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Risk factors for community-acquired pneumonia diagnosed by general practitioners in the community
RESPIRATORY MEDICINE (2000) 94, 422±427 doi:10.1053/rmed.1999.0743, available online at http://www.idealibrary.com on
Risk factors for community-acquired pneumonia diagnosed by general practitioners in the community B. M. FARR*, M. A. WOODHEAD{ J. T. MACFARLANE{ C. L. R. BARTLETT} J. S. MCCRACKEN} J. WADSWORTH**1 AND D. L. MILLER* *Department of Internal Medicine, University of Virginia School of Medicine Charlottesville, VA 22908, U.S.A. { Department of Respiratory Medicine, Manchester Royal Infirmary, Manchester, { Department of Thoracic Medicine, City Hospital, Nottingham, } Communicable Disease Surveillance Centre, London, } Department of General Practice, Medical School, University of Nottingham, and **Department of Epidemiology and Public Health, St. Mary's Hospital Medical School, University of London, U.K. The purpose of this study was to identify risk factors for pneumonia diagnosed in the community by general practitioners, using a case control study in 29 general practices in Nottingham, U.K. Patients with radiographically con®rmed pneumonia were compared with adults randomly selected from electoral registers corresponding to the catchment areas of the general practices taking part in the study. Sixty-six cases and 489 controls participated. Signi®cant risk factors in univariate analysis included age, chronic obstructive pulmonary disease, congestive heart failure and lifetime consumption of cigarettes. Multiple logistic regression analysis of these four variables showed that age [adjusted odds ratio = 269 (for 30 year increment), 95%CI =l66±435] and chronic obstructive pulmonary disease (adjusted odds ratio=199, 95%CI = 115±345) were independent risk factors. Only age and chronic obstructive pulmonary disease were independent risk factors for pneumonia in this study. Since cigarette smoking is the major cause of chronic obstructive pulmonary disease, these data suggest that cigarette smoking is the main avoidable risk factor for community-acquired pneumonia in adults. Key words: community-acquired pneumonia; risk factors; smoking; epidemiology. RESPIR. MED. (2000) 94, 422±427
Introduction Pneumonia, which was personi®ed as the `captain of the men of death' by Osler at the turn of the century (1), has remained a major cause of death worldwide, accounting for more than ®ve million deaths per year (2). In developed countries, case fatality and crude mortality rates declined dramatically during the middle of this century with the dawn of the antimicrobial era. Nevertheless, pneumonia coupled with in¯uenza remains the sixth leading cause of death overall and the ®fth leading cause of death for those Received 16 July 1999 and accepted in revised form 9 October 1999. 1 Jane Wadsworth died on 12 July 1997 after making signi®cant contributions to this manuscript. Correspondence should be addressed to: Dr. Barry Farr, University of Virginia Health System, Box 473, Charlottesville, VA 22908 U.S.A.
0954-6111/00/050422+06 $35?00/0
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above 65 years of age in the United States, where it kills more than 60 000 persons per year (3). In 1979, the U.S. Surgeon General declared a national commitment to reduce the rate of premature death due to pneumonia and in¯uenza in adults (4). Despite this commitment, the rate of death due to pneumonia in the U.S. increased among adults above 65 years of age from 1979 to 1986, while the rate of death from all other causes in this age group fell during the same period (5). More than 54 000 deaths are attributed to pneumonia annually in England and Wales, where diseases of the respiratory system are the third leading cause of death, with pneumonia accounting for 61% of these deaths (6,7). The overall incidence of pneumonia reported in dierent studies in developed countries has ranged from 12±15 per 1000 persons per year with no appreciable change in the last several decades (8±11). Knowledge of risk factors for a disease is necessary before eective strategies for primary prevention can be # 2000 HARCOURT PUBLISHERS LTD
RISK FACTORS FOR PNEUMONIA 423 devised. Men have had a higher incidence of pneumonia than women in most studies, but the reason for this has never been clearly determined in an epidemiological study (1, 4, 9±26). Most studies that have investigated risk factors for community-acquired pneumonia have included only cases severe enough to be admitted to hospital (4,12,13,26,27). Such studies exclude the majority of pneumonia cases which are not admitted to hospital and may reveal a combination of risk factors, some for pneumonia and others for hospital admission. Nevertheless, one study, which evaluated risk factors for all cases of pneumonia diagnosed in a small town in Finland, found that ®ve of the six risk factors for pneumonia treated at home were also risk factors for more severe cases of pneumonia requiring hospitalization (16). The public health burden of pneumonia is expected to increase during the next decade as the mean age of the population in developed countries is predicted to increase. The development of preventive measures must rely on epidemiological studies to identify risk factors that are amenable to intervention. We report the results of a case±control study of risk factors for pneumonia diagnosed in the community by general practitioners in England.
Materials and methods SELECTION OF CASES Cases consisted of patients between 15 and 79 years of age who were diagnosed as having acute, community-acquired pneumonia in a prospective study by 29 general practitioners in the city of Nottingham between 1 October, 1984 and 30 September, 1985 (28). Pneumonia was de®ned as an acute lower respiratory tract infection for which an antibiotic was prescribed associated with new focal signs on chest examination and new radiographic pulmonary shadowing. Review of preliminary data suggested that 200 cases of pneumonia could be diagnosed during the study period.
SELECTION OF CONTROLS The electoral wards corresponding to the catchment areas of the general practices taking part in the study were identi®ed. A random sample of 661 persons was selected from the electoral registers for these wards with the aim of identifying at least three satisfactory controls for each case. Responses from persons who stated that they had previously had pneumonia as an adult or who were not between the ages of 15 and 79 during the period of the study were excluded.
THE QUESTIONNAIRE A Respiratory Health Survey questionnaire, developed for this study, recorded demographic data and elicited information about regular contact with children, the number of
people living in the home, the number of rooms and bedrooms in the home, type and amount of domestic heating used in winter, type of cooking fuel, exposures to animals and birds, occupation, history of occupational dust exposure, history of tobacco smoke exposure, alcohol consumption, history of pneumonia, tuberculosis, chest injury, chronic illnesses and symptoms of chronic illnesses, hospital admission within 5 years, immunization with in¯uenza vaccine and current medications. Questions on respiratory symptoms were taken from the MRC chronic respiratory disease questionnaire (29). The questionnaire was piloted on adults working at the Communicable Disease Surveillance Centre in London and their adult family members. The questionnaire and study protocol were approved by the Ethical Committee of the Nottingham Health Authority.
PROTOCOL FOR MAILING QUESTIONNAIRES Questionnaires were sent to all cases and controls between March 1985 and June 1985 with an explanatory letter inviting their participation. The letters emphasized the public health importance of pneumonia and the need for a better understanding of risk factors for this condition without discussing any particular risk factor. Non-respondents were sent a second questionnaire and letter one month later, and if this elicited no response within a month, a third was mailed. Questionnaires returned by the post oce marked `gone away' without a forwarding address were abandoned. Questionnaires with unanswered questions were returned with a request for the missing information.
DATA MANAGEMENT AND STATISTICAL METHODS Forms were checked and coded before computer entry, and entries were veri®ed by a dierent computer operator. Occupation was used to code social class using the U.K. Registrar General's Occupational Class Groups (30). The strength of univariate relationships between cases and controls and categorical variables was assessed using w2 or Fisher's exact test. Quantitative variables, which were not normally distributed were analyzed using non-parametric methods. The planned sample size (200 cases and 600 controls) was selected to provide high statistical power to detect dierences as small as 10% in the prevalence of risk factors (e.g., 99% power for detecting with an alpha value of 005, a signi®cant dierence between a 12% prevalence among cases and a 2% prevalence among controls). A stepwise, multiple logistic regression was used for multivariate analysis of the variables which showed statistical signi®cance (P 005) in univariate analysis. The analyses were conducted using SAS on a VAX computer (31). Measurement of the odds ratio from the logistic regression analysis was performed as described by Fleiss et al. (32).
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Results
patients initially diagnosed by the general practitioners as having pneumonia were excluded because of normal chest radiographs (Table 1). Of those responding, 66 cases and 489 controls satis®ed criteria for inclusion in the analysis.
RESPONSE RATE Questionnaires were mailed to the ®rst 200 individuals diagnosed as having pneumonia by the general practitioners and to 661 controls in the Nottingham area. Usable responses were received from 173 (865%) of the 200 patients diagnosed as having pneumonia and from 506 (765%) of the 661 potential controls. A majority of the
DEMOGRAPHICS The mean age of cases (54 years) was a decade older than for controls (P = 0001). The proportion of cases who were
TABLE 1. Disposition of subjects and reasons for exclusion Disposition and reasons for exclusion
Cases
Total forms mailed Forms never returned Forms returned Included in the analysis Excluded Case with negative chest radiograph Forms returned unopened by post oce `moved away' Exceed age limits of study Written letter of refusal Subject blind Subject illiterate Deceased Case not actually pneumonia (alternative diagnosis made) Case of pneumonia due to obstruction Case already included for previous pneumonia History of pneumonia as adult
Number (%)
Controls
200 14 (7%) 186 (93%) 66 (33%) 120 107 (535%) 0 0 0 1 (05%) 0 5 (25%) 2 (1%)
661 90 (136%) 571 (864%) 489 (739%) 82 Ð 31 (46%) 23 (34%) 5 (08%) 0 1 (01%) 6 (09%) Ð
3 (15%) 2 (1%) Ð
Ð Ð 16 (24%)
TABLE 2. Demographic variables and environmental exposures Variables Demographic Male sex Age Married Unemployed Social class I II III non-manual III manual IV V Environmental Exposures Child contact Gas stove Gas heat Bird Animal Dusty occupation
Cases
Controls
Odds ratio
95% CI
36/66 (55%) 544+SEM 48/66 (73%) 6/66 (9%)
220/489 (45%) 439+SEM 075 324/489 (66%) 37/489 (8%)
147
085±254
136 122
074±251 044±319
077 067 092 095 056 171
042±139 039±117 046±185 040±218 031±099 096±304
11 13 29 5
0 (19%) (22%) (50%) (9%) 0
20/65 (31%) 33/64 (52%) 51/64 (80%) 8/64 (13%) 23/64 (36%) 25/63 (40%)
13 (3%) 87 (20%) 97 (23%) 145 (34%) 61 (14%) 28 (7%) 178/486 (37%) 300/489 (61%) 394/486 (81%) 63/480 (13%) 239/476 (50%) 134/482 (28%)
RISK FACTORS FOR PNEUMONIA 425 men was higher than for controls, but this dierence was not signi®cant. The distributions of social class, marital status and employment were similar for cases and controls (Table 2).
EXPOSURES Cases were somewhat more likely to record a history of a dusty occupation than were controls (40% vs. 28%, P=0071), but there was no more contact with children, gas stoves, gas heating, birds, or other animals among cases (Table 2).
SMOKING HISTORY Cases and controls were equally likely to be current smokers but cases were signi®cantly more likely to be exsmokers (Table 4). Lifetime consumption of cigarettes (computed as the product of the number of cigarettes smoked per day currently or 1 year before, whichever was greater, and the number of years smoked) was signi®cantly greater for cases than for controls (P = 003). There were trends toward higher numbers of cigarettes smoked by cases than by controls in each age stratum when the two groups were strati®ed by age. The reported rates of passive smoke exposure were similar for cases and controls (Table 4).
UNDERLYING ILLNESSES The only diseases which were signi®cantly more frequent among cases were chronic obstructive pulmonary disease (COPD) and congestive heart failure (Table 3).
ALCOHOL HISTORY There was no signi®cant dierence between the rates of current or lifetime alcohol consumption for cases and controls.
MULTIVARIATE ANALYSIS Each variable showing signi®cance in univariate analysis was then analysed in a stepwise, multiple logistic regression. Only age (adjusted odds ratio = 269 [for 30-year increment], 95% CI 166±435) and chronic obstructive pulmonary disease (adjusted odds ratio = 199, 95% CI = 115 ± 345) were found to be independent risk factors in this multivariate analysis (Table 5).
TABLE 3. Underlying illnesses as risk factors for pneumonia
Respiratory Chronic obstructive pulmonary disease Asthma Tuberculosis Chest Injury Hay fever Acute sinusitis Chronic sinusitis Pneumonia in childhood Non-respiratory Diabetes Cancer Chronic renal failure Congestive heart failure
Cases
Controls
Odds Ratio
95% CI
27/66 (41%)
103/478 (22%)
252
142±446
3/62 (5%) 1/65 (2%) 1/63 (2%) 4/58 (7%) 6/56 (11%) 4/57 (7%) 6/57 (11%)
16/479 (3%) 12/486 (2%) 17/484 (4%) 50/477 (10%) 48/460 (10%) 9/478 (2%) 29/449 (6%)
147 049 044 063 103 393 170
033±558 002±361 002±324 019±192 038±267 098±1462 060±457
2/65 (3%) 1/66 (2%) 0/63 (0%) 9/65 (14%)
6/479 (1%) 14/486 (3%) 2/482 (04%) 7/483 (2%)
250 052 000 1093
034±1411 003±386 000±3163 356±3412
Odds ratio
95% CI
098 078 080 199
052±188 040±150 043±147 114±347
TABLE 4. Exposure to cigarette smoke Cases Passive smoking in home in childhood in adulthood Current smokers Former smokers
45/61 15/65 18/66 29/66
(74%) (23%) (27%) (44%)
Controls
358/483 117/421 155/485 137/485
(74%) (28%) (32%) (28%)
426
B. M. FARR ET AL.
TABLE 5. Signi®cant results of multiple logistic regression Variable Age 30-year increment 63-year increment COPD
Adjusted odds ratio
95% CI
269 825 199
166±435 296±2300 115±345
Discussion Most previous controlled studies of risk factors for community-acquired pneumonia have dealt only with patients admitted to hospital, probably because most investigators are hospital-based and patients admitted to hospital have more severe disease. However, since most patients with pneumonia are treated as outpatients, the majority of cases of community-acquired pneumonia are excluded from such studies (16,28,33). Published case series have identi®ed chronic obstructive pulmonary disease and age as possible risk factors for pneumonia among patients with disease severe enough to warrant hospital admission (11,14,15,17±25,34±38) Four epidemiological studies have con®rmed that chronic obstructive pulmonary disease was associated with cases of pneumonia admitted to hospital (5,12,16,26). One of these studies found that chronic obstructive lung disease was also a signi®cant risk factor for pneumonia cases not admitted to hospital (RR=30. 95%CI 23±39) (16); other signi®cant risk factors included alcoholism, asthma, immunosuppressive therapy, heart disease (type unspeci®ed) and age. Two of these epidemiological studies demonstrated that cigarette smoking was an independent risk factor after accounting for chronic obstructive pulmonary disease and age (5,26). Another controlled study of patients with pneumococcal infections, a majority of which were pneumonias, also found a signi®cant excess of smoking in cases as compared with controls (13). The present study found that patients with pneumonia diagnosed by general practitioners in the community were signi®cantly older and had a higher frequency of chronic obstructive pulmonary disease than randomly selected controls from the same communities. These data suggest that the milder cases of pneumonia diagnosed in the community, which generally do not result in hospital admission, share an epidemiology similar to that of the more severe cases which require admission. The study of pneumonia epidemiology conducted in Finland also found that risk factors were similar for cases of communityacquired pneumonia whether or not they were admitted to the hospital. The only discrepancy in that study for pneumonia cases admitted and those not admitted to hospital was the ®nding that alcoholism was a signi®cant risk factor only for cases not admitted to the hospital (16). Patients with pneumonia in the present study were signi®cantly more likely to have congestive heart failure than control subjects con®rming an association with heart disease noted by Koivula et al. (16) Lipsky et al. also found
an association with heart failure in a study of pneumococcal infections, 92% of which were pneumonias (13). Heart failure did not remain signi®cantly associated with cases in the multiple logistic regression analysis of the present study, but as with smoking history, this may have been due to the relatively small number of cases involved and low statistical power to detect such an association. The sample size was smaller than planned because two thirds of those diagnosed as having pneumonia based upon history and physical exam had no in®ltrate on chest radiograph. This in turn resulted in a lower statistical power than planned (i.e., 88% power to detect a signi®cant dierence with an alpha value of 005 between a prevalence rate of 12% in cases and 2% in controls). This power calculation applies to a univariate statistical test, however. Power for detecting statistical signi®cance in such a dierence in multivariate analysis after adjusting for other signi®cant dierences would be still lower. It should be noted that the present study occurred during a year in which very few Mycoplasma pneumoniae infections were diagnosed (28). This disease occurs with a dierent epidemiology more as a contagious disease among young adultsÐin marked contrast to the types of bacterial pneumonia that predominated in this study (39,40). The results of the present study suggest that the human lung is compromised by age and by cigarette-induced chronic lung disease and thereby predisposed to episodes of acute bacterial pneumonia. Both of these factors are biologically plausible as the rate of mucociliary cleansing of the respiratory tract is diminished both with age and with cigarette smoking (41). Smoking appears to be the major avoidable risk factor for acute, community-acquired pneumonia in adults.
Acknowledgements This study was supported by a grant from the Milbank Memorial Fund, New York, N.Y. Mark Woodhead was supported by a grant from the Chest, Heart and Stroke Association. We thank Donna McGraw, Linda Wilson, Janet Moore-Coll, Helen Nor¯eet-Shi¯ett, and Angelia S. Cempre for their assistance in preparing the manuscript.
Reference 1. Osler W. Medicine in the nineteenth century. In: Aequanimitas, With Other Addresses. Philadelphia: P. Blakiston's Son and Co., 1905. 2. Rao KN. Presidential Address at the Joint Annual Conference. In: Ciba Symposium on Health of Mankind. Mangalore. India. 1971. 3. Anonymous. Pneumonia and in¯uenza death ratesÐ United States, 1979±1994 MMWR 1995; 44: 535±537. 4. Institute of Medicine. Healthy people: the Surgeon General's report on health promotion and disease prevention. Washington, US Department of Health, Education and Welfare, Public Health Service, 1979. 5. Lacroix AZ, Lipson S, Miles TP, White L. Prospective study of pneumonia hospitalizations and mortality of
RISK FACTORS FOR PNEUMONIA 427
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U.S. older people: the role of chronic conditions. health behaviors, and nutritional status. Public Health Reports 1989; 104: 350±360. Oce of National Statistics. Mortality Statistics; Cause 1996, Series DH2 no. 23. London: The Stationery Oce, 1998. Charlton JRH, Manley RM, Silver R. Holdend WN. Geographical variation in mortality from conditions amenable to medical intervention in England and Wales. Lancet 1983; 33: 691±695. Foy JM, Wentworth B, Kenny GE, KIoeck JM, Grayston JT. Pneumococcal isolations from patients with pneumonia and control subjects in a prepaid medical care group. Am Rev Respir Dis 1975; 111: 595± 603. Foy HM, Cooney MK, Allan I, Kenny GE. Rates of pneumonia during in¯uenza epidemics in Seattle, 1964 to 1975. JAMA 1979; 241: 253±258. Foy HM, Kenny GE. Cooney MK, Allan ID. Longterm epidemiology of infections with Mycoplasma pneumoniae. J Infect Dis 1979; 139: 681±687. Jokinen C, Heiskanen L, Juvonen H, et al. Incidence of community-acquired pneumonia in the population of four municipalities in Eastern Finland. Am J Epidemiol 1993; 137: 977±988. Fekety FR, Caldwell J, Gump D, et al. Bacteria, viruses, and mycoplasmas in acute pneumonia in adults. Am Rev Respir Dis 1971; 104: 499±507. Lipsky BA, Boyko EJ, Inui TS, Koepsell TD. Risk factors for acquiring pneumococcal infections. Arch Intern Med 1986; 146: 2179±2185. Moine P, Vercken J, Chevret S, et al. Severe community-acquired pneumonia. Etiology, epidemiology, and prognosis factors. Chest 1994; 105: 1487±1495. Torres A, Serra-Batlles S, Ferrer A, et al. Severe community-acquired pneumonia. Epidemiology and prognostic factors. Am Rev Respir Dis 1991; 144: 312±318. Koivula I, Sten M, Makela PH. Risk factors for pneumonia in the elderly. Am J Med 1994; 96: 313±320. Marrie TJ. Epidemiology of community-acquired pneumonia in the elderly. Sem Respir Infect 1990; 5: 260±268. White RJ, Blainey AD, Harrison KJ, Clarke SKR. Causes of pneumonia presenting to a district general hospital. Thorax 1981; 36: 566±570. Prout S, Potgieter PD, Forder AA, Moodie JW, Matthews J. Acute community-acquired pneumonias. SA Mediese Tydskrif 1983; 64: 443±446. McNabb WR, Williams TDM, Shanson DC, Lant AF. Adult community-acquired pneumonia in central London. J R Soc Med 1984; 77: 550±555. MacFarlane JT, Ward MJ, Finch RG, Macrae AD. Hospital study of adult community-acquired pneumonia. Lancet 1982; 2: 255±258. Lim I, Shaw DR, Stanley DP, Lumb R, McLennan G. A prospective hospital study of the aetiology of community-acquired pneumonia. Med J Aust 1989; 151: 87±91.
23. Farr BM, Sloman AJ, Fisch MJ, Predicting death in patients hospitalized for community-acquired pneumonia. Ann Intern Med 1991; 115: 428±436. 24. Bath JCJL, Boissard GPB, Calder MA. Moat MA. Pneumonia in hospital practice in Edinburgh 1960± 1962. Br J Dis Chest 1964; 58: 1±16. 25. Aguirre I, Bilbao JJ, Olarreaga M, et al. Acquired pneumonias in the community of Andoain [Spanish]. Atencion Primaria 1993; 12: 359±362. 26. Lange P, Vestbo J, Nyboe J. Risk factors for death and hospitalization from pneumonia. A prospective study of a general population. Eur Respir J l995; 8: 1695±1698. 27. Sullivan RJ, Dowdle WR, Marine WM, Hierholzer JC. Adult pneumonia in a general hospital: Etiology and host risk factors. Arch Intern Med 1972; 129: 935±942. 28. Woodhead MA, MacFarlane JT, McCracken JS, Rose DH, Finch RG. Prospective study of the aetiology and outcome of pneumonia in the community. Lancet 1987; 1: 671±674. 29. MRC Committee on the Aetiology of Chronic Bronchitis. Standardized questionnaire on respiratory symptoms. Br Med J 1960; ii: 1665. 30. Hart N. Social and economic environment and human health. In: Holland WW, Detets R, Knox G, (eds): Oxford Textbook of Public Health. 2nd ed. London, Oxford University Press, 1991; pp. 158. vol I. 31. SAS Institute Inc. SAS user's guide: Statistics. In: 5 ed. Gary. NC: SAS Institute Inc., 1985. 32. Fleiss JL, Williams JBW, Dubro AF. The logistic regression analysis of psychiatric data. J Psychiatr Res 1986; 20: 145±209. 33. Everett MT. Major chest infection managed at home. The Practitioner 1983; 227: 1743±1754. 34. Fang GD, Fine M, Orloif J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: A prospective multicenter study of 359 cases. Medicine 1990; 69: 307±316. 35. Ort S, Ryan JL, Barden G, D'Esopo N. Pneumococcal pneumonia in hospital patients: Clinical and radiological presentations. JAMA 1983; 249: 214±218. 36. Bates JH, Campbell GD, Barron AL, et al. Microbial etiology of acute pneumonia in hospitalized patients. Chest 1992; 101: 1005±1012. 37. Jay SJ, Johanson WG, Pierce AK. The radiographic resolution of Streptococcus pneumoniae pneumonia. New Engl J Med 1975; 293: 798±801. 38. Klimek JJ, Ajemian E, Fonteochio S, Gracewski J, Klemas B, Jimenez L. Community-acquired bacterial pneumonia requiring admission to hospital. Am J Infect Control 1983; 11: 79±82. 39. Clyde WA. Mycoplasma pneumonia. Sem Infect Dis 1983; 5: 81±92. 40. Noah ND, Urguhart AM. Epidemiology of Mycoplasma pneumoniae infection in the British Isles, 1974±9. J lnfect 1980; 2: 191±194. 41. Goodman RM, Yergin BM, Landa JF, Golinvaux LM, Sackner MA. Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers,young smokers, ex-smokers,andpatientswith chronic bronchitis. Am Rev Respir Dis 1978; 117: 205±214.
Risk factors for community-acquired pneumonia diagnosed by general practitioners in the community B. M. FARR*, M. A. WOODHEAD{ J. T. MACFARLANE{ C. L. R. BARTLETT} J. S. MCCRACKEN} J. WADSWORTH**1 AND D. L. MILLER* *Department of Internal Medicine, University of Virginia School of Medicine Charlottesville, VA 22908, U.S.A. { Department of Respiratory Medicine, Manchester Royal Infirmary, Manchester, { Department of Thoracic Medicine, City Hospital, Nottingham, } Communicable Disease Surveillance Centre, London, } Department of General Practice, Medical School, University of Nottingham, and **Department of Epidemiology and Public Health, St. Mary's Hospital Medical School, University of London, U.K. The purpose of this study was to identify risk factors for pneumonia diagnosed in the community by general practitioners, using a case control study in 29 general practices in Nottingham, U.K. Patients with radiographically con®rmed pneumonia were compared with adults randomly selected from electoral registers corresponding to the catchment areas of the general practices taking part in the study. Sixty-six cases and 489 controls participated. Signi®cant risk factors in univariate analysis included age, chronic obstructive pulmonary disease, congestive heart failure and lifetime consumption of cigarettes. Multiple logistic regression analysis of these four variables showed that age [adjusted odds ratio = 269 (for 30 year increment), 95%CI =l66±435] and chronic obstructive pulmonary disease (adjusted odds ratio=199, 95%CI = 115±345) were independent risk factors. Only age and chronic obstructive pulmonary disease were independent risk factors for pneumonia in this study. Since cigarette smoking is the major cause of chronic obstructive pulmonary disease, these data suggest that cigarette smoking is the main avoidable risk factor for community-acquired pneumonia in adults. Key words: community-acquired pneumonia; risk factors; smoking; epidemiology. RESPIR. MED. (2000) 94, 422±427
Introduction Pneumonia, which was personi®ed as the `captain of the men of death' by Osler at the turn of the century (1), has remained a major cause of death worldwide, accounting for more than ®ve million deaths per year (2). In developed countries, case fatality and crude mortality rates declined dramatically during the middle of this century with the dawn of the antimicrobial era. Nevertheless, pneumonia coupled with in¯uenza remains the sixth leading cause of death overall and the ®fth leading cause of death for those Received 16 July 1999 and accepted in revised form 9 October 1999. 1 Jane Wadsworth died on 12 July 1997 after making signi®cant contributions to this manuscript. Correspondence should be addressed to: Dr. Barry Farr, University of Virginia Health System, Box 473, Charlottesville, VA 22908 U.S.A.
0954-6111/00/050422+06 $35?00/0
# 2000 HARCOURT PUBLISHERS LTD
above 65 years of age in the United States, where it kills more than 60 000 persons per year (3). In 1979, the U.S. Surgeon General declared a national commitment to reduce the rate of premature death due to pneumonia and in¯uenza in adults (4). Despite this commitment, the rate of death due to pneumonia in the U.S. increased among adults above 65 years of age from 1979 to 1986, while the rate of death from all other causes in this age group fell during the same period (5). More than 54 000 deaths are attributed to pneumonia annually in England and Wales, where diseases of the respiratory system are the third leading cause of death, with pneumonia accounting for 61% of these deaths (6,7). The overall incidence of pneumonia reported in dierent studies in developed countries has ranged from 12±15 per 1000 persons per year with no appreciable change in the last several decades (8±11). Knowledge of risk factors for a disease is necessary before eective strategies for primary prevention can be # 2000 HARCOURT PUBLISHERS LTD
RISK FACTORS FOR PNEUMONIA 423 devised. Men have had a higher incidence of pneumonia than women in most studies, but the reason for this has never been clearly determined in an epidemiological study (1, 4, 9±26). Most studies that have investigated risk factors for community-acquired pneumonia have included only cases severe enough to be admitted to hospital (4,12,13,26,27). Such studies exclude the majority of pneumonia cases which are not admitted to hospital and may reveal a combination of risk factors, some for pneumonia and others for hospital admission. Nevertheless, one study, which evaluated risk factors for all cases of pneumonia diagnosed in a small town in Finland, found that ®ve of the six risk factors for pneumonia treated at home were also risk factors for more severe cases of pneumonia requiring hospitalization (16). The public health burden of pneumonia is expected to increase during the next decade as the mean age of the population in developed countries is predicted to increase. The development of preventive measures must rely on epidemiological studies to identify risk factors that are amenable to intervention. We report the results of a case±control study of risk factors for pneumonia diagnosed in the community by general practitioners in England.
Materials and methods SELECTION OF CASES Cases consisted of patients between 15 and 79 years of age who were diagnosed as having acute, community-acquired pneumonia in a prospective study by 29 general practitioners in the city of Nottingham between 1 October, 1984 and 30 September, 1985 (28). Pneumonia was de®ned as an acute lower respiratory tract infection for which an antibiotic was prescribed associated with new focal signs on chest examination and new radiographic pulmonary shadowing. Review of preliminary data suggested that 200 cases of pneumonia could be diagnosed during the study period.
SELECTION OF CONTROLS The electoral wards corresponding to the catchment areas of the general practices taking part in the study were identi®ed. A random sample of 661 persons was selected from the electoral registers for these wards with the aim of identifying at least three satisfactory controls for each case. Responses from persons who stated that they had previously had pneumonia as an adult or who were not between the ages of 15 and 79 during the period of the study were excluded.
THE QUESTIONNAIRE A Respiratory Health Survey questionnaire, developed for this study, recorded demographic data and elicited information about regular contact with children, the number of
people living in the home, the number of rooms and bedrooms in the home, type and amount of domestic heating used in winter, type of cooking fuel, exposures to animals and birds, occupation, history of occupational dust exposure, history of tobacco smoke exposure, alcohol consumption, history of pneumonia, tuberculosis, chest injury, chronic illnesses and symptoms of chronic illnesses, hospital admission within 5 years, immunization with in¯uenza vaccine and current medications. Questions on respiratory symptoms were taken from the MRC chronic respiratory disease questionnaire (29). The questionnaire was piloted on adults working at the Communicable Disease Surveillance Centre in London and their adult family members. The questionnaire and study protocol were approved by the Ethical Committee of the Nottingham Health Authority.
PROTOCOL FOR MAILING QUESTIONNAIRES Questionnaires were sent to all cases and controls between March 1985 and June 1985 with an explanatory letter inviting their participation. The letters emphasized the public health importance of pneumonia and the need for a better understanding of risk factors for this condition without discussing any particular risk factor. Non-respondents were sent a second questionnaire and letter one month later, and if this elicited no response within a month, a third was mailed. Questionnaires returned by the post oce marked `gone away' without a forwarding address were abandoned. Questionnaires with unanswered questions were returned with a request for the missing information.
DATA MANAGEMENT AND STATISTICAL METHODS Forms were checked and coded before computer entry, and entries were veri®ed by a dierent computer operator. Occupation was used to code social class using the U.K. Registrar General's Occupational Class Groups (30). The strength of univariate relationships between cases and controls and categorical variables was assessed using w2 or Fisher's exact test. Quantitative variables, which were not normally distributed were analyzed using non-parametric methods. The planned sample size (200 cases and 600 controls) was selected to provide high statistical power to detect dierences as small as 10% in the prevalence of risk factors (e.g., 99% power for detecting with an alpha value of 005, a signi®cant dierence between a 12% prevalence among cases and a 2% prevalence among controls). A stepwise, multiple logistic regression was used for multivariate analysis of the variables which showed statistical signi®cance (P 005) in univariate analysis. The analyses were conducted using SAS on a VAX computer (31). Measurement of the odds ratio from the logistic regression analysis was performed as described by Fleiss et al. (32).
424
B. M. FARR ET AL.
Results
patients initially diagnosed by the general practitioners as having pneumonia were excluded because of normal chest radiographs (Table 1). Of those responding, 66 cases and 489 controls satis®ed criteria for inclusion in the analysis.
RESPONSE RATE Questionnaires were mailed to the ®rst 200 individuals diagnosed as having pneumonia by the general practitioners and to 661 controls in the Nottingham area. Usable responses were received from 173 (865%) of the 200 patients diagnosed as having pneumonia and from 506 (765%) of the 661 potential controls. A majority of the
DEMOGRAPHICS The mean age of cases (54 years) was a decade older than for controls (P = 0001). The proportion of cases who were
TABLE 1. Disposition of subjects and reasons for exclusion Disposition and reasons for exclusion
Cases
Total forms mailed Forms never returned Forms returned Included in the analysis Excluded Case with negative chest radiograph Forms returned unopened by post oce `moved away' Exceed age limits of study Written letter of refusal Subject blind Subject illiterate Deceased Case not actually pneumonia (alternative diagnosis made) Case of pneumonia due to obstruction Case already included for previous pneumonia History of pneumonia as adult
Number (%)
Controls
200 14 (7%) 186 (93%) 66 (33%) 120 107 (535%) 0 0 0 1 (05%) 0 5 (25%) 2 (1%)
661 90 (136%) 571 (864%) 489 (739%) 82 Ð 31 (46%) 23 (34%) 5 (08%) 0 1 (01%) 6 (09%) Ð
3 (15%) 2 (1%) Ð
Ð Ð 16 (24%)
TABLE 2. Demographic variables and environmental exposures Variables Demographic Male sex Age Married Unemployed Social class I II III non-manual III manual IV V Environmental Exposures Child contact Gas stove Gas heat Bird Animal Dusty occupation
Cases
Controls
Odds ratio
95% CI
36/66 (55%) 544+SEM 48/66 (73%) 6/66 (9%)
220/489 (45%) 439+SEM 075 324/489 (66%) 37/489 (8%)
147
085±254
136 122
074±251 044±319
077 067 092 095 056 171
042±139 039±117 046±185 040±218 031±099 096±304
11 13 29 5
0 (19%) (22%) (50%) (9%) 0
20/65 (31%) 33/64 (52%) 51/64 (80%) 8/64 (13%) 23/64 (36%) 25/63 (40%)
13 (3%) 87 (20%) 97 (23%) 145 (34%) 61 (14%) 28 (7%) 178/486 (37%) 300/489 (61%) 394/486 (81%) 63/480 (13%) 239/476 (50%) 134/482 (28%)
RISK FACTORS FOR PNEUMONIA 425 men was higher than for controls, but this dierence was not signi®cant. The distributions of social class, marital status and employment were similar for cases and controls (Table 2).
EXPOSURES Cases were somewhat more likely to record a history of a dusty occupation than were controls (40% vs. 28%, P=0071), but there was no more contact with children, gas stoves, gas heating, birds, or other animals among cases (Table 2).
SMOKING HISTORY Cases and controls were equally likely to be current smokers but cases were signi®cantly more likely to be exsmokers (Table 4). Lifetime consumption of cigarettes (computed as the product of the number of cigarettes smoked per day currently or 1 year before, whichever was greater, and the number of years smoked) was signi®cantly greater for cases than for controls (P = 003). There were trends toward higher numbers of cigarettes smoked by cases than by controls in each age stratum when the two groups were strati®ed by age. The reported rates of passive smoke exposure were similar for cases and controls (Table 4).
UNDERLYING ILLNESSES The only diseases which were signi®cantly more frequent among cases were chronic obstructive pulmonary disease (COPD) and congestive heart failure (Table 3).
ALCOHOL HISTORY There was no signi®cant dierence between the rates of current or lifetime alcohol consumption for cases and controls.
MULTIVARIATE ANALYSIS Each variable showing signi®cance in univariate analysis was then analysed in a stepwise, multiple logistic regression. Only age (adjusted odds ratio = 269 [for 30-year increment], 95% CI 166±435) and chronic obstructive pulmonary disease (adjusted odds ratio = 199, 95% CI = 115 ± 345) were found to be independent risk factors in this multivariate analysis (Table 5).
TABLE 3. Underlying illnesses as risk factors for pneumonia
Respiratory Chronic obstructive pulmonary disease Asthma Tuberculosis Chest Injury Hay fever Acute sinusitis Chronic sinusitis Pneumonia in childhood Non-respiratory Diabetes Cancer Chronic renal failure Congestive heart failure
Cases
Controls
Odds Ratio
95% CI
27/66 (41%)
103/478 (22%)
252
142±446
3/62 (5%) 1/65 (2%) 1/63 (2%) 4/58 (7%) 6/56 (11%) 4/57 (7%) 6/57 (11%)
16/479 (3%) 12/486 (2%) 17/484 (4%) 50/477 (10%) 48/460 (10%) 9/478 (2%) 29/449 (6%)
147 049 044 063 103 393 170
033±558 002±361 002±324 019±192 038±267 098±1462 060±457
2/65 (3%) 1/66 (2%) 0/63 (0%) 9/65 (14%)
6/479 (1%) 14/486 (3%) 2/482 (04%) 7/483 (2%)
250 052 000 1093
034±1411 003±386 000±3163 356±3412
Odds ratio
95% CI
098 078 080 199
052±188 040±150 043±147 114±347
TABLE 4. Exposure to cigarette smoke Cases Passive smoking in home in childhood in adulthood Current smokers Former smokers
45/61 15/65 18/66 29/66
(74%) (23%) (27%) (44%)
Controls
358/483 117/421 155/485 137/485
(74%) (28%) (32%) (28%)
426
B. M. FARR ET AL.
TABLE 5. Signi®cant results of multiple logistic regression Variable Age 30-year increment 63-year increment COPD
Adjusted odds ratio
95% CI
269 825 199
166±435 296±2300 115±345
Discussion Most previous controlled studies of risk factors for community-acquired pneumonia have dealt only with patients admitted to hospital, probably because most investigators are hospital-based and patients admitted to hospital have more severe disease. However, since most patients with pneumonia are treated as outpatients, the majority of cases of community-acquired pneumonia are excluded from such studies (16,28,33). Published case series have identi®ed chronic obstructive pulmonary disease and age as possible risk factors for pneumonia among patients with disease severe enough to warrant hospital admission (11,14,15,17±25,34±38) Four epidemiological studies have con®rmed that chronic obstructive pulmonary disease was associated with cases of pneumonia admitted to hospital (5,12,16,26). One of these studies found that chronic obstructive lung disease was also a signi®cant risk factor for pneumonia cases not admitted to hospital (RR=30. 95%CI 23±39) (16); other signi®cant risk factors included alcoholism, asthma, immunosuppressive therapy, heart disease (type unspeci®ed) and age. Two of these epidemiological studies demonstrated that cigarette smoking was an independent risk factor after accounting for chronic obstructive pulmonary disease and age (5,26). Another controlled study of patients with pneumococcal infections, a majority of which were pneumonias, also found a signi®cant excess of smoking in cases as compared with controls (13). The present study found that patients with pneumonia diagnosed by general practitioners in the community were signi®cantly older and had a higher frequency of chronic obstructive pulmonary disease than randomly selected controls from the same communities. These data suggest that the milder cases of pneumonia diagnosed in the community, which generally do not result in hospital admission, share an epidemiology similar to that of the more severe cases which require admission. The study of pneumonia epidemiology conducted in Finland also found that risk factors were similar for cases of communityacquired pneumonia whether or not they were admitted to the hospital. The only discrepancy in that study for pneumonia cases admitted and those not admitted to hospital was the ®nding that alcoholism was a signi®cant risk factor only for cases not admitted to the hospital (16). Patients with pneumonia in the present study were signi®cantly more likely to have congestive heart failure than control subjects con®rming an association with heart disease noted by Koivula et al. (16) Lipsky et al. also found
an association with heart failure in a study of pneumococcal infections, 92% of which were pneumonias (13). Heart failure did not remain signi®cantly associated with cases in the multiple logistic regression analysis of the present study, but as with smoking history, this may have been due to the relatively small number of cases involved and low statistical power to detect such an association. The sample size was smaller than planned because two thirds of those diagnosed as having pneumonia based upon history and physical exam had no in®ltrate on chest radiograph. This in turn resulted in a lower statistical power than planned (i.e., 88% power to detect a signi®cant dierence with an alpha value of 005 between a prevalence rate of 12% in cases and 2% in controls). This power calculation applies to a univariate statistical test, however. Power for detecting statistical signi®cance in such a dierence in multivariate analysis after adjusting for other signi®cant dierences would be still lower. It should be noted that the present study occurred during a year in which very few Mycoplasma pneumoniae infections were diagnosed (28). This disease occurs with a dierent epidemiology more as a contagious disease among young adultsÐin marked contrast to the types of bacterial pneumonia that predominated in this study (39,40). The results of the present study suggest that the human lung is compromised by age and by cigarette-induced chronic lung disease and thereby predisposed to episodes of acute bacterial pneumonia. Both of these factors are biologically plausible as the rate of mucociliary cleansing of the respiratory tract is diminished both with age and with cigarette smoking (41). Smoking appears to be the major avoidable risk factor for acute, community-acquired pneumonia in adults.
Acknowledgements This study was supported by a grant from the Milbank Memorial Fund, New York, N.Y. Mark Woodhead was supported by a grant from the Chest, Heart and Stroke Association. We thank Donna McGraw, Linda Wilson, Janet Moore-Coll, Helen Nor¯eet-Shi¯ett, and Angelia S. Cempre for their assistance in preparing the manuscript.
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