The ˦tiology of the Tsutsugamushi disease and tropical typhus in the Federated Malay States. Part II

57 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE ANDHYGIENE.

Vol. XXIII. No. 1. June, 1929.

THE

ZETIOLOGY

OF

THE

TSUTSUGAMUSHI

DISEASE

AND T R O P I C A L T Y P H U S IN T H E F E D E R A T E D M A L A Y S T A T E S . PART

II.*

BY

WILLIAM FLETCHER, J. E. LESSLAR, AND RAYMOND LEWTHWAITE, Institute for Medical Research, Kuala Lumpur, F . M . S .

T R O P I C A L TYPHUS. Thirty years ago, the late Dr. NATHAN BRILL (1898) drew attention to the presence of the sporadic, typhus-like disease in New York which is now called endemic typhus. It occurs in the towns throughout the eastern states of America, it is present in nearly all the seaports from New York southwards, and has attained the widest distribution in Alabama, Georgia, and Florida. During the last ten years, cases of the same or of a like nature have been reported from all parts of the world, including several British Dominions, Colonies and Protectorates. In the Federated Malay States, a mild, typhus-like fever occurs from one end of the country to the other. At first, it was considered to be identical with the similar fevers reported from other countries, and it was called tropical typhus because these fevers occur in tropical places or in more temperate climates, only during the hotter months. DEFINITION. The tropical typhus of Malaya is an acute, specific fever, which begins rather suddenly with headache and vomiting, and terminates by crisis or rapid lysis on about the fourteenth day. It is rarely fatal, except in the aged or infirm, and the mortality is less than 5 per cent. It is clinically indistinguishable from mild typhus fever, and is characterized by a typhus-like rash which appears on e Part I, concerning the tsutsugamushi disease, was published in these TItANSACTIONS, Vol. xxii, p. 161 ; August, 1928.

58

2"ETIOLOGY OF TSUTSUGA~4USIIIDISEASE AND TROPICAL TYPHUS.

about the fifth day of the disease ; this is almost always present in European patients, but is rarely seen on the dark skins of Asiatics. Nervous symptoms, such as sleeplessness and delirium, are prominent features, and bronchitis is present in almost every case. In spite of its clinical similarity to epidemic typhus (typhus exanthematicus), tropical typhus differs widely from that disease in its epidemiology and ~etiology. It is not a highly infectious disease which prevails in widespread epidemics, nor is it associated with destitution and overcrowding ; it does not spread direct from man to man, nor do the sick pass on the disease to other occupants of a house or hospital ; the patients are not infested by lice, and there is no evidence that lice are the vectors of the virus. A detailed description of tropical typhus in the Malay States has been published in the series, Bulletins from the Institute for Medical Research, Kuala Lumpur, No. 2 of 1925. T H E T W O KINDS OF TROPICAL TYPHUS CONTRASTED.

We have shown already (FLETCHER and LESSLAR, 1926) that there are two kinds o~ tropical typhus in the Malay States. Though they are much alike in their course and their symptoms, they are really two distinct diseases, and are distinguished from one another by (1) the Well-Felix reaction; (2) Wilson's agglutinabilis reaction ; and (3) their epidemiology. (1) THE WEIL-FELIX REACTION. In the first form, the Well-Felix reaction is positive with the ordinary indologenic strains of Bacillus proteus X. 19, such as No. 67 and Warsaw of the National Collection of Type Cultures. This form we have called the Warsaw or W. Form, because the strain Warsaw is agglutinated. In the second form, the Well-Felix reaction is not positive with the indologenic strains, but the blood agglutinates in high dilutions a strain of B. proteus known as " Kingsbury," which does not produce indol and is not agglutinated either in epidemic typhus or in tropical typhus of the W. form. This second form we have named the Kingsbury or K. form. A description of the Kingsbury strain of B. proteus is given in the series Bulletins from the Institute for Medical Research, Kuala Lumpur, No. 1. of 1928. It was given to us, as a strain of B. proteus X. 19, by Dr. A. N. KINGSBURY,in 1924. He had brought it to the Malay States from the Bland Sutton Institute in the previous year, and he informed us that it had been obtained from the National Collection of Type Cultures in 1921. (2) WILSON'S AGGLUTINABILIS REACTION.

At the end of 1926, Professor W. J. WILSON,of Belfast, kindly gave us a culture of an organism, isolated from the fmces of a typhus patient, which he has found to be agglutinated by the blood of persons suffering from typhus exanthematieus (WILSON, 1927). He has named it Bacillus agglutinabilis U2. This

WILLIAM FLETCHER~ J. E. LESSLAR AND RAYMOND LEWTHWAITE.

69

bacillus is a gram-negative, coliform organism which grows well on ordinary media without spreading in a proteus-like film. It is non-motile, it does not produce indol in peptone water, it forms acid in glucose and mannite with a small bubble of gas in the latter after four days, it forms acid in saccharose in ten days, it does not ferment lactose or dulcite. B. agglutinabilis is agglutinated in tropical typhus of the W. form in the same way that it is agglutinated in typhus exanthematicus, but agglutination does not occur in dilutions quite so high as with the National Collection strain, Warsaw, of B. proteus X. 19, which we use for routine tests. In four cases where the maximum agglutination of X. 19, Warsaw, was 1 in 1,000, 1 in 3,000, 1 in 7,000, and 1 in 8,000, respectively, the corresponding agglutinations of WlLSON'S organism were 1 in 500, 1 in 1,000, 1 in 1,000, and 1 in 4,000. This reaction with B. agglutinabilis affords an additional distinction between the two forms of tropical typhus ; though the organism is agglutinated by the blood of W. form patients in high dilutions, it is not agglutinated by the blood of people with tropical typhus of the K. form. Parallel tests with the Kingsbury strain of B. proteus and with B. agglutinabilis were carried out in twenty-six K.-form cases with the following results : B. proteus, Kingsbury, was agglutinated by the sera of the patients in dilutions of 1 in 20,000 in five cases, 1 in 3,000 in nine, 1 in 1,000 in eight, 1 in 500 in four. B. agglutinabilis, on the contrary, was not agglutinated by any of the sera in dilutions higher than 1 in 60. Control tests were made with B. agglutinabilis and the blood of 478 persons who were not suffering from tropical typhus, with the result that agglutination did not occur in a dilution above 1 in 60, except in one instance, where the titre reached 1 in 120 ; this was a case of the tsutsugamushi disease, which is closely allied to typhus. Most of these controls were hospital patients whose blood had been sent to the laboratory for Wassermann or agglutination tests. B. agglutinabilis therefore acts in the same way as the ordinary indologenic strains of B. proteus X. 19 ; that is to say, the agglutination reaction is positive in epidemic typhus and in tropical typhus of the W. form, but it is negative in the K. form.

(3) EPIDEMIOLOGY. The two kinds of tropical typhus are divided as sharply by their distribution and epidemiology as by their serological reactions. The W. form is essentially a disease of the house and town ; the K. form, on the contrary, is a disease of the open country.

Epidemiology of the Urban or W. Form (? Endemic Typhus, Brill's Disease). We have investigated forty-one W.-form cases ; twenty-one of them occurred in towns ; the other twenty were in villages and estates. It is a disease of clerks and other indoor workers, and in this it differs much from the K. form which attacks those who work in the open field. Fifteen, or 36 per cent., of the forty-one W.-form cases were clerks and office workers; nine, or 22 per cent., were

60

7ETIOLOGY

OF

TSUTSUGAMUSHI DISEASE AND

TROPICAL

TYPHUS.

s h o p k e e p e r s . T h e r e w e r e o n l y e i g h t o u t d o o r l a b o u r e r s ; six o f t h e s e w e r e estate coolies a n d t w o w e r e c o w h e r d s . T h e social s t a t u s o f t h e p a t i e n t s in t h e W . f o r m was h i g h e r t h a n in t h e K . f o r m , b e c a u s e so m a n y o f t h e m w e r e t o w n d w e l l e r s . T h e fifteen office w o r k e r s c o m p r i s e d a E u r o p e a n g o v e r n m e n t officer, t h e m a n a g e r o f a m e r c a n t i l e f i r m , six g o v e r n m e n t clerks, t h e w i v e s o f t w o clerks, a draughtsman, a law-court interpreter, a stationmaster, an overseer, and a r a i l w a y s i g n a l l e r . T h e n u m b e r o f s h o p k e e p e r s in t h e W . f o r m is r e m a r k a b l e - one was a m o n e y l e n d e r , o n e a j e w e l l e r , o n e a b a r b e r , a n d n o less t h a n six w e r e Malabar Mahomedans employed in food-shops. T h e endemic typhus or Brill's disease of the United States, which is clinically identical with tropical typhus, has a distribution similar to that of the W. form. Endemic typhus was recently investigated b y MAxcY (1926) in the states of Alabama and Georgia. He reported that though there were a few scattered cases in rural areas, the great majority occurred in the large cities and small towns, particularly in those parts of them where the retail stores and markets were situated. I n Montgomery City he found that 62 per cent. of the patients were engaged in trade (clerks, managers, salesmen, dealers, and the like). I n Savannah City 44 per cent. were in trade, and in both towns some 34 per cent. were engaged in handling food-stuffs or groceries. MAXCy concluded that " those engaged in trade and especially those employed in food-depots, groceries, food-stores and restaurants, are exposed to a distinctly increased risk of infection." He added that the disease did not select the poor or uncleanly, but affected all classes. The majority of the cases were in persons cleanly in their houses and in their personal habits. T h e typhus-like fever of Australia described by HONE (1927) is probably identical. Details of a number of cases are given in the Medical and Scientific Archives of the Adelaide Hospital, 1923-1926. T h e occupation of thirteen of the patients is mentioned ; in eight of them it had to do with food-stuffs, and HONE (1923) remarks that " in the majority of shop assistants who have contracted the disease, the shops they worked in were related to food." T h e Adelaide fever appeared to be strictly sporadic when it was first studied, but extended observation showed that in a few instances several cases occurred in the same bakery or warehouse with intervals of months or even years between them. T h e same applies to the endemic typhus of America, and MAXCY states that " although cases have rarely been observed in the same family in such close sequence as to suggest communication of the disease, several instances have been noted in which cases have recurred on the same premises separated by intervals of six months or more." On these grounds, MAXCY considers it probable that a reservoir of the disease may exist, other than in man, a rodent reservoir with accidental transmission to man through the bite of some parasite--blood-sucking insect, or arachnid. " Obviously," he writes, " the rodents upon which suspicion immediately falls are rats and mice, and the parasite intermediaries which are first suspected are fleas, mites, or possibly ticks." T h e W . f o r m o f t r o p i c a l t y p h u s has n o t b e e n s t u d i e d s u f f i c i e n t l y l o n g i n M a l a y a to d e t e r m i n e w h e t h e r t h e i n f e c t i o n c l i n g s to c e r t a i n s h o p s o r offices as it does i n A d e l a i d e a n d t h e U n i t e d S t a t e s ; t w o o f t h e M a l a y a n cases c a m e f r o m t h e s a m e office w i t h an i n t e r v a l o f six m o n t h s b e t w e e n t h e d a t e s w h e n t h e y w e r e t a k e n ill, b u t n o a p p a r e n t c o n n e c t i o n c o u l d b e t r a c e d b e t w e e n a n y o f t h e r e m a i n i n g cases. The main points of resemblance between the W. form of tropical typhus on the one hand and the endemic typhus of America and Australia on the other are, in s h o r t , as f o l l o w s : F i r s t l y , t h e c l i n i c a l d e s c r i p t i o n s o f t h e d i s e a s e in t h e t h r e e c o u n t r i e s a r e a l m o s t i d e n t i c a l ; s e c o n d l y , t o w n - d w e l l e r s i n e a c h case,

W I L L I A M FLETCHER,

j. n . LESSLAR AND RAYMOND LEWTHXYAITE.

~Jl

and especially those engaged in trade, are most often attacked; thirdly, those who handle food and grain are peculiarly prone to infection; fourthly, the Weil-Felix reaction with the ordinary indologenic strains of X. 19 is positive in all three. It is probably correct to assume on these grounds, that the W. form of Malayan tropical typhus and the endemic typhus, or Brill's disease, of America and Australia are one and the same disease. Additional animal experiments are required to settle this point ; guineapigs have been successfully inoculated with the blood of persons suffering from endemic typhus in America, and the virus has been carried on by passage ; in Australia and the Malay States, on the other hand, the disease has not been conveyed to animals and, in the Malay States at least, there is little evidence to incriminate any particular insect or acarine as the vector.

Epidemiology of the Rural or K. Form (Scrub-typhus, ? Megaw's Disease). The distribution of the K. form of tropical typhus is very different from that of the W. form. The K. form is essentially a disease of the open country and not of the town. This is clearly shown by the following figures which relate to 113 cases investigated in the Federated Malay States. Sixty, or 53 per cent., were labourers working on plantations ; twenty-eight, or 25 per cent., were cowherds or bullock-cart drivers ; six were soldiers encamped on old mining land ; six were labonrers on high-roads or railways. No indoor workers were affected, and with ten exceptions all the patients were members of the coolie class. The ten exceptions comprised the following :--A planter who was superintending the clearing of a neglected estate where undergrowth and weeds had sprung up, an engineer employed in draining a piece of waste swampy land, a tin-miner working on a dredge in a swamp, a boy-scout who had been in camp, and the six soldiers mentioned above who were also in camp. These ten patients were all Europeans except the boy-scout. The K. form has a patchy distribution, and its virus, like the virus of the tsutsugamushi disease, has its home in circumscribed areas of untilled open country, particularly in land which after being cleared of jungle has been allowed to grow up in weeds and scrub. Examples of such places are : old worked-out mining land covered with rank grass where cattle graze, Chinese market-gardens abandoned because the soil has been exhausted, neglected rubber plantations where coarse grass and undergrowth have been allowed to grow up. Because cases of the K. form have their origin in such places, we propose that this kind of tropical typhus should be called scrub-typhus. The epidemiology of this rural, or scrub-typhus, is very similar to that of the sporadic typhus-like disease of India which MEGAW attributes to the bites of ticks. Since he first drew attention to it, in 1921, cases of tick-typhus, as it is called, have been reported from all parts of India, from Malakand on the NorthWest Frontier to Trichinopoly in the south. In a series of cases recently reported by MEOAW and RAO (1.928) there was definite evidence of tick bites in eight, but

62

3ETIOLOGY OF TSUTSUGAMUSHI DISEASE AND TROPICAL T Y P H U S .

no evidence of this kind has been found in the Malayan cases. It seems probable that in India, as in the Malay States, it is not a question of one disease but of several, and the illustrated description of a case recently published by GI-IosE (1928) of Allahabad leaves little doubt that the tsutsugamushi disease is among them. A

RECENT

OUTBREAK

OF SCRUB-TYPHUS.

A recent outbreak of scrub-typhus in the Federated Malay States is of interest, not only because of the large number of persons attacked and the very definite circumscription of the area involved, but also because it throws further light on the epidemiology of the disease. It occurred on the oil-palm estate which we have already mentioned in connection with the tsutsugamushi disease, and its epidemiology shows how near akin that disease and scrub-typhus are to one another. The outbreak was discovered when we inspected Oil-Palm Estate because cases of the tsutsugamushi disease had occurred among the members of the European staff. There is no hospital on the estate, and the sick are sent to one seven miles away, at Sungei Buloh, which serves the needs of a group of six estates. Sixty-one cases of scrub-typhus were admitted to this hospital during the twelve months June, 1926, to June, 1927. Our first visit was made in August, 1926, with the kind permission of Dr. G. C. MCGREGOR who is the medical officer in charge. In view of the occurrence of the tsutsugamushi disease on Oil-Palm Estate, Dr. MCGREGORand his staff had been keeping a sharp look-out for cases among the coolies employed there. They had found none ; but we were told at the time of our visit that a number of coolies had been admitted with a curious fever which lasted for about two weeks and ceased somewhat abruptly. The outstanding features of the disease were fever, headache, cough, and occasionally delirium. All the cases had come from Oil-Palm Estate, none had been seen among the patients from the other five estates which are served by the Sungei Buloh Hospital. The disease was first noticed by Dr. MCGREGOR in June, 1926, when five cases were admitted; in July there were nine more, and in August there were eight. At the time of our visit, there were ten patients in the hospital, and the dresser-in-charge showed us the temperature charts of those who had been discharged. We concluded, as the result of our examination, that the disease was probably tropical typhus, and we collected samples of blood for agglutination tests. These tests confirmed the provisional diagnosis, and showed that the cases belonged to the K. form, that is to say they were scrubtyphus. Thirty-six of these cases, four of them fatal, were admitted to the hospital during the seven months, June to December, 1926, and all of them came from Oil-Palm Estate ; the other five estates in the group remained free. The pressure of other work prevented our visiting the hospital more than a few times in 1926 ; in the following year we were more happily situated, and, early in February, 1927, Dr. MCGREGORasked for our assistance as the disease had not abated. Subsequently, the hospital was visited by one or other ot

WILLIAM FLETCHER, J. E. LESSLAR AND RAYMOND LEWTHWAITE.

g~

us five or six times a month up to the end of June, 1927, which is as far as this report carries the story of the outbreak. Twenty-five Tamils were admitted to hospital from Oil-Pahn Estate during this period; two in January, three in February, six in March, four in April, three in May, and seven in June. This account deals more particularly with these twenty-five cases which were under our personal observation, and with the epidemiological features of the disease during the six months in which they occurred. The blood of all the patients was examined by agglutination tests both with the indologenic strain of B. proteus X. 19, Warsaw, and with the non-indologenic strain, Kingsbury. These examinations were repeated when possible on several occasions in each case. The serum of the twenty-five patients did not agglutinate the indologenic strain, Warsaw, in a single instance, but nearly all of them agglutinated the non-indologenic strain, Kingsbury, in high dilutions. Four sera agglutinated it in dilutions higher than 1 in 20,000, one at 1 in 15,000, four between 1 in 5,000 and 1 in 10,000, eight between 1 in 2,000 and 1 in 5,000, and two between 1 in 1,000 and 1 in 2,000. Three patients absconded before the titre of agglutination had risen above 1 in 500, another was not examined until fortythree days after the beginning of her illness when the agglutination titre was only 1 in 240, the two remaining patients of the twenty-five died during the first ten days of their illness before agglutinins had time to develop. One of the fatal cases was an old woman with broncho-pneumonia, the other was a weakly girl eleven years of age who was very ill with diarrhaea, bronchitis and delirium. The disease is very rarely fatal except in those who are already debilitated, and though patients sometimes appear so ill as to be at the point of death, yet they almost always recover. Oil-Palm Estate, where these cases occurred, is a large area of more than 3,000 acres. Felling of the jungle was begun in 1920, and, by 1926, when tropical typhus appeared, some 1,800 acres had been cleared and planted with oil-palms. The estate is split up into three divisions for purposes of administration. The whole of Division I, nearly 1,000 acres, was cleared by 1923, and is planted with palms ; 800 acres of Division II, which contains 1,100 acres, were cleared in 1924, and have since been planted ; clearing was not begun on Division I I I until 1926, and there has been no tropical typhus among the coolies employed there. The regular labour force consists of Tamils ; some recruited from India, and others from among those already settled in the Malay States. Each division has its own coolie-lines, those on one division are about two miles from those on the next. The boundary between one division and the next is purely one of convenience, there is no dividing fence. The coolies on Division I, where most of the cases occurred, live in six long buildings or lines. A record was kept of the cases which occurred in each building, but it afforded no evidence of any grouping of the cases or of any connection of one with another. The children who did not go out to work were not attacked, and this, together with the even

64

] R T I O L O G Y OF TSUTSUGAMUSHI DISEASE AND TROPICAL T Y P H U S .

distribution of the cases among the different buildings, showed that the disease was more probably acquired in the field than in the lines where the coolies lived. T h e majority of those admitted to hospital with scrub-typhus were fresh recruits to the labour-force. No fewer than twenty-two of the twenty-five patients admitted during the first half of 1927 had been working on the estate for less than twelve months ; this figure is out of all proportion to the total number of recruits employed. An attack of scrub-typhus appears to confer an immunity which explains the freedom of the older residents. No second attacks occurred during the outbreak on Oil-Palm Estate, nor have we met with cases elsewhere. T h e coolies who had been recruited locally proved as susceptible as those recruited in India ; from this it may be inferred that they had not previously been exposed to infection. This shows that, although cases have been recorded from one end of the Malay States to the other, the disease is not uniformly disseminated over the whole country. Four of the patients had been recruited from a district on the west coast of the Malay Peninsula, twenty or thirty miles from Oil-Palm Estate, where some of the oldest rubber plantations in the country are situated. One of these men had lived there all his life, and the others had worked there for upwards of fifteen years ; yet all four became infected with scrub-typhus soon after their arrival on Oil-Palm Estate. Sir MALCOLM WATSON, who practised in the coast district for nearly thirty years, tells us that he never saw a case of tropical typhus there. Even on Oil-Palm Estate itself the disease was not evenly distributed among the three divisions, but was almost entirely restricted to Division I. T h e conditions on Division I and Division II were similar in most respects, about 1,000 acres of the former and 800 of the latter were planted with palms. Work on Division I I I was not begun until 1926, and, as we have said already, no cases of scrubtyphus occurred there. T h e labour forces of the first two divisions were approximately equal, and on 12th March, 1927, there were 337 coolies on Division I and 362 on Division II. T he incidence of the disease, however, was far from equal, for the twenty-five patients who were admitted to hospital between January and June came almost entirely from Division I ; there were only two cases from Division II. We attribute the uneven distribution of the disease to differences in the cultivation of the two divisions. Division I was not kept clear of weeds during the bad times through which the country passed a few years ago, and in many places coarse grass and secondary jungle or scrub grew up in profusion. Division II, on the contrary, was comparatively free from weeds. On many estates in Malaya, what is known as a " cover-crop " is planted between the young rubber trees or oil-palms. This is usually some creeping plant which enriches the soil and at the same time saves labour by spreading over the ground and preventing the growth of weeds. Division II was planted with such a cover-crop, and this kept it almost entirely clear of undergrowth. There were, however, a few places

WILLIAM FLETCHER, J. E. LESSLAR AND RAYMOND LEWTHWAITE.

65

in Division II where weeds had sprung up, and it is significant that one of the two patients from this Division was a coolie specially employed in clearing them away. There is abundant evidence in the Federated Malay States that the virus of scrub-typhus (the K. form of tropical typhus) is connected in some way with undergrowth and possibly with the rats which live in it, and we are of opinion that the prevalence of the disease on Division I, with its almost complete absence from Division II, was due to the great profusion of weeds on the first and their suppression by the cover-crop on the second. This outbreak of tropical typhus provides additional evidence that the K. form or scrub-typhus, and the W. form or endemic typhus, are two distinct diseases. The outbreak consisted of one sort of typhus only, and that was scrub-typhus ; there was not a single case in which the blood agglutinated the ordinary indologenic strains of B. proteus X. 19 (Warsaw and No. 67). Another interesting feature of the outbreak was its association with the tsutsugamushi disease. Between June and July, in the year 1926, three of the four Europeans employed on the estate were attacked by the tsutsugamushi disease, and, at about the same time, the first cases of scrub-typhus occurred in the Tamil labour force. All, or almost all, the coolies who suffered from scrubtyphus were attacked within a few weeks of their arrival on the estate, but the Europeans escaped altogether, and it is possible that the tsutsugamushi disease protects against scrub-typhus. The resemblance of the two diseases to each other is so close in many respects as to suggest that they may have a similar ~etiology , and serological evidence tends to show that they are due to kindred viruses. THE RELATIONSHIP OF SCRUB-TYPHUS TO THE TSUTSUGAMUSHI DISEASE OF THE EAST INDIES." THE C L I N I C A L COURSE.

There is, in some respects, a fairly close clinical resemblance between scrubtyphus on the one hand and the tsutsugamushi disease of Sumatra and the Malay States on the other. The prominence and rapid development of nervous symptoms, the severe headache, the stuperose and irritable condition by day, the restlessness and delirium by night, the loss of knee-jerks and the deafness in the late stages, the tendency to bed-sores : all these are common to both diseases. The rash, which appears on about the fifth day and resembles the rash of typhus, is the same. In both diseases the spleen and lymphatic glands are often enlarged. There is some bronchitis in most cases of scrub-typhus, and MAASLAND(1926) states that bronchitis is the most frequent complication in the tsutsugamushi disease of Sumatra. There are, however, several features peculiar to each disease which serve to distinguish the one from the other. In the first place, the course of the fever is not the same ; scrub-typhus resembles the epidemic typhus of

6~

3ETIOLOGY

OF

TSUTSUGAMUSHI

DISEASE

AND

TROPICAL

TYPHUS.

Europe more closely in this respect, the onset is usually sudden, the fever reaches its highest point on the eighth or ninth day, and the temperature which is usually more remittent than in epidemic typhus comes down suddenly to normal at the end of the second week either by crisis or quick lysis, the pulse slows down at the same time. I n the tsutsugamushi disease on the contrary the onset is less sudden and the fever is more prolonged ; as MAASLAND (1926) states the fever " is strikingly similar to the fever of typhus abdominalis,and can show all its variations. T h e temperature nearly always comes down b y lysis, which distinguishes it from typhus fever in which a more acute onset and a more critical ending are the r u l e . " Chart No. 1 illustrates the course of s c r u b - t y p h u s in a

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WILLIAM FLETCHER, J. E. LESSLAR AND RAYMOND LEWTHWAITE.

67

the fever came down gradually, and convalescence was prolonged. MAASLAND (1926) states that in the Sumatran tsutsugamushi convalescence is even slower than in typhoid fever, and that " an important characteristic of the disease is the failure of consciousness to become normal until the patient has been convalescent for several days."

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C h a r t N o . 2. T h e T s u t s u g a m u s h i Disease in a E u r o p e a n .

THE PRIMARY LESION. The second and most important distinguishing feature is the presence of the primary ulcer and bubo in the tsutsugamushi disease and their absence in scrub-typhus. In the Malay States 113 cases of scrub-typhus have been investigated without the discovery of a single primary ulcer even in Europeans. AGGLUTINATION REACTIONS.

The agglutination reaction with the non-indologenic strain of B. proteus, known as the Kingsbury strain, also serves to separate scrub-typhus from the tsutsugamushi disease, because the titre of agglutination is far higher in the

68

3ETIOLOGY OF TSUTSUGAMUSHI DISEASE AND TROPICAL TYPHUS.

former than in the latter ; at the same time this test shows the close relationship of the two fevers, because tsutsugamushi is the only disease, except scrub-typhus, in which the blood has been found to agglutinate the Kingsbury strain in dilutions higher than 1 in 200. We have made over 1,000 control tests with this strain and have found that the blood of normal persons, and of those suffering from diseases other than scrub-typhus or tsutsugamushi, usually agglutinates this strain in a dilution of 1 in 10. Agglutination rarely occurs in dilutions higher than 1 in 60, and we have taken a titre of 1 in 200 as the limit of the normal. In scrub-typhus, the agglutinins for the Kingsbury strain usually reach their maximum in the early part of the fourth week. In sixty cases of this fever, where agglutinations were carried out at this period of the disease, the maximum titres were as follows : in seven it was between 1 in 1,000 and 1 in 2,000, in twenty-two it was between 1 in 2,000 and 1 in 5,000, in twenty-one it was between 1 in 5,000 and 1 in 20,000, in ten the titre was above 1 in 20,000. Agglutination did not occur at anything approaching these figures in the seven cases of the tsutsugamushi disease (five Europeans and two Tamils) which we have seen in Kuata Lumpur. In one which was fatal on the fifteenth day a titre of 1 in 80 was reached, in two there was no agglutination in the first week but the titre rose to 1 in 120 during convalescence, in another case the titre was 1 in 60 on the eleventh and the seventeenth days of illness, in the three remaining cases a maximum titre of 1 in 240 was reached at the end of the third week. These figures are in sharp contrast with those of scrub-typhus, where the titre was above 1 in 5,000 in half the cases. EPIDEMIOLOGY.

The course of the fever, the absence of the primary lesions, and the high titre of agglutination with the Kingsbury strain of B. proteus all serve to distinguish scrub-typhus from the tsutsugamushi disease of the East Indies, but the conditions under which they arise are so much alike that it appears probable that they have a similar setiology. In both, the virus of the disease is associated with waste scrub-covered land ; particularly with land which has been cleared of jungle for mining or agricultural purposes, and afterwards has been allowed to grow up in long grass and bushes. T h e earlier cases of scrub-typhus which came to our notice were connected with abandoned mining land on which coarse grass and bushes had grown up and where cattle grazed. We thought at first that the cause was connected in some way with cattl~ because so many bullock-cart drivers and cow-herds became infected, but the prevalence of the disease in places where there are no cattle shows that this is not so. Cow-herds and bullock-cart drivers probably suffer because they pasture their cattle in the waste places where the infection lurks. More recently we have seen numbers of cases among estate employees, and when these were investigated they were found to occur on estates which were not clean-weeded. The European planter, for instance, whose temperature chart

WILLIAM FLETCHER~ J. E. LESSLAR AND RAYMOND LEWTHWAITE.

69

(Chart No. 1) is given here, had been superintending the clearing of a 300-acre patch on a rubber estate where undergrowth had sprung up during a period of depression in the rubber market. The tsutsugamushi disease arises under similar conditions; KEUKENSCHRIJVER'S cases (1925) occurred in connection with the clearing of an estate which had been allowed to grow up in weeds during a slump in the price of rubber. SCHOFrNER'S (1909, 1915, 1921) cases of tsutsugamushi in Sumatra became infected while they were engaged in clearing ground which had been lying fallow for several years after tobacco-planting (WALCH, 1922). The epidemiology of the two diseases is, in short, so very much alike that one is driven to conclude that they have a similar origin ; and we consider it highly probable that scrub-typhus, like the tsutsugamushi disease, is carried by trombicul~e. An analogy exists in the case of epidemic typhus and relapsing fever ; they are both associated with dirt and privation, and are both carried by lice ; the diseases with which we are dealing are both associated with waste weed-covered land, and are both, we suggest, carried by mites. SUMMARY.

Tropical typhus bears a close clinical resemblance to mild typhus fever, but it does not spread from man to "man, nor does it give rise to epidemics. Lice are not the vectors of the virus. There are two kinds of tropical typhus, the W. form and the K. form. In the W. form, the serum agglutinates the ordinary strains of B. proteus X. 19, and Wilson's B. agglutinabilis, but it does not agglutinate the non-indologenic strain, Kingsbury. In the K. form the serum agglutinates the non-indologenic strain, Kingsbury, but it does not agglutinate the ordinary strains of B. proteus X. 19, or B. agglutinabilis. The W. form of tropical typhus is a disease of the house and the town ; the majority of those affected are indoor workers, such as clerks and shopkeepers, particularly those who deal with foodstuffs. MAXCYhas found that the " endemic typhus " or Brill's disease of the United States, which is clinically identical with tropical typhus, has a similar distribution. The like is true of the typhus-like fever described by HONE in Australia which is probably the same disease as the W. form of tropical typhus. The distribution of the K. form is very different, it is essentially a disease of the open country and affects outdoor workers. It has a patchy distribution and outbreaks occur particularly in areas which, after being cleared of jungle, are allowed to grow up in weeds and scrub. For this reason, we propose the name scrub-typhus for the K. form of tropical typhus. Some of the cases of typhus-like diseases described in India are probably the same as scrub-typhus. An account is given of an outbreak of sixty-one cases of scrub-typhus on an oil-palm estate where cases of the tsutsugamushi disease had occurred among

70

.XETIOLOGY OF TSUTSUGAMUSHI DISEASE AND TROPICAL T Y P H U S .

the European staff• This outbreak illustrates the limited distribution of the disease. Five adjacent estates, served by the same hospital, were unaffected, and the outbreak was confined almost entirely to one of the three Divisions of the oil-palm estate. This Division differed from the other two in being overrun with weeds and undergrowth, with which scrub-typhus is always associated. An attack appears to confer immunity. T h e cases occurred among the newly recruited labourers, those who had been on the estate for a long time escaped infection. Coolies recruited in the Federated Malay States were as susceptible as those from India, from which it appears that the Indian population of Malaya has not been generally exposed to infection. T h e outbreak consisted entirely of the K. form of tropical typhus (scrub-typhus) ; there were no cases of the W. f o r m (? endemic typhus). Attention is drawn to the relationship of scrub-typhus and the tsutsugamushi disease b y the occurrence of the latter on the same estate. T h e tsutsugamushi disease of the East Indies and scrub-typhus both occur in circumscribed areas which are covered with undergrowth, and their symptoms are m u c h alike T h e r e are, however, the following points of distinction : (a) T h e fever of tsutsugamushi does not end abruptly at the end of the second week as it does in scrub-typhus, nor is convalescence so rapid. (b) A primary sore and bubo are present in tsutsugamushi, but absent in scrub-typhus. (c) T h e titre of agglutination with B. proteus, Kingsbury, is low in the tsutsugamushi disease but very high in scrub-typhus. In some cases of the tsutsugamushi disease, the serum agglutinates B. proteus, Kingsbury, in higher dilutions than that of normal persons, but not to titres nearly so high as in scrub-typhus. It is suggested that the two diseases have a similar ~etiology and that scrubtyphus, like the tsutsugamushi disease, is carried by trombicula~.

REFERENCES.

BRILL,E . N . (1898). New York Med.Jl. lxvii, 48 and 77. FLETCHER, W., and LESSLAR,J.E. (1925). Bulletins from the Inst. for Med. Res., Kuala Lumpur, F.M.S., No. 2 of 1928. FLETCHER, W., and LESSLAR,J. E. (1926). Bulletins from the Inst for IVied. Res., Kuala Lumpur, F.M.S., No. 1 of 1926. GHOSE, G. (1928)• Indian Med. Gaz., lxiii, 634. KEUKENSCHRIJVER,N. C. R. (t925). Siantar Dokter Fonds. Kohler & Co., Medan. HONE, F. S. (1923). Supplement to Annual Report of Adelaide Hospital. • (1927). Med.Jl. of Australia, 213. MAASLAND,J . H . (1926). " De pseudotyphus." Amsterdam, Universiteits-Boekhandel. MAXCY, K. F. (1926). U.S. Pub. Health Repts., p. 2967 ; 24 Dec. MEGAW,J. W. D. (1921). Indian iVied. Gaz., lvi., 361. MEGAW, J. W. D , and RAO, S. S. (1928). Indian A/fed. Gaz., lxiii, 306. SC~I/3FFNER,W. (1909). Ztschr. Klin. Med., lxxxi, (1 & 2). (1915). PhilippineJl. ofNc. xix, 345. • (1921). Trans. of the 4th Cong. of the Far East Assoc. of Trop. Med., Java. WALCH, E. (1922). Kitasato Archives, v, 63. WILSON, W.J. (1927). ffl. ofHyg., xxvi, 213.