Rabies

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    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] Citation 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]
    .

     

    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 bats a Citation a. In the event of direct contact with bats, check national recommendations.

    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 (povidone 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 patients b Citation b. For example, for HIV-infected patients: CD4 ≤ 25% in children < 5 years and < 200 cells/mm³ in children ≥ 5 years and adults.
      (http://apps.who.int/iris/bitstream/handle/10665/272371/WER9316.pdf?ua=1)
      (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.
    Infiltrate rabies immunoglobulin into the wound even if it has already healed. 
    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] Citation 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]

    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 excluded c Citation c. 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. . Several different types of rabies vaccines prepared from cell cultures (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 regimens [1] Citation 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]

    Date No pre-exposure prophylaxis or unknown prophylaxis status
    or incomplete pre-exposure prophylaxis or complete pre-exposure prophylaxis with an NTV
    IM route (a) Citation a. IM route: there are two possible schedules, the Zagreb regimen (2-0-1-0-1) over 21 days or the 4-dose Essen regimen (1-1-1-1-0) over 14 to 28 days. The IM injection is administered into the anterolateral part of the thigh in children < 2 years; into the deltoid muscle (arm) in children ≥ 2 years and adults; do not administer into the gluteal muscle.
    1 dose = 0.5 or 1 ml depending on the manufacturer
    ID route (b) Citation b. ID route: inject into the deltoid muscle (or the suprascapular region or the anterolateral part of the thigh). Incorrect ID technique results in failure of post-exposure prophylaxis. If correct ID technique cannot be assured, use IM route.
    1 dose = 0.1 ml

    D0

    2 doses (c) Citation c. As well as a single dose of rabies immunoglobulin on D0 if indicated.
    (1 dose in each arm or thigh)

    1 dose (c) Citation c. As well as a single dose of rabies immunoglobulin on D0 if indicated.

    2 doses (c) Citation c. As well as a single dose of rabies immunoglobulin on D0 if indicated.
    (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

     

    1 dose (d) Citation d. The last injection can be administered between D14 and D28.

     

    D21

    1 dose

       

    Notes:

    • In immunocompromised patients: 1 dose on D0, 1 dose on D7 and 1 dose between D21 and D28. [1] Citation 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]
    • 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/antibiotic prophylaxis [2] Citation 2. Spencer O, Banerjee S. Animal bites. BMJ Best practice 2018 [Accessed 25 october 2018]

    Infection present No infection
    and
    No infection
    and
    • local: redness, oedema, serosanguinous or purulent drainage
    • locoregional or general: lymphangitis, lymphadenopathy, localised cellulitis, bone or joint infection, fever
    • 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 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 d Citation d. 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).

    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
    • (a)In the event of direct contact with bats, check national recommendations.
    • (b)For example, for HIV-infected patients: CD4 ≤ 25% in children < 5 years and < 200 cells/mm³ in children ≥ 5 years and adults.
      (http://apps.who.int/iris/bitstream/handle/10665/272371/WER9316.pdf?ua=1)
    • (c)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.
    • (d)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).
    • (a)IM route: there are two possible schedules, the Zagreb regimen (2-0-1-0-1) over 21 days or the 4-dose Essen regimen (1-1-1-1-0) over 14 to 28 days. The IM injection is administered into the anterolateral part of the thigh in children < 2 years; into the deltoid muscle (arm) in children ≥ 2 years and adults; do not administer into the gluteal muscle.
    • (b)ID route: inject into the deltoid muscle (or the suprascapular region or the anterolateral part of the thigh). Incorrect ID technique results in failure of post-exposure prophylaxis. If correct ID technique cannot be assured, use IM route.
    • (c) As well as a single dose of rabies immunoglobulin on D0 if indicated.
    • (d)The last injection can be administered between D14 and D28.
    References