Rabies


– Rabies is a viral infection of wild and domestic mammals, transmitted to humans by the saliva of infected animals through bites, scratches or licks on broken skin or mucous membranes. 
– In endemic areas (Africa and Asia), 99% of cases are due to dog bites and 40% of cases are children under 15 years of age.1
– Before symptoms develop, rabies can effectively be prevented by post-exposure prophylaxis.
– Once symptoms develop, rabies is fatal. There is no curative treatment; care is palliative. 

Clinical features

– The incubation period averages 20 to 90 days from exposure (75% of patients), but can be shorter (in severe exposure, e.g. bites to face, head and hands; multiple bites), or longer (20% of patients develop symptoms between 90 days and 1 year, and 5% more than 1 year after exposure).

– Prodromal phase: itching or paraesthesiae or neuropathic pain around the site of exposure, and non-specific symptoms (fever, malaise, etc.).

– Neurologic phase:
• Encephalitic form (furious form): psychomotor agitation or hydrophobia (throat spasms and panic, triggered by attempting to drink or sight/sound/touch of water) and aerophobia (similar response to a draft of air); sometimes seizures. The patient is calm and lucid between episodes. Infection evolves to paralysis and coma.
• Paralytic form (less common, 20% of cases): progressive ascending paralysis resembling Guillain-Barré syndrome; evolves to coma.

Diagnosis is often difficult: there may be no history of scratch or bite (exposure through licking) or wounds may have healed; a reliable history may be difficult to obtain.

Post-exposure prophylaxis

Definitions of exposure categories (WHO)

Category I

Contact with animal, or licks on intact skin

No exposure

Category II

Nibbles on exposed skin
Minor bite(s) or scratch(es) without bleeding

Minor exposure

Category III

Transdermal bite(s) or scratch(es)
Licks on broken skin
Contamination of mucous membranes by animal’s saliva (licks)
Direct contact with bats1

Severe exposure

Post-exposure prophylaxis is carried out for Category II and III exposures.

Treatment of the wound

In all cases
Prolonged cleansing of the wound or contact site for 15 minutes to eliminate the virus, as soon as possible after exposure, is of critical importance. For skin: use soap, rinse copiously with running water, remove all foreign material; application of a disinfectant (polyvidone iodine 10% or other) is an additional precaution which does not take the place of thorough wound washing. For mucous membranes (eye, mouth, etc.): rinse thoroughly with water or 0.9% sodium chloride. Local cleansing is indicated even if the patient presents late.

According to condition/type of wound
In order to avoid inoculating virus deeper into the tissues, wounds are either not sutured at all (e.g. superficial, non-mutilating or puncture wounds), or are left open and re-evaluated in 48-72 hours, with a view to possible closure. Highly contaminated wounds, or wounds that may compromise function, require surgical management (exploration, removal of foreign material, excision of necrotic tissue, copious irrigation with sterile 0.9% sodium chloride or Ringer lactate, with local or general anaesthesia). When suturing is indicated (face), rabies immunoglobulin should be administered several hours before wound closure (see below). Infected wounds are not sutured and reassessed daily.

Passive and active immunisation

Given the duration of incubation, administration of vaccine/immunoglobulin is always a priority, even for patients exposed several months previously.

Anti-rabies serotherapy
Rabies immunoglobulin is indicated after:
– Category III exposures (except in patients who have received a full course of pre-exposure prophylaxis against rabies, see Prevention); 
– Category II and III exposures in immunocompromised patients2 (even in patients who have received a full course of pre-exposure prophylaxis against rabies).

It is intended to neutralize virus in the exposure site. It is given as a single dose on D0, with the first dose of rabies vaccine.
human rabies immunoglobulin:
Children and adults: 20 IU/kg
or
highly purified rabies immunoglobulin F(ab')2 fragments:
Children and adults: 40 IU/kg

Infiltrate rabies immunoglobulin into and around the previously washed wound(s). Ensure it is not injected into a blood vessel (risk of shock).
For finger wounds, infiltrate very cautiously to avoid increased pressure in the tissue compartment (compartment syndrome).
In the event of multiple wounds, dilute the dose 2- to 3-fold with sterile 0.9% sodium chloride to obtain a sufficient quantity to infiltrate all the sites exposed.
For mucosal exposures with no wound, rinse with rabies immunoglobulin diluted in sterile 0.9% sodium chloride.

Monitor the patient during and after the injection (low risk of anaphylactic reaction).

If rabies immunoglobulin is not available on D0, the first dose of rabies vaccine is administered alone. Administer rabies immunoglobulin as soon as possible between D0 and D7; from D8, it is not necessary to administer rabies immunoglobulin as vaccine-induced antibodies begin to appear.1

Post-exposure rabies prophylaxis 
A complete prophylaxis series is indicated for Category II and III exposures. It should be started on D0 and continued to completion if the risk of rabies has not been excluded3 . Several different types of rabies vaccines prepared from cell cutures (CCEEV) exist.  These vaccines must replace nerve tissue vaccines (NTV). 
Prophylaxis schedules may vary from country to country, check national recommendations. The patient must be administered the full course of doses indicated. 

Main post-exposure prophylaxis regimens1



Date

No pre-exposure prophylaxis or unknown prophylaxis status
or incomplete pre-exposure prophylaxis or complete pre-exposure prophylaxis with an NTV

IM route(b)
1 dose = 0.5 or 1 ml depending on the manufacturer

ID route(c)
1 dose = 0.1 ml

D0(a)

2 doses
(1 dose in each arm or thigh)

1 dose

2 doses
(1 dose in each arm)

D3


1 dose

2 doses
(1 dose in each arm)

D7

1 dose

1 dose

2 doses
(1 dose in each arm)

D14(d)


1 dose


D21

1 dose



(a) As well as a single dose of rabies immunoglobulin if indicated.
(b) IM route: in the anterolateral thigh in children < 2 years; in the deltoid muscle (arm) in children ≥ 2 years and adults; never inject into the gluteal muscle.
(c) ID route: in the deltoid muscle (or the suprascapular region or the anterolateral thigh). Incorrect ID technique results in failure of post-exposure prophylaxis: if correct ID technique cannot be assured, use the IM route.
(d) The injection can be administered between D14 and D28.

Notes:
• In immunocompromised patients: 1 dose on D0, 1 dose on D7 and 1 dose between D21 and D281
• In patients that have received a full course of pre-exposure prophylaxis (see  Prevention), the post-exposure regimen is: 1 dose on D0 and 1 dose D3 by IM or ID route or 4 doses by ID route on D0.

Other measures

Antibiotherapy/antibioprophylaxis2

Infection present

• local: redness, oedema, serosanguinous or purulent drainage
• local or general: lymphangitis, lymphadenopathy, localised cellulitis, bone or joint infection, fever

No infection
and

• wounds on the face or hands or genital region
•  wounds involving joint, tendon, ligament or fracture
• deep puncture wounds
• wounds with crush injury
• wounds very contaminated or requiring debridement
• wounds where correct debridement is not possible
• immunocompromised patients

No infection
and

• no criteria requiring antibiotic prophylaxis
• wounds more than 24-48 hours old

Antibiotherapy PO 7 days in the event of local non severe infection;
14 days in the event of severe local infection, or widespread generalised infection.

Antibiotic prophylaxis PO 5 to 7 days

No antibiotic prophylaxis

The same dosage is used for both treatment and prophylaxis:
The treatment of choice is amoxicillin/clavulanic acid (co-amoxiclav) PO 4
Use formulations in a ratio of 8:1 or 7:1. The dose is expressed in amoxicillin:
Children < 40 kg: 25 mg/kg 2 times daily 
Children ≥ 40 kg and adults: 
Ratio 8:1: 2000 mg daily (2 tablets of 500/62.5 mg 2 times daily)
Ratio 7:1: 1750 mg daily (1 tablet of 875/125 mg 2 times daily)

Tetanus vaccination and serotherapy
Check prophylaxis status. If unknown or not up-to-date, see Tetanus, Chapter 7.

Prevention

Pre-exposure prophylaxis with a CCEEV for people at risk (prolonged stay in rabies endemic areas, professionals in contact with animals susceptible of carrying the virus, etc): 1 dose by IM route or 2 doses by ID route on D0 and D7.



Footnotes
Ref Notes
1 In the event of direct contact with bats, check national recommendations.
2 For example, for HIV-infected patients: CD4 ≤ 25% in children < 5 years and < 200 cells/mm³ in children ≥ 5 years and adults.1
3 Either through observation of the captured animal (if domestic) or through laboratory diagnosis of the animal (killed). The WHO recommends a 10-day observation period of the animal, if captured. If no signs of rabies develop during the observation period, the risk of rabies is excluded, and post-exposure prophylaxis is discontinued. Laboratory diagnosis of the dead animal involves sending the head to a specialised laboratory, which confirms or excludes rabies in the animal. If laboratory diagnosis is negative, risk of rabies is excluded, and post-exposure prophylaxis is discontinued.
4

In penicillin-allergic patients: 
• Children: co-trimoxazole (30 mg SMX + 6 mg TMP/kg 2 times daily) + clindamycin (10 mg/kg 3 times daily) 
• Adults: co-trimoxazole (800 mg SMX + 160 mg TMP 2 times daily) or doxycycline (100 mg 2 times daily or 200 mg once daily, except in pregnant and lactating women) + metronidazole (500 mg 3 times daily).


References

  1. Weekly epidemiological record/Relevé épidémiologique hebdomadaire, 20 April 2018, 93th year/20 avril 2018, 93e année. No 16, 2018, 93, 201–220.
    http://apps.who.int/iris/bitstream/handle/10665/272371/WER9316.pdf?ua=1 [Accessed 25 october 2018]

  2. Spencer O, Banerjee S. Animal bites. BMJ Best practice 2018 [Accessed 25 october 2018]