Predicts Incident Airflow Limitation and Mortality Risk

ONLINE REPOSITORY

Chronic Bronchitis Before Age 50 Years

Predicts Incident Airflow Limitation and Mortality Risk

Methods

Study population

The Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD) is a population-based prospective cohort study initiated in Tucson, AZ in 1972. Details of the enrollment process have been previously reported(1). At the enrollment survey, 2,754 white participants (age range: 6 to 95 years) completed both a standardized respiratory questionnaire and spirometric lung function tests with a pneumotachygraphic device. Twelve additional follow-up surveys were completed approximately every two years between 1974 and 1996. All participants were eligible to take part in the first 11 follow-up surveys, whereas the last follow-up survey was conducted on selected subgroups based on previous reports of respiratory symptoms/disease or residence in Arizona. During each follow-up survey, participants completed questionnaires and, with the exception of survey 4, performed follow-up spirometric lung function tests. Protocols for lung function testing were consistent across surveys and ATS guidelines were integrated into the protocols after their publication in 1979(2). Methods used to perform lung function tests before 1979 are described elsewhere(3).

Definitions of additional covariates from the enrollment survey

Before lung function tests, participants had their weight and height measured by the study nurses with standardized equipment. Body Mass Index (BMI) was computed as weight in Kg divided by the square of height in meters.

Skin prick tests were completed for five allergens: house dust; Bermuda grass; tree mix; weed mix; and Dematiaceae mold mix. Positive skin prick tests were defined as a wheal at least two mm larger than the control wheal for at least one of the five tested allergens.

Measurement of serum total IgE were carried out in duplicate according to the paper radioimmunosorbent test (PRIST) (Pharmacia Diagnostics, Piscataway, NJ) method(4).

Eosinophils were measured as percentages from stained slides and blood eosinophilia was defined as eosinophils > 4%.

Assessment of outcomes

Incident airflow limitation was defined as an FEV1/FVC ratio < 70% in any of the follow-up surveys (up to 1996). Because the FEV1/FVC ratio declines significantly with aging, sensitivity analyses were also repeated after defining incident airflow limitation as the first survey with an FEV1/FVC ratio below the lower limit of normal(5). Twenty-six participants whowere eligible for this study but had FEV1/FVC ratio below the lower limit of normal at baseline were excluded from these sensitivity analyses.

Statistical analyses

The relation of chronic bronchitis to incident airflow limitation and to all-cause mortality was investigated in Cox proportional hazards models. In the analyses on incident airflow limitation, time to event was defined as the time between enrollment and the first survey with an FEV1/FVC ratio < 70% for incident cases and between enrollment and the last completed survey for subjects who did not develop airflow limitation. In the analyses on mortality, time to event was defined as the time between enrollment and date of death for deceased cases and between enrollment and January 1st, 2005 for subjects who were still alive as of that date.

In Cox models, effect modification by smoking and age was tested by including interaction terms between chronic bronchitis and smoking (ever smoked ≥ 1 pack-year versus never smoked 1 pack-year) and between chronic bronchitis and age (< 50 years versus ≥ 50 years). Linear contrasts were used to estimate from the same models the Hazard Ratios associated with chronic bronchitis in the different smoking and age strata. The age cut-off of < 50 years versus ≥ 50 years was selected based on the median age of the study population (50 years).

The study was approved by the Human Subjects Committee at the University of Arizona and all participants provided informed consent.

Results

Additional Tables

Table E1. Cox Proportional Hazards models to predict incident airflow limitationincluding also 145 subjects with physician-confirmed diagnosis of asthmawho were excluded from the main analyses. All predictors were measured at the enrollment survey (1972-73). N is 1555(two subjects had missing information).

MULTIVARIATE
Model 1 / MULTIVARIATE
Model 2
HR* / 95% CI / P / HR* / 95% CI / P
Sex: male / 1.16 / (0.95 – 1.43) / 0.15 / 1.12 / (0.91 – 1.37) / 0.29
Age in years / 1.03 / (1.02 – 1.04) / <0.001
Formal Education: > 12 years / 0.90 / (0.74 – 1.11) / 0.34 / 0.85 / (0.69 – 1.05) / 0.13
FEV1/FVC ratio in % / 0.90 / (0.88 – 0.91) / <0.001 / 0.89 / (0.88 – 0.91) / <0.001
Packyears
< 1 pack-year
1-19.9 pack-years
20-49.9 pack-years
≥ 50 pack-years / Ref.
1.42
1.63
1.99 / (1.09 – 1.85)
(1.26 – 2.11)
(1.41 – 2.80) / 0.01
<0.001
<0.001 / Ref.
1.26
1.61
1.99 / (0.97 – 1.65)
(1.24 – 2.09)
(1.40 – 2.81) / 0.08
<0.001
<0.001
Asthma / 2.10 / (1.60 – 2.75) / 0.001 / 2.10 / (1.60 – 2.76) / <0.001
Chronic Bronchitis / 1.41 / (1.05 – 1.89) / 0.02 / 2.15‡ / (1.39 – 3.32) / 0.001
Categorical Age: ≥ 50 years / 2.16 / (1.69 – 2.76) / <0.001
Interaction Term:
Chronic Bronchitis * Age ≥ 50 years / 0.46 / (0.26 – 0.82) / 0.008

* Hazard Ratios

‡This Hazard Ratio represents the increase in risk associated with chronic bronchitis among subjects < 50 years old

Table E2. Cox Proportional Hazards models including chronic cough instead of chronic bronchitis to predict incident airflow limitation. All predictors were measured at the enrollment survey (1972-73). N is 1410 (two subjects had missing information).

MULTIVARIATE
Model 1 / MULTIVARIATE
Model 2
HR* / 95% CI / P / HR* / 95% CI / P
Sex: male / 1.15 / (0.92 – 1.44) / 0.23 / 1.12 / (0.89 – 1.40) / 0.34
Age in years / 1.03 / (1.02 – 1.04) / 0.001
Formal Education: > 12 years / 0.86 / (0.69 – 1.08) / 0.20 / 0.81 / (0.65 – 1.02) / 0.07
FEV1/FVC ratio in % / 0.89 / (0.88 – 0.91) / <0.001 / 0.89 / (0.87 – 0.91) / <0.001
Packyears
< 1 pack-year
1-19.9 pack-years
20-49.9 pack-years
≥ 50 pack-years / Ref.
1.51
1.73
2.24 / (1.12 – 2.02)
(1.31 – 2.29)
(1.54 – 3.26) / 0.006
<0.001
<0.001 / Ref.
1.32
1.71
2.21 / (0.99 – 1.77)
(1.29 – 2.27)
(1.52 – 3.23) / 0.06
<0.001
<0.001
Chronic Cough / 1.48 / (1.12 – 1.95) / 0.006 / 2.33‡ / (1.52 – 3.57) / <0.001
Categorical Age: ≥ 50 years / 2.34 / (1.78 – 3.08) / <0.001
Interaction Term:
Chronic Bronchitis * Age ≥ 50 years / 0.44 / (0.25 – 0.76) / 0.003

* Hazard Ratios

‡This Hazard Ratio represents the increase in risk associated with chronic coughamong subjects < 50 years old

Additional Figures

Figure E1.Unadjusted Kaplan-Meier survival curves for incident airflow limitationincluding also 145 subjects with physician-confirmed diagnosis of asthma who were excluded from the main analyses. Figure E1a shows survival curves for the four groups generated by the combination of smoking status (ever smoked at least one pack-year versus never smoked one pack-year) and chronic bronchitis at enrollment. Figure E1b shows survival curves for the four groups generated by the combination of age (< 50 years versus ≥ 50 years) and chronic bronchitis at enrollment. N is 1557.

Figure E2.Unadjusted Kaplan-Meier survival curves for incident airflow limitation. Figure E2a shows survival curves for the four groups generated by the combination of smoking status (ever smoked at least one pack-year versus never smoked one pack-year) and chronic cough at enrollment. Figure E2b shows survival curves for the four groups generated by the combination of age (< 50 years versus ≥ 50 years) and chronic cough at enrollment.

References

1.Lebowitz MD, Knudson RJ, Burrows B. Tucson epidemiologic study of obstructive lung diseases. I: Methodology and prevalence of disease. Am J Epidemiol 1975;102(2):137-52.

2.ATS statement--Snowbird workshop on standardization of spirometry. Am Rev Respir Dis 1979;119(5):831-8.

3.Knudson RJ, Slatin RC, Lebowitz MD, Burrows B. The maximal expiratory flow-volume curve. Normal standards, variability, and effects of age. Am Rev Respir Dis 1976;113(5):587-600.

4.Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 1989;320(5):271-7.

5.Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 1999;159(1):179-87.