Seminar Topic: Rabies Research Article: Epidemiology and Molecular Virus Characterization of Reemerging Rabies, South Africa Introduction/Background • Viral disease of Mammals • Bullet shaped RNA virus in Rhabdoviridae family. Introduction/Background • Virus infects the central nervous system, causing encephalopathy. • Encephalopathy is disease or inflammation of the brain. • Grim prognosis, death typically occurs within days of onset of symptoms. Transmission • All mammals susceptible to rabies virus. • Some important mammals are reservoirs for virus: – Raccoons – Skunks – Foxes – Coyotes – Several species of insectivorous bats. Transmission • Transmission usually begins when infected saliva of host is passed to uninfected individual. • Most common transmission is by bite. • Various other forms including: – Mucous membrane contact – Aerosol Transmission – Transplantations Transmission • • • • • • Following Primary Infection: Virus enters eclipse phase Last several days to months Virus is good antigen Cell mediated immunity is likely Virus progresses through uptake into peripheral nerves. Transmission/Primary Infection Transmission Transmission • After peripheral nerve uptake, virus travels to CNS. • Incubation period may last a few days to several years. • Typical time period is 1 to 3 months. • No sign of illness is present during this time. Signs and Symptoms • First Symptoms non-specific flu-like – – – – Malaise Fever Headache. Last few days • Quickly progresses to symptoms of: – – – – – cerebral dysfunction anxiety confusion agitation, progressing to delirium abnormal behavior, hallucinations and insomnia. (Latinmadness, rage, fury) • Acute period ends in 2-10 days Exposure Graph Signs and Symptoms • Once clinical signs appear, disease is nearly always fatal, treatment is entirely supportive. • Non-lethal exceptions are extremely rare. • To date only six documented cases of human survival from clinical rabies have been reported. • Kare 11? Diagnosis • No single test sufficient, multiple tests needed. • Ante-Mortem: – Saliva – Serum – CSF – Skin Biopsies • Brain tissue can be analyzed to diagnose post-mortem. Epidemiology in U.S. • • • • • • • Developed vs. Undeveloped Country In 2006 49 states reported cases. Hawaii rabies free. CDC states 6,940 animal cases in 2006. Wild Animals 92% Domestic Animals approx. 8%. 3 Human cases in 2006 Epidemiology in U.S. • Prior to 1940’s: – 100 or more per year – Now 2 or 3. • Vaccination of domesticated animals as prevention. • Effective human vaccines and immunoglobulins have recently been developed. (Current Treatment) Cost of Rabies in U.S. • 300 million annually (Most dog vaccine) • 40,000 post-exposure prophylaxis treatments each year. • Immunoglobulin and five doses of vaccine. • $1000 minimum. Article • Epidemiology and Molecular Virus Characterization of Reemerging Rabies, South Africa. • Cheryl Cohen, Benn Sartorius, Claude Sabeta, et. al. Introduction • Developing Countries of Asia and Africa, – 55,000 cases per year. • Most humans cases from exposure to infected dogs. • Vaccine and PEP prohibitively expensive for African govt’s. Introduction • Set in Limpopo Province, South Africa – – – – Northernmost province in SA Shares borders with Zimbabwe and Botswana Variable Climate; temperate and subtropical Most of pop. live in rural areas, subsist by farming maize and livestock. 1981 last confirmed case prior to 2004 Human Rabies cases: – 5 in 2004 to – 100 in 2006. Paper to investigate outbreak Introduction • Since 1970’s most human rabies cases in South Africa have occurred in KwaZuluNatal Province, where major animal vector is dog. • Prior to past few years: – Rabies relatively uncommon – Major animal vector is wild jackal. Introduction • Prior to current research paper – 2 most recent lab-confirmed cases in Limpopo were in 1980 and 1981. • Speculation of undocumented cases. • Paper to investigate epidemiologic, clinical and viral molecular features of rabies outbreak in Limpopo, South Africa, in 2005-2006. Introduction • Research significant due to public health concerns. Why remission and then such an outbreak? • Little previous information or data to build on due to lack of documentation, developing country. Animal Rabies Surveillance • Began by analyzing animal rabies • Brain specimens from suspected infected animals submitted to Rabies Reference Lab in Pretoria, Africa. • Archived data on confirmed animal cases since 1994 were reviewed. • An animal case was defined as any lab confirmed case only. Results: Animal Rabies Cases • 1994 to 2004 • 8 to 76 lab confirmed cases/yr in Limpopo. • Most were in C. mesomelas (black-backed jackal) and in livestock (cattle). • Less than 10/yr in domestic dogs, however, exponential increase; • 2004=5, 2005=35, 2006=100. Results: Animal Rabies Cases • Vhembe district dominated (79% or 106/135) • Vhembe district vaccination coverage from 1997 to 2005; • Approx 39% overall • 4% to 60% annually • SEE FIGURES 2 and 3 Human Rabies Surveillance • Humans cases diagnosed from – – – – brain specimens saliva serum CSF • Done at National Institute for Communicable Diseases, Johanesburg. • All tests look for antirabies antibodies. Epidemiologic Investigation of Human Cases • Study team visited hospitals in outbreak area in Feb. 2006. • Potential cases of rabies (meeting clinical definition) in the previous 12 months were identified by clinician interviews. • Active surveillance done for new suspected cases. Epidemiologic Investigation of Human Cases • Data collected on standardized data collection form – – – – – included demographic data clinical and lab features history of animal exposure management of the initial bite exposure patient outcomes. • See TABLE • For 3 probable cases, no clinical records were available, interview of clinician only. Epidemiologic Investigation of Human Cases • Data on cost and number of vaccines and immunoglobulin collected. • Obtained from manufacturers and distributors of supplies. – Really given to pt’s? Case Definitions • Clinical case, possible case, probable case and confirmed case. • Clinical Case: Clinical case-patient defined as any person who died after Jan 1, 2005. – – – – – – – – Must have resided in Limpopo prior to onset of symptoms Must have had one of the following symptoms Delirium Hydrophobia Salivation Acute psychosis, acute flaccid paralysis Convulsion or respiratory paralysis No other identified cause of death Case Definitions • Possible Case: Defined as person who met clinical case definition but, – Not laboratory confirmed – Had no documentation of history of animal exposure. • Probable Case: Met clinical case definition but: – Not lab confirmed – Had history of animal exposure. Case Definitions • Confirmed Case: – Met the clinical case definition – Laboratory confirmed rabies Results: Human Rabies Cases/Description of Outbreak • • • • • Jan 1, 05-Dec 31, 06 21 confirmed 4 probable 5 possible FIGURE 3 Outbreak • • • • • Earliest Aug 5, 2005 Peak March 2006 28/30 from Vhembe District. 27 children from 3-12 yrs old. All hospitalized with median duration from admission to death of 4 days (1-25 day range). Clinical and Lab Features of Human Cases • Median incubation period 8 wks (3-28). • Most common clinical feature salivation (19/21, 90%) • Agitation (14/21, 67%) • Weakness (14/21, 67%) • Fever (14/21, 67%) • Hallucinations (11/21, 52%) • SEE TABLE Clinical and Lab Features of Human Cases • 9 had elevated leukocyte count • 11 elevated urea levels • No abnormalities in hemoglobin level, platelet count, or erythrocyte sedimentation rate. • 7 pt’s liver functions tested; • 6 had elevated alkaline phosphatase enzyme levels. -More tests done, see table. No reason given for taking these tests? Significance? Management of Exposures • 24 pt’s asked about exposure – All had history of potential rabid animal exposure • • • • • • • 16 pt’s site of exposure reported 8 lower limb 3 upper limb 2 trunk 3 head and neck. Most by unknown dogs, 5 by own dog. 67% did not report to clinic upon exposure Management of Exposures • Sadly only one pt. truly treated. • 4yr old boy bitten in left cheek Sept. 6, 2006. • Received vaccinations and immunoglobulin within 12 hrs of exposure. (PEP) • Wound cleaned, not sutured though. • Unsuccessful Treatment • Unfortunately rabies developed 17 days later, pt died 2 days after development. Molecular Analysis • • • • Very complicated In short; Extracted RNA Used RT-PCR to amplify a 592-bp nucleotide portion. • Phylogenetic tree constructed • Used to compare strains, possible new strain, related to other strains? Molecular Analysis Molecular Epidemiology • Final analysis of nucleotide sequencing • 6 separate viruses identified labeled A through F. • Virus from dogs in Vhembe district identical to human strains. • Other districts and province isolates did not suggest any close link with outbreak virus. • Outbreak virus=new strain Control Measures • As a result of study • Intensified dog vaccination during amplification period. • Community awareness • Education of healthcare workers on appropriate management. • Registration and Documentation emphasized Control Measures • Availability of human vaccines and immunoglobulin increased. • Still far under par. • Vaccine doses – 3,000 in 2004 – 56,000 in 2006. • Immunoglobulin – 100 doses in 2004 – 2,500 in 2006. • Estimated 8 million in cost Discussion • Outbreak of rabies in South Africa after more than 10 yrs of control. • Late recognition • Incorrect diagnosis due to other causes: • Confusion common to rural Africa – cerebral malaria – bacterial infections – HIV. Discussion • Traditional medicines alter signs and symptoms? – May result in toxicities – Abnormal and psychiatric symptoms – Abnormal liver function results? • Neurological symptoms from herbal intoxication? Discussion • Only one pt. given post exposure treatment, still ineffective, why? • Facial location of wound? • Inadequate wound cleaning? • Improper administration? Discussion • Possible reasons for outbreak? – Low dog vaccination – Decreased and diverted resources – Lack of vaccine recently • Virus reestablishment Discussion • Immigration to Limpopo as possible cause? • Molecular analysis and phylogenetic tree suggest possible virus extension from Zimbabwe? Not clear. Discussion • Decrease in cases after May 2006. • To date no further cases since June 30, 2007. • Introduction of control measures? • Still overall poor dog vaccination, PEP too expensive. • Why the disappearance? Discussion • Acknowledgements of lack of documentation • Poor hospital records. • Pt’s not visiting hospitals, dying at home. • Increase of awareness after Feb 2006 – Alter data by public response Discussion • Outbreak highlights that rabies is transboundary disease and can reemerge in areas with previous effective control. • Sustained awareness • Political and economic commitment to animal and human rabies controls programs • Vaccination of dogs My Analysis/Questions • Research significant. • No real hypothesis given, but main question fairly clear. • Little previous info. • Goal of experiment to answer why such an outbreak suddenly occurred. • Goal, and main question answered? My Analysis/Questions • • • • Why did they do the blood tests? Liver tests? Article did not explain at all? No p-values or other statistics given to identify if data was significant or not. My Analysis/Questions • Methods effective, data presented effectively? • Poor methods, documentation, but did best with what they had to work with. • Definite problems with data. • More experiments with more precise documentation, methods, etc… • Ultimate Conclusion? References • • • • • www.cdc.gov www.who.org www.nlm.nih.gov/medlineplus/rabies.html www.emedicinehealth.com Meslin FX. Rationale and Prospects for Rabies Elimination in Developing Countries. Curr Top Microbiol Immunol 1994;187:1-26. • Current Research Article and CDC contained majority of pertinent information. THE END • ANY QUESTIONS/COMMENTS?
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