35. Virology 💢 Flashcards
2 theories of how viruses fit into the tree of life?
- RNA world theory: life arose with the viruses 2. Reductionist theory: viruses came after cellular life, they are reduced versions of cellular organisms * mimiviruses and megaviruses may be the missing link
What are Ribozymes?
- RNAs that can catalyze specific reactions (similar to enzymes) - ribozymes (produced in lab) can catalyze their own synthesis - natural fans: cleave RNA, viral replication, tRNA biosynthesis
Examples of DNA viruses?
- herpes, smallpox, mimivirus DNA -> RNA -> protein
Examples of RNA viruses?
- Rhino, influenza, SARS RNA-> protein
Examples of Retroviruses?
- HIV RNA -> DNA (through reverse transcriptase) -> RNA -> protein
Pros and cons of a DNA virus
pros: lower mutation rate, more stable (can carry more genes), no dsRNA phase cons: lower mutation rate, slower replication
Pros and cons of RNA virus
pros: fast replication rate, high mutation rate cons: high mutation rate, limited sequence space (less stable), dsRNA phase, degrades faster, humans don’t have dsRNA (easy to identify)
What happens frequently in reverse transcriptase?
- 1 mutation per virus, much more common in retrovirus
What are some challenges in developing HIV vaccines?
- high mutation rate - integration into host genome - infects immune privileged region of host - targets immune system - multiple serotypes - costs and time involved in development - vaccine safety concerns
What is the diversity in HIV strains
- 25-30% in circulating HIV strains - mutation rate is - 1 base change per genome
What effects can a mutation have on a virus?
- not all mutations are advantageous: some hinder the virus, some prevent virus replication, and some are silent ( have no effect) - Some allow a competitive advantage, and some allow escape from antiviral drugs
antiretroviral drug classes
- reverse transcriptase inhibitors (NRTIs) - Fusion/entry inhibitors - Integrase inhibitors - Protease inhibitors
Difference b/t nucleosides and nucleotides?
- nucleosides: sugar+ base 3 phosphorylation events required for activity -nucleotide: sugar+base+phosphate, 2 phosphorylation events required for activity
Nucleoside analogs??
prevent adding of next nucleoside on to the chain looks like nucleoside but doesn’t have site to bind to next nucleoside so it is a chain terminator
3TC (Epivir/Iamivudine)
-FDA approved 1995 - reverse transcriptase inhibitor - nucleoside analog: mimics cytidine -> acts as a chain terminator
DLV (Rescriptor/delavirdine)
- FDA approved 1997 - Reverse transcriptase inhibitor (non-nucleoside) - binds RT catalytic site, blocking polymerase fxn
Reverse transcriptase mutations?
- only takes 1 or 2 mutations of virus to make reverse transcriptase drugs ineffective
DRV (darunavir/Prezista)
- FDA approved 2006 protease inhibitor: binds the active site preventing the processing of viral protein precursors - compete with the natural substrate
EVG (Elvitegravir)
- FDA approved 2014 - Allosteric integrase inhibitor (prevents functional multimers from forming (dimers of dimers= tetramer)
MVC (Selzentry/maraviroc)
- FDA approved 2007 - entry inhibitor (receptor antagonist) drug binds receptor (CCR5), preventing HIV from binding - mutant bind receptor in a different conformation
T20 (Fuzeon/entuvirtide)
- FDA approved 2003 - HIV fusion inhibitor - mimics viral protein to displace it in the fusion complex (binds p41 and prevents formation of the entry pore)
Vacc-4x
therapeutic vaccine in clinical trials 9phase 2) peptide vaccine -> dropped viral load but didn’t slow CD4 T cell decline
SB-728T gene therapy
in phase 1/2 trials modifies a CD4 T cell CCR5 receptor, making it non-functional, prevents HIV entry - harvest patient T cells, make mutation and replicate, and put back into pt - this mutation occurs naturally and confers HIV resistance - expensive and time consuming
Interleukin
IL-7: trial abandoned b/c IL-7 increased the number of CD4+ T cells but that increased viral load too IL-2: increased number of CD4+ T cells but didn’t significantly decrease clinical events or death, even when combined with antiretrovirals
Chloroquine
- antimalarial - drops pH in vacuoles - disrupts Env protein gp120, inhibits maturation - drops viral load, doesn’t affect T cells so doesn’t stop T cells from decreasing
What can be done to prevent escape mutants?
- combo drugs Atripla (3) Complera (4) Stribild (4) Triumeq (3) Combivir (4)
Difference b/t viral and human evolution
- humans: complicated, multiple polymerases, error prone, and non-error prone sites, at most 1 mistake/ 100 million, proofreading and correcting machinery, and we only have a couple kids in a lifetime - viruses: often 1 mistake per genome, no proofreading, often whole populations knocked out, billions of genomes made per day
Potential effects of viruses on human evolution
- immune system diversity - ABO blood system (decreased A allele frequency after smallpox epidemic) - endogenous retroviruses (1% of genome) - cell surface mutations (ex: CCR5)
What does it mean that viruses are a part of us?
- they are a part of our regulation of host gene expression - they take part in placental formation - reason why there is immunosuppression during pregnancy - promoters, enhancers and proteins can be coopted by the host for its own purposes (placenta formation) - can be fixed or mobile, and no human endogenous retroviruses (ERVs) are capable of replication
What are endogenous retroviruses (ERVs) associated with in humans?
- MS - schizophrenia - cancer - autoimmune diseases - amayotrophic lateral sclerosis (ALS)
Mutation in humans that allow them to be resistant to HIV infection?
-mutation prevents an HIV corrector from being made by the cell, and therefore HIV can’t infect people with this mutation (CCR5 delta 32 mutation) -> positive selection for this mutation
Hypothesis for why mutation has been selected in specific regions (Europe, Asia, North Africa)?
- either plague (bacteria) or smallpox (virus)
How can humans drive viral evolution?
- each infection is a population - zoonosis: virus mutating to be able to pass from one species to another - humans as an enviro: immune system and viral recombination - antiviral drugs: promote resistance and mutations
difference b/t epidemic and pandemic?
- epidemic: greater than expected incidence “outbreak” ex: SARS, Dengue - pandemic: spread over a large geographical area (b/t continents) ex: HIV, smallpox, H1N1 (seasonal flu not a pandemic)
Why do viruses start epidemics and then pandemics?
- increased virulence (severity of disease or ability to spread) - intro into novel setting - changes in host susceptibility to the infectious agent - changes in host exposure to the infectious agent
Transmission modes of viruses?
- iatrogenic (blood transfusion) - vertical - vector borne - droplet - fecal-oral - sexually
Zoonosis?
- disease that can pass from another species to humans or humans to another species - often diseases are adapted to their host and more deadly when they jump hosts (ex: Ebola) - Many viruses can pass from animal reservoir to humans, but have difficulties transmitting human to human - issues: domestication, deforestation, bush meat
BSL-4 viruses
- aerosol viruses - severe/fatal viruses w/ no vaccines or other txs: - bolivian and argentine hemorrhagic fevers - marburg virus - ebola virus - lassa virus - crimean-congo hemorrhagic fever - small pox
What are some challenges in developing HIV vaccines?
- high mutation rate - integration into host genome - infects immune privileged region of host - targets immune system - multiple serotypes - costs and time involved in development - vaccine safety concerns
What is the diversity in HIV strains
- 25-30% in circulating HIV strains - mutation rate is - 1 base change per genome
What effects can a mutation have on a virus?
- not all mutations are advantageous: some hinder the virus, some prevent virus replication, and some are silent ( have no effect) - Some allow a competitive advantage, and some allow escape from antiviral drugs
antiretroviral drug classes
- reverse transcriptase inhibitors (NRTIs) - Fusion/entry inhibitors - Integrase inhibitors - Protease inhibitors
Difference b/t nucleosides and nucleotides?
- nucleosides: sugar+ base 3 phosphorylation events required for activity -nucleotide: sugar+base+phosphate, 2 phosphorylation events required for activity
Nucleoside analogs??
prevent adding of next nucleoside on to the chain looks like nucleoside but doesn’t have site to bind to next nucleoside so it is a chain terminator
3TC (Epivir/Iamivudine)
-FDA approved 1995 - reverse transcriptase inhibitor - nucleoside analog: mimics cytidine -> acts as a chain terminator
DLV (Rescriptor/delavirdine)
- FDA approved 1997 - Reverse transcriptase inhibitor (non-nucleoside) - binds RT catalytic site, blocking polymerase fxn
Reverse transcriptase mutations?
- only takes 1 or 2 mutations of virus to make reverse transcriptase drugs ineffective
DRV (darunavir/Prezista)
- FDA approved 2006 protease inhibitor: binds the active site preventing the processing of viral protein precursors - compete with the natural substrate
EVG (Elvitegravir)
- FDA approved 2014 - Allosteric integrase inhibitor (prevents functional multimers from forming (dimers of dimers= tetramer)
MVC (Selzentry/maraviroc)
- FDA approved 2007 - entry inhibitor (receptor antagonist) drug binds receptor (CCR5), preventing HIV from binding - mutant bind receptor in a different conformation
T20 (Fuzeon/entuvirtide)
- FDA approved 2003 - HIV fusion inhibitor - mimics viral protein to displace it in the fusion complex (binds p41 and prevents formation of the entry pore)
Vacc-4x
therapeutic vaccine in clinical trials 9phase 2) peptide vaccine -> dropped viral load but didn’t slow CD4 T cell decline
SB-728T gene therapy
in phase 1/2 trials modifies a CD4 T cell CCR5 receptor, making it non-functional, prevents HIV entry - harvest patient T cells, make mutation and replicate, and put back into pt - this mutation occurs naturally and confers HIV resistance - expensive and time consuming
Interleukin
IL-7: trial abandoned b/c IL-7 increased the number of CD4+ T cells but that increased viral load too IL-2: increased number of CD4+ T cells but didn’t significantly decrease clinical events or death, even when combined with antiretrovirals
Chloroquine
- antimalarial - drops pH in vacuoles - disrupts Env protein gp120, inhibits maturation - drops viral load, doesn’t affect T cells so doesn’t stop T cells from decreasing
What can be done to prevent escape mutants?
- combo drugs Atripla (3) Complera (4) Stribild (4) Triumeq (3) Combivir (4)
Difference b/t viral and human evolution
- humans: complicated, multiple polymerases, error prone, and non-error prone sites, at most 1 mistake/ 100 million, proofreading and correcting machinery, and we only have a couple kids in a lifetime - viruses: often 1 mistake per genome, no proofreading, often whole populations knocked out, billions of genomes made per day
Potential effects of viruses on human evolution
- immune system diversity - ABO blood system (decreased A allele frequency after smallpox epidemic) - endogenous retroviruses (1% of genome) - cell surface mutations (ex: CCR5)
What does it mean that viruses are a part of us?
- they are a part of our regulation of host gene expression - they take part in placental formation - reason why there is immunosuppression during pregnancy - promoters, enhancers and proteins can be coopted by the host for its own purposes (placenta formation) - can be fixed or mobile, and no human endogenous retroviruses (ERVs) are capable of replication
What are endogenous retroviruses (ERVs) associated with in humans?
- MS - schizophrenia - cancer - autoimmune diseases - amayotrophic lateral sclerosis (ALS)
Mutation in humans that allow them to be resistant to HIV infection?
-mutation prevents an HIV corrector from being made by the cell, and therefore HIV can’t infect people with this mutation (CCR5 delta 32 mutation) -> positive selection for this mutation
Hypothesis for why mutation has been selected in specific regions (Europe, Asia, North Africa)?
- either plague (bacteria) or smallpox (virus)
How can humans drive viral evolution?
- each infection is a population - zoonosis: virus mutating to be able to pass from one species to another - humans as an enviro: immune system and viral recombination - antiviral drugs: promote resistance and mutations
difference b/t epidemic and pandemic?
- epidemic: greater than expected incidence “outbreak” ex: SARS, Dengue - pandemic: spread over a large geographical area (b/t continents) ex: HIV, smallpox, H1N1 (seasonal flu not a pandemic)
Why do viruses start epidemics and then pandemics?
- increased virulence (severity of disease or ability to spread) - intro into novel setting - changes in host susceptibility to the infectious agent - changes in host exposure to the infectious agent
Transmission modes of viruses?
- iatrogenic (blood transfusion) - vertical - vector borne - droplet - fecal-oral - sexually
Zoonosis?
- disease that can pass from another species to humans or humans to another species - often diseases are adapted to their host and more deadly when they jump hosts (ex: Ebola) - Many viruses can pass from animal reservoir to humans, but have difficulties transmitting human to human - issues: domestication, deforestation, bush meat
BSL-4 viruses
- aerosol viruses - severe/fatal viruses w/ no vaccines or other txs: - bolivian and argentine hemorrhagic fevers - marburg virus - ebola virus - lassa virus - crimean-congo hemorrhagic fever - small pox
What is a maculopapular rash?
Some areas are raised and some areas are flat
What is a dermatomal distribution of a rash indicative of?
Shingles
What components of the virus can be used in virus detection?
Virus isolation and electron microscopy to visualise the virus itself Protein components (antigens) Genetic components (RNA or DNA) The host response (antibody or cell responses)
What is the main method of virus detection?
PCR
What technique is used for antibody detection?
Enzyme immunoassay – detects antibodies and antigens
Define sensitivity.
Low rate of false negatives
Define specificity.
Low rate of false positives
What does quantification of the genomes allow assessment of?
Viral load
What is the difference between IgM and IgG in terms of when theirlevels rise following infection?
IgM is a marker of RECENT infection IgG rises later on
What does positive IgG and absent IgM indicate?
Past infection or immunisation
What is targeted in the detection of HIV?
Antibody and p24 antigen
What other investigations are performed on people who are identified as HIV positive?
Typing (HIV 1 or HIV2) Repeat blood sample and EDTA blood for HIV viral load (for genotyping and baseline resistance testing)
What test is used to confirm a positive IgM result?
Antibody avidity testing
Describe how antibody avidity changes in infection.
Early on in the infection, avidity is LOW Then you get maturation of the antibody response so the avidity will increase over a period of 3-6 months If you have HIGH antibody avidity, then it is unlikely that the infection occurred in the last 3 months
What is immunofluorescence useful for?
Direct detection of viral antigens
What is the term given to the method of PCR that allows testing for more than one virus using a single test tube?
Multiplex PCR
What is sampled when testing for meningitis/encephalitis?
CSF Stools and throat swab (for enterovirus detection) Blood
What is sampled when testing for causes of diarrhoea/vomiting?
Stool (and vomit)
What must happen first before PCR is performed to identify the genome of an RNA virus?
The RNA must be reverse transcribed by reverse transcriptase to dsDNA dsDNA is the start point of PCR
Describe the process of PCR.
The dsDNA is denatured by heating it The primers then bind to the single stranded DNA and Taq polymerase joins complementary nucleotides to the template strand
What are the applications of sequencing viral genomes?
Antiviral resistance testing Phylogenetic analysis
What is a virus made of?
No cell wall, made up of nucleic acid components: -protein coat (capsid) -nucleic acid core, or genome -some have lipoprotein envelope -viruses containing envelope are antigenic in nature -Viruses are obligate intracellular parasites - Use host enzymes, don’t have metabolic machinery of their own.
Where do viruses replicate in the host?
certain ones multiply in cytoplasm and others do so in the nucleus -most have to replicate so many times before they illicit symptoms in the host and before the dx is made.
Process of viral infection and replication?
- Absorption: binds to host cell 2. Penetration: virus injects genome into host cell 3.Viral genome replication: viral genome replicates using the host’s cellular machinery 4. Assembly: viral components and enzymes are produced and begin to assemble. 5. Maturation: viral components assemble and viruses fully develop. 6. Release: newly produced viruses are expelled from the host cell.
What must antiviral drugs do to be effective?
must either: - block viral entry into or exit from the cell - be active inside the host cell
What is the MOA of most anti-viral drugs?
many are purine or pyrimidine analogs. -Many are prodrugs: so they must be phosphorylated by viral or cellular enzymes in order to become active. - anti-viral agents inhibit active replication so the viral growth resumes after drug removal.
What is an important part of fighting viral infections?
current anti-viral agents don’t eliminate non-replicating or latent virus ***Effective host immune response remains essential for recovery from viral infection. -clinical efficacy depends on achieving inhibitory concentration at site of the infection within the infected cells
What are the anti-HSV/VZV agents? Herpes/Varicella/Zoster
acyclovir (zovirax) famciclovir (famvir) valacyclovir (valtrex)
MOA of anti-HSV/VZV agents?
All 3 are guanine nucleoside analogs. - all are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs. ** The analog inhibits viral DNA-polymerase and only actively replicating viruses are inhibited
Acyclovir (zovirax)
guanosine analog -topical, oral, and IV
Spectrum of Acyclovir?
HSV 1 and 2, VZV, and possible EBV *DOC for HSV genital infections, herpes labialis/orolabial, HSV encephalitis, HSV infections in immunocompromised and pregnant pt
Pharmokinetics of acyclovir?
oral bioavailability: 20-30% distribution to all tissues including CNS -renal excretion: >80% -half life: 2-5 hours -topical, oral and IV
Acyclovir safety
Pregnancy: B lactation: safe renal dosing: adjust if CrCl
Acyclovir MOA
inhibition of viral synthesis of DNA -uptake by infected cell -competes with deoxyguanosine triphosphate for viral DNA polymerases: *chain termination -> inactivated viral DNA polymerase
What cells is acyclovir selectively activated in?
in cells infected with herpes virus -uninfected cells don’t phosphorylate acyclovir.
When would you take acyclovir for genital/mucocutaneous HSV?
Take it for first episode: frequent dosing (trying to prevent it from reocurring) Recurrence and suppression if pt has frequent recurrence.
Adverse effects of Acyclovir
-reversible renal toxicity -Neuro symptoms: encephalopathic changes - somnolence, hallucinations, confusion and coma. -TTP/HUS in immunocompromised -GI sxs -HA -rash -photosensitivity -anemia
Resistance to acyclovir and MOA of resistance
MIC>2-3 mcg/mL -mostly occurs in immunocompromised - 3 basic resistance mechanisms exist: 1. reduced or absent thymidine kinase 2. altered TK substrate specifity 3. alterations in DNA poly. - there is cross resistance to famciclovir and valacyclovir
Why tx with acyclovir?
genital herpes: shortens duration of sxs, viral shedding time, and time to resolution of lesions recurrent genital herpes: shortens course of time by 1-2 days long term tx: decreases frequency of both symptomatic recurrences and asymptomatic viral shedding -> decreases sexual transmissions. Varicella Zoster: decreases total number of lesions and duration of varicella (if begun w/in 24 hours after onset of rash).
Famciclovir (Famvir)
cyclic guanine analong: -converted to penciclovir in the liver and intestines -penciclovir is used only topically whereas famciclovir can be administered orally. - PO only
Spectrum of famciclovir
HSV 1 & 2, VZV, maybe in EBV - in vitro to HBV
Pharmacokinetics of famciclovir
oral bioavailability: 77% 1st pass metabolism in intestine and liver: results in conversion to penciclovir Renal excretion: > 80% half life: 2-3 hours - Just PO
Famciclovir safety
Pregnancy: B lactation: unknown, caution advised Renal dosing: adjust dose for CrCl
MOA of famciclovir
Similar to acyclovir -> inhibition of viral synthesis of DNA, uptake by infected cell and competes with deoxyguanosine triphosphate for viral DNA polymerases -> inactivates viral DNA polymerase -it is converted to penciclovir triphosphate and compared to acyclovir triphosphate, penciclovir 3xP has lower affinity for viral DNA polymerase but does have longer intracellular half life
Famciclovir uses
zoster (shingles), and genital and orolabial HSV (for 1st occurence, recurrence and suppression)
Famciclovir adverse effects
-neutropenia -thrombocytopenia -neurological sxs: encephalopathic changes -> somnolence, hallucinations and delirium - GI sxs -HA, fatigue -abnormal LFT’s
Resistance to Famciclovir
- mutations in viral TK or DNA polymerase -cross resistance with acyclovir in TK negative strains -May still have activity in TK altered strains -resistance to HBV due to pt mutation (viral DNA polymerase)
Valacyclovir (Valtrex)
Prodrug of acyclovir: rapidly and almost completely converted to a acyclovir, same MOA, same spectrum, same mechanism of resistance
Pros and cons of Valacyclovir
Advantage: more convenient dosing, better oral bioavailability (55%) cons: more pricey than acyclovir
Pharmokinetics of Valacyclovir
oral bioavailability: 55% -undergoes rapid and extensive 1st pass effect to yield acyclovir -food doesn’t affect absorption -renal excretion: >50% Half life: 2-3 hours Administration: oral
Valacyclovir safety
Pregnancy: B lactation: safe renal dosing: adjust for CrCl
dosing of Valacyclovir
varies with infection type/severity -1st episode of HSV: hit em’ hard -> 1000 mg PO bid x 7-10 days shingles: PO tid x 7 days
Adverse effects of Valacyclovir
-reversible renal toxicity -neuro sxs: encephalopathic changes -> somnolence, hallucinations, confusion, coma -TTP/HUS: immunocompromised -GI, HA, rash, photosensitivity, elevated LFTs
What is the cheapest of the 3 HSV drugs and most preferred?
Acyclovir cheapest, but you have to admin more often. Can tx encephalitis with this too by IV - used b/c it has broader spectrum -> recommended for varicella or zoster in immunocompromised
What is used to treat HSV keratoconjunctivitis?
trifluridine (viroptic -> ophthalmic application) - this is active against acyclovir resistant strains
Anti-CMV agents
Ganciclovir
Spectrum of Ganciclovir
oral, IV, intraocular CMV, EBV, HSV/VZV, human herpesvirus 6 (for CMV and EBV: 10x more potent than acyclovir)
Ganciclovir is DOC for?
CMV retinitis in immunocompromised pt, and prevention of CMV disease in transplant patients
pharmacokinetic of Ganciclovir
oral bioavailability: 50% is excreted unmodified in urine renal excretion: >90% half life: 2-4 hours admin: oral, IV, intraocular
Ganciclovir safety
pregnancy: C (adverse fetal effects in animal studies) lactation: unsafe renal dosing: adjust dose for CrCl
MOA of Ganciclovir
competes with deoxyguanosine triphosphate similar to acyclovir - but in CMV -> viral encoded phosphotransferase coverts to ganciclovir triphosphate -unlike acyclovir, ganciclovir contains 3’ OH group allowing for DNA to continue
Adverse effects of Ganciclovir
reversible pancytopenia, fever, rash, phlebitis (IV), confusion, renal dysfunction, psychiatric disturbances, seizures
Influenza agents
- oseltamivir - zanamivir - amantadine (used in parkinsons now) - Rimantadine
MOA of influenza and neuraminidase inhibitors -> oseltamivir/zanamavir
influenza: contains an enzyme neuraminidase which is essential for the replication of the virus -so neurominidase inhibitors prevent the release of new visions and their spread from cell to cell.
Neuraminidase inhibitors effectiveness
effective against both types of influenza A and B -don’t interfere with immune response to influenza A vaccine -can be used for both prophylaxis and acute tx
Oseltamivir (Tamiflu) MOA
oral neuraminidase inhibitor: cleaves terminal sialic acid residues on glycoconjugates and destroys receptors -newly formed visions adhere to cell surface and limit spread.
Spectrum of Oseltamivir (Tamiflu)
Influenza A and B in kids and adults, avian flu, H5N1 disease
Adverse effects of Tamiflu
N/V, HA
When do you want to administer Oseltamivir (Tamiflu)
for tx of Influenza A and B: w/in 48 hours of sx onset, if high risk -> 72 hours - prophylaxis: w/in 48 hours of exposure
Zanamivir (Relenza)
Neuraminidase inhibitor, given via inhalation spectrum: uncomplicated influenza A and B and some strains of Avian influenza
Adverse effects of Zanamivir (Relenza)
nasal and throat discomfort -bronchospasm
Amantadine (Symmetrel) and Rimantadine (Flumadine)
MOA: prevents release of viral nucleic acid into host cell spectrum: influenza A, however resistance is frequent (Symmetrel not as effective anymore -> doesn’t work on B) Adverse effects: seizures, anticholinergic, CNS, edema, blurry vision
Is Amantadine or Rimantadine recommended in US?
NO not currently recommended for influenza because too much resistance - it is being used for extrapyramidal sx and parkinsonism though
Pharmacokinetics of Amantadine
oral bioavailability: 50-90% - crosses BBB extensively, and Rimantadine doesn’t. -PO
Ribavarin
purine nucleoside analog MOA: not fully understood, inhibition of RNA polymerase Spectrum: DNA and RNA viruses are susceptible, including influenza, HCV, parainfluenza, RSV, Lassa virus
Therapeutic uses of Ribavarin
DOC for: RSV bronchitis and pneumonia in hospitalized children (aerosol), lassa fever alternate drug: influenza, parainfluenza, measles virus in immunocompromised pts - used in combo with interferons for HCV
Safety of Ribavarin
Available: PO and inhalation IV available through CDC Preg: X (teratongenic) lactation: probably unsafe
Adverse effects of Ribavirin
BBW-hemolytic anemia resp. deterioration depression suicidal ideation bacterial infections psych. effects anxiety, fatigue, dizziness
Hepatitis?
swelling or inflammation of the liver in response to: drugs, toxins, excessive alcohol, infections from bacteria or viruses
Hepatitis A
typically spreads when infected individuals improperly handle food or water
Hepatitis B
often transmitted by sexual intercourse, sharing of needles or contact with contaminated blood (vaccine available)
Hepatitis C
more likely to cause permanent liver damage, genes mutate very fast, new genotypes make developing an effective vaccine impossible so far
Hepatitis A tx
clears on its own with rest and adequate hydration
Hepatitis B tx
May clear on its own. Chronic cases may be tx with: - interferon - Nucleoside Reverse Transcriptase inhibitors (NRTI) such as -> emtricitabine tenofavir entacavir lamivudine (some patients may need liver transplant)
Hepatitis C epidemiology
chronic infection that afflicts about 170 million people worldwide -annual mortality: 350,000 15,000 in the US
Hepatitis C standard treatment
synthetic, injectable version of interferon plus the antiviral drug ribavarin - this combo shows benefit or cure in 25-75% of patients -SE: significant or intolerable -> severe flu-like sxs, fatigue, depression, anemia -Virus often becomes resistant to medication, allowing disease to worsen
Anti-viral drugs for hepatic viral infections
- interferons - lamivudine - cytosine analog - HBV -Entecavir - guanosine analog- HBV (lamivudine resistance strains) -Ribavarin - Hep C (w/ interferons)
New drugs for Hep C
To be effective - drug has to incorporate itself in the virus’s genetic code so as to halt replication - to avoid potentially debilitating side effects the med needs to enter the liver quickly and directly avoiding as many other organs as possible
New formulation for Hepatitis
called sofosbuvir (Sovaldi) study showed 295/327 patients treated with sofosbuvir as well as ribavarin and interferon showed no signs of virus in blood after 12 weeks -> approved by FDA in 2013 in combo with rivabarin
Sofosbuvir paired with ledispasvir
cured at least 94% of patients with genotype 1 disease, mixed in single daily pill (Harvoni) -> cure rates >90% with 12 weeks and no significant SE’s.
What is downfall of new drugs for Hep C
>$100,000 for 12 week course of treatment. Many people with Hep C poor and/or incarcerated
Cost of sofasbuvir?
$594 dose, treatment would run nearly $12 billion dollars - much cheaper in Canada and Germany -What the heck U.S.?
What is a virus?
- submicroscopic, obligate intracellular parasite (Can’t survive outside of cell, use host machinery -> can’t replicate or express genes w/o help of living cell) - Formed within cells from the assembly of preformed components, whereas other agents reproduce - Virons are the complete infective particle and don’t grow. It lacks needed components that cells have to reproduce. - No viruses known to have the genetic info needed to produce metabolic energy for replication - When a virus infects a cell, it marshals the cell’s ribosomes, enzymes and much of cellular machinery to replicate - Viral replication produces many progeny, that when complete, leave the host cell to infect other cells in the organism
What kind of cells do viruses infect?
- all types of living cells - animals, plants and bacteria - viroids: small circular RNA molecules with a rod like secondary structure that possess no capsid or envelope
What is a virus made of?
A virus particle, also known as a vision is essentially a nucleic acid (DNA or RNA) enclosed in a protein shell or coat. - Viruses are extremely small, approx: 15-25 nm in diameter
Variations in viruses?
- may be dsDNA, dsRNA, ssDNA, or ssRNA - The type of genetic material found in a particular virus depends on the nature and function of the specific virus - so dsDNA viruses must enter the host cell’s nucleus before it can replicate - ssRNA viruses replicate in host cell’s cytoplasm. - the genetic material isn’t typically exposed but covered by a protein coat. The viral genome can consist of a very small number of genes or up to hundreds of genes depending on the type of virus
The viral capsid?
- the protein coat that envelopes viral genetic material - composed of protein subunits called capsomeres - have several shapes: polyhedral, rod, or complex - fxn is to protect the viral genetic material from damage - in addition to protein coat: some viruses have specialized structures -> the flu virus has a membrane-like envelope around it’s capsid, and the envelope has both host cell and viral components and assists the virus in infecting its host
The process of the viral infection?
- adsorption: virus binds to host cell - penetration: virus injects its genome into host cell - viral genome replication: viral genome replicates using host’s cellular machinery - assembly: viral components and enzymes are produced and begin to assemble - Maturation: viral components assemble and viruses fully develop - release: newly produced viruses are expelled from the host cell
Key components of current classification system?
- type of symmetry of the virus capsid - presence or absence of a lipid envelope - type and structure of the viral nucleic acid and the strategy used in its replication
What does hemagglutinin allow viruses to do?
- binds to host cells, this is how viruses can switch b/t strains so they can infect other species -> virulent, lethal to humans -> can become pandemics
What are the Class 1 viruses?
HAPP viruses: dsDNA - Herpesvirus (cold sores, genital herpes, chicken pox, mono) - Adenovirus (resp diseases) - Papovavirus (warts, cervical cancer) - Poxvirus (small pox, cowpox)
Class II viruses?
ssDNA - parvovirus
Class III viruses?
- dsRNA coronavirus picornavirus (polio, common cold) Togavirus (rubella, yellow fever) Hep C virus
Class IV viruses?
positive ssRNA itself acting as mRNA - Rhabdovirus (rabies) - Paramyxovirus (measles, mumps) - Orthomyxovirus (influenza viruses) - Bunyavirus (Korean hemorrhagic fever) - Arenaviruses
Class V viruses
- negative ssRNA used as template for mRNA synthesis Reovirus (diarrhea)
Class VI viruses
positive ssRNA with DNA intermediate in replication - retrovirus (leukemia, AIDS)
Class VII viruses
dsDNA with an RNA intermediate in replication - Hep B virus
Viral exanthematous diseases?
- chickenpox/Herpes zoster - infectious mono - Roseola infantum (6th disease or Erythema subitum) - 5th disesae (Erythema infectiosum) - Measles - Rubella - Enteroviral exanthems: coxsackievirus, echovirus
What does exanthematous disease mean?
- characterized by or of the nature of an eruption or rash - the most frequent cause of exanthematous diseases are viral infections, which provoke skin alterations either directly or via the reaction of the immune system - in many distinct parainfectious clinical pictures, several viruses from quite different groups are able to produce a specific exanthem
Ddx of exanthematous eruptions?
- Rickettsial infections (tick borne illnesses) - Mycoplasma pneumoniae - syphilis (hands and soles) - typhoid fever - bacterial toxins (staph aureus: TSS -> pinpoint rash on abdomen - drug eruptions - live-virus vaccinations
All of the Human Herpes Viruses?
HHV-1: Herpes Simplex Virus 1 (HSV1) HHV-2: HSV2 HHV-3: VZV HHV-4: EBV (mono: elev lympho) HHV-5: CMV HHV-6: exanthema or Roseola HHV-7: T-lymphotropic virus HHV-8: virus assoc with Kaposi’s sarcoma (AIDS defining illness)
HSV 1 and 2 generally associated with what?
orolabial herpes: typically HSV-1 genital herpes: HSV-2 can affect almost all body tissue - these are mutlinucleated giant cells, intranuclear inclusion bodies (where viral assembly is taking place)
Epidemiology of HSV
>90% have abs to HSV-1 by age 30 - HSV 2 abs are rare b/f puberty 10-40% of general U.S. adult pop. have HSV-2 abs
Pathophysiology of HSV?
virus infects through mucosal membranes or abraded skin - latent infections are harbored in neuronal cells: in trigeminal ganglia and in pre-sacral ganglia
Clinical presentation of HSV oral-facial lesions?
- dew-drop on a rose petal - oral-facial lesions: primary infections: Gingivostomatitis (painful -> swollen lips) and pharyngitis most frequent, this is commonly seen in children and young adults - fever, malaise, myalgias, inability to eat, irritability and cervical adenopathy lasts 3-14 days - recurrence: Herpes labialis (cold sores)
Clinical presentaion of HSV urogenital lesions
- dew drop on rose petal - caused by either HSV-1 or 2 - systemic: HA, fever, malaise, and myalgia local: vesicular lesions of external genitalia with pain, itching, dysuria, vagina and urethral d/c, tender inguinal lymph adenopathy - usually present with early, tingly sensation and tenderness in affected area, with low grade fever - tx during this time= best results
What is often more severe primary infection or recurrent infections?
- primary infection usually more severe than recurrences but may be asymptomatic - vesicles form moist ulcers after several days, and crust over in 1-2 weeks if left unaddressed recurrences often: involve fewer lesions - tend to be labial - heal faster - are induced by stress, fever, infection, sunlight, chemo, pregnancy
What complications can HSV cause?
- ocular disease (#1 cause of blindness (hepatic keratitis) - Neonatal and congenital infections - Bells palsy (facial droop) - Encephalitis and recurrent meningitis - Herpes is most common cause of viral encephalitis in US - will see disseminated herpes in immunocompromised (AIDS)
What should be tested during pregnancies?
TORCHS: To: toxoplasmosis R: rubella C: CMV H: herpes and HIV S: syphilis
Dx of HSV?
- usually clinically made - clinical dx should be confirmed with lab testing, the dx can be made by viral culture( can’t be crusted over), PCR, Tzanck prep, direct fluorescence AB, and type-specific serologic tests. The choice of test varies with the clinical presentation - Viral culture - 50% sensitive - real-time HSV PCR: more sensitive to confirm HSV in clinical specimens obtained from genital ulcers, mucocutaneous sites, and CSF (amplifies the virus), its particularly useful for the detection of asymptomatic HSV shedding - ****There is enhanced sensitivity of HSV PCR compared to viral culture
What is the preferred dx test of HSV?
- PCR assay
Describe the HSV direct fluorescent ab test?
- many dx labs provide a rapid type-specific direct fluorescent ab (DFA) test to detect HSV in clinical specimens. This test is specific and reproducible (have to have an immune response though)
- What is the HSV serology test?
- type specific abs to HSV develop during the first several weeks after infection and persist indefinitely. The availability of type-specific abs has also facilitated greater accuracy in epidemiological surveys
Tzanck smear for HSV?
- Tzanck smear: may demonstrate the cytopathic effect of the virus (multinucleate giant cells), and can be performed on lesion scrapings from pts with active genital lesions. However it has limited utility since it has low sensitivity and specificity and is only helpful if + - furthermore, only a viral culture can determine whether the infection is due to HSV-1 or HSV-2
Management of HSV?
- acute infections: antiviral agents only shorten duration of sxs by 1-2 days (acyclovir, famciclovir, valcyclovir) -suppressive therapy: taken daily to prevent reactivation (spendy)
Where will Herpes present?
- can present on fingers (herpetic whitlow) -in the mouth -> primary: gingivostomatitis (sores all over mouth) - On the cornea (hepatic keratitis) - genitals (don’t miss the cervix)
What are the 2 clinical presentations of VZV?
- primary infection: chicken pox - recurrent infections: Herpes zoster
Epidemiology of VZV?
- humans only known reservoir of VZV - primary infection: transmission likely by resp. route - recurrent infection: VZV probably infects dorsal root ganglia during primary infection. Mechanism or stimulus for reactivation of latent infection in unknown.
Pathophys of VZV?
incubation pain: 10-21 days (usually 14-17) - infected persons are infectious 48 h before onset of vesicular rash, throughout vesicle formation (4-5 days), and until all vesicles are crusted.
Clinical presentation of primary infection: chickenpox
- rash, fever (100-103F), lasting 3-5 days, malaise - skin lesions are hallmark of disease: maculopapules, vesicles, and scabs in varying stages of development (“crops” of lesions - compared to small pox which lesions occur at same time ) on an erythematous base of 5-10 mm - distribution is centripetal (see on trunk) - Not as umbilicated as smallpox
Clinical presentation of recurrent VZV recurrent infection: Herpes zoster or “shingles”
- unilateral vesicular eruptions which develop within a single dermatome (T3 to L3 most common). Often assoc. with severe pain
Dxs in VZV?
- usually clinically made - tests can include: specialized complement fixation and virus neutralization in cell culture Fluorescent ab test of smear of lesions
progress of VZV infection?
- thin walled vesicle with clear fluid forms on a red base 2. The vesicle becomes cloudy and depressed in center (umbiliicated) with and irregular (scalloped) border 3. A crust forms in the center and eventually replaces the remaining portion of the vesicle at the periphery
When would you tx Herpes Zoster with IV acyclovir?
- when it is on the face and the eye is involved (can lead to blindness)
Management of VZV infections?
- primary infection prevention: vaccination (reduce outbreak by 50%) - primary disease: prevent secondary infections - Recurrent infection: zoster take antivirals (high dose): - acyclovir, famciclovir and analgesics - can give immunoglobulin w/in days of outbreak will decrease severity of outbreak
Infectious mononucleosis (EBV) epidemiology
- EBV (HHV-4) -> 2 variants: EBV-1, EBV-2 - B-cell lymphotropic virus primarily transmitted in saliva (4-8 wk incubation period) - 50% have had primary infection before adolescence (80% of daycare kids exposed to mono -> get over it easily) -Peak incidence occurrence: (big problem in adolescents and adults) ages 14-16 for girls ages 16-18 for boys - EBV shed from oropharynx for up to 18 months post-infection
Clinical presentation of mono (EBV) - clinical triad?
- subclinical or mild when infected during childhood - infectious mono defined by transient appearance of heterophil Ab and clinical triad: - fever/chills: 7-14 days duration (may be prodromal) - lymphadenopathy: rarely exceed 3 weeks duration (posterior chain -B cells multiplying) - Severe pharyngitis with exudates: maximal for 5-7 days and resolved over following 7-10 days (only exception when virus causes exudates)
Other common signs/sxs of primary infection of mono?
-HA, malaise, anorexia - soft palatal petechiae - maculopapular rash (especially with admin. of amoxicillin/PCN) - splenomegaly and mild hepatic tenderness in up to 50%
What neoplasms is EBV associated with?
- nasopharyngeal carcinoma - B-cell lymphomas (Burkitt’s lymphoma)
Lab findings in infectious mono (EBV)
- throat culture to check for B-hemolytic strep - monospot - Heterophil abs (90-95% of adolescents will be Ab +) become positive w/in 4 weeks after onset of sxs, are specific but not sensitive in early illness - atypical lymphocytosis in about 75% - EBV-specific immune response: EBV ab titers directed at several Ags -> EB virus capsid antigen (VCA), ABs to EBV nuclear antigen - EBNA
Complications of infectious mono?
- bacterial strep pharyngitis (develop a rash) - hematologic: thrombocytopenia, neutropenia - splenic rupture - neurologic: CN palsies (Bell’s palsy); Guillain-Barre syndrome; encephalitis
Management of infectious mono? (EBV)
- 95% of pts have self-limited disease in most cases requiring only supportive therapy - Acetaminophen or NSAIDS - warm salt water gargles - adequate rest (return to work/school based upon sx) - avoid contact sports for 6-8 weeks from onset - fever disappears in 10 days - lymphadenopathy and splenomegaly in 4 weeks
Epidemiology of CMV
- approx 1% of newborns infected - virus spread by: prolonged close contacts, blood/body fluids: transfusion (containing viable leukocytes), maternal-fetal transmission, STD - lifelong “infection” once infected - Congenital CMV occurs almost exclusively when preg. woman acquires primary infection (vs. reactivation) - perinatal CMV occurs when infant is infected at time of delivery through an infected birth canal or postnatal contact with maternal milk or or other secretions (40-60% transmission rate through nursing if mother infected)
When are the three times that you are most likely going to see CMV (worry about infection)?
- in pregnancy (babies) - transplant patients - in HIV (AIDS defining illness, shows up when CD4
Clinical presentation of congenital CMV?
- cytomegalic inclusion disease - ranges from inapparent infection (most) to severe/disseminated (-5%) - Petechiae, hepatosplenomegaly, jaundice common (60-80%) - microcephaly, growth retardation, prematurity (30-50%)
Clinical presentation of perinatal CMV?
- poor wt gain, adenopathy, rash, hepatitis, anemia, and atypical lymphocytosis
Clinical presentation of CMV mono?
- heterophil Ab negative mono syndrome (looks like mono but negative for mono spot, usually don’t have strep throat) - prolonged high fevers, profound fatigue and malaise - myalgias, HA, and splenomegaly are frequent - exudative pharyngitis and cervical adenopathy are rare - occasional rubelliform rash
Dx of CMV mono
- viral culture: MOST impt dx study in the eval of suspected CMV disease is the viral culture - CMV may be cultured from virtually any body fluid or organ system. Blood, urine, saliva, cervicovaginal secretions, CSF, bronchoalveolar lavage fluid, and tissues from bx specimens are all approp. specimens for culture - PCR - Ag assays - Tissue confirmation w/ AIDS related CMV : CMV GI or neuron disease, CMV pneumonitis = death
What is characteristic to CMV congenital infection in babies?
blueberry muffin lesions
Tx of CMV
Ganciclovir
What is fifth disease (Erythema infectiosum)?
caused by Human parvovirus B19 - respiratory tract is probably route of transmission
Clinical presentation of fifth disease?
- mild febrile exanthematous disease with little or no prodrome - low-grade fever, varying degrees of conjunctivitis, upper respiratory complaints, cough, myalgia, itching, nausea, and diarrhea are initial signs and sxs - Classic “slapped face” lesion: indurated, confluent erythema of the cheeks, fiery red - circumoral pallor - bilateral symmetric eruptions (maculopapular slightly raised blotchy areas with reticular or lacy pattern) appear on the arms, legs and trunk about one day later - Rash (when it occurs) usually lasts 1 week and may disappear then reappear in the same area a few hours later
Dx of Fifth disease?
- usually made clinically in kids - labs: elevated titer of IgM anti-parvovirus abs - PCR in serum
Tx of Fifth disease?
- symptomatic tx: NSAIDS
Roseola (infantum) epidemiology and pathophysiology?
- epidemiology: benign disease of infants 6 m to 4 yo (most commonly seen in children
Clinical presentation of Roseola (infantum)?
- first manifestations occur after 5-15 days incubation period with abrupt onset irritability and fever (up to 105 F) lasting 3-5 days - rash appears several hours after sudden drop in temp: faint small (2-3 mm) macules or maculopapules over neck and trunk extending to thighs and buttocks will last a few hours or up to 1-2 days management: symptomatic only
If child has seizure what test should be done?
- Lumbar puncture because you are worried about meningitis and encephalitis
Measles (Rubeola) epidemiology
- occurs only in human and remains worldwide health problem despite a vaccine - transmitted through nasopharyngeal secretions (directly or airborne droplets) to respiratory mucous membranes or conjunctivae of susceptible persons - Highly contagious: infectious from 5 days after exposure to 5 days after skin lesions appear
Clinical presentation of measles (rubeola)
- Koplik’s spots (small, red, irregular lesions with blue white centers) appear on oral mucosa 1-2 days before rash (look like salt on mucosa) - Brick red, irregular maculopapular rash: first appears on forehead, spreads downward over face, neck, and trunk and appears on feet by 3rd day “outward and downward” - can affect palms and soles last - lesions usually coalescence and disappear in same order as appearance after about 3 days - prodromal sxs subside 1-2 days after rash appears
Dx Measles (rubeola)
- usually clinical - labs: neutropenia, detection for IgM abs with ELIZA
Tx of measles (rubeola)
- isolation of pt - bedrest - antpyuretics - fluids - can have some bacterial disease complications, if so, tx with approp. abxs. - This is a vaccine preventable disease!!! complications: heart, and encephalitis
Rubella (german measles, 3-day measles) epidemiology
- nasopharyngeal secretions transmit virus - caused by Togavirus - transplacental transmission results in congenital rubella syndrome - age is an important determinant of the severity of Rubella (milder than measles)
Clinical presentation of Rubella?
- viral exanthemous primary disease is generally milder than rubeola - no prodromal in children - adults: prodromal illness precedes rash by 1-8 days and consists of malaise, HA, and fever (devastating in pregnancy: congenital rubella syndrome) - lymphadenopathy: large, tender, post-auricular and sub occipital nodes are most often involved, splenomegaly or generalized lymphadenopathy may be present - Rash appears 14-21 days after exposure and follows same pattern as rubeola (starts cephalically) lesions have lighter hue than measles, lesions usually remain discrete versus coalescent form and last 1-5 days (most commonly 3 days). Small red lesions (Forchheimer’s spots) may appear on soft palate (not pathognomonic)
Clinical presentation of congenital rubella syndrome?
-heart malformations (patent ductus arteriosus, interventricular septal defect, pulmonic stenosis) - eye lesions (corneal clouding, cataracts, chorioretinitis, microphthalmia) -microcephaly - mental retardation - deafness - thrombocytopenic purpura - hepatosplenomegaly - intrauterine growth retardation
Management of congenital rubella syndrome?
- Prevention - vaccinate all women of childbearing age (if already pregnant, wait until 2nd trimester when not as immunocompromised because it is a live virus
Dx and Tx of rubella
- leukonpenia - virus isolation and serologic tests of immunity: fluorescent ab tests, IgM abs to Togavirus Tx: acetaminophen provides symptomatic relief
Complications of Rubella
- exposure during pregnancy: congenital rubella: heart defects, cataracts, glaucoma, psychomotor retardation - post infectious encephalopathy - This is vaccine preventable disease!!!!
Epidemiology of mumps?
- etiologic agent: paramyxovirus - disease occurs most frequently in the spring - spread by respiratory route but less contagious than measles or chickenpox
Clinical presentation of the mumps
12-25 days incubation period - at least 25% of infections are subclinical - parotitis: parotid swelling (salivary adenitis) is first indication of illness and usually occurs suddenly: may be preceded by prodrome of malaise, anorexia, fever (up to 103F) and pharyngitis - glandular enlargement progresses over 1-3 days and subsides about a week after max enlargement - pain and tenderness may be marked or absent - epididymoorchitis: complicates 20-35% of post pubertal males, testicular involvement usually appears 7-10 days after onset of parotitis but may precede it or be simultaneous: - usually unilateral - acutely tender painful swollen testicle persist 3-7 days and subsides gradually - epididymis often palpable as swollen tender cord - heralded by recurrence of malaise, fever (103-106F), chills, HA, N/V -tx: no specific tx
Worst possible complication of mumps:
meningitis
What are the common cold viruses?
rhinovirus coronavirus adenovirus
influenza like illnesses?
influenza A virus influenza B virus
Influenza etiology?
- caused by members of Orthomyxoviridae family of viruses - Types A, B, and C are based on antigenic characteristics of the nucleoprotein (NP) and matrix (M) protein Ags. - Type A viruses undergo further surface antigenic classification: Hemagglutinin (H) ags (H1-3) Neuraminidase (N) ags (N1-2) - major antigenic shifts occur regularly: type A viruses about every 3 years (changes frequently, can swap with swine or avian, makes it very deadly) type B viruses about every 5 years - influenza outbreaks occur every year
Clinical presentation of influenza?
- abrupt onset of systemic sxs: HA, fever (38-41C), chills, myalgia, malaise: - accompanied by respiratory signs/sxs: cough, pharyngitis - dyspnea, hyperpnea, cyanosis, diffuse rales or signs of consolidation are evidence of pulmonary complications - acute illness generally resolves within a week
Complications of influenza?
- pneumonia (staph aureus) - Reye’s syndrome (especially children 2-16 yo) - Myositis, rhabdomyolysis, myoglobinuria (elderly: dehydrated and confused) - myocarditis and pericarditis
Dx influenza?
- rapid flu swab (Nasal, throat) - Leukopenia
Symptomatic tx for influenza?
- acetaminophen - rest - fluids - abx if pneumonia suspected
Anti-influenza virus drugs
- Neuraminidase inhibitors (used the most) Oseltamivir (Tamiflu) Zanamivir (Relenza) - Adamantane derivatives/M2 inhibitors (proton channel through viral envelope -> blocks acidification): amantadine rimantadine
Management and prevention of influenza?
- vaccination: trivalent inactivated influenza virus vaccine provides partial immunity for few months to 1 year - given in Oct or Nov of each year - CI when allergic eggs - Vaccination of high risk groups: - chronic cardiac or pulmonary disease (including asthma) - pregnant women - residents of chronic care/nursing facilities - over age 65 - chronic medical disorders: DM, renal disease, hemoglobinopathies, immunosuppressed - individuals who care for high risk populations
Epidemiology of Bronchiolitis?
RSV (member of paramyxovirus genus) major respiratory pathogen of young children - transmitted primarily by close contact with contaminated fingers or fomites - annual epidemics occur in late fall, winter or spring - incidence rates are highest in infants 1-6 months of age and accounts for 20-25% of hospitalizations in infants/young children (babies can’t cough up the thick bronchial secretions) - disease is milder in older children/adults
Clinical presentation of Bronchiolitis (RSV)?
infants: commonly presents as rhinorrhea, low-grade fever, cough, wheezing, mild systemic sxs severe illness: tachypnea, dyspnea, hypoxia, cyanosis even apnea may ensue - diffuse wheezing, rhonchi and rales (may not see wheezing) - clinical presentation of adults/older children: common cold presentation - younger children/infants: bronchiolitis, tracheobronchitis and pneumonia
Dx of bronchiolitis?
Get O2 sats!!! - rapid RSV with nasal washings using viral Ag ID using ELIZA or immunofluorescent assay - culture of nasopharyngeal secretions
Tx of bronchiolitis?
- antiviral therapy: ribavirin - sx relief: contact isolation, respiratory therapy, oxygen, secretion removal, hydration, antibronchospastic agents
Epidemiology of Croup
- caused by parainfluenza viruses: 4 major serotypes type 1: most frequent cause of croup (laryngotracheobronchitis) in children type 2: similar but less severe type 3: causes bronchiolitis and pneumonia in infants - account for up to 22% of respiratory illness in children, very mild disease in adults
Clinical presentation of Croup?
- acute febrile illness in children (50-80%) - coryza, sore throat, hoarseness, and variably croupy cough - breathing difficulty accompanied by a barking cough - much worse at night (day 3 the worst!)
Management of croup
sx relief: cool or moist air can bring relief - try bringing child into steamy bathroom or outside into the cool night air - a cool air vaporizer, set it up in the child’s bedroom and use it for the next few nights - Acetaminophen - ER tx: aerosolized racemic epinephrene predisone in ER and to go (oral) - after 3 hours of good presentation -> send them home - avoid cough medicines because they suppress coughs and you want to get rid of inflammation, but don’t want to suppress cough and make child lethargic and sleepy
Rabies epidemiology
-caused by rhabdovirus - 2 epidemiologic forms: urban: unimmunized domestic cats/dogs sylvatic: skunks, foxes, raccoons, wolves and bats
Clinical presentation of rabies (4 stages)
1) Prodrome: usually persists 1-4 days. Fever, HA, malaise, myalgias, increased fatigability, anorexia, N/V, pharyngitis, nonproductive cough -paresthesias and/or fascicultations around site of inoculation suggestive of rabies 2) Acute encephalitis: development of excessive motor activity, excitation, and agitation - confusion, hallucinations, combativeness, muscle spasms, meningismus, seizures and focal paralysis quickly follows - hyperesthesia with excessive sensitivity to bright light, noise or touch is common - Fever (up to 105F), dilated irregular pupils, increased lacrimation, salivation, perspiration, and postural hypotension occur -3) Profound brainstem dysfunction: occur shortly after onset of encephalitic phase, difficulty swallowing (with increased salivation) produces characteristic foaming at the mouth. Violent involuntary contractions of diaphragm and accessory, respiratory, pharyngeal and laryngeal muscles - coma and respiratory failure follow - recovery (rarely)
lab findings of Rabies
- isolation of virus (saliva, CSF or brain tissue) - indirect serologic evidence of immune response - direct antigent detection (skin or brain bxs)
Management of rabies?
- prevention: pre-exposure vaccinations: domestic animals, high risk individuals: animal handlers, veterinarians, cave explorers, lab workers - post-exposure prophylaxis: immunoglobulin
Ddx Variola versus varicella?
Variola (smallpox): rash starts on the face, lesions same stage, deep lesions, often palms, soles, centrifugal rash, Back>abdomen, multiloculated vesicles Varicella: rash starts trunk, lesions in crops, superficial lesions, never palms/soles, centripedal rash, back=abdomen, uniloculated vesicles
disease course of smallpox?
- Day 0 -> exposure - Day 12-14 -> fever, malaise, non-productive cough, HA, backache, joint pain -Day 14-16 -> papular rash on face -> extremities - Day 16-18 -> papular -> vesicular -> pustular - Day 22-26 -> crusted lesions - Day 28-30 -> resolving 10% will develop malignant disease and die 5-7 days after incubation
Vaccine for small pox?
- d/c’d in early 1970’s, but has been reinstituted b/c of concerns about bioterrorism, - routine vaccine, in the absence of a case of small pox is not recommended for those under 18 live vaccine: site becomes red, itchy in 3-4 days vesicle umbilicates and evolved into well formed pustule by day 6-11 - pustule scabs over b/t week 2 and 3 - scab falls off by end of 3rd week, leaving a scar
What is a key difference between internal virus proteins and surface antigens?
Internal viral proteins vary less
Describe the process of presentation of viral peptides on MHC Class I.
Viral peptides are chopped up by the proteasome These peptides are then fed through the TAP protein into the endoplasmic reticulum In the endoplasmic reticulum, it will be loaded onto an MHC class I molecule and it will then move to the cell surface where T cells can recognise the antigen
State three viruses (and the proteins involved) that evade antigen loading onto TAP.
EBV – EBNA1 – this cannot be chopped up by the proteasome HSV – ICP47 – blocks access of the peptides to the TAP protein CMV – US6 – blocks ATP binding to TAP
State two viruses (and the proteins involved) that modulate tapasin function and prevent MHC transport.
NOTE: tapasin is involved in loading MHC molecules Adenovirus E3-19K – prevents recruitment of TAP to tapasin and retains MHC in the ER CMV – US3 – binds to tapasin and prevents loading of peptides onto MHC
State one virus (and the protein involved) that interferes with MHC presentation at the cell surface.
KSHV (Kaposi Sarcoma Herpes Virus) – kK3 – induces polyubiquitination and internalisation of MHC
What do NK cells recognise on the cell surface that triggers killing of cells?
Missing self – lack of MHC on the cell membrane is not healthy
How do viruses evade this mechanism of NK-mediated killing infected cells?
Viruses encode MHC analogues (e.g. CMV gp UL40) – virally encoded MHC is useless but it fools the NK cells Upregulate MHC
Which cells does HIV target?
CD4+ T cells
Which cells does Ebola kill?
Dendritic cells Macrophages T cells (by the bystander response)
In what subset of the population does HMCV (human cytomegalovirus) cause disease?
Immunocompromised
What is the problem with HCMV with regards to bone marrow transplantation?
HCMV infects 60-90% of the population If HCMV is present in donated bone marrow, it could cause problems in the immunocompromised recipient
Explain how our knowledge about HCMV has allowed improved medical outcomes in bone marrow transplantation.
HCMV encodes UL138, which leads to loss of MRP-1 from the infected cell surface MRP-1 is a transporter of toxic drugs out of the cell Loss of MRP-1 leads to accumulation of certain molecules in the infected cell Vincristine is a toxic drug that accumulates in the infected cells and kills them So treating donated cells with vincristine before the transplant can eliminate CMV
What is antigenic drift?
Continued rapid evolution driven by antigenic pressure from the host
What is antigenic shift?
Introduction of new subtypes of the virus from an animal source NOTE: when they come from an animal source, the antigens don’t look like anything that humans have seen before
How else can viruses cause regular infections without changingtheir antigen profile?
They can have several genetically stable serotypes that co-circulate E.g. rhinovirus has more than 120 antigenically distinct serotypes
How many serotypes of influenza are there?
4
How many serotypes of poliovirus are there and what type of vaccine was produced for polio?
3 – trivalent vaccine NOTE: one of the serotypes has been eradicated now
What are the features of dengue haemorrhagic fever (DHF)?
Leakage of plasma from capillaries leads to: Increased haematocrit Increased red cell count Decrease in protein Tendency to severe bruising and bleeding
What is the treatment for DHF?
IV fluids
How many serotypes of dengue are there?
4
Explain the significance of the presence of multiple serotypes ofdengue with regards to the pathogenesis of DHF.
Infection with one serotype will cause antibody production Antibody generated against this serotype will bind to but NOT neutralise infection with another dengue serotype This can lead to ANTIGEN DEPENDENT ENHANCEMENT (ADE) causing Dengue Haemorrhagic Feve
What can viruses do to glycoprotein antigens that hinder antibody access to the antigens?
Heavily glycosylate the antigens
What does Ebola viruse have a high content of that makes them appear like apoptotic bodies?
Phosphatidyl serine lipids
What is the benefit to Ebola virus of appearing like apoptotic bodies?
They are rapidly taken up by macropinocytosis and, hence, taken away from antibody surveillance
How does the structure of Ebola affect antibody access to antigens?
Ebola has a long filamentous shape with lots of folds The folds may make the glycoproteins inaccessible to antibody
Name two factors produced by Ebola that allow it to evade detection by the innate immune system.
VP35 VP24
What important factor does Ebola encode that also helps deal with the antibody response?
Soluble glycoprotein – this acts as an antibody decoy and it is immunosuppressive (inhibits neutrophils) NOTE: GP2 and retrovirus glycoproteins also have an immunosuppressive peptide
Which virus is only suppressive in macaques?
Reston virus
How does Measles infect cells?
Via SLAM proteins (CD150)
Why did the measles vaccine have a much larger effect on childhood mortality than expected?
Measles can infect memory lymphocytes (these are SLAM positive) and erase immunological memory So a measles virus infection can result in a 2-3 year decrease in immunological memory that leads to morbidity and mortality from otherdiseases
What is the most common cause of sporadic encephalitis worldwide?
Herpes simplex encephalitis
Which subset of the population is herpes encephalitis most common in?
Most common in childhood – affecting previously healthy individuals on primary infection with HSV-1
What is interferon?
Transferrable factor produced when the cells are exposed to virus
What is the effect of interferon binding to interferon receptors on cells?
It binds to specific receptors and signals the de novo transcription of hundreds of interferon stimulated genes (ISG)
What are the three functions of type I interferons?
Induce antimicrobial state in infected and neighbouring cells Modulate innate immune response to promote antigen presentation and NK cells but inhibit proinflammation Activate the adaptive immune response
What are the type I interferons?
IFN alpha and IFN beta
What is the first interferon to be produced in a viral infection?
IFN beta
Which cells produce IFN beta?
All cells produce IFN beta and all tissues have IFNAR receptors
What is IFN beta induction triggered by?
IRF-3
Name a cell type that is specialised for producing IFN alpha.
Plasmacytoid dendritic cells
What do these cells express high levels of?
IRF-7
How many genes are there for IFN alpha and IFN beta?
Alpha – 13/14 isotypes Beta – ONE
Which IFN comes under type II interferon?
IFN-gamma - specialist immune signalling molecule
Which cell types produce this IFN?
Produced by activated T cells and NK cells
Which receptor do these IFNs signal through?
IFNGR
Which IFN falls under type III IFN?
IFN-lambda
Which receptors do type III IFNs signal through?
L-28 receptors IL-10 beta receptors
Where are these receptors mainly present?
Epithelial surfaces E.g. respiratory epithelium and gut
Which organ is IFN lambda very important in?
Liver
How does the innate immune system recognise non-self?
PRRs (pattern recognition receptors) on innate immune cells recognise PAMPs (pathogen-associated molecular patterns) NOTE: they often sense nucleic acids
Name two receptors that are involved in detecting the presence of viruses and state where they are found.
RIG-I like receptor (RLRs) – cytoplasmic Toll-like receptors (TLRs) – plasma membrane + endosomal membrane
Describe RIG-I signalling.
RIG-I like receptors will recognise single stranded RNA in the cytoplasm of the cell and it will signal through MAVS (mitochondrial) This will signal further downstream, leading to generation of IFN-beta transcripts
Describe TLR signalling.
TLR detects nucleic acids in the endosome (this isn’t normal) It will signal to molecules outside the endosome (MyD88) and send various transcription factors to the nucleus It will result in the switching on of expression of IFN alpha
Describe DNA sensing.
Mainly done by cGAS This is an enzyme that binds to dsDNA in the cytoplasm and synthesises cGAMP (second messenger) cGAMP diffuses to STING (found on endoplasmic reticulum) This triggers phosphorylation of the same sets of transcription factors and signalling molecules the RNA viruses were triggering
Describe the structure of IFN receptors for IFN alpha and IFN beta
They are heterodimers of IFNAR 1 and IFNAR 2
Describe the signalling from IFNAR receptors
IFN binds and the IFN receptor activates Jak and Tyk, which goes on to phosphorylate the STAT molecules STAT molecules dimerise and combine with IRF-9 It then goes to the nucleus, binds to a promoter and regulates transcription
What is IFITM3?
Interferon-induced transmembrane protein 3 These sit on the membrane of endosomes, in cells that have been previously stimulated by IFN It prevents fusion of the virus membrane with the endosomal membrane so the virus gets trapped in the endosome NOTE: mice and people lacking IFITM3 get more severe influenza
What are Mx1 and Mx2?
GTPases with a homology to dynamin Mx can form multimers that wrap around nucleocapsids of incoming viruses – this nullifies the viral genomes Mx1 – inhibits influenza Mx2 – inhibits HIV
Describe the actions of Protein Kinase R.
It phosphorylates the alpha subunit of eIF2 (initiation factor) that is important in translation This prevents ribosomes from binding to mRNA so NO NEW GENES WILL BE TRANSLATED It also phosphorylates NFkB, which is an important transcription factor that is part of the interferon and inflammatory response
When is PKR activated by cells?
It is an extreme measure and a last resort – only activated when the cell has no other option
Name a family of genes that suppress the cytokine signalling and turn off the response.
SOCS
State some mechanisms of viral evasion of the IFN response.
Avoid detection by hiding the PAMP Interfere globally with host cell gene expression and/or protein synthesis Block IFN induction cascades Inhibit IFN signalling Activate SOCS Replication strategy that is insensitive to IFN
Explain how hepatitis C controls the interferon response.
NS3/4 This is a protease that cleaves MAVS MAVS is important in detecting Hep C through the RIG-I pathway So Hep C is not detected
Explain how influenza controls the interferon response.
NS1 Acts an antagonist to interferon induction by binding to the RIG-I/TRIM25/RNA complex and preventing activation of the signalling pathway It also prevents nuclear processing of newly induced genes NS1 also migrates to the nucleus where it prevents the export of newly synthesised genes
What type of virus are Pox and Herpes viruses?
Large DNA viruses
What do Pox viruses encode that helps deal with the interferonresponse?
They encode soluble cytokine receptors that mop up IFN and prevent it from reaching its receptors
Describe a potential therapeutic use of this feature
This could be useful in autoimmune or inflammatory conditions where IFN and other cytokines are produced in abundance
Name two proteins produced by HIV that helps deal with restriction factors and state what they target.
Vif – APOBEC Vpu – Tetherin
Describe the normal action of APOBEC.
APOBEC is involved in the innate immune resistance to retroviruses and hepadnaviruses APOBEC modifies some of the nucleotides in reverse transcription and makes them into the wrong version APOBEC deaminates dC to dU in the minus strand of viral cDNA during reverse transcription This leads to G to A hypermutation resulting in ERROR CATASTROPHE This results in so many mutations that the viral genome becomes nonsense and the virus can’t replicate
What is the effect of Vif on APOBEC?
Vif counteracts the activity of APOBEC and targets it for degradation This removes the interference of APOBEC with reverse transcription
Describe the normal action of tetherin.
Tetherin sits on the cell surface of infected cells and binds to viruses that try to escape the cell to go and infect other cells This limits the spread of viral infection
What is the effect of Vpu on tetherin?
Vpu pulls tetherin back from the cell surface and targets it for degradation
What are two proteins produced by Ebola virus that are particularly important in dealing with the immune response?
VP35 VP24
What do these proteins do?
VP35 – inhibits the RIG-I pathway VP24 – stops the signal getting through from the IFN beta receptor to the nucleus (stops the STAT1 molecule from getting to the nucleus)
What two techniques can be used to observe the skewing of the immune response by viruses?
Transcriptomimics – shows changes in mRNA production Proteomimics – shows changes in protein expression
Describe how viral infections can cause cytokine storm.
Lots of virus propagation –> lots of interferon being produced –> massive release of TNF alpha and other cytokines
What is a serious consequence of cytokine storm?
Pulmonary fibrosis – due to accumulation of immune cells in the lungs
Explain why viruses that cannot control the interferon can beused as the next generation of live attenuated vaccines.
They will be able to infect the cells and it will replicate sufficiently to be able to mount an immune response but it wont replicate to the extent where it causes disease
The downside of this feature of the viruses is that these virus particles can’t be propagated in normal healthy cells. What is the solution to this issue?
Propagate the viruses in cells that are deficient in the IFN response
Explain why interferons are not frequently used as an antiviral therapy.
They stimulate the production of several cytokines and this causes several unpleasant side effects
What disease is IFN used to treat?
Hepatitis C (a combination of pegylated IFN is used with ribavirin
Explain the reasoning behind using IFN-lambda as a treatment for influenza.
Receptors for IFN lambda are only found on epithelial surfaces (the site of infection of influenza is respiratory epithelium) IFN lambda cannot signal through immune cells and cause immunopathology It will only induce an antiviral state in the epithelial cells
Explain how oncolytic viruses would work.
Viruses are engineered that can uniquely replicate in tumour cells and kill them Generally speaking, cancer cells are deficient in their ability to mount a proper interferon response So, a virus that is unable to control the IFN response will NOT be able to replicate in normal healthy cells but they will be able to infect and replicate in cancer cells
What surrounds the genetic material in viruses?
Capsid (protein shell surrounding the genetic material)
What type of genetic material do the following viruses have: a. Hepatitis B b. Hepatits C c. HIV d. Herpes Simplex Virus e. Influenza
a. Hepatitis B Hepadnavirus – it is a DNA virus that also involves reverse transcriptase in its replication b. Hepatitis C RNA virus c. HIV Retrovirus d. Herpes Simplex Virus DNA virus e. Influenza RNA virus
Describe the relative curability of Hep B and Hep C.
Hep B – not curable Hep C – CURABLE
At what point do you start treating someone who has recently got infected by Hep B or Hep C?
When the infection becomes chronic The immune system, in some people, is able to clear Hep B and Hep C infections by itself
What is the treatment for Hep B? What type of drug is this?
Tenofovir Nucleotide reverse transcriptase inhibitor
What are the treatment options for Hep C? State the drug types.
Ribavirin (+ pegylated interferon) Ribavirin is a nucleoside analogue (purine analogue) Boceprivir – protease inhibitor (only works on Hep C genotype 1)
Describe the receptor interaction involved in HIV attachment and entry.
HIV GP120 binds to CD4 and CCR5 or CXCR4 Then HIV GP41 penetrates the host cell membrane and the viral capsid enters
State two drugs that interfere with HIV attachment and entry and state their targets.
Enfuvirtide – GP41 Maraviroc –CCR5
Name a nucleoside reverse transcriptase inhibitor. How are they activated?
Zidovudine Three step phosphorylation
Name a nucleotide reverse transcriptase inhibitor.
Tenofovir
How do non-nucleoside reverse transcriptase inhibitors act? Give an example of an NNRTI.
They bind to the reverse transcriptase and cause a change in shape of the enzyme so it blocks HIV replication Example: Efavirenz
Give an example of an integrase inhibitor.
Raltegravir
What viral gene encodes all the viral structural proteins?
Gag gene
What must happen to the protein product of this gene, in order to produce fully functioning virus particles?
This must be cleaved by a protease into the constituent proteins so that it can make the fully formed virus
Name a drug that acts a protease inhibitor and state one problem with its pharmacokinetics.
Saquinavir It has a low bioavailability
What drug can be given to boost the level of the protease inhibitor in the circulation?
Ritonavir This decreases the metabolism of saquinavir
What is the herpes virus surrounded by?
Tegument and a lipid bilayer
What do the two different types of herpes cause?
HSV1 – cold sores HSV2 – genital herpes
What is the treatment for HSV?
Acyclovir Nucleoside analogue that is specific because its activation requires viral kinases
What envelope protein of influenza is important for the release of the virus into the host cell?
Neuraminidase
Name an inhibitor of this envelope protein
Oseltamivir
2 theories of how viruses fit into the tree of life?
- RNA world theory: life arose with the viruses 2. Reductionist theory: viruses came after cellular life, they are reduced versions of cellular organisms * mimiviruses and megaviruses may be the missing link
What are Ribozymes?
- RNAs that can catalyze specific reactions (similar to enzymes) - ribozymes (produced in lab) can catalyze their own synthesis - natural fans: cleave RNA, viral replication, tRNA biosynthesis
Examples of DNA viruses?
- herpes, smallpox, mimivirus DNA -> RNA -> protein
Examples of RNA viruses?
- Rhino, influenza, SARS RNA-> protein
Examples of Retroviruses?
- HIV RNA -> DNA (through reverse transcriptase) -> RNA -> protein
Pros and cons of a DNA virus
pros: lower mutation rate, more stable (can carry more genes), no dsRNA phase cons: lower mutation rate, slower replication
Pros and cons of RNA virus
pros: fast replication rate, high mutation rate cons: high mutation rate, limited sequence space (less stable), dsRNA phase, degrades faster, humans don’t have dsRNA (easy to identify)
What happens frequently in reverse transcriptase?
- 1 mutation per virus, much more common in retrovirus
What are some challenges in developing HIV vaccines?
- high mutation rate - integration into host genome - infects immune privileged region of host - targets immune system - multiple serotypes - costs and time involved in development - vaccine safety concerns
What is the diversity in HIV strains
- 25-30% in circulating HIV strains - mutation rate is - 1 base change per genome
What effects can a mutation have on a virus?
- not all mutations are advantageous: some hinder the virus, some prevent virus replication, and some are silent ( have no effect) - Some allow a competitive advantage, and some allow escape from antiviral drugs
antiretroviral drug classes
- reverse transcriptase inhibitors (NRTIs) - Fusion/entry inhibitors - Integrase inhibitors - Protease inhibitors
Difference b/t nucleosides and nucleotides?
- nucleosides: sugar+ base 3 phosphorylation events required for activity -nucleotide: sugar+base+phosphate, 2 phosphorylation events required for activity
Nucleoside analogs??
prevent adding of next nucleoside on to the chain looks like nucleoside but doesn’t have site to bind to next nucleoside so it is a chain terminator
3TC (Epivir/Iamivudine)
-FDA approved 1995 - reverse transcriptase inhibitor - nucleoside analog: mimics cytidine -> acts as a chain terminator
DLV (Rescriptor/delavirdine)
- FDA approved 1997 - Reverse transcriptase inhibitor (non-nucleoside) - binds RT catalytic site, blocking polymerase fxn
Reverse transcriptase mutations?
- only takes 1 or 2 mutations of virus to make reverse transcriptase drugs ineffective
DRV (darunavir/Prezista)
- FDA approved 2006 protease inhibitor: binds the active site preventing the processing of viral protein precursors - compete with the natural substrate
EVG (Elvitegravir)
- FDA approved 2014 - Allosteric integrase inhibitor (prevents functional multimers from forming (dimers of dimers= tetramer)
MVC (Selzentry/maraviroc)
- FDA approved 2007 - entry inhibitor (receptor antagonist) drug binds receptor (CCR5), preventing HIV from binding - mutant bind receptor in a different conformation
T20 (Fuzeon/entuvirtide)
- FDA approved 2003 - HIV fusion inhibitor - mimics viral protein to displace it in the fusion complex (binds p41 and prevents formation of the entry pore)
Vacc-4x
therapeutic vaccine in clinical trials 9phase 2) peptide vaccine -> dropped viral load but didn’t slow CD4 T cell decline
SB-728T gene therapy
in phase 1/2 trials modifies a CD4 T cell CCR5 receptor, making it non-functional, prevents HIV entry - harvest patient T cells, make mutation and replicate, and put back into pt - this mutation occurs naturally and confers HIV resistance - expensive and time consuming
Interleukin
IL-7: trial abandoned b/c IL-7 increased the number of CD4+ T cells but that increased viral load too IL-2: increased number of CD4+ T cells but didn’t significantly decrease clinical events or death, even when combined with antiretrovirals
Chloroquine
- antimalarial - drops pH in vacuoles - disrupts Env protein gp120, inhibits maturation - drops viral load, doesn’t affect T cells so doesn’t stop T cells from decreasing
What can be done to prevent escape mutants?
- combo drugs Atripla (3) Complera (4) Stribild (4) Triumeq (3) Combivir (4)
Difference b/t viral and human evolution
- humans: complicated, multiple polymerases, error prone, and non-error prone sites, at most 1 mistake/ 100 million, proofreading and correcting machinery, and we only have a couple kids in a lifetime - viruses: often 1 mistake per genome, no proofreading, often whole populations knocked out, billions of genomes made per day
Potential effects of viruses on human evolution
- immune system diversity - ABO blood system (decreased A allele frequency after smallpox epidemic) - endogenous retroviruses (1% of genome) - cell surface mutations (ex: CCR5)
What does it mean that viruses are a part of us?
- they are a part of our regulation of host gene expression - they take part in placental formation - reason why there is immunosuppression during pregnancy - promoters, enhancers and proteins can be coopted by the host for its own purposes (placenta formation) - can be fixed or mobile, and no human endogenous retroviruses (ERVs) are capable of replication
What are endogenous retroviruses (ERVs) associated with in humans?
- MS - schizophrenia - cancer - autoimmune diseases - amayotrophic lateral sclerosis (ALS)
Mutation in humans that allow them to be resistant to HIV infection?
-mutation prevents an HIV corrector from being made by the cell, and therefore HIV can’t infect people with this mutation (CCR5 delta 32 mutation) -> positive selection for this mutation
Hypothesis for why mutation has been selected in specific regions (Europe, Asia, North Africa)?
- either plague (bacteria) or smallpox (virus)
How can humans drive viral evolution?
- each infection is a population - zoonosis: virus mutating to be able to pass from one species to another - humans as an enviro: immune system and viral recombination - antiviral drugs: promote resistance and mutations
difference b/t epidemic and pandemic?
- epidemic: greater than expected incidence “outbreak” ex: SARS, Dengue - pandemic: spread over a large geographical area (b/t continents) ex: HIV, smallpox, H1N1 (seasonal flu not a pandemic)
Why do viruses start epidemics and then pandemics?
- increased virulence (severity of disease or ability to spread) - intro into novel setting - changes in host susceptibility to the infectious agent - changes in host exposure to the infectious agent
Transmission modes of viruses?
- iatrogenic (blood transfusion) - vertical - vector borne - droplet - fecal-oral - sexually
Zoonosis?
- disease that can pass from another species to humans or humans to another species - often diseases are adapted to their host and more deadly when they jump hosts (ex: Ebola) - Many viruses can pass from animal reservoir to humans, but have difficulties transmitting human to human - issues: domestication, deforestation, bush meat
BSL-4 viruses
- aerosol viruses - severe/fatal viruses w/ no vaccines or other txs: - bolivian and argentine hemorrhagic fevers - marburg virus - ebola virus - lassa virus - crimean-congo hemorrhagic fever - small pox
What is a virus?
- submicroscopic, obligate intracellular parasite (Can’t survive outside of cell, use host machinery -> can’t replicate or express genes w/o help of living cell) - Formed within cells from the assembly of preformed components, whereas other agents reproduce - Virons are the complete infective particle and don’t grow. It lacks needed components that cells have to reproduce. - No viruses known to have the genetic info needed to produce metabolic energy for replication - When a virus infects a cell, it marshals the cell’s ribosomes, enzymes and much of cellular machinery to replicate - Viral replication produces many progeny, that when complete, leave the host cell to infect other cells in the organism
What kind of cells do viruses infect?
- all types of living cells - animals, plants and bacteria - viroids: small circular RNA molecules with a rod like secondary structure that possess no capsid or envelope
What is a virus made of?
A virus particle, also known as a vision is essentially a nucleic acid (DNA or RNA) enclosed in a protein shell or coat. - Viruses are extremely small, approx: 15-25 nm in diameter
Variations in viruses?
- may be dsDNA, dsRNA, ssDNA, or ssRNA - The type of genetic material found in a particular virus depends on the nature and function of the specific virus - so dsDNA viruses must enter the host cell’s nucleus before it can replicate - ssRNA viruses replicate in host cell’s cytoplasm. - the genetic material isn’t typically exposed but covered by a protein coat. The viral genome can consist of a very small number of genes or up to hundreds of genes depending on the type of virus
The viral capsid?
- the protein coat that envelopes viral genetic material - composed of protein subunits called capsomeres - have several shapes: polyhedral, rod, or complex - fxn is to protect the viral genetic material from damage - in addition to protein coat: some viruses have specialized structures -> the flu virus has a membrane-like envelope around it’s capsid, and the envelope has both host cell and viral components and assists the virus in infecting its host
The process of the viral infection?
- adsorption: virus binds to host cell - penetration: virus injects its genome into host cell - viral genome replication: viral genome replicates using host’s cellular machinery - assembly: viral components and enzymes are produced and begin to assemble - Maturation: viral components assemble and viruses fully develop - release: newly produced viruses are expelled from the host cell
Key components of current classification system?
- type of symmetry of the virus capsid - presence or absence of a lipid envelope - type and structure of the viral nucleic acid and the strategy used in its replication
What does hemagglutinin allow viruses to do?
- binds to host cells, this is how viruses can switch b/t strains so they can infect other species -> virulent, lethal to humans -> can become pandemics
What are the Class 1 viruses?
HAPP viruses: dsDNA - Herpesvirus (cold sores, genital herpes, chicken pox, mono) - Adenovirus (resp diseases) - Papovavirus (warts, cervical cancer) - Poxvirus (small pox, cowpox)
Class II viruses?
ssDNA - parvovirus
Class III viruses?
- dsRNA coronavirus picornavirus (polio, common cold) Togavirus (rubella, yellow fever) Hep C virus
Class IV viruses?
positive ssRNA itself acting as mRNA - Rhabdovirus (rabies) - Paramyxovirus (measles, mumps) - Orthomyxovirus (influenza viruses) - Bunyavirus (Korean hemorrhagic fever) - Arenaviruses
Class V viruses
- negative ssRNA used as template for mRNA synthesis Reovirus (diarrhea)
Class VI viruses
positive ssRNA with DNA intermediate in replication - retrovirus (leukemia, AIDS)
Class VII viruses
dsDNA with an RNA intermediate in replication - Hep B virus
Viral exanthematous diseases?
- chickenpox/Herpes zoster - infectious mono - Roseola infantum (6th disease or Erythema subitum) - 5th disesae (Erythema infectiosum) - Measles - Rubella - Enteroviral exanthems: coxsackievirus, echovirus
What does exanthematous disease mean?
- characterized by or of the nature of an eruption or rash - the most frequent cause of exanthematous diseases are viral infections, which provoke skin alterations either directly or via the reaction of the immune system - in many distinct parainfectious clinical pictures, several viruses from quite different groups are able to produce a specific exanthem
Ddx of exanthematous eruptions?
- Rickettsial infections (tick borne illnesses) - Mycoplasma pneumoniae - syphilis (hands and soles) - typhoid fever - bacterial toxins (staph aureus: TSS -> pinpoint rash on abdomen - drug eruptions - live-virus vaccinations
All of the Human Herpes Viruses?
HHV-1: Herpes Simplex Virus 1 (HSV1) HHV-2: HSV2 HHV-3: VZV HHV-4: EBV (mono: elev lympho) HHV-5: CMV HHV-6: exanthema or Roseola HHV-7: T-lymphotropic virus HHV-8: virus assoc with Kaposi’s sarcoma (AIDS defining illness)
HSV 1 and 2 generally associated with what?
orolabial herpes: typically HSV-1 genital herpes: HSV-2 can affect almost all body tissue - these are mutlinucleated giant cells, intranuclear inclusion bodies (where viral assembly is taking place)
Epidemiology of HSV
>90% have abs to HSV-1 by age 30 - HSV 2 abs are rare b/f puberty 10-40% of general U.S. adult pop. have HSV-2 abs
Pathophysiology of HSV?
virus infects through mucosal membranes or abraded skin - latent infections are harbored in neuronal cells: in trigeminal ganglia and in pre-sacral ganglia
Clinical presentation of HSV oral-facial lesions?
- dew-drop on a rose petal - oral-facial lesions: primary infections: Gingivostomatitis (painful -> swollen lips) and pharyngitis most frequent, this is commonly seen in children and young adults - fever, malaise, myalgias, inability to eat, irritability and cervical adenopathy lasts 3-14 days - recurrence: Herpes labialis (cold sores)
Clinical presentaion of HSV urogenital lesions
- dew drop on rose petal - caused by either HSV-1 or 2 - systemic: HA, fever, malaise, and myalgia local: vesicular lesions of external genitalia with pain, itching, dysuria, vagina and urethral d/c, tender inguinal lymph adenopathy - usually present with early, tingly sensation and tenderness in affected area, with low grade fever - tx during this time= best results
What is often more severe primary infection or recurrent infections?
- primary infection usually more severe than recurrences but may be asymptomatic - vesicles form moist ulcers after several days, and crust over in 1-2 weeks if left unaddressed recurrences often: involve fewer lesions - tend to be labial - heal faster - are induced by stress, fever, infection, sunlight, chemo, pregnancy
What complications can HSV cause?
- ocular disease (#1 cause of blindness (hepatic keratitis) - Neonatal and congenital infections - Bells palsy (facial droop) - Encephalitis and recurrent meningitis - Herpes is most common cause of viral encephalitis in US - will see disseminated herpes in immunocompromised (AIDS)
What should be tested during pregnancies?
TORCHS: To: toxoplasmosis R: rubella C: CMV H: herpes and HIV S: syphilis
Dx of HSV?
- usually clinically made - clinical dx should be confirmed with lab testing, the dx can be made by viral culture( can’t be crusted over), PCR, Tzanck prep, direct fluorescence AB, and type-specific serologic tests. The choice of test varies with the clinical presentation - Viral culture - 50% sensitive - real-time HSV PCR: more sensitive to confirm HSV in clinical specimens obtained from genital ulcers, mucocutaneous sites, and CSF (amplifies the virus), its particularly useful for the detection of asymptomatic HSV shedding - ****There is enhanced sensitivity of HSV PCR compared to viral culture
What is the preferred dx test of HSV?
- PCR assay
Describe the HSV direct fluorescent ab test?
- many dx labs provide a rapid type-specific direct fluorescent ab (DFA) test to detect HSV in clinical specimens. This test is specific and reproducible (have to have an immune response though)
- What is the HSV serology test?
- type specific abs to HSV develop during the first several weeks after infection and persist indefinitely. The availability of type-specific abs has also facilitated greater accuracy in epidemiological surveys
Tzanck smear for HSV?
- Tzanck smear: may demonstrate the cytopathic effect of the virus (multinucleate giant cells), and can be performed on lesion scrapings from pts with active genital lesions. However it has limited utility since it has low sensitivity and specificity and is only helpful if + - furthermore, only a viral culture can determine whether the infection is due to HSV-1 or HSV-2
Management of HSV?
- acute infections: antiviral agents only shorten duration of sxs by 1-2 days (acyclovir, famciclovir, valcyclovir) -suppressive therapy: taken daily to prevent reactivation (spendy)
Where will Herpes present?
- can present on fingers (herpetic whitlow) -in the mouth -> primary: gingivostomatitis (sores all over mouth) - On the cornea (hepatic keratitis) - genitals (don’t miss the cervix)
What are the 2 clinical presentations of VZV?
- primary infection: chicken pox - recurrent infections: Herpes zoster
Epidemiology of VZV?
- humans only known reservoir of VZV - primary infection: transmission likely by resp. route - recurrent infection: VZV probably infects dorsal root ganglia during primary infection. Mechanism or stimulus for reactivation of latent infection in unknown.
Pathophys of VZV?
incubation pain: 10-21 days (usually 14-17) - infected persons are infectious 48 h before onset of vesicular rash, throughout vesicle formation (4-5 days), and until all vesicles are crusted.
Clinical presentation of primary infection: chickenpox
- rash, fever (100-103F), lasting 3-5 days, malaise - skin lesions are hallmark of disease: maculopapules, vesicles, and scabs in varying stages of development (“crops” of lesions - compared to small pox which lesions occur at same time ) on an erythematous base of 5-10 mm - distribution is centripetal (see on trunk) - Not as umbilicated as smallpox
Clinical presentation of recurrent VZV recurrent infection: Herpes zoster or “shingles”
- unilateral vesicular eruptions which develop within a single dermatome (T3 to L3 most common). Often assoc. with severe pain
Dxs in VZV?
- usually clinically made - tests can include: specialized complement fixation and virus neutralization in cell culture Fluorescent ab test of smear of lesions
progress of VZV infection?
- thin walled vesicle with clear fluid forms on a red base 2. The vesicle becomes cloudy and depressed in center (umbiliicated) with and irregular (scalloped) border 3. A crust forms in the center and eventually replaces the remaining portion of the vesicle at the periphery
When would you tx Herpes Zoster with IV acyclovir?
- when it is on the face and the eye is involved (can lead to blindness)
Management of VZV infections?
- primary infection prevention: vaccination (reduce outbreak by 50%) - primary disease: prevent secondary infections - Recurrent infection: zoster take antivirals (high dose): - acyclovir, famciclovir and analgesics - can give immunoglobulin w/in days of outbreak will decrease severity of outbreak
Infectious mononucleosis (EBV) epidemiology
- EBV (HHV-4) -> 2 variants: EBV-1, EBV-2 - B-cell lymphotropic virus primarily transmitted in saliva (4-8 wk incubation period) - 50% have had primary infection before adolescence (80% of daycare kids exposed to mono -> get over it easily) -Peak incidence occurrence: (big problem in adolescents and adults) ages 14-16 for girls ages 16-18 for boys - EBV shed from oropharynx for up to 18 months post-infection
Clinical presentation of mono (EBV) - clinical triad?
- subclinical or mild when infected during childhood - infectious mono defined by transient appearance of heterophil Ab and clinical triad: - fever/chills: 7-14 days duration (may be prodromal) - lymphadenopathy: rarely exceed 3 weeks duration (posterior chain -B cells multiplying) - Severe pharyngitis with exudates: maximal for 5-7 days and resolved over following 7-10 days (only exception when virus causes exudates)
Other common signs/sxs of primary infection of mono?
-HA, malaise, anorexia - soft palatal petechiae - maculopapular rash (especially with admin. of amoxicillin/PCN) - splenomegaly and mild hepatic tenderness in up to 50%
What neoplasms is EBV associated with?
- nasopharyngeal carcinoma - B-cell lymphomas (Burkitt’s lymphoma)
Lab findings in infectious mono (EBV)
- throat culture to check for B-hemolytic strep - monospot - Heterophil abs (90-95% of adolescents will be Ab +) become positive w/in 4 weeks after onset of sxs, are specific but not sensitive in early illness - atypical lymphocytosis in about 75% - EBV-specific immune response: EBV ab titers directed at several Ags -> EB virus capsid antigen (VCA), ABs to EBV nuclear antigen - EBNA
Complications of infectious mono?
- bacterial strep pharyngitis (develop a rash) - hematologic: thrombocytopenia, neutropenia - splenic rupture - neurologic: CN palsies (Bell’s palsy); Guillain-Barre syndrome; encephalitis
Management of infectious mono? (EBV)
- 95% of pts have self-limited disease in most cases requiring only supportive therapy - Acetaminophen or NSAIDS - warm salt water gargles - adequate rest (return to work/school based upon sx) - avoid contact sports for 6-8 weeks from onset - fever disappears in 10 days - lymphadenopathy and splenomegaly in 4 weeks
Epidemiology of CMV
- approx 1% of newborns infected - virus spread by: prolonged close contacts, blood/body fluids: transfusion (containing viable leukocytes), maternal-fetal transmission, STD - lifelong “infection” once infected - Congenital CMV occurs almost exclusively when preg. woman acquires primary infection (vs. reactivation) - perinatal CMV occurs when infant is infected at time of delivery through an infected birth canal or postnatal contact with maternal milk or or other secretions (40-60% transmission rate through nursing if mother infected)
When are the three times that you are most likely going to see CMV (worry about infection)?
- in pregnancy (babies) - transplant patients - in HIV (AIDS defining illness, shows up when CD4
Clinical presentation of congenital CMV?
- cytomegalic inclusion disease - ranges from inapparent infection (most) to severe/disseminated (-5%) - Petechiae, hepatosplenomegaly, jaundice common (60-80%) - microcephaly, growth retardation, prematurity (30-50%)
Clinical presentation of perinatal CMV?
- poor wt gain, adenopathy, rash, hepatitis, anemia, and atypical lymphocytosis
Clinical presentation of CMV mono?
- heterophil Ab negative mono syndrome (looks like mono but negative for mono spot, usually don’t have strep throat) - prolonged high fevers, profound fatigue and malaise - myalgias, HA, and splenomegaly are frequent - exudative pharyngitis and cervical adenopathy are rare - occasional rubelliform rash
Dx of CMV mono
- viral culture: MOST impt dx study in the eval of suspected CMV disease is the viral culture - CMV may be cultured from virtually any body fluid or organ system. Blood, urine, saliva, cervicovaginal secretions, CSF, bronchoalveolar lavage fluid, and tissues from bx specimens are all approp. specimens for culture - PCR - Ag assays - Tissue confirmation w/ AIDS related CMV : CMV GI or neuron disease, CMV pneumonitis = death
What is characteristic to CMV congenital infection in babies?
blueberry muffin lesions
Tx of CMV
Ganciclovir
What is fifth disease (Erythema infectiosum)?
caused by Human parvovirus B19 - respiratory tract is probably route of transmission
Clinical presentation of fifth disease?
- mild febrile exanthematous disease with little or no prodrome - low-grade fever, varying degrees of conjunctivitis, upper respiratory complaints, cough, myalgia, itching, nausea, and diarrhea are initial signs and sxs - Classic “slapped face” lesion: indurated, confluent erythema of the cheeks, fiery red - circumoral pallor - bilateral symmetric eruptions (maculopapular slightly raised blotchy areas with reticular or lacy pattern) appear on the arms, legs and trunk about one day later - Rash (when it occurs) usually lasts 1 week and may disappear then reappear in the same area a few hours later
Dx of Fifth disease?
- usually made clinically in kids - labs: elevated titer of IgM anti-parvovirus abs - PCR in serum
Tx of Fifth disease?
- symptomatic tx: NSAIDS
Roseola (infantum) epidemiology and pathophysiology?
- epidemiology: benign disease of infants 6 m to 4 yo (most commonly seen in children
Clinical presentation of Roseola (infantum)?
- first manifestations occur after 5-15 days incubation period with abrupt onset irritability and fever (up to 105 F) lasting 3-5 days - rash appears several hours after sudden drop in temp: faint small (2-3 mm) macules or maculopapules over neck and trunk extending to thighs and buttocks will last a few hours or up to 1-2 days management: symptomatic only
If child has seizure what test should be done?
- Lumbar puncture because you are worried about meningitis and encephalitis
Measles (Rubeola) epidemiology
- occurs only in human and remains worldwide health problem despite a vaccine - transmitted through nasopharyngeal secretions (directly or airborne droplets) to respiratory mucous membranes or conjunctivae of susceptible persons - Highly contagious: infectious from 5 days after exposure to 5 days after skin lesions appear
Clinical presentation of measles (rubeola)
- Koplik’s spots (small, red, irregular lesions with blue white centers) appear on oral mucosa 1-2 days before rash (look like salt on mucosa) - Brick red, irregular maculopapular rash: first appears on forehead, spreads downward over face, neck, and trunk and appears on feet by 3rd day “outward and downward” - can affect palms and soles last - lesions usually coalescence and disappear in same order as appearance after about 3 days - prodromal sxs subside 1-2 days after rash appears
Dx Measles (rubeola)
- usually clinical - labs: neutropenia, detection for IgM abs with ELIZA
Tx of measles (rubeola)
- isolation of pt - bedrest - antpyuretics - fluids - can have some bacterial disease complications, if so, tx with approp. abxs. - This is a vaccine preventable disease!!! complications: heart, and encephalitis
Rubella (german measles, 3-day measles) epidemiology
- nasopharyngeal secretions transmit virus - caused by Togavirus - transplacental transmission results in congenital rubella syndrome - age is an important determinant of the severity of Rubella (milder than measles)
Clinical presentation of Rubella?
- viral exanthemous primary disease is generally milder than rubeola - no prodromal in children - adults: prodromal illness precedes rash by 1-8 days and consists of malaise, HA, and fever (devastating in pregnancy: congenital rubella syndrome) - lymphadenopathy: large, tender, post-auricular and sub occipital nodes are most often involved, splenomegaly or generalized lymphadenopathy may be present - Rash appears 14-21 days after exposure and follows same pattern as rubeola (starts cephalically) lesions have lighter hue than measles, lesions usually remain discrete versus coalescent form and last 1-5 days (most commonly 3 days). Small red lesions (Forchheimer’s spots) may appear on soft palate (not pathognomonic)
Clinical presentation of congenital rubella syndrome?
-heart malformations (patent ductus arteriosus, interventricular septal defect, pulmonic stenosis) - eye lesions (corneal clouding, cataracts, chorioretinitis, microphthalmia) -microcephaly - mental retardation - deafness - thrombocytopenic purpura - hepatosplenomegaly - intrauterine growth retardation
Management of congenital rubella syndrome?
- Prevention - vaccinate all women of childbearing age (if already pregnant, wait until 2nd trimester when not as immunocompromised because it is a live virus
Dx and Tx of rubella
- leukonpenia - virus isolation and serologic tests of immunity: fluorescent ab tests, IgM abs to Togavirus Tx: acetaminophen provides symptomatic relief
Complications of Rubella
- exposure during pregnancy: congenital rubella: heart defects, cataracts, glaucoma, psychomotor retardation - post infectious encephalopathy - This is vaccine preventable disease!!!!
Epidemiology of mumps?
- etiologic agent: paramyxovirus - disease occurs most frequently in the spring - spread by respiratory route but less contagious than measles or chickenpox
Clinical presentation of the mumps
12-25 days incubation period - at least 25% of infections are subclinical - parotitis: parotid swelling (salivary adenitis) is first indication of illness and usually occurs suddenly: may be preceded by prodrome of malaise, anorexia, fever (up to 103F) and pharyngitis - glandular enlargement progresses over 1-3 days and subsides about a week after max enlargement - pain and tenderness may be marked or absent - epididymoorchitis: complicates 20-35% of post pubertal males, testicular involvement usually appears 7-10 days after onset of parotitis but may precede it or be simultaneous: - usually unilateral - acutely tender painful swollen testicle persist 3-7 days and subsides gradually - epididymis often palpable as swollen tender cord - heralded by recurrence of malaise, fever (103-106F), chills, HA, N/V -tx: no specific tx
Worst possible complication of mumps:
meningitis
What are the common cold viruses?
rhinovirus coronavirus adenovirus
influenza like illnesses?
influenza A virus influenza B virus
Influenza etiology?
- caused by members of Orthomyxoviridae family of viruses - Types A, B, and C are based on antigenic characteristics of the nucleoprotein (NP) and matrix (M) protein Ags. - Type A viruses undergo further surface antigenic classification: Hemagglutinin (H) ags (H1-3) Neuraminidase (N) ags (N1-2) - major antigenic shifts occur regularly: type A viruses about every 3 years (changes frequently, can swap with swine or avian, makes it very deadly) type B viruses about every 5 years - influenza outbreaks occur every year
Clinical presentation of influenza?
- abrupt onset of systemic sxs: HA, fever (38-41C), chills, myalgia, malaise: - accompanied by respiratory signs/sxs: cough, pharyngitis - dyspnea, hyperpnea, cyanosis, diffuse rales or signs of consolidation are evidence of pulmonary complications - acute illness generally resolves within a week
Complications of influenza?
- pneumonia (staph aureus) - Reye’s syndrome (especially children 2-16 yo) - Myositis, rhabdomyolysis, myoglobinuria (elderly: dehydrated and confused) - myocarditis and pericarditis
Dx influenza?
- rapid flu swab (Nasal, throat) - Leukopenia
Symptomatic tx for influenza?
- acetaminophen - rest - fluids - abx if pneumonia suspected
Anti-influenza virus drugs
- Neuraminidase inhibitors (used the most) Oseltamivir (Tamiflu) Zanamivir (Relenza) - Adamantane derivatives/M2 inhibitors (proton channel through viral envelope -> blocks acidification): amantadine rimantadine
Management and prevention of influenza?
- vaccination: trivalent inactivated influenza virus vaccine provides partial immunity for few months to 1 year - given in Oct or Nov of each year - CI when allergic eggs - Vaccination of high risk groups: - chronic cardiac or pulmonary disease (including asthma) - pregnant women - residents of chronic care/nursing facilities - over age 65 - chronic medical disorders: DM, renal disease, hemoglobinopathies, immunosuppressed - individuals who care for high risk populations
Epidemiology of Bronchiolitis?
RSV (member of paramyxovirus genus) major respiratory pathogen of young children - transmitted primarily by close contact with contaminated fingers or fomites - annual epidemics occur in late fall, winter or spring - incidence rates are highest in infants 1-6 months of age and accounts for 20-25% of hospitalizations in infants/young children (babies can’t cough up the thick bronchial secretions) - disease is milder in older children/adults
Clinical presentation of Bronchiolitis (RSV)?
infants: commonly presents as rhinorrhea, low-grade fever, cough, wheezing, mild systemic sxs severe illness: tachypnea, dyspnea, hypoxia, cyanosis even apnea may ensue - diffuse wheezing, rhonchi and rales (may not see wheezing) - clinical presentation of adults/older children: common cold presentation - younger children/infants: bronchiolitis, tracheobronchitis and pneumonia
Dx of bronchiolitis?
Get O2 sats!!! - rapid RSV with nasal washings using viral Ag ID using ELIZA or immunofluorescent assay - culture of nasopharyngeal secretions
Tx of bronchiolitis?
- antiviral therapy: ribavirin - sx relief: contact isolation, respiratory therapy, oxygen, secretion removal, hydration, antibronchospastic agents
Epidemiology of Croup
- caused by parainfluenza viruses: 4 major serotypes type 1: most frequent cause of croup (laryngotracheobronchitis) in children type 2: similar but less severe type 3: causes bronchiolitis and pneumonia in infants - account for up to 22% of respiratory illness in children, very mild disease in adults
Clinical presentation of Croup?
- acute febrile illness in children (50-80%) - coryza, sore throat, hoarseness, and variably croupy cough - breathing difficulty accompanied by a barking cough - much worse at night (day 3 the worst!)
Management of croup
sx relief: cool or moist air can bring relief - try bringing child into steamy bathroom or outside into the cool night air - a cool air vaporizer, set it up in the child’s bedroom and use it for the next few nights - Acetaminophen - ER tx: aerosolized racemic epinephrene predisone in ER and to go (oral) - after 3 hours of good presentation -> send them home - avoid cough medicines because they suppress coughs and you want to get rid of inflammation, but don’t want to suppress cough and make child lethargic and sleepy
Rabies epidemiology
-caused by rhabdovirus - 2 epidemiologic forms: urban: unimmunized domestic cats/dogs sylvatic: skunks, foxes, raccoons, wolves and bats
Clinical presentation of rabies (4 stages)
1) Prodrome: usually persists 1-4 days. Fever, HA, malaise, myalgias, increased fatigability, anorexia, N/V, pharyngitis, nonproductive cough -paresthesias and/or fascicultations around site of inoculation suggestive of rabies 2) Acute encephalitis: development of excessive motor activity, excitation, and agitation - confusion, hallucinations, combativeness, muscle spasms, meningismus, seizures and focal paralysis quickly follows - hyperesthesia with excessive sensitivity to bright light, noise or touch is common - Fever (up to 105F), dilated irregular pupils, increased lacrimation, salivation, perspiration, and postural hypotension occur -3) Profound brainstem dysfunction: occur shortly after onset of encephalitic phase, difficulty swallowing (with increased salivation) produces characteristic foaming at the mouth. Violent involuntary contractions of diaphragm and accessory, respiratory, pharyngeal and laryngeal muscles - coma and respiratory failure follow - recovery (rarely)
lab findings of Rabies
- isolation of virus (saliva, CSF or brain tissue) - indirect serologic evidence of immune response - direct antigent detection (skin or brain bxs)
Management of rabies?
- prevention: pre-exposure vaccinations: domestic animals, high risk individuals: animal handlers, veterinarians, cave explorers, lab workers - post-exposure prophylaxis: immunoglobulin
Ddx Variola versus varicella?
Variola (smallpox): rash starts on the face, lesions same stage, deep lesions, often palms, soles, centrifugal rash, Back>abdomen, multiloculated vesicles Varicella: rash starts trunk, lesions in crops, superficial lesions, never palms/soles, centripedal rash, back=abdomen, uniloculated vesicles
disease course of smallpox?
- Day 0 -> exposure - Day 12-14 -> fever, malaise, non-productive cough, HA, backache, joint pain -Day 14-16 -> papular rash on face -> extremities - Day 16-18 -> papular -> vesicular -> pustular - Day 22-26 -> crusted lesions - Day 28-30 -> resolving 10% will develop malignant disease and die 5-7 days after incubation
Vaccine for small pox?
- d/c’d in early 1970’s, but has been reinstituted b/c of concerns about bioterrorism, - routine vaccine, in the absence of a case of small pox is not recommended for those under 18 live vaccine: site becomes red, itchy in 3-4 days vesicle umbilicates and evolved into well formed pustule by day 6-11 - pustule scabs over b/t week 2 and 3 - scab falls off by end of 3rd week, leaving a scar
What technique is used to prove that a virus causing a particular disease?
Koch’s Postulates
Define virus.
Infectious obligate intracellular parasites
What is the average size of a virus?
100nm
What are the two broad types of virus morphology?
Non-enveloped – protein capsid Enveloped – membrane derived from host membrane
What is the main classification of viruses and what is it based on?
Baltimore Classification – based on the genome
What are the different groups under this classification?
DNA Viruses (double stranded, single stranded) RNA Viruses (positive sense, negative sense, double stranded) DNA and RNA Viruses (retroviruses, double stranded DNA (RT))
What is the difference between positive sense RNA and negative sense RNA?
Positive sense RNA can be translated straight away Negative sense RNA must be transcribed into a positive sense copy
What are some common features among RNA viruses and retroviruses?
Small genome limited by instability of RNA No proofreading capacity – high mutation rate
What are some common features among DNA viruses?
Larger because DNA is more stable so there is space for accessory genes
What are the good and bad aspects of having a segmented genome?
Good – allows an opportunity for exchanges of genetic material and fast evolution Bad – all the segments need to be assembled when the virus leaves the cell
Describe the replication cycle of HIV-1.
GP120 receptors on the HIV bind to CD4 receptors on T cells and bind to co-receptors (CCR5 or CXCR4) allowing the membranes to fuse and the viral contents to enter the cell Some copies of the virus genome gets replicated Some gets reverse transcribed to viral DNA, which is integrated into the host genome. It is then transcribed and translated into proteins The proteins and copies of the genome then assemble to form new virus particles, which exit the cell.
What is the cytopathic effect?
Death of a cell as a result of being infected by a virus
How can viral plaques be used to quantify the amount of virus in a sample?
Plaque Assay – the virus undergoes serial 10-fold dilutions and is then spread on a monolayer of susceptible cells A plaque will appear where an individual virus has killed some cells The number of plaques can be counted and scaled up to quantify the amount of virus in a sample
What are two other ways of detecting the presence of virus in a sample?
Syncytia formation Immunostaining
What are the three phases of growth of a virus?
Eclipse Logarithmic Cell Death
What are the five techniques used to diagnose a viral infection?
Genome (PCR) Antigen (Indirect Fluorescence Antibody, ELISA) Viral Particles (Electron Microscopy, Haemagglutination Assay) Cytopathic Effect Antibodies to the virus
What is a virus made of?
No cell wall, made up of nucleic acid components: -protein coat (capsid) -nucleic acid core, or genome -some have lipoprotein envelope -viruses containing envelope are antigenic in nature -Viruses are obligate intracellular parasites - Use host enzymes, don’t have metabolic machinery of their own.
Where do viruses replicate in the host?
certain ones multiply in cytoplasm and others do so in the nucleus -most have to replicate so many times before they illicit symptoms in the host and before the dx is made.
Process of viral infection and replication?
- Absorption: binds to host cell 2. Penetration: virus injects genome into host cell 3.Viral genome replication: viral genome replicates using the host’s cellular machinery 4. Assembly: viral components and enzymes are produced and begin to assemble. 5. Maturation: viral components assemble and viruses fully develop. 6. Release: newly produced viruses are expelled from the host cell.
What must antiviral drugs do to be effective?
must either: - block viral entry into or exit from the cell - be active inside the host cell
What is the MOA of most anti-viral drugs?
many are purine or pyrimidine analogs. -Many are prodrugs: so they must be phosphorylated by viral or cellular enzymes in order to become active. - anti-viral agents inhibit active replication so the viral growth resumes after drug removal.
What is an important part of fighting viral infections?
current anti-viral agents don’t eliminate non-replicating or latent virus ***Effective host immune response remains essential for recovery from viral infection. -clinical efficacy depends on achieving inhibitory concentration at site of the infection within the infected cells
What are the anti-HSV/VZV agents? Herpes/Varicella/Zoster
acyclovir (zovirax) famciclovir (famvir) valacyclovir (valtrex)
MOA of anti-HSV/VZV agents?
All 3 are guanine nucleoside analogs. - all are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs. ** The analog inhibits viral DNA-polymerase and only actively replicating viruses are inhibited
Acyclovir (zovirax)
guanosine analog -topical, oral, and IV
Spectrum of Acyclovir?
HSV 1 and 2, VZV, and possible EBV *DOC for HSV genital infections, herpes labialis/orolabial, HSV encephalitis, HSV infections in immunocompromised and pregnant pt
Pharmokinetics of acyclovir?
oral bioavailability: 20-30% distribution to all tissues including CNS -renal excretion: >80% -half life: 2-5 hours -topical, oral and IV
Acyclovir safety
Pregnancy: B lactation: safe renal dosing: adjust if CrCl
Acyclovir MOA
inhibition of viral synthesis of DNA -uptake by infected cell -competes with deoxyguanosine triphosphate for viral DNA polymerases: *chain termination -> inactivated viral DNA polymerase
What cells is acyclovir selectively activated in?
in cells infected with herpes virus -uninfected cells don’t phosphorylate acyclovir.
When would you take acyclovir for genital/mucocutaneous HSV?
Take it for first episode: frequent dosing (trying to prevent it from reocurring) Recurrence and suppression if pt has frequent recurrence.
Adverse effects of Acyclovir
-reversible renal toxicity -Neuro symptoms: encephalopathic changes - somnolence, hallucinations, confusion and coma. -TTP/HUS in immunocompromised -GI sxs -HA -rash -photosensitivity -anemia
Resistance to acyclovir and MOA of resistance
MIC>2-3 mcg/mL -mostly occurs in immunocompromised - 3 basic resistance mechanisms exist: 1. reduced or absent thymidine kinase 2. altered TK substrate specifity 3. alterations in DNA poly. - there is cross resistance to famciclovir and valacyclovir
Why tx with acyclovir?
genital herpes: shortens duration of sxs, viral shedding time, and time to resolution of lesions recurrent genital herpes: shortens course of time by 1-2 days long term tx: decreases frequency of both symptomatic recurrences and asymptomatic viral shedding -> decreases sexual transmissions. Varicella Zoster: decreases total number of lesions and duration of varicella (if begun w/in 24 hours after onset of rash).
Famciclovir (Famvir)
cyclic guanine analong: -converted to penciclovir in the liver and intestines -penciclovir is used only topically whereas famciclovir can be administered orally. - PO only
Spectrum of famciclovir
HSV 1 & 2, VZV, maybe in EBV - in vitro to HBV
Pharmacokinetics of famciclovir
oral bioavailability: 77% 1st pass metabolism in intestine and liver: results in conversion to penciclovir Renal excretion: > 80% half life: 2-3 hours - Just PO
Famciclovir safety
Pregnancy: B lactation: unknown, caution advised Renal dosing: adjust dose for CrCl
MOA of famciclovir
Similar to acyclovir -> inhibition of viral synthesis of DNA, uptake by infected cell and competes with deoxyguanosine triphosphate for viral DNA polymerases -> inactivates viral DNA polymerase -it is converted to penciclovir triphosphate and compared to acyclovir triphosphate, penciclovir 3xP has lower affinity for viral DNA polymerase but does have longer intracellular half life
Famciclovir uses
zoster (shingles), and genital and orolabial HSV (for 1st occurence, recurrence and suppression)
Famciclovir adverse effects
-neutropenia -thrombocytopenia -neurological sxs: encephalopathic changes -> somnolence, hallucinations and delirium - GI sxs -HA, fatigue -abnormal LFT’s
Resistance to Famciclovir
- mutations in viral TK or DNA polymerase -cross resistance with acyclovir in TK negative strains -May still have activity in TK altered strains -resistance to HBV due to pt mutation (viral DNA polymerase)
Valacyclovir (Valtrex)
Prodrug of acyclovir: rapidly and almost completely converted to a acyclovir, same MOA, same spectrum, same mechanism of resistance
Pros and cons of Valacyclovir
Advantage: more convenient dosing, better oral bioavailability (55%) cons: more pricey than acyclovir
Pharmokinetics of Valacyclovir
oral bioavailability: 55% -undergoes rapid and extensive 1st pass effect to yield acyclovir -food doesn’t affect absorption -renal excretion: >50% Half life: 2-3 hours Administration: oral
Valacyclovir safety
Pregnancy: B lactation: safe renal dosing: adjust for CrCl
dosing of Valacyclovir
varies with infection type/severity -1st episode of HSV: hit em’ hard -> 1000 mg PO bid x 7-10 days shingles: PO tid x 7 days
Adverse effects of Valacyclovir
-reversible renal toxicity -neuro sxs: encephalopathic changes -> somnolence, hallucinations, confusion, coma -TTP/HUS: immunocompromised -GI, HA, rash, photosensitivity, elevated LFTs
What is the cheapest of the 3 HSV drugs and most preferred?
Acyclovir cheapest, but you have to admin more often. Can tx encephalitis with this too by IV - used b/c it has broader spectrum -> recommended for varicella or zoster in immunocompromised
What is used to treat HSV keratoconjunctivitis?
trifluridine (viroptic -> ophthalmic application) - this is active against acyclovir resistant strains
Anti-CMV agents
Ganciclovir
Spectrum of Ganciclovir
oral, IV, intraocular CMV, EBV, HSV/VZV, human herpesvirus 6 (for CMV and EBV: 10x more potent than acyclovir)
Ganciclovir is DOC for?
CMV retinitis in immunocompromised pt, and prevention of CMV disease in transplant patients
pharmacokinetic of Ganciclovir
oral bioavailability: 50% is excreted unmodified in urine renal excretion: >90% half life: 2-4 hours admin: oral, IV, intraocular
Ganciclovir safety
pregnancy: C (adverse fetal effects in animal studies) lactation: unsafe renal dosing: adjust dose for CrCl
MOA of Ganciclovir
competes with deoxyguanosine triphosphate similar to acyclovir - but in CMV -> viral encoded phosphotransferase coverts to ganciclovir triphosphate -unlike acyclovir, ganciclovir contains 3’ OH group allowing for DNA to continue
Adverse effects of Ganciclovir
reversible pancytopenia, fever, rash, phlebitis (IV), confusion, renal dysfunction, psychiatric disturbances, seizures
Influenza agents
- oseltamivir - zanamivir - amantadine (used in parkinsons now) - Rimantadine
MOA of influenza and neuraminidase inhibitors -> oseltamivir/zanamavir
influenza: contains an enzyme neuraminidase which is essential for the replication of the virus -so neurominidase inhibitors prevent the release of new visions and their spread from cell to cell.
Neuraminidase inhibitors effectiveness
effective against both types of influenza A and B -don’t interfere with immune response to influenza A vaccine -can be used for both prophylaxis and acute tx
Oseltamivir (Tamiflu) MOA
oral neuraminidase inhibitor: cleaves terminal sialic acid residues on glycoconjugates and destroys receptors -newly formed visions adhere to cell surface and limit spread.
Spectrum of Oseltamivir (Tamiflu)
Influenza A and B in kids and adults, avian flu, H5N1 disease
Adverse effects of Tamiflu
N/V, HA
When do you want to administer Oseltamivir (Tamiflu)
for tx of Influenza A and B: w/in 48 hours of sx onset, if high risk -> 72 hours - prophylaxis: w/in 48 hours of exposure
Zanamivir (Relenza)
Neuraminidase inhibitor, given via inhalation spectrum: uncomplicated influenza A and B and some strains of Avian influenza
Adverse effects of Zanamivir (Relenza)
nasal and throat discomfort -bronchospasm
Amantadine (Symmetrel) and Rimantadine (Flumadine)
MOA: prevents release of viral nucleic acid into host cell spectrum: influenza A, however resistance is frequent (Symmetrel not as effective anymore -> doesn’t work on B) Adverse effects: seizures, anticholinergic, CNS, edema, blurry vision
Is Amantadine or Rimantadine recommended in US?
NO not currently recommended for influenza because too much resistance - it is being used for extrapyramidal sx and parkinsonism though
Pharmacokinetics of Amantadine
oral bioavailability: 50-90% - crosses BBB extensively, and Rimantadine doesn’t. -PO
Ribavarin
purine nucleoside analog MOA: not fully understood, inhibition of RNA polymerase Spectrum: DNA and RNA viruses are susceptible, including influenza, HCV, parainfluenza, RSV, Lassa virus
Therapeutic uses of Ribavarin
DOC for: RSV bronchitis and pneumonia in hospitalized children (aerosol), lassa fever alternate drug: influenza, parainfluenza, measles virus in immunocompromised pts - used in combo with interferons for HCV
Safety of Ribavarin
Available: PO and inhalation IV available through CDC Preg: X (teratongenic) lactation: probably unsafe
Adverse effects of Ribavirin
BBW-hemolytic anemia resp. deterioration depression suicidal ideation bacterial infections psych. effects anxiety, fatigue, dizziness
Hepatitis?
swelling or inflammation of the liver in response to: drugs, toxins, excessive alcohol, infections from bacteria or viruses
Hepatitis A
typically spreads when infected individuals improperly handle food or water
Hepatitis B
often transmitted by sexual intercourse, sharing of needles or contact with contaminated blood (vaccine available)
Hepatitis C
more likely to cause permanent liver damage, genes mutate very fast, new genotypes make developing an effective vaccine impossible so far
Hepatitis A tx
clears on its own with rest and adequate hydration
Hepatitis B tx
May clear on its own. Chronic cases may be tx with: - interferon - Nucleoside Reverse Transcriptase inhibitors (NRTI) such as -> emtricitabine tenofavir entacavir lamivudine (some patients may need liver transplant)
Hepatitis C epidemiology
chronic infection that afflicts about 170 million people worldwide -annual mortality: 350,000 15,000 in the US
Hepatitis C standard treatment
synthetic, injectable version of interferon plus the antiviral drug ribavarin - this combo shows benefit or cure in 25-75% of patients -SE: significant or intolerable -> severe flu-like sxs, fatigue, depression, anemia -Virus often becomes resistant to medication, allowing disease to worsen
Anti-viral drugs for hepatic viral infections
- interferons - lamivudine - cytosine analog - HBV -Entecavir - guanosine analog- HBV (lamivudine resistance strains) -Ribavarin - Hep C (w/ interferons)
New drugs for Hep C
To be effective - drug has to incorporate itself in the virus’s genetic code so as to halt replication - to avoid potentially debilitating side effects the med needs to enter the liver quickly and directly avoiding as many other organs as possible
New formulation for Hepatitis
called sofosbuvir (Sovaldi) study showed 295/327 patients treated with sofosbuvir as well as ribavarin and interferon showed no signs of virus in blood after 12 weeks -> approved by FDA in 2013 in combo with rivabarin
Sofosbuvir paired with ledispasvir
cured at least 94% of patients with genotype 1 disease, mixed in single daily pill (Harvoni) -> cure rates >90% with 12 weeks and no significant SE’s.
What is downfall of new drugs for Hep C
>$100,000 for 12 week course of treatment. Many people with Hep C poor and/or incarcerated
Cost of sofasbuvir?
$594 dose, treatment would run nearly $12 billion dollars - much cheaper in Canada and Germany -What the heck U.S.?
What is an important part of fighting viral infections?
current anti-viral agents don’t eliminate non-replicating or latent virus ***Effective host immune response remains essential for recovery from viral infection. -clinical efficacy depends on achieving inhibitory concentration at site of the infection within the infected cells
What are the anti-HSV/VZV agents? Herpes/Varicella/Zoster
acyclovir (zovirax) famciclovir (famvir) valacyclovir (valtrex)
MOA of anti-HSV/VZV agents?
All 3 are guanine nucleoside analogs. - all are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs. ** The analog inhibits viral DNA-polymerase and only actively replicating viruses are inhibited
Acyclovir (zovirax)
guanosine analog -topical, oral, and IV
Spectrum of Acyclovir?
HSV 1 and 2, VZV, and possible EBV *DOC for HSV genital infections, herpes labialis/orolabial, HSV encephalitis, HSV infections in immunocompromised and pregnant pt
Pharmokinetics of acyclovir?
oral bioavailability: 20-30% distribution to all tissues including CNS -renal excretion: >80% -half life: 2-5 hours -topical, oral and IV
Acyclovir safety
Pregnancy: B lactation: safe renal dosing: adjust if CrCl
Acyclovir MOA
inhibition of viral synthesis of DNA -uptake by infected cell -competes with deoxyguanosine triphosphate for viral DNA polymerases: *chain termination -> inactivated viral DNA polymerase
What cells is acyclovir selectively activated in?
in cells infected with herpes virus -uninfected cells don’t phosphorylate acyclovir.
When would you take acyclovir for genital/mucocutaneous HSV?
Take it for first episode: frequent dosing (trying to prevent it from reocurring) Recurrence and suppression if pt has frequent recurrence.
Adverse effects of Acyclovir
-reversible renal toxicity -Neuro symptoms: encephalopathic changes - somnolence, hallucinations, confusion and coma. -TTP/HUS in immunocompromised -GI sxs -HA -rash -photosensitivity -anemia
Resistance to acyclovir and MOA of resistance
MIC>2-3 mcg/mL -mostly occurs in immunocompromised - 3 basic resistance mechanisms exist: 1. reduced or absent thymidine kinase 2. altered TK substrate specifity 3. alterations in DNA poly. - there is cross resistance to famciclovir and valacyclovir
Why tx with acyclovir?
genital herpes: shortens duration of sxs, viral shedding time, and time to resolution of lesions recurrent genital herpes: shortens course of time by 1-2 days long term tx: decreases frequency of both symptomatic recurrences and asymptomatic viral shedding -> decreases sexual transmissions. Varicella Zoster: decreases total number of lesions and duration of varicella (if begun w/in 24 hours after onset of rash).
Famciclovir (Famvir)
cyclic guanine analong: -converted to penciclovir in the liver and intestines -penciclovir is used only topically whereas famciclovir can be administered orally. - PO only
Pharmacokinetics of famciclovir
oral bioavailability: 77% 1st pass metabolism in intestine and liver: results in conversion to penciclovir Renal excretion: > 80% half life: 2-3 hours - Just PO
Cost of sofasbuvir?
$594 dose, treatment would run nearly $12 billion dollars - much cheaper in Canada and Germany -What the heck U.S.?
What is downfall of new drugs for Hep C
>$100,000 for 12 week course of treatment. Many people with Hep C poor and/or incarcerated
Sofosbuvir paired with ledispasvir
cured at least 94% of patients with genotype 1 disease, mixed in single daily pill (Harvoni) -> cure rates >90% with 12 weeks and no significant SE’s.
New formulation for Hepatitis
called sofosbuvir (Sovaldi) study showed 295/327 patients treated with sofosbuvir as well as ribavarin and interferon showed no signs of virus in blood after 12 weeks -> approved by FDA in 2013 in combo with rivabarin
New drugs for Hep C
To be effective - drug has to incorporate itself in the virus’s genetic code so as to halt replication - to avoid potentially debilitating side effects the med needs to enter the liver quickly and directly avoiding as many other organs as possible
Anti-viral drugs for hepatic viral infections
- interferons - lamivudine - cytosine analog - HBV -Entecavir - guanosine analog- HBV (lamivudine resistance strains) -Ribavarin - Hep C (w/ interferons)
Hepatitis C standard treatment
synthetic, injectable version of interferon plus the antiviral drug ribavarin - this combo shows benefit or cure in 25-75% of patients -SE: significant or intolerable -> severe flu-like sxs, fatigue, depression, anemia -Virus often becomes resistant to medication, allowing disease to worsen
Hepatitis C epidemiology
chronic infection that afflicts about 170 million people worldwide -annual mortality: 350,000 15,000 in the US
Hepatitis B tx
May clear on its own. Chronic cases may be tx with: - interferon - Nucleoside Reverse Transcriptase inhibitors (NRTI) such as -> emtricitabine tenofavir entacavir lamivudine (some patients may need liver transplant)
Hepatitis A tx
clears on its own with rest and adequate hydration
Hepatitis C
more likely to cause permanent liver damage, genes mutate very fast, new genotypes make developing an effective vaccine impossible so far
Hepatitis B
often transmitted by sexual intercourse, sharing of needles or contact with contaminated blood (vaccine available)
Hepatitis A
typically spreads when infected individuals improperly handle food or water
Hepatitis?
swelling or inflammation of the liver in response to: drugs, toxins, excessive alcohol, infections from bacteria or viruses
Adverse effects of Ribavirin
BBW-hemolytic anemia resp. deterioration depression suicidal ideation bacterial infections psych. effects anxiety, fatigue, dizziness
Safety of Ribavarin
Available: PO and inhalation IV available through CDC Preg: X (teratongenic) lactation: probably unsafe
Therapeutic uses of Ribavarin
DOC for: RSV bronchitis and pneumonia in hospitalized children (aerosol), lassa fever alternate drug: influenza, parainfluenza, measles virus in immunocompromised pts - used in combo with interferons for HCV
Ribavarin
purine nucleoside analog MOA: not fully understood, inhibition of RNA polymerase Spectrum: DNA and RNA viruses are susceptible, including influenza, HCV, parainfluenza, RSV, Lassa virus
Pharmacokinetics of Amantadine
oral bioavailability: 50-90% - crosses BBB extensively, and Rimantadine doesn’t. -PO
Is Amantadine or Rimantadine recommended in US?
NO not currently recommended for influenza because too much resistance - it is being used for extrapyramidal sx and parkinsonism though
Amantadine (Symmetrel) and Rimantadine (Flumadine)
MOA: prevents release of viral nucleic acid into host cell spectrum: influenza A, however resistance is frequent (Symmetrel not as effective anymore -> doesn’t work on B) Adverse effects: seizures, anticholinergic, CNS, edema, blurry vision
Adverse effects of Zanamivir (Relenza)
nasal and throat discomfort -bronchospasm
Zanamivir (Relenza)
Neuraminidase inhibitor, given via inhalation spectrum: uncomplicated influenza A and B and some strains of Avian influenza
When do you want to administer Oseltamivir (Tamiflu)
for tx of Influenza A and B: w/in 48 hours of sx onset, if high risk -> 72 hours - prophylaxis: w/in 48 hours of exposure
Adverse effects of Tamiflu
N/V, HA
Spectrum of Oseltamivir (Tamiflu)
Influenza A and B in kids and adults, avian flu, H5N1 disease
Oseltamivir (Tamiflu) MOA
oral neuraminidase inhibitor: cleaves terminal sialic acid residues on glycoconjugates and destroys receptors -newly formed visions adhere to cell surface and limit spread.
Neuraminidase inhibitors effectiveness
effective against both types of influenza A and B -don’t interfere with immune response to influenza A vaccine -can be used for both prophylaxis and acute tx
MOA of influenza and neuraminidase inhibitors -> oseltamivir/zanamavir
influenza: contains an enzyme neuraminidase which is essential for the replication of the virus -so neurominidase inhibitors prevent the release of new visions and their spread from cell to cell.
Influenza agents
- oseltamivir - zanamivir - amantadine (used in parkinsons now) - Rimantadine
Adverse effects of Ganciclovir
reversible pancytopenia, fever, rash, phlebitis (IV), confusion, renal dysfunction, psychiatric disturbances, seizures
MOA of Ganciclovir
competes with deoxyguanosine triphosphate similar to acyclovir - but in CMV -> viral encoded phosphotransferase coverts to ganciclovir triphosphate -unlike acyclovir, ganciclovir contains 3’ OH group allowing for DNA to continue
Ganciclovir safety
pregnancy: C (adverse fetal effects in animal studies) lactation: unsafe renal dosing: adjust dose for CrCl
pharmacokinetic of Ganciclovir
oral bioavailability: 50% is excreted unmodified in urine renal excretion: >90% half life: 2-4 hours admin: oral, IV, intraocular
Ganciclovir is DOC for?
CMV retinitis in immunocompromised pt, and prevention of CMV disease in transplant patients
Spectrum of Ganciclovir
oral, IV, intraocular CMV, EBV, HSV/VZV, human herpesvirus 6 (for CMV and EBV: 10x more potent than acyclovir)
Anti-CMV agents
Ganciclovir
What is used to treat HSV keratoconjunctivitis?
trifluridine (viroptic -> ophthalmic application) - this is active against acyclovir resistant strains
What is the cheapest of the 3 HSV drugs and most preferred?
Acyclovir cheapest, but you have to admin more often. Can tx encephalitis with this too by IV - used b/c it has broader spectrum -> recommended for varicella or zoster in immunocompromised
Adverse effects of Valacyclovir
-reversible renal toxicity -neuro sxs: encephalopathic changes -> somnolence, hallucinations, confusion, coma -TTP/HUS: immunocompromised -GI, HA, rash, photosensitivity, elevated LFTs
dosing of Valacyclovir
varies with infection type/severity -1st episode of HSV: hit em’ hard -> 1000 mg PO bid x 7-10 days shingles: PO tid x 7 days
Valacyclovir safety
Pregnancy: B lactation: safe renal dosing: adjust for CrCl
Pharmokinetics of Valacyclovir
oral bioavailability: 55% -undergoes rapid and extensive 1st pass effect to yield acyclovir -food doesn’t affect absorption -renal excretion: >50% Half life: 2-3 hours Administration: oral
Pros and cons of Valacyclovir
Advantage: more convenient dosing, better oral bioavailability (55%) cons: more pricey than acyclovir
Valacyclovir (Valtrex)
Prodrug of acyclovir: rapidly and almost completely converted to a acyclovir, same MOA, same spectrum, same mechanism of resistance
Resistance to Famciclovir
- mutations in viral TK or DNA polymerase -cross resistance with acyclovir in TK negative strains -May still have activity in TK altered strains -resistance to HBV due to pt mutation (viral DNA polymerase)
Famciclovir adverse effects
-neutropenia -thrombocytopenia -neurological sxs: encephalopathic changes -> somnolence, hallucinations and delirium - GI sxs -HA, fatigue -abnormal LFT’s
Famciclovir uses
zoster (shingles), and genital and orolabial HSV (for 1st occurence, recurrence and suppression)
MOA of famciclovir
Similar to acyclovir -> inhibition of viral synthesis of DNA, uptake by infected cell and competes with deoxyguanosine triphosphate for viral DNA polymerases -> inactivates viral DNA polymerase -it is converted to penciclovir triphosphate and compared to acyclovir triphosphate, penciclovir 3xP has lower affinity for viral DNA polymerase but does have longer intracellular half life
Famciclovir safety
Pregnancy: B lactation: unknown, caution advised Renal dosing: adjust dose for CrCl
Spectrum of famciclovir
HSV 1 & 2, VZV, maybe in EBV - in vitro to HBV
What is the MOA of most anti-viral drugs?
many are purine or pyrimidine analogs. -Many are prodrugs: so they must be phosphorylated by viral or cellular enzymes in order to become active. - anti-viral agents inhibit active replication so the viral growth resumes after drug removal.
What must antiviral drugs do to be effective?
must either: - block viral entry into or exit from the cell - be active inside the host cell
Process of viral infection and replication?
- Absorption: binds to host cell 2. Penetration: virus injects genome into host cell 3.Viral genome replication: viral genome replicates using the host’s cellular machinery 4. Assembly: viral components and enzymes are produced and begin to assemble. 5. Maturation: viral components assemble and viruses fully develop. 6. Release: newly produced viruses are expelled from the host cell.
Where do viruses replicate in the host?
certain ones multiply in cytoplasm and others do so in the nucleus -most have to replicate so many times before they illicit symptoms in the host and before the dx is made.
What is a virus made of?
No cell wall, made up of nucleic acid components: -protein coat (capsid) -nucleic acid core, or genome -some have lipoprotein envelope -viruses containing envelope are antigenic in nature -Viruses are obligate intracellular parasites - Use host enzymes, don’t have metabolic machinery of their own.
Define tropism.
The predilection of viruses to infect some tissues and not others
What three factors are tropisms based on?
Susceptibility – receptor interactions Permissivity – ability to use the host cell to complete replication Accessibility – ability of the virus to reach the tissue
Describe the type of tropism exhibited by HIV.
GP120 on HIV interacts with CD4 on the T cell It attaches to co-receptors CCR5 and CXCR4
Describe the type of tropism exhibited by Measles.
Measles bind to SLAM on immune cells when they enter the host They bind to Nectin 4 on airway epithelia when the leave the host
Describe the type of tropism exhibited by Influenza.
Haemagglutinin on influenza binds to sialic acid to gain entry to the cell Sialic acid is ubiquitous so, in theory, influenza can infect all cells Once it’s in the endosome, the low endosomal pH allows a massive conformational change that is required for the virus to fuse with the endosome membrane and uncoat The cleaving of the protein of the virus is essential for the viral genome to gain access to the host cell genetic material So influenza can only infect cells that have the necessary proteases to cleave the protein The fluid that lines our lungs have these proteases present
How can influenza tropism be changed?
Influenza tropism is extended by mutation of the HA cleavage site The mutation could change the cleavage site meaning that more proteases, found in other parts of the body, can cleave the protein
At what point does Varicella-Zoster infection become symptomatic?
After the secondary viraemia
What is the classic triad of Rubella?
Eye Abnormalities (e.g. cataracts) Deafness Congenital Heart Disease
Describe the latency of Herpes simplex virus.
Herpes simplex virus can remain latent on nerve cells and then become activated in an attack of shingles The virus then moves end of the neurones and replicates through the skin (forming a cold sore)
Give four examples of oncogenic viruses and the types of cancer that they cause.
HHV8 – Kaposi Sarcoma HTLV-1 – Leukaemia Merkel Cell Polyoma Virus – Merkel Cell Polyoma HPV – Cervical Cancer
What type of cancer do Hepatitis B and C cause?
Hepatocellular Carcinoma
What types of cancer can Epstein-Barr Virus cause?
Burkitt’s Lymphoma Hodgkin’s Lymphoma Nasopharyngeal Carcinoma
Give an example of viral load affecting the outcome of an infection.
Second child in a household infected with chicken pox will have a worse infection because they’ll get a large dose from the first child
Give an example of co-infections affecting the outcome of an infection.
HHV8 can cause Kaposi Sarcoma in people who are infected with HIV and hence are immunocompromised Hepatitis Delta Virus only infects people with Hepatitis B
Give an example of genetic resistance to a viral disease.
Delta 32 mutation causes the formation of a different CCR5 receptor and so these people are naturally resistant to HIV
Define prophylaxis.
Preventing the diseases before the aetiological agent is acquired, by vaccination or giving the drug before infection
What are the four broad types of virus vaccines?
Live Attenuated Inactivated Purified Subunit Cloning
Describe each of the types of virus vaccines.
Live Attenuated – live virus has its virulence reduced and then is administered to the patient Inactivated – the virus is taken and its genome is destroyed so that it is still stimulates a response but can no longer be infectious – given with adjuvant Purified Subunits – the viral genome is taken and treated with proteases which chops it into small pieces. These subunits have antigens that can trigger an immune response. Cloning – viral genome is cloned in a bacterium and the copies of the genome are either: Injected into people Put into virus-like particles A new virus is made with a little segment of virulent material from the original virus
State what type of vaccine has been produced for each of these diseases:
Polio – inactivated + live attenuated Smallpox – live attenuated Rubella – live attenuated Hepatitis B – cloned subunit Influenza – inactivated + live attenuated HPV – cloned subunit
How are Live Attenuated Vaccines made?
The virus is passed through the wrong type/wrong species of cells this makes the virus evolve and change its virulence e.g. if a virus is passed through monkey cells then it will become a monkey virus and it will no longer be as virulent to humans
What are some differences between live attenuated vaccines and inactivated vaccines?
Live attenuated vaccines give rapid, broad, long-lived immunity, dose sparing Inactivated vaccines often require boosters, high doses needed, safe
What types of vaccines exist for influenza?
Purified subunit vaccine Live-attenuated (nasal spray)
What types of vaccines exist for polio?
SALK – inactivated SABINE – live attenuated
How are recombinant attenuated virus vaccines made?
The virulence gene is either mutated or deleted
What type of vaccine does rotavirus have?
Live attenuated reassortant
Give two examples of subunit vaccines.
HPV Hepatitis B Virus
What is the best available broad antiviral therapy and what are the limitations of it?
Interferons – it activates inflammation and fever and can make the patient feel even more ill
What are the two strategies for inhibiting influenza?
Blocking the M2 channel Neuraminidase inhibition
Describe inhibition of the M2 channel in influenza.
When endocytosed, influenza virus enters the endosome The low pH of the endosome opens the M2 channel allowing protons to move into the endosome and break the bonds holding together the protein capsid of influenza This allows influenza to uncoat and release its contents into the cytoplasm of the cell Adamantes (rimantadine and amanatadine) can fit in the M2 channel and prevent protons from moving in, thus meaning that the influenza is locked in its protein shell
Describe neuraminidase inhibition in influenza.
Neuraminidase is usually produced by influenza to destroy sialic acid on the surface of the host cell thus meaning that the virus doesn’t bind to the same cell again By blocking neuraminidase you can limit the spread of the virus to other cells
Give two examples of neuraminidase inhibitors.
Oseltamivir (Tamiflu) Zanamivir (Relenza)
Give eight examples of HIV drugs.
Zidovudine Stavudine Efavirenz Viramune Atazanavir Reltagravir Maraviroc
State two treatments for Hepatitis C.
Interferons Ribavirin
What is the leading infectious cause of death worldwide?
- HIV - it is a global pandemic - spreading most rapidly in Asia U.S. has > 1 mill infected, 25% unaware of infection - Resurgence in U.S. among MSM: blacks and hispanics
Mode of transmission of HIV
similar to Hep B - sexual, parenteral, and vertical (perinatal) Through body fluids: blood products, semen, vaginal fluids, and breast milk
relative risk per encounter
- *receptive anal intercourse: 1:30-1:100 - insertive anal intercourse: 1:1000 - Receptive vaginal intercourse: 1:1000 - insertive vaginal intercourse: 1: 10,000 - Receptive fellatio: 1:1000 -*Needlestick from known HIV + source: 1:300 -*IVDU sharing needles: 1:150 - Blood transfusion w/ HIV + blood: 95% - vertical spread: 25% - decreased use of safer sex practices among MSM causing increase in cases - increased use of meth among MSM coupled with unsafe practices shows resurgence in this group
How many people are living with HIV in Montana?
- 496 - 22 new cases of HIV since 2009
Where is AIDs spreading the fastest?
- spreading fastest in Asia - largest infection rate is in Africa
Why is there a new increase in number of HIV positive people in the U.S.?
- because infected are living longer due to HAART - sex practices among high risk groups are worsening again - % of new infections is growing fastest in females compared with males - Hispanics and Blacks in America are disproportionately affected: higher risk if IVDU higher risk of “closet” MSM behavior Poorest medical care and compliance with HAART more homeless and less support system
What is the difference between HIV and AIDs?
Both are the result of the retrovirus, HIV. When CD4 count gets to a certain low point it is considered AIDs , this usually takes an average of 10 years (w/o tx) to progress to AIDs. So they are just different phases of the disease.
What is HIV?
- Human Immunodeficiency Virus - retrovirus, RNA virus capable of infecting cells and with RNA transcriptase is capable of developing ds DNA that is identical to RNA -> rapidly produce viruses once in cell. - HIV invades the helper T cells to replicate itself - No cure
What is AIDs?
- Acquired Immunodeficiency syndrome - HIV is the virus that causes AIDs - disease limits the body’s ability to fight infection - A person with AIDs has a very weak immune system - No cure
increase likelihood of contracting HIV if you?
- sharing needles w/o sterilization -intercourse, oral, and anal - mother to baby: before birth -> rupture in the placenta (mixing of maternal and fetal blood), during birth and after birth (through breast milk)
Stage 1 of HIV (primary stage)
- short, flu-like illness, occurs 1-6 weeks after infection - no sxs at all - infected person can infect other people ( probably highest chance b/c of millions of viruses in blood during this phase)
Stage 2 of HIV
- asymptomatic - lasts for an avg of 10 years - may be swollen glands - level of HIV in blood drops to very low levels (b/c it is in the CD4 T cells, highest number of these are in the gut) - HIV abs are detectable in blood, ags may detectable too
Stage 3 of HIV - symptomatic
- sxs are mild - immune system deteriorates - emergence of opportunistic infections and cancers
Pathogenesis of HIV virus
- retrovirus affects CD4 T-cells, macrophages, and dendritic cells - reverse transcription of viral RNA genome into dsDNA occurs - imported into cell nucleus and integrated into cellular DNA - After entering the body, rapid viral replication up to several million virus particles/ml blood - this is accompanies by drop on CD4 T cells and activation of CD 8 T cells -> to kill HIV infected cells
What does HIV target?
- selectively targets CD4 helper T cells - also infects B cells and macrophages (infected macrophages will be impt in CNS sxs) - Acute infection results in over 10 billion HIV visions being produced/day - T cells become non-fxnl following infection therefore there is a qualitative defect in T cells which overshadows the simple quantitative defect - **the infection of B cells, T cells and macrophages results in a mixed immunodeficiency
What are the 3 mechanisms that will cause a clinical presentation of the syndrome?
- Immunodeficiency: direct result of immunosupression, spectrum of infections and neoplasms, very low incidence of certain infections seen in other causes of immunodeficiency (listeriosis, aspergillosis), higher incidence of other infections (Kaposi’s sarcoma) - Autoimmunity: lymphocytic infiltrate of organs (lymphocyte interstitial pneumonitis), auto production (immunologic thrombocytopenia) - Allergy/Hypersensitivity rxns: higher rates of allergic runs to unknown allergens (eosinophilic pustular folliculitis), increased rates of hypersensitivity to meds
HIV is a continuum, what are the 4 phases of it?
- primary HIV infection - asymptomatic infection - symptomatic infection - AIDs - the length and severity of each phase is dependent on host and virus-> use of antiretroviral therapy use of chemoprophylaxis for opportunistic infections generally: primary - 3-14 days, asymptomatic - 4-8 years, symptomatic - 4-8 years, AIDs os 2-20 years
Clinical presentation of primary infection
- brief, mono type of illness sxs: fever, sweats, lethargy, malaise, myalgias, arthralgias, HAs, photophobia, diarrhea, sore throat, lymphadenopathy, truncal maculopapular rash - sudden onset ( lasts 3-14 days) - more than 50% of HIV pts have sxs of primary infection - most common neuro sxs: are HA and photophobia - most commonly seen sx in all HIV pts is gen. lymphadenopathy
Clinical presentation of the asymptomatic phase
- longest of the 4 phases - most variable of the 4 phases - w/o tx, lasts 4-8 years - lack of overt evidence of HIV disease - only evidence is sero-positivity - pts can easily spread the disease w/o knowing b/c of being asymptomatic
Clinical presentation of symptomatic seropositivity (still HIV)
- onset ushers in 1st physical evidence of immune dysfunction - persistent gen. lymphadenopathy - localized fungal infections: toes, fingernails, mouth, women with recurrent vaginal candidiasis or trichomonal infections - oral hairy leukoplakia ( one of most commonly missed signs of HIV) is very prevalent - cutaneous manifestations include widespread warts, molluscum, psoriasis, and seborrheic dermatitis, multidermational zoster, and herpes simplex - night sweats, wt loss, and diarrhea
Clinical presentation of AIDS in general:
- PEs are often normal - abnormal physical findings may be non-specific - HIV/AIDs is a multi-system disease and therefore a complete H & P becomes very important - the official dx of AIDs reqrs a combo of factors based on WHO/CDC guidelines - Bottom line: Any “AIDS defining illness” regardless of CD4 count or other opportunistic infections with CD4 count less than 500 is dx - Generally best to look past effect on systems
Systemic clinical presentation of AIDS
- fever, night sweats, and wt loss - persistent fever w/o focal signs requires work up: blood cultures, chest X-ray, sinus imaging - WT loss: can be quite severe and is generally muscle mass loss. anorexia, nausea, vomiting and diarrhea add to wt loss - increased metabolic rate due to virus compounds the problem - growth hormone and anabolic steroids are used to try to get wt back and marijuana is used for nausea (or rx: dronabinol)
Pulmonary clincal presentation of AIDS
- pneumocystis pneumonia is the most common opportunistic infection seen in AIDs (people w/o AIDs don’t get this) - community acquired pneumonia is most common cause of pulmonary disease in HIV infected pt: bacterial, mycobacterial, and viral - TB occurs in 4% of HIV + people in US - non-infectious causes of lung disease: kaposi’s, non-Hodgkins lymphoma, interstitial pneumonitis - sinusitis: both acute and chronic
CNS clinical presentation of AIDS
-toxoplasmosis: most common space occupying lesion in HIV, focal near deficits, seizures, altered mental status, dx by CT or MRI -CNS lymphoma: 2nd most common space occupying lesion in HIV, imaging may be able to differentiate, may need brain bx - AIDs dementia complex: dx of exclusion based on brain imaging and CSF eval, difficulty w/ cognitive skills and diminished motor speed, sxs may wax and wane
CNS clinical presentation of AIDS continued……
- cryptococcal meningitis: fever and HA w/ less than 20% having meningismus, dx based on + latex agglutination of CSF, + latex agglutination (CRAG) of serum is + in 70-90% - HIV myelopathy: leg weakness and incontinence due to spinal cord impairment, spastic paresis and ataxia are seen on PE, dx of exclusion so need LP, and MRI - Progressive multifocal leukoencephalopathy (PML): viral infection of white matter of the brain, aphasia, hemiparesis, and cortical blindness
PNS clinical presentation of AIDS
- inflammatory demyelinating polyneuropathy: similar to Guillan-Barre - Transverse myelitis due to herpes zoster or CMV - Peripherial neuropathy common in many HIV pts: numbness, tingling, pain in LEs, ***may be drug induced due to some HAART drugs - CMV can cause an ascending polyradiculopathy: LE weakness, neutrophilic ploeocytosis in CSF with negative bacterial cultures
Rheumatologic manifestations in AIDS
- Arthritis is very common (may look like RA) single or mult. joints, w/ or w/o effusions, involvement of large joints most common - several inflammatory syndromes have been reported: Reiter’s syndrome, psoriatic arthritis, SICCA syndrome (dry eyes and mouth), SLE - Avascular necrosis of femoral head
Ocular manifestations of AIDS
- complaints of visual changes must be evaluated in +HIV pt - CMV retinitis: perivascular hemorrhages and white fluffy exudates, most common retinal infection in HIV and is rapidly progressive, need immediate referral to ophtho - Herpes infection common - toxoplasmosis is frequently recurrent
GI manifestations in AIDS
- candidal esophagitis: very common in HIV pts, suggestive sxs are treated and only non-responsive pts are given endoscopy - hepatic disease: autopsy shows liver is very frequent site for disease/neoplasms, many of these are subclinical, co-infection with Hep B and C is common, low-level hepatic disease may be cause for persistent N/V - Biliary Disease: acalculous cholecystitis with sclerosing cholangitis - Enterocolitis: very common in HIV pts, may be due directly to HIV macrophage infection, secondary causes include bacteria, viruses, and protozoans. More severe and chronic sxs than non-HIV pts, may present with high fever and severe abdominal pain. Need repeat stool cultures and stool for ova and parasites. If repeat stool studies negative, endoscopy is indicated. Sxs for > 1 month and no identifiable cause, presumptive for AIDS enteropathy
Skin manifestations in AIDS
- HSV infection: occur more frequently and tend to be more severe, due to risk of dissemination, all must be treated with oral medications - Herpes zoster: occur more frequently and tend to be more severe, due to risk of dissemination, all must be treated with oral meds - Molluscum contagiosum: tend to spread widely, doesn’t disseminate, tx with liquid nitrogen - Folliculitis/Furuncles: staph most common bacterial cause of skin infections in HIV pts, due to risk of dissemination, must tx aggressively. Always assume it is MRSA- tx accordingly - Bacillary angiomatosis: Bartonella henselae and Bartonella quintana, zoonotic infection from fleas of domesticated cats, raised, red, high vesicular lesions that can mimic Kaposi’s, fever is common with bone, lymph node and liver involvement (more flesh-violet colored)
HIV malignancies of AIDS
- Kaposi’s sarcoma: lesions may appear anywhere, careful exam of eyelids, conjunctiva, pinnae, palate and toe webs. Visceral disease will present in 40% of pts with skin lesions - Non-Hodgkin’s lymphoma: usually of B-cell origin and are large cell tumors ( kids -> Burkitt’s lymphoma), >70% are extra nodal, depending on advancement of disease and CD4 count, prognosis may be for only few months survival
GYN manifestations on AIDS
- recurrent vaginal candidiasis is very common - cervical dysplasia is present in >40% of women -> pap every 6 months - Cervical neoplasia much more aggressive in HIV+, most women die from cervical cancer, not HIV, cervical neoplasia is so common in HIV, added to CDC definition of AIDS in 1995 - PID: more common in HIV women, bacteria are same as those seen in non-HIV women
T cell activation: co–stimulation
- requires T cell binding to other surface receptors on an APC: dendritic cells and macrophages produce surface B7 proteins when innate defenses are mobilized, B7 binding with CD28 receptor on T cell is crucial co-stim signal, Cytokines: interleukin 1 and 2 from APC’s or T cells, trigger proliferation and differentiation of activated T cell w/o co-stimulation anergy (no rxn to AG) occurs: - T cells become tolerate to AG, are unable to divide, don’t secrete cytokines - T cels that are activated: enlarge, proliferate, and form clones, differentiate and perform functions according to their T cell class
When does primary T cell response peak?
- within a week - T cell apoptosis occurs b/t days 7 and 30 - effector activity wanes as amount of ag declines - benefits of apoptosis: activated T cells are a hazard - memory T cells remain and mediate secondary responses
Cytokines
- mediate cell development, differentiation, and responses in the immune system - include interleukins and interferons - IL-1 released by macrophages co-stimulates bound T cells - IL-2 is a key growth factor, acting on cells that release it and other T cells - Other cytokines and or cheekiness (CCR5) amplify and regulate innate and adaptive responses
Roles of Helper T cells
- play a central role in the adaptive immune response - once primed by APC presentation of AG, they: help activate T and B cells, induce T and B cell proliferation, activate macrophages and recruit other immune cells - w/o Th there is no immune response
Roles of Cytotoxic T cells
- directly attack and kill other cells - activated T c cells circulate in blood and lymph and lymphoid organs in search of body cells displaying AG they recognize - targets: virus-infected cells cells w/ intracellular bacteria or parasites cancer cells foreign cells (transfusion or transplants)
Natural killer cells
- recognize other signs of abnormality: lack of class 1 MHC AB coating a target cell different surface marker on stressed cells - Use the same key mechanisms as Tc cells for killing their target cells
Regulatory T cells
- dampen the immune response by direct contact or inhibitory cytokines - important in preventing autoimmune reactions
How long does it take for viral load to be positive on a PCR?
- 10 days the PCR will be positive for HIV RNA
Acute illness -> symptomatic disease
- often precedes positive ab test (15-25 days following the infection)
Eclipse phase of HIV infection
- time between infection and detectable HIV RNA (0-10 days following HIV transmission) - no serological or blood test that will tell you that you have HIV
What is the window period of HIV infection?
- time b/t infection and detectable HIV abs (25 days following HIV transmission)
stage 3 HIV infection (AIDS)
- lab confirmation of HIV and CD4 count
Stage 1 HIV infection
- laboratory confirmation of HIV and CD4 count >500 cells/mm3 or CD4% >29%
Stage 2 HIV infection
- lab confirmation of HIV and CD4 count 200-499 cells/mm3 or CD4% 14-28
How many people are living with HIV in the US?
-1.1 mill persons living with HIV in US - 2.7-3.9 mill persons living with HCV in US
During the past 10 years, what has happened regarding the number of persons living with HIV in the U.S.?
the number has increased.
Why has the number of people living with AIDS increased in the U.S.?
- because of HAART, antiretroviral drugs that help keep the CD4 count up and extend HIV pt lifespans.
What % of HIV infected persons are unaware of their HIV status?
- 21% (1/5 people that have HIV unaware) - this meds to an increased amount of HIV infections
What are the races/ethnicities that have the highest HIV rate in the US?
- Black and hispanics
Routine screening guidelines for HIV infection
- voluntary testing - permission from pt required - written consent shouldn’t be required - prevention counseling not required in conjunction with screening
Goals of routine HIV screening?
-HIV screening -> HIV dx -> link to care -> improve survival and quality of life and prevent new HIV infections
Compare a normal molluscum contagious finding and non-normal finding?
- normal: just see a couple, common in daycare children - not normal: way too many, growing on top of one another, or just out of control distribution
Other findings that may be normally seen in immunocompetent person but is out of control in HIV infected person?
- herpes simplex -> distal lesions -> ulcerate - seborrheic dermatitis - herpes zoster (shingles) -> see in a young pt or see hemorrhagic zoster, which covers 2-3 dermatomes - kaposi’s sarcoma (really only seen in AIDS -> see all over skin, and palate - oral hairy leukoplakia (not common in immunocompetent pts) - out of control oral candidiasis
What is considered the cut-off for a positive tb skin test in an HIV-infected persons?
- greater than 5 mm of induration - might be positive but doesn’t mean it is an active case of TB, could be latent
- Tx of latent TB?
- isoniazid x 9 months - pyridoxine x 9 months
Major indication of prophylaxis tx for pneumocystis pneumonia?
CD4 less than 200 or oropharyngeal candidiasis - tx: Bactrim
major indication of prophylaxis tx for Toxoplasma encephalitis?
- CD4 less than 100 and Toxoplasma IgG positive - tx: bactrim
major indication of prophylaxis tx for disseminated Mycobaterium avium complex?
- CD4 less than 50 cells tx: azithro
39 yo HIV pt presents with with 2 week hx of low grade fever, HA, and slight decline in mental status. CD4 count is 65 cells/mm3. What is this presentation consistent with?
- cryptococcal meningitis - shows no signs of focal abnormalities or dementia (slight decline in mental status, but no dementia - pt is 39)
What will be positive in crytococcal meningitis?
- CSF cryptococcal antigen: positive in > 95% of cryptococcal meningitis cases
Preferred tx of cryptococcal meningitis?
- Amphotericin B + Fluctyosine
What is true regarding CNS toxoplasmosis? 1. most patients have solitary lesion 2. w/ tx >75% improve by day 14 3. most have a CD4 count 200-300 cells/mm3 4. Preferred therapy is Dapsone+ azithro
- w/ tx >75% improve by day 14
Preferred acute therapy for Toxoplasma encephalitis?
- Pyrimethamine + Sulfadiazine+ Leucovorin
Preferred tx of Pneumocystis Pneumonia?
- if severe Bactrim IV - if mild-moderate oral Bactrim (100% bioavailable)
When would you give a pt with pneumocystis pneumonia corticosteroids?
if PO2 less than 70
What would you recommend as a tx for thrush?
- fluconazole
What would you do if a pt presents with IRIS after starting HIV meds?
- give steroids to decrease inflammation, don’t stop the HIV meds
What are the four indications for initiating antiretroviral therapy regardless of CD4 count?
- clinical AIDS - pregnancy - Chronic HBV - HIVAN - anyone infected with HIV should be tx with antiretroviral drugs
Should a woman with CD4 count of 470 and decreasing count and a boyfriend who is not infected with HIV start antiretroviral tx?
- yes she should, CD4 is decreasing and less chance of infecting boyfriend if viral load is low - recommended that tx start below 500 CD4
Why do you want to start therapy earlier than later?
- more effective regimens - more convenient regimens - better tolerated therapy - less long-term toxicity - better immune recovery - lower rates of resistance - more tx options - concerns for uncontrolled viremia - decrease HIV transmission
When should you initiate ART? at what CD4 count?
- strongly recommended for all CD4 counts
What does a protease inhibitor do?
- used to boost the effectiveness of other drugs - ritonavir
What is the backbone of ART?
- NUCs -> nucleoside reverse transcriptase inhibitor (truvada: combo of tenofovir/emtricitabine)
When should the viral load be undetectable during the ART regimen?
- within 12 -24 weeks, viral load should be undetectable - if it is still detectable think about patient compliance or drug resistance
when does the viral load increase during the HIV infection?
- typically increases sharply after initial HIV infection, often reaching levels of 10s of millions, thereafter (4-8 weeks) the viral load typically settles into a lower level that remains relatively constant over the next several years. This level is called the baseline viral load, and it correlates with progression of disease, in general the higher the viral load, the faster CD4 cells are destroyed and the faster the patient will progress to AIDS. Also common to see baseline viral load increase to higher levels in end-stage disease
What is a signature sign of PCP?
- bat wings on CXR
What is norwegian scabies?
- plaque like lesions that will flourish in a person who is immunocompromised (HIV/AIDS)
How may international travel upset a person’s equilibrium making them susceptible to disease?
- sudden exposure to sig changes in altitude, humidity, microbial flora, sunlight, and temperature, exacerbated by stress and fatigue, may result in ill-health and an inability to achieve purpose of travel
What are key factors determining health risks to which travelers may be exposed?
- destinations - duration of visit - purpose of visit - std of accommodation and food hygiene - behavior of traveler
What are some pre-trop recommendations?
- basic medical kit - analgesics (acetaminophenm aspirin, ibuprofen) - abx for self-tx of diarrhea (chipper, azithro) - anti-diarrheals: bismuth subsalicylate (pepto), loperamide (imodium) - antihistamines - antimalarials - antinausea/motion sickness (benedryl, dramamine) meds - sleeping meds - insect repellent - water purifier or tablets - cold/sinus/cough med - sunscreen - wound dressings - antiseptic
Pre-travel consultation with pt?
- risk assessment: itinerary traveler demographics, emphasis on not traveling while sick - discussion with pt: vaccinations, prophylaxis, specific advice about self tx (traveler’s diarrhea), pre-tx of chronic health issues
Medical planning: determine destination?
- investigate specific risks associated with that region - ID travel clinic that can acquire specific vaccines read
What enivironmental precautions should you be aware of?
-air travel - jet lag (melatonin) - sun protection - extreme heat and cold: dehydration, heat stroke, hypothermia, frostbite - altitude - water recreation
Food and water precautions?
- bottled water!!! - selection of foods: well cooked and hot - avoid: salads, raw veggies, unpasteurized dairy products, street vendors, ice
Pre-existing health status concerns?
Flying: CVD: less than 3 weeks post MI, longer “wait” following complicated courses, 2 weeks post CABG pulmonary disease: 2-3 weeks post chest tube removal, PaO2:
What vaccines should be up to date?
- polio - Hep A and B - meningococcal - influenza - tetanus, diptheria, pertusis - MMR - Varicella
Vaccines you may need?
- Typhoid - yellow fever - rabies - japanese Encephalitis - cholera - tick-borne encephalitis - TB
When should you have Hep A vaccine?
endemic areas- Asia, central America, Africa, Mexico, caribbean
Motion sickness prophylaxis?
-meclizine -promethazine (need Rx) -Transdermal scopolamine (Rx) - most must be taken before trip - prometh. works after sxs start - drowsiness can be sig
Why does jet lag occur?
- disturbance of circadian rhythms due to crossing time barriers - sxs: fatigue, irritability, nausea, difficulty concentrating
Destination altitude sickness sxs?
- HA and one or more of the following: - nausea - vomiting - fatigue - malaise - insomnia - due to relative hypoxemia and delay in development of compensatory erythrocytosis
Acute mountain sickness?
- usually acclimatization occurs in 2-3 days - 30% incidence at 3000 M, 75% at 4500 M
Prevention of altitude sickness?
- gradual ascent - 300 M/day - spend a few days at intermediate altitudes - slowly ascend at > 2500 m - spend an extra night for every 600-900 m if continuing to ascend, climb high and sleep low - avoid alcohol and sedative hypnotics
High altitude pulmonary edema (HAPE)
- combo of low hypoxic ventilatory drive and over perfusion - young physically fit males most susceptible sxs: weakness, decreased exercise performance, chest congestion, dyspnea, wheezing signs: wheezing, crackles (rales), cyanosis, tachycardia - must have 2 signs and 2 sxs for dx
TX of HAPE?
- Rx: Diamox aka - acetazolamide: mild diuretic that increases amount of excreted bicarb, which in turn increases the blood pH which in turn causes you to hyperventilate which increases O2 saturation. - steroids: dexamethasone - Nifedipine: decreases pulmonary hypertension, improves oxygen saturations
High altitude cerebral edema (HACE) signs and sxs?
- Hallucinations - focal near signs - seizures - stupor - coma - MEDICAL emergency: pts need high flow O2 and prompt descent to lower altitude - dexamethasone to reduce edema - can have HACE and HAPE simultaneously
What are you worried about with snorkeling and diving?
- stings and envenomization - coelenterate family: sea urchins, jellyfish, anemones, portuguese man-o-war - release nematocysts from tentacles - tx with vinegar
Tx for sea bathers eruption (sea lice)
- papulovesicular rash caused by larvae of coelenterates Rx: shower, soak affected part in vinegar, throw away bathing suit, more susceptible after initial infestation: future infestations can cause severe allergic rxns
Where can you get cholera?
- 0-5 cases per year in US, major cause of epidemic diarrhea throughout the developing world. Its an ongoing global pandemic in Asia, Africa, and Latin America for the last four decades
Sign of cholera?
- rice water diarrhea - vomiting, circulatory collapse and shock. Many infections may only have milder diarrhea or be asymptomatic - prognosis: 5-50% typical cases are fatal if untx
Prevention of cholera?
routine immunization isn’t recommended for conventional travelers from US, although vaccination is approp. for aid and refugee workers to endemic areas in high risk situations
Prevention/tx of cholera?
- natural infection and currently available vaccines offer incomplete protection of relatively short duration, no multivalent vaccines available - simple rehydration tx saves lives, but logistics of delivery in remote areas remains difficult during epidemic periods - adjunct abx tx is helpful but may be difficult b/c of growing antimicrobial resistance - natural reservoir in warm coastal waters makes eradication very unlikely
Locations of Hepatitis A and B
- worldwide: can be isolated cases or epidemic - 1.25 million chronic Hep B infections in US
Signs of Hepatitis?
- jaundice, fatigue, abdominal pain, loss of appetite, nausea, vomiting, joint pain, 30% asymptomatic
Tx of Hep B?
- Adefovir, dipivoxil, interferons, lamivudine, entecavir, and telbivudine used for tx of chronic Hep B - new txs: high cure rates -> Harvoni
Typhoid?
infection with salmonella typhi - 16 mill cases & 600K deaths/year - mainly in undeveloped countries with contaminated water supplies
sxs and tx of typhoid?
- high fever - rose colored rash******* - abdominal pains - diarrhea -tx: ampicillin, SMX/TMP, cipro
locations of typhoid?
- greatest risk for travelers to S. Asia, developing countries in Asia, Africa, Caribbean, and Central and S. America (approx. 400 cases occur in US/ year 75% international travel)
Signs of typhoid?
high fever 103-104 - HA, malaise, anorexia, splenomegaly, rash of flat rose-colored spots and bradycardia - many mild and atypical infections occur
Prognosis of Typhoid
- life threatening if left untx
Tx/prevention of typhoid?
- vaccination recommended for those who will be traveling in rural areas - travelers should be cautioned that none of avail. vaccines are 100% effective (not a sub. for careful selection of food and drink) - specific antimicrobrial therapy shortens clinical course and reduces risk of death.
How is typhoid spread?
- lives only in humans in intestinal tract and blood - spread oral/fecal route: raw fruits and veggies, milk and shellfish - small number of carriers: both ill and carriers can shed bacteria in their stool
Typhoid vaccines?
- injectable: contains inactivated polysaccharide ag (given as single IM injection, single dose is adequate) - oral: live virus -> one enteric coated capsule in four doses
How long does immunity last with typhoid vaccine?
- IM: 2 years - oral: 5 years, after 5 years get a booster
CIS and precautions of Typhoid vaccine?
- severe allergic reaction to vaccine component or following a prior dose - immunosuppression - moderate or severe acute illness: acute GI illness - pregnancy - age
Yellow Fever
- acute viral hemorrhagic disease - RNA virus in the Flavivridae family - transmitted by mosquitoes - found in Africa, S. American with several epidemics in the 19th century - 200,000 estimated cases of yellow fever/year - 90% of infections occur in Africa
Signs of Yellow Fever
- infection ranges from asymptomatic (5-50% of cases) to hemorrhagic fever - onset is Sudden with fever 39-40 C. Chills, HA, dizziness, and myalgias - Pulse first tachycardic - gets bradycardic (facets sign*****) - face will be flushed and eyes will be injected, N/V, constipation, severe prostration, restlessness, irritability are common.
Clinical features of Yellow Fever
- incubation period: 3-6 days - 85% of cases will have only midl sxs including: fever, HA, chills, back pain, N/V, loss of appetite - 15% will enter a second, toxic phase with recurring fever accompanied by other sxs - toxic phase is fatal in approx 20-50% of cases - surviving the infection results in life-long immunity and normally there is no permanent organ damage
Tx of Yellow fever?
- up to 20% mortality - tx mainly supportive - bleeding may be tx with Ca gluconate. Prophylaxis against GI bleeding with a proton pump inhibitor or H2 blocker - prevention: reduce number of mosquitoes and limit mosquito bites by using DEET mosquito netting and protective attire
Yellow Fever vaccine recommendations?
- attenuated live vaccine - single dose is adequate - lasts 10 years - recommended for pts traveling to affected areas over age of 9 months, people living in endemic areas b/t 9-12 months, lab personnel who might be exposed to virus or vaccine virus - bed netting, mosquito repellant recommended SEs of vaccine: HAs, fever, myalgias
CIs and precautions for Yellow Fever vaccine?
- immunosuppression - thymic disorders - age
Malaria?
- parasitic infection transmitted by mosquitoes: Plasmodium falciparum, P. Vivax, P. ovale, P. malariae - > 1 mill deaths/year - transmitted by anopheles mosquito
signs of malaria?
fever, chills, sweats, HAs, muscle pains, N/V, severe malaria caused by P. falciparum - confusion, coma, neuro focal signs, severe anemia, resp. difficulties, dx by direct visualization and Ag detection
Prophylaxis for malaria?
- bed nets tx with permethrin, insecticides, and antimalarial drugs: Atovaquone/proguanil (malarone), cholorquine (some strains resistant), doxy (works well), Mefloquine (Larium): cause hallucinations
Clinical manifestations of Malaria?
- cyclic fevers - anemia: erythrocyte destruction - hepatosplenomegaly - capillary occlusion - intravascular hemolysis (blackwater fever) - dormant sporozoites.. recurrent lapses
Dx of malaria?
- thick/thin smears - serologic tests
Tx of malaria?
- Atovaguone/proguanil (Malarone) - Artemether/Lumefantrine (coartem)
What is schistosomiasis?
- 200 million worldwide infected - parasitic infection caused by trematodes (parasitic freshwater worms that live in snails)
Clinical picture of schistosomiasis?
- dermatitis - katayama syndrome: fatigue, malaise, fever, cough, hepatosplenomegaly - clinical manifestations may not show up for several weeks post exposure - chronic infection can cause CNS disease, colon polyps, bloody diarrhea
Dx of schistosomiasis?
- thick stool smears reveal eggs - eosinophilia on peripheral blood smear - serologic testing- IFA available
Tx of schistosomiasis
- praziquantel-quinolone - oxaminiquine
Fish (scrombroid) poisoning
- scrombroidea family: tuna, mackerel, albacore - poor fish preservation causes decarboxylization of histidine to histamine - illness begins 90 min and lasts for up to 12 hrs after ingestion - flushing, tachycardia, N/V
Tx of Fish (scombroid) poisoning
supportive care, antihistamines, epi
non scrombroidea fish poisoning
- mainly in caribbean - ciguatera poisoning from fish that have ingested dinoflagellates - competitive inhibitors of Ca channels - sxs occur w/in 24 hours: Gi- nausea, vomiting, diarrhea neuro paresthesias: pruritus, tremors, fascicultations - ***temp reversal burning of skin exposed to cold is classic sx
Shellfish poisoning?
- caused by saxitoxin after algae blooms - incubation hours to days - dx made when 2 sensroy and 2 motor sxs are found in pts with approp. hx: sensory - numbness, dizziness, paresthesia, HA, dysethesia, pruritus motor dysphagia: paralysis, paresis, dyspnea, diplopia, dysphonia - mortality rate: 2-20%
What is the biggest risk for travelers?
- travelers diarrhea
Traveler’s diarrhea?
- can be from parasites or other organisms - most commonly from diff. strains of E. coli - prevention and tx: Pepto bismol loperamide cipro azithro
Epidemiology of Travelers’ diarrhea
bacterial: 80-90% viral: 5-10% parasitic: >/10%
Signs of travelers’ diarrhea?
- onset usually w/in first week - abrupt with increasing frequency and volume of stool - 4-5 loose stools/day: also N/V, abdominal cramping, bloating, fever, urgency, malaise - most resolve 1-2 days w/o tx
Cause of travelers diarrhea and what to avoid?
- bacterial enteropathogens: E. coli prevention/avoid: street vendor foods/drinks, raw/undercooked meats, raw fruits and veggies
Prophylaxis for travelers’ diarrhea?
- bismuth subsalicylate (pepto) antibacterial and antisecretory
Tx of travelers’ diarrhea?
- replacement fluids/electrolytes: mostly clear fluids - antibiotics: N/V, cramping, bloody stools, fever - anti motility agents - loperamide (imodium): not for blood stool!!!! Reduces duration of diarrhea
rabies?
- caused by the rabies virus: almost always fatal - RNA virus: part of Rhabdoviruses - virus is transmitted through a bite or scratch from an infected animal. These are the most common species: raccoons, skunks, foxes, coyotes, bats
What country has the most rabies cases?
India has about half of all rabies cases worldwide
clinical features of rabies?
- prodrome: HA, fever, rhinorrhea, sore throat, myalgias, GI upset, back pain, and muscle spasms - agitation and anxiety may result in dx of psychosis or intoxication - paresthesias, pain or severe itching at site may be first near sx - over several days symptoms progress
Two forms of rabies?
- furious/encephalitic forms: agitation, hydrophobia, extreme irritability, hyperexcitability periods fluctuate with lucidity: pt will exhibit: tachycardia, tachypnea, fever - dumb or paralytic rabies: similar to Guillain-Barre - prominent limb weakness. Consciousness initially spared the 2 forms can overlap or progress from one to the other - coma after one week of neuro sxs with death a few days after
Rabies vaccine:
inactivated vaccine, pre-exposure vaccine should be offered to people in high risk groups (anyone who is likely to come in contact with rabid animals - immediate access to approp. medical care is limited
Post-exposure vaccine is recommended for who?
- all individuals who have had contact with animal (bites or abrasions) that they believe may be or which is proven to be rabid - unvaccinated: 4-5 doses in 2-4 weeks + RIG - vaccinated: 2 doses, no rabies immunoglobulin
Rabies vaccine CIs and precautions
- hypersensitivity - moderate or severe acute illness - immunocompromised and pregnant women who are exposed to rabies may receive vaccine
What is Japanese encephalitis?
- mosquito borne flavivirus - most common vaccine preventable cause of encephalitis in Asia - RNA virus - 35,000-50,000 cases annually (less than 1 case / year in US)
Clinical features of JE
- incubation period: 6-8 days - most asymptomatic or mild signs - acute encephalitis: HA, high fever, stiff neck, stupor -severe encephalitis: paralysis, seizures, convulsions, coma and death Neuropsychiatric sequelae: 45-70% of survivors - in utero infection possible: abortion of fetus
JE vaccine
- inactivated Vero Cell Culture - derived vaccine - recommended for those at increased risk such as: lab workers, travelers spending more than one month in endemic/epidemic areas during transmission season - 2 doses (days 0, 28)
TB
caused by bacteria Mycobacterium tb - 2 types of infection: active or latent - respiratory transmission: it is currently estimated that 1/3 of world pop is infected with TB (doesn’t mean it is active) - with increased incidence of AIDS, TB #s have increased in US
Clinical features of TB
- cough, hemoptysis - persistent fever/night sweats - wt loss - malaise - adenopathy - pleuritic chest pain
Complications with TB
- w/o tx may be fatal. Untx active disease typically affects the lungs but it can spread to other parts of body causing: pneumothorax bronchiectasis cardiac aneurysms meningitis renal failure
TB vaccine
- BCG live strain - lasts 10 years - given intradermally
Who should receive the TB vaccine?
- newborns and health care workers in countries where TB prevalence is moderate to high, close contacts of pts with TB - in countries where prevalence is low, not recommended that health care workers get vaccine unless in close contact with pts from endemic countries
TB vaccine CIs and precautions
- hypersensitivity - moderate or severe acute illness - immunosuppression - pregnancy is CI - local skin reactions are common
Summary of recommendations for traveling
- follow recommendations for destination - begin vaccinations early - find travel clinic for immunizations - plan ahead if you are traveling with children or have other special needs or chronic illnesses
