Update on Some Emerging and Evolving Viral Infections

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Update on Some Emerging and Evolving Viral
Infections

• Henry Fraimow, MD
• Division of Infectious Diseases

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Update on Some Emerging and Evolving Viral
Infections(other than Influenza)

• Henry Fraimow, MD
• Division of Infectious Diseases

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Schemes of 21 virus families infecting humans
showing a number of distinctive criteria
presence of an envelope or (double-) capsid and
internal nucleic acid genome
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Goals and Objectives

• Review several examples of emerging and evolving
  viral Diseases
• Arboviruses (arthopod-borne viruses)
• Dengue
• West Nile Virus (Japanese Encephalitis group)
• Chikungunya fever
• Hemorrhagic Fever Viruses
• Norovirus

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Case 1 June, 2007

• 36 yo female admitted with 4 day Hx of abrupt
  onset of HA, diffuse myalgias, nausea, fever
• HA predominant complaint 10/10 in intensity
• Temp 102.7, P 127, BP 98/86, moaning
• Pharyngeal erythema, tender cervical LN
• Diffuse muscle tenderness predominately plantar
  surfaces of both feet
• Skin No rash/lesions hyperemic flush
• Throat swab done. Blood cultures drawn, LP done
  for persistent fevers, HA, photophobia.
• Empiric Vancomycin and Ceftriaxone started
• Returned from Puerto Rico 1 week ago after 8 day
  stay. Pt was well in PR. exposure to mosquitos

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Labs

• CBC WBC-7.5Hgb 10.6 Plts 84 (Diff S49 B41
  L7M2)
• CSF WBC 9 (S 74 L 14 M 12), Glucose 78 no
  Protein

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Hospital course

• Day 3 Pt c/o of acute abdominal pain. Noted to
  be dyspneic, hypotensive requiring fluid
  resuscitation.
• CT of abdomen and pelvis revealed bilateral
  pleural effusions (Right gtgtleft)
• Peripheral blood smear schistocytes and
  plasmacytoid atypical cells
• Noted to be confused, incoherent
• BP remained low initiated on Neosynephrine-
  Intubated for impending respiratory failure
• Shiley placed to initiate hemodialysis

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Differential Diagnosis

• Malaria
• Typhoid fever
• Leptospirosis
• Meningococcemia
• Rickettsial infections
• Tick Borne Illnesses
• Bacterial (toxin mediated) sepsis
• Viral hemorrhagic fevers
• Influenza
• Measles
• Rubella

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Anti-Dengue Antibody By MAC-ELISA (M-antibody
capture)

•      
• IGM AB   72
• IGG AB   92

Reference range gt11
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• The CDC included Puerto Rico August 8, 2007 in
  an outbreak notice warning tourists of the spread
  of dengue in South and Central America and the
  Caribbean, noting similar increases in Mexico,
  Brazil and Nicaragua.
• It advised travelers to use insect repellents
  containing DEET or Picaridin on exposed skin to
  wear loose, long pants and long-sleeved shirts
  and to empty or cover containers that can collect
  water.

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Dengue Virus

• Arbovirus transmitted by Aeges aegypti mosquito
  (and Aedes albopictus)
• Single-stranded RNA virus of Flaviviridae
• Causes dengue and dengue hemorrhagic fever

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Aedes aegypti Mosquito
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Worldwide Distribution of Dengue and Aeges
aegypti in 2006 (Agricultural Research Service)
Risk Area 1981
Risk Area 2002
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Dengue Viruses

• 4 different serotypes (DEN-1,2,3,4)
• Each provides specific lifetime immunity, and
  short-term cross-immunity
• All can cause severe and fatal disease
• Genetic variation within serotypes Some variants
  appear to be more virulent or have greater
  epidemic potential

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Primary vs Secondary Infection

• The kinetics of virus-specific Ab in secondary
  dengue infections differ from primary infections
• Low concentrations of Ab to the virus serotype
  are present before exposure to the virus.
• Concentrations of virus-specific Ab increase
  earlier, reach higher peak titers, and have a
  lower IgMIgG ratio, suggestive of an anamnestic
  response.
• Levels of virus-specific Ab are much higher
  during the late stage of viremia in secondary
  infections, with greater potential for forming
  immune complexes and activating complement.

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Replication and Transmissionof Dengue Virus
(Part 1)
1. Virus transmitted to human in mosquito
saliva
2. Virus replicates in target organs
3. Virus infects white blood cells and
lymphatic tissues
4. Virus released and circulates in blood
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Replication and Transmissionof Dengue Virus
(Part 2)
5. Second mosquito ingests virus with blood
6. Virus replicates in mosquito midgut
and other organs, infects salivary glands
7. Virus replicates in salivary glands
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Dengue Clinical Syndromes

• Undifferentiated fever
• Classic dengue fever
• Dengue hemorrhagic fever (DHF)
• Dengue shock syndrome (DSS)

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Undifferentiated Fever

• May be the most common manifestation of dengue
• Prospective study found that 87 of students
  infected were either asymptomatic or only mildly
  symptomatic
• Other prospective studies including all age-
  groups also demonstrate silent transmission

DS Burke, et al. A prospective study of dengue
infections in Bangkok. Am J Trop Med Hyg 1988
38172-80.
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Clinical Features of Dengue Fever (Break-bone
fever)

• Fever
• Headache
• Muscle and joint pain
• Nausea/vomiting
• Rash
• Hemorrhagic manifestations

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Hemorrhagic Manifestations of Dengue

• Skin hemorrhages petechiae, purpura, ecchymoses
• Gingival bleeding
• Nasal bleeding
• Gastro-intestinal bleeding
  hematemesis, melena, hematochezia
• Hematuria
• Increased menstrual flow

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CNS Findings in Acute Dengue Infection

• Decreased level of consciousness lethargy,
  confusion, coma
• Seizures
• Nuchal rigidity
• Paresis

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Clinical Case Definition for Dengue Hemorrhagic
Fever (DHF)
4 Necessary Criteria

• Fever, or recent history of acute fever
• Hemorrhagic manifestations
• Low platelet count (100,000/mm3 or less)
• Objective evidence of leaky capillaries
• elevated hematocrit (20 or more over baseline)
• low albumin
• pleural or other effusions

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Four Grades of DHF

• Grade 1
• Fever and nonspecific constitutional symptoms
• Positive tourniquet test is only hemorrhagic
  manifestation
• Grade 2
• Grade 1 manifestations spontaneous bleeding
• Grade 3
• Signs of circulatory failure (rapid/weak pulse,
  narrow pulse pressure, hypotension, cold/clammy
  skin)
• Grade 4
• Profound shock (undetectable pulse and BP)

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Tourniquet Test

• Inflate blood pressure cuff to a point midway
  between systolic and diastolic pressure for 5
  minutes
• Positive test 20 or more petechiae per 1 inch2
  (6.25 cm2)

Pan American Health Organization Dengue and
Dengue Hemorrhagic Fever Guidelines for
Prevention and Control. PAHO Washington, D.C.,
1994 12.
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Positive Tourniquet Test
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Signs and Symptoms in 57 Hospitalized Cases of
DHF,Puerto Rico,1990 - 1991
SIGNS AND SYMPTOMS FREQUENCY PERCENT
Fever 57 100 Rash 27
47.4 Hepatomegaly 6 10.5 Effusions
3 5.3 Frank shock 3 5.3 Coma
2 3.5 Any hemorrhage 57 100
Minimum estimate, search was not uniform for
all patients Only 2 (3.5) cases had severe
hemorrhagic manifestations
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Hemorrhagic Signs and Sx in 57 Hospitalized Cases
of DHF, Puerto Rico, 1990-91
Minimum estimate the search was not uniform
for all patients Percents were calculated
using the number of patients among whom
each symptom was sought as the denominator
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Clinical Case Definition for Dengue Shock Syndrome

• All 4 criteria for DHF plus
• Evidence of circulatory failure manifested
  indirectly by all of the following
• Rapid and weak pulse
• Narrow pulse pressure (? 20 mm Hg) OR hypotension
  for age
• Cold, clammy skin and altered mental status
• Frank shock is direct evidence of circulatory
  failure

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Warning Signs for Dengue Shock

• Alarm Signals
• Severe abdominal pain
• Prolonged vomiting
• Abrupt change from fever
  
  
  
  
  to hypothermia
• Change in level of
• consciousness (irritability
  
  
  
  
  or somnolence)

• Four Criteria for DHF
• Fever
• Hemorrhagic manifestations
• Excessive capillary permeability
• ? 100,000/mm3 platelets

• Initial Warning Signals
• Disappearance of fever
• Drop in platelets
• Increase in hematocrit

• When Patients Develop DSS
• 3 to 6 days after onset of
  
  
  
  
  symptoms

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Laboratory Tests in Dengue Fever

• Clinical laboratory tests
• CBC--WBC, platelets, hematocrit
• Albumin
• Liver function tests
• Urine--check for microscopic hematuria
• Dengue-specific tests
• Virus isolation to determine serotype of the
  infecting virus
• Serology IgM ELISA test for serologic diagnosis

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Serologic testing

• The HI assay historically has been and remains
  the gold standard for serologic testing for
  dengue virus-specific antibodies
• Analysis of paired acute and convalescent serum
  a 4 fold rise in HI antibody titer between acute
  and convalescent samples
• Convalescent phase serum should be obtained at
  least 10 to 14 days after the acute phase serum.

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Testing During Acute Infection

• An acute phase serum plasma sample should be
  obtained.
• The IgM immunoassay (MAC-ELISA or equivalent) is
  the procedure of choice for rapid confirmation of
  the diagnosis.
• Virus-specific IgM antibodies are typically
  detected by the MAC-ELISA by the sixth day of
  illness and persist for 30 to 90 days.
• Sensitivity and specificity of this assay is much
  lower than the HI assay.

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Treatment of Dengue Fever

• Fluids
• Rest
• Antipyretics (avoid aspirin and non-steroidal
  anti-inflammatory drugs)
• Monitor blood pressure, hematocrit, platelet
  count, level of consciousness
• Unknown if the use of steroids, intravenous
  immune globulin, or platelet transfusions to
  shorten the duration or decrease the severity of
  thrombocytopenia is effective

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Treatment of Dengue Fever

• Continue monitoring after defervescence
• If any doubt, provide intravenous fluids, guided
  by serial Hct, BP, and urine output
• Fluid volume typically 5-8 isotonic deficit
• Indications for Hospital Discharge
• Visible improvement in clinical picture, absence
  of fever for 24 hours, return of appetite, Stable
  hematocrit, Plts ? 50,000/mm3, 3 days post
  recovery from shock,No respiratory distress from
  pleural effusions/ascites

Pan American Health Organization Dengue and
Dengue Hemorrhagic Fever Guidelines for
Prevention and Control. PAHO Washington, D.C.,
1994 69.
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Unusual Presentations of Severe Dengue Fever

• Encephalopathy
• Hepatic damage
• Cardiomyopathy
• Severe gastrointestinal hemorrhage

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Dengue in the Continental USA

• Disease in Returning Travelers
• Dengue epidemics occurred in the USA in the 1800s
  and the first half of the 1900s
• Recent indigenous transmission (Texas)
• 1980 23 cases, 1st locally acquired since 1945
• 1986 9 cases
• 1995 7 cases
• 1997 3 cases
• 1998 1 case
• 1999 18 cases
• 2005 3 cases

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Dengue in Key West 2009
Dengue virus returns to Florida after more than
50 years, UF researchers say Filed under Florida,
Health, Research on Monday, November 23, 2009.
GAINESVILLE, Fla. University of Florida
mosquito researchers are watching with a wary eye
as dengue virus returns to the state after more
than 50 years. By late last week, 20 cases of
locally transmitted dengue had been confirmed in
Key West. Monroe County officials have issued a
health alert and launched an education campaign
urging residents to eliminate water sources in
and around their homes where mosquitoes can breed.
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Viral Hemorrhagic Fevers (VHF)

• VHFs diverse group of animal and human illnesses
  caused by multiple families of enveloped RNA
  viruses Arenaviradae, Filoviridae, Bunyaviridae,
  and Flaviviridae
• VHF characterized by fever and bleeding
  disorders, can progress to high fever, shock and
  death, though severity of illnesses very variable
• Viral survival requires natural reservoir (animal
  or insect) and thus geographically restricted
• Human infection sporadic and occurs from contact
  with reservoir, but human to human transmission
  can occur

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Marburg and Ebola

• Central Africa but Imported cases/outbreaks
• Contact with infected primates/bats
• Incubation 2-21 days
• HA, fever, malaise, progress to bleeding and
  shock
• Mortality 20-90
• RxSupportive

• Central and West Africa
• Contact with primates or other infected mammals
• Incubation 2-21 days
• Fever, rash, HA, exhaustion, bleeding
• Mortality 50-90
• Rx Supportive

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Other VHFs

• Crimean-Congo HF
• Rift Valley Fever
• Hanta virus HF with Renal Syndrome
• Lassa Fever
• Multiple others

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Case 2

• 72 yo Italian born male from central Camden
  admitted mid August 01 with 2 day Hx of fever,
  chills and anorexia, episode of shaking in his
  sleep followed by confusion and incontinence
• Denied HA or other localizing symptoms
• No recent travel or exposures
• PE 102.4, 123/72, 111
• Neck supple, no rash, no LN
• severe ataxia, marked tremor, diffusely weak ,
  otherwise non focal

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Case 2

• Lab data
• WBC 12.2 79P 4B 9L 8M Hg 11.8 plts 206
• Na 130 CO2 19 Glucose 168 Cr. 1.1
• Head CT Neg
• LP149 WBC 7 RBC11P 74L15M, Glu 77, Pro 92
• Hospital Course
• Started on Ceftriaxone, Acyclovir, Phenytoin with
  Slow improvement
• All additional CSF studies negative Cultures,
  VDRL, Lyme, HSV

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Case 2

• Hospital Day 4
• Fever curve improved, all animitobials D/Cd
• Remained very ataxic, tremor, Headache
• Strength better, Mental status norma
• MRI meningeal enhancement, no focality
• Repeat LP 106 WBC, 53 RBC, 17P 65L 10M, 24
  Plasmacytoid L, protein120, glu 53
• CSF and serum sent to NJ State Health Dept lab
  for confirmation of West Nile Infection

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West Nile Virus Infections

• Flavivirus (ssRNA virus) of the Japanese
  Encephalitis serologic group
• Arbovirus transmitted by a variety of mosquito
  species, most commonly Culex spp
• 50 different species carry WNV in the US
• Major reservoirs are wide variety of birds
• Initially found in Uganda and subsequently thru
  Africa, the Mideast and parts of Europe
• 1st recognized in the US in 1999 in NYC, virus
  strain genetically related to a strain from Israel

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Evolution of WNV Epidemic in the Western
Hemisphere

• Largest Arboviral epidemic ever in the Western
  Hemisphere
• Novel Epidemiologic features
• New modes of transmission recognized
• Blood transfusion
• Organ transplantation
• Breast feeding/ transplacental
• New Neurologic syndromes recognized
• 10 mortality in those with CNS disease

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Neuroinvasive West Nile, US
2009
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Human West Nile in New Jersey
2003
2005
2009
2007
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Transmission occurs from mosquito biting an
infected bird with high level viremia Bird
species vary in susceptibility to infection
(crows, jays most susceptible) Humans and other
mammals (horses) do not develop high level
viremia Vaccine available for horses
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Transmission

• The most common route of infection is bite of
  infectious mosquito
• 2002 revealed other modes
• Blood Transfusion
• Organ Transplantation
• Intrauterine
• Percutaneous exposure (occ. exposure)
• Breastmilk (probable)

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WNV Human Infection Iceberg
10 of CNS disease is fatal (lt0.1 of total
infections)
For every case of illness involving the brain or
spinal cord, 140 total infections
lt1 CNS disease
20 West Nile Fever
80 Asymptomatic
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WN Virus Infections Clinical features

• Incubation period 2-14 days
• 80 of those infected never develop symptoms
  (reservoir for transmission via transfusions,
  etc)
• 20 of those infected develop West Nile Fever
• Fever
• Headache
• Fatigue
• Skin rash on the trunk of the body (occasionally)
  
• Swollen lymph glands (occasionally)
• Eye pain (occasionally)
• Mortality of WNF low, but symptoms can persist
  for long periods 63 had some Sx at 30 days

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West Nile Virus Severe Disease (Neuro-invasive
Disease, WNND)

• Occurs in 10 of cases of symptomatic illness
  (one /150 WNV infections)
• Age is the major risk for severe disease
• 20-fold increase for age gt 70
• Other risk factors for severe disease
• Organ transplantation
• ? other immunosupression
• Genetics CCR5 receptor deficiency
• Mortality with WNND estimated at 10

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Figure 3 Incidence of West Nile virus
neuroinvasive disease by age81
DeBiasi RL and Tyler KL (2006) West Nile virus
meningoencephalitis Nat Clin Pract Neurol 2
264275 10.1038/ncpneuro0176
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Neuroinvasive Disease Syndromes

• Encephalitis or Meningoencephalitis 60-75
• Fever, nucchal rigidity, HA, decreased LOC, focal
  findings, ataxia, tremors
• Less common Seizures, cranial nerve
  abnormalities, optic neuritis, myelitis
• Meningitis 25-35, very low mortality
• Fever, headache, nucchal rigidity, CSF
  lymphocytic pleocytosis
• Acute Flaccid Paralysis (motor) Syndromes up to
  10
• Poliomyelitis-like rather than GB like more
  common involvement of anterior horn cells
• Younger age than other WNND
• Recovery of function variable

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Diagnosis of WNF and WNND

• Routine Tests
• WBC responses variable
• Hyponatremia
• CSF with lymphocytic pleocytosis and elevated
  protein
• CAT scans not generally helpful, MRI may show
  meningeal enhancement or focal abnormalities in
  25-35 of cases

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Diagnosis of WNF and WNND

• IgM antibody by MAC-ELISA in serum (8-14 days
  after onset) or CSF (8 days after onset)
• Cross reactivity with other JE group viruses
• Confirmatory serum testing IgM and IgG Ab in
  Plaque Neutralizing Assay
• PCR for WNV Sensitivity only 50 in CSF but
  specificity high
• Culture rarely done

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Treatment of WNND

• Supportive Rx
• No proven treatments for severe neurologic
  disease but several in clinical trials
• Alpha Interferon therapy
• Monoclonal Antibody against WNV
• Other treatments used (no controlled trials)
• Immunoglobulin
• Ribavirin

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Prevention of Transfusion and Transplant
Associated WNV Infection

• Many (80) individuals with WNV infection are
  asymptomatic
• Since 2003 blood screened by nucleic acid
  amplification testing (NAT) and most viremic
  donors identified, though can still miss rare
  donors who are low level viremic
• Organ donors are not routinely screened by NAT
  due to time pressure

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Other Neuroinvasive Arboviral Encephalitis Cases
in the US, 1964-2008
640 Cases (but lt 2/yr since 1986)
3544 Cases
257 Cases
14 Cases
4676 Cases (but lt 15/yr since 2004)
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Chikungunya Virus

• Arbovirus of the Togavirus family
• Transmitted by Aedes mosquitoes
• A. aegypti (yellow fever mosquito) and more
  recently A. albopictus (Asian Tiger mosquito)
• A. albopictus recently introduced into the US
• Animal reservoir humans, ?monkeys
• Cyclic epidemics in Africa and Asia but recent
  infections in Europe (Italy) as well
• Epidemic in South India 2006 after 32 year
  absence, over 1.4 Million cases, attack rates of
  up to 45
• 2009 Thailand, Malaysia, Singapore

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Chikungunya Virus
US Distribution of Aedes albopictus
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Clinical Illness

• Acute debilitating illness, most often
  characterized by fever, headache, fatigue,
  nausea, vomiting, muscle pain, rash, and joint
  pain. that which bends up
• Incubation typically 3-7 days
• Silent infections can occur ? 10-15 prevalence
• Typically symptoms last days to weeks but some
  Sx, especially joint pain can last months
• Not a hemorrhagic fever virus, fatality rate low
  but higher in some recent epidemics (Reunion
  Island)

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Diagnosis and Treatment

• Diagnosis
• Serology (Acute IgM)
• Viral PCR typically high level viremia
• In USsend to CDC (imported cases)
• Treatment
• Supportive Rx, no specific antiviral Rx available
• The best treatment is prevention

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Norovirus Infections

• Genus of the Calciviridae family
• Prototype virus Norwalk agent
• Leading cause of epidemic gastroenteritis and
  important cause of sporadic gastroenteritis
  worldwide
• Multiple genogroups and genotypes, but most
  infections due to Genogroup II, genotype 4
• Genetic drift of the virus, new pandemic strains
  every 2-4 years
• Human pathogen- no animal reservoir

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Phylogenetic Analysis of Noroviruses
Glass R et al. N Engl J Med 20093611776-1785
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Outbreaks of Noroviruses in the United States,
1994 to 2006, According to Genotype and Genogroup
Glass R et al. N Engl J Med 20093611776-1785
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Noroviruses Transmission

• Fecal oral spread, also infectious vomitus
• Virus can persist and is temperature stable, so
  role of fomites, etc
• Virus can be shed before symptoms and long after
  resolution of symptoms
• Infectious dose low
• Thus secondary attack rate high (30 of close
  household contacts)
• In various studies (adults and children) 5-35 of
  sporadic gastroenteritis seen as inpatients or
  outpatients are due to Norovirus

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Glass R et al. N Engl J Med 20093611776-1785
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Glass R et al. N Engl J Med 20093611776-1785
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