Editorial_ _ _ _ _ _ _ _ _ _ _ _ _ __ Does Measles Really Predispose to Tuberculosis?
Summa~-----------------------------
In recent years, textbooks and reviews on mechanisms involved in cellular immunity have emphasized that measles adversely influences tuberculous lesions. The medical literature was critically investigated for the basis of this claim. All field studies reviewed possessed strong deficiencies in the pertinent data and the methods of their collection. These deficiencies rendered invalid conclusions concerning the ability of measles to activate tuberculosis. Indirectly, there are also no adequate epidemiologic data to support the concept that measles suppresses tuberculous immunity when it suppresses tuberculin skin reactivity. Considering all the available information, one may conclude that if measles does have a deleterious influence on tuberculoSis, it is probably at low frequency in most populations. A belief has persisted that measles activates tuberculosis, either by converting a latent infection to active tuberculosis or by aggravating an active one. As an indication of the current prevalence of this belief, there are mild to strong statements connecting measles and tuberculous activation in 4 of 7 internal medicine texts and in all of 6 pediatric texts recently surveyed. That measles can reduce tuberculin reactivity for a week or 2 in many persons is well established (1-5). Since von Pirquet's (6) report of a child whose measles flowed into fatal tuberculosis, immunity and delayed hypersensitivity have often been equated functionally, thus offering an explanation for the reputed activation by measles. The sole question posed here is whether or not the published evidence adequately supports the hypothesis that measles activates tuberculosis. To arrive at an answer, studies purporting
either to support or to deny the hypothesis have been scrutinized for adequacy. When statistical analysis could be applied to data, I have routinely used the chi square test with Yates correction (7). Other statistical tests are identified when needed.
Pro-Hypothesis Studies Klein (8) studied tuberculosis in children who had contracted measles during the epidemic of 1925 in Essen, Germany. He wished to determine whether tuberculosis was more common among children whose tuberculin reactivity (and, presumably, their immunity) was inhibited by measles compared to control subjects in whom measles caused no inhibition. He applied the insensitive and inconsistent Moro skin test (Old Tuberculin in an ointment base) to each child once during measles. Five months later, the children were retested. Children with positive reactions were examined for tuberculosis. As indicated in table l, Klein compared the tu· berculosis rates of 2 groups. Group A included those with positive Moro tests during measles, and Group B included those whose reactions converted from negative to positive. Because the rate of tuberculosis in group B was 3.5 times that in group A, he believed that his data supported the hypothesis that measles activates tuberculosis. Klein included 4 children in group A and 6 in group B who had had tuberculosis before measles. These cases should be deleted for lack of activation by measles, thus reducing the rates at 5 months correspondingly in both groups. Klein's support for the hypothesis is nullified by several considerations. (1) The single Moro test seems'inadequate for making a valid separation of hypersensitivity-depressed versus nondepressed subjects during measles. Repeated, accurate skin testing is required to detect the depression in
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 114, 1976
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EDITORIAL
TABLE 1 FREQUENCY OF TUBERCULOSIS AMONG CHILDREN 5 MONTHS AFTER MEASLES: UNCORRECTED DATA FROM KLEIN, 1927 (8) Tuberculin Reactivity during Measles Group
OT-Positive (no.)
A
27
B
c
OT -Negative (no.) 42 103t
5 Months Later, When Tuberculin-Positive No. with Tuberculosis 4 22
Per Cent of Group 14.8* 52.4*
• Application of the chi square test indicated a significant difference. tThese subjects remained OT-negative at 5 months and were not examined further.
some persons. Therefore, a number of the non- 5 per cent of such children had measles sufficientdepressed group A subjects really belonged in ly close to onset of tuberculosis and a developthe tuberculin-depressed group. Because none mental sequence suggesting a relationship. of the group A children developed fresh tuberGoebel (13), Constantino (14), and Lieseculosis at 5 months, this transposition could only gang (15) all proposed that in only certain perreduce the frequency of tuberculosis in the hy- sons was tuberculosis activated by measles. This persensitivity-depressed group B subjects. (2) limited conclusion must be classified as a guess. No bacteriologic confirmation of the diagnosis These studies are paradigms of many smaller was indicated, and only the children in group ones, which also have been used improperly to B and 4 children in group A were roentgenosupport the hypothesis and which did not elimgraphed at 5 months. (3) The high rate of tuinate coincidental development of tuberculosis berculosis after measles reported by Klein (8) after measles. prompted Slotved (9) to suggest an alternate Saame (16) collected 206 histories of children cause, that the abnormal, radiologic pulmonary hospitalized between 1928 and 1945 for tubershadows were mostly due to measles, not tuberculosis and who had concurrent measles. Radioculosis. Klein (8) stated that in all but one child logically, 12.1 per cent developed extensions of the pulmonary lesions subsequently cleared their pulmonary infiltrates within 6 weeks of rapidly. This supports Slotved's contention: onset of measles. No meningeal tuberculosis folmeasles pulmonary lesions detectable by radiolowed measles. Saame believed that patients withgraphy only may persist for 6 months or more out measles would provide approximately 8 per (10-12). cent tuberculous extensions. He proposed that The following 3 studies have been quoted his observations supported the concept that in support of the hypothesis that measles actimeasles activates tuberculosis. Assuming that his vates tuberculosis; but because no control groups control estimate was not a guess but was based were included, such a conclusion is not warranton an observed group comparable to the group ed. In 1929 Goebel (13) reported 69 children with measles, the difference in rates is not sigwith strongly positive tuberculin reactions who nificant (P = 0.23). Therefore, his data do not contracted measles. During the ensuing 12 support his hypothesis. months, 17 (25 per cent) developed an exacerTwo large measles epidemics occurring in esbation of the tuberculosis, including 5 and 3, sentially virgin populations in southern Greenrespectively, in whom the disease progressed land in 1951 and western Greenland in 1962 to miliary or meningeal forms. Sixteen who had provided new opportunities for studying the rehad active tuberculosis before measles showed lationship between measles and tuberculosis. Tuno exacerbation. The 12-month interval after berculosis among adult Greenlanders has been measles seems excessive today and might account frequent; among children, the frequency has for Goebel's high rate. been decreasing, perhaps owing to the introIn 1932 Constantino (14) and Liesegang (15) duction of bacille Calmette Guerin vaccination reported similar studies of 200 and 86 tubercuin 1949 and its administration to all newborns lous children, respectively, among whom they from approximately 1953 (17). The measles epidetermined the frequency with which measles demic of 1951 has been described by Christenpreceded tuberculosis. Both found that only 4 to sen and associates (18) and by Bech (19). Dur-
259
EDITORIAL
ing April, Christensen and co-workers (20) surveyed 79 per cent of the townspeople o£ Narssak (population, 463 persons) for pulmonary tuberculosis, using fluoroscopy. Tuberculosis was discovered in 16 per cent, with 52 per cent confirmed by the presence o£ acid-fast bacilli in smears. Then, in May, measles struck; in the Narssak area among a total population of 4,614 persons, only 6.4 per cent failed to contract measles during a 3-montlt period. Because these were mostly persons with known, active tuberculosis who had been given gamma globulin prophylactically, there was no group without measles for comparison. In September, after termination of the epidemic, a larger, more sensitive survey was made for pulmonary tuberculosis. Included were all survivors in Narssak who had been examined 5 months previously. The pertinent data are given in table 2. In Narssak, 19 new cases of tuberculosis appeared. Among the survivors who had had active tuberculosis before measles, 35 per cent showed increases in their pulmonary infiltrates in September, and 82 per cent of these had acid-fast rods in the sputum. In the larger area (including Narssak), the September examination uncovered a tuberculosis rate of 13 per cent. The highest frequency, 30 per cent, occurred among elderly men. Christensen and associates (20) believed that their observations supported the ac-
cepted concept that measles activates tuberculosis. They were impressed particularly by the 19 new cases in N arssak, the marked increase in pulmonary infiltrates after measles, and the ominously high rate of tuberculosis after measles in the elderly men of the entire area. Perhaps by comparing the tuberculosis rates in various groups after measles with the rates in N arssak before the epidemic, we can arrive at some evaluation of the role played by measles. The rate of tuberculosis in Narssak increased from 16 to 19 per cent during the epidemic period, a difference that is not significant (P = 0.28). This ignores the short period for the development of the 19 new cases, but there is no control period. The 30 per cent rate of tuberculosis after measles among elderly men of the entire area is not significantly different from the 23 per cent among the small group of elderly men in Narssak (P = 0.42 by the Fisher exact test). In addition, among the small group of elderly women in Narssak, the rate of tuberculosis was 44 per cent before measles, but only 20 per cent after measles in the larger group, just the reverse. To obtain a larger pre-measles sample of elderly persons from N arssak, one can combine the rates for both sexes. Then, 34 per cent had tuberculosis before the epidemic; afterward, only 24 per cent in the larger area had tuberculosis. The increase in pulmonary infiltrates
TABLE 2 TUBERCULOSIS RATES IN ASSOCIATION WITH THE MEASLES EPIDEMIC OF 1951 IN SOUTHERN GREENLAND, FROM CHRISTENSEN AND CO-WORKERS, 1953 (20) Before Measles
Area Narssak Total Persons> 55 years of age Men Women Sexes combined Narssak and environs Total Persons> 55 years of age Men Women Sexes combined
No. Examined
Persons with Tuberculosis
(no.)
(%)
5 Months After Start of Epidemic Persons with Tuberculosis
No. Examined
(no.)
68* 19 new cases
(%) 19 5 increase)
364
58
16
352 (352
13 16
3 7
23 44 34
12 15
2 7
17 47 :33
3,231
409
13
26 29
30 20 24
85 147
*Of the 58 tuberculous persons discovered before the measles epidemic, 9 in various age groups died during the epidemic.
260
EDITORIAL
observed in 35 per cent of the tuberculous subjects could well have been due to an artifact of the examination, rather than the measles. For diagnosis, fluoroscopy alone was used before measles, whereas more sensitive fluoroscopic photography was used after the epidemic. Also, the investigators must have had an influential belief that measles activates tuberculosis; otherwise, prophylactic gamma globulin would not have been administered to known tuberculous patients. These factors would have modified the interpretation of pulmonary shadows to a degree, and affected the conclusions drawn. I believe, then, that no conclusions are warranted concerning the interaction of measles and tuberculosis from this study. The 1962 measles epidemic in western Greenland, described in part by Bech (21), afforded a control group without measles. Among a population of approximately 34,000 persons, there were 10,722 recorded cases of measles, many of the others having had measles between 1954 and 1955; however, along the northern coast around Umanak, the lack of any prior contact with measles among the Greenlanders made a total epidemic inevitable (22). Therefore, initially deliberate exposure of this populace to fresh measles cases on a planned, staggered basis was accomplished in order to have the epidemic completed before winter. The villages were routinely visited on a yearly schedule by a medical team
aboard a ship, especially to uncover new tuberculosis. In the entire area, Lange (17) found a slightly greater frequency of new tuberculosis in the group without measles than in the population with measles; but when he analyzed his data according to age subgroups, there were marked differences in the other direction as depicted in table 3. For persons less than 20 years of age, there was no significant difference between tuberculosis rates among persons with and without measles; however, in the last 3 age groups listed, the adults, the rates were much greater among those with measles than those without measles, and these differences, I find, were significant. Lange noted that acid-fast smears and cultures together were positive in approximately 50 per cent of those clinically diagnosed as having tuberculosis and that using only proved cases would result in the same interpretations. Apparently, Lange discovered late in the study that 19 of the 109 cases of tuberculosis found after the measles epidemic did not, in fact, belong in that group, because their pulmonary disease had existed before they contracted measles. Consistency requires that these 19, not specified by age, be deleted from the data to be analyzed. Although it is evident from table 3 that four fifths of the post-measles tuberculosis occurred in adults, to determine how the deletion might influence the analysis, I made the most
TABLE 3 FREQUENCY OF NEW TUBERCULOSIS AFTER THE MEASLES EPIDEMIC OF 1962 AMONG GREENLANDERS WITH AND WITHOUT MEASLES: UNCORRECTED DATA FROM LANGE, 1970 (17)
Age (years} 1-4 5-9 1 ()--14 15-19 Subtotal (Children) 2()--39 4()--59 60 + Subtotal (Adults) Total
No.• with Measles
Persons with Tuberculosis
(no.}
(%}
Persons with Tuberculosis
No. without Measles
(no.}
(%}
P Value
3,117 2,787 840 532
4 5 5 8
0.13 0.18 0.60 1.50
621 1,179 2,139 1,793
3 2 6 18
0.48 0.17 0.28 1.00
0.65t 0.20t 0.48
7,276 1,232 604 205
22 42 30 15
0.30 3.41 4.97 7.32
5,732 4,942 2,651 886
29 87 57 15
0.51 1.76 2.15 1.69
< 0.01 < 0.01 < 0.01
2,041 9,317
87 109
4.26 1.17
8,479 14,211
159 188
1.88 1.32
• Numbers erroneously include 19 persons of unidentified age whose tuberculosis was present before measles. tThese probabilities were computed by Fisher's exact test; the others, by the chi square test with Yates correction.
EDITORIAL
stressful assumption that the 19 be deleted only from the 3 adult groups, and in the ratio of 7:7:5 cases, respectively. Despite these deletions, significant differences still favor the hypothesis in 2 of the 3 age groups: for 20 to 39 years, P = 0.014; 40 to 59 years, very borderline, with P = 0.028; "'= 60 years, P = 0.011, or by Fisher's exact test, P = 0.009. Other assumed ratios of deletions offer no advantages. There was a variable period as long as 1 year between measles and detection of tuberculosis. A long interval (perhaps longer than 3 months) should certainly disqualify a case as being measles related; however, in the Greenland study, such an excessive time interval probably did not unfairly overload the post-measles, tuberculosis group. Tuberculosis among persons without measles was also being detected at each village visited. The Umanak area, with 6 per cent of the population, was an exception, because of the lack of a group without measles. A rough estimate of this error can be calculated from the size of the local population (2,000 persons) and the frequency of tuberculosis among Greenlanders without measles of all ages from the entire area (1.32 per cent). Then, approximately 26 cases of tuberculosis in the Umanak district would have occurred in the absence of measles, and four·fifths, or 21 would be assignable to the adults for transfer to the group without measles. Now the Lange (17) data of table 3 for the adult groups can be approximately corrected. The 87 post-measles cases of tuberculosis must be reduced by 15 adult deletions (four fifths of the total of 19); this correction and the 21 Umanak adult transfers yield a caseload of 51 in a population of 2,005 adults. The 21 transfers increase the tuberculosis rate among adults without measles from 1.88 to 2.12 per cent. Use of this corrected rate yields 42 cases of tuberculosis expected among the adults after measles, compared to the 51 cases found, or an excess of only 9. Another hypothesis replacing measles activation of tuberculosis can explain the remaining excess cases of tuberculosis in the measles groups. Littauer and Sorensen (22) described the process of intentional cross infection (early measles patients coughing in the faces of the uninfected) used in the Umanak area to terminate before winter the near-total epidemic. Through this procedure, some young and some old persons lacking tuberculous immunity could have acquired a new Mycobacterium tubeF•tlosis infection coincidently with measles. Because of the
261
large amount of short-range, interpersonal coughing involved, the natural process of tuberculosis transmission would be accelerated somewhat, to yield an increased incidence. That pulmonary lesions of reinfection can occur in the elderly, especially in populations in which tuberculosis is common, as in Greenland, has been emphasized in recent years by Romeyn (23) through his reanalysis of the epidemiologic data of Stead (24). In summary, the Lange (17) study, the best in the group, offered no support for the measles hypothesis in children, but did superficially support it for adults. Reanalysis of the information for adults, however, indicates that the excessive tuberculosis after measles can be explained both by the application of 2 corrections to the data, and by an alternate hypothesis that easily fits the situation in the Umanak district. My conclusion is that the Lange study fails to support the concept that measles activates tuberculosis. In New York City, Starr and Berkovich (25) studied for exacerbations hospitalized, tuberculous children receiving para-aminosalicylic acid andfor isoniazid therapy either with or without measles virus infection. The children were examined monthly by roentgenograms and gastric cultures. Cases of measles were followed for a minimum of 3 months. Among the 218 control subjects without measles, only 64 were followed for 3 months or more and would, therefore, be comparable to the subjects with measles, in degree of activity of their tuberculosis and number of examinations per child. During therapy, 7 of these 64 control subjects had a bacteriologic relapse, but one was infected with a drug-resistant tubercle bacillus and was, therefore, deleted by Starr and Berkovich as equivalent to an untreated child. This left 6 bacteriologic exacerbations, or 9.5 per cent. Among the 154 children discharged from the hospital in less than 3 months were 3 who showed transient exacerbations by roentgenograms only. Starr and Berkovich thus implied a corrected frequency of activation of 4.2 per cent, based on the 217 cases without measles; however, I suggest that the better control frequency is 9.5 per cent, based solely on corrected, comparable cases of tuberculosis without measles. The children with measles were categorized into 3 subgroups. One subgroup received live measles vaccine, had no activations, and was deleted from consideration by Starr and Berko-
262
EDITORIAL
vich. Another subgroup of 10 was given prophylactic gamma globulin and developed modified measles, with fevers of 101 o F (38.5° C) or more and lasting I to 6 days in 7 children. This subset included 2 with cultural exacerbations, one having drug-resistant M. tuberculosis. This child was not deleted by Starr and Berkovich, as was a similar control child; but I do delete-this one from consideration. In a third subgroup of 25 children with unmodified, mild measles, 6 developed exacerbations; 2 had radiographic changes, and 4 had single, gastric cultural relapses. I find it appropriate to combine these latter 2 subgroups, because all members of both had wild measles virus infections, and the clinical courses in both groups probably overlapped in severity. The corrected frequency of relapses was 7 among a total of 34 children with measles, or 20.6 per cent. When compared to the proper control group, the difference was not significant (P = 0.23). If one believes that the unmodified and modified measles subgroups should be kept separate, then the difference between the unmodified group and the control subjects also was not significant (P = 0.16 by the Fisher exact test). A better check might be to compare the 2 sets and the control group by the F test. Then, P = 0.20, and the differences were still not significant. Thus, I must disagree with the conclusions of Starr and Berkovich (25) that measles is deleterious for treated tuberculosis. Anti-Hypothesis Studies
Some investigators have opined that their data negated the hypothesized relationship between measles and tuberculosis. Do the articles that purport to discredit this relationship actually accomplish their purpose? During World War I, Francine (26) and Berghoff (27) examined, respectively, 513 and 596 U.S. Army men for tuberculosis approximately I month after they had had measles. Francine (26) found the frequency of tuberculosis to be 3.1 per cent, whereas a previous, routine physical examination given to the men of the entire division had yielded 0.92 per cent tuberculosis. He concluded that the difference was really inappreciable because the quality of the 2 examinations and the criteria used for diagnosis were quite different, a reasonable explanation that implies an invalid control. Berghoff (27) could find only one man with tuberculosis, the rate being 0.17 per cent. Both stud-
ies seem defective because of the brevity of the interval allowed after measles for the development of tuberculosis and because of the diagnostic uncertainties of the era. During the 1923 to 1924 epidemic of measles in Freiberg, Germany, Noeggerath and Eckstein (28) observed that the mortality of children from all causes markedly increased in relation to the peaks of measles. The tuberculosis mortality at corresponding periods showed no appreciable increases, indicating an immeasurable influence of measles on tuberculosis. This study offers an insensitive approach, detecting only the minority of tuberculous subjects dying of their disease, and there was no autopsy evaluation. Beisken (29) reviewed childhood tuberculous meningitis observed in the Dusseldorf clinic during the years I 908 to I 924. Measles had occurred in some children before onset of tuberculous meningitis. As depicted in table 4, the incidence of meningitis approximately halved from the first to the third trimester after measles. This result might seem to contradict Beisken's conclusion that measles does not "activate" tuberculous meningitis, but a trimester shift of I or 2 cases due to error in timing of onset of measles or meningitis would markedly change the incidences. For the 17 years of the study, Beisken graphed the annual number of cases of measles and deaths from tuberculous meningitis. Measles rates varied dramatically, but meningitis rates changed only slightly. The uncertainties in the histories and in defining the population at risk could place Beisken's conclusion in doubt. Nalbant (30) observed 43 children hospitalized for tuberculosis who had concurrently contracted measles, with 75 per cent having active disease at the onset of the latter. Fourteen per TABLE 4 FREQUENCY OF PRECEDING MEASLES FROM HISTORY AMONG 162 CHILDREN WITH TUBERCULOUS MENINGITIS, FROM BEISKEN, 1924 (29) Interval between Measles and Onset of Tuberculous Meningitis
Summa~-----------------------------
In recent years, textbooks and reviews on mechanisms involved in cellular immunity have emphasized that measles adversely influences tuberculous lesions. The medical literature was critically investigated for the basis of this claim. All field studies reviewed possessed strong deficiencies in the pertinent data and the methods of their collection. These deficiencies rendered invalid conclusions concerning the ability of measles to activate tuberculosis. Indirectly, there are also no adequate epidemiologic data to support the concept that measles suppresses tuberculous immunity when it suppresses tuberculin skin reactivity. Considering all the available information, one may conclude that if measles does have a deleterious influence on tuberculoSis, it is probably at low frequency in most populations. A belief has persisted that measles activates tuberculosis, either by converting a latent infection to active tuberculosis or by aggravating an active one. As an indication of the current prevalence of this belief, there are mild to strong statements connecting measles and tuberculous activation in 4 of 7 internal medicine texts and in all of 6 pediatric texts recently surveyed. That measles can reduce tuberculin reactivity for a week or 2 in many persons is well established (1-5). Since von Pirquet's (6) report of a child whose measles flowed into fatal tuberculosis, immunity and delayed hypersensitivity have often been equated functionally, thus offering an explanation for the reputed activation by measles. The sole question posed here is whether or not the published evidence adequately supports the hypothesis that measles activates tuberculosis. To arrive at an answer, studies purporting
either to support or to deny the hypothesis have been scrutinized for adequacy. When statistical analysis could be applied to data, I have routinely used the chi square test with Yates correction (7). Other statistical tests are identified when needed.
Pro-Hypothesis Studies Klein (8) studied tuberculosis in children who had contracted measles during the epidemic of 1925 in Essen, Germany. He wished to determine whether tuberculosis was more common among children whose tuberculin reactivity (and, presumably, their immunity) was inhibited by measles compared to control subjects in whom measles caused no inhibition. He applied the insensitive and inconsistent Moro skin test (Old Tuberculin in an ointment base) to each child once during measles. Five months later, the children were retested. Children with positive reactions were examined for tuberculosis. As indicated in table l, Klein compared the tu· berculosis rates of 2 groups. Group A included those with positive Moro tests during measles, and Group B included those whose reactions converted from negative to positive. Because the rate of tuberculosis in group B was 3.5 times that in group A, he believed that his data supported the hypothesis that measles activates tuberculosis. Klein included 4 children in group A and 6 in group B who had had tuberculosis before measles. These cases should be deleted for lack of activation by measles, thus reducing the rates at 5 months correspondingly in both groups. Klein's support for the hypothesis is nullified by several considerations. (1) The single Moro test seems'inadequate for making a valid separation of hypersensitivity-depressed versus nondepressed subjects during measles. Repeated, accurate skin testing is required to detect the depression in
AMERICAN REVIEW OF RESPIRATORY DISEASE, VOLUME 114, 1976
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EDITORIAL
TABLE 1 FREQUENCY OF TUBERCULOSIS AMONG CHILDREN 5 MONTHS AFTER MEASLES: UNCORRECTED DATA FROM KLEIN, 1927 (8) Tuberculin Reactivity during Measles Group
OT-Positive (no.)
A
27
B
c
OT -Negative (no.) 42 103t
5 Months Later, When Tuberculin-Positive No. with Tuberculosis 4 22
Per Cent of Group 14.8* 52.4*
• Application of the chi square test indicated a significant difference. tThese subjects remained OT-negative at 5 months and were not examined further.
some persons. Therefore, a number of the non- 5 per cent of such children had measles sufficientdepressed group A subjects really belonged in ly close to onset of tuberculosis and a developthe tuberculin-depressed group. Because none mental sequence suggesting a relationship. of the group A children developed fresh tuberGoebel (13), Constantino (14), and Lieseculosis at 5 months, this transposition could only gang (15) all proposed that in only certain perreduce the frequency of tuberculosis in the hy- sons was tuberculosis activated by measles. This persensitivity-depressed group B subjects. (2) limited conclusion must be classified as a guess. No bacteriologic confirmation of the diagnosis These studies are paradigms of many smaller was indicated, and only the children in group ones, which also have been used improperly to B and 4 children in group A were roentgenosupport the hypothesis and which did not elimgraphed at 5 months. (3) The high rate of tuinate coincidental development of tuberculosis berculosis after measles reported by Klein (8) after measles. prompted Slotved (9) to suggest an alternate Saame (16) collected 206 histories of children cause, that the abnormal, radiologic pulmonary hospitalized between 1928 and 1945 for tubershadows were mostly due to measles, not tuberculosis and who had concurrent measles. Radioculosis. Klein (8) stated that in all but one child logically, 12.1 per cent developed extensions of the pulmonary lesions subsequently cleared their pulmonary infiltrates within 6 weeks of rapidly. This supports Slotved's contention: onset of measles. No meningeal tuberculosis folmeasles pulmonary lesions detectable by radiolowed measles. Saame believed that patients withgraphy only may persist for 6 months or more out measles would provide approximately 8 per (10-12). cent tuberculous extensions. He proposed that The following 3 studies have been quoted his observations supported the concept that in support of the hypothesis that measles actimeasles activates tuberculosis. Assuming that his vates tuberculosis; but because no control groups control estimate was not a guess but was based were included, such a conclusion is not warranton an observed group comparable to the group ed. In 1929 Goebel (13) reported 69 children with measles, the difference in rates is not sigwith strongly positive tuberculin reactions who nificant (P = 0.23). Therefore, his data do not contracted measles. During the ensuing 12 support his hypothesis. months, 17 (25 per cent) developed an exacerTwo large measles epidemics occurring in esbation of the tuberculosis, including 5 and 3, sentially virgin populations in southern Greenrespectively, in whom the disease progressed land in 1951 and western Greenland in 1962 to miliary or meningeal forms. Sixteen who had provided new opportunities for studying the rehad active tuberculosis before measles showed lationship between measles and tuberculosis. Tuno exacerbation. The 12-month interval after berculosis among adult Greenlanders has been measles seems excessive today and might account frequent; among children, the frequency has for Goebel's high rate. been decreasing, perhaps owing to the introIn 1932 Constantino (14) and Liesegang (15) duction of bacille Calmette Guerin vaccination reported similar studies of 200 and 86 tubercuin 1949 and its administration to all newborns lous children, respectively, among whom they from approximately 1953 (17). The measles epidetermined the frequency with which measles demic of 1951 has been described by Christenpreceded tuberculosis. Both found that only 4 to sen and associates (18) and by Bech (19). Dur-
259
EDITORIAL
ing April, Christensen and co-workers (20) surveyed 79 per cent of the townspeople o£ Narssak (population, 463 persons) for pulmonary tuberculosis, using fluoroscopy. Tuberculosis was discovered in 16 per cent, with 52 per cent confirmed by the presence o£ acid-fast bacilli in smears. Then, in May, measles struck; in the Narssak area among a total population of 4,614 persons, only 6.4 per cent failed to contract measles during a 3-montlt period. Because these were mostly persons with known, active tuberculosis who had been given gamma globulin prophylactically, there was no group without measles for comparison. In September, after termination of the epidemic, a larger, more sensitive survey was made for pulmonary tuberculosis. Included were all survivors in Narssak who had been examined 5 months previously. The pertinent data are given in table 2. In Narssak, 19 new cases of tuberculosis appeared. Among the survivors who had had active tuberculosis before measles, 35 per cent showed increases in their pulmonary infiltrates in September, and 82 per cent of these had acid-fast rods in the sputum. In the larger area (including Narssak), the September examination uncovered a tuberculosis rate of 13 per cent. The highest frequency, 30 per cent, occurred among elderly men. Christensen and associates (20) believed that their observations supported the ac-
cepted concept that measles activates tuberculosis. They were impressed particularly by the 19 new cases in N arssak, the marked increase in pulmonary infiltrates after measles, and the ominously high rate of tuberculosis after measles in the elderly men of the entire area. Perhaps by comparing the tuberculosis rates in various groups after measles with the rates in N arssak before the epidemic, we can arrive at some evaluation of the role played by measles. The rate of tuberculosis in Narssak increased from 16 to 19 per cent during the epidemic period, a difference that is not significant (P = 0.28). This ignores the short period for the development of the 19 new cases, but there is no control period. The 30 per cent rate of tuberculosis after measles among elderly men of the entire area is not significantly different from the 23 per cent among the small group of elderly men in Narssak (P = 0.42 by the Fisher exact test). In addition, among the small group of elderly women in Narssak, the rate of tuberculosis was 44 per cent before measles, but only 20 per cent after measles in the larger group, just the reverse. To obtain a larger pre-measles sample of elderly persons from N arssak, one can combine the rates for both sexes. Then, 34 per cent had tuberculosis before the epidemic; afterward, only 24 per cent in the larger area had tuberculosis. The increase in pulmonary infiltrates
TABLE 2 TUBERCULOSIS RATES IN ASSOCIATION WITH THE MEASLES EPIDEMIC OF 1951 IN SOUTHERN GREENLAND, FROM CHRISTENSEN AND CO-WORKERS, 1953 (20) Before Measles
Area Narssak Total Persons> 55 years of age Men Women Sexes combined Narssak and environs Total Persons> 55 years of age Men Women Sexes combined
No. Examined
Persons with Tuberculosis
(no.)
(%)
5 Months After Start of Epidemic Persons with Tuberculosis
No. Examined
(no.)
68* 19 new cases
(%) 19 5 increase)
364
58
16
352 (352
13 16
3 7
23 44 34
12 15
2 7
17 47 :33
3,231
409
13
26 29
30 20 24
85 147
*Of the 58 tuberculous persons discovered before the measles epidemic, 9 in various age groups died during the epidemic.
260
EDITORIAL
observed in 35 per cent of the tuberculous subjects could well have been due to an artifact of the examination, rather than the measles. For diagnosis, fluoroscopy alone was used before measles, whereas more sensitive fluoroscopic photography was used after the epidemic. Also, the investigators must have had an influential belief that measles activates tuberculosis; otherwise, prophylactic gamma globulin would not have been administered to known tuberculous patients. These factors would have modified the interpretation of pulmonary shadows to a degree, and affected the conclusions drawn. I believe, then, that no conclusions are warranted concerning the interaction of measles and tuberculosis from this study. The 1962 measles epidemic in western Greenland, described in part by Bech (21), afforded a control group without measles. Among a population of approximately 34,000 persons, there were 10,722 recorded cases of measles, many of the others having had measles between 1954 and 1955; however, along the northern coast around Umanak, the lack of any prior contact with measles among the Greenlanders made a total epidemic inevitable (22). Therefore, initially deliberate exposure of this populace to fresh measles cases on a planned, staggered basis was accomplished in order to have the epidemic completed before winter. The villages were routinely visited on a yearly schedule by a medical team
aboard a ship, especially to uncover new tuberculosis. In the entire area, Lange (17) found a slightly greater frequency of new tuberculosis in the group without measles than in the population with measles; but when he analyzed his data according to age subgroups, there were marked differences in the other direction as depicted in table 3. For persons less than 20 years of age, there was no significant difference between tuberculosis rates among persons with and without measles; however, in the last 3 age groups listed, the adults, the rates were much greater among those with measles than those without measles, and these differences, I find, were significant. Lange noted that acid-fast smears and cultures together were positive in approximately 50 per cent of those clinically diagnosed as having tuberculosis and that using only proved cases would result in the same interpretations. Apparently, Lange discovered late in the study that 19 of the 109 cases of tuberculosis found after the measles epidemic did not, in fact, belong in that group, because their pulmonary disease had existed before they contracted measles. Consistency requires that these 19, not specified by age, be deleted from the data to be analyzed. Although it is evident from table 3 that four fifths of the post-measles tuberculosis occurred in adults, to determine how the deletion might influence the analysis, I made the most
TABLE 3 FREQUENCY OF NEW TUBERCULOSIS AFTER THE MEASLES EPIDEMIC OF 1962 AMONG GREENLANDERS WITH AND WITHOUT MEASLES: UNCORRECTED DATA FROM LANGE, 1970 (17)
Age (years} 1-4 5-9 1 ()--14 15-19 Subtotal (Children) 2()--39 4()--59 60 + Subtotal (Adults) Total
No.• with Measles
Persons with Tuberculosis
(no.}
(%}
Persons with Tuberculosis
No. without Measles
(no.}
(%}
P Value
3,117 2,787 840 532
4 5 5 8
0.13 0.18 0.60 1.50
621 1,179 2,139 1,793
3 2 6 18
0.48 0.17 0.28 1.00
0.65t 0.20t 0.48
7,276 1,232 604 205
22 42 30 15
0.30 3.41 4.97 7.32
5,732 4,942 2,651 886
29 87 57 15
0.51 1.76 2.15 1.69
< 0.01 < 0.01 < 0.01
2,041 9,317
87 109
4.26 1.17
8,479 14,211
159 188
1.88 1.32
• Numbers erroneously include 19 persons of unidentified age whose tuberculosis was present before measles. tThese probabilities were computed by Fisher's exact test; the others, by the chi square test with Yates correction.
EDITORIAL
stressful assumption that the 19 be deleted only from the 3 adult groups, and in the ratio of 7:7:5 cases, respectively. Despite these deletions, significant differences still favor the hypothesis in 2 of the 3 age groups: for 20 to 39 years, P = 0.014; 40 to 59 years, very borderline, with P = 0.028; "'= 60 years, P = 0.011, or by Fisher's exact test, P = 0.009. Other assumed ratios of deletions offer no advantages. There was a variable period as long as 1 year between measles and detection of tuberculosis. A long interval (perhaps longer than 3 months) should certainly disqualify a case as being measles related; however, in the Greenland study, such an excessive time interval probably did not unfairly overload the post-measles, tuberculosis group. Tuberculosis among persons without measles was also being detected at each village visited. The Umanak area, with 6 per cent of the population, was an exception, because of the lack of a group without measles. A rough estimate of this error can be calculated from the size of the local population (2,000 persons) and the frequency of tuberculosis among Greenlanders without measles of all ages from the entire area (1.32 per cent). Then, approximately 26 cases of tuberculosis in the Umanak district would have occurred in the absence of measles, and four·fifths, or 21 would be assignable to the adults for transfer to the group without measles. Now the Lange (17) data of table 3 for the adult groups can be approximately corrected. The 87 post-measles cases of tuberculosis must be reduced by 15 adult deletions (four fifths of the total of 19); this correction and the 21 Umanak adult transfers yield a caseload of 51 in a population of 2,005 adults. The 21 transfers increase the tuberculosis rate among adults without measles from 1.88 to 2.12 per cent. Use of this corrected rate yields 42 cases of tuberculosis expected among the adults after measles, compared to the 51 cases found, or an excess of only 9. Another hypothesis replacing measles activation of tuberculosis can explain the remaining excess cases of tuberculosis in the measles groups. Littauer and Sorensen (22) described the process of intentional cross infection (early measles patients coughing in the faces of the uninfected) used in the Umanak area to terminate before winter the near-total epidemic. Through this procedure, some young and some old persons lacking tuberculous immunity could have acquired a new Mycobacterium tubeF•tlosis infection coincidently with measles. Because of the
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large amount of short-range, interpersonal coughing involved, the natural process of tuberculosis transmission would be accelerated somewhat, to yield an increased incidence. That pulmonary lesions of reinfection can occur in the elderly, especially in populations in which tuberculosis is common, as in Greenland, has been emphasized in recent years by Romeyn (23) through his reanalysis of the epidemiologic data of Stead (24). In summary, the Lange (17) study, the best in the group, offered no support for the measles hypothesis in children, but did superficially support it for adults. Reanalysis of the information for adults, however, indicates that the excessive tuberculosis after measles can be explained both by the application of 2 corrections to the data, and by an alternate hypothesis that easily fits the situation in the Umanak district. My conclusion is that the Lange study fails to support the concept that measles activates tuberculosis. In New York City, Starr and Berkovich (25) studied for exacerbations hospitalized, tuberculous children receiving para-aminosalicylic acid andfor isoniazid therapy either with or without measles virus infection. The children were examined monthly by roentgenograms and gastric cultures. Cases of measles were followed for a minimum of 3 months. Among the 218 control subjects without measles, only 64 were followed for 3 months or more and would, therefore, be comparable to the subjects with measles, in degree of activity of their tuberculosis and number of examinations per child. During therapy, 7 of these 64 control subjects had a bacteriologic relapse, but one was infected with a drug-resistant tubercle bacillus and was, therefore, deleted by Starr and Berkovich as equivalent to an untreated child. This left 6 bacteriologic exacerbations, or 9.5 per cent. Among the 154 children discharged from the hospital in less than 3 months were 3 who showed transient exacerbations by roentgenograms only. Starr and Berkovich thus implied a corrected frequency of activation of 4.2 per cent, based on the 217 cases without measles; however, I suggest that the better control frequency is 9.5 per cent, based solely on corrected, comparable cases of tuberculosis without measles. The children with measles were categorized into 3 subgroups. One subgroup received live measles vaccine, had no activations, and was deleted from consideration by Starr and Berko-
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EDITORIAL
vich. Another subgroup of 10 was given prophylactic gamma globulin and developed modified measles, with fevers of 101 o F (38.5° C) or more and lasting I to 6 days in 7 children. This subset included 2 with cultural exacerbations, one having drug-resistant M. tuberculosis. This child was not deleted by Starr and Berkovich, as was a similar control child; but I do delete-this one from consideration. In a third subgroup of 25 children with unmodified, mild measles, 6 developed exacerbations; 2 had radiographic changes, and 4 had single, gastric cultural relapses. I find it appropriate to combine these latter 2 subgroups, because all members of both had wild measles virus infections, and the clinical courses in both groups probably overlapped in severity. The corrected frequency of relapses was 7 among a total of 34 children with measles, or 20.6 per cent. When compared to the proper control group, the difference was not significant (P = 0.23). If one believes that the unmodified and modified measles subgroups should be kept separate, then the difference between the unmodified group and the control subjects also was not significant (P = 0.16 by the Fisher exact test). A better check might be to compare the 2 sets and the control group by the F test. Then, P = 0.20, and the differences were still not significant. Thus, I must disagree with the conclusions of Starr and Berkovich (25) that measles is deleterious for treated tuberculosis. Anti-Hypothesis Studies
Some investigators have opined that their data negated the hypothesized relationship between measles and tuberculosis. Do the articles that purport to discredit this relationship actually accomplish their purpose? During World War I, Francine (26) and Berghoff (27) examined, respectively, 513 and 596 U.S. Army men for tuberculosis approximately I month after they had had measles. Francine (26) found the frequency of tuberculosis to be 3.1 per cent, whereas a previous, routine physical examination given to the men of the entire division had yielded 0.92 per cent tuberculosis. He concluded that the difference was really inappreciable because the quality of the 2 examinations and the criteria used for diagnosis were quite different, a reasonable explanation that implies an invalid control. Berghoff (27) could find only one man with tuberculosis, the rate being 0.17 per cent. Both stud-
ies seem defective because of the brevity of the interval allowed after measles for the development of tuberculosis and because of the diagnostic uncertainties of the era. During the 1923 to 1924 epidemic of measles in Freiberg, Germany, Noeggerath and Eckstein (28) observed that the mortality of children from all causes markedly increased in relation to the peaks of measles. The tuberculosis mortality at corresponding periods showed no appreciable increases, indicating an immeasurable influence of measles on tuberculosis. This study offers an insensitive approach, detecting only the minority of tuberculous subjects dying of their disease, and there was no autopsy evaluation. Beisken (29) reviewed childhood tuberculous meningitis observed in the Dusseldorf clinic during the years I 908 to I 924. Measles had occurred in some children before onset of tuberculous meningitis. As depicted in table 4, the incidence of meningitis approximately halved from the first to the third trimester after measles. This result might seem to contradict Beisken's conclusion that measles does not "activate" tuberculous meningitis, but a trimester shift of I or 2 cases due to error in timing of onset of measles or meningitis would markedly change the incidences. For the 17 years of the study, Beisken graphed the annual number of cases of measles and deaths from tuberculous meningitis. Measles rates varied dramatically, but meningitis rates changed only slightly. The uncertainties in the histories and in defining the population at risk could place Beisken's conclusion in doubt. Nalbant (30) observed 43 children hospitalized for tuberculosis who had concurrently contracted measles, with 75 per cent having active disease at the onset of the latter. Fourteen per TABLE 4 FREQUENCY OF PRECEDING MEASLES FROM HISTORY AMONG 162 CHILDREN WITH TUBERCULOUS MENINGITIS, FROM BEISKEN, 1924 (29) Interval between Measles and Onset of Tuberculous Meningitis
