Rabies Post-Exposure Prophylaxis in the ED—Review of Therapy and Key Opportunities to Improve Dissemination of Care

Background Despite only 17 documented human cases of rabies in the United States since 2015, rabies remains one of the deadliest infections known to medicine, with a mortality rate exceeding 99.9%.1,2 Rabies is a Lyssavirus transmitted through mammal bites. Worldwide, canines are responsible for most human rabies cases and account for 99% of human deaths.2 However, due to vaccination campaigns in the United States, the incidence of rabies in canines is exceedingly rare, making them a less likely vector of transmission. Most rabies cases in the United States are reported in wildlife, with more than 90% occurring in bats, raccoons, skunks, and foxes.1Once transmitted, rabies occurs in five stages: Incubation period Prodromal phase Acute neurologic period Coma Death2,3 While human exposures are exceptionally rare in the United States, it is reported that 75% of Americans live in a community where the disease is present in animals.1 Additionally, 1.6 million patients seek medical attention following an animal bite each year in the United States with around 100,000 receiving rabies postexposure prophylaxis (PEP).1 Therefore, it is imperative emergency medicine clinicians understand how to properly provide treatment to patients in the form of rabies PEP. CDC/ACIP/WHO Rabies PEP Treatment Recommendations Rabies PEP recommendations from the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP) include wound care, human rabies immune globulin (HRIG), and rabies vaccination.4 Meanwhile, the World Health Organization (WHO) has created guidance to define and assess degree of exposure (Category I, II, or III) and provide corresponding treatment recommendations. These are further described in Table 1.5 Every patient presenting with a potential rabies exposure should be screened for appropriate components of PEP. Additionally, it is important clinicians know that both HRIG and rabies vaccination are considered safe for children of all ages and during pregnancy and should not be withheld when indicated.4,6 Table 1 - WHO Categories of Exposure and Post-Exposure Prophylaxis Indication. WHO category Description PEP recommendations Category I (ie, no exposure) Touching or feeding an animal Licks on intact skin PEP not indicated Category II (ie, exposure)a Minor scratches or abrasions without bleeding PEP indicated: - Wound washing and vaccine only Category III (ie, severe exposure) Single or multiple transdermal bites or scratches Contamination of mucous membrane/broken skin with saliva from animal licks Exposure due to direct contact with bats PEP indicated: - Wound washing - Rabies immune globulin - Vaccine Abbreviations: PEP, post-exposure prophylaxis; WHO, World Health Organization.aTreat bat exposures as category III Wound Care Thorough wound cleansing lessens the viral load at the wound site to reduce the potential inoculation of rabies virus, and it has been shown in multiple animal studies to be potentially the most protective step in PEP.7,8 Proper wound care should begin with washing the wound(s) with soap and water for 15 minutes, followed by irrigation with a virucidal agent (eg, povidone-iodine), if available.4,9 Other important considerations include avoidance of tight wound coverings/dressings and closing the wound with sutures. If sutures are needed (eg, continued bleeding), attempt to delay placement until a few hours after administration of HRIG, when therapy is necessary.9 Rabies Immune Globulin (RIG) RIG is indicated for WHO Category III exposures for patients that have not previously been administered the rabies vaccine. RIG is infiltrated into wound(s) to provide neutralizing antibodies until the body can produce antibodies in response to vaccination.10 There are currently two concentrations of HRIG available in the United States: 150 IU/mL (KEDRAB) and 300 IU/mL (HyperRAB).11,12 Current CDC/ACIP recommendations state to infiltrate wound(s) with HRIG at 20 IU/kg actual body weight.4 HRIG should be infiltrated deep into or as close to all wounds, avoiding compartment syndrome.9 If the calculated dose of HRIG is inadequate to infiltrate all wounds (eg, due to extensive trauma), HRIG may be diluted with a compatible diluent (saline or 5% dextrose in water), following manufacturer's recommendations.9,11,12 Additionally, clinicians may experience instances in which excess of HRIG is left after maximal wound infiltration. In these cases, the remaining dose should be administered intramuscularly at a site distant from the rabies vaccine.4 HRIG can neutralize the rabies vaccine, making it critical that clinicians are aware of proper administration to ensure the vaccine will be efficacious.13 Lastly, please refer to the publication by Bookstaver et al, for additional volume- and wound-based HRIG infiltration guidance.14 Some rural health care facilities may carry a small amount of HRIG (or none), leading individuals to present later for HRIG administration. If HRIG was not administered concomitantly with the day 0 vaccine dose, it can be given up to and on day 7 after the vaccine series has been initiated.13 Vaccination Current rabies vaccines are highly efficacious (approaching 100%).15 Therefore, CDC/ACIP recommends rabies vaccination be included in PEP for all bite and nonbite exposures.4 The appropriate vaccine schedule is dependent upon patient-specific factors, which include immunocompetence and previous rabies vaccine status. A summary of current CDC/ACIP vaccine schedules can be found in Table 2.4 Table 2 - CDC/ACIP Rabies Vaccine Schedule. Number of total doses Day 0 Day 3 Day 7 Day 14 Day 28 Individuals without previous rabies vaccination (immunocompetent) Four doses of HDCV/PCECV ✓ ✓ ✓ ✓ Immunocompromised individuals without previous rabies vaccination Five doses of HDCV/PCECV ✓ ✓ ✓ ✓ ✓ Individuals with previous rabies vaccine Two doses of HDCV/PCECV ✓ ✓ Abbreviations: ACIP, Advisory Committee on Immunization Practices; CDC, Centers for Disease Control and Prevention; HDCV, Human Diploid Cell Rabies Vaccine; PCECV, Purified Chick Embryo Cell Vaccine. There are two available rabies vaccine formulations in the United States: Human Diploid Cell Rabies Vaccine (HDCV) and Purified Chick Embryo Cell Vaccine (PCECV). Both should be administered as 1.0 mL intramuscular injections into the deltoid (anterolateral thigh is acceptable for children).4 While recommended vaccine schedules should be adhered to, clinicians may experience instances where a patient misses a vaccine dose. In the case of minor deviations (eg, few days), the vaccine schedule can be resumed as though the patient were on schedule. However, if a substantial delay occurs (eg, weeks), the vaccine schedule should be finished, followed by serologic testing 7-14 days after the final dose to assess immune status.13,16 WHO PEP Recommendations WHO PEP recommendations are mostly congruent with CDC/ACIP. However, slight differences do exist. In the 2018 WHO position paper on rabies PEP, WHO removed the recommendation for intramuscular administration of excess RIG for most circumstances (exception: bat exposures). They are currently recommending RIG infiltration in and around wound(s) up to max calculated volume. Also, the WHO allows for the use of equine RIG or HRIG.17 The WHO based this update on evidence published by Bharti and colleagues. The authors observed that RIG infiltration into and around wounds alone in 269 Category III exposures resulted in no deaths with patients being followed for 9 months.18 Additionally, a subgroup of 26 patients with no previous rabies vaccination that were severely bitten by laboratory-confirmed rabid canines were followed for a duration of 58-70 weeks with no observed mortality.19 Also, there is published pharmacokinetic evidence demonstrating intramuscularly administered RIG is minimally absorbed in systemic circulation.20,21 Opportunities for Improvement Providing PEP following potential rabies exposure is important to improve patient outcomes. However, as with many therapeutic interventions, costs associated with care must be considered. In 2019, the average cost for HRIG was $312 per 150-IU dose and $290 per dose of the rabies vaccine.22 Assuming a healthy 165-pound patient presents for PEP, the average total cost would be $3,120 for HRIG and $1,160 for a four-dose vaccine series. With such a high expense associated with care, clinicians may be able to take advantage of PEP cost-containment strategies like HRIG dose rounding.23 From March 2011 to December 2021, one university health system utilized a dose-rounding strategy that resulted in a total of 40,572 IU of HRIG saved, correlating with a total savings of $144,815.23 Similar models can be implemented within other institutions as a cost-savings initiative. Additional opportunities to improve rabies PEP care can occur through partnerships with urgent cares, local health departments, and pharmacies to disseminate follow-up rabies vaccine doses. Rabies PEP is often provided within the emergency department (ED) setting; however, an estimated 20% of these patients present back to the ED for subsequent vaccine doses.24 Multiple large health systems have demonstrated success in reducing unnecessary ED visits through coordinating patient care with partners who can provide vaccination.25 Conclusion Rabies remains one of the most fatal infections, yet it is preventable with timely and appropriate PEP. Despite its rarity in the United States, the ongoing prevalence in wildlife makes it necessary for clinicians to be aware of and adhere to established CDC/ACIP and WHO treatment recommendations. Proper wound care, HRIG administration, and adherence to vaccine schedules remain critical components for PEP to be efficacious. Additionally, implementing strategies such as HRIG dose rounding and coordination of subsequent vaccine doses, may potentially help alleviate costs and reduce the burden on emergency departments associated with providing rabies PEP.