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The opsonic index in tuberculosis
x2o
THE
BRITISH
JOURNAL
OF TUBERCULOSIS
THE OPSONIC INDEX IN TUBERCULOSIS. BY W. H. B R A Z I L , M.D. LOND., D.P.H. CAME., B.SC. MANCH.
IN 19o 3 Wright and Douglas 1 demonstrated the existence in serum of certain bodies which have the power of so acting on bacteria as to render them more readily ingested by phagocytic cells. This was independently confirmed in the following year by Neufeld and Rimpau, 2 who described a bacteriotropic substance in immune sera apparently identical with the bodies discovered by Wright, and to which he gave the name of @sonim. These bodies have been compared to the various sauces used to stimulate appetite for different dishes, and the derivation of the w o r d @ o r seasoning,sa~tce--seems to correspond with that view. T h e matter is not, however, so simple as this comparison would suggest. It has been shown that opsonins possess a double structure, one of the constituents a complement-like b o d y ~ b e i n g destroyed by heat; the other--an amboceptor-like body--being thermostabileY It is important to note that opsonins act on the bacteria themselves, and that this is entirely independent of any action on the phagocytes. The bacteria are not injuriously affected by the action of opsonins, but may retain their Vitality and virulence unimpaired. 4 As to the specific character of opsonins towards different bacteria, the results of investigators are somewhat conflicting. It appears to be definitely established, however, that while normal serum contains opsonins which are of general availability against bacteria of all kinds, there exist in immune sera opsonins which are specific to particular organisms. 5 T h e quantitative estimation of these bodies is effected by a method devised by Wright, and termed by him the opsonic index. Regarding the accuracy of this method as affording an index of the true opsonic content of the blood, much difference of opinion exists ; some observers having obtained results so discrepant as to render them obviously unreliable, while in other hands figures have been obtained not only consistent in themselves, but in general conformity with clinical indications. The explanation of this discrepancy of results probablylies in the extreme delicacy of the technique and the numerous pitfalls of error which have to be avoided in carrying it out ; and the method, though not attaining mathematical accuracy, appears to be 1 W r i g h t and Douglas : Proceedings of the Royal Society, vol. lxxii., September, 19o3. 2 Neufeld and Rimpau : Deatlsche iVied. Wochenschrift, I9o 4. a Alien, R. W. : " V a c c i n e - T h e r a p y . " Third Edition. London : H. K. L e w i s . I91o. 4 E m e r y : " I m m u n i t y and Specific T h e r a p y . " London. i9o 9. 1bid., p. 27~ ; Allen : op. ~t., p. 7.
CRITICAL
REVIEWS
12I
reliable enough in reliable hands. 1 As the criticism directed against it has been chiefly in its application to tuberculosis, it may here be noted that the above remarks apply especially to the tubercnlo-opsonic index. The further question of its utility as a clinical guide in tuberculosis may now be discussed. The
Opsonic
Index
in the
Diagnosis
of Tuberculosis.
The indications which opsonic estimation affords in diagnosis depend not only upon the low index obtained in many cases, but also upon the fact that in infection the oscillations of negative and positive phase produced by inoculation are much more pronounced than in health ; and this applies both to auto-inoculation and to vaccine injection. Thus, if after auto-inoculation by passive movement of a doubtful hip-joint the index to the tubercle bacillus shows a considerable fall, followed by a pronounced rise, as in a case quoted by Atlen, 2 we may conclude that we are dealing with a tubercular infection. Instances of its utility might easily be multiplied, but the following will suffice: A symmetrical hydrops of the knee-joints in a child was considered on clinical grounds to be Syphilitic, but the application of an Esmarch's bandage so disturbed the opsonic index that the diagnosis of tubercle wa s unhesitatingly made, and was upheld by the subsequent course of the case. 3 In cases of multiple infection, where we cannot tell which of several bacteria is the cause of the symptoms, the value of the opsonic index may be very marked. For example, in a case of middle-ear suppuration w i t h enlarged cervical glands, it was impossible to determine whether the lesion was due to tubercle or to a pyogenic microorganism. The 0psonic index to the tubercle bacillus was found to be 0"56, that to the suspected staphylococcus i'o. From this it was inferred that the case was one of tubercular infection, and injections of tuberculin were commenced. A pronounced rise of the index followed, and this was accompanied by marked improvement in the symptoms, so that after two months' treatment the discharge from the ear had completely ceased. 4 The
Opsonic
Index
as a Guide
in Vaccine
Therapeutics.
Here the opsonic index is of distinct ~¢alue, especially in relation to the interval between repeated doses, for it has been shown that too frequent dosage leads to cumulation of negative phase, while cumulation of positive phase cannot be produced in tuberculosis. ~ Proper spacing 1 Fleming : Practitioner, May, 19o8. "z Loc. tit., p. 72. 3 Collier, H. Stansfield: Practitioner, loc. tit. 4 Tod, Hunter F., and Western : Ibid. Allen : lov. cit., p. 7o.
122
THE
BRITISH
JOURNAL
OF TUBERCULOSIS
of doses is therefore a matter of great importance. The guidance furnished by the opsonic index is entirely in accord with clinical evidence. Thus it has been shown that in phthisis the temperature bears an inverse ratio to the opsonic index, 1 and that the associated pulse-rate follows the same rule3 It has also been demonstrated that an inoculation which has a beneficial effect is accompanied by a rise in the opsonic index, whereas an overdose of tuberculin causes fever, headache, malaise, and loss of appetite, and that these symptoms are accompanied by a fall in the opsonic index. Similar results have been noted in auto-inoculation as carried out at Frimley by Dr. Paterson's system of graduated labour. 3 These observations while indicating the general reliability of the method, at the same time demonstrate that, though useful, it is not indispensable as a therapeutic guide. The Opsonic Index
in the Prognosis of Tuberculosis.
After a period of inoculation or sanatorium treatment, it is often extremely difficult to determine when the patient m a y be considered immune. Here the opsonic index furnishes information available from no other quarter, for it is only while infection persists that marked oscillations of the index occur, whereas when immunity is attained it becomes normal and remains steady. The fact that in general tuberculosis and other acute infections death may be preceded by an abnormally high index has proved a stumbling-block to many in the acceptance of the opsonic theory. But there is really no difficulty here at all. The high opsonic index in these cases simply represents a final effort of one of the protective mechanisms, which is ineffective owing to the overpowering of vital centres by toxins already formed. What is here wanted is an antitoxin to come to the aid of another protective mechanism, which has broken down owing to the acuteness and severity of the attack. Wright points out also that it is useless to have an abundance of opsonins in the blood if these, from any cause, fail to reach the focus of disease--a condition which has been shown to exist in certain cases. x Emery : loc. cir., p. 269. 2 Allen :loc. cit.,.p. 216. 3 Inman : Practitioner, loc. dr.
THE
BRITISH
JOURNAL
OF TUBERCULOSIS
THE OPSONIC INDEX IN TUBERCULOSIS. BY W. H. B R A Z I L , M.D. LOND., D.P.H. CAME., B.SC. MANCH.
IN 19o 3 Wright and Douglas 1 demonstrated the existence in serum of certain bodies which have the power of so acting on bacteria as to render them more readily ingested by phagocytic cells. This was independently confirmed in the following year by Neufeld and Rimpau, 2 who described a bacteriotropic substance in immune sera apparently identical with the bodies discovered by Wright, and to which he gave the name of @sonim. These bodies have been compared to the various sauces used to stimulate appetite for different dishes, and the derivation of the w o r d @ o r seasoning,sa~tce--seems to correspond with that view. T h e matter is not, however, so simple as this comparison would suggest. It has been shown that opsonins possess a double structure, one of the constituents a complement-like b o d y ~ b e i n g destroyed by heat; the other--an amboceptor-like body--being thermostabileY It is important to note that opsonins act on the bacteria themselves, and that this is entirely independent of any action on the phagocytes. The bacteria are not injuriously affected by the action of opsonins, but may retain their Vitality and virulence unimpaired. 4 As to the specific character of opsonins towards different bacteria, the results of investigators are somewhat conflicting. It appears to be definitely established, however, that while normal serum contains opsonins which are of general availability against bacteria of all kinds, there exist in immune sera opsonins which are specific to particular organisms. 5 T h e quantitative estimation of these bodies is effected by a method devised by Wright, and termed by him the opsonic index. Regarding the accuracy of this method as affording an index of the true opsonic content of the blood, much difference of opinion exists ; some observers having obtained results so discrepant as to render them obviously unreliable, while in other hands figures have been obtained not only consistent in themselves, but in general conformity with clinical indications. The explanation of this discrepancy of results probablylies in the extreme delicacy of the technique and the numerous pitfalls of error which have to be avoided in carrying it out ; and the method, though not attaining mathematical accuracy, appears to be 1 W r i g h t and Douglas : Proceedings of the Royal Society, vol. lxxii., September, 19o3. 2 Neufeld and Rimpau : Deatlsche iVied. Wochenschrift, I9o 4. a Alien, R. W. : " V a c c i n e - T h e r a p y . " Third Edition. London : H. K. L e w i s . I91o. 4 E m e r y : " I m m u n i t y and Specific T h e r a p y . " London. i9o 9. 1bid., p. 27~ ; Allen : op. ~t., p. 7.
CRITICAL
REVIEWS
12I
reliable enough in reliable hands. 1 As the criticism directed against it has been chiefly in its application to tuberculosis, it may here be noted that the above remarks apply especially to the tubercnlo-opsonic index. The further question of its utility as a clinical guide in tuberculosis may now be discussed. The
Opsonic
Index
in the
Diagnosis
of Tuberculosis.
The indications which opsonic estimation affords in diagnosis depend not only upon the low index obtained in many cases, but also upon the fact that in infection the oscillations of negative and positive phase produced by inoculation are much more pronounced than in health ; and this applies both to auto-inoculation and to vaccine injection. Thus, if after auto-inoculation by passive movement of a doubtful hip-joint the index to the tubercle bacillus shows a considerable fall, followed by a pronounced rise, as in a case quoted by Atlen, 2 we may conclude that we are dealing with a tubercular infection. Instances of its utility might easily be multiplied, but the following will suffice: A symmetrical hydrops of the knee-joints in a child was considered on clinical grounds to be Syphilitic, but the application of an Esmarch's bandage so disturbed the opsonic index that the diagnosis of tubercle wa s unhesitatingly made, and was upheld by the subsequent course of the case. 3 In cases of multiple infection, where we cannot tell which of several bacteria is the cause of the symptoms, the value of the opsonic index may be very marked. For example, in a case of middle-ear suppuration w i t h enlarged cervical glands, it was impossible to determine whether the lesion was due to tubercle or to a pyogenic microorganism. The 0psonic index to the tubercle bacillus was found to be 0"56, that to the suspected staphylococcus i'o. From this it was inferred that the case was one of tubercular infection, and injections of tuberculin were commenced. A pronounced rise of the index followed, and this was accompanied by marked improvement in the symptoms, so that after two months' treatment the discharge from the ear had completely ceased. 4 The
Opsonic
Index
as a Guide
in Vaccine
Therapeutics.
Here the opsonic index is of distinct ~¢alue, especially in relation to the interval between repeated doses, for it has been shown that too frequent dosage leads to cumulation of negative phase, while cumulation of positive phase cannot be produced in tuberculosis. ~ Proper spacing 1 Fleming : Practitioner, May, 19o8. "z Loc. tit., p. 72. 3 Collier, H. Stansfield: Practitioner, loc. tit. 4 Tod, Hunter F., and Western : Ibid. Allen : lov. cit., p. 7o.
122
THE
BRITISH
JOURNAL
OF TUBERCULOSIS
of doses is therefore a matter of great importance. The guidance furnished by the opsonic index is entirely in accord with clinical evidence. Thus it has been shown that in phthisis the temperature bears an inverse ratio to the opsonic index, 1 and that the associated pulse-rate follows the same rule3 It has also been demonstrated that an inoculation which has a beneficial effect is accompanied by a rise in the opsonic index, whereas an overdose of tuberculin causes fever, headache, malaise, and loss of appetite, and that these symptoms are accompanied by a fall in the opsonic index. Similar results have been noted in auto-inoculation as carried out at Frimley by Dr. Paterson's system of graduated labour. 3 These observations while indicating the general reliability of the method, at the same time demonstrate that, though useful, it is not indispensable as a therapeutic guide. The Opsonic Index
in the Prognosis of Tuberculosis.
After a period of inoculation or sanatorium treatment, it is often extremely difficult to determine when the patient m a y be considered immune. Here the opsonic index furnishes information available from no other quarter, for it is only while infection persists that marked oscillations of the index occur, whereas when immunity is attained it becomes normal and remains steady. The fact that in general tuberculosis and other acute infections death may be preceded by an abnormally high index has proved a stumbling-block to many in the acceptance of the opsonic theory. But there is really no difficulty here at all. The high opsonic index in these cases simply represents a final effort of one of the protective mechanisms, which is ineffective owing to the overpowering of vital centres by toxins already formed. What is here wanted is an antitoxin to come to the aid of another protective mechanism, which has broken down owing to the acuteness and severity of the attack. Wright points out also that it is useless to have an abundance of opsonins in the blood if these, from any cause, fail to reach the focus of disease--a condition which has been shown to exist in certain cases. x Emery : loc. cir., p. 269. 2 Allen :loc. cit.,.p. 216. 3 Inman : Practitioner, loc. dr.