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1.  Bat rabies surveillance in Finland 
Background
In 1985, a bat researcher in Finland died of rabies encephalitis caused by European bat lyssavirus type 2 (EBLV-2), but an epidemiological study in 1986 did not reveal EBLV-infected bats. In 2009, an EBLV-2-positive Daubenton’s bat was detected. The EBLV-2 isolate from the human case in 1985 and the isolate from the bat in 2009 were genetically closely related. In order to assess the prevalence of EBLVs in Finnish bat populations and to gain a better understanding of the public health risk that EBLV-infected bats pose, a targeted active surveillance project was initiated.
Results
Altogether, 1156 bats of seven species were examined for lyssaviruses in Finland during a 28–year period (1985–2012), 898 in active surveillance and 258 in passive surveillance, with only one positive finding of EBLV-2 in a Daubenton’s bat in 2009. In 2010–2011, saliva samples from 774 bats of seven species were analyzed for EBLV viral RNA, and sera from 423 bats were analyzed for the presence of bat lyssavirus antibodies. Antibodies were detected in Daubenton’s bats in samples collected from two locations in 2010 and from one location in 2011. All seropositive locations are in close proximity to the place where the EBLV-2 positive Daubenton’s bat was found in 2009. In active surveillance, no EBLV viral RNA was detected.
Conclusions
These data suggest that EBLV-2 may circulate in Finland, even though the seroprevalence is low. Our results indicate that passive surveillance of dead or sick bats is a relevant means examine the occurrence of lyssavirus infection, but the number of bats submitted for laboratory analysis should be higher in order to obtain reliable information on the lyssavirus situation in the country.
doi:10.1186/1746-6148-9-174
PMCID: PMC3846527  PMID: 24011337
EBLV; Lyssavirus; Rabies; Seroprevalence
2.  Rabies Postexposure Prophylaxis, New York, 1995–2000 
Emerging Infectious Diseases  2005;11(12):1921-1927.
Bats are now the leading source of rabies postexposure prophylaxis.
The epidemiology of human rabies postexposure prophylaxis (PEP) in 4 upstate New York counties was described from data obtained from 2,216 incidences of PEP recorded by local health departments from 1995 to 2000. Overall annual incidence for the study period was 27 cases per 100,000 persons. Mean annual PEP incidence rates were highest in rural counties and during the summer months. PEP incidence was highest among patients 5–9 and 30–34 years of age. Bites accounted for most PEP (51%) and were primarily associated with cats and dogs. Bats accounted for 30% of exposures, more than any other group of animals; consequently, bats have replaced raccoons as the leading rabies exposure source to humans in this area.
doi:10.3201/eid1112.041278
PMCID: PMC3367620  PMID: 16485480
Rabies; epidemiology; animal exposure; vaccination; zoonoses; research
3.  Host immunity to repeated rabies virus infection in big brown bats 
The Journal of General Virology  2010;91(Pt 9):2360-2366.
Bats are natural reservoirs for the majority of lyssaviruses globally, and are unique among mammals in having exceptional sociality and longevity. Given these facets, and the recognized status of bats as reservoirs for rabies viruses (RABVs) in the Americas, individual bats may experience repeated exposure to RABV during their lifetime. Nevertheless, little information exists with regard to within-host infection dynamics and the role of immunological memory that may result from abortive RABV infection in bats. In this study, a cohort of big brown bats (Eptesicus fuscus) was infected intramuscularly in the left and right masseter muscles with varying doses [10−0.1–104.9 median mouse intracerebral lethal doses (MICLD50)] of an E. fuscus RABV variant isolated from a naturally infected big brown bat. Surviving bats were infected a second time at 175 days post-(primary) infection with a dose (103.9–104.9 MICLD50) of the same RABV variant. Surviving bats were infected a third time at either 175 or 305 days post-(secondary) infection with a dose (104.9 MICLD50) of the same RABV variant. When correcting for dose, similar mortality was observed following primary and secondary infection, but reduced mortality was observed following the third and last RABV challenge, despite infection with a high viral dose. Inducible RABV-neutralizing antibody titres post-infection were ephemeral among infected individuals, and dropped below levels of detection in several bats between subsequent infections. These results suggest that long-term repeated infection of bats may confer significant immunological memory and reduced susceptibility to RABV infection.
doi:10.1099/vir.0.020073-0
PMCID: PMC3052523  PMID: 20519458
4.  Rabies Virus Infection in Eptesicus fuscus Bats Born in Captivity (Naïve Bats) 
PLoS ONE  2013;8(5):e64808.
The study of rabies virus infection in bats can be challenging due to quarantine requirements, husbandry concerns, genetic differences among animals, and lack of medical history. To date, all rabies virus (RABV) studies in bats have been performed in wild caught animals. Determining the RABV exposure history of a wild caught bat based on the presence or absence of viral neutralizing antibodies (VNA) may be misleading. Previous studies have demonstrated that the presence of VNA following natural or experimental inoculation is often ephemeral. With this knowledge, it is difficult to determine if a seronegative, wild caught bat has been previously exposed to RABV. The influence of prior rabies exposure in healthy, wild caught bats is unknown. To investigate the pathogenesis of RABV infection in bats born in captivity (naïve bats), naïve bats were inoculated intramuscularly with one of two Eptesicus fuscus rabies virus variants, EfV1 or EfV2. To determine the host response to a heterologous RABV, a separate group of naïve bats were inoculated with a Lasionycteris noctivagans RABV (LnV1). Six months following the first inoculation, all bats were challenged with EfV2. Our results indicate that naïve bats may have some level of innate resistance to intramuscular RABV inoculation. Additionally, naïve bats inoculated with the LnV demonstrated the lowest clinical infection rate of all groups. However, primary inoculation with EfV1 or LnV did not appear to be protective against a challenge with the more pathogenic EfV2.
doi:10.1371/journal.pone.0064808
PMCID: PMC3669413  PMID: 23741396
5.  Ecology of Rabies Virus Exposure in Colonies of Brazilian Free-Tailed Bats (Tadarida brasiliensis) at Natural and Man-Made Roosts in Texas 
Abstract
Previous studies have investigated rabies virus (RABV) epizootiology in Brazilian free-tailed bats (Tadarida brasiliensis) in natural cave roosts. However, little is known about geographic variation in RABV exposure, or if the use of man-made roosts by this species affects enzootic RABV infection dynamics within colonies. We sampled rabies viral neutralizing antibodies in bats at three bridge and three cave roosts at multiple time points during the reproductive season to investigate temporal and roost variation in RABV exposure. We report seropositive bats in all age and sex classes with minimal geographic variation in RABV seroprevalence among Brazilian free-tailed bat colonies in south-central Texas. While roost type was not a significant predictor of RABV seroprevalence, it was significantly associated with seasonal fluctuations, suggesting patterns of exposure that differ between roosts. Temporal patterns suggest increased RABV seroprevalence after parturition in cave colonies, potentially related to an influx of susceptible young, in contrast to more uniform seroprevalence in bridge colonies. This study highlights the importance of life history and roost ecology in understanding patterns of RABV seroprevalence in colonies of the Brazilian free-tailed bat.
doi:10.1089/vbz.2008.0163
PMCID: PMC2944840  PMID: 19492942
Brazilian free-tailed bat; Epizootiology; Rabies virus; Roost ecology
6.  Using Serology to Assist with Complicated Post-Exposure Prophylaxis for Rabies and Australian Bat Lyssavirus 
Background
Australia uses a protocol combining human rabies immunoglobulin (HRIG) and rabies vaccine for post-exposure prophylaxis (PEP) of rabies and Australian bat lyssavirus (ABLV), with the aim of achieving an antibody titre of ≥0.5 IU/ml, as per World Health Organization (WHO) guidelines, as soon as possible.
Methodology/Principal Findings
We present the course of PEP administration and serological testing for four men with complex requirements. Following dog bites in Thailand, two men (62 years old, 25 years old) received no HRIG and had delayed vaccine courses: 23 days between dose two and three, and 18 days between dose one and two, respectively. Both seroconverted following dose four. Another 62-year-old male, who was HIV-positive (normal CD4 count), also suffered a dog bite and had delayed care receiving IM rabies vaccine on days six and nine in Thailand. Back in Australia, he received three single and one double dose IM vaccines followed by another double dose of vaccine, delivered intradermally and subcutaneously, before seroconverting. A 23-year-old male with a history of allergies received simultaneous HRIG and vaccine following potential ABLV exposure, and developed rash, facial oedema and throat tingling, which was treated with a parenteral antihistamine and tapering dose of steroids. Serology showed he seroconverted following dose four.
Conclusions/Significance
These cases show that PEP can be complicated by exposures in tourist settings where reliable prophylaxis may not be available, where treatment is delayed or deviates from World Health Organization recommendations. Due to the potentially short incubation time of rabies/ABLV, timely prophylaxis after a potential exposure is needed to ensure a prompt and adequate immune response, particularly in patients who are immune-suppressed or who have not received HRIG. Serology should be used to confirm an adequate response to PEP when treatment is delayed or where a concurrent immunosuppressing medical condition or therapy exists.
Author Summary
In Australia, the administration of rabies post-exposure prophylaxis (PEP) occurs for potentially exposed returned travellers from endemic regions or for potential local exposure to Australian Bat Lyssavirus. For Australian tourists, delays in commencing PEP or not receiving HRIG or all recommended doses of vaccine are common. We report a case series where serology provided information in four patients with delayed, incomplete, or complicated PEP treatment. Three of these patients reported a dog bite in Thailand and the fourth was scratched by a bat and had bat urine enter his eye in Australia. Management was complicated by lack of HRIG administration, delays in the recommended timeframe for receipt of vaccine doses, and immunosuppression caused by co-administration of steroids and by HIV infection with a normal CD4 count. All patients seroconverted but this was delayed in some cases, and in the HIV-positive subject required a double dose of vaccine delivered intradermally and subcutaneously. In complex or non-standard PEP delivery, including delayed treatment and immunosuppression due to steroid treatment, HIV or another immunosuppressing medical condition, serology can be used to guide further treatment and should be used to confirm seroconversion.
doi:10.1371/journal.pntd.0002066
PMCID: PMC3584984  PMID: 23469301
7.  Characteristics of bat rabies in Alberta. 
Rabies in bats was monitored in Alberta from 1971 to 1978 Big brown bats replaced silver-haired bats as the species most frequently reported rabid during these years. Rabies infection was comparatively high among little brown bats in central Alberta in 1973 and has subsequently declined. Only one rabid little brown bat was discovered in southern Alberta which is populated by a different subspecies. Outbreaks of rabies in little brown and big brown bat colonies tended to be brief events. Observations of free-ranging bats with probable furious rabies suggested that bats do not generally identify humans as targets for attack. Independent trends in infection rates suggested that spread of rabies is primarily intraspecific but there is evidence that migratory bats play a role in introduction and maintenance of rabies in northern temperate bat communities. The dynamics of bat rabies in Alberta are discussed.
PMCID: PMC1320036  PMID: 7397600
8.  Human Rabies: A Reemerging Disease in Costa Rica? 
Emerging Infectious Diseases  2003;9(6):721-723.
Two human rabies cases caused by a bat-associated virus variant were identified in September 2001 in Costa Rica, after a 31-year absence of the disease in persons. Both patients lived in a rural area where cattle had a high risk for bat bites, but neither person had a definitive history of being bitten by a rabid animal. Characterization of the rabies viruses from the patients showed that the reservoir was the hematophagous Vampire Bat, Desmodus rotundus, and that a sick cat was the vector.
doi:10.3201/eid0906.020632
PMCID: PMC3000141  PMID: 12781014
human rabies; bat; Costa Rica; dispatch
9.  Rabies in a nine-year-old child: The myth of the bite 
A nine-year-old boy died from rabies encephalitis caused by a rabies virus variant associated with insectivorous bats. The patient was most likely infected in the Laurentian Mountains of western Quebec, but neither the patient nor his parents remembered any direct contact with an animal. The diagnosis was made seven days after the start of symptoms. After examining the most recent cases of rabies in North America, it is obvious that rabies following bat exposure can occur without history of a documented bite. The present case report emphasizes that the general public and medical care providers need better information about the risks associated with exposure to bats.
PMCID: PMC2094861  PMID: 18159381
Bat; Children; Encephalitis; Prophylaxis; Rabies
10.  Bat Rabies in Canada 1963-1967 
Six hundred and twenty-eight insectivorous bats originating from seven provinces were submitted to this Institute for rabies diagnosis between August 1, 1963 and December 31, 1967. Brain tissue was examined by the fluorescent antibody technique and the mouse infectivity test was carried out with brain, salivary gland, interscapular adipose tissue and kidney samples. Rabies virus was detected in 44 bats, 29 of which were from Ontario, 12 from British Columbia and three from Manitoba. Most of the positive cases were diagnosed in summer months. Seven species were represented among the specimens found to be rabid; there were 32 big brown bats, three hoary bats, three silver-haired bats, two little brown bats, one eastern pipistrelle, one Keen myotis and one red bat. Another bat which was not identified also proved to be infected with rabies.
PMCID: PMC1319378  PMID: 4242773
11.  High Diversity of Rabies Viruses Associated with Insectivorous Bats in Argentina: Presence of Several Independent Enzootics 
Background
Rabies is a fatal infection of the central nervous system primarily transmitted by rabid animal bites. Rabies virus (RABV) circulates through two different epidemiological cycles: terrestrial and aerial, where dogs, foxes or skunks and bats, respectively, act as the most relevant reservoirs and/or vectors. It is widely accepted that insectivorous bats are not important vectors of RABV in Argentina despite the great diversity of bat species and the extensive Argentinean territory.
Methods
We studied the positivity rate of RABV detection in different areas of the country, and the antigenic and genetic diversity of 99 rabies virus (RABV) strains obtained from 14 species of insectivorous bats collected in Argentina between 1991 and 2008.
Results
Based on the analysis of bats received for RABV analysis by the National Rabies system of surveillance, the positivity rate of RABV in insectivorous bats ranged from 3.1 to 5.4%, depending on the geographic location. The findings were distributed among an extensive area of the Argentinean territory. The 99 strains of insectivorous bat-related sequences were divided into six distinct lineages associated with Tadarida brasiliensis, Myotis spp, Eptesicus spp, Histiotus montanus, Lasiurus blosseviilli and Lasiurus cinereus. Comparison with RABV sequences obtained from insectivorous bats of the Americas revealed co-circulation of similar genetic variants in several countries. Finally, inter-species transmission, mostly related with Lasiurus species, was demonstrated in 11.8% of the samples.
Conclusions
This study demonstrates the presence of several independent enzootics of rabies in insectivorous bats of Argentina. This information is relevant to identify potential areas at risk for human and animal infection.
Author Summary
In Argentina, successful vaccination and control of terrestrial rabies in the 1980s revealed the importance of the aerial route in RABV transmission. Current distribution of cases shows a predominance of rabies by hematophagous bats in the Northern regions where rabies is a major public health concern; in contrast, in Central and Southern regions where rabies is not a major public health concern, little surveillance is performed. Based on the analysis of insectivorous bats received for RABV analysis by the National Rabies system of surveillance, the positivity rate of RABV in insectivorous bats in these regions ranged from 3.1 to 5.4%. This rate is comparable to other nations such as the United States (9–10%) where insectivorous bats are an important cause of concern for RABV surveillance systems. Antigenic and genetic analysis of a wide collection of rabies strains shows the presence of multiple endemic cycles associated with six bat insectivorous species distributed among an extensive area of the Argentinean territory and several countries of the Americas. Finally, inter-species transmission, mostly related with Lasiurus species, was demonstrated in 11.8% of the samples. Increased public education about the relationship between insectivorous bats and rabies are essential to avoid human cases and potential spread to terrestrial mammals.
doi:10.1371/journal.pntd.0001635
PMCID: PMC3348165  PMID: 22590657
12.  Potential and Actual Terrestrial Rabies Exposures in People and Domestic Animals, Upstate South Carolina, 1994–2004: A Surveillance Study 
BMC Public Health  2009;9:65.
Background
Although there has been a reduction of rabies in pets and domestic animals during recent decades in the United States, rabies remains enzootic among bats and several species of terrestrial wildlife. Spillover transmission of wildlife rabies to domestic animals therefore remains a public health threat
Methods
Retrospective analysis of surveillance data of reported animal incidents (bites, scratches, mucous membrane contacts) from South Carolina, 1995 to 2003, was performed to assess risk factors of potential rabies exposures among human and animal victims.
Results
Dogs and cats contributed the majority (66.7% and 26.4%, respectively) of all reported incidents, with stray dogs and cats contributing 9.0% and 15.1 respectively. Current rabies vaccination status of dogs and cats (40.2% and 13.8%, respectively) were below World Health Organization recommended levels. Owned cats were half as likely to be vaccinated for rabies as dogs (OR 0.53, 95% CI 0.48, 0.58). Animal victims were primarily exposed to wildlife (83.0%), of which 27.5% were rabid. Almost 90% of confirmed rabies exposures were due to wildlife. Skunks had the highest prevalence of rabies among species of exposure animals (63.2%). Among rabid domestic animals, stray cats were the most commonly reported (47.4%).
Conclusion
While the majority of reported potential rabies exposures are associated with dog and cat incidents, most rabies exposures derive from rabid wildlife. Stray cats were most frequently rabid among domestic animals. Our results underscore the need for improvement of wildlife rabies control and the reduction of interactions of domestic animals, including cats, with wildlife.
doi:10.1186/1471-2458-9-65
PMCID: PMC2651164  PMID: 19236696
13.  Novel Vaccines to Human Rabies 
Rabies, the most fatal of all infectious diseases, remains a major public health problem in developing countries, claiming the lives of an estimated 55,000 people each year. Most fatal rabies cases, with more than half of them in children, result from dog bites and occur among low-income families in Southeast Asia and Africa. Safe and efficacious vaccines are available to prevent rabies. However, they have to be given repeatedly, three times for pre-exposure vaccination and four to five times for post-exposure prophylaxis (PEP). In cases of severe exposure, a regimen of vaccine combined with a rabies immunoglobulin (RIG) preparation is required. The high incidence of fatal rabies is linked to a lack of knowledge on the appropriate treatment of bite wounds, lack of access to costly PEP, and failure to follow up with repeat immunizations. New, more immunogenic but less costly rabies virus vaccines are needed to reduce the toll of rabies on human lives. A preventative vaccine used for the immunization of children, especially those in high incidence countries, would be expected to lower fatality rates. Such a vaccine would have to be inexpensive, safe, and provide sustained protection, preferably after a single dose. Novel regimens are also needed for PEP to reduce the need for the already scarce and costly RIG and to reduce the number of vaccine doses to one or two. In this review, the pipeline of new rabies vaccines that are in pre-clinical testing is provided and an opinion on those that might be best suited as potential replacements for the currently used vaccines is offered.
doi:10.1371/journal.pntd.0000515
PMCID: PMC2742899  PMID: 19787033
14.  Community Survey after Rabies Outbreaks, Flagstaff, Arizona, USA 
Emerging Infectious Diseases  2012;18(6):932-938.
Educational outreach should inform the public about dangers of translocation of wild animals and general aspects of rabies.
Flagstaff, Arizona, USA, experienced notable outbreaks of rabies caused by a bat rabies virus variant in carnivore species in 2001, 2004, 2005, 2008, and 2009. The most recent epizootic involved transmission among skunk and fox populations and human exposures. Multiple, wide-ranging control efforts and health communications outreach were instituted in 2009, including a household survey given to community members. Although the Flagstaff community is knowledgeable about rabies and the ongoing outbreaks in general, gaps in knowledge about routes of exposure and potential hosts remain. Future educational efforts should include messages on the dangers of animal translocation and a focus on veterinarians and physicians as valuable sources for outreach. These results will be useful to communities experiencing rabies outbreaks as well as those at current risk.
doi:10.3201/eid1806.111172
PMCID: PMC3358150  PMID: 22607999
rabies virus; lyssavirus; rabies; health knowledge; attitudes; practice; outbreak; epizootic; community survey; viruses; zoonosis; Arizona; United States; USA; translocation; wild animals; wildlife; education
15.  Cross sectional survey of human-bat interaction in Australia: public health implications 
BMC Public Health  2014;14:58.
Background
Flying foxes (megachiroptera) and insectivorous microbats (microchiroptera) are the known reservoirs for a range of recently emerged, highly pathogenic viruses. In Australia there is public health concern relating to bats’ role as reservoirs of Australian Bat Lyssavirus (ABLV), which has clinical features identical to classical rabies. Three deaths from ABLV have occurred in Australia. A survey was conducted to determine the frequency of bat exposures amongst adults in Australia’s most populous state, New South Wales; explore reasons for handling bats; examine reported practices upon encountering injured or trapped bats or experiencing bat bites or scratches; and investigate knowledge of bat handling warnings.
Methods
A representative sample of 821 New South Wales adults aged 16 years and older were interviewed during May and June 2011, using a computer assisted telephone interview (CATI) method. Frequencies, proportions and statistical differences in proportion were performed. Using an α-value of 0.05 and power of 80%, it was calculated that a sample size of 800 was required to provide statistical significance of +/− 5% for dichotomous variables.
Results
One-hundred-and-twenty-seven (15.5%) respondents indicated that they had previously handled a bat, being 22% (48/218) rural and 13% (78/597) urban respondents (χ2 = 9.8, p = 0.0018). Twenty one percent of males (63/304) had handled bats compared with 12% (64/517) of females (χ2 = 10.2, p = 0.0014). Overall, 42.0% (n = 345) of respondents reported having seen or heard a warning about handling bats. If faced with an injured or trapped bat, 25% (206/821) indicated that they would handle the bat, with 17% (36/206) saying that they would use their bare hands. For minor scratches, 14% (117/821) indicated that they would ignore the injury while four respondents would ignore major scratches or bites.
Conclusions
Previous human-bat interactions were relatively common. Bat exposures most frequently occurred with sick or injured bats, which have the highest risk of ABLV. On encountering an injured or sick bat, potentially high risk practices were commonly reported, particularly among rural males. It is important to understand why people still handle bats despite public health warnings to inform future communication strategies.
doi:10.1186/1471-2458-14-58
PMCID: PMC3908316  PMID: 24443960
16.  Variability in Seroprevalence of Rabies Virus Neutralizing Antibodies and Associated Factors in a Colorado Population of Big Brown Bats (Eptesicus fuscus) 
PLoS ONE  2014;9(1):e86261.
In 2001–2005 we sampled permanently marked big brown bats (Eptesicus fuscus) at summer roosts in buildings at Fort Collins, Colorado, for rabies virus neutralizing antibodies (RVNA). Seroprevalence was higher in adult females (17.9%, n = 2,332) than males (9.4%, n = 128; P = 0.007) or volant juveniles (10.2%, n = 738; P<0.0001). Seroprevalence was lowest in a drought year with local insecticide use and highest in the year with normal conditions, suggesting that environmental stress may suppress RVNA production in big brown bats. Seroprevalence also increased with age of bat, and varied from 6.2 to 26.7% among adult females at five roosts sampled each year for five years. Seroprevalence of adult females at 17 other roosts sampled for 1 to 4 years ranged from 0.0 to 47.1%. Using logistic regression, the only ranking model in our candidate set of explanatory variables for serological status at first sampling included year, day of season, and a year by day of season interaction that varied with relative drought conditions. The presence or absence of antibodies in individual bats showed temporal variability. Year alone provided the best model to explain the likelihood of adult female bats showing a transition to seronegative from a previously seropositive state. Day of the season was the only competitive model to explain the likelihood of a transition from seronegative to seropositive, which increased as the season progressed. We found no rabies viral RNA in oropharyngeal secretions of 261 seropositive bats or in organs of 13 euthanized seropositive bats. Survival of seropositive and seronegative bats did not differ. The presence of RVNA in serum of bats should not be interpreted as evidence for ongoing rabies infection.
doi:10.1371/journal.pone.0086261
PMCID: PMC3899234  PMID: 24465996
17.  The epidemiology of bat rabies in New York State, 1988-92. 
Epidemiology and Infection  1994;113(3):501-511.
In 1993 New York and Texas each reported a human rabies case traced to a rare variant of rabies virus found in an uncommon species of bat. This study examined the epidemiology of bat rabies in New York State. Demographic, species, and animal-contact information for bats submitted for rabies testing from 1988-92 was analysed. The prevalence of rabies in 6810 bats was 4.6%. Nearly 90% of the 308 rabid bats identified to species were the common big brown bat (Eptesicus fuscus), which comprised 62% of all submissions. Only 25 submissions were silver-haired bats (Lasionycterus noctivagans), the species associated with the two 1993 human cases of rabies, and only two of these bats were positive. Rabies was most prevalent in female bats, in bats submitted because of human [corrected] contact, and in animals tested during September and October. These results highlight the unusual circumstances surrounding the recent human rabies cases in the United States. A species of bat rarely encountered by humans, and contributing little to the total rabies cases in bats, has been implicated in the majority of the indigenously acquired human rabies cases in the United States. The factors contributing to the transmission of this rare rabies variant remain unclear.
Images
PMCID: PMC2271321  PMID: 7995360
18.  First Human Rabies Case in French Guiana, 2008: Epidemiological Investigation and Control 
Background
Until 2008, human rabies had never been reported in French Guiana. On 28 May 2008, the French National Reference Center for Rabies (Institut Pasteur, Paris) confirmed the rabies diagnosis, based on hemi-nested polymerase chain reaction on skin biopsy and saliva specimens from a Guianan, who had never travelled overseas and died in Cayenne after presenting clinically typical meningoencephalitis.
Methodology/Principal Findings
Molecular typing of the virus identified a Lyssavirus (Rabies virus species), closely related to those circulating in hematophagous bats (mainly Desmodus rotundus) in Latin America. A multidisciplinary Crisis Unit was activated. Its objectives were to implement an epidemiological investigation and a veterinary survey, to provide control measures and establish a communications program. The origin of the contamination was not formally established, but was probably linked to a bat bite based on the virus type isolated. After confirming exposure of 90 persons, they were vaccinated against rabies: 42 from the case's entourage and 48 healthcare workers. To handle that emergence and the local population's increased demand to be vaccinated, a specific communications program was established using several media: television, newspaper, radio.
Conclusion/Significance
This episode, occurring in the context of a Department far from continental France, strongly affected the local population, healthcare workers and authorities, and the management team faced intense pressure. This observation confirms that the risk of contracting rabies in French Guiana is real, with consequences for population educational program, control measures, medical diagnosis and post-exposure prophylaxis.
Author Summary
Until 2008, rabies had never been described within the French Guianan human population. Emergence of the first case in May 2008 in this French Overseas Department represented a public health event that markedly affected the local population, healthcare workers and public health authorities. The antirabies clinic of French Guiana, located at Institut Pasteur de la Guyane, had to reorganize its functioning to handle the dramatically increased demand for vaccination. A rigorous epidemiological investigation and a veterinary study were conducted to identify the contamination source, probably linked to a bat bite, and the exposed population. Communication was a key factor to controlling this episode and changing the local perception of this formerly neglected disease. Because similar clinical cases had previously been described, without having been diagnosed, medical practices must be adapted and the rabies virus should be sought more systematically in similarly presenting cases. Sharing this experience could be useful for other countries that might someday have to manage such an emergence.
doi:10.1371/journal.pntd.0001537
PMCID: PMC3283561  PMID: 22363830
19.  Rabies Situation in Cambodia 
Background
Rabies, a fatal but preventable zoonosis, is a major public health problem in developing countries. In Cambodia the disease burden is largely underestimated because patients with encephalitis following dog bites are rarely hospitalized and die at home. Since 1998 Institut Pasteur in Cambodia (IPC), Phnom Penh has been the only source of free post-exposure prophylaxis (PEP) and post-mortem diagnosis.
Methods
The 1998–2007 data compiled by IPC was analyzed to describe all treated patients for PEP, results of human testing and confirmed rabies cases, and results of animal testing. From dog bites' characteristics, we defined a suspected rabid dog bite injury (SRDBI) in humans as a bite that was unprovoked, from a dog that died spontaneously, or from a dog that was reported sick. We applied a deterministic probability model to estimate 2007 rabies human mortality nationwide from the estimated incidence of rabid dog bites, the body distribution of bite wounds, and the probability of PEP access.
Results
During 1998–2007, 124,749 patients received PEP at IPC (average 12,470; range 8,907–14,475), and 63 fatal human cases presenting with encephalitis following a dog bite were reported, in which 73% were confirmed positive for rabies by direct immunofluorescence assay or by reverse-transcriptase polymerase chain reaction. During 1998–2007, IPC tested 1,255 animal brain samples; 1,214 (97%) were from dogs including 610 (49%) positive samples. In 2007, 14,475 patients received PEP (100 PEP/100,000 people in Cambodia) including 95% who resided in Phnom Penh (615 PEP/100,000) or five neighboring provinces. The predictive model estimated 810 human rabies deaths would occur in 2007 (95%confidence interval [CI] 394–1,607), an incidence of 5.8/100,000 (95% CI 2.8–11.5).
Conclusions
Access to PEP is only sufficient for Phnom Penh residents. In 2007, the estimated rabies related mortality exceeded that of malaria and that of dengue. A national rabies control program is needed to improve surveillance and access to PEP, and to initiate vaccination campaigns in dogs.
Author Summary
In Cambodia, rabies still elicits fear in the communities. Since 1998 the Institut Pasteur in Cambodia (IPC), Phnom Penh has been the only source of free post-exposure prophylaxis (PEP) and post mortem diagnosis. During 1998–2007, on average ∼12,400 patients received PEP annually at IPC (range 8,907–14,475) and 63 fatal human cases presenting with encephalitis following a dog bite were reported including 73% who tested positive by fluorescent-antibody test on brain samples or/and by reverse-transcriptase polymerase chain reaction on skin, cerebrospinal fluid, or urine. In 2007, 14,475 patients received PEP (100 PEP/100,000 people in Cambodia) including 95% who resided in Phnom Penh city (615 PEP/100,000) or five neighboring provinces. Using a step-by-step probability model, we estimated that 810 human rabies deaths would occur in 2007 (95% confidence interval [CI] 394–1,607); an incidence of 5.8/100,000 (95%CI 2.8–11.5). As a result, despite high attendance at the IPC's PEP center most Cambodians living in peripheral provinces in Cambodia may not have adequate access to PEP. Finally, the model generated one of the highest incidences of rabies worldwide. A national rabies control program is needed to improve surveillance and access to PEP, and to initiate vaccination campaigns in dogs.
doi:10.1371/journal.pntd.0000511
PMCID: PMC2731168  PMID: 19907631
20.  Human Rabies and Rabies in Vampire and Nonvampire Bat Species, Southeastern Peru, 2007 
Emerging Infectious Diseases  2009;15(8):1308-1311.
After a human rabies outbreak in southeastern Peru, we collected bats to estimate the prevalence of rabies in various species. Among 165 bats from 6 genera and 10 species, 10.3% were antibody positive; antibody prevalence was similar in vampire and nonvampire bats. Thus, nonvampire bats may also be a source for human rabies in Peru.
doi:10.3201/eid1508.081522
PMCID: PMC2815962  PMID: 19751600
Rabies virus; rabies; viruses; outbreak investigation; reservoir; vampire bats; Peru; dispatch
21.  Human rabies postexposure prophylaxis during a raccoon rabies epizootic in New York, 1993 and 1994. 
Emerging Infectious Diseases  1999;5(3):415-423.
We describe the epidemiology of human rabies postexposure prophylaxis (PEP) in four upstate New York counties during the 1st and 2nd year of a raccoon rabies epizootic. We obtained data from records of 1,173 persons whose rabies PEP was reported to local health departments in 1993 and 1994. Mean annual PEP incidence rates were highest in rural counties, in summer, and in patients 10 to 14 and 35 to 44 years of age. PEP given after bites was primarily associated with unvaccinated dogs and cats, but most (70%) was not attributable to bites. Although pet vaccination and stray animal control, which target direct exposure, remain the cornerstones of human rabies prevention, the risk for rabies by the nonbite route (e. g., raccoon saliva on pet dogs' and cats' fur) should also be considered.
PMCID: PMC2640781  PMID: 10341178
22.  Use of Rabies Postexposure Prophylaxis Supplied by the Alaska Section of Epidemiology, Alaska, 2002–2007 
Public Health Reports  2009;124(2):262-266.
SYNOPSIS
Objective
The aim of this study was to summarize the Alaska experience in centralizing distribution of rabies postexposure prophylaxis (PEP).
Methods
Data were collected from standard treatment sheets used to track doses and notes related to the exposure investigations.
Results
From 2002 to 2007, the annual PEP usage rate was 2.2 per 100,000. Dogs were involved in 79% (68/86) of exposures. More than 50% (49/87) of people were exposed to a confirmed rabid animal; 31 (63%) of those people experienced nonbite exposures. Conversely, of the remaining 38 people exposed to an animal for which rabies status could not be confirmed, 35 (92%) sustained a bite or puncture. Direct and indirect costs averaged more than $3,000 per person.
Conclusions
The Alaska PEP usage rate was lower and the proportion of people exposed to confirmed rabid animals was higher when compared with other states. Alaska public health personnel invested significant time to ensure that PEP was only given when indicated. Without this gatekeeper approach, PEP would likely be administered at a much higher rate because medical facility staff lacks the time or ability to investigate animal exposures to rule out rabies. In Alaska, centralizing rabies PEP not only serves the patient's best interest, but it also makes efficient use of a potentially scarce product and supports rabies surveillance efforts by guaranteeing animals for testing. Such a program might not be feasible for a more populous state or jurisdiction, or areas with different rabies epizootiology; however, that may change if the supply of rabies biologics changes in the future.
PMCID: PMC2646483  PMID: 19320368
23.  Molecular Diversity of Rabies Viruses Associated with Bats in Mexico and Other Countries of the Americas 
Journal of Clinical Microbiology  2006;44(5):1697-1710.
Bat rabies and its transmission to humans and other species in Mexico were investigated. Eighty-nine samples obtained from rabid livestock, cats, dogs, and humans in Mexico were studied by antigenic typing and partial sequence analysis. Samples were further compared with enzootic rabies associated with different species of bats in the Americas. Patterns of nucleotide variation allowed the definition of at least 20 monophyletic clusters associated with 9 or more different bat species. Several lineages associated with distinctive antigenic patterns were found in rabies viruses related to rabies in vampire bats in Mexico. Vampire bat rabies virus lineages associated with antigenic variant 3 are widely spread from Mexico to South America, suggesting these lineages as the most likely ancestors of vampire bat rabies and the ones that have been moved by vampire bat populations throughout the Americas. Rabies viruses related to Lasiurus cinereus, Histiotus montanus, and some other not yet identified species of the genus Lasiurus were found circulating in Mexico. Long-range dissemination patterns of rabies are not necessarily associated with migratory bat species, as in the case of rabies in Desmodus rotundus and Histiotus montanus. Human rabies was associated with vampire bat transmission in most cases, and in one case, rabies transmission from free-tailed bats was inferred. The occurrence of rabies spillover from bats to domestic animals was also demonstrated. Genetic typing of rabies viruses allowed us to distinguish trends of disease dissemination and to address, in a preliminary fashion, aspects of the complex evolution of rabies viruses in different host-reservoir species.
doi:10.1128/JCM.44.5.1697-1710.2006
PMCID: PMC1479161  PMID: 16672396
24.  Rabies viral encephalitis with proable 25 year incubation period! 
We report a case of rabies viral encephalitis in a 48-year-old male with an unusually long incubation period, historically suspected to be more than 20 years. The case was referred for histological diagnosis following alleged medical negligence to the forensic department. The histology and immunocytochemical demonstration of rabies viral antigen established the diagnosis unequivocally. The case manifested initially with hydrophobia and aggressive behavior, although he suddenly went to the bathroom and drank a small amount of water. History of dog bite 25 years back was elicited retrospectively following clinical suspicion. There was no subsequent history to suggest nonbite exposure to a rabid dog to consider recent event causing the disease, although this cannot be totally excluded.
doi:10.4103/0972-2327.99728
PMCID: PMC3424805  PMID: 22919200
Long incubation period; Negri bodies; rabies; viral antigen
25.  Intravenous Inoculation of a Bat-Associated Rabies Virus Causes Lethal Encephalopathy in Mice through Invasion of the Brain via Neurosecretory Hypothalamic Fibers 
PLoS Pathogens  2009;5(6):e1000485.
The majority of rabies virus (RV) infections are caused by bites or scratches from rabid carnivores or bats. Usually, RV utilizes the retrograde transport within the neuronal network to spread from the infection site to the central nervous system (CNS) where it replicates in neuronal somata and infects other neurons via trans-synaptic spread. We speculate that in addition to the neuronal transport of the virus, hematogenous spread from the site of infection directly to the brain after accidental spill over into the vascular system might represent an alternative way for RV to invade the CNS. So far, it is unknown whether hematogenous spread has any relevance in RV pathogenesis. To determine whether certain RV variants might have the capacity to invade the CNS from the periphery via hematogenous spread, we infected mice either intramuscularly (i.m.) or intravenously (i.v.) with the dog-associated RV DOG4 or the silver-haired bat-associated RV SB. In addition to monitoring the progression of clinical signs of rabies we used immunohistochemistry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to follow the spread of the virus from the infection site to the brain. In contrast to i.m. infection where both variants caused a lethal encephalopathy, only i.v. infection with SB resulted in the development of a lethal infection. While qRT-PCR did not reveal major differences in virus loads in spinal cord or brain at different times after i.m. or i.v. infection of SB, immunohistochemical analysis showed that only i.v. administered SB directly infected the forebrain. The earliest affected regions were those hypothalamic nuclei, which are connected by neurosecretory fibers to the circumventricular organs neurohypophysis and median eminence. Our data suggest that hematogenous spread of SB can lead to a fatal encephalopathy through direct retrograde invasion of the CNS at the neurovascular interface of the hypothalamus-hypophysis system. This alternative mode of virus spread has implications for the post exposure prophylaxis of rabies, particularly with silver-haired bat-associated RV.
Author Summary
Rabies virus (RV) infects mammalian neurons and cycles in regionally distinct animal populations such as the red fox in Europe, domestic canines in Asia, or raccoons, skunks and bats in Northern America. Although human rabies can be prevented by pre- and post-exposure prophylaxis, more than 50,000 people die annually from the severe encephalopathy caused by RV. Recently, two cases of RV transmission by organ transplantation were reported. In our study, using intravenous inoculation of mice, we evaluated the pathogenetic relevance of virions that reach the bloodstream. Mice inoculated intravenously with a canine-derived RV survived the infection in contrast to intramuscularly injected mice, while mice infected with a silver-haired bat-related RV succumbed to the disease regardless of the route of inoculation. We found that the silver-haired bat-related RV was able to transit from the blood to the brain by invading neurosecretory fibers of the hypothalamus, which form neurohemal synapses lacking a blood-brain-barrier. This newly described route of brain invasion might reflect how RV reached the central nervous system from transplanted organs, since it takes longer to establish the neural connections between host and grafted tissue necessary for classical RV migration than the time until the infection became symptomatic in the two reported cases.
doi:10.1371/journal.ppat.1000485
PMCID: PMC2691950  PMID: 19543379

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