Treatment of rabies

INTRODUCTION — Rabies remains an important disease because there are at least 60,000 human deaths every year worldwide, particularly in Asia and Africa where dog rabies is endemic [1]. In geographic locations where human rabies is rare, the diagnosis may not be considered until relatively late in the clinical course. There is no known effective treatment for rabies.

Although rabies is usually preventable after recognized exposures with post-exposure rabies prophylaxis (eg, wound cleansing and administration of rabies vaccine and rabies immune globulin), the need for prophylaxis is not always recognized and may not be readily available in some areas. In addition, human rabies may present without a history of an animal exposure, usually because a bat bite was not recognized.

This topic will address the approach to managing patients with suspected or confirmed rabies. The epidemiology, clinical manifestations, diagnosis, and prevention of rabies are discussed elsewhere. (See "Clinical manifestations and diagnosis of rabies" and "Rabies immune globulin and vaccine" and "Indications for post-exposure rabies prophylaxis".)

CHOOSING A TREATMENT APPROACH — In patients with confirmed or suspected rabies, management options include a palliative or aggressive approach. As of January 2023, there have been 30 well-documented rabies survivors (table 1) [2-28]; the most recent survivors were from India. None of these patients received timely administration of a full course of a recommended post-exposure rabies prophylaxis regimen, and only a minority received rabies immune globulin. These cases do not include patients who had atypical features of rabies without the development of rabies virus-neutralizing antibodies (since they were likely not cases of rabies) [29,30] or reports that did not have sufficient documentation [31-34].

Many factors influence the therapeutic approach in patients with rabies, including prognostic factors (table 2) and the risks of treatment (see 'Combination therapies' below). Although the relative importance of each of these factors is uncertain, in general:

●A palliative approach is typically pursued in patients who are unlikely to survive or who would not accept survival with severe neurological sequelae. Factors associated with a poor prognosis include older age, comorbid conditions, late disease, no history of rabies vaccination, and diagnostic testing that is positive for rabies virus antigen/RNA and negative for neutralizing anti-rabies virus antibodies. (See 'Palliative approach' below.)

●Consideration of an aggressive approach would be reasonable for patients who have an increased likelihood of survival and who would accept severe neurologic sequelae. Factors that may be associated with a more favorable disease course include young age, lack of comorbidities, receipt of one or more doses of rabies vaccine prior to the onset of symptoms or signs, clinical manifestations consistent with early disease, and diagnostic testing that is negative for rabies virus antigen/RNA and positive for neutralizing anti-rabies antibodies. (See 'Aggressive approach' below.)

PALLIATIVE APPROACH — Once a decision has been made to take a palliative approach for the care of a patient with rabies, the focus should be on comfort care in a hospital with liberal use of sedatives and analgesics in order to alleviate suffering [35]. As examples:

●A quiet private room is highly desirable.

●Pharmacologic restraints are preferred whenever possible over physical restraints. Benzodiazepines such as diazepam are useful for sedation and muscle relaxation and can be given intravenously, intramuscularly, or per rectum. Lorazepam and midazolam are alternative benzodiazepines, and both can be given intravenously or subcutaneously.

●Haloperidol, which can be administered subcutaneously or intramuscularly, can be used for a variety of clinical manifestations, including restlessness, agitation, hyperexcitability, delirium, hallucinations, and aggression [36].

●For analgesia, morphine can be administered intravenously or subcutaneously, including a subcutaneous infusion using a syringe driver that avoids the need for multiple injections [37]. Both haloperidol and midazolam can also be given subcutaneously using this method, and also in two- or three-drug combinations (eg, morphine, haloperidol, and midazolam).

●Excessive salivary secretions can be treated with anticholinergics, including scopolamine and glycopyrrolate. The sensation of thirst can be alleviated with ice chips in the mouth.

●Fever can be treated with sponging and antipyretics, including acetaminophen and/or ibuprofen.

Although palliative care in a hospital is preferred, in some cultures, it may be important for the patient to leave the hospital and return home for privacy, to reduce hospital costs, and/or for religious rites to be performed before death [38].

AGGRESSIVE APPROACH — On rare occasions, patients with rabies have survived after aggressive care in critical care units (table 1). An aggressive treatment approach involves a combination of supportive care and the off-label use of presently available therapies that, although unproven, may have benefit based upon our current understanding of the disease. An improved understanding of basic mechanisms underlying the pathogenesis of rabies may provide insights for the future development of novel therapies [39]. (See "Clinical manifestations and diagnosis of rabies", section on 'Pathogenesis'.)

Supportive care in a critical care unit — Supportive care in a critical care unit is essential for an aggressive approach [40]. There are many potential complications of rabies, particularly cardiac and respiratory [41,42], that can best be addressed by a team of specialists with broad expertise.

It is very likely that supportive care in critical care units was the most important factor for all rabies survivors to date (table 1), including a 15-year-old girl in Wisconsin who did not receive rabies vaccine [19]. Her therapy, subsequently dubbed the "Milwaukee protocol," also included therapeutic coma with benzodiazepines and phenobarbital, ketamine, and antiviral therapy with ribavirin and amantadine; this approach has not proved to be efficacious beyond the provision of supportive care [43]. Studies comparing the use of aggressive supportive care alone with aggressive supportive care plus combination of therapies are needed.

Combination therapies — There are no data to support a specific approach to treatment for patients with rabies. However, similar to the therapeutic approach to certain cancers, human immunodeficiency virus (HIV) infection and chronic hepatitis C virus infection, the use of a combination of therapies may have the best chance of success in treating rabies [40]. This involves combining treatments in different therapeutic categories (eg, immunotherapy, antiviral therapy, and neuroprotective therapy) as described below.

Immunotherapies — Immunotherapy with either rabies vaccine or human rabies immune globulin is controversial [40]. However, all but one patient who survived rabies infection had received one or more doses of rabies vaccine before the onset of symptoms (none received a full course of a recommended post-exposure prophylaxis regimen) (table 1).

●Rabies vaccine – It is reasonable to administer rabies vaccine if the patient has not received a complete course of post-exposure prophylaxis (see "Rabies immune globulin and vaccine"). Viral clearance in rabies is associated with the development of an immune response, and an important hallmark of this response is the presence of neutralizing anti-rabies virus antibodies in the serum and cerebrospinal fluid [44].

However, it is unknown if it is advantageous to give rabies vaccine to a patient with rabies. Inactivated rabies vaccines do not elicit a cytotoxic T-cell response [45], and therefore their value for viral clearance may be limited. No live attenuated rabies vaccines are licensed for use in humans.

●Human rabies immune globulin (HRIG) – HRIG is not routinely administered to patients with rabies because immunoglobulins do not cross an intact blood-brain barrier, and therefore, it is unknown to what extent immunoglobulins would facilitate viral clearance [40]. In animal models of rabies, there is limited entry of immune effector cells across the blood-brain barrier [46]. In experimentally infected, symptomatic mice, intramuscular and intraventricular administration of human antirabies virus monoclonal antibodies have been associated with improved outcomes [47].

However, the use of HRIG in conjunction with a strategy to enhance drug delivery into the central nervous system (CNS) (eg, osmotic agents or ultrasound waves) [48,49] may be beneficial. The efficacy and safety of intrathecal administration of HRIG are unknown. (See 'Drug delivery into the central nervous system' below.)

Antiviral therapy — An aggressive treatment approach includes the use of one or more antiviral agents with the goal of reducing viral spread to uninfected cells [48]. Antiviral therapy is used despite the lack of evidence supporting the efficacy of any available agent. Since there are no data to suggest one agent over another, the approach to therapy is solely opinion based and is often influenced by which toxicities the provider and the patient (or the patient's family) are willing to accept.

Three agents (interferon-alfa, ribavirin, and amantadine) have been used in the treatment of adults with rabies. These agents have been associated with neuropsychiatric, hematologic, gastrointestinal, and/or autoimmune complications. A fourth drug, favipiravir, has failed to show efficacy in animal models of rabies and is not approved for human use in most countries outside of the research setting.

If interferon-alfa is used, it should be administered intrathecally (eg, with at least 300,000 international units/day) via a lumbar infusion or an intraventricular infusion (eg, with an Ommaya reservoir). CNS penetration may be limited with intravenous or intramuscular administration. Since there are concerns about CNS penetration of ribavirin, if used, it should also be administered intrathecally or with an agent to enhance CNS penetration, if possible. (See 'Drug delivery into the central nervous system' below.)

Studies of specific antiviral agents include the following:

●Interferon-alfa – Rabies virus triggers an immune response after entering the nervous system, which includes a type I interferon (interferon-alpha/beta) response that may help limit viral replication. Although early reports of combined intramuscular and intrathecal administration [50] and combined intravenous and intrathecal administration [51] did not show a beneficial effect on the progression of the clinical disease in humans with rabies, there is some antirabies virus activity of interferon in cell culture and animal models [48].

●Ribavirin – Ribavirin is a broad-spectrum antiviral agent that is a purine analogue and RNA mutagen. Ribavirin has in vitro activity against rabies virus infection but no demonstrated efficacy in mouse models [52,53]. Multiple attempts at therapy of human rabies with intravenous ribavirin, with or without intrathecal administration, were not successful [51,54,55]. Because ribavirin is known to shift the immune response toward a Th1-type inflammatory response [56], and because of the importance of a balanced Th1/Th2 immune response for the clearance of rabies virus infection, there are concerns that ribavirin could suppress antibody production essential for recovery from rabies [48].

●Amantadine – Amantadine is a synthetic antiviral agent that can inhibit in vitro replication of certain viruses, including rabies virus [57,58]. However, amantadine did not show efficacy when inoculated at daily intervals into the site of intramuscular inoculation of rabies virus in a mouse model [52]. Hence, there is little evidence to indicate that amantadine will be a useful therapeutic agent for the treatment of human rabies despite its inclusion in the Milwaukee protocol [19,43]. A more detailed discussion of the Milwaukee protocol is found elsewhere. (See 'Supportive care in a critical care unit' above and 'Therapies to avoid' below.)

●Favipiravir – Favipiravar (T-705) is a broad-spectrum viral RNA polymerase inhibitor that has been approved only in Japan to treat cases of influenza unresponsive to conventional therapy and has shown promise in in vitro and in vivo studies in a variety of viral infections [59]. Favipiravir activity against rabies virus has been shown in vitro and in mouse model studies for post-exposure rabies prophylaxis but not for the therapy of rabies [60,61]. In one report, therapy with favipiravir failed in six patients with rabies, including three adults and three children [62].

Neuroprotective therapies — Neuroprotective therapies produce benefits by favorably influencing the underlying etiology or pathogenesis and forestalling onset of disease or clinical decline [63]. The development of neuroprotective therapies for acute neurologic disorders remains in its infancy despite many published research studies.

There are no known effective neuroprotective agents for use in rabies. However, therapeutic (induced) brain hypothermia (targeted temperature management), administered with either a cooling helmet or intranasal cooling, could be considered as a potential adjunctive therapy for rabies in order to slow progression of the disease, reduce neuronal injury, and provide time for the development of an immune response [44]. Brain hypothermia is the only effective neuroprotective therapy demonstrated for acute brain injury in witnessed cardiac arrest [64,65] and is used in clinical practice for this indication, although some evidence suggests further studies should be done to confirm efficacy [66].

Early studies suggested that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine might be a promising neuroprotective therapy for rabies [67], but subsequent investigations performed in vitro and in a mouse model of rabies failed to show efficacy [68]. In addition, ketamine was used in the Milwaukee protocol, which, after the initial case report, was not found to be successful [43]. NMDA receptor antagonists have also been shown to lack efficacy in clinical trials of acute stroke and traumatic brain injury [69,70].

Therapeutic coma, which involves the administration of high-dose anesthetic agents in order to achieve maximal metabolic suppression and neuronal preservation, has also been used for neuroprotection. However, we suggest that therapeutic coma be avoided; the rationale for this is described below. (See 'Therapeutic coma' below.)

Therapies to avoid — We suggest that therapies such as corticosteroids, minocycline, therapeutic coma, and prophylaxis for cerebral vasospasm not be used for the treatment of rabies. The rationales are described below.

Two of these strategies, therapeutic coma and prophylaxis for cerebral vasospasm, are included in the Milwaukee protocol, an aggressive approach to treatment that also includes the use of ketamine and amantadine. This protocol was developed, at least in part, based upon a possible excitotoxic mechanism of neuronal injury in rabies virus infection. Although this protocol was used to treat one survivor in 2004 [14,19], it was found to be ineffective for the treatment of at least 61 subsequent cases [43,44,71]. In addition, there is a lack of supportive evidence for an excitotoxic mechanism of neuronal injury in rabies [68].

Corticosteroids — Corticosteroids should not be used in the treatment of rabies. Immune-mediated injury is not thought to play a significant role in the pathogenesis of rabies [39,45]. In addition, corticosteroids reduce entry of other agents into the brain and spinal cord [40]. In mouse models of rabies infection, they shorten the incubation period and increase mortality [72]. Corticosteroids may also have a negative effect on the immune response needed for viral clearance.

Minocycline — Minocycline has broad spectrum antimicrobial activity with anti-inflammatory, anti-apoptotic, and antioxidant properties [48]. However, the empiric use of minocycline is strongly discouraged because harmful effects were observed in rabies virus infection of neonatal mice [73] and also in a variety of animal models of neurodegenerative diseases [74].

Therapeutic coma — Therapeutic coma involves the administration of high-dose anesthetic agents in order to achieve maximal metabolic suppression and neuronal preservation; however, its use is not supported by a solid scientific rationale [43]. In addition, repeated use of therapeutic coma as part of the Milwaukee protocol has not been successful [43,44,71]. Given the potential adverse effects and complications of therapeutic coma (eg, vasopressor dependency, increased risk of infection, association with intensive care unit mortality and complications), this strategy should not be used for the management of rabies [43].

Prophylaxis of cerebral vasospasm — The prophylactic use of the calcium channel antagonist nimodipine, vitamin C, sapropterin supplementation, and L-arginine for cerebral vasospasm are not recommended [43]. Although there have been occasional reports of cerebral vasospasm using transcranial doppler ultrasound in rabies patients [75], the clinical relevance of these findings is uncertain since neuropathological reports do not support the occurrence of cerebral vasospasm in rabies [76]. In addition, it is unlikely that vasospasm plays an important role in the pathogenesis of rabies encephalitis. If cerebral vasospasm is present, it should be treated by raising the mean arterial pressure, similar to the way it would be managed in the setting of aneurysmal subarachnoid hemorrhage [77].

Drug delivery into the central nervous system — The blood-brain barrier, and the blood-spinal cord barrier [78], are important barriers that affect entry of therapeutic agents into the CNS and also the trafficking of cells into the CNS [79]. Various strategies have been taken to allow drugs to cross these barriers, including the use of a prodrug to improve entry into the CNS or by using nanoparticles, intranasal drug delivery, intraventricular administration, or disruption of the blood-brain barrier with either osmotic agents or ultrasound waves [48,49]. Development of blood-brain barrier permeability enhancers may in the future improve the entry of drugs and rabies virus-specific antibodies and immune cells into the CNS.

INFECTION PREVENTION — There are no documented cases of rabies virus infection being transmitted from a patient to a health care worker. However, given the theoretic risk, individuals caring for a patient with rabies should use strategies to reduce the risk transmission. Oral secretions are of particular concern because of the possibility that they may contain infectious rabies virus.

Prevention strategies include:

●Infection control precautions – Infection control precautions should be practiced by all visitors and health care workers caring for patients with suspected or confirmed rabies. Different institutions may vary in their approach, but at a minimum, consistent standard precautions should be utilized by family members and health care workers when caring for a patient with rabies to minimize the need for post-exposure prophylaxis [80-84]. As an example, health care workers should wear gowns, masks, gloves, and eye/face protection when there is risk of aerosols and splashes (eg, intubation and suctioning).

●Post-exposure prophylaxis – A percutaneous, mucous membrane, or nonintact skin exposure to a patient's body fluids (including salivary secretions) or tissues justify initiation of post-exposure rabies prophylaxis (wound cleansing and administration of rabies vaccine and rabies immune globulin). Such exposures typically occur before the diagnosis of rabies is considered.

More detailed discussions of infection control precautions and rabies post-exposure prophylaxis are presented elsewhere. (See "Infection prevention: Precautions for preventing transmission of infection" and "Indications for post-exposure rabies prophylaxis" and "Rabies immune globulin and vaccine".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rabies".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients or their family members. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Rabies (The Basics)")

●Beyond the Basics topic (see "Patient education: Rabies (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Importance of post-exposure prophylaxis – There is no known effective treatment for symptomatic rabies. However, the disease can be very effectively prevented after recognized exposures using recommended courses of post-exposure rabies prophylaxis. (See 'Introduction' above and "Indications for post-exposure rabies prophylaxis" and "Rabies immune globulin and vaccine", section on 'Post-exposure prophylaxis'.)

●Approach to management of symptomatic disease – When rabies is either strongly suspected or has already been confirmed with laboratory tests, a clinical decision needs to be made whether to embark on a palliative or aggressive management approach. Many factors should be considered in making this decision (table 2). (See 'Choosing a treatment approach' above.)

•Palliative therapy – Palliative therapy typically includes liberal administration of sedatives, major tranquilizers, and analgesics in a quiet environment. (See 'Palliative approach' above.)

•Aggressive therapy – An aggressive approach involves supportive care and a combination of experimental immunotherapy, antiviral, and neuroprotective treatments, although none of these therapies are proven to be effective. (See 'Aggressive approach' above.)

●Therapies to avoid – We suggest that certain therapies not be used for the treatment of rabies (Grade 2C). These include corticosteroids, minocycline, therapeutic coma, and the use of agents to prevent cerebral vasospasm. (See 'Aggressive approach' above.)

●Infection control – There are no documented cases of rabies virus infection being transmitted from a patient to a health care worker. However, given the potential risk, individuals caring for a patient with rabies should use consistent infection control precautions. In addition, they should receive post-exposure prophylaxis if there was a percutaneous, mucous membrane, or nonintact skin exposure to the patient’s body fluids or tissues. (See 'Infection prevention' above.)