Abstract
This study evaluates the association of inflammation in late adolescence as measured by erythrocyte sedimentation rate with cause-specific mortality among healthy Swedish men assessed for conscription in the military.
Inflammation is implicated in various diseases, including cancer and cardiovascular disease (CVD). Despite increasing interest in the role of childhood and adolescent exposures in later-life disease, little is known about the long-term implications of early inflammation. Here, we evaluate the association of inflammation in late adolescence as measured by erythrocyte sedimentation rate (ESR) with cause-specific mortality among ostensibly healthy men assessed for conscription in the Swedish military.
Methods
This study is drawn from a cohort of 248 488 men born between 1952 and 1956 who were assessed for compulsory military conscription at age 16 to 20 years, at which time physical and psychological examinations were completed and blood samples were collected. Analyses were restricted to adolescents with no known health conditions or marked physical weakness (n = 108 443) and excluded men missing ESR data or covariates, resulting in a final sample of 106 120 men. Permissions for this study were granted by Regional Ethical Review Board in Uppsala, Sweden, and the Harvard T. H. Chan School of Public Health Institutional Review Board. Informed consent was waived because we used deidentified national register data and had no contact with study participants.
Inflammation was measured by ESR, a nonspecific marker of inflammation.1 Erythrocyte sedimentation rate was categorized as low (≤10 mm/h), moderate (>10-<15 mm/h), and high (≥15 mm/h); the threshold from moderate to high ESR corresponds to the clinical cutoff for normal ESR among adolescents and men in this age group.1,2 Men were observed for death until January 1, 2010, unless censored because of emigration. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs. Statistical significance was assessed at an α less than .05 using a 2-sided test; all P values presented were calculated using the Wald test. Sensitivity analyses were conducted allowing inclusion of adolescents with health conditions deemed minor by the military (n = 203 204).
Results
Of the 106 120 Swedish men included in the analysis, 105 460 (99.4%) were aged 18 to 20 years at the time of examination. Men were observed for a mean of 35 years up to a maximum age of 57 years, over which time 4835 deaths occurred, including deaths due to cancer (n = 1105), CVD (n = 874), alcohol or drugs (n = 280), and suicide, traffic collisions, or falls (n = 1502). Selected covariates, by ESR, are shown in Table 1. The full list of covariates is provided in the footnote of Table 2.
Table 1. Population Description and Adjusted Percentage of Those With Moderate or High Erythrocyte Sedimentation Rate (ESR).
| Characteristic | Total, No. (%) | Men With ESR >10 mm/h, Adjusted %a |
|---|---|---|
| Overall | 106 120 (100) | 3.3 |
| Age at conscription, y | ||
| 16-17 | 660 (0.6) | 2.5 |
| 18-20 | 105 460 (99.4) | 3.3 |
| Household crowding (persons per room) | ||
| <1 | 7003 (6.6) | 2.4 |
| 1 | 13 658 (12.9) | 3.0 |
| >1-2 | 63 197 (59.6) | 3.3 |
| >2-3 | 15 629 (14.7) | 3.5 |
| >3 | 6633 (6.3) | 3.9 |
| Muscular strength | ||
| Weakest (1-3) | 11 495 (10.8) | 3.9 |
| Moderate (4-6) | 70 231 (66.2) | 3.3 |
| Strongest (7-9) | 24 394 (23.0) | 2.9 |
| Physical working capacity | ||
| Lowest (1-3) | 3888 (3.7) | 3.6 |
| Moderate (4-6) | 48 440 (45.7) | 3.9 |
| Highest (7-9) | 53 792 (50.7) | 2.8 |
| Body mass indexb | ||
| Underweight (<18.5) | 10 620 (10.0) | 3.6 |
| Normal weight (18.5-<25) | 89 145 (84.0) | 3.2 |
| Lower overweight (25-<27.5) | 4979 (4.7) | 3.7 |
| Upper overweight (27.5-<30) | 1109 (1.1) | 5.6 |
| Obese (≥30) | 267 (0.3) | 5.7 |
Adjusted for erythrocyte volume fraction.
Calculated as weight in kilograms divided by height in meters squared.
Table 2. Erythrocyte Sedimentation Rate (ESR) in Late Adolescence in Relation to Overall and Cause-Specific Mortality.
| ESR, mm/h | No. (%) | Adjusted HR (95% CI) | ||
|---|---|---|---|---|
| Total (N = 106 120) | Deaths (n = 4835) | Minimallya | Multivariableb | |
| Overall mortality | ||||
| Low (≤10) | 102 631 (96.7) | 4628 (95.7) | 1 [Reference] | 1 [Reference] |
| Moderate (>10-<15) | 1930 (1.8) | 109 (2.3) | 1.30 (1.07-1.57) | 1.25 (1.04-1.52) |
| High (≥15) | 1559 (1.5) | 98 (2.0) | 1.46 (1.19-1.78) | 1.36 (1.11-1.67) |
| P value for trend | NA | NA | <.001 | <.001 |
| Mortality associated with cancer | ||||
| Low (≤10) | 102 631 (96.7) | 1051 (95.1) | 1 [Reference] | 1 [Reference] |
| Moderate (>10-<15) | 1930 (1.8) | 25 (2.3) | 1.27 (0.85-1.89) | 1.24 (0.83-1.85) |
| High (≥15) | 1559 (1.5) | 29 (2.6) | 1.83 (1.26-2.66) | 1.78 (1.23-2.59) |
| P value for trend | NA | NA | .001 | .002 |
| Mortality associated with cardiovascular disease | ||||
| Low (≤10) | 102 631 (96.7) | 830 (95.0) | 1 [Reference] | 1 [Reference] |
| Moderate (>10-<15) | 1930 (1.8) | 25 (2.9) | 1.75 (1.17-2.62) | 1.65 (1.10-2.46) |
| High (≥15) | 1559 (1.5) | 19 (2.2) | 1.67 (1.06-2.64) | 1.54 (0.97-2.43) |
| P value for trend | NA | NA | .001 | .006 |
| Mortality associated with myocardial infarction | ||||
| Low (≤10) | 102 631 (96.7) | 280 (93.7) | 1 [Reference] | 1 [Reference] |
| Moderate (>10-<15) | 1930 (1.8) | 9 (3.0) | 1.95 (1.00-3.81) | 1.80 (0.92-3.52) |
| High (≥15) | 1559 (1.5) | 10 (3.3) | 2.73 (1.44-5.16) | 2.50 (1.32-4.73) |
| P value for trend | NA | NA | <.001 | .001 |
Abbreviations: HR, hazard ratio; NA, not applicable.
Model adjusted for age (time axis of analysis) and erythrocyte volume fraction (continuous).
Model adjusted for age (time axis of analysis), erythrocyte volume fraction (continuous), household crowding (categorical; persons per room: <1, 1, >1-≤2, >2-≤3, >3), systolic blood pressure (continuous), diastolic blood pressure (continuous), muscular strength (continuous), physical working capacity (categorical; lowest, 1-2; middle, 3-6; highest, 7-9), cognitive function (categorical; lowest, 1-3; middle, 4-6; highest, 7-9), and body mass index, calculated as weight in kilograms divided by height in meters squared (categorical; <18.5, 18.5-<25, 25-<27.5, 27.5-<30, ≥30).
Erythrocyte sedimentation rate was associated with overall mortality (high vs low ESR: multivariable-adjusted HR, 1.36; 95% CI, 1.11-1.67; P for trend < .001) (Table 2). Similar patterns were observed for cancer mortality (HR, 1.78; 95% CI, 1.23-2.59; P for trend = .002) and CVD mortality (HR, 1.54; 95% CI, 0.97-2.43; P for trend = .006). No statistically significant associations were observed for death due to alcohol or drugs (high vs low ESR: HR, 1.17; 95% CI, 0.48-2.86; P for trend = .61) or suicide, traffic collisions, or falls (high vs low ESR: HR, 0.96; 95% CI, 0.63-1.47; P for trend = .89).
To address potential occult disease, sensitivity analyses were conducted excluding the first 5 years of follow-up; results were unchanged (data not shown). Similarly, sensitivity analyses including adolescents with minor health conditions did not differ in interpretation (data not shown). Excluding cancers with an established smoking etiology3 yielded results similar to overall cancer mortality (HR, 1.66; 95% CI, 1.03-2.65; P for trend = .02). Lastly, given heterogeneity of CVD, myocardial infarction–specific mortality was examined, yielding stronger associations between inflammation and mortality due to myocardial infarction (HR, 2.50; 95% CI, 1.32-4.73; P for trend = .001) than for overall CVD mortality (Table 2).
Discussion
In this large study, we observed inflammation during late adolescence to be positively associated with premature mortality due to cancer and CVD. While the exact underlying mechanisms are unclear, inflammation has been implicated in the development of both cancer and atherosclerosis,4,5 and these data highlight the existence of detectable markers of premature mortality at an early stage of life.
Inflammation was measured at a single time; thus, we could not evaluate the role of earlier or subsequent inflammation. We were also unable to adjust for smoking. However, smoking is not strongly associated with ESR,2 cancer mortality findings were robust after excluding sites with known smoking etiology, and prior research found the association of adolescent ESR with myocardial infarction risk robust after adjusting for smoking.2 Lastly, analyses may not be generalizable to women.6
Results suggest that ESR among ostensibly healthy men in late adolescence marks something beyond that captured by manifested adolescent health conditions. Results demonstrate the need to better understand the role of subclinical early-life inflammation in relation to later-life health outcomes.
References
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