FROM THE AUTHOR. CAUSAL THERAPEUTICS IN THE INFECTIOUS DISEASES. y. C. WILSON, M.D. [REPRINTED FROM THE THERAPEUTIC GAZETTE, NOVEMBER 15, 1888.] CAUSAL THERAPEUTICS IN THE INFECTIOUS DISEASES. Read before the Association of American Physicians at its third annual meeting, held at Washington, D.C., September 18 to 20, 1888. A CLINICAL EXPERIMENT (enteric fever—phthisis). BY J. C. WILSON, M.D., PHILADELPHIA, PA., Attending Physician to the Philadelphia Hospital and to the Jefferson Hospital. THE discoveries of Hoffa, Brieger,Vaughan,. Bourget, and others within the last few years have done much to clear up the relation between the special pathogenic germs of the infectious diseases and their symptomatology. They have also rendered necessary a new defi- nition of the infectious diseases. In the words of Vaughan and Hovy,* “An infectious dis- ease arises when a specific, pathogenic micro- organism, having gained admittance to the body, and having found the conditions favor- able, grows and multiplies, and in so doing elaborates a chemical poison which induces its characteristic effects.” The germ theory as a working hypothesis has revolutionized surgery and robbed mid- wifery of the chief of its terrors. It has given us an antiseptic procedure which reaches the perfection of simplicity in ideal cleanliness and recently-boiled water. It has made quarantine reasonable, preventive medi- cine a power, and prophylactic measures in- telligible to the people. Isolation and disin- fection have now an obvious and definite * “ Ptomaines and Leucomalnes,” 1888. 4 purpose. But until it came to be known that pathogenic micro-organisms produced the definite chemical poisons called ptomaines the demonstrated facts of bacteriology shed but little light upon the clinical phenomena of the infectious diseases ; still less did they directly influence treatment except locally. For countless investigations have shown that antiseptic medication by way of the mouth has little effect upon the specific bacteria of a developed disease. Nevertheless, despite innumerable failures, something has already been accomplished, and, to quote Welch,* “ One need not be of a very sanguine tem- perament to hope that our steadily-increasing knowledge will bear fruit, not only, as in the past, in the prevention of these diseases, but also in a rational system of causal therapeu- tics.” The production of special ptomaines by specific bacteria is probably a necessity of the growth and multiplication of these bac- teria, and that which interferes with the split- ting up of the complex chemical compounds of the body proportionately interferes with that growth and multiplication. It is in this way, doubtless, that antiseptics render organic sub- stances insusceptible to the action of putre- factive germs rather than by direct action upon the germs themselves. What may be the mode of action of vac- cination or of the inoculation of attenuated virus is at present past finding out, but the effects are manifested upon the tissues and the fluids of the body. It is by acting upon the substances that constitute the culture media of the bacteria that their growth and multiplication are to be interfered with by therapeutic means, rather than by directly acting upon the bacteria themselves when they have already invaded the organism and caused disease. The cases which form the basis of this communication are submitted to your consid- eration as illustrations of a mode of treat- ment not hitherto employed in enteric fever and pulmonary tuberculosis. I have no the- ory to offer to the Association as to whether or not the salts of mercury undergo possible * “ Modes of Infection.” Annual Address, 1887. 5 modifications when taken by the mouth, which they escape when administered hypo- dermically, nor as to possible differences in their effects when undergoing slow absorp- tion and acting continuously, as compared with their action when given in separate doses in a form permitting rapid absorption and elimination. The cases are submitted as a contribution to the subject of causal or etiological thera- peutics in contradistinction to all forms of symptomatic and expectant treatment. Rendot,* in 1887, treated with satisfactory results a series of cases of enteric fever by the administration of mercuric chloride in daily doses of from 2 to 5 milligrammes C3V t0 tt Sra'n)- This quantity was given in divided doses at intervals of two hours. To the objection that in these minute doses the drug is inadequate to produce physiological effects, Dr. Rendot replies that the doses are scientifically rational, and that they fulfil a positive indication of the typhoid infection. They are insufficient to destroy the vitality of the bacteria of typhoid fever, but possess, he believes, the power of neutralizing the toxic principles produced by their functional activity. Is it not possible that the action of the mercuric chloride tends rather to restrain the formation of these toxic principles ? Some months ago, while investigating the method of treating syphilis by the intra- muscular injection of calomel, as first sug- gested in 1864 by Scarenzio and revived in 1885 by Neisser, it occurred to me that this plan might prove valuable in other forms of infection.f It has certain definite advan- tages over the ordinary methods of medica- tion, among which are infrequent administra- tion, precision of dosage, and promptness of action. As the calomel thus introduced into the organism undergoes gradual conversion into the albuminate of mercury, and, in the presence of the alkaline fluids of the tissues, into a double chloride of mercury and sodium, * Gaz. Hebdom. Sciences Med., Bordeaux, December ii, 1887. f J. C. Wilson, M.D., “Note on the Treatment of Syphilis by the Hypodermic Injection of Calomel” (Medical News, June 2, 1888). 6 this method has the further advantage of ex- posing the organism to the continuous action of mercury in small amounts. It, moreover, possesses the cardinal advantages of sparing the digestive tract all direct irritation, and the certainty of absorption without regard to the state of the alimentary canal. The calomel is suspended in a mixture of glycerin and water, and injected deeply into the gluteal or deltoid muscles under rigid antiseptic precautions. The operation is usually followed by transient pain, and by circumscribed irritation and deep induration ; if properly performed, abscesses do not fol- low. The induration usually disappears in the course of a week. The dose of calomel injected is i to 2 grains ; it is repeated every four or five days. I have no experience with the red oxide of mercury used in this way, nor with the “gray oil” of Lang. ENTERIC FEVER. Case I.—E. G., male, set. 31, unmarried, Italian seaman, was admitted to the medical ward of the Jefferson Medical College Hos- pital on the 1st of November, 1887, on the eighth day of an attack of enteric fever, con- tracted while aboard ship in the Delaware River, opposite Philadelphia. The evening temperature on three occasions after his ad- mission to the ward reached 105° F. ; the morning temperature range was about 103° F. The temperature fell to normal on the twenty- first day of the attack, and, with the exception of occasional transient febrile exacerbations, remained at the normal until the fortieth day. During this time, however, it was noted that the area of splenic dulness continued to be enlarged. On the fortieth day a relapse oc- curred, with recurrence of the rash and diar- rhoea, and the febrile movement reached 103° F. This relapse was complicated by the occurrence of a large abscess in the left inguinal region. Defervescence was com- plete on the fifty-ninth day from the begin- ning of the primary attack and the nineteenth day from the beginning of the relapse. From this time convalescence was uninterrupted. Hypodermic injections of calomel in grain doses were employed in this case throughout, 7 the administration of the dose being on several occasions followed by a distinct and permanent lowering of the temperature range.* Case II.—H. O., male, aet. 21, an acrobat by profession, was admitted to Ward 8, Bed 5, of the Philadelphia Hospital, on the 19th of December, 1887, on the seventh day of an attack of enteric fever. In this case the evening temperature ranged between 103° and 104° F. There was splenic enlargement, no tympany, scanty eruption, copious diar- rhoea, amounting to from five to eight pas- sages daily. The morning temperature reached the normal on the twentieth day of the attack, and the defervescence was complete on the twenty-third day. (See Chart I.) Case III.—J. C., male, aet. 24, born in Ireland, a laborer, unmarried, had been for a long time an inmate of Ward 8, Bed 6, of the Philadelphia Hospital, suffering from pulmo- nary consumption affecting the upper lobes of both lungs, with cavities. While absent from the hospital on leave in November, 1887, he contracted enteric fever. On the fifth day the evening temperature reached 104° F., and on the eighth day the rash ap- peared. The case was characterized by the intensity of the abdominal symptoms, splenic enlargement, tympany, moderate diarrhoea, and scanty but well-defined eruption. The temperature fell to normal on the twenty-fifth day and to subnormal ranges on the twenty- eighth, when collapse occurred, with an axil- lary temperature of 94.50 F. After marked oscillations, which continued for several days, the temperature range became that of the man’s original condition. This case was treated throughout with calomel injections, and ran a remarkably favorable course. Case IV.—D. H., male, aet. 19, laborer, ad- mitted to Ward 2, Bed 30, of the Philadelphia Hospital, on the 23d of January, 1888, on the tenth day of a well-characterized attack of enteric fever, that had been ushered in with a _* The temperature charts, with the exception of those of Cases II., IV., and VIII., are not reproduced for want of space. They were shown at the time of the reading of the paper. Case II.—Enteric fever. H. O., male, ret. 21. CHART I. Day of disease. Number of movements of bowels. 9 distinct chill. The temperature on the even- ing of admission was 104° F. ; the following morning, 102.40 F. The patient was deliri- ous, tongue dry and fissured, spleen enlarged, rose spots abundant, stools thin and yellow, from two to five in the course of twenty-four hours, slight epistaxis, moderate tympany. The patient received four intramuscular injections of 1 grain of calomel each in the course of eight days following admission. Defervescence was complete on the twenty- first day of the attack, the form of lysis pre- senting a distinct modification of the usual type. (See Chart II.) Case V.—W. N., male, set. 50, unmarried, a native of Canada, mechanic, was admitted to Ward 2, Bed 13, of the Philadelphia Hospital, on the 6th of January, 1888, suffering from high fever, attended by muttering delirium, with vomiting, constipation, and great prostration. No history could at that time be obtained. The febrile movement, with the exception of a period extending from the 10th to the 18th of February, continued until the 23d of March. The case proved to be one of enteric fever of a very severe type. It was subsequently learned that the sickness began two weeks prior to the patient’s admission to the hospi- tal, and was, therefore, of a whole duration, including the afebrile period already men- tioned, of about ninety days. It consisted, as shown by an analysis of the temperature chart, of a primary attack, terminating about the 20th of January, succeeded immediately by a relapse, lasting until the 10th of Feb- ruary, and a second relapse, which set in upon the 18th of February. During the greater part of this time the patient was very delirious. A few characteristic rose spots appeared upon the abdomen during each re- lapse. On the 2d of February intestinal hemorrhage of moderate amount occurred. This patient, from the time of the recogni- tion of the nature of his sickness, was treated by calomel hypodermically. He made a com- plete recovery, and left the hospital at the end of May. It is scarcely necessary to say that the foregoing cases of enteric fever were man- aged in accordance with accepted rules as CHART II. Number of movements of bowels. Case IV.—Enteric fever. D. H., male, jet. 19. Day of disease. x indicates hypodermic injections of calomel. 11 regards diet, bathing, quietude, and the like. Cold compresses were employed, and repeated 5-grain doses of antipyrin were administered in Case V., when the temperature rose above 104° F. The other cases received no medi- cation other than the hypodermic injections of calomel, except an occasional opium sup- pository, or dose of bismuth subnitrate, for the control of too frequent diarrhoea, and in one or two instances only a single dose of antipyrin. PHTHISIS IN SYPHILITIC SUBJECTS. Case VI.—Widow, aet. 38 ; ill three years with teasing cough, attended by scanty ex- pectoration, occasional night-sweats, slight loss of flesh, appetite fairly good, evening temperature normal. The history renders it more than probable that the patient suffered from syphilis shortly after her marriage, twelve years ago. Physical examination revealed extensive dulness over the right lung, anteriorly in the mammary line, with abundant crepitant and subcrepitant rales heard in the infraclavicular area, and extending down the anterior border of the lung. Percussion elsewhere yields good resonance, and especially is this noted in the supraclavicular regions on both sides. Exam- ination of the sputa showed no bacilli. This patient came under observation the 10th of February, 1888. On the 29th of the same month treatment by hypodermic injec- tions of calomel was commenced, and con- tinued until the end of April, eight injections in all being administered. The area of per- cussion dulness was then noted to be much less extensive, subcrepitant rales were not heard, and a few crepitant rales only could be detected on forced inspiration after efforts at coughing. The patient left for her home much improved in all respects.* Case VII.—C. G., male, aet. 35, unmarried, an Englishman, by occupation a painter, was admitted to Ward 2, Bed 25, of the Philadel- * This is Case IX. of the series in the “ Note on the Treatment of Syphilis” in the Medical ATews. It was thought to be a case of gummatous infiltration of the lung. The subsequent history is unknown. 12 phia Hospital, on the 8th of May, 1888. Syphi- lis, with well-characterized secondary manifes- tations, eight years ago ; cough and moderate loss of flesh for the past six months ; five weeks ago slight blood-spitting, severe pain in the left side, diarrhoea, night-sweats, great shortness of breath. He gives an account of having been tapped three times in the left ax- illary region, with the removal of bloody fluid. Patient emaciated, extremely sallow, not jaun- diced, moderate cough, scanty muco-purulent expectoration, containing numerous bacilli. The physical signs indicated moderate tubercular infiltration of both apices, with a small cavity on the left side opposite the second intercostal space. Extensive coarse friction sound is heard over the base of the right lung, anteriorly and posteriorly, whereas, in the corresponding position on the left side, there is retraction of the chest and restricted respiratory movement without friction sounds. The night-sweats at the time of admission were profuse and distressing, and the general condition of the patient wretched. The morning temperature ranged about ioo° F., and the evening temperature from 102° to 103° F.; the patient weak and depressed, unable to leave his bed. Treatment by hypodermic injections of cal- omel was commenced on the nth of May, and steadily continued, at intervals of four or five days, until the 26th of June, when the pa- tient left the hospital of his own accord, having gained in weight and strength to such an ex- tent that he regarded himself as a well man. The following note is taken from the hospital record : “ Great improvement, subjectively and ob- jectively, no cough or expectoration what- ever, no night sweats ; for the past fortnight the temperature range has been normal. At the right apex, anteriorly and posteriorly, there are crepitant and subcrepitant rales in abundance. At the right base pleural fric- tion sounds are no longer heard, although patient occasionally complains of sharp pains in this region on deep inspiration. The local- ized tympanitic percussion resonance in the second intercostal space to the left of the sternum, as previously noted, has disappeared. The dulness on the left side continues very 13 marked below the clavicle, less so over the mammary region, but increases almost to flat- ness at the base. On the left side there is faint bronchial respiration, without rales an- teriorly, and at the apex posteriorly. Tongue clean ; patient looks well, has a good appetite, and weighs one hundred and forty pounds. The finger-nails show a series of well-marked transverse ridges.” This patient had no other treatment what- ever except a few doses of picrotoxine for the relief of night-sweats. PHTHISIS. Case VIII.—J. E., male, set. 25, unmarried, Irish, iron-moulder, was admitted to Ward 2, Bed 27, of the Philadelphia Hospital, on the 18th of May, 1888. His illness began seven months before, after exposure, with cough and morning expectoration ; has had blood- spitting in small amounts, suffered recently from chest pains, and has lost a great deal of flesh : no history of syphilis. On admis- sion the patient was pale, much emaciated, and very weak. Cough annoying, especially at night, and accompanied by moderate muco- purulent expectoration, which contains numer- ous tubercle-bacilli. The chest is well formed and capacious, with the exception of localized retraction at both apices. On the right side there are the signs of large cavities in the upper lobe, with extensive infiltration of the middle and lower lobes. On the left side there is dulness, bronchial respiration over upper lobe, and coarse crepitant and sub- crepitant rales in the mammary region. Calomel injections were begun on the 22d of May, and repeated at intervals of four or five days, 2 grains being the usual dose. On the nth of June it is noted that the patient feels much improved, has gained consider- able flesh, weighs one hundred and ten pounds; appetite good ; bowels regularly moved each day ; cough has entirely disap- peared, except before breakfast. At this time there is slight expectoration, which con- tains tubercle-bacilli ; pulmonary signs un- changed. Treatment was continued until the 30th of June, when, the patient complaining bitterly Case VIII.—Phthisis. J. E., male, set. 25. CHART III. x indicates hypodermic injections of calomel. Date. May Chart III.—Continued. x indicates hypodermic injections of calomel. Date. June 16 of the local pain of the injections, it was stopped. At this time the temperature was practically normal. In the course of eight days the evening temperature rose to ioo° F., and in a short time reached 102° F. The calomel injections were then resumed, with the result of speedily bringing the tempera- ture range to the normal. (See Chart III.) It must be added, though without much bearing upon the case, that this patient during some part of the treatment took at his own request teaspoonful doses of cod-liver oil three times daily. I have thus systematically treated in ac- cordance with this plan five cases of enteric fever, all of which were severe, and all of which recovered, three of them running an exceptionally favorable course; and three cases of phthisis, in two of which there was a distinct history of syphilis. In the three chest cases marked and rapid amelioration of the constitutional symptoms took place without very great change in the physical signs of local pulmonary trouble. In one of the two cases in which tubercle-bacilli were found, the cough and expectoration wholly disappeared. In the other case, the bacilli persisted in the expectoration. These cases taken together constitute a clinical experiment, the result of which, con- sidered without prejudice, has forced upon me the conviction that calomel thus intro- duced into the organism exerts a decided therapeutic influence in ameliorating the symptoms, and in modifying the temperature range of enteric fever and of pulmonary phthisis. In the case of enteric fever with relapses (Case V.) it is impossible to ascribe any very great benefit to the treatment. Nevertheless, those who saw the case in the wards of the hospital were of the opinion that the injections of calomel were on several occasions followed by distinct amelioration of the symptoms.