CHEST DISEASES IN THE ARMY

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1 48 CHEST DISEASES IN THE ARMY A SURVEY AT THE CONNAUGHT HOSPITAL IN 1950 J. F. BOYD M.D., M.R.C.P.(Edin.), M.C. Path., late Captain, R.A.M.C. (Continued/rom page 243 0/ Volume 109) CHAPTER IV COMPARISON OF THE GROUPS (concluded) Discussion-Part 11 LET us now consider how the findings of the foregoing chapters agree with the previously accepted views on the pathology and epidemiology of tuberculosis. In this country most individuals become infected with the causal organism, which lives "in symbiosis" without causing symptoms in most people so that only a small proportion of the population becomes ill with the disease. A basic fact concerning any infectious disease is its incubation period; with regard to tuberculosis this has been termed the pre-allergic phase by some, although the two terms are not really synonymous. It has been determined by WaIlgren (1943) and by Pagel and Price (1943) to vary between four and seven weeks iri the majority of cases with a scatter of two to seven weeks; the series by Bevan et al. (1951) suggests six to nine weeks; my series fails to give further guidance. Another feature of an infectious disease is that immunity develops at a variable period after infection. This immunity may not be very strong, or it may be virtually life-long. In tuberculosis, immunity begins to develop from the onset of infection (Cobbett 1917) and is accompanied by allergy, although Rich (1944) has pointed out that one may be present without the other. The average duration of immunity is not clear. Clawson's experiments (1938) suggests that it lasts fora long time and his opinion is supported by Francis (1949). The persistence of a positive tuberculin reaction has been used as a guide to the duration of immunity although it may be false in this respect occasionally. Many surveys have reported reduction in sensitivity to tuberculin with the passage of time, and also the occurrence of tuberculin reversion (Blacklock 1947; Daniels et al. 1948; Hart 1932; Lunn 1951). In the Prophit Survey (Daniels et al. 1948), the varied reversion rates of the different groups were believed to be due to the varied opportunities for fresh infections. Once a person has become tuberculin negative, with assumed coincident loss of immunity, a: fresh infection will provoke a fresh primary lesion, i.e. reinfection (Danie1s et al. 1948; McPhedran and Opie 1935). When a normal person's tuberculin reaction wanes and reverts to negative, it is not only accepted that the latent primary infection has healed but also that all tubercle bacilli in the body have died. Attempts to culture M. tuberculosis from clinically, radiologicaily and histologically effete lesions, most of which are of one to two years' duration, have shown these lesions to be sterile (Sweany et al. 1943); on the other hand, Heaf's evidence (1946) did not confirm this. Persistence of a positive tuberculin reaction has been considered by some to be due to fresh sub-clinical infections (Daniels et al. 1948; Opie, McPhedran and Putnam 1935), although this

2 J. F. Boyd 49 assumption appears to be invalid. A more acceptable explanation would be that persistence of the positive tuberculin reaction is due to the continued presence of viable tubercle bacilli, which may be descendants of those which produced the primary infection. These bacilli may not be producing active disease, but in all instances they are potentially dangerous. Against this suggested interpretation of a positive result is the finding of a higher level of tuberculin sensitivity among the healthy members of a family in which a person with active tuberculosis exists, and also among nurses in contact with tuberculosis compared with a group having no recognizable contact with tuberculosis (Daniels et al. 1948; Hart 1932; Lloyd and Dow 1931; McPhedran et al. 1935). These differences in sensitivity, however, could be due to relatively greater primary infecting doses in the first two groups. The theoretical problem to which I should like to draw attention is the attempt to culture M. tuberculosis from all the healed or latent foci scattered throughout one person who has shown a continued positive tuberculin reaction but without Clinical evidence of active disease. This is an impossible task, but attention is drawn to it because it has been inferred on other occasions that, because a primary complex or primary focus or scattered calcified lesions are sterile, the person as a whole is free from tubercle bacilli, a fallacy which has been referred to by Pinner (1945). It is suggested, therefore, that a persisting positive tuberculin reaction indicates the presence of viable tubercle bacilli within the patient even although there is no evidence of active disease. This view has become more acceptable in recent years, and it leads to a comparison between tuberculosis and syphilis. To assume that because the primary lesion of syphilis heals in an untreated patient; the whole patient is sterile, is known to be false. When the Wasserman reaction is positive it implies that the patient has untreated or inadequately treated syphilis, which may be latent at the time of testing. The same significance should be accorded to a positive tuberculin reaction, i.e. that viable tubercle bacilli exist somewhere in the patient tested, and are arousing an allergic reaction, but may not be producing active lesions at the time. Another feature of an infectious disease is the absence of superinfection by the same organism. If during the' course of a disease a fresh infecting dose of the same organism is acquired, a second (superimposed) infection does not develop. This is the basis of all vaccination and inoculation programmes. However, there are situations where further attacks are possible either during or immediately after the first, and in these cases the explanation is usually that the immunity evolved during the first attack is highly specific for the organism causing it, while the second attack is due to a different strain of the organism whose activity is not restricted by the immunity developed against the first strain. As far as tuberculosis in humans is concerned only two strains of mycobacterium are involved, the. human and the bovine. From the above arguments, if primary tuberculosis is caused by one strain it may be possible for superinfection due to the other strain to occur; I suggest that superinfection occurs in these circumstances only, and if it is possible to show that there are sub-groups of. human or bovine strains which ellicit different immunological responses, then superinfection occurs frequently. On the other hand, if there is evidence that cross-immunity between the two strains exists, then super-infection would be uncommon; such evidence exists in three forms. The existence of cross-immunity was first expressed in Marfan's

3 50 Chest Diseases in the Army law which states that adult tuberculosis rarely develops in those who have had tuberculous adenitis in childhood (Marfan 1886; Rich 1944). In analysing this statement, we can assume that most "adult tuberculosis" at the end of the 19th century was due to the human strain for Mollers' figures (1928) quoted by Rich (1944) show that more than 97 per cent of adult tuberculosis was due to the human strain; and for "extensive tuberculous adenitis" we can assume the bovine strain, for Mitchell (1914) showed that 90 per cent of tuberculous cervical adenitis was due to the bovine strain. Secondly, no antigenic difference has been demonstrated between human and bovine strains (Wilson 1925; Topley and Wilson 1955). Thirdly, the use of B.C.G. (an attenuated bovine strain) as a means of reducing infection by M. tuberculosis (human or bovine) implies the existence of a fair degree of cross-immunity between the two strains. These three facts suggest therefore that superinfection is uncommon. Finally, while superinfection is an event which only occurs in well-defined circumstances, endogenous exacerbation of an infectious disease is a phenomenon which is accepted widely. Why has there been doubt in the case of tuberculosis for so long? In support of this occurrence in tuberculosis there is the response of an infected animal to a second infection as exhibited by Koch's phenomenon. In this case the second infection is not commonly established while the first is still active (Browning and Mackie 1949; Kayne et al. 1948; Pinner 1945). The analogy of the guinea-pig may be held by some to be inapplicable to the human sittiation because the primary infection in the first instance is a progressive one, while in most humans who are susceptible to a "second" infection, the first infection is considered to be nonprogressive or inactive. As suggested above, however, viable bacilli probably persist in the host; if the persistence of a positive tuberculin reaction is accepted as an indication of the presence of viable bacilli within the host, the analogy with Koch's phenomenon is complete.! It will be appreciated that these arguments favour the theory of endogenous exacerbation of the primary complex or of its seql1elre as the origin of post-primary tuberculosis in most cases nowadays, although the possibility of superinfection is not excluded in a small proportion of cases. Some authors believe endogenous exacerbation to be the only process of development of post-primary tuberculosis, while others believe that superinfection plays a more important part, but none has attempted to define the limits of the two methods of development of the disease. I suggest that the definition of "superinfection" should be confined to tuberculosis in which a strain of bacillus different from the one which was responsible for the primary infection is involved, and reasons have been detailed above for believing that superinfection accounts for only a small proportion of post-primary tuberculosis at the present time. The results which have been recorded in the previous chapters of this article may support this view. In previous years, however, the theory of exogenous reinfection (or superinfection) was commonly held, and probably correctly,since a large proportion of the population acquired bovine alimentary primary infection, and a proportion of these people later developed pulmonary tuberculosis due to the human strain. Such a situation showed that cross-immunity was incomplete rather than nonexistent. One other argument employed by those who believe that superinfection is the

4 J. F. Boyd 51 common mode of origin of post-primary tuberculosis at the present time is that the campaigns waged in search of tuberculosis among contacts of tuberculous persons are wasted time, money and energy if one is to accept the theory that most postprimary tuberculosis is the result of the primary infection (Daniels et al. 1948; Lloyd et al. 1936; McPhedran et al. 1935; Opie et al. 1935); I disagree with this because the search for persons with active tuberculosis is still very important even if it is accepted that most phthisis is the result of exacerbation of previously acquired disease. If infected milk disappears completely as a source of infection, the disease will be - acquired in the vast majority of cases by inhalation. It is a general rule for any infectious disease acquired by inhalation that carriers be tracked down, and this applies to tuberculosis. It should be made clear, however, that the aim is to prevent the development of further primary complexes in a tuberculin-negative population (Miller 1949). If this is the aim, then by the time a person has become tuberculin positive (he may be free from active disease) the search for contacts with active disease so that they may be isolated is too late. The patient has acquired a tuberculous infection, be the infecting dose too great for his natural resistance or otherwise. It is advisable, nevertheless, to follow up persons who are tuberculin positive and who are contacts of actively tuberculous persons in case the infecting dose has been so great that progressive disease results at a later date; ideally all tuberculin-positive persons should be followed up. Fortunately the infecting dose overcomes the patient's natural resistance in only a small proportion of cases. In general, no future contact with the disease will influence the course of the infection already acquired unless a different strain is involved. Thus, belief in the endogenous theory makes the search for cases of phthisis all the more essential. It is natural that the source of the disease should be in the family in many cases. Lack of contact wbuld ensure a tuberculin-negative community which would be world-wide eventually (Miller 1949), and this should be the ultimate aim of the medical profession. From the above arguments it would appear that B.C.G. should provide moderate immunity against bovine tuberculosis, and at the same time a degree of cross-immunity to human tuberculosis. But its protection against the latter may not be complete, and thus a small number of cases of post-b.c.g. tuberculosis may be expected, and most of these will be examples of superinfection. Such reports are now appearing (Backman and Wallgren 1954; Brit. med. J. 1955), but these are mainly clinical reports and so far do not enter into bacteriological details. Indeed, an occasional case may be due to bovine infection for no vaccination or immunization procedure is sure of 100 per cent success. In conclusion, if the above discussion is substantially correct, what are the factors which lead to endogenous exacerbation of disease which has lain latent for varying periods? Not much is known at the present time about the alterations of the internal environment which favour the multiplication of tubercle bacilli, but it must be by this route that poor social conditions, pregnancy, poor health and excessive smoking (Lowe 1956) play their part in lowering the state of immunity of the subject. It is my opinion that factors of this nature were responsible to some extent for the disease in the bandsmen reported by Protheroe (1957) rather than a small local epidemic occurring in a rather isolated community, and it may be that domestic animals are as susceptible as humans to poor social conditions (Hawthorne et al. 1957). The

5 52 Chest Diseases in the Army above suggestions could also explain the greater breakdown rate among females in the age-group years-the occurrence of marriage, continued working, attending to a home and rearing a family-compared with the later breakdown rate in men which occurs when the general powers of resistance are on the wane (Springett 1952). Further, Doig (1955) suggests that most racial susceptibility may be explained on the basis of the prevailing social conditions at the time. The above discussion brings to the forefront once more Ranke's analogy with syphilis and Wallgren's timetable for tuberculosis (Clarke 1952). There are two points which I would make. First, the timetable for tuberculosis is not as constant from one person to another as it appears to be in the case of syphilis; secondly, the average timetable for tuberculosis may be altering from decade to decade, which is not apparently so with syphilis. Figure 4 shows the course of tuberculosis as I consider it to be at the present time. It is noted that there are four stages at which lymphatic spread may occur, and clinically the lymphatic disease may be the most prominent feature in some cases. The present series suggests that the average interval between the primary infection in males aged years in 1950 and the onset of post-primary tuberculosis is about three years, with the proviso that clinically manifest tuberculosis occurs only in a small percentage of those acquiring a primary infection. There may be a wide scatter around this mean. Contact may J~ 1;0_ , i r t Cl Cl I a brcui -Tuberculous Ad<mi tis tiwpczrson ailry""/'yell,rhilb'c SprHd) r ~+ bact!raemla _ miliary tuberculo"is ± m.. ninqitis 1 (.IUI29 S systemic, orboth) H~matogenous foci _C.N.S.,G U.S. Bona sjt. et;c (.gnywji~ mcllui19j. 1 * (;l4lry.l.vmphatlc Spr_d) r hea n9.-aacilli _ Tuberculin... Fresh Infection or die ravet"'sion by the same or + by othel" stnain Tubercle bacilli (R/r..innzctJon) nzmain viable somewhere in the body thisto logical react;ion. Pas. tuberculin rasponse parsists. possibly varyinq in daqree from year to year. Fresh InfectIon strets. Poor Health. etc. (~ii2l'=t/on) t.. by different ---r-+'raactivatlon of old foci strain. or '". L.. Post Primary _.!,.inqu"d,larynqeaj. lntestinal\ Tuberculosis! (ErOl7cho9U2ic mainly)....., (3sry.. y.!z'~t:jc Spre,ad/ (+.gruyj7u>!htj'c $,pread) with tr.:ratm.. nt.. I... or V\Zry J\Sl"2Jy... _----'' _~. spontaneously. Fiq.4

6 J. F. Boyd 53 Summary and Conclusions 1. The average age of the patients with primary tuberculosis is high-because this series deals particularly with adolescent and adult males. 2. The cases of primary tuberculosis revealed no significant number of tuberculous contacts. This is not unexpected in such a series, although the results are contrary to other publications. 3. The present series fails to provide any data which might confirm or refute the suggestion that the incubation period for tuberculosis is two to nine weeks in humans. 4. The present series reveals a build-up period of contacts extending over three years before a presumed tuberculin-negative individual acquires primary tuberculosis. 5. In 1950, the average period between tuberculin conversion and the appearance of post-primary tuberculosis in male adolescents was about three years. 6. It is suggested that the occurrence of this fresh disease, at this interval after the primary infection, is due in part to a fall in the immunity response produced by the primary infection three years earlier. 7. The patients with post-primary tuberculosis reveal a highly significant number of contacts with tuberculosis compared with those of the other disease groups, and especially with the control group of healthy soldiers. These contacts arise particularly from family and social sources, while Army sources are also important but less so. 8. While Table 4 (see Chapter II) and Figs. 1 and 2 (see Chapter Ill) suggest that further contacts are necessary in order to develop this phase of the disease, Fig. 3 suggests that this is not necessarily the complete explanation. 9. It is suggested that post-primary infection by a different strain of tubercle bacillus is not likely while viable bacilli from the primary complex persist in the body as shown by a persistently positive tuberculin reaction, unless there is minimal crossimmunity between one strain and the other. There are several observations which suggest that a reasonable degree of cross-immunity exists between the human and bovine strains. The limitations of superinfection are defined. 10. The results detailed in these reports, together with certain general principles, suggest that at the present time, most post-primary tuberculosis is the result of exacerbation of the activity of bacilli lodged in the latent foci formed at the time of the primary infection, or rarely from the primary complex itself. Acknowledgments I should like to thank the unfortunate N.C.O.s and men who were the victims of tuberculosis and other chest diseases for being so painstaking in their answers to my rather intensive interrogations. It may be small comfort to the former to realize that one of the underlying themes of this final chapter has been to imply that the only difference between them and the "healthy" population is that their disease has become so active that treatment has become necessary, while the "healthy",population has tuberculosis which has not yet done so. I am very indebted to Dr. R. A. Robb of the Mathematics Department of Glasgow University for the large amount of time which he devoted to me to guide me through ~he methods of statistical analysis required of this material. His constant encouragement has enabled me to report an extensive mass of detail fairly succinctly. I am also very indebted to Dr. J. E. Geddes, Chief Supervising Tuberculosis Physician, Glasgow,

7 I 54 Chest Diseases in the Army for devoting a large amount of time to me in order to bring me up to date with current thoughts and trends with regard to tuberculosis.. It also gives me very sincere pleasure to reacknowledge the encouragement given to me by the various Officers Commanding, Connaught Hospital, in the period 1949 to 1951 when this material was gathered, and to Major E. F. Taylor, R.A.M.C., now retired, for his constant encouragment during the last few years while these articles were in preparation. REFERENCES BAcKMAN, A., ANDWALLGREN, E. I. (1954). Acta Padiatr., 43, 252. BEvAN, R. T., BRAY, P. T., AND HANLY, J. F. (1951). Brit. med. J., 2, 828. BLACKLOCK, J. W. S. (1947). Brit. med. J., 1,707. Brit. med. J., (1955), 1, BROWNING, C. H., AND MACKIE, T. J. (1949). Textbook of Bacteriology. Oxford Univ. Press. CLARKE, B. R. (1952). Causes and Prevention of Tuberculosis. Livingstone, Edin. CLAWSON, B. J. (1938). Arch. Path. (Chicago), 26,966. CoBBETT, L. (1917). The Causes of Tuberculosis Together with Some Account of the Prevalence and Distribution of the Disease. Cambridge Univ. Press. DANIELS, M., RIDEHALGH, F., SPRINGETf, V. H., AND HALL, I. M. (1948). The Prophit Survey on Tuberculosis in Young Adults. H. K. Lewis and Co. DAWSON OF PENN (1941), Spec. Rep. Ser. med. Res. Coun. (Lond.), No DOlO, R. S. (1955). Lancet, 1, 152. FRANCIS, J. (1949). Lancet, 2, 549. HART, P. D'A. (1932). Spec. Rep. Ser. med. Res. Coun. (Lond.), No HAWTHORNE, V. M., JARRETT, W. F. H., LAUDER, I., MARTIN, W. B., AND ROBERTS. G. B. S. (1957). Brit. med. J., 2, 675. HEAF, F. (1946). Brit. med. J" 2, 975. ISRAEL, H. L., HETHERINGTON, H. W., AND ORD, J. G. (1941). J. Amer. med. Ass., 117, 839. KAYNE, G. G. (1935). Brii. med. J., 1, 692. KAYNE, G. G., PAGEL, W., O'SHAUGNESSY, L., AND SIMMONDS, F. A. H. (1948). Pulmonary Tuberculosis; pathology, diagnosis, management and prevention. Oxford Univ. Press. LLOYD, W. E., AND Dow, D. J. (1931), Brit. med. J., 2, 183. LLOYD, W. E., AND MACPHERSON, A. M. C. (1936). Brit. med. J., 2,1130. LoWE, C. R. (1956). Brit. med. J., 2, LUNN, M. J. (1951), Lancet, 1, 370. MARFAN, A. (1886). Arch. gen. de Med., 57, 423 and 575. McPHEoRAN, F. M., AND OPIE, E. L. (1935). Amer. I. Hyg., 22, 565. MILLER, F. J. W. (1949). Lancet, 2, 274. MITCHELL, A. P. (1914). Brit. med. J., 1, 125. MOLLERS, B. (1928). Quoted by RICH, A. R. Vide infra. OPIE, E. L., AND McPHEDRAN, F. M. (1935). Amer. J. Hyg., 22, 539. OPIE, E. L., MCPHEDRAN, F. M., AND PuTNAM, P. (1935). Amer. J. Hyg., 22, 644. PAGEL, W., AND PRICE, D. (1943). Quoted by KAYNE, G. G., et al (1948). Vide supra. PINNER, M. (1945). Pulmonary Tuberculosis in the Adult. Its Fundamental Aspects. C. C. Thomas, Springfield. PROTHEROE, C. (1957). Brit. med. I., 1, 80. RICH, A. R. (1944). The Pathogenesis of Tuberculosis. C. C. Thomas, Springfield. SPRINGETT, V. H. (1952). Lancet, 1, 521 and 575. SWEANY, H. C., LEVINsoN, S. A., AND STADNICHENKO, A. M. S. (1943). Amer. Rev. Tuberc., 48, 131. TOPLEY AND' WILSON (1955). Principles of Bacteriology and Immunity, 4th Edition. Edward Arnold and Co., Lond. WALLGREN, A. (1943). Quoted by Brit. med. 1.,1,260. WILSON, G. S. (1925). J. Path. Bact., 28, 69.