Rabies Treatment & Management

When the patient presents with a bite, the wound should be cleansed immediately with soap and water, flushing it thoroughly to remove saliva. Debridement and careful exploration for foreign body (eg, broken tooth) are essential; this should take at least 10 minutes. Generally, leave wounds to heal by secondary intention to permit drainage of wound fluids and prevent infection. ^{[33, 34]}

Inpatient care

Inpatient care of patients with rabies may be needed if wounds are extensive or are on the face and hands, if surgical repair or replacement of blood loss is required, or if infection occurs.

Transfer

For a patient with an illness consistent with rabies, transfer to a tertiary care center with intensive care support and capability of providing timely diagnostic workup is essential.

Follow-up

Coordinate follow-up evaluations of patients with the primary caregiver, the local health department, and, if applicable, the veterinarian who quarantined the animal.

Preexposure, active prophylaxis or immunization is recommended for individuals who are exposed to rabies virus or who handle specimens considered high risk for rabies and persons who visit countries where rabies is a significant problem. The US Advisory Committee on Immunization Practices (ACIP) updated recommended risk categories and preexposure prophylaxis based on evolving rabies epidemiology, availability and logistics of rabies vaccine administration (especially prior to planned travel), and optimized cost-to-benefit ratio. (See Table 1, below, with detailed review and examples available at https://read.qxmd.com/doi/10.15585/mmwr.mm7118a2)

Table 1. Risk Categories for Active Preexposure Immunization and Rabies Titer Monitoring, ACIP 2022   (Open Table in a new window)

 

In the United States, the CDC recommends rabies postexposure prophylaxis only with intramuscular (IM) cell-cultured vaccines; intradermal (ID) formulations are not approved by the US Food and Drug Administration (FDA) for use in the United States.

Outside the United States, in areas where cost and vaccine supply are limiting factors, alternatives to the IM regimens may be more feasible. In addition, rabies vaccination may be the norm in some countries where rabies is endemic, and anamnestic response may permit effective alternative dosing. In 1998, the World Health Organization (WHO) released guidelines for ID use of human diploid cell vaccine (HDCV), purified chick embryo cell vaccine, and purified duck embryo cell vaccine. ^[42] The WHO published updated postexposure prophylaxis guidelines that included ID regimens often used outside the United States. ^[43]

A Rapid Fluorescent Foci Inhibition Test (RFFIT) titer greater than or equal to 0.5 IU/mL (or complete neutralization at a serum dilution of 1:5) is considered an acceptable antibody response for protection against rabies.

Booster immunization is indicated for individuals at continuous or frequent risk for rabies, who should undergo periodic rabies antibody testing as per the ACIP guidance above (Table 1).

Passive immunization consists of the administration of human rabies immunoglobulin (HRIG) pooled from the sera of immunized human donors.

As previously stated, washing and wound debridement at the time of a bite is essential, along with careful cleaning of the wound for longer than 10 minutes. Generally, leave wounds to heal by secondary intention. ^{[33, 34]} Antibiotic prophylaxis should be considered. ^{[34, 44]}

Administer HRIG to any person not previously vaccinated against rabies, at a dose of 20 IU/kg (for adults and children). Apply as much of the dose as possible at the injury site and the remainder as a deep IM injection in the gluteal area. HRIG may be administered as long as 7 days after the first dose of vaccine if it is not immediately available when the patient presents for evaluation. ^{[18, 33]}

Equine rabies immunoglobulin may be available in other countries. Minimal adverse effects occur if it is in the purified form. If unpurified, however it may cause serum sickness and anaphylaxis. Recombinant monoclonal rabies antibody has been developed and licensed outside the United States, with the advantages of greater neutralizing activity, greater specificity for the viral target, a more standardized product, and lower side effect profile.  ^[45]

Two different inactivated rabies vaccines are licensed and produced in the United States, as follows:

• Human diploid cell vaccine (HDCV; Imovax) - Usual dosing for postexposure prophylaxis to be administered as IM injection

• Purified chick embryo cell vaccine (PCEC; RabAvert) - Licensed in the United States in 1997 for IM use only

Doses of all the vaccines for postexposure prophylaxis are 1 mL IM in the deltoid or in the upper outer thigh in infants.

Mild local and systemic adverse reactions to these vaccines and immunoglobulin may occur but are usually treatable with supportive care, antihistamines, and anti-inflammatory medications. Local pain, erythema, headache, nausea, and abdominal pain may occur. If prophylaxis is warranted, do not postpone or discontinue treatment because of mild adverse effects.

Before the onset of rabies symptoms, optimal results require immediate, vigorous wound cleansing; passive immunization with immunoglobulin; and active immunization with rabies vaccine. ^[25] Children are prone to extensive wounds on the face, upper body, and hands because of their short stature. ^[46] These wounds may require extensive debridement and inpatient management.

Do not administer immunoglobulin and vaccine with the same syringe or in the same site. Do not administer vaccine in the gluteus, as antibody response may be reduced.

Passive immunoglobulin provides protection for 1-2 weeks until the vaccine elicits protective antibody.

If the patient has had no prior rabies vaccination, if they are of unknown status, or if more than 5 years have passed since their last vaccination, rabies vaccine and immunoglobulin should be administered as follows (these dosages being applicable to products available in the United States):

• Rabies vaccine IM (deltoid) - 1 mL on Days 0, 3, 7, and 14
• In the immunocompromised individual, antibody response to vaccination may be inadequate. Perform RFFIT at least 1 week after last dose and/or consider an additional dose on day 28. ^{[47, 48, 49]}
• Rabies immunoglobulin - 20 IU/kg infiltrated as much as feasible around and under the bite wound; if any left over, give IM (gluteus)
• The pediatric dose of HRIG, calculated by body weight, may be of insufficient volume to infiltrate all of the wounds. The immunoglobulin may be diluted with sterile saline so that more volume can be used without exceeding the total recommended dose. ^[50]

If the patient has had prior rabies vaccination, rabies vaccine should be administered IM (deltoid) 1 mL on Days 0 and 3 (this dosage again being applicable to US vaccine).

The World Health Organization (WHO) has revised PEP guidance for previously unimmunized individuals in order to reduce cost and spare vaccine doses without reducing effectiveness. Currently recommended guidance for rabies PEP outside the United States, in order of preference, includes the following ^{[25, 51]} :

• Two-site intradermal (ID) vaccine administration on Days 0, 3, and 7
• One-site IM vaccine administration on Days 0, 3, 7 and the fourth dose between Days 14 and 28
• Two-site IM vaccine administration on Day 0 and one-site IM administration on Days 7 and 21

Empiric treatment for rabies should be guided by local public health recommendations, whenever feasible, taking into account whether viral shedding periods are known for the species, the animal's history and risk for rabies exposure, and local epidemiology. Some countries and limited areas in US territories are considered rabies-free, and no prophylaxis is administered. 

High-risk wild or feral animals implicated in exposures will be captured, if possible, and euthanized for both humane reasons and for examination of brain tissue. Because of the exceedingly low prevalence of rabies in domestic animals in the United States, healthy, unvaccinated domestic dogs, cats, and ferrets are often observed for 10 days for signs of illness. If the animal remains healthy, no treatment is administered. Vaccinated animals in the United States have not transmitted rabies; outside the United States, rare instances of transmission occur. Note that an assessment of whether a bite was provoked is subjective and does not significantly affect the chances that the animal is rabid. Therefore, this is not helpful in determining the need for prophylactic treatment. ^[5]

In most settings where rabies is a risk, prophylaxis should be initiated regardless of whether or not the animal is in custody and being observed.  Prophylaxis may be discontinued if the animal does not develop rabies within 10 days or is found to be free of rabies upon sacrifice.The median duration of rabies illness in dogs, cats, and ferrets is less than 10 days, and viral shedding in saliva occurs within a few days of onset of illness and death.

Pregnancy is not a contraindication to postexposure prophylaxis against rabies, which is warranted to protect the life of the fetus and mother. No adverse pregnancy outcomes have been documented with postexposure prophylaxis. No mother-to-fetus transmission has been described, and spread of the virus is not hematogenous; thus, neither rabies exposure nor diagnosis in the mother is an indication for pregnancy termination. ^{[52, 53]}

Intradermal (ID) regimens have not been approved by the US Food and Drug Administration (FDA) or recommended by the CDC for use in the United States. WHO recommends ID regimens for use outside the United States when IM vaccine is unavailable or its use is not feasible.

In previously vaccinated individuals, studies have shown that single-visit, 4-site ID booster regimens offer satisfactory anamnestic response. A retrospective study at The Queen Saovabha Memorial Institute (QSMI) investigated booster regimens in more than 5000 previously immunized individuals who presented with rabies exposures. The study found that the single-visit, 4-site ID booster regimen using cell-cultured vaccine demonstrated superior anamnestic response, more rapid rise in Nab levels, and more persistently high Nab levels 1 year after prophylaxis than did the standard WHO 2-visit booster regimen. ^[54] Advantages of the single-visit booster also included reduced time and reduced costs from loss of work or from delayed travel, along with enhanced compliance.

Inpatient care

Symptomatic rabies cannot be managed in the outpatient setting. Intensive cardiopulmonary supportive care is the only treatment available for patients with symptomatic rabies. Rabies vaccination and administration of HRIG is ineffective at this point, since the CNS does not possess humoral immune mechanisms to mount antibodies and inflammation is insufficient to allow B lymphocytes to cross the blood-brain barrier and mount a defense. In animal studies, rabies immunoglobulin has been associated with “early death”; it has been suggested that HRIG may also pose a risk for early death in humans and should be avoided. ^[55]  However, there is animal data supporting the use of human monoclonal antibody to reverse rabies, albeit by concomitant administration intramuscularly and via cerebroventricular infusion. ^[56] Treatment in the United States would require at minimum an emergent Investigational New Drug application on a compassionate use basis. ^[57]

However, it must be noted that there is no current scientific consensus on the management of rabies, and management is symptomatic. Therapeutic coma is no longer recommended, and sedation should be limited to that required for comfort and management of spasms. Nimodipine may be used for cerebrovascular spasm but may cause severe hypotension. ^[26]

Regardless of treatment, symptomatic rabies is almost invariably fatal, with autonomic dysfunction leading to cardiac arrhythmia and hypotension. Some role for combination treatments including ribavirin, interferon, ketamine, and immunomodulatory therapies has been proposed and may be considered in future cases under investigational protocols.

The survival of a teenaged girl from Wisconsin received substantial attention in October 2004 as the first reported case of human survival of rabies in the absence of preceding vaccination or postexposure prophylaxis. ^[58] Notably, she received an investigational regimen of ribavirin, amantadine, and a ketamine-midazolam–induced coma. However, this therapy has not been validated and has not been reproducible in several subsequent cases. It is no longer recommended, and the University of Wisconsin no longer maintains the Rabies Registry website. Furthermore, the bat rabies virus isolated in this case may be less neurovirulent than canine or other variants that are responsible for most human cases of rabies. ^{[26, 59]}

The rarity of human rabies hinders timely testing of therapies. Immunomodulatory therapies such as rabies immunoglobulin, rabies vaccine, and interferon have not altered outcomes in trials.

Steroids, which usually are indicated in the treatment of local vaccine reactions or cerebral edema, are contraindicated because of increased mortality noted in animal studies and because they reduce the response to the vaccine.

Transfer

For a patient with an illness consistent with rabies, timely diagnostic workup is essential. Transfer to a tertiary care center with high-level intensive care support and clinicians knowledgeable in managing rabies is optimal whenever feasible.

In the community

Patient education

The need for adherence to local public health recommendations regarding the control and vaccination of domestic animals and the vaccination of individuals who may be exposed to rabies in their occupation cannot be stressed enough. The case of the Wisconsin survivor, who did not seek medical attention after being bitten, underscores the need for ongoing public education about preventing this almost uniformly fatal infection.

Counsel patients regarding the subjective nature of provocative behavior toward animals. Especially stress avoiding contact with unfamiliar or wild animals. Wild animals seen in areas or at times of day that seem unusual are reason to suspect rabid behavior. Wild animals that are rabid may seem unusually docile or fearless. Hypersalivation, or “foaming at the mouth,” is pathognomonic for rabies but is often absent.

Prompt, vigorous cleansing of any injury or bite from any animal is critical and may reduce the risk of rabies transmission. Provide extensive reassurance after any injury that may be related to rabies transmission. Fear of rabies is primal and is known to induce hysterical reactions that mimic the disease manifestations.

Promote educational efforts at home and at schools teaching children about safety procedures and precautions regarding pets and wild animals. Many communities have programs through camps, schools, and public libraries, as well as information through local health department Web sites. ^[60] Veterinarians and public health officials are excellent resources for concerns regarding animal rabies prevention. ^{[18, 61]}

In addition, the public should be advised to do the following:

• Teach children at an early age not to handle stray animals or wildlife, especially bats found on the ground

• Report any animals that are sick or acting strange to local public health authorities

• Consult public health authorities if a bat is seen in the home at night, even if a bite is not suspected

• Keep pets indoors at night and fenced in or on a leash when outdoors

• Keep pet food and water dishes indoors

• Have professional animal trappers remove bat colonies from homes and barns

• Handle sick or dead animals with heavy gloves and shovels

• Keep trash container lids tight and maintain compost piles away from dwellings

• Wash hands with soap and water after contact with wildlife

• If an animal scratch or bite occurs, especially if due to a bat, fox, raccoon, skunk, or unvaccinated dog or cat, (1) immediately wash the areas vigorously with soap and water and (2) immediately seek care at an emergency department. Aside from rabies, bites may become infected, and preventive care is available if sought.

For patient education information, see the Infections Center, as well as Rabies.

Healthcare workers

Universal precautions and respiratory precautions during respiratory therapy are indicated for healthcare providers. Rabies postexposure prophylaxis of health care workers is indicated only for high-risk exposures as determined with the assistance of local infection control and public health authorities.

Organ transplant recipients

Pretransplantation screening for potential rabies infection or exposure should be performed on organ donors. ^[18] Recipients of corneal and neurally derived tissues are at highest risk for rapid development of rabies; however, solid organ transplant recipients have also become infected.

Clinical screening of potential organ donors should include a history of animal bites, presence of clinical features of rabies, and a travel history (within a period of months) to areas where rabies is endemic; preexposure rabies immunization of potential organ recipients is being evaluated as an alternative approach to prevent transmission associated with organ transplantation. ^[23]

Control of rabies in the animal population

Because rabies is a zoonosis, primary prevention requires control of rabies in the animal population. In 1997, approximately 100,000 animal brains were tested for rabies virus antigen using a direct fluorescent assay. Of these specimens, 8509 (8.5%) had positive results.

Mass control and mandatory vaccination of domesticated dogs and cats are effective in controlling rabies in the United States; however, developing nations have found cost to be a barrier to such campaigns.

Live viral vaccines containing modified live rabies or recombinant vaccinia-rabies glycoprotein virus, placed in a bait, are used for disease control in Europe and North America. ^[21] In the United States, more than 22 million doses of vaccinia-rabies glycoprotein vaccine were distributed between 1990 and 2000. The baits were mainly used to control rabies in raccoons in the eastern United States and in foxes and coyotes in Texas. People will inevitably find vaccine-laden baits. Dogs are frequently attracted to the baits and bring them to their owners. Luckily, adverse events are rare. ^[21]

Consultation with infectious disease specialists, neurologists, and neurosurgeons may be necessary to assist in diagnosis and management of patients with rabies or patients exposed to rabies.

Consultation with public health authorities is appropriate to assist in management of bite wound prophylaxis and animal epidemiology. ^[62]

The Centers for Disease Control and Prevention maintains a 24/7 Emergency Operations Center for consultation at 770-488-7100.

Also, consult with animal control officers and veterinarians for the management, disposal, and testing of animals that have attacked and injured a human.