Nov.. 1921.] KALA-AZAR : NAPIER. 401

Original Articles.

K KALA-AZAR: NOTES ON THE DIAG-

NOSIS AND TREATMENT. J

By L. E. NAPIER, m.r.c.s., l.r.c.p. (Lonjl / Imlozv- Kala-asar Research Worker (Tea Association Eti inent), Calcutta School of 7 ropical Medicine and

Hygiene.

ThivRK are three principal foci for kala-azar in India, namely, Bengal, Assam and Madras. The clinical manifestations of the disease vary ?somewhat in these three districts, but the response to treatment is uniform. It is with the Bengal type of the disease that T propose to deal in this

paper. The disease is very much more prevalent in

Calcutta and the surrounding districts than is

generally supposed. Of the patients who apply for treatment at the kala-azar clinic at the Calcutta School of Tropical Medicine about 70 per cent, are found to he definite cases of kala-

azar, diagnosed by the finding of Leishman- Donovan bodies in the material obtained from their spleens by

"

spleen puncture." Certainly, most of the patients whom we see are sent to us .

from the Medical College Hospital Out-patient Dispensary and by local practitioners because

they have symptoms which suggest kala-azar. On the other hand, of the patients who are eventually diagnosed kala-azar in the Medical College Hospital, more than half have been admitted not as kala-azar patients but as patients suffering from one of the common complications of this disease as, for instance, broncho-pneumonia or

cancrum oris, or from some other disease such as

typhoid or malaria. Both sexes are equally liable to the disease and

the disease appears to be equally common amongst Hindus, Mohamedans and Christians.

Possibly the poorer class of Christian is most

commonly attacked. Childhood and adolescence are reputed to be the ages most liable to the

disease, but 1 have not found this to be the case in Calcutta. All ages from one year to sixty appear to be equally susceptible. It is, however, a very noticeable fact that the signs and symptoms are more characteristic at ages from 4 to 14, and most severe at ages from 14 to 24. In men, and lo a less extent in women, over the age of 35 the disease is extraordinarily difficult to diagnose clinically. Frequently, the only symptoms are long continued irregular fever unrelieved by quinine, and spleen enlargement, but even the letter is not always marked. The onset.?This may be with fever, of the

typhoid type; of the malarial type, or of a low

irregular type. At the onset the temperature ( hart seldom shows the characteristic double rise. I n the typhoid type the temperature reaches its

height about the middle of the third week and a

"

relapse "

occurs in about the sixth week. It is

frequently not until a second relapse has occurred that/{he true nature of the disease is suspected,

ii the malarial type of onset the fever is

^companied by rigors. At first quinine appears 'to have some effect, but soon the fever occurs

daily and quinine fails to have any effect on it. Another characteristic mode of onset is with

an attack of severe ? diarrhoea or dysentery followed by a low irregular fever.

It is usually about the third month of the disease that the patient begins to suspect that he is suffering from an unusual type of fever, or that the doctor in charge begins to realise that neither expectant treatment nor quinine are

going to cure the case. About this time the most characteristic condition with which one meets is as follows, although it is seldom that all the signs and symptoms are present at one time in one

patient. Fever: Double or triple daily remittent

pyrexia, without rigors, unaffected by quinine. Appetite: Good.

Digestion: Bad. Bowels : Diarrhoea or constipation. Mucous membranes: Bleeding from gums, epis-

taxis, melaena or haematemesis. Hair: Falling out. Complexion: Becoming noticeably darker. Nourishment: Progressive loss of weight. Chest symptoms : Slight cough. Spleen: Patient complains of enlargement. Heart: Palpitations. Dealing with the symptoms first; the type of

fever is by no means consistent : not more than 10 per cent, of patients will volunteer the infor- mation, and even if a three-hourly temperature chart be kept, the characteristic double rise is

only detectable in from 30 per cent, to 40 per cent, of cases. The progressive loss of weight, the bleeding

from the gums, and the loss of hair are the most consistent and, from a diagnostic point of view, the most useful symptoms.

Physical signs:? The patient is thin or emaciated. Anaemia: Not very marked in an uncompli-

cated case. Hair: Thin, dull and dry. Skin: Dry and rough, dark shadows on the

forehead and temples. Over the tibiae it has a

glossy appearance and the periostium underneath pits markedly on pressure. These last signs are entirely independent of the general oedema of the feet and legs which sometimes occurs, especially in cases complicated with ankylostomiasis. Neck: Marked visible pulsation of the carotids

in the neck.

Abdomen^: Congestion of the abdominal veins. Liver enlarged to one inch below the costal

margin, soft and tender. Spleen enlarged to

about three inches below the costal margin, soft and spongy (in marked contrast to the hard chronic malarial spleen') but not tender. Tongue: Clean.

402 THE INDIAN MEDICAL GAZETTE. [Nov., 1921.

Gums: Soft and bleeding. Heart: Rapid, 120 per minute, with possibly a

haemic murmur.

Lungs: A few moist sounds over both bases. Temperature: 100? F. or more (at 10 a.m.). Of these the most characteristic signs are en-

largement and softness of the spleen, enlarge- ment of the liver, increased pulse rate, pulsation of the carotids and emaeiation.

Although there are many cases of which one can, on clinical evidence alone, definitely say " This patient is suffering from kala-azar," it is never safe to say of any patient who has an en- larged spleen,

" This patient is not suffering from kala-azar." Therefore, except in a very small

percentage of the cases the final diagnosis rests

with the pathologist. The blood count.?The typical blood count of

an uncomplicated case is:

Red blood corpuscles . . 4,000,000 per c. mm.

White blood corpuscles 4,000 per c. mm.

Polymorphonuclears .. 1,600 or 40 per cent.

Small lymphocytes .. 2,000 or 50 per cent.

Large mononuclears .. 320 or 8 per cent.

Eosinophils .. 80 or 2 per cent.

It is stated that a white blood count below

5,000 in a case of long continued fever is diag- nostic of kala-azar. This is probably true

provided that the red blood count is normal, or, in other words, if there is a relative reduction of leucocytes by about 50 per cent. To put it

The R. B. C.

mathematically, if = one

1,000 X the W. B. C. or more than one, the case is probably kala- azar. A polymorphonuclear count of less than 50 per cent, is also suggestive. ,

The only absolutely conclusive piece of evidence that the case is one of kala-azar is the

recovery of the Leishman-Donovan body from the patient. The finding of the parasites in the peripheral blood is a comparatively rare occur- rence. In a very large number of cases the

herpetomonas forms of the parasite can be grown by adding a few drops of blood to suitable

medium, but this is not a practical means of

diagnosis, in Calcutta at any rate, during the hot weather and the rains. The only practical method of obtaining the parasite, then, is by spleen puncture. This operation, if done with

rigid adherence to certain rules, appears to be almost devoid of risk. Dr. Muir performed the operation over a thousand times at Kalna without any cases suffering from haemorrhage and I, myself, have done some hundreds of spleen punctures without any accidents. I will give a short description of the technique.

Spleen puncture.?The patient should not have taken food for at least two hours previously. If

possible, a dose of calcium lactate gr. xxx should be given on the previous night and again in the morning, but if there is any difficulty about this, it is sufficient to give him one dose half an hour before the operation and another immediately

after it. The patient lies in a comfortable position on his back. It is a good plan to tell him to put his hands behind his head, as by this means you can control his hands without giving him the.

impression that he is being held down. The best spot to choose for the skin puncture

is the point just below the costal arch, which is

equidistant between the anterior and posterior margins of the spleen. This is touched with a match that has been dipped in pure carbolic acid, thereby both sterilising and anaesthetising the spot. The operator stands on the patient's left, the assistant on the right. The latter places his hand on the patient's abdomen below the spleen and prevents all downward movement of the organ. A sterilised 10 c.c. syringe, all glass or " R cord," with a sharp bright needle of the size usually supplied with a 10 c.c. syringe is chosen. There should be no trace of water left in the

syringe. The needle should be first pushed through the

skin at a very oblique angle and then, by a second movement, pushed into the spleen in the direction of the long axis of the viscus in a backward, outward and upward direction, the syringe now being held at an angle of 45? with the skin surface. The needle should be passed for about one inch into the spleen substance and then suc- tion applied by two or three sharp strokes of the plunger. Blood may rush into the syringe, but one should not wait for this, as a minute trace of spleen pulp is almost certain to have found its way into the tip of the needle, and this trace is all that is required. The needle is then withdrawn rapidly and pressure applied over the spot to control, as far as possible, the movements of the spleen for at least half an hour, a firm binder is then wrapped round the abdomen, and the patient is allowed to get up. Meanwhile, the contents of the syringe are squirted out on a number of glass slides, films are made which, when dry, are stained with Leishman stain and examined for the presence of Leishman-Donovan bodies.

It seems to me to be of the utmost importance that an absolutely certain diagnosis should be made in every case before treatment is com-

menced, as it is unfair to condemn a patient to a long and unpleasant treatment for a disease from which he is not suffering, or that a patient who has got kala-azar should be allowed to stop treatment after the temporary improvement that the first few injections frequently cause, and thence to become a victim to a chronic form of the disease, because his doctor has since begun to doubt his original perfectly sound diagnosis.

Treatment.?The treatment of kala-azar can

be dealt with under two headings: (a) Specific; (&) Subsidiary or symptomatic. (a) The only specific that has ever met with

any success in the treatment of leishmaniasis is

antimony. It has been administered in innumer- able forms with varying amounts of success, but the most generally accepted form of treatment is with potassium antimonyl tartrate, i.e., tartar

Nov,. 1921.] KALA-AZAR : NAPIER. 403

emetic, or with sodium antimony tartrate, both given by intravenous injection.

Choice of salt.?Potassium salts are, as a

general rule, supposed to be more toxic than the corresponding sodium salt, and this is said to be the case with antimony tartrate, but it is a point on which all workers on the subject do not agree. I, myself, have found that not only is the potas- sium salt not more toxic but it is more efficacious. This is only a matter of opinion, and whichever salt is used, as long as it is a pure one, satis-

factory results will be obtained. Strength of the solution.?Both 1 per cent, and

2 per cent, solutions of the salts of antimony are commonly used. It is nQt a matter of great importance which solution is chosen. The advocates of the 1 per cent, solution say that this solution being weaker is less toxic, and that a

given amount of salt can be injected more slowly if in weaker solution. On the other hand, it is

suggested that the introduction of a large quantity of the solution might cause a certain amount of haemolysis. We have been in the habit of giving a 1 per cent, solution dissolved in normal saline. At this point it might be as well to mention

that it is of the utmost importance that the solu- tion should be freshly made up. We do not use a solution that has been prepared for more than three days. If, however, it is inconvenient to prepare a solution as often as this, it can be

preserved by the addition of carbolic acid sufficient to make the solution 0.5 per cent,

strength. Distilled water should be used in the

preparation of the solution, and the solution should be sterilised by boiling for a few minutes. Dosage.?For an adult who is not particularly

debilitated, the first- dose should be 1 c.c. of a 1 per cent, solution. The dose should be increased by 1 c.c. until a dose of 10 c.c. is reached: sulDsequently 10 c.c. should be given at each dose. If, however, at any point during the treatment the injection is followed by coughing, nausea or giddiness, on the next occasion the dose should not be increased, and further, if the

injection is followed by vomiting, on the next occasion the dose should be decreased by 1 c.c.

It will seldom be found that an adult shows any resistance to the treatment up to a dose of 10 c.c. For debilitated patients and children, the

initial dose should be 0.5 c.c., and the dose should be increased by 0.5 c.c. each time. It will usually be found that for children up to the age of 10

years it will not be possible to increase the dose to more than 5 c.c. The injections should be given three times

weekly. The technique of the intravenous injection of

antimony salts.?The risk of vomiting will be lessened if the patient has not taken food recently. The patient should lie on a bed and the doctor

sit on a chair beside the bed. It is important that both should be comfortable. A good light is required. Any vein may be chosen, but the most con-

venient are those at the bend of the elbow, and

on the back of the hand or wrist. There is a

large vein at the back of the wrist running over the outer side of the head of the radius between the tendons of the extensor pollicis brevis and the tendon of the extensor carpi radialis longior which is extremely useful, especially in children, in whom it is often as big as their little finger. A sterilised syringe with a small sharp needle

is filled with about 0.5 c.c. more of solution than the dose to be given. The skin is sterilised with

spirit in preference to iodine. Congestion of the vein is caused by gentle constriction of the limb by an assistant above the point which is to be

punctured. The needle is then passed through the skin and into the vein in the direction of the flow of the blood. The plunger of the syringe is withdrawn slightly. If blood does not rush into the syringe, it means that the point of the needle is not in the lumen of the vein, in which case it should be withdrawn and another attempt made to puncture the vein by a sharp jabbing movement. When it is certain that the point of the needle is in the lumen of the vein, the assistant releases the constriction and the plunger of the syringe may now be slowly pressed in until only 0.5 c.c. remains in the syringe. It is very important to give the drug slowly, at least two minutes being taken over the injection of 10 c.c. The advantage of leaving 0.5 c.c. in the syringe is that a few bubbles of air may have found their

way past the plunger, and if a little solution is left in the syringe all danger of injecting air into the vein will be avoided. The needle is now withdrawn and pressure applied over the spot for a minute or two. The puncture may be sealed with collodion. The patient should lie still for about half an

hour after the injection. The two dangers to be avoided are the intro-

duction of air into the vein and the escape of any antimony solution into the subcutaneous tissues. The former accident might prove fatal and the latter give rise to a swollen and painful arm due to necrosis of the tissues.

Duration of the treatment.?It has not been

finally decided what is the minimum duration of treatment necessary. Muir(l) advocates four months' treatment with injections three times

weekly and claims that under these circumstances relapses never occur. Knowles(2) considers that 200 c.c. of a 1 per cent, solution, or 2 grammes, are, as a rule, sufficient, but admits that

. with this dose relapses occasionally occur.

Brahmachari(3) suggests that the patient should be treated for one month after the temperature has become permanently normal, but also admits that relapses do occur. Two points are absolutely certain: firstly, that

it is not safe to discontinue treatment directly the temperature becomes normal, and on the othei

hand, that it is unnecessary to continue treatment until the spleen becomes normal in size, as the spleen will continue to diminish for some time after the treatment has been stopped. Probably the best plan to follow is to give 2 grammes to an

404 THE INDIAN MEDICAL GAZETTE, [Nov., 1921.

adult who responds readily to treatment, but in cases where there is any delay in the fall of the

temperature to carry it on to three grammes. Should a relapse at any time occur, fortunately it will always again respond to treatment. In no case- should the treatment be discontinued until the white blood-count has returned to normal.

The general course of the disease under

antimony treatment.?The temperature com-

mences to come down almost immediately and usually reaches the normal line during the third or fourth week of treatment. -The weight often decreases at first on account

of the diminution in the size of the spleen and the disappearance of the oedema, but after this it steadily increases. The spleen usually shrinks slightly at the com-

mencement, but frequently no marked difference in size occurs until the end of the course of treat- ment. If it has been much enlarged, it seldom returns to its normal size. It is as well to warn the patient of this fact.

Subsidiary treatment.?For all patients who are at all debilitated, it is a good plan, as a routine measure, to put them on to a digitalis mixture of some kind. We usually give the following:?

Tinct. digitalis .. .. min. 5 Tinct. nux vomica . . . . min. 5 Tinct. rhei co. . . . . min. 20 Tinct. card. co. . . . . min. 15

Aqua chloroformi . . ad ^ oz The mixture should be given for a few days

before commencing antimony treatment and may be continued for the first few weeks of the treat- ment. After this, a mixture containing iron and quinine is useful, as malaria and kala-azar often co-exist in the same patient, and a patient seems more liable to malarial attacks when he is re-

covering from kala-azar. Such attacks are very discouraging to the patient, who imagines that he is getting a return of his kala-azar.

1 f the patient, when first seen, is in a very weak condition, it is usually advisable to withhold the antimony treatment for a short time, and under these circumstances an intra-muscular injection of the following is found very beneficial:?

Turpentine . . 1 part. Creosote .. 1 ?

Camphor . . 1 ?

Olive oil . . ? . 2-^ parts.

The best site for injection is the gluteal region. It may give rise to a certain amount of pain and even to the formation of an abscess. This will have the effect of causing a leucocytosis. This intra-muscular injection is also very useful

during the course of treatment when a patient, who at first responds well, commences to run a temperature rising daily to 100? F. without

showing any sign of. falling to normal. An in-

jection will often be followed by a sharp rise to 103? F. with a rapid drop to normal where it will remain. Diet.?Common sense should guide one with

regard to diet/ The patient will naturally be

kept on low diet while the fever is high. He should be warned against overeating. After a few injections of antimony, his condition often

improves very much, and with it his appetite: he is very liable at this point to eat too much, upset his digestion, and thereby give rise to a severe

dysentery. Complications.?'The commonest amongst

these are:?

(a) Broncho-pneumonia: This may occur at

any stage of the disease. It is a common termi- nation of untreated cases, but it unfortunately occurs during treatment as well. It has been stated that it is caused by the treatment, but there is little justification .for this statement, as it occurs so frequently in untreated cases. It is advisable to withhold antimony treatment while a patient is suffering from any severe lung condition. It is very frequently but by no means always a fatal complication. If the patient recovers from the pneumonia, he is usually well on his way to recovery from his kala-azar, and many cases are recorded in which kala-azar has been completely cured by an intercurrent attack of pneumonia.

(b) Dysentery: Most authorities now agree that this is not of a specific nature but is either amoebic or bacillary, more frequently the former. It usually reacts well to emetin. Better results are obtained by withholding magnesium sulphate and giving some sedative such as pulv. cret.

aromat cum opio. (r) Cancrum oris: this is not an indication for

the withholding of antimony treatment, in fact rather the contrary. Most cases will improve rapidly with antimony injections. Naturally a

mouth wash will also be given. Ankylostomiasis is a very frequent concomitant

condition. We have found it the safer practice to commence the antimony treatment and to wait until the patient's condition improves slightly before giving oil of chenopodium. It is, however, very important that the patient should be cleared of hookworms, otherwise improvement will be slow.

References.

(1) Kala-azar: its diagnosis and treatment. E. Muir.

(2) A study of kala-azar. Indian Journal of Medical Research, ^1920.

(3) Kala-azar anchifs treatment. U. N. Brahmachari. ancMt

7