Describe rabies virus with its pathogenesis, clinical features and post-exposure prophylaxis.

The Virus

• A rhabdovirus — characteristically bullet-shaped, enveloped, with helical symmetry and single-stranded negative-sense RNA
• Surface glycoprotein G binds the nicotinic acetylcholine receptor at the neuromuscular junction, and is the antigen that induces protective neutralising antibody — hence the vaccine target
• NEGRI bodies — eosinophilic cytoplasmic inclusions in neurons, most abundant in the hippocampus (Ammon horn) and cerebellar purkinje cells. They are pathognomonic but are absent in about 20% of cases, so their absence does not exclude rabies
• Fragile outside the body — rapidly killed by soap, detergents, alcohol, iodine, drying and sunlight. This is precisely why washing the wound is so effective
• Two epidemiological forms — urban rabies, in which the dog is the reservoir and accounts for over 95% of human cases in India; and sylvatic (wildlife) rabies in foxes, bats, jackals and mongooses

Pathogenesis

Virus in saliva is introduced by a bite, scratch, or a lick on broken skin or mucous membrane → It replicates locally in muscle at the site of entry — this local phase accounts for the long and variable incubation, and is the window in which post-exposure prophylaxis works → It binds acetylcholine receptors and enters peripheral nerve endings → retrograde axonal transport to the spinal cord and brain — travelling within the nerve, where antibody cannot reach it → Replication in the brain, producing encephalitis with remarkably little inflammation relative to the severity → centrifugal spread along nerves to the salivary glands, cornea, skin and other organs → Virus in the saliva of the now-symptomatic host transmits the infection by biting

Clinical Features

• Incubation is typically 1 to 3 months but ranges from days to over a year. It is shorter when the bite is on the face, head or neck, or is severe or multiple, because these sites are richly innervated and closer to the brain
• Prodrome — fever, malaise, and characteristically pain, tingling or numbness AT the site OF the healed bite, which is the most suggestive early symptom
• Furious rabies (about 80%) — agitation alternating with lucid intervals; hydrophobia (violent painful spasm of the pharynx on attempting to drink, and eventually at the sight or sound of water); aerophobia (spasm provoked by a draught of air, which is virtually diagnostic); hypersalivation, hallucinations and autonomic instability
• Paralytic ("dumb") rabies (about 20%) — ascending flaccid paralysis resembling Guillain-Barré syndrome, without hydrophobia; it is frequently misdiagnosed, and is commoner after bat exposure
• Death from respiratory or cardiac failure within days to a couple of weeks; the case fatality is effectively 100%, and management is palliative — sedation, analgesia and comfort
• Diagnosis in life — RT-PCR on saliva, a nuchal skin biopsy containing hair follicles, or corneal impression; antibody in serum or cerebrospinal fluid in the unvaccinated. Post mortem — Negri bodies and immunofluorescence on brain tissue

Post-exposure Prophylaxis

• Wound washing is the single most effective measure — thorough washing with soap and running water for at least 15 minutes, followed by povidone-iodine or alcohol. It alone reduces the risk substantially, because the virus is destroyed by soap
• Do not suture the wound immediately where possible; suturing is delayed and, if unavoidable, done loosely after immunoglobulin infiltration
• Do not apply irritants — chillies, oil, lime, turmeric or herbal preparations, which are traditional in parts of India, cause harm and delay
• Vaccine — modern cell culture vaccines (human diploid cell, purified chick embryo cell, Vero cell) have replaced the old nerve-tissue Semple vaccine, which caused neuroparalytic complications. Given intramuscularly (Essen 5-dose or 4-dose regimen) or intradermally, which is dose-sparing, much cheaper and widely used in India
• Rabies immunoglobulin (human or equine) for category III — infiltrated into and around the wound to neutralise virus locally, with any remainder given intramuscularly at a distant site. It must never be given in the same syringe or at the same site as the vaccine
• Previously vaccinated people need only two booster doses and NO immunoglobulin
• Pre-exposure prophylaxis for veterinarians, animal handlers, laboratory workers and travellers to endemic areas

Prevention at Population Level

• Mass dog vaccination is the only measure that eliminates human rabies; vaccinating about 70% of the dog population interrupts transmission, as has been shown in Latin America and in parts of Asia
• Animal birth control and responsible ownership reduce the stray population, though culling alone is ineffective and is opposed on welfare grounds
• Public education — immediate wound washing, prompt attendance, avoidance of traditional applications, and not provoking dogs; children are the commonest victims and are least likely to report a bite
• Ensuring vaccine and immunoglobulin availability at peripheral level; the intradermal regimen makes this affordable, since one vial serves several patients
• India’s National Rabies Control Programme combines human prophylaxis with animal vaccination and surveillance, with the stated aim of eliminating dog-mediated human rabies
• Rabies is notifiable in many Indian states, and reporting is essential for the surveillance on which control depends

Applied Aspects

• India has the largest rabies burden in the world, with thousands of deaths annually, overwhelmingly from dog bites and mostly in children — and essentially all of them preventable
• Post-exposure prophylaxis is never contraindicated, including in pregnancy, infancy and immunosuppression; the disease is invariably fatal and the vaccine is safe
• Do not delay prophylaxis to observe the animal; start immediately and stop only if the dog or cat remains healthy after 10 days of observation
• Infiltrate the immunoglobulin into the wound, not merely intramuscularly; its purpose is local neutralisation at the site where the virus is still accessible
• Mass dog vaccination is what eliminates human rabies, as it has in several countries; treating bitten people is necessary but it does not reduce the reservoir
• Consider paralytic rabies in an unexplained ascending paralysis with a history of animal contact, since it is regularly mistaken for Guillain-Barré syndrome and the diagnosis has implications for staff exposure
• The intradermal regimen makes prophylaxis affordable and should be used where several patients attend, since it uses a fraction of the vaccine of the intramuscular schedule
• Bat contact is category III however trivial it seems, because bat bites may be unnoticed and bat rabies has caused human deaths
• Counsel that vaccination after a bite is not optional; the commonest reason for a rabies death in India is that prophylaxis was never sought or was left incomplete
• Complete the full course; patients frequently stop attending once the wound has healed and they feel well, which is precisely when the virus is still travelling
• A previously vaccinated person needs neither immunoglobulin nor a full course — two booster doses suffice, which is a strong argument for pre-exposure prophylaxis in those at occupational risk
• Rabies has been transmitted by corneal and organ transplantation from donors dying of undiagnosed encephalitis, which is why donor screening matters
• Do not attempt aggressive treatment once symptoms begin; the illness is essentially uniformly fatal, and the humane course is palliation, sedation and support for the family
• Every dog bite is an opportunity to check tetanus status too, and to consider antibiotic prophylaxis for the bacterial infection that bites also carry
• Children are bitten on the face and hands most often, which means both a shorter incubation and a greater need for immunoglobulin infiltration — and they may not report the bite at all
• Wash the wound even if the patient presents late; washing remains worthwhile at any interval, and prophylaxis is given however long ago the bite occurred if the patient has not yet developed symptoms
• Equine immunoglobulin requires a test dose and carries a risk of serum sickness, but its lower cost makes it the practical option in much of India and it should not be withheld for fear of reaction
• Monkey and cat bites also transmit rabies, and are common in India; the same categories and the same prophylaxis apply, and a monkey bite in a temple town is not a trivial event
• Rabies vaccine may be given during pregnancy and lactation without restriction, and hesitancy on this ground has cost lives
• Record the category and the treatment given, and give the patient a card with the dates of the remaining doses; incomplete courses are the commonest preventable failure