What are the early symptoms of rabies in humans. How long does it take for rabies symptoms to appear. Can rabies be treated after symptoms start. What are the final stages of rabies infection.

The Nature of Rabies: A Deadly Viral Disease

Rabies is a severe viral infection that primarily affects the central nervous system of mammals, including humans. This zoonotic disease is typically transmitted through the bite or scratch of an infected animal, most commonly wild animals such as bats, raccoons, skunks, and foxes. However, domestic animals like dogs and cats can also carry and transmit the virus if they are not properly vaccinated.

The rabies virus belongs to the Lyssavirus genus of the Rhabdoviridae family. Its structure is characterized by a bullet-shaped virion, approximately 180 nm long and 75 nm wide, containing a single-stranded RNA genome. This genome encodes five essential proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and polymerase (L).

How Does Rabies Spread?

The primary mode of rabies transmission is through the saliva of infected animals. When an infected animal bites or scratches a human or another animal, the virus in its saliva can enter the new host’s body through the wound. In rare cases, rabies can also be transmitted through organ transplantation from an infected donor or through exposure to aerosolized rabies virus in laboratory settings.

• Bite from an infected animal
• Scratch from an infected animal
• Contact with infected saliva on open wounds or mucous membranes
• Rare cases of organ transplantation or laboratory exposure

The Incubation Period: A Silent Threat

One of the most challenging aspects of rabies is its variable incubation period. This is the time between initial infection and the onset of symptoms. In humans, the incubation period typically ranges from 2 to 8 weeks but can vary widely from as short as a few days to as long as several years.

The length of the incubation period depends on several factors:

• The site of the bite or exposure (closer to the brain generally means a shorter incubation period)
• The severity of the wound
• The amount of virus introduced
• The victim’s immune system

During this incubation period, the virus travels from the site of infection along the peripheral nerves to the central nervous system. This slow progression is one reason why immediate post-exposure prophylaxis is so crucial in preventing the disease from developing.

Early Symptoms: The Prodromal Phase

The initial symptoms of rabies in humans are often nonspecific and can easily be mistaken for other illnesses. This prodromal phase typically lasts 2-10 days and may include:

• Fever
• Headache
• General malaise or feeling unwell
• Fatigue
• Loss of appetite
• Nausea and vomiting
• Anxiety or agitation
• Sore throat
• Pain, tingling, or itching at the site of the bite (in some cases)

These initial symptoms are often mild and may not raise immediate concern. However, as the virus continues to replicate and spread within the central nervous system, more severe and characteristic symptoms begin to emerge.

Acute Neurological Phase: The Furious and Paralytic Forms

As rabies progresses, it typically manifests in one of two forms: furious (encephalitic) rabies or paralytic rabies. Each form has distinct characteristics, although some patients may exhibit elements of both.

Furious Rabies

Furious rabies, the more common form, is characterized by hyperactivity, excitability, and agitation. Symptoms may include:

• Hyperactivity and restlessness
• Confusion and hallucinations
• Aggressive behavior
• Hydrophobia (fear of water) due to painful spasms of the throat when attempting to swallow
• Aerophobia (fear of drafts or fresh air)
• Hypersalivation
• Seizures

Paralytic Rabies

Paralytic rabies, also known as dumb rabies, is less common and characterized by gradual paralysis. Symptoms may include:

• Muscle weakness starting at the site of the bite
• Gradual paralysis spreading to other parts of the body
• Loss of sensation
• Difficulty swallowing
• Paralysis of respiratory muscles

Final Stages and Coma

Regardless of the form, rabies ultimately leads to coma, multiple organ failure, and death. In the final stages, patients may experience:

• Delirium
• Severe spasms
• Inability to swallow, leading to frothing at the mouth
• Respiratory failure
• Cardiovascular collapse

Without intensive supportive care, death typically occurs within 2-10 days after the onset of neurological symptoms. Even with advanced medical care, rabies is almost always fatal once symptoms appear.

Diagnosis and Testing

Diagnosing rabies in humans can be challenging, especially in the early stages when symptoms are nonspecific. Several tests can be used to confirm a rabies infection:

• Direct fluorescent antibody (DFA) test: This is the gold standard for rabies diagnosis, but it requires brain tissue and is typically performed post-mortem.
• Reverse transcription polymerase chain reaction (RT-PCR): This test can detect rabies virus RNA in saliva, cerebrospinal fluid, or tissue.
• Serology: Tests for rabies antibodies in serum or cerebrospinal fluid.
• Skin biopsy: Can detect rabies virus antigen in the cutaneous nerves at the base of hair follicles.

Given the rapid progression and high fatality rate of rabies, treatment is typically initiated based on clinical suspicion and exposure history, rather than waiting for confirmatory tests.

Prevention and Post-Exposure Prophylaxis

Prevention is crucial in managing rabies, as the disease is almost always fatal once symptoms appear. The most effective preventive measures include:

1. Vaccinating domestic animals against rabies
2. Avoiding contact with wild animals, especially those acting unusually
3. Seeking immediate medical attention after any potential rabies exposure
4. Administering post-exposure prophylaxis (PEP) when necessary

Post-exposure prophylaxis is highly effective in preventing rabies if administered promptly after exposure. It typically consists of:

• Thorough wound cleaning
• Rabies immune globulin (RIG) to provide immediate antibodies
• A series of rabies vaccinations to stimulate the body’s own immune response

The effectiveness of PEP decreases as the time between exposure and treatment increases, emphasizing the importance of seeking medical attention immediately after a potential rabies exposure.

Global Impact and Ongoing Challenges

Despite being a preventable disease, rabies continues to pose a significant global health threat, particularly in developing countries. The World Health Organization estimates that rabies causes approximately 59,000 human deaths annually, with 95% of cases occurring in Africa and Asia.

Several factors contribute to the ongoing challenge of rabies control:

• Limited access to healthcare and post-exposure prophylaxis in some regions
• Inadequate animal vaccination programs
• Lack of awareness about rabies risks and prevention
• Challenges in controlling rabies in wildlife populations

Efforts to eliminate human deaths from rabies focus on several key strategies:

1. Increasing access to post-exposure prophylaxis
2. Expanding dog vaccination programs
3. Improving public education about rabies risks and prevention
4. Enhancing surveillance and reporting systems
5. Promoting interdisciplinary collaboration in a One Health approach

By implementing these strategies and continuing research into rabies prevention and treatment, the global health community aims to eliminate human deaths from rabies by 2030.

Emerging Research and Future Prospects

While rabies remains a formidable challenge, ongoing research offers hope for improved prevention and treatment strategies. Some areas of current research include:

• Development of more effective and longer-lasting rabies vaccines
• Exploration of novel antiviral therapies for treatment after symptom onset
• Investigation of genetic factors that may influence rabies susceptibility and progression
• Improvement of diagnostic techniques for earlier and more accurate detection
• Development of oral vaccines for wildlife populations

One particularly promising area of research is the development of monoclonal antibodies that could potentially neutralize the rabies virus more effectively than current treatments. These antibodies could provide a more targeted and potent approach to post-exposure prophylaxis.

Additionally, advances in understanding the molecular mechanisms of rabies virus replication and pathogenesis may lead to new therapeutic targets. For example, researchers are exploring ways to block the virus’s ability to evade the immune system or to interfere with its neurotropic properties.

Another area of interest is the potential use of gene therapy approaches to treat rabies. While still in early stages, these techniques could potentially deliver therapeutic genes or RNA molecules directly to infected neurons, offering a new avenue for treatment even after symptom onset.

As our understanding of rabies continues to grow, so too does the potential for more effective prevention and treatment strategies. However, it’s important to note that even with these advancements, prevention through vaccination and prompt post-exposure prophylaxis remains the most effective approach to combating this deadly disease.

In conclusion, while rabies remains a serious global health threat, particularly in developing regions, ongoing research and public health initiatives offer hope for a future where human deaths from rabies are a thing of the past. By combining improved vaccination strategies, enhanced surveillance, and novel treatment approaches, we can work towards eliminating the threat of this ancient and deadly disease.

What is Rabies? | Rabies

Rabies is a preventable viral disease most often transmitted through the bite of a rabid animal. The rabies virus infects the central nervous system of mammals, ultimately causing disease in the brain and death. The vast majority of rabies cases reported to the Centers for Disease Control and Prevention (CDC) each year occur in wild animals like bats, raccoons, skunks, and foxes, although any mammal can get rabies.

The Rabies Virus

Rabies virus belongs to the order Mononegavirales, viruses with a nonsegmented, negative-stranded RNA genomes. Within this group, viruses with a distinct “bullet” shape are classified in the Rhabdoviridae family, which includes at least three genera of animal viruses, Lyssavirus, Ephemerovirus, and Vesiculovirus. The genus Lyssavirus includes rabies virus, Lagos bat, Mokola virus, Duvenhage virus, European bat virus 1 & 2 and Australian bat virus.

Structure

Rhabdoviruses are approximately 180 nm long and 75 nm wide. The rabies genome encodes five proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and polymerase (L). All rhabdoviruses have two major structural components: a helical ribonucleoprotein core (RNP) and a surrounding envelope. In the RNP, genomic RNA is tightly encased by the nucleoprotein. Two other viral proteins, the phospoprotein and the large protein (L-protein or polymerase) are associated with the RNP.

The glycoprotein forms approximately 400 trimeric spikes which are tightly arranged on the surface of the virus. The M protein is associated both with the envelope and the RNP and may be the central protein of rhabdovirus assembly. The basic structure and composition of rabies virus is depicted in the longitudinal diagram below.

Rabies is an RNA virus. The genome encodes 5 proteins designated as N, P, M, G, and L. The order and relative size of the genes in the genome are shown in the figure below. The arrangement of these proteins and the RNA genome determine the structure of the rabies virus.

Replication

The fusion of the rabies virus envelope to the host cell membrane (adsorption) initiates the infection process. The interaction of the G protein and specific cell surface receptors may be involved.

After adsorption, the virus penetrates the host cell and enters the cytoplasm. The virions aggregate in the large endosomes (cytoplasmic vesicles). The viral membranes fuse to the endosomal membranes, causing the release of viral RNP into the cytoplasm (uncoating). Because lyssaviruses have a linear single-negative-stranded ribonucleic acid (RNA) genome, messenger RNAs (mRNAs) must be transcribed to permit virus replication.

A viral-encoded polymerase (L gene) transcribes the genomic strand of rabies RNA into leader RNA and five capped and polyadenylated mRNAs, which are translated into proteins. Translation, which involves the synthesis of the N, P, M, G and L proteins, occurs on free ribosomes in the cytoplasm. Although G protein synthesis is initiated on free ribosomes, completion of synthesis and glycosylation (processing of the glycoprotein), occurs in the endoplamsic reticulum (ER) and Golgi apparatus. The intracellular ratio of leader RNA to N protein regulates the switch from transcription to replication. When this switch is activated, replication of the viral genome begins. The first step in viral replication is synthesis of full-length copies (postive strands) of the viral genome. When the switch to replication occurs, RNA transcription becomes “non-stop” and stop codons are ignored. The viral polymerase enters a single site on the 3’ end of the genome, and proceeds to synthesize full-length copies of the genome. These positive strands of rabies RNA serve as templates for synthesis of full-length negative strands of the viral genome.

During the assembly process, the N-P-L complex encapsulates negative-stranded genomic RNA to form the RNP core, and the M protein forms a capsule, or matrix, around the RNP. The RNP-M complex migrates to an area of the plasma membrane containing glycoprotein inserts, and the M-protein initiates coiling. The M-RNP complex binds with the glycoprotein, and the completed virus buds from the plasma membrane. Within the central nervous system (CNS), there is preferential viral budding from plasma membranes. Conversely, virus in the salivary glands buds primarily from the cell membrane into the acinar lumen. Viral budding into the salivary gland and virus-induced aggressive biting-behavior in the host animal maximize chances of viral infection of a new host.

Rabies virions are bullet-shaped with 10-nm spike-like glycoprotein peplomers covering the surface. The ribonucleoprotein is composed of RNA encased in nucleoprotein -(), phosphorylated or phosphoprotein -Illistration of virus, and polymerase -virus.

The cross-sectional diagram demonstrates the concentric layers: envelope membrane bilayer, M protein, and tightly coiled encased genomic RNA.

The rabies virus genome is single-stranded, antisense, nonsegmented, RNA of approximately 12 kb. There is a leader-sequence (LDR) of approximately 50 nucleotides, followed by N, P, M, G, and L genes.

1: Adsorption (receptors and virion interation). 2: Penetration (virus entry). 3: Uncoating (envelope removal). 4. Transcription (synthesis of mRNAs). 5. Translation (Synthesis of structural proteins). 6. Processing (G-protein gycosylation). 7. Replication (production of genomic RNA from intermediate strand. 8. Assembly. 9: Budding (complete virions).

Rabies

Rabies


MM 487-491; Id 1154-1167

Previous Lecture

Next Lecture

Table of Contents

NAME OF DISEASE:     Rabies

                                       
Hydrophobia

ETIOLOGICAL AGENT:     Rabies virus (a rhabdovirus)

THE DISEASE:

    This is primarily a viral infection of non-human
carnivores. Transmission to man is rare and is usually effected through
a bite. Clinical evidence of involvement of the CNS appears after an extremely
variable period of incubation. A deep-seated fear of rabies is almost instinctual
despite the actual rarity of the infection in man, perhaps reflecting a
primordial knowledge of the virtual certainty of death once disease is
overt.

PATHOLOGY:

    The rabies virus is usually transmitted to man by
a bite that implants saliva containing an infective dose of virus in muscle
and near nerve tissue. The virus may undergo a limited amount of reproduction
in the muscle cells at the site of inoculation. The virus travels along
the nerves from the point of inoculation to the CNS. The dense concentration
of sensory nerve endings in the head, face, neck and fingers accounts for
the higher fatality rate observed when these areas are exposed. Similarly,
the more extensive or severe the bite wounds, the higher the mortality,
because more nerve tissue is exposed to an infective dose of rabies virus.
After entering the CNS, the virus replicates in the neurons of the gray
matter before traveling centrifugally along nerves from the CNS to invade
a variety of organs and tissues. Humans and animals dying of rabies commonly
exhibit characteristic cytoplasmic inclusion bodies in neurons of the brain;
these are called Negri bodies. The presence of Negri bodies is pathognomonic
of rabies infection, but their absence does not preclude the disease. In
humans who have died from rabies, Negri bodies are prominent in ganglion
cells, particularly in the hippocampus and cerebellum. Other changes also
present in the CNS include edema, hemorrhage, congestion, and perivascular
cuffing in all parts, but most severe in the pons and medulla. In the cranial,
spinal, and sympathetic ganglia, there are actual foci of necrosis with
neuronophagia and infiltration with lymphocytes. The severity of the histopathologic
changes in the spinal cord often corresponds to the site of bite – for
example, the lumbar cord is most extensively affected when the bite is
on the foot. Gross changes are inconspicuous.

DIAGNOSIS:

    Where there is a history of bite by a known rabid
animal and the bitten person shows typical symptoms, the clinical diagnosis
of rabies is usually evident. In many instances, a history of exposure
is lacking, and the diagnosis of rabies may be missed unless revealed by
postmortem laboratory tests.

    The manifestations of rabies begins in man anywhere
from 10-240 days after exposure. However, the incubation period is usually
30-90 days. The length of this incubation period is a function of:

    1.     The number of sensory
nerves ending in the bitten area

    2.     The dose of virus

    3.     The severity of the bite
wounds

    4.     The distance from the
bite wound to the CNS

    There are three clinical phases of the disease:

    1.     Prodromal phase – the
onset of clinical rabies in man includes 2-4 days of prodromal

           
manifestations, most of which are non-specific. A low fever, malaise, headache,
anorexia,

            
nausea and sore throat are common. There may also be increasing nervousness,
anxiety,

           
irritability and depression and melancholia, with or without a sense of
impending death.

           
Hyperesthesia, an increased sensitivity to bright light and loud noise,
excessive salivation,

           
lacrimation and perspiration have been noted. The general muscle tone may
be increased,

           
and facial expression can be overactive. Dilated pupils, an increased pulse
rate and shallow

           
respirations are seen. However, by far, the most significant symptoms are
abnormal

           
sensations referred to the site of inoculation; noted by 80% of patients,
these include pain

           
(local or radiating), a sensation of cold, pruritus (itching) and tingling.

    2.     Excitation phase – the
excitation phase begins gradually and may persist to death. It may be

           
punctuated at any time by depression and paralysis. There usually are increasing
anxiety,

           
apprehension and a sense of impending doom. Although the tone of the somatic
musculature

           
is increased, there may be weakness of the muscle groups around the location
of the bite.

           
Cranial nerve malfunctions result in ocular palsies with:

            a.    
Strabismus – failure of the eyes to follow one another in any movement.
This is due to

                   
incoordination of the extra-ocular muscles.

            b.    
Dilation or constriction of the pupils that may be asymmetric and associated
with:

                   
(1)     Hippus (abnormal exaggeration of the rhythmic
contraction and dilation of the

                             
pupil, independent of changes in illumination or in fixation of the eyes).

                   
(2)     Nystagmus (continuous rolling of eyeball)

                   
(3)     Diplopia

            c.    
Absence of corneal reflexes

            d.    
Weakness of facial muscles

            e.    
Hoarseness

            f.    
Babinski and Chaddock signs

            g.    
Papilledema

            There
may be tachycardia or bradycardia (slow heart beat), cyclic respiration,
urinary

            
retention and constipation.

            Hydrophobia,
the classical diagnostic manifestation of rabies, is an affliction of the
excitatory

           
phase of the disease. When the patient attempts to swallow liquids, forceful,
painful

           
expulsion occurs as a consequence of spasmodic contraction of the muscles
of swallowing

           
and respiration. Once experienced, the sight, sound or smell of liquids
may provoke the

           
syndrome. The ensuing choking may cause severe apnea (temporary cessation
of breathing)

           
and cyanosis. Death frequently occurs during the course of such a convulsive
attack.

           
Dehydration is a common consequence.

    3.     Paralytic phase – hydrophobia,
if present, disappears and swallowing becomes possible,

           
although difficult, as the paralytic phase sets in. A progressive, general,
flaccid paralysis

           
develops. Apathy shades into stupor, progressing to coma. There is urinary
incontinence.

           
Peripheral vascular collapse ensues and death follows.

            Definitive
diagnosis of rabies depends on laboratory procedures:

            1.    
Isolation of the virus from saliva, CSF, urine, nerve tissue

            2.     
Fluorescent rabies antibody (FRA) test on brain tissue

            3.    
Presence of Negri bodies

PROGNOSIS:

    Only 6 people have ever recovered from rabies. CNS
sequelae are common.

TREATMENT:

    The most important immediate treatment includes:

    1.     Washing the wound with
copious amounts of soap and water.

    2.     Apply 1% quaternary ammonium
compounds after all traces of soap have been removed.

    3.     Apply antirabies serum
by careful instillation into the wound and by infiltration around the

           
wound. Administer serum systemically.

    4.     Postpone suturing the
wound.

    5.     Institute antitetanus
procedures

    6.     Start administration of
vaccine pending autopsy of animal involved in the bite. Stop

           
treatment  if animal is normal.

    7.     If rabies symptoms ensue
give extensive supportive care (treat symptoms as they appear):

            a.    
Tracheostomy to prevent hypoxia

            b.    
Careful tracheal suctioning

            c.    
Use of supplemental oxygen

            d.    
Relieve intracranial pressure by insertion of a CSF reservoir connected
to the lateral

                   
ventricle (cavity in the forebrain, one in each cerebral hemisphere)

            e.    
Control focal seizures with anticonvulsant therapy

VACCINES AVAILABLE:

    1.     Rabies vaccine

            a.    
Semple – type of nerve tissue vaccine – no longer commercially available
in U.S.

                   
Causes severe immune reactions against the neural tissue.

            b.    
Duck embryo vaccine – hypersensitivity to eggs may result in a reaction
to this vaccine.

                   
This may include:

                   
(1)     Abdominal cramps

                   
(2)     Nausea

                   
(3)     Vomiting

                   
(4)     Transient urticaria (skin reaction)

                   
(5)     Anaphylactoid reactions

                   
Generally, however, the reactions are only local erythema and induration.

                   
Dose (minimum) – 1 ml/day subcutaneous for 14 days; (maximum) – 23 doses

                   
(requires 7-10 days for response).

            c.    
Attenuated virus vaccine grown in human diploid cells. Injected IM in any
part of the

                   
body. 1 ml dose. 5 injections at 3,7,14 and 28 days after first injection.

            d.    
Recombinant vaccine – vaccinia virus with rabies glycoprotein gene.