How long does rabies last in humans

Even in these days of modern plagues such as AIDS and Ebola virus disease, rabies is regarded with terror. Undoubtedly much of the terror derives from the inexorable death that follows after the development of symptoms and the long incubation period that leaves dangling the risk of rabies for months and even years. Although we are now very successful at preventing rabies after known exposure, neither the pathogenesis of disease nor the mechanism of protection is completely understood, which adds interest for the scientist. Moreover, for the public health professional, rabies is a headache both in developed countries where the occasional case causes panic and in developing countries where control of the disease in dogs is elusive. Rabies is an ancient disease that remains a modern problem in much of the developing world and in the United States, where the disease is enzootic in bats and wild terrestrial mammals.

Clinical Description

The incubation period of rabies in humans is generally 20–60 days. However, fulminant disease can become symptomatic within 5–6 days; more worrisome, in 1%–3% of cases the incubation period is >6 months. Confirmed rabies has occurred as long as 7 years after exposure, but the reasons for this long latency are unknown.

The first signs of illness are nonspecific: fever, anxiety, and malaise. Often there is tingling and severe pruritus at the site of the animal bite. After 2–10 days, frank neurological signs become manifest, ranging from hyperactivity to paralysis. Indeed, the disease is usually divided into encephalitic and paralytic forms. In the former form, signs of irritation of the CNS predominate, including agitation, confusion, hydrophobia, aerophobia, hyperventilation, hypersalivation, priapism, and convulsions. These symptoms reflect both cerebral dysfunction and autonomic dysfunction. The unnerving aspect of this hyperactivity, both to the patient and to the physician, is its episodic nature, between which the patient is cooperative and oriented.

In some cases, paralysis involving the peripheral nerves is the presenting sign, which is usually accompanied by fever but in the absence of sensory involvement. Eventually, however, patients who present with signs of encephalitis also become paralyzed. The principal differential diagnosis in paralytic cases includes rabies and Guillain-Barré Syndrome. In the latter form, there is sensory involvement, absence of fever, and absence of encephalitic signs in oxygenated patients. Specific diagnostic tests for rabies, which are discussed below, are valuable in making the distinction between rabies and Guillain-Barré syndrome.

Within 2–12 days, coma begins, and cardiorespiratory failure is only a matter of time. A handful of recoveries from rabies have been claimed, although these recoveries are associated with severe neurological disabilities (and almost always occur in patients who have been partly vaccinated). No known treatment is of avail.

Virology

Rabies virus is serotype 1 of 7 serotypes of the genus Lyssavirus, which belongs to the larger classification of rhabdoviruses. At least 6 of these viruses have been found in bats, and it is possible that rabies virus itself is really a bat virus that has crossed species. The lyssaviruses are bullet-shaped, with the core containing the viral RNA, a nucleocapsid protein, a phosphoprotein, and a viral transcriptase. The outer part of the cartridge contains the matrix protein and a glycoprotein on which are located the epitopes that induce neutralizing anti-bodies.

Both the glycoprotein and the nucleocapsid protein induce protection against rabies in experimental animals, the former through the induction of neutralizing antibodies and the latter through the induction of cytotoxic T cells. The glycoprotein contains 524 amino acids, and changes in the sequence have a strong influence on viral virulence. The glycoprotein alone has been used successfully to protect animals against rabies.

Cases of rabies caused by Lyssavirus serotypes 2–7 are rare, and protection by standard rabies vaccine has thus far been uniform in humans; however, because animal experiments sometimes reveal vaccine failures, there is still speculation as to whether antigens from additional viruses need to be added to the vaccine.

Pathogenesis

Although much is known about the pathogenesis of rabies, some essential points yet remain mysterious. Clearly, early after implantation the virus is cell-free, since both washing of the wound and injection of antiserum reduce infection. However, in the absence of specific prophylaxis, the virus becomes hidden, only to invade the CNS weeks, months, or years later. Where is the virus during this period? There is some evidence for slow replication in muscle cells and for latency in macrophages, but there is no certainty that these account for the long incubation periods.

The next clear point is that the rabies virus glycoprotein has homologies to neurotoxins and that the virus attaches to neural axons through lipoprotein receptors, including that for acetylcholine. Other receptors, such as the neutral cell adhesion molecule (NCAM), may also be involved. The virus then enters the axon and travels passively to the nucleus of the neuron at rates variously estimated as 1–40 cm/d. The virus replicates in neurons and passes to other neurons through the fiber connections. Virus also passes down axons to the skin and to the salivary glands, where it is released into the saliva.

Damage in the brain is curiously limited. Neuronal death is not pronounced, but neuronal dysfunction is considerable, perhaps mediated through inhibition of the synthesis of neural transmitters. The Negri body is in fact a virus-induced cytoplasmic inclusion, which contains considerable amounts of viral antigen. Anatomically, most of the damage is in the hypothalamus, but it is interference with cardiorespiratory control that results in death.

Immune Responses

During the incubation period, rabies virus is evidently segregated from the immune system, since no antibody responses are seen. Only after neurological symptoms develop do antibodies appear in the serum and later in the CSF. Antibodies in the CSF reflect active local production in the CNS, as well as passive transfer, and are absent after vaccination. Demonstration of antibodies is thus useful diagnostically only in late phases of the disease. Prior vaccination of a patient with rabies may confuse the issue, but in disease, titers increase to levels not seen in vaccinees.

Immunopathologic studies in mice show that neutralizing antibodies are an essential component of the protective response. However, “knockout” mice who are unable to mount a T cell-mediated IFN response do less well than control mice, despite the presence of antibodies, and it is evident that cellular immunity plays at least a minor role in protection.

Diagnosis

As in many diseases, clinical suspicion is critical to a timely diagnosis of rabies. Rabies should be included in the differential diagnosis of any case of encephalitis of unknown origin, particularly when the patient has a history of an animal bite and signs of autonomic disturbance in the absence of coma. Thus, hyperventilation, hypersalivation, aerophobia, and hydrophobia are all part of the clinical picture. Flaccid paralysis and localized paresthesias may also be signs of rabies. Clinically, rabies may be confused with Guillain-Barré syndrome, poliomyelitis, and other viral encephalitides.

Postmortem diagnosis is relatively easy and is based on demonstration of rabies virus antigens in brain tissue specimens by fluorescent antibody techniques or ELISA and, more recently, by demonstration of rabies virus nucleic acid by reverse transcriptase (RT)-PCR analysis. Eosinophilic intracytoplasmic inclusions, called Negri bodies, may also be seen during routine histological examination, but this technique may have false-positive and false-negative results. Virus isolation in cell culture or from animals can be used as a confirmatory technique, but it takes time.

Intravitam diagnosis depends on the demonstration of antibodies to rabies virus in serum or CSF specimens from patients with a prolonged clinical course, viral antigen in touch impressions from the cornea, viral antigen in highly innervated hair follicles obtained by biopsies along the hairline of the neck, and virus isolation from or nucleic acid detection in saliva. However, negative results early in the disease do not rule out the diagnosis of rabies, and in most cases rabies is diagnosed clinically at autopsy.

Noah et al. [1] summarized the diagnostic and epidemiological findings of 32 United States cases of human rabies that occurred during 1980–1996. The median incubation period from bite to symptoms was 85 days, with hospitalization following usually 1–10 days later. As shown in table 1, the test that gave the best results (positive in 100% of cases) was RT-PCR analysis, which revealed viral RNA in saliva. The next best test for antemortem diagnosis was nuchal skin biopsy (positive in 67% of cases).

Epidemiology

The epidemiology of human rabies is an exact reflection of the epizootiology of the disease in animals. From the viewpoint of public health, the dog or other canid species are the only important vector for humans, being responsible for most infections in Asia, Africa, and Latin America. However, with the retreat of canine rabies from most of the developed world, rabies transmitted by wild mammals, including bats, has become more prominent.

Thus, in the United States at this point, raccoons and skunks account for most rabies virus-infected animals. However, in terms of risk to humans, bats, dogs, and cats are the most likely threats to transmit rabies to Americans. The distribution of major terrestrial reservoirs of rabies in the United States is shown in figure 1 [2]. The major change in recent years has been the extension of raccoon rabies into the northeast.

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Distribution of major terrestrial reservoirs of rabies in the United States. Reprinted with permission from W. B. Saunders [2]. The skunk and the fox are infected with several geographic variants.

Rabid bats have become the predominant rabies risk to humans in the United States because of a combination of virological, biological, and ecological factors. In particular, the silver-haired and eastern pipistrelle bats have been prominent recently because the virus recovered from them may infect human skin more easily than other rabies virus strains and because the small teeth of the bat may leave little evidence of a bite. Moreover, human exposures appear to be more frequent, perhaps because of increasing encroachment of human habitation in formerly rural areas. From 1980 to 1996, 21 of 36 cases of domestic human rabies could be attributed to bats by nucleic acid analysis; of these 21 patients, only 1 had a firm history of a bite [4]. These facts have led to new recommendations relative to prophylaxis for rabies, which are given below.

Bats are the source of another type of human rabies, aerosol infection, that is fortunately rare; aerosol infection may occur in caves inhabited by millions of bats. Rabies in research laboratory workers who are accidentally exposed to aerosols of the virus is also rare but well documented.

Although dogs and cats are uncommonly rabid in the United States owing to the widespread use of prophylactic vaccines and other public health measures, these pet animals may frequently expose humans to rabies, particularly along the border with Mexico.

Corneal transplants from donors who died of unspecified encephalitis have transmitted rabies in the past, but transplantation practice now forbids the use of tissues from such donors.

The major foci of rabies in the world today are the Indian subcontinent, Southeast Asia, and most of Africa. Data from India suggest that there are 30,000 cases each year in that country, and one estimate of the death rate associated with rabies is 35.5 deaths per 1 million people. Although rabies vaccination services in Thailand are well organized, ∼75 Thai people still die of rabies each year. The World Health Organization estimates that there are 50,000 cases of fatal rabies in the world each year. On a list of worldwide causes of mortality, rabies ranks ahead of yellow fever, polio, and meningococcal meningitis. However, some countries, particularly islands, are free of rabies. The prominent vectors for rabies in various regions of the world are listed in table 2; this list may be useful in assessing the risk for travelers.

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Principal animal vectors of rabies.

Vaccination

The principles of prophylaxis for rabies have not changed for many years, but there have been important recent modifications that deserve emphasis. The basic principles are to remove free virus from tissues by both washing and neutralization and to induce a rabies virus-specific immune response in the exposed individual before rabies virus can replicate in the CNS.

The history of vaccine development for rabies is a colorful one. It starts with the well-known and dramatic story of Louis Pasteur and his rabbit spinal cord vaccine and continues to this day with the demonstration of protection in animals by rabies virus reverse transcriptase DNA plasmid vaccination or by feeding them plants that contain chimeric plant viruses that code for rabies virus glycoprotein. However, in terms of use in humans, vaccines may be divided into nerve tissue vaccines, avian embryo vaccines, and cell culture vaccines.

Regrettably, nerve tissue vaccines are still the most widely used type for prophylaxis for rabies. They are dangerous in terms of induction of autoimmune CNS disease, require multiple injections, and are not always efficacious. The Fuenzalida vaccine, which is produced from rabies virus grown in suckling mouse brain, is an improvement over prior vaccines with regard to reduced myelin content, but it still provokes neurological problems. The vaccines originally produced from rabies virus grown in duck embryo contained no myelin, but the potency of the unconcentrated vaccine was low.

Today the optimal rabies vaccine is one produced by the growth of virus in cell culture or culture of avian embryos, followed by inactivation, purification, and concentration. The first one commercially developed, which is still the standard, was human diploid cell culture vaccine (HDCV). The advantages of HDCV and the cell culture vaccines that followed are freedom from heterologous protein, a high level of immunogenicity that permits a rational dosing schedule, and efficacy demonstrated in trials that were not placebo-controlled but were at least done with careful observation. The disadvantage of these vaccines is cost of production, particularly for the original HDCV. Subsequently developed vaccines have used less expensive cellular substrates to reduce their price.

The cell culture vaccines are considered equivalent in terms of efficacy and freedom from serious allergic reactions (table 3). If necessary (although it is not recommended), these vaccines may be used interchangeably in the same patient, at least for the intramuscular regimens.

Preexposure Vaccination

The advent of cell culture rabies vaccines has allowed safe immunization of people likely to be exposed to rabies, according to the same principles that govern the use of other vaccines. As summarized in table 4, 2 doses of a cell culture vaccine are given 1 week apart, and a third booster dose is given 2–3 weeks later. Antibody response is virtually 100%, and the individual remains sensitized indefinitely.

If a person who has been vaccinated previously is exposed to rabies, 2 doses of vaccine are administered 3 days apart. An anamnestic response is seen within 1 week. A vaccinated person at continuous risk should receive a single booster dose 1 year after primary immunization. We have observed that a titer of antibody to rabies virus that is measured 14 days after this fourth dose is useful in predicting the need for further booster doses: titers >30 IU indicate prolonged seropositivity, whereas subjects with lower titers should undergo more frequent retesting to be certain that their titers remain >0.5 IU, which is generally considered to be an acceptable level [3].

Preexposure vaccination is recommended for people who will be exposed to rabies virus in the laboratory or who will have contact with mammals, including bats. Included on this list are veterinarians, trappers, dog catchers, speleologists, biologists who work with mammals, and laboratory workers likely to come in contact with rabies virus-infected specimens. Individuals with less certain indications for preexposure vaccination, which should be influenced by geography and by information from veterinary authorities, include hunters, mail carriers, and travelers to countries where rabies is enzootic. Travelers who keep to the usual tourist routes are probably not in much danger. However, those travelers who remain in remote areas, particularly children, are at risk; vaccination is recommended for peace corps workers. One survey conducted in Thailand showed that 0.5% of travelers needed rabies vaccination because of exposures to potentially or proven rabid animals; therefore, there is ample justification for preexposure immunization.

Children living in areas where rabies is enzootic can be easily immunized against rabies (even as part of routine infant vaccination), although such practice is not yet recommended, in part for financial and logistic reasons.

Postexposure Prophylaxis

Optimal postexposure treatment consists of local cleansing, administration of passive antibody, and active immunization. All 3 elements are essential, since rabies has occurred when 1 of the elements was omitted.

The choice of cleaning solution is probably less important than the copiousness of the fluid administered. Soap and water are fine, although 0.1% benzalkonium chloride, 70% alcohol, or 1% povidone-iodine may be usefully applied to the wound after washing. Tetanus vaccine, tetanus antiserum, and antibiotic treatment should be provided as indicated.

After a wound has been cleansed, the physician can decide whether the threat of rabies justifies vaccination. The factors influencing that decision include the following:

1. If there is high suspicion that the biting animal has rabies on the basis of compatible clinical signs, prophylaxis should be started immediately.

2. If the biting animal has always been a domestic pet, such as a dog, cat, or ferret, it can be quarantined and observed for rabies for 10 days. Dogs and cats are still potential vectors in a few areas of the United States, particularly along the southern border. If the animal remains healthy, no vaccination is needed. In countries where dog rabies is enzootic, prophylaxis should be started immediately and should be discontinued if the animal remains healthy.

3. If the biting animal is wild and has been killed, the brain can be examined for signs of rabies. This step is particularly important for raccoons, skunks, foxes, bats, and woodchucks (groundhogs). The fluorescent antibody test for rabies virus antigen in the brain is highly sensitive and specific.

4. If the biting animal has escaped, reference to veterinary authorities should be made to determine whether the species involved may possibly be infected with rabies in that particular geographic area.

5. If the biting animal was a bat, prophylaxis for rabies should always be given (see the section on bats below).

6. Provocation of the bite or lack of it is not a good criterion for decision.

7. Exposure of mucous membranes to secretions of a rabid animal is not as dangerous as a bite but is associated with the risk of rabies. Exposure of intact skin is not a risk (see the section on bats below).

If a decision is made to proceed with prophylaxis for rabies, rabies immune globulin (RIG) should be administered. Two forms of RIG exist: human RIG and equine RIG. However, only human RIG is available in the United States. The currently used equine RIGs are purified products and are associated with relatively few allergic reactions and only rarely with anaphylaxis. Unfortunately, because strict regulation to eliminate extraneous viral contamination, human RIG is in short supply.

The dose of human RIG is 20 IU/kg, whereas that for equine RIG is 40 IU/kg. United States and WHO recommendations call for local infiltration of the total dose at the site of the bite to the extent that is anatomically feasible, rather than 50% of the dose formerly recommended. The change in recommendation was made because blood levels of antibodies to rabies virus are not high after parenteral administration of RIG, and local neutralization of the virus is key.

Active immunization against rabies should be started simultaneously with administration of antiserum. Although no effort should be made to induce active immunization and passive immunization at different times, if one product is available before the other, it should be administered promptly, and the second product should be given when it becomes available. However, if RIG is available >1 week after vaccination has been started, it is probably unnecessary as an active antibody response will have begun.

A 5-dose schedule for postexposure vaccination against rabies is internationally accepted, and im injection is the only route acceptable in the United States. (However, see the section on intradermal vaccination below.) Doses are given at 0, 3, 7, 14, and 28 days (table 4). After the fifth dose, antibodies are always present, usually at a titer of >10 IU. Another vaccination schedule, called 2-1-1, is used in some countries, but this schedule is not as immunogenic if used together with human RIG. Vaccine and antiserum should never be mixed or injected in the same limb.

In the United States, there is a choice of 3 vaccines (table 5): HDCV, purified chick embryo cell culture vaccine, and fetal rhesus lung cell culture vaccine (or rabies vaccine adsorbed, which is temporarily unavailable). They are interchangeable, but it is normal practice to use 1 for the complete vaccination series. Outside of the United States, there are other choices, including primary hamster kidney cell culture vaccine, monkey vero cell vaccine, purified duck embryo vaccine, and numerous nerve tissue vaccines. If a traveler returns to the United States after having received 1 of the cell culture vaccines, the vaccination schedule may be completed with 1 of the 3 licensed vaccines, but if the patient has received a nerve tissue vaccine, rabies vaccination should be started without reference to the prior doses.

Titers should be measured in immunosuppressed persons, including those with HIV infection, after vaccination, to ensure that seroconversion has occurred.

There has been concern that vaccination might not protect against Lyssavirus serotypes 2–7, but fortunately, experimental studies suggest that there should be sufficient cross-neutralization with most strains to give protection.

The 1999 recommendations concerning postexposure prophylaxis for rabies by the Advisory Committee on Immunization Practices [4] are summarized in tables 6 and 7.

Intradermal Vaccination

The higher cost of cell culture vaccines has induced physicians to look for ways of reducing doses. Accordingly, Warrell et al. [5] and Wilde and et al. [6] have developed vaccination schedules by using the intradermal route. In the United States, the intradermal route is approved only for preexposure vaccination. Details of the intradermal immunization schedules are provided in table 4. The principles that allow intradermal vaccination are the better response to an equal volume of antigen when placed in contact with the Langerhans' cells of the epidermis and the use of multiple sites of vaccination to obtain maximum drainage of antigen-presenting cells to the lymph nodes. The intradermal regimens have had remarkable success, particularly in Thailand. However, some expertise is necessary for correct intradermal injection, and the choice of vaccine is important. The intrasdermal dose is one-fifth of a vial for inteded intramuscular injection, which may be 0.1 mL or 0.2 mL, depending on the brand of vaccine.

Individuals receiving antimalarial prophylaxis with chloroquine or related compounds should be vaccinated by the im route, since their antibody responses to intradermal vaccination may be lower than normal.

Bats or the Return of Dracula

Rabies virus is only one of a number of lyssaviruses enzootic in bats and indeed may have been the original source of the virus for other species. Bat rabies is an important problem for the Americas, including the United States, where it occurs in all 49 continental states. Although <1% of bats screened for rabies are positive, in Colorado, 30% of bats who bit people and 50% of bats found in houses by wakening individuals were rabid [7].

In recent years, insectivorous bats have been the predominant source of human infections in the United States, in particular the silver-haired bat, Lasionycteris noctivagans, and the eastern pipistrelle bat, Pipistrellus subflavus. The virus indigenous to these bats is a genetic variant of Lyssavirus serotype 1 that adapts to epithelial and fibroblast cells in culture and may be more infectious than other strains. Disturbingly, most human patients with rabies caused by the virus variant from these bats give no history of contact with bats or only a history of contact without a bite. However, bat bites may be small or may be inflicted on a sleeping person who does not awaken. Therefore, a new recommendation by the Advisory Committee on Immunization Practices [4] states the following: “Consequently, post-exposure prophylaxis should be considered when direct contact between a human and a bat has occurred, unless the exposed person can be certain a bite, scratch, or mucous membrane exposure did not occur. In instances in which a bat is found indoors and there is no history of bat-human contact, the likely effectiveness of postexposure prophylaxis must be balanced against the low risk such exposures appear to present. In this setting, postexposure prophylaxis can be considered for persons who were in the same room as the bat and who might be unaware that 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 the room with a previously unattended child, mentally disabled person, or intoxicated person) and rabies cannot be ruled out by testing the bat. Postexposure prophylaxis would not be warranted for other household members.” Vampire bats in Latin America also may transmit rabies. Fortunately, standard rabies vaccination elicits good neutralizing antibody to viruses from bats.

Human-to-Human Transmission

Aside from transmission through transplanted tissues, human-to-human transmission lies largely in the realm of folklore. However, rabies virus may be present in the saliva of humans with rabies, and possible contact transmission has been reported recently and in the past. Thus, bites, scratches, and mucous membrane exposures to a rabid patient are considered indications for vaccination. The latter indication includes sexual exposure shortly before the onset of symptoms.

Reactions and Contraindications to Vaccination

Reactions to human RIG are uncommon. Currently, manufactured equine RIGs are associated with relatively few allergic reactions: serum sickness in only 1% of cases and very rare cases of anaphylaxis. Nerve tissue vaccines may induce local, systemic, or neuroparalytic reactions. The latter reactions are based on the induction of antibodies to myelin proteins or gangliosides. Reactions to cell culture vaccines are relatively mild, although local pain, erythema, and swelling at the injection site are commonly seen. Systemic reactions with headache and malaise occur less frequently. Guillain-Barré syndrome has been rarely reported after receipt of modern rabies vaccine, but its association with the vaccine is uncertain.

The most significant problem is type I or III allergic reactions consisting of urticaria, arthritis, and angioedema, which are seen in about 6% of patients who receive a booster dose of HDCV. These reactions have been attributed to the formation of antibodies to the human albumin stabilizer chemically altered by β-propiolactone. These reactions can be treated with the usual drugs employed for allergic reactions, and another rabies vaccine can be substituted for HDCV. The use of steroids should be avoided, but if these agents are administered, titers of antibody should be measured after completion of the vaccine series.

There are no true contraindications, and vaccination is safe in pregnancy. HIV-infected patients with CD4+ cell counts below 300/µL respond poorly, and may need additional doses of vaccine. Antibody titers can be monitored to verify responses.

Treatment Failures

In nearly all cases of rabies occurring despite vaccination, some aspect of the treatment did not follow the guidelines. The common faults are late start of prophylaxis, insufficient cleansing of the wound, total omission of antiserum administration, or failure to inject antiserum into all wound sites. One treatment failure did occur in a person prevaccinated by the intradermal route; in that case, concomitant chloroquine medication may have suppressed the patient's response. However, it should be recognized that the size and placement of the challenge dose of rabies virus are influential on the outcome. A highly contaminated bite on the face, for example, may allow for rapid CNS invasion, and failures of protection have been reported in that situation despite standard treatment.

The best solution to human rabies still lies in the suppression or vaccination of animal reservoirs where feasible, particularly among domestic animals. More than 2000 years after the description of hydrophobia by Celsus, human rabies is far from extinct.

Acknowledgments

I thank Dr. Charles Rupprecht and Dr. Henry Wilde for critical reading of the manuscript.

A supplemental reading list reading appears in the online edition of CID (http://journals.uchicago.edu.CID/journal/).

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Economical multiple-site intradermal immunisation with human diploid-cell strain vaccine is effective for post-exposure rabies prophylaxis