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Epidemiology of Cases of H5N1 Virus Infection in Indonesia, July 2005–June 2006

  1. Dr. Endang R. Sedyaningsih1,
  2. Siti Isfandari1,
  3. Vivi Setiawaty1,
  4. Lutfah Rifati1,
  5. Syahrial Harun1,
  6. Wilfred Purba2,
  7. Sholah Imari2,
  8. Sardikin Giriputra3,
  9. Patrick J. Blair4,
  10. Shannon D. Putnam4,
  11. Timothy M. Uyeki5 and
  12. Triono Soendoro1
  1. 1. National Institute of Health Research and Development, Jakarta, Indonesia
  2. 2. Directorate General of Disease Control and Environmental Health, Ministry of Health, Jakarta, Indonesia
  3. 3. Infectious Disease Hospital Sulianti Saroso, Jakarta, Indonesia
  4. 4. US Naval Medical Research Unit No.2, Jakarta, Indonesia
  5. 5. Centers for Disease Control and Prevention, Atlanta, Georgia
  1. Reprints or correspondence: Dr. Endang R. Sedyaningsih National Institute of Health Research and Development Jl. Percetakan Negara no. 29 Jakarta 10560 Indonesia (esedyani{at}indo.net.id).

  1. Presented in part: International Conference on Emerging Infectious Diseases, Atlanta, 19–22 March 2006; Chemical and Biological Medical Treatment Symposium VI, Spiez, Switzerland, 30 April-5 May 2006; 11th International Conference on Emerging Infectious Diseases in the Pacific Rim, Singapore, 16–18 November 2006.

 
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Abstract

Background. Highly pathogenic avian influenza A (H5N1) virus was detected in domestic poultry in Indonesia beginning in 2003 and is now widespread among backyard poultry flocks in many provinces. The first human case of H5N1 virus infection in Indonesia was identified in July 2005.

Methods. Respiratory specimens were collected from persons with suspected H5N1 virus infection and were tested by reverse-transcriptase polymerase chain reaction and viral culture. Serum samples were tested by a modified hemagglutinin inhibition antibody and/or microneutralization assay. Epidemiological, laboratory, and clinical data were collected through interviews and medical records review. Close contacts of persons with confirmed H5N1 virus infection were investigated.

Results. From July 2005 through June 2006, 54 cases of H5N1 virus infection were identified, with a case-fatality proportion of 76%. The median age was 18.5 years, and 57.4% of patients were male. More than one-third of cases occurred in 7 clusters of blood-related family members. Seventy-six percent of cases were associated with poultry contact, and the source of H5N1 virus infection was not identified in 24% of cases.

Conclusions. Sporadic and family clusters of cases of H5N1 virus infection, with a high case-fatality proportion, occurred throughout Indonesia during 2005–2006. Extensive efforts are needed to reduce human contact with sick and dead poultry to prevent additional cases of H5N1 virus infection.

Highly pathogenic avian influenza A (H5N1) virus infection among poultry was first recognized in Indonesia in December 2003 [1]. Large commercial poultry farms raising breeder and broiler chickens were affected initially, although H5N1 spread rapidly and widely to small farms and backyard poultry. By the end of June 2006, 27 of 33 provinces had identified outbreaks of H5N1 in poultry, resulting in >16 million poultry deaths from sickness and culling (Indonesia Ministry of Agriculture, unpublished data).

The first case of human infection with H5N1 virus in Indonesia was confirmed in July 2005 and was part of a family cluster located in western Java [2]. Since 2005, cases of H5N1 virus infection have continued to occur, and more H5N1 virus infections were identified in Indonesia during 2006 than in any other country [3]. In the present article, we describe the epidemiology of cases of human H5N1 virus infection in Indonesia from July 2005 through June 2006.

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Patients and Methods

Ill patients who met the World Health Organization (WHO) case definition for a suspected case of H5N1 virus infection [4] were reported to the Indonesia Ministry of Health. If clinically stable, patients with suspected H5N1 virus infection were transferred to 1 of 44 designated H5N1 referral hospitals throughout Indonesia. Available clinical specimens (throat and nasal swabs, endotracheal aspirates and washes from patients having undergone intubation, and lung-biopsy samples from 3 deceased persons) were obtained from patients with suspected H5N1 virus infection during hospitalization for testing at laboratories in Jakarta. Testing included detection of H5-specific viral RNA in respiratory specimens by conventional or real-time reverse-transcriptase polymerase chain reaction (RTPCR), and serum samples were tested by a modified horse red blood cell hemagglutination inhibition assay to detect H5N1 antibody using H5-specific antisera [5].

Clinical specimens were shipped to WHO H5 Reference Laboratories at the University of Hong Kong (HKU) and the US Centers for Disease Control and Prevention (CDC) for confirmation of all cases identified in Indonesia. Confirmatory H5N1 testing included detection of H5-specific viral RNA by real-time RT-PCR in biosafety level (BSL) 2 conditions, viral isolation, and detection of H5N1 neutralizing antibodies by microneutralization assay in BSL3 enhanced conditions as described elsewhere [6].

Epidemiological and clinical data from suspected cases of H5N1 virus infection were collected through interviews with case patients, family members, and close contacts and by review of medical records. Data were collected about physical contact with domestic poultry (touching, handling practices, slaughtering, butchering, etc.), proximity to and disease status of any domestic poultry (healthy-appearing, diseased, or dead chickens and ducks) or poultry products (e.g., chicken feces fertilizer) and other animals (pet birds, cats, dogs, pigs, wild birds, and other poultry species). In addition, investigators collected data on poultry, poultry products, and animal consumption (raw, partially cooked, and well cooked) and the presence and proximity of any poultry species (including live poultry markets) and other animals near case patients' homes.

Once a case patient tested positive for H5N1 by RT-PCR at laboratories in Indonesia, a field epidemiological investigation was initiated. Close contacts were defined as persons who had been within 1 m of a case patient during illness and included household and family members, coworkers, and health care workers. Contacts were checked for fever and respiratory symptoms, and serum samples were collected from them. Respiratory specimens were obtained from ill contacts for H5N1 testing. Final case classification was assigned according to WHO H5N1 case definitions [7]. A cluster of cases of H5N1 virus infection was defined as at least 2 epidemiologically linked ill persons with laboratory evidence of H5N1 virus infection among close contacts. Location of residence was classified as urban for case patients who lived in cities or towns and rural for case patients who lived in districts. Direct poultry contact was defined as touching healthy-appearing, sick, or dead poultry. Indirect poultry contact was defined as the presence of poultry within 25 m of a case patient's home. This study was part of an ongoing public health outbreak investigation and was determined to be exempt from institutional review board review in Indonesia.

We included all confirmed human cases of H5N1 virus infection identified in Indonesia from July 2005 through June 2006. Data from questionnaires were double-entered into Epi-Info software (version 6.0; CDC). Age was categorized into groups of <5, 5–9, 10–19, 20–29, 30–39, and 40 years, on the basis of WHO standard age distributions.

Descriptive and advanced statistical analyses were conducted using SPSS software (version 14.0; SPSS). To test the statistical significance among discrete variables (i.e., proportions), Mantel-Haenszel χ2 or Fisher's exact test was used. For 2-group significant testing between continuous variables, either Student's t test (parametric) or the Wilcoxon rank sum test (nonparametric) were used. For multiple groups comparison, the Kruskal-Wallis test or analysis of variance was used. McNemar's test was used for analysis of matched pairs. Statistical significance was 2-tailed and was set at P = .05 for all analyses.

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Results

Between July 2005 and June 2006, 598 suspected cases of H5N1 virus infection were investigated. Of these, 54 were confirmed and 41 were fatal, for a case-fatality proportion of 76%. Confirmed cases were reported in 8 of 33 Indonesia provinces (figure 1). Of the 54 confirmed cases, 35 were identified in 2006, with 83% case fatality (29/35), compared with 19 cases identified in 2005, with 63% mortality (12/19) (χ2 = 2.6; df = 1; P = .2).

Figure 1.
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Figure 1.

Locations of officially reported poultry outbreaks and confirmed human H5N1 virus infections, Indonesia, 2003–2006

The epidemic curve shows that an average of 5 new confirmed cases of H5N1 virus infection were reported each month throughout the study period (figure 2). A large increase in cases of H5N1 virus infection occurred in May 2006 but was due to one large family cluster in North Sumatra (Karo District) [8]. Most (93%) of all confirmed cases of H5N1 virus infection were identified through surveillance, but 4 cases (7%) were identified during field investigations.

Figure 2.
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Figure 2.

No. of confirmed human H5N1 virus infections by month of illness onset, Indonesia, June 2005–June 2006.

Demographic characteristics. The median age of confirmed patients with H5N1 virus infection was 18.5 years (range, 18 months–45 years). More than half (53%) of case patients were <20 years old, 96.3% were <40 years old, and 24% were children <10 years old. All case patients were reported to have been previously healthy. The male:female ratio was 3 :2 (33:21). There were no significant differences observed in the male:female ratio across age groups (χ2 = 3.7; df = 4; P = .8). Nearly two-third of case patients (n = 33) lived in rural areas, and the rest (n = 21) lived in urban areas.

Epidemiological investigations. We investigated 1127 contacts associated with 54 confirmed cases of H5N1 virus infection for illness. Paired serum samples were available for 130 contacts. During these investigations, we identified 4 ill persons who tested positive for H5N1, 3 by RT-PCR and 1 by a 4-fold increase in H5N1 antibody titer between paired acute and convalescent serum samples.

Source of H5N1 virus infection. All case patients with confirmed H5N1 virus infection were investigated to ascertain the most likely source of H5N1 virus exposure. Forty-one case patients (76%) had direct or indirect contact with poultry (healthy appearing, sick, or dead) during the 2 weeks preceding illness onset. The source of H5N1 virus was inconclusive in 24% of case patients.

Among the 41 case patients who had poultry exposures, only 23 had direct contact, such as slaughtering or handling of sick birds; the 18 other case patients with indirect contact had healthy, sick, or dead poultry in their neighborhood, although handling of such birds could not be confirmed. Six case patients (11%) with direct poultry contact had poultry-related occupations, including 3 poultry farm workers, 2 live poultry market workers, and 1 shuttlecock feather selector. There was no significant difference in exposure sources between case patients living in urban and rural areas (χ2 = 1.3; df = 1; P = .2).

Clusters. More than one-third (39%; n = 21) of 54 cases of H5N1 virus infection occurred in 7 clusters (table 1). There was 1 probable case patient in each of the first and sixth clusters. These were persons who had close contact with patients with confirmed H5N1 virus infection, had illness onset within the incubation period of a confirmed case of infection, and died of severe respiratory distress. However, no specimens were available for H5N1 testing from these cases, because the patients died before being suspected of having H5N1 virus infection.

Table 1.
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Table 1.

H5N1 clusters in Indonesia by province, illness onset of first case and fatality proportion, July 2005–June 2006 (20 confirmed, 2 probable cases).

The median age of case patients in the clusters was 14 years; there was no significant difference between the median ages of case patients in the clusters and in those with sporadic infection throughout Indonesia (14 vs. 23 years; P = .2, median test).

Medical care. The median duration from onset of symptoms until the first medical care visit was 4 days (range, 0–14 days; n = 53 cases). Medical care was sought from public and private health center clinics and from hospital clinics. Thirteen case patients (24%) were assessed as outpatients, prescribed antibiotics, and discharged home. All of these 13 case patients worsened clinically and were admitted to hospitals a median of 2 days later (range, 1–7 days).

Among all case patients, the median duration from onset of symptoms until hospitalization was 5 days (range, 1–14 days). Female case patients were hospitalized earlier than were male case patients (median, 4 vs. 5 days), but the difference was not statistically significant (P = .6, median test). Case patients were admitted to hospitals in 8 provinces, and 35% were admitted to the national referral hospital (Infectious Disease Hospital in Jakarta).

Admission clinical and laboratory findings. The most common signs and symptoms at admission were fever, shortness of breath, and cough. Some case patients also reported diarrhea, constipation, and convulsions. Leukopenia and thrombocytopenia were common (table 2). Lymphopenia was noted in 55% of case patients (16/29). All case patients had evidence of pneumonia on chest radiograph.

Table 2.
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Table 2.

Admission clinical and laboratory findings of 54 confirmed cases of H5N1 virus infection in Indonesia, July 2005–June 2006.

Fifty case patients (93%) were confirmed as having H5N1 virus infection by real-time RT-PCR, and 4 (7%) were confirmed through serological testing. Throat swabs had a much higher yield of detection of H5N1 viral RNA by real-time RTPCR than did nasal swabs (92% and 39%, respectively) (P < .0001, McNemar's test).

Hospitalization. The median time from hospital admission to death was 3.5 days (range, 0–14 days; n = 40; 1 case patient who died was not hospitalized). There was no statistically significant difference in median duration from admission to death between female and male case patients who died (4 vs. 3 days; P = .8, median test). Seven case patients (18%) died within 24 h of hospitalization. Among surviving case patients, the median duration of hospitalization was 18 days (range, 7–75 days; n = 13) (1 case patient had a very prolonged hospital course for unrelated complications from a parasitic disease). Among fatal cases, the median duration from onset of symptoms to death was 9 days (range, 5–19 days; n = 41).

Outcomes. The overall case-fatality proportion was 76% and ranged from 0% in case patients ⩾40 years old (n = 2) to 100% in case patients 30–39 years old (n = 9) (table 3). The difference in mortality among age groups was statistically significant (P = .03, Fisher's exact test). Overall, the case-fatality proportion for female case patients was higher than that for male case patients (90% vs. 67%; χ2 = 4.0; df = 1; P = .04). When stratified by age, there were no differences in the case-fatality proportion for girls and boys among children !10 years old (80% vs. 50%; χ2 = 1.2; df = 1; P = .3) or among case patients ⩾10 years old (94% vs. 72%; χ2 = 2.9; df = 1; P = .1).

Table 3.
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Table 3.

H5N1 case-fatality proportion by sex and age group (n = 54).

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Discussion

Our study summarizes the descriptive epidemiology of the highest number of cases of H5N1 virus infection in humans in any country to date, including sporadic and clusters of H5N1 cases. The epidemiology of H5N1 cases in Indonesia was similar to that reported in other countries (age and sex distribution and history of poultry contact) [9–14], although a substantial number of cases were reported in family clusters. Case patients were identified in 8 provinces and every month during July 2005 through June 2006, reflecting exposures related to the ongoing widespread H5N1 epizootic among backyard poultry in Indonesia [15]. The 34 cases of H5N1 virus infection identified from January through June 2006 was the highest number reported by any country in the world during this period [3]. Additional cases of H5N1 virus infection have been identified in Indonesia since June 2006. All cases of H5N1 virus infection in Indonesia to date have been with clade 2, subclade 1 H5N1 viruses [16].

Several factors might contribute to the very high H5N1 mortality observed. Similar to other countries in which case patients were hospitalized a median of 4 days after onset [9], most Indonesian case patients with H5N1 virus infection sought medical care late during the course of their illness and therefore did not receive early antiviral treatment or supportive care. Although antiviral treatment with neuraminidase inhibitors is recommended [17], late administration of antiviral therapy likely does not effectively treat the massive host inflammatory process triggered by H5N1 virus infection [18]. Many case patients were not initially suspected as having H5N1 virus infection by health care providers; 13 patients (24%) were evaluated as outpatients and sent home before hospital admission. This might be due to early nonspecific signs and symptoms of H5N1, a failure to elicit a history of contact with sick or dead poultry, or an unfamiliarity of medical providers with the clinical features of H5N1.

Furthermore, H5N1 case-finding has not focused on the identification of asymptomatic or mild cases of H5N1 virus infection [2, 19–21] that would likely decrease the overall case-fatality proportion, although one limited clade 1 H5N1 virus seroprevalence study published to date did not identify any asymptomatic infections [22]. Four clinically mild cases of H5N1 virus infection in Indonesia in 2005–2006 were identified during field investigations of severely ill index case patients in 3 clusters and would have been missed by hospital-based surveillance for severe respiratory disease [2]. More studies are needed, including clade 2 H5N1 virus seroprevalence studies in Indonesia and other countries. Such studies should be conducted among many different populations, including poultry workers, persons exposed to backyard poultry (including family members of case patients), health care workers, contacts of case patients, and the general population.

The high percentage of case patients identified in family clusters suggests potential opportunities for intervention and highlights the importance of early identification and rapid investigation of every case of H5N1 virus infection. All H5N1 cases that have occurred in clusters in Indonesia to date have been among blood relatives. Such cases, as noted in other countries [23–25], suggest a possible genetic susceptibility to H5N1 virus infection. Whether case clustering could be due to common-source poultry exposure, different H5N1 sources, or limited person-to-person transmission, early administration of oseltamivir chemoprophylaxis among household members and close contacts might prevent additional cases after an initial case patient is identified [17]. Research is needed to better understand the occurrence and prevention of H5N1 virus infection in family clusters in Indonesia and elsewhere.

There are a number of limitations to our findings. It is very likely that the number of confirmed cases of H5N1 virus infection identified during 2005–2006 underestimated the true incidence of H5N1 virus infection that occurred in Indonesia. Specimens were not available for H5N1 testing from a few fatal cases that were classified as probable cases. Other case patients might not have been identified because they did not seek medical attention or received a diagnosis of other diseases; did not meet the surveillance suspect case definition if they had asymptomatic infection or mild illness, as noted previously; or had atypical symptoms [26]. In addition, it is possible that some H5N1 virus infections were not identified by RT-PCR because of the initial use of clade 1 virus primers and probes before clade 2 subclade 1 primers and probes were available or because of suboptimal respiratory specimens. Serum collected >21 days after exposure to poultry or to case patients was not available for all suspected cases and contacts, and serological testing may have missed some persons with milder or asymptomatic infection who had not developed detectable H5N1 antibodies. However, convalescent serum samples were available for some mildly ill contacts of case patients in whom H5N1 virus infection had been confirmed serologically. Our assessment of exposures was based on information obtained through interviews with case patients and their household and family members. However, many case patients who died could not be interviewed, and it is possible that some potential exposures were missed, especially for the 24% of case patients without an identifiable exposure. For case patients with indirect poultry exposure in which healthy-appearing, sick, or dead poultry were reported in the neighborhood of some case patients, the exact exposures remain unknown.

Our findings in Indonesia indicate that, despite the highest number of cases of H5N1 virus infection reported worldwide in 2006, H5N1 remains a very rare disease among humans there. However, human infection with H5N1 virus is clearly associated with severe disease and high mortality in Indonesia, and many interventional efforts must be initiated and sustained to reduce the risk of human infection with H5N1 virus. Expanded H5N1 surveillance to include investigations of cases of severe pneumonia of unknown origin, acute respiratory distress syndrome, and unexplained respiratory deaths; implementation of antiviral chemoprophylaxis among contacts of case patients; education of health care workers; raising public awareness about H5N1 and the need to avoid contact with sick or dead poultry; and close collaborations between researchers in animal health and public health are urgently needed to prevent more cases. Ultimately, control of H5N1 among poultry will reduce the public health threat of H5N1 in Indonesia.

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Acknowledgments

We thank our many colleagues at the Directorate General of Disease Control and Environmental Health and National Institute of Health Research and Development, Ministry of Health, Jakarta, Indonesia; provincial, district and subdistrict health offices; health care providers at Indonesian hospitals who cared for case patients; US Naval Medical Research Unit No. 2; World Health Organization Indonesia; Hong Kong University; and the US Centers for Disease Control and Prevention, for their contributions to our epidemiological, clinical, and laboratory investigations.

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Footnotes

  • Potential conflicts of interest: none reported.

  • Views expressed in this article are those of the authors and do not reflect the official policy or position of the Indonesian Ministry of Health, the US Department of Defense, the US Department of the Navy, or the US Centers for Disease Control and Prevention.

  • Received December 7, 2006.
  • Accepted February 14, 2007.
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  1. J Infect Dis. (2007) 196 (4): 522-527. doi: 10.1086/519692
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