Shigella spp. surveillance in Indonesia: the emergence or reemergence of S. dysenteriae.

From June 1998 through November 1999, Shigella spp. were isolated in 5% of samples from 3,848 children and adults with severe diarrheal illness in hospitals throughout Indonesia. S. dysenteriae has reemerged in Bali, Kalimantan, and Batam and was detected in Jakarta after a hiatus of 15 years.

Vibrio parahaemolyticus associated with cholera-like diarrhea among patients in North Jakarta, Indonesia.

A diarrhea study was conducted in North Jakarta, Indonesia from December 1996 through December 1997. Vibrio parahaemolyticus was isolated from 333 (6.1%) of 5442 rectal swab samples collected from patients with cholera-like diarrhea. Vibrio cholerae O1 was isolated from 545 (10.0%) and V. cholerae non-O1 from 183 samples (3.4%), respectively. Patients positive for V. parahaemolyticus were mostly adults between 20 and 40 years of age, with males constituting 62%. A majority (65%) of these patients demonstrated watery diarrhea with a frequency of fewer than 10 episodes per 24 hour. A large number of the patients had abdominal pain (83%) and vomiting (76%) and were non-febrile (90%). The highest isolation rate (9.6%) of V. parahaemolyticus was found during the dry season (June, July) and the lowest (4.5%) in the rainy season (December, January, February). All of the V. parahaemolyticus isolates were hemolytic on human blood agar (positive Kanagawa) but none was urease positive. Disk diffusion antibiotic susceptibility tests performed on the isolates demonstrated resistance to ampicillin (98%), cephalothin (24%), kanamycin (15%), colistin (97%), neomycin (2%) and ceftriaxone (0.3%). All isolates (100%) were sensitive to chloramphenicol, tetracycline, trimethoprim-sulfamethoxazole, gentamicin, and ciprofloxacin.

Cholera in Indonesia in 1993-1999.

Cholera-specific surveillance in Indonesia was initiated to identify the introduction of the newly recognized Vibrio cholerae non-O1, O139 serotype. Findings from seven years (1993-1999) of surveillance efforts also yielded regional profiles of the importance of cholera in both epidemic and sporadic diarrheal disease occurrence throughout the archipelago. A two-fold surveillance strategy was pursued involving 1) outbreak investigations, and 2) hospital-based case recognition. Rectal swabs were transported to Jakarta for culture and isolates were characterized by serotypic identification. Outbreak findings showed that V. cholerae O1, Ogawa serotype, was the predominant etiology in all 17 instances of investigated epidemic transmission. Monitoring of eight hospitals representing seven provinces provided 6,882 specimens, of which 9% were culture positive for V. cholerae: 589 (9%) for O1 and 20 (< 1%) for non-O1 strains. Proportional representation of V. cholerae O1 among cases of sporadic diarrheal illness was variable, ranging from 13% in Jakarta to < 1% in Batam. Overall, 98% of V. cholerae O1 cases were the Ogawa serotype. There was no instance of non-O1, O139 serotype introduction in either epidemic or sporadic disease form. Anti-microbial drug susceptibility was consistently demonstrated, both temporally and spatially, except against colistin. Evidence is provided that epidemic and sporadic cholera occurrence in western Indonesia is associated with periods of low rainfall. Conversely, in the more eastern portion of the country, heavy rainfall may have contributed to epidemic cholera transmission.

Efficacy trial of single-dose live oral cholera vaccine CVD 103-HgR in North Jakarta, Indonesia, a cholera-endemic area.

A randomized, double-blind, placebo-controlled efficacy trial of one dose of CVD 103-HgR live oral cholera vaccine was performed in Indonesia from 1993 to 1997. 67,508 persons aged 2-41 years ingested vaccine or placebo and were followed for four years, detecting cholera cases using hospital-based surveillance. A nested reactogenicity study (538 vaccinees, 535 controls) revealed no vaccine-attributable side effects. A nested immunogenicity study (N=657) showed vibriocidal seroresponses in 64-70% of vaccinees vs 1-2% of controls. Cholera incidence was lower than expected. 103 cases of Vibrio cholerae O1 El Tor diarrhea were detected, 93 evaluable for vaccine efficacy (43 vaccine, 50 placebo; efficacy=14%). A suggestion of protection was observed among persons with blood group O [P=0.12]. Only seven cases occurred within six months of vaccination, precluding assessment of short-term efficacy. In Jakarta, single-dose CVD 103-HgR did not confer long-term protection. Short-term protection from a single-dose and long-term protection from two doses have yet to be studied.

Safety and immunogenicity of combined diphtheria-tetanus-pertussis (whole cell and acellular)-Haemophilus influenzae-b conjugate vaccines administered to Indonesian children.

A randomized double-blind trial was conducted to evaluate the safety and immunogenicity of vaccines comprised of diphtheria (D) and tetanus (T) toxoids combined with either a whole cell (P) or an acellular (aP) pertussis component and Haemophilus influenzae type b polyribosylphosphate (PRP) tetanus toxoid conjugate (PRP-T) in Indonesian infants. Three doses of either DTaP, DTaP-PRP-T, or DTP-PRP-T were administered to 930 infants approximately 2-3 months of age and at 2 month intervals thereafter. A booster dose of either DTP-PRP-T or DTaP-PRP-T was administered at 15-18 months of age. Both local and systemic reactions occurred at a significantly (p < 0.001-0.026) higher rate in the group that received whole cell pertussis vaccine versus groups which were immunized with aP containing vaccines. There was no significant difference (p > 0.05) in the rate of adverse events between groups immunized with DTaP or DTaP PRP T. One month after the third dose of vaccine, 99% of subjects had achieved > or =0.1 IU of anti-D and anti-T antibody per ml of serum. The geometric mean titer (GMT) to D was significantly (p < 0.001) higher in the group immunized with DTaP versus the other two groups whereas the anti-T GMT was significantly (p < 0.006) higher for the group immunized with DTP-PRP-T. Both the anti-pertussis toxin (PT) and anti-filamentous hemagglutinin (FHA) antibody levels were significantly (p < 0.001) higher in recipients of acellular versus whole cell pertussis vaccine. In contrast, the anti-B. pertussis agglutinating antibody response was significantly (p < 0.0001) higher in the group immunized with whole cell pertussis vaccine. The anti-PRP GMTs (microg antibody/ml) at 7 months were 0.096, 3.35 and 6.11 for groups immunized with DTaP, DTaP-PRP-T and DTP-PRP-T, respectively. The GMT for those immunized with DTP-PRP-T was significantly (p < 0.001) higher compared to recipients of DTaP-PRP-T. The percent of children who attained > or =0.15 or > or =1 microg/ml after immunization was 18 and 2% for the DTaP group, 93 and 76% for the DTaP-PRP-T group and 97 and 88% for the DTP-PRP-T group. At the > or =1 microg/ml level the difference between the DTaP-PRP0-T and DTP-PRP-T groups was significant (p < 0.01). Children immunized with either DTaP, DTaP-PRP-T, or DTP-PRP-T were reimmunized with DTaP-PRP-T whereas a portion of children immunized with DTP PRP T where also boosted with this vaccine at 15-18 months of age. There was a vigorous anamnestic response to the D and T components with all children possessing > or =0.1 IU/ml. There was also a substantial increase in anti-PT, anti-FHA and B. pertussis agglutinating antibodies. The poorest anti-PT response was seen among children receiving DTP-PRP-T for both primary and reimmunization while the highest agglutinating antibody response followed receipt of 4 doses of DTP-PRP-T. Greater than 80% of children immunized with either DTP PRP T or DTaP-PRP-T possessed > or =0.15 microg/ml before boosting versus 38% for those vaccinated with DTaP (p < 0.001). Primary immunization with DTP-PRP-T resulted in a significantly (p < 0.05) higher percentage (72%) maintaining > or =1 microg/ml compared to those immunized with DTaP-PRP-T (46%). Prior to reimmunization, the anti-PRP GMT was significantly (p < 0.005) higher for children immunized with 3 doses of DTP-PRP-T versus DTaP-PRP-T. Subsequent to reimmunization, > or =95% of subjects attained > or =1 microg/ml.

Impact of epidemic influenza A-like acute respiratory illness in a remote jungle highland population in Irian Jaya, Indonesia.

A suspected epidemic of unknown etiology was investigated in April/May 1996 in the remote jungle highlands of easternmost Indonesia. Trend analysis demonstrates the area-wide occurrence of a major respiratory infection outbreak in November 1995 through February 1996. The monthly mean rate of respiratory infection episodes for the peak outbreak months (2,477 episodes/100,000 persons) was significantly higher (P < .0001) than for the 34 months leading up to the outbreak (109 episodes/100,000 persons). Notable were the high attack rates, particularly among adults: 202 episodes/1,000 persons aged 20-50 years in one community. Excess morbidity attributed to the outbreak was an estimated 4,338 episodes. The overall case-fatality rate was 15.1% of outbreak cases. Laboratory evidence confirmed the circulation of influenza A/Taiwan/1/86-like viruses in the study population, and high hemagglutination inhibition titer responses were indicative of recent infections. Historical documents from neighboring Papua New Guinea highlight the role of influenza A virus in repeated area outbreaks.

Enterotoxigenic Escherichia coli diarrhea among young children in Jakarta, Indonesia.

The incidence of diarrhea and enterotoxigenic Escherichia coli (ETEC) infection was evaluated in children six months to five years of age from an urban community in Jakarta, Indonesia. From January through May 1994, 408 children were monitored in their homes for diarrheal disease. Thirty-six percent (148 of 408) of the study children had at least one episode of diarrhea during the study period. Twenty-nine (19.6%) of the 148 children with diarrhea had ETEC isolated from a rectal swab sample at least once during the surveillance period; five children had ETEC isolated from two distinct episodes of diarrhea, giving a total of 34 episodes of ETEC positive diarrhea in the study group. Ten of 34 episodes were associated with heat-labile toxin, 15 of 34 with heat-stable toxin, and seven of 34 with both toxins. The mean age of children with diarrhea (1.7 years), whether ETEC positive or negative, was significantly lower than those who did not have diarrhea (2.4 years) during the study period; 82% of the children with ETEC were less than two years of age. This study demonstrates a high incidence of ETEC diarrhea among young children in Jakarta, and suggests this site would be suitable for ETEC vaccine efficacy trials.

PIP: During a 4-month period in 1994, 408 children 6 months to 5 years of age (mean, 2.4 years) from a densely populated slum section (Kapuk) of West Jakarta, Indonesia, were monitored in their homes for diarrheal disease. Many homes in this community lack running water or toilet facilities. Overall, 148 (36%) of these children had at least one diarrhea episode during the study period. 29 children (19.6%) with diarrhea had enterotoxigenic Escherichia coli (ETEC) isolated from a rectal swab sample at least once during the surveillance period and five children had ETEC isolated from two distinct diarrhea episodes, for a total of 34 episodes of ETEC-positive diarrhea. 10 of the 34 episodes were associated with heat-labile toxin, 15 with heat-stable toxin, and 7 with both toxins. Annualized rates of diarrhea and ETEC infections were estimated at 2.2 and 0.3 per child, respectively. The rate of children with diarrhea declined steadily with increasing age: 52% at 6-11 months, 48% at 12-23 months, 28% at 24-35 months, 30% at 36-47 months, and 12% at 48-60 months. 82% of children with ETEC were under 2 years of age. The high incidence of ETEC diarrhea recorded in this study suggests the feasibility of ETEC vaccine efficacy trials in this population.

Emerging disease surveillance in Southeast Asia.

The emergence of infectious disease causing agents/pathogens necessitates a rational surveillance approach leading to early detection and appropriate intervention. Surveillance activities with support from the US Naval Medical Research Unit No. 2 (NAMRU-2), targeting susceptible populations/areas in Southeast Asia, have been organised using a multi-design strategy: 1) systematic multi-size (usually hospital-based) study; 2) investigation of (suspected) outbreak events involving significant case populations (and associated fatalities); and 3) monitoring of unique "risk opportunities" that include pre- and post-screening of immunologically naïve (susceptible) persons (including military personnel and tourists) travelling in groups to areas of likely disease transmission/occurrence. Recognition of new (or old) disease agents or emerging antimicrobial resistance requires a standardised study effort with complementary advanced diagnostic capabilities. Collaborative research involving NAMRU-2 includes surveillance of 01 and non-01 Vibrio cholerae strains in epidemic and sporadic transmission, profiling regional patterns of antimicrobial resistance associated with Mycobacterium tuberculosis, describing the molecular epidemiology of HIV genotypic spread, and investigating foci of epidemic hepatitis E virus transmission. Focused surveillance efforts, as described, provide for recognition of emerging and/or re-emerging diseases, optimising the investment of generally scarce public health resources.

Enterotoxigenic Escherichia coli diarrhea in children less than five years of age in central Java.

A community-based prospective study was performed from December 1993 through March 31, 1994 in Indonesia in children less than five years of age. Enterotoxigenic Escherichia coli (ETEC) was identified in diarrheic stool by colony hybridization assay, using toxin probes, and this bacterium was isolated from 19% of 340 episodes of diarrhea. Sixty-one percent of ETEC produced heat-labile toxin (LT) only, 325 LT and heat-stable toxin (ST), and 75 ST only. The age-specific incidence rates of diarrhea among children 0-1 and 2-3 years of age were 77% and 61%, respectively, during the study period; ETEC was isolated from 26% of children 0-1 years of age versus 53% for children 2-3 years of age. As many as seven episodes of diarrhea were repeatedly experienced by a single child during the four-month study period; however, only two children had more than one episode of known ETEC-associated diarrheal disease during the period of observation.

Safety, immunogenicity, and transmissibility of single-dose live oral cholera vaccine strain CVD 103-HgR in 24- to 59-month-old Indonesian children.

Recombinant A-B+ Vibrio cholerae O1 strain CVD 103-HgR is a safe, highly immunogenic, single-dose live oral vaccine in adults in industrialized countries. Safety, excretion, immunogenicity, vaccine transmissibility, and environmental introduction of CVD 103-HgR were investigated among 24- to 59-month-old children in Jakarta. In 81 households, 1 child was randomly allocated a single dose of vaccine (5 x 10(9) cfu) and another, placebo. Additionally, 139 unpaired children were randomly allocated vaccine or placebo. During 9 days of follow-up, diarrhea or vomiting did not occur more often among vaccines than controls. Vaccine was minimally excreted and was isolated from no controls and from 1 (0.6%) of 177 unvaccinated family contacts. A 4-fold or higher rise in serum vibriocidal antibody was observed in 75% of vaccines (10-fold rise in geometric mean titer over baseline). Of 135 paired placebo recipients or household contacts, 5 had vibriocidal seroconversions. Moore swabs placed in sewers and latrines near 97 households failed to detect vaccine. These observations pave the way for a large-scale field trial of efficacy.

Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine.

When tested under conditions of moderate transmission of typhoid fever, a liquid formulation of the oral typhoid fever vaccine Ty21a had a protective efficacy of 96% in Egypt, and an enteric coated capsule formulation had an efficacy of 67% in Chile. We compared the two formulations under conditions of intense transmission of typhoid fever in Indonesia in a randomised, double-blind trial. 20,543 subjects (age range 3-44 years) received either three doses of enteric coated capsules containing placebo or live Ty21a, or three doses of lyophilised placebo or live Ty21a reconstituted with phosphate buffer. During 30 months of follow-up, the rate of blood-culture-positive typhoid fever among controls was 810/100,000 per year. Rates of typhoid fever were 379/100,000 per year for subjects who received the liquid formulation of vaccine and 468/100,000 per year for subjects who received enteric coated capsules. The protective efficacies of the liquid and enteric coated formulations were 53% and 42%, respectively. Neither formulation protected against infection with Salmonella paratyphi A. No major side-effects were noted, but the overall incidence of side-effects was greater in the vaccine groups. Under conditions of intense transmission, Ty21a protected against typhoid fever; however, because Ty21a will not protect all individuals, there is a need for additional approaches to prevent the disease.

PIP: When tested under conditions of moderate transmission of typhoid fever, a liquid formulation of the oral typhoid fever vaccine, Ty21a, had a protective efficacy of 96% in Egypt, and an enteric coated capsule formulation had an efficacy of 67% in Chile. The authors compared the 2 formulations under conditions of intense transmission of typhoid fever in Indonesia in a randomized, double blind trial. 20,543 subjects (age range 3-44 years) received either 3 doses of enteric-coated capsules containing placebo or live Ty21a, or 3 doses of lyophilized placebo or live Ty21a reconstituted with phosphate buffer. During 30 months of followup, the rate of blood-culture-positive typhoid fever among controls was 810/100,000/year. Rates of typhoid fever were 379/100,000/year for subjects who received the liquid formulation of vaccine and 468/100,000/year for subjects who received enteric coated capsules. The protective efficacies of the liquid and enteric coated formulations were 53% and 42%, respectively. Neither formulation protected against infection with Salmonella paratyphi A. No major side effects were noted, but the overall incidence of side effects was greater in the vaccine groups. Under conditions of intense transmission, Ty21a protected against typhoid fever; however since it will not protect all individuals, there is a need for additional approaches in prevention of the disease.

Streptokinase clot culture compared with whole blood culture for isolation of Salmonella typhi and S. paratyphi A from patients with enteric fever.

The sensitivities of whole blood and clot cultures were compared in 155 patients with typhoid or paratyphoid fever. Salmonella typhi or S. paratyphi A were isolated from 98.7% of 5 ml 1:10 blood:broth ratio blood cultures and 94.8% of 5 ml streptokinase clot cultures (P greater than 0.05). There was no difference in the speed of isolation. Whole blood culture and clot culture were of nearly equal sensitivity in this group of patients.

Rehydration and maintenance therapy of cholera patients in Jakarta: citrate-based versus bicarbonate-based oral rehydration salt solution.

We compared the therapeutic efficacy of a World Health Organization standard bicarbonate-based oral rehydration salt solution (BBORS) with a citrate-based oral rehydration solution (CBORS) in a randomized, double-blind, controlled trial in 130 dehydrated patients with cholera aged three to 82 years. On admission the 70 patients who received CBORS and the 60 who received BBORS were similar except that the serum CO2 content (mmol/liter) was significantly lower in the CBORS group (10.8 +/- 3.6 vs. 12.5 +/- 5.3). The incidence of vomiting postadmission (41% vs. 62%, respectively), the stool output during the first 24 hr (4,252 +/- 3,900 ml vs. 6,025 +/- 4,389 ml, respectively), and the time until the patients' conditions were considered normal (38.9 +/- 14.5 hr vs. 46.3 +/- 22.7 hr, respectively) were all significantly less in the CBORS group. The serum CO2 content increased more rapidly during the first 48 hr in the CBORS group (87% +/- 74% vs. 61% +/- 68% for the BBORS group); 23% of the patients receiving CBORS and 35% of the patients receiving BBORS were considered oral-therapy treatment failures. The results indicate that CBORS was superior to BBORS for rehydration and maintenance therapy of hospitalized cholera patients in Jakarta.

Chloroquine-resistant falciparum malaria in East Kalimantan, Indonesia.

Following the discovery of four imported chloroquine-resistant P. falciparum infections in the Province of Yogyakarta (Island of Java) sensitivity tests were carried out in the Province of East Kalimantan Island of Borneo). Twenty subjects were given 25 mg. of chloroquine base per kilogram of body weight over three days. Two infections were found resistant at the RII level and a third at the RI level with early recrudescence on day 7. In the other 17 cases followed up to day 21, six were found again with asexual parasites between day 9 and day 14 and a seventh on day 21. These results confirm the presence of chloroquine resistance in P. falciparum in East Kalimantan and, together with previous findings, suggest a widespread distribution of chloroquine-resistant falciparum malaria in this Province of Indonesia. It is particularly interesting to note that chloroquine-resistant falciparum malaria has now been detected in almost all the area of dispersion of A. balabacensis.