DD 02-26-14 08-10am Common Viral Pathogens - Curtis Flashcards
Infection vs. Disease
Infection = virus has replicated in host Disease = infection that causes symptoms
Lab Tests to Dx Viral Infection
- Culture: can grow SOME viruses in TISSUE
- Antigen assays
- PCR
- ELISA (Enzyme-Linked Immunosorbent Assay)
Antigen assays for viral Dx
- various assays using enzymatic rxns or immunofluorescence to detect specific Ags of virus in question (ex: rapid flu test)
PCR for viral Dx
- copying & amplifying portion of viral genome
- very sensitive & specific
- can be done on blood, nasal wash, CSF, biopsies
Results may be…
- qualitative (+ or -)
- quantitative (# of copies/mL)
ELISA (Enzyme-Linked Immunosorbent Assay to Dx virus
- to look for host’s immune response to viral infection by looking for Abs specific for that virus
Most commonly, ELISA would…
- Coat plate w/ viral Ag (whole virus or part)
- Incubate host’s serum on plate to let Abs attach to Ag on bottom of wells
- Then incubate plate w/ an antibody that detects the host antibody (i.e., a secondary antibody)
- Then incubate plate w/ a substrate that will allow visualization of the secondary antibody
Herpes virus (type of virus, who they infect)
- double-stranded DNA viruses
- infect most animals.
Hallmark of a herpes infection
Once a host is infected, the host is always infected.
- establishes latency after infection
- latent virus can become reactivated
- reactivated infection doesn’t always cause disease
Antiviral medications for Herpes Viruses
- work against some of the human herpes viruses
Acyclovir
= most common
= works by inhibiting the viral DNA polymerase
= indicated for HSV and VZV infections
Herpes Viruses that infect humans (8)
- HHV-1: Herpes Simplex Virus-1 (HSV-1)
- HHV-2: HSV-2
- HHV-3: Varicella Zoster Virus (VZV)
- HHV-4: Epstein Barr Virus (EBV)
- HHV-5: Cytomegalovirus (CMV)
- HHV-6: Roseola (HHV-6a, HHV-6b)
- HHV-7: Roseola
- HHV-8: HHV-8
Clinical Manifestations of Herpes Simplex viruses 1 & 2 (HSV-1, HSV-2)
- Oral and genital herpes
- Neonatal herpes
- Herpes keratitis (eye)
- Herpes encephalitis
- Herpetic whitlow (finger lesion)
- Herpes gladiotorum (“wrestlers”)
- Encephalitis
Clincal Manifestations of Varicella zoster virus
VZV
- Chickenpox,
- In immunocompromised: vasculitis, encephalitis, pneumonia
Clincal Manifestations of Epstein-Barr virus
EBV
- Infectious mononucleosis
- Burkitt’s lymphoma-
- Encephalitis
- In immunocompromised: lymphoma
Clincal Manifestations of Cytomegalovirus
CMV
- Infectious mononucleosis-like syndrome
- In immunocompromised: retinitis, pneumonia
- In newborns: congenital CMV
Clincal Manifestations of Human herpesvirus 6 & 7
- Roseola or exanthem subitum
- In immunocompromised: fever, encephalitis
Clincal Manifestations of Human herpesvirus 8
- Kaposi’s sarcoma (only occurs in immunocompromised)
Signs/Symptoms of Herpes Simplex viruses 1 & 2 (HSV-1, HSV-2)
-painful vesicles at the site of inoculation
Differences between of HSV-1 & HSV-2
Though both can cause oral & genital herpes…
- HSV-1 is predominantly oral lesions
- HSV-2 is predominantly genital lesions
- These differences are becoming less strong with time, mainly as a result of oral sex allowing the two viruses to now infect other body sites
Incubation Period of HSV-1 & -2
2-12 days
typically ~4 days
Transmission of HSV-1 & -2
Transmission occurs through inoculation from someone who is shedding virus into a mucosal surface or cut of another person.
Clinical patterns of HSV-1 & HSV-2 depend on…
whether infection is primary or recurrent
Primary infection vs. Latent infection vs. Reactivation infection with HSV-1/HSV-2: Clinical pattern
Primary:
- most are asymptomatic
- usually worse than recurrent infection
- If symptomatic, lesions usually develop 1-3 days after inoculation
- Vesicular rash +/- fever
- Usually occurs during childhood w/ HSV gingivostomatitis (historically HSV-1)
Latent:
- asymptomatic
Reactivation:
- Contagious, though may be asymptomatic
- If symptomatic, usually less than primary infection
- Can be infrequent or very frequent
- Provoked by variety of stimuli
HSV-1 & -2 Rash in Immunocompromised vs. Immunocompetent Hosts
Immune competent hosts:
- area of vesicular rash stays contained to area of inoculation
Immunocompromised host:
- Infection may involve larger areas of skin
- Can disseminate to specific/multiple organs (systemic)
- EX: encephalitis, hepatitis
Neonatal HSV-1 & -2 infection: Locations
Skin Eye Mucous Membrane CNS Disseminated
Latent infection with HSV-1/HSV-2: where infection occurs
Occurs in sensory ganglia of areas infected w/ the primary infection
- Orofacial infection: trigeminal ganglia
- Genital infection: sacral ganglia
HSV-1/-2 Diagnosis:
Often clinical Dx
If need definitive Dx:
- Tzanck smear
- HSV culture
- Direct Fluorescent Antigen stain
- PCR of lesions
Triggers of Reactivation of HSV-1/HSV-2 Infection
- sunlight
- stress
- febrile illness
- menstruation
- immunosuppression
HSV Treatment
Severe HSV infections:
<– IV acyclovir
= for neonatal HSV, HSV in immunocompromised hosts, encephalitis/meningoencephalitis
Oral antiviral therapy (acyclovir or related antiviral)
= for oral or genital outbreaks
= standing Rx for ppl w/ frequent outbreaks not on suppressive therapy, so they can fill it & start treatment at very onset of reactivation / outbreak
Tzanck smear to Dx HSV-1/-2 infection
- direct specimen (scrape base of lesion)
- put specimen on slide & stain
- look for multinucleated giant cells
- not specific for HSV (also VZV and CMV)
- rarely used in favor of easier & more sensitive / specific testing
HSV-1/-2 Prevention of Reactivation Infection (& what warrants it)
Prophylactic Acyclovir
- in lower doses than used for treatment
- difficult to maintain
Used for pts with:
- frequent outbreaks of oral / genital lesions
- recurrent keratitis & encephalitis
HSV-1/-2 Prevention of Primary Infection
- NO vaccine available
- Hand hygiene
- Physical barriers: gloves, condoms
- Avoid contact
Varicella Zoster Virus (VZV) - Clinical Syndrome
VZV causes 2 clinical syndromes of importance:
• Chickenpox (varicella)
• Shingles (zoster)
Primary Varicella Zoster Virus (VZV) Infection
= Varicella, or Chicken pox
Clinical Pattern of Primary VZV infection (Chickenpox/Varicella)
- Fever, malaise, headache, +/- cough
- Rash develops, in successive waves
- Typically lasts 7 days
- No longer contagious when lesions all crusted over
Primary VZV Infection (Chickenpox / Varicella) Rash
- itchy
- vesicular
- “dew drop on rose petal” = clear fluid + red base
- Usually starts on trunk & spreads to face & limbs
- Lesions appear in successive waves, so lesions will be in various stages on physical exam
Pathogenesis of Primary VZV Infection (Chickenpox / Varicella)
- Virus gains entry via respiratory tract
- Spreads to regional lymphoid system & replicates over next 2-4 days
- Causes primary viremia (~4-6 days after incoc.)
- Replicates in liver, spleen & other organs causing secondary viremia.
- Secondary viremia spreads viral particles to skin 14-16 days after initial exposure & causes typical vesicular rash.
Primary VZV Infection - Age, Spread, Incubation, Prevention
- common childhood disease
- highly contagious
- incubation of 10-21 days
- preventable by vaccination (introduced in 1995)
Varicella Treatment
- Typically self-limited & requires no treatment
- Treatment accelerates resolution of chickenpox & decreases symptoms
- Immunocompromised patients should always receive treatment
Varicella Prevention/Prophylaxis
Varicella vaccine: is a live-attenuated vaccine
- Beware in immunocompromised hosts
- 2-dose series at 12-15 mo & 4-6 yo
- Can be used post-exposure in certain situations
Varicella-zoster immune globulin (Varizig)
- for reducing severity of varicella in high-risk individuals if given w/in 4 days of exposure
= pooled Abs from ppl w/ high VZV Ab titers
Pathogenesis of Latency and Reactivation of VZV
- Latent in cranial, dorsal root and/or trigeminal ganglia
= Only herpes virus w/out asymptomatic viral shedding in normal hosts - Reactivation is ALWAYS SYMPTOMATIC
- Reactivates in ganglion & tracks down sensory nerve to skin innervated by the nerve
- Causes dermatomal rash that is pathognomonic for Zoster
Zoster (Shingles) Infection = Reactivation of Primary VZV
- in up to 30% of population
- 1st symptom is pain at site where vesicles will erupt in a few days.
Lesions
- develop in single dermatome.
- itchy, but main symptom is pain
- usually crust over within 2 weeks
Complications of Zoster (Shingles):
- Similar to Varicella
- Secondary skin infections
- VZV ophthalmicus
- Encephalitis
- CNS vasculitis
- Myelitis (spinal cord inflammation)
- Cranial-nerve palsies: Ramsay-Hunt syndrome, Bell’s palsy
- Peripheral nerve palsies
- Post-herpetic neuralgia (PHN): can be very debilitating & last weeks to months after lesions resolve
Immune response to VZV reactivation
- Cell-mediated immunity is crucial to maintaining latency & preventing reactivation of VZV
- Cell-mediated immunity decreases w/ age & is often affected by immunosuppression and HIV
Complications of Varicella (Primary VZV)
Secondary infection:
- Group A Strep
- Necrotizing fasciitis
- Pneumonia (bacterial or viral)
- Encephalitis or encephalomyelitis
- Hepatitis
- Congenital varicella (TORCH infection, severe)
Adolescents & adults have more severe disease
Pregnant / immunocompromised ppl have higher morbidity / mortality from primary VZV
Zoster treatment
Acyclovir
- decreases number & duration of lesions
- decreases pain
PAIN
= often worst part of shingles
- can be treated w/ NSAIDS & opiates, occasionally with steroids
Zoster Prevention/Prophylaxis:
- Live-attenuated vaccine, Zostavax (ZOS)
- One dose age 60+ recommended by ACIP
- Boosts immune response to VZV, thereby preventing reactivation
- Can also use acyclovir for people w/recurrent shingles (usually the immunocompromised)
Epstein Barr Virus - Primary Infection
- very common (almost all ppl infected by age 40)
- primary infections often occur in early childhood
- either asymptomatic or are a mild febrile illness
- incubation period is 4-6 weeks
- Transmission via saliva: kissing, sharing utensils/food/drink
Infectious mononucleosis
= clinical syndrome that occurs when older child, adolescent or adult gets primary EBV infection (or less commonly CMV)
= in ~40-50% of primary infections in this age group
= “kissing disease”
Symptoms include:
- fever
- sore throat
- swollen lymph nodes
- fatigue
Physical exam:
- Exudative tonsillitis
- Enlarged cervical nodes
- Splenomegaly, occasionally hepatomegaly
Symptoms usually resolve in 4-8 weeks
Pathogenesis of EBV infection
- Infects nasopharyngeal epithelium
- Results in cell lysis & viral spread to adjacent structures (salivary glands, oropharyngeal lymphoid tissue, etc.)
- Viremia occurs w/ distribution to liver, spleen, & infection of B lymphocytes
- Remains dormant/latent in nasopharyngeal epithelium & B cells
- Periodically, can reactivate (normally asymptomatic) & is commonly found intermittently in saliva of infected persons
Diagnosis of EBV (Infectious Mono)
- Often clinical diagnosis
- Atypical lymphocytes on peripheral blood smear & often are >10% on the differential
- Monospot/heterophile tests
- If definitive Dx needed, can do EBV serology
Monospot/heterophile tests for EBC/Infectious mononucleosis
- Detects presence of Abs that agglutinate horse / sheep / cattle RBCs
- After acute infection w/EBV, 75-90% of pts develop Abs that cross-react & agglutinate RBCs
- Heterophile Abs highest during 1st four weeks of infection
EBV serology
- used if definitive Dx of EBV is needed
- measures development of Abs to EBV antigens: EBNA and VCA (viral capsid antigen)
IgM response to VCA indicates recent infection:
- appears early in infection & disappears in 4-6 wks
- seen by the time symptoms appear
IgG response to VCA indicates prior infection:
- appears at 2-4 weeks after symptoms begin & persists for life
EBNA (IgG) indicates past infection:
- infection at least a few months back
- NEVER positive in an acute infection
EBV Prevention/Prophylaxis
- NO vaccine available
- Prevention of primary infection through preventing contact w/ infectious saliva
Cancers associated with EBV
- Not part of a primary infection, but occur later
Burkitt’s Lymphoma:
- endemic in Africa & sporadic elsewhere
- B cell tumor often affecting the jaw
Hodgkin’s lymphoma
Nasopharyngeal carcinoma: esp. in Chinese
Lymphoproliferative disease:
- in immunocompromised patients
<– uncontrolled proliferation of EBV-infected B cells
EBV Treatment
In normal hosts
- treated supportively (fluids, antipyretics)
Steroids
- for pts w/impending tonsillar enlargement threatening to occlude airway
- for pts w/ severe hepatitis
In immunocompromised hosts
- very difficult to treat
- mainstay is restoring immune function (reducing immunosuppression) if possible
Cytomegalovirus (CMV) Transmission
Transmission through contact w/ infected body fluids
- Saliva, milk, sexual contact, blood, tears, urine
- Blood transfusions & organ transplantation
Infected pregnant women can pass the virus to their unborn babies (in utero or perinatally)
Zoster/Shingles diagnosis
- Usually diagnosed clinically
- can use Direct IFA, PCR, or culture
Pathogenesis of CMV:
- Infects epithelial cells of salivary gland or genital tract
- Persistent infection & intermittent viral shedding
* All cells where CMV becomes latent UNKNOWN - Likely viremia causing wide distribution of virus to other organs & tissues
* Infection of GU system leads to shedding in urine
Primary Infection with CMV in normal, healthy people
In most healthy persons acquiring CMV after birth:
- Almost always asymptomatic
- Sometime mild febrile illness
- Sometimes mono-like syndrome (similar to EBV) w/ fever, swollen lymph nodes, & mild hepatitis
- no longterm consequences
Incubation period 2 weeks to 2 months
Primary Infection with CMV in Immunocompromised
- serious & can infect most organs
- severity parallels degree of impairment of cell-mediated immunity
- severe disease most common in pts with organ / marrow transplants or HIV (w/very low CD4 counts)
- -> CMV pneumonia, colitis, retinitis, hepatitis, encephalitis
- -> CMV retinitis & colitis in HIV patients
Pregnancy & CMV
- Most common in utero infection in US
- When pregnant woman develops primary CMV infection, 3-5% chance that child will be born w/ congenital CMV infection.
- Infection of fetus can also occur if pregnant women reactivates CMV, but much lower risk (<1% infected & even fewer symptomatic)
Congenital CMV Syndrome
- Most congenitally infected infants asymptomatic
- Only 10-15% have symptoms at birth (this is 3-5% of infants born to mothers w/ primary infections)
Syndrome:
- Low birth weight
- Microcephaly
- Hearing loss
- Mental impairment
- Hepatosplenomegaly & Jaundice
- Skin rash (blueberry muffin spots)
- Chorioretinitis
Latency and Reactivation of CMV:
- Latent in monocytes & lymphocytes
- May reactivate from time to time, during which infectious virions appear in urine & saliva
Reactivation of CMV in Pregnant Women
- can lead to vertical transmission (mom to fetus)
- more common in mothers w/ primary infection
Epidemiology of CMV Infection
- In developed countries w/ high standard of hygiene, 50-80% of entire population is infected by 40 yo
- In developing countries, over 90% are infected
Reactivation of CMV in immunocompromised individuals
- may produce serious disease w/ high morbidity & mortality
Disease can be…
- non-focal viral syndrome
- organ-specific infection (ex:hepatitis, pneumonitis)
Diagnosis of CMV infection
- Serology (CMV IgM & IgG)
- Viral culture (easy to grow, takes several days)
- PCR
- Direct fluorescence test
- Tissue histology
Reactivation of CMV in persons with normal immune systems
- asymptomatic
- BUT virus is being shed in bodily secretions
Tissue histology in CMV infection
“Owl’s Eye” appearance of infected cells
= densely staining body surrounded by a halo
- due to intranuclear inclusion bodies (viral proteins or particles)
Intracytoplasmic inclusions (multiple smaller inclusions) are also seen in CMV infection
Treatment of CMV in Immunocompetent hosts
No treatment indicated
Treatment of CMV in Pregnant woman
- Some protection offered by immunoglobulin preparation w/ high titer of CMV Abs (CMV-IG)
Treatment of CMV in Infants w/ Congenital CMV
- Gancyclovir in infants w/congenital CMV is currently being studied
- NEW standard of practice will likely be treatment of symptomatic congenital CMV infection for first 6 mos of life w/ oral valganciclovir
Prevention of CMV
- NO vaccines available
In Immunocompromised pts at very high risk for severe CMV disease:
- IV CMV-IG once a month as prophylaxis
- Ganciclovir or valganciclovir as prophylaxis in some circumstances (ex: post-transplant)
Respiratory Syncytial Virus (RSV) – Family & Structure
- Paramyxoviridae family
- Enveloped
- ssRNA genome
- 2 important surface proteins: G-protein & F-protein
2 Important Surface Proteins in RSV
G-protein - for viral attachment to host cells
F-protein (Fusion protein)
- fusion of infected cells to neighboring cells to form syncytia (multinucleated giant cells)
Primary Infection w/ RSV (w/ ages)
- Usually Symptomatic
- lasts 7-21 days
- Acute respiratory disease in patients of all ages
- Bronchiolitis: children <1 yr of age
- Viral pneumonia: young children & elderly
- Upper respiratory tract infection: children & adults
Transmission of RSV & Incubation period
- By contact w/ droplets (respiratory secretions) on fomites, with subsequent contact w/eye, nose, or mouth
- By aerosol droplets also possible
- Incubation period is 5 days
Clinical patterns of RSV in premature infants & young children
Most frequent cause of bronchiolitis & viral pneumonia
Almost all children infected at least once by 2yo
Symptoms include:
- fever
- runny nose
- cough
- wheezing w/ involvement of lower respiratory tract
Clinical patterns of RSV infection (seasonality, hospitalizations)
- Seasonal illness, peaking in Winter
- Up to 125,000 hospitalizations annually
Reinfection w/ RSV
- In adults and older children
- Rarely Asymptomatic
- Generally resembles severe cold
- Usually confined to upper respiratory tract
Bronchiolitis w/ RSV
- URI w/ congestion, sore throat, fever
- Cough deepens & becomes more prominent
- Lower respiratory tract involvement develops w/
- increased respiratory rate
- intercostal muscle retraction
- wheezing
Wheezing in child <2 yr of age is most likely bronchiolitis
Pathogenesis of RSV infection
- Entry through mucosa of eye & nose
- Infects respiratory tract locally
- Cell-to-cell transfer of virus leads to spread from upper to lower respiratory tract
- Syncytia formed through fusion of adjacent cell membranes
Pathogenesis of Bronchiolitis in RSV infections
Bronchiolitis results from:
- Mucosal edema
- Cell necrosis & sloughing
- Increased mucous secretion & plugging of bronchiolar lumina w/ epithelial debris & mucous
Airway hyper-reactivity & bronchoconstriction also occur as a result of inflammation –> wheezing
High-risk patients for RSV infections
Infants at high risk for severe RSV bronchiolitis
- Premature infants (< 32 weeks gestation)
- Pts w/ Chronic lung disease
- Pts w/Complicated congenital heart disease
Adults & older children at high risk for severe RSV disease are those w/significant immunosuppression (bone marrow or solid organ transplant)
High risk infants vs. Non-high risk infants with RSV infection
High risk (premature) infants:
- 8-10 x higher hospitalization rates
- Higher need for ICU care & mechanical ventilation
- 2-6 x higher Mortality rates
Treatment of CMV in Immunocompromised hosts:
- Treat with gancyclovir or valganciclovir
- Choice of med & duration of treatment depends on the disease
Treatment of RSV
-Mostly supportive
Can use inhaled bronchodilators (albuterol)
Ribavirin = only antiviral available for Tx of RSV
- Currently limited use (only in dire circumstances – bone marrow transplant, complicated congenital heart disease, etc.)
- Controversial efficacy / safety
- Modest effects in studies
- Given as an aerosol
- VERY Expensive
RSV Prevention
- Humoral immunity (antibodies)
- NO licensed vaccine available
- Primary prevention via avoiding infected secretions
Humoral immunity (antibodies) in Prevention of RSV infection
Infants w/ high levels of maternal Abs to RSV are less likely to be infected
RSV F-protein mAb prep
- can be given IM to high risk infants
- -> ~50% reduction in hospitalizations due to RSV
- Administered monthly during RSV season
- Very expensive
Rotavirus (Family, Structure, etc.)
Reoviridae family
Double stranded RNA virus w/ segmented genome
–> Allows for reassortment & genetic diversity
Several serotypes (strains) of rotavirus - 5 strains responsible for >90% of rotavirus disease in the U.S.
Diagnosis of RSV:
- usually clinical
- Viral culture
- Serology
- Direct fluorescent antibody
Transmission of Rotovirus
- Fecal oral transmission most common
- Kids excrete 100 billion rotavirus particles per mL of feces
- Infectious dose is 10-100 virus particles
- 43% of rotavirus virions survive on human fingers for 60 minutes
- Rotavirus in feces may survive for days to weeks on environmental surfaces
Pathogenesis of Rotavirus & Recovery
- Infects mature absorptive epithelial cells or enterocytes (at tips of villi) in proximal 2/3 of ileum
- Cell death leads to:
- Reduced absorptive surface area of sm. intestine
- Loss of enzymes that break down complex sugars
- Increased fluid & osmotic load –> diarrhea
Regeneration of villi takes 7-10 days (recovery period)
Natural Immunity to Rotovirus
- 1st infections –> severe gastroenteritis
- Subsequent infections –> milder or asymptomatic
- Protective immunity develops after each infection which protects against symptomatic disease
Epidemiology of Rotovirus infection
- Leading single cause of severe diarrhea and/or gastroenteritis in infants & young children
- Prior to vaccine, nearly every child had been infected at least once w/ rotavirus by age 5
Rotovirus Treatment
- No antivirals available
- Supportive management
= Attention to fluids (Pedialyte, 50/50 Gatorade / water, IV fluids for severe dehydration)
Rotovirus Prevention/Prophylaxis
2 oral, live-attenuated rotavirus vaccines licensed for use in infants:
- RotaRix (2 doses): monovalent human
- RotaTeq (3 doses): pentavalent human-bovine reassortment
Both vaccines roughly equivalent in safety & efficacy
Both highly protective in prevention of moderate & severe rotavirus disease
- ~90% reduction in all types of health care visits
Diagnosis of rotavirus
ELISA on stool samples
