The epidemiology of acute respiratory infections in children and adults: a global perspective.

Vol. 12, 1990

EPIDEMIOLOCIC REVIEWS

Copyright © 1990 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved

Printed in U.S.A.

THE EPIDEMIOLOGY OF ACUTE RESPIRATORY INFECTIONS IN CHILDREN AND ADULTS: A GLOBAL PERSPECTIVE NEIL M. H. GRAHAM

Although recognition of acute respiratory infections as important causes of mortality (primarily among children in the developing world) and morbidity (in both developed and developing countries) has been slow in coming (1, 2), important advances have been made in understanding the epidemiology of these infections. Studies of risk factors for acute respiratory infections have been conducted predominantly in the developed world for reasons of funding availability, logistics, and availability of an infrastructure capable of supporting large multidimensional epidemiologic studies. In general, results of epidemiologic studies conducted in the developed world have limited applicability in developing countries where risk factor exposures are often of a significantly greater magnitude or nature. However, despite chronic underfunding of this type of research, a number of promising areas of epidemiologic investigation are being pursued, including nutritional risk factors and the effects of indoor and outdoor air pollution. In this paper, the current state of knowledge regarding the magnitude, etiology, and risk factors for acute respiratory infections is reviewed, in addition to addressing the major methodologi-

Received for publication November 30, 1989, and in final form May 3, 1990. Abbreviations: AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; RR, relative risk; CI, confidence interval. From the Department of Epidemiology, The Johns Hopkins University School of Hygiene and Public Health, 624 N. Broadway, Room 895, Baltimore, MD 21205. (Reprint requests to Dr. N. M. H. Graham.) The author thanks Dr. Antonio Pio of the World Health Organization, Dr. Ronald Davis of the Office on Smoking and Health, and Dr. Robert M. Douglas of the Australian National University for their assistance. 149

cal problems and requirements for future research. MAGNITUDE OF THE PROBLEM

Developing countries The greatest problem for developing countries is the mortality from acute respiratory infections in children less than 5 years of age. Estimates of mortality associated with respiratory infection have been developed from the work of Bulla and Hitze (3), Gwatkin (4), and Leowski (5). Gwatkin (4) estimated that each year in the late 1970s and early 1980s approximately 15 million children under the age of 5 years died. Based on estimates that 25-33 percent of this mortality would have been attributed to acute respiratory infections, Leowski (5) calculated that 2.5 million infants and 1.5 million children aged 1-4 years would die from these infections each year. If developed countries can be defined as those with infant mortality rates of 25/ 1,000 or less, 98 percent of those deaths from acute respiratory infections in infants and 99 percent of those in children 1-4 years of age occur in less developed countries. Following the same reasoning, countries with infant mortalities of > 100/1,000 contribute 58 percent of the deaths in infants and 66 percent of those in children 14 years of age. These estimates may underestimate the magnitude of the problem since they are based on national mortality reporting systems of varying quality. Even the better systems may underreport overall and specific mortality rates, while data from less established systems may be highly unreliable. Apart from these estimates, other published data also reflect large differences in

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mortality rates from respiratory infections between developed and developing countries. In 1977, infant deaths from pneumonia and influenza were five times higher in Costa Rica, and 30 times higher in Paraguay, than in the United States (6). For Filipino infants, pneumonia death rates have been reported to be 24 times higher than in Australian infants and 73 times higher than in Australian children aged 14 years (7). The Pan American Health Organization has reported pneumonia deaths in Peru as being 37 times higher in infants and 43 times higher in children aged 1-4 years compared with rates in North America (8). Although the accuracy of these rates must be open to question (since they rely on reporting mechanisms of variable fallibility) they do illustrate the magnitude of the differential. Despite this large difference in mortality, data from a number of studies suggest that morbidity rates from respiratory infections may be similar in developed and developing countries. In Tecumseh, Michigan, infants experienced a mean of 6.1 episodes of respiratory illness per year and children aged 1-4 years experienced a mean of 5.2 episodes per year (9). In the Seattle (Washington) Virus Watch from 1965-1969, infants experienced 4.5 mean episodes per year (10). These rates are remarkably similar to those reported in urban settings in Costa Rica, 4.9 and 5.7 episodes of respiratory illness per year, respectively (11); India 7.3 in children aged

< 3 years and 6.2 in children aged 3-5 years (12); and Ethiopia 7.9 in children aged < 3 years and 6.6 in children aged 3-5 years (13). These data suggest that severity, rather than incidence of acute respiratory infection, explains the developed/developing world differentials in mortality. However, these data should be reviewed with some caution, since the studies used widely differing methodologies and may not be directly comparable. More recent data from the National Research Council studies of respiratory infection in young children in 12 countries (14) suggest that the incidence in the first year of life is in the range of five to nine episodes. Developed countries The incidence rates of minor episodes of respiratory illness (chiefly upper respiratory tract infections) do not appear to have varied much over the past 60 years in the United States (9, 15-17). Although studies have examined populations of differing compositions, as well as utilizing differing study methodologies and definitions of acute respiratory illness, the reported agespecific incidence rates have remained remarkably stable (9, 15-17). In contrast to this, pneumonia mortality rates have fallen in all age groups, except the elderly, over a similar time period. Age-specific mortality rates from pneumonia and influenza in the United States from 1968 to 1986 are shown in table 1. Since 1981, mortality rates have

TABLE 1

Age-specific mortality rates from pneumonia and influenza in the United States, 1968-1986* Age (years)

Year 1968 1970 1971 1973 1975 1977 1979 1981 1983 1986

60 per minute,

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TABLE 2

Classification of acute respiratory infection clinical syndromes Case management classification (children aged 2 months-4 years) Stridor

Wheezing

Mild Mild Hoarseness plus Improves with "barking" bronchodilator; cough; no strirespiratory rate dor when calm •• 70/ min. = severe bronchiolitis or asthma Admit; bronchodilators; consider oxygen and antibiotics

Severe Respiratory rate >50/min.; chest indrawing = severe pneumonia Admit; antibiotic

Lower respiratory tract syndromes Bronchiolitis Bronchitis Pneumonia

Very severe Cyanosis or inability to drink = very severe bronchiolitis or asthma Admit; bronchodilators; oxygen; consider antibiotic

Very Severe Cyanosis or inability to drink = very severe pneumonia Antibiotic; admit; oxygen

" URI, upper respiratory tract infection.

EPIDEMIOLOGY OF ACUTE RESPIRATORY INFECTIONS

severe chest indrawing, respiratory grunt) when deciding whether to give antibiotics and to admit into hospital (29).

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ondary bacterial infection. In children, lower respiratory viral illnesses are chiefly caused by respiratory syncytial virus, parainfluenza virus types 1, 2, and 3, influenza Clinical classifications of acute respiratory virus types A and B, adenoviruses, and infections enteroviruses. These viruses can all cause Although somewhat arbitrary, acute re- bronchiolitis, croup, and pneumonia in spiratory infection syndromes have been children, but respiratory syncytial virus is often classified by the site of primary pa- most commonly associated with bronchiothology (table 2). This system of classifi- litis and parainfluenza virus (especially cation does lead to some confusion since type 1) with croup (35-38). In developing infections are not always limited to one part countries the spectrum of viruses causing of the respiratory tract and clinicians often croup may be different, with measles playdisagree on what is "upper," "middle," and ing a more important role (39, 40). Al"lower." In addition, stridor-causing con- though often classified as a viral exanthem, ditions have often been classified as upper the frequent association of measles with respiratory tract infections, which leads to severe acute lower respiratory tract infecanother source of confusion since this clas- tion in developing countries means it is sification is often held to be synonymous often considered as an etiologic agent of with mild disease. Since these conditions acute respiratory illness in that setting (41). can be fatal and may inadvertently be clas- In the developed world it is not a serious sified as acute lower respiratory infection cause of mortality in children (42). In genby primary health care workers (on the eral, however, virologic causes of acute inbasis of respiratory distress), consideration fection of the lower respiratory tract in has been given to classifying stridor causing children appear to be similar in both deconditions within this category (32). None- veloped and developing countries (39, 41, theless, classification by anatomic site re- 43-50). mains the preferred system for most phyViral causes of pneumonia in adults are sicians and is compatible with the generally less important than nonviral International Classification of Diseases sys- causes. However, influenza has been assotem. ciated with a significant proportion of adult pneumonias, perhaps causing as many as half of viral pneumonias and about 8-10 ETIOLOGIC AGENTS IN COMMUNITY percent overall (18, 51). Respiratory synACQUIRED ACUTE RESPIRATORY cytial virus and parainfluenza have also INFECTION been identified in some cases but appear to Viruses be less important than influenza (52). In In both children and adults, upper respi- adults aged 65 years and over, influenza ratory viral illnesses are caused by rhino- epidemics are associated with markedly inviruses (30-50 percent), coronaviruses (5- creased mortality and hospitalization rates 20 percent), influenza virus, parainfluenza from acute respiratory illness and represent virus, respiratory syncytial virus, adenovi- a major health risk to this age group in ruses, and certain enteroviruses (33, 34). developed countries (53). Viral causes of Upper respiratory tract infections are gen- lower respiratory tract infection in adults erally mild, self-limiting, and do not involve in developing countries have not been respiratory distress. Their importance in widely studied, but may be similar to dedeveloped countries is largely economic veloped countries. through days lost from work and school In most epidemiologic studies, isolation and costs of symptomatic treatment. How- of viral agents has been limited in the past ever, in developing countries, they may her- by the laboratory techniques available. Isoald the onset of pneumonia caused by sec- lation of virus from 20 to 25 percent of

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specimens has been the maximum rate in a number of well-conducted studies (21, 36, 54-56). However, recent improvements in these techniques might make higher isolation rates more common. A recent study of lower respiratory tract infection in infants reported a 66 percent positive isolation rate using combinations of viral culture and immunofluorescence techniques to identify viral antigens from throat and nasopharyngeal swabs (22).

countries causing somewhere between < 1 to 30 percent of hospital cases of community acquired pneumonia (see Reingold (63)). In otitis media, S. pneumoniae and H. influenzae are the most commonly isolated bacteria (64), but Branhamella cattarrhalis has been isolated in 27 percent of cases in some series (65). S. pneumoniae and H. influenzae are also important in acute sinusitis in children (66) and adults (67, 68). Bacteria also cause pharyngitis/ tonsillitis (Streptococcus pyogenes, CoryneBacteria bacterium diptheriae), acute epiglottitis (H. The major methodological problem en- influenzae type B), and whooping cough countered in studying the bacterial causes (Bordello pertussis) (34, 69, 70). of pneumonia is contamination of sputum Other agents specimens by nasopharyngeal and orophaThe most important nonbacterial, nonryngeal organisms (57). Thus, sputum cultures are of limited value. Bronchoscopic viral respiratory pathogens are Mycoplasma and transtracheal aspirates are also at risk pneumoniae, Chlamydia sp., and Pneumoof contamination (58, 59), so most investi- cystis carinii. M. pneumoniae is most imgators rely on percutaneous needle lung portant as a cause of pneumonia and acute aspirates and blood culture for accurate bronchitis in both children and adults (21, diagnosis (60). In the developed world most 37, 71, 72). It may also cause upper respicases of lower respiratory infection in chil- ratory illness (71, 73). Chlamydia trachodren are viral in etiology (19, 21), but in matis causes pneumonia in young infants developing countries mortality from bacte- (74), but Chlamydia pneumoniae (also rial pneumonia is the major problem. Stud- called TWAR) appears to be more impories of bacteria isolated from children in tant as a cause of acute respiratory illness developing countries using lung aspiration (including pneumonia) in older children techniques have been reviewed by Berman and adults (74-76). P. carinii, a previously and Mclntosh (34). The most important rare cause of pneumonia, has rapidly acorganisms identified in these studies were quired major importance as a respiratory Hemophilus influenzae, Streptococcus pathogen in persons afflicted with the pneumoniae (together accounting for 54 acquired immunodeficiency syndrome percent of isolates), and Staphylococcus au- (AIDS). Approximately 60-80 percent of reus (accounting for 17 percent of isolates). AIDS patients will develop P. carinii pneuA small recent study from Zimbabwe ap- monia at some stage during the course of pears to confirm the findings of these older their illness (77, 78). In developed counstudies (61). The best data on etiology of tries, both children and adults are at sigpneumonia in adults come chiefly from hos- nificant risk, but the importance of P. pital studies in developed countries (52). S. carinii (secondary to human immunopneumoniae is by far the most important deficiency virus infection) in the developing cause of pneumonia in adults, being asso- world, although apparently less, has not ciated with up to 70 percent of cases (51, been clearly defined (79). 62), with H. influenzae and Staph. aureus RISK FACTORS being relatively less important than in children (together about 10 percent of cases). Demographic factors—age and sex Legionella sp. are also important bacterial A large number of studies have shown etiologic agents in adults in developed that the incidence of viral respiratory ill-

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ness peaks in infancy and early childhood and steadily reduces with age (10, 15-17, 80, table 3). This trend is generally attributed to changing patterns of exposure and the acquisition of specific immunity to an increasingly large array of virus types occurring with age. However, a different pattern of age-related change is observed when examining markers of more severe conditions such as pneumonia and influenza mortality rates. Although infants are at greater risk from pneumonia than older children and young to middle aged adults, mortality rates are highest in the elderly (table 1). Factors such as reduced respiratory muscle strength, reduced vital capacity, and impaired local and general immune defenses in older age groups may explain the increased susceptibility of this age group to severe acute lower respiratory infection. Pneumonia and influenza mortality rates have increased in recent years within older age groups (table 1) for reasons that are not known, but possibilities that should be investigated include changing virulence of respiratory pathogens and increased cumulative exposures to environmental factors such as smoking and air pollution in the relevant age cohorts. The simplest explanation may be that many more at-risk persons are surviving into this age group (e.g., with cardiovascular disease and chronic airways obstruction) and suffering pneumonia as a terminal event. Data on pneumonia mortality rates over the entire age range in developing countries are sparse, with many nations in Africa and Asia, in particular, not reporting to the World Health Organization (81). Nonetheless, data from Costa Rica and Cuba are available, and although they are not among the poorest nations of the world, they do reflect developing country mortality patterns (6). Both countries show an excess burden of mortality in infants and young children. In Costa Rica, in particular, rates in older children and younger adults are not greatly higher than those in the United States. In all three countries, mortality rates rise rapidly in the

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Outdoor air pollution In the earlier part of this century, episodes of acute, severe, particulate air pollution (Meuse Valley, Belgium, 1930; Donora, Pennsylvania, 1948; New York, New York, 1953 and 1962; and Greater London, England, 1948,1952, and 1956) led to rises in all-cause mortality chiefly because of increased deaths from pneumonia and cardiovascular disease (82-88). In the disastrous London fog of 1952, an

•H 00 CO respectively, in children (89). In 1971, Collins et al. (96) reported that pneumonia and respiratory disease mortality in England and Wales from 19581964 were most strongly associated with air pollution in infants. A weaker but still significant relation was also observed in children aged 1-4 years. In a study of Los Angeles college students, Durham (97) found that upper respiratory symptoms reported by students presenting to campus health centers were significantly correlated with sulfur dioxide and nitrogen dioxide levels independent of the effects of age, weather, and smoking levels. French et al. (98) studied sulfur dioxide and suspended sulfate levels in the Great Salt Lake Basin, Utah, the Rocky Mountains, New York, New York, and Chicago, Illinois. In the Great Salt Lake Basin and the Rocky Mountains, high pollution levels were associated with excess reports of croup in children (age-, sex-, social class-adjusted rates) who resided in a high pollution area for more than 3 years. In Chicago, acute upper and lower respiratory tract illness attack rates were reported to be higher in both adults and children, but in New York only lower respiratory tract illness attack rates were significantly higher in residents of high pollution areas. Levy et al. (99) found that high levels of sulfur dioxide and particulate matter, but not nitrogen dioxide, carbon monoxide, or pollen, predicted hospital admission for acute respiratory disease in children and adults, after adjusting for the effects of temperature. More recent studies have examined the effects of air pollution at much lower levels than earlier work, and have endeavored to ascertain which components of air pollution are the most important. Study designs that allow concurrent comparisons with similar demographic areas and adjustment

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for confounding factors (e.g., the Six Cities Study (100)) have also been helpful in clarifying the role of outdoor air pollution in increasing susceptibility to acute respiratory illness in recent times. Ware et al. (100) found that between city annual mean differences in particulate and suspended sulfate concentrations as low as 80 /xg/m3 doubled the risk of acute cough and substantially increased risk of bronchitis and other lower respiratory illness in children. Associations with sulfur dioxide were weaker, but significant. Derriennic et al. (101) found sulfur dioxide (but not particulates or nitrogen dioxide) levels predicted deaths from respiratory disease in adults over 65 years of age. Mean monthly peaks of sulfur dioxide did not exceed the 80-200 Aig/m3 range. In another study (102), 24hour fine-particulate levels as low as 50 /xg/ m3 were associated with significantly increased hospitalization rates in children and adults for acute respiratory disease. The associations were stronger for bronchitis/asthma than for pneumonia/pleurisy, and persisted when adjustments were made for meteorologic variables. Other studies have confirmed the importance of the association between particulates, sulfur dioxide, and respiratory symptoms in children (103, 104), but the importance of ambient levels nitrogen dioxide as a risk factor for respiratory illness is less certain (103, 105). Ozone exposures below the US ambient air quality standard have been associated with acute changes in ventilatory function (106) and increased risk of cough and lower respiratory illness (107). Overall, the evidence is now supportive of the hypothesis that suspended particulates, suspended sulfates, and sulfur dioxide at levels currently being measured in ambient air significantly increase risk of morbidity from acute respiratory illness in adults and children. However, since most studies do not include virologic sampling, it is unclear whether this morbidity is chiefly caused by bronchial reactivity and respiratory tract irritation or by the effects of infection. Studies supported by virologic

culture and serology are needed to answer this question. In those persons at greater risk (e.g., the elderly), in addition to increased respiratory morbidity there may also be a concomitant increase in risk of mortality. Data on nitrogen dioxide are somewhat less convincing and it is too early to assess the importance of ozone as a risk factor for acute respiratory illness. Indoor air pollution Passive smoking, nitrogen dioxide from gas cooking/heating, and smoke from biomass fuels are the three sources of indoor air pollution most often investigated in relation to acute respiratory infections. In children, many studies have focussed on chronic respiratory symptoms or pulmonary function test abnormalities in relation to passive smoking (108-111), but a substantial body of data also exists for risk of acute respiratory illness with exposure to passive tobacco smoking (112-118). Exposure to passive smoking is only associated with increased risk of acute respiratory illness in the first 2 years of life (117), and maternal smoking seems more important than paternal smoking (112, 117,118). Exposure to maternal cigarette smoke appears to approximately double the risk of lower respiratory tract illness in the first 2 years of life (116,118,119). Negative studies have also been reported (120-122), but have been hampered by factors such as small numbers (122) or did not report on smoking effects in children under 2 years of age (120, 121). More recently, studies have focussed on the effects of maternal smoking during pregnancy on risk of respiratory infection in infants. Taylor and Wadsworth (123) reported that prenatal smoking was a stronger risk factor for bronchitis in infants than postnatal smoking. Woodward et al. also examined this issue (118). Results were equivocal but suggest that postnatal smoking was at least as important as prenatal smoking. The number of women who change smoking habit during or after pregnancy is small, and it may remain difficult to identify large enough comparison groups


to fully settle this question in the future. The effect of passive smoking on respiratory infections in adults has not been well characterized and reports of its effects on chronic respiratory disease in adults have been inconsistent (124-126). Natural gas cooking and heating stoves increase exposure of household members to nitrogen dioxide (127, 128), but at the relatively low levels attained in houses in developed countries it remains unclear whether these exposures significantly increase risk of respiratory illness despite numerous studies designed to test this question in children and adults (105, 109, 129-132). In our studies of children in Adelaide, those who had gas heating in their homes were more likely to be prone to acute respiratory illness than those with electric heating, but the level of significance was marginal (odds ratio = 1.6; 95 percent confidence interval (CI) 1.0-2.6) (133). Based on current data, any effects attributable to nitrogen dioxide exposures are likely to be very small, if they exist at all (134). Of potentially far greater public health importance are the effects in children of smoke from the biomass fuels used for cooking in developing countries. Children in many developing countries are exposed to peak and daily indoor concentrations of respirable particles from these fuels that have been estimated to be about 20 times higher than the levels experienced in a developed country where two packs of cigarettes are smoked per day (134), a level at which the risk of many respiratory symptoms approximately doubles (119). In a study in Nepal, Pandey et al. (135) found a relation between hours per day spent near a stove and episodes of severe acute lower respiratory tract illness in children under age 2 years. However, in this study no adjustment was made for confounding factors (such as parental smoking). Campbell et al. (136) recently reported that children carried on their mother's back during cooking periods were at 2.8 times greater risk of an episode of "fast or difficult breathing" than children not so carried. Maternal reports of fast or

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difficult breathing were predictive of acute lower respiratory illness in another study (137). Kossove (138) found that Zulu infants presenting to a medical clinic with acute lower respiratory illness were more likely to be exposed to cooking smoke at home than children without respiratory illness, but the study was small and poorly controlled. These studies have been methodologically difficult, because in high acute respiratory infection incidence areas, exposure to indoor smoke is universally high and measurement of exposure dose is problematic. Intervention studies in high incidence areas appear to be the answer, but interventions such as building fluted stoves or providing smokeless fuel might not be economically feasible in many instances. Interestingly, in a US study (139, 140), children from homes with wood-burning heating stoves experienced more acute upper and lower respiratory tract illness than children from homes without stoves. Unfortunately, the levels of the many gases, chemicals, and respirable particulates in wood smoke were not reported for either group, but the relation was not explained by social class, smoking, or other indoor sources of air pollution. Another study in the United States, using a retrospective design, found no relation between wood smoke exposure and respiratory illness in school-age children, suggesting that younger children may be those most at risk (141). Smoking Smoking was first linked to acute respiratory infection in a number of prospective studies conducted in the late 1950s (142— 148). These data suggested that smokers were at increased risk of dying from pneumonia and influenza. From these seven studies, the overall pneumonia/influenza mortality ratio in smokers was 1.4, although the ratios ranged from 0.7 to 2.6. Since these early reports, there have been surprisingly few studies of smoking and acute respiratory disease, with most attention focusing on the much stronger rela-

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tions of smoking to lung cancer and chronic obstructive lung disease (148-150). Nonetheless, it has been shown in a number of studies that smoking is associated with increased severity and incidence of influenza (151-154). Kark et al. (154) reported that the attributable proportion of influenza ascribable to smoking was 31 percent for all influenza cases and 41 percent for severe influenza cases. Monto et al. (155) studied the incidence of respiratory illness in smokers and nonsmokers in the Tecumseh study; in otherwise healthy index cases in this family-based study, both male and female smokers experienced more episodes of acute respiratory illness than nonsmokers. This was also the case with index cases who had low forced expiratory volume values, but not those who reported having "chronic bronchitis." In another report, Monto and Ross found no direct association between smoking and acute respiratory illness but did between history of chronic respiratory symptoms and acute symptoms (156). However, in a number of other studies, adolescents and young adults who smoke have reported more respiratory symptoms than nonsmokers (157-159). In addition to the recognition of smoking as an important independent risk factor for Legionnaires' disease (63), the available data suggest that smoking significantly increases the risk of pneumonia incidence and mortality. In a recent community based study of pneumonia, Woodhead et al. (160) reported that only 100 of 236 cases (42 percent) were current smokers, but that 175 of 236 cases (74 percent) had smoked "at some time." No data from a control group were available in this study. Lipsky et al. (161) found that smoking independently increased the risk of pneumococcal infections fourfold in their study of "high risk" adults. Petitti and Friedman (162) also found smokers to be at greater risk of pneumonia (and influenza), but the risk appeared to be lower in those smoking low-tar cigarettes. Simberkoff et al. (163), on the other hand, found no relation between pneumonia mortality and smoking in high-risk patients. In

the American Cancer Society's 25-state study in 1959-1965, male smokers were at greater risk of dying from influenza and pneumonia (International Classification of Diseases, Seventh Revision, codes 480-481, 490-493) than male nonsmokers (relative risk (RR) = 1.82; 95 percent CI 1.45-2.27), but women smokers were not at increased risk. However, in the 50-cities study in 1982-1986, risk of mortality from pneumonia and other respiratory disease (International Classification of Diseases, Ninth Revision, codes 010-012, 480-489, 493) was significantly increased in both current male (RR = 1.99; 95 percent CI 1.52-2.61) and female (RR = 2.18; 95 percent CI 1.602.97) smokers aged 35 years and over (164). Crowding—housing, day care, family size Because respiratory infections are contagious diseases, general conditions of crowding favor their propagation. Woods (165), as far back as 1927, reported a highly significant correlation between the proportion of overcrowded houses in a borough (two or more persons per room) and pneumonia mortality in England and Wales. The strongest correlations were in the 0-5 year age group, although an effect was also seen in the 45-64 and 65-74 year age groups. In 1945, Payling-Wright and Payling-Wright (166) confirmed these findings by reporting strong correlations between crowding (persons per room and number of children per family) and mortality from bronchopneumonia in children under 2 years of age. Pneumonia epidemics have also been observed in crowded living conditions in South African mining camps, during the construction of the Panama Canal, and in Civilian Conservation Corps barracks (167). Collins et al. (96) also reported significant correlations between crowding and death from bronchopneumonia in infancy, but pointed out that the relation was confounded by indices of air pollution, social class, and educational status, given the high intercorrelation of these factors. More recent studies have focussed on family size as a measure of crowding.


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The number and age of siblings in families lower respiratory infection, there are repredicts the incidence of bronchitis and markably few epidemiologic data available pneumonia in infants (114), rates of acute that conclusively support this view. Since respiratory illness in older children and malnutrition is very closely correlated with adults (156), and rates of acute lower respi- crowding, poverty, poor education, and ratory tract infection in infants (122). Aaby poor housing in developing countries, it has et al. (168) reported that a decline in mea- proved difficult to identify an independent sles mortality in Guinea-Bissau following effect of this factor on risk for respiratory introduction of a vaccination program oc- infection (168, 169, 176). However, when curred despite increasing malnutrition and taken together with studies of vitamin A lower age at infection. Lower mortality was and breast feeding, the picture regarding associated with low clustering of cases (i.e., malnutrition and respiratory infection is isolated cases had a lower mortality than becoming somewhat clearer. clustered cases). Aaby (169) has argued that Gomez et al., in 1956, reported that morintensive exposure to measles virus through tality in hospitalized, underweight Mexican overcrowding and case clustering is a more children was often associated with severe important factor than malnutrition in pre- diarrhea and acute bronchopneumonia dicting mortality from this disease. He cites (177). In 1972, James (11) published the evidence that mortality is high when a high results of a study from Costa Rica where proportion of measles patients have sec- the relation of malnutrition (comparison of ondary cases as support for this hypothesis weight with standard measures) and respi(169). Given the extreme level of confound- ratory illness was examined in poor chiling between malnutrition and crowding as dren under the age of 5 years. Low-weight risk factors for acute respiratory infection, children experienced no more upper respiit will require some considerable effort and ratory illness than normal-weight children, care to tease out the separate effects of but episodes were of longer duration. Howthese factors. Nonetheless, this is not a ever, in unadjusted analyses, malnourished trivial question and should be pursued fur- children experienced 2.7 times more bronther. With limited resources for interven- chitis, 19 times more pneumonia, and were tion, determining more precisely the attrib- far more likely to be hospitalized. Escobar utable risks for crowding/clustering and et al. (41) studied children hospitalized with malnutrition in relation to acute lower re- lower respiratory illness and found that spiratory infection in developing countries mortality increased in relation to level of would help in focussing interventions and malnutrition (weight for age). Berman et improving cost effectiveness. al. (39) found a significant relation between In developed countries, the increasing malnutrition and pneumonia, but not bronutilization of day-care centers for children, chitis or tracheobronchitis in children atas mothers increasingly enter the paid tending health centers in Cali, Columbia. workplace, has led to another illustration More recently, Tupasi et al. (176) reported of the effects of crowding. Children attend- an increased relative risk of 27 for mortality ing group day-care centers are at increased from pneumonia in hospitalized children risk of acute upper and lower respiratory with third degree malnutrition, with relatract infections (122, 170,) and, in particu- tive risks of 11.3 and 4.4 for second and lar, increased risk of acute otitis media first degree malnutrition, respectively. In (171-174), although not all studies have the same report, malnutrition was not related to incidence of respiratory morbidity shown a relation (175). in multivariate analyses, reportedly because of strong confounding from socioecoNutrition nomic status. Despite the widely held belief that malInterest in the relation between vitamin nutrition increases risk of severe, acute

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A and respiratory infection started with the finding of Sommer et al. that vitamin A deficiency in children was associated with increased morbidity from respiratory infection and increased overall mortality (178, 179). In a subsequent intervention study in Indonesia (180, 181), the same group reported a 34 percent reduction in overall mortality, but the reduction attributable to respiratory infections was not reported. Vitamin A supplementation has also been reported to reduce mortality from measles in a hospital-based study in Tanzania (182). In well nourished Adelaide children, Pinnock et al. undertook two placebo controlled Vitamin A intervention studies (183, 184). In the first study, respiratory morbidity in children with a history of frequent respiratory illness was reduced by 19 percent in those taking the supplement (183). However, this finding was not replicated in the second study where children aged 2-7 years who had an episode of bronchiolitis in the first year of life were followed up for 12 months; no differences in respiratory morbidity were found (184). In Thailand, children with deficient serum retinol were four times more likely to experience respiratory morbidity than nondeficient children (185). This study also found supplementation with vitamin A offered some protection against respiratory illness, but this varied by age and length of follow-up, probably because of small sample size. Clearly, further studies are needed to more conclusively determine what effects vitamin A supplementation has on morbidity and mortality from acute respiratory infections. It seems likely that beneficial effects will be limited to populations whose diets are significantly deficient in the vitamin. Vitamin C has been advocated as a prophylaxis and treatment for upper respiratory tract infections. A number of placebocontrolled trials have been undertaken but, generally, the results have been unimpressive in both treatment (186, 187) and prophylactic situations (188). In developed countries breast feeding ap-

pears to be clearly protective against the risk of acute otitis media (189, 190), but perhaps not against other types of respiratory morbidity. Many studies have reported that breast-fed babies were at significantly lower risk of respiratory illness in bivariate analyses, only to have the relation disappear after adjusting for confounding factors (118, 191-195). However, two recent reports suggest the possibility of an interaction between breast feeding and other factors such as passive smoking (118), crowding, and minority status (196). In developing countries, the weight of evidence tends to support a protective effect of breast feeding. In Rwanda, mortality from acute lower respiratory infection in hospitalized children under 2 years of age was lower in those who were breast fed (197). In Brazil, breast feeding reduced respiratory infection mortality in children in a community based study (198) and the incidence of upper respiratory morbidity, otitis media, and pneumonia in young infants (199). Whether the protective effect of breast milk is from its conferred antiinfective properties (190), improved hygiene, or from nutritional factors per se is not entirely clear. Nonetheless, improved hygiene is more likely to protect against diarrheal diseases than respiratory infections (198), and nutritional factors are less likely to be important in developed countries as the antiinfective properties of breast milk. At the opposite end of the spectrum from malnutrition, obesity was reported to be associated with increased incidence of respiratory illness in infants in one study (200), but the normal weight comparison group was breast fed far longer and were from higher socioeconomic groups, so any effect of obesity may have been confounded by these factors. Lower respiratory tract infection in early infancy A number of studies have now reported a relation between acute lower respiratory tract infection in the first 2 years of life and chronic respiratory disease in later life.


Childhood acute lower respiratory infection has been related to chronic cough in young adults (158, 201), adult mortality from bronchitis (202), and reduced ventilatory function and increased bronchial reactivity (203-206). However, the relation between early lower respiratory tract infection and subsequent acute respiratory infection morbidity has not been as thoroughly studied. Data from two studies in Adelaide suggest that a similar relation to that identified with chronic respiratory illness may exist. In a 3-year study of pneumococcal vaccine in young children, the strongest predictor of acute respiratory morbidity (recorded in respiratory-symptom diaries by the mothers) in any 6-month period was the level of morbidity from the previous 6 months (183, 207). In a case-control study in 1985 (133), young children who experienced high levels of respiratory illness morbidity (cases) were 11 times more likely to have experienced an episode of bronchitis, bronchiolitis, or pneumonia in the first year of life than children who had experienced low levels of morbidity (controls). After adjusting for use of child care, number of siblings, breast feeding, maternal stress levels, parental occupational status, sex, exposure to gas heating, low birth weight, and parental history of respiratory illness, the relation remained strong (odds ratio = 9.5; 95 percent CI 5.516.6). These preliminary data, from a prospective and a retrospective study, suggest that chest infections in infancy may predict subsequent levels of respiratory infection morbidity, at least in childhood. However, both of these analyses do not entirely disentangle acute from chronic morbidity nor did they address the etiology of symptomatology, i.e., whether it was infective or noninfective. Thus, further research is necessary to settle these questions. Another central issue is whether lower respiratory infection in early life acts as an early marker for genetically preprogrammed subsequent respiratory morbidity (chronic or acute) or whether it acts as a true risk factor by causing long-term damage to the lower respiratory tract. Until an effective inter-

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vention is available, such as a vaccine for respiratory syncytial virus, it may be difficult to determine which factor is more important. If previous respiratory morbidity predicts the level of subsequent morbidity from respiratory infections, there are also implications for statistical analyses of these types of data. Autocorrelation of this type suggests the need to control or adjust for repeated episodes of acute lower respiratory illness or the first episode can be used as the outcome for analysis. In prospective studies, Kaplan-Meier curves and Cox regression are then often used to estimate "survival time" (22). For more frequent outcomes like upper respiratory tract infections, use of the first episode as an outcome would result in loss of too much data. Fortunately, techniques such as autoregression (208) exist that allow adjustment for autocorrelated variables in multivariate models. Autoregression techniques have not been widely used in studies of acute respiratory infections. This is most likely because the magnitude and nature of autocorrelation has not been clearly defined for respiratory infections in longitudinal studies. Psychosocial factors

Studies of relations between psychosocial factors and respiratory infections have been conducted in experimental settings (209-211) and in both cross-sectional/retrospective (212-218) and prospective epidemiologic studies (219-221). All of the studies used upper respiratory infections/ illnesses as the outcomes of interest, so data on lower respiratory illness are lacking. Early cross-sectional studies reported relations between anxiety and upper respiratory illness (212), and between life changes, maladaptive coping, social isolation, unresolved role crisis, and illness behavior related to respiratory infection (213, 214). In the first report it was unclear how the outcome was measured, while in the other two studies illness behavior was addressed, but not the effects of psychosocial factors on the prevalence of respiratory infection. In

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1977, Boyce et al. (215) undertook a longitudinal study of acute respiratory infections in children but did not measure stress levels (or rigidity of family routines) until the end of the study. Nonetheless, they controlled for the effects of age, sex, race, family income, and family size in the analyses and found that high life-event scores and strict family routines were associated with increased duration and severity of respiratory illness. Other cross-sectional studies have found relations between maternal stress and bronchitis in children (217), type A personality and respiratory illness in college students (216), and poor family functioning and doctor visits for acute respiratory infections in children (218). None of these three studies could address the temporal relation between psychosocial factors and respiratory illness, and none controlled for confounding factors. However, there have also been a number of prospective studies showing that psychosocial factors may increase susceptibility to upper respiratory tract infections. In a series of studies involving experimentally induced colds at the Common Cold Unit in the United Kingdom, cognitive dissonance was associated with increased symptoms, introversion was associated with highersymptom and virus-shedding scores, and certain life changes (resulting in decreased activity) predicted virus shedding (209211). Although those reporting higher stress or anxiety levels or who appear to be more introverted might be expected to report more symptoms, the finding that these factors were also associated with virus shedding in two of the studies is more interesting. Meyer and Haggerty (221), in a longitudinal study of 16 families (n = 100), reported that stressful life events in families were four times more likely to precede an episode of streptococcal pharyngitis than to follow it. High stress levels were also significantly associated with rises in antistreptolysin 0 titer in this study. Although no adjustments were made for confounding factors, the objective outcome

measures and prospective design were strengths of this study. In another prospective study, Kasl et al. (220) studied the relation between a combination of high motivation and poor academic performance with clinical infectious mononucleosis in US Military Academy cadets at West Point, New York. During this 4-year study, cadets who seroconverted against EpsteinBarr virus were monitored, and those with an "overachieving" father, high motivation, and a poor academic record were significantly more likely to have clinical infectious mononucleosis than a subclinical infection. High motivation and poor academic record interacted in this study to substantially increase risk of clinical disease. Disease severity was confirmed by ascertaining the heterophile antibody titers in the clinical and subclinical cases. Finally, we studied the relation between stress and upper respiratory tract infection in a prospective study in Adelaide (219). Episodes of illness were divided into definite, uncertain, and doubtful in a blinded fashion and confirmed, where possible, by a study nurse and/or virologic culture. To improve the precision of stress measurement, a combination of three measures (major life events, minor life events, and psychologic distress) was used in initial analyses. Prestudy stress levels predicted both episodes and symptom days of respiratory illness. Prestudy stress variables also predicted nurse-confirmed episodes and symptom days in "definite" episodes even after adjusting for a range of confounding factors. These data cannot yet be considered conclusive, but enough evidence exists to suggest that psychosocial variables should be further investigated as risk factors for acute respiratory infection. At the present time there are no data exclusively addressing the relation between psychosocial factors and acute lower respiratory tract infection. Stress and anxiety might predispose to respiratory infection by two mechanisms. First, high stress levels may lead to disruption of normal hygiene measures usually used to reduce transmission of respiratory viruses. Use of tissues


and even hand washing (222-224) may help reduce virus transmission, and high stress or anxiety levels may reduce adherence to these techniques. This seems unlikely, however, since transmission factors were controlled in experimental cold studies (209-211). Second, since psychologic stress and other psychologic factors appear to suppress many components of immune function (225), this may lead to increased susceptibility to respiratory infection. However, the immune function fluctuations observed to be associated with psychologic factors may not have high clinical relevance, and until more data are available to address this issue its importance will remain uncertain. Socioeconomic status Socioeconomic status has been measured in a number of different ways, including rankings of occupational prestige, level of income, and educational status. While these measures are intercorrelated, they do not all measure the same thing and tell us little about the components of socioeconomic status that may act as risk factors for acute respiratory infections. Nonetheless, it has been clear for many years that socioeconomic status, no matter how it is measured, is associated with increased susceptibility to acute lower respiratory tract infections. Measures of occupational prestige, and the proportion of families with incomes below the poverty line, have been associated with increased mortality from bronchitis and pneumonia in children (166), as has educational status (96). Social class (as measured by occupational prestige) is also related to respiratory morbidity from predominantly lower respiratory tract conditions (93, 158). However, the risk associated with lower socioeconomic status is not always consistent, since Schenker et al. (108), in a retrospective study, found relations between low socioeconomic status (occupational status/educational level of parents) and severe chest illness in the first 2 years of life, as well as chronic respiratory symptoms, but not with pneumonia or

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bronchitis. Gardner et al. (122) used a combined measure of family income, insurance status, and parental educational level to measure socioeconomic status, and found it to be related to lower but not upper respiratory illness. Monto and co-workers (9, 156) found that lower income families experienced more episodes of respiratory illness, but that lower education-level families experienced less episodes. This latter finding was unexpected and was attributed to differential symptom reporting rates by lower and high educational groups. This finding illustrates how differently alternate measures of socioeconomic status can behave in predicting respiratory illness, but may also indicate that lower social class is a stronger risk factor for lower rather than upper respiratory illness as found in other studies (122). The differentials in pneumonia and influenza mortality observed between economically developing and developed countries (table 4) also reflect the association of low socioeconomic development with susceptibility to pneumonia, in particular. However, the relatively similar levels of upper respiratory illness reported in developing and developed countries lends support to findings in developed countries that low socioeconomic status does not increase risk of these conditions (9-17). Tupasi et al. (176) confirmed that socioeconomic status within developing countries also strongly predicts risk of acute respiratory infection (they did not differentiate between upper and lower), but were unable to separate out the effects of factors such as malnutrition, immunization status, and crowding. This, of course, begs the key question—What is it about lower socioeconomic status that increases risk of respiratory infection? Poverty and lower social status are associated with large family size, crowded living conditions, poorer access to medical care, higher smoking rates, potential for nutritional deficit, lower breast-feeding rates, exposure to environmental pollutants (tobacco smoke, wood smoke, urban air pollution), and stressful living environments. These factors may

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contribute individually or perhaps interact to increase susceptibility to respiratory infections in these groups. In a study of young children who were prone and not prone to respiratory illness in Adelaide, lower parental occupational status was associated with having a prone child in bivariate analyses (226). However, after adjusting for factors such as maternal smoking, sex, number of siblings, parental history of respiratory illness, use of child care, maternal stress levels, and breast feeding the relation between social class and respiratory proneness disappeared. These data in young children help reflect the "grab-bag" nature of socioeconomic status as a risk factor and importance of identifying the specific components that increase risk. Meteorologic factors

The seasonality of epidemics of acute respiratory infections has long been established, seeming to correlate best with low temperature, humidity, and/or precipitation. These factors are generally associated with increased time spent indoors either at home or at school where many respiratory infections are transmitted (227-229). In these situations crowding allows more efficient viral transmission. Whether meteorologic factors contribute to increased host susceptibility or enhanced viral integrity independent of this crowding effect has remained a matter of conjecture. One factor that has been closely studied is the effects of low temperature or "chilling" on host susceptibility. Volunteers experimentally infected with rhinoviruses have been exposed to combinations of cold temperatures, wet clothes, and fatigue in both the United States and the United Kingdom. In none of these studies were the volunteers who were exposed to chilling or cold more susceptible to infection (230-232). Other studies have found that low temperatures correlate with increases in mortality from pneumonia and bronchitis (166, 233), but confounding from increased time spent indoors (leading to crowding) and higher levels of air pollution during winter makes

these findings uninterpretable. This is well illustrated in a recent study of air pollution and hospitalization for respiratory disease (102). Peak levels of respirable particulate air pollution occurred in midwinter, presumably because condensation, cloud cover, and precipitation act to prevent dispersal of particulates and gases. In this study, low temperature was the meteorologic variable most closely correlated with hospitalization for respiratory disease, and together with mean fine particulate levels explained 83 percent of the variance in total monthly hospital admissions for respiratory disease. Once again, it is impossible to disentangle the crowding effects of cold weather from any direct effects from these data. Another meteorologic factor that might play a role is humidity. Gwaltney (234) has pointed out that rhinoviruses may survive better at higher humidities. Thus, it might be postulated that higher humidity might favor transmission. However, in temperate or warm climates high humidity is often associated with the rainy season, so even in the absence of low temperatures, crowding from increased time spent indoors is likely to confound this relation too. Human immunodeficiency virus infection The newest risk factor for acute respiratory infection is infection with the human immunodeficiency virus (HIV). The HIV epidemic has led to a dramatic increase in the incidence of P. carinii pneumonia in the United States and other developed countries (235). In 60 percent of newly diagnosed cases of AIDS, P. carinii pneumonia is the AIDS-defining illness, and up to a further 20 percent of AIDS patients will develop P. carinii pneumonia during the course of their illness (77, 78). Children with AIDS are also at risk from P. carinii but at a slightly lower rate than adults (236-238). P. carinii pneumonia does not appear to be an important pulmonary complication of AIDS in Africa (79). This lack of association in Africa may be in part because of the difficulty of diagnosing this


condition when bronchoscopy is not readily available (77). However, introduction of sputum induction techniques currently used in developed countries (239) may prove useful in improving the diagnostic accuracy of studies in Africa. This should lead to a more definitive picture of the incidence of P. carinii pneumonia in HIVinfected persons on that continent. Adults and children infected with HIV are also at increased risk from bacterial pneumonia (77, 240). S. pneumoniae and H. influenzae are the most commonly isolated organisms in community-acquired, HIV-associated bacterial pneumonia. Risk of pneumonia appears to be increased in HIV-infected patients with and without AIDS (241-245). The most common viral pulmonary infection found in both adult and child AIDS patients is cytomegalovirus (77, 237, 238). However, the pathogenicity of this virus in the lung is not always entirely clear, since it is sometimes isolated in the absence of histologic evidence of cytopathic change to lung parenchyma (246). The etiologic agents causing acute lower respiratory tract infections in HIV-infected patients in Africa have not been completely elucidated at the present time. In general, gastrointestinal and dermatologic complications are more common than in the United States, where pulmonary complications most often manifest (79). In one study, only 14 percent of HIV-infected Africans living in Europe had P. carinii pneumonia (247). The most common pulmonary complication of HIV infection in Africa appears to be tuberculosis (248, 249) although few studies have used appropriate microbiologic techniques to establish accurate estimates of risk in comparison with other organisms. It seems likely that HIV-infected children and adults in Africa will be at greatly increased risk from pneumonia caused by pyogenic bacteria such as S. pneumoniae, H. influenzae, and Staph. aureus, since these organisms are already important causes of pneumonia in that part of the world. Whether HIV infection is associated with increased susceptibility to upper respira-

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tory tract infections or respiratory viruses in general, is not known. It is also not known whether these less serious conditions can predispose to secondary bacterial invasion and pneumonia in AIDS patients. If immune system activation (via antigenic stimulation) is important in the pathogenesis of AIDS, as has been postulated, another issue that needs to be explored is whether viral respiratory infections play a role in accelerating disease progression. Low birth weight Pio et al. (6) have hypothesized that low birth weight may be an important risk factor for acute respiratory infections. They cite the high incidence of low-weight births in developing countries and the higher mortality rates of low birth weight infants in the first year of life as support for this hypothesis. A recent study reporting on a 7-year birth cohort follow-up found that low birth weight (< 2,000 g) was associated with subsequent chronic cough, but not wheeze (250). No data were collected on acute respiratory symptoms in this study. Drillien (251), in 1958 reported that low birth weight babies (< 4 lb, 8 oz (< 2,000 g)) experienced higher rates of respiratory illness in the first 2 years of life than higher weight babies. This relation persisted when she stratified by a "maternal care" index. Maternal care was poorly defined but was reportedly closely correlated with the number of siblings in the family. However, after stratification by quality of housing and maternal care, low birth weight did not predict respiratory illness. Datta et al. (252) studied low birth weight infants in India. Low birth weight infants (< 2,500 g) experienced the same respiratory illness attack rate as normal weight infants in the first year of life (4.65 vs. 4.56 episodes) but had a much higher case fatality rate (24.6 vs. 3.2 per 100 episodes of moderate or severe respiratory illness). Victora et al. (253) also found that a birth weight of < 2,500 g was associated with increased mortality from respiratory infections, and this relation persisted after adjustment for parental em-

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ployment status, income, and education. These data suggest that low birth weight children do not experience higher rates of respiratory illness, but do experience more severe infections. Confounding from other factors associated with low birth weight (crowding, poverty, poor nutrition) makes it difficult to ascertain whether the relation is a causal one.

ameters (255) and higher virus-specific immunoglobulin E responses to respiratory syncytial (256) and parainfluenza viruses (257). From a public health perspective, the most important host factor may be the observation that maternal antibodies, in cord blood, to respiratory syncytial and influenza viruses appear to be protective against subsequent infection in infants (258, 259). If maternal immunity can be Other host factors passively transferred to infants, vaccinaA long list of factors are purported to tion of pregnant women could be beneficial increase risk of pneumonia in adults. These when appropriate vaccines become availinclude age, smoking, alcoholism, chronic able. obstructive lung disease, cardiovascular DATA COLLECTION—QUESTIONNAIRES disease, diabetes, renal disease, and various malignancies (161). Many of these associWhile the optimal situation in any proations have been observed from clinical spective study of acute respiratory infection practice or in uncontrolled studies of pneu- is to confirm diagnosis through bacterial monia cases. Surprisingly, there are rela- and viral culture, detection of organism tively few adequately controlled epidemio- antigens in body fluids, and/or serologic logic studies of pneumonia risk factors. confirmation of a rise in specific antibody Lipsky et al. (161) confirmed that increas- titer (260), there is a concurrent need for ing age, smoking, chronic obstructive lung symptom data in many situations. Unfordisease, and congestive cardiac failure were tunately, no standardized questionnaires independently associated with increased exist for collection of acute respiratory inrisk of pneumonia. They also found that fection symptom data. Standardized instrudementia, cerebrovascular disease, and in- ments developed by the American Thoracic stitutionalization independently predicted Society (261) and the British Medical Repneumonia. However, they found no rela- search Council (262) were designed to tion between diabetes mellitus, heavy al- measure chronic respiratory symptomatolcohol use, or malignancy and risk of pneu- ogy. These questionnaires do contain quesmonia. Simberkoff et al. (163) also studied tions about the frequency of some acute high risk outpatients. They found that symptoms (e.g., the American Thoracic Sochronic pulmonary, cardiac, and renal dis- ciety children's questionnaire), but the foease predicted incidence of pneumonia, but cus is so squarely set on symptoms of airnot alcoholism, diabetes mellitus, or he- way reactivity and allergy that they cannot patic disease. be readily adapted for studies of acute reIn children, a number of host factors spiratory infections. Thus, many researchappear to influence susceptibility to lower ers have used either nonstandardized rerespiratory illness. Family history of spiratory symptom diaries (see figure 1) or asthma is associated with increased risk of recall questionnaires. Respiratory diaries bronchiolitis in infancy and appears to have the advantage of largely eliminating strongly interact with exposure factors recall bias and are useful in studies where such as passive smoking and presence of an specific symptom complexes are important. older sibling in the house (254). This poten- They are also more likely to be accurate tial role of genetic factors appears to be records of symptom duration than recall supported by other studies reporting in- questionnaires. The chief problem associcreased rates of wheeze-related respiratory ated with their use is that they require daily infection in infants with small airway di- recording by the study participant, which

EPIDEMIOLOGY OF ACUTE RESPIRATORY INFECTIONS 1

DECEMBER 1988 Is he/she completely well ? Y-yes N.no Do you think he/she has a cold? Y o r N Record each symptom he/she experiences each day. Marti with X. Runny nose

2

ai

6

7

.RESPIRATORY EVENTS IN EARLY CHILDHOOD 9 8 12 13 14 15 16

m•

mn

19 2 0 21 22

23 tag

169 2 6 27 28 29 30

"I

111111111111111111111i 11111111

Slopped-up nose Hoarse throat Wheezy/noisy breathing Moist cough Dry cough Fever (feels hot) Pulling at ears Medication given ( M ) ' ' Doctor visits

(D)

'

Hospital visils(V); Hospital slays(S) * ('more details on back) OTHER ILLNESSES (give brief details)

FIGURE 1. Example of an acute respiratory illness symptom diary used in a 2-year cohort study of infants in Adelaide, Australia, 1988-1990.

although not problematic in short studies may potentially contribute to loss of followup in multiyear projects. An often used alternative is to have research assistants call or visit study participants on a 1 week or 2 week basis to inquire about symptom frequency and duration in the preceding period. This approach has all the problems associated with recall data but has advantages of sustainability over long periods and the ability of the interviewer to define symptoms more clearly than would otherwise be possible using a diary approach. It is also likely to be easier to standardize a questionnaire than a symptom diary. Gold et al. (263) recently examined both approaches. The compliance rate was greater with the questionnaire over the 2 years of the study. No differences in reporting of upper respiratory illness were found but an excess of lower respiratory illness was reported in the questionnaires. The authors suggest that lower respiratory symptoms (e.g., phlegm, wheezing, chest pain) may be easier to define by direct questioning. The diary method also recorded a higher ratio of male to female lower respiratory illness than the questionnaire method. Although the author's interpretation may well be cor-

rect, both of these findings may equally reflect recall bias from the questionnaire. In Australian families, respiratory diaries have been found to be superior to recall questionnaires as a method of symptom recording, and this approach has been used successfully in long-term studies (207). They are particularly useful when accurate determination of onset and duration of respiratory episodes are important, and allow more accurate timing of virologic sampling. Ultimately, studies of both methods will be needed which utilize virologic culture and serologic methods as confirmation of episodes to determine the most sound method of collecting symptom data for epidemiologic studies. The need for standardized questionnaires in developing countries is even greater (264). Not only are there considerable difficulties standardizing measures of exposure between studies, but in many instances the clinical and laboratory expertise/facilities are not available for confirmation of diagnosis. In these circumstances simpler approaches to collecting outcome data are often necessary. A major attempt to standardize data collection/study protocols was undertaken in the recently com-

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pleted National Research Council 12 countries project (14). Although some variation in methods was inevitable, these data are probably the most comparable so far available. Overall, most effort has focussed on developing criteria for identifying acute lower respiratory infections from simple clinical signs. A number of studies have now shown that tachypnea and a history of fast breathing (27, 265-267) are highly sensitive and specific predictors of lower respiratory tract infections in both hospital (27, 265, 266) and community (267) settings. Consideration of chest indrawing appears to improve the sensitivity and specificity of tachypnea as a diagnostic criterion (267). However, lower respiratory tract infections include a number of different diagnostic categories, including pneumonias of differing severity, bronchiolitis, and bronchitis. Often stridorcausing conditions are also included. Campbell et al. (268) recently reported that the best predictors of lobar pneumonia in infants were temperature > 38.5° C and a respiratory rate > 60 per minute. Thus, more specific diagnoses than "acute lower respiratory infection," such as severe pneumonia, are not well predicted by a respiratory rate of > 50 per minute. However, in studies of respiratory infection in developing countries it may not be entirely practical to aim for more specific diagnoses in every instance. Given the high sensitivity and specificity of maternal history of fast breathing as predictor of acute lower respiratory tract infection, this is a potentially extremely useful measure in epidemiologic studies. More specific diagnoses may not always be possible within the resources of many studies, and in areas where wheezerelated conditions are not highly prevalent, they may not always be necessary. SUMMARY

While a number of advances have been made in our understanding of the epidemiology of acute respiratory infections in the past two decades, a number of serious questions still require urgent answers. The

associations of factors such as chronic disease in adults, direct smoking, passive smoking, crowding, and breast feeding to acute respiratory infections are now well documented. Appropriate changes in public health policy need not be predicated on results from still further studies. However, in virtually all of the other areas cited in this review, further data are required. In developing countries, studies being currently conducted on vitamin A supplementation, malnutrition, and indoor air pollution will help address the most pressing issues. More studies are also needed on the relations between HIV infection and acute respiratory infections, as well as low birth weight and respiratory infection. The National Research Council studies have provided important additional data on etiologic agents in children in developing countries, but data on adult pneumonia remain sparse (269, 270). In developed countries the issues that may be of greatest interest are the relation between maternal antibody levels and passive immunity in infants, the reasons for the increase in pneumonia mortality in older age groups, and the relation between air pollution and acute respiratory infections (as opposed to morbidity from bronchial reactivity). From a methodological viewpoint, the relation between previous respiratory infection (particularly in the first year of life) and subsequent acute respiratory infection morbidity has been inadequately explored. Adjustment for autocorrelation in multivariate models may be necessary if this relation is strong. Greater standardization of data collection methods in developed and developing countries also needs to be more seriously addressed. Given that some advances have been made in this area, the time may be right for development of acute symptom questionnaires, akin to the American Thoracic Society chronic respiratory questionnaire, for use in both developed and developing countries. Standardization of diaries, although somewhat more difficult, would also be extremely useful in many instances.

EPIDEMIOLOGY OF ACUTE RESPIRATORY INFECTIONS REFERENCES

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