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The Etiology of Acute Febrile Illness Requiring Hospitalization

(AFIRE)
ABSTRACT
Febrile illnesses account for approximately 20-25% of hospitalizations in Indonesia and
present a major cause of morbidity and mortality. Fever can be attributed to noninfectious causes.
However in developing countries a clinical presentation with fever is usually linked to an infectious
etiology. Though several studies have been implemented to study specific infectious disease agents
such as dengue, diarrhea, or influenza-like illness, large-scale studies to identify causes of febrile
illnesses in Indonesia have not been conducted. Further there are a reasonable percentage of patients
for whom the cause of the infectious etiology is unknown. To identify the etiology of infectious
diseases, microscopic examinations, bacterial and viral cultures, molecular, antigen or antibody assays
are needed. Clinicians often make the diagnoses solely on the clinical presentation as laboratory
diagnostic capacities are lacking, high costs involved in specialized diagnostic testing, or the inability
of a majority of patients to afford testing. This can lead to inappropriate clinical management and
inappropriate use of expensive antibiotics, which may contribute to increasing drug resistance.
Several studies have been conducted to evaluate febrile illness in various contexts in Indonesia. These
studies have identified pathogens in specimens collected from several acute undifferentiated fever
studies. One of the first reports was from Jakarta (Anderson et al.) based on the collection of
specimens from hospitalized patients with an unapparent febrile illness in 1971-72. Salmonella and
arbovirus infections were the major etiologies identified whereas leptospira, rickettsia, brucella and
toxoplasma infections were serologically identified in a few patients. Another study during this
decade was conducted in Klaten, Central Java in 1978 (Olson et al.) and identified alphavirus and
flavivirus as the etiologies of fever. In 1995, Suharti et al. found that dengue comprised only 49% of
total clinically suspected dengue cases in Semarang, Central Java. Other etiologies included rickettsia,
hantavirus, leptospira, rubella, chikungunya, and influenza. In 2002-2003, Vollaard et al identified the
high prevalence of SalmonelIa typhi and parathyphi infections (9% and 3%, respectively) as
confirmed by bacterial culture, in ambulatory and hospitalized febrile patients in Jakarta. In 20052006, Gasem et al. emphasized the importance of considering leptospira and rickettsia infections in
patients with acute undifferentiated fever in primary health centers and hospitals in Semarang. During
the same period Suwandono et al published findings suggesting that dengue should be monitored
carefully, as it contributed 15% of acute febrile illness in patients who visited the primary care
facilities in Jakarta. Chikungunya shared similar prevalence, but there was no evidence of endemicity.

An observational study from 2000-2008 among adults in Bandung by Alisjahbana et al showed


similar etiologies of fever among ambulatory and hospitalized patients. In their study the proportion
of cases attributable to the different etiologies were: dengue 12%, influenza 10%, chikungunya 8%,
and typhoid 2.4%. Unlike in Jakarta, chikungunya cases in Bandung were found all year round. These
studies and a national influenza surveillance also detected novel and/or emerging infectious agents
such as zika virus in Klaten, hantavirus in Semarang and Bandung, and influenza H5N1 subtype in
many areas. As the studies were designed to test for specific agents, a large proportion of cases
remained unidentified. The most frequent etiologies from these studies were also the important agents
found in Thailand, Myanmar, Thailand border and Malaysia (Ellis et al., Leelarasamee et al, Brown et
al.). However, these above mentioned studies though useful were limited in their scope to particular
regions or etiologies and did not collect clinical data, outcomes, and etiologies to measure disease
burden systematically. This protocol is designed to provide data that represents the epidemiologic
profile of infectious diseases in several large hospitals, by conducting a study to record
epidemiological data and identify the etiologies of fever. It will attempt to do so by including
hospitals and clinical centers in different parts of the country and collaboration with physicians and
researchers across Indonesia. It is hoped that this will lead to recommendations that will impact
clinical care and management of patients which could include changes in the diagnostic testing profile
currently available as standard of care (SoC) for patients with febrile illnesses. It will also enable the
implementation of an effective clinical research network for the study of infectious diseases in
Indonesia.

AFIRE study is an observational cohort study of hospitalized patients with fever. The
amount of sample used in this study N = 1600, which consisted of 100 subjects children and
100 subjects adult in each site, where there are 8 sites are conducting this study. The study
population consisted of men and women aged 1 year. Subject recruitment period for 1 year
The study collects demographic data, history of illness, signs and symptoms, results of
laboratory tests, clinical course, treatment and outcome. The primary objective of the study is
to identify the etiology of acute febrile illness cases and evaluate clinical manifestations and
outcomes. Moreover, the secondary objectives are to provide clinical data that are essential
for improving and/or developing clinical management and health policies, to enhance
research capacity and networking for infectious diseases in Indonesia by improving clinical
research site capability in conducting research relevant to public health, and to establish a
repository of biological specimens for future study, such as determining the etiology of
undiagnosed fever and/or its pathogenicity and its public health importance.

Untill now, the total enrolled from national data were 626 subjects, there were 2022
subjects screened (adult 1163 and pediatric 859). The total subjects already analysed were
269 subjects consist of laboratorium confirmed 126 subject (46,7%) and not laboratorium
confirmation 137 subject (50,9%).
The total enrolled from local data (Sanglah Hospital/site 520) since July 2013 until
November 2014 were 122 subject, there were 630 subjects screened (adult 415 and pediatric
215).Most clinical diagnosis based on research data from Sanglah Hospital (site 520) since
July 2013 until November 2014 were dengue infection, respectively respiratory infection,
thypoid infection, gastro intestinal infection. The total laboratorium confirmed 40 subject
(32,8%), consist of serology (18) Viral (9), Bacterial (6) ; Culture (12): Bacterial (9), Fungal
(3) ; serology and culture (5): Bacterial (4), Bacterial and viral (1) ; antigen (2): Viral (2) ;
microscopy (3): Amoeba (3). The total not laboratorium confirmation were 82 subjects
(67,2% ).
Keyword: acute febrile, subject adult and pediatric, blood culture, antibiotica

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