1 MRC Environmental Epidemiology Unit, Community Clinical Sciences, University of Southampton, Southampton, United Kingdom.
2 Department of Respiratory Medicine, Heartlands Hospital, Birmingham, United Kingdom.
3 New Cross Hospital, Wolverhampton, United Kingdom.
4 Occupational Lung Disease Unit, Heartlands Hospital, Birmingham, United Kingdom.
Received for publication May 17, 2002; accepted for publication August 19, 2002.
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ABSTRACT |
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ferrous compounds; occupational exposure; pneumonia; welding
Abbreviations: Abbreviations: CI, confidence interval; OR, odds ratio.
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INTRODUCTION |
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Taken together, these findings strongly suggest that inhalation of metal fume increases susceptibility to infectious pneumonia, and that the effect is reversible following cessation of exposure. It is not clear, however, whether the additional risk applies to all categories of pneumonia or only to those caused by certain specific microorganisms, whether it is the same for all types of metal, and whether the effect is on the incidence of infections or on their fatality. To address these questions, we conducted a hospital-based case-control study.
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MATERIALS AND METHODS |
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The controls were men admitted acutely to the hospital under the same medical teams as the cases with nonrespiratory illnesses other than attempted suicide. They were group matched to the cases for age. Exclusion criteria were the same as for the cases, except that we also rejected men who had been unemployed 6 months before coming into the hospital as a consequence of the disorder that had subsequently led to their admission. The controls were identified by regular (at least weekly) visits to admission wards at each of the hospitals, in a predefined, rotating sequence. At each visit, the clinical records of all potential controls were reviewed, and those who were eligible and available for interview were invited to participate.
Cases and controls who agreed to take part in the study were interviewed by one of four research assistants, using a structured questionnaire. This covered all jobs held for a year or longer (coded according to the Standard Occupational Classification 1990) (6) and whether they involved exposure to metal fume or other specified respiratory hazards; more detailed information about jobs and occupational exposure to metal fume in the 18 months before admission (including the types of metal giving rise to fume); whether the patient had ever carried out certain activities (either at work or elsewhere) that would be expected to entail exposure to metal fume (welding, flame cutting or burning, flame gouging, metal spraying, use of a plasma arc, or pouring and casting molten metal); and various nonoccupational factors that might confound associations between pneumonia and metal fume.
For cases, the timing of exposures to metal fume and other risk factors, including potential confounders, was assessed relative to the day on which they had fallen ill (the "effective date"). Most cases were interviewed at home, on average approximately 6 months after entry to the hospital. Therefore, to ensure comparability of recall, for controls, all of whom were interviewed while still in the hospital, the effective date was set at 6 months before the day of admission and the most recent exposure history was censored.
For participating cases, additional information was abstracted from the medical records on any microbiologic findings. In addition, the chest radiograph on admission was reviewed by a trained physician (K. T. P.). Where present, the appearance of radiologic shadowing was scored using a standardized schedule as homogeneous and affecting the whole of one or more lobes (lobar), segmental, or multifocal and scattered (bronchopneumonia). The medical records and radiographs were examined without knowledge of the subjects history of employment or exposure to metal fume.
Associations between pneumonia and metal fume were assessed by unconditional logistic regression, with adjustment for age, hospital, and other potential confounders (generally as dichotomous outcomes), and summarized as odds ratios with 95 percent confidence intervals. To explore the possibility of recall bias and to test the specificity of the findings, we compared the associations with those for other reported occupational exposures (to metal dust, wood dust, cement dust, asbestos, man-made mineral fibers, coal dust, and oil mists). We also assessed the relation of pneumonia to three occupations (welder; molder, coremaker, or die caster; and foundry furnaceman) in which exposure to metal fume was considered likely a priori and that had previously been found to have high mortality from the disease (4, 7).
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RESULTS |
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Altogether, 1,188 men were approached to serve as controls, but of these 52 were excluded, either because their current illness had rendered them unemployed 6 months previously (n = 42) or because they fulfilled the exclusion criteria applied to the cases (n = 10). This left 1,136 eligible controls, of whom 1,122 were successfully interviewed (response rate, 99 percent). Among those interviewed, the most frequent reasons for admission were ischemic heart disease (n = 343); other cardiovascular diseases, including heart failure and venous thrombosis (n = 161); gastrointestinal disease, including hemorrhage and inflammatory bowel disease (n = 181); neurologic diseases, including stroke and epilepsy (n = 152); and diabetes (n = 68).
The cases and controls both had a mean age of 46 years with a range of 2064 years. Table 1 compares the distribution of other potential confounding factors between cases and controls. No important differences were found in race, employment status at the effective date, or past history of pulmonary tuberculosis, and few subjects had undergone splenectomy. However, cases and controls differed in their smoking habits, use of corticosteroids during the 3 months before the effective date, and history of chronic airways disease, childhood pneumonia, diabetes, and influenza vaccination. Therefore, in subsequent analyses adjustment was made for these six variables (as defined in table 1) as well as for age and hospital.
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Table 4 shows the association of pneumonia with recent occupational exposure to metal fume according to the type of metal and also the radiologic pattern of disease. Among the cases were 158 men whose chest radiographs showed confluent shadowing affecting the whole of one or more lobes (classic lobar pneumonia), 142 with homogeneous shadowing in a segmental or subsegmental distribution, and 225 with shadowing suggestive of bronchopneumonia. Overall, risks were significantly elevated for lobar and segmental pneumonia (ORs = 1.8) but less marked for bronchopneumonia (OR = 1.3). Exposures that involved iron or steel carried a higher risk of pneumonia (OR = 2.0) than those that were limited to nonferrous metals or alloys (OR = 0.8), and in men exposed to ferrous fumes, higher risks were again seen for lobar and segmental patterns of disease (OR = 2.3 compared with OR = 1.6 for bronchopneumonia).
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During the year before the effective date, 22 cases (4 percent) and 21 controls (2 percent) had worked as a welder, molder, coremaker, die caster, or foundry furnaceman (OR = 1.9, 95 percent CI: 1.0, 3.6).
Among the subjects who did not report any occupational exposure to metal fume, 20 cases and 56 controls indicated that they had welded, cast metal, or used hot metal-cutting techniques on at least one occasion in the year leading up to the effective date (OR = 0.8, 95 percent CI: 0.5, 1.4).
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DISCUSSION |
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To ensure that our ascertainment of cases was as complete as possible, we not only searched the computerized discharge records of participating hospitals but also recruited cases opportunistically when visiting admission wards to interview controls. A substantial minority of the patients identified from this supplementary source were not subsequently picked up through the computer search. In some cases, although pneumonia was documented in the case notes, the recorded discharge diagnosis was less specific. In others, an error may have occurred in coding. Whatever the explanation, the discrepancy suggests that we did not detect all of the cases that occurred in the study population over the course of the investigation, nor did we manage to interview all of the cases whom we did identify. Some 26 percent were lost because they had died, could not be contacted, or declined to participate. It seems unlikely, however, that our failure to include all eligible cases would have seriously biased risk estimates for occupational exposures. In particular, there is no reason to expect that it would have produced a spurious association with recent occupational exposure to metal fume but not with earlier exposures or with recent exposure to other respiratory hazards.
The control group included patients with a wide range of diagnoses, and the response from those approached was almost complete. Moreover, we excluded men admitted because of a chronic illness that might have affected their employment during the relevant time period. For these reasons, we would expect the occupational exposures of the controls to be adequately representative of those in the study population.
Another possible source of error was biased recall of exposures. Ideally, cases and controls would have been interviewed in similar circumstances (home or hospital) and without knowledge of their case or control status. This was not practical, but to reduce bias, we did not inform the interviewers of the hypotheses on which the investigation was based. Moreover, in the course of the interview, we asked first about the jobs that subjects had held and about a range of possible exposures in each job. Only later did we go into detail about metal fume and metalworking activities specifically. Again, therefore, the absence of associations with other respiratory hazards argues against important bias. Furthermore, an increased risk was found for occupations that were expected a priori to entail exposure to metal fume. Errors are less likely in the recall of job title than of detailed occupational exposures.
Various nonoccupational exposures are known or suspected risk factors for pneumonia and, where their prevalence differed importantly between cases and controls, we adjusted for these variables in the regression analyses to minimize any possible confounding. In addition, it is unlikely that the association with metal fume can be explained by a confounding effect of concomitant occupational exposures. There was a correlation between exposure to metal fume and oil mists that made it difficult to resolve their independent influences in a regression model, but an elevated risk of pneumonia was clearly apparent in welders, molders, coremakers, and die castersoccupations that would not be expected to entail heavy exposure to oil mists.
The association could not be explained by concomitant exposure to other noxious agents in welding fume (e.g., ozone and oxides of nitrogen). Most cases and controls who reported occupational exposure to metal fume in the year before the effective date (103 of the 129 subjects) did not weld, and in these subjects the relation between pneumonia and metal fume was similar to that in all subjects (data not shown).
Occupational exposure to metal fume sometimes causes a chemical pneumonitis, and exposure to oil mists has been linked with hypersensitivity pneumonitis (extrinsic allergic alveolitis), both of which may mimic pneumonia. However, misdiagnosis is unlikely to explain associations that were also apparent for microbiologically confirmed cases of disease and for clinical patterns of disease not normally observed in patients with pneumonitis (such as homogeneous lobar shadowing). Moreover, in our earlier study of mortality (4), in which many cases went to necropsy, the postmortem findings indicated infectious pneumonia rather than pneumonitis as the underlying cause of death.
Our findings suggest that the increased susceptibility to pneumonia from inhalation of metal fume persists for longer than a week, although probably not for more than a few years. More precise conclusions about its duration are not possible because there were too few cases with a reported last exposure in the critical time window. An elevated risk was observed in men who worked only with ferrous metal, but the numbers with exposures solely to nonferrous metals and alloys were insufficient to exclude a hazard also from these other sources. The lack of association with nonoccupational metalworking activities suggests that risk is importantly increased with only relatively heavy exposures. Although a clear elevation of risk was seen for pneumococcal infections and with lobar pneumonia (in which S. pneumoniae is the usual organism implicated), other types of infection appeared to be affected also.
At least two pathogenic mechanisms could explain this pattern of observations. First, it is possible that metal fume (ferrous and perhaps some other types of metal) causes oxidative damage to the lungs immune defenses. This is similar to the mechanism of free-radical injury at the bronchioalveolar level that has been postulated to underlie the toxicity of fine particulate pollution in the general environment of cities (810). It is known that free iron, iron released from ferritin, and other transition metals can catalyze the generation of reactive hydroxyl radicals (1113) and that free radicals can impair the function of lymphocytes and normal immune responses, such as the migration of macrophages (14). Furthermore, there is direct evidence that fine particles of metal and of metal-coated carbon are cytotoxic to macrophages (15).
Alternatively, it may be that free iron serves as a nutrient for microorganisms and promotes their growth. This would be consistent with the observation that, in patients with sickle cell disease, iron released during hemolytic crises may increase susceptibility to pneumonia and pneumococcal infection (16, 17). In addition, there is some evidence to suggest that iron may enhance bacterial pathogenicity if the hosts ability to withhold iron from the invading organism is reduced (7, 18).
With either of these two proposed mechanisms, the increased risk of pneumonia would only be temporary, disappearing once the excess of free iron in the lung had been bound to transferrin and any damage to immune cells had been repaired or compensated.
Research now needs to focus more closely on the mechanism by which metal fumes promote pneumonic infection. A first step might be to establish 1) whether exposure to metal fume provokes a generalized inflammatory reaction (such as a rise in white cell count or C-reactive protein), 2) whether free iron is more abundant and pulmonary macrophages are more iron loaded and impaired in function in exposed workers as compared with controls, and 3) whether an oxidant effect of transitional metals potentiates bacterial multiplication locally. If relevant biomarkers could be established in this way, they might provide a means of assessing the relation of risk to exposure with greater accuracy than is possible from retrospective case-control studies and thereby enable controls on exposure to be set at an appropriate level.
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ACKNOWLEDGMENTS |
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The authors are grateful to the clinical, radiographic, administrative, and clerical staffs who assisted us at each of the hospitals (City Hospital, Good Hope Hospital, Heartlands Hospital, Queen Elizabeth Hospital, Selly Oak Hospital, Solihull Hospital, Russell Hall and Wordsley hospitals, Dudley; New Cross Hospital, Wolverhampton; and Manor Hospital, Walsall) and particularly to the chest physicians who enlisted local support for the study. The interviews were conducted by Teresa Rowe, Sarah Hoffman, Marian Griffin, and Susan Leeke. Vanessa Cox provided computing support and Denise Gould typed the manuscript.
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NOTES |
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REFERENCES |
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