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Infectious Disease > Week 4 > Flashcards

Week 4 Flashcards

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1
Q

Immunity

A

protection against disease (not necessarily infection)

More rapid and greater response to subsequent exposure (e.g. vaccin)

“Natural” and acquired

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2
Q

Immunology

A

study of the mechanisms of immunity against infection and adverse effects of immune response

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3
Q

Components of immune function: (4)

A

1) Anatomic (skin, mucosal barriers)
2) Phagocytes (neutrophils, macrophages)
3) Cellular immunity (CD4+, CD8+ T cells, NK cells)
4) Humoral immunity (specific antibodies, B cells, complement)

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4
Q

HIV/AIDS:

what are the immune defects? (4)

A

1) Low CD4+ T cell number, decreased CD4+ T cell function
2) NK cell dysfunction

3) B cell dysfunction:
- Hypergammaglobulinemia, increased activation
- Decreased memory B cells
- Decreased response to new antigens
- High rates of autoimmunity

4) Phagocytic function: PMN and macrophages OK

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5
Q

3 stages of HIV/AIDs infection in terms of T cell number

A

Early stage = > 500
Intermediate = 200-500
Advanced, AIDS = < 200

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6
Q

Complement

A

Classical, Alternative, and Lectin converge at C3 → C5-C9 (MAC) and C5a

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7
Q

C1-C4 deficiency

A

classical pathway, present with PYOGENIC infections

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8
Q

C5-C9 deficiency

A

terminal pathway, show serious Neisseria infections

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9
Q

Most common complement deficienct

A

C2 deficiency

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10
Q

Antibody structure and function: Fc vs. Fab

A

Variable region F(ab): antigen binding region, each is unique

Constant region: Fc

  • Defines isotype (IgG, IgM, IgA, IgE)
  • Activates complement
  • Binds phagocytes via Fc receptors
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11
Q

C5a

A
  • potent chemoattractant
  • promote anaphylactic activity
  • recruit neutrophils and other inflammatory cells.
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12
Q

Classical complement pathway

A

Immune complex (IgG or IgM) + C1 activation —> C2, C3, C4 activation –> C5-C9

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13
Q

Alternative complement pathway

A

C3b + microbial surface, endotoxin, aggregated IgA –> C5-C9 activation

DOES NOT require C1, C4, or C2

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14
Q

C3 deficiency can predispose to what kinds of infections?

A

severe, recurrent pyogenic sinus and respiratory tract infections

increased risk for type III hypersensitivity reactions

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15
Q

Mannose-binding lectin pathway

A

mannose-binding lectin replaces C1 and does not require the presence of ab to be activated –> C2, C3, C4 –> C5-C9

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16
Q

Decay accelerating factor (DAF)

-responsible for what disease?

A

aka CD55

inhibits C3 and C5 convertases, prevents inappropriate complement activate

Paroxysmyl nocturnal hemoglobinuria due to GPI anchor defect that attaches DAF (CD55) and prevents complement activation –> complement mediated lysis of RBCs, WBCs, and platelets

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17
Q

Selective IgA deficiency

A

LOW IgA, NORMAL IgG, IgM

-can see increased airway and GI infections

  • limited increase in infection due to protection by compensatory IgM
  • majority asymptomatic
  • Increased autoimmune +/- malignancy
  • Increased risk of atopy and anaphylaxis
  • Susceptible to transfusion reactions (with anti-IgA)
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18
Q

Primary immunodeficiency:

disease of adult (3) vs. childhood (3) presentation

A

Usually due to single gene defects

Most present in childhood:

1) X-Linked Agammaglobulinemia
2) SCID
3) Wiskott-Aldrich

Most common in adults:

1) CVID
2) IgG(2) subclass deficiency
3) Hyper-IgE syndrome (Job’s Syndrome)

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19
Q

Secondary immunodeficiency:

A

Developing country: Malnutrition, HIV/AIDS, Age (very young, very old), Measles

Developed country: chronic corticosteroids, chemotherapy, anti-TNF antibodies, HIV/AIDS, transplantation

Other causes: CLL (low Igs due to B “arrest”), multiple myeloma (high IgG but monoclonal, low IgM, IgA), renal and GI loss

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20
Q

Common variable immunodeficiency (CVID)

epidemiology
defect in what?

A

most common serious primary defect in adults (Onset in teens or 20’s)

Defect in B cell differentiation (many causes)

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21
Q

Common variable immunodeficiency (CVID)

labs and presentation

A

Recurrent PYOGENIC sinopulmonary infections (especially S. pneumoniae)

  • bronchiectasis
  • lymphoma
  • increased risk of autoimmune disease

Chronic diarrhea with GI lymphoid hyperplasia and increased risk of bacteremia

Some PCP, fungi, mycobacteria, recurrent HSV

Labs: low IgG, IgM, IgA. NORMAL B cells, “NORMAL” T cells, LOW plasma cells

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22
Q

Chronic Granulomatous Disease (CGD)

A

sufficient phagocyte number but decreased function (NADPH oxidase deficiency = oxygen radicals decreased)

NBT negative

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23
Q

Chronic Granulomatous Disease (CGD)

increased susceptibility to…

A

Increased susceptibility to: “CATs Need PLACES to Belch Hairballs” = catalase + organisms

Nocardia
Pseudomonas
Listeria
Aspergillus
Candida
E. Coli
Serratio, Staph
B. cepacia
H. pylori

Recurrent skin abscesses, severe prolonged pneumonia, bone infections

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24
Q

If you have a cell mediated immunodeficiency, then you are more suscpetible to what bugs:

1) Bacterial (5)
2) Fungal (5)
3) Viral (4)
4) Protazoan (2)
5) Helminths (1)

A

*=TMP/SMX prophylaxis

Bacterial: Listeria, Nocardia, Mycobacterium, Salmonella*, Legionella

Fungal: Cryptococcus, Pneumocystis*, Aspergillus, Cocci. Immitis, Candida

Viral: HSV, Varicella, CMV, adenovirus
-Acyclovir prophylaxis for HSV and Varicella

Protozoan: Toxoplasma*, Cryptosporidium

Helminths: Strongyloides

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25
TRECs
pieces of DNA cut out during intrathymic T-cell receptor gene rearrangement V(D)J Recombination: take pieces of VDJ gene segments to generate a T cell receptor D→ J and then V → DJ
26
SCID: Severe Combined Immunodeficiency Possible defects: (2)
1) Defective IL-2R gamma chain (XR, most common) | 2) Adenosine deaminase deficiency (AR)
27
Pediatric emergency to recognize SCID early: why?
Exposure to non-irradiated blood product transfusions, live vaccines, and common infections in patients in SCID can be life-threatening Less complications, better prognosis, save money
28
Clinical presentation of SCID child
Failure to thrive, diarrhea, recurrent pulmonary infections Opportunistic infections: viruses, fungi, intracellular bacteria -PJP, Candida, Aspergillus, CMV, Enteroviruses, Mycobacteria Absence of lymphoid tissue - ABSENT thymus Alopecia, erythroderma, hepatosplenomegaly Decreased TRECs
29
Genome structure of retroviruses ``` Structural proteins (4) Viral enzymes (3) Viral genome? ```
Structural proteins: - Envelope (gp120, gp41) - Gag = matrix (p17) and capsid (p24) Viral enzymes: - Reverse transcriptase: inefficient and error-prone - Integrase: required for virus replication and transcription - Protease: required for viral maturation Viral genome: two RNA molecules
30
Retroviruses accessory proteins (6)
Tat (Tax): transactivator - required for viral gene transcription* Rev (Rex): nuclear exporter Vif: blocks APOBEC3G restriction Vpr: multiple functions, nucleus importer Vpu: multiple functions, virus assembly Nef: multiple functions, host immune invasion
31
Long terminal repeats (LTRs)
cis elements required for reverse transcription, viral gene transcription, splicing, virus integration, and packaging
32
Life cycle of retroviruses (6 steps)
1) Binding and Entry 2) Reverse transcription 3) Genome integration 4) Viral gene transcription 5) Virus assembly and release 6) Viral maturation
33
Genome integration requires _______ Viral gene transcription requires ________ Virus assembly and release requires ______ Viral maturation requires _______
Genome integration (viral integrase) Viral gene transcription (Tat transactivator) Virus assembly and release: (Vpu required for virus release) Viral maturation requires protease
34
protease in retroviruses
protease required for virus maturation and cleaves proteins in multi-linked chain to individual proteins
35
HERV: Human Endogenous Retrovirus
Comprises 8-10% of human genome Most HERVs are defective and cannot produce infectious viruses but may be associated with human cancers
36
AIDS defining cancers: (3)
``` Kaposi sarcoma (HHV8) Non-hodgkin’s lymphoma (HHV8, EBV) Cervical cancer (HPV) ```
37
Non-AIDS defining cancers (7)
Anal cancer (HPV) Hodgkin’s lymphoma (EBV) Liver cancer (HBV, HCV) Skin cancer (HPV?) Head and neck cancer (HPV) Lung cancer Kidney cancer
38
What are the unique characteristics of HIV-positive cancers
- HIV associated cancers are more aggressive and progress faster - Atypical pathology, higher tumor grade - Poorer outcomes - Higher rate of relapse - Rapidly invasive - Develops at a younger age Significant improved survival rate of persons with HIV due to HAART → shift spectrum of HIV diseases from AIDS defining cancers to more Non-AIDS defining cancers Antiretrovirals and chemotherapeutic agents have interactions and overlapping toxicities making therapy challenging
39
Potential contributing factors of HIV-positive cancers
1) Behavior risk factors 2) Direct effects of HIV: - Transactivation of proto-oncogenes by HIV Tat - Inhibition of tumor suppressor genes (p5s) by HIV - Endothelial abnormalities by HIV (pro angiogenesis)
40
HTLV: Human T Cell Lymphocytic Virus
Oncovirus Causes lymphoproliferative disorders Epidemiology: Japan, Caribbean, South America, Africa, Iran
41
Lymphoproliferative disorders caused by HTLV
Adult T cell leukemia/Lymphoma (ATL) HTLV-1-associated myelopathy (HAM) Uveitis
42
Origins of AIDS epidemic
HIV entered human pop. from chimps in east central Africa
43
Markers of HIV disease and response to treatment: (2)
1) CD4+ lymphocytes = main host cell for HIV CD4+ count correlates with disease progression 2) Plasma HIV RNA level - viral load is a measure of the extent of ongoing replication in lymphoid tissue
44
CCRH-d32 mutation
naturally occurring human genetic polymorphism 32 base pair deletion in CCR5 gene Causes translational frameshift and protein truncation → CCR5 NOT expressed on cell surface
45
Initial infection with HIV presents with what symptoms?
acute febrile illness, mononucleosis-like illness +/- aseptic meningitis Usually occurs 2-3 weeks after HIV exposure Occurs in > 50% of patients (usually unrecognized) Signs and Symptoms: fever, fatigue, maculopapular rash, myalgia, headache, pharyngitis, cervical lymphadenopathy, arthralgia, oral ulcers, odynophagia, weight loss, diarrhea, oral candidiasis, photophobia
46
Opportunistic infection
Infection that takes advantage of weakened immune system to cause an illness Many only occur when CD4 < 200 Restoring CD4 count with antiretrovirals can minimize opportunistic infections
47
Opportunistic infection - 6 common ones with HIV/AIDS patients
1) Pneumocystis Pneumonia (PCP) 2) Kaposi Sarcoma 3) Thrush (mouth and esophagus) 4) CMV retinitis 5) CNS Toxoplasmosis (ring enhancing abscess) 6) Extrapulmonary TB
48
Effects of antiretroviral therapy: - Virologic and immunologic effect (3) - Clinical effects?
Virologic and immunologic effect: - Potent inhibition of viral replication - Early HIV → prevent immunologic deterioration - Advanced HIV → allows immunologic recovery Clinical effect: - Prevent opportunistic infections, improve existing OIs - Reduce hospitalizations, long-term care facility use, medications for OIs, and cost
49
Expected response to antiretroviral therapy (5)
- Reduces plasma HIV RNA levels (viral load) - Increase CD4 count - Improve existing OIs, prevent new OIs - Decrease morbidity and mortality - Reduced HIV transmission
50
HIV evolution
leads to increased pathogenicity, and drug resistance -Genetic diversity (introduction of mutations) Error-prone nature of viral replication → genetically distinct viral variants evolve from initial virus inoculum Fast replication rate Selective pressures (genetic bottlenecks)
51
Retroviral targets
1) Protease inhibitors 2) Entry inhibitors: target fusion, CD4, or CCR5 3) Reverse transcriptase (RT) inhibitors (includes NRTIs and NNRTIs) 4) Integrase inhibitors
52
HIV Prevention Strategies
Abstention and other behavioral changes Male circumcision Condoms Pre-exposure prophylaxis Post-exposure prophylaxis ART in HIV+ patient HIV vaccine Microbicides
53
Diagnosis of HIV
initial ELISA, positive tests confirmed by Western blot Viral load from qRT-PCR → help monitor efficacy of drug therapy
54
ELISA and Western Blot for diagnosis of HIV False negative/False positive can be seen in what situations?
Can be falsely negative in first 1-2 months post HIV infection Can be falsely positive in infants born to HIV+ mothers (anti-gp120 crosses placenta)
55
Diseases seen when CD4 < 500 (6)
1) Candida albicans 2) EBV 3) Bartonella Henselae 4) HHV-8 5) Cryptosporidium 6) HPV
56
Diseases seen when CD4 < 500 EBV vs. Candida
Candida albicans: oral thrush (scrapable plaque) EBV: oral hairy leukoplakia (unscrapable plaque on lateral tongue)
57
Diseases seen when CD4 < 500 Bartonella Henselae vs. HHV-8
Bartonella Henselae: bacillary angiomatosis with neutrophilic inflammation on biopsy HHV-8: Kaposi sarcoma, lymphocytic infiltrate on biopsy
58
Diseases seen when CD4 < 500 Cryptosporidium - sx? - what do you see in stool?
chronic, watery diarrhea, acid-fast oocysts in stool
59
Diseases seen when CD4 < 500 HPV
resulting in squamous cell carcinoma (anus or cervix)
60
Diseases seen when CD4 < 200 (3)
1) Pneumocystis jirovecii 2) JC virus reactivation 3) HIV dementia
61
Diseases seen when CD4 < 200 Pneumocystis jirovecii - sx? - appearance on imaging? - increased value on what lab?
pneumonia, ground-glass appearance on imaging, elevated serum lactate dehydrogenase
62
Diseases seen when CD4 < 200 JC virus reactivation - disease it causes? - appearance on MRI?
resulting progressive multifocal leukoencephalopathy with nonenhancing areas of demyelination on MRI
63
Diseases seen when CD4 < 100 (8)
1) Aspergillus fumigatus 2) Histoplasma capsulatum 3) Candida albicans 4) Cryptococcus neoformans 5) CMV 6) Mycobacterium avium-intracellulare (MAC) 7) EBV 8) Toxoplasma gondii
64
Diseases seen when CD4 < 100 Aspergillus fumigatus - sx - appearance on chest imaging?
hemoptysis, pleuritic pain, cavitation or infiltrates on chest imaging
65
Diseases seen when CD4 < 100 Histoplasma capsulatum - sx? - appearance on histology?
nonspecific symptoms - fever, weight loss, fatigue, cough, dyspnea, nausea, vomiting, diarrhea Oval yeast cells within macrophages
66
Diseases seen when CD4 < 100 Candida albicans sx? appearance on microscopy?
esophagitis, white plaques on endoscopy, yeast/pseudohyphae on microscopy
67
Diseases seen when CD4 < 100 Cryptococcus neoformans sx? appearance on microscopy?
meningitis, thickly encapsulated yeast on India ink stain on microscopy
68
Diseases seen when CD4 < 100 CMV
retinitis, esophagitis Retinitis → cotton-wool spots on fundoscopy Esophagitis → linear ulcers on endoscopy Biopsy with intranuclear (owl eye) inclusion bodies
69
Diseases seen when CD4 < 100 Mycobacterium avium-intracellulare (MAC) - sx? - which two labs will be elevated?
anemia, increased alk phosphatase, increased lactate dehydrogenase, hepatosplenomegaly
70
Diseases seen when CD4 < 100 EBV - sx? - appearance on brain imaging?
B cell lymphoma with single or multiple ring enhancing lesions on brain imaging (fewer that Toxoplasma)
71
Diseases seen when CD4 < 100 Toxoplasma gondii -appearance on MRI?
brain abscesses that appear as multiple ring-enhancing lesions on MRI
72
HHART includes what combination of drugs?
2 NRTIs + Integrase inhibitor, protease inhibitor, or NNRTI
73
Nucleoside reverse transcriptase inhibitors (NRTIs): Mechanism of action
prodrug activated by cellular kinases to triphosphorylated active form → inhibit reverse transcription by competing with host cell triphosphate nucleotides for access to active site of HIV reverse transcriptase → Prevents genome replication and establishment of provirus
74
Nucleoside reverse transcriptase inhibitors (NRTIs): Mechanism of resistance
``` high rate of resistance, associated with mutations in amino acid positions of HIV reverse transcriptase CROSS RESISTANCE within class is common ```
75
Nucleoside reverse transcriptase inhibitors (NRTIs): what happens if levels are too low? too high?
Levels fall too low → increase resistance developing, levels too high → toxicity
76
Nucleoside reverse transcriptase inhibitors (NRTIs): Drug names (6)
1) *Tenofovir AF 2) *Emtricitabine 3) Abacavir 4) *Lamivudine 5) Stavudine 6) Zidovudine (formerly AZT)
77
*Tenofovir AF mechanism? ADR? metabolism? TDF vs. TAF?
NRTI Mechanism: nucleoTIDE reverse transcriptase inhibitor -*Does NOT require intracellular phosphorylation to be active ADRs: Fanconi syndrome Renal excretion Lower systemic exposure than TDF because action primarily intracellular
78
*Emtricitabine
Best tolerated NRTI Also active against HBV Renal excretion
79
Abacavir -metabolism? - ADRs? - what can you screen for to prevent ADR?
NRTI Hepatic metabolism ADRs: hypersensitivity reactions HLAB*57:01 screening performed prior to initiating treatment with abacavir to avoid Type IV hypersensitivity reaction
80
*Lamivudine
Best tolerated NRTI Also active against HBV Renal excretion
81
Zidovudine -main use?
NRTI (formerly AZT): Can be given prophylactically after birth along with Nevirapine to decrease risk of HIV acquisition from mom
82
NRTIs: Adverse Drug Reactions common to all the drugs in this class (4)
1) Some activity against mitochondrial DNA polymerase → Myopathy, anemia, granulocytopenia, neuropathy 2) Lactic acidosis 3) Hepatic steatosis 4) Renal impairment potential
83
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs): Mechanism
bind and directly inhibit reverse transcriptase (non-competitive inhibition) Do NOT require phosphorylation to be active Do NOT compete with nucleotides
84
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs): Mechanism of resistance
``` single AA substitutions in binding site of NNRTIs on HIV reverse transcriptase Resistance to one NNRTI → resistance to remaining class members ``` **Must be used with as least two other antiretroviral agents to prevent acquisition of strain resistance
85
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs): ADRs (2)
rash, hepatotoxicity
86
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs): Drug names (3)
1) *Efavirenz 2) Nevirapine 3) Delavirdine
87
*Efavirenz 2 ADRs unique to this drug contraindicated in who?
NNRTI vivid dreams, CNS symptoms CONTRAINDICATED in pregnancy
88
Nevirapine can be given with Zidovudine to do what?
Can be given prophylactically after birth along with Zidovudine to decrease risk of HIV acquisition from mom
89
Nevirapine ADRs (3)
potential for severe hepatotoxicity, hepatic failure, and death - not used really anymore NNRTI
90
Delavirdine
NNRTI CONTRAINDICATED in pregnancy Least potent NNRTI, rarely used
91
Fusion inhibitors mechanism?
interfere with binding, fusion, and entry of HIV virion into CD4 cells
92
Fusion inhibitors 2 drug names?
1) *Enfuvirtide | 2) *Maraviroc
93
Enfuvirtide Mechanism?
blocks gp41 conformational change → prevent fusing with CD4 cells
94
Enfuvirtide Mechanism of resistance?
gp41 mutations
95
Maraviroc Mechanism?
CCR5 antagonists → prevent fusion between viral gp120 and CCR5 receptors on macrophages → prevent viral entry
96
Maraviroc ADRs (1)
hepatotoxicity (with high dose treatment)
97
Maraviroc mechanism of resistance?
mutations in gp120, no cross resistance
98
Maraviroc has no activity against what strain of HIV?
No activity against “X4” or “dual tropic” HIV-1 strains - HIV-1 virions that target CXCR4, associated with later stages of HIV infection and disease progression Means CXCR4 used over CCR5 to enter cell
99
Integrase inhibitors: mechanism?
prevent insertion of viral dsDNA into host genome via reverse transcription of RNA, no action against human DNA polymerase
100
Integrase inhibitors: Mechanism of resistance
lower genetic barrier to resistance, single point mutation
101
Integrase inhibitors: Drug names? (3)
*Raltegravir Elvitegravir Dolutegravir
102
Integrase inhibitors ADRs (2)
hypercholesterolemia, increase in creatine kinase Generally well tolerated
103
Protease inhibitors Mechanism of action
bind and prevent virally encoded proteases (HIV-1 protease, pol gene) from cleaving polyproteins into mature proteins
104
Protease inhibitors: Mechanism of resistance
single AA substitution, typically SPECIFIC for individual protease inhibitors Resistance development is rapid when used as a single drug → must combine
105
Protease inhibitors: ADRs
1) Lipodystrophy (fat redistribution, central fat accumulation) 2) Hyperglycemia, hyperlipidemia, hyperinsulinemia 3) GI intolerance 4) QT prolongation 5) Hepatotoxicity 6) **Rifampin (CYP450 inducer) CONTRAINDICATED with protease inhibitors
106
Protease inhibitors: Drug names (4)
(-navir) Darunavir Atazanavir Fosamprenavir Ritonavir

Infectious Disease (9 decks)

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