25 part n...(b) quinine and cacodylate of soda. (i) ravaut'streatment. (ii) intensive oral...

25

MALARIA IN MACEDONIA, 1915-1919.

PART n .

. CLINICAL OBSERVATIONS ON THE TREATMENT OF 'MALARIA IN MACEDONIA.

By A. GREIG ANDERSON. 1 emp. Major, Royal Army Medical Oorps.

IN the treatment of malaria 'there are two distmct ends in view, first, tl;le control of the a-ctual febrile paroxysm, and second,. the prevention of relapse. It is with thf? second· of these objects that the present repo,rt deals." ,

, In estimating the results of any method of treatm~nt it is essential to have evidence on certainpoint~: (1) The number of cases treated; (2) the type of infection present; (3) the result of blood eXftmination after treatment; (4) the duration of observation after treatment.

In all cases adm,itted to the special ward.s, 'a positive blood film had been obtained. The majority of cases were admitted from' other hospitals, but all had with them a record of one recent positive blood film.

Practically all were benign tertian infections with frequent relapses. When this is not so it is stated under tlIe description of the particular form of treatment used. .

Treatment in'the majority of eases was commenced duri~gan apyrexic interval. The examination of daily blood films in allc.ases under treatmentwas. not practicable. At first weekly examinations were .carried out in all cases, but these yielded such a high percentage of negative results that the method WftS abandoned. Finally, it was decided to examine the blood, films of every case in which the temperatur~rose to 1000 F. or over. After the conclusion of any method of treatment no further quinine was given. If the ,temperature rose a blood film was taken and treatment postponed until the result of the blood film was known. The criterion of relapse is therefore a rise of temperature to 1000 F. or over, with a positive blood -film result. A rise of temperature without positive blood film is disregarded in estimating the effects of treatment .

. Temperatures were recorded four times a day: at 7 a,m., 11 a.m., 3p.m.; and 7 p.m. All temperatures were taken in the mouth for not less' than ten minutes. .

- An attempt was made to retain all non-relapse cases in hospital for a period of 100 days, giving an observation period of not less than seven to eight weeks. Under the different methods' of treatment the shortest and longest p~riods of observation are stated in all non-relapse cases. In

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26 Treatment of ,Malaria in Macedonia

\ every case where, quinine was administered orally it was given as the hydrochloride of quinine. Whe~e .the intramuscular route was employed, bihydrochloride of quinine was dissolved in 0'75 per. cent sterile sodium chloride solution and autoclaved for one hour. All intramuscular injections 'were given in the buttocks.

The following classification gives a review of the different methods of treatment employed, and the results of the varIOUS methods will be dealt with in this order.

'I.-Control group of cases. H.-Quinine administration.

(A) Continuous dosage:-(1) Long sterilizing courses.

(a) C17 recommended by Colonel Sir Ronald Ross. (b) Oral course for one month. {(i) forty-five grains per day.

(ii) twemy grains per day. (2) Short sterilizing courses."

(a) Intensive' or~l course. (b) Intensive intramusGular course.

(B) Interrupted dos,age:.,-Quinine on two successive days weekly for 'a period of eight

. weeks. (i) Twenty-grain series.

(ii), Thirty-grain series. (iii) Forty-fi ve-grain series.

,lII.-Combination of quinine and arsenic. (A) Quinine and galy1.

~. (i) Intensive oral course plus galy 1. . (ii) Intensive ,int'ramuscular course plus galyl.

(B) Quinine and cacodylate of soda. (i) Ravaut'streatment.

(ii) Intensive oral course and cacodylate. IV.- Provoc~tive drugs.

(1) Liquor strychnine injections. ,(2) Liquor adrenalin injections. (3) Liquid extract of ergot ?y mouth.

SECTION I.-CONTROL, GROUP OF CASES. . ,

In the control group one wished to find what happened to cases treated only during an acute attack, and to whom after the attack was over' no further quinine was given. Forty-four such cases were admitted to. the icontrol ward-all 'were cases: of relapsing benign .tertian iufection.\ All were placed on a simple iron tonic mixture. In the ~vent of. a relapse ~he patient was put upon oral quinine· in doses varying from thirty to sixty grains per day ,according to the necessities of the case,. and the ,administration of qUInine was continued until ~he temperature h~d been. , .

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normal for'twenty-four hours.' The quinine was then stopped and the iron tonic mixture 'resumed. Of the forty-four cases fourteen showed no relapse ,during the period of observation. ThE:jobservation periods in these cases were: 31, 100, 63, 108, 93, 99, 83, 83, 82, 8$, 96, 78, 100, and 83 days., All gave histories o~ frequent previous attagks. (One of these cases', ' though not showing a positive relapse, ran a constant subfebrile tem-

, perature varying from 990 to 1000 F., and was evacuated by hospital ship.) The remaining thirty cases all showed relapses varyi:p.g in number from one to six according to' the length of the observation period. Many of these cases ,showed an almost exact p~l'iodicity in' their relapsing times, the most common period was twenty 'days., , ',

,Four cases are quoted in illustration of this :~ , ' , ,M:60l2:-]'our relapses; re~apse intervals, twenty-o~e, \eighteen, and

twenty-three days. ' M.6018-Four ~elapses; -relapse intervals, seventeen, twenty-two, and

twenty-two days.' ' M,6004~Three relapses; relapse intervals, twenty-one and eighteen

days. ' . M.6005-Four relapse~; relapse intervals, eighteen, twenty-t~o, and

eighteen days." - ' In this connexion it should be noted in the detailed analysis of the relapses

occurring after treatment that ,the majority of tbe relapses' occur within a period of from three ,to four weeks after treatment. 'This periodicity is most manifest during the hot 'season. It is obvious that the patients who show this periodicity are not likely to be effective soldiers at least throughout the hot, weather, and unless disposed' of otherwise, will pass the hot season between the hospital and the convalescent camp. In view qf this it would appear reasonable that cases of malaria should be retained in hospital for at least three weeks after the temperature has become normal. In connexion with such cases the results of the Liverpool School of Tropical Medicine are of imp6r,tance. ' They state that '~if a case of simple tertian malariiL has not relapsed parasitically within four weeks of cessation of treatment, he can be d,ischaq~ed from hospital with a risk of relapse , of only about thirteen per cent." The risk of relapse in Macedonia is somewhat greater than these figures would indicate, but t4eir results, obtained under more favourahlecircumstances, are an additional support for the argument that malarial patients should be retain~d for at least three weeks III hospital after tl1e acute attack is over; , ' '

," " SECTION H.-QUININE ADMINIS'rRATION.

(A) Continuous dosage. " (1) Long sterilizing courses.

(a) C17 recomm~nded byColonel Sir RonaldRoss. . ,In the interim report oil; the treatment of malaria presented to', the War Office by Colonel Sir Ronald Ross, K.C.B" and in' a later more


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Treatment of Malaria in Macedonia

'detailed memorandum, .this fprm of' tr~atment is recomlllend~d as being' , " apparently the best treatment for old cases of malaria which has yet been used." The directions for treatrpent are _ as follows: "The patient is put to bed for twelve days and given daily for all this period, namely, fifteen grains of the bihydrochloride of quinine intramuscularly in e\1ch deltoid muscle,together with ten grains ,of hydrochloride of quinine in mistura anticachexia No. 1 thrice daily, totalling sixty grains of quinine daily for the twelve days .. After this the patient is allowed up andis,given

, mistura anticachexia No. 2 four times a day;' this is' sixty grains of quinine ,daily by the mouth, this treatment being continued for three days. , After' this the patient is given mistura anticache'xia No. 3 four times daily for fourteen days; this is twenty grains of quinine daily, the patient being allowed to do light work all this time." . ,

"The total nm;nber of cases treated was forty-nine." " These were treated from July 10, 1917, to October, 1917. Of these'

ca~es only five, i,e., ten .per cent., relapsed up to Decer;nber, 1917. The observation. period ,after treatment varied from sixteen to seventy-two days."

This treatment was carried out in the wards according to the above. directions. The treatment differed from the original only in one minor detail, viz., that the intram~scular' injections were given' in the buttocks. instead of into the deltoid muscles.

The total number of cases which completed the course, and were observed for a sufficiently long period subsequent to treatment, was forty-four .. All were cases of relapsing benign tertian infections. '

Of this nUjnber, twenty-six cases (fifty·nine per cent) relapsed with positive blood films and fever; eighteen cases (forty-one per cent) did not relapse during'the observation period:

Of the twenty-six cases which relapsed, the shortest interval·after treatment in which a positive' relapse was obtained was sixteen days, the longest

, interval was sixty-six days. ~. . The following table shows the numbers of cases.relapsing in each seven-

day period after treatment. ' Days:, 1-7 14-21' 22-28 29-35 36-42 43-49 50-56 57-63 64-70 71-17 •

158713 1

Of those cases which did not relapse the observation period after treat'ment varied from fifty-two days to III nays.

According to the memora~dum, "the ,treatment was well borne by the patients ,except for the deafness' and tinnit'us, and there was very little

'vomiting." In a later comlllnnicll:tion dated April 15, ColoneL Rossstates that the treatmeljltis by no means always well borne., ",

This latter statement is in accordance with our experience.' It is difficult in many cases to persuade the patie~ts to complete the treatment. Of the total cases 93'7 per cent complained of loss of appetite, 81 per cent ofnausea .. 54 per cent of vomiting, 80 per cent of headache, 91 per, cent of


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tinnitus, 87 'per cent of deafness. The' loss' of appetite varied from a slight loss, at the beginning of the course to a condition where, only the lightest

? food could be taken during the latter half of the -intramuscular course. VomitiI;lg continued in two cases from one to twelve days, and in three cases from one to seven days.

All cases at the conclusion of treatment showed well defined indurat'ion , of the buttocks, varying in degree from a few small shotty nodules to large indurated masses the size of a hen~s egg. In every case this indura-tion disappeared entirely within three or four weeks. ,

Four cases complained of blurred vi§ion during the course. No diminution of the fields of vision was found by rough testing in any of twenty-four cases exammed. '

The high percentage of relapses, occurring here is in striking contrast with the high percentage of non-relapses obtained amongst the cases

/ treated in England: The reason for this variation is discussed later on. Cb) Oral course for one ,month.

(i) Forty-five grains quinine hydrochloride per, day. (ii) Twenty grains quinine hydrochloride per day.

Two series' of cases were treated, one in which the patieptsreceived daily for thirty days three fifteen-grain doses of quinine hydrochloride, the other in which the patients received daily for thirty days, two ten-grain doses: ,At the conclusion of the quinine treatr~lent_all patients were placed on a simple iron tonic mixture.

Results of Treatment. 45-grain series 20-grain seriQs·

Total number who completed treatment 18 16 and a sufficient observation period

Number who relapsed .. 8 (44'4 per cent) 10 (62'5 per cent) Number who 'did not relapse,. 10(55'6) 6,(37'5, " )

In the forty-five.-grain series, the shortest interval after conclusion of treatment at which relapse occurred was fifteen days, and the longest fortytwo days. In the twenty-grain series, the shortest interval was .seven days, the longest forty~six days.

The following table shows the. total numbers of cases in each serIes relapsing in each seven-day period after treatment. '

Days: 1-7

45 grains .. 20" 1

8-14 .. 2

15-21

5 3

22'-28

2 2 1

36-42

1 43-49

. . 1

50-56 57-63

Onhose cases which did not relapse the shortes't observation period was , fifty days, the longest 120 days.'

An the cases in this series were relapsing benign tertian malaria. As both series were tre~ted at the same time,the results are strictly

comparable. Of the two methods the forty-five-grain method is more effective in preventing relapse. In no ca/se had treatment to,be abandoned owing to intolerance of quinine.


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30, Treatmentoj Malaria ~n Macedonia

(~) Short sterilizing courses. (a) Intensive oral course.

During the first four days the patient is kept in bed, and is given 0

on each day three twenty-grain doses of quinine hydrochloride. An interval of ten days is allowed to elapse, the patient is put to bed aii.d the

. course repeated. The total amount of quinine administered is 480 'grains.

Results of Treatment. Total number who completed treatment and observation Number who relapsed .. Number who did not relapse ..

. 49 . '. 15 (34'6 per cent)

34 (69'4 '" )

. In ~his series the shorte~t relapse jnte~val was three days, the longest' eighty-two days. J p

The following tahle gives the numbers of cases relapsing in each sevenday period after treatmept :-

, t

Days: 1--;-7 8-14 15-21 22-28 29...,85 '86-42 48'-49 50-56 57-68' 64~70 71-77 78-84

1 23.3 1. l' 11 11

In the non-relapse cases the shortest observation period after treatment, was sixty-nine days} thelonges't ninety-five days. " . "

Of the 49 cases 47 were benign tertian infection~ and 2 malignant tertian infections; of the 47 benign tertian infections, 43 were relapsing cases and ,4 cases gave histories ~f having had only one previous attack.

(b) Intensive intramuscular course. . During this treatmenp the patient is kept in 'bed duripg the first four

days. On each of these days two intramuscular injections of quinine bihydrochloride are given, and in addition twe'uty grains of quinine hydrochloride in mixture, by mouth. All injections' are made in the gluteal region. The patient is allowed up and after an interval of ten days the . course is repeated. . After the second course the pati_ent wasp~t upon an iron tonic mixture.

Results of Treatment. Total number who completed treatment and observation Number who relapsed .. Number who did -not relapse ..

,"

58 23 (39'6 per-cent) 35 (60.'4 )

. Of the twenty-three relapse cases the shortest in~erval after conclusion of treatment was ten days and the longest sixty-eight days.

The following table gives the nu~bers of cases relapsing in each sevenday period after treatment :-

, Days 1-7 8-14 15-21 22-28 2~-85 36-42 48-49 50-56 57--68 64-70

1663211 3

'Of the non-relapse cases the shortest' period of observation after treatment was seventy-two days, the longest period was 116 days.

Of the 58 cases treated, 55 were cases of relapsing benign tertian infections and 3 were malignant tertian infections.

In practically all these cases treatment was commenced durilJ~ an


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apyrexicinterval. Forty-eight cases showed a febrile reaction, either during or immediately after the intramuscular course. A rise of temperature to 100° F. or over was regarded las a febrile reaction. Thirty-seven cases showed such reaction during both courses, eleven cases showed the reaction during 9ne or other of the courses. ,This reaction: has already beeri pointea out by Major Guns~~, R.A.M.C., and it is :riot accompanied by any rigor.

A large' number of cases showing this reaction have been examined by daily blood films. In no ease has a positive blood film been found.' Two temperature charts are shown as, examples of this, one a mild and one a moderate reaction.

OAYofmS. 3 4 5 6. IS 16 I~ 18 .. 20

" :cp,;,); :z. : : : : :c "rJef: 101°

., : :

1000 : :

: : : t -1:1 j ~ ~ ~V: ~ ~ [l 99' :, : ~ :.. u.. .,

j ":" if-!" : If: : IV' : i'lt : V- i : Iv. : "i.J ! 98'

,

-

CHART I.-Type of mild reaction occurring during intramuscular course and persisting for . two days after:. temperature not above 1000 F. .

DAYofDtS. I 2 3 4 ,5 6 7 14 IS "

17 18 I. 20

__ Fo !c u~).~ .' :c ~rl.!.l I 02~ "

: : 1:1 : : ;, : : : : : :.. : : .. : : ..

101°

:J ': If V,' J.1 '10 J. 100°

~ ~ ~ . j ~ ~ V: I~ ;.i-" 9.'

f : : : : : : : : : : : 1 : : : : : : : : : : : : : : : : 9<1'

0>.

CHART n.-Type of moderate reaction occurring during intramuscular course and persisting . f?ur or five days. ,

It was thought that the reaction might possibly depend on the method of pr'eparation of the quinIne for' intramuscular injections. and a certain number of cases were therefore treated with ampoules of quinine prepared b¥ Parke; Davis & Co .. The results were precisely similar. .

, It has' also been. suggested that the fever is caused by the' destruction of malarial parasites elsewhere in the body than in the peripheral circulation and caused by toxins thus liberated. If this were so, a similar pyretic effeqt of quinine should be observed in eases treated by the double intensive oral course. In forty-nine cases treated by the double intensive oral course no such reaction has'been observed.

The naked-eye e~amination of the site cif the intramuscular injection post mortem preset;1ts a'striking appearance. Over a wide area depending

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32 Treatment of Malaria in Macedom:a

on the number of injections given, the muscular tissue is black or greenish-hlack in coFmf. HisJological e:(Caminationshows large area's of necrosis of the muscular bundles. The febrile reaction is also accompanied by a rise in the total leucocyte count varying in-several cases from twentyfour to twenty-seven thousand per cubic millimetre. From the. morbid anatomy of the muscle and the ri~e in the total leucocyte count we believe that the febrile reaction is a response to the local' destructive action of the quinine on the nthsc]1~ar substance. - '_

In the treatment of these cases some 9_60 injections have been given. Abscess has occurred in one case.

(B) Interrupted dosage (week-end, series). In a series of cases quinine was administered on two successive days of

each w~ek for a period of not less than eight weeks. Three groups were made accOl;ding to the amount of quinine given. ,

Group (i) received 20 grains of quinine on twO successi ve days, the patient . receiving on each day two 10-grain doses of quinine hydrochloride ; ,Group (ii) received 30 grains in three 10-grain doses on each day; Group (iii) received 45 grains in three 15-grain doses on each day.,

-Results of Treatment.

The twenty-grain series have not completed a sufficientlylong observation period to be included. In the thirty-grain series two cases relapsed . during treatment, one of these relapsed after the first two-days' treatment. Treatment in this case was carried on to the full eight weeks and 1).0

further relapse -took place up to fifty-riine da¥safter the last dose of qumme. The second case relapsed after six week-end· doses had been given and was not further. observed. In the forty-five-grainseries no case relapsed during treatment.

Total number who completed treatment and a sufficient 0 bserva tion period

Number who relapsed Numberwho did not relapse

30·grain series 57

li (19'3 per cent) 46 (8(n ') ..

.45-grain leries 2L

8 (38'1 per oent) 13 (61'9 ",)

In the tqirty-grain series, in the relapse cases the shortest interval was six (lays, the longest forty-five; in the forty'-five:grain seri~s the shortest interval was one day, the longest thirty-three.

- The following table gives the relapses in -each seven-day period after treatment ;-

Days: 1--:-7 ,'8-14 15-21 ,22-28 29-35 36-42 43-49 W-,-56

30 grains 1 4 2 3 1 45" 1 3 1- 2 1

In the thirty-grain series, of the cases which did not relapse the shortest observation period after treatment was t:w'enty-four d~vs, the longest fiftynine; in the forty-five-grain series the shortest was thirty-nine days, the longest forty-six.


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In both series all cases were benign tertian relapsing ,infectiom. It will berioted·that in the week-end series the observation periods are

sorriewhat shorter than in some of the oth~r series. An endeavour was made to retain all non:-relap'se cases in hospital upt,? the hundredth day, but 'even so the period of observation after treatment amounts only to forty-four days.

, Th.einterrupted administration of quinine is much better tolerated than the continuous administration.

SECTION III.-COMBINA'TION OF QUININE AND ARSENIC.

(A). QuinineandgaYyl.. . '(i) Intensive oral.course plus galyl. (ii) Intensive intramuscular course plus galyl.

I A considerable body of literature has be.en published on the newer arsenical preparations in, /the tre~tment of mall\lria .. · rrhe c<?ITsensus. of opinion.is favourabie in the acute pernicious and in the chronic relapsing cases. A certain amount of experience had already been gained in the. use ·of galyl in both types of, cases. The, mo'st hopeful metho'd appeared, to be the combination of intensive quinine eith.er by the oral or intramuscul:;Lr route combined with a full course of galyl. '

(i) Gml Quinine and Ga,lyl.~The 9.ouble intensive oral c~urse .of quinine is carried out as already described. In .addition, five intravenous injections of galy 1, dose forty centigrammes, are given at intervals of one' week. An initial' dose of twenty centigrammes is given followed by five full doses of forty centigrammes. The full course amounted to 480 grains of quinine hydrochloride and 2'2 grammes of galyl.

Owing to the shor,tage of galyl in the command the full COurse could not be carried 'out in every case. The number of cases is therefore divided into groups according to the total quantity of galyl administered.

. .

Results of Treatment. ' Total number who were treated with quinine and galyl and who

. completed. a sufficient observation period Number of relapses .. Number who did not relapse

39 22 (56'4 per cent) 17(43'6 " )

. Of the 39 cases, 26 received the full galyl course of 2;2 grammes, 12 received 1'4 grammes galyl, and 2 received 0'6 gramme galyl. " .

N ocaserelapsed during'the first six weeks of treatment, i.e., while the weekly doses of galyl were being given. '

The shortest interval in which a relapse took place after the last dose of galyl was ten days ; the longest interval was fifty-four days. . '

The following table shows the number of cases relapsi'ng in each sevenday period after the conclusion of treatment, i.e., calculated from the date {)f tbe'last dose of galyl.

Days: 1-7

3

8-14

8 15-21

9 22-27

4 28-35 .. 36-42 43-49

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34 -Treatment of Malaria in Macedonia

In the cases which. did not relapse the observation period varied, from forty-four to ninety-two days after treatment._

All cases treated in-this series were cases of benign tertian infections. -(ii) Intramuscular Quinine and Galyl.-This IIlethod is simi1;u to the

oraL quinine and galyl except that of the three twenty-grain' doses of quinine gIven daily, two are given by the intramuscular route and one bY.Il1outh:

Results of,Treatinent. Total number treated by. intramuscular quinine and galyl and

who completed a sufficient observation- period Number who relapsed Number who did not relapse

58 28 (48-2 per cent) :30 (51'7 " )

These are further subdivided into groups according to the total amount of galyl received: -

(i) Those who received 2'2 grammes galyl : Total number, 24-Number who relapsed .-. .. .. • ;. .'. Number who did not relapse ..

(ii) Those who received 1'8 grammes galyl: Total number, 7-.' Number who relapsed .. . . . . - ..

[ Number who did not relapse . . . . (iii) Thos.e who received 1 gramme galyI: Total number, 5-

Number who relapsed .. ~. • . . , Number who did not relapse ..

(iT) Those who received 0'6 gram!lle galyl ; Total number, 22-- Number who relapsed .. .. .. ..

Number who did not relapse

15 (62 per cent) '9 (38 ,

3 (42'8 " ) 4 (57'2 )

3-(60 2 (40

7 (31'8 15 (68'2

" "

One case relapsed during treatment. He relapsed six days after the conclusion of the first intramuscular course and one day after second dose of galyl. The shortest period in which a relapse took place after the conclusion of treatment was twelve days, the longest forty:-nine. -

The following table shows the total number of cases' r~lapsing in eaC!l seven-day period after the conclusion of treatment. The case which relapsed

, during the treatment is not shown on this table.

Days: 1-1 8~14

16 15_21

5 22-28

5 29-35 '1

36-42 50-56

In the non-relapse cases the shortest observation period' was thirty~ eight days,. the longest seventy-eight days.

All cases in this series were benign tertian infections . . In all cases the galyl was given intravenously in concentrated solution.

On the day previous to injection the patient .was kept in bed, given milk diet and a laxative. One case only was intolerant and - tr(jatment w!).s: abandoned ..

A comparison of the two methods is slightly in favour of the combined· intrari:lUscujar quinine and galyl, but the'difference is negligible~

In the intramuscular series some 1,000 injections were given, and inno case did, abscess result.

(B) Quinine and cacodylate of soda. (i) Ravaut's treatment'.


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Ravaut recommends that the patient should be given a_ daily hypo-dermic injection of 0'20 gramme cacodylate of soda for four days. During the next four days the patient (is given daily two fifteen-grain doses of quinine hydrochoride by mouth. The cacodylate and quinine are given alternately for thirty-two days irrespective of relapse. This meth'od has at least the merit of simplicity. The total a~bunt of quinine administered during the thirty-two days' treatment is 480 grains; and the' total amount of cacodylate of soda 3'2 grammes. . ,

Results, of T'reatment.

Forty-four cases completed treatment and were observed for a sufficiently. , Icing period. Four .cases relapsed during treatment. One relapsed o~ the

tenth and twenty-ninth days of treatment, and was not further observed. Another relapsed on'the second day of treatment, and again six days after conclusion of treatment. The third relapsed twice during· treatment on fourt'eenth and twenty-fourth days,' and again three days after the con'elusion of treatment, 'and the fourth relapsed on the fifth day. He completed treatment and did not relapse again wit~in a period of forty days.

Total number of cases who completed treatment and a sufficient observation period '43

Number who relapsed .. .. I 22 (51 per cent) :t'fumber who did not relapse 21 (49 " )

Of the relapse cases the shortest interval after the conclusion of b:eat-pJent was three days, the longest fifty-three days. . .

The following 'table gives the total.number of relapses in each seven-day, period after treatment.' ,-

- The first' case which relapsed during t.reatment is not shown on this table.

Days: 1-1 8-14 15"':'21 22-28 29-35 36-42 43-49 50-56 51-63 64,-10

4 ,2 5 6 I 3 1

Of the non-relapse caseg; the shortest observation period was fifty-two days, the longest lQS days. All were cases of benign tertian infections. The treatment was well borne. _

: (ii) Intensive oral course and cacodylate of soda. The intensive o'ral course was carried out as already described. In addition', on three days of each week the patient was injected hypo

dermicaJ:ly with three grains o! cacodylate of. soda. The cacodylate injec-tions were given for five weeks. . I

Total quantity of quihine given, 480 graihs; total cacodylate of soda. given, 45 grains. '

Results of Tr·eatment. Total number who completed treatment and observation Number who relapsed •• Number who did not relapse.

25 8 (32 per cent)

.17 (68 " )

Of the eight Cases which relapsed, two did so during treatment-I.e.; within the first five weeks; S1X r.!'llar>sed after treatment. The shortest


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'relapse Interval calculated from the ,last dose of quininewa"s thirteen 'days,' .the longest forty-four days.

Of the cases which did not relapse" the shortest observation period :was seventy-five days, the longest was 108 days. All were cases of benign tertian infection; two cases,gave a history of having had only one atta?k of malaria previous to treatment., " -

SEOTION IY.-PROVOOATIVE DRUGS.

(1) Hypodermic injections of strychnine sulphate. , (2) Hypo'dermic injections of adrenalin chloride. ' (3) Liqujd extract of ergot by mouth. In all cases blood films were examined on the day before the drug

was given and on the two subsequent days. (1) Strychnine sulphate. Eight cases, were given hypodermic injections of this drug; dose 15 grain

at intervals of six to nine days. Seven of the cases had five injections and one three injections.

(2) Adrenalin chloride. ]'our cases were given .hypodermicaUy ten~minim doses of adr~nalin

chloride solution (1 in 1,000) at nine day intervals, in all five injections each. Four cases were giv~n twenty-mi~im doses, in all five injections each. ' -, '(3) Liq uid extract of ergot. ' , .' .

Nine cases were given thirty~minim doses by mouth I1t intervals of nine -days-five doses in all to each patient. .

All cases tested were chronic relapsing benign t'ertian inf~Ctions.While these drugs were being given-, quinine was withheld save to control a relapse. . '

Ainongst the whole series (mly niri.e positive relapses. t()ok place, and these at varying intervals a'fter the dose. No patient had two positive relapses. -, From the small numbe~ of relapses which occurred from the irregu: larity of the time intervening b~~ween a dose and the relapse,and from the fact that no patient had two rylapses, it is evident that none of these

, drugs have any effect. . . The table on next page' shows the total number of cases tre!ttedby all

methods, the number of relapses, the number of non-relapses and the / . percentage ·of each. The' figures in this table include relapses 'lmder

treatment. . , As these results stand it would appear that the two .methods most effective in preventing relapses are the thirty grains on two successive days in each week, I],ud the intensjve oral cour~e. Itw-as noted, however, in the an!J.1ysis of the figures of the cases treated 'by intramuscular quinine (Lndgalyl that as the quantity of g'alyl diminished" tl;le quinine dosage :telllaining constant, .the percentage of non-relapse cases, increased. Again,


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intbe ,intramuscular series it was not unusual to find in the cases treated in the later part of the ye~ra dozen or more copsecutive admissions which/ did not show. any relapse. '

Nuniber Non. Percentage Percen~age Treatment of '. Relapses non- ,Remarks

cases relapses ralaps~s r.lapses

------------ -----------C17 Ross treatment .. 44 26 18 59'0: 41-0 -Oralcourse,45 gra.ins -. 18 8 10 44'4 55'6 -Oral course, 20 , ; , .. 16 10- .6 62'5, 37'5 -Intensive oral course .. 49 15 34 30-6 ,69'4 -

. Intensiv'e intramuscular 58 23 .35 39'61 60'4 -course - --

38'11 Week-end, 45 grains .. 21 8 13 61'9 - .

Week:end,30 "

.. 58 13 45 22-4: 77'6 Two relapsed during 'treatment, 'one after first week.

j . -end, one after six , week-ends Intensive oral and ga\y 1 .. 39 22 17 56'4

1 43'6 -

Intensive intramuscular 58 28 30 48-2 51:8 One relapsed dur-and'galyl 'ing treatment

Ravaut .. .. .. 44 24 '. 20 54'5 45'5 Four relapsed dur-ing treatment;

I one of them was ,not further ob.

L -' served Oral course and cacody- 25

I

8 17 32'() 68'0 Tw'orelapsed dur-late ' . . ing treatment

Control series .. .. 44 30 14 68'1 31'8 -Inj~Qtion series .. .. 25 .. .. .. .. -Miscellaneous ... .. 1 .. .. .. i .. -·Total ' .. .. . . 500 .. .. . . .. -

- i - I

\ It is of interest to discuss solely the' intramuscular series of cases. The dosage of quinine and the method of its administration remained. constant throughcmt the wholeperi9d under review. There was no reason to s'!lPpose that there had been any variation in the ,pot~ncy of the quinine it~e1f, all the quinine had been supplied by the same 'makers throughout. The type of case did not vary m~terially .• Of the fifty~eight cases 'tre~ted, fifty-five were cases of relapsin:g benign tertian infection, and three were cases of malignant tertian infec:tion .. The three malignant cases occuri'ed in the later group of cases, but) the numbers are too small to rriakeany appreciable difference in thi3 resul;ts. The period of observation after treatment remained the same~ i The' possibility that the disappointing results could be attributed- to more numerous reinfections can be dismissed as all cases were protected by:nets j and the area in which the hospital was situated was kn.own to be practically free from anopheline mosq uitoes.

The only other explanation which suggested itself was that the results. depended on the season of the,-year at which treatment was carried out.

In view of the possibili'ty of a seasonal variation, a second analysis oUhe· figures was made. The first batch of patients was admitte'Citowards the end

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, -Treatment of Malaria in Macedonia,

of April; these ~emained till middle of July, -when a fresh batch of patients was admitted to the wards. The cases were ther-efore divided into two groups, the first group including-those who were admitted and completed. treatment before July 1, and the second group those admitted and treated after July l.

The following ~able shows the results in the, two groups of cases. ,'"

GROUP J.,"':Admitted and troated before July 1 GROUP n.-Admitted and treated after July 1

-, I Num'ber R No';. 'I Per· Number Non· Per- ,Per,

Per-. , centage Re· oentage Type of treatment I of lap~~s re· centage tl non- of re· cerrtage lapses 'cases lapses lapses ra.laps~A

non· cases I elapses! relapses relapses , , ------------- -------~i7 -;0:--treat-I-~ --;- 18 59'0 41'0 None ..

ment, I Oral quinine and 25 18 7 720 28'0 14 4 10. 28'5 71'5

galyl - . Intramuscular qui- 21 15 6 71'4 28'6 37 13 24 35'1 64'9

nine and galyl \ , - .-

Ravaut's treatment 22 15 7 ' 68'1 31'9 22 - 8 14 00'3 63'7 , Oral quinine, 45 gr. 18 8 10 44'4 55'5 1 Numbers too smail to analyse in

one month two series. Of total: 16 admitted Oral quinine, 20 gr: 16 10 6 62'5 37'5 ' previous to July 1, 18 after -

one month Double intensive 24 17 7 70'8 - 29'2 34 6 28 17'6

I 8~H

intramuscular Double intensive 0 .. .. . . .. 49 15 34 30'6 69-4

oral quinine -Double oral quinine 0 .. .. .. .. ' 25 8, 17 32'0 68'0

and cacodylate of -soda

Week-end, 30 gr. 0 - 58 13 45 22'4 _ 77-6 ., .. .. . . .. Week-end, 45 gr .. , .0 .. .. .. .. 21 8 13 . 38:1 61'9

Control ., ., 17 13 4 76'4 23'6 27 17 I 10 62'9 37'1 .

Five methods of treatment we~e employed thronghout the whole period. The continuous oraJ courses are disregarded, as the total nmubers for any one period are too small to allow of accurate' comparison. The· four methods remaining are the oral quinine alld galyl, the intramuscular quinine and galyl, Ravaut's treatment, and the intensive intramuscular course. By all these methods the (percentage of non-relapse cases is very much higher amongst the second group of cases. In the first gronpthe highest percentage of non-relapse cases is 31'9 per cent; in-the second group the highest percentage of non-relapse cases is 82'4 per cent. In the" control series the second group of cases also shows a higher percentage of non-relapse cases. Regarding the figures as a whole we find that in the first group of cases. the percentage of non-relapse cases is iow,_ and that in the second group of cases the percentage of non-relapses is high. no matter what method is used.

Lieutenant:.Colonel Wenyon, C;M;G., R.A.M.C., has kindly supplied


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.A. Greig A nderson 39

a curve sho-wing the c-alculated number of benign tertian and malignant tertian cases in hospitals throughout 1917 and 1918 (see Part I). -

It will be lloted that in the 1918 benign tertian curve the maximum is -attained in the Juiddleof June ,and from that point onwards there is a rapid ~ecline in the number of benign tertiariadmissions to hospital. r.J'he date at which tlie curve attains its maximum corresponds closely with the 'date fixed upon for the division of the cases into two groups. The latter date was arri ved at from an analysis of the figures and only after-wards compared with the curve. --

Provided that the number of troops in the area remains co~stant we may deduce that, apart altogether from the question'of treatment! there is a natural tendency for th.e benign tertian infections to become quiescent d,?ring the later part of -the year. 'rh~ results of treatment are thus intimately connected with the natural rise and fall of the benign tertian curV!3. Cases treated at a period of the year when" the curve is rising, no matter what is the treatment, will show a high percentage of relapses; cases treated when the curve is falling will show a high percentage otnonrelapses .. An examination of the previous history of a number of cases of benign tertian malaria led to the same conclusion. Many of these cases r:elapse frequently during the hot season; during the cold season, the relapses become much less numerous or even disappear, to commence again in the early part of theyear long before reinfection is'probable.

This seasonal variation is at least <.me of the factors in explaining the differences obtained in the results of treatment at home and the results obtained in Salonika:

It should be strongly _ erilphasized therefore that the results of treatment can be compared only when the same types of case are treated in the same place and at the same time of the year.

If we compare the results' of the different methods of treatment under Group I, excluding the continuous oralcourse, we f1nd that there is very

. little to choose between the different methods of treatment. All give relapses varying from fifty-nine to seventy-two pe!' cent. The lowest' relap~ percentage is given by the C17 treatment._ Again between the treated cases and the control cases there is not a great difference. It has to be borne in -mind, h0wever, that the treated cases showed only one relapse after treatment, while many of the control cases. relapsed two, three or more times within the same length of time. '

If we compare the results of treatment under Group Il, we find again that there is nota great deal of difference between the results of the -xariouFf methods. The highest percentage of non-relapses is given by the double intensive intramuscular course-, and the next highefit is the thirtygrain week-end series. OIl- the other hand, the treated cases in this 'group show- a very much higher percentage, of non-relapses than does the controlsenes. - In the control series the non-relapses amount only ~o 36 per cent, while the treated cases show from 63 to 82 per cent of non-relapse cases.


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40 Treatment of Malaria in Macedonia

From a consideration. of all the methods of treatment which have been used, it is re.con1mended that. these cases should be treated by a short intensive oral quinine course a.nd the -treatment carried on for not .less than eight weeks, by thirty gra~ns on -two successive days weekly.

This refers only to o:p.e type of case, viz., the ch:ronic relapsing benign t.ertian infections without acute symptoms. .

To the medical' officers in the special malaria ,vards,Captain T. Winning, Captain G. ~. Johnstone, <)aptain r.: D. Ramsay and Captain W. B. Whamond, I am greatly indebted. for the skill and attention to detail with which' they have carried out the various methods ,of treatment, and the care with which they have kept the records.

, To Colonel Phear, A.M.S., to 'Lieutenant-Colonel, Falconer, D.S.O., RA.M.C., and Lieutenant-Colonel Wenyon, C.M.G., R.A.M.C., I am. indebted for much valuable assistance anq advice.

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25 part n...(b) quinine and cacodylate of soda. (i) ravaut'streatment. (ii) intensive oral...

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