Recommended treatment for severe rabies exposure in unvaccinated individuals includes wound cleaning, administration of rabies immunoglobulins (RIG), and rabies vaccination. We conducted a survey of rabies treatment outcomes in the Philippines. This was a case series involving 7,660 patients (4 months to 98 years of age) given purified equine RIG (pERIG) at the Research Institute for Tropical Medicine (Muntinlupa, Philippines) from July 2003 to August 2004 following Category II or III exposures. Data on local and systemic adverse reactions (AR) within 28 days and biting animal status were recorded; outcome data were obtained by telephone or home visit 6–29 months post-exposure. Follow-up data were collected for 6,464 patients. Of 151 patients with laboratory-confirmed rabies exposure, 143 were in good health 6–48 months later, seven could not be contacted, and one 4-year-old girl died. Of 16 deaths in total, 14 were unrelated to rabies exposure or treatment. Two deaths were considered PEP failures: the 4-year old girl, who had multiple deep lacerated wounds from a rabid dog of the nape, neck, and shoulders requiring suturing on the day of exposure, and an 8-year-old boy who only received rabies PEP on the day of exposure. This extensive review of outcomes in persons with Category III exposure shows the recommended treatment schedule at RITM using pERIG is well tolerated, while survival of 143 laboratory-confirmed rabies exposures confirms the intervention efficacy. Two PEP intervention failures demonstrate that sustained education and training is essential in rabies management.
Rabies is a zoonotic disease characterized by progressive and incurable viral encephalitis, invariably fatal if untreated and usually transmitted by the bite (s) or scratches of an infected animal. Data from the Department of Health show that every year, over 100,000 people at risk in the Philippines receive rabies post-exposure prophylaxis (PEP), which varies according to the categorization of the exposure as defined by the World Health Organization (Table 1). The most severe cases, Category III, require wound cleaning, rabies vaccination, and direct wound infiltration with rabies immunoglobulin (RIG) and where possible, observation of the biting animal if it does not already display clinical symptoms of rabies for a period of 10 days [1], [2]. Infiltration of RIGs into the wound (s) is essential in the management of severe bites to provide passive antibody protection during the first 1–2 weeks while the body develops its own immune response to vaccination. The WHO recommends the use of human RIG (HRIG) or equine (ERIG) in category III exposures [2]. For multiple severe Category III exposure HRIG is recommended, however, when not available or accessible, ERIG or pERIG must be used. As availability of HRIG is constrained by the limited production capacities imposed when using human plasma as the immunoglobulin source, bite victims in highly endemic countries are more likely to receive ERIG or pERIG. F (ab' ) 2 fragment rabies immunoglobulin (Favirab, Sanofi Pasteur, Lyon, France) is a highly purified pERIG, characterized in animal models [3] and in humans [4] and is currently used in over 40 countries. Industrial chromatographic purification results in a product with a high purity with selective extraction of active immunoglobulin molecules (IgG) from plasma and a final purification of F (ab' ) 2 from the IgG peptic digest. The final pasteurized solution for wound infiltration has a high specific activity, containing mainly F (ab' ) 2 molecules (85%). The clearance of Favirab is more rapid than ERIG and HRIG, documented by certain experimental animal data, however, this is not considered to influence the efficacy. Fewer than 1% of patients report adverse events to Favirab, these consisting mainly of mild allergic type reactions. We report the results of a review of consultation records and follow-up investigations to determine the health status of persons who received PEP, including Favirab as a source of ERIG, at the Research Institute of Tropical Medicine, Manila.
Whenever possible, as part of standard treatment procedures, and in order to confirm the presence of rabies virus in biting animals that had died or were killed, a direct Fluorescent Antibody Test (dFAT) was performed at the rabies laboratory of the RITM following standard procedures [5].
During follow-up investigations (by telephone, by home visit or by hospital record) a total of 7,604 (99. 3%) subjects could be contacted as 56 subjects moved out of the area or their contact address or telephone number were inadequate. A total of 3,970 (51. 8%) subjects were contacted by telephone, 3,595 (46. 9%) subjects by home visit and 18 (0. 23%) by telephone followed by a home visit. Health status could be documented in 6,468 (84. 8%) subjects, but for 1,164 (15. 3%) subjects no follow-up information was obtained as they had moved from the original address, etc. The interval between PEP-and follow-up event varied between 35 days and 29 months.
This primary objective of the evaluation was to document the health status of subjects given rabies PEP which included use of the purified equine rabies immunoglobulin (pERIG), Favirab. The health status of patients treated after Category II/III exposure with the standard of care described in the RITM guidelines was documented by an active survey by telephone or home visits. The RITM guidelines are in accordance with the WHO guidelines [2], [6], the local Philippine recommendations and those developed in other countries [7]. Not unexpectedly, exposure was seen predominantly in children 5 years or younger, with over 23. 28% of exposures occurring below 5 years of age; twice as many boys exposed when compared to girls. A similar age and sex distribution was reported in Thailand [8], although the age distribution was different to that recently reported in India [9]. The records made no reference to washing of the wounds, however, the standard recommendations of the RITM are likely to have been implemented carefully. Attending staff of the different animal bite treatment centers are trained in the appropriate management of patients with animal bites and those with Category III exposure are referred to the RITM Admitting Section. Wound washing is followed by an infiltration of pERIG into the wound site and injection of the remaining pERIG by IM route. This split administration was documented in 97. 8% of the cases, only 108 cases (1. 4%) having pERIG infiltration into the wound alone. 61 patients received pERIG by IM only; 16 of whom were exposed to rabid patients and 6 had healed wounds at the time of the consultation. Over 54% of subjects had exposure in highly innervated body regions, such as the head, hands or feet, and one 23-year-old subject was bitten on the penis. Specific reference to exposure involving fingers or toes was documented in 24 subjects (2–61 years-old) and following treatment, no compartment syndrome was reported. This experience is similar to that observed in Thailand [10]. A first dose of rabies vaccine was administered to 98. 5% of the study population. Rabies vaccination for the second and third dose was continued, as documented in the RITM records, in 53. 8% and 43. 5%, respectively. During the follow-up investigation, data on rabies vaccination in local animal bite treatment centers was not requested to avoid introducing a recall bias. For the 6,468 subjects for whom follow-up information was obtained, the mean interval between exposure and follow-up was 11. 5 months (ranging from 35 days to 29 months). During the survey window, 16 deaths were recorded in the whole study popualtion, in subjects from 4 to 72 years of age, occurring between 35 days and 16 months following exposure. The causes of 14 deaths were clearly identified as being unrelated to the rabies exposure, but two deaths were considered PEP intervention failures. Other clinical conditions reported by the patients or their parents occurred between 8 and 28 months but none were considered related to the treatment. The documented healthy outcome of 143 subjects exposed to laboratory-proven rabid animals showed that the combination of pERIG, rabies vaccine and wound treatment is effective in protecting against canine rabies virus infection. The results confirm the clinical effectiveness of pERIG when used in PEP, notwithstanding the questions raised by scientific research, such as a more rapid clearance and a reported difference in protection associated with the use of pERIG against different rabies strains in animal models [11]. Nonetheless, no treatment intervention is 100% successful as illustrated by two tragic outcomes. The first case concerned a malnourished girl with severe lacerations in critical anatomical areas [12]. She was the first bite victim of the dog, and therefore probably received a large inoculum of the virus in highly innervated areas. Further, given her extensive lacerations with persistent bleeding, her wounds were sutured. She did subsequently develop an adequate immune response to the vaccine, as described for other malnourished children [13], but still succumbed to the rabies infection (Figure 1). The WHO recommendations (TRS931) state that in cases of multiple severe exposures, HRIG if available should be infiltrated in the wounds, otherwise pERIG should be used and a maximum quantity must be infiltrated undiluted in the lesions. We can only speculate whether the use of HRIG, or indeed refraining from suturing the wounds, could have prevented the course of disease in this case. The second case concerned a boy who only received treatment on the day he was bitten by a rabid dog, although this was not confirmed. With no subsequent vaccinations the boy died. What is notable in this case is that a cousin bitten by the same animal on the same day, and who completed the recommended rabies vaccination series through 90 days, was in good health 10 months post exposure. These two cases are defined as rabies PEP intervention failures. In summary, records of 7,660 patients given rabies PEP at the RITM during the period July 2003 to August 2004 were considered in this case series. Although the true extent of rabies exposure in all 7,660 patients is unknown, of 144 cases of laboratory-proven rabies Category III exposure available for follow-up, there was one rabies PEP intervention failure. A second presumed PEP intervention failure, there being no confirmation of rabies infection in the biting animal, highlights the importance of the potential of rabies infection by animals not being examined for their rabies status and illustrates that the burden of disease is more important. Thus, the RITM rabies PEP guidelines, i. e. , wound cleaning and treatment, antibiotic and tetanus prophylaxis, rabies vaccination and use of pERIG for Category III exposures by potential rabid animals are deemed satisfactory. Whereas further consideration of the development of alternative treatments to the current RIGs, such as monoclonal antibodies, is merited [11], the real-world, clinical experience presented here emphasizes that, in the meantime, correct implementation of the rabies prevention recommendations is of paramount importance to save lives. Continued training of treating physicians and attending staff should further improve the quality of treatment and care. Extensive lesions in highly innervated body regions are of particular concern and may demand specific clinical interventions, such as immediate suturing. It must be borne in mind that such deviations from the recommendations are often basic and unavoidable when working under field conditions, and must be considered with great caution when interpreting unexpected outcomes. The experience from the RITM is that pERIG, when administered as recommended and as part of the rabies PEP in conjunction with wound treatment and rabies vaccination, is safe and effective and contributes to the prevention of otherwise fatal consequences of rabies infection.
Infection from a bite by a rabid animal is fatal unless rapid treatment (thorough cleaning of the wound, administration of rabies immunoglobulins (RIG), and a full anti-rabies vaccination course) is provided. Ideally human RIG should be used, but cheaper, more readily available purified horse RIG (pERIG) are widely used in developing countries. Follow-up of over 7,600 patients previously given pERIG at the rabies treatment reference center in Manila (Philippines) provided updated health status for 6,458 patients 39 days to 29 months after treatment. A total of 151 patients had been bitten by animals with laboratory-confirmed rabies. Two rabies deaths were reported, one in a 4-year-old girl with bites on the back, shoulder, and neck so severe that stitching was required to prevent bleeding (against recommended practice), and another in an 8-year-old boy who only received rabies vaccination on the day of initial treatment. A 7-year-old cousin of this boy, bitten by the same animal, who did receive the full vaccination course was still healthy 10 months later. Fourteen other reported deaths had causes unrelated to rabies. These data illustrate the effectiveness of pERIG as part of the recommended treatment regimen, while highlighting the importance of adhering to current recommendations.
infectious diseases/infectious diseases of the nervous system
infectious diseases/viral infections
pathology/neuropathology
virology/emerging viral diseases
Rabies Post-Exposure Prophylaxis in the Philippines: Health Status of Patients Having Received Purified Equine F(ab')2 Fragment Rabies Immunoglobulin (Favirab)