INTRODUCTION
Dengue fever (DF) and dengue hemorrhagic fever (DHF) are diseases that have long been endemic in tropical and subtropical regions of the world. Epidemic DHF emerged in southeast Asia following World War II. The first recorded DHF epidemic in this area occurred in Manila, the Philippines, in 1953–1954,1 followed by another in 1956. Fourteen years after the 1953–1954 Philippines epidemic, DHF epidemics were reported in the Indonesian cities of Surabaya and Jakarta. Since then, outbreaks of the disease have spread to involve most of the major urban areas in Indonesia, as well as some of the rural areas of the country.2–,4
In 1998, a record number of dengue (DEN) cases occurred in Indonesia, giving rise to thousands of clinically diagnosed DHF cases. An outbreak investigation in Palembang in southern Sumatra from January to April 1998 showed a monthly mean number of outbreak-related DEN cases of 833.5 A review of hospital data from two Palembang hospitals showed that a sizeable number of severe DEN cases occurred in individuals ≥15 years old.
Adult cases of DEN, some severe, were associated with epidemics in Cuba. During the 1981 DEN-2 outbreak in Cuba that followed the 1977 DEN-1 epidemic, many adult secondary infections were documented, but the occurrence of DHF or dengue shock syndrome (DSS) was limited mostly to children.6 Sixteen years later, a second DEN-2 epidemic resulted in a death rate that was significantly higher in adults compared with the earlier DEN-2 epidemic.7 This suggested that the longer interval between primary DEN-1 and secondary DEN-2 virus infections correlated with more severe disease.
The above epidemiologic findings, together with the fact that candidate DEN vaccines must ultimately be evaluated in adult populations in DEN-endemic regions, emphasizes the need to generate more information on DEN virus infections in adults. To further examine the epidemiology of DF and DHF in an adult population, a prospective cohort study was initiated in adult textile factory workers living in Bandung, West Java, Indonesia.
West Java was chosen for the following reasons. Based on the number of cases reported as of September 1998, the provinces recording the most adult ( ≥18 years old) DHF cases were Jakarta (13,813), West Java (10,730), East Java (8,546), Central Java (6,879), and Yogyakarta (3,257). Compared with Jakarta Province, West Java has a larger number of factories from which study volunteers can be recruited. Of the five largest municipalities in West Java, Cirebon, Bogor, and Bandung had the largest number of cases per 100,000 population, with averages over a four-year period (1995 to 1998) of 44, 54.7, and 31.7, respectively. Although Bandung had the lowest case rate of the three, this city (or Kotamadya) was chosen as the desired site because of the presence of highly capable health care personnel and academic research facilities. Located in Bandung, Padjadjaran University is the largest university and medical school in West Java. Hasan Sadikin Hospital, the largest hospital in West Java, is also located in Bandung and serves as a teaching hospital for the medical school. Bandung, the capital city of West Java, is the fourth largest city in Indonesia and has an estimated population of two million. It is located at an altitude of approximately 750 meters above sea level and has a cool climate (18–28°C) throughout the year. The subdistrict within Bandung that consistently reports the largest number of hospitalized adult DHF cases is Cibeunying Kidul. In 1998, 42 DHF cases/ 100,000 population were reported there. In Ujung Berung, another subdistrict 1.5 km east of Cibeunying Kidul, the reported DHF incidence was 40/100,000 population. The results of the first two years of this study (August 2000 through July 2002) are the subject of this report.
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MATERIALS AND METHODS
Study site.
The PT Naintex textile factory in Cibeunying Kidul was enlisted to participate in the study. In Acramanik (neighboring Ujung Berung), employees at the PT Grandtex factory were recruited to participate. PT Naintex employs 1,500 people and PT Grandtex employs 4,000 people. The absentee rate due to illness averages seven per day at Naintex and four per day at Grandtex. The ages of the employees ranged from 18 to 66 years old, with the majority (estimated at 90%) being 18–45 years of age. The employees work six days a week in three rotating shifts of eight hours. The shifts are rotated every two weeks. The working hours for each shift are 6:00 am to 2:00 pm, 2:00 pm to 10:00 pm, and 10:00 pm to 6:00 am. These working hours result in all study participants having DEN vector exposures both at work and at home. Fogging takes place at both companies on a regular basis to reduce mosquito populations.
Enrollment and study design.
Prior to enrollment, a series of seminars was conducted to introduce the study to factory personnel and to answer any questions. Consent forms were distributed for advanced reading prior to the start of enrollment. Prior to entering into the study, the consent forms were completed and signed by each volunteer. The cohort study protocol was reviewed and approved by the Institutional Review Boards at the Naval Medical Research Unit No. 2 and the National Institutes of Health Research and Development, Ministry of Health, Indonesia.
All volunteers completed medical history questionnaires and demographic data forms. Physical examinations were conducted on each volunteer and blood samples were obtained for baseline routine laboratory tests that included a complete cell blood count (CBC) with differential, electrolytes, liver enzymes, urinalysis, PT, PTT, protein, and albumin. Baseline tourniquet tests were also performed on each volunteer. Peripheral blood mononuclear cells (PBMCs) and plasma were obtained and stored for later evaluation of baseline anti-DEN immune status. Volunteers were excluded from participation if they were afflicted by, or had a history of, anemia (hemoglobin level < 8 g/dL), infection with human immunodeficiency virus, non-DEN-related bleeding disorder, or any immunologic disorder.
Active surveillance of the volunteer cohort occurred whereby the factory personnel office would notify the study coordinator in the event an employee volunteer failed to show up for work. Evaluation by the factory physician was required for an employee to be officially excused from work. Upon receiving notification of the absenteeism, the study coordinator would immediately contact the volunteer by telephone to determine the reason for the absence. Within 24 hours of making phone contact, a medical evaluation was conducted and blood samples were obtained. For volunteers not possessing a telephone, the study nurse or physician visited his or her residence no later than 24 hours of absenteeism notification. The detection of a febrile illness warranted a medical evaluation. Most of the volunteers who had febrile illnesses were identified through this system.
Follow-up and evaluation of febrile illness.
If absenteeism was due to a febrile illness, a medical evaluation was performed and blood samples were obtained for CBC with differential and platelet count, DEN virus isolation, a DEN reverse transcriptase-polymerase chain reaction (RT-PCR), and serology. Automated CBC and differential counts were performed in the Hasan Sadikin Hospital Hematology Laboratory. Volunteers with thrombocytopenia (platelet count < 100,000/mm3) or those who were severely ill as determined by the attending study physician were hospitalized for observation and/or further evaluation. During their hospital stay, automated hematocrit and platelet determinations were made daily, and sonograms were performed almost daily to look for plasma leakage as shown by hemoconcentration or by the development of ascites and/or pleural effusion. Ultrasound has a higher degree of accuracy with a positive predictive value of 92% compared with a lateral decubitus chest radiographs.8 Because ultrasound does not involve exposure to radiation, this was the technique chosen for use in the study. The hematocrit and platelet counts were performed in the hospital hematology laboratory and the sonograms in the hospital radiology department. Serum protein and albumin measurements were also obtained and used as another tool to monitor volunteers for plasma leakage. These additional tests were performed in the Hasan Sadikin Hospital chemistry laboratory. Febrile volunteers who were not severely ill or who had platelet counts of 100,000–150,000/mm3 were followed as outpatients. Sonograms, serial hematocrits, and platelet determinations were not performed. Seven to 14 days post-illness, convalescent blood samples were obtained from all febrile patients.
Detection of asymptomatic or mild DEN virus infection.
To evaluate the cohort for the occurrence of asymptomatic and mild DEN illness, blood samples were obtained from the entire cohort every three months. Although samples were collected from all volunteers, the hemagglutination-inhibition (HI) test was used to screen serum samples from 250 randomly selected volunteers not experiencing a DEN-related febrile illness to detect DEN seroconversion. Randomization was performed using SPSS software (SPSS Inc., Chicago, IL). A volunteer was said to seroconvert if there was a ≥four-fold increase HI titer between successive serosurveys. The plaque reduction neutralization test (PRNT) was used to confirm HI seroconversions. On alternating blood draws, PBMCs were collected and stored in liquid nitrogen for later evaluation of pre-infection anti-DEN cellular immune status. During the cohort serosurveys, brief questionnaires were administered to the volunteers to inquire about the occurrence of any DEN-like symptoms or illnesses since the preceding serosurvey.
Diagnosis of symptomatic DEN virus infection.
A volunteer was considered to have a DEN virus infection if he or
INTRODUCTION
Dengue fever (DF) and dengue hemorrhagic fever (DHF) are diseases that have long been endemic in tropical and subtropical regions of the world. Epidemic DHF emerged in southeast Asia following World War II. The first recorded DHF epidemic in this area occurred in Manila, the Philippines, in 1953–1954,1 followed by another in 1956. Fourteen years after the 1953–1954 Philippines epidemic, DHF epidemics were reported in the Indonesian cities of Surabaya and Jakarta. Since then, outbreaks of the disease have spread to involve most of the major urban areas in Indonesia, as well as some of the rural areas of the country.2–,4
In 1998, a record number of dengue (DEN) cases occurred in Indonesia, giving rise to thousands of clinically diagnosed DHF cases. An outbreak investigation in Palembang in southern Sumatra from January to April 1998 showed a monthly mean number of outbreak-related DEN cases of 833.5 A review of hospital data from two Palembang hospitals showed that a sizeable number of severe DEN cases occurred in individuals ≥15 years old.
Adult cases of DEN, some severe, were associated with epidemics in Cuba. During the 1981 DEN-2 outbreak in Cuba that followed the 1977 DEN-1 epidemic, many adult secondary infections were documented, but the occurrence of DHF or dengue shock syndrome (DSS) was limited mostly to children.6 Sixteen years later, a second DEN-2 epidemic resulted in a death rate that was significantly higher in adults compared with the earlier DEN-2 epidemic.7 This suggested that the longer interval between primary DEN-1 and secondary DEN-2 virus infections correlated with more severe disease.
The above epidemiologic findings, together with the fact that candidate DEN vaccines must ultimately be evaluated in adult populations in DEN-endemic regions, emphasizes the need to generate more information on DEN virus infections in adults. To further examine the epidemiology of DF and DHF in an adult population, a prospective cohort study was initiated in adult textile factory workers living in Bandung, West Java, Indonesia.
West Java was chosen for the following reasons. Based on the number of cases reported as of September 1998, the provinces recording the most adult ( ≥18 years old) DHF cases were Jakarta (13,813), West Java (10,730), East Java (8,546), Central Java (6,879), and Yogyakarta (3,257). Compared with Jakarta Province, West Java has a larger number of factories from which study volunteers can be recruited. Of the five largest municipalities in West Java, Cirebon, Bogor, and Bandung had the largest number of cases per 100,000 population, with averages over a four-year period (1995 to 1998) of 44, 54.7, and 31.7, respectively. Although Bandung had the lowest case rate of the three, this city (or Kotamadya) was chosen as the desired site because of the presence of highly capable health care personnel and academic research facilities. Located in Bandung, Padjadjaran University is the largest university and medical school in West Java. Hasan Sadikin Hospital, the largest hospital in West Java, is also located in Bandung and serves as a teaching hospital for the medical school. Bandung, the capital city of West Java, is the fourth largest city in Indonesia and has an estimated population of two million. It is located at an altitude of approximately 750 meters above sea level and has a cool climate (18–28°C) throughout the year. The subdistrict within Bandung that consistently reports the largest number of hospitalized adult DHF cases is Cibeunying Kidul. In 1998, 42 DHF cases/ 100,000 population were reported there. In Ujung Berung, another subdistrict 1.5 km east of Cibeunying Kidul, the reported DHF incidence was 40/100,000 population. The results of the first two years of this study (August 2000 through July 2002) are the subject of this report.
Previous SectionNext Section
MATERIALS AND METHODS
Study site.
The PT Naintex textile factory in Cibeunying Kidul was enlisted to participate in the study. In Acramanik (neighboring Ujung Berung), employees at the PT Grandtex factory were recruited to participate. PT Naintex employs 1,500 people and PT Grandtex employs 4,000 people. The absentee rate due to illness averages seven per day at Naintex and four per day at Grandtex. The ages of the employees ranged from 18 to 66 years old, with the majority (estimated at 90%) being 18–45 years of age. The employees work six days a week in three rotating shifts of eight hours. The shifts are rotated every two weeks. The working hours for each shift are 6:00 am to 2:00 pm, 2:00 pm to 10:00 pm, and 10:00 pm to 6:00 am. These working hours result in all study participants having DEN vector exposures both at work and at home. Fogging takes place at both companies on a regular basis to reduce mosquito populations.
Enrollment and study design.
Prior to enrollment, a series of seminars was conducted to introduce the study to factory personnel and to answer any questions. Consent forms were distributed for advanced reading prior to the start of enrollment. Prior to entering into the study, the consent forms were completed and signed by each volunteer. The cohort study protocol was reviewed and approved by the Institutional Review Boards at the Naval Medical Research Unit No. 2 and the National Institutes of Health Research and Development, Ministry of Health, Indonesia.
All volunteers completed medical history questionnaires and demographic data forms. Physical examinations were conducted on each volunteer and blood samples were obtained for baseline routine laboratory tests that included a complete cell blood count (CBC) with differential, electrolytes, liver enzymes, urinalysis, PT, PTT, protein, and albumin. Baseline tourniquet tests were also performed on each volunteer. Peripheral blood mononuclear cells (PBMCs) and plasma were obtained and stored for later evaluation of baseline anti-DEN immune status. Volunteers were excluded from participation if they were afflicted by, or had a history of, anemia (hemoglobin level < 8 g/dL), infection with human immunodeficiency virus, non-DEN-related bleeding disorder, or any immunologic disorder.
Active surveillance of the volunteer cohort occurred whereby the factory personnel office would notify the study coordinator in the event an employee volunteer failed to show up for work. Evaluation by the factory physician was required for an employee to be officially excused from work. Upon receiving notification of the absenteeism, the study coordinator would immediately contact the volunteer by telephone to determine the reason for the absence. Within 24 hours of making phone contact, a medical evaluation was conducted and blood samples were obtained. For volunteers not possessing a telephone, the study nurse or physician visited his or her residence no later than 24 hours of absenteeism notification. The detection of a febrile illness warranted a medical evaluation. Most of the volunteers who had febrile illnesses were identified through this system.
Follow-up and evaluation of febrile illness.
If absenteeism was due to a febrile illness, a medical evaluation was performed and blood samples were obtained for CBC with differential and platelet count, DEN virus isolation, a DEN reverse transcriptase-polymerase chain reaction (RT-PCR), and serology. Automated CBC and differential counts were performed in the Hasan Sadikin Hospital Hematology Laboratory. Volunteers with thrombocytopenia (platelet count < 100,000/mm3) or those who were severely ill as determined by the attending study physician were hospitalized for observation and/or further evaluation. During their hospital stay, automated hematocrit and platelet determinations were made daily, and sonograms were performed almost daily to look for plasma leakage as shown by hemoconcentration or by the development of ascites and/or pleural effusion. Ultrasound has a higher degree of accuracy with a positive predictive value of 92% compared with a lateral decubitus chest radiographs.8 Because ultrasound does not involve exposure to radiation, this was the technique chosen for use in the study. The hematocrit and platelet counts were performed in the hospital hematology laboratory and the sonograms in the hospital radiology department. Serum protein and albumin measurements were also obtained and used as another tool to monitor volunteers for plasma leakage. These additional tests were performed in the Hasan Sadikin Hospital chemistry laboratory. Febrile volunteers who were not severely ill or who had platelet counts of 100,000–150,000/mm3 were followed as outpatients. Sonograms, serial hematocrits, and platelet determinations were not performed. Seven to 14 days post-illness, convalescent blood samples were obtained from all febrile patients.
Detection of asymptomatic or mild DEN virus infection.
To evaluate the cohort for the occurrence of asymptomatic and mild DEN illness, blood samples were obtained from the entire cohort every three months. Although samples were collected from all volunteers, the hemagglutination-inhibition (HI) test was used to screen serum samples from 250 randomly selected volunteers not experiencing a DEN-related febrile illness to detect DEN seroconversion. Randomization was performed using SPSS software (SPSS Inc., Chicago, IL). A volunteer was said to seroconvert if there was a ≥four-fold increase HI titer between successive serosurveys. The plaque reduction neutralization test (PRNT) was used to confirm HI seroconversions. On alternating blood draws, PBMCs were collected and stored in liquid nitrogen for later evaluation of pre-infection anti-DEN cellular immune status. During the cohort serosurveys, brief questionnaires were administered to the volunteers to inquire about the occurrence of any DEN-like symptoms or illnesses since the preceding serosurvey.
Diagnosis of symptomatic DEN virus infection.
A volunteer was considered to have a DEN virus infection if he or
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