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Risk factors for hemorrhage in severe dengue infections
Risk factors for hemorrhage in severe dengue infections Lucy Chai See Lum, MBBS, MRCP, EDIC, Adrian Yu Teik Goh, MBBS, MMed, MRCP, Patrick Wai Keong Chan, MBBS, MMed, MRCP, Abdel-Latif Mohd El-Amin, MBBS, MPH, MPH (Epid), and Sai Kit Lam, MSc, PhD, FRCPath, FRCP, FASc The purpose of this study was to identify the early indicators of hemorrhage in severe dengue infections in 114 patients; 24 patients had severe hemorrhage and 92 had no hemorrhage. The platelet counts were not predictive of bleeding. The duration of shock (OR, 2.11; 95% CI, 1.13 to 3.92; P = .019) and low-normal hematocrit at the time of shock (OR, 0.72; 95% CI, 0.55 to 0.95; P = .020) were risk factors of severe hemorrhage. (J Pediatr 2002;140:629-31)
Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is characterized by capillary permeability and a bleeding diathesis. Hypovolemic shock ensues after the loss of fluid into interstitial and serosal spaces. Hemorrhage, usually in the gastrointestinal tract, may accompany DHF/DSS. Bleeding and the concurrent plasma leakage that causes hemoconcentration result in inherent difficulties in the use of laboratory criteria for recognition of hemorrhage. The fear of a fatal outcome in DHF/DSS has led to the growing practice of anticipatory administration of platelet concentrates to prevent hemorrhage. As a guide to a more evidence-based management of severe dengue infections, we reviewed cases of dengue admitted to the Department of Pediatrics, University of Malaya Medical Center,
Kuala Lumpur, between January 1991 and December 1999, searching for risk factors that were early indicators of hemorrhage.
during their illness.1 Patients with dengue fever (DF) and severe hemorrhage also were included. A standard format for obtaining clinical and laboratory information have been applied for patients with dengue in the department; data were retrieved through a review of medical records of patients studied retrospectively. Retrieved data were verified independently by one of the authors. Patients were classified accordingly: Group 1 had significant hemorrhage and group 2 had mild or no hemorrhage.
Definitions
METHODS Patients Patients with DSS admitted to the Pediatric Intensive Care Unit between January 1991 to December 1999 were studied prospectively. Patients who were admitted to the general pediatric wards during the same period were enrolled retrospectively. The inclusion criteria were acute dengue infection confirmed either by a 4-fold or more increase in hemagglutination inhibition antibodies, using standard commercial rapid test1 between acute and convalescent sera or isolation of dengue virus plus a diagnosis of DSS at any time
From the Department of Pediatrics and Department of Medical Microbiology, University of Malaya Medical Center, Kuala Lumpur, Malaysia.
Submitted for publication Aug 21, 2001; revision received Jan 7, 2002; accepted Feb 6, 2002. Reprint requests: Dr Lucy Chai See Lum, Department of Pediatrics, University of Malaya Medical Center, 59100 Kuala Lumpur, Malaysia. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/22/123665 doi:10.1067/mpd.2002.123665
Shock in DSS is categorized as grade III, in which circulatory failure is manifest by rapid and weak pulse with narrowing of the pulse pressure1; grade IV shock is profound shock with an undetectable pulse and blood pressure. Hypotension was defined as systolic blood pressure below 80 mm Hg for patients more than 1 year old and below 70 mm Hg for infants. Abnormal glycemia was defined as a blood glucose concentration outside of the range of 3.5 to 8.0 mmol/L. DHF/DSS DF
Dengue hemorrhagic fever/dengue shock syndrome Dengue fever
Significant hemorrhage was defined as hemorrhage accompanied by a drop in hematocrit and hemodynamic disturbances. Encephalopathy was any state of consciousness below normal alert state. Liver failure was defined as severe impairment of prothrombin time ratio and hepatic transaminases. Duration of shock was based on the occur629
LUM ET AL
THE JOURNAL OF PEDIATRICS MAY 2002
Table I. Clinical and laboratory data (univariate analysis) and outcome of severe hemorrhage in DSS
Clinical/laboratory data Age (y)* Hypotension (%) Mottling (%) Encephalopathy (%) Liver failure (%) Abnormal glycemia (%) Duration of shock (h)* Platelet count at admission (109/L)* Hematocrit at admission (%)* Lowest platelet count* Prothrombin time ratio* Partial thromboplastin time (s)* Serum creatinine (µmol/L) at admission*
Group 1 (significant hemorrhage) n = 22*
Group 2 (no/mild hemorrhage) n = 92*
P value
7.0 (0.3–12.0) 68.1 45.0 63.3 63.6 61.9 12.0 (2.0–24.0) 60.5 (7.0–219.0) 39.5 (14.0–64.0) 17.0 (7.0–90.0) 2.16 (1.0–4.0) 120.0 (48.5–200.0) 198.0 (448.0–938.0)
6.0 (0.2–11.7) 37.8 22.0 28.3 22.0 17.4 4.0 (0–10.2) 61.0 (11.5–187.9) 45.0 (31.3–60.0) 22.0 (5.3–99.5) 1.19 (1.0–2.4) 72.2 (36.8–182.8) 74.0 (24.5–637.7)
.801 .010 .027 .002 .000 .000 .000 .902 .032 .227 .000 .001 .022
*Data shown are median (2.5-97.5 percentile). Number of deaths was 6 of 22 for group 1; none for group 2 (P = .001).
Table II. Multivariate logistic regression analysis of clinical and laboratory features
Clinical and laboratory features Encephalopathy Mottling Hypotension Duration of shock Hematocrit at admission Liver failure Renal failure at admission Prothrombin time ratio Abnormal glycemia Partial thromboplastin time
rence of symptoms of shock, oliguria, or postural giddiness. A secondary dengue infection was defined as a convalescent (hemagglutination inhibition) titer of 1:1280 or more.2
Statistical Analysis Data were managed with SPSS statistical package version 10.0.1 for Windows 1998 (Chicago, Ill). Dichotomous measures were compared by means of the χ2 test. If the minimum expected frequency requirements for the χ2 test were not met, the Fisher exact test was used instead. The Mann-Whitney U test was used for continuous variables. Mul630
Odds ratio
95% CI
β
P value
0.01 0.08 2.28 2.11 0.72 1.8 104 1.44 0.10 2.71 1.03
0.00–41.89 0.00–15.50 0.18–28.19 1.13–3.92 0.55–0.95 0.50–6.80 108 0.10–249.90 0.00–46.89 0.22–33.68 0.98–1.07
–4.40 –2.50 0.08 0.75 –0.33 9.83 0.37 –2.30 1.00 0.03
.289 .350 .521 .019 .020 .067 .889 .454 .437 .262
tivariate logistic regression analysis was used to weight the parameters found to be significant in the univariate analysis. A value of P < .05 was considered statistically significant.
RESULTS One hundred fourteen patients fulfilled the enrollment criteria of DSS and severe dengue infection; 76 were admitted to the Pediatric Intensive Care Unit and 38 to the general pediatric wards. They were between 7 days and 12.3 years of age (mean age, 5.96 years); 85
patients had DSS grade III, 25 had DSS grade IV, and 4 had DF. There were 22 patients in group 1 and 92 in group 2. All cases fulfilled serologic criteria for infection; virus isolation was attempted in all cases and was positive in 17. Hemorrhage occurred in the gastrointestinal tract in 21 cases and in the brain in 1 case. Of the 4 cases with DF, 2 had received a nonsteroidal analgesic medication. They were excluded from the analysis of thrombocytopenia. All infants younger than 1 year of age had primary infections, whereas 78.3% of patients older than 1 year of age had secondary infections.
LUM ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 140, NUMBER 5 Univariate analysis (Table I) showed that factors associated with severe hemorrhage included hypotension, mottling, encephalopathy, organ failure, prolonged duration of shock, abnormal glycemia, normal-low hematocrit at the diagnosis of shock, and abnormal coagulation (P < .05). However, multivariate logistic regression (Table II) identified the duration of shock and a normal-low hematocrit at the diagnosis of shock as significant associations with severe hemorrhage.
DISCUSSION Our data showed that the platelet count at admission or the lowest recorded platelet count did not correlate with bleeding, concurring with a previous report3 suggesting that severe hemorrhage in DHF/DSS was not only caused by thrombocytopenia. The use of a platelet count value of <50 109/L as an admission criteria in dengue infection4 cannot be supported. Severe hemorrhage occurring with the use of nonsteroidal analgesic agents supports the role of platelet dysfunction5,6 (or possibly enhancement of viral replication) in the pathogenesis of bleeding in DHF/DSS. The strongest risk factors for hemorrhage in DHF/DSS were prolonged duration of shock and a hematocrit within the normal-low range at the time of shock, suggesting that patients with prolonged shock not only had plasma
leakage but also bleeding. Prolonged prothrombin time and partial thromboplastin time were not directly responsible for the severe bleeding but were more likely to be prolonged in protracted shock, in keeping with previous reports.7 Multiorgan failure in severe hemorrhage was most likely a function of the duration of hypoperfusion. The incidence of encephalopathy in our series was 35%. We postulate that fluid restriction imposed in cases of acute encephalopathy, when applied to DSS, might result in failure to correct hypovolemia, thus prolonging the shock. Infants younger than 1 year of age, who formed the largest age group of children with DSS (18%), had exclusively primary infections, supporting the hypothesis that passively acquired maternal dengue antibodies are a risk factor for severe DHF/DSS.8,9 The high rate of primary infection in our cases of DHF/DSS could be due to the virulence of the virus.10 The risk factors of hemorrhage in DHF/DSS are prolonged shock with a normal or low hematocrit at the time of shock. The prevention of hemorrhage in DHF/DSS should be directed at early recognition of shock and prompt correction of circulatory status.
REFERENCES 1. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd ed. WHO Geneva Publication, 1997. Chapter 2:15-6.
2. Lam SK. Rapid dengue diagnosis and interpretation. Malays J Pathol 1993; 15:9-12. 3. Chuansumrit A, Philmothares V, Tardtong P, Tapaneya-Olarn C, Tapaneya-Olarn W, Kowsathit P, et al. Transfusion requirements in patients with dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 2000;31:10-4. 4. Chin CK. Outpatient management of dengue infection in the University Hospital, Kuala Lumpur. Malays J Pathol 1993;15:21-3. 5. Mitrakul C, Poshyachinda M, Futrakul P, Sangkawibha N, Ahandrik S. Hemostatic and platelet kinetic studies in dengue hemorrhagic fever. Am J Trop Med Hyg 1977;26:975-84. 6. Srichaikul T, Nimmannitya S, Sripaisarn T, Kamolsilpa M, Pulgate C. Platelet function during the acute phase of dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 1989;20:19-24. 7. Mitrakul C. Bleeding diathesis in dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 1979;10:434-7. 8. Halstead SB, Nimmannitya S, Cohen SN. Observations related to pathogenesis of dengue hemorrhagic fever, IV: relation of disease severity to antibody response and virus recovered. Yale J Biol Med 1970;42:311-28. 9. Kliks SC, Nimmanitya S, Nisalak A, Burke DS. Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am J Trop Med Hyg 1988;38:411-9. 10. Murgue B, Roche C, Chungue E, Deparis X. Prospective study of the duration and magnitude of viraemia in children hospitalised during the 19961997 dengue-2 outbreak in French Polynesia. J Med Virol 2000;60:432-8.
631
Dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) is characterized by capillary permeability and a bleeding diathesis. Hypovolemic shock ensues after the loss of fluid into interstitial and serosal spaces. Hemorrhage, usually in the gastrointestinal tract, may accompany DHF/DSS. Bleeding and the concurrent plasma leakage that causes hemoconcentration result in inherent difficulties in the use of laboratory criteria for recognition of hemorrhage. The fear of a fatal outcome in DHF/DSS has led to the growing practice of anticipatory administration of platelet concentrates to prevent hemorrhage. As a guide to a more evidence-based management of severe dengue infections, we reviewed cases of dengue admitted to the Department of Pediatrics, University of Malaya Medical Center,
Kuala Lumpur, between January 1991 and December 1999, searching for risk factors that were early indicators of hemorrhage.
during their illness.1 Patients with dengue fever (DF) and severe hemorrhage also were included. A standard format for obtaining clinical and laboratory information have been applied for patients with dengue in the department; data were retrieved through a review of medical records of patients studied retrospectively. Retrieved data were verified independently by one of the authors. Patients were classified accordingly: Group 1 had significant hemorrhage and group 2 had mild or no hemorrhage.
Definitions
METHODS Patients Patients with DSS admitted to the Pediatric Intensive Care Unit between January 1991 to December 1999 were studied prospectively. Patients who were admitted to the general pediatric wards during the same period were enrolled retrospectively. The inclusion criteria were acute dengue infection confirmed either by a 4-fold or more increase in hemagglutination inhibition antibodies, using standard commercial rapid test1 between acute and convalescent sera or isolation of dengue virus plus a diagnosis of DSS at any time
From the Department of Pediatrics and Department of Medical Microbiology, University of Malaya Medical Center, Kuala Lumpur, Malaysia.
Submitted for publication Aug 21, 2001; revision received Jan 7, 2002; accepted Feb 6, 2002. Reprint requests: Dr Lucy Chai See Lum, Department of Pediatrics, University of Malaya Medical Center, 59100 Kuala Lumpur, Malaysia. Copyright © 2002, Mosby, Inc. All rights reserved. 0022-3476/2002/$35.00 + 0 9/22/123665 doi:10.1067/mpd.2002.123665
Shock in DSS is categorized as grade III, in which circulatory failure is manifest by rapid and weak pulse with narrowing of the pulse pressure1; grade IV shock is profound shock with an undetectable pulse and blood pressure. Hypotension was defined as systolic blood pressure below 80 mm Hg for patients more than 1 year old and below 70 mm Hg for infants. Abnormal glycemia was defined as a blood glucose concentration outside of the range of 3.5 to 8.0 mmol/L. DHF/DSS DF
Dengue hemorrhagic fever/dengue shock syndrome Dengue fever
Significant hemorrhage was defined as hemorrhage accompanied by a drop in hematocrit and hemodynamic disturbances. Encephalopathy was any state of consciousness below normal alert state. Liver failure was defined as severe impairment of prothrombin time ratio and hepatic transaminases. Duration of shock was based on the occur629
LUM ET AL
THE JOURNAL OF PEDIATRICS MAY 2002
Table I. Clinical and laboratory data (univariate analysis) and outcome of severe hemorrhage in DSS
Clinical/laboratory data Age (y)* Hypotension (%) Mottling (%) Encephalopathy (%) Liver failure (%) Abnormal glycemia (%) Duration of shock (h)* Platelet count at admission (109/L)* Hematocrit at admission (%)* Lowest platelet count* Prothrombin time ratio* Partial thromboplastin time (s)* Serum creatinine (µmol/L) at admission*
Group 1 (significant hemorrhage) n = 22*
Group 2 (no/mild hemorrhage) n = 92*
P value
7.0 (0.3–12.0) 68.1 45.0 63.3 63.6 61.9 12.0 (2.0–24.0) 60.5 (7.0–219.0) 39.5 (14.0–64.0) 17.0 (7.0–90.0) 2.16 (1.0–4.0) 120.0 (48.5–200.0) 198.0 (448.0–938.0)
6.0 (0.2–11.7) 37.8 22.0 28.3 22.0 17.4 4.0 (0–10.2) 61.0 (11.5–187.9) 45.0 (31.3–60.0) 22.0 (5.3–99.5) 1.19 (1.0–2.4) 72.2 (36.8–182.8) 74.0 (24.5–637.7)
.801 .010 .027 .002 .000 .000 .000 .902 .032 .227 .000 .001 .022
*Data shown are median (2.5-97.5 percentile). Number of deaths was 6 of 22 for group 1; none for group 2 (P = .001).
Table II. Multivariate logistic regression analysis of clinical and laboratory features
Clinical and laboratory features Encephalopathy Mottling Hypotension Duration of shock Hematocrit at admission Liver failure Renal failure at admission Prothrombin time ratio Abnormal glycemia Partial thromboplastin time
rence of symptoms of shock, oliguria, or postural giddiness. A secondary dengue infection was defined as a convalescent (hemagglutination inhibition) titer of 1:1280 or more.2
Statistical Analysis Data were managed with SPSS statistical package version 10.0.1 for Windows 1998 (Chicago, Ill). Dichotomous measures were compared by means of the χ2 test. If the minimum expected frequency requirements for the χ2 test were not met, the Fisher exact test was used instead. The Mann-Whitney U test was used for continuous variables. Mul630
Odds ratio
95% CI
β
P value
0.01 0.08 2.28 2.11 0.72 1.8 104 1.44 0.10 2.71 1.03
0.00–41.89 0.00–15.50 0.18–28.19 1.13–3.92 0.55–0.95 0.50–6.80 108 0.10–249.90 0.00–46.89 0.22–33.68 0.98–1.07
–4.40 –2.50 0.08 0.75 –0.33 9.83 0.37 –2.30 1.00 0.03
.289 .350 .521 .019 .020 .067 .889 .454 .437 .262
tivariate logistic regression analysis was used to weight the parameters found to be significant in the univariate analysis. A value of P < .05 was considered statistically significant.
RESULTS One hundred fourteen patients fulfilled the enrollment criteria of DSS and severe dengue infection; 76 were admitted to the Pediatric Intensive Care Unit and 38 to the general pediatric wards. They were between 7 days and 12.3 years of age (mean age, 5.96 years); 85
patients had DSS grade III, 25 had DSS grade IV, and 4 had DF. There were 22 patients in group 1 and 92 in group 2. All cases fulfilled serologic criteria for infection; virus isolation was attempted in all cases and was positive in 17. Hemorrhage occurred in the gastrointestinal tract in 21 cases and in the brain in 1 case. Of the 4 cases with DF, 2 had received a nonsteroidal analgesic medication. They were excluded from the analysis of thrombocytopenia. All infants younger than 1 year of age had primary infections, whereas 78.3% of patients older than 1 year of age had secondary infections.
LUM ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 140, NUMBER 5 Univariate analysis (Table I) showed that factors associated with severe hemorrhage included hypotension, mottling, encephalopathy, organ failure, prolonged duration of shock, abnormal glycemia, normal-low hematocrit at the diagnosis of shock, and abnormal coagulation (P < .05). However, multivariate logistic regression (Table II) identified the duration of shock and a normal-low hematocrit at the diagnosis of shock as significant associations with severe hemorrhage.
DISCUSSION Our data showed that the platelet count at admission or the lowest recorded platelet count did not correlate with bleeding, concurring with a previous report3 suggesting that severe hemorrhage in DHF/DSS was not only caused by thrombocytopenia. The use of a platelet count value of <50 109/L as an admission criteria in dengue infection4 cannot be supported. Severe hemorrhage occurring with the use of nonsteroidal analgesic agents supports the role of platelet dysfunction5,6 (or possibly enhancement of viral replication) in the pathogenesis of bleeding in DHF/DSS. The strongest risk factors for hemorrhage in DHF/DSS were prolonged duration of shock and a hematocrit within the normal-low range at the time of shock, suggesting that patients with prolonged shock not only had plasma
leakage but also bleeding. Prolonged prothrombin time and partial thromboplastin time were not directly responsible for the severe bleeding but were more likely to be prolonged in protracted shock, in keeping with previous reports.7 Multiorgan failure in severe hemorrhage was most likely a function of the duration of hypoperfusion. The incidence of encephalopathy in our series was 35%. We postulate that fluid restriction imposed in cases of acute encephalopathy, when applied to DSS, might result in failure to correct hypovolemia, thus prolonging the shock. Infants younger than 1 year of age, who formed the largest age group of children with DSS (18%), had exclusively primary infections, supporting the hypothesis that passively acquired maternal dengue antibodies are a risk factor for severe DHF/DSS.8,9 The high rate of primary infection in our cases of DHF/DSS could be due to the virulence of the virus.10 The risk factors of hemorrhage in DHF/DSS are prolonged shock with a normal or low hematocrit at the time of shock. The prevention of hemorrhage in DHF/DSS should be directed at early recognition of shock and prompt correction of circulatory status.
REFERENCES 1. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd ed. WHO Geneva Publication, 1997. Chapter 2:15-6.
2. Lam SK. Rapid dengue diagnosis and interpretation. Malays J Pathol 1993; 15:9-12. 3. Chuansumrit A, Philmothares V, Tardtong P, Tapaneya-Olarn C, Tapaneya-Olarn W, Kowsathit P, et al. Transfusion requirements in patients with dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 2000;31:10-4. 4. Chin CK. Outpatient management of dengue infection in the University Hospital, Kuala Lumpur. Malays J Pathol 1993;15:21-3. 5. Mitrakul C, Poshyachinda M, Futrakul P, Sangkawibha N, Ahandrik S. Hemostatic and platelet kinetic studies in dengue hemorrhagic fever. Am J Trop Med Hyg 1977;26:975-84. 6. Srichaikul T, Nimmannitya S, Sripaisarn T, Kamolsilpa M, Pulgate C. Platelet function during the acute phase of dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 1989;20:19-24. 7. Mitrakul C. Bleeding diathesis in dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 1979;10:434-7. 8. Halstead SB, Nimmannitya S, Cohen SN. Observations related to pathogenesis of dengue hemorrhagic fever, IV: relation of disease severity to antibody response and virus recovered. Yale J Biol Med 1970;42:311-28. 9. Kliks SC, Nimmanitya S, Nisalak A, Burke DS. Evidence that maternal dengue antibodies are important in the development of dengue hemorrhagic fever in infants. Am J Trop Med Hyg 1988;38:411-9. 10. Murgue B, Roche C, Chungue E, Deparis X. Prospective study of the duration and magnitude of viraemia in children hospitalised during the 19961997 dengue-2 outbreak in French Polynesia. J Med Virol 2000;60:432-8.
631