**4. Treatment**

Although the rabies disease has been documented for thousands of years, it is still largely considered incurable after the onset of symptoms [34]. This is due to the small window of time during which aggressive treatment is practical and effective. With that knowledge, most often treatment resolves to be mostly palliative with aggressive treatment proving to be essentially ineffective after RABV is established in the patient.

#### **4.1 Aggressive approach**

If a patient presents for treatment early in the process of the clinical disease, the choice may be made to apply an aggressive approach. At this point, the patient must be immediately admitted to an intensive care hospital and post-exposure prophylaxis (PEP) should be administered [26]. PEP consists of immediate washing of the wound with soap and water, a post-exposure vaccination, and injection of an anti-rabies immunoglobulin (RIG) directly into the wound [35].

Active immunization has evolved greatly since the first rabies vaccine was developed and administered in 1885 [36, 37]. Louis Pasteur is credited with this first vaccine that consisted of injecting the patient with homogenates of RABV-infected rabbit spinal cord multiple times over a period of days. The initial injection was believed to be fully inactivated after an extended desiccation period, and each subsequent inoculation was increasingly more virulent as the desiccation period was decreased. While this was found to be somewhat effective, two major issues presented themselves. First, the inactivation of the RABV was inconsistent which led to some patients becoming infected after receiving the vaccine. Second, there was an inequity in the supply of the RABV-infected rabbits and the demand of the human population. These were rectified with the introduction of RABV-infected sheep and goat brain vaccines

[36, 37]. These new vaccines were inactivated via chemical agents such as phenol; this proved to be much more consistent. However, soon it was understood that vaccines produced from mature brain material contained an excess of myelin which caused sensitization and ultimately killed the patients [38]. From this discovery emerged the current methodology by which rabies vaccines are created. Chick embryos served the same role as the previous tissues, but they have markedly less myelin due to the young age [39]. The same can be said of the lines of human diploid cells infected with fixed RABV for vaccines [36, 37]. In the United States, there are two CDC-approved vaccines: the human diploid cell culture vaccine (HDCV) and the purified chick embryo cell culture vaccine (PCECV) [15].

The post-exposure vaccine is primarily an intramuscular vaccine that ought to be given on day 0, 3, 7, 14, and 30 [36]. An intradermal vaccine has recently been developed in an attempt to decrease the amount of vaccine needed per injection [40]. While the decreased cost of the vaccine is an attractive option, intradermal injections are generally considered more difficult which could decrease the effectiveness of the vaccine due to improper injections. The World Health Organization (WHO) strongly recommends purified cell culture and embryonated egg-based vaccines [41].

Although the vaccines have been proven to stimulate an appropriate immune response to RABV, this immune response is often too delayed to prevent the virus from entering the nerves [42]. With this knowledge, passive immunization is recommended for all patients that have no previous history with the disease or a preexposure vaccination. At this time, two types of rabies immunoglobulin are available – human rabies immunoglobulin (HRIG) and equine rabies immunoglobulin (ERIG). These have been used since the 1970's to temporarily increase the concentration of rabies virus neutralizing antibodies (RVNA) specifically at the site of exposure [43]. If the patient has multiple bites or wounds, the RIG needs to be applied at each site to be effective [44]. HRIG is to be administered at a dosage or 20 IU/kg while the recommended dosage for ERIG is 40 IU/kg [42, 44]. Due to higher odds of sensitization as well as quicker elimination of the RVNA, HRIG is generally the most preferred option for passive immunization. However, it is approximately five times more expensive than ERIG. This results in a major deficiency in many of the countries most in need of rabies treatment [44].

Because the available RIGs are generally inaccessible to developing countries, WHO encouraged researchers to pursue synthetization of a human monoclonal antibodies (mAbs) cocktail that can be used to treat rabies [45]. At this time, there are a number of rabies mAbs products in clinical trials, but none have been approved by the US Food and Drug Administration [46]. In 2018, WHO officially adjusted their recommendations for treatment of rabies to include mAbs products in place of RIG if available [46].

A protocol known as the Milwaukee Protocol was presented as a potential cure in the late 20th century, but it has since been proven to be inconsistent and generally ineffective in reverting or curing the patient of the disease [47–49]. This protocol consisted of an induced coma and one or more antivirals. The coma was soon determined to be ineffective. It is now recommended that sedation should be limited to prevent the use of ventilatory support if possible [48, 49].

Antivirals could serve an important role in the treatment of the rabies virus as they act as inhibitors of viral replication. An effective antiviral could slow the progression of the rabies virus enough for the patient's innate immune response to develop and react appropriately. However, at this time, there are few antivirals supported for the treatment of RABV. Ribavirin is a purine analogue that acts as an RNA mutagen and has shown to be clinically effective for multiple viruses including Hepatitis

#### *The Diagnosis, Clinical Course, Treatment, and Prevention of the Rabies Virus DOI: http://dx.doi.org/10.5772/intechopen.97691*

C and Lassa fever virus [50, 51]. Despite its inclusion in the sporadically effective Milwaukee Protocol, it has repeatedly proven to be ineffective against the rabies virus. Interferon-α (IFN-α) is a signaling protein used to trigger an immune response which has been shown to limit RABV spreading in mice trials [50, 51]. However, additional trials in which primates were administered intramuscular and intrathecal IFN-α determined the effects of immediate inoculation to be incomplete while the effects of delayed inoculation were nonexistent [52, 53]. Six human patients have been treated with IFN-α on two different dosage schedules and despite evidence of increased IFN in serum and CSF, there was no evidence of a beneficial effect on the disease itself [54]. Another therapy previously included in the Milwaukee Protocol is ketamine [50, 51]. At low concentrations, approximately 1 μM, ketamine works as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor which causes a state of dissociative anesthesia. A study from 1991 showed that a high concentration of ketamine could induce inhibitory effects on the RABV genome transcription [55]. Since that time, multiple other trials using neuron cultures and infected mice have produced evidence that ketamine is generally ineffective against the disease [56]. With that knowledge, it is believed that ketamine should not be used for treatment of the rabies virus until further studies produce more promising results. Amantadine is the third and final antiviral that was considered in the Milwaukee Protocol [47, 51]. It is a synthetic inhibitor of viral replication by impeding the release of viral genetic material into the host cell. Although amantadine demonstrated some interference in cellular trials, it failed in animal trials [57]. Minocycline, a broad spectrum antimicrobial, was considered for RABV treatment as it has proven benefits for multiple other viruses [58]. However, when applied to rabies-infected animals, Minocycline caused a number of harmful effects causing an increase in mortality [59].

More recently, researchers have addressed the use of favipiravir in treatment of rabies [50]. Available for influenza treatment in some countries, favipiravir has shown some activity against the rabies virus in mice trials [60]. Continued studies are needed to assess the future of this and other antivirals. It ought to be noted that despite variations in the effectiveness of these antivirals, all have shown that an early start of treatment greatly improves the efficacy of these therapies.

#### **4.2 Palliative care**

As previously mentioned, there is a small window of effectiveness for an aggressive treatment of RABV; after that window has passed, the focus of treatment is purely one of comfort for the patient. Many patients develop phobias that will likely require seclusion in a calm, quiet room. Although there is little to no evidence of human-to-human transmission, visitors and medical professionals need to be cautious of potential contamination via the patient's secretion [61]. Dehydration is a major concern as paralytic rabies often inhibits the patient's ability to swallow and furious rabies can cause intense hydrophobia. Treatment for the dehydration is typically a secured intravenous line. If additional nutrients are needed, they can be administered through the same line.

Rabies typically causes a generalized inflammation that induces a fever, but it can also trigger a neurogenic (central) fever as well [62]. Many antipyretics, such as acetaminophen and ibuprofen, have been successfully used to treat the generalized fever. However, those are generally ineffective towards the central fever. There is some evidence to support the use of baclofen, bromocriptine, chlorpromazine, and morphine in the treatment of a central fever [63]. However, these have not been studied

specifically for a rabies-induced central fever and so practitioners should be mindful of potential side effects. Additionally, these drugs are rarely available in the developing countries where RABV is most prevalent [61]. In this case, external, physical means of cooling the patient can be used as needed.

The majority of patients infected with furious RABV develop intense agitation and fear. A variety of sedatives and tranquilizers are used to calm these symptoms. Because benzodiazepines are included on the WHO's list of essential medicines, they are commonly used to treat rabies-induced agitation as well as many other forms [61]. They can be administered intramuscularly, intravenously, or intrarectally as needed. However, as previously mentioned, it is important to administer any sedative slowly to ensure the patient retains consciousness and does not lose respiratory function [64].

Lastly, clinicians will likely need to address the patient's pain level. This can be accomplished using opioids such as morphine or other highly effective analgesics. These can be delivered intravenously, intramuscularly, intrarectally, or even transdermally as needed [61]. Although many of these methods of treatment are expensive and generally unlikely to cure a patient once rabies symptoms are present, palliative care is a responsibility of caretakers and clinicians.
