An emergency physician friend texted me about whether I thought he should get rabies postexposure prophylaxis (RPEP). He said that while he was out for an evening stroll, a bat flew into him, hitting him in the forehead not just once but twice. Although he could not find evidence of a bite or wound, he wondered what he should do.

Emergency physicians are presented with these types of patient questions frequently, usually related to dog bites but from other types of exposures, too, with various degrees of circumstantial bite evidence. The calculous around the decision to give RPEP is portentous. Rabies, with extremely rare exceptions, is an untreatable fatal disease, but if the exposure is identified and prophylaxed, it’s also 100 percent preventable.

In some cases, the animal can be captured and observed or killed and tested immediately, and a new polymerase chain reaction test is likely to be available soon to facilitate rapid animal testing. However, when the animal is unavailable, the decision for RPEP is made in the emergency department. Over time, the RPEP regimen has gotten easier, four instead of five vaccinations, but no less expensive. The cost of the rabies immune globulin (RIG) and vaccine regimen is in the neighborhood of $4,000 to $5,000 total based on Red Book pricing, although charges have been noted to vary greatly on hospital bills.¹ There’s also a new RIG formulation called HyperRAB, which has some advantages. Before we get back to the answer to my friend’s question, let’s review the latest RPEP recommendations and options.²

Treatment

Initially, it’s most important to thoroughly irrigate and clean the wound. Since incubation periods of more than one year have been reported in humans, when a likely exposure has occurred, RPEP should be given regardless of the length of the delay.

RIG, a pooled human donor product, should be given in the emergency department, infiltrating as much of the full 20 IU/kg dose as possible into the subcutaneous tissue at the wound site and the remainder given intramuscularly, typically in the deltoid opposite the vaccine administration site. HyperRAB, approved in February 2018, is a more potent version of the previously licensed HyperRAB S/D (both Grifols Therapeutics, Inc.), Imogam Rabies-HT (Sanofi Pasteur SA), and Kedrab (Kedrion Biopharma and Kamada, Ltd). HyperRAB requires less volume to achieve the recommended 20 IU/kg dose, allowing more RIG to be delivered at the site of potential rabies virus inoculation.

For example, the concentration of older RIG formulations is 150 IU/mL. For a 75 kg person, 20 IU/kg requires 1,500 IU in 10 mL. Imagine trying to infiltrate a 10 mL syringe of RIG into the tip of a finger. Alternatively, the concentration of HyperRAB is 300 IU/mL, which in this example would equate to half of the previous amount, or 5 mL; it would still be difficult to get all of it in a finger wound, but twice as much could be injected. For my friend, this would represent the difference between having a small bump on his forehead or one that more resembles Pott’s puffy tumor. According to Red Book prices, the new HyperRAB formulation costs the same as the older HyperRAB S/D and the other RIG products, about $3,200 for 1,500 IU.

If the price that hospitals and insurers negotiate is similar among formulations, pharmacies may decide to stock HyperRAB, both for its theoretical greater effectiveness by allowing more immunoglobulin to be injected into the wound and for the less pain associated with the remaining lower-volume intramuscular injection.

Rabies remains endemic in raccoons, foxes, and skunks regionally in the United States (see Figure 1) and bats everywhere, and each year between 60 and 70 dogs and more than 250 cats are found rabid. However, only 23 cases of human rabies have been reported in the past decade compared to 60,000 cases annually worldwide, and none were due to RPEP failure. So it does not appear that our previously available RIG preparations have been ineffective. RPEP failures have rarely occurred due to RIG injected only intramuscularly and not into all the wounds.

There are potential drawbacks with higher-concentrated RIG. For example, for extensive wounds, the Advisory Committee on Immunization Practices recommends diluting RIG to ensure sufficient volume to infiltrate all of the wounds. In this scenario, the doubly concentrated formulation might require additional dilution, which must be done with 5 percent dextrose in water rather than normal saline. Thus, the standard concentration might be preferred in this situation. Also, the change in concentration may increase the risk of miscalculating the dosage if clinicians mistakenly use the previous standard concentration.

In addition to RIG, rabies vaccine should be administered intramuscularly in the deltoid area, 1 mL initially (day 0) and then again on days 3, 7, and 14 (also day 28 if the patient is immunocompromised). Two licensed vaccines are currently available in the United States: human diploid cell vaccine (Imovax Rabies, Sanofi Pasteur) and purified chick embryo cell vaccine (RabAvert, Novartis Vaccine and Diagnostics).

Vaccine should not be administered in the gluteal area because this may result in lower antibody titers. The deltoid is the only acceptable intramuscular site of vaccine administration in adults and older children; the outer thigh can be used in young children. Vaccines cost about $300 per dose. Vaccine shortages have occurred, and the Centers for Disease Control and Prevention (CDC) maintains a website for rabies vaccine availability, www.cdc.gov/rabies/resources/availability.html.

Because of the cost, some public health experts have been concerned about ED overprescription. However, when we studied RPEP from more than 2,000 animal exposures presenting to our CDC EMERGEncy ID NET sites, we found that emergency physicians were in fact conservative in their use based on local guidelines.³

Back to our friend, the emergency physician “batted” in the head. Human rabies epidemiology in the United States helps provide the answer.

According to the CDC, the most common rabies virus variants responsible for human rabies in the United States are bat-related.2 During 1990–2007, 34 bat-associated human cases of rabies were reported in the United States. In six cases, a bite was reported; in two cases, contact with a bat and a probable bite were reported; in 15 cases, physical contact was reported (eg, the removal of a bat from the home or workplace or the presence of a bat in the room where the person had been sleeping), but no bite was documented; and in 11 cases, no bat encounter was reported. In these cases, an unreported or undetected bat bite remains the most plausible hypothesis because the genetic sequences of the rabies virus closely matched those of specific species of bats.

Rabid bats are more aggressive and have difficulty flying. The little sono-geeks do not normally fly flat into the foreheads of people, not once and especially not twice. So the bat in question was very likely rabid. And since bat bites can be imperceptible, this type of exposure requires RPEP. When in doubt, call the local health department, which is available 24-7 for these sometimes difficult and expensive ED decisions. My friend’s hospital bill was $16,240.

Acknowledgment: I would like to thank Dr. Brett Petersen and Dr. Andrea McCollum at the CDC for their review and suggestions.

Read the drug summary for HyperRAB, then complete the CME activity.

Dr. Talan is professor of medicine in residence (emeritus) at the David Geffen School of Medicine at UCLA and chairman emeritus of the department of emergency medicine and faculty in the Division of Infectious Diseases at the Olive View-UCLA Medical Center.

References

1. Red Book Online [database online]. Greenwood Village, CO: Truven Health Analytics. Accessed July 14, 2018.
2. Manning SE, Rupprecht CE, Fishbein D, et al. Human rabies prevention—United States, 2008: recommendations of the Advisory Committee of Immunization Practices. MMWR Recomm Rep. 2008;57(RR-3):1-28.
3. Moran GJ, Talan, DA, Newdow M, et al. Appropriateness of emergency department rabies postexposure prophylaxis for animal exposures. Emergency ID Net Study Group. JAMA. 2000;284(8):1001-1007.