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Arboviral Diseases Stephen J. Thomas, MD

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1 Arboviral Diseases Stephen J. Thomas, MD
Director, Viral Diseases Branch Walter Reed Army Institute of Research JUL 2013 Paul B. Keiser, Feb 2014 UNCLASSIFIED

2 What is a virus? Defined: A sub-cellular agent consisting of a core of nucleic acid surrounded by a protein coat that must use the metabolic machinery of a living host to replicate and produce more viral particles. Viruses are known to infect almost all organisms, including bacteria, fungi, plants, insects, and vertebrates. nm in diameter; a “filterable” agent. What is a virus? Well the name suggests that it is something toxic or “virulent.” At one point (end of the 19th century) they were called “filterable agents” to distinguish them from bacteria which were large enough to be retained by the filters used in laboratories at the time (Chamberland filters). This picture here shows the relative differences in size between bacteria and virus. Viruses are generally too small to be seen with a light microscope. Viruses can only replicate within other cells and are known to infect cells from all types of organisms: bacteria, fungi, plants, insects and animals.

3 This shows an individual virus particle or “virion
This shows an individual virus particle or “virion.” This is essentially a package of DNA that is enclosed in an envelope. Surface proteins determine what cell types it will infect.

4 Arboviruses are Arthropod-borne.
What is an arbovirus? Arboviruses are Arthropod-borne. They are transmitted to vertebrates by hematophagous (blood feeding) arthropod vectors mosquitoes other biting flies ticks So the term “arbovirus” does not refer to a structural family. As you saw on the earlier slide, viruses from several different structural families are transmitted by arthropods.

5 Occur in nearly all parts of the world.
Arboviruses Occur in nearly all parts of the world. Over 500 distinct viruses, ~100 causing human infections Nearly all arboviruses fall into one of 4 families: Flaviviridae Togaviridae Bunyaviridae Reoviridae

6 Classification Scheme
This chart shows the different classifications of RNA viruses. Here you can see viruses that are already familiar to you (rabies, flu, dengue) arranged by family. This talk will focus on the “arboviruses,” which are almost all RNA viruses and come from these families: bunyavirus, flavivirus, reovirus, togavirus Note that when we refer to viruses as “families,” we are not necessarily talking about phylogeny in the same sense as with higher species. Source: Flint et al Principles of virology Introduction to Virology

7 Classification Scheme
Nucleic acid Symmetry of capsid Naked or enveloped------ Genome architecture---- Baltimore class Family name Virion polymerase Virion diam. (nm) Genome size (total in kb)- Properties Classification criteria Here are the DNA viruses, which include other familiar viruses like smallpox and herpes which is very familiar to some of you. Source: Flint et al Principles of virology

8 Factors in Arboviral Disease
Virus Vector Ecology Host Reservoir Ecology What the arboviruses do share is a complex life cycle that involves multiple species. Here is this three-way interrelationship that characterizes vector-borne diseases that I showed earlier.

9 Arbovirus Features Able to replicate in both the arthropod vector and the vertebrate (bird or animal) host. Transmission to vertebrate occurs as the vector regurgitates while taking its blood meal. Viremia must reach high enough levels in the host to continue the cycle before reduced by the host immune system. Able to infect multiple species of animals and birds, but usually limited to a specific arthropod vector. So just because a mosquito bites 12 different species doesn’t mean that the virus will replicate enough in all 12 to maintain its life cycle.

10 Arbovirus Features In the tropics, transmission is year-round.
In temperate climates, transmission to vertebrates is seasonal and the virus requires an overwintering strategy. Transovarial transmission in the vector. Migration with avian host. Disease is usually more severe in newly exposed hosts and species. Deforestation Irrigation Urbanizatiom Travel In the tropics, the vector is active all year round and transmission is on-going. But in temperate climates, the arthropod becomes less active, the blood meals stop, and the virus must have a strategy to perpetuate itself. This can be to infect the next generation of arthropods trans-ovarially, which means mother to offspring, or to infect migrating birds. Note that when a virus first enters a new species, the disease is generally more severe than what is seen in the reservoir species. This is a common theme and not unique to viruses. The virus doesn’t want to “kill” you, it wants to survive which usually means *not* killing you. But when it first enters a new species it hasn’t figured out how to gently infect.

11 As a result of involving multiple species, a lot of factors that affect those other species, such as predators and climate, can affect the spread of arboviral disease.

12 How do you determine if a vector is involved?
Four criteria establish vector competence: Isolation of the disease-producing agent from wild- caught specimens Demonstration of its ability to become infected by feeding upon a viremic host Demonstration of its ability to transmit by bite Field evidence confirming association of the infected arthropod with the vertebrate population in which the infection is occurring. From Harley 2001, these are four criteria to establish the vector competence of a mosquito species. The reference provided is Sudia, W. D., V. F. Newhouse, and W. A. Chappell Venezuelan equine encephalitis virus-vector studies following a human case in Dade County, Florida, Mosq. News 29:596–600.

13 Hundreds of arboviruses have been identified thus far
Hundreds of arboviruses have been identified thus far. The CDC maintains an on-line catalog to accommodate the growing list.

14 Arboviral diseases: clinical syndromes
Systemic Febrile Illness Chikungunya, O’nyong-nyong, Ross River, Dengue, Zika Fever with Arthritis Chikungunya, Ross River, O’nyong-nyong Encephalitis JE, WNV, TBE, EEE, WEE Hemorrhagic Fever Yellow Fever, Dengue, Rift Valley Fever, Chikungunya, CCHF Arboviral diseases generally occur as one of the following… Note that these disease syndromes overlap and are not specific to the d\ifferent structural families of arboviruses. Togavirus (blue), Flavivirus (gold), Bunyavirus (brown)

15 Arboviruses Family Flaviviridae Genus Flavivirus Tick-borne viruses
Mammalian tick-borne virus group Kyasanur forest disease virus (KFDV) Tick-borne encephalitis virus (TBEV) Mosquito-borne viruses Dengue virus group Dengue virus (DENV) Japanese encephalitis virus group Japanese encephalitis virus (JEV) Murray Valley encephalitis virus (MVEV) St. Louis encephalitis virus (SLEV) West Nile virus (WNV) Yellow fever virus group Yellow fever virus (YFV) Zika Virus Dengue Now moving on to the flaviviruses. These can be divided according to the vector, whether they are tick-borne or mosquito borne. Tick borne encephalitis is endemic in parts of Germany, so our allies in the Bundeswehr all get vaccinated. Among the mosquito-borne viruses you can see some familiar names.

16 Threat Assessment – ID Risk
Disease 2010 COCOM panel ID-IDEAL Malaria 1 2 Dengue 3 Diarrhea, bacterial MDR wound pathogens 4 NA Leishmaniasis 5 19 Q fever (Coxiella burnetti) 6 26 Norovirus / viral diarrhea 7 Influenza 8 Leptospirosis 10 Diarrhea, protozoal 11 TB 12 CCHF 13 HIV 14 HFRS 15 17 Chikungunya 16 Meningococcal meningitis 20 Plague 18 27 Rickettsioses Viral encephalitides This is the IDEAL, a list of top military threats, as of Not that Chikungunya virus is not only in the top 20, but also on the rise. Because of its importance, we will have a whole separate talk on dengue.

17 Japanese Encephalitis (JEV)
Most common cause of viral encephalitis worldwide 160,000 reported cases 1966 16,000 reported in 1996, decline is due to Large-scale vaccination programs in Thailand Urbanization in Japan, Taiwan, ROK Annual est > 50K 2.5 cases/10,000 population at risk Primarily a disease of children Naïve adults at risk -- i.e., travelers Most infections are subclinical/self-limited Clinical cases have high mortality, morbidity CFR ~25 -30% Long-term disability % First Japanese encephalitis. This is a leading cause of viral encephalitis, but the incidence is declining thanks, in part, to effective vaccination programs. Most infections are asymptomatic, but those who do get sick get very sick. So 2.5 cases per 10,000 population is actually a significant incidence, but the key here is population *at risk.* Many people living in endemic areas are not at risk because they had it as a child and are now immune.

18 JEV - Clinical Findings
Incubation period 4 – 14 days Sudden onset fever, chills and aches Lethargy, HA, meningismus, N/V Acute Flaccid Paralysis Rapid onset paralysis despite normal consciousness Weakness legs > arms, asymmetric Flaccid paralysis also occurs in 5%-20% of comatose patients with "classic" JE Course Occasionally fulminant Short prodrome, deep coma, respiratory depression, posturing, death Usually, improvement over ~ 1 week Neuropsychiatric sequelae resolves over years or is permanent Long-term sequelae is a common theme.

19 JEV - Transmission Vector: Culex mosquitoes Culex tritaeniorhynchus
Breeds in marshes, rice paddies Night-biting Zoonotic amplification Domestic pigs Migratory waterfowl Domestic waterfowl? Ducks Seasonal/climate factors Summertime / post-rainy season Increased vector number, feeding behaviors Increased viral replication Here is the mosquito vector. It breeds in marshes and rice paddies, which accounts for the rural distribution of disease. Note that there is a seasonality to infection. This was particularly significant in defining risk to travelers back when the vaccine had such significant side effects.

20 On this map, the areas in yellow are the higher incidence areas
On this map, the areas in yellow are the higher incidence areas. But for JEV, higher incidence still means less than 1% of the unvaccinated.

21 JEV - Prevention Vector control – difficult in endemic regions
Impractical, historically ineffective Twilight-biting, marsh-breeding mosquitoes Reservoir control – difficult in endemic regions Swine Segregation impractical vaccination expensive Other potential reservoirs Vaccination Mass pediatric vaccinations Apparently highly effective To prevent disease, you can control the vector and you can control the reservoir. But the most effective is vaccination. This graph from the Thai Ministry of Health shows the incremental effect of these measures, and you can see the disease incidence is not affected until vaccination is done on a large scale.

22 West Nile Virus Widely distributed; Infects >300 bird species
Infects >60 mosquito species Transmission by blood product transfusion documented before routine screening. Most infections are sub-clinical/self-limited. 1:5 develop fever 1:150 develop CNS disease Incidence increases with age.

23 Yellow Fever Finally, yellow fever. The virus that made Walter Reed famous.

24 Yellow Fever Virus Molecular sequencing 1 serotype, 5 genotypes
Phylogenetic analyses Evolved over 3000 yrs YF virus originated in Africa Divided into West and East African lineages West African lineage Imported into S. America and New World

25 Yellow Fever Transmission
Urban, sylvatic and savannah cycles Non-human primates can be a reservoir. Aedes spp. Haemagogus spp. (Africa) (Americas) Vertical transmission, infected ova survival In Africa there are urban, sylvatic and savannah cycles that are maintained by different species of Aedes mosquitoes. In South America, there is just the sylvatic cycle. Overall the disease burden is much less in South America.


27 Yellow Fever – South America

28 Yellow Fever - Africa

29 Yellow Fever: Acute Period
Incubation of 3 to 6 days Clinical spectrum of disease Mild, febrile illness → Fatal VHF Severe YF Fever, Chills, Headache Lumbosacral pain, Myalgia Anorexia, Nausea, Vomiting Gingival hemorrhages, Epistaxes Bradycardia despite ↑ temperature (Faget's sign)

30 Yellow Fever: Acute Period
Symptoms for ~ 3 days (period of viremia) Defervescence and improvement (~ 24 hours) Fever and symptoms return Vomiting, Epigastric pain, Prostration, Jaundice This slide shows the pre-icteric phase with conjunctival congestion.

31 Yellow Fever: Hemorrhagic Phase
Hemorrhage “Coffee-ground” hematemesis (vomito negro) Melena, Petechiae, Ecchymoses Intravascular volume depletion Liver damage/jaundice Renal failure ↑ Albuminuria ↓ Urine output (UO) About 15% of infections will develop into hemorrhagic or toxic phase.

32 Yellow Fever: Hemorrhagic Phase
Death (in 20% to 50% of severe cases) 7th to 10th day of illness ↑ jaundice, hemorrhages, ↑ HR, ↓ BP, ↓ UO, ↓ Temp. Agitated delirium, Intractable hiccups, Stupor, Coma Laboratory findings ↓ WBC, ↓ Plts ↑ Bilirubin, ↑ Serum transaminase levels ↑ PT and PTT < synthesis of clotting factors + > consumption ST-T wave changes in the electrocardiogram. The clinical picture is that of a hemorrhagic fever but with more pronounced jaundice.

33 Yellow Fever: Convalescent Phase
Prolonged convalescence Profound asthenia lasting 1 to 2 weeks Late death End of convalescence Weeks after recovery from the acute illness Rare phenomenon Attributed to cardiac complications or renal failure Elevations of serum transaminase levels Persist for at least 2 months after onset of acute illness

34 20-50% This shows the biphasic nature of the illness.

35 Yellow Fever: Diagnosis
Clinical Diagnosis Exposure history Advanced Diagnostics: Virus Isolation (culture) Rapid Diagnostics PCR may not be positive late in disease Antibody or Antigen detection (ELISA) IgM for acute phase, coupled with convalescent antibodies (IgM/IgG) Neutralization Ab are more specific for YF Exposure history should take into account travel within the incubation period (3 to 6 days) and vaccination status.

36 Yellow Fever: Treatment Overview
Supportive Care -- no specific therapy Maintain nutrition and prevent hypoglycemia NG tube to prevent gastric distention Treatment of hypotension (IVF, pressors) Supplemental oxygen Correction of bleeding abnormalities Dialysis Treatment of secondary infections Treatment of DIC PROTECT FROM FURTHER MOSQUITO EXPOSURE Certain medications should be avoided, such as aspirin or other non-steroidal anti-inflammatory drugs (such as ibuprofen and naproxen), because these may increase the risk for bleeding. Supportive care. Don’t make the bleeding worse with aspirin or NSAIDs. And don’t let the mosquitos bite them or they will get loaded with virus and give it to somebody else. And we talked about the vaccine in the first lecture.

37 Zika virus Zika virus is an emerging arboviral infection.
Like other flaviviruses it has the capacity to mutate, adapt and infect urban mosquitoes in particular Aedes aegytpi. Like dengue, we are observing an emerging human infection influenced by human migration and urban transmission. It is the first Flaviviridae of the genera flavivirus that has demonstrated sexual transmission.

38 Figure 1 Approximate known distribution of Zika virus, 1947–2007
Figure 1 Approximate known distribution of Zika virus, 1947–2007. Red circle represents Yap Island. Yellow indicates human serologic evidence; red indicates virus isolated from humans; green represents mosquito isolates.

39 Arboviruses Family Togaviridae Genus Alphavirus
Eastern equine encephalitis virus (EEE) Ross River Virus (RRV) Venezuelan equine encephalitis virus (VEE) Western equine encephalitis virus (WEE) Chikungunya Now we’ll go through them by family, pausing to discuss in more detail those that are most relevant to your geographical area of interest. Of the Togaviruses, several fall into the genus Alphavirus. Within this family are seven complexes: Barmah Forest virus complex, EEE complex, Middleburg virus complex, Ndumu virus complex, Semliki Forest virus complex (include Chikungunya and Ross River virus), VEE conplex and WEE complex. The name “alphavirus” derives from these being previous classified as “group A arboviruses.” Besides the Alphaviruses, the other Togavirus genus is Rubivirus, whose sole member is Rubella virus.

40 Ross River Virus Ross River virus (RRV) is a mosquito-transmitted Alphavirus that is endemic and enzootic in Australia and Papua New Guinea RRV causes the most common arboviral disease in Australia Asymptomatic infections occur in ~30% Symptomatic infections typically include constitutional effects, rash, and rheumatic manifestations Symptoms may last for months, longer in those with co- morbidities This virus was first isolated from mosquitoes trapped near the Ross River in Queensland. In 1956 the disease was called epidemic polyarthritis.

41 A febrile arthritic disease was observed in 1956 in Queensland to be reminiscent of Chikungunya, implicated an alphavirus infection. RRV was first isolated in 1959 in mosquitoes from the Ross River near Townsville. Testing of patient sera showed the most reactivity with a strain called T(ownsville)48, which was then named Ross River Virus. In 1979 epidemics were described in Fiji and the Cook Islands.


43 Ross River Virus Disease
RRV usually incubates for 7 to 9 days Constitutional Fever affects from one third to one half of patients Rash, fever, and arthralgia occur in any sequence Myalgia is common Lymphadenopathy occurs quite often Sore throat and coryza less frequently Diarrhea is rare Fatigue typically affects over 50% of patients What is coryza? It just means inflammation of the mucous membranes and could be applied to the common cold. The joint pain and rash distinguish it.

44 Ross River Virus Disease
Joint manifestations Symmetrical and acute in onset Variable tenderness, effusions are common Peripheral joints are predominantly involved: Ankles, fingers, wrists, and knees Rash Usually lasts 5 to 10 days May be the sole manifestation of infection Mainly on the limbs and trunk Maculopapular, vesicular, or purpuric The arthritis mostly affects the peripheral joints. Rash may be the only sign.


46 Ross River Virus Disease
Diagnosis Serology: 4x rise in IgG over 14 days Treatment No known treatment will alter the disease course Treat symptoms NSAIDS Physical therapy, hydrotherapy, etc. Reassurance Diagnosis is by serology, and treatment is symptomatic. (What is hydrotherapy? Are patients immune to re-infection?)

47 Chikungunya Chikungunya can also occur in epidemics and can result in a more severe disease requiring hospitalization.

48 Threat Assessment – ID Risk
Disease 2010 COCOM panel ID-IDEAL Malaria 1 2 Dengue 3 Diarrhea, bacterial MDR wound pathogens 4 NA Leishmaniasis 5 19 Q fever (Coxiella burnetti) 6 26 Norovirus / viral diarrhea 7 Influenza 8 Leptospirosis 10 Diarrhea, protozoal 11 TB 12 CCHF 13 HIV 14 HFRS 15 17 Chikungunya 16 Meningococcal meningitis 20 Plague 18 27 Rickettsioses Viral encephalitides This is the IDEAL, a list of top military threats, as of Note that Chikungunya virus is not only in the top 20, but also on the rise.

49 Chikungunya - Threat Assessment
Travelers Historically South and Southeast Asia, Africa. Transmission in the Caribbean confirmed in Dec 2013. Military Lethality low, 1-7 LDD expected, Prolonged convalescence due to arthritis. Viet Nam : 15% of FUO caused by dengue or CHIK Reunion Island outbreak (French) Attack rate (~33%) Lingering clinical manifestations French troops in Gabon: outbreaks in A disease doesn’t have to be lethal to be of military significance. More important is the high attack rate. If an outbreak of this occurs during a combat operation, an unit can be rendered ineffective because so many soldiers come down with symptoms at the same time. (Political circumstances (Defense Intelligence Study, DIA A [7 MAR 2012]) of the Gabon deployment and effect on operations?)

50 Chikungunya distribution
The geographic distribution also contributes to the military significance of this virus. Should we, on short notice, be called upon to invade Australia, this virus could shut us down.

51 Chikungunya -- Historical Outbreaks
Outbreak of Chikungunya detected in Tanzania, Africa . Robinson and Lumsden describe Chikungunya fever. 1963/64 – Urban centers in India (Calcutta); >100,000 cases, >200 deaths. Sri lanka. Vietnam and Myanmar. Indonesia. 1999- Malaysia 2004 – Kenya 2005 – Mauritius 3,500, Madagascar, Mayotte and the Seychelles 2005/ Reunion Islands: 258,000 cases (1/3 of the population). 219 deaths. Indian Subcontinent (1.3M) 2007/2008 – Maldives, Pakistan, Italy, Singapore, and Australia. Thailand (54k) Cambodia, Philippines Caribbean Mutation- primary vector change Current Epidemic Get references on this mutation/vector change.

52 Historic Movement of Chikungunya
This map just shows the spread in recent years.

53 Chikungunya: Clinical Manifestations
Clinical attack rates vary by population: 25-90% Children and older adults with co-morbidities experience largest burden of disease Hospitalization rates up to 66%. High Case:Fatality ratios Despite the peak number of cases occurring among adults in mid-life, the greatest morbidity occurs among children and older adults.

54 Chikungunya: Clinical Manifestations
This table of symptoms shows similarities to RRV, though perhaps back pain is more significant with Chikungunya.

55 Chikungunya: Clinical Manifestations

56 Chikungunya vs. Dengue In terms of distinguishing this from dengue, note that with dengue myalgias predominate (“break-bone fever”) and while with chikungunya, arthritis is more common. Abnormalities on CBC are also more common with dengue.

57 Chikungunya -- Atypical Manifestations

58 Chronic Chikungunya Distal mono- or polyarthritis; improves with NSAIDs. Frequent tenosynovitis of the hands, wrists, or ankles, sometimes leading to carpal or tarsal tunnel syndromes; highly sensitive to systemic steroids. Exacerbation of pain in previously injured joints and bones requiring painkillers.

59 Chronic Chikungunya Here you can see swollen joints.

60 Chronic Chikungunya Calcifications in shoulder tendon 18 months after infection Inflammatory osteoarthritis, foot, 5 years after infection

61 Chikungunya - Treatment
No vaccine or antiviral licensed Illness is usually self-limiting Symptomatic treatment only Rest to the patient and mild movements of joints Cold compresses to inflamed joints Liberal fluid intake or IV fluids Analgesics and NSAIDS Convalescence can last weeks to years Like Ross River virus, treatment is symptomatic.

62 Arboviruses Family Bunyaviridae Genus Nairovirus
Crimean–Congo hemorrhagic fever virus (CCHF) Genus Orthobunyavirus California encephalitis virus La Crosse encephalitis virus (LACV) Bunyamwera virus Genus Phlebovirus Rift Valley fever virus (RVFV) Toscana virus (TOSV)

63 Threat Assessment – ID Risk
Disease 2010 COCOM panel ID-IDEAL Malaria 1 2 Dengue 3 Diarrhea, bacterial MDR wound pathogens 4 NA Leishmaniasis 5 19 Q fever (Coxiella burnetti) 6 26 Norovirus / viral diarrhea 7 Influenza 8 Leptospirosis 10 Diarrhea, protozoal 11 TB 12 CCHF 13 HIV 14 HFRS 15 17 Chikungunya 16 Meningococcal meningitis 20 Plague 18 27 Ricketsioses Viral encephalitides This is the IDEAL, a list of top military threats, as of Not that Chikungunya virus is not only in the top 20, but also on the rise.

64 Crimean Congo Hemorrhagic Fever
Transmitted by ticks (Hyalomma species) Milkers, shepherds, abbatoir workers. Blood from patients is highly infectious. Nosocomial outbreaks with fatalities reported. Infects reticuloendothelial system and hepatocytes. Mortality rates range from 20% to 35% Covered previously.

65 Arboviruses: Summary Arboviruses represent significant threats to military readiness. Clinical presentations vary from asymptomatic to fulminant, Monophasic to biphasic, fever +/- rash, +/- arthritis, +/- encephalitis. Treatment is supportive. A significant proportion of patients have prolonged convalescence or long-term sequelae.

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