Original Article
Racial Differences in Susceptibility to Infection by Mycobacterium tuberculosis
N Engl J Med 1990; 322:422-427February 15, 1990
- Abstract
- Abstract
The prevalence of tuberculosis among blacks is known to be about twice that among whites. When we looked at infection rates among the initially tuberculin-negative residents of 165 racially integrated nursing homes in Arkansas, we were stimulated to investigate whether this difference could be due in part to racial differences in susceptibility to Mycobacterium tuberculosis infection. A new infection was defined by an increase of ≥12 mm of induration after a tuberculin skin test (5 tuberculin units) administered at least 60 days after a negative two-step test.
On repeat skin testing of the 25,398 initially tuberculin-negative nursing home residents, we found that 13.8 percent of the blacks and only 7.2 percent of the whites had evidence of a new infection (relative risk, 1.9; 95 percent confidence interval, 1.7 to 2.1). Blacks were infected more frequently, regardless of the race of the source patient. In homes with a single source patient who was white, 17.4 percent of the black and 11.7 percent of the white residents became infected (relative risk, 1.5; 95 percent confidence interval, 1.2 to 1.9); in homes with a single source patient who was black, 12.4 percent of the black and 7.7 percent of the white residents became infected (relative risk, 1.6; 95 percent confidence interval, 1.2 to 2.1). However, there was no racial difference in the percentage of residents who had recently converted to positive status who, in the absence of preventive therapy, were later found to have clinical tuberculosis (blacks, 11.5 percent; whites, 10.6 percent). Data from three outbreaks of tuberculosis in two prisons also showed that blacks have about twice the relative risk of whites of becoming infected with M. tuberculosis.
We conclude that blacks are more readily infected by M. tuberculosis than are whites. The data also suggest that susceptibility to M. tuberculosis infection varies independently of the factors governing the progression to clinical disease. (N Engl J Med 1990; 322:422–7.)
Media in This Article
Table 1
Prevalence of Positive Tuberculin Reactions among Patients Entering Nursing Homes, According to the Percentage of Black Residents in the Home.*Table 2
Incidence of Tuberculin Conversion in Nursing Homes, According to the Percentage of Black Residents in the Home.*Article Activity
- Article
THE incidence of tuberculosis correlates closely with the prevalence of tuberculous infection in the population. In residents of nursing homes in Arkansas, both the incidence and the prevalence are consistently about twice as high in blacks as in whites.1 2 3 The basis of this racial difference is unknown, but it is usually ascribed to social factors, such as crowding and poverty.4 This paper describes the unexpected finding that under the same social conditions, blacks are apparently infected more readily by Mycobacterium tuberculosis than whites. This observation is derived from the analysis of a data base of more than 53,000 residents of Arkansas nursing homes. An analysis of data from three tuberculosis outbreaks among the inmates of two geographically and structurally disparate prisons provides support for this finding.
Methods
Arkansas Nursing Homes
Our data base is maintained to help control tuberculosis in nursing homes and has been described elsewhere.2 , 3 Patients admitted to any nursing home in the state undergo an intradermal tuberculin test performed with a 0.1-ml solution of Tween-stabilized purified protein derivative (PPD-T, 5 tuberculin units [TU], Tubersol, Connaught). The induration was measured in millimeters with the Sokal ballpoint-pen technique.5 If induration measured less than 10 mm in diameter, the test was repeated 7 to 21 days later (two-step test). Induration with a diameter of at least 10 mm on either test was considered to indicate a positive result. Conversion was defined as an increase of at least 12 mm in the diameter of the induration on retesting at least 60 days later, as advocated by Narain.6 The data base includes entries for 53,518 residents of the 227 nursing homes in Arkansas. About 4 percent (1905) were known before entering a nursing home to be tuberculin-positive. All but 407 of the remainder were tested with tuberculin, 90 percent of them by the two-step method.
Two environmental variables were computed for each home —the percentage of tuberculin-positive residents and the percentage of black residents. The univariate analysis of the risk of conversion to positive status was limited to the 25,398 residents over the age of 50 who were initially tuberculin-negative, lived in one of the 165 homes that were racially mixed, and underwent retesting at least 60 days after the initial two-step test. The residents were 81 percent white and 67 percent female. Their mean age at entry to the nursing home was 75.1 years, the women being an average of 5 years older than the men. The nursing homes were stratified into three groups according to the percentage of black residents: 78 homes had less than 10 percent blacks, 68 had 10 to 49 percent, and 19 had more than 50 percent black residents. Age did not differ among these strata.
Probabilities were computed by the chi-square statistic from two-by-two contingency tables. The relative risks of conversion for blacks as compared with whites are shown with 95 percent confidence intervals.7 A multivariate analysis of the risk of conversion of the tuberculin skin test to a positive result was performed with a proportional-hazards model with use of the LIFEREG procedure of SAS.8 The model tests the effect of race on the time to conversion, with adjustment for the covariates of sex, age, and (as an environmental variable) the percentage of the nursing home residents who were tuberculin-positive at entry. The other computed environmental variable, the percentage of black residents, showed no additional effect and was dropped from the model. The analysis was restricted to nursing homes in which there was at least one conversion to positive status and in which there were results of retesting for both races. These restrictions resulted in an analysis of 1786 residents who converted among 13,122 residents.
The analysis of the risk of clinical tuberculosis was limited to the 5481 untreated residents of racially mixed nursing homes who tested positive at or before entry and the 763 untreated residents of these homes who had recently converted to positive status.
Arkansas and Minnesota Prisons
All inmates of a large Arkansas prison who had previously been tuberculin-negative were retested on two occasions after the detection of an infectious case of tuberculosis. On one occasion, 205 male inmates (mean age, 31.7 years, with no significant difference between races) were retested after a heavy exposure (with an identified source patient and many inmates who converted to positive status); on another, 1431 inmates were retested after a light exposure (with an identified source patient but few conversions). The tuberculin tests were administered and interpreted as in the nursing homes. There was a strict policy of integration in the bed assignments and in the use of dining and recreational facilities. The inmates slept largely in Army-style barracks, with only a few sleeping in individual cells.
After a heavy exposure to tuberculosis (with a white source patient and many conversions) in a large prison in Minnesota, 543 previously nonreactive male inmates (mean age, 33.5 years) were retested by the nursing personnel of the Minnesota Department of Health. The techniques used were similar to those employed in Arkansas, except that the results of the tests were determined by inspection and digital palpation (MacDonald KL: personal communication). This prison was also integrated, but the inmates slept in cells containing one or two inmates each, with a centrally distributed supply of air that varied from being largely fresh in clement weather to being largely recirculated during the long northern winter.
Results
The numbers of white and black residents in each of the three groups of nursing homes and the proportion of residents who were tuberculin-positive at entry are shown in Table 1Table 1
Prevalence of Positive Tuberculin Reactions among Patients Entering Nursing Homes, According to the Percentage of Black Residents in the Home.*. The percentage of residents of either race who had a positive reaction tended to be larger in homes with a higher proportion of blacks. The prevalence of infection at entry was consistently about twice as high in blacks as in whites in all three groups (P<0.001; relative risk, 2.1; 95 percent confidence interval, 1.95 to 2.18). This difference was seen in both sexes and in three age groups. In both races, more men than women had a positive test (data not shown).Table 2Table 2
Incidence of Tuberculin Conversion in Nursing Homes, According to the Percentage of Black Residents in the Home.* shows the proportion of residents who entered with a negative two-step test but who had a definite conversion to positive tuberculin status on retesting (mean size of induration, 19.4 mm), signifying a new infection.2 , 3 The proportion of conversions among the blacks in all three groups of residents was about twice that of the whites (P<0.001; relative risk, 1.9; 95 percent confidence interval, 1.7 to 2.1). The racial difference in the rate of tuberculin conversions was unaffected by the length of residence.Table 3Table 3
Incidence of Tuberculosis According to Race among Untreated Nursing Home Residents with Positive Skin Tests. shows no racial difference in the percentage of untreated residents positive either at entry or after conversion in whom clinical tuberculosis developed. Eighty percent of these cases were proved by culture. Many of the remainder involved new infections that had a clinical and radiographic response to antituberculous chemotherapy. It is noteworthy, however, that regardless of race, tuberculosis was 4.2 times more likely to develop in untreated residents with new infection (P<0.001; relative risk, 4.8; 95 percent confidence interval, 3.2 to 5.5) than in residents who were tuberculin-positive on admission (Table 3).There was a racial difference with respect to the severity of disease, however. Among blacks, 42.9 percent (21 of 49) of those with culture-proved tuberculosis had positive smears, as compared with only 28.5 percent (53 of 186) of whites with culture-proved disease (P = 0.08; relative risk, 1.50; 95 percent confidence interval, 0.88 to 2.54). This is in accordance with the fact that among the 3725 cases of tuberculosis in Arkansas from 1976 through 1988, blacks were 1.25 times as likely as whites to have positive smears (P<0.0001; relative risk, 1.25; confidence interval, 1.14 to 1.36).
The proportional-hazards model confirmed the results of the univariate analysis, giving an adjusted risk of conversion in blacks that was 1.78 times that in whites (95 percent confidence interval, 1.61 to 1.98), after control for sex, age, and percentage of nursing home residents who had a positive tuberculin test at entry.
The case for a racial difference in infectibility was strengthened when the nursing homes were stratified according to the race of persons with culture-proved tuberculosis. In Table 4Table 4
Incidence of Tuberculin Conversion in Nursing Homes, According to the Race of Culture-Positive Patients.*, the data are restricted to the 23,144 residents of 157 homes with culture-proved cases of tuberculosis who were subsequently retested. The relative risk of conversion averaged 1.8 (P<0.001; 95 percent confidence interval, 1.4 to 2.4), whether the potentially infectious residents were either all white or all black. This analysis was restricted to homes in which between 10 and 90 percent of the residents were black.A still more stringent evaluation (Table 5Table 5
Incidence of Tuberculin Conversion in Nursing Homes with a Single Source Patient.*) considered only data from the 30 nursing homes in which there was a single source patient with a positive smear and positive results on culture and in which there were between 10 and 90 percent black residents. A single white resident with a positive smear typically infected 17.4 percent of the blacks and 11.7 percent of the whites (P<0.001; relative risk, 1.5; 95 percent confidence interval, 1.2 to 1.9), whereas a comparable black resident typically infected 12.4 percent of the blacks and 7.7 percent of the whites (P<0.001; relative risk, 1.6; 95 percent confidence interval, 1.2 to 2.1). A comparison of the data according to columns reveals the surprising finding that black residents with positive smears were significantly less infectious for both blacks and whites than comparable white residents.The results of an analysis of data from the studies of outbreaks of tuberculosis among men in two prisons support the greater infectibility of blacks. Table 6Table 6
Incidence of Tuberculin Conversion among Male Inmates of Two Prisons, According to Race. shows the results of an analysis of two levels of exposure to M. tuberculosis in an Arkansas prison. The ratios of blacks to whites with respect to the incidence of new infections range from 1.8 to 2.9 (0.01<P<0.025). The findings were similar after an outbreak in a prison in Minnesota (Table 6) (MacDonald KL: personal communication). No comparison of the rate of development of tuberculosis could be made in these groups, because all inmates who converted were treated with isoniazid, and no clinical tuberculosis developed.Discussion
Our data confirm the well-known fact that the prevalence of tuberculous infection among blacks is about twice that among whites. However, our data also reveal the surprising finding that blacks are almost twice as likely as whites to become infected by M. tuberculosis as a result of the inadvertent exposure that is common in nursing homes. When this latter difference was first noted in an analysis of the entire data base, comprising data on more than 53,000 residents, it was assumed to be due to the greater degree of association of blacks with other blacks, in whom the incidence of tuberculosis was relatively high. To narrow the focus of the analysis, racially mixed nursing homes were stratified according to the percentage of black residents. This changed neither the difference according to race in the prevalence of infection at entry (Table 1) nor the difference in the rate of tuberculin conversions after entry (Table 2).
The possibility that the apparent difference in infectibility could be a result of a longer residence of blacks in the homes was excluded by multivariate analysis of the data with the proportional-hazards model. Next, we limited the analysis to homes with residents who had culture-proved cases of tuberculosis and enough blacks (10 to 90 percent) to facilitate the expression of racial preference in the choice of associates. This resulted in little change in the disparity according to race (Table 4). Finally, we analyzed the 30 homes in which there was a single highly infectious case of tuberculosis (positive on sputum smear and culture) and a proportion of black residents that was between 10 and 90 percent. Even with this severe restriction, the analysis showed that a significantly higher proportion of black than white residents who were tuberculin-negative at entry had become infected. Thus, the race of the source patient appeared to be immaterial (Table 5).
The difference in infectibility according to race was borne out by the observations in two prisons of very different design and location. In the Arkansas prison (Table 6), the ratio of 2:1 held for outbreaks that followed both a heavy exposure and a light exposure. The findings from an outbreak in a Minnesota prison were similar (Table 6).
The finding that blacks are more infectible is in accord with the observations of Long and Jablon,9 whose review of 3099 Army medical records after World War II revealed a higher incidence of apparently new (progressive primary) infection among blacks (4.2 percent) than among whites (2.8 percent; P<0.05). Long and Jablon conclude, "The incidence of apparently new tuberculosis developing in servicemen under comparable environmental conditions was significantly greater in non-white than in white men."
That tubercle bacilli in circulated air are more important in the transmission of infection than the choice of close associates is consistent with the experimental work of Riley et al.10 and several earlier epidemiologic studies of the spread of tuberculosis in enclosed environments.11 12 13 14 Bunk assignments proved to be more important in transmission than the choice of daytime associates. However, none of these studies involved members of more than one race (Kent DC, Houk VN: personal communication).
The fact that blacks with pulmonary tuberculosis were significantly more likely than whites to be highly infectious (with positive sputum smears) might lead one to think that blacks would infect more of the persons they contacted than whites. However, the spread of infection also depends on the duration of exposure. So, although blacks with pulmonary tuberculosis more often had positive sputum smears, there was an interesting paradox (Table 5): a single black person with a positive smear infected about 30 percent fewer persons of both races than a comparable white person. This was probably due to the more chronic nature of the disease in whites,15 which affords more time for the spread of the infection before death or the start of treatment. In other words, a black person with pulmonary tuberculosis may spread more organisms per day, but because of the longer duration of disease, whites may ultimately spread the infection more widely.
Among the residents of the Arkansas nursing homes, preventive therapy was recommended for all who had a definite conversion (with an increase of at least 12 mm in the size of the tuberculin reaction from previous negative tests) and for those with a positive reaction who had additional risk factors (diabetes, scarring of the apexes, or corticosteroid therapy). However, this advice was not always accepted by the attending physicians, particularly in the early years of our work. This makes it possible to observe that despite the apparent difference in infectibility by M. tuberculosis, there is no racial difference in the risk of disease among either those with a positive reaction of long standing or those who convert to positive status and do not receive preventive therapy (Table 3). This suggests that the defense before infection is quite separate from that after infection. This finding does not contradict the common observation or Rich's statement15 that tuberculosis is a more rapidly progressive disease in blacks than in whites. Among the inmates of the two prisons, the recommendations for preventive therapy were implemented so commonly that it is impossible to draw any conclusions about progression to clinical tuberculosis.
That a conversion of the tuberculin reaction as defined above truly represents a new infection and not simply the boosting of a diminished reactivity is shown by the wide difference in the percentage of the two groups in whom clinical tuberculosis developed in the absence of preventive therapy (Table 3): 2 to 3 percent of those who were positive at entry, as compared with 7.6 to 11.7 percent of those who converted.3 (The lower figures are for women, and the higher for men.)
Various racial differences in human tuberculosis are discussed at length by Rich15 with regard to the clinical course (more rapid in blacks) and pathological features (greater caseation in blacks). In an extensive review of the literature, Torchia16 found no evidence of a racial difference in susceptibility to tuberculosis. In a recent exhaustive review, Kushigemachi et al.17 found no evidence of a difference between blacks and whites with respect to the percentage of infected persons in whom clinical tuberculosis developed. This agrees with our findings.
Until the 1960s, when public facilities in the South were integrated, large numbers of blacks and whites were rarely housed together so that they shared the same air 24 hours a day. In the several reports of tuberculosis outbreaks in institutions, race was not mentioned.18 19 20 21 22 Of the 109 epidemics reviewed by Lincoln,23 none involved blacks. Of more recent reports, only two involved both blacks and whites. Both showed a racial disparity in those who converted to positive tuberculin status that was consistent with the disparity we found,24 , 25 although the second study was too small to achieve statistical significance.
To cause tuberculosis in a new host, M. tuberculosis must surmount two separate systems of defense. The first is innate resistance — i.e., ciliary action and ingestion and lysis by unstimulated macrophages.26 If the organisms survive these obstacles, an infection may become established and activate the immune system. Then, sensitized T lymphocytes stimulate macrophages and enhance their lysis of engulfed tubercle bacilli. This change is signaled by conversion to a positive reaction to the tuberculin skin test, and only then is the host considered infected. If cellular immunity is adequate to cope with the bacillary load, the infection is generally rendered clinically dormant. If not, clinical tuberculosis may develop. As Biggs27 conceptualized in 1888, there is variation among individuals in the threshold that must be overcome by the inoculum of bacilli to establish an infection. This may explain how some doctors and nurses remain tuberculin-negative during prolonged exposure over many years.
The mechanism of a racial difference in infectibility is only speculative. Davies28 has suggested a deficiency in vitamin D as a factor in the higher susceptibility to tuberculosis of dark-skinned people, and Crowle et al.29 have shown calcitriol to be essential to phagocytosis of the bacilli by macrophages. Vitamin D levels have also been shown to be lower in blacks than in whites,30 and certainly both groups in this study had suboptimal exposure to sunlight. However, a recent review of the role of vitamin D in tuberculosis31 offers little encouragement for this explanation.
Classic studies in animals by Lurie et al.32 and more recent ones by Skamene33 suggest that variation in infectibility by M. tuberculosis is due to genetic differences in the ability of unstimulated macrophages to ingest and lyse the bacilli. Crowle34 has shown that there is considerable variation in the vigor with which human macrophages ingest and kill M. tuberculosis.
In more recent work with the same in vitro model, Crowle and Elkins35 have shown that macrophages from blacks permit significantly more replication of M. tuberculosis than those from whites (P<0.001). This appears to furnish an explanation at the cellular level of the difference in infectibility we have observed. We suggest there are individual variations in the threshold that an inoculum of M. tuberculosis must exceed to establish an infection and that this threshold is significantly higher in whites than in blacks.
A heritable basis for susceptibility to tuberculosis has had its advocates for many years,36 37 38 39 40 41 because of the correlation between morbidity from the disease and genetic proximity among persons — a correlation that is strongest between monozygotic twins, less strong between dizygotic twins, even less strong among siblings, and least strong among unrelated persons. In 1886, Hirsch39 wrote: "That phthisis [tuberculosis] propagates itself in many families from generation to generation is so much a matter of daily experience, that the severest sceptic can hardly venture to deny a hereditary element in the case." Puffer40 concluded in 1944: "Therefore, two factors — heridity [sic] susceptibility and exposure to tubercle bacilli —may be responsible for the development of manifest tuberculosis." Finally, in 1960 the geneticist Motulsky41 stated: "Resistance [to tuberculosis] is unrelated to acquired immunity. It appears that resistance is caused by the inherited ability of the animal to phagocytose the tuberculosis organism, thus preventing spread."
There are well-recognized racial differences in the defense against two other infectious diseases, malaria and coccidioidomycosis. The reduced infectibility of some blacks by malarial parasites is based on a hereditary difference in the hemoglobin molecule. In the case of coccidioidomycosis, morbidity and mortality are both much higher among Filipinos and blacks than among whites,42 , 43 but we know of no data to show that this is due to a difference in infectibility. Certainly, members of these ethnic groups are subjected to much higher exposure in the agricultural fields44 than are whites.
The data presented here strongly suggest heritable differences between individuals and groups with respect to the innate defense system that functions before infection develops as distinct from the immune system that develops afterward. Although various factors affect ethnic and racial differences in the prevalence of tuberculous infection and tuberculosis, our data indicate that the role of differences in infectibility is significant. On the basis of these observations, it is intriguing to speculate that it might be possible to enhance pre-infection defense mechanisms to prevent the implantation of tubercle bacilli. This would make it possible to prevent not only the disease but the infection that causes it.
Presented in part at the annual meeting of the American Thoracic Society, Las Vegas, May 8–11, 1988.
We are indebted to the many nurses in the 227 nursing homes in Arkansas who performed the tuberculin tests and reported the results to us semiannually; to Ron Henley and James Jenkins, who did likewise in the Arkansas prison; to Dory Moers, chief nurse consultant, and the 10 communicable-disease nurse specialists of the Tuberculosis Program who supplied training and quality control to the nursing homes in their efforts to control tuberculosis; to Christopher Murphy for preparing the tables and to Nancy Brannan for keeping us informed about new cases of tuberculosis reported by the nursing homes; to Willis Henderson and David Bradley for mycobacteriologic testing; to Dr. Kristine MacDonald of the Minnesota Department of Health for the data from the Minnesota prison; to Dr. Alfred J. Crowle, Dr. Diego Provvedini, Dr. Richard V. Ebert, Dr. Paul B. Beeson, Dr. Joycelyn Elders, Dr. Henry Masters, Dr. George Comstock, Dr. Joseph H. Bates, Dr. Jerrold Ellner, and Dr. Dixie Snider for helpful suggestions about the manuscript; and to Cassandra R. Shack for attention to detail in the data analysis and assistance in the preparation of the manuscript.
Source Information
From the Tuberculosis Program, Arkansas Department of Health (W.W.S, J.W.S., W.T.R., J.P.L.), and the Department of Medicine, University of Arkansas for Medical Sciences (W.W.S.), Little Rock. Address reprint requests to Dr. Stead at the Tuberculosis Program, Arkansas Department of Health, 4815 W. Markham St., Little Rock, AR 72205–3867.
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