Browse the corpus

CHAPTER 158: Rabies 1051 extremity. Arthus reactions occur most often in adults with high serum tetanus antitoxin levels who have received frequent doses of tetanus toxoid, which is the reason this therapy is limited to 10-year intervals. Contraindications to tetanus-diphtheria or Tdap include a history of serious allergic reaction (respiratory compromise or cardiovascular collapse) to vaccine components. History of encephalopathy (e.g., coma or prolonged seizures) not attributable to an identifiable cause within 7 days of administration of a pertussis vaccine is a contraindication to Tdap. Reasons to defer tetanus-diphtheria or Tdap include Guillain-Barré syndrome ≤6 weeks after a previous dose of tetanus toxoid-containing vaccine, moderate to severe acute illness, unstable neurologic condition, or history of an Arthus reaction to a tetanus toxoid–containing vaccine administered <10 years previously. 25 If tetanus toxoid is contraindicated, consider passive immunization with tetanus immunoglobulin. REFERENCES The complete reference list is available online at www.TintinalliEM.com. PATHOPHYSIOLOGY Rabies virus is the prototype member of the genus Lyssavirus .11,12 All lyssaviruses are adapted to replicate in the mammalian CNS, are transmitted by direct contact, and are not associated with transmission by or natural replication in insects. Viral infection of the salivary glands of the biting animal is respon sible for the infectivity of saliva. 5-7,13 After a bite, saliva containing infectious rabies virus is deposited in muscle and subcutaneous tissues. The virus remains close to the site of exposure for the majority of the long incubation period (typically 20 to 90 days). Rabies virus binds to the nicotinic acetylcholine receptor in muscle, which is expressed on the postsynaptic membrane of the neuromuscular junction. Subsequently, the virus spreads across the motor end plate and ascends and replicates along the peripheral nervous axoplasm to the dorsal root ganglia, the spinal cord, and the CNS. Following CNS replication in the gray matter, the virus spreads outward by peripheral nerves to virtually all tissues and organ systems. Histologically, rabies is an encephalitis, resulting in infiltration of lymphocytes, polymorphonuclear leukocytes, and plasma cells, and focal hemorrhage and demyelination in the gray matter of the CNS, the basal ganglia, and the spinal cord. Negri bodies, in which CNS viral replication occurs, are eosinophilic intracellular lesions found within cerebral neurons and are highly specific for rabies. Negri bodies are found in about 75% of proven cases of animal rabies. Although their presence is pathognomonic for rabies, their absence does not exclude it. Transmission of rabies virus usually begins when the contaminated saliva of an infected host is passed to a susceptible host, usually by the bite of a rabid animal. Of note, the bite of a bat may escape notice; human rabies cases with no known animal exposure are most commonly attributed to bats. 2 Other, less common routes of documented transmission include contamination of mucous membranes (i.e., eyes, nose, mouth), aerosol transmission during spelunking (caving) in bat-infested caves, exposure while working in the laboratory with rabies virus, and infected organ transplantation (e.g., cornea, liver, kidney, vascular graft, lung).

outes of documented transmission include contamination of mucous membranes (i.e., eyes, nose, mouth), aerosol transmission during spelunking (caving) in bat-infested caves, exposure while working in the laboratory with rabies virus, and infected organ transplantation (e.g., cornea, liver, kidney, vascular graft, lung). PREEXPOSURE PROPHYLAXIS Preexposure prophylaxis with rabies vaccine is highly recommended for persons whose recreational or occupational activities place them at risk for rabies (Tables 158-2 and 158-3). 14-16 Although the initial rabies preexposure vaccine regimen is similar for all risk groups, the need for booster doses, the timing of booster doses, and the need for and timing of serologic tests to confirm immunity differ based on the degree of individual risk for exposure to rabies. Preexposure prophylaxis may be obtained from the local health department or from a local physician or veterinarian. Preexposure vaccination does not eliminate the need for additional therapy after a rabies exposure but simplifies postexposure prophylaxis by eliminating the need for human rabies immunoglobulin (HRIG) and by decreasing the number of doses of vaccine required (see later section “Postexposure Prophylaxis in Special Populations”). Individuals receiving preexposure prophylaxis should be counseled regarding the continued need for postexposure prophylaxis following an exposure. POSTEXPOSURE PROPHYLAXIS  RISK ASSESSMENT The risk of developing rabies following a bite or scratch by a rabid animal depends on whether the wound was a bite, scratch, or nonbite exposure; the number of bites; the depth of the bites; and the location of the wounds (Table 158-4). Risk assessment for postexposure prophylaxis includes determin ing the epidemiology of animal rabies in the area where the contact occurred; knowing the species of animal involved; understanding the type of exposure (e.g., bite vs. nonbite); clarifying the circumstances of the exposure incident; and determining if the animal can be safely captured and tested for rabies (Table 158-5). 18 The distinction between a “provoked” and “nonprovoked” attack should not be used for risk CHAPTER Rabies Zachary I. Willis David J. Weber INTRODUCTION AND EPIDEMIOLOGY This chapter reviews the pathophysiology and epidemiology of rabies, pre- and postexposure rabies prophylaxis, and clinical presentation and treatment of rabies. Current information is available from the Centers for Disease Control and Prevention (http://www.cdc.gov/rabies/). More than 3 billion people are at risk of rabies in over 100 countries. Rabies is responsible for approximately 60,000 fatalities annually worldwide, with India accounting for approximately one third of cases.2,3 The World Health Organization estimates that more than 15 million people receive a postexposure preventive regimen annually. Rabies is primarily a disease of animals. 5-7 The epidemiology of human rabies reflects both the distribution of the disease in animals and the degree of human contact with these animals. A summary of major rabies vectors is provided in Table 158-1. In the United States, rabies is endemic in many wild animal popula tions, with more than 5500 rabid animals reported in 2015. 8 Although human rabies is rare in the United States, postexposure rabies pro phylaxis is provided to between 40,000 and 50,000 persons each year. 9 The cost of rabies prevention in the United States is greater than $300 million, most of which is spent on dog vaccinations. 10 From January 2003 to September 2016, 38 cases of human rabies were reported in the United States, of which 12 cases were contracted in other countries. Bats represent the most common exposure for human rabies cases in the United States.

States is greater than $300 million, most of which is spent on dog vaccinations. 10 From January 2003 to September 2016, 38 cases of human rabies were reported in the United States, of which 12 cases were contracted in other countries. Bats represent the most common exposure for human rabies cases in the United States. 8 Worldwide, greater than 99% of human rabies cases are acquired by dog bite.2 TABLE 158-1 Major World and U.S. Rabies Vectors Vector Region Dogs Asia, Latin America, Africa Foxes Europe, Arctic, North America Skunks Midwest United States, Western Canada Coyotes Asia, Africa, North America Mongooses Asia, Africa, Caribbean Bats North America, Latin America, Europe No rabies Hawaii, United Kingdom, Australasia, Antarctica Tintinalli_Sec13_p0997-1100.indd 1051 8/2/19 8:12 PM

America, Africa Foxes Europe, Arctic, North America Skunks Midwest United States, Western Canada Coyotes Asia, Africa, North America Mongooses Asia, Africa, Caribbean Bats North America, Latin America, Europe No rabies Hawaii, United Kingdom, Australasia, Antarctica Tintinalli_Sec13_p0997-1100.indd 1051 8/2/19 8:12 PM 1052 SECTION 13: Infectious Diseases assessment. Most animal bites are “provoked” from the standpoint of the animal (e.g., interfering with the animal’s food, offspring, feeding habits). In addition, approximately 15% of animals with rabies do not exhibit aggressive behavior but are apathetic (“dumb rabies”). The local health department can provide information about the epidemiology of animal rabies in the area. Evaluation for postexposure prophylaxis is indicated for persons bitten by, scratched by, or exposed to saliva from a wild or domestic animal that could be rabid ( Figure 158-1). Give postexposure prophylaxis as soon as possible after exposure to rabies-prone wildlife (Tables 158-5 and 158-6). Bites For the purpose of rabies postexposure prophylaxis, a bite exposure is defined as any penetration of the skin by the teeth of an animal. 14 Bites to the face and hands carry the highest risk, but the site of the bite does not influence the decision to begin therapy. Nonbite Exposures A nonbite exposure is contamination of scratches, abrasions, open wounds, or mucous membranes with saliva or brain tissue from a rabid animal. For example, animal licks to nonintact skin have transmitted rabies. Nonbite exposures from animals very rarely cause rabies. If the material containing the virus is dry, the virus can be considered noninfectious. Petting a rabid animal or contact with blood, urine, or feces (e.g., guano) of a rabid animal does not constitute an exposure and is not an indication for prophylaxis. Exposures to Animals Previously Vaccinated for Rabies A fully vaccinated dog or cat (i.e., two vaccinations) is unlikely to become infected with rabies. No documented vaccine failures have been reported TABLE 158-2 Rabies Preexposure Risk Assessment and Recommendations Risk Category Nature of Risk Typical Population Preexposure Recommendations Continuous Virus present continuously, often in high concentrations; specific exposures likely to go unrecognized; bite, nonbite, or aerosol exposure Rabies research laboratory workers, * rabies biologicals production workers Primary course: serologic testing every 6 months; booster immunization if antibody titer is below acceptable level † Frequent Exposure usually episodic with source recognized, but exposure also might be unrecognized; bite, nonbite, or aerosol exposure Rabies diagnostic laboratory workers, * cavers, veterinarians and staff, and animal-control and wildlife workers in rabies-endemic areas; all persons who regularly handle bats Primary course: serologic testing every 2 years; booster immunization if antibody titer is below acceptable level † Infrequent (greater than population at large) Exposure nearly always episodic with source recognized; bite or nonbite exposure Veterinarians and animal-control and wildlife workers working with terrestrial animals in areas where rabies is uncommon or rare, veterinary students, travelers visiting areas where rabies is endemic and immediate access to appropriate medical care, including biologicals, is limited Primary course: no serologic testing or booster immunization Rare (population at large) Exposure always episodic with source recognized; bite or nonbite exposure U.S. population at large, including persons in rabies-endemic areas No immunization necessary *Judgment of relative risk and extra monitoring of immunization status of laboratory workers is the responsibility of the laboratory supervisor.

large) Exposure always episodic with source recognized; bite or nonbite exposure U.S. population at large, including persons in rabies-endemic areas No immunization necessary *Judgment of relative risk and extra monitoring of immunization status of laboratory workers is the responsibility of the laboratory supervisor. †Minimum acceptable antibody level is complete virus neutralization at 1:5 serum dilution by the rapid fluorescent focus inhibition test. A booster dose should be administered if the titer falls below this level. TABLE 158-3 Rabies Preexposure Prophylaxis Schedule—United States (2008) Type of Immunization Route Regimen Primary Intramuscular * HDCV or PCECV; 1.0 mL (deltoid area), one dose on days 0, † 7, and 21 or 28 Booster‡ Intramuscular* HDCV or PCECV; 1.0 mL (deltoid area), one dose on day 0 † only Abbreviations: HDCV = human diploid cell vaccine; PCECV = purified chick embryo cell culture vaccine. *Use deltoid area for adults and older children. For young children, use anterolateral thigh. Do not administer vaccine in the gluteal area. †Day 0 is the day the first dose of vaccine is administered. ‡Persons in the continuous risk category should have a serum sample tested for rabies neutralizing anti body every 6 months, and persons in the frequent risk category should be tested every 2 years. An IM booster dose of vaccine should be administered if the serum titer falls to maintain the value of at least complete neutralization at a 1:5 serum dilution by rapid fluorescent focus inhibition test. See recom mendations by the Centers for Disease Control and Prevention 14 for more details. TABLE 158-4 Risk of Rabies in the Absence of Postexposure Prophylaxis After Exposure to a Rabid Animal •  Multiple  severe bites around the face: 80%–100% •  Single  bite: 15%–40% •  Superficial  bite(s) on an extremity: 5% •  Contamination  of a recent wound by saliva: ~0.1% •  Contact  with rabid saliva on a wound older than 24 hours: 0% •  Transmission  via fomites (e.g., tree branch): theoretical* •  Indirect  transmission (e.g., raccoon saliva on a dog): theoretical* *Literature review revealed no cases due to this theoretical method of transmission. TABLE 158-5 Rabies Postexposure Risk Assessment and Recommendations (2012)18 Animal Type Evaluation and Disposition of Animal Postexposure Prophylaxis Recommendations Dogs, cats, and ferrets Healthy and available for 10 d of observations

iterature review revealed no cases due to this theoretical method of transmission. TABLE 158-5 Rabies Postexposure Risk Assessment and Recommendations (2012)18 Animal Type Evaluation and Disposition of Animal Postexposure Prophylaxis Recommendations Dogs, cats, and ferrets Healthy and available for 10 d of observations Rabid or suspected rabid Unknown (e.g., escaped) Persons should not begin vaccination unless animal develops clinical signs of rabies. * Immediate immunization. Consult public health officials. Skunks, raccoons, foxes, and most other carnivores; bats † Regard as rabid unless animal proven negative for rabies virus by laboratory tests ‡ Consider immediate immunization. Livestock, horses, rodents, rabbits and hares, and other mammals Consider individually Consult public health officials; bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks, mice, rats, rabbits, hares, and other small rodents almost never require rabies postexposure prophylaxis. *During the 10-day observation period, begin postexposure prophylaxis at the first sign of rabies in a dog, cat, or ferret that has bitten someone. If the animal exhibits clinical signs of rabies, it should be euthanized immediately and tested. †Provide postexposure prophylaxis immediately. ‡The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. Tintinalli_Sec13_p0997-1100.indd 1052 8/2/19 8:12 PM

itten someone. If the animal exhibits clinical signs of rabies, it should be euthanized immediately and tested. †Provide postexposure prophylaxis immediately. ‡The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. Tintinalli_Sec13_p0997-1100.indd 1052 8/2/19 8:12 PM CHAPTER 158: Rabies 1053 in the United States among dogs or cats that received two vaccinations. Rare cases have been reported among animals that had received only a single dose of vaccine. In the United States, animals other than dogs, cats, and ferrets that can transmit rabies and are the source of an animal bite or scratch to a human should be euthanized and tested for rabies even if the animals have been vaccinated. Exposures to Bats Any direct contact between a human and a bat should be evaluated for a rabies exposure. Seeing a bat does not con stitute an exposure. Postexposure prophylaxis is not indicated if the person can be certain that a bite, scratch, or mucous membrane exposure did not occur or if the bat is available for testing and results are nega tive for the presence of rabies virus. All bats that might be a source of exposure, if available, should be sent to the public health department and tested for rabies, because approximately 94% of submitted bats in the United States have tested negative for rabies. 19 The Advisory Committee on Immunization Practices recommends consideration of postexposure prophylaxis for persons who were in the same room as a bat and who were unaware if a bite or direct contact had occurred (e.g., a sleeping person awakens to find a bat in the room, or an adult witnesses a bat in a room with an unattended child, mentally disabled person, or intoxicated person). 14,18 One article calculated the incidence of rabies following bedroom exposure with contact as 0.6 cases per bil lion person-years,19 whereas another article reported that the number needed to treat to prevent a single case of rabies in this context would be 314,000 to 2.7 million persons. TABLE 158-6 Summary of Risk of Acquiring Rabies in the United States Risk Exposures Moderate to high Bite by skunk, raccoon, fox, and other wild carnivores (unless animal tested negative for rabies) Bite or direct contact with bat (unless animal tested negative for rabies) Exposure by percutaneous injury, mucous membrane exposure, or inhalation to live rabies virus in a laboratory Dog bite in a country with endemic rabies and inadequate immunization of dogs (or bite by feral dog) Very low to low Bite by inadequately vaccinated cat or dog that has access to the outdoors (or feral cat or dog) Contamination of open wound or abrasion (including scratches) with, or mucous membrane exposure to, saliva or other poten tially infectious material (e.g., neural tissue) from a possibly rabid animal (skunk, raccoon, fox, and other wild carnivores, bat) Awakening in a room with a bat present No risk identified Contact of animal fluids (e.g., saliva, blood, neural tissue) with intact skin Indirect contact with saliva from a wild animal (e.g., by cleaning a dog or cat that has had contact with a wild animal) 1. Lab accident with known rabies virus exposure to wound/mucous membrane 2. Significant inhalational exposure Collect information: Animal species? Salivary exposure to wound/mucous membrane? Animal available for observation? 1. Bird, reptile, rodent (hamster, squirrel, guinea pig, gerbil, mouse, rat, rabbit) 2.

nimal) 1. Lab accident with known rabies virus exposure to wound/mucous membrane 2. Significant inhalational exposure Collect information: Animal species? Salivary exposure to wound/mucous membrane? Animal available for observation? 1. Bird, reptile, rodent (hamster, squirrel, guinea pig, gerbil, mouse, rat, rabbit) 2. Nonsalivary exposure Prophylaxis not needed unless unusual circumstances exist † Carnivore, livestock (livestock are not carnivores) or bat* with bite or salivary exposure Dog, cat, or ferret Animal escaped Vaccine + HRIG Vaccine + HRIG Escaped Captured and quarantined Strange behavior at capture or subsequently under observation Normal behavior for 10 days Animal released; prophylaxis not needed Epidemiologic rabies exists for species in geographic area or inadequate data Prophylaxis not needed Vaccine + HRIG Sacrifice animal, refrigerate, and send to qualified lab; examine brain (Negri bodies and FAT); initiate vaccine + HRIG pending results of examination Complete course vaccine + HRIG Discontinue vaccine; prophylaxis not needed Epidemiologic absence of rabies risk in species and in geographic area Captured and quarantined Other carnivore (skunk, raccoon, bobcat, coyote, fox); livestock (cow, horse); or bat Animal rabid Animal not rabid FIGURE 158-1. Clinical guidelines for administration of postexposure prophylaxis. (*) Consider postexposure prophylaxis for persons who were in the same room as a bat and who might be unaware that a bite or direct contact had occurred. (†) The small mammals listed here have never been reported to transmit rabies to humans in the United States, but theoretically, such animals could acquire and transmit rabies. Therefore, postexposure prophylaxis following a bite or scratch from one of these mammals would be indicated only if such an animal had signs typical of rabies or a positive laboratory test for rabies. Consult with local public health officials for reports of rabies in atypical animals. FAT = fluorescent antibody testing; HRIG = human rabies immune globulin. Tintinalli_Sec13_p0997-1100.indd 1053 8/2/19 8:12 PM

ld be indicated only if such an animal had signs typical of rabies or a positive laboratory test for rabies. Consult with local public health officials for reports of rabies in atypical animals. FAT = fluorescent antibody testing; HRIG = human rabies immune globulin. Tintinalli_Sec13_p0997-1100.indd 1053 8/2/19 8:12 PM 1054 SECTION 13: Infectious Diseases Bites From Healthy-Appearing Animals The Centers for Disease Control and Prevention recommends that a healthy dog, cat, or ferret that bites a person be confined and observed for 10 days. 14,18 At the first sign of illness during confinement, such animals should be evaluated by a veterinarian and a report immediately made to the local health department. If signs suggestive of rabies develop, the animal should be euthanized and its head removed and shipped under refrigeration (not frozen) for examination of the brain by a qualified laboratory designated by the local or state health department. Bites From Stray Animals Any stray or unwanted dog, cat, or ferret that bites a person may be euthanized immediately and the head submitted for rabies examination. Animals that might have exposed a person to rabies should be reported immediately to the local health department. An animal other than a dog, cat, or ferret that received prior vac cination may still require euthanasia and testing if the period of virus shedding is unknown for that species. Person-to-Person Transmission There are anecdotal reports of person-to-person transmission of rabies. Fluids from the upper and lower respiratory tracts of humans frequently test positive for rabies virus. Despite the lack of proven healthcare-associated transmission, about 30% of healthcare personnel who have had contact with a human diagnosed with rabies have received postexposure prophylaxis. Given the mechanism of disease transmission and concern among healthcare workers, contact isolation precautions should be used for patients with known or suspected rabies, and healthcare workers who care for such patients should wear either masks and eye protection or face shields. Healthcare personnel with nonintact skin or mucous membrane exposure to infective saliva or neural tissue from patients with rabies should receive postexposure prophylaxis. Patients Concerned About Rabies For unusual exposures, the state veterinarian or local public health agency can be contacted for more information. However, for patients who voice concern about rabies exposure even if the risk assessment is virtually nil (Table 158-6), vaccination can be offered, along with an explanation of the risks and benefits of vaccination. If the risk of rabies is virtually nil, we discourage the administration of HRIG.  WOUND CARE First, assess wounds for the presence of a life-threatening condition, such as arterial laceration or pneumothorax. 21 Provide proper wound care, including tetanus prophylaxis, wound cleansing with soap and water and (if available) a dilute solution of povidone-iodine (1 mL povidone-iodine in 9 mL of water or normal saline), antibiotics (if indicated) to prevent bacterial infection (see Chapter 46, “Puncture Wounds and Bites”), and rabies prophylaxis as indicated.  POSTEXPOSURE PROPHYLAXIS TREATMENT In the United States, postexposure prophylaxis consists of a regimen of one dose of HRIG and four doses of rabies vaccine over a 14-day period, except for immunocompromised persons , who should receive a fivedose series of vaccine over a 28-day period ( Table 158-7). 15,18 The shift from a five-dose to a four-dose series of rabies vaccine occurred in 2010 and is based on rabies virus pathogenesis, experimental animal studies, clinical trials, epidemiologic surveillance, and economic analyses.

ons , who should receive a fivedose series of vaccine over a 28-day period ( Table 158-7). 15,18 The shift from a five-dose to a four-dose series of rabies vaccine occurred in 2010 and is based on rabies virus pathogenesis, experimental animal studies, clinical trials, epidemiologic surveillance, and economic analyses. 15 No other aspects of postexposure prophylaxis were altered from the 2008 recommendations (e.g., use of HRIG, site of injection). HRIG and the first dose of rabies vaccine should be given as soon as possible after exposure, preferably within 24 hours. If HRIG was not administered when vaccination was begun, it can be administered up to 7 days after administration of the first dose of the vaccine. Follow the Centers for Disease Control and Prevention recommendations for postexposure prophylaxis exactly (Table 158-7). Note that rabies vaccine should never be administered in the gluteal area; only the deltoid or anterolateral thigh (for younger children) is acceptable. Although no postexposure prophylaxis vaccine failures have been reported in the United States since the licensing of human diploid cell vaccine in 1980, several persons outside the United States have contracted rabies after postexposure prophylaxis with tissue culture–derived vaccine. 5 Most of these cases involved deviation from the recommended protocol; wounds were not cleansed, passive immunization with HRIG was not provided, or rabies vaccine was injected into the gluteal rather than the deltoid area. A small number of failures of apparently properly administered postexposure prophylaxis have been reported; however, such cases are rare and factors such as use of HRIG of inadequate potency cannot be definitively ruled out. 22 Nonetheless in the context of the worldwide burden of human rabies exposure, the efficacy of timely, properly administered postexposure prophylaxis is very nearly 100%. Rabies Vaccines Rabies vaccines available in the United States include human diploid cell vaccine (produced in human diploid cells; Imovax®, Sanofi Pasteur, Lyon, France) and purified chick embryo cell culture vaccine (produced in chick embryo cells; RabAvert®, Novartis Vaccines, Emeryville, CA). The active antibody response requires approximately 7 to 10 days to develop, and detectable rabies virus–neutralizing antibodies generally persist for several years. All currently used vaccines are produced in cell cultures and are significantly less toxic than older vaccines that were produced in neural tissue. Side effects of human diploid cell vaccine, including mild erythema, swelling, and pain at the injection site, have been reported in 10% to 90% of vaccine recipients. Systemic reactions, such as headache, nausea, abdominal pain, muscle aches, and dizziness, have been reported in 5% to 40% of recipients. Serum sickness–like reactions (type III hypersensitivity) have been TABLE 158-7 Rabies Postexposure Prophylaxis Schedule—United States, 2010 Immunization Status Treatment Regimen* Not previously immunized Wound cleansing HRIG

a, abdominal pain, muscle aches, and dizziness, have been reported in 5% to 40% of recipients. Serum sickness–like reactions (type III hypersensitivity) have been TABLE 158-7 Rabies Postexposure Prophylaxis Schedule—United States, 2010 Immunization Status Treatment Regimen* Not previously immunized Wound cleansing HRIG Vaccine Cleanse all wounds with soap and water; irrigate wounds with 9:1 diluted solution of povidone-iodine (if available). Administer 20 IU/kg actual body weight. If anatomically feasible, infiltrate the full dose around the wound(s) and give any remaining volume IM at an anatomic site distant from vaccine administration; do not give HRIG in the same syringe as vaccine. HRIG may partially suppress active production of rabies virus antibody, so do not give more than the recommended dose . HDCV or PCECV 1.0 mL (deltoid area †), one dose on days 0,‡ 3, 7, and 14.# Previously immunizedf Wound cleansing HRIG Vaccine Cleanse all wounds with soap and water; irrigate wounds with 9:1 povidone-iodine solution. HRIG should not be administered. HDCV or PCECV 1.0 mL (deltoid area †), one dose on days 0‡ and 3. Abbreviations: HDCV = human diploid cell vaccine; HRIG = human rabies immunoglobulin; PCECV = purified chick embryo cell culture vaccine. *These regimens are appropriate for all age groups, including children. †The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh (anterolateral aspect) may be used. Vaccine should never be administered in the gluteal area. ‡Day 0 is the day the first dose of vaccine is administered. #Day 28 vaccine dose no longer recommended by the Advisory Committee on Immunization Practices, unless the patient is immunocompromised (see later section, Immunocompromised Persons). See http://www .cdc.gov/rabies/resources/acip_recommendations.html. fAny persons with a history of preexposure prophylaxis with HDCV or PCECV; prior postexposure prophylaxis with HDCV or PCECV; or previous immunization with any other type of rabies vaccine and a documented history of antibody response to the prior immunization. Tintinalli_Sec13_p0997-1100.indd 1054 8/2/19 8:12 PM

html. fAny persons with a history of preexposure prophylaxis with HDCV or PCECV; prior postexposure prophylaxis with HDCV or PCECV; or previous immunization with any other type of rabies vaccine and a documented history of antibody response to the prior immunization. Tintinalli_Sec13_p0997-1100.indd 1054 8/2/19 8:12 PM CHAPTER 158: Rabies 1055 noted in approximately 6% of persons receiving booster doses of human diploid cell vaccine and occur 2 to 21 days after administration of the booster dose. Such reactions have not been life threatening and have not been reported with purified chick embryo cell culture vaccine. Anaphylaxis and neurologic symptoms have only rarely been associated with the current rabies vaccines. Severe egg allergy is a contraindication to the use of purified chick embryo cell culture vaccine. Rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine. 21 Usually such reactions can be successfully managed with anti-inflammatory and antipyretic agents. When a person with a history of serious hypersen sitivity to rabies vaccine must be revaccinated, antihistamines may be given. Epinephrine should be readily available to counteract anaphylactic reactions, and the person should be observed carefully immediately after vaccination (as after any other injection given in a healthcare setting). Human Rabies Immunoglobulin HRIG is administered only once, at the beginning of antirabies prophylaxis, to provide immediate antibodies until the patient responds to rabies vaccine by producing antibodies. A passive antibody titer is evident in 24 hours. Failure to administer HRIG has led to rabies despite appropriate postexposure prophylaxis with human diploid cell vaccine. If HRIG was not given when vaccination was begun, it can be given through the seventh day after administration of the vac cine. 15 Beyond the seventh day after vaccination is begun, HRIG is not indicated, because an antibody response is presumed to have occurred. The Centers for Disease Control and Prevention recommends that as much as possible of the full dose be infiltrated around the wound. HRIG should never be administered in the same syringe or into the same anatomic site as the vaccine, as the antibody and vaccine will neutralize each other. Even if the wound has to be sutured, it should be infiltrated locally with HRIG. This practice is safe and does not create an additional risk of infection. However, caution is needed when injecting into a tissue compartment, such as the finger pulp, because excessive HRIG can increase compartment pressure and lead to necrosis. 23 Any remaining HRIG that cannot be administered into the local wound area should be injected intramuscularly at a site distant from vaccine administration. HRIG is prepared from plasma of hyperimmunized donors and screened for known viruses (e.g., human immunodeficiency virus, hepatitis). No cases of virus transmission from HRIG that is commercially available in the United States or Australia have been reported. HRIG should not be given to those with immunoglobulin A deficiencies and known antibodies of immunoglobulin A, because small amounts of immunoglobulin A may be present in HRIG and can cause a severe allergic reaction. WORLD HEALTH ORGANIZATION POSTEXPOSURE PROPHYLAXIS GUIDELINES In the United States, only regimens recommended by the Advisory Committee on Immunization Practices should be used. The World Health Organization has provided recommendations for rabies postex posure prophylaxis that also consider the cost and availability of vaccines and HRIG.

ATION POSTEXPOSURE PROPHYLAXIS GUIDELINES In the United States, only regimens recommended by the Advisory Committee on Immunization Practices should be used. The World Health Organization has provided recommendations for rabies postex posure prophylaxis that also consider the cost and availability of vaccines and HRIG. 24,25 Per the World Health Organization, the indication for postexposure prophylaxis depends on the contact with the suspected rabid animal: • Category I: touching or feeding animals, licks on intact skin (i.e., no exposure) • Category II: nibbling of uncovered skin, minor scratches or abrasions without bleeding • Category III: single or multiple transdermal bites or scratches, con tamination of mucous membrane with saliva from licks, licks on broken skin, exposure to bats For category I exposures, no prophylaxis is required. For category II, immediate vaccination is recommended. For category III, immediate vaccination and administration of rabies immunoglobulin are recom mended. Per the World Health Organization, factors that should be taken into consideration when deciding whether to initiate postexpo sure prophylaxis include the epidemiologic likelihood of the implicated animal being rabid, the category of exposure (i.e., I, II, or III), and the clinical features of the animal, as well as its availability for observation and laboratory testing. In most situations in developing countries, the vaccination status of the implicated animal alone should not be consid ered when deciding whether to give or withhold prophylaxis. For IM administration, the World Health Organization recommends the following postexposure regimens. The postexposure vaccination schedule is based on injecting 1 mL or 0.5 mL (volume depends on the type of vaccine) into the deltoid muscle (or anterolateral thigh in children <1 year of age) of patients with category II and III exposures. Rabies vaccine should never be injected in the gluteal area. The recom mended regimen consists of either a five- or a four-dose schedule: • The five-dose schedule consists of one dose on each of days 0, 3, 7, 14, and 28. • The four-dose schedule consists of two doses on day 0 (one dose in each of the two deltoid or thigh sites) followed by one dose on each of days 7 and 21. An alternative for healthy, fully immunocompetent, exposed persons who receive wound care plus high-quality rabies immunoglobulin plus World Health Organization–prequalified rabies vaccines is a postexpo sure regimen consisting of four doses administered IM on days 0, 3, 7, and 14 (consistent with current U.S. recommendations). Intradermal administration requires a smaller dose and is used to reduce the cost of vaccine in some countries. However, intradermal administration is technically more demanding and requires appropri ate staff training. For intradermal administration, the World Health Organization recommends the following postexposure regimen: The two-site regimen prescribes injection of 0.1 mL at two sites (deltoid and thigh) on days 0, 3, 7, and 28. This regimen may be used for people with category II and III exposures in countries where the intradermal route has been endorsed by national health authorities.  POSTEXPOSURE PROPHYLAXIS IN SPECIAL POPULATIONS Persons With Prior Rabies Immunization If exposed to rabies, persons previously vaccinated should receive two intramuscular doses (1 mL each) of vaccine, one immediately and one 3 days later.15,18 “Previously vaccinated” refers to persons who have received one of the recommended preexposure or postexposure prophylaxis regimens of human diploid cell vaccine or purified chick embryo cell culture vaccine, or those who have received another vaccine and had a documented acceptable rabies antibody titer.

s later.15,18 “Previously vaccinated” refers to persons who have received one of the recommended preexposure or postexposure prophylaxis regimens of human diploid cell vaccine or purified chick embryo cell culture vaccine, or those who have received another vaccine and had a documented acceptable rabies antibody titer. HRIG is unnecessary and should not be given in these cases, because an anamnestic antibody response will follow the administration of a booster regardless of the prebooster antibody titer. Immunocompromised Persons Immunization of immunocompro mised persons presents special challenges. First, vaccines may represent a danger to the immunocompromised individual. Second, the immune response to vaccination may be insufficient. Higher doses or additional immunizations may be required, and even with these modifications, the immune response may be suboptimal. The severely immunocompromised are those who have congenital immunodeficiency, human immunodeficiency virus infection, leukemia or lymphoma, aplastic anemia, or generalized malignancy, or who are being treated with alkylating agents, antimetabolites, radiation, or large amounts of corticosteroids. Because rabies vaccine is formulated with inactivated virus, it does not represent a danger to immunocompromised persons and may be administered to such persons using the standard recommended doses and schedule ( Table 158-7). However, a five-dose schedule should be used in immunocompromised persons. The recommendations for the use of HRIG are the same for immunocompromised and immunocompetent persons. However, corticosteroids, antimalarials, other immunosuppressive agents, and immunosuppres sive illnesses can interfere with the development of active immunity and predispose the patient to developing rabies. Immunosuppressive agents should not be administered during postexposure prophylaxis, unless they are essential for the treatment of other conditions. When rabies postexposure prophylaxis is administered to persons receiving steroids or other immunosuppressive therapy, it is especially important that serum be tested for rabies antibody to ensure that an adequate response has developed. 14 To confirm the adequacy of the immune response, serum collected 1 to 24 weeks after the postexposure prophylaxis course Tintinalli_Sec13_p0997-1100.indd 1055 8/2/19 8:12 PM

mmunosuppressive therapy, it is especially important that serum be tested for rabies antibody to ensure that an adequate response has developed. 14 To confirm the adequacy of the immune response, serum collected 1 to 24 weeks after the postexposure prophylaxis course Tintinalli_Sec13_p0997-1100.indd 1055 8/2/19 8:12 PM 1056 SECTION 13: Infectious Diseases should completely neutralize challenge virus at a 1:5 serum dilution, as measured by a rapid fluorescent focus inhibition test. 14 If no acceptable antibody response is detected, consult an infectious disease expert and appropriate public health officials. Travelers Preexposure prophylaxis is recommended for certain inter national travelers based on the local incidence of rabies in the countries to be visited, the availability of appropriate antirabies biologicals, and the intended travel activity. 26,27 Such persons include veterinarians, animal handlers, field biologists, spelunkers, missionaries, and certain laboratory workers. It is recommended to consult the CDC Y ellow Book (https://wwwnc.cdc.gov/travel/page/yellowbook-home) prior to travel for updated guidance. Chloroquine phosphate (and possibly other structurally related antimalarials such as mefloquine, which is adminis tered for malaria chemoprophylaxis) may interfere with the antibody response to intradermal rabies vaccine administered for preexposure prophylaxis. The IM route, not the intradermal route, should be used for people taking chloroquine concurrently (the intradermal route is not approved for use in the United States); ideally, the rabies preexposure vaccination series should be completed before beginning chloroquine. Between 2003 and September 2016, nine persons died in the United States from rabies after having been exposed (most often via dog bite) while visiting a foreign country. 8 For this reason, all persons who have returned from abroad should be questioned regarding whether they received an animal bite or scratch in an area with endemic rabies. Per sons bitten or scratched by an animal in an area with endemic rabies should receive appropriate postexposure prophylaxis if the injury has occurred within the known incubation period (which may rarely extend up to 5 or more years). U.S. citizens and residents who are exposed to rabies while traveling in countries where rabies is endemic may sometimes receive postexposure prophylaxis with regimens or biologicals that are not used in the United States. If postexposure prophylaxis is begun outside the United States using a regimen or biological of nerve tissue origin not approved by the U.S. Food and Drug Administration, it may be necessary to pro vide additional treatment when the patient reaches the United States. State and local health departments should be contacted for specific advice in such cases. The major modification used abroad, usually in an attempt to reduce cost, is the substitution of various schedules for intradermal injection or the use of vaccines not approved by the U.S. Food and Drug Administration. Pregnant Women Adverse pregnancy outcomes or fetal abnormalities have not been associated with rabies vaccination. Because of the potential consequences of inadequately treated rabies exposure and because adverse events have not been associated with rabies postex posure prophylaxis during pregnancy, pregnancy is not considered a contraindication to rabies postexposure prophylaxis or HRIG. 14 If there is substantial risk of exposure to rabies, preexposure prophylaxis may also be indicated during pregnancy. Children The dose of rabies vaccine for preexposure and postex posure prophylaxis is the same in infants and children as in adults (Table 158-7). 14 The dose of HRIG for postexposure prophylaxis is based on actual body weight.

l risk of exposure to rabies, preexposure prophylaxis may also be indicated during pregnancy. Children The dose of rabies vaccine for preexposure and postex posure prophylaxis is the same in infants and children as in adults (Table 158-7). 14 The dose of HRIG for postexposure prophylaxis is based on actual body weight. For small children with multiple bites, the calculated dose of HRIG may be insufficient to infiltrate all wounds. However, sterile saline can be used to dilute the volume twofold or threefold to permit thorough infiltration. CLINICAL RABIES Rabies virus causes acute encephalitis in all warm-blooded hosts, including humans, and the outcome is almost always fatal. Although patients with rabies may manifest a variety of clinical symptoms and signs, the disease tends to follow a characteristic course ( Table 158-8). Most commonly, the incubation period after a bite ranges from 20 to 90 days. 5 However, incubation periods have been reported that are as short as 4 days and as long as 6 years. For patients who died from rabies in the United States between 1980 and 1996 and in whom a definite animal bite occurred, the median incubation period was 85 days (range, 53 to 150 days). 28 The incubation period is shorter when the site of the bite is on the head than when it is on an extremity.5  CLINICAL FEATURES During the prodrome, the symptoms and signs are nonspecific. Early in the course, some patients may report symptoms suggestive of rabies such as limb pain, limb weakness, and paresthesias at or near the pre sumed exposure site. The prodrome merges into the acute neurologic phase, which begins when the patient develops objective signs of CNS disease. There are two clinical forms of rabies: an encephalitic form in 80% and a paralytic form in 20%. 13 In encephalitic rabies, there are often episodes of generalized arousal or hyperexcitability, disorientation, hallucinations, and bizarre behavior, often separated by lucid inter vals. Autonomic dysfunction is common and includes hypersalivation, hyperthermia, tachycardia, hypertension, piloerection, cardiac arrhyth mias, and priapism. Paralytic rabies generally begins with paresis in the bitten extremity with spread to quadriparesis and bilateral facial weak ness. There is progression of paralytic rabies to coma and organ failure, typically with a longer clinical course than in encephalitic rabies. 13 About 50% of patients have classic hydrophobia, in which attempts to drink fluids result in severe spasms of the pharynx, larynx, and diaphragm. Coma almost always occurs within 10 days of the onset of symptoms. Death occurs due to a variety of complications, including pituitary dysfunction, seizures, respiratory dysfunction with progressive hypoxia, cardiac dysfunction with dysrhythmias and arrest, autonomic dysfunction, renal failure, and secondary bacterial infections. Only 14 patients are known to have survived rabies; most survivors have had severe neurologic sequelae. In all but three cases, the patient had received postexposure prophylaxis with rabies vaccine (e.g., duck embryo, suckling mouse brain) before the onset of symptoms.  DIAGNOSIS AND TREATMENT Rabies should be included in the differential diagnosis of any patient with unexplained acute, rapidly progressive encephalitis, especially in the presence of anatomic instability, dysphagia, hydrophobia, paresis, or parasthesias.

uck embryo, suckling mouse brain) before the onset of symptoms.  DIAGNOSIS AND TREATMENT Rabies should be included in the differential diagnosis of any patient with unexplained acute, rapidly progressive encephalitis, especially in the presence of anatomic instability, dysphagia, hydrophobia, paresis, or parasthesias. 29-32 Diseases that may be confused with rabies include tetanus, poliomyelitis, Guillain-Barré syndrome, botulism, transverse myelitis, postvaccinal encephalomyelitis, intracranial mass lesions, TABLE 158-8 Natural History of Clinical Rabies in Humans After Incubation Period Clinical Stage Defining Event Usual Duration Common Symptoms and Signs * Prodrome First symptom 2–10 d Pain or paresthesia at site of bite Malaise, lethargy Headache Fever Nausea, vomiting, anorexia Anxiety, agitation, depression Acute neurologic phase First neurologic sign 2–7 d Anxiety, agitation, depression Hyperventilation, hypoxia Aphasia, incoordination Paresis, paralysis Hydrophobia, pharyngeal spasms Confusion, delirium, hallucinations Marked hyperactivity Coma Onset of coma 0–14 d Coma Hypotension, hypoventilation, apnea Pituitary dysfunction Cardiac arrhythmia, cardiac arrest Death or recovery (extremely rare) Death or initiation of recovery Months (recovery) Pneumothorax Intravascular thrombosis Secondary infections *Not every symptom or sign may be present in each case. Tintinalli_Sec13_p0997-1100.indd 1056 8/2/19 8:12 PM