Am. J. Trop. Med. Hyg., 73(2), 2005, pp. 441-444
Copyright © 2005 by The American Society of Tropical Medicine and Hygiene
ENDOSCOPIC FINDINGS AND MANAGEMENT OF DENGUE PATIENTS WITH UPPER GASTROINTESTINAL BLEEDING
YI-CHUN CHIU,
KENG-LIANG WU,
CHUNG-HUANG KUO,
TSUNG-HUI HU,
YEH-PIN CHOU,
SENG-KEE CHUAH,
CHUNG-MOU KUO,
KWONG-MING KEE,
CHI-SIN CHANGCHIEN,
JIEN-WEI LIU, AND
KING-WAH CHIU*
Division of Gastroenterology, Department of Internal Medicine, and Department of Infection Control, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China
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ABSTRACT
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There are 100 million cases of dengue infection, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths annually due to dengue worldwide. Gastrointestinal bleeding is the most common type of severe hemorrhage in dengue fever. However, there are no reports about the clinical applications of endoscopic therapy for upper gastrointestinal bleeding (UGI) in dengue patients. From June 17, 2002 to January 30, 2003, 1,156 patients with confirmed dengue virus infection were treated at Kaohsiung Chang Gung Memorial Hospital in Taiwan. We analyzed those patients who had received endoscopic therapy for UGI. The characteristic endoscopic findings, therapeutic courses, and amount of blood component transfused were collected from their charts for statistical analysis. Among the 1,156 dengue patients, 97 (8.4%) had complications of UGI bleeding during hospitalization. The endoscopic findings included hemorrhagic (and/or erosive) gastritis in 67% of the patients, gastric ulcer in 57.7%, duodenal ulcer in 26.8%, and esophageal ulcer in 3.1%. Of the 73 patients with peptic ulcer, 42 (57.5%) met the endoscopic criteria (recent hemorrhage) for endoscopic hemostasis therapy. Peptic ulcer patients with recent hemorrhage required more transfusions with packed red blood cells (P = 0.002) and fresh frozen plasma (P = 0.05) than those without recent hemorrhage. Among these 42 patients with recent hemorrhage, endoscopic injection therapy was conducted in 15 patients (group A). The other 27 patients (group B) did not receive endoscopic therapy. After endoscopy, patients in group A required more transfusions with packed red blood cells (P = 0.03) and fresh frozen plasma (P = 0.014) than did patients in group B. There were no significant differences between groups A and B in duration of hospital stay and amounts of transfused platelet concentrate after endoscopy. Medical treatment with blood transfusion is the mainstay of management of UGI bleeding in dengue patients. Patients having peptic ulcer with recent hemorrhage require more transfusions with packed red blood cells and fresh frozen plasma for management of UGI bleeding than those without recent hemorrhage. However, when peptic ulcer with recent hemorrhage is encountered during the endoscopic procedure, endoscopic injection therapy is not an effective adjuvant treatment of hemostasis in dengue patients with UGI bleeding.
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INTRODUCTION
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Dengue fever (DF) is an acute mosquito-transmitted disease caused by the dengue fever virus of the family Flaviviridae, which is the most common cause of arboviral disease in the world. Clinical manifestations of dengue infection range from fever, headache, arthralgia, myalgia, and skin rash, to severe hemorrhage, shock, and death.1 It is estimated that there are 100 million cases of dengue infection, 500,000 cases of dengue hemorrhagic fever, and 25,000 deaths due to dengue annually worldwide.2 Dengue hemorrhagic fever is a leading cause of hospitalization and death among children in many southeast Asian countries.2 Taiwan has been a disease-endemic area for DF since 1870,3 and several major island-wide outbreaks of DF have occurred.4 The most recent outbreak of DF occurred in southern Taiwan beginning in July 2002.
Gastrointestinal bleeding is the most common type of severe hemorrhage in DF.5 There have been few reports concerning upper gastrointestinal (UGI) endoscopic findings1,6–9 and none about the clinical application of endoscopic therapy in UGI bleeding of dengue patients. In general, peptic ulcers with recent hemorrhage, including active arterial bleeding, nonbleeding visible vessels, nonbleeding adherent clots, or persistent oozing, are recommended to be treated endoscopically.10,11 However, the role of endoscopic therapy in treating UGI bleeding of dengue patients has not been thoroughly investigated. The aim of this study was to investigate the endoscopic findings, treatment, and the following prognosis of UGI bleeding of the patients in this recent outbreak.
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PATIENTS AND METHODS
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From June 17, 2002 to January 30, 2003, we treated 1,156 patients with clinically proven DF at Kaohsiung Chang Gung Memorial Hospital. All patients were from the DF-endemic area in southern Taiwan. Serologic tests were conducted for further confirmation of DF. A positive serologic test result was defined as a 
4-fold change in reciprocal IgG antibody titers to one or more dengue virus antigens in paired serum samples, or a positive IgM antibody test result on a late acute or convalescent phase serum specimen by enzyme-linked immunosorbent assay. Viral isolation and serologic studies indicated that type II dengue fever was the cause.
We collected data of dengue patients who were treated by endoscopy (GIF-Q240; Olympus Optical Co., Ltd., Tokyo, Japan) due to complications of UGI bleeding. Ulcers with recent hemorrhage, including active arterial bleeding, non-bleeding visible vessels, nonbleeding adherent clots, and persistent oozing, were indicators for endoscopic hemostasis therapy.10,11 The clinical characteristics, endoscopic findings, therapeutic courses, and numbers of transfusions required for treating thrombocytopenia, anemia, coagulopathy, and hypovolemia were obtained from the charts for statistical analysis. A P value 
0.05 was considered statistically significant.
We conducted the study in accordance with the Declaration of Helsinki. All dengue patients who underwent UGI endoscopy were informed of the details and possible complications of this procedure, and written informed consent was obtained from all patients.
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RESULTS
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Ninety-seven (8.4%) of 1,156 patients had complications of UGI bleeding during hospitalization. Fifty of these patients were female and 47 were male. Fourteen (14.4%) of the 97 patients had a history of peptic ulcer disease. None of them received aspirin, nonsteroidal anti-inflammatory drugs, or steroids before or during hospitalization. The mean ± SD age of the patients was 59 ± 14 years (age range = 20–80 years). The clinical manifestations at the time of admission included fever in 92 cases (94.8%), melena in 67 (69.1%), hematemesis in 25 (25.8%), and abdominal pain in 22 (22.7%). Upper gastrointestinal bleeding occurred a median of 4 days (range = 1–9) after the onset of fever, with a median duration of hospital stay of 7 days (range = 2–30). Hematologic investigation at the time of admission detected leukopenia in 37 patients (38.1%), anemia in 55 (56.7%), and thrombocytopenia in 95 (97.9%). Prolonged prothrombin time (PT, normal range = 10–14 seconds) and activated partial thromboplastin time (APTT, normal range = 23.3–39.3 seconds) were observed in 5 (7.5%) of 67 and 47 (70.1%) of 67 patients, respectively. Increased levels were observed for aspartate aminotransferase (mean ± SD = 285.3 ± 723.6 U/L) and alanine aminotransferase (198.3 ± 316.2 U/L) in 69 (85.2%) of 81 patients and 63 (85.1%) of 74 patients, respectively. The mean ± SD amounts of blood components transfused were 26.2 ± 20.5 units of platelet concentrate, 1.6 ± 3.9 units of packed red blood cells (PRBCs), and 1.3 ± 3.5 units of fresh frozen plasma (FFP).
Endoscopic findings and their rate of incidence are shown on Table 1
. Hemorrhagic (and/or erosive) gastritis was the most common finding among these patients (67.0%), followed by gastric ulcer (57.7%), duodenal ulcer (26.8%), and esophageal ulcer (3.1%). Peptic ulcer was found in 73 patients (75.3%). However, there was no significant difference in histories of peptic ulcer disease between ulcer and non-ulcer patients (P > 0.5, by Fisher’s exact test) (Table 2). Of the 73 patients with peptic ulcer, 42 (57.5%) had endoscopic findings that met the criteria of recent hemorrhage, which indicated the need for endoscopic hemostasis therapy (Table 3).
Comparison of the clinical characteristics and transfusion requirements between peptic ulcer patients with and without recent hemorrhage is shown in Table 4. There were no significant differences in age, sex, lowest platelet count, PT, APTT, duration of hospital stay, rebleeding rate, mortality rate, and amounts of transfused platelet concentrate between patients having peptic ulcer with and without recent hemorrhage. However, there was a significant difference in transfusion requirements of PRBCs (P = 0.002, by Mann-Whitney U test) and FFP (P = 0.05, by Mann-Whitney U test). Peptic ulcer patients with recent hemorrhage required more transfusions with PRBCs and FFP for management of UGI bleeding than those without recent hemorrhage. Among the 42 patients with peptic ulcer and recent hemorrhage, endoscopic injection therapy with 6–10 mL of epinephrine diluted 1: 0,000 was given to 15 patients (group A), whereas the other 27 patients (group B) did not receive endoscopic therapy due to the awareness of the physicians of an underlying bleeding tendency or intolerance and poor compliance of the patients. After the endoscopic procedure, medical treatment with intravenous proton pump inhibitor had been used in all 42 patients until the bleeding stopped, and an oral proton pump inhibitor was then prescribed.
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TABLE 4 Comparison of the clinical characteristics and transfusion requirements between patients having peptic ulcers with and without recent hemorrhage*
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Comparison of the clinical characteristics and transfusion requirements between groups A and B is shown in Table 5. There were no significant differences in age, sex, lowest platelet count, PT, and APTT between groups A and B. The median duration of hospital stay after endoscopy was 7.5 days (range = 2–20 days) in group A and 5 days (range = 2–15 days) in group B (P = 0.209, by Mann-Whitney U test). The rebleeding rate was 6.7% (1 of 15) in group A and 0% (0 of 27) in group B (P = 0.357, by Fisher’s exact test). There were significant differences in transfusion requirements of PRBCs (P = 0.03, by Mann-Whitney U test) and FFP (P = 0.014, by Mann-Whitney U test) after endoscopy between groups A and group B, but no significant difference in transfusion requirements of platelet concentrate after endoscopy (P = 0.254, by Mann-Whitney U test). After endoscopy, patients in group A required more transfusions with PRBCs and FFP than patients in group B. None of the patients received surgical intervention to stop UGI bleeding. Two patients in group A died on the day after admission due to toxic hemorrhagic shock. Consequently, the overall mortality rate was 2.1%. There was no significant difference in mortality rate between groups A and B (P = 0.122, by Fisher’s exact test).
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TABLE 5 Comparison of the clinical characteristics and transfusion requirements after endoscopy between groups A and B*
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DISCUSSION
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Bleeding, one of the major problems encountered in DF, contributes to a worsening morbidity. The toxic hemorrhagic stage appears during the third to fifth day of the illness, following the onset of fever, followed by the convalescent stage.12 The pathogenesis of hemorrhage could be multifactorial and include vasculopathy, platelet deficiency and dys-function, and blood coagulation defects.13 The most common hemorrhagic manifestations are epistaxis, skin hemorrhages, and gastrointestinal hemorrhages.14 The reported prevalence of gastrointestinal bleeding in dengue patients varies from 5% to 30%.5–8 Most UGI bleeding occurs on the fourth day after the onset of fever.9 The most severe thrombocytopenia was reported on days 4–5 after the onset of fever.12 In addition, almost all of the dengue patients recovered after 7–14 days.12 In our series, UGI bleeding developed in 8.4% of the 1,156 patients and occurred a median of 4 days (range = 1–9 days) after the onset of fever, with a median duration of hospital stay of 7 days (range = 2–30 days). During this period of thrombocytopenia, blood transfusion therapy with platelet concentrate, PRBCs, and FFP became the mainstay of treatment to correct the bleeding tendency, anemia, coagulopathy, and hypovolemic shock.14 Close monitoring of vital signs and hematocrit to evaluate the severity of hemorrhage is mandatory to reduce morbidity. However, this acute disease will soon subside, and platelet count and function will spontaneously return to normal.
In the few reports of endoscopic findings for dengue patients with UGI bleeding, hemorrhagic gastritis was the most common finding (40.9–58.5%).1,9 In our study, hemorrhagic (and/or erosive gastritis) was also the most common finding in these patients (67.0%), followed by gastric ulcer (57.7%), duodenal ulcer (26.8%), and esophageal ulcer (3.1%). There was no significant difference in histories of peptic ulcer disease between the ulcer and non-ulcer groups. Of the 73 patients with peptic ulcer, 42 (57.5%) had endoscopic findings that met the criteria of recent hemorrhage. The prevalence of recent hemorrhage has been reported with a wide range for active arterial bleeding (2–8%), non-bleeding visible vessel (4–35%), nonbleeding adherent clot (30–43%), and persistent oozing (3–18%).15–18 To the best of our knowledge, there has been no study concerning the prevalence of recent hemorrhage in patients with thrombocytopenia and coagulation disorder. In our study, the prevalence of active arterial bleeding, non-bleeding visible vessel, nonbleeding adherent clot, and persistent oozing was 0%, 6.8%, 35.6%, and 15.1%, respectively. Furthermore, there were no differences in lowest platelet count, PT, and APTT between dengue patients having peptic ulcer with and without recent hemorrhage. The presence of recent hemorrhage may represent an eroded vessel on the ulcer base,19 It also indicates a higher risk of rebleeding and mortality.15–18 In our series, there were no differences in rebleeding rate and mortality rate between dengue patients having peptic ulcer with and without recent hemorrhage. However, more transfusions of PRBCs and FFP were required with the presence of recent hemorrhage in bleeding peptic ulcers.
The role of endoscopic therapy in UGI bleeding of dengue patients is still unknown. In general, bleeding peptic ulcers can be treated effectively with the standard endoscopic therapies including injection therapy, coagulation therapy, and mechanical therapy.10,11,20 Peptic ulcers with active arterial bleeding, nonbleeding visible vessels, nonbleeding adherent clots, or persistent oozing are recommended to be treated endoscopically.10,11 Among these therapeutic modalities, endoscopic injection with a variety of agents such as epinephrine (1:10,000 dilution) have been used successfully alone or in combination with thermal contact devices to achieve hemostasis and prevent rebleeding.11 Although injection therapy creates 3–5 tiny needle holes around the bleeding ulcers, the resulting effects of tamponade and vasoconstriction can be used to stop bleeding.21 The activation of coagulation cascade with platelet aggregation can then secure the effect of hemostasis achieved by injection therapy. However, in cases of extreme bleeding tendency, such as severe thrombocytopenia and coagulation disorder, the temporary effect of tamponade and vasoconstriction may not work consistently, and could increase the possibility of recurrent bleeding from the injection sites. Indeed, bleeding from the injection sites was observed immediately after injection therapy in two patients in our series. Temporary hemostasis achieved by injection therapy does not stop ongoing bleeding persistently, and bleeding from injection sites might increase blood loss after injection therapy. This may be the reason why more transfusions of PRBCs and FFP were required after the dengue patients received endoscopic injection therapy in our study. Therefore, blood transfusion therapy with platelet concentrate, PRBCs, and FFP to correct the bleeding tendency, anemia, coagulopathy, and hypovolemia is still the mainstay of treatment of UGI bleeding in dengue patients. Endoscopic injection therapy cannot play an assisting role in stopping bleeding. Further studies to investigate other endoscopic modalities are needed to prove their safety and effectiveness.
In conclusion, DF is an acute disease that may induce severe hemorrhage by multifactorial pathogenesis with spontaneous recovery within 7–14 days. Medical treatment with blood transfusion is the mainstay of management for UGI bleeding in the acute stage of DF. Patients having peptic ulcer with recent hemorrhage require more transfusions with PRBCs and FFP for management of UGI bleeding than do those without recent hemorrhage. It should also be noted that when peptic ulcer with recent hemorrhage is encountered during an endoscopic procedure, endoscopic injection therapy is not an effective adjuvant treatment of hemostasis in dengue patients with UGI bleeding.
Received August 18, 2004.
Accepted for publication February 16, 2005.
Acknowledgments: We thank the members of the Infection Control Committee of Chang Gung Memorial Hospital–Kaohsiung Medical Center for their permission to use the data in this report, and J. C. Bartimus (Kaohsiung Medical University) for his help with the English.
* Address correspondence to Dr. King-Wah Chiu, Division of Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Kaohsiung 83305, Taiwan, Republic of China. E-mail: chiuku{at}ms14.hinet.net 
Authors’ addresses: Yi-Chun Chiu, Keng-Liang Wu, Chung-Huang Kuo, Tsung-Hui Hu, Yeh-Pin Chou, Seng-Kee Chuah, Chung-Mou Kuo, Kwong-Ming Kee, Chi-Sin Changchien, and King-Wah Chiu, Division of Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Kaohsiung, 83305, Taiwan, Republic of China. Jien-Wei Liu, Department of Infection Control, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan, Republic of China.
Reprint requests: King-Wah Chiu, Division of Gastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123 Ta-Pei Road, Kaohsiung, 83305, Taiwan, Republic of China, Telephone: 886-7-731-7123 extension 8301, Fax: 886-7-731-8762, E-mail: chiuku{at}ms14.hinet.net.
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ABSTRACT
INTRODUCTION
