Danger signs in Thai hemorrhagic fever (dengue)

Danger signs in Thai hemorrhagic fever (dengue)

TROPICAL PEDIATRICS Danger signs in Thai hemorrhagic An increased incidence o[ certain symptoms, signs, and laboratory findings in patients with the...

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TROPICAL PEDIATRICS

Danger signs in Thai hemorrhagic

An increased incidence o[ certain symptoms, signs, and laboratory findings in patients with the severe [orms o[ dengue hemorrhagtc [ever (shock or [atal termination) as compared with the relatively low incidence o[ these mani[estations in the more mild [orms o[ the disease was [ound on analysis o[ 70 virologically proved non[atal cases and 38 [atal cases. The symptoms include hematemesis, melena, dyspnea, cyanosis, restlessness, and convulsions; the laboratory and roentgen findings include leukocytosis, marked thrombocytopenia, hemoconcentration, pleural effusion, albuminuria, and~or urinary casts. All o[ these may occur be[ore the onset o[ shock and, there[ore, are considered as danger signs in the disease.

Ethel R. Nelson, M.D.,* and Ruchee Chulajata, M.D.** BANGKOK~

F o R

T H E

THAILAND

P A S T

ten

years

dengue has

in 1963. s The disease has become widespread geographically, and owing to its potential seriousness, is of particular concern to physicians treating children. In Bangkok epidemics of 1958 and 1959, the case fatality rates were approximately 10 per cent. 9 This high mortality rate has not been repeated largely for two reasons: (1) Most parents are now aware of the seriousness of the disease and do not wait until their children are in deep shock before seeking medical care, and (2) physicians have become more adept in treating the disease. Case fatality rates, however, are still in the range of 5 per cent, indicating the need for careful medical management of the individual patient. The disease begins with rapidly rising fever, which is often accompanied by nausea and vomiting, abdominal pain, and occasion-

been occurring in epidemic proportions as a hemorrhagic disease of children in many of the countries of southeast Asia and the western Pacific areas. Hemorrhagic fever was first recognized as an epidemic in the Philippines in 1954', 2; then in Thailand (Bangkok) in 19583-~; in Malaysia (Singapore) in 1960, 6 (Penang) in 1962; in South Vietnam (Saigon) in 19637; and in India (Calcutta)

From the Departments o[ Pathology and Pediatrics, Bangkok Sanitarium and Hospital, and Department o[ Pathology, Loma Linda University School o[ Medicine. Preliminary report o[ these data was made at the S E A T O sponsored Hemorrhagic Fever Conference held in February, 1964, in Bangkok, Thailand. ~Pathologlst, Bangkok San{tarlum and Hospital, 430 Pitsanuloke Road, Bangkok, Thailand. **Pediatrician.

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8

ne W I

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Z

4

2

I

2

3

4 DAY

8

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DISEASE

Fig. 1. Incidence of death in hemorrhagic fever according to the day of disease.

ally diarrhea. As the disease progresses, the throat may become injected. There is generalized lymphadenopathy, and the liver gradually enlarges. By the third or fourth day, a maculopapular or moribiliform rash may appear, or there may be no rash but only showers of petechiae on the extremities and occasional ecchymotic spots. By this time there are usually thrombocytopenia and/or leukopenia. A dry cough m a y be noted, and, although there m a y be few physical findings on examination, a roentgenogram of the chest often reveals a pleural effusion, almost invariably involving the right thorax initially. More severe bleeding may occur such as hematemesis or melena, bleeding from the gums, or e'pitaxis. Dyspnea and cyanosis ensue and are often accompanied by convulsions. One of the most ominous signs is the onset of shock, with cold, clammy extremities. The mortality rate in children in this stage is high, if vigorous treatment is not initiated early. With little variation the more serious cases of the disease follow this general pattern regardless of geographic location. The issue

posed here is: Are there helpful signs or findings that can serve to warn the physician of impending danger in a given case of hemorrhagic fever? M E T H O D S AND M A T E R I A L S Seventy cases of dengue hemorrhagic fever from the 1960, 1963, and 1964 Bangkok epidemics were selected because of their virologic confirmation for a retrospective analysis of the signs, symptoms, laboratory, and roentgen findings. These were nonfatal cases with varying degrees of severity of the disease. It was found that there were m a n y differences between patients exhibiting shock and the more mild nonshock cases, and so two categories were formed with 15 "shock" cases, and 55 "nonshock" cases. For further more meaningful analysis, 38 fatal cases, collected from 1958 to 1964 are compared. These cases were all studied at the Bangkok Sanitarium and Hospital. The virologic testing by hemagglutination inhibition, neutralization, and complement fixation was done on sera .in 1960 by the Department of Epidemiology and Microbiology

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Danger signs in Thai hemorrhagic [ecer (dengue)

465

% sO0

ZL

GO

z

sO

z

ZO

Z r--I HEMATEMESIS MELENA

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Fig. 2. Percentage incidence of various symptoms and laboratory findings according to severity of disease. The clear bar denotes mild, nonshock; lined bar, shock; and black bar, fatal.

of the Graduate School of Public Health at the University of Pittsburg. In the 1963 and 1964 epidemics, hemagglutination inhibition testing was done by the S E A T O Virology Laboratory in Bangkok. Complete blood counts were performed by standard methods; platelet counts by the indirect method; packed cell volumes by microhematocrit; hemoglobin levels by the cyanmethemoglobin method; and urinary albumin with Robert's reagent. Serum electrolyte, sodium and potassium determinations were performed by the macro method on a BairdAtomic clinical flame photometer. RESULTS Analysis of the deaths according to day of disease shows that the peak incidence of death occurred on the fourth day with practically all deaths occurring between the third and sixth days of disease (Fig. 1). It is during these days, therefore, that the children must be carefully observed for danger signs. Any symptom which was found relatively infrequently in the nonshock case, but commonly in the shock or fatal cases, was considered significant in indicating a grave trend of the disease. Twenty-one per cent of the patients with nonfatal disease went into shock, but 88 per cent of those with fatal cases exhibited shock before death. Diagnosis of impending shock would, therefore, be most helpful.

The more serious bleeding tendencies may comprise a danger sign. Hematemesis or "coffee ground" gastric contents aspirated by Levine tube were found in only 9 per cent of nonshock cases, but in 20 per cent of shock cases, and 53 per cent of fatal cases. Likewise melena was found in only 5 per cent of nonshock, and 7 per cent of shock cases, but in 21 per cent of fatal cases. A severe thrombocytopenia of less than 50,000 per cubic millimeter was found in 74 per cent of fatal cases, 87 per cent of shock cases, but in only 31 per cent of the nonshock cases (Fig. 2). Patients, therefore, with platelets at the level of spontaneous bleeding, or showing hematemesis, or melena merit special watchfulness. Cough was found in an equal number of the mild and serious cases; however, dyspnea was found in only 2 per cent of nonshock cases, 13 per cent of shock cases, but in 69 per cent of fatal cases. Cyanosis was likewise an ominous sign as it occurred in only 2 per cent of nonshock cases, but in 33 per cent of shock cases and 79 per cent of fatal cases. Pleural effusion (by roentgenogram) was found in 30 per cent of nonshock cases, but in 71 per cent of shock and 64 per cent of fatal cases. The respiratory symptoms of dyspnea and cyanosis or the finding of pleural effusion should alert one to impending danger (Fig. 2). Extreme restlessness was seen in only 5

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Nelson and Chulajata

September 1965

% I0O

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CONVUI.li.

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12,000

Fig. 3. Hemoconcentration if hemoglobin over 15 Gin. per cent, erythrocyte count over 5,000,000 per c. mm., or hematocrit over 45 per cent. The clear bar denotes mild, nonshock; lined bar, shock; and black bar, fatal.

per cent of mild cases, b u t in 40 per cent of shock a n d 63 p e r cent of fatal cases. Likewise convulsions were observed in only 7 per cent of the mild cases and occurred before the third day of disease in association with high fever; by contrast they occurred in 26 per cent of the patients in shock a n d in 74 p e r cent of the fatal cases (Fig. 3). L e u k o p e n i a (less than 5,000 per cubic millimeter has been found in the m a j o r i t y of nonshock cases of h e m o r r h a g i c fever?" A leukocytosis above 12,000 per cubic millimeter, however, was found in this study in the m o r e critical cases. O n l y 16 per cent of mild cases h a d a leukocytosis, whereas 67 per cent of shock cases a n d 66 p e r cent of fatal cases showed a p r o n o u n c e d leukocytosis. A simultaneous absolute rise in neutrophils with a r a t h e r m a r k e d "shift to the left," including not only metamyelocytes, but also occasional myelocytes a n d myeloblasts, was usually seen. H e m o c o n c e n t r a t i o n of m o r e t h a n 15 Gm. per cent hemoglobin, 5 million per cubic millimeter erythrocyte, or 45 per cent p a c k e d cell volume a p p e a r e d to be a constant d a n g e r sign. H e m o c o n c e n t r a t i o n was found in 13 p e r cent of nonshock cases, c o m p a r e d with 100 per cent of shock cases, a n d 50 p e r cent of fatal cases (Fig. 3). T w o u r i n a r y findings m a y be significant, but are p r o b a b l y seen relatively late in the

course of the disease since the v a r i a t i o n in occurrence between the "nonshock" a n d "shock" cases was slight. A trace o r 1 plus a l b u m i n u r i a was found in 20 per cent of nonshock a n d in 18 p e r cent of shock cases, but in 67 p e r cent of the fatal cases. H y a l i n e or g r a n u l a r casts were present in 5 per cent of nonshock a n d 8 per cent of shock cases, a n d in 84 p e r cent of the fatal cases (Fig.

3). Electrolyte d e t e r m i n a t i o n s of potassium a n d sodium were done on sera of 9 patients in shock as well as on 6 who died (immediately after d e a t h ) d u r i n g 1964. Six of the 9 shock cases (67 per cent) a n d 4 of 6 fatal cases (67 p e r cent) showed h y p o n a t r e m i a . T h r e e of the 9 shock cases (33 per cent) a n d 4 of 6 fatal cases (67 per cent) showed hyperkalemia (Table I). CASE STUDIES T h r e e fatal cases are selected to illustrate the a p p e a r a n c e of the " d a n g e r signs" in the course of the disease. Case~:l, N.N.S. This 8-year-old Chinese boy was admitted on the fourth day of illness at 2:30 p.~. with fever, abdominal pain, nausea and vomiting, anorexia, cough, and drowsiness. The blood pressure was 90/70; the skin was clear, the throat injected, and the liver enlarge d 2 cm. below the costal margin. The initial laboratory reports were: hemoglobin level 15.8 Gm.; erythrocyte count, 4.94 million per cubic millimeter,

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Number 3

Danger signs in Thai hemorrhagic [ever (dengue)

467

T a b l e I. S e r u m e l e c t r o l y t e s i n h e m o r r h a g i c f e v e r

Case No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

A~e 5 3 10 3 2 7 5 months 6 9 8 2 3 months 4 5 7

Sex

Nationality

r (mEq./L.)

~F F M F M M IV[ M F M M F F M M

Chinese Chinese Chinese Thai Thai Thai Chinese Thai Thai Chinese Chinese Thai Chinese Chinese Chinese

123 140 126 126 126 133 140 146 127 135 123 122 -132 144

{

"~K (mEq./L )

I Period o[ shock

Death or Recovery

4.3 5.2 7.4 6.4 4.0 4.6 7.0 4.0 4.8 6.0 6.6 5.8 6.0 4.4 2.6

18 hours 14 hours 12 hours 6 hours 15 hours 15 hours 12 hours 7 hours 13 hours 6 hours 18 hours 5 hours 19 hours 20 hours None

Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Recovered Died Died Died Died Died Died

"~Normal value 137-147 rnEq. per liter. tNoHnal value 3.5-5.3 mEq. per lite,.

leukocyte count, 3,950 per cubic millimeter, with 70 per cent neutrophils, 6 per cent b a n d forms, 20 per cent lymphocytes, and 4 per cent monocytes; platelets, 24,700 cubic millimeter. T h e chest roentgenogram was negative. At 6:00 P.~i. he vomited "coffee ground" material. At midnight his blood pressure was 100/60 and he was slightly dyspneic. O n the fifth day at 8 : 0 0 A.,~t. the blood pressure was 0/0, but by 10:00 A.M. the blood pressure was 90/70. T h e childr was restless. Laboratory reports were then: hemoglobin level 16.8 Gm.; erythrocyte count, 5.41 million per cubic millimeter; leukocyte count, 10,200 per cubic millimeter with 53 per cent neutrophils, 5 per cent band forms, and 41 per cent lymphocytes. Urinalysis showed specific gravity 1.030, p H 4.5, a l b u m i n and sugar negative, hyaline casts. At 7:00 P.M. the blood pressure was 100/70. T h e patient was very restless and dyspneic and there was bleeding from the gums. At 10:00 P.M. the blood pressure was 100/70. O n the sixth day of illness at 4.00 A.~t. the blood pressure was 100/60 with improved condition. T h e skin was warm. T h e patient again became restless at 6:00 A.M. and was dyspneic; the blood pressure was 100/50. At 7:00 A.M. he h a d a generalized convulsion. O l d blood was aspirated by Levine tube at 9 : 0 0 A.~t. T h e r e were frequent convulsions until 10.00 A.X~. T h e laboratory reports then showed leukocytes, 21,300 per cubic millimeter with 33 per cent neutrophils, 23 per cent band forms, 2 per cent metamyelocytes, 1 per cent myelocytes, and 38 per cent lymphocytes; platelets, 35,640 per cubic

millimeter. T h e urinalysis revealed specific gravity 1.018, p H 4.5, albumin trace, sugar n e g a t i v e , ' granular and hyaline casts. T h e chest roentgenogram was negative. At 4 : 0 0 P.~,t. there was no blood pressure. Rales were f o u n d in both lungs. T h e child was dyspneic, cyanotic, a n d had recurring convulsigns. He died at 10:00 l'.M. on the sixth day of disease, 56 hours after admission. Case 2, N.P, This 2-year-old Chinese boy was a d m i t t e d on the fifth day of illness at 7:30 P.M. with high fever, drowsiness, no cough, or vomiting. O n examination, the blood pressure was 80/60. He was conscious, had a generalized petechial rash and liver enlarged 4 cm. below the costal margin. He had a generalized convulsion shortly after admission. T h e laboratory reports disclosed a hemoglobin level of 16.8 Gm.; erythrocyte count, 5,250,000 per cubic millimeter; hematocrit, 48; leukocyte count, 13,600 with 50 per cent neutrophils, 5 per cent band forms, 3 per cent metamyelocytes, 2 per cent myeloblasts, and 39 per cent lymphocytes; platelets 52,500 per cubic millimeter. At 10:00 P.M. the blood pressure was 70/40; at 11:00 p.M. 70/30. He became cyanotic and restless. O n the sixth day of disease at 4 : 0 0 A.M. the blood pressure was 70/60. T h e child vomited brown fluid and was very restless. At 6:00 A.M. he h a d a convulsion. At 7:30 A.M. he was dyspneic and cyanotic; and at 8 : 0 0 A.M. the blood pressure was 60/30. Laboratory reports at this time showed a hemoglobin level of 13.1 Gm.; hematocrit, 42;

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leukocyte count, 26,750 per cubic millimeter with 18 per cent neutrophils, 8 per cent band forms, 2 per cent metamyelocytes, and 69 per cent lymphocytes. A chest roentgenogram showed right pleural effusion. Urinalysis was as follows: pH 4.5, albumin and sugar negative, hyaline and granular casts present. At 10:00 A.M. there was no blood pressure. Old and fresh blood was suctioned from the stomach. Convulsions recurred. He died at 2:30 P.M. on the sixth day of illness, 19 hours after admission. An autopsy revealed bilateral pleural effusions, patchy interstitial pneumonia, small hemorrhages in the septum of the heart, old blood throughout the stomach and small bowel, ascitic fluid, fatty degeneration of the liver, and generalized lymphadenopathy. Case 3, P.T. This 3-month-old Thai female was admitted on the third day of illness at 7:30 e.M. with fever, slight cough, and drowsiness, but no rash or purpura. There were no rales in the lungs, but slight cyanosis. The liver was enlarged 4 cm. There was no lymphadenopathy. The laboratory reported: Hemoglobin level, 11.1 Gin.; erythrocyte count, 3,300,000 per cubic millimeter; hematocrit, 34; leukocyte count, 13,550 per cubic millimeter with 42 per cent neutrophils, 24 per cent band forms, 3 per cent metamyelocytes, and 3l per cent lymphocytes; platelets, none. A chest x-ray showed right pleural effusion. On the fourth day of illness at 6:00 A..~t. the blood pressure was 70/40. Laboratory reports were: hemoglobin level 7.7 Gin.; erythrocyte count, 2,580,000 per cubic millimeter; hematocrit, 26; leukocyte count, 29,050 per cubic millimeter with 25 per cent neutrophils, 56 per cent band forms, 19 per cent lymphocytes, and 1 per cent normoblasts; platelets, none. At 8:30 A.M. the patient was unconscious; there was twitching of the left leg; she was in shock. There was no spontaneous purpura. The infant died at 11:00 A.M. on the fourth day of illness, 16 hours after admission. DISCUSSION T h e m a j o r i t y of symptoms in h e m o r r h a g i c fever such as vomiting, a b d o m i n a l pain, fever, d i a r r h e a , headache, malaise, drowsiness, anorexia, epistaxis, and the findings such as l y m p h a d e n o p a t h y , injected throat, hepatomegaly, rash, petechiae, or ecchymosis

September 1965

have little prognostic significance. O n the o t h e r hand, the a p p e a r a n c e of 3 or more of the previously n a m e d findings m a y serve as useful prognostic aids. H e m a t e m e s i s a n d melena m a y be a reflection of the degree of t h r o m b o c y t o p e n i a , a n d when the platelet count falls into the range of spontaneous bleeding level (below 50,000 per cubic m i l l i m e t e r ) , one would expect m o r e h e m o r r h a g i c p h e n o m e n a of a serious or unusual nature. A c t u a l l y there are few cases of h e m o r r h a g i c fever in which the imm e d i a t e cause of d e a t h is due to massive h e m o r r h a g e , but bleeding m a y be a complication a d d i n g to the shock. Shock is p r o b a b l y the t e r m i n a l state in a chain of events beginning with loss of fluid from the circulating blood into e x t r a v a s c u l a r c o m p a r t m e n t s , such as pleural and a b d o m inal cavities. Loss of the fluid c o m p o n e n t from the circulating blood results in hemoconcentration which, in turn, gives rise to the shock. Local e d e m a of the p u l m o n a r y alveolar walls a n d interstitial p n e u m o n i a interfere with oxygen exchange and give rise to d y s p n e a and cyanosis. Pleural effusions are an a d d i t i o n a l stress on oxygen exchange. T h e resultant respiratory e m b a r r a s s m e n t a n d hypoxia contribute to restlessness and convulsions. T h e detection of any one or m o r e of these events, all of which m a y precede shock, should arouse one to the i m p e n d i n g crisis. Children often pass in and out of shock in response to t r e a t m e n t , as d e m o n s t r a t e d in Case 1. T h e finding of h e m o c o n c e n t r a t i o n in 100 p e r cent of the patients in the shock category but in 50 per cent of the patients in the fatal category can be e x p l a i n e d when the actual values of hemoglobin, e r y t h r o cytes, or h e m a t o c r i t are examined. T h e m a j o r i t y of the patients who died failing to d e m o n s t r a t e h e m o c o n c e n t r a t i o n in the presence of shock were found m a r k e d l y anemic ( p r o b a b l y due to blood loss during the disease, but also possibly due to pre-existing a n e m i a ) , so t h a t a tremendous loss of fluid would be necessary before the p a c k e d cell volume could exceed 45 per cent of the total (Case 3). W e purposely placed the d e m a r -

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Danger signs in Thai hemorrhagic fever (dengue)

cation level for hemoconcentration high to differentiate between a lesser hemoconcentration due to dehydration (vomiting, decreased fluid intake, and occasional diarrhea) and the more significant fluid shifts to extravascular compartments. Leukocytosis in 16 per cent of the mild cases was found to occur after the eighth day, during the recovery stage, and not during the period of potential danger (days 3 to 6). T h e leukocytosis in the shock and fatal cases was found, on the other hand, during this critical period. Leukocytosis as a prognostic sign is well demonstrated in all 3 case studies. In Case 1 the abrupt rise from an initial leukopenic level of 3,950 to 10,200 per cubic millimeter the following day, should have suggested the trend, for by the next day there was a definite leukocytosis of 21,300 per cubic millimeter. It has been previously considered that leukocytosis was due to an intercurrent secondary, usually pyogenic, infection, but this has not been proved in our cases. We also observed, however, that a shift to the left of neutrophils became greater if the patient's condition deteriorated, al This "shift to the left" of neutrophils and, also, the frequent very high counts (20,000 to 40,000 per cubic millimeter) indicate that the leukocytosis is also apparently not merely an expression of an accompanying hemo2oncentration. SUMMARY

1. Seventy cases of virologically proved hemorrhagic fever (dengue) and 38 fatal cases of the disease are analyzed. 2. T h e days of danger in the disease are the third to the sixth. 3. A n u m b e r of significant differences are found in the incidence of various symptoms, signs, laboratory, and roentgenographic findings between the mild, nonshock, and serious shock cases of Thai hemorrhagic fever. These same findings are even more marked in fatal cases. 4. Hematemesis (or "coffee ground" gastric contents), melena, dyspnea, cyanosis, restlessness, and convulsions are danger symtoms in the disease, since these are found

469

relatively infrequently in the mild cases, but in a high percentage of patients during shock and in the fatal cases. 5. L a b o r a t o r y findings of leukocytosis greater than 12,000 per cubic millimeter (during days 3 to 6) ; a platelet count of less than 50,000 per cubic millimeter; hemoconcentration as manifested by hemoglobin values of greater than 15 Gin. per cent, erythrocyte counts greater than 5 million per cubic millimeter, or hematocrit exceeding 45 per cent; pleural effusion; and albuminuria a n d / o r granular casts in the urine are evidence of impending danger and demand special watchfulness and early, rigorous therapeutic measures. We wish to thank Drs. W. McD. Hammon of the University of Pittsburg, Scott B. Halstead of the SEATO Virology Laboratory in Bangkok, and their staffs for their contribution to our studies by providing virologic confirmations. REFERENCES 1. Quintos, F. N., Lim, L., Julians, L., Reyes, A., and Lacson, P.: Hemorrhagic fever observed among children in the Philippines, Philippine J. Pediat. 3: 1, 1954. 2. Hammon, W. McD., Rudnick, A., Sather, G. E., Rogers, K. D., LaMotte, L. C., Jr., Chan, V., Basaca-Sevitia, V., and Diznm, J. J_: Studies on Philippine hemorrhagic fever: Relationship to dengue virus, Ninth Pacific Science Congress, Bangkok, 1957, p. 187. Abst. 3. Nelson, E. R." Hemorrhagic fever in children in Thailand, J. PEr)rAT. 56: 101, 1960. 4. Hammon, W. McD., Rudnick, A., Sather, G. E., Rogers, K. D., and Morse, L. J.: New hemorrhagic fevers of children in the Philippines and Thailand, Tr. A. Am. Physicians 73: 140, 1960. 5. Dasaneyavaia, A., and Pongsupat, S.: Observations on Thai hemorrhagic fever, J. Trop. Med. 64: 310, 1961. 6. Chew, A., Leng, G. A., Yuen, H., Teik, K. O., Kiat, L. Y., Hong, L. C., and Wells, R.: A hemorrhagic fever in Singapore, Lancet 280: 307, 1961. 7. Halstead, S. B., Voulgaropoulos, E., Tien, N. H., and Udom-Sakdi, S.: Dengue hemorrhagic fever in Vietnam, report of the 1963 outbreak, Am. J. Trop. Med. In press. 8. Ramakrishnan, S. P., Gelfand, H. M., Bose, P. N., Sehgal, P. N., and Mukherjee, R. N.: The epidemic of acute haemorrhagic fever, Calcutta 1963: Epidemiological inquiry, Indian J. M. Res. 52: 633, 1964. 9. Jatanasen, S.: Occurrence of haemorrhagic

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fever in Thailand 1958-1964, (IR/Haem. Fever/Sem. I / W P / I ) WHO seminar on mosquito-borne haemorrhagic fevers in southeast Asia and western Pacific regions, Bangkok, October, 1964. 10. Nelson, E. R., Bierman, H. R., and Chulajata, R.: Hematologic findings in the 1960 hemor-

September 1965

rhagic fever epidemic (dengue) in Thailand, Am. J. Trop. Med. 13: 642, 1964. 11. Dasaneyavaja, A., Robin, Y., and Yenbutra, D.: Laboratory observations related to prognosis in Thai haemorrhagic fever, J. Trop. Med. 66: 35, 1963.