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1262 CID 2009:48 (1 May) BRIEF REPORT

B R I E F R E P O R T

Lack of Efcacy of ProphylacticPlatelet Transfusion for SevereThrombocytopenia in Adultswith Acute UncomplicatedDengue Infection

David C. Lye,1 Vernon J. Lee, 2,3 Yan Sun,4 and Yee Sin Leo 1

Departments of1Infectious Disease and2Clinical Epidemiology, Tan Tock SengHospital,3Biodefence Center, Ministry of Defence, and4Clinical ProjectManagement and Planning, National Healthcare Group, Singapore

Thrombocytopenia in dengue infection raisesconcerns aboutbleeding risk. Of 256 patients with dengue infection whodeveloped thrombocytopenia (platelet count, ! 320 10platelets/ mL) without prior bleeding, 188 were given platelettransfusion. Subsequent bleeding, platelet increment, andplatelet recovery were similar between patients given trans-fusion and patients not given transfusion. Prophylactic plate-let transfusion was ineffective in preventing bleeding in adultpatients with dengue infection.

Acute dengue infection is endemic to many tropical countries,and its incidence is increasing globally [1]. Thrombocytopenia

is common in acute dengue infection [2], and many experi-mental therapies, including corticosteroid treatment [3] andintravenous immunoglobulin treatment [4], have been used totreat severe thrombocytopenia in dengue hemorrhagic fever,because of the fear of potential bleeding.

Although severe bleeding and coagulopathy occur in dengueshock syndrome (DSS) [5], the cause is multifactorial [6, 7]and is not caused by thrombocytopenia alone. Thrombocyto-penia was not an independent predictor of severe bleeding inpediatric DSS [8]. Prophylactic transfusion with platelets andfresh frozen plasma was also not benecial in pediatric DSS[9]. Despite this, platelet transfusion was frequently given forsevere thrombocytopenia to adults with acute dengue infection

Received 7 October 2008; accepted 5 January 2009; electronically published 17 March2009.

D.C.L. and V.J.L. contributed equally to this article.Reprints or correspondence: Dr. Vernon J. Lee, 42 How Sun Dr., Singapore 538611, Republic

of Singapore (vernonljm@hotmail.com).

Clinical Infectious Diseases 2009;48:126252009 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2009/4809-0018$15.00DOI: 10.1086/597773

in Singapore and Taiwan [2, 10]. We studied the impact of prophylactic platelet transfusion for severe thrombocytopeniain a large retrospective cohort of adults with acute dengue.

Methods. We studied all patients with acute dengue in 2004who were admitted to the Department of Infectious Diseases,Tan Tock Seng Hospital, Singapore [2]. Only patients who ful-lled the World Health Organization criteria for acute dengue(fever and 2 of the following symptoms: headache, eye pain,myalgia, arthralgia, leukopenia, rash, and bleeding) and whohad results of laboratory diagnostic tests positive for denguewere included. All cases were classied as dengue fever, denguehemorrhagic fever (all 4 criteria present: fever, thrombocyto-penia [platelet count, ! platelets/ mL], bleeding man-3100 10

ifestation, and plasma leakage), or DSS [5]. Patients with prob-able cases had acute dengue with positive results of serologicalanalysis (Dengue Duo IgM & IgG Rapid Strip Test; Panbio),and those with conrmed cases had positive results of PCR.Medical chart review was performed to extract demographiccharacteristics, serial clinical and laboratory data, and treatmentand outcome data.

Severe thrombocytopenia was dened as platelet count! platelets/ mL, on the basis of local clinical practice.320 10Prophylactic platelet transfusion was dened as platelet trans-fusion without clinical bleeding, in contrast to therapeuticplatelet transfusion with clinical bleeding. Clinical bleeding ex-

cluded petechiae. We excluded all patients with clinical bleedingbefore and on the day that their platelet count decreased to! platelets/ mL. Patients whose platelet count decreased320 10to ! platelets/ mL without clinical bleeding and who320 10were given prophylactic platelet transfusion were comparedwith those who were not given prophylactic platelet transfusion.Prophylactic platelet transfusion was given on the basis of aclinicians assessment. Outcome measures consisted of clinicalbleeding after prophylactic platelet transfusion, platelet countincrement the day after transfusion, time to platelet count1 platelets/ mL, length of hospitalization, and death.350 10

The x 2 test and Fishers exact test were used to comparecategorical variables, and Students t test and the Mann-Whit-ney U test were used to compare continuous variables. Allstatistical analyses were performed using Stata, version 9.0(Stata Corp), and tests were conducted with the signicancelevel at 5%. Corresponding percentages, 5th and 95th percen-tiles, ORs, and 95% CIs are reported.

Results. In 2004, 1973 patients were admitted to our de-partment at Tan Tock Seng Hospital who fullled the WorldHealth Organization criteria for acute dengue and who had

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positive results of laboratory diagnostic tests. Of the cases, 54%were probable, and 46% were conrmed. There were 1855 pa-tients with dengue fever and 118 patients with dengue hem-orrhagic fever; 10 of the patients with dengue hemorrhagic feverhad DSS. Seven patients required admission to the intensivecare unit, and 1 patient died; all 8 of these patients had denguehemorrhagic fever.

The median age was 32 years (5th95th percentiles, 1757 years), and 64% of patients were male. The median durationof illness at presentation was 5 days (5th95th percentiles, 37 days), and the median length of hospital stay was 4 days (5th95th percentiles, 27 days). At presentation, clinical bleedingoccurred in 220 patients (85% had gum bleeding, 16% hadepistaxis, 5% had menstrual bleeding, and 1% had gastroin-testinal bleeding). The median platelet count nadir for patientswith dengue fever was platelets/ mL (5th95th percen-351 10tiles, platelets/ mL), compared with a median of 31197 10

platelets/ mL (5th95th percentiles, plate-3 349 10 990 10

lets/mL) for patients with dengue hemorrhagic fever ( ).P 1 .05Platelet transfusion was given to 249 patients (12.6%) duringhospitalization (either prophylactic or therapeutic platelet trans-fusion); 61 of these patients received therapeutic transfusion.

Of the 1973 patients, 1666 had a platelet count nadir1 platelets/ mL, and 51 patients had bleeding and/or320 10received platelet transfusion when the platelet count was1 platelets/ mL; these patients were excluded from fur-320 10ther analysis. The remaining 256 patients without bleedingwhose platelet count decreased to ! platelets/ mL were320 10included in subsequent analysis, and 188 received prophylacticplatelet transfusion.

The baseline demographic and clinical variables on the day that the platelet count decreased to ! platelets/ mL for320 10the 256 patients who either were or were not given prophylacticplatelet transfusion are shown in table 1. The median plateletcount for both patients given transfusion and patients not giventransfusion was platelets/ mL (OR, 1.02; 95% CI, 0.94315 101.09; ). Patients given transfusion were more likely toP p .87have fever (temperature, 1 38 C), compared with patients notgiven transfusion (33% vs. 18%; OR, 2.30; 95% CI, 1.154.59;

), and had signicantly higher systolic blood pressureP p .02(OR, 1.03; 95% CI, 1.011.06; ) and pulse pressure (OR,P p .011.02; 95% CI, 1.001.05; ). The median time from dis-P p .03ease onset to hospital admission was 3 days (5th95th percen-tiles, 26 days) for patients given transfusion, compared with3 days (5th95th percentiles, 16 days) for patients not giventransfusion ( ). The median time from disease onset toP p .38platelet count ! platelets/ mL and platelet transfusion320 10was 5 days (5th95th percentiles, 37 days) for patients giventransfusion, compared with 4.5 days (5th95th percentiles, 38 days) for patients not given transfusion ( ). There wereP p .94

no other signicant demographic or clinical differencesbetweenthe 2 groups.

The incidence of clinical bleeding was 6% among pa-tients with platelet count 1 platelets/ mL, 12%3150 10among patients with platelet coun t of plate-3100149 10lets/mL, 11% among patients with platelet count of

platelets/ mL, 10% among patients with platelet38099 10

count of platelets/ mL, 11% among patients with3

5079 10platelet count of platelets/ mL, 13% among patients32049 10with platelet count of platelets/ mL, and 0% among31019 10patients with platelet count ! platelets/ mL ( , by 310 10 P p .22test for trend).

Among patients whose platelet count decreased to! platelets/ mL, prophylactic transfusion was given to320 10188 patients at a median of 4 units of platelets (range, 112units). Clinical bleeding subsequently occurred in 1 (0.5%) of 188 patients given prophylactic transfusion (severe gastroin-testinal bleeding in a patient with known peptic ulcer diseasewho died due to disseminated intravascular coagulation andacute renal failure), compared with 2 (2.9%) of 68 patients notgiven transfusion ( ) (both instances of bleeding wereP p .17mild and did not require additional intervention). The medianplatelet increment on the day after platelet transfusion in pa-tients given transfusion ( platelets/ mL) was lower than37 10the median platelet increment on the day after platelet countrst decreased to ! platelets/ mL in patients not given320 10transfusion ( platelets/ mL; OR, 1.00; 95% CI, 0.981.01;311 10

). The median time to platelet count 1 plate-3P p .26 50 10lets/mL was similar for patients given transfusion and patientsnot given transfusion (3 days; OR, 1.05; 95% CI, 0.791.39;

). The median length of hospital stay was 6 days forP p .59patients given transfusion, compared with 5 days for patientsnot given transfusion ( ). One patient died in the groupP p .09given transfusion, compared with none in group not giventransfusion ( ).P p 1.00

Discussion. Prophylactic platelet transfusion is given be-cause of the fear of severe bleeding in patientswithacutedengueand thrombocytopenia. Experimental use of corticosteroidtreatment and intravenous immunoglobulin treatment [3, 4]and the overuse of platelet transfusion [2, 10] have been re-ported. Platelet transfusion was given to 50.3% of hospitalizedpatients with dengue in Taiwan [10] and 12.6% in Singapore[2]. Only 7 patients in our study had severe bleeding1 wasin the group given transfusion, and the other 6 had a meanplatelet count of platelets/ mL (range,3 378 10 23111 10platelets/ mL) during the bleeding episode without ever reachingthe platelet count nadir of ! platelets/ mL. Notably, a320 10randomized study showed that intravenous immunoglobulintreatment did not hasten recovery from thrombocytopeniaamong patients with secondary dengue infection [4].

Our study further strengthens the evidence that thrombo-

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Table 1. Baseline demographic characteristics, clinical and laboratory data on the day the platelet count decreased to ! platelets/ mL, and clinical outcomes for patients with acute dengue infection who did or did not receive320 10prophylactic platelet transfusion.

Variable

Patients givenplatelet transfusion

( )n p 188

Patients not givenplatelet transfusion

( )n p 68 P

Demographic characteristics

Age, years 40 (2264) 39 (2258) .54Male sex 144 (77) 45 (66) .11

Dengue diagnosisDengue hemorrhagic fever 4 (2) 2 (3) .66Positive results of PCR 124 (66) 46 (68) .88Test results positive for IgG 60/86 (70) 24/32 (75) .65

Preexisting medical conditionsDiabetes mellitus 11 (6) 2 (3) .52Hypertension 18 (10) 5 (7) .80Hyperlipidemia 9 (5) 1 (1) .30Ischemic heart disease 0 (0) 0 (0) 1.00

Clinical featuresFever 46 (24) 22 (32) .26

Headache 13 (7) 3 (4) .57Myalgia/arthralgia 27 (14) 12 (18) .56Eye pain 1 (1) 0 (0) 1.00Anorexia 17 (9) 4 (6) .61Nausea 21 (11) 6 (9) .82Vomiting 17 (9) 5 (7) .80Diarrhea 14 (7) 3 (4) .57Rash 27 (14) 8 (12) .68Temperature, C 37.5 (36.639) 37.2 (36.539.4) .09

Temperature 38 C 62 (33) 12 (18) .02Systolic blood pressure, mm Hg 115 (95140) 110 (95130) .01Diastolic blood pressure, mm Hg 70 (5087) 70 (5085) .12Systolic blood pressure ! 90 mm Hg 0 (0) 1 (1) .27Pulse pressure, mm Hg 45 (3070) 40 (3060) .03Pulse, beats/min 70 (5593) 70 (6094) .84Pulse ! 60 beats/min 18 (10) 2 (3) .11Abdominal tenderness 3 (2) 0 (0) .57Pleural effusion or ascites 0 (0) 0 (0) 1.00

Laboratory results

Hematocrit, % 45.7 (36.752.1) 44.9 (35.450.3) .24Hematocrit 50% 23 (12) 4 (6) .17Leukocyte count, 10 3 leukocytes/ mL 3.4 (1.77.2) 3.6 (1.78.2) .46Leukocyte count ! leukocytes/ mL33.3 10 86 (46) 26 (38) .32Platelet count, 10 3 platelets/ mL 15 (719) 15 (819) .87

Clinical outcomesAny bleeding 1 (1) 2 (3) .17Platelet increment the next day, 10 3 platelets/ mL 7 ( 7 to 50) 11 ( 4 to 41) .26Time to platelet count platelets/ mL, days350 10 3 (14) 3 (15) .59Length of hospital stay, days 6 (48) 5 (47) .09

Death 1 (1) 0 (0) 1.00

NOTE. For dichotomous variables, data are no. (%) of patients; for continuous variables, data are median (5th95th percentiles).

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cytopenia in acute dengue infection does not correlate withbleeding risk. In pediatric DSS, thrombocytopenia did not pre-dict severe bleeding in univariate analysis; the only 2 indepen-dent predictors of severe bleeding were shock and low hemat-ocrit [8]. Another prospective pediatric study found thatbleeding score did not correlate with platelet count [11]. Ourlarge cohort of adults with acute dengue revealed that the in-

cidence of clinical bleeding at hospital admission was inde-pendent of platelet count.

The efcacy of prophylactic platelet transfusion and thethreshold for transfusion is questionable. In a prospective study of acute myeloid leukemia, lowering the platelet threshold forprophylactic platelet transfusion from platelets/ mL to320 10

platelets/ mL did not increase the incidence of bleeding310 10but signicantly reduced the number of patients who receivedplatelet transfusion [12]. In pediatric DSS, prophylactic trans-fusion of platelets and fresh frozen plasma did not reduce bleed-ing or expedite platelet recovery; instead, it caused uid over-load and prolonged hospitalization [9]. In addition, the

improvement in platelet count was transient, lasting ! 5 h [9].We have shown that prophylactic platelet transfusion did notimprove relevant outcome measures, such as clinical bleeding,platelet increment, and platelet recovery.

Our study has several limitations. Its retrospective cohortdesign does not allow for increased recruitment, and the overallnumber of episodes of clinical bleeding was small (3 [1%] of 256 patients). The lack of randomization may have resulted intreatment bias, although both the transfusion and the non-transfusion groups had similar baseline features. Our cohort of patients with platelet count ! platelets/ mL was limited320 10to adult patients and included only 6 patients with denguehemorrhagic fever, limiting the generalizability of our ndings.Additional research on the role of prophylactic platelet trans-fusion in a randomized study with a larger cohort is needed.

Because our results revealed that there were no signicantbenets of prophylactic platelet transfusion among adult pa-tients with dengue, which are similar to results of other studiesinvolving different cohorts, we no longer advocate prophylacticplatelet transfusion given on the basis of platelet count foradults with acute uncomplicated dengue infection. This ap-

proach will save precious blood products and will reduce un-necessary patient exposure to transfusion risks.

Acknowledgments

Financial support. National Healthcare Group (small innovative grantSIG/05048); National Medical Research Council (individual research grantNMRC/1006/2005).

Potential conicts of interest. All authors: no conicts.

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