Michelle Aguirre, PharmD

RABIES CASE PRESENTATION Medical Center Hospital

September 8th, 2017
PART I: CASE INTRODUCTION AND Michelle Aguirre, PharmD
Medical Center Hospital
DISEASE OVERVIEW September 8th, 2017
 CASE INTRODUCTION
Chief complaint
 Unobtainable at the moment
History of present illness
 JC is a 49-year-old male who was walking down the street and was
drinking one liter of vodka roaming exhibiting signs of confusion. He was
called by his neighbor to go back to his house, as it was hot in the day.
The patient refused to go back to this home and had recurrent falls on
his head and sustained multiple injuries on his limbs and left knee. Along
his journey, a dog came and bit him on his left knee and then ran away.
Afterwards, one of the neighbors called the ambulance and the patient
was transferred to the ER for further care.
CASE INTRODUCTION

PMH Allergies
 Hypertension  Sulfa (reaction unknown)
 Bipolar disorder
 Chronic active alcoholism
Home Medications
 Seroquel 400 mg PO daily
Family history  Lithium 300 mg PO TID
 Unknown  Lisinopril 20 mg PO daily

Social history
 Drinks about one liter of vodka
every day for the last 20 years
and has multiple admissions for
alcohol withdrawal symptoms
CASE INTRODUCTION
Review of systems:
 General appearance: Patient was awake and alert and in severe acute distress
 Head: Normocephalic. No raccoon’s eyes or battle signs
 Neck: Mild tenderness in the upper cervical spine/posterior scalp
 Eyes: PERRLA, extraocular muscles intact
 Respiratory: Lungs clear to auscultation bilaterally, no respiratory distress
 Cardiovascular: Regular rate and rhythm, no murmurs, rubs, or gallops
 Abdomen: Soft, nontender, nondistended
 Neuro: GCS 15, awake alert, and oriented x4
 Skin: Multiple bruises noted from patient’s posterior shoulder to his right flank;
There is a large bruise over the patient’s left knee with good range of motion.
Also, presence of dog bite with minor skin abrasions
 Extremities: Left knee bruise, normal range of motion
CASE INTRODUCTION
Vital Signs
HR: 77 RR: 13 BP: 58/25 Temp: 101F Weight: 91kg Height: 6’6’’
Labs

Na 129 L Glucose 76 WBC 14.8 H

K 4.0 Mg Hgb 9.2
Cl 75 L Albumin 3.6 Plts 124 L
CO2 16 L AST 42 H Lact. Acid 3.1 H
BUN 112 H ALT 38 PT 18.0 H
SCr 20.6 H Bili 0.9 INR 1.53 H
CASE INTRODUCTION
JC is admitted to the ICU where the admitting physician decides to
start this patient on a rabies vaccine schedule
The whole ICU team is now on the case and will follow the patient
clinically and make adjustments as necessary
RABIES: BACKGROUND
Rabies is a zoonotic disease caused by RNA viruses in the family
Rhabdoviridae, genus Lyssavirus
Virus is transmitted in the saliva of rabid mammals via a bite
After entry to the central nervous system, these viruses cause an acute
progressive encephalomyelitis
The incubation period usually ranges from 1 to 3 months after
exposure, but can range from days to years
The vast majority of rabies cases reported to the Centers for Disease
Control and Prevention (CDC) each year occur in wild animals like
raccoons, skunks, bats, and foxes
EPIDEMIOLOGY
Over the last 100 years, rabies in the United States has changed
dramatically
More than 90% of all animal cases reported annually to CDC now
occur in wildlife (before 1960, the majority were domestic animals)
The principal rabies hosts today are wild carnivores and bats
The number of rabies-related human deaths in the United states has
declined from more than 100 annually at the turn of the century to
one or two per year in the 1990’s
Prompt wound care and the administration of rabies immune globulin
(RIG) and vaccine are highly effective in preventing human rabies
following exposure
TRANSMISSION
The route of infection is usually, but not necessarily, by a bite
In many cases the affected animal is exceptionally aggressive, may
attack without provocation, and exhibits otherwise uncharacteristic
behavior
Transmission may also occur via an aerosol through mucous membranes
(transmission in this form may have happened in people exploring
caves populated by rabid bats)
Transmission between humans is extremely rare, although it can
happen through transplant surgery, or, eve, more rarely through bites
or kisses
Various routes of transmission have been documented and include
contamination of mucous membranes (i.e., eyes, nose mouth), aerosol
transmission, and corneal transplantations
PATHOPHYSIOLOGY: OVERVIEW

• The virus directly or indirectly enters the peripheral nervous system

Infection by • It then travels along the nerves towards the central nervous system
bite

• Rapid encephalitis develops and symptoms appear

Virus reaches • The spinal cord may inflame producing myelitis
brain

• Lymphocytes, polymorphonuclear leukocytes, and plasma cells may

leak throughout the entire CNS
Perivascular • Virus enters salivary glands and other organs of victim
infiltration

Am J Vet Res. 1966 Jan;27(116):24-32

SIGNS AND SYMPTOMS
When a person contracts rabies, they do not show symptoms
immediately
The disease takes a period of time to manifest in the body which is
known as its period of incubation
Once symptoms arise, the patients condition deteriorates rapidly
FIVE STAGES OF RABIES
Incubation period: 5 days to > 2 years
U.S. median ~ 35 days

Pro-dome State: 0-10 days

Early flu-like symptoms

Acute neurologic period: 2-7 days

Neurologic symptoms begin

Coma: 5-14 days

Requires mechanical ventilation

Death
SIGNS AND SYMPTOMS
Early Symptoms Late Symptoms
• Fever • Insomnia
• Headache • Anxiety
• Generalized weakness • Confusion
• Generalized discomfort • Slight or partial paralysis
• Excitation
• Hallucinations
• Agitation
• Hypersalivation
• Difficulty swallowing
• Hydrophobia

*Death usually occurs within day of the onset of late symptoms

DIAGNOSIS
In animals, rabies is diagnosed using the direct fluorescent antibody
(DFA) test, which looks for the presence of rabies virus antigens in
brain tissue
Several tests are required in humans to diagnose rabies ante-mortem
(before death); no single test is sufficient
Saliva can be tested by virus isolation or reverse transcription
followed by polymerase chain reaction (RT-PCR)
Serum and spinal fluid are tested for antibodies to rabies virus
Skin biopsy specimens are examined for rabies antigen in the
cutaneous nerves at the base of hair follicles
 Schizophrenia Final

PART II: DRUG THERAPY DISCUSSION Presentation

Michelle Aguirre, PharmD
Candidate 2017
EARLY MANAGEMENT
Wash any wounds immediately
 One of the most effective ways to decrease the chance for infection is to
wash the wound thoroughly with soap and water

Refer to a doctor
 For attention for any trauma due to the animal attack before considering
the need for rabies vaccination
 The doctor, possibly in consultation with state or local health department,
will decide on the need of rabies vaccination
 Decisions to start vaccination, known as post-exposure prophylaxis (PEP) are
up to the discretion of the physician, but two organizations have developed
recommendations:
 Advisory Committee on Immunization Practices (ACIP) schedule for rabies vaccine (2010)
 World Health Organization (WHO) pre- and post-exposure prophylaxis 2010
EARLY MANAGEMENT
Post-exposure prophylaxis (PEP)
 CDC recommends following ACIP 2010 vaccination schedule
 Consists of one dose of immune globulin and four doses of rabies vaccine over a 14-
day period
 Rabies immune globulin and the first dose of rabies vaccine should be given by a
health care provider as soon as possible after exposure
 Additional doses or rabies vaccine should be given on days 3, 7, and 14 after the
first vaccination
 Current vaccines are relatively painless and are given in the arm, like a flu vaccine
 Rabies immunoglobulin is referred to as “passive immunization” while rabies vaccine is
referred to as “active immunization”
*Recommendations for PEP schedules are based on vaccination status: not
previously vaccinated vs. previously vaccinated*
POST-EXPOSURE PROPHYLAXIS
Goal: To neutralize the virus at the site of infection before it can enter
the human nervous system  generally ensures survival
Rabies Immune Globulin
 The administration of RIG provides immediate virus-neutralizing antibodies until
protective antibodies are generated in response to vaccine
 HRIG has a half-life of approximately three weeks
 Two preparations of HRIG are licensed and available in the U.S.

Rabies Vaccines
 Rabies vaccine induces the production for protective virus-neutralizing antibodies
within approximately 7 to 10 days that persist for several years
 Two licensed vaccines are currently available in the U.S.
DYNAMICS OF RABIES AND PEP

Figure 1. Schematic of dynamics of rabies virus pathogenesis in the

presence and absence of PEP-mediated immune responses
NOT PREVIOUSLY VACCINATED
Intervention Regimen
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water. If
available, a virucidal agent (e.g., povidine-iodine
solution) should be used to irrigate the wounds
Human rabies Administer 20 IU/kg body weight on day 0. If
immune globulin anatomically feasible, the full dose should be
(HRIG) infiltrated around and into the wound(s), and any
remaining volume should be administered
intramuscularly at an anatomical site distant from the
vaccine administration
Vaccine Human diploid cell vaccine (HDCV) or purified chick
embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid
area), 1 each on days 0, 3, 7 and 14
PREVIOUSLY VACCINATED
Intervention Regimen
Wound cleansing All PEP should begin with immediate thorough
cleansing of all wounds with soap and water. If
available, a virucidal agent (e.g., povidine-iodine
solution) should be used to irrigate the wounds
Human rabies HRIG should not be administered
immune globulin
(HRIG)
Vaccine Human diploid cell vaccine (HDCV) or purified chick
embryo cell vaccine (PCECV) 1.0 mL, IM (deltoid
area), 1 each on days 0 and 3
POST-EXPOSURE PROPHYLAXIS FOR
UNVACCINATED PERSONS
1. The combination of RIG and vaccine is recommended for both bite
and non-bite exposures, regardless of the time interval between
exposure and initiation of PEP
2. If PEP has been initiated and appropriate laboratory diagnostic
testing (i.e., the direct fluorescent antibody test) indicates that the
animal that caused the exposure was not rabid, PEP may be
discontinued
3. If HRIG was not administered when vaccination was begun on day
0, it can be administered up to and including day 7 of the PEP
series
4. Even when PEP is administered imperfectly or not according to the
schedule, it might generally be effective
OTHER KEY POINTS
HRIG is not administered in the same syringe or at the same anatomic
site as the first vaccine dose
The gluteal area should not be used because administration of vaccine
in this area may result in diminished immunologic response
Children should receive the same vaccine dose (i.e., vaccine volume) as
recommended for adults
SEROLOGIC TESTING
All healthy persons tested in accordance with ACIP guidelines after
completion of at least a 4-dose regimen of rabies PEP should
demonstrate an adequate antibody response against rabies virus
No routine testing of healthy patients completing PEP is necessary to
document seroconversion
When titers are obtained, serum specimens collected 1-2 weeks after
prophylaxis should completely neutralize challenge virus
The titers will decline gradually since the last vaccination
ADVERSE REACTIONS AND PRECAUTIONS
Adverse effects with modern human rabies vaccination are uncommon
Pregnancy and infancy are not contraindications
Immunosuppression
 All rabies vaccines licensed in the United States are inactivated cell-culture vaccines
that can be administered safely to persons with altered immunocompetence
 Use of corticosteroids, other immunosuppressive agents, antimalarials, and
immunosuppressive illnesses might reduce immune responses to rabies vaccines and
should receive a 5-dose vaccine regimen
PRICING AND AVAILABILITY
Rabies Immune Globulin
Injection (HyperRAB S/D Intramuscular)
 150 units/mL (2mL): $852.14

Injection (Imogam Rabies-HT Intramuscular)

 150 units/mL (2mL): $867.05

Rabies Virus Vaccine

Injection (Imovax Rabies Intramuscular)
 2.5 units/mL (1): $386.76

Location at Medical Center Hospital

Immunoglobulin is stored in Gloria’s office in the first refrigerator
Vaccines are dispensed from the central pharmacy
WHO VACCINE RECOMMENDATIONS
Definition of categories of exposure and use of rabies biologicals
from the World Health Organization (2010)

Immune Transdermal bites or scratches, licks on

globulin + broken skin, contamination of mucous
vaccine membrane with saliva, or contact with bats

Vaccine Minor scratches or abrasions without

bleeding or and nibbling of uncovered
only skin

No Touching, feeding of animals, or licks on

prophylaxis intact skin
INFECTIOUS DISEASES SOCIETY OF
AMERICA
Skin and Soft Tissue Infection Guidelines (2014)
 Specific recommendations are made for dog bites, including indications for
antimicrobials
 IDSA briefly mention PEP in their guidelines

Therapy Recommendation

Post-exposure • May be indicated; consultation with local health officials

prophylaxis is recommended to determine if vaccination should be
initiated
PART III: CLINICAL COURSE Michelle Aguirre, PharmD
Candidate 2017
CLINICAL COURSE
Day 1: JC received the following regimen on day 0:

 No documentation of wound care was found

 Dog that bit patient was presumably killed by neighbor who owned dog
CLINICAL COURSE
Was this treatment appropriate?
 Correct treatment
The recommendation is to administer:
Immune globulin 20 IU/kg x 91 kg = ~18,000 units
Chick embryo cell vaccine 2.5 mL/mL x 2.5 mg = 1 mL
Both should be given intramuscularly on day 0!

However, we do not know if he received proper wound care…

CLINICAL COURSE
Days that followed:

Day 0
RIG and Day 7 Day 14
vaccine 1 Vaccine 3 Scheduled vaccine
1 mL 1 mL never given

Day 4 Day 12
Vaccine 2 Patient
1 mL discharged

Is this regimen appropriate?

PATIENT COURSE CONCLUSION
 JC received the correct doses for RIG and vaccines
 ACIP recommends immune globulin + vaccines (CDC
preferred); WHO classification is difficult to determine
but likely recommends vaccine only for this patient
 Wound care was never documented in the patient chart
± Although the treatment plan did not follow the vaccine schedule
days exactly and the patient did not receive the last vaccine,
he is expected to have some general immunity
QUESTIONS?
REFERENCES
1. CDC. Rabies. Centers for Disease Control and Prevention [cited
September 1, 2017]. Available from
[https://www.cdc.gov/rabies/index.html].
2. CDC. Rabies prevention – Unites States, 2010: recommendations
of the Immunization Practices Advisory Committee (ACIP). Y40(No.
RRR-3)
3. Dietzschold B, Schnell M, Koprowski H. Pathogenesis of rabies. Curr
Top Microbiol Immunol. 2005;292:45-56.
4. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for
the diagnosis and management of skin and soft tissue infections:
2014 update by the infectious diseases society of America. Clin
Infect Dis. 2014;59(2):147-59.