At the onset of the rabies outbreak, the human rabies management systems in Bali were unprepared. Doctors were not experienced in rabies diagnosis. Intensive training on rabies diagnosis and management was provided to health care workers following rabies confirmation in the index case. A case definition was developed under the guidance of the Ministry of Health , and it included clinical signs of rabies and a dog bite history. Initial case management often depended on the patient's complaints on arrival at the hospital and some misidentified cases ended up in cardiology for chest pain; others in internal medicine wards because of dyspepsia, typhoid fever, urinary colic, or paralytic ileus or pulmonology section for breathing difficulties, or abdominal surgery because of suspected appendicitis. Only after classical rabies symptoms appeared were patients transferred to Neurology departments for management. Given the largely passive rabies surveillance in Bali, it is possible that some cases will not have been recorded.
Standard diagnostic procedures were also not yet available in Bali at the onset of the rabies epidemic. Initial detection by RT-PCR was performed at Udayana University to confirm the outbreak. The initial goal was to find a positive sample that could be confirmed by sequencing, because RT-PCR sensitivity had not yet been evaluated. The standard fluorescent antibody test (FAT)  was not performed because the required equipment was not available. Samples collected included CSF, saliva, and corneal swabs along with ante- and post-mortem CSF. Cervical skin samples, although reported as a reliable source for diagnosis of human rabies , were not collected.
A diagnosis of rabies can also be established clinically and is the official standard for human cases . Although the results of a RT-PCR test may be negative, rabies cases can still be clinically confirmed. A clinical diagnosis is not difficult if there is a history of a rabid or suspected dog bite. In other instances, rabies can be considered when there is an acute neurological disease that progresses to coma and death .
The Province of Bali, Indonesia, was not known to be a rabies endemic area prior to November 2008. The index human rabies case was reported in the Badung District (Figure 2) and it was followed by rabies detection in many dogs. The local government control policy was initially a combination of dog vaccination and dog elimination. However, the movement of dogs during the incubation period to rabies-free areas probably contributed to the spread of the virus (Figure 2). By early 2010, the disease had spread throughout the entire island and the initial extensive dog culling was not successful in stopping the outbreak. Data also indicated that most cases occurred in the Karangasem and Buleleng districts in densely populated but rural areas. Large numbers of semi-feral, unvaccinated dogs along with a lack of rabies knowledge, and poor socioeconomic conditions common to other outbreaks [10, 11] also contributed to uncontrolled rabies spread among dogs and the poor management of human infections.
This report illustrates that most patients did not receive proper first aid, rabies vaccination, or passive immunization post-exposure. Of 104 patients, only 5.8% sought medical help and received post-exposure vaccination. RIG was not available to them. Among those given initial treatment, the vaccination regimens were not completed because of a short incubation period and the onset of symptoms within two weeks of bites on the head and neck region.
All epidemiological features of the human rabies cases in Bali resemble those reported elsewhere. Rabies victims in Bali were mostly male, similar to China . The bite locations were mostly on patients' legs and arms. Bites on the head and neck were less frequent. In China  and Tanzania , bites on the head and neck contributed significantly to the number of human rabies cases. The age distribution of rabies patients in Bali was similar to those in reported in China and Taiwan.
Dogs were the source of human rabies infections in Bali. Infections in other animals that might theoretically transmit the virus to humans, such as cats and bats, have not yet been confirmed. Dogs are known as the most common source of rabies transmission to humans throughout the world, especially in Asia, Latin America, and Africa .
In this study, the incubation period of human rabies ranged from 60-90 days post bite in most cases. A shorter incubation period of 12-21 days was recorded in patients with bites around the head and neck. This is a typical picture of rabies in humans. It is well understood that the rabies incubation period is one of the most variable among all infections. The average incubation period is around 1-3 months but may range from less than 7 days to 6 years [1, 13]. The incubation period depends on several factors such as bite site, virus quantity in the saliva, type and depth of the bite wound, and viral virulence . Longer incubation periods might lead to problems in making a diagnosis when the history of a bite might be forgotten .
Rabies infection in humans is triphasic, i.e., prodromal, acute neurologic, and coma proceeding to death . The prodromal signs are mostly non-specific, including fever, headache, myalgia, nausea, vomiting, and abnormal sensation around bite sites, such as itching, burning, numbness, or paraesthesia . These non-specific complaints may lead to a misdiagnosis of rabies at this early stage . In nearly 50% of paralytic rabies cases and 30% of furious rabies cases, local manifestation in the form of itching, pain or paresthesia at the bite site may be the earliest symptom .
The vagueness of prodromal signs was evident in the human rabies cases in Bali. The three most common prodromal signs observed in this study were paraesthesia at the bite site, nausea, vomiting, and fever. In Bali, about 30% of the rabies patients complained of these signs on admission to the medical facilities.
Most patients (98%) were in the acute neurological phase on arrival at the hospitals. The most dominant signs were acute neurological and autonomic dysfunction. Typically, human rabies patients show anxiety, agitation, dysphagia, hypersalivation, paralysis, and episodes of delirium. A case is classified as being furious rabies if the hyperactivity signs are dominant, or as paralytic or dumb rabies if the patient presents with varying degrees of paralysis and lethargy (review in ). However, this classification does not seem to be clear-cut. Clinically, furious rabies should be easier to establish than paralytic rabies. The paralytic type is caused by virus infection in the spinal cord . In some cases of human rabies in Bali, the patients showed paralytic symptoms on admission and then developed furious symptoms in the later stages.
The standard methods for rabies diagnosis in humans are virus isolation, antigen detection, and viral genome detection [19–21]. Confirmation should be made after virus detection using FAT and immunohistochemistry from CNS specimens [22, 20, 23]. The infrastructure to perform such testing was not available in Bali. RT-PCR has been recommended to detect virus specific RNA [20–24]. The specimens selected for this technique include brain, saliva, and other affected tissues. Accordingly, a RT-PCR system was developed to detect and confirm human rabies infections in Bali. Primer sets were selected based on an existing Indonesian rabies-genome database available in GenBank, and commercially purchased. The system was proven to detect the rabies genome in patients. RT-PCR has been reported to have a high specificity (up to 100%) and a moderate level of sensitivity . This is similar to our detection level of about 50% of the clinical rabies patients. Rabies infection cannot be ruled out of the RT-PCR negative specimens. Our observations indicate that among the samples taken, the best sample for RT-PCR detection is CSF. Other publications found a higher PCR positivity rate early in the disease progression when neutralizing antibodies are not present or are at a low titre . While a positive PCR result is indicative of rabies, a negative result does not exclude it.
Rabies prevention is all about awareness. The public must be informed about all relevant aspects of rabies and rabies control. Community initiatives should ensure sustainable control of canine rabies and proper management of dog bites to prevent rabies infections in humans. Such initiatives rely on community knowledge and a willingness to cooperate. Information on the cause of rabies, its seriousness, how it is transmitted, its signs in animals and humans, and on the medical management of dog bites need to be widely disseminated. The adequacy of government policies on rabies control should be reviewed and international policy standards should be met. The most efficient measure for human protection is actually the vaccination of dogs. As proven worldwide, the elimination of canine rabies and the prevention of human rabies mortality is feasible through mass vaccination of domestic dogs [12, 25–27]. Public awareness must be continuously maintained, not only in rabies infected areas but also on neighbouring islands that have never experienced the disease [28, 29].
Unsuccessful control of canine ra cbies and inadequate post-exposure prophylaxis (PEP) in humans are the main factors leading to the high incidence of human rabies infection in Bali. Publicity and education about the risk and prevention of rabies, as well as high rates of dog vaccination, properly trained medical personnel, and adequate vaccine and RIG supplies are necessary and important for the elimination of human rabies cases and the care of those potentially exposed.