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I. Epidemic haemorrhagic fever
(The previous number of these Transactions, Vol. 48, No. 1, w a s published on 2nd February, 1954.)
ORDINARY
MEETING
of the ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, held at M a n s o n H o u s e , 26, Portland
Place, London, W.I., on Thursday, 21st January, 1954, at 7.30 p.m.
The President, F. NORMAN WHITE, C.I.E., M.D., D.P.H., in the Chair
PAPERS
I.
EPIDEMIC HAEMORRHAGIC FEVER BY
Lieut-Colonel K. P. BROWN, M.Bm., M.B., M.R.C.P.*
Royal Army Medical Corps
Haemorrhagic fever is an acute infection which only of recent years has been known to the western world of medicine. It seems to have been known for very many years to the Russians in Siberia and in Manchuria and was well recognized by the physicians of China in bygone ages. There are various other fevers of a haemorrhagic nature which occur in Russia, which differ from haemorrhagic fever and from each other. They are named for the most part from the regions in which they occur. This disease has been endemic for many years along the Lower Amur River and it was first described in South Eastern Siberia between the Amur River and the Pacific Ocean. The Russians have been studying it for the best part of 20 years on their side of the Amur, and they regarded it as a form of kidney ailment which they called, in 1936, acute haemorrhagic nephrosonephritis and, in 1950, endemic haemorrhagic nephrosonephritis. Between 1936 and 1942 outbreaks occurred year by year in the Imperial Japanese Army in Manchuria; it was called " ryukosei syukketsu netsu," or febris epidemica haemorrhagica. The most heavily affected areas of Manchuria are east of 124°E., other parts being thought to be free. Cases also occurred along the Korean border and in Korea itself. In the Japanese Army the outbreaks remained limited to certain units and the numbers affected varied from 1 per cent. to 10 per cent. in different outbreaks. In this the Russian experience was similar. EPIDEMIOLOGY
The disease is sporadic throughout the year with peaks of incidence in the spring (May and June) and the fall (November). It is mainly rural in its incidence, being endemic in * I have to thank the Director-General, Army Medical Services, for permission to present this paper. A
106
EPIDEMIC HAEMORRHAGIC FEVER
scrubby, marshy and swampy ground, and in Manchuria it was noted that it was most prevalent among those dealing with hay. In the Japanese Army the cavalry suffered most heavily. In the United Nations troops in Korea the outbreaks have come as isolated events, no large n u m b e r of men being affected in any one area. T h e endemic area has been north of Seoul running north-east along the battle line, and fewer cases have come from the southern end of the line than from farther north. T h e west central sector has been the most heavily hit area. T h u s the Commonwealth Division has been relatively less affected than some other formations, and in the heavy outbreak of the fall of 1951 we had only some 50 cases all told as against the Americans' 1,100 cases; this difference was out of proportion to the numbers of troops involved. Generally speaking it was not common to find many men from the same unit going down at the same time for, as a rule, the cases do not come in large numbers from any one locality. As ANDREW (1953) has pointed out, in the Commonwealth Division the cases came from 15 regiments and corps, and the maximum from any single unit did not exceed four during any m o n t h in the period under consideration, that is from June 1951 to January 1952. T h e r e was no evidence of cross infection and no case has been reported of any attendant on patients catching the disease himself. AETIOLOGY
Both Russians and Japanese thought that the agent was a virus. Russian workers inoculated human volunteers intranasally,intravenously, intramuscularly and intragastrically with human blood, urine and naso-pharyngeal washings from cases of epidemic haemorrhagic fever in the febrileperiod. Both blood and urine were effectivein reproducing the disease when given by injectionbut not otherwise. The Japanese reported that they had reproduced the disease in monkeys by inoculating them with an emulsion of mites obtained from field rodents. The Russian and Japanese work has not been confirmed, and at the present time the aetiological agent in acute haemorrhagic fever is stillunknown. TRANSMISSION
T h e mode of transmission of the disease is not known but it is plain that the vector must be some arthropod which is widely distributed in the endemic area, is active throughout the year with its maximum activity in the spring and autumn months, is only mobile to a limited extent and does not leave any evidence of its having bitten a human being. Of the likely parasites the most suitable is some form of mite. T h e Japanese considered that Laeleps ]ettmari is the vector, but those who are now working on the subject consider that a trombiculid mite is a more likely vector on various grounds, namely that these mites show a seasonal variation in incidence which follows that of the fever and they are abundant in the areas affected, outnumbering the other parasites such as laelaptid mites by as much as 10 : 1 ; their distribution in an area is spotty, that is to say that one part may be well supplied while another only a short distance away may be pretty well free. T h e y hatch out and spend the greater part of the life cycle on or in the ground, in scrub or in bush. T h e larvae alone are parasitic. T h e y are small enough to be overlooked and they do not leave any trail behind them in the way of an eschar or of itching. T h e laelaptid mites are found mostly on the host or in its nest or burrows rather than on the surface of the ground. T h u s while these mites may be responsible for cases occurring when men are engaged in digging or are living
K. P. B R O W N
107
in the ground which is infested with the hosts, it is not thought that they are responsible for a great proportion of the total cases. Other possible parasites such as fleas and ticks are thought to be unlikely to be culprits because of their size and the fact that it is obvious enough when they about and biting, and no large number of either has been reported from any of the affected areas. It is not known for certain whether Apodemus agrarius, thought by the Japanese to be the reservoir of the intermediate host, really is so or not. Of the various types of indigenous rodents regarded as possible hosts Apodemus is the most abundant in all areas and although the r61e is probably not confined to Apodemus, the others are unlikely to play a big part. So far there is no certainty whether the rodent is the host of the vector only or is a reservoir of infection. CLINICAL
MANIFESTATIONS
Epidemic haemorrhagic fever is an acute infectious disease which is characterized by fever, constitutional symptoms, renal damage, a bleeding tendency and increased capillary permeability. Its course can be divided broadly, as it was by POW~LL (1953), into Invasive, Toxic and Convalescent phases.
The Invasive Phase The invasive, or febrile, phase opens with possibly some vague prodromal symptoms but more often abruptly with severe chills and headache. The latter is frontal and there is retro-orbital pain made worse by ocular movement. This headache is often extremely severe. The temperature rises rapidly, commonly to 102-103 °, maybe to 105 °, and it persists irregularly for from 3 to 6 days. The patient feels very ill, has complete loss of appetite with restlessness and generalized pains and weakness. Occasionally in the early days, dizziness, even syncope on standing, is a feature. There is often great thirst and this is a point of some importance, as it may lead to the patient's taking too much fluid. Nausea and vomiting may start at this time and it is plain that too much fluid aggravates the vomiting and seems also to have some influence on the lumbar backache and high bellyache which are often prominent symptoms in the febrile stage. Meningeal irritation has been described as occurring, not infrequently. These are the symptoms, mainly nonspecific, with which this illness opens. Physical examination is somewhat more helpful than anamnesis in the early days and particularly so are the remarkably constant flush on face and neck with conjunctival and palatal injection. The latter is sometimes accompanied by sore throat. From the 3rd day petechiae may be seen first on the soft palate and under the tongue, later on the palpebral conjunctivae, the folds of the neck and axillae, the trunk, the buttocks and at sites of trauma. A generalized small lymphatic enlargement is seen often, but splenomegaly and hepatomegaly are seldom encountered. Chemosis and periorbital oedema often appear towards the end of the febrile stage and the face may appear grossly puffy, but oedema elsewhere is not seen. Vomiting may go on for several days and is often entirely unresponsive to treatment. No doubt it is aggravated by travelling as we found in many of our patients who had come back by air, train and ambulance from Korea to Japan. Too much fluid makes i t worse
108
EPIDEMIC
H A E M O R R H A G I C FEVER
and it seemed that small quantities of fluid at short intervals were the best measure. The vomiting weakened the patients considerably and the effort of frequent retching played a large part in the production of subconjunctival haemorrhages which are less commonly seen now than in the early days, probably because of methods of evacuation which have cut down trauma to the minimum. In the late febrile phase the first evidence of renal damage appears, in the occurrence of albuminuria. This may come on very abruptly; for instance, urine examined in the morning may b e quite normal whereas in the evening there may be 4 + of albumin. The urine m a y boil solid. At this stage the specific gravity of the urine is fairly high and there are casts and red Cells in the deposit, but thereafter the specific gravity declines.
The Toxic Phase The invasive febrile stage is succeeded by the toxic stage and it is then that the worst of the manifestations occur. The temperature falls, as a rule, by rapid lysis and far from improving with the drop in temperature the patient's condition deteriorates. The headache and the generalized pains become less but the backache and often the pain in the belly get worse. In'most patients there is some hypotension with the lysis, but this only reaches shock levels in about 25 per cent. of patients. A blood pressure of 90/60 is not uncommon, but as a rule this requires no special measures for its correction. In the 25 per cent. who go into shock the pressure may fall to 60/50, and this condition may last from a matter of hours to 2 days and in such cases there is marked restlessness, confusion, perhaps delirium, and blurring of vision. There is a reduction in circulating plasma volume as indicated by a rising haematocrit reading. Oedema of the conjunctivae often increases. At this stage haemorrhages occur, petechiae increase and bleeding from nose, lungs, stomach and kidneys takes place. As a rule the haemorrhage is not a very serious affair, but occasionally a large alimentary hzemorrhage gives rise to anxiety. In two of our patients there were severe epistaxes and one of them died in spite of replacement of blood. Gross haematuria is common and microscopic haematuria is almost the rule. Needle punctures and even handling the patient may produce large ecchymoses. Severe shock has been noted to occur in association with prolonged high fever, with delay in getting the patient to strict rest and with excessive fluid intake in the first few days. The majority of the patients start to get better as the shock regresses; haemorrhages become less marked and oedema subsides as the fluid lying in the tissues, particularly in the retroperitoneal tissues, is reabsorbed into the circulation. The Oliguric Phase After the shock phase the next hazard that the patient has to face is oliguria. This is always present to some extent and most patients pass straight from the febrile phase to oliguria. As has been said, in the early days the specific gravity of the urine is high but by the time oliguria sets in this has fallen to as low as 1010. The stage o f oliguria persists for from 36 hours to as long as several days, and may proceed to anuria. There is no close correlation between the degree of hypotension and the severity of oliguria, for uraemia of marked degree may occur even when there has been no notable shock. During oliguria there is a rise in blood pressure to hypertensive levels. Blood urea rises and the patient begins to exhibit the signs and symptoms of uraemia. There is evidence of a hypervolaemia (that is to say, an increased circulating blood volume) high blood pressure,
K. P. BROWN
109
venous distension and sometimes pulmonary oedema. Convulsions not uncommonly occur and there is usually irritability. The hypervolaemia is said by those who have investigated the problem to be not a true but a relative hypervolaemia. The circulating volume is not raised, and the apparent contradiction is explained by the supposition, based on histological evidence, that small vessel congestion in many organs reduces the flow through those organs and so the effective vascular space available. Be that as it may, the manifestations are relieved by venesection. In this stage haemorrhage may recur if it had previously stopped or get worse if it had not already stopped. With the end of the oliguria the toxic gives place to the convalescent stage. Diuresis begins about the 10th day. The patient starts to pass large quantities of urine of low specific gravity (1002). Diuresis happens in almost every case in some degree and in many cases it is often extremely difficult to keep up with, for the amount of urine is commonly 3,000-4,000 c.c. daily and as much as 20-30 g. of NaCI may be lost by the kidneys in 24 hours. Electrolyte balance may be seriously upset and intravenous therapy has been necessary to maintain balance. Blood urea falls but often only slowly and it may persist at a level of: 100 mg. per cent. for many days into diuresis. Albumin disappears from the urine early in this stage and formed elements are no longer seen in the deposit. : The stage of inefficient renal concentrating power lasts up to 3 months not uncommonly, and it has taken as long as 6 months to return to a specific gravity of 1025 after a 12-hour test. The patient regains weight; appetite and energy begin to return to normal, in most cases pretty rapidly once the recovery stage has begun. However, there are some who continue to suffer from anorexia and to tire very easily for several weeks. Troublesome backache is frequent, usually coming on after the patient has been up for some hours. It is perhaps an indication that the man has been mobilized too soon. There do not appear to be any sequelae from this disease once the illness has run its course, but it is tempting to wonder what the future holds in store for those people whose kidneys have been so badly damaged in the acute illness. In this connection it is interesting that LOWE (1952) has noted a lowering of renal reserve years after crush injury. PHYSIOLOGICAL CONSIDERATIONS
The fundamental disturbance seems to be one of the arterioles and capillaries: There is dilatation, as is shown by the facial flush which is more than a response to fever, and there is increased permeability and fragility of capillaries. That the latter is present is obvious from the occurrence of spontaneous petechiae and of ecchymoses after minor traumata and from the frequently positive Hess test. Abnormal permeability is demonstrated by the leakage of fluid from the circulating blood into the tissues. The biggest collection of such fluid is in the retroperitoneal tissues where it appears as a gelatinous mass at autopsy Increased permeability is presumably also responsible for the loss of the large quantities of albumin from the kidneys. The generalized arteriolar dilatation and reduced circulating blood volume are the factors causing the shock, and it is understandable that in such a case the renal circulation should be seriously impaired. But what of those cases in :whiCh there is no appreciable shock ? It is clear that there must be a selective diminution in renal blood flow in all cases and probably arteriolar dilatation persists for a time after the: ~apillaries have begun to return to normal permeability, for the period of oliguria is the perio.d Of relative hypervolaemia, when hypertension appears and the symptoms of uraem~a devel6p.
110
EPIDEMIC HAEMORRHAGIC FEVER
Why the diuresis occurs is not known but from that time on, glomerular function appears to run ahead of tubular function. It had been noted early in the study of this disease that in fatal cases there was necrosis and haemorrhage into the pituitary body, and it seemed possible that the prolonged and profuse diuresis might be in part due to pituitary damage. It was therefore thought worth while to give some of the patients pitressin but there was no significant response; this experience was shared by others. CLINICAL
PATHOLOGICAL
FEATURES
These will be discussed more fully by Dr. KNUDSEN but there are some points which I should mention. The occurrence of albuminuria has already been described. The blood shows certain characteristic changes of which the most striking is the marked teucocytosis which starts at about the 3rd day and peaks at the end of the 1st week. Commonly between 10,000 and 20,000 it may reach 100,000 per c.mm. The increase is mainly in the granular series. In the oliguric phase the blood urea level rises considerably and the highest figure reached was 510' mg. per cent. in one patient on the 8th day of illness. In this case diuresis started at the 13th day and the urea was down to 410 at the 15th day. DIAGNOSIS
Albuminuria appears t o be necessary for a diagnosis of acute haemorrhagic fever, together with evidence of capillary damage and renal affection. In the early days, as has been Said, there are no specific symptoms nor signs, and in mild cases it can often only be suspected; obviously any febrile disease occurring in those parts must be brought into consideration. The appearance of the patient is frequently of help--the flushed face, intense headache and general misery. The regimental medical officers achieved a remarkably high level of correct diagnoses in the first days of the illness with consequent benefit to the patients for that meant that they got to proper conditions reasonably early. After about the 3rd day of illness the characteristic features appear and the diagnosis becomes relatively easy. PROGNOSIS
In general the mortality is about 5 per cent. Factors affecting the severity of the course appear to be the stage at which strict rest is instituted and restriction of fluid in the early days. A poor prognosis is associated with high and persisting leucocytosis, prolonged high fever persisting into the hypotensive stage, obstinate hypotension and long anuria. Death has most commonly come in the hypotensive stage but it may occur from haemorrhage, from pulmonary oedema when the tissue fluid is reabsorbed into the circulation, from uraemia and from electrolyte imbalance in the diuretic stage. TREATMENT
There is no specific treatment for this disease. Antibiotics have no influence on the course. At one time it was thought that benefit was to be obtained from the use of convalescent serum in the first 2 days but later work did not confirm this and the treatment is not now used. Probably the greatest single advance in the treatment was the establishment of a special
I<. e. BROWN
111
hospital near Seoul to which all these patients are taken by helicopter as soon as the diagnosis is suspected, so that they have a smooth journey and are in the best possible conditions in a short time. Absolute rest is essential from the earliest stage possible. In the febrile phase sedation is called for. Fluid is given, by mouth, sufficient to maintain balance but it is preferable to err on the side of too little rather than too much. Sometimes, if there is severe and persistent vomiting, it may be necessary to give fluid by intravenous drip but if this is so it must be given with the utmost caution. The mild cases of hypotension can be dealt with satisfactorily by raising the bed-end and by the use of elastic bandages on the lower limbs. In severe cases salt-p0or albumin and norepinephrine given by drip have been of great value. One of the most distressing symptoms is hiccups and it can be most obstinate. We had some success by using intramuscular ether 4-5 c.c., and also intramuscular 8 per cent. magnesium sulphate solution, but often there was no response to any measures. There can be no hard and fast rules in treatment and each case has to be treated on its merits. In the early days the main thing is to make the patient as comfortable as possible and in the convalescent stage he must not be allowed to become ambulant too quickly. He should be kept abed until the kidney is obviously beginning to recover its power of concentration, the white cell count is normal, the sedimentation rate has settled to normal and the blood chemistry is back to normal limits. Other points in the estimation of recovery are the appetite and the degree of lassitude. S U M M A R Y A survey has been made of epidemic haemorrhagic fever, a disease of the Far East, the causative agent of which is so far unknown and in which the vector is thought to be a trombiculid mite. The disease is marked by fever, by dilatation and undue permeability of the small vessels, by haemorrhagic manifestations and by renal damage. It is a self-limiting illness attended by a mortality of about 5 per cent., for which there is no specific treatment but in which it is possible to influence the course and severity of the illness greatly by early and careful supportive treatment in conditions of absolute rest. It would have been impossible to make this survey on the basis of my own experience only and I have to acknowledge the help given me by my late colleague Dr. R. ANDREWon whose account of our cases I have drawn freely, and particularly the generous hospitality of the physicians of the Haemorrhagic Fever Hospital at Seoul whose guest I was lucky to be and who gave me permission to make use of the information which they gave me so freely.
REFERENCES ANDREW,R. (1953) Brit. med. ft., 1, 1063. B~mBEaO,G. J., KATZ, S. & KRAtrS,H. (1953) U.S. Forces med. ft., 4, 207. KATZ, S., LF_~DHAM,C. L. & K~SLEa, W. H. (1952) ft. Amer. med. Ass., 150j 1363. LowE, K. G. (1952) Lancet, 1, 1086. McNtNcI{, J. H., Lm~DHAM,C. L. et al. (1953) Ann. intern. Med. 38, 53. MAY~R, C. F. (1952) Milit. Surg., 110, 276. POW~LL,G. M. (1953)ft. Amer. med. Ass., 151, 1261. TECHNICALBOLL~rlN (Med.) (1953) U.S. Array, 240. TRAUB, R., HE3RTIG,M., LAWRENCE,W. & HAimlS, T. Entomological observations during studies epidemic haemorrhagic fever in Korea, 1952. (unpublished).
on
ORDINARY
MEETING
of the ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, held at M a n s o n H o u s e , 26, Portland
Place, London, W.I., on Thursday, 21st January, 1954, at 7.30 p.m.
The President, F. NORMAN WHITE, C.I.E., M.D., D.P.H., in the Chair
PAPERS
I.
EPIDEMIC HAEMORRHAGIC FEVER BY
Lieut-Colonel K. P. BROWN, M.Bm., M.B., M.R.C.P.*
Royal Army Medical Corps
Haemorrhagic fever is an acute infection which only of recent years has been known to the western world of medicine. It seems to have been known for very many years to the Russians in Siberia and in Manchuria and was well recognized by the physicians of China in bygone ages. There are various other fevers of a haemorrhagic nature which occur in Russia, which differ from haemorrhagic fever and from each other. They are named for the most part from the regions in which they occur. This disease has been endemic for many years along the Lower Amur River and it was first described in South Eastern Siberia between the Amur River and the Pacific Ocean. The Russians have been studying it for the best part of 20 years on their side of the Amur, and they regarded it as a form of kidney ailment which they called, in 1936, acute haemorrhagic nephrosonephritis and, in 1950, endemic haemorrhagic nephrosonephritis. Between 1936 and 1942 outbreaks occurred year by year in the Imperial Japanese Army in Manchuria; it was called " ryukosei syukketsu netsu," or febris epidemica haemorrhagica. The most heavily affected areas of Manchuria are east of 124°E., other parts being thought to be free. Cases also occurred along the Korean border and in Korea itself. In the Japanese Army the outbreaks remained limited to certain units and the numbers affected varied from 1 per cent. to 10 per cent. in different outbreaks. In this the Russian experience was similar. EPIDEMIOLOGY
The disease is sporadic throughout the year with peaks of incidence in the spring (May and June) and the fall (November). It is mainly rural in its incidence, being endemic in * I have to thank the Director-General, Army Medical Services, for permission to present this paper. A
106
EPIDEMIC HAEMORRHAGIC FEVER
scrubby, marshy and swampy ground, and in Manchuria it was noted that it was most prevalent among those dealing with hay. In the Japanese Army the cavalry suffered most heavily. In the United Nations troops in Korea the outbreaks have come as isolated events, no large n u m b e r of men being affected in any one area. T h e endemic area has been north of Seoul running north-east along the battle line, and fewer cases have come from the southern end of the line than from farther north. T h e west central sector has been the most heavily hit area. T h u s the Commonwealth Division has been relatively less affected than some other formations, and in the heavy outbreak of the fall of 1951 we had only some 50 cases all told as against the Americans' 1,100 cases; this difference was out of proportion to the numbers of troops involved. Generally speaking it was not common to find many men from the same unit going down at the same time for, as a rule, the cases do not come in large numbers from any one locality. As ANDREW (1953) has pointed out, in the Commonwealth Division the cases came from 15 regiments and corps, and the maximum from any single unit did not exceed four during any m o n t h in the period under consideration, that is from June 1951 to January 1952. T h e r e was no evidence of cross infection and no case has been reported of any attendant on patients catching the disease himself. AETIOLOGY
Both Russians and Japanese thought that the agent was a virus. Russian workers inoculated human volunteers intranasally,intravenously, intramuscularly and intragastrically with human blood, urine and naso-pharyngeal washings from cases of epidemic haemorrhagic fever in the febrileperiod. Both blood and urine were effectivein reproducing the disease when given by injectionbut not otherwise. The Japanese reported that they had reproduced the disease in monkeys by inoculating them with an emulsion of mites obtained from field rodents. The Russian and Japanese work has not been confirmed, and at the present time the aetiological agent in acute haemorrhagic fever is stillunknown. TRANSMISSION
T h e mode of transmission of the disease is not known but it is plain that the vector must be some arthropod which is widely distributed in the endemic area, is active throughout the year with its maximum activity in the spring and autumn months, is only mobile to a limited extent and does not leave any evidence of its having bitten a human being. Of the likely parasites the most suitable is some form of mite. T h e Japanese considered that Laeleps ]ettmari is the vector, but those who are now working on the subject consider that a trombiculid mite is a more likely vector on various grounds, namely that these mites show a seasonal variation in incidence which follows that of the fever and they are abundant in the areas affected, outnumbering the other parasites such as laelaptid mites by as much as 10 : 1 ; their distribution in an area is spotty, that is to say that one part may be well supplied while another only a short distance away may be pretty well free. T h e y hatch out and spend the greater part of the life cycle on or in the ground, in scrub or in bush. T h e larvae alone are parasitic. T h e y are small enough to be overlooked and they do not leave any trail behind them in the way of an eschar or of itching. T h e laelaptid mites are found mostly on the host or in its nest or burrows rather than on the surface of the ground. T h u s while these mites may be responsible for cases occurring when men are engaged in digging or are living
K. P. B R O W N
107
in the ground which is infested with the hosts, it is not thought that they are responsible for a great proportion of the total cases. Other possible parasites such as fleas and ticks are thought to be unlikely to be culprits because of their size and the fact that it is obvious enough when they about and biting, and no large number of either has been reported from any of the affected areas. It is not known for certain whether Apodemus agrarius, thought by the Japanese to be the reservoir of the intermediate host, really is so or not. Of the various types of indigenous rodents regarded as possible hosts Apodemus is the most abundant in all areas and although the r61e is probably not confined to Apodemus, the others are unlikely to play a big part. So far there is no certainty whether the rodent is the host of the vector only or is a reservoir of infection. CLINICAL
MANIFESTATIONS
Epidemic haemorrhagic fever is an acute infectious disease which is characterized by fever, constitutional symptoms, renal damage, a bleeding tendency and increased capillary permeability. Its course can be divided broadly, as it was by POW~LL (1953), into Invasive, Toxic and Convalescent phases.
The Invasive Phase The invasive, or febrile, phase opens with possibly some vague prodromal symptoms but more often abruptly with severe chills and headache. The latter is frontal and there is retro-orbital pain made worse by ocular movement. This headache is often extremely severe. The temperature rises rapidly, commonly to 102-103 °, maybe to 105 °, and it persists irregularly for from 3 to 6 days. The patient feels very ill, has complete loss of appetite with restlessness and generalized pains and weakness. Occasionally in the early days, dizziness, even syncope on standing, is a feature. There is often great thirst and this is a point of some importance, as it may lead to the patient's taking too much fluid. Nausea and vomiting may start at this time and it is plain that too much fluid aggravates the vomiting and seems also to have some influence on the lumbar backache and high bellyache which are often prominent symptoms in the febrile stage. Meningeal irritation has been described as occurring, not infrequently. These are the symptoms, mainly nonspecific, with which this illness opens. Physical examination is somewhat more helpful than anamnesis in the early days and particularly so are the remarkably constant flush on face and neck with conjunctival and palatal injection. The latter is sometimes accompanied by sore throat. From the 3rd day petechiae may be seen first on the soft palate and under the tongue, later on the palpebral conjunctivae, the folds of the neck and axillae, the trunk, the buttocks and at sites of trauma. A generalized small lymphatic enlargement is seen often, but splenomegaly and hepatomegaly are seldom encountered. Chemosis and periorbital oedema often appear towards the end of the febrile stage and the face may appear grossly puffy, but oedema elsewhere is not seen. Vomiting may go on for several days and is often entirely unresponsive to treatment. No doubt it is aggravated by travelling as we found in many of our patients who had come back by air, train and ambulance from Korea to Japan. Too much fluid makes i t worse
108
EPIDEMIC
H A E M O R R H A G I C FEVER
and it seemed that small quantities of fluid at short intervals were the best measure. The vomiting weakened the patients considerably and the effort of frequent retching played a large part in the production of subconjunctival haemorrhages which are less commonly seen now than in the early days, probably because of methods of evacuation which have cut down trauma to the minimum. In the late febrile phase the first evidence of renal damage appears, in the occurrence of albuminuria. This may come on very abruptly; for instance, urine examined in the morning may b e quite normal whereas in the evening there may be 4 + of albumin. The urine m a y boil solid. At this stage the specific gravity of the urine is fairly high and there are casts and red Cells in the deposit, but thereafter the specific gravity declines.
The Toxic Phase The invasive febrile stage is succeeded by the toxic stage and it is then that the worst of the manifestations occur. The temperature falls, as a rule, by rapid lysis and far from improving with the drop in temperature the patient's condition deteriorates. The headache and the generalized pains become less but the backache and often the pain in the belly get worse. In'most patients there is some hypotension with the lysis, but this only reaches shock levels in about 25 per cent. of patients. A blood pressure of 90/60 is not uncommon, but as a rule this requires no special measures for its correction. In the 25 per cent. who go into shock the pressure may fall to 60/50, and this condition may last from a matter of hours to 2 days and in such cases there is marked restlessness, confusion, perhaps delirium, and blurring of vision. There is a reduction in circulating plasma volume as indicated by a rising haematocrit reading. Oedema of the conjunctivae often increases. At this stage haemorrhages occur, petechiae increase and bleeding from nose, lungs, stomach and kidneys takes place. As a rule the haemorrhage is not a very serious affair, but occasionally a large alimentary hzemorrhage gives rise to anxiety. In two of our patients there were severe epistaxes and one of them died in spite of replacement of blood. Gross haematuria is common and microscopic haematuria is almost the rule. Needle punctures and even handling the patient may produce large ecchymoses. Severe shock has been noted to occur in association with prolonged high fever, with delay in getting the patient to strict rest and with excessive fluid intake in the first few days. The majority of the patients start to get better as the shock regresses; haemorrhages become less marked and oedema subsides as the fluid lying in the tissues, particularly in the retroperitoneal tissues, is reabsorbed into the circulation. The Oliguric Phase After the shock phase the next hazard that the patient has to face is oliguria. This is always present to some extent and most patients pass straight from the febrile phase to oliguria. As has been said, in the early days the specific gravity of the urine is high but by the time oliguria sets in this has fallen to as low as 1010. The stage o f oliguria persists for from 36 hours to as long as several days, and may proceed to anuria. There is no close correlation between the degree of hypotension and the severity of oliguria, for uraemia of marked degree may occur even when there has been no notable shock. During oliguria there is a rise in blood pressure to hypertensive levels. Blood urea rises and the patient begins to exhibit the signs and symptoms of uraemia. There is evidence of a hypervolaemia (that is to say, an increased circulating blood volume) high blood pressure,
K. P. BROWN
109
venous distension and sometimes pulmonary oedema. Convulsions not uncommonly occur and there is usually irritability. The hypervolaemia is said by those who have investigated the problem to be not a true but a relative hypervolaemia. The circulating volume is not raised, and the apparent contradiction is explained by the supposition, based on histological evidence, that small vessel congestion in many organs reduces the flow through those organs and so the effective vascular space available. Be that as it may, the manifestations are relieved by venesection. In this stage haemorrhage may recur if it had previously stopped or get worse if it had not already stopped. With the end of the oliguria the toxic gives place to the convalescent stage. Diuresis begins about the 10th day. The patient starts to pass large quantities of urine of low specific gravity (1002). Diuresis happens in almost every case in some degree and in many cases it is often extremely difficult to keep up with, for the amount of urine is commonly 3,000-4,000 c.c. daily and as much as 20-30 g. of NaCI may be lost by the kidneys in 24 hours. Electrolyte balance may be seriously upset and intravenous therapy has been necessary to maintain balance. Blood urea falls but often only slowly and it may persist at a level of: 100 mg. per cent. for many days into diuresis. Albumin disappears from the urine early in this stage and formed elements are no longer seen in the deposit. : The stage of inefficient renal concentrating power lasts up to 3 months not uncommonly, and it has taken as long as 6 months to return to a specific gravity of 1025 after a 12-hour test. The patient regains weight; appetite and energy begin to return to normal, in most cases pretty rapidly once the recovery stage has begun. However, there are some who continue to suffer from anorexia and to tire very easily for several weeks. Troublesome backache is frequent, usually coming on after the patient has been up for some hours. It is perhaps an indication that the man has been mobilized too soon. There do not appear to be any sequelae from this disease once the illness has run its course, but it is tempting to wonder what the future holds in store for those people whose kidneys have been so badly damaged in the acute illness. In this connection it is interesting that LOWE (1952) has noted a lowering of renal reserve years after crush injury. PHYSIOLOGICAL CONSIDERATIONS
The fundamental disturbance seems to be one of the arterioles and capillaries: There is dilatation, as is shown by the facial flush which is more than a response to fever, and there is increased permeability and fragility of capillaries. That the latter is present is obvious from the occurrence of spontaneous petechiae and of ecchymoses after minor traumata and from the frequently positive Hess test. Abnormal permeability is demonstrated by the leakage of fluid from the circulating blood into the tissues. The biggest collection of such fluid is in the retroperitoneal tissues where it appears as a gelatinous mass at autopsy Increased permeability is presumably also responsible for the loss of the large quantities of albumin from the kidneys. The generalized arteriolar dilatation and reduced circulating blood volume are the factors causing the shock, and it is understandable that in such a case the renal circulation should be seriously impaired. But what of those cases in :whiCh there is no appreciable shock ? It is clear that there must be a selective diminution in renal blood flow in all cases and probably arteriolar dilatation persists for a time after the: ~apillaries have begun to return to normal permeability, for the period of oliguria is the perio.d Of relative hypervolaemia, when hypertension appears and the symptoms of uraem~a devel6p.
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EPIDEMIC HAEMORRHAGIC FEVER
Why the diuresis occurs is not known but from that time on, glomerular function appears to run ahead of tubular function. It had been noted early in the study of this disease that in fatal cases there was necrosis and haemorrhage into the pituitary body, and it seemed possible that the prolonged and profuse diuresis might be in part due to pituitary damage. It was therefore thought worth while to give some of the patients pitressin but there was no significant response; this experience was shared by others. CLINICAL
PATHOLOGICAL
FEATURES
These will be discussed more fully by Dr. KNUDSEN but there are some points which I should mention. The occurrence of albuminuria has already been described. The blood shows certain characteristic changes of which the most striking is the marked teucocytosis which starts at about the 3rd day and peaks at the end of the 1st week. Commonly between 10,000 and 20,000 it may reach 100,000 per c.mm. The increase is mainly in the granular series. In the oliguric phase the blood urea level rises considerably and the highest figure reached was 510' mg. per cent. in one patient on the 8th day of illness. In this case diuresis started at the 13th day and the urea was down to 410 at the 15th day. DIAGNOSIS
Albuminuria appears t o be necessary for a diagnosis of acute haemorrhagic fever, together with evidence of capillary damage and renal affection. In the early days, as has been Said, there are no specific symptoms nor signs, and in mild cases it can often only be suspected; obviously any febrile disease occurring in those parts must be brought into consideration. The appearance of the patient is frequently of help--the flushed face, intense headache and general misery. The regimental medical officers achieved a remarkably high level of correct diagnoses in the first days of the illness with consequent benefit to the patients for that meant that they got to proper conditions reasonably early. After about the 3rd day of illness the characteristic features appear and the diagnosis becomes relatively easy. PROGNOSIS
In general the mortality is about 5 per cent. Factors affecting the severity of the course appear to be the stage at which strict rest is instituted and restriction of fluid in the early days. A poor prognosis is associated with high and persisting leucocytosis, prolonged high fever persisting into the hypotensive stage, obstinate hypotension and long anuria. Death has most commonly come in the hypotensive stage but it may occur from haemorrhage, from pulmonary oedema when the tissue fluid is reabsorbed into the circulation, from uraemia and from electrolyte imbalance in the diuretic stage. TREATMENT
There is no specific treatment for this disease. Antibiotics have no influence on the course. At one time it was thought that benefit was to be obtained from the use of convalescent serum in the first 2 days but later work did not confirm this and the treatment is not now used. Probably the greatest single advance in the treatment was the establishment of a special
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hospital near Seoul to which all these patients are taken by helicopter as soon as the diagnosis is suspected, so that they have a smooth journey and are in the best possible conditions in a short time. Absolute rest is essential from the earliest stage possible. In the febrile phase sedation is called for. Fluid is given, by mouth, sufficient to maintain balance but it is preferable to err on the side of too little rather than too much. Sometimes, if there is severe and persistent vomiting, it may be necessary to give fluid by intravenous drip but if this is so it must be given with the utmost caution. The mild cases of hypotension can be dealt with satisfactorily by raising the bed-end and by the use of elastic bandages on the lower limbs. In severe cases salt-p0or albumin and norepinephrine given by drip have been of great value. One of the most distressing symptoms is hiccups and it can be most obstinate. We had some success by using intramuscular ether 4-5 c.c., and also intramuscular 8 per cent. magnesium sulphate solution, but often there was no response to any measures. There can be no hard and fast rules in treatment and each case has to be treated on its merits. In the early days the main thing is to make the patient as comfortable as possible and in the convalescent stage he must not be allowed to become ambulant too quickly. He should be kept abed until the kidney is obviously beginning to recover its power of concentration, the white cell count is normal, the sedimentation rate has settled to normal and the blood chemistry is back to normal limits. Other points in the estimation of recovery are the appetite and the degree of lassitude. S U M M A R Y A survey has been made of epidemic haemorrhagic fever, a disease of the Far East, the causative agent of which is so far unknown and in which the vector is thought to be a trombiculid mite. The disease is marked by fever, by dilatation and undue permeability of the small vessels, by haemorrhagic manifestations and by renal damage. It is a self-limiting illness attended by a mortality of about 5 per cent., for which there is no specific treatment but in which it is possible to influence the course and severity of the illness greatly by early and careful supportive treatment in conditions of absolute rest. It would have been impossible to make this survey on the basis of my own experience only and I have to acknowledge the help given me by my late colleague Dr. R. ANDREWon whose account of our cases I have drawn freely, and particularly the generous hospitality of the physicians of the Haemorrhagic Fever Hospital at Seoul whose guest I was lucky to be and who gave me permission to make use of the information which they gave me so freely.
REFERENCES ANDREW,R. (1953) Brit. med. ft., 1, 1063. B~mBEaO,G. J., KATZ, S. & KRAtrS,H. (1953) U.S. Forces med. ft., 4, 207. KATZ, S., LF_~DHAM,C. L. & K~SLEa, W. H. (1952) ft. Amer. med. Ass., 150j 1363. LowE, K. G. (1952) Lancet, 1, 1086. McNtNcI{, J. H., Lm~DHAM,C. L. et al. (1953) Ann. intern. Med. 38, 53. MAY~R, C. F. (1952) Milit. Surg., 110, 276. POW~LL,G. M. (1953)ft. Amer. med. Ass., 151, 1261. TECHNICALBOLL~rlN (Med.) (1953) U.S. Array, 240. TRAUB, R., HE3RTIG,M., LAWRENCE,W. & HAimlS, T. Entomological observations during studies epidemic haemorrhagic fever in Korea, 1952. (unpublished).
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