• View in gallery

    Time-course of laboratory data (mean ± SD) obtained from 62 patients with DF. The onset of fever is assigned as day 1. The areas between the two gray horizontal lines show the normal range of each laboratory test at Metropolitan Komagome Hospital.

  • View in gallery

    Time-course of immune responses to dengue virus serotype 2 and JE virus in 61 cases of DF. The onset of fever is assigned as day 1.

  • 1

    World Health Organization, 1997. Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Second edition. Geneva: World Health Organization.

  • 2

    Hotta S, 2000. Dengue fever and dengue virus—a challenge to tropical medicine. Jpn J Trop Med Hyg 28 :369–381.

  • 3

    Yamada KI, Takasaki T, Nawa M, Nakayama M, Arai YT, Yabe S, Kurane I, 1999. The features of imported dengue fever cases from 1996 to 1999. Jpn J Infect Dis 52 :257–259.

    • Search Google Scholar
    • Export Citation
  • 4

    Kurane I, Takasaki T, Yamada K, 2000. Trends in flavivirus infections in Japan. Emerg Infect Dis 6 :569–571.

  • 5

    Judicial System Department, Ministers Secretariat, 2001. Ministry of Justice. Annual Report of Statistics on Legal Migrants. Tokyo, Ministry of Justice.

  • 6

    Konishi E, Suzuki T, 2002. Ratios of subclinical to clinical Japanese encephalitis (JE) virus infections in vaccinated populations: evaluation of an inactivated JE vaccine by comparing the ratios with those in unvaccinated populations. Vaccine 21 :98–107.

    • Search Google Scholar
    • Export Citation
  • 7

    Hoke CH, Nisalak A, Sangawhipa N, Jatanasen S, Laorakapongse T, Innis BL, Kotchasenee S, Gingrich JB, Latendresse J, Fukai K, Burke DS, 1988. Protection against Japanese encephalitis by inactivated vaccines. N Engl J Med 319 :608–614.

    • Search Google Scholar
    • Export Citation
  • 8

    Yamada K, Nawa M, Takasaki T, Yabe S, Kurane I, 1999. Laboratory diagnosis of dengue virus infection by reverse transcriptase polymerase chain reaction (RT-PCR) and IgM-capture enzyme-linked immunosorbent assay (ELISA). Jpn J Infect Dis 52 :150–155.

    • Search Google Scholar
    • Export Citation
  • 9

    Yamada K, Takasaki T, Nawa M, Yabe S, Kurane I, 2003. Antibody responses determined for Japanese dengue fever patients by neutralization and hemagglutination inhibition assays demonstrate cross-reactivity between dengue and Japanese encephalitis viruses. Clin Diagn Lab Immunol 10 :725–728.

    • Search Google Scholar
    • Export Citation
  • 10

    Clarke T, 2002. Dengue virus: Break-bone fever. Nature 416 :672–674.

  • 11

    Kalayanarooj S, Vaughn DW, Nimmannitya S, Green S, Suntayakorn S, Kunentrasai N, Viramitrachai W, Ratanachueke S, Kiatpolpoj S, Innis BL, Rothman AL, Nisalak A, Ennis FA, 1997. Early clinical and laboratory indicators of acute dengue illness. J Infect Dis 176 :313–321.

    • Search Google Scholar
    • Export Citation
  • 12

    Schwartz E, Mendelson E, Sidi Y, 1996. Dengue fever among travelers. Am J Med 101 :516–520.

  • 13

    Guard RW, Stallman ND, Wiemers MA, 1984. Dengue in the northern region of Queensland, 1981–1982. Med J Aust 140 :765–769.

  • 14

    Infectious Diseases Control Division, Ministry of Health and Welfare, Infectious Disease Surveillance Center, National Institute of Infectious Diseases, 1996. Annual Report 1996. National Epidemiological Surveillance of Vaccine-Preventable Diseases. Tokyo, Ministry of Health and Welfare.

  • 15

    Peragallo MS, Nicoletti L, Lista F, D’Amelio R, East Timor Dengue Study Group, 2003. Probable dengue virus infection among Italian troops, East Timor, 1999–2000. Emerg Infect Dis 9 :876–880.

    • Search Google Scholar
    • Export Citation

 

 

 

CLINICAL FEATURES OF 62 IMPORTED CASES OF DENGUE FEVER IN JAPAN

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  • 1 Department of Infectious Diseases, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan; Department of Infectious Diseases, Tokyo Women’s Medical University, Tokyo Japan; Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan

To describe the clinical features of dengue cases in Japan, a retrospective study was conducted on 62 laboratory-confirmed Japanese dengue cases presented to Tokyo Metropolitan Komagome Hospital between 1985 and 2000. Age distribution was from 18 to 62 years old (mean, 31.5 years). All cases were imported from abroad and diagnosed as dengue fever. Clinical manifestations included fever (100%), headache (90%), and skin rash (82%). Laboratory examinations revealed leukocytopenia (71%), thrombocytopenia (57%), elevated levels of serum aspartate aminotransferase (78%), and lactate dehydrogenase (71%). Antibody responses were consistent with that of secondary flavivirus infection in 60% of cases. Severity of symptoms in patients with primary dengue antibody response and those with secondary flavivirus antibody responses didn’t show statistical significance. Dengue virus infection should be taken into consideration in the differential diagnosis of febrile patients who recently entered Japan from tropical or subtropical countries.

INTRODUCTION

Dengue fever (DF)/dengue hemorrhagic fever (DHF) is an acute febrile illness caused by dengue viruses. Dengue viruses, which consist of four serotypes (DEN1, 2, 3, and 4), belong to the family Flaviviridae. Dengue viruses are mosquito-borne and principally transmitted by Aedes aegypti mosquitoes that thrive close to human habitats and adapt well to urban environments. DF, a common form of febrile illness caused by dengue viruses, is a global health problem in the tropics and subtropics. DHF is the severe form of illness caused by dengue viruses. DHF is primarily a disease of children and the leading cause of hospitalization and death among children in Asian countries.1

In Japan, there were large epidemics between 1942 and 1944 in Nagasaki, Kobe, and Osaka, originating in the repatriation from the tropics during the Second World War.2 A total of 23,338 cases were reported in Nagasaki and 1,134 were reported in Kobe. Domestic transmission has not been reported in Japan since 1946. The description of imported dengue cases has been limited to a relatively small number of cases.3,4

Because of the increase in air travel to the tropics and subtropics, it is assumed that a larger number of oversea travelers are at risk to dengue virus infection. In 2000, 17.8 million Japanese went abroad, and > 2.6 million went to Southeast Asia.5 There is a possibility that a substantial number of dengue cases remain undiagnosed.4

Most of the population are immune to Japanese encephalitis (JE) virus because of repeated JE vaccination and possibly occasional boost by JE virus6 in Japan. It has been reported that immunity caused by previous flavivirus infection or immunization modulates immune response when infected with dengue virus.7 The aim of this study was to precisely define the clinical features of dengue virus infections among Japanese travelers coming back from overseas countries, most of whom have immunity to the JE virus.

MATERIALS AND METHODS

The study was conducted using the data obtained from the hospital case records of Japanese patients diagnosed as DF at Tokyo Metropolitan Komagome Hospital between 1985 and 2000. This hospital is a metropolitan-based general hospital with 800 beds in Tokyo, and specializes in cancer and infectious diseases. The department of infectious diseases has 30 beds and a special outpatient unit for those including travelers and patients with HIV. The most common causes of visit are fever, diarrhea, and rash.

Dengue virus infections were confirmed by 4-fold or greater rise in hemagglutination inhibition (HI) antibody titers to DEN2 in paired serum samples or by detection of HI antibody titers ≥ 1:320 in single serum samples. Since 1998, IgM-capture enzyme-linked immunosorbent assay (ELISA) has been routinely performed on serologically positive cases. Since 1992, reverse transcriptase-polymerase chain reaction (RT-PCR) has been performed on serologically positive cases to determine the serotype. Laboratory diagnosis of dengue virus infection was performed at the National Institute of Infectious Diseases, Tokyo, Japan, as previously reported.8,9

Data were analyzed with EpiInfo (Version 6.04d; Centers for Diseases Control and Prevention, Atlanta, GA). The χ2 test was used to compare clinical features. The Wilcoxon rank sum test was used to test for non-parametric data analysis. P < 0.05 was considered significant.

RESULTS

A total of 62 Japanese cases (44 men and 18 women) were confirmed to have DF during the study period. All the cases were treated as DF based on clinical diagnosis and later confirmed by HI antibody test. No cases were treated for other diseases before establishment of DF. The number of cases increased in spring and summer when a large number of Japanese people travel abroad.

The mean age was 31.5 ± 10.5 years, with a range from 18 to 62 years. Forty-eight cases (75%) were in their 20s and 30s. Presumptive places of infection are shown in Table 1. Forty-two cases (68%) were infected in Southeast Asia. The length of stay in the presumptive countries of infection ranged from 3 to 1,201 days, the median period being 17 days. Twenty-one cases (34%) developed illness during the travel. The remaining 41 cases (66%) developed illness after returning home, and the mean duration between the last day of travel (assigned as day 0) and the onset of fever was 3.2 ± 3.3 days (range: 0–18 days).

The clinical manifestations are shown in Table 2. Fever was detected in all the cases, and the mean duration of fever was 5.6 ± 2.0 days (range: 1–10 days). In some cases, fever was modulated by antipyretics given by doctors who saw the patients before us. Small macular rashes similar to those of rubella or measles were seen in 41 cases (arms and/or legs, 31 cases; trunk, arms and/or legs, 7 cases; face, arms, and legs: 3 cases). The mean time between onset of fever and appearance of skin rash was 5.7 days (range: −3–9 days). Skin itching at defervescence was present in 14 cases (arms and/or legs, 3 cases; palms or soles, 6 cases; unknown, 5 cases). Hemorrhagic manifestations were observed in 9 cases (epistaxis, 2 cases; gingival hemorrhage, 2 cases; melena, 2 cases; all, 3 cases). Upper respiratory tract symptoms were not evident except for one case with bacterial bronchitis who responded well to antibiotics administration. Depression was not seen during the observed period.

Leukocytopenia (leukocyte count < 3,500/mm3) was detected in 71% of the cases (41/58; the mean leukocyte count on admission was 3,062/mm3; range, 1,000–9,700/mm3), thrombocytopenia (platelet count < 100,000/mm3) in 57% (34/60; the mean platelet count was 101,400/mm3; range, 10,000–298,000/mm3), increased serum aspartate aminotransferase (AST) in 78% (45/58; mean AST = 82 IU/L; range, 13–375 IU/L; reference range, 11–32 IU/L), and increased lactate dehydrogenase (LDH) in 71% (41/58; mean LDH = 336 IU/L; range, 120–1,195 IU/L; reference range, 120–220 IU/L) on admission.

Figure 1 shows the time-course of laboratory data obtained from 62 cases. The mean leukocyte count and the mean platelet count reached the nadir on the sixth and eighth days of illness, respectively. The mean AST level reached the peak on the ninth day. The mean leukocyte and platelet counts returned to the normal levels within 10 days, whereas the mean AST level stayed at the normal range after > 3 weeks.

Figure 2 shows the time-course of HI antibody titers to dengue and JE virus antigens in 61 cases. Thirty-seven cases (60%) showed convalescent titers ≥ 1:2,560. These cases also showed elevated HI antibody titers to JE virus. History of JE vaccination was not asked to all the cases. Dengue virus-specific IgM was positive in 21 of 22 tested cases, using blood specimens drawn between the first and twentieth days of illness. RT-PCR determined dengue serotypes in 19 of 27 tested cases (Table 1).

Primary and secondary infections were determined, according to World Health Organization (WHO) criteria: primary dengue antibody response, HI antibody titer ≤ 1:1,280; secondary flavivirus antibody response, convalescent HI anti-body titer ≥ 1:2,560. Twenty-five cases (40%) were determined to be primary dengue antibody response and 37 (60%) to be secondary flavivirus antibody response. We compared these two groups for the clinical manifestations and laboratory tests showed in Table 2 but they didn’t show statistical significance. There were no differences in age distribution between these two groups (Table 3). These two groups were also compared for clinical features: duration of fever, tourniquet test, hemorrhagic manifestation, and platelet count (Table 4). There was no significance between two groups.

DISCUSSION

The number of imported dengue fever cases has been increasing in our hospital in recent years. Classic DFs are characterized by fever, headaches, bone or joint and muscular pains, skin rashes, and leukocytopenia.1 Historically, DF has been called “break-bone fever” because of its intractable pain.10 Clinical manifestation included flu-like illness associated with fever in most of the patients. The skin rash appeared around the day of defervescence in most of the rash-positive cases. Leukocytopenia, thrombocytopenia, and elevation of AST or LDH, which are well-recognized features of DF,1113 were observed in a high percentage of the cases. The changes in these laboratory markers were transient, and patients recovered accordingly.

In Japan, a national JE vaccination program has been successfully implemented, and children < 15 years old have been repeatedly vaccinated since 1954. Of all the DF cases in this study, 50 cases (81%) were born after 1954. It is reported that > 80% of the Japanese population had positive neutralizing antibody to JE virus during national surveillance.14 Although the history of JE vaccination or JE virus was not confirmed for all the cases, it is likely that most of the cases were immune to JE virus. Indeed, HI antibody titers were consistent with the secondary flavivirus antibody response in 60% of the cases. Our data showed that severity of symptoms in the primary dengue antibody group and secondary flavivirus antibody group didn’t show statistical significance. Previous studies reported that JE vaccination might decrease severity of subsequent DHF7 or protect from developing dengue illness.15 A larger-scaled, case control study should be performed to clarify whether immunity to JE virus has a beneficial effect on dengue virus infection.

Two cases (30- and 33-year-old women) were considered as DHF, according to the WHO case definition. Both cases showed mild hemorrhagic manifestations, platelet counts < 100,000/mm3, and drop in hematocrit after fluid administration > 20%. Both cases were clinically mild and improved shortly after administration of fluid and thus were diagnosed as DF clinically. Both cases had no history to travel to endemic areas but showed secondary flavivirus antibody response.

There is no domestic dengue virus transmission today in Japan, and all DF/DHF cases were imported ones. Dengue viruses are endemic in many neighboring countries in Asia and Oceania to which many Japanese people visit for sightseeing or business. Individuals previously infected by one serotype of dengue virus may be at higher risk of developing DHF or dengue shock syndrome after secondary infection with other serotypes. Such risks should be taken into consideration for diagnosis.

DF/DHF is also a disease to be considered for differential diagnosis of other severe febrile illnesses, including malaria, typhoid and paratyphoid fever, and rickettsiosis. The symptoms in DF cases in Japan seem to be less severe than those described in the textbook. When dengue virus infection is suspected, one could avoid treatment that may cause bleeding such as aspirin administration and avoid excess treatment such as steroid administration or platelet transfusion so that the duration of hospitalization can be shortened. Skin rashes are highly suggestive that the clinical diagnosis is dengue. Laboratory tests for confirmation are recommended, especially in the cases that resemble other communicable diseases (e.g., measles or rubella). In some patients, small macular rashes resembling to those of measles or rubella with or without itchy sensation on extremities, in particular, in palms and/or soles, were the only skin manifestations.

In conclusion, DF/DHF is important not only as an infectious disease in tropical and subtropical countries but also as an imported infectious disease in countries in the temperate zone including Japan. DF/DHF should be considered in the differential diagnosis of febrile patients returning or coming from dengue-endemic countries, even when they lack typical signs and symptoms. It is possible that a substantial number of DF/DHF patients are unrecognized and under-reported at present. Under careful observation, with the appearance of skin rashes, one can suspect dengue and send blood specimens for confirmation early to avoid excess and inappropriate treatment.

Table 1

Presumptive places of infection and dengue serotypes

Presumptive place of infectionNumber of patientsNumber of dengue serotypes
Thailand14DEN1, 3; DEN2, 2; DEN3, 2; DEN4, 1
India11DEN1, 1; DEN2, 1; DEN4, 1
Indonesia8DEN2, 1
Philippines7DEN1, 1; DEN2, 1
Myanmar2
Maldives2
Laos2
Taiwan2
East Timor2DEN2, 1
Malaysia1
Nigeria1
Cambodia1DEN1, 1
Guatemala1
Singapore1
Vietnam/Laos2
Thailand/Malaysia2
Thailand/India1DEN2, 1
Thailand/Cambodia1DEN1, 1
Thailand/Vietnam1DEN3, 1
Table 2

Clinical manifestations and laboratory tests

ManifestationPercent (%) positive cases (positive/numbers)
* Diarrhea was defined as loose bowel movements equal to or more than twice a day.
Fever100 (62/62)
Headache90 (54/60)
Skin rashes82 (41/50)
Itchy of the skin74 (14/19)
Profuse sweating61 (19/31)
Myalgia60 (31/49)
Platelet count < 100,000/mm357 (34/60)
Chills56 (28/50)
Retroorbital pain55 (24/44)
Diarrhea*53 (31/59)
Hemorrhagic manifestation45 (9/20)
Tourniquet test30 (7/23)
Table 3

Age distribution of patients with primary dengue antibody response and with secondary flavivirus antibody response

Number of patients
Age (years)Primary dengue antibody responseSecondary flavivirus antibody response
10–1911
20–291517
30–3979
40–4905
50–5915
60–6910
mean age (range)29.5 (18–62)32.8 (19–56)
Table 4

Clinical features of patients with primary dengue antibody response and with secondary flavivirus antibody response

Patients with primary dengue antibody responsePatients with secondary flavivirus antibody responseP value
Mean duration of fever (range)5.1 days6.0 days1.55
Percent positive tourniquet test (positive/case numbers)11% (1/9)43% (6/14)0.23
Percent positive hemorrhagic manifestation (positive/case numbers)25% (2/8)58% (7/12)0.31
Percent cases with platelet count < 100,000/mm3 (positive/case numbers)50% (12/24)61% (22/36)0.65
Figure 1.
Figure 1.

Time-course of laboratory data (mean ± SD) obtained from 62 patients with DF. The onset of fever is assigned as day 1. The areas between the two gray horizontal lines show the normal range of each laboratory test at Metropolitan Komagome Hospital.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 75, 3; 10.4269/ajtmh.2006.75.470

Figure 2.
Figure 2.

Time-course of immune responses to dengue virus serotype 2 and JE virus in 61 cases of DF. The onset of fever is assigned as day 1.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 75, 3; 10.4269/ajtmh.2006.75.470

*

Address correspondence to Ichiro Itoda, Department of Infectious Diseases, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 1628666, Japan. E-mail: itoda@gol.com

Authors’ addresses: Ichiro Itoda and Kyoichi Totsuka, Department of Infectious Diseases, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 1628666, Japan, Telephone: +81-3 3353-8111, Fax: +81-3-3358-8995, E-mail: itoda@gol.com. Gohta Masuda, Tokyo Metropolitan Kita Medical and Rehabilitation Center, Tokyo, Japan. Akihiko Suganuma, Akifumi Imamura, Atsushi Ajisawa, and Masayoshi Negishi, Department of Infectious Diseases, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan. Ken-Ichiro Yamada, Sadao Yabe, Tomohiko Takasaki, and Ichiro Kurane, Department of Virology 1, National Institute of Infectious Diseases, Tokyo, Japan.

REFERENCES

  • 1

    World Health Organization, 1997. Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. Second edition. Geneva: World Health Organization.

  • 2

    Hotta S, 2000. Dengue fever and dengue virus—a challenge to tropical medicine. Jpn J Trop Med Hyg 28 :369–381.

  • 3

    Yamada KI, Takasaki T, Nawa M, Nakayama M, Arai YT, Yabe S, Kurane I, 1999. The features of imported dengue fever cases from 1996 to 1999. Jpn J Infect Dis 52 :257–259.

    • Search Google Scholar
    • Export Citation
  • 4

    Kurane I, Takasaki T, Yamada K, 2000. Trends in flavivirus infections in Japan. Emerg Infect Dis 6 :569–571.

  • 5

    Judicial System Department, Ministers Secretariat, 2001. Ministry of Justice. Annual Report of Statistics on Legal Migrants. Tokyo, Ministry of Justice.

  • 6

    Konishi E, Suzuki T, 2002. Ratios of subclinical to clinical Japanese encephalitis (JE) virus infections in vaccinated populations: evaluation of an inactivated JE vaccine by comparing the ratios with those in unvaccinated populations. Vaccine 21 :98–107.

    • Search Google Scholar
    • Export Citation
  • 7

    Hoke CH, Nisalak A, Sangawhipa N, Jatanasen S, Laorakapongse T, Innis BL, Kotchasenee S, Gingrich JB, Latendresse J, Fukai K, Burke DS, 1988. Protection against Japanese encephalitis by inactivated vaccines. N Engl J Med 319 :608–614.

    • Search Google Scholar
    • Export Citation
  • 8

    Yamada K, Nawa M, Takasaki T, Yabe S, Kurane I, 1999. Laboratory diagnosis of dengue virus infection by reverse transcriptase polymerase chain reaction (RT-PCR) and IgM-capture enzyme-linked immunosorbent assay (ELISA). Jpn J Infect Dis 52 :150–155.

    • Search Google Scholar
    • Export Citation
  • 9

    Yamada K, Takasaki T, Nawa M, Yabe S, Kurane I, 2003. Antibody responses determined for Japanese dengue fever patients by neutralization and hemagglutination inhibition assays demonstrate cross-reactivity between dengue and Japanese encephalitis viruses. Clin Diagn Lab Immunol 10 :725–728.

    • Search Google Scholar
    • Export Citation
  • 10

    Clarke T, 2002. Dengue virus: Break-bone fever. Nature 416 :672–674.

  • 11

    Kalayanarooj S, Vaughn DW, Nimmannitya S, Green S, Suntayakorn S, Kunentrasai N, Viramitrachai W, Ratanachueke S, Kiatpolpoj S, Innis BL, Rothman AL, Nisalak A, Ennis FA, 1997. Early clinical and laboratory indicators of acute dengue illness. J Infect Dis 176 :313–321.

    • Search Google Scholar
    • Export Citation
  • 12

    Schwartz E, Mendelson E, Sidi Y, 1996. Dengue fever among travelers. Am J Med 101 :516–520.

  • 13

    Guard RW, Stallman ND, Wiemers MA, 1984. Dengue in the northern region of Queensland, 1981–1982. Med J Aust 140 :765–769.

  • 14

    Infectious Diseases Control Division, Ministry of Health and Welfare, Infectious Disease Surveillance Center, National Institute of Infectious Diseases, 1996. Annual Report 1996. National Epidemiological Surveillance of Vaccine-Preventable Diseases. Tokyo, Ministry of Health and Welfare.

  • 15

    Peragallo MS, Nicoletti L, Lista F, D’Amelio R, East Timor Dengue Study Group, 2003. Probable dengue virus infection among Italian troops, East Timor, 1999–2000. Emerg Infect Dis 9 :876–880.

    • Search Google Scholar
    • Export Citation
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