has been described in detail elsewhere (2). The participants, all volunteers, were smokers who did not consider themselves ill but had evidence of airway obstruction and little evidence of other disease. Researchers recruited participants from the community using a wide variety of techniques (5). In 10 clinical centers, 5887 participants were randomly assigned to 3 groups. Two special intervention groups received an intensive 10-week smoking cessation program. Briefly, the cessation intervention consisted of a strong physician message and 12 two-hour group sessions, using behavior modification and nicotine gum. Quitters entered a maintenance program that stressed coping skills. One special intervention group also received ipratropium, while the other received a placebo inhaler. A third group received usual care. About 75% of the original participants were followed continuously for the subsequent 10 years by biannual telephone contacts and 1 clinic visit at approximately 11 to 12 years after randomization (6). Telephone contacts served to check smoking status, morbidity, and mortality and were not part of the intervention. All study participants provided written informed consent for the original LHS before beginning the study. The consent documents stated that smoking increases the risk for chronic obstructive pulmonary disease, respiratory tract cancer, and cardiovascular disease and that smoking cessation would decrease such risks. Additional written informed consent was obtained from persons who participated in the biannual telephone calls. Institutional review boards at each of the 10 clinical centers and the coordinating center approved the study design and consent documents. When biannual phone calls revealed a participant death, staff attempted to collect death certificates, autopsy reports, relevant medical records, and interviews with attending physicians or eyewitnesses. An independent mortality and morbidity review board examined these data and classified causes of death. In addition, a National Death Index review provided date and cause of death for all U.S. study participants through the end of 2001. Vital status at 31 December 2001 or 14.5 years, whichever was earlier, was successfully determined for 98.3% of all participants; missing individuals were Canadians who had been lost to follow-up and were not accessible through the National Death Index. Mortality end points were classified in 7 categories: coronary heart disease, cardiovascular disease including coronary heart disease, lung cancer, other cancer, respiratory disease excluding lung cancer, other, and unknown. The other category included but was not limited to liver disease, kidney disease, sepsis, accidents, suicide, and AIDS. Analyses were performed on an intention-to-treat basis, comparing the special intervention group with the usual care group. The special intervention group was a combination of the groups originally assigned to receive inhaled ipratropium or placebo therapy. Both of these groups, which were very similar at baseline, received the smoking cessation program and exhibited similar rates of smoking cessation (3). Participants were also divided into 3 groups according to smoking history during the initial 5 years of the trial. Sustained quitters were participants who stopped smoking in the first year after randomization and maintained biochemically validated abstinence (3) throughout follow-up. Continuing smokers were participants who reported smoking at all follow-up visits. Intermittent quitters were participants who reported smoking at some but not all of their follow-up visits or during the time between visits. Statistical Analysis Baseline differences between the special intervention and usual care groups were tested by using t-tests for continuous variables and chi-square statistics for categorical variables. Cause-specific death rates and times to events were analyzed by using the KaplanMeier product-limit method (7). Survival was compared among groups by using the log-rank test. Hazard ratios and adjusted analyses were obtained by using the Cox proportional hazards model. Interactions were assessed by comparing hierarchically related proportional hazards models. All P values result from 2-sided tests; no adjustments were made for multiple comparisons. Role of the Funding Source This study was funded by a contract and grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health. The funding source had a role in the design of the study and approved the manuscript before it was submitted for publication. Results Baseline characteristics of LHS participants are shown in Table 1. Most were middle-aged; smoked heavily; and had substantial smoking histories, airway obstruction (FEV1FVC ratio 70%), and borderline low FEV1 values. On average, participants were normotensive and had normal body mass indices. Most participants were of white ethnicity; 37% were women. The average participant had some postsecondary education and did not drink heavily. The special intervention and usual care groups did not significantly differ at baseline, except in percentage of participants who were married, which was higher in the special intervention group (P= 0.04). Smoking status after the first 5 years differed significantly between treatment groups (P 0.001). Among special intervention participants and usual care participants, respectively, 21.7% and 5.4% were sustained quitters, 29.3% and 23.3% were intermittent quitters, and 49.0% and 71.3% were continuing smokers. Table 1. Baseline Characteristics of Lung Health Study Participants There were 731 known deaths among LHS participants, as shown in Table 2. Lung cancer was the most common cause of death (n= 240 [33%]). Coronary heart disease accounted for 77 deaths (10.5%), and cardiovascular disease including coronary heart disease accounted for 163 deaths (22%). One hundred fifty-four participants (21%) died of cancer of organs other than the lung. Deaths due to respiratory disease other than cancer were relatively uncommon (n= 57 [7.8%]). The cause of death was unknown in only 17 participants (2.3%). Mortality did not significantly differ between the special intervention groups originally assigned to ipratropium or placebo (Table 2). Table 2. Causes of Death by Treatment Group Figure 1 shows all-cause survival rates in the 2 treatment groups. Death rates were significantly higher in the usual care group than in the special intervention group (10.38 per 1000 person-years vs. 8.83 per 1000 person-years; P= 0.03). The hazard ratio for mortality in the usual care group was 1.18 (95% CI, 1.02 to 1.37) compared with the special intervention group. Figure 2 shows categorical causes of death in the 2 treatment groups. In all categories except other, death rates were higher in the usual care group than in the special intervention group, but the difference was significant only for deaths from respiratory diseases not related to lung cancer (1.08 per 1000 person-years vs. 0.56 per 1000 person-years; P= 0.01). Figure 1. All-cause 14.5-year survival. P Figure 2. Mortality rates at 14.5 years by cause. When survival was analyzed according to smoking habit, it differed significantly between groups (P< 0.001), even after adjustment for baseline differences (data not shown). Mortality was 6.04 per 1000 person-years in sustained quitters, 7.77 per 1000 person-years in intermittent quitters, and 11.09 per 1000 p

Steroid Response in Stable Chronic Obstructive Pulmonary Disease

We compared a 2-week course of 32 mg/d methylprednisolone with placebo in a double-blind crossover trial in 46 well-characterized patients with stable chronic obstructive pulmonary disease. Placebo and steroid trials were separated by 2 weeks when no tablets were given. Response was assessed by measuring forced expiratory volume in 1 second (FEV1.0). Placebo responses were normally distributed (mean, 0.8% change in FEV1.0; range, -30% to 33%). Six patients showed a greater than 50% increase of FEV1.0 in response to steroid; a seventh showed a 36% increase and an eighth, a 29% increase. Because of these patients the group as a whole showed a significantly greater FEV1.0 after steroid than after placebo. The eight steroid responders did not differ from nonresponders in age, sex, smoking history, or duration and intensity of symptoms including wheeze. Baseline lung function and eosinophilia of blood or sputum did not differ between the two groups. Patients who responded to steroids also responded to inhaled beta agonists: Acute bronchodilator response averaged 25% in steroid responders and 13% in nonresponders, a difference that was statistically significant although there was overlap between the two groups.

Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children

We studied a cohort containing 368 children at high risk of developing atopy and atopic disorders and 540 parents of those children to investigate whether the IL13 Arg130Gln and C−1112u2009T polymorphisms were associated with these outcomes. We also investigated whether haplotypes consisting of any two polymorphisms of IL13 Arg130Gln, IL13 C−1112u2009T and IL4 C−589u2009T were associated with these phenotypes. In 288 white children, the IL13 130Gln allele was associated with atopy (RR=1.9, P=0.047), and with atopic dermatitis (RR=2.5, P=0.014). The associations were confirmed using a family-based test of association (P=0.027 and 0.030, respectively) in all subjects. In white subjects there were associations of haplotypes consisting of IL13 Arg130Gln and IL4 C−589u2009T with atopic dermatitis (P=0.006) and with atopy (P=0.009). Our data suggest that the IL13 Arg130Gln polymorphism and haplotypes consisting of IL13 Arg130Gln and IL4 C−589u2009T were associated with the development of atopy and atopic dermatitis at 24 months of age.

The Natural History of Primary First-Degree Atrioventricular Heart Block

The long-term prognosis of first-degree heart block in the absence of organic heart disease has not been clearly defined. We addressed this question in a 30-year longitudinal study of 3983 healthy men. We identified 52 cases that were present on entry into the study and 124 incident cases during follow-up. The incidence rose steadily after age 40 and was 1.13 per 1000 person-years over the entire period. Two thirds of the cases had only moderate prolongation of the PR interval (0.22 to 0.23 second). We compared four age-matched controls with each case for histories of scarlet fever, rheumatic fever, diphtheria, smoking, blood pressure, and body-mass index. No significant differences (P greater than 0.05) were found. Likewise, mortality from all causes did not differ between cases and controls. Although somewhat higher rates of morbidity and mortality from ischemic heart disease were observed in the cases than in the controls, the differences were not significant. Progression to higher grades of heart block occurred in only two cases. In view of the prognostic findings and the rare occurrence of advanced degrees of heart block, we conclude that primary first-degree heart block with moderate PR prolongation is a benign condition. This conclusion may not apply, however, to persons with more marked prolongation of the PR interval, a very rare condition.

The relationship between smoking and total immunoglobulin E levels

Results of skin testing to common allergens, total serum IgE levels, and the responses to a respiratory questionnaire were obtained for 1768 individuals participating in a survey of a rural population. The geometric mean total IgE levels in a group of subjects without skin-test reactions and with no histories of asthma or hay fever was 14.8 U/ml for men and 11.9 U/ml for women. When individuals were classified according to skin reactivity and smoking history there was a significant difference in IgE levels among nonsmokers, exsmokers, and smokers, with smokers having the highest levels. The percentage of subjects with elevated total IgE levels was higher in smokers than in nonsmokers regardless of skin reactivity to common allergens. Among smokers there was no relationship between intensity and duration of smoking and IgE levels. Among exsmokers IgE levels tended to be lower in those who had stopped smoking earlier.

Tuberculosis as a Primary Cause of Respiratory Failure Requiring Mechanical Ventilation

Tuberculosis as a primary cause of respiratory failure requiring mechanical ventilation (TBMV) is an uncommon occurrence. Over a 10 yr period in the province of Manitoba, Canada (population 1,091,942 in 1991), 13 patients with TBMV were identified. Non-drug-resistant M. tuberculosis was isolated from each case. The patients fell into two categories: miliary or disseminated tuberculosis (n = 7) and tuberculous pneumonia (n = 6); eight developed ARDS (adult respiratory distress syndrome) and another two probable ARDS. The hospital mortality for TBMV was compared with that for mechanically ventilated nontuberculous pneumonia and ARDS patients. Hospital mortality for patients with TBMV (69%, nine of 13) was significantly worse than hospital mortality for patients with nontuberculous pneumonia requiring mechanical ventilation (36%, 34 of 94; p < 0.025) and similar to the hospital mortality for patients with ARDS of any cause (56%, 15 of 27; p > 0.10). APACHE II scores for all groups of patients were similar. Compared with patients with tuberculous pneumonia, patients with miliary or disseminated tuberculosis were significantly more likely to develop TBMV (18.9 versus 0.8%, p < 0.0001). Despite the availability of effective antituberculous drugs, TBMV is often associated with ARDS and carries a similarly high mortality rate. Among patients with pulmonary tuberculosis, those with miliary or disseminated disease are especially prone to develop TBMV.

Serum total immunoglobulin E levels in Canadian adults

A history of respiratory and allergic disorders was obtained in a white, rural population with ages 20 to 65 yr. Allergy skin testing was performed, and total IgE was measured by PRIST method. One thousand eight hundred and fourteen subjects were studied. Those subjects with positive allergic skin reactions and a history of allergic disorders and smoking were excluded to provide a reference group to derive normal values of total IgE. The mean level of the total IgE of this reference group was 12.1 U/ml. The upper limit of the normal range of total IgE levels was estimated at 87.3 U/ml. IgE levels did not differ between the sexes or with age in our adult population.

The Natural History of Electrocardiographic Preexcitation in Men: The Manitoba Follow-up Study

OBJECTIVEnTo examine the natural history of preexcitation occurring on the routine electrocardiogram (ECG).nnnDESIGNnA longitudinal cohort study of 3983 originally healthy men followed prospectively for 40 years.nnnSETTINGnFree-living (community-dwelling) study members residing predominantly in Canada.nnnPARTICIPANTSnNineteen male study members with preexcitation occurring during routine examination in the 40-year follow-up of the Manitoba Follow-up Study.nnnMEASUREMENTSnRoutinely requested clinical examinations and ECGs, supplemented by information supplied by the study member or his physician.nnnMAIN RESULTSnTen study members were found to have preexcitation at enrollment, for a prevalence of 2.5 per 1000 (95% CI, 1.2 to 4.6). A delta wave was first detected during follow-up in an additional nine study members. Seventeen of 19 study members did not have the delta wave at some later time, and preexcitation was intermittently present in most of these members. Over time there was a loss of preexcitation, with 15 of 19 study members no longer exhibiting a delta wave by the end of follow-up. Five of 11 study members with symptoms had physician confirmation of an arrhythmia. Fourteen study members remain alive, and none of the five deaths was attributed to preexcitation.nnnCONCLUSIONSnPreexcitation found on routine ECG in our originally healthy male study group did not confer excess morbidity or mortality, even in those study members who developed symptomatic arrhythmias. Most preexcitation was intermittent and disappeared over time.

Cord blood IgE: its determinants and prediction of development of asthma and other allergic disorders at 12 months

BACKGROUNDnThe value of cord blood IgE in predicting the development of asthma and other IgE-mediated allergic diseases is unclear.nnnOBJECTIVEnThe purpose of this study is twofold: (1) to determine factors affecting cord blood IgE level and (2) to determine whether cord blood IgE predicts the development of asthma and other IgE-mediated allergic diseases in high risk (defined as those with at least one first degree relative with asthma or 2 first degree relatives with other IgE-mediated allergic diseases) infants at 12 months.nnnMETHODSnThe study utilized cord blood obtained from a group of high risk infants who took part in a randomized controlled trial to assess the effectiveness of an intervention program in the primary prevention of asthma and other IgE-mediated allergic diseases. Total IgE and cotinine in the cord blood were measured. Assessment of the infants was done at 12 months for these diseases.nnnRESULTSnSixty-four (17.8%) infants had detectable total IgE in cord blood >0.5 kU/L. The proportion of infants with elevated cord blood IgE was significantly higher among nonwhites, birth during winter months, and those with a maternal history of asthma. There was no correlation between cord blood IgE and cord blood cotinine level. Cord blood IgE was found to be a significant predictor for the development of urticaria due to food allergy but not for other outcomes.nnnCONCLUSIONnBoth genetic and environmental risk factors play a role in determining the level of IgE in cord blood. Cord blood IgE was a significant risk factor for the development of urticaria due to food allergy at 12 months of life. As urticaria due to food allergy is a prodrome for anaphylaxis, measurement of IgE in cord blood may be indicated in infants at high risk for developing allergic diseases so that preventive measures can be applied.