1119

pass from infected tissues into the blood stream byway of the lymph channels.

I am indebted to my colleagues on the staff of theBristol Royal Infirmary for the clinical histories ofthe cases.

REFERENCES

1. Shaw, A. F. B. : Arch. Dis. Child., 1929, iv., 155.2. Fraser, A. D. : Ibid., 1932, vii., 181.3. Klinge, F. : Virchows Arch. f. path. Anat., 1932, cclxxxvi.,

344.4. Fraser, A. D.: THE LANCET, 1930, i., 70.

AGRANULOCYTIC ANGINA

ITS TREATMENT WITH PENTOSE NUCLEOTIDE

WITH REPORT OF A CASE

BY ERNEST BULMER, M.D., M.R.C.P. EDIN.,M.R.C.P. LOND.

ASSISTANT PHYSICIAN TO THE GENERAL HOSPITAL, BIRMINGHAM

Schultz in 1922 described the condition of agranu-locytic angina, and an extensive literature has grownup ; the outlook on this peculiar blood response hasbeen widened, and recent therapeutic work has

brightened the prognosis.Two types of the disease are encountered : true

agranulocytic angina, for which no cause can befound, and malignant neutropenia in which a failureof the polymorphonuclear leucocytes (granulocytes)is secondary to an obvious acute infection.

Agranulocytic Angina.-To follow Jackson 2 thisterm is used to cover those cases in which, withoutknown aetiology, there is an extreme lowering of theleucocyte count and the granulocytes may bebanished from the circulation. Commonest in

middle-aged women, the condition is usually acutewith ulcerative lesions in the mouth or other mucousmembranes; these may become gangrenous, buttheir presence is not invariable. Whilst usuallyfatal, there is a form in which slow, spontaneousrecovery takes place with later, perhaps fatal,recurrence.

The aetiology is obscure ; in a few cases a lowleucocyte count has preceded the illness, but suchinformation is usually lacking; experimentallyFried and Dameshek 3 produced a comparablecondition in rabbits by the injection of overwhelmingdoses of Salmonella suipestifer ; ; Conner 4 suggeststhree mechanisms for the response-defective granu-locyte formation, excessive destruction, or improperdistribution or delivery of these cells into the circu-lation-the first being the most likely. It is probablethat the disease is due to an unknown infectionproducing neutropenia, and there are analogies withglandular fever from both the clinical and hsemato-logical points of view ; I have studied one case whichstarted as a fairly typical glandular fever to endfatally as a fulminating agranulocytosis. A secondtheory ascribes the disease to a primary failure ofgranulocyte production-a partial marrow aplasia-so that the removal of the body’s cellular defenceallows the invasion of the orificial mucosse by theirnormal bacterial flora.

Malignant jVMopeM-M..—Not inaptly this termcovers cases of agranulocytosis following a definiteseptic process such as pneumonia or pan sinusitis,and routine blood counts have shown the not infre-quent occurrence of minor grades of the condition.

PROGNOSIS

Whatever the type-primary agranulocytosis or

malignant neutropenia--the prognosis has been

uniformly bad. Table I., quoted from Doan,5 wascompiled in 1932 from various sources.

TABLE I

In addition to the classical type of the primarydisease there is a group in which spontaneousrecovery occurs. Harkins 6 describes four cases andquotes 24 others. Certain of them have succumbedto later attacks.

THE NUCLEOTIDE TREATMENT

Nucleic acid has long been recognised as havingthe property of stimulating leucocytosis, often aftera preliminary leucopenia. In 1924 Jackson 7 demon-strated pentose nucleotides in normal human blood,and Doan 5 has suggested that the bone-marrow maynormally be stimulated by the disintegration pro-ducts of leucocytes. There have been occasionalreports of the use of such products in the treatmentof agranulocytosis-adenine, guanine, &c.

In 1931 Jackson and others 8 reported a markedtemporary improvement in a case of acute myelo-blastic leukaemia following the injection of pentosenucleotide ; at their instigation a soluble, stable,and non-irritant solution of pentose nucleotide wasprepared under the trade name of K 96, and inNovember, 1931,9 they reported their results in20 cases. Seven out of 13 cases of agranulocyticangina recovered, five cases of malignant neutro-penia were treated and all recovered, and the rapidityof recovery of two cases of chronic benzol poisoningwas much hastened.

In a later paper 2 the same writers describe theirfurther experience, and give the results of a totalof 69 cases adequately treated ; they exclude patientswho died within 72 hours of the beginning of treat-ment, those in whom treatment was stopped duringthat period, and those in whom recovery occurredafter a brief period. Of 54 cases of agranulocyticangina, 38 recovered and are now well; seven

recovered, and after a relapse responded again totreatment ; two patients who recovered died laterin fulminating relapses. The average duration ofthe disease before treatment was started was 7-2 days.

Thirteen cases of malignant neutropenia were

treated with 11 recoveries. Certain features in theresponse to treatment are noteworthy ; there wasa fairly constant interval of four to five days beforeimprovement occurred, and then it was found thatthe temperature fell pari passu with the rise in theleucocyte count-no improvement was expectedduring the first few days. In three cases as the whitecount rose pus developed-acute pyelitis, ischiorectalabscess, and acute appendicitis ; an infection couldnot become purulent in the absence of granulocytes.

7’technique and Reactions.-Jackson recommendsin acute and urgent cases 0-7 g. of K 96 in 100 c.cm.of normal saline intravenously, and 0-7 g. in 10 c.cm.of water (one ampoule of the solution) intramuscularlydaily for four days; then 0-7 g. intramuscularlytwice daily until the white blood count is normal;thereafter the same dose twice daily for three days.In less urgent cases the intramuscular route may beused entirely.

After intravenous injections, even though given

1120

very slowly, severe reactions may occur- acutedistress, praecordial pain, dyspnoea ; these occur

seldom after intramuscular injections. Reactions

may be minimised by a preliminary injection ofatropine.

CASE RECORDS

Mrs. A., aged 2 7 years. The patient had had no previousillnesses of note, and was in her usual good health untilFeb. 3rd, 1933. On this day she noticed some pain in hergums ; this increased on the following day, and there wassome pain in the glands below the mandible. She did notgo to bed nor feel ill, but on the night of the 4th-5th thepain became most severe in the gums, and she could notsleep. I saw her on the afternoon of the 5th in consultationwith Dr. F. E. Gould, of Aston. The patient looked ill,

TABLE II

her temperature was 101° F. ; the gums of the upper jawwere hyperoemic, and the interdental papillae swollen.There was not any ulceration of the mouth, but in theneck and axillas there was a diffuse adenitis ; the spleenwas impalpable. A leucocyte count was 3000 per c.mm.,and blood was taken for a film examination.On this night sleep was impossible because of pain in

the gums, and a feeling of acute malaise ; the followingmorning she looked very ill; the gums were swollen andbleeding, and the mouth had the odour encountered inacute leukeemia from superficial ulceration. The, bloodfilm taken the previous day showed only 0-4 per cent. ofgranulocytes-an absolute count of 16 per c.mm., and adiagnosis of agranulocytic angina was made-grs. 6 of

TABLE III

gran. = granulocytes. iv. = intravenously ;im. = intramuscularly.

sodium nucleinate was given intramuscularly. She wasadmitted to the private wards of the General Hospital, andMessrs. Philip Harris and Co. were asked to obtain a supplyof K 96 at once. Through their courtesy and that of Messrs.Martindale, of London, this arrived within six hours.She was seen in the evening in consultation with Prof.

J. G. Emanuel and Prof. L. G. Parsons, who concurred inthe diagnosis and in the advisability of treatment withK 96. An intravenous injection of 0-7 g. was given, andthe following day it was obvious that the precipitatedeterioration in the patient’s condition had not only beenarrested, but that an improvement had set in-the gumchanges were less marked, the temperature had dropped,she felt better, and the blood count had improved. Thespleen was now palpable.

Treatment was continued with K 96, and the furtherprogress was uneventful, although unpleasant reactionsoccurred after each injection. Details of the treatmentand the blood counts are given in Tables II. and III. Thepatient was able to go home at the end of three weeks, andshe remains in good health ; the latest blood counts showa leucocytosis and a mild secondary anaemia improvingwith iron medication. Table II. shows the blood countsand differential counts of the white cells expressed in per-centages. In Table III. the granulocytes have beenexpressed in absolute numbers in each cubic millimetre.The normal count is between 4000 and 7500 per c.mm.

It is not claimed that the recovery was the resultof this treatment ; a study of American records

suggests that a latent period of a few days betweenthe beginning of treatment and the onset of improve-ment is a necessary criterion for this assumption.In this case an almost immediate response occurred;treatment was instituted, however, at a very earlystage.

It is believed that this is the first case recordedin this country of the use of pentose nucleotide inagranulocytic angina.

In conclusion I would express my thanks to Dr.W. T. Hillier, clinical pathologist to the GeneralHospital, for carrying out the numerous bloodcounts, and to Prof. Emanuel and Prof. Parsons fortheir valued help.

REFERENCES

1. Schultz, W. : Deut. med. Woch., 1922, xlviii., 1495.2. Jackson, H., Jr., et al.: Amer. Jour. Med. Sci., 1932,

clxxxiv., 297.3. Fried, B. M., and Dameshek, W. M. : Arch. Internal Med.,

1932, xlix., 105.4. Conner, H. M., et al. : Ibid., p. 1233.5. Doan, C. A. : Jour. Amer. Med. Assoc., 1932, xcix., 194.6. Harkins, H. N. : Arch. Internal Med., 1931, xlvii., 408.7. Jackson, H., Jr. : Jour. Biol. Chem., 1924, lix., 529.8. Jackson, H., Jr., et al.: Folia Hæmat., 1931, xliv., 33.9. ,, ,, ,, : Jour. Amer. Med. Assoc., 1931,

xcvii., 1436.

A CASE OF CALCULOUS ANURIA

BY G. T. COOK, M.B. CAMB.LATE HOUSE SURGEON, UROLOGICAL DEPARTMENT, KING’S

COLLEGE HOSPITAL

With a note on the Previous History of the Patient byMr. JOHN EVERIDGE

CALCULOUS anuria is relatively uncommon; and thefollowing case presents some unusual features.The patient, a woman aged 50, had suffered from

renal calculi for many years, during which time shehad frequently passed small stones down her leftureter. Pyonephrosis developed in the left kidney,secondary to a renal calculus, and in February,1932, the kidney was removed by Mr. John Everidge.At that time the patient was known to have a smallstone in the right kidney (Fig. 1) (see Mr. Everidge’snote, appended). The patient made a satisfactoryrecovery from her nephrectomy and passed no morestones, nor suffered from any further attacks of painuntil the end of September, 1932.On Sept. 28th the patient had an attack of right

renal colic, the pain commencing in the loin andradiating down to the groin and the right leg. Sheremained in bed, but did not take a very serious viewof her condition, having frequently suffered from leftrenal colic in the past. The attack was not accompaniedby any obvious haematuria. The pain continuedon and off for several days, and on Oct. 1st vomitingbegan. She was observed by her relations to be

passing into a drowsy state, and during the 24 hoursbefore her admission only 1 oz. of urine was passed.This contained a large amount of pus and albumin.