DIPHTHERIA; ITS BACTERIAL DIAGNOSIS AND TREATMENT WITH THE ANTITOXIN. BY HENRY W. BETTMANN, M.D., OF CINCINNATI, OHIO; CURATOR AND MICROSCOPIST, CINCINNATI GENERAL HOSPITAL. FROM THE MEDICAL NEWS, July 6, 1895. [Reprinted from The Medical News, July 6, 1895.] DIPHTHERIA; ITS B ACT ER I AL DIAGNOSIS AND TREATMENT WITH THE ANTITOXIN ? By HENRY W. BETTMANN, M.D., OF CINCINNATI, OHIO CURATOR AND MICROSCOPIST, CINCINNATI GENERAL HOSPITAL. In 1884 Loeffler announced the cause of diph- theria, but the medical world was little interested. Five years later Roux declared that the bacterial diagnosis of suspected cases was of the greatest im- portance, and Baginsky added further proof, and still the medical world heeded little. In 1894 Roux and Behring announced independently that they had discovered a cure for diphtheria, and in six months the medical world is aflame. The scientific structure is complete : the etiology first, the bacterial diagnosis second, the prophylaxis and cure the capping-stones. The task before the medical profession is to see if the structure can stand. If it stands, it is the highest achievement of the new medical era, and a glorious and memorable tribute to scientific medicine. I shall say nothing about the etiologic relation between the Loeffler bacillus and diphtheria. In the minds of all except the ultra-skeptical, the cause of the vast majority of cases of Bretonneau's diph- theria is the Loeffler bacillus; this fact was incon- 1 A paper read before the Cincinnati Academy of Medicine, June 3,1895. 2 trovertibly demonstrated years ago, and need no longer form the basis of discussion. The questions that concern us to-night are far more practical and more important to us as physicians. They may be enumerated as follows: 1. What clinical significance has the bacterial investigation of throat-exudates? 2. Can diphtheria be cured by the antitoxin ? 3. Can diphtheria be prevented by the antitoxin ? 4. Is the antitoxin a specific remedy for diph- theria in the sense advocated by Behring, Aronson, and Roux? 1. The Clinical Significance of Bacterial Investi- gation of Throat-exudates. My conclusions are based on the bacterial investigations of 122 throat- cases. These studies were made in the laboratory of the Cincinnati Hospital by Dr. A. H. Freiberg and myself, with the generous assistance of Dr. Charles H. Castle. We are also indebted to the assistance of Superintendent Hendley, who first suggested the investigation. Our methods were copied from those of the New York City Board of Health, and our way of distributing, collecting, and examining tubes was modelled after that of New York. Altogether we examined about 160 inocu- lated tubes. A majority of the local profession did not avail themselves of the opportunity for diag- nosis that was offered. On the other hand, a large number realized the value of the bacterial examina- tion and lent us their support and their interest. The vast majority of the tubes examined were sent to us in January, February, and March of this year. In all cases we used Loeffler's serum for diagnos- tic purposes. This is by far the best medium with 3 which to demonstrate the presence of the Loeffler bacillus. Investigators who use glycerin-agar, peptone-agar, or even plain blood-serum cannot expect reliable results.1 As a rule, we were able to make a diagnosis after the tubes had remained in the incubator from twelve to sixteen hours; and if the inoculation was at all successful, twenty-four hours sufficed in all cases. With some experience it is possible to distinguish diphtheria-colonies from cocci-colonies macroscopically, diphtheria-colonies of sixteen hours' duration looking gray and small as compared with the larger and whiter cocci-colonies ; of course, it is best in all cases to resort to micro- scopic examination with alkaline methylene-blue. Early in January we were puzzled occasionally by the appearance in the cultures of short, thick bacilli, and very long, slender, evenly staining ones. We soon found out, however, that these colonies devel- oped in imperfectly sterilized tubes, and later ruled out all doubt by sterilizing the serum more perfectly. After this we were never seriously puzzled to know whether a tube contained Loeffler bacilli or not. After the statistical report of the New York Board of Health, covering 5611 cases, it might seem super- fluous for us to report our series of 122. Yet even so small a series is full of interest and instruction. The Loeffler bacillus was present in forty-seven cases; of these, eight, or 17 per cent., died. The bacil- lus was absent from seventy-five cases; of these, three 1 C. Fraenkel: Die Aetiologische Bedeutung des Loeffler'sche Bacillus (Deutschemed. Woch., 1895, No. ri). AlsoSilberschmid: Miinchener med. Woch., Feb. 26,1895. Compare also the defec- tive results obtained by Vierordt (Deutsche med. Woch., 1895, No. 11, p. 169), by use of plate-cultures of glycerin-agar. 4 (4 per cent.) died. In one of these fatal cases the ex- amination was made after the disease had existed two weeks, and proved negative; in another, on the eighth day, two days before death, and it was also negative. Everyone familiar with the subject knows, and the New York report has sufficiently emphasized the fact, that examinations made quite late in the disease are not reliable, and we may properly ex- clude these two last-mentioned cases from our consideration. Thus, out of seventy-three cases in which no Loeffler bacilli were found under proper conditions of examination, only one proved fatal, or nearly per cent., while 17 per cent, of those died in whom the Loeffler bacillus was found. This teaches one important lesson, viz., the presence of the Loeffler bacillus in the throat adds very seri- ously to the gravity of our prognosis. But mortality is not the only test of severity. A few weeks ago I sent postal cards to the physicians who had had cases examined, asking for clinical data, laying special stress upon the duration of the disease, the presence of alarming symptoms, the oc- currence of sequelae and complications, and the con- dition of the heart. I received complete data con- cerning forty-one cases, in which the Loeffler bacil- lus had been found ; in eighteen of these (just 40 per cent.) the physicians reported the patients as dangerously sick, in many cases from weakness of the heart; of the non-diphtheric cases, aside from the three that died, only one patient was reported as having been in danger, and that one from laryngitis ; i. e., seventy-one out of seventy-five cases from which the Loeffler bacillus was absent ran a mild course without arousing any alarm. 5 Can anything be more convincing than that the bacillary sore-throat is a very different disease from the non-bacillary sore-throat ? So much for gross figures. I think, however, that examination into the details of several series of cases will prove still more striking and show still more forcibly the value of bacterial diagnosis. On January 5th a tube was sent with the diagnosis of tonsillitis. The physician in charge said that there was no suspicion of diphtheria, and the patient was not isolated. Two days later the child's brother contracted an angina. Bacterial examination of the first case revealed the presence of many cocci and few Loeffler bacilli; the second throat contained almost a pure culture of Loeffler bacilli. Both children were markedly prostrated, out of all pro- portion to the apparent throat-lesion ; the first child was weak for a month after recovery; the second child was in great danger from heart-failure for a week, and suffered later from paralysis of the pharyngeal and ocular muscles. On February 14th a tube was sent with the diag- nosis of severe tonsillitis. Examination revealed almost a pure culture of Loeffler bacilli. The case ran a very mild and favorable course for four days; on the fifth the patient, sixteen years old, died very suddenly from heart-failure. In January a tube was sent with the diagnosis of non-diphtheric croup. No membranes were visible in the throat, and the temperature was normal. Intubation was performed. Bacterial examination revealed the Loeffler bacillus; stenosis returned, tracheotomy was performed, large tough mem- branes were found occluding the trachea, and the child died on the ninth day, after extension of the membrane to the lungs. In March a tube was sent, and Loeffler bacilli 6 were found in abundance. The first physician in attendance had diagnosticated catarrhal laryngitis, and had let the case run on from bad to worse for several days. He was then discharged. The second physician immediately had the case examined microscopically, and intubation was performed, but death followed after sixteen hours. In all of these cases early bacterial examination would have thrown much light on the diagnosis and prognosis, and lives might have been saved. Other similar cases might be cited, but those de- tailed are sufficiently striking to show the great value to the clinician of bacterial investigation. A few words in regard to the fatal cases in which no Loeffler bacilli were found. One was in a child, fourteen months old, that suffered from purulent coryza for two weeks, laryngeal stenosis and pro- found sepsis being present on its admission to the hospital. Only cocci were found after a minute examination. The antitoxin was used, and the child revived considerably. Cultures were made at intervals of two days, and no Loeffler bacilli were ever found. The child died seven days after ad- mission to the hospital. Case No. II occurred in a family in which several members suffered from true Loeffler diphtheria. All the cases were malignant, and this one fatal, although no Loeffler bacilli were found. Only one culture was made, and lam inclined to believe that I must have made an imperfect examination, as Loeffler bacilli were found in other members of the same family. Case No. Ill was the one referred to. A six- months-old baby suffered with large extensive mem- 7 branes in the throat; no culture was made until the eighth day, two days before the fatal issue. I am not informed as to whether the cause of death was croup or sepsis. There is no doubt that some cases of diphtheria occur in which Loeffler bacilli play no role. Fischer1 reports a case of septic diphtheria in which cultures made daily for seven consecutive days failed to discover the Loeffler bacillus, and even a post-mortem culture revealed nothing but cocci. Fraenkel2 admits also that there is such a thing as coccus-diphtheria, although its occurrence is quite rare. For the present we must simply shrug our shoulders at these rare and unfortunate cases, and leave their explanation to further investigation. I approach with some diffidence the subject of the therapeutic effects of the antitoxin. Veterans in medicine have tried it in a large series of cases, and have been reticent as regards the scientific value of their results. Rapidly, however, a large litera- ture on the subject is accumulating, and it behooves us at least to keep in touch with the advanced thought. No one, I think, can follow what has been written on the subject during the past six months and regard it with indifference. Certainly no one can read the calm judicial testimony of medical experts in all parts of the world that classes of cases that formerly died do now recover, that a smaller percentage of cases die than formerly, and that severe cases now recover without need of operative interference, without wishing in his heart that such testimony is true. When men of world-wide repu- tation range themselves one after the other on the 1 N.Y. Med. Rec., April 6, 1895, p. 420. 2 Loc. cit. 8 side of the new remedy we are compelled, with all our natural skepticism, to be encouraged. The names of Virchow, Escherich, Ganghofner, Ranke, Vierordt, all on one side, are strong testimony of themselves. In February of this year Foster1 col- lected statistics of 2740 cases treated with antitoxin ; of these 18.5 per cent, died ; also of 4445 cases treated without antitoxin ; of these 45 per cent. died. I shall not load down your minds with bald statis- tics. Nothing is more tiresome or unprofitable. Since January of this year I have had occasion to observe closely seventeen cases of diphtheria. Dur- ing February and March Dr. Forchheimer very generously placed his diphtheric patients at the City Hospital under my charge, and I am greatly indebted to him for the cases treated in that insti- tution. In January two brothers were admitted to the hos- pital suffering from a very severe form of diphtheria. The younger brother, four years old, had been sick eight days and had a very intense nephritis, with weak heart and complete anorexia. Many Loeffler bacilli were present; two days later they were absent from the throat. No antitoxin was used, owing to the condition of the kidneys and the advanced stage of the disease.2 The nephritis grew worse daily, notwith- standing active treatment, and the child died twelve days after admission. The older brother, aged eight years, had contracted the disease three days before admission. At first he presented indications of only a moderately severe pharyngeal diphtheria and re- ceived tonic treatment. Soon, however, he de- 1 Foster : The Medical News, Philadelphia, Feb. 2, 1895. 2 Neither of these conditions, however, is a contraindication against the use of antitoxin. 9 veloped a marked nephritis, like his brother, and five days after admission had severe symptoms of laryngeal stenosis; his temperature rose to 103.8°, and his condition became very critical. Ten c.cm. of the Roux antitoxin were injected in the inter- scapular space. During the next twenty-four hours the temperature fell steadily, the pulse-rate and frequency of respiration remained about the same, and the dyspnea was markedly moderated, recurring only for short intervals. The further course was favorable, the albuminuria lasted two weeks, Loeffler bacilli persisted only two days after the injection, and the boy made a slow but complete recovery. This, my first case, made a very favorable impression on me. A week later a child aged fourteen months was brought to the hospital in an apparently moribund condition; the pulse was scarcely palpable; opis- thotonos was marked, and the fetid odor from the throat scarcely endurable. The mother at first refused treatment, saying she did not wish the child uselessly tormented, and death seemed a ques- tion of only a few hours. We injected, however, 5 c.cm. of Behring's antitoxin, No. 2, and were much astonished to see in the course of twelve hours a remarkable change in the child's condition. It now sat up in bed and took nourishment greedily, but during the course of the day relapsed into its former condition. Injections of the antitoxin were repeated twice, both times causing a very marked and unmistakable change for the better. On the fourth day we were inclined to make a favorable prognosis; the heart, however, became very weak, the respirations rapid, fetid diarrhea set in, and the child died with high fever on the seventh day. Repeated examinations in this case failed to reveal Loeffler bacilli. Here was a case ending fatally, which, nevertheless, afforded to the few of us who 10 witnessed it the greatest encouragement regarding the value of the antitoxin. A few days later five children were placed under my charge at once. Two sisters, Mary and Gertrude E., aged respectively six and nine years, had exten- sive exudations with almost pure cultures of Loeffler bacilli, and yet the local and constitutional symp- toms were so slight that no treatment was instituted, except rest in bed and light diet. Both cases developed albuminuria of moderate degree, which persisted sixteen days. Three other sisters, aged respectively four months, four years, and six years, all had extensive exuda- tions in which the Loeffler bacillus was demon- strated. One case ran so favorable a course that no antitoxin was used; on the second day the infant's temperature rose to 103 8° and the mem- branes extended. Five c.cm. of Behring's No. 2 were injected at 10 p.M.,and the change for the better began in a few hours, and after that the tem- perature remained below ioo° F., and no threaten- ing symptoms recurred. The oldest sister received two injections of the antitoxin, each 5 c.cm., which seemed to affect the course of the disease very favorably. These children also had albuminuria lasting two weeks, the one in which no antitoxin had been used no less than the others. I shall not detail all the cases treated. One child, aged ten years, received 10 c.cm. of the antitoxin for laryngeal obstruction present on admission, and died four hours afterward from sudden increase of stenosis. All the other cases recovered, some with and some without the antitoxin. Altogether, nine cases received the antitoxin; two of these died, as already recited. Of the seventeen cases observed, three died, representing a mortality of 17.6 per cent. The mortality in the city during January, Febru- 11 ary, and March was 26 per cent. I do not lay any stress on the results obtained by us in the hospital. The number of cases is too small to be convincing. All who saw the cases treated with the antitoxin felt sure that we had in our possession a wonderful remedy. This subjective feeling of trust in the value of the antitoxin is almost universal among those who have tried it in any number of cases, and speaks more in favor of the remedy than the published figures. I shall reserve for another occasion a critical estimate of the antitoxin-literature thus far published. Of some things I am convinced : 1. That the antitoxin does undoubtedly affect favorably a large number of diphtheria-cases. 2. That it is the duty of physicians to use the anti- toxin early in every case of severe diphtheria occurring in children. 3. That the mortality from diphtheria is destined to be largely diminished by prompt use of the antitoxin. I cannot urge upon physicians too strongly to use the antitoxin early in their cases of diphtheria. The testimony is universal that the earlier the remedy is used the more certain is its curative effect. In Foster's table, of the 44 cases injected on the first day none died; of 106 cases injected on the second day 3 died. Later the mortality ranged from 10 per cent, to 40 per cent. In Ganghofner's table,1 of 68 cases treated during the first three days 5 died ; of 42 cases treated after the third day 10 died. In Kossel's well-known table, of 82 cases treated during the first four days only 2 died ; of 35 1 Ganghofner: Prag. med. Woch., 1895, Nos. 1, 2, 3. 12 cases treated after the fourth day n died. To wait for sepsis or laryngeal stenosis before using the anti- toxin is folly. The chances of success are greater the sooner the remedy is used. All observers agree that when the antitoxin is used in pharyngeal diphtheria the larynx is not thereafter affected. Bad effects from the antitoxin we did not see, although about twenty injections were made. I prefer the fleshy part of the thigh as the seat of injection. Pain was remarkably slight or wholly absent, and absorption took place in a very few min- utes. One child had a slight erythema after the fifth day. Can we prevent diphtheria with the antitoxin ? The published reports of prophylactic injections are not very encouraging. As the antitoxin does not prevent the growth of the bacillus, it is hard to understand how it can prevent diphtheria. It has been noted that relapses after cure by the antitoxin are not infrequent; this itself is a strong argument against belief in any prophylactic virtue of the new medicine. As a matter of fact, diphtheria is not a highly contagious disease. Henoch says that in seventeen consecutive years only one attendant caught diphtheria in his diphtheria-pavilion. It is, therefore, a very difficult question to decide, especially as diphtheria occurs not infrequently in those prophylactically injected. Brewer1 injected two children for the purpose of prophylaxis. One of them developed a membrane the next day, the other in six days after inoculation. Richter2 made 72 preventive injections, and 7 of the persons were 1 Brewer: The Medical News, Philadelphia, Jan. 19, 1895. 2 Richter: Deutsche med. Woch., 1895, No. 7. 13 nevertheless affected. Sonnenburg1 made 16 in- jections ; diphtheria occurred in 2 of the cases. Hager2 immunized 35 children and 3 took sick. Brunstein3 immunized 28 cases and 1 took sick. Pear? immunized 67 persons between the ages of four months and fifteen years; 13 contracted diph- theria and 2 died. Summing up these reports we find that of 220 persons injected, 28 (12.7 per cent.) were never- theless affected. This is certainly not a good show- ing. If one out of eight people had smallpox, Jenner's name would not be celebrated as it is to- day, and smallpox is far more contagious than diphtheria. On the whole, we are compelled to say that evidence of the value of prophylactic injec- tions of the antitoxin is still wanting. Is the antitoxin a specific against diphtheria in the sense advocated by Behring and Roux ? By the question we mean, does the antitoxin neutralize the effects of the disease in the system and thereby in- sure recovery ? In one thing all authors agree, i.e., that the antitoxin does not kill the Loeffler bacillus or prevent its further development. In several of our hospital-cases the bacilli persisted in the throat for days and even weeks, notwithstanding the use of the antitoxin. Other observers have demon- strated that the bacilli not only persist in the throat but also retain their virulence for guinea-pigs.5 Therefore the antitoxin cannot be called a specific 1 Sonnenburg: Deutsche med. Woch., 1894, No. 50. 2 Hager: Therap. Monatsh., February, 1895, p. 91. 3 Brunstein: Wiener klin. Woch., 1895, No. 3. 4 Pearl: Ibid. 5 Virulence for guinea-pigs should by no means be made the test for human beings, as it is in no sense conclusive. Each species of animal is a law only unto itself. 14 for diphtheria in the sense that quinin is a specific for malaria. It certainly does not destroy the cause of the disease. Mercury is called a specific for syphilis without presumably destroying the cause of syphilis; in some way it neutralizes for the time being the syph- ilitic virus. It is difficult to say just to what extent this is true of the antitoxin of diphtheria. The children seem certainly to improve under its use, as every eye-witness can testify. And yet there is much evidence to show that the poison is not neu- tralized. Diphtheric nephritis and post-diphtheric paralysis are commonly assumed to be the result of the action of the diphtheric virus on the kidneysand nervous system respectively. Certainly the poison that leads to nephritis and paralysis is not neutral- ized by the antitoxin ; so in the sense of mercury for syphilis, we can scarcely speak of the antitoxin as a specific for diphtheria. In a word, all our the- orizing about the antitoxin is as yet without avail. The clinical fact is plain that a larger percentage of cases recover with it than ever did under any other form of treatment. This is the one practical fact, testified to almost universally, that makes the use of the antitoxin a matter of duty in cases of diphtheria in children. And now a few words regarding the relations of the city to the question of the bacterial diagnosis of diphtheria. Modern custom has relegated to the city officials all over the world the task of dealing with the health-questions of the respective cities. The more advanced cities in Europe and America have already established disinfecting bureaux and stations for the destruction or disinfection of con- tagious material. Cincinnati has done little that is 15 efficient in that regard. New York was the first city- in the world to make adequate arrangements for the control of diphtheria and tuberculosis by means of bacteriologic examinations. The fact has been made perfectly plain that only by repeated bacterial ex- aminations of the throat can we test whether a case of diphtheria has became free from infecting power or not. It is known that Loeffler bacilli remain in the throats of diphtheria-convalescents for many days and even weeks. One series of examinations at the City Hospital revealed the presence of the germ up to the fortieth day of convalescence; and repeatedly have we found the germ at the end of the third week. Nothing is more evident than that our present mode of placarding houses is not only un- just to the occupants, but also inadequate for public safety; many a family is seriously discommoded, its children kept from the schools-because the physi- cian assumed a simple angina to be diphtheric. It has been my fortune more than once during the past five months to see cases which other physicians had called diphtheria, and which proved to be non- diphtheric. Patients have a right to demand bac- teriologic examination before submitting to weeks of isolation, often with considerable detriment to business and always to convenience and comfort. The ipse dixit of the attending physician is by no means sufficient, be he who he may. On the other hand, placards are removed from houses four days after the physician signs a certificate that the patient is well, no matter whether the patient still be a source of public danger or not. The only possible control is the bacterial control-and it is now a matter of public necessity that every municipal health-department should be under the management 16 of a professional and expert bacteriologist, with as- sistants and clerks who should devote all their time to the work in hand. Cincinnati has recently applied salve to its own conscience by providing for the expenditure of $500 to pay for apparatus, office-work, and the salary of the city bacteriologist; while everyone knows that that sum is ridiculously inadequate to supply what is needed. Other cities have out- stripped us. Brooklyn has adopted the same sys- tem as New York. In Boston the work has been done for the past seven months. In November and December of 1894 1002 cultures were examined by the city bacteriologist, who was relieved of all other work; in January, 1895, 842 cultures were examined. Boston has also provided for the manufac- ture of antitoxin, and has seven horses under treat- ment. The Philadelphia Board of Health has ap- propriated $15,000 to establish a bacteriologic bureau. In St. Louis the City Board of Health has for some months been examining for tubercle- bacilli and Loeffler bacilli, having established eighteen stations in the city for the receiving of specimens. New Orleans has for more than a year had a fully equipped and active bacteriologic bureau. Cleveland is supplied with antitoxin from the Western Reserve University. Buffalo has two pro- fessional bacteriologists who devote all their time to the work. Tubes for diphtheria-diagnosis are dis- tributed to the thirteen police-stations of the city, and examinations are also made for tuberculosis. The tap-water and reservoir-water are examined daily; the mik and ice at proper intervals. Detroit has begun the work of bacterial diagnosis, and In- dianapolis will fall into line this autumn. The Medical News. Established in 1843. A WEEKLY MEDICAL NEWSPAPER. Subscription, $4.00 per Annum. 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