VHF Encephalitis Prof Dr Mehmet BAKIR Definition of

VHF Encephalitis Prof. Dr. Mehmet BAKIR

Definition of Viral Hemorrhagic Fever l l l Fever Myalgia Bleeding including dermal, intradermal, gastrointestinal system, and vaginal or another organ/system

The etiology of VHF l Filoviridae (Marburg virus ve Ebola virus) l Arenaviridae (Lassa virus, Junin, Machupo, Sabia, and Guanarito virus) • l Lassa , and Junin virus can cause encephalitis, and menengitis Bunyaviridae (Crimean-Congo hemorrhagic fever virus [CCHFV], Rift Valley fever virus [RVFV] , Hantavirus) • l RVF and Toscana virus can cause encephalitis, and menengitis Flaviviridae • Yellow fever virus and Dengue virus, West Nile virus • DENV and WNF can cause encephalitis, and menengitis

West Nile Virus l From Flaviviridae family and the Flavivirus genus l WNV is a positive sense single stranded RNA virus and an important pathogen for humans, horses, dogs, birds and reptiles l Birds are considered to be the main reservoir hosts of WNV, l Migratory birds play an important role in its spreading l The natural cycle of WNV typically involves ornithophilic Culex mosquitoes feeding on avian hosts l From human to human can be transported by transfusion or transplantation of organs Monath and Heinz 1996, Rappole et al. 2000, Apperson et al. 2004, Iwamoto 2003, Pealer LN 2003,

l Horses are highly susceptible l The latest outbreaks of WNV include an increased proportion of neurological disease in both humans and horses l Mortality rates among clinically affected horses have been estimated around 38%, 28%, 44% and 42% during outbreaks in the USA, France (2000), Morrocco and Italy (1998), respectively l West Nile virus has a wide geographical distrubution that includes countries of Europe, Asia, Africa, Australia, and America l WNND were confirmed by European countries such as Greece (197 cases) , Romania (54 cases), Italy (3 cases), Hungary (15 cases), Portugal (1 case) and Spain (1 case) [5] in 2010 Castillo- Olivares and Wood 2004, Petersen and Roehrig 2001, Tber Abdelhaq 1996, Cantile et al. 2001, Murgue et al. 2001, Ostlund et al. 2001 , Hubalek and Halouzka 1999, Savage et al. 1999, Hayes et al. 2005

West Nile Vırus l The first acute human WNV infection cases were documented and reported from Manisa province in Turkey. l From July to November in 2010, 47 cases of WNV infection were detected (35 were probable, 12 were confirmed) l The central nervous system manifestations were found in 40 patients

WNV l An other study was performed at Hacettepe University Hospital. Paired serum and cerebrospinal fluid (CSF) samples from 87 adult patients with the preliminary diagnosis of aseptic meningitis/encephalitis of unknown etiology were evaluated retrospectively to identify WNV-related syndromes. l WNV Ig. M and Ig. G antibodies were detected in 9. 2% (8/87) and 3. 4% (3/87) of the serum samples, respectively. Ergünay K, et al, 2010

• In this study, 371 sample from 234 individuals were collected from Ankara and Izmir • Two cases of WNV CNS infections and 14 cases of TOSV infections were identified via serological testing

Surveillance and outbreak reports Emergence of West Nile virus infections in humans in. Turkey, 2010 to 2011 H Kalaycioglu (h. kalaycioglu@hotmail. com)1, G Korukluoglu 1, A Ozkul 2, O Oncul 1, S Tosun 3, O Karabay 4, A Gozalan 1, Y Uyar 1, D Y Caglayık 1, G Atasoylu 5, A B Altas 1, S Yolbakan 1, T N Ozden 5, F Bayrakdar 1, N Sezak 3, T S Pelıtlı 6, Z O Kurtcebe 6, E Aydın 6, M Ertek 1 1. Refik Saydam National Public Health Agency, Ankara, Turkey 2. Ankara University, Faculty of Veterinary Medicine, Department of Virology, Ankara, Turkey 3. State Hospital, Manisa, Turkey 4. Training and Research Hospital, Sakarya, Turkey 5. Provincial Health Directorate, Manisa, Turkey 6. Ministry of Health, General Directorate of Primary Health Care, Ankara, Turkey Age group (years) Number of cases Incidence (per 100, 000 population) Province of residence Ankara 1 0. 02 Adana 1 0. 05 Antalya 1 0. 05 <20 8 0. 10 Kocaeli 1 0. 06 20 -29 3 0. 07 Afyon 1 0. 14 Konya 3 0. 15 30 -39 1 0. 03 Manisa 2 0. 15 40 -49 6 0. 19 Izmir 8 0. 21 Isparta 1 0. 24 50 -59 8 0. 33 Balikesir 3 0. 26 60 -69 4 0. 28 Diyarbakir 4 0. 26 Aydin 4 0. 41 Karaman 1 0. 43 Mugla 4 0. 50 Sakarya 12 1. 39 Total 47 0. 19 70 -79 12 1. 29 The overall incidence of WNV infections was >80 5 1. 63 deteced in 0. 19 cases per 100, 000 population in humans in a sureveillance study in Turkey, 2010 to 2011

United States, 2011 MMWR / July 13, 2012 / Vol. 61 / No. 27

l WNV recognized in North America in 1999 and is the most frequent cause of epidemic meningoencephalitis in North America. l Between 1999 and 2009, over 12, 000 cases of WNND were reported in the United States. Debiasi RL, 2011

In WNV infection l Pathological changes within the central nervous system develop as a direct result of viral proliferation within neuronal and glial cells, cytotoxic immune response to infected cells, diffuse perivascular inflammation, and microglial nodule formation Smith RD, Hum Pathol 2004; Agamanolis DP, Ann Neurol 2003 Gyure KA. J Neuropathol Exp Neurol 2009

West Nile Vırus l Incubation period is 2 -15 days. l Asymptomatic infection, West Nile Fever, and West Nile neuroinvasive disease (WNND) follow this incubation period. l Of all cases, 80% is asymptomatic and 20% is symptomatic. l Less than 1% of symptomatic cases have a neuroinvasive disease. l Most of illnesses is seen as “West Nile fever” and observed as clinical symptoms and findings as follows: Self-limited dengue-like illness • Fever, headache, retro-orbital pain, back pain, fatigue, arthralgia, and myalgia, anorexia, nausea, vomiting, diarrhea, maculopapular rash, lymphadenopathy Hayes et al. 2005, Petersen and Marfin 2002, Solomon and Vaughn 2002

West Nile neuroinvasive disease (WNND) l WNND includes severe neurologic illness categories • Clinical and laboratory findings seen in the WNV meningitis include fever, nuchal rigidity, CSF pleocytosis. • Encephalitis includes 60% of WNND cases and there is ususally altered mental status in these cases consisting of people less than 55 years old or immunocompromised patients • The other neuroinvassive disorders of WNV include • • meningoencephalitis, acute flaccid paralysis, tremor, myoclonus or both tremor and myoclonus, and parkinsonism

Diagnosis of WNND l Many patients with WNND have normal neuroimaging status but abnormalities may be present in areas including the basal ganglia, thalamus, cerebellum, and brainstem l CSF protein is elevated l Cerebrospinal fluid invariably shows a pleocytosis, with a predominance of neutrophils in up to half the patients. With demonstration of WNV-specific Ig. M antibodies in cerebrospinal fluid or serum approximatelly half of all cases will be positive in the first 7 days whereas Ig G Antibodies will be positive in 7 -21 days RNA in serum and/or CSF can be detected by PCR method. l l

Therapy and prevention Therapy Prevention l there is no proven therapy for WNND, l several vaccines and antiviral therapy with antibodies, antisense oligonucleotides, and interferon preparations are currently undergoing human clinical trials. l Supportive carried out. therapy has to be l Repellents and body protective clothing can use to avoid the bite of the mosquito l It can use insecticides for mosquitoes l There are studies for vaccine but not available for general use

Dengue Haemorrhagic Fever virus l Virus is from Flaviviridae family and Flavivirus genus l Dengue is an RNA virus that is grouped into four serotypes (DENV-1 through DENV-4). l This virus is l non-enveloped, l spherical with a diameter of 50 nm l and a positive-sense, single-stranded RNA genome.

DENV epidemiology l This infection is the most destructive arboviral disease l The number of countries reporting outbreaks has increased 10 -fold since the last 30 years. l Dengue is a worldwide condition spread throughout the tropical and subtropical zones between 30 N and 40 S. l These countries are: • l Pacific-Asian region, Americas, Middle East, and Africa. Approximately 50 -100 million infections occur each year resulting in approximately 25, 000 deaths. l Vectors are the mosquitoes Aedes aegypti and Aedes albopictus l Dengue represents the second leading cause of acute fever in travellers

l The incidence of neurological symptoms among dengue patients varies from 1% to 25% in all dengue admissions l In Indonesia, 70% of virologically confirmed fatal dengue infections (n=30) presented with one or more neurological signs, and 7% of those admitted for viral encephalitis turned out to be dengue-infected. l In another study , 4. 2% of patients with neurological symptoms tested positive for dengue. Thakare J, . et al 1996, Kankirawatana P, et al. 2000, Solomon T, et all, 2000, Puccioni-Sohler et al. , 2000, . Jackson et al. , 2008, Garcia-Rivera EJ, et all, 2002

In this study, the authors reviewed the etiology of viral menengitis and encephalitis in a dengue endemic region, in Brazil. Dengue viral encephalitis brought about 47% of all encephalitis cases. Journal of the Neurological Sciences 303 (2011) 75– 79

In the same study mentioned above, Dengue viral menengitis is 10% of all menegitis cases. Journal of the Neurological Sciences 303 (2011) 75– 79

çççççççççççççzvöbcööööööööcbzvnbnb. önbn In this study, the authors included 265 cases of AFE and 39 patients were evaluated as dengue encephalopathy

Neurological Manifestations of Dengue l From the pathogenesis point of view, neurological manifestations of dengue can be grouped into three categories: l (1) Related to neurotropic effect of virus (encephalitis); l (2) Related to systemic complication of dengue infection (encephalopathy); l (3) Post infectious like acute disseminated encephalomyelitis, Guillain-Barre syndrome, optic neuritis. Murthy JMK. Neurological complication of dengue infection. Neurol India. 2010; 58: 581 -84.

Clinical manifestations Patients with Dengue Hemorrhagic Fever and Shock Syndrome (the most severe form) have: Patients with Symptomatic Dengue Fever have: l l malaise, headache, myalgias, l Hepatomegaly retro-orbital pain, bone pain, l Hemorrhage (including epistaxis, arthralgias, nausea, vomiting gingival hemorrhage, and petechiae, and a diffuse gastrointestinal hemorrhage) erythematous maculopapular rash l Disseminated intravascular coagulation, plasma leak, and shock may be fatal during this phase. Neurological complications are uncommon manifestations of dengue fever, Neurological dengue is classified as a form of Severe Dengue (WHO 1997, 2009).

Neurlogical complications l Encephalitis is the most common clinical status (from 4. 2% to as much as 51%) and has following characteristics: • Fever, headaches, altered consciousness or personality, seizures, or focal neurological signs • myalgias, diarrhea, joint or abdominal pain, rash, and bleedings are reported in only 50% of encephalitis cases l The other clinical statues include meningitis and myelitis l Acute disseminated encephalomyelitis (ADEM) is rarely described in association with dengue infection

Laboratory findings l CT and MRI findings: • • hemorrhages, diffuse cerebral edema, focal abnormalities involving the globus pallidus, the hippocampus, the thalamus, and the internal capsule l Analysis of CSF: lymphomononuclear pleocytosis and normal glucose levels l However, normal CSF cellularity has been shown in more than half of patients with dengue encephalitis.

Diagnosis l Cell culture for DENV l RT-PCR for detecting of viral RNA in serum, plasma, or CSF l ELISA for identifying dengue virus specific Ig. M and or immunoglobulin G in serum obtained during the acute and convalescent phases of infection

Management of Dengue Fever l There is no specific anti viral treatment and l The management is essentially supportive and symptomatic (Bedrest) l The key to success is frequent monitoring and changing strategies depending on clinical and laboratory evaluations l (Fluid, electrolyte, blood and blood products)

Prognosis l Mortality rates vary from 5% to 22% l Causes of death include multi-organ failure, hemorrhagic complications, and circulatory collapse. l Most patients completely recover by the time of hospital discharge l Neurological sequelae include: • • • spastic paresis, static myelopathy following transverse myelitis, residual spasticity, prolonged drowsiness, residual paralysis and Parkinsonian syndrome.

Prevention l Tissue culture-based vaccines for dengue virus types are immunogenic but not available for general use l Repellents and body protective clothing can use to avoid the bite of the mosquito l It can use insecticides for mosquitoes

Arenaviridae l At least eight arenaviruses are known to cause human disease l New World viruses, • Junin virus (JUNV), Machupo virus (MACV), Guanarito virus (GTOV), and Sabia virus (SABV) (all members of lineage B) are etiologic agents of hemorrhagic fever syndromes in South America, • Whitewater Arroyo virus (WWAV) (lineage A) has been linked to two fatalities in North America. l Old World viruses • Lassa virus (LASV), Lujo virus, and lymphocytic choriomeningitis virus (LCMV

Arenaviridae l Arenaviridae is a spherical or pleomorphic virion ( with a diameter of 50– 300 nm) with envelope and has single-stranded RNA l Virus is inactivated by: • • • l heating to 56 o. F, p. H<5. 5 or >8. 5, and UV/gamma irradiation Chemical agents like 0. 5% sodium hypocorite, 0. 5% phenol and 10% formalin are sufficiently good inactivants against the virus.

Lassa virus l Lassa virus and Lujo virus can cause hemorrhagic fevers and Lassa fever accounts for 10 to 15% of adult medical admissions in West Africa l Rodent-to-human transmission (the “multimammate rat”, Mastomys l Infected rodents remain as carriers throughout their life (no clinical l species-complex) symptoms) Infected rodents excrete the virus through the urine, saliva, respiratory secretion

Lassa virus l Human infections can occur : • • when individuals are exposed to aerosol forms of the virus or after direct contact between infectious materials and abraded skin. • Ingestion of food or materials contaminated by infected rodent excreta l The virus can be isolated in the blood, faeces, urine, throat swab, vomit, semen and saliva of infected persons ( during 30 days or more ) l Infected persons present serious threat to the environment l Health care workers are at risk if proper barrier nursing and infection control are not maintained.

Pathogensis l The ilness is developed by : l endothelial cell damage/capillary leak, l platelet dysfunction, l suppressed cardiac function, l cytokines and other soluble mediators of shock and inflammation

Clinical aspects l Incubation period is approximately 5 -21 days l Typical symptoms include: • • gradual onset of fever, headache, malaise, pharyngitis, myalgias, retro-sternal pain, cough, vomiting arthralgia, weakness, sizziness, abdominal pain, diarrhea l A minority group present with classic symptoms of bleeding, neck/facial swelling and shock.

Lassa virus l Neurological signs include confusion, disorientation, locomotor dysfunction, tremors, convulsions and coma. l The clinical picture can vary. l Encephalopathy was the most prominent syndrome. l Severely ill patients may die and the mortality rate is particularly high among pregnant women. l Convalescence can be prolonged in patients who recover. l Transient or permanent deafness often occurs.

Diagnosis l Virus isolation l ELISA for antigen of virus and Ig. M or Ig. G for virus l Immunohistochemistry (for post-mortem diagnosis) l RT-PCR for detecting RNA of virus

Treatment l It includes supportive measures and ribavirin. l Ribavirin is most effective when started within the first 6 days of illness • Its major toxicity is mild hemolysis and suppression of erythropoesis. Both is reversible. • Presently, it contraindicates in pregnancy, although it may be warranted if mother’s life is at risk

Poor prognosis l Poor prognosis can be due to: • • • high viremia, high serum AST levels as more than 150 IU/L bleeding encephalitis edema third trimester of pregnancy

Prevention and control l Programs for rodent control and avoidance l Health education strategies for preventing infections in people living in endemic area l Hospital training programs to avoid nosocomial spread l Diagnostic technology transfer l Specific antiviral chemotherapy (ribavirin) l There are studies for vaccine but not available for general use

Bunyaviridae family, Phlebovirus genus (10 sercomplex) Sandfly fever serocomplex l Sandfly fever Naples group • Granada virus • Massila virus • Punique virus • Sandfly fever Naples virus • Toscana virus l Sandfly fever Sicilian group • Belterra virus • Chagres virus • Corfu virus • Rift Valley fever virus • Sandfly fever Cyprus virus • Sandfly fever Sicilian virus • Sandfly fever Turkey virus l Virus has a single-stranded RNA genome with lipidenveloped l The genome consists of three segments: the large(L), the medium (M), the small (S)

Phlebovirus (RVFV) l RVFV is a highly pathogenic virus that can cause lethal disease in both humans and ruminant animals l RVFV is transmitted primarily by Aedes mcintoshi mosquitoes, l The virus has been detected in 23 species of mosquitoes l RVF outbreaks in human populations vary in size, intensity and location with these parameters dependent upon rainfall and mosquito abundance l Humans is infected by direct contact or aerosol. l Tissue or body fluids of animals (aborted fetuses, slaughter, necropsy) are contagious

Chronology of Phlebovirus (RVFV) epidemia l 1987: Senegal l 1997 -98: Kenya Largest outbreak reported (89, 000 humans cases 478 deaths) l 2000 -01: Saudi Arabia and Yemen (First outbreak outside of Africa) l 2003: Egypt (45 cases; 17 deaths) l 2006 -7: Kenya ( Spread to surrounding areas, 1000+ human cases, 300 deaths) l The largest recorded outbreak of RVF was in Egypt in 1977 with 10, 000 to 20, 000 human cases [8, 9]. l 2010: South Africa (over 250 laboratory confirmed cases with an approximate case fatality rate of 11%)

Phlebovirus (Sandfly and Toscona virus) l Virus transmitted to humans by insects of Phlebotomus genus (P. perniciosus and Phlebotomus perfiliewi ) l The virus has been detected in Italy and Spain l Virus recently spread to many other Mediterranean and Europe countries such as: • l Turkey, Cyprus, Greece, France, Portugal, Germany Most cases of the disease have been reported in residents in or travellers to the Mediterranean area. l (Amaro et al. , 2011; Brisbarre et al. , 2011; Depaquit et al. , 2010, Di Nicuolo et al, 2005 , Ergünay 2012, F. de Ory et al, 2013, Colomba et al 2011, et all.

Phlebovirus (Sandfly and Toscona virus) l l l Incubation period ranges from a few days to 2 weeks, Clinical symptoms are: • headache (100%, ), • fever (76%– 97%), • nausea and vomiting (67%– 88%) • myalgias (18%). Physical examination findings are: • neck rigidity (53%– 95%), Kernig signs (87%), • poor levels of consciousness (12%), • Tremors (2. 6%), • paresis (1. 7%), and nystagmus (5. 2%) (L. Laboratory findings of CSF include cells more than 5– 10 with normoglycorachia and normoproteinorachia. Blood samples may show leukocytosis (29%) or leukopenia (6%). Charrel et al, 2005

Phlebovirus (Rift Valley fever virus) l Incubation period is 2 to 6 days and it occurs often asymptomatic and with Influenza-like illness (Fever, headache, myalgia, vomiting). The patients recover between 2 to 7 days. l A small percentage (1%) of patients has: • • • Encephalitis, Retinal vasculitis, Hemorrhagic fever with melena, hematemesis, petechia, jaundice, shock, coma and • case-fatality is about 50%

Diagnosis l l l Diagnosis is based on • virus isolation • antigen detection • RT-PCR • serology Treatment includes: • • Symptomatic and supportive therapy Replacement of coagulation factors Ribavirin may also be helpful

Prevention and control for RVFV l There attenuated and inactivated vaccine for animal l But there is a limited use for humans l Vector control l Animal housing control l Barrier precautions

Conclusion l Different viruses in VHF group can be the cause of ilnesses such as encephalitis, mengitidis and other neuroinvassive diseaases in contaminated parts of the world and in travellers l Our aim is mainly to diagnosis such illnesses , and to make appropriate treatment in due time and to prevent l For this purpose severel research works have to be carried out, in order to develope new treatment methods and medicine