The pathogenesis and prognosis of tuberculous pleurisy with effusion

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The Pathogenesis and Prognosis of Tuberculous Pleurisy with Effusion By JAMES J. WARING Professor of Medicine, Emeritus, University of Colorado School of Medicine Although the main purpose of tiffs presentation is a discussion of the pathogenesis and the immediate and the remote prognoses of acute primary tuberculous pleurisy with effusion, it seems important to start with brief comment on the varied tuberculous conditions with which pleural effusion may be associated. Our Scandinavian colleagues, notably Hjelm and Laurell (i93i), Laurell (i935) and Muller, Lofstedt (I945) have developed roentgenographic techniques which have revealed surprisingly small amounts of pleural fluid under equally surprising circumstances. Pictures made in the horizontal side position or the inclined side position put the costal gutter at the lowest point and make it possible to demonstrate a small amount of fluid accumulating in this position. All this has been well set forth by Ingemar Hessen ix] in his monograph on 'q~he Roentgen Examination of Pleural Fhfid'. Small effusions are not very infrequent in association with miliary tuberculosis of the lungs but here the effusion is of little clinical significance since the pulmonary lesion and the disseminated nature of the disease are most menacing. The significance of bilateral effusion as a manifestation of disseminated tuberculous infection did not escape older clinicians. This type of effusion is not infrequently associated with extrathoracic tuberculosis especially in the American Negro (Jones and Dooley [2]. It is well known that any person who has or has had manifest pulmonary tuberculosis may have an attack of pleurisy with effusion. The Germans call this 'bcglcits' or pleurisy associated with or complicating phthisis. hnportant as this may be, it is not the type

of pleural effusion here under consideration. Nor at the moment are we interested in the effusions associated with artificial pneumothorax. In passing, however, it might be noted that artificial pneumothorax is fiastlosing in popularity in America even though it seems that the specific antibiotics have made tuberculous empyema, the dreaded complication of artificial pneumothorax, almost non-existent. Clinicians of fifty years ago viewed acute pleurisy with effusion with complacency. Frequent failure to find tubercle bacilli in the fluid, illness of short duration, complete disappearancc of the effusion, ignorance of pulmonary lesions ~ yet unrevealed by the roentgen ray, apparent perfcct recovery all deludcd physicians and therefore their patients into false sccurity. An acute scrofibrinous pleurisy with undemonstrated aetiology was called 'idiopathic', if tuberculous origin was proven it was still 'a happy accident' since immediate recovery was practically assured. At the very outset, let me state m y conviction in summary fashion. Acute serofibrinous pleurisy .with effusion (the term idiopathic should be discarded) is in the vast majority of circumstances tuberculous in origin, is a dominant local manifestation of a disseminated infection if not a disseminated disease, is closely associated with primary infection and therefore one of the early clinicat manifestations of tuberculous disease, is not infrequently associated with extrathoracic tuberculosis, and foUowed by remote relapse in an important percentage of cases in pre-chemotherapeutic years and therefore should not be treated with complacency but vigorously with adequate rest and chemotherapy.

*A paper read to the B.T.A. at Oxford,July 8, t954.

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Free exudation into the pleural space occurs only when the pleura of a hypersensitive (previously infected) animal is infected M t h tubercle bacilli, as from the rupture of a subpleural caseous tubercle into the pleural space. Experimental proof of this was given in I9I 7 by Paterson [3] who failed to induce effusion in normal guineapigs by inoculation of tubercle bacilli into the pleural space, but succeeded after sensitizing the animals by a preceding subcutaneous injection of relatively avirulent bacilli. It would appear that this type of pleural effusion might arise in the following ways: (i) By primary blood or lymphatic vascular transport from a primary complex and localization of bacilli in tile pleura. (2) By discharge of living bacilli into the pleural space. (3) By discharge of a quantity of caseous material with or without living and dead bacilli from a subpleural tubercle into the pleural space. (4) By progression of infection from a mediastinal tuberculous adenitis into the pleural space. In any case, all agree that this type of pleural effusion means infection of the pleural space in a hypersensitive person. Hugh E. Burke [4] of Canada has for some years been interested in the association of skeletal tuberculosis with pleurisy with effusion. He reported some experimental work confirming the ease with which pleural effusion could be produced in the tuberculous guinea-pig by intrapleural injection of living bacilli. However, he pushed his observations further with apparent important clinical implications. His experimental, anatomical and clinical observations support the assumption that tubercle bacilli from a tuberculous pleuritis may be transported to the parasternal lymph nodes which become caseous, rupture and burrow externaUy to form a cold abscess in the chest wall or they may be transported from the pleural space to the para-aortic lymph nodes which eventually develop into tuber-

February

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culous abscesses and by contiguity or communicating lymph channels involve the vertebral column. Burke is inclined to think Mth Walter Pagel that tuberculous pleuritis without involvement of the underlying lung may occur from a primary localization of tubercle bacilli in the pleura by blood stream dissemination. In brief, the primary focus will be in the pleura and the regional gland involvement of the primary complex is found in the parasternal and para-aortic lymph nodes. Burke thus explains some of the skeletal complications associated with this type of pleural effusions and supports his conception by illustrative histories of patients with skeletal tuberculosis preceded by acute pleurisy with effusion. Burke did another very interesting experiment. He found that rapid dissemination of file tuberculous infection took place if his guinea-pigs were exercised on a treadmill after intrapleural inoculation of tubercle bacilli. The clinical implications are obvious: the patient with acute pleurisy with effusion should be at bed rest. That pleurisy with effusion should not be looked upon as an isolated local .infection of the pleura but rather as the conspicuous and dramatic sign of a systemic disease is borne out by a personal communication from Dr John Anderson of the staff of St. Thomas' Hospital, London, which I quote with his permission. Anderson did liver biopsies on eight young adults with acute pleurisy with effusion and found unmistakable tuberculous lesions in 3 of these 8. It is further well known to all those dealing with experimental tuberculosis in animals that tubercle bacilli are widely disseminated throughout the animal within one hour after subcutaneous inoculation of virulent bacilli (Soltys and Jennings [5])" The Time Relationship of Pleurisy with Effusion to Primary Infection

A. Wallgren [6] has most carefully constructed what he calls a 'time-table of tuberculosis', which shows the most probable time after infection for the appearance of the important clinical manifestations of tuber-

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culous disease. In infancy he notes the frequency with which acute miliary tuberculosis and tuberculous meningitis appear during the first Six months after tuberculous infection evidenced by the development of a positive tuberculin test and appearance of acute pleurisy with effusion in the second six months after infection. All clinical experience supports his conception (Robson [7], Edwards [8]; Prophit Survey [9]; Thompson [IO]; Roper and Waring [II], among many others). Immediate and Remote Prognosis of Pleural Effusion

How often do adult consumptives give a previous history of pleural effusion? How often do persons with pleural effusion after apparent perfect (clinical and radiologic) recovery later have recurrence somewhere of active tuberculosis? Robson [7] thinks the wide divergence of published figures on relapse after pleurisy must be due to: (i) Lack of clear statements as to whether parenchymal tuberculosis was or was not already in evidence at the time of onset of the pleurisy; some reports did not include roentgenograms; (2) failure to record dates of onset of recurrences of active tuberculous disease; (3) examination of a large group after a long interval will usually miss those patients who have unrecognized and relatively minor relapse from which they recover spontaneously; (4) failure to evaluate statistically patients lost to sight. Reports of later relapse after pleurisy are innumerable; only a few can be noted here. Trudcau [i2] gave a most favourable report. Three to twenty-five years after discharge from the Trudeau Sanatorium only 4 of 54 patients without radiologic demonstrable lesions relapsed while 8 of 29 with minimal parenchymal lesions relapsed. Of i ii patients with serofibrinous pleurisy followed three to thirteen years by Farber [i3], 38 or 34 per cent relapsed mainly with pulmonary tuberculosis. Twenty-seven (27) or 71 per cent of the 38 died. Jones and Dooley [2] found that 35 per cent of 99

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patients (mainly Negroes) foUowed more than one year relapsed. In this series, I out of every 6 died of tuberculosis, chiefly extrapulmonary. In the Negro in this Maryland area, pleurisy with effusion is often a manifestation of widespread tuberculosis. Thompson [IO] says about 25 per cent (by the life-table method) of 19o patients with primary pleurisy x~dth effusion developed systemic tuberculosis within five years after the pleurisy. Half of the relapses occurred within the first year. Fifteen (I5) per cent of the tuberculous recurrences were extrapulmonary. Mitchell [i4] gave a valuable report on I94 patients with primary tuberculous pleurisy with effusion with and without minimal pulmonary infection, treated with modified bed rest and followed for five to twcnty-fiye years after discharge. Although there was a 24 per cent cumulative rate of relapse and a 5 per cent cumulative tuberculosis mortality in twenty years, 85 per cent of those with whom contact was maintained were well and able to work five to twenty-five years after discharge. Ninety (9 o) per cent of the initial reactivations of tuberculosis had occurred within five years following discharge. The rate of relapse during the first five years after discharge was apparently related to the presence and extent of minimal pulmonary infiltration. Mitchell's study revealed no relationship between duration of sanatorium treatment and the incidence of subsequent relapse, but significantly there were no five-year relapses in I8 patients who spent eighteen or more months away from full employment. Pleural Effusion in Military Personnel

During World War II in association with W. H. Roper, a study [I I] was made of I78 young adults (military personnel) with acute serofibrinous pleurisy with effusion. Space does not permit complete summary of all the interesting observations, but certain pertinent conclusions can be given here. None of these patients received chemotherapy since these drugs had not yet become available at the time of their acute

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illness. O f the 178 persons, 37 h a d h a d their first attack o f pleural effusion before induction into sen, ice. O f these, 28 relapsed d u r i n g military service a n d 2 after discharge. Five (5) entered the A r m y within the first year after onset o f the original pleurisy, 4 o f these 5 relapsed d u r i n g o r following military service. Eleven (i I) e n t e r e d the A r m y in the second or third year after pleurisy, 9 relapsed. F o u r (4) entered the A r m y in the fourth y e a r after pleurisy and all 4 relapsed. Seventeen (i 7) entered the A r m y m o r e t h a n five years after the original a t t a c k o f pleurisy and 13 relapsed. O f the I41 who h a d their first attack o f pleurisy after entering the A r m y , 8o or 62-9 per cent relapsed. O f So patients r e t u r n e d to d u t y after six months or less o f rest, 69 or 86- 3 p e r cent relapsed. O f 78 resting more than six months 3o per cent relapsed. O v e r half o f the relapses took place within the first two years after r e t u r n to duty. I n 20 of 178 persons, progression o f disease occurred before release from the first hospitalization. E x t r a t h o r a c i c spread occurred in 8 o f these 2o cases d u r i n g the initial illness.

Conclusions (1) Acute serofibrinous pleurisy with effusion in the vast majority o f cases is o f tuberculous origin a n d follows frequently within the year u p o n the p r i m a r y infection period. (2) I n m a n y instances it is not a benign affair n o r just a localized infectious process since it is not infrequently a c c o m p a n i e d or followed shortly b y signs a n d symptoms o f e x t r a t h o r a c i e tuberculosis or remotdy b y relapse with active disease. (3) W h e n unilateral it is most frequently due to r u p t u r e o f a subpleural tubercle into the pleural space o f a person with h y p e r sensitivity to tuberculosis. (4) T h e i m m e d i a t e a n d r e m o t e prognoses are related to the u n d e r l y i n g p u l m o n a r y lesions, general and focal a t the site o f perforation, but also to m e t h o d o f treatment.

February 1955

Bibliography [z] Hessen, I. (x95Q Roentgen examination of pleural fluid. (From the Roentgen Clinic of the University of Uppsala, Sweden.) Stockholm. [~] Jones, E. G., and Dooley, M. 0946) Tuberculous pleurisy with effusion, Am. Rev. Tuberc., LW, 133. [3] Paterson, R. C. (x9t7) The pleural reaction to inoculation with tubercle bacilli in vaccinated and normal guinea-plgs, Am. Ref. Tuberc., x, 353. [4] Burke, H. E. (I953) The pathogenesis of tuberculosis, Tr. Am. CIbz. & Cllmatol. Assoc., LX~; x3. [5] Soltys, M. A., and Jennings, A. R. (I95O) The dissemination of tubercle bacilli in the guinea-pig, Am. Roy. Tuberc., LXI,399[6] Wallgren, A. 0948) The time-table of tuberculosis, Tubercle, xxlx, 245. [7] Robson, K. 0944) Modern views in primary pleurisy, Practitioner, eLm, 344" [8] Edwards, P. W., Penman, A. C., and Blair, L. G. 09.45) Primary tuberculous infection in a sanatorium staff, Lancet, x, 429. [9] Tuberculosisin Young Adults, Report in the ProphitTuberculosis Survey t935-1944, H. K. Lewis & Co., x948. [xo] Thompson, B. C. (~947) Prognosis of primary pleurisy with effusion,Brit. M. J., No. 45ol, 487• [it] P,oper, W. H., and Waring, J. J. (x95°-) Primary sero-fibrinous pleural effusion, .A'atl. Tuberc. Assoc. Tr., p. 15o. [Io] Trudean, F. B. (x939) Pleural effusion, Am. Roy. Tuberc., xxxlx. 57. [13] Farber, J, E. 0943) Prognosis in cases of serofibrinous pleurisy, ~ew England J . ~Iled., ccxxvm, 784• Ix4] Mitchell, R. S. (1953) I.ate results of tlle treatment of prinmry tuberculous pleurisy5vith effusionwith modified bed rest, Am. R¢~'. Tuberc., i.XVli,42I.

Annual Report L E I C E S T E R C O U N T Y C O U N C I L . Annual Report of tile County Medical Officer of Health, G. H. Gibson, for the Year x953. I7, Friar Lane, Leicester. August I954 . This report concerns tile health of a population of 345,832, rather more than half of whom live in rural districts. Tile death-rate was IO.I. The birth-rate was I5"4, with an infant mortality of 28, which is rather high in these.days for so rural an area. A graph, reproduced, shows how many more deaths than of old occur at late ages of life. But this altered age distribution does not mean any greater longevity; it is due to a greater resistance to death at the earlier periods of life. An instance of this increased resisting power is seen in deaths from tttberculosis; out ot" 65 deaths