Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in industrialised societies.1 Ecological and individual data studies in adults and children have all pointed to early life origins of COPD.2 3 Furthermore, individuals with early life lung impairment are also at higher risk of cardiovascular disease (CVD), although the mechanisms that relate these conditions are unclear.4 Studies investigating early life associations with disease in adults are often based on recall of their past childhood illnesses with the potential for recall bias of exposures among adults suffering from respiratory diseases in adulthood.3 Reports from parents on illnesses in their offspring are also often misclassified.3 Follow-up studies of children have examined whether lung function in adulthood is related to early life exposures but few have sufficient long term follow-up to investigate whether and how these affect the pattern of adult disease risk.2 Observational studies of historical cohorts can evaluate these hypotheses and report long term follow-up of cause specific disease risk. Although residual confounding due to the limitations of historically collected data can limit inferences based on these data, evaluating the specificity of associations between exposures and different causes of death can nevertheless help to identify potential confounders. The objective of this study was to investigate whether individuals with a history of bronchitis, pneumonia or asthma in early life have a higher mortality and/or morbidity risk in adulthood in a historical cohort of male students who attended Glasgow University between 1948 and 1968. We additionally investigated whether a higher haematocrit among people with impaired lung function could explain a potential association between respiratory disease and CVD mortality.

METHODS Detailed information on the Glasgow Alumni Cohort is available elsewhere.5 Briefly, between 1948 and 1968, students in Glasgow University were invited to attend a health examination carried out by physicians. All data were recorded using a standard questionnaire. Information on sociodemographic characteristics, health behaviours and past medical history, including bronchitis, asthma, pneumonia and childhood diseases, were obtained. Data collected during the physical examination included measurements of height, weight, blood pressure and haemoglobin levels. A total of 11756 men, representing about 50% of the complete male student population, participated in the study. Since 1998, 84.5% (n = 9932) of the male cohort has been successfully traced through the National Health Service Central Register, which provides continuous updates on the date and cause of death for members of the cohort. Only men are included in this report because of the small number of women attending university at that time and the low number of female deaths. Students aged more than 30 years at the time of examination (n = 382) and those with an unknown date of censoring (n = 6) were excluded from these analyses, which comprised a total of 9544 students. Between 2001 and 2002, members of the cohort who were still alive (n = 8410) were contacted through a postal questionnaire that sought to determine additional childhood and adulthood information. About 50% of the male cohort (n = 4044) responded to this follow-up. The authors obtained ethics approval for the follow-up study and informed consent from participants. Variable description Every student was asked about his past medical history. Among other diseases, the physician recorded whether the student had had bronchitis, asthma, pneumonia, hay fever, eczema and/or urticaria and a number of childhood infections, including mumps, measles, rubella, chickenpox, whooping cough, scarlet fever, diphtheria and jaundice. These were ticked in the questionnaire if the student reported ever having had them. The number of childhood infections was summed and this was coded as an ordinal variable from 0 to 8. Socioeconomic position at university was assigned by coding father’s occupation into social class, a five point scale from I (highest social class) to V (lowest social class), using the Registrar General’s classification.6 7 Age (years), number of siblings, whether the student was first born, height (cm), body mass index (BMI) (kg/m2), systolic and diastolic blood pressure (mm Hg) and smoking (none versus moderate or heavy) were considered as potential confounders. Haemoglobin levels were also measured using two techniques throughout the study period (Haldane and Sahli methods) and these were analysed separately. We used the first non-missing haemoglobin value for each student (some students had haemoglobin levels measured at subsequent medical examinations). For the analysis, age specific (in years) z scores of haemoglobin levels were calculated. Among former students who participated in the postal follow-up in 2001–2002, the following adult characteristics were obtained through a self-response questionnaire: height (cm), BMI (kg/m2), leg length (cm), adult socioeconomic position based on the main occupation held (I to V), smoking (never versus former or current), physical activity (no exercise versus exercise long enough to work up a sweat or a rapid heart beat at least once a week), doctor’s diagnosis of CVD (angina, stroke or heart attack), high cholesterol, high blood pressure, asthma, bronchitis or emphysema, cancer (lung, bowel/colon, prostate or other) and diabetes. All disease variables were coded as present or absent. The MRC Respiratory Questionnaire was used to define chronic phlegm (“Do you usually bring up phlegm in the morning on most days for as much as 3 months in winter?”) and dyspnoea, which were both coded as present or absent.8 In addition, respondents reported their birth weight. Cause specific mortality Date for death for all causes was recorded. ICD9 and ICD10 codes were used to group cause specific mortality: respiratory disease (ICD9: 460–519; ICD10: J40–J47); COPD mortality included bronchitis and emphysema (ICD9: 490–492; ICD10: J40–J44); CVD (ICD9: 390–459; ICD10: I00–I99, G45); coronary heart disease (CHD) (ICD9: 410–414, 429.2; ICD10: I20–I25, I51.6); stroke, excluding subarachnoid haemorrhage (ICD9: 431–438; ICD10: I61–I69, G45); all cancer (ICD9: 140–208; ICD10: C00–C97); lung cancer (ICD9: 162; ICD10: C34); prostate cancer (ICD9: 185; ICD10: C61); colon cancer (ICD9:153; ICD10: C18); and external causes of death, including accidents, suicide and violence (ICD9: 800–999, E800–E999; ICD10: S00–T98, V01–Y89). Statistical analysis Descriptive characteristics are presented as age and year of survey (if specified) adjusted through multivariable regression analysis. A smoothed trend in the proportion of students with a medical history of bronchitis, pneumonia or asthma was obtained by calculating a locally weighted regression (lowess function in Stata) with a bandwidth of 0.8. Cox proportional hazards models, with age as the time scale, were used to estimate the risk of overall and cause specific mortality associated with a medical history of bronchitis, asthma and pneumonia in early life, adjusting for potential confounders. The assumption of proportional hazards was graphically investigated with log–log plots and formally tested with the Schoenfeld test. If the assumption was violated because of a confounder variable, the analysis was carried out stratifying for this variable. In stratified analysis, in the context of Cox analysis, the baseline hazards are allowed to differ across the stratifying variable but the coefficient of the exposure variable is the same across strata. The main disadvantage of a stratified model is that the effect of the stratifying variable is not estimated, but its effects are controlled for without assuming proportional hazards. This was the case for smoking and CVD and CHD mortality. The assumption of proportionality was violated for respiratory disease and COPD mortality associated with a history of asthma because of a different risk in deaths occurring at a young age. Thus only those dying after the age of 50 years were considered for this specific cause of death; in this group, the proportionality assumption held. Continuous variables were centred at their mean value. Participants with missing information on confounders, such as smoking status, height, BMI and systolic blood pressure at university (n = 556), were excluded. Additional analysis adjusting for haemoglobin level—a measure of haematocrit level—was carried out to assess the hypothesis that higher haematocrit among people with impaired lung function could explain a potential association between respiratory diseases and CVD mortality. Logistic regression analyses were carried out to quantify the association between a medical history of respiratory disease in early life and adult symptoms of chronic phlegm, dyspnoea and doctor’s diagnosis of several chronic diseases among the subsample that responded to the adult postal questionnaire. Those who did not report their smoking status in adulthood (n = 28) were excluded from this analysis. To control for potential residual confounding caused by smoking, these analyses were repeated among never smokers, defined as those participants who reported being non-smokers at university and also stated being never smokers in adulthood. In addition, Cox analyses were carried out separately for two periods, before and after 1960, to evaluate the influence of a potential misclassification of history of asthma on the results, as the reported history of asthma was decreasing in the Glasgow cohort after 1960 but reports from the literature were pointing to an increase in the prevalence of asthma in the population during this time period.9

RESULTS The proportion of students with a medical history of bronchitis and pneumonia decreased throughout the study period whereas the proportion of those reporting asthma remained fairly constant until the beginning of the 1960s when it also declined (fig 1). Students with a medical history of bronchitis, pneumonia or asthma were more likely to be the firstborn, were slightly thinner and were more likely to have a history of hay fever, eczema and/or urticaria, and reported a higher mean number of childhood infectious diseases (table 1) compared with those who did not have a history of these respiratory ailments. Descriptive characteristics for each respiratory disease category were similar with the exception of moderate or heavy smoking which was more frequent among those who reported a past history of bronchitis. Hay fever and eczema/urticaria were more common among those who reported bronchitis or asthma but not among those who reported a past history of pneumonia. Figure 1 Proportion of students reporting a medical history of bronchitis, pneumonia and asthma at university. Glasgow Alumni Cohort, 1948–1968. Table 1 Age and survey year adjusted early life descriptive characteristics of former students (full sample) by presence or absence of respiratory disease in early life In the subsample that replied to the adult self-reported questionnaire, those individuals who had reported a medical history of bronchitis, pneumonia or asthma at university were slightly older than those without such a medical history (table 2). A higher proportion of them reported chronic phlegm and dyspnoea, or had been given a doctor’s diagnosis of asthma and bronchitis and/or emphysema. Among former students who reported asthma in early life, 71.7% reported a doctor’s diagnosis of asthma whereas among those who did not have asthma in early life 5.8% reported a doctor’s diagnosis of asthma (p<0.001). There were no differences in the proportion of other chronic diseases or risk factors such as CVD, hypertension, high cholesterol, diabetes or cancer. These characteristics were similar when each respiratory disease was analysed separately (results not shown). Table 2 Age adjusted descriptive characteristics of former students who responded to the adulthood postal questionnaire, by presence or absence of respiratory disease in early life During the study follow-up there were 1553 deaths (17.3%): 6.3% respiratory disease deaths, 38.6% CVD deaths, 35.4% cancer deaths, 5.3% due to external causes and 14.4% due to other causes. Overall, a history of past respiratory disease was not associated with higher all-cause mortality (table 3). There was strong evidence that a past history of pneumonia was associated with a doubling of the risk of respiratory mortality and of COPD (bronchitis, emphysema) mortality. A past history of asthma was also associated with 2.6-fold higher COPD mortality risk, but this association did not reach statistical significance at the 0.05 level. Students with a past history of bronchitis had a 38% higher risk (adjusted hazard ratio (HR) 1.38; 95% confidence interval (CI) 1.06, 1.80) of CVD mortality, which was mostly caused by death from stroke (adjusted HR 1.77; 95% CI 1.00, 3.13). This association remained the same after adjusting for haemoglobin level, a correlate of haematocrit (results not shown). A history of bronchitis, pneumonia or asthma was not associated with external causes of death, overall cancer mortality or with lung or colon cancer mortality (see supplementary table 1 online). There was evidence that students reporting pneumonia had a higher risk of prostate cancer mortality (adjusted HR 2.23; 95% CI 1.13, 4.41). Table 3 Hazard ratio (HR) and 95% confidence interval (CI) for association between past history of respiratory diseases in early life and cause specific mortality* A history of bronchitis in early life was moderately associated with chronic phlegm, dyspnoea and a doctor’s diagnosis of asthma, and was very strongly associated with a doctor’s diagnosis of bronchitis and emphysema in adulthood (table 4). An early life history of asthma was moderately associated with later dyspnoea, and a doctor’s diagnosis of bronchitis and emphysema and was very strongly associated with a doctor’s diagnosis of asthma (OR 33.38; 95% CI 22.48, 49.58). These results were similar, or even stronger, among never smokers (see supplementary table 2 online). Table 4 Odds ratio (OR) and 95% confidence interval (CI) for association of past history of bronchitis, pneumonia, asthma in early life and adult self-reported outcomes and symptoms