FURTHER OBSERVATIONS UPON TYPHOID CARRIERS.

723 in patients free from carcinoma. I have, so far, only tried this test in six patients, all with negative results. Three of these had sera which, in vitro, hsemolysed the

were

corpuscles injected. Conclusions. It is evident that the possession of iso-hasmolysins is very far from being pathognomonic of cancer. But then very few signs of the disease in its curable stages will bear this in 50 per cent. interpretation. A reaction which is positive of patients with cancer deserves, I think, to be weighed in the balance with other facts in the endeavour to arrive at a diagnosis. The only other conditions likely to be confounded with cancer in which haemolysis is frequently met with are tuberculosis and pernicious anaemia, especially the former. In such cases, if hæmolysis be proved, it is possible that one of the forms of tuberculin reaction would be of value. A negative hæmolytic reaction can, of course, carry no

weight. Bibliography.—Blumgarten; Medical Record, 1909, vol. lxxv., p. 61. Butler: Journal of the American Medical Association, 1909, vol. lii., p. 1919 Crile: Ibid., 1908, vol. li., p. 2036. Dudgeon : Proceedings of the Royal Society, 1908, vol. lxxx., p. 531; 1909, vol. lxxxi., p. 207. Eason: Journal of Pathology and Bacteriology, 1906, vol. xi., p. 167. Elsberg : American Journal of the Medical Sciences, 1910, vol cxxxix., p. 264. Janeway: Annals of Surgery, 1909, vol. xlix., p. 27. Johnstone and Canning : Journal of the American Medical Association, 1909, vol. liii., p. 1479. Kelling: Weiner Klinische Wochenschrift, 1909, vol. xxxii., p. 1292. Ottenberg and Epstein: Archives of Internal Medicine, 1909, vol. iii., p. 467. Richartz: Deutsche Medizinische Wochenschrift, 1909, vol. xxxv., No. 31. Smithies: Medical Record, 1909, vol. lxxvi., p. 901. Weil : Journal of Medical Research, 1908, vol. xix., p. 281. Whittemore: Boston Medical and Surgical Journal, 1909, vol. clx., p. 77. Hull.

FURTHER OBSERVATIONS UPON TYPHOID

CARRIERS.1 BY D. S.

DAVIES, M.D. LOND.,

MEDICAL OFFICER

OF HEALTH OF

BRISTOL;

AND

I. WALKER HALL, M.D. VICT., PROFESSOR OF PATHOLOGY, BRISTOL UNIVERSITY, AND PATHOLOGIST TO THE BRISTOL ROYAL INFIRMARY.

E.

With the Assistance of EMRYS-ROBERTS, M.D. LIVERP.,

PROFESSOR OF PATHOLOGY, UNIVERSITY COLLEGE, CARDIFF ; FORMERLY DEMONSTRATOR OF PATHOLOGY, BRISTOL UNIVERSITY, AND PATHOLOGIST TO THE BRISTOL GENERAL HOSPITAL;

AND

JAMES FLETCHER, M.D. ABERD., MEDICAL SUPERINTENDENT OF THE MONSALL FEVER HOSPITAL, MAN-

CHESTER ;

LATE RESIDENT MEDICAL OFFICER, HAM GREEN HOSPITAL, BRISTOL.

SINCE the publication of the last reportwe have investiseveral methods of treatment and have made daily examinations3 of the excreta of another typhoid carrier for a period of 15 months. The results obtained appear to justify the prolonged study of one particular case, and to suggest that some of the conclusions and recommendations of those who claim successful eradication of the typhoid bacillus from the human tissues by means of this or that method of treatment would be modified or withdrawn were the carriers subjected to more rigorous and continued examinations. These daily examinations made such great demands upon our time that we were compelled to limit the methods employed. Consequently, we were unable to make any experiments upon the bactericidal, or opsonic, properties of the blood setum and had to confine our observations to the enumeration of the typhoid organisms in faeces and urine, to the agglutinin contents of the serum, and to the action of

gated

therapeutic agents. 1 D S. Davies is responsible for the public health aspect of the case, J. Fletcher for the clinical observations and collection of material,

and I. Walker Hall and E. Emrys-Roberts for the bacteriological examinations. 2 THE LANCET, Nov. 28th, 1908, p. 1585. 3 There were several occasions when the daily sample did not reach us owing to some difficulty in transport, but for practical purposes the phrase is, perhaps, permissible. The exact dates are given in a separate report to the health committee of the Bristol corporation.

The Action of Lactic Acid Bacilli upon B. typlcnsus and B. coli. Prior to the discovery of our further typhoid carrier, one of us (I. W. H.) examined some 15 strains of lactic acid bacilli, and a number of yeasts, in order to determine the inhibiting action of these organisms upon the typhoid and coli strains isolated from the carriers previously reported upon. A summary of the results shows that while varying degrees of inhibition of coli growth were obtained, the inhibitory effect upon the typhoid bacilli was very slightpractically nil. This finding is in accord with the experience of some who have given the soured milk therapy a prolonged trial. It suggests that in those reported cases in which the typhoid bacilli disappeared from the excreta after a course of this treatment, the typhoid organisms were of an attenuated type, or that the disappearance of the typhoid bacilli from the excretions was a natural event rather than an effect of the therapy. It lies near to hand, also, to think that the latent bacillary period may have exceeded the period of examination in these cases. As yet the data for defining these periods are too few. The Present Carrier Case. X. Y., a female, aged 33 years, had typhoid fever in July, 1905. In 1905, September, her sister had an attack of typhoid fever. 11 December, her brother and father had typhoid fever. " 1907, July, another sister had typhoid fever. " X. Y. took a situation as cook. In July of the same year the parlour-maicl and housemaid were attacked by the same -

,

"

disease.

" 1908, September, her kitchenmaid had typhoid fever. December, a nurse who was looking after the carrier patient developed typhoid fever. (X. Y. had been admitted voluntarily intothe Bristol General Hospital under Professor J. Michell Clarke.) While in the Bristol General Hospital in 1908 typhoid bacilli were identified and isolated from her urine, and upon two occasions from her fasces, while her blood serum gave good agglutination reactions. She was later transferred to the Bristol Ham Green Fever Hospital for further observaThe organisms disappeared from the urine on tions. April 13th, 1909, and the agglutinative power of the blood serum fell gradually during 1909. Although daily examinations of the faeces have been made throughout no further excretion of typhoid bacilli has occurred, and it is probable that the two early findings were due to contamination of the fasces by urine. The carrier has therefore been classed as one of the urinary type. No typhoid organisms appeared in the urine during the remainder of 1909, but on Jan. 4th, 1910. typhoid bacilli appeared in the urine and the agglutinating power of the blood commenced to rise. The organisms continued to be excreted until Feb. 27th, 1910. Since then, although the urine has contained many coliform and other organisms, typhoid bacilli have been absent. Clinical course.-On admission to the Bristol General Hospital on Nov. 28th, 1908, under Professor Michell Clarke, the general condition of the carrier was fair, the only symptom complained of being an occasional throbbing in the abdomen. She was somewhat thin, but the thoracic and abdominal organs were healthy. A trace of albumin was present in the urine. On removal to Ham Green Hospital on Jan. 26th, 1909, under Dr. D. S. Davies and Dr. J. Fletcher, she continued in fair health and gradually gained in weight. The slight albuminuria persisted. At the commencement of 1910, when typhoid bacilli reappeared in the urine-the patient was not made aware of the fact-she complained of slight malaise, a "crampy " feeling in the lower part of the abdomen, and pain across the small of the back. There were also occasional headache and vomiting. About the middle of March the symptoms disappeared. From January to March she lost weight but regained the loss during April. Throughout there has been neither bladder pain nor pain during micturition, nor increased frequency. Temperature.-This has been subnormal in type, varying from 970 (morning) to 980 F. (evening). When the vaccine injections reached a dose of 1000 millions there was a slight rise to 98°-98 5°, persisting for 14 days. On Jan. 9th, 1910, about a week after the typhoid bacilli appeared in the urine, the temperature gradually rose to 99 4° and fell within 14 days to its usual level. Since then it has remained about 97.5°-98 50. Collection of mate-rial and methods.—These details call for mention here only because of the difficulties of inhibiting bacterial growth in human excreta. Ham Green Hospital is situated some distance from our laboratories and we were "

724 TABLE I.—1909.

TABLE II.—1910.

Excretion

of Typhoid Bacilli.

Excretion of

TABLE

Typhoid

Bacilli

III.—Agglutinins.

Under urotropine 7 grains daily

(after

Six Months’ Vaccine

Curve for 15 Months.

Treatment.)

725

compelled to devise some means of cold storage transmission. Unfortunately, it was found impossible to carry out our ideas owing to the difliculty of obtaining ice in a country place, and the samples of urine were therefore sent to us in boxes lined with felt but minus ice. In spite of this, we are convinced that the enumeration of typhoid bacilli in urine, however carefully carried out, is associated with a number of fallacies in addition to the "personal equation," and hence we are compelled to regard our figures simply as

rough comparative calculations. Although we have tried the several recently

devised forms of differential media, we have obtained our best results with those of MacConkey and Conradi and Drigalski, and with these we have worked throughout. When examining the urine we have employed dilution methods combined with surface plating on solid media, and in the investigation of the stools we have always used the entire stool collected in parchment and stored in stoneware jars. The typhoid organisms have been isolated, frequently compared freely with other strains, and tested against standard anti-serums. -Results and Observations. The results of the daily examinations may be discussed more advantageously in relation to the objects in view rather than presented in tabular form. We may, therefore, consider the elimination of bacilli with regard to treatment, and the evidence of the reaction of the tissue to the typhoid bacilli. The effect of dricga on tlte bacillary output.-Under this heading we are able to compare the number of bacilli excreted

Further course of drugs.-After the apparent cessation of the bacillary excretion in February, 1910, an attempt was made to encourage thewashing out"of any remaining organisms by administering a course of potassium citrate. Three weeks of this form of treatment did not effect any further expulsion of the typhoid organisms. The evidences of tissue reaction.-The agglutinin content of the blood was determined in periods of four days each about every fortnight. In order to make the observations roughly comparative the following method was adopted :A large quantity of typhoid bacillary emulsion was prepared from a well-tested laboratory strain according to the technique recommended by Dreyer.4 This was roughly standardised by counting as in the preparation of vaccines, and the same measured quantity of the emulsion was used throughout the series of determinations. The serum was diluted and used within 24 hours of its collection. The readings were made after incubation at 500 C. for two hours, and confirmed after standing for 24 hours. In cases of doubt microscopical and saturation methods were employed. The accompanying diagram (Table III.) shows the results obtained and their probable relation to the factors of the case. In February, 1909, the agglutination was complete in 1 in 1000 dilution. When the bacillary excretion ceased the dilution was 1 : 500. During the period of vaccine injection the dilution fell gradually to 1 : 25 on June 12th. When the dose injected reached 1000 millions there was a slight rise to 1 : 230-1 : 460. When the vaccine injections were suspended onwards to Dec. 22nd the amount of agglutinin diminished to 1 : 25. On Dec. 30th there was a rise to 1 : 250, and this was succeeded by a further rise to 1 :920 on Jan. 21st, 1910, to 1 : 1500 by Feb. 14th, to 1 : 1860 on March 16th, and the same dilution was present in May and June. On Jan. 28th there was a good reaction (1 : 50) with organisms isolated from the patient’s urine a few days previously. The excretion of typhoid bacilli stopped on Feb. 26th, 1910. It has been asked whether the Widal reaction might be applied as a routine measure in dealing with typhoid convalescents and suspected carriers. Although we are paying considerable attention to this point, we feel that the data already accumulated are insufficient to permit of the slightest attempt at generalisation or deduction. Location of focus.—In this case it is not very probable that the focus is a renal one. Pus was rarely present, and then only in small amounts. Segregation of urine was not attempted. We have no data affording indications of a possible focus, and we cannot exclude the kidney altogether, but on account of the long intermittent periods, the absence of pus, and the location of the symptoms, we are disposed to consider the lesion as extra-renal.

during two separate periods-viz., January to April, 1909, and January to April. 1910. During the 1909 period, urotropine (7 grains twice, thrice, and four times daily) was given continuously. In the 1910 attack neither drug nor other treatment was attempted. The results are appended in Tables I. and II. In the second period there was a gradual rise in the number of organisms excreted, a fall succeeded by a further rise, and another fall followed by a slight rise and a sudden stoppage. In the first period the output was less and practically equal throughout. In both instances the period of excretion was about the same. The urotropine appears, therefore, to have limited the number of organisms per cubic centimetre, but not to have reduced the time during which the processes of tissue irritation and bacterial proliferation were paramount. On both occasions the excretion ceased when the proliferation and virulence of the organism were limited by tissue changes, a point which will be evident on inspection of the rise in the agglutinin curve shown in Table III. When the 1909 bacillary excretion terminated either naturally or through the action of urotropine, we decided to use an autogenous vaccine as a prophylactic measure. Remarks. Vaccine.—Accordingly on April 21st, 1909, we injected a dose of 50,000 dead typhoid bacilli at intervals of five days. Were we to venture upon any statement based upon the No reaction was produced. After three injections the dose experience gained in this and other cases it would take the was increased to 75,000, 100,000, 150,000, and 200,000 form of emphasising the necessity for keeping a register of bacilli. On May 14th the injection contained 500,000 all typhoid convalescents and making frequent bacteriological organisms, and the patient complained of headache and examination of their excreta, and recommending the further sickness for two days after each injection. The temperature general use of hygienic measures suggested in one of our The dose was increased gradually and on was not affected. previous communications. In Bristol we are endeavouring June 13th it had reached 50 millions. Henceforth there were to carry out both these suggestions. local redness and swelling, but the headache and sickness The results we here state make us a little hesitant in did not recur, neither when 100 millions were given nor accepting the permanency of some of the cures"already afterwards. At the end of August the dosage was increased published, since we fear that had the excreta been examined to 1000 millions, and coincident with the third dose the every day for a year or so the cases might have yielded temperature for the first time rose one degree. This rise was similar results to this one. maintained for about seven days ; subsequent injections were not followed by any temperature changes. After eight 4 Dreyer: Journal of Pathology, 1909, vol. xiii., p. 331. weekly doses of 1000 millions the injections were discontinued on Sept. 29th, 1909. THE MEDICAL DIRECTORY.-Messrs. J. and A. At this time the bacillus coli appeared in the urine, and treatment by coli vaccine was directed towards its removal. The measures adopted were not entirely successful, and the organism continued to be excreted in small numbers up to the period of their replacement by typhoid bacilli. While it cannot be denied that this course of vaccination produced a slight rise in the agglutinins of the patient’s blood serum and may have suspended the July ’’ effective period" to which she was prone, there is no doubt that it did not effect a removal of the typhoid organism from the tissues, although in November we were led to hope that an interval of seven months freedom from typhoid organisms indicated an actual cure.

Churchill ask

us to state that the circular sent annually to each member of the profession will be posted on Sept. 1st. It will be recollected that this is a month later than was recently the case. The change of date has proved to be an advantage in that the making of applications for returns during the holiday month of August is avoided. Practitioners The are asked to return the circular without any delay. "Medical Directory " will be published before Christmas, and it will be found that the climatological and balneological section by Mr. Norman Hay Forbes, F.R.C.S. Edin., has been extended to include continental as well as British spas and health resorts