Week 14 Flashcards
What is the malignant species that causes malaria?
Plasmodium falciparum
Name three benign plasmodium species.
Pl. Vivax
Pl. ovale
Pl. malariae
What species of mosquito is malaria typically spread by (pl. falciparum)?
Anopheles species
True or false… there is an increasing trend for malaria in the unites states since 1973
True
What are some symptoms of cerebral malaria?
Seizures
Acidosis
Anemia (coma with eyes open, may lead to heart failure)
Skin becomes lighter
What four groups of people are at risk for death if they get malaria?
Children 6mo to 6 years
Non-immune adults
Pregnancy - especially primigravida
Emigrants returning from home visits
Severe Malaria rarely occurs in what groups of people?
Sickle cell trait (heterozygous)
People from endemic areas (become immune)
Note that these people can still get malaria, just not severe malaria
Describe the life cycle of plasmodium falciparum
Parasite develops in mosquitos. The sporozoites are released into the mosquito saliva. Mosquito bites a human host. Sporozoites enter the blood and in the liver. Note that there is no latent stage in the liver, here they are called hypnozoites. When they infect RBCs they are called merozoites. The life cycle in the RBCs is called shizogany
Describe shizogany. The life cycle of pl. falciparum in the RBCs.
Ring trophozoites
Rings with Maurer’s clefts
Rings: appliqué forms
Maturing trophozoites
Shizont (early stage)
Mature shizont (looks like a RBC filled with stuff)
Where are the mature shizonts located?
Adhered to the microvessels of the brain. (Cytoadhesion)
Explain why malaria shizonts are sequestered to the microvasculature of the brain
Malaria parasite secrete a complex of proteins that incorporate into the membrane of RBCs called ‘knobs’ pf-EMP-1 is expressed through the membrane so it is in contact with the plasma. This will bind to receptors of endothelial cells in the brain.
What is opisthotonos?
This is a hyperextended position the body takes due to severe cerebral malaria because of its effect on the CNS
What are the benefits to the parasite of sequestration?
Evades splenic clearance - free intravasculature replication
Post capillary venue blood ph is low which favors replication
Post capillary venue pco2 is high which also favors replication
The parasite infects RBCs of any age.
All lead to enormous parasite mass in severe malaria
What is the three pronged approach for combating malaria?
Incesticide impregnated bed nets
Residual insecticide spraying
Preimptive treatment with ACT (artemisinin based combination therapy
True or false… bacteremia with septic shock results in multiple organ failure, whereas malaria results in selective organ pathology
True
What are some ways to prevent malaria?
Prophylaxis with anti-malarials
Mosquito repellent
Permethrin-impregnated bed nets
Permethrin-treated clothing
What is the difference between antigenic drift and antigenic shifts?
Antigenic drift - antigens involve a few mutations that reduces the hosts immune system’s ability to recognize the virus
Antigenic shifts - drastic changes to the antigen via mutation that frequently results in viral resistance, leading to epidemics
Describe how Antivirals for DNA-encoded viruses, like Herpes virus, work
They inhibit viral transcription via inhibiton of DNA polymerase
How do Antivirals for RNA-encoded viruses, like rhinoviruses, work?
Inhibitors of viral uncoating (M2 protein )
HSV-1 typically resides in the ___ ganglion. HSV-2 typically resides in the ___ ganglion
Trigeminal
Sacral
Name the following…
HSV-1 HSV-2 HHV-3 HHV-4 HHV-5
Herpes simplex 1 (oral herpes)
Herpes simplex 2 (genital herpes)
HHV-3 also known as VSV (varicella zoster virus (chicken pox))
HHV-4 - EBV (Epstein Barr virus)
HHV-5 - CMV (cytomegalovirus)
What are some triggers that can cause latent herpes infections to become active?
Stress, fatigue, sun, surgery, fever, menstrual periods, immunocompromised
What is immunosenescence?
Age-related decline in immune function
Name four antiviral drugs for HSV and/or VSV
Acyclovir
Valacyclovir
Penicyclovir
Famcyclovir
Acyclovir is 10x more potent against ___ than ____. It is typically inexpensive. It can be administered oral, IV, or topical
HSV-1 or HSV-2
VZV
What is valacyclovir?
It is administer orally only but then is converted in the body to acyclovir to levels that are 3-5x greater than oral acyclovir
Which antiviral drug for HSV is administered topically only?
Penicyclovir
Which drug is administered orally only but is metabolized into penicyclovir? It is mainly used for VZV
Famcyclovir.
Patients must always hydrate well while on any -cyclovir drug to avoid ____
Crystalline nephropathy (damage to kidneys)
Name two drugs that are used to trear HSV and or CMV infections
Gamcyclovir
Foscarnet
Gancyclovir is used for prophylaxis or treatment of ___ or ___
CMV
HHV-6
What are some contraindications or adverse effects of gancyclovir?
Contraindicated during pregnancy and in males (shrinks testes 😵)
Due to its high risk of cytotoxicity, it must be administer in a clinical setting and monitored closely
True or false…. both gancyclovir and foscarnet can only be administered via IV
True
Foscarnet is used to treat…
CMV and viral induced retinitis in immunocompromised patients.
Useful in acyclovir or gancyclovir resistant HSV or CMV infections
Note that this drug is much safer than gancyclovir although it has possible nephrotoxic effects
What is the method of action for Foscarnet?
Selectively inhibits viral DNA polymerase enzymes (not kinases)
The cyclovir drugs depend on___. Why is this an issue?
Viral enzymes.
Herpes simplex uses thymadine kinase and DNA polymerase
This is an issue because these enzymes can mutate
What is the method of action of oseltamivir? Is it active against influenza A, B, or both? Why is early administration crucial?
Neuroaminidase inhibitor. Prevents cleavage of cell receptor keeping virus particle bound to host
***active against both influenza A and B
Early administration is crucial because replication peaks at 24-72 hours after the onset of illness. (When a 5 day course of treatment is initiated within 2 days of onset, the duration of flu symptoms are decreased by up to 1-2 days
note that there may be a disulfuram like reaction
What is the mechanism of zanamivir? What is its clinical use? How is it administered? What are its contraindications?
It is a neuraminidase inhibitor
Clinical use: treatment and prophylaxis of influenza A and B
Administer via inhaler only
Contraindications: sever asthma, COPD, severe allergies to milk proteins
What is the mechanism of amantadine? Is it used to treat influenza A, B, or both? Contraindications/adverse effects?
Antiviral: interferes with viral M2 protein and thus blocks the uncoating in the host (not used anymore cause it has 100% resistance)
Anti Parkinson’s disease: a weak antagonist of the NMDA receptor, increases dopamine release and prevents its reuptake
Only active against influenza A!!!
Contraindications: patients with renal impairment, epilepsy, pregnancy, glaucoma
Adverse effects: ataxia, dizziness, anxiety, slurred speech
Th17 cells release ___ and ___ which induces the epithelial cells to produce ___
IL-17
IL-22
Antimicrobial peptides
What are the three purposes of antimicrobial peptides?
Destroy pathogens
Select commensal communities
Initiate inflammation
What does cathelicidin do?
Disrupts membranes of bacteria. Additional toxic effects intracellularly. Kill cells and disable viruses
Barriers are sites of ongoing innate and adaptive immunity. ___, ___, and ___ monitor tissue health
Macrophages
Dendritic cells
Gamma-delta T cells
What are some things that granulocytes release?
Elastase
Histamine
Proteases
Antimicrobial peptides
Etc.
-Note that they do not release perforin or granzyme
How long does it take a single lymphocyte to completely circulate?
~24 hours
Macrophages promote an inflammatory response. List 5 cytokines they release to promote inflammation and briefly describe what they do.
IL-1b: activates vasculature, tissue destruction to allow access of effector cells
TNF-a: activates vasculature (permeability)
IL-6: induces acute-phase protein production in liver. Increase antibody production
CXCL8: attracts neutrophils, basophils, T cells
IL-12: activates NK cells. Induces differentiation of CD4 cells to Th1
Which cytokine stimulates the liver’s acute phase response? What are some proteins produced in this phase?
IL-6
C-reactive protein
Mannose binding lectins
Serum amyloid protein
What are the three killing mechanisms of neutrophils?
Phagocytosis
Degranulation
Nets
After the establishment of a viral infection the cells produce interferons. Which attacks first, NK cells or CD8 T cells?
Typically, NK cells kill first, then CD8 T cells
What are the three effects of interferons?
Induce resistance to viral replication in all cells
Increase expression of ligands for receptors on NK cells
Activate NK cells to kill virus-infected cells
Name the three classical APCs. Name one other APC
Dendritic cells
Macrophages
B cells
Gamma-delta T cells can also be APCs
When the cognate pair first moves to the primary focus, proliferation of ___ secreting plasma cells occurs driven by interleukins ___ and ___
IgM
IL-5
IL-6
When the cognate pair moves to the secondary focus, B cells rapidly divide every 6 hours to form ___ and ___ driven by ___, ___, and ___
Centroblasts
Germinal centers
IL-6
IL-15
BAFF
What four interleukins do Th17 cells release? What is the overall function?
IL-17
IL-21
IL-22
IL-26
enhance the neutrophil response to fungal and extracellular bacterial infections
What five cytokines are released by Th1 cells? What is the overall function?
IFN-gamma GM-CSF TNF-a LT IL-2
Help macrophages to suppress intracellular infections
What five cytokines do Th2 cells release? What is the overall function?
IL-4 IL-5 IL-10 IL-13 TGF-beta
Help basophils, mast cells, eosinophils, and B cells respond to parasite infections
What three cytokines do TFH cells release? What is the overall function?
IL-21
IL-4
IFN-gamma
Help B cells become activated, switch isotype, and increase antibody affinity
What three cytokines do Treg cells release? What is the overall function?
TGF-beta
IL-10
IL-35
Suppress the activities of other effector T cell populations
Immune responses resolve and tissue is repaired by what four ways?
Reduction in proinflammatory cytokines
Increase in anti-inflammatory cytokines
Treg cell signaling and development
T cell CTLA4 expression
True or false… inhibiton of peripheral Th17 cells by IL-4 or IFN-gamma induces Treg cell development
True
___ and ___ act to inhibit activation and growth of Th1 cells
TGF-beta
IL-10
____ acts on Th2 cells to inhibit proliferation
IFN-gamma
What are the differences in the presentations of acute hepatitis vs. chronic hepatitis?
Acute: incubation = several weeks. Flu-like symptoms. Jaundice, enlarged, painful liver. Resolves spontaneously
Chronic: *often asymptomatic. Physical exam can show problems with liver. Persists for years/decades
Out of HepA, B, C, and E, which cause acute or chronic hepatitis?
A and E cause acute hepatitis
B can cause both
C causes chronic
What type of a virus is hepatitis A? How is it trasmitted? What is its incubation period?
Non-enveloped ssRNA virus
Transmission = fecal-oral route
Incubation period = 28 days
Incidence of HepA in children in developing countries reaches ___%. Footborne Hep A outbreaks are commonly related to…
100
Overcrowding
Poor sanitation
Polluted water sources
What is the most common cause of acute hepatitis? What are its risk factors?
Hepatitis A
No known risk factors
Shedding of Hep A occurs ___prior to acute hepatitis and ___ after onset of jaundice
1-3 weeks
1 week
True or false.. in regards to Hep A, most children have symptoms while most adults are asymptomatic
False. Its the opposite. Most adults have symptoms while 70% of children are asymptomatic
True or false… Hep A is a self-limited illness with rare complications. Once you’ve had Hep A and recovered, it usually 100% cleared.
True
True or false… the hepatitis A vaccine is really effective
True. Everyone should get vaccinated
What kind of a virus is Hep E? How is it transmitted? How are its clinical presentations different from Hep A? What is its incubation time?
Non-enveloped ssRNA
Spread via fecal-oral route (fecal contamination of water) person to person spread is rare
Acute hepatitis is clinically indistinguishable from Hep A
Incubation = 40 days
What is the smallest DNA virus that infects humans?
Hep B
What kind of a virus is Hep B? What are some things it’s genome codes for?
Enveloped DNA virus. DsDNA/ssDNA
Compact, overlapping reading frames produce..
HBsAg (surface antigen)
HBcAg (core nucelocapsid protein)
DNA pol
HBxAg (no known function)
What is the most common blood-borne virus in a hospital setting? Describe the rule of 3s.
HepB
If you are not vaccinated and get pricked by a patient who has the virus, you have a 30% chance of getting HBV, 3% chance for HCV, and 0.3% for HIV
Describe the ways hepatitis B is transmitted
Perinatal: infants who are born to mothers who have HBV are 90% likely to get it (if mother is HBeAg+). However the neonatal vaccine has 95% efficacy
Parenteral: most common blood-borne virus in health care settings
Sexual: most common mode of transmission in low-prevalence areas
What is the most common mode of transmission of HBV in low-prevalence areas?
Sexual
___% of newly infected adults will have acute hepatitis from Hep B
30
True or false.. perinatal/childhood primary infections of hepB is asymptomatic
True
The rate of progression to chronic hepatitis B ____ correlates with age
Inversely
True or false… chronic HepB always results in severe symptoms
False. It is a broad spectrum of illness form asymptomatic to cirrhosis and liver cancer
True or false… men are more likely to have acute flares of hepB when they have chronic HepB. Also alcohol consumption worsens it
True
What are some lab predictors of poor outcomes of chronic hepB?
HBeAg positivity (means the virus is replicating a lot)
HBV serum DNA level (>2000 IU/mL)
High titer HBsAg
Necrosis-inflammation on liver biopsy
Describe how HBV surface antigen is used to diagnosis HepB
HBsAg, if persistent for > 6mo, its a chronic infection
Clearance of HBsAg followed by development of anti-HBs confers life-long immunity
HBsAg positive indicates you have HepB. anti-HBs indicates you have had it in the past but are over it. HBsAg and anti-HBs indicate chronic
Other than HBV surface antigen, what is other ways to diagnose HepB?
HBV core antigen (HBcAg) (Note-however that this is intracellular and never detected in serum)
HBV e antigen (HBeAg is a marker of replication and infectivity)
HBV serum DNA PCR
In regards to HBV what is the first antigen our immune system sees and produces antibodies for?
surface antigen (HBsAg)
What is the treatment for HepB?
Two types of Antivirals: IFN and nucleoside analogs
Tenofovir and entecavir are first lines of defense in US
When should you treat HepB?
When there is HBV DNA > 20,000 (HBeAg+) or >2,000 HBeAg-)
AND
Disease
True or false.. there is a vaccine for HepB and everyone should be vaccinated
True
What kind of a virus is HepD? What is special about this virus?
Defective ssRNA
It is a passenger virus accompanying HBV
It infects 10% of those with HBV
What do simultaneous infections with HBV and HDV look like?
Looks like HBV alone
How do you diagnose and manage HepD?
Diagnosis: PCR or anti-HDAg IgM/IgD
Management: IFN-a is the only approved treatment (low success rate)
What kind of a virus is HepC? How is it transmitted?
Enveloped RNA virus in Flavivirus family (related to yellow fever, dengue west Nile.
Blood borne transmission
There are ___major genotypes of HCV worldwide. genotype #___ is most prevalent in the US
6
1a
What are the two tests available for HepC diagnosis? How do you interpret these?
HCV antibody:
Negative HCV ab = no infection
Positive HCV ab = past or present infection, need to check for virus
HCV RNA:
Positive = active infection
Negative = cleared infection
Who should be tested for HepC?
Everyone born between 1945 and 1965
IV drug users
Transfusion recipients
HIV infection
Etc.
What are some things you do to manage HepC?
Always test for HIV and HepB
Determine genotype (important for drug selection)
Evaluate for liver damage
What are the treatment guidelines for HpepC?
They are continually updated
Antivirals for HCV polymerase and protease
What is the worldwide prevalence of TB (latent and active)
33%
More than 2 billion people worldwide
2nd most common infectious cause of death in adults worldwide
Mycobacteria have cell membranes composed of ___ which makes it acid fast. Doubling time in culture is about every ~___hours, which is slow
Mycolic acid
24
True or false… humans are the only known reservoirs of M. Tuberculosis
True
What are the four possible outcomes of TB exposure?
Clearance
Latent infection
Primary disease (active on first exposure)
Reactivation disease (most common form of active disease)
Although most adults will contain primary TB infection in a latent form (asymptomatic) primary TB is most common in what groups of people?
Children <4 years of age
Immune compromised
If you have latent TB, it is asymptomatic with a __% lifetime chance of reactivation
10
What are some high risk factors for reactivation of latent TB?
HIV (100% chance)
Jejunoileal bypass (60%)
IV drug use (30%)
Lots of others
Describe the pathogenesis and host response of TB
MTB replicate in the phagosomes of macrophages (prevent lysosome fusion with phagosome)
Granulomas form to wall off the infection
What are the clinical manifestations of latent TB?
No symptoms!
What are the clinical manifestations of active TB?
Pulmonary symptoms: cough, hemoptysis, lung collapse, chest pain
“Consumption”: fevers, fatigue, weight loss, night sweats
TB can be present in virtually any organ
Why is it that you should only test for LTBI in low incidence settings if the population is high risk?
Only test people with the intention of treating them if they are positive. So only test people who are at risk and would need treatment
What groups of people are considered high risk of exposure?
Known contacts of active TB case
Immigrants from endemic areas
Residents/employees of institutions with high risk of TB
Who is at a high risk of disease for LTBI?
HIV infection
IV drug use
Medical conditions such as diabetes, chronic renal failure, and malignancy
Immune suppressed
(Note that TNF-alpha blocking drugs for treatment of inflammatory diseases are likely to crack open granulomas to bring it to reactivation)
What are the two ways to diagnosis LTB? What is a flaw with this system?
There are no current means to test directly the presence of latent infection so we rely on surrogate measures of the host immune response.
PPD: skin test looking for hypersensitivity
IGRA: look for IFN-gamma release when blood cells are exposed to TB antigens in vitro
What is a key difference between the IFN-gamma test and the skin test for TB?
IFN-gamma test is either positive or negative while the skin test has some more grey area
What is the preferred regimen for treating LTBI?
Isoniazid daily for 9 months
What are the ways to diagnose active TB?
Combination of exposure history, signs and symptoms, and imaging (remember that the skin tests or IFN-gamma tests wont work well because the immune system isn’t working well)
AND
Lab evidence of TB: granulomas, AFB stain on smear
Name four anti-TB drugs and their roles in combination therapy
Rifampin - target slowly dividing mycobacterial persisters
Isoniazid - efficient cleared of rapidly dividing mycobacteria
Pyrazinamide - target slowly dividing mycobacterial persisters
Ethambutal - prevention of resistance
What are the treatment guidelines for treating active TB?
4 four 2,2 for 4
Isoniazid, rifampin, pyrazinamide, and ethambutal for two months.
Rifampin and isoniazid for four more months
What is the difference between MDR TB (multi-drug resistant) and XDR TB?
MDR TB: resistant to INH and RIF
XDR TB: resistant to INH, RIF, all fluoroquinolones, and any injectable
___ is the most powerful known risk for reactivating latent TB. TB is the most common cause of death for ___ patients
HIV
AIDS
-risk of TB reactivation in HIV patients is 5-8% every year
If a patient has HIV and TB… ___ should not be given with ___. ___ should be used instead
RIF
Pls
RAL (rifabutin)
