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بسم هللا الرحمن الرحيم 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 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 Virus in the 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 Virus in the 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 • Rabies virus is no longer active in dried saliva • Is killed by bleach, ethyl alcohol, soap, detergent, and quaternary ammonium compounds. 8 Pathogenesis of Rabies Widespread CNS involvement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 of Rabies 10 Descriptive epidemiology and occurrence 11 Clinical epidemiology of Rabies Definition and public health importance Etiologic agents 1) 2) 3) 4) 5) 6) 7) 8) 9) 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 Prevention : primary, secondary, tertiary 12 1 -Incubation 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 محدوده دوره كمون هاري 14 2 - Natural 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 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 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 manifestations • First phase: asymptomatic • Virus IP: 10-90 days (4d-19yr) 18 Rabies/clinical 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 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 manifestations • Forth phase: coma, death • • • • Extensive cortical virus spread Death usually in 7 days Respiratory arrest Myocarditis 21 Rabies/clinical 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 Diagnosis • Meningitis/Encephalitis: Japanese, eastern equine, West Nile V., enterovirus 71, Nipah V. • Epilepsy • Drug toxicity • Acute hepatic porphyria, neuropsychiatric disturbances • Substance abuse, acute serotonin syndrome 24 3 – Geographical 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 25 Fact Sheet N°99, July 2014 3 – Geographical distribution • در 44كشور يا منطقه به مرحله حذف رسيده و موردي گزارش نشده است • قطب جنوب و تعدادي از جزاير ،در ساير مناطق جهان عاري ازهاري است. • در جنوب شرقي آسيا ،فيليپين ،آفريقا ،شبه قاره هند و مناطق گرمسيري آمريكاي جنوبي از شيوع بيشتري برخورداراست 26 وضعيت هاري درايران • تقريبا همه استانها كم و بيش با مشكل هاري مواجه هستند بيشترين موارد هاري در : • حاشيه درياي خزر • شمال شرقي • جنوب غربي 27 28 گزارش 2مورد ناش ي ازپيوند قرنيه درايران 29 گزارش 2مورد ناش ي ازپيوند قرنيه درايران 30 تاثيرفصل • در بعض ي از مناطق گرمسيري ،در فصل پاييز و زمستان به دنبال شيوع هاري سگسانان، موارد هاري انساني هم افزايش مييابد. 31 5 – Age, Gender, Occupation, Social conditions 32 تاثيرسن و جنس ّ قريب دوسوم تا سه چهارم موارد هاري ،در جنس ّ مذكر و به طور كلي ،بيشترين موارد بيماري ،در سنين كمتراز 20سالگي بروزمينمايد. %40هارگزيدگان را كودكان كمتراز 15ساله تشكيل ميدهند ()2014 33 6 – Predisposing factors & suitable 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 7 – Susceptibility and Resistance • All mammals are susceptible • Humans are more resistant than several animal species 35 Susceptibility of various animal to rabies Very High Wolves Foxes Coyotes Kangaroo rats Cotton rats Jackals Voles High Hamsters Skunks Raccoons Domestic cats Rabbits Bats Cattle Moderate Low Dogs Opossums Primates 36 8 – Secondary attack rate با توجه به عدم گزارش مستند انتقال هاري ازطريق تماس يا گازگرفتن انسان و يا وجود گزارشهاي بسيار ناچيز ،ميتوان چنين نتيجه گرفت كه ميزان حملت ثانويه آن ازانسان به انسان درحد ِصفرتا بسيارپايين، ميباشد. 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 ميمون پوزه دراز • Europe: Red fox • Iran: Wolf • Africa: Jackal 40 Global distribution of mammalian rabies reservoirs and vectors 41 Animal bite in Iran 42 Animal bite and human rabies in Iran 43 Animal rabies in Iran 44 Rabid wolves are associated with severe bites and human 45deaths 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 Prevention: Pre-exposure prophylaxis: • vaccination of people in high risk groups: • • • • Veterinarians Animal handlers Certain lab workers Travel to areas where canine rabies is common 54 Primary Prevention: Pre-exposure 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 vaccines • Human Diploid Cell Vaccine (HDCV) • Purified vero cell vaccine (PVRV) • Purified chicken embryo cell (PCEC) 56 Post-exposure wound 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 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 Prophylaxis Human Exposure with 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 Prophylaxis ... پزشكان،اقدامات الزم براي مراقبين (پرستاران • • • • • 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 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 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 2 - Secondary Prevention: Identification And intervention in early stages of disease 64 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 1st wk of illness • CSF: viral meningoencephalitis • EEG and head CT may be normal early in illness 65 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 Tissue 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 2 - Secondary Prevention Treatment of Rabies • No specific treatment once symptoms have begun • Intensive care • Almost all patients succumb to disease in a few weeks 72 Secondary Prevention Treatment of 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 N°99, 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. ، بيماريهاي مهم مشترك بين انسان و حيوان در ايران: در، بيماري هاري، سوسن، ـ سيماني33• .165-203 صفحات،1384 سال، چاپ اطالعات،معاونت آموزشي و امور دانشجويي وزارت بهداشت • 76 77