| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
 |
ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Generally, the greatest risk for DHF is thought to be with the second virus serotype exposure (although this risk may also be affected by the particular serotype and sequence of infection). Monkey studies showed that multivalent neutralizing antibodies may reduce the risk of detectable dengue viremia with heterologous challenge and have suggested that after the second DENV infection enough cross-immunity may be present to prevent significant disease.9–12 The risk for DHF with a third or fourth DENV infection relative to a first or second exposure is not known. To estimate the risk of DHF during repeated DENV infections, we performed an analysis of our dengue diagnostics database for children admitted to the Queen Sirikit Institute of Child Health (formerly the Bangkok Children’s Hospital) and the Kamphaeng Phet Provincial Hospital for suspected dengue.
|
MATERIALS AND METHODS |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Clinical diagnoses, if available, were recorded from the final diagnosis on the patient’s hospital chart (DF, DHF, or a specific grade of DHF according to World Health Organization [WHO] criteria).13 For the purposes of analysis, all stages of DHF were categorized simply as DHF. Japanese encephalitis (JE) vaccination status, if available, was recorded from the patients’ history along with the age of the patient when the vaccine was given. Unfortunately, no record of the number of doses received was available.
All acute and convalescent samples were serologically tested using combined dengue/JE enzyme immunoassay (EIA). Serologic results indicating acute primary dengue virus infection or acute secondary dengue virus infection were used in this analysis; all other results (i.e., recent flavivirus infection or acute JE virus infection) were excluded from the analysis. Dengue EIA results were classified as primary if anti-dengue IgM was 
40 units and anti-dengue IgM:anti-IgG ratio was 1.8. EIA results were classified as secondary if anti-dengue IgM was 40 units and anti-dengue IgM:anti-IgG ratio was < 1.8.14 For specimens with subdiagnostic levels of IgM and elevated IgG, a hemagglutination inhibition assay was performed and interpreted according to WHO guidelines.13,15,16
The infecting DENV serotype was identified by virus isolation in live Toxorhynchitis splendens mosquitoes or by reverse transcriptase-polymerase chain reaction (RT-PCR). Viruses isolated in mosquitoes were serotyped using an antigen capture EIA.17–19 Molecular identification of DENV serotype in acute serum was performed using RT-PCR modified after Lanciotti and others.20 There was one sample where the RT-PCR and typing EIA were in conflict; the PCR was DENV-3 and the EIA was DENV-2. An admission 335 days later was PCR positive for DENV-2 (EIA was negative), so the first admission was considered to be caused by DENV-3.
2 with Yates correction was used for categorical comparisons, except if expected cells were less than five; then, a Fisher exact test was used. A two-sided t test was used to compare means. Statistical comparisons were made using SPSS version 10.1 and Epi Info version 3.3.2.
|
RESULTS |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
One hundred one (52.9%) of the 191 patients with multiple dengue admissions were female. The mean age at the first admission was 6.9 years (range, 0.33–19 years), and the mean age at the second admission was 10.4 years (range, 1.6–22 years). The mean time between admissions was 3.5 years (range, 0.33–8.8 years); limiting this to isolation or RT-PCR–confirmed pairs, the mean interval was 3.5 years (range, 0.59–7.7 years).
There were 125 (65%) repeat dengue admission patients that had complete data regarding JE vaccination and serologic responses at both admissions. Based on this data, we categorized the patients and assigned a plausible DENV infection sequence (Table 1
). We found that 36 (29%) of paired admissions were caused by a first and second DENV infection (primary response followed by a secondary response), 13 (10%) could be attributed to a third or fourth infection (those with sequential secondary responses and no history of JE vaccination), and 76 (61%) could be caused by several possibilities (first followed by second, second by third, and third by fourth infection). Thus, at a minimum, 0.08% (13/16,016) of admissions were caused by third or fourth dengue virus infections. Assuming the same fraction of possible third or fourth infections in those without JE vaccination history available, the total caused by third or fourth infections would be 0.12% (20/16,016). At the maximum, 0.6% (89/16016) were caused by third or fourth dengue virus infections. Assuming the same fraction in those without JE vaccination history, it would be 0.8% (136/16,016).
|
Evaluations of associations with DHF versus DF.
Table 2 classifies the clinical diagnosis by the serologic response and admission sequence. At the first admission, there were 54 primary and 135 secondary DENV infections; at the second admission, all 191 dengue patients had secondary antibody response patterns.
|
There was no significant difference in age between DHF and DF cases for the first (6.5 versus 6.9 years, P = 0.5) and second (10.4 versus 10.6 years, P = 0.7) admissions. The time between admissions was not different between DHF and DF cases at the second admission (3.6 versus 3.6 years, P = 0.8). A diagnosis of DHF at the first admission did not significantly decrease the likelihood of a diagnosis of DHF with the second admission (55 of 79 versus 26 of 37 DHF cases, OR = 0.79 [0.29, 2.11], P = 0.8).
Among these hospitalized patients, there was no difference in the risk of DHF versus DF between a second dengue virus infection (primary response followed by secondary response) and third or fourth dengue virus infection (secondary response in those without prior JE vaccination followed by secondary response; 18 of 27 versus 9 of 12 DHF cases, OR = 0.67 [0.11, 3.78], P = 0.7).
Based on virus isolation and RT-PCR data, the following sequences led to a diagnosis of DHF: 1 followed by 2, 3, or 4; 2 followed by 1, 3, or 4; 3 followed by 1, 2, or 4; and 4 followed by 2 (Table 3). When we looked at just those pairs where the first admission showed a primary antibody response (excluding the possibility of undocumented first dengue infection), there remained sequences resulting in DHF at the second infection that have not previously been documented in the literature (two patients with a serotype 1 followed by a serotype 4 infection, one patient with a serotype 2 followed by a serotype 3 infection, one patient with a serotype 3 followed by a serotype 4 infection, and two patients with a serotype 3 followed by a serotype 1 infection) in addition to the prior documented sequences of 1–2, 1–3, 2–1, and 3–2.4,6,21–23 No sequence could be statistically shown to be a higher risk for subsequent DHF than other sequences.
|
|
DISCUSSION |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
An earlier unpublished study looking at data from 1974–1990 found that 53 (0.5%—compared with 1.2% for this analysis) out of 10,446 admissions were second admissions. The rate of second admissions may have increased in our study due to more intense transmission of all four DENV serotypes. The older analysis found that 41% of children with first dengue admissions had primary antibody response patterns compared with 29% for the more recent study. This may reflect more frequent JE vaccination as well as more intense DENV transmission. The mean time between admissions for both studies was similar (3.9 and 3.5 years).
In this study, JE vaccination did not increase the risk of DHF.24,25 Based on our comparison of first DENV infections, JE vaccination was not statistically associated with a delay in the first dengue admission (P = 0.13).
Our finding of decreased risk of DHF compared with DF for primary compared with secondary responses is consistent with other studies.26 The odds ratio for protection from DHF during a primary infection was 0.30 (0.13, 0.71) (Table 2
). The degree of protection increased to 0.22 (0.09, 0.57) when infants experiencing a primary infection were removed from the analysis. While the infants experienced first dengue virus infections, the presence of maternal antibody likely increases the risk of severe disease.24,25
Including this report, we believe that all sequences of dengue serotype infection have been shown to lead to DHF except serotype 4 followed by serotype 1 and serotype 4 followed by serotype 3. In addition, this study is the first to virologically (PCR or virus isolation) document the sequences.
Limitations. The data are limited to hospitalized dengue patients only, clinical diagnoses were not confirmed by chart review, and JE vaccination history was based on parental recall. It is also possible that some cases identified as second DENV infections on the first admission could be caused by naturally acquired JE virus infection rather than vaccination followed by DENV infection.
Despite these significant limitations, the age data of our DENV infection numbers (Table 1) suggest that the data are reliable. Considering those without a history of JE vaccination, there was a significant difference in the ages at first admission between those with a primary and secondary responses (4.1 versus 7.1 years, P = 0.03, reflecting that first DENV infections occur at a younger mean age than second infections), whereas second DENV infections occurred at essentially the same age (7.1 and 7.2 years). Likewise, considering those with a history of JE vaccination, there was a difference between the age at first DENV infection and what we considered to be the second, third, or fourth infections (6.1 and 10.2 years, P < 0.001). In addition, our data reaffirm other studies showing the risk for DHF is greater for secondary versus a primary response.
Conclusions. Although no confirmed third dengue admissions were found, our results suggest that 0.08% to 0.8% of dengue admissions may be caused by third or fourth infections. Though the risk for a subsequent hospitalization caused by dengue after one hospitalization for dengue seems to be low, once admitted, the risk for DHF versus DF is similar. Finally, we document new dengue serotype infection sequences leading to DHF of 1–4, 2–3, 3–1, and 3–4.
Received March 15, 2007. Accepted for publication July 11, 2007.
Acknowledgments: The authors thank Tipawan Thipwong for outstanding database support, making this research and publication possible. We also acknowledge the assistance of Panor Srisongkram, Napaporn Latthiwongsakorn, Sumitda Narupiti, Vipa Thirawuth, and Butsaya Thaisomboonsuk; without their assistance, this study could not have been completed. Last, we thank all of our collaborators at QSNICH, especially Suchitra Nimmannitya.
Financial support: Funding was partially provided by the US Military Infectious Diseases Research Program, Fort Detrick, MD, and the National Institutes of Health (NIH-P01-AI34533).
Disclosure: The opinions or assertions contained herein are the personal views of the authors and are not to be construed as official or reflecting the views of the Armed Forces Research Institute of Medical Sciences, the United States Department of the Army, or the United States Department of Defense.
* Address correspondence to Robert V. Gibbons, APO-AP, Bangkok 96546, Thailand. E-mail: Robert.gibbons{at}afrims.org 
Authors’ addressses: Robert V. Gibbons, USAMC-AFRIMS APO AP, 96566, Telephone: 662-6444674, Fax: 662-6444760, E-mail: robert.gibbons{at}afrims.org. Siripen Kalanarooj, Queen Sirikit National Institute of Child Health, 420/8 Rajvithi Road, Bangkok, Thailand 10400, Telephone: 662-354-8434, E-mail: ph sirip{at}health.moph.go.th. Richard G. Jarman, USAMC-AFRIMS APO AP, 96566, Telephone: 662-6444674, Fax: 662-6444760, E-mail: richard.jarman{at}afrims.org. Ananda Nisaluk, AFRIMS, 315/6 Rajvithi Road, Bangkok, Thailand 10400, Telephone: 662-6444674, Fax: 662-6444760, E-mail: Ananda.nisaluk{at}afrims.org. David W. Vaughn, GlaxoSmithKline, 2301 Renaissance Boulevard, RN0220, King of Prussia, PA 19406, Telephone: 610-787-3907, Fax: 610-787-7057, E-mail: d.w.vaughn{at}usa.net. Timothy P. Endy, WRAIR, Division of Communicable Diseases and Immunology, 503 Robert Grant Ave., Silver Spring, MD 90210, Telephone: 301-319-3053, Fax: 301-319-3053, E-mail: endyt{at}upstate.edu. Mammen P. Mammen Jr, Product Manager, Pharmaceutical Systems Division, US Army Medical Material Development Activity (USAMMDA), 1430 Veterans Drive, Ft. Detrick, MD 21702, Telephone: 301-619-2069, Fax: 301-619-2304, E-mail: mammen.mammen{at}amedd.army.mil. Anon Srikiatkhachorn, Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, 55 Lake Avenue, North Worcester, MA 01557, Telephone: 508-856-4182, Fax: 508-856-4890, E-mail: anon.srikiatkhachorn{at}umassmed.edu.
|
REFERENCES |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  M. Recker, K. B. Blyuss, C. P. Simmons, T. T. Hien, B. Wills, J. Farrar, and S. Gupta Immunological serotype interactions and their effect on the epidemiological pattern of dengue Proc R Soc B, July 22, 2009; 276(1667): 2541 - 2548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Suaya, D. S. Shepard, J. B. Siqueira, C. T. Martelli, L. C. S. Lum, L. H. Tan, S. Kongsin, S. Jiamton, F. Garrido, R. Montoya, et al. Cost of Dengue Cases in Eight Countries in the Americas and Asia: A Prospective Study Am J Trop Med Hyg, May 1, 2009; 80(5): 846 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Kuno Emergence of the Severe Syndrome and Mortality Associated with Dengue and Dengue-Like Illness: Historical Records (1890 to 1950) and Their Compatibility with Current Hypotheses on the Shift of Disease Manifestation Clin. Microbiol. Rev., April 1, 2009; 22(2): 186 - 201. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
