• View in gallery

    Age distribution and liver function tests in patient groups. The age distribution (A), and liver functional tests including levels of alanine aminotransferase (ALT, B) and asparate aminotransferase (AST, C) are shown. There were 41 healthy controls (HBV−DV−), 307 patients with only dengue infection (HBV−DV+), 47 patients with only HBV chronic infection (HBV+DV−), and 27 patients with both viral infections (HBV+DV+). The ALT and AST values were compared among groups, and significant differences are marked by their respective P values. The box-and-whiskers show median and 25th and 75th percentiles of data distribution.

  • View in gallery

    Comparison of serum cytokine levels in the study groups. Serum cytokines are measured as described in the Materials and Methods in the same subjects shown in Figure 1. Each dot represents an individual patient’s value, which is expressed in picograms per milliliter. The differences in cytokine levels were compared among study groups. Significant differences are marked by their respective P values.

  • View in gallery

    Associations between platelet counts and cytokine levels. Linear regression analyses between platelet counts and serum cytokine levels were performed in 307 patients who have only dengue infection (HBV−DV+ group in Figure 1). Platelet counts have significant negative correlations with IL-10 levels (r = −0.1988, P = 0.0005, C), but not with the levels of IL-4, IL-6, IFN-γ, or TNFα (A, B, D, and E).

  • 1

    Wilder-Smith A, Schwartz E, 2005. Dengue in travelers. N Engl J Med 353 :924–932.

  • 2

    Mackenzie JS, Gubler DJ, Petersen LR, 2004. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med 10 :S98–S109.

    • Search Google Scholar
    • Export Citation
  • 3

    Halstead SB, Heinz FX, Barrett AD, Roehrig JT, 2005. Dengue virus: molecular basis of cell entry and pathogenesis, 25–27 June 2003, Vienna, Austria. Vaccine 23 :849–856.

    • Search Google Scholar
    • Export Citation
  • 4

    Green S, Rothman A, 2006. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis 19 :429–436.

  • 5

    Russell PK, Nisalak A, 1967. Dengue virus identification by the plaque reduction neutralization test. J Immunol 99 :291–296.

  • 6

    Porterfield JS, 1980. The Togaviruses—Biology, Structure, Replication. New York: Academic Press.

  • 7

    Halstead SB, 1988. Pathogenesis of dengue: challenges to molecular biology. Science 239 :476–481.

  • 8

    Halstead SB, 1970. Observations related to pathogensis of dengue hemorrhagic fever. VI. Hypotheses and discussion. Yale J Biol Med 42 :350–362.

    • Search Google Scholar
    • Export Citation
  • 9

    Xu G, Dong H, Shi N, Liu S, Zhou A, Cheng Z, Chen G, Liu J, Fang T, Zhang H, Gu C, Tan X, Ye J, Xie S, Cao G, 2007. An outbreak of dengue virus serotype 1 infection in Cixi, Ningbo, People’s Republic of China, 2004, associated with a traveler from Thailand and high density of Aedes albopictus. Am J Trop Med Hyg 76 :1182–1188.

    • Search Google Scholar
    • Export Citation
  • 10

    Qiu FX, Gubler DJ, Liu JC, Chen QQ, 1993. Dengue in China: a clinical review. Bull World Health Organ 71 :349–359.

  • 11

    Qiu FX, Chen QQ, Ho QY, Chen WZ, Zhao ZG, Zhao BW, 1991. The first epidemic of dengue hemorrhagic fever in the People’s Republic of China. Am J Trop Med Hyg 44 :364–370.

    • Search Google Scholar
    • Export Citation
  • 12

    Li FS, Yang FR, Song JC, Gao H, Tang JQ, Zou CH, Hu BN, Wen SR, Qiu FX, 1986. Etiologic and serologic investigations of the 1980 epidemic of dengue fever on Hainan Island, China. Am J Trop Med Hyg 35 :1051–1054.

    • Search Google Scholar
    • Export Citation
  • 13

    Luo H, He J, Zheng K, Li L, Jiang L, 2002. Analysis on the epidemiologic features of Dengue fever in Guangdong province, 1990–2000. Zhonghua Liu Xing Bing Xue Za Zhi 23 :427–430.

    • Search Google Scholar
    • Export Citation
  • 14

    Zhang FC, Chen YQ, Lu YC, Wang J, Chen WS, Hong WX, 2005. Analysis on clinical and epidemiological characteristics of 1032 patients with Dengue fever in Guangzhou. Zhonghua Liu Xing Bing Xue Za Zhi 26 :421–423.

    • Search Google Scholar
    • Export Citation
  • 15

    CDC, 2007. Progress in hepatitis B prevention through universal infant vaccination–China, 1997–2006. Morb Mortal Wkly Rep 56 :441–445.

    • Search Google Scholar
    • Export Citation
  • 16

    WHO, 1996. Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Geneva: World Heath Organization.

  • 17

    Vazquez S, Hafner G, Ruiz D, Calzada N, Guzman MG, 2007. Evaluation of immunoglobulin M and G capture enzyme-linked immunosorbent assay Panbio kits for diagnostic dengue infections. J Clin Virol 39 :194–198.

    • Search Google Scholar
    • Export Citation
  • 18

    Fang DY, Zhou JJ, Huang JB, Han YP, Jiang LF, 2006. Identification and analysis of virulence of dengue virus isolated from patient serum. Biotechnology (NY) 16 :26.

    • Search Google Scholar
    • Export Citation
  • 19

    Zhou JJ, Fang DY, Yan HJ, Huang JB, Jiang LF, 2007. Gene sequencing and analysis of the whole length of E gene from dengue virus type 1 isolated in Guangzhou area. Chin J Zoonoses 23 :48.

    • Search Google Scholar
    • Export Citation
  • 20

    Halstead SB, 2007. Dengue. Lancet 370 :1644–1652.

  • 21

    Lee MS, Hwang KP, Chen TC, Lu PL, Chen TP, 2006. Clinical characteristics of dengue and dengue hemorrhagic fever in a medical center of southern Taiwan during the 2002 epidemic. J Microbiol Immunol Infect 39 :121–129.

    • Search Google Scholar
    • Export Citation
  • 22

    Nguyen TL, Nguyen TH, Tieu NT, 1997. The impact of dengue haemorrhagic fever on liver function. Res Virol 148 :273–277.

  • 23

    Kuo CH, Tai DI, Chang-Chien CS, Lan CK, Chiou SS, Liaw YF, 1992. Liver biochemical tests and dengue fever. Am J Trop Med Hyg 47 :265–270.

    • Search Google Scholar
    • Export Citation
  • 24

    Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, Suntayakorn S, Endy TP, Raengsakulrach B, Rothman AL, Ennis FA, Nisalak A, 2000. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 181 :2–9.

    • Search Google Scholar
    • Export Citation
  • 25

    Balmaseda A, Hammond SN, Perez L, Tellez Y, Saborio SI, Mercado JC, Cuadra R, Rocha J, Perez MA, Silva S, Rocha C, Harris E, 2006. Serotype-specific differences in clinical manifestations of dengue. Am J Trop Med Hyg 74 :449–456.

    • Search Google Scholar
    • Export Citation
  • 26

    Corwin AL, Larasati RP, Bangs MJ, Wuryadi S, Arjoso S, Sukri N, Listyaningsih E, Hartati S, Namursa R, Anwar Z, Chandra S, Loho B, Ahmad H, Campbell JR, Porter KR, 2001. Epidemic dengue transmission in southern Sumatra, Indonesia. Trans R Soc Trop Med Hyg 95 :257–265.

    • Search Google Scholar
    • Export Citation
  • 27

    Egger JR, Coleman PG, 2007. Age and clinical dengue illness. Emerg Infect Dis 13 :924–925.

  • 28

    Nguyen TH, Nguyen TL, Lei HY, Lin YS, Le BL, Huang KJ, Lin CF, Do QH, Vu TQ, Lam TM, Yeh TM, Huang JH, Liu CC, Halstead SB, 2005. Association between sex, nutritional status, severity of dengue hemorrhagic fever, and immune status in infants with dengue hemorrhagic fever. Am J Trop Med Hyg 72 :370–374.

    • Search Google Scholar
    • Export Citation
  • 29

    Nguyen TH, Lei HY, Nguyen TL, Lin YS, Huang KJ, Le BL, Lin CF, Yeh TM, Do QH, Vu TQ, Chen LC, Huang JH, Lam TM, Liu CC, Halstead SB, 2004. Dengue hemorrhagic fever in infants: a study of clinical and cytokine profiles. J Infect Dis 189 :221–232.

    • Search Google Scholar
    • Export Citation
  • 30

    Hober D, Poli L, Roblin B, Gestas P, Chungue E, Granic G, Imbert P, Pecarere JL, Vergez-Pascal R, Wattre P, Maniez-Montreuil M, 1993. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am J Trop Med Hyg 48 :324–331.

    • Search Google Scholar
    • Export Citation
  • 31

    Libraty DH, Endy TP, Houng HS, Green S, Kalayanarooj S, Suntayakorn S, Chansiriwongs W, Vaughn DW, Nisalak A, Ennis FA, Rothman AL, 2002. Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J Infect Dis 185 :1213–1221.

    • Search Google Scholar
    • Export Citation
  • 32

    Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy PT, Lampertico P, Das A, Lopes AR, Borrow P, Williams K, Humphreys E, Afford S, Adams DH, Bertoletti A, Maini MK, 2007. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 204 :667–680.

    • Search Google Scholar
    • Export Citation
  • 33

    Tilg H, Vogel W, Tratkiewicz J, Aulitzky WE, Herold M, Gruber M, Geissler D, Umlauft F, Judmaier G, Schwulera U, Thrun A, Huber C, 1993. Pilot study of natural human interleukin-2 in patients with chronic hepatitis B. Immunomodulatory and antiviral effects. J Hepatol 19 :259–267.

    • Search Google Scholar
    • Export Citation
  • 34

    Zhang W, Yue B, Wang GQ, Lu SL, 2002. Serum and ascites levels of macrophage migration inhibitory factor, TNF-alpha and IL-6 in patients with chronic virus hepatitis B and hepatitis cirrhosis. Hepatobiliary Pancreat Dis Int 1 :577–580.

    • Search Google Scholar
    • Export Citation
  • 35

    Akpolat N, Yahsi S, Godekmerdan A, Demirbag K, Yalniz M, 2005. Relationship between serum cytokine levels and histopathological changes of liver in patients with hepatitis B. World J Gastroenterol 11 :3260–3263.

    • Search Google Scholar
    • Export Citation
  • 36

    Halstead SB, 1981. The Alexander D. Langmuir Lecture. The pathogenesis of dengue. Molecular epidemiology in infectious disease. Am J Epidemiol 114 :632–648.

    • Search Google Scholar
    • Export Citation
  • 37

    Rothman AL, 2004. Dengue: defining protective versus pathologic immunity. J Clin Invest 113 :946–951.

 

 

 

 

 

Unique Impacts of HBV Co-infection on Clinical and Laboratory Findings in a Recent Dengue Outbreak in China

View More View Less
  • 1 Department of Laboratory Medicine, Guangzhou 8th People’s Hospital, Guangzhou, China; Department of Medicine, University of Rochester, Rochester, New York

High prevalence of hepatitis B virus (HBV) infection in China offers a unique setting to examine HBV’s influence on the presentation of dengue fever. In 398 patients admitted for suspected dengue fever, 89% (353/398) were positive for dengue IgM antibodies. Among dengue-infected patients, 8% (29/353) had chronic HBV co-infection. Only dengue virus serotype 1 was identified by virus isolation and reverse transcriptase-polymerase chain reaction assays. No case of dengue hemorrhagic fever/dengue shock syndrome was diagnosed. In addition to routine clinical tests, inter-leukin 2 (IL-2), IL-4, IL-6, IL-10, interferon γ (IFNγ), and tumor necrosis factor α (TNFα) levels were measured in the sera of 95% (334/353) of dengue-infected subjects as well as controls. Surprisingly, HBV/dengue co-infected patients made less IL-6 (P < 0.05) and TNFα (P < 0.05) than patients with only dengue infection. Similar levels of IL-4, IL-10, and IFNγ were found in both groups. Thus, HBV co-infection seems to alter the cytokine production pattern when patients contract dengue infection.

INTRODUCTION

Dengue fever is a mosquito-borne disease affecting 50–100 million people annually. It is caused by infection with dengue virus (DENV), a single-stranded RNA virus of the Flaviviridae family that exists as four serotypes: DENV1, 2, 3, and 4.16 Primary DENV infection usually presents as a self-limiting febrile illness. Some secondary infections and primary infections in infants can lead to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), possibly caused by a mechanism known as antibody-dependent enhancement (ADE).4,7,8

Since first being reported in the 1770s in Asia, Africa, and North America, dengue fever has spread to more than 100 countries. In China, dengue was first documented in the 1940s in the southern coastal regions of Shanghai city, Fujian, and Guangdong provinces, followed by a major outbreak in 1945 in Hubei province, which was the only in-land epidemic ever reported. No dengue epidemics were documented in the next three decades. Dengue outbreaks have re-emerged since 1978. The most heavily dengue affected area is the Guangdong province. Its warm climate and high humidity are particularly suited for mosquito growth and the spread of dengue virus. All four DENV serotypes have circulated in Guangzhou and surrounding counties. Recent outbreaks since 1995 are all caused by DENV1.914 Guangzhou, the capital city of Guangdong, is densely populated by 12 million local residents and migrant workers and is the epicenter of the current dengue epidemic.

Hepatitis B virus (HBV) infection is a leading cause of liver diseases and death in China. Approximately 60% of the 1.3 billion Chinese has a history of HBV infection, and 9.8% of them are chronically infected.15 The manifestation of dengue infection in a population with high HBV prevalence has never been comprehensively studied. In a 2006 dengue outbreak in Guangzhou, we identified 353 patients with dengue fever including 29 with chronic HBV co-infection. We found significant differences in serum cytokine profiles between the HBV-positive and -negative groups. This is the first time that such an observation has been made.

MATERIALS AND METHODS

Study subjects.

Three hundred ninety-eight suspected dengue fever patients were admitted to the Guangdong 8th People’s Hospital from August 8 to October 27, 2006. Three hundred fifty-three of them were confirmed as having dengue by either anti-dengue antibody tests or virus isolation in C6/36 mosquito cells. According to World Health Organization (WHO) criteria,16 all patients were diagnosed as having dengue fever and none as having DHF/DSS. Blood, urine, and feces samples were obtained and tested during the hospital stay (ranged from Day 0 to Day 11 after the onset of fever). Sera were collected and stored at −80°C. Sera from 41 healthy donors and 47 chronic HBV-infected subjects were also obtained as study controls. Informed consents were obtained from adult patients or legal guardians of younger patients. Chinese rules and regulations for human subject protection were strictly followed.

Clinical and laboratory tests.

Standard tests including complete blood counts, coagulation tests, liver function tests, and occult blood tests were performed in the hospital laboratories. Dengue IgM and IgG capture ELISA kits (Panbio, Brisbane, Queensland, Australia) were used to diagnose dengue infection according to the manufacturer’s protocol.17 For HBV infection, HBs, HBe antigens, IgG antibodies specific for HBs, HBe, and HBc, and IgM antibody for HBc were measured in sera using standard domestic diagnostic ELISA kits (InTec Products, Xiamen, China). A diagnosis of HBV chronic infection was made if a patient was positive for HBsAg and negative for anti-HBc IgM. Serum cytokine levels for interleukin 2 (IL-2), IL-4, IL-6, IL-10, interferon γ (IFNγ), and tumor necrosis factor α (TNFα) were measured using ELISA kits (Diaclone, Besancon Cedex, France) according to the manufacturer’s instructions.

Statistical analysis.

Statistical analysis was performed with GraphPad Prism Version 4.0 (GraphPad Software, San Diego, CA). One-way analysis of variance (ANOVA) was performed for group comparisons. Associations between laboratory measurements were analyzed by Spearman rank correlation test. A value of P < 0.05 was considered significant.

RESULTS

Epidemiologic features of the 2006 dengue outbreak in Guangzhou.

Approximately 90% (353/398) of admitted patients were diagnosed as having dengue, 60% (212/353) of them were positive for anti-dengue IgM, and 40% (141/353) were positive for both anti-dengue IgM and IgG antibodies. In the first 125 admitted patients, only DENV1 serotype was identified by either virus isolation or reverse transcriptase-polymerase chain reaction (RT-PCR) assays.18,19 Hence, this was considered a DENV1 epidemic. The dengue cases spread over a wide age range and was equal in both sexes. There were no DHF/DSS cases. Clinical and routine laboratory findings were unremarkable (Table 1) and similar to what was expected for primary DENV1 infection.20 Eight percent (29/353) of all patients had chronically HBV infection according to criteria described in the Materials and Methods section. This offered a unique opportunity to study the effect of HBV on the presentation of dengue infection.

Aberrant cytokine secretion in patients with HBV co-infection.

Because elevated cytokine level is a regular feature of dengue infection, we decided to compare cytokine levels between 307 subjects with dengue infection only (HBV−DV+), and 27 subjects who have dengue and HBV co-infection (HBV+DV+). These subjects were randomly selected from all subjects in whom we stored sufficient serum. As controls, we also included 41 healthy subjects (HBV−DV−) and 47 patients with only chronic HBV infection (HBV+DV−). The age distributions of these four groups were overlapping, with a median age of ~40 years (Figure 1A). In comparison to healthy controls, alanine aminotransferase (ALT) levels were elevated in patients with either HBV or dengue infection (Figure 1B), but aspartate aminotransferase (AST) levels were only increased in dengue-infected patients, irrespective of HBV status (Figure 1C). Similar abnormal liver function tests were common in patients with dengue.2123

Serum levels of IL-2, IL-4, IL-6, IL-10, IFNγ, and TNFα were measured as described in the Materials and Methods section. In these 442 subjects, we detected no cytokines in the 41 healthy controls and variable amounts of all cytokines, except for IL-2, in the other groups. No significant differences were detected in IL-4 levels among all groups (Figure 2A). Levels of IL-6, IL-10, IFNγ, and TNFα were significantly elevated during dengue infection (Figures 2Bndash;2E). Unexpectedly, dengue infection only up-regulated IL-10 and IFNγ levels (Figures 2B and 2D) but not IL-6 and TNFα among those who were HBV positive (Figures 2B and 2E).

Although there were no DHF cases, many patients had thrombocytopenia. We thus analyzed correlations between cytokine levels and platelet counts. By Spearman rank correlation test, platelet counts showed a significant negative correlation with serum IL-10 levels (r = −0.1988, P < 0.0005; Figure 3C) but had no statistically significant correlation with levels of IL-4 (r = −0.0147, P = 0.7968; Figure 3A), IL-6 (r = −0.0612, P = 0.2852; Figure 3B), IFNγ (r = −0.0545, P = 0.3410; Figure 3D), or TNFα (r = −0.0643, P = 0.2615; Figure 3E). Additionally, AST, but not ALT, levels were positively associated with IL-10 levels (P = 0.015, data not shown).

DISCUSSION

By a careful examination of 353 patients with dengue fever, we reconstructed epidemic and immunologic features of a major dengue outbreak in 2006 in the southern China coastal city Guangzhou. For the first time, we discovered that chronic HBV infection led to an aberrant cytokine secretion profile in patients when experiencing dengue infection.

This dengue epidemic was caused by DENV1 infection, which presented clinically as dengue fever only, without a single case of DHF/DSS, although there were thrombocytopenia, neutropenia, and abnormal liver function tests in most patients. These are in agreement with published data that DENV1 infections are often associated with less severe disease.2426 The infected population was equally distributed in both sexes, and 63% were adults. This again is consistent with earlier reports that adults are more likely to have clinical dengue.27,28

Approximately 8% of dengue-infected patients had chronic HBV co-infection, close to the 9.8% national average.15 This offers a unique opportunity to examine the effect of HBV on dengue infection. Unexpectedly, those with HBV co-infection made less IL-6 and TNFα, but had similar levels of IL-4, IL-10, and IFNγ in comparison to those with only dengue infection. These intriguing alterations of cytokine levels, as far as we know, have never been previously reported.

It is common to find elevation of IL-6, IL-10, IFNγ, and TNFα levels in dengue-infected patients without HBV co-infection.2931 In patients with chronic HBV infection, the elevations of these cytokines are usually modest.3235 None of these cytokines are detectable in normal healthy individuals. The magnitude of IL-10, but not IL-4, IL-6, IFNγ, or TNFα, is proportional to the severity of thrombocytopenia (r = −0.1988, P = 0.0005), similar to a previous report.31 Moreover, IL-10 levels were positively associated with abnormal AST tests (data not shown), similar to published data.29

What causes the aberrant cytokine production in chronic HBV-infected patients when infected by dengue? One obvious reason is that patients with chronic HBV infection tend not to be as well nourished as healthy subjects and hence may be incapable of making some cytokines quickly in response to a viral infection. This is certainly the case for malnourished children in whom DHF/DSS is rarely seen,36 possibly because of their inability to make the inflammatory cytokines implicated in causing vascular plasma leakage.37 Further studies may offer mechanistic explanations on why the elevation of some, but not all, cytokines during dengue infection is suppressed by HBV co-infection.

Table 1.

Clinical characteristics and laboratory findings of study subjects

Greater than 14 years oldLess than or equal to 14 years old
MaleFemaleMaleFemaleNormal range
Cases180150149
Age (years)35.6 ± 14.340.9 ± 15.67.0 ± 5.210.7 ± 2.1
HBV+19/180 (10.6%)10/150 (6.7%)00
Hematocrit (%)40.4 ± 3.535.9 ± 3.737.2 ± 4.134.7 ± 3.540~50 (%)
Petechiae49/180 (27.2%)35/150 (23.3%)3/14 (21.4%)2/9 (22.2%)
PT (> 14 s)8/163 (4.9%)6/136 (4.4%)0011~14 seconds
Thrombocytopenia (< 100 × 103/mm3)145/180 (80.6%)110/150 (73.3%)9/14 (64.3%)3/9 (33.3%)100~300 × 103/mm3
Neutropenia (< 2.0 × 103/mm3)159/180 (88.3%)141/150 (94.0%)14/14 (100%)8/9 (88.9%)2.0~7.5 × 103/mm3
ALT (> 40 U/L)110/174 (63.2%)82/145 (56.6%)5/14 (35.7%)2/8 (25.0%)5~40 U/L
AST (> 40 U/L)155/174 (89.1%)120/145 (82.8%)14/14 (100%)6/8 (75.0%)5~40 U/L
Figure 1.
Figure 1.

Age distribution and liver function tests in patient groups. The age distribution (A), and liver functional tests including levels of alanine aminotransferase (ALT, B) and asparate aminotransferase (AST, C) are shown. There were 41 healthy controls (HBV−DV−), 307 patients with only dengue infection (HBV−DV+), 47 patients with only HBV chronic infection (HBV+DV−), and 27 patients with both viral infections (HBV+DV+). The ALT and AST values were compared among groups, and significant differences are marked by their respective P values. The box-and-whiskers show median and 25th and 75th percentiles of data distribution.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 79, 2; 10.4269/ajtmh.2008.79.154

Figure 2.
Figure 2.

Comparison of serum cytokine levels in the study groups. Serum cytokines are measured as described in the Materials and Methods in the same subjects shown in Figure 1. Each dot represents an individual patient’s value, which is expressed in picograms per milliliter. The differences in cytokine levels were compared among study groups. Significant differences are marked by their respective P values.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 79, 2; 10.4269/ajtmh.2008.79.154

Figure 3.
Figure 3.

Associations between platelet counts and cytokine levels. Linear regression analyses between platelet counts and serum cytokine levels were performed in 307 patients who have only dengue infection (HBV−DV+ group in Figure 1). Platelet counts have significant negative correlations with IL-10 levels (r = −0.1988, P = 0.0005, C), but not with the levels of IL-4, IL-6, IFN-γ, or TNFα (A, B, D, and E).

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 79, 2; 10.4269/ajtmh.2008.79.154

*

Address correspondence to Xiaoping Tang, Guangzhou 8th People’s Hospital, Guangzhou 510060, China, E-mail: xtang@21cn.com or Xia Jin, Department of Medicine, Infectious Diseases Division, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 689, Room 3-5103, Rochester, NY 14642. E-mail: xia_jin@urmc.rochester.edu

These authors contributed equally to this paper.

Authors’ addresses: Yangbo Tang, Guangzhou 8th People’s Hospital, Guangzhou 510060, China, Tel: 0086-20-83710937, Fax: 0086-20-83866127. Zhihua Kou, Department of Medicine, Infectious Diseases Division University of Rochester, 601 Elmwood Avenue, Box 689, Rochester, NY 14642, Tel: 585-275-3924, Fax: 585-442-9328. Xiaoping Tang, Departments of Laboratory Medicine, Guangzhou 8th People’s Hospital, Guangzhou 510060, China, Tel: 0086-20-83710688, Fax: 0086-20-83828442. Fuchun Zhang, Guangzhou 8th People’s Hospital, Guangzhou 510060, China, Tel: 0086-20-83710912, Fax: 0086-20-83828422. Xian Yao, Guangzhou 8th People’s Hospital, Guangzhou 510060, China, Tel: 0086-20-83710851, Fax: 0086-20-83866127. Shengyong Liu, Department of Medicine, Infectious Diseases Division University of Rochester, 601 Elmwood Avenue, Box 689, Rochester, NY 14642, Tel: 585-275-3924, Fax: 585-442-9328. Xia Jin, Department of Medicine, Infectious Diseases Division, University of Rochester, 601 Elmwood Avenue, Box 689, Room 3-5103, Rochester, NY 14642, Tel: 585-275-6515, Fax: 585-442-9328.

Acknowledgments: The authors thank Maria Arevalo for editorial assistance.

Financial support: This study was supported by intramural research grants provided by the Guangzhou 8th People’s Hospital.

REFERENCES

  • 1

    Wilder-Smith A, Schwartz E, 2005. Dengue in travelers. N Engl J Med 353 :924–932.

  • 2

    Mackenzie JS, Gubler DJ, Petersen LR, 2004. Emerging flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile and dengue viruses. Nat Med 10 :S98–S109.

    • Search Google Scholar
    • Export Citation
  • 3

    Halstead SB, Heinz FX, Barrett AD, Roehrig JT, 2005. Dengue virus: molecular basis of cell entry and pathogenesis, 25–27 June 2003, Vienna, Austria. Vaccine 23 :849–856.

    • Search Google Scholar
    • Export Citation
  • 4

    Green S, Rothman A, 2006. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis 19 :429–436.

  • 5

    Russell PK, Nisalak A, 1967. Dengue virus identification by the plaque reduction neutralization test. J Immunol 99 :291–296.

  • 6

    Porterfield JS, 1980. The Togaviruses—Biology, Structure, Replication. New York: Academic Press.

  • 7

    Halstead SB, 1988. Pathogenesis of dengue: challenges to molecular biology. Science 239 :476–481.

  • 8

    Halstead SB, 1970. Observations related to pathogensis of dengue hemorrhagic fever. VI. Hypotheses and discussion. Yale J Biol Med 42 :350–362.

    • Search Google Scholar
    • Export Citation
  • 9

    Xu G, Dong H, Shi N, Liu S, Zhou A, Cheng Z, Chen G, Liu J, Fang T, Zhang H, Gu C, Tan X, Ye J, Xie S, Cao G, 2007. An outbreak of dengue virus serotype 1 infection in Cixi, Ningbo, People’s Republic of China, 2004, associated with a traveler from Thailand and high density of Aedes albopictus. Am J Trop Med Hyg 76 :1182–1188.

    • Search Google Scholar
    • Export Citation
  • 10

    Qiu FX, Gubler DJ, Liu JC, Chen QQ, 1993. Dengue in China: a clinical review. Bull World Health Organ 71 :349–359.

  • 11

    Qiu FX, Chen QQ, Ho QY, Chen WZ, Zhao ZG, Zhao BW, 1991. The first epidemic of dengue hemorrhagic fever in the People’s Republic of China. Am J Trop Med Hyg 44 :364–370.

    • Search Google Scholar
    • Export Citation
  • 12

    Li FS, Yang FR, Song JC, Gao H, Tang JQ, Zou CH, Hu BN, Wen SR, Qiu FX, 1986. Etiologic and serologic investigations of the 1980 epidemic of dengue fever on Hainan Island, China. Am J Trop Med Hyg 35 :1051–1054.

    • Search Google Scholar
    • Export Citation
  • 13

    Luo H, He J, Zheng K, Li L, Jiang L, 2002. Analysis on the epidemiologic features of Dengue fever in Guangdong province, 1990–2000. Zhonghua Liu Xing Bing Xue Za Zhi 23 :427–430.

    • Search Google Scholar
    • Export Citation
  • 14

    Zhang FC, Chen YQ, Lu YC, Wang J, Chen WS, Hong WX, 2005. Analysis on clinical and epidemiological characteristics of 1032 patients with Dengue fever in Guangzhou. Zhonghua Liu Xing Bing Xue Za Zhi 26 :421–423.

    • Search Google Scholar
    • Export Citation
  • 15

    CDC, 2007. Progress in hepatitis B prevention through universal infant vaccination–China, 1997–2006. Morb Mortal Wkly Rep 56 :441–445.

    • Search Google Scholar
    • Export Citation
  • 16

    WHO, 1996. Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Geneva: World Heath Organization.

  • 17

    Vazquez S, Hafner G, Ruiz D, Calzada N, Guzman MG, 2007. Evaluation of immunoglobulin M and G capture enzyme-linked immunosorbent assay Panbio kits for diagnostic dengue infections. J Clin Virol 39 :194–198.

    • Search Google Scholar
    • Export Citation
  • 18

    Fang DY, Zhou JJ, Huang JB, Han YP, Jiang LF, 2006. Identification and analysis of virulence of dengue virus isolated from patient serum. Biotechnology (NY) 16 :26.

    • Search Google Scholar
    • Export Citation
  • 19

    Zhou JJ, Fang DY, Yan HJ, Huang JB, Jiang LF, 2007. Gene sequencing and analysis of the whole length of E gene from dengue virus type 1 isolated in Guangzhou area. Chin J Zoonoses 23 :48.

    • Search Google Scholar
    • Export Citation
  • 20

    Halstead SB, 2007. Dengue. Lancet 370 :1644–1652.

  • 21

    Lee MS, Hwang KP, Chen TC, Lu PL, Chen TP, 2006. Clinical characteristics of dengue and dengue hemorrhagic fever in a medical center of southern Taiwan during the 2002 epidemic. J Microbiol Immunol Infect 39 :121–129.

    • Search Google Scholar
    • Export Citation
  • 22

    Nguyen TL, Nguyen TH, Tieu NT, 1997. The impact of dengue haemorrhagic fever on liver function. Res Virol 148 :273–277.

  • 23

    Kuo CH, Tai DI, Chang-Chien CS, Lan CK, Chiou SS, Liaw YF, 1992. Liver biochemical tests and dengue fever. Am J Trop Med Hyg 47 :265–270.

    • Search Google Scholar
    • Export Citation
  • 24

    Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, Suntayakorn S, Endy TP, Raengsakulrach B, Rothman AL, Ennis FA, Nisalak A, 2000. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 181 :2–9.

    • Search Google Scholar
    • Export Citation
  • 25

    Balmaseda A, Hammond SN, Perez L, Tellez Y, Saborio SI, Mercado JC, Cuadra R, Rocha J, Perez MA, Silva S, Rocha C, Harris E, 2006. Serotype-specific differences in clinical manifestations of dengue. Am J Trop Med Hyg 74 :449–456.

    • Search Google Scholar
    • Export Citation
  • 26

    Corwin AL, Larasati RP, Bangs MJ, Wuryadi S, Arjoso S, Sukri N, Listyaningsih E, Hartati S, Namursa R, Anwar Z, Chandra S, Loho B, Ahmad H, Campbell JR, Porter KR, 2001. Epidemic dengue transmission in southern Sumatra, Indonesia. Trans R Soc Trop Med Hyg 95 :257–265.

    • Search Google Scholar
    • Export Citation
  • 27

    Egger JR, Coleman PG, 2007. Age and clinical dengue illness. Emerg Infect Dis 13 :924–925.

  • 28

    Nguyen TH, Nguyen TL, Lei HY, Lin YS, Le BL, Huang KJ, Lin CF, Do QH, Vu TQ, Lam TM, Yeh TM, Huang JH, Liu CC, Halstead SB, 2005. Association between sex, nutritional status, severity of dengue hemorrhagic fever, and immune status in infants with dengue hemorrhagic fever. Am J Trop Med Hyg 72 :370–374.

    • Search Google Scholar
    • Export Citation
  • 29

    Nguyen TH, Lei HY, Nguyen TL, Lin YS, Huang KJ, Le BL, Lin CF, Yeh TM, Do QH, Vu TQ, Chen LC, Huang JH, Lam TM, Liu CC, Halstead SB, 2004. Dengue hemorrhagic fever in infants: a study of clinical and cytokine profiles. J Infect Dis 189 :221–232.

    • Search Google Scholar
    • Export Citation
  • 30

    Hober D, Poli L, Roblin B, Gestas P, Chungue E, Granic G, Imbert P, Pecarere JL, Vergez-Pascal R, Wattre P, Maniez-Montreuil M, 1993. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am J Trop Med Hyg 48 :324–331.

    • Search Google Scholar
    • Export Citation
  • 31

    Libraty DH, Endy TP, Houng HS, Green S, Kalayanarooj S, Suntayakorn S, Chansiriwongs W, Vaughn DW, Nisalak A, Ennis FA, Rothman AL, 2002. Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J Infect Dis 185 :1213–1221.

    • Search Google Scholar
    • Export Citation
  • 32

    Dunn C, Brunetto M, Reynolds G, Christophides T, Kennedy PT, Lampertico P, Das A, Lopes AR, Borrow P, Williams K, Humphreys E, Afford S, Adams DH, Bertoletti A, Maini MK, 2007. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage. J Exp Med 204 :667–680.

    • Search Google Scholar
    • Export Citation
  • 33

    Tilg H, Vogel W, Tratkiewicz J, Aulitzky WE, Herold M, Gruber M, Geissler D, Umlauft F, Judmaier G, Schwulera U, Thrun A, Huber C, 1993. Pilot study of natural human interleukin-2 in patients with chronic hepatitis B. Immunomodulatory and antiviral effects. J Hepatol 19 :259–267.

    • Search Google Scholar
    • Export Citation
  • 34

    Zhang W, Yue B, Wang GQ, Lu SL, 2002. Serum and ascites levels of macrophage migration inhibitory factor, TNF-alpha and IL-6 in patients with chronic virus hepatitis B and hepatitis cirrhosis. Hepatobiliary Pancreat Dis Int 1 :577–580.

    • Search Google Scholar
    • Export Citation
  • 35

    Akpolat N, Yahsi S, Godekmerdan A, Demirbag K, Yalniz M, 2005. Relationship between serum cytokine levels and histopathological changes of liver in patients with hepatitis B. World J Gastroenterol 11 :3260–3263.

    • Search Google Scholar
    • Export Citation
  • 36

    Halstead SB, 1981. The Alexander D. Langmuir Lecture. The pathogenesis of dengue. Molecular epidemiology in infectious disease. Am J Epidemiol 114 :632–648.

    • Search Google Scholar
    • Export Citation
  • 37

    Rothman AL, 2004. Dengue: defining protective versus pathologic immunity. J Clin Invest 113 :946–951.

Author Notes

Reprints requests: Xiaoping Tang, Departments of Laboratory Medicine, Guangzhou 8th People’s Hospital, Guangzhou 510060, China, E-mail: xtang@21cn.com.
Save