Epidemiology of Rabies - sbmu.ac.ir

Epidemiology of Rabies - sbmu.ac.ir

Clinical Epidemiology of Rabies 1 Definition History Etiology 2 Definition

A fatal viral disease (encephalomyelitis) In human and most other mammals One of the most common viral causes of mortality 15 million people annually receiving post-exposure vaccination to prevent the disease . 3 Definition 55000-100000 deaths occur each year because of rabies. Rabies is a neglected disease of

poor and vulnerable populations whose deaths are rarely reported. 4 Etiologic Etiologic agent agent Rabies virus

Genus : Lyssavirus (lyssa: rage in Greek) Family : Rabdoviridae family Enveloped bullet-shaped virus 5 structural proteins SS RNA, non-segmented 5 Rabies Virus Rabies virus particles 6

Rabies Rabies Virus Virus in in the the Environment Environment Normally, rabies virus cannot live long in a warm, putrefied environment, Survives in the body less than 24 hours after death. A few minutes in direct sunlight will inactivate rabies virus.

7 Rabies Rabies Virus Virus in in the the Environment Environment under cool conditions (in refrigerator) it may live for many days If the virus is frozen at -70oC, it can live for years. Rabies virus is no longer active in

dried saliva Is killed by bleach, ethyl alcohol, soap, detergent, and quaternary ammonium compounds. 8 Pathogenesis Pathogenesis of of Rabies Rabies Widespread CNS involvement Spreads to the CNS in the endoneurium of the Schwann cells

Enters the peripheral nerves through the neuromuscular junction Inoculation, the virus 9 replicates in the striated or connective tissue Pathogenesis Pathogenesis of of Rabies Rabies 10 Descriptive

epidemiology and occurrence 11 Clinical epidemiology of Rabies Definition and public health importance Etiologic agents Incubation period Natural couarse Geographical distribution Timeline trend

Age, Gender, Occupation, Social situation Predisposing factors Susceptibility & Resistance Secondary attack rate Modes of transmission, period of communicability OCCURRENCE 1) 2) 3) 4) 5) 6)

7) 8) 9) Prevention : primary, secondary, tertiary 12 11 -Incubation -Incubation Period Period 4 days or 19 years (rarely) Average : 30-90 days Depends on:

Wound severity Wound site (nerve supply) Distance from the brain Amount & strain of virus 13 14

22 -- Natural Natural course course Stage Duration Incubation period < 30 days (25%) 30-90 days (50%) 90-365 days (20%) > 365 days (5%)

Prodrome & early symptoms 2-10 days Acute neurologic disease Furious rabies (80%) Paralytic rabies (20%) 2-7 days 2-7 days Coma, Death

0-14 days Recovery Very rare 15 Natural Natural course course Exposure (usually from contaminated saliva through animal bites) Incubation

30-90 days Prodromal symptoms (fever, chills, malaise, fatigue, insomnia, anorexia, headache, anxiety and irritability) Up to 10 days Local Neurologic symptoms (pain, paresthesias, weakness) Classic (encephalitic) rabies symptoms -80% cases Paralytic rabies -20% cases Coma, Death ~~~ 100% 16

Rabies/clinical Rabies/clinical manifestations manifestations 5 phases of illness First phase: asymptomatic Second (prodromal) phase Third phase: neurologic signs

Forth phase : coma, death Fifth phase : recovery 17 Rabies/clinical Rabies/clinical manifestations manifestations First phase: asymptomatic Virus IP: 10-90 days (4d-19yr) 18 Rabies/clinical Rabies/clinical manifestations

manifestations Second (prodromal) phase 2-10d Viral invasion of CNS (limbic system, spinal cord, brain stem) Respiratory symptoms Gastrointestinal symptoms Behavioral & emotional symptoms Local pain itching, (50%) 19 Rabies/clinical Rabies/clinical manifestations manifestations

Third phase: neurologic signs Widespread infection of the brain Furious: Aggressiveness, biting, yelling, hallucinating Triggered by sensory stimuli Hydrophobia Aerophobia Violent diaphragmatic contractions Hyper-reflexia, cholinergic manifestations lacrimation, salivation, mydriasis, pyrexia 20 Rabies/clinical Rabies/clinical manifestations

manifestations Forth phase: coma, death Extensive cortical virus spread Death usually in 7 days Respiratory arrest Myocarditis 21 Rabies/clinical

Rabies/clinical manifestations manifestations Fifth phase: recovery Rare survivors Atypical presentations 1972: bat related, dysarthria, hemiparesis 1976: dog bite, quadreparesis,myoclonus, cerebellar signs,frontal lobe signs 1977: Lab worker, aerosol exposure to highly

concentrated fixed rabies virus 1992-1995: 4 Mexican children (3:dog, 1: vampire bat), received vaccine, no Ig 22 Non-Classical Rabies/clinical manifestations Neuropathic pain, radicular pain, objective sensory and motor deficits Choreiform movements of the bitten limb during prodromal phase Focal brain stem signs, myoclonus Hemiparesis, hemisensory loss, ataxia, vertigo Seizures, ataxia

23 Rabies/Differential Rabies/Differential Diagnosis Diagnosis Meningitis Meningitis//Encephalitis Encephalitis:: Japanese, Japanese, eastern eastern equine, equine, West West Nile Nile V.,

V., enterovirus enterovirus 71, 71, Nipah Nipah V. V. Epilepsy Epilepsy Drug Drug toxicity toxicity Acute Acute hepatic hepatic porphyria

porphyria,, neuropsychiatric neuropsychiatric disturbances disturbances Substance Substance abuse abuse,, acute acute serotonin serotonin syndrome syndrome 24 33 Geographical Geographical distribution

distribution Rabies occurs in more than 150 countries and territories Worldwide, more than 55 000 people die of rabies every year mostly in Asia and Africa. 40% of people who are bitten by suspect rabid animals are children Fact Sheet N99, July 2014 25 33 Geographical

Geographical distribution distribution 44 . 26

: 27 28

2 2 29

2 2 30

. 31 5 Age, Gender, Occupation, Social conditions 32

20 . 40% 15 33

Predisposing Predisposing factors factors 6 6 suitable suitable conditions conditions& & A bite with prominent salivary contamination (Bare skin ( Multiple bites Bites on the face Salivary contamination of broken skin

Mucus contamination Aerosolization (Respiratory tract) 34 77 Susceptibility Susceptibility and and Resistance Resistance All mammals are susceptible Humans are more resistant than several animal species 35

Susceptibility Susceptibility of of various various animal animal to to rabies rabies Very High Wolves Foxes Coyotes High

Hamsters Skunks Raccoons Kangaroo rats Cotton rats Jackals Voles Domestic cats Rabbits Bats

Cattle Moderate Low Dogs Opossums Primates 36 88 Secondary Secondary attack attack rate rate

.. 37 9 - Transmission

Bite of the rabid animals A fresh break in the skin Intact mucous membrane Person to person ? Organ transplantation Airborne spread from bats Airborne spread in laboratory 38 Period of communicability In dogs and cats for 3-7 days before onset of clinical signs and throughout the course of the disease

14 days before onset, in Ethiopian dogs In bats 12 days before evidence of illness Skunks , 8 days before . . . 39 Reservoir Caribbean: Mongoose Europe: Red fox Iran: Wolf Africa: Jackal

40 Global distribution of mammalian rabies reservoirs and vectors 41 Animal Animal bite bite in in Iran Iran 42

Animal Animal bite bite and and human human rabies rabies in in Iran Iran 43 Animal Animal rabies

rabies in in Iran Iran 44 45 Rabid wolves are associated with severe bites and human d Raccoons are social animals Well adapted to living at high population densities (urban/suburban) Prefer forested habitat 46

A productive pathogenesis cycle of animal rabies: virus entry into peripheral nerves via a bite, 47 movement to the central nervous system resulting in encephalitis, and transit to the salivary glands, mediating infection of another host. Rupprecht CE et al, The Lancet Infectious Diseases Vol 2 June 2002 48 Foxes maintain rabies from Arctic areas to temperate and tropical latitudes Arctic fox 49 50

The Jackal is an important candid reservoir of rabies in the old world Hosts 6/7 lyssavirus genotypes Widespread throughout North America, Latin America Infection rates in bats varies (4% to > 15%) Humans encounter bats that are sick, incapacitated Different bat species vary in their human interaction Primary reservoir for rabies in

All continents. 51 Prevention and Control 52 Prevention and Control Primary Prevention: Prevention of disease in well individuals

Secondary Prevention: Identification and intervention in early stages of disease Tertiary Prevention: Prevention of further deterioration, reduction in complications 53

Primary Primary Prevention: Prevention: Pre-exposure Pre-exposure prophylaxis: prophylaxis: vaccination of people in high risk groups:

Veterinarians Animal handlers Certain lab workers Travel to areas where canine rabies is common 54 Primary Primary Prevention: Prevention: Pre-exposure Pre-exposure prophylaxis prophylaxis::

vaccination: intramuscular, 1ml (3 doses): at 0, 7, 21-28 days Antibodies usually persist for 2 yrs Repeat titers q6-24 months depending on level of exposure Acceptable titer levels are 0.5 IU/ml 55 Rabies

Rabies vaccines vaccines Human Diploid Cell Vaccine (HDCV) Purified vero cell vaccine (PVRV) Purified chicken embryo cell (PCEC) 56 Post-exposure Post-exposure wound wound care care

Prevent virus in wound from reaching neural tissue Prompt and thorough cleaning: flush wound with soap and water Benzalkonium chloride not superior to soap Update tetanus immunization Treat secondary bacterial infection Do not suture wound if possible 57 58

Post-exposure Post-exposure Prophylaxis Prophylaxis Exposure other than bite rarely causes infection Prophylaxis to patients with open wound scratch mucous membrane contaminated by : saliva or potentially infectious material from rabid 59

animal Post-exposure Post-exposure Prophylaxis Prophylaxis Human Human Exposure Exposure with with Rabies Rabies Prophylaxis to people with sig. exposure to a rabies pt. if scratch bite

mucous membrane exposure to saliva or infectious tissue No prophylaxis if casual contact (touching) or exposure to non-infectious material (urine, stool) 60 Post-exposure Post-exposure Prophylaxis Prophylaxis

))... ... Standard universal precautions Respiratory precautions Pre-exposure prophylaxis

Check the antibody titer (~ 0.5 IU/mL) Exposures to potentially contaminated secretions or tissues should lead to standard PET 61 Post-exposure Post-exposure immunoprophylaxis immunoprophylaxis

Passive and active Start ASAP (As soon as possible) RIG and rabies vaccine Vaccine : one of the 3 types (5 doses), same dose for all ages 1.0 ml IM at 0, 3, 7, 14, 28 d

Intradermal regimens:used alternatively Avoid gluteal injection: less antibody response than deltoid . Red Book 2003 62 Post-exposure Post-exposure immunoprophylaxis immunoprophylaxis Human RIG is Given at the same time with the vaccine (ASAP) Dose: 20 IU/kg

As much as possible to infiltrate the wound Remainder is given IM (is not the first choice) RIG and vaccine are Give at different sites & in different syringes Purified equine RIG : dose is 40 IU/kg, may need desensitization 63 22 -- Secondary Secondary Prevention: Prevention: Identification Identification And

And intervention intervention in in early early stages stages of of disease disease 64 Rabies/Diagnosis

Rabies/Diagnosis Frequently missed Lab tests are non diagnostic Hyponatremia: inadequate intake, SIADH hypernatremia,: rare CSF analysis normal in 1/3 of patients in the 1 st wk of illness CSF: viral meningoencephalitis

EEG and head CT may be normal early in illness 65 Rabies/Diagnosis Rabies/Diagnosis MRI: abnormal, ill defined, increase signal intensity on T-2 images Areas involved: brainstem, hippocampi, hypothalami, deep & subcortical white and grey matter 66

Rabies/Diagnosis Rabies/Diagnosis Tissue Tissue studies studies Brain tissue: culture, histology for Negri bodies Immunohistochemistry on tissue Brain tissue: Immunostain 67 Rabies/Diagnosis

Rabies specific antibodies in serum or CSF (RFFIT) Serology positive in serum in 7 days of symptoms Serology positive in CSF in 13 days of symptoms Rabies vaccine does not cause positive CSF antibodies Molecular studies, monoclonal antibodies in epidemiologic studies Hammond GW (Principles and Practice of Pediatric Infectious diseases) 68

Section of rabid human brain processed by the DFA test, showing widespread viral inclusions, staining apple-green in colour 69 Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002 A neuron from a formalin-fixed section of a brain from a patient with rabies, showing reddish-brown viral inclusions in the cytoplasm. Processed by immunohistochemistry. 70 Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002 Diagnosis of Rabies Negri Body in neuron cell

(source: CDC) Positive DFA test (Source: CDC 71 22 -- Secondary Secondary Prevention Prevention Treatment Treatment of of Rabies Rabies

No specific treatment once symptoms have begun Intensive care Almost all patients succumb to disease in a few weeks 72 Secondary Secondary Prevention Prevention Treatment Treatment of of Rabies

Rabies The 3 patients in the 1970s survived A child in 1994 which received only rabies vaccine No effective drug No benefit of interfrons, Ribavirin & Cytosine arabinoside 73 3 - Tertiary Prevention: Surgical intervention

74 Sources : Mandell, Douglas, Bennett; Principles and Practice of Infectious Diseases, 6th edition, 2015. Kasper, Braunwald, Fauci, Hauser, Longo, Jameson : Harrison's Principles of Internal Medicine; 18th Edition, 2012 Feigin, Cherry, Demmler, Kaplan : Textbook of Pediatric Infectious Diseases, 6th edit., Saunders, 2008. David L. Heymann (edit.): Control of Communicable Diseases Manual, 19th Edition, 2008, CDC Internet Site, 2011 WHO, Fact Sheet N99, September 2014 Tony J. and Leoni G. Causes, Effects, in Animals and Humans Tony J. and

Leoni G. Lillian A. Orciari, Epidemiology of Rabies 75 Sources : Rabies Management Guideline, A compendium of rabies control measures and planning strategies compiled by the Maine Rabies Work Group 2005, pp. 1-107. WHO Expert Consultation on Rabies (2004 : Geneva, Switzerland) WHO Expert Consultation on Rabies : first report.(WHO technical report series ; 931), World Health Organization 2005, PP. 1-121 Arjun Srinivasan, Elizabeth C. Burton . . . Transmission of Rabies Virus from an Organ Donor to Four Transplant Recipients, New England Journal

of Medicine, 2005; 352: 1103-11. Rodney E. Willoughby, Jr. . . . Survival after Treatment of Rabies with Induction of Coma, New England Journal of Medicine, 2005;352:2508-14. Charles E. Rupprecht, Robert V. Gibbons, Prophylaxis Against Rabies, New England Journal of Medicine, 2004;351:2626-35. : 33

.165-203 1384 76 77

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