VHF Encephalitis

Prof. Dr. Mehmet BAKIR

Definition of Viral Hemorrhagic Fever

Fever Myalgia Bleeding including dermal, intradermal, gastrointestinal

system,and vaginal or another organ/system

The etiology of VHF Filoviridae (Marburg virus ve Ebola virus)

Arenaviridae (Lassa virus, Junin, Machupo, Sabia, and Guanarito virus)

• Lassa ,and Junin virus can cause encephalitis,and menengitis

Bunyaviridae (Crimean-Congo hemorrhagic fever virus [CCHFV], Rift Valley

fever virus [RVFV] ,Hantavirus)

• 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

From Flaviviridae family and the Flavivirus genus

WNV is a positive sense single stranded RNA virus

and an important pathogen for humans, horses, dogs, birds and

reptiles

Birds are considered to be the main reservoir hosts of WNV,

Migratory birds play an important role in its spreading

The natural cycle of WNV typically involves ornithophilic Culex

mosquitoes feeding on avian hosts

From human to human can be transported by transfusion or

transplantation of organsMonath and Heinz 1996, Rappole et al. 2000, Apperson et al. 2004, Iwamoto 2003, Pealer LN 2003,

Horses are highly susceptible

The latest outbreaks of WNV include an increased proportion of neurological

disease in both humans and horses

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

West Nile virus has a wide geographical distrubution that includes countries of

Europe, Asia, Africa, Australia, and America

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

The first acute human WNV infection cases were documented

and reported from Manisa province in Turkey.

From July to November in 2010, 47 cases of WNV infection

were detected (35 were probable, 12 were confirmed)

The central nervous system manifestations were found in 40

patients

WNV

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.

WNV IgM and IgG 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 reportsEmergence of West Nile virus infections in humans inTurkey, 2010 to 2011H Kalaycioglu (h.kalaycioglu@hotmail.com)1, G Korukluoglu1, A Ozkul2, O Oncul1, S Tosun3, O Karabay4, A Gozalan1, Y Uyar1,D Y Caglayık1, G Atasoylu5, A B Altas1, S Yolbakan1, T N Ozden5, F Bayrakdar1, N Sezak3, T S Pelıtlı6, Z O Kurtcebe6, E Aydın6,M Ertek11. Refik Saydam National Public Health Agency, Ankara, Turkey2. 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, Turkey6. Ministry of Health, General Directorate of Primary Health Care, Ankara, Turkey

Age group (years)

Number ofcases

Incidence(per 100,000 population)

<20 8 0.10

20-29 3 0.07

30-39 1 0.03

40-49 6 0.19

50-59 8 0.33

60-69 4 0.28

70-79 12 1.29

>80 5 1.63

Province of residence

Ankara 1 0.02

Adana 1 0.05

Antalya 1 0.05

Kocaeli 1 0.06

Afyon 1 0.14

Konya 3 0.15

Manisa 2 0.15

Izmir 8 0.21

Isparta 1 0.24

Balikesir 3 0.26

Diyarbakir 4 0.26

Aydin 4 0.41

Karaman 1 0.43

Mugla 4 0.50

Sakarya 12 1.39

Total 47 0.19

The overall incidence of WNV infections was

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

WNV recognized in North America in 1999 and is the

most frequent cause of epidemic

meningoencephalitis in North America.

Between 1999 and 2009, over 12,000 cases of

WNND were reported in the United States.

Debiasi RL, 2011

In WNV infection

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

Incubation period is 2-15 days.

Asymptomatic infection, West Nile Fever, and West Nile neuroinvasive disease

(WNND) follow this incubation period.

Of all cases, 80% is asymptomatic and 20% is symptomatic.

Less than 1% of symptomatic cases have a neuroinvasive disease.

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)

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 Many patients with WNND have normal neuroimaging status

but abnormalities may be present in areas including the basal ganglia, thalamus, cerebellum, and brainstem

CSF protein is elevated Cerebrospinal fluid invariably shows a pleocytosis, with a

predominance of neutrophils in up to half the patients. With demonstration of WNV-specific IgM 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.

Therapy and prevention

Therapythere is no proven therapy for

WNND,

several vaccines and antiviral

therapy with antibodies,

antisense oligonucleotides,

and interferon preparations are

currently undergoing human

clinical trials.

Supportive therapy has to be

carried out.

Prevention

Repellents and body protective

clothing can use to avoid the

bite of the mosquito

It can use insecticides for

mosquitoes

There are studies for vaccine

but not available for general use

Dengue Haemorrhagic Fever virus

Virus is from Flaviviridae family and Flavivirus genus

Dengue is an RNA virus that is grouped into four serotypes

(DENV-1 through DENV-4).

This virus is

non-enveloped,

spherical with a diameter of 50nm

and a positive-sense,single-stranded RNA genome.

DENV epidemiology This infection is the most destructive arboviral disease

The number of countries reporting outbreaks has increased 10-fold since the last

30 years. Dengue is a worldwide condition spread throughout the tropical and subtropical

zones between 30 N and 40 S.

These countries are:

• Pacific-Asian region, Americas, Middle East, and Africa.

Approximately 50-100 million infections occur each year resulting in

approximately 25,000 deaths.

Vectors are the mosquitoes Aedes aegypti and Aedes albopictus

Dengue represents the second leading cause of acute fever in travellers

The incidence of neurological symptoms among dengue patients

varies from 1% to 25% in all dengue admissions

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.

In another study , 4.2% of patients with neurological symptoms tested

positive for dengue.

Thakare J, . et al1996, 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

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In this study, the authors included

265 cases of AFE and

39 patients were evaluated as

dengue encephalopathy

Neurological Manifestations of Dengue

From the pathogenesis point of view, neurological manifestations of

dengue can be grouped into three categories:

(1) Related to neurotropic effect of virus (encephalitis);

(2) Related to systemic complication of dengue infection

(encephalopathy);

(3) Post infectious like acute disseminated encephalomyelitis, myelitis,

Guillain-Barre syndrome, optic neuritis.

Murthy JMK. Neurological complication of dengue infection. Neurol India. 2010; 58: 581-84.

Clinical manifestations

Patients with Symptomatic Dengue Fever have:

malaise, headache, myalgias,

retro-orbital pain, bone pain,

arthralgias, nausea, vomiting

petechiae, and a diffuse

erythematous maculopapular rash

Patients with Dengue Hemorrhagic Fever and Shock Syndrome (the most severe form) have:

Hepatomegaly

Hemorrhage (including epistaxis,

gingival hemorrhage, and

gastrointestinal hemorrhage)

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

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

The other clinical statues include meningitis and myelitis

Acute disseminated encephalomyelitis (ADEM) is rarely described in

association with dengue infection

Laboratory findings

CT and MRI findings:

• hemorrhages, diffuse cerebral edema,

• focal abnormalities involving the globus pallidus, the

hippocampus, the thalamus, and the internal capsule

Analysis of CSF:lymphomononuclear pleocytosis and normal

glucose levels

However, normal CSF cellularity has been shown in more than

half of patients with dengue encephalitis.

Diagnosis

Cell culture for DENV

RT-PCR for detecting of viral RNA in serum, plasma,

or CSF

ELISA for identifying dengue virus specific IgM and

or immunoglobulin G in serum obtained during the

acute and convalescent phases of infection

Management of Dengue Fever

There is no specific anti viral treatment and

The management is essentially supportive and

symptomatic (Bedrest)

The key to success is frequent monitoring and

changing strategies depending on clinical and

laboratory evaluations

(Fluid, electrolyte, blood and blood products)

Prognosis Mortality rates vary from 5% to 22%

Causes of death include multi-organ failure, hemorrhagic

complications, and circulatory collapse.

Most patients completely recover by the time of hospital discharge

Neurological sequelae include:

• spastic paresis,

• static myelopathy following transverse myelitis,

• residual spasticity,

• prolonged drowsiness,

• residual paralysis and Parkinsonian syndrome.

Prevention

Tissue culture-based vaccines for dengue virus types

are immunogenic but not available for general use

Repellents and body protective clothing can use to

avoid the bite of the mosquito

It can use insecticides for mosquitoes

Arenaviridae

At least eight arenaviruses are known to cause human disease

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 .

Old World viruses

• Lassa virus (LASV), Lujo virus, and lymphocytic choriomeningitis

virus (LCMV

Arenaviridae

Arenaviridae is a spherical or pleomorphic virion ( with a

diameter of 50–300 nm) with envelope and has single-stranded

RNA

Virus is inactivated by:

• heating to 56oF,

• pH<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

Lassa virus and Lujo virus can cause hemorrhagic fevers

and Lassa fever accounts for 10 to 15% of adult medical

admissions in West Africa

Rodent-to-human transmission (the “multimammate rat”,

Mastomys species-complex)

Infected rodents remain as carriers throughout their life (no

clinical symptoms)

Infected rodents excrete the virus through the urine, saliva,

respiratory secretion

Lassa virus

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

The virus can be isolated in the blood, faeces, urine, throat swab,

vomit, semen and saliva of infected persons ( during 30 days or more )

Infected persons present serious threat to the environment

Health care workers are at risk if proper barrier nursing and infection

control are not maintained.

Pathogensis

The ilness is developed by :

endothelial cell damage/capillary leak,

platelet dysfunction,

suppressed cardiac function,

cytokines and other soluble mediators of shock and

inflammation

Clinical aspects

Incubation period is approximately 5-21 days

Typical symptoms include:

• gradual onset of fever, headache, malaise,

• pharyngitis, myalgias, retro-sternal pain, cough, vomiting

arthralgia, weakness, sizziness, abdominal pain, diarrhea

A minority group present with classic symptoms of bleeding,

neck/facial swelling and shock.

Lassa virus Neurological signs include confusion, disorientation, locomotor

dysfunction, tremors, convulsions and coma.

The clinical picture can vary.

Encephalopathy was the most prominent syndrome.

Severely ill patients may die and the mortality rate is

particularly high among pregnant women.

Convalescence can be prolonged in patients who recover.

Transient or permanent deafness often occurs.

Diagnosis

Virus isolation

ELISA for antigen of virus and IgM or IgG for virus

Immunohistochemistry (for post-mortem diagnosis)

RT-PCR for detecting RNA of virus

Treatment It includes supportive measures and ribavirin.

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

Poor prognosis can be due to:

• high viremia,

• high serum AST levels as more than150 IU/L

• bleeding

• encephalitis

• edema

• third trimester of pregnancy

Prevention and control

Programs for rodent control and avoidance Health education strategies for preventing infections

in people living in endemic area

Hospital training programs to avoid nosocomial spread

Diagnostic technology transfer

Specific antiviral chemotherapy (ribavirin)

There are studies for vaccine but not available for general use

Bunyaviridae family, Phlebovirus genus (10 sercomplex)

Sandfly fever serocomplex Sandfly fever Naples group

• Granada virus

• Massila virus

• Punique virus

• Sandfly fever Naples virus

• Toscana virus 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

Virus has a single-stranded

RNA genome with lipid-

enveloped

The genome consists of

three segments: the large(L),

the medium (M),the small (S)

Phlebovirus (RVFV)

RVFV is a highly pathogenic virus that can cause lethal disease in

both humans and ruminant animals

RVFV is transmitted primarily by Aedes mcintoshi mosquitoes,

The virus has been detected in 23 species of mosquitoes

RVF outbreaks in human populations vary in size, intensity and

location with these parameters dependent upon rainfall and

mosquito abundance

Humans is infected by direct contact or aerosol.

Tissue or body fluids of animals (aborted fetuses, slaughter, necropsy)

are contagious

Chronology of Phlebovirus (RVFV) epidemia 1987: Senegal

1997-98: Kenya Largest outbreak reported (89,000 humans cases -

478 deaths)

2000-01: Saudi Arabia and Yemen (First outbreak outside of Africa)

2003: Egypt (45 cases; 17 deaths)

2006-7: Kenya ( Spread to surrounding areas, 1000+ human cases,

300 deaths)

The largest recorded outbreak of RVF was in Egypt in 1977 with

10,000 to 20,000 human cases [8,9].

2010: South Africa (over 250 laboratory confirmed cases with an

approximate case fatality rate of 11%)

Phlebovirus (Sandfly and Toscona virus)

Virus transmitted to humans by insects of Phlebotomus genus (P.

perniciosus and Phlebotomus perfiliewi )

The virus has been detected in Italy and Spain

Virus recently spread to many other Mediterranean and Europe

countries such as:

• Turkey, Cyprus, Greece, France, Portugal, Germany

Most cases of the disease have been reported in residents in or

travellers to the Mediterranean area.

(Amaro et al., 2011; Brisbarre et al., 2011; Depaquit et al., 2010, Di Nicuolo et al,2005 , Ergünay et all. 2012,F.de Ory et al, 2013, Colomba et al 2011,

Phlebovirus (Sandfly and Toscona virus)

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)

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.

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

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

There are attenuated and inactivated vaccine for

animal

But there is a limited use for humans

Vector control

Animal housing control

Barrier precautions

Conclusion

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

Our aim is mainly to diagnosis such illnesses ,and to make

appropriate treatment in due time and to prevent

For this purpose severel research works have to be carried out,

in order to develope new treatment methods and medicine