ID Unit 2 Flashcards

Question

SCID newborn assay

Answer 1

T cell excision circles TRECs: - pieces of DNA cut out during intrarhythmic T cell receptor gene rearrangement - VDJ cut-out recombinations give you different circles of genes and T cell receptors (and therefore T cells) when TRECs are low: - do confirmatory testing - blood draw and look for CD3 (T cells) via flow cytometry - -CD45/RA (naive CD4 T cells) should be at least 50% of total CD4 T cells - -CD45/RO (memory CD4 T cells) - -CD8 - -CD16/CD56 NK cells - CD19 or CD20 B cells CBC lab abnormality: - low absolute lymphocyte count (ALC) - anemia (Reticulocyte count to look for production vs destruction problem; Coombs test to look for RBC antibodies/destruction) Early recognition of SCID is considered a pediatric emergency: - exposure to non-irradiated blood product transfusions, live vaccines, and common infections in pts in SCID can be life-threatening - part of newborn screen because it saves lives and saves money treatment choices for SCID: -bone marrow transplant is 1st choice

Answer 2

lymphocyte enumeration shows: -normal T, B, and NK cell numbers Immunoglobulin levels: -low IgM, IgA, and IgG CVID diagnostic criteria: - Recurrent sinopulmonary infections +/- autoimmune/inflammatory complications - two serum immunoglobulins (IgG and IgA +/- IgM) at least 2 SD's below age-specific mean - poor (absent) vaccine responses - B cell phenotype suggestive of arrest of maturation - no profound CD4 T cell defects - excluded secondary hypogammaglobulinemia - at least 4 yo Vaccine titers: check response to 3 types of vaccines: - T cell independent vaccines (B cells can respond to polysaccharide vaccine like pneumovax); IgM secretion - T cell dependent vaccines (need interaction of both T and B cells like Tetanus, Hib or diphtheria); IgG secretion

Answer 3

CVID clinical presentation is variable: - autoimmunity: ITP, AIHA, Evans Syndrome, SLE, RA - GI disease: IBD-like disease, malabsorption - Chronic lung disease: GILD - Malignancy: lymphoid predominant - Immunodeficiency: recurrent sinupulmonary infections (pneumonias: Strep pneumao, Hib, mycoplasma)

Answer 4

Confirm active infection of HIV: -HIV RNA by PCR with a LLOQ of 20 or 50 copies/mL ELISA: - detects anti-HIV Ab in sera using recombinant HIV proteins - fast and sensitive - high throughput - high false positive - cannot detect HIV in window period Western Blot: - detects anti-HIV antibodies - more specific than ELISA - less false positives - less sensitive - takes more time and effort than ELISA - use after 2 positive ELISAs to confirm RT-PCR: - detects viral DNA - very sensitive - can detect very recent infection - costly; requires special equipment - can perform immediately disease status: -CD4 < 200 = AIDS ELISA/Western blot tests look for antibodies to viral proteins; these tests often are falsely ⊝ in the 1st 1–2 months of HIV infection and falsely ⊕ initially in babies born to infected mothers (anti-gp120 crosses placenta). Presumptive diagnosis made with ELISA (sensitive, high false ⊕ rate and low threshold, rule out test); ⊕ results are then con rmed with Western blot assay (speci c, low false ⊕ rate and high threshold, rule in test). Viral load tests determine the amount of viral RNA in the plasma. High viral load associated with poor prognosis. Also use viral load to monitor effect of drug therapy.

Answer 5

Trimethoprim-Sulfamethoxazole (TMX-SMZ) treatment regimens available in infant/pediatric HIV are different from adults -AZT/3TC + LPV/r Zidovudine ZDV (formerly AZT) or Lamivudine 3TC MOA: - nucleoside/tide reverse transcriptase inhibitor NTRI - need to be phosphorylated to be activated - Competitively inhibit nucleot(s)ide binding to reverse transcriptase and terminate the DNA chain (lack a 3′ OH group) - can be given in mother prophylactically to decrease risk of fetal transmission Lopinavir (-navir) MOA: - protease inhibitor (-navir tease a protease) - prevent maturation of new viruses by preventing a protease cleave that assembles virions into functional parts Dolutegravir (DTG) MOA - integrase inhibitor (-tegra) - Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase used in combination to prevent resistance need lifelong tx to ensure CD4 count stays high and viral load stays load -the ART tx will never completely eliminate HIV

Answer 6

retinal damage pneumonia PCP- tx w/ TMP-SMX thrush- tx w/ fluconazole Pneumocystitis jiroveci pneumonia

Answer 7

Improves and preserves immune func in most pts regardless of baseline CD4 count - earlier HAART may result in better immunologic responses and clinical outcomes - HAART strongly indicated for all pts w/ low CD4 count or symptoms can reduce risk of HIV transmission -recommended combinations are effective and well tolerated most effective HAART contains: - backbone of 2 nucleoside/tide reverse transcriptase inhibitors (NRTI) - plus - Base of integrate strand transfer inhibitor (INSTI)

Answer 8

Preferred: - INSTI based - INSTI (-tegravir) + 2 NRTIs - ex. Dolutegravir + Tenofovir AF-Emtricitabine - ex. Dolutegravir + Abacavir-Lamivudine Alternative: PI-based (-navir) - PI + 2 NRTIs - ex. Darunavir-Cobicstat or Ritonavir boosted + Tenofovir AF-Emtricitabine Alternative: NNRTI-based - NNRTI + 2 NRTIs - ex. Rilpivirine + Tenofovir AF-Emtricitabine

Answer 9

Risk of HIV infection following occupational exposure: - percutaneous exposure: 0.33% - mucosal exposure: 0.03% - intact skin exposure: no cases in 1 study Recommendations: - start w/in 72 hrs - continue for 4 weeks - F/U HIV Ab testing for >4-6 weeks post-exposure Regimen: - 3 or more active drugs should be used - Preferred: Tenofovir DF-Emtricitabine + Dolutegravir

Answer 10

MOA: - activation by intracellular kinases to activate triphosphate - phosphorylated analogs competitively inhibit viral RT and cause termination when incorporated into viral DNA - prevents genome replication and est of provirus Resistance: - assoc w/ various mutations on RT - cross-resistance within class is common- basis for avoiding certain NRTI combinations Tenofovir TDF = safer from of TAF - minimizes renal and bone effects - high potency for suppressing HIV Pharmacokinetics: - important consideration is NRTI plasma levels (too low= risk resistance; too low = risk toxicity) - Abs: oral; must consider food/pH effects on abs - Elimination: Hepatic glucuronidation (Abacavir and Zidovudine) or Renal excretion (all others)- know elimination to avoid DDIs ADRs: - activity against DNA polymerase (anemia, myopathy, granulocytopenia, neuropathy) - lactic acidosis (hepatic steatosis, potentially fatal) - renal impairment potential (Tenofovir DF-TAF is less) - Lamivudine (3TC) and Emtricitabine (FTC) are best tolerated NRTIs; both agents are also active against HBV in co-infected pts

Answer 11

MOA: - do NOT require activation by intracellular kinases - bind to non-catalytic hydrophobic region - non-competitively inhibit HIV RT - prevents genome replication/establishment of provirus Resistance: - assoc w/ single AA substitutions at various RT positions - developing resistance to one NNRTI converse cross-resistance to other class members - newer member Etravirine appears to have higher barrier to resistance Pharmacokinetics: -oral; (Rilpivirine must be admin w/ meal); PPIs impair absorption -Elim: innumerable DDIs via induction/inhibition of CYP450; may alter levels of co-admin PIs (Rilpivirine: P450 substrate only NOT induce-inhibitor) (Efavirenz: CYP3A4 inducer (decreases methadone levels)) (Eftravirine: CYP3A4 inducer) ADRs: - Rilpivirine: generally well tolerated; most commonly see depression, insomnia, HA, rash; cautious use in pts w/ long QT - Efavirenz: most common are rash, dizziness, HA, insomnia, impaired conc, more severe CNS side effects possible; only antiretroviral agent in pregnancy category D - Etravirine: generally well tolerated; Rash (rare but can be severe), nausea, HTN, peripheral neuropathy - Hepatotoxicity

Answer 12

end in -navir MOA: - noncleavable peptidomimetic agents that selectively target retroviral aspartyl proteases (not host proteases) - HIV protease cleaves and processes HIV gag and pol proteins necessary for survival and replication, thus inhibition prevents viral maturation Resistance: - resistance requires multiple mutations- seldom develops in "boosted" PI-based regimens - relatively higher barrier to resistance vs NNRTIs and Integrase inhibitors Pharmacokinetics: - Abs: oral; some best w/ food, some w/ no food, some don't matter - Elim: metabolized by CYP3A4 and innumerable DDIs occur due to inhibition of CYP3A4 - admin w/ "boosters" increases potential for DDIs Boosters: - Ritonavir (most potent of PIs for inhibition of CYP3A4; used in low doses for boosting of co-admin PIs; also boosts Elvitegravir; many DDIs due to inhibition AND induction of CYP) - Cobicistat (more selective w/ no enzyme inducing properties; lower drug interaction profile) ADRs: - many PIs cause DI distress, hyperglycemia, insulin resistance, hyperlipidemia, and inc risk of CAD - peripheral lipoatrophy: central fat accumulation - hepatotoxicity more common in pts w/ HPV-HCV - Atazanavir: less effects on lipid profiles; reversible jaundice; mild-mod rash - Darunavir: rash can be severe (Stevens-Johnson Syndrome)

Answer 13

Raltegravir, Dolutegravir, Elvitegravir end in -tegravir MOA: - viral integrate involved in processing of DNA strands and catalyzing direct insertion of viral DNA into host cell DNA - Raltegravir inhibits integrate activity preventing HIV-1 replication - no effect on human DNA polymerases alpha, beta, or gamma Resistance: - Raltegravir and Elvitegravir- low genetic barrier - Dolutegravir- unlikely to develop resistance mutations (high barrier) Pharmacokinetics: - good oral abs - avoid cadmic with cations for DTG - DTG and RAL eliminated via phase 2 glucuronidation- levels decreased by inducers (eg Rifampin) - EVG substrate for CYP3A4- administered w/ "booster" - DTG or EVG once daily (vs BID for RAL) ADRs: - Generally well tolerated - Diarrhea, Nausea, HA

Answer 14

Maraviroc MOA: - HIV-1 visions using CCR5 called "R5 tropic", present during initial and chronic phases - HIV-1 visions using CXCR4 called "X4 tropic", associated with later stages and disease progression - Maraviroc is a small molec antagonist of CCR5 receptor that inhibits its interaction with viral gp120 - Indicated for tx experienced adults with R5-tropic virus (assay to determine R5, X4, or dual tropism) Resistance: - has been observed, esp when X4 strains are present - also assoc w/ mutations in viral gp120 Pharmacokinetics: - good oral abs - dose BID - substrate of CYP3A4--> DDIs possible w/ strong CYP3A4 inducers or inhibitors (eg NNRTIs or DDIs) ADRs: - generally well tolerated - mild effects incl: cough, fever, URI, dizziness, abdominal pain - hepatotoxicity possible w/ higher dose

Answer 15

Enfuvirtide MOA: - synthetic peptidomimetic of the viral gp41 HR2 sequences - binds to HR1 sequences- unavailable for hemiperfusion stalk --> prevention of viral entry into cell and infection Resistance: -from mutations in gp41 binding regions Pharmacokinetics: - MUST be administered subcutaneously - eliminated by proteolytic hydrolysis- no CYP involvement, so NO potential for DDIs ADRs: - injection site reactions in almost all pts - Eosinophilia - Hypersensitivity rxns - increase in bacterial pneumonia

Answer 16

Dual-NRTIs: Advantages: -established backbone of combination therapy -minimal drug interactions Disadvantages: -Lactic acidosis and hepatic steatosis (lower with TDF and FDC) -Lipodystrophy ``` NNRTIs: Advantages: -long half lives -less metabolic toxicity than PIs -PIs and INSTIs preserved for future use Disadvantages: -low genetic barrier to resistance- single mutation -cross resistance among most NNRTIs -rash, hepatotoxicity (esp Nevirapine) -Potential CYP450 drug interactions -transmitted resistance to NNRTIs more common than resistance to PIs ``` ``` PIs: Advantages: -higher genetic barrier to resistance -PI resistance uncommon even w/ sub-optimal adherence (boosted PI) Disadvantages: -Metabolic implications (fat maldistribution, insulin resistance, dyslipidemia) -GI intolerance -Potential for CYP450 drug interactions ``` INSTIs: Advantages: -neutral effects on triglycerides and cholesterol -high barrier for resistance w/ Dolutegravir -fewer adverse events than efavirenz -fewer drug interactions than w/ NNRTIs or PIs -NNRTIs and PIs preserved for future use Disadvantages: -BID dosing (QD for Dolutegravir) -lower genetic barrier to resistance than PIs (RAL-EVG) -Myopathy, rhabdomyolysis, skin reactions reported, but rare CCR5 Antagonist: Advantages: -virologic response non inferior to efavirenz -fewer adverse events than efavirenz -NNRTIs, PIs, and IIs preserved for future use Disadvantages: -requires tropism testing before use (CCR5 vs CXCR4) -BID dosing -less experience than w/ PI or NNRTI based ART- limited data w/ NRTIs other than ZDV-3Tc -CYP3A4 substrate- dosage adjustment required w/ concomitant inducers or inhibitors

Answer 17

pneumonia is infection of lung parenchyma from alveoli often misdiagnosed, mistreated, and underestimated - highest death from an infectious disease worldwide - majority of deaths are in children; kills more children than any other illness

Answer 18

Respiratory syndrome could incl: - cough, SOB, Sputum - Head: sinusitis, pharyngitis - Upper resp: bronchitis, exacerbation of COPD - Lower resp: PNEUMONIA Pneumonia has: - cough - fever - +/- sputum (young children don't make it, seniors can't cough it up) - Chest pain (from pleuritis with inspiration) - tachypnic - abnormal lung exam (pretty definitive) - positive CXR (pretty definitive) Dx Community Acquired Pneumonia CAP: - cough, SOB, fever, chest pain, sputum, DOE - tachypnea, fever, abnl lung exam - elevated WBCs, gram stain, blood culture - CXR is GOLD STANDARD for pneumonitis - -distinguish pneumonia from proximal resp tract process (compare w/ previous CXR) Pneumonia is 3rd most common pneumococcal disease in US - otitis media - bronchitis - pneumonia - bacteremia - meningitis How sick is a pt w/ CAP? CURB-65 - Confusion - Uremia (BUN >7) - RR >30 - BP (<90/60) - >65 yo - number of risks correlates w/ sickness

Answer 19

Risks for CAP: - COPD - age - Hospitalized within last yr - asthma - prednisone - CHF - cancer (lung, other) - male - diabetes Pneumococcus produces a lot of H2O2 and epithelial injury - chemotaxis --> diapedesis - alveoli and neutrophils are full of bugs and releasing factors causing inflammation/injury Prevention of pneumonia: - managing risk, incl: - breast milk - avoid smoking, smoke in home - underlying disease - vaccines Prevention of Pneumonia: - aspiration (thick food; sleep upright) - Smoking/environemantal smoke (esp cooking) - passive immunoglobulin (RSV) - Antimicrobials (Oseltamavir (Flu)) - Vaccine (S pneumoniae, influenza)

Answer 20

CAP is a big problem in children and seniors Lung infections: - acute, 19yo: mycoplasma - acute, 65yo diabetic: S pneumoniae - Subacute, Asian immigrant: TB - Subacute, HIV-1: Pneumocystis jirovecii (PCP) CAP: - Typical w/ purulent sputum (Pneumococcus) - Typical w/ gram neg org (H influenzae) - Typical w/ lobar infiltrate on CXR (M catarrhalis or S aureus / MRSA) - Atypical w/ prominent cough (M pneumoniae) - Atypical w/ Gram neg PMNs, few organisms (C pneumoniae) - Patchy or diffuse infiltrate on CXR (L pneumonophila, Influenza, RSV, adenovirus) CAP complications: - effusion/empyema - respiratory failure - cavitation - pneumothorax - pulmonary embolism - cardiovascular complications (CHF, a fib, MI, CVA/stroke) Mortality from CAP: - S pneumoniae - H influenzae (not common in adults) - Mycoplasma pn. - Legionella sp. - Influenza A - Unknown 4 Risk groups of CAP: - Previously healthy outpatients (Tx w/ macrolide; doxycycline) - Outpatients w/ co-morbidities or aspiration (prior antibiotics; Tx Resp fluoroquinolone; macrolide + amox/Clav) - Inpatients not in ICU (Tx: resp fluoroquinolone; macrolide + beta-lactam (ceftriaxone) - ICU pts (tx ceftriaxone + resp fluoroquinolone or macrolide)

Answer 21

Goal of vaccine: - need antibodies to get bug into neutrophils - need antibodies and phagocytes Therapy of CAP: -not one answer- find out what the bugs are in this pt Problem in Adults: - 23-valend pneumococcal vaccine: effective for bacteremia (systemic), but not effective for pneumonia (mucosal) - 7-valent pneumococcal conjugate vaccine in children: reduced colonization, reduced bacteremia, reduced bacteria pneumonia, some reduction in otitis media and meningitis, AND reduces invasive pneumococcal disease adults (indirect effect- HERD PROTECTION) - it's also protecting you from a disease that will eventually not exist

Answer 22

- seasonal (usually Dec-April) - cough and fever - ranges asymptomatic --> ICU - Dx w/ rapid test, PCR, culture (too long) - Tx w/ Oseltamavir - Vaccine: efficacy highest 6mo-7yr; falls off - complicated by S pneumoniae!!, S aureus, Group A strep - RSV- Respiratory Syncytial Virus (impact on adults?)

Answer 23

Meningitis: (High mortality) - Strep pneumoniae - Neisseria meningitis - (H influenzae) (unencapsulated) Bacterial Pneumonia: - strep pneumoniae (most common) - H influenzae (non-dyeable strains) Otitis media: (High morbidity and healthcare costs) - strep pneumoniae (most common) - Moraxella sp - H influenzae (unencapsulated)

Answer 24

most commonly strep pneumo, Neisseria meningitidis, and H influenzae type B bacteria have crossed BBB

Answer 25

decreased a little with polysaccharide vaccines in the 1980's then introduced conjugate vaccine and the incidence dropped drastically

Answer 26

H influenzae is encapsulated H influenzae requires special media for growth: - chocolate agar contains Factors V (NAD+) and X (hematin) - requires BOTH X and V factors H flu likes to grow near staphylococci on blood agar - Staph secretes NAD, and H flu uses it - called satellite colonies)

Answer 27

virulent Strep pneumo have capsules -looks different in blood vs Strep pneumo and normal flora strep (viridans) are frequently located in the same place (resp tract) and are both alpha hemolytic - -although S pneumo is optochin sensitive - -S viridans is optochin resistant

Answer 28

-N meningitidis is a close relative of N gonorrhoeae - it grows well on blood agar - Gram neg diplococci

Answer 29

H influenzae, Strep Pneumo, Neisseria meningitidis are encapsulated Antibodies to capsules is is important for: - ID of organism once it's isolated - tell the virulence of its strain - protect against disease - agglutination test can do a countercurrent immunoelectrophoresis test to detect the presence of capsule in bodily fluids: spinal fluid, blood, urine --This could be very useful if the patient has already been treated with antibiotics because these organism shed the capsular polysaccharide where it can be detected (e.g. into their urine).

Answer 30

H influenzae: - GN cocci - Dx using X and V factor; capsule type S pneumo: - GP lancet shaped diplococci - Dx using alpha hemolytic, optochin sensitive, presence of capsule N meningitidis: - GN coffee-bean shaped diplococci - Dx using oxidase test, sugar utilization, presence of capsule

Answer 31

H influenzae: - 6 serotypes a-f - >90% caused by type B in unvaccinated pop - chemistry: Type b,, ribose-ribitol-P - cross reactivity: Telchoic acids of many Gram pos normal flora organisms - Vaccines to type B only S pneumoniae: - >90 serotypes - 12 serotypes make up >80% of invasive diseases - Chemistry: Type 14, N-acetyl D-glucosamine - Cross creativity: Human ABO antigens (!!!!) - 2 vaccines in use: PPSV23 and PCV13 N meningitidis: - 9 serogroups - Type A serogroup assoc w/ most epidemics - chemsitry: serogroup B, N-acetyl neuraminic acid - cross reactivity: K1 capsule of E coli and brain gangliosides - Vaccines: for all pathogenic types

Answer 32

frequently occurs in environments where there is constant close contact of susceptible populations - daycare homes/schools - military camps - college dorms preceding an epidemic (mini or major) a significant proportion of the population become colonized in the upper respiratory tract w/ an encapsulated strain sporadic cases, not from these environments, may be related to trauma to the head, w/ direct invasion of bacteria to meninges The majority of deaths during the influenza pandemic of 1918-1919 were NOT caused by the influenza virus acting alone. Rather, most deaths were caused by secondary bacterial pneumonia from S pneumo, H influenzae, S pyogenes, S aureus, and others Despite the extraordinary number of global deaths, the vast majority of influenza cases in 1918 (>97% in industrialized nations) were self-limited and essentially indistinguishable from influenza cases today. Additionally, influenza severity and death in 1918 to 1919 correlated with the frequency of well-understood secondary bacterial pneumonias caused by common pneumopathogens

Answer 33

aerosol: - causes colonization of nasopharynx/otitis media - inhalation causes colonization of the lung - the capsule escapes phagocytosis - the teichoic acid and peptidoglycan cause inflammation - the pneumolysin causes direct damage to the endothelial cells ---> pneumonia ---> bacteremia pneumococci in bloodstream ---> meningitis Pathogenesis: - presence of anti capsular IgG or IgM in bloodstream protects against serious (invasive) disease (meningitis) - persons w/ NO anti capsular antibody to colonizing strain are at high risk for meningitis - persons w/ IgA blocking antibody response have a higher risk for meningitis, even if they have anti capsular antibody

Answer 34

unencapsulated strains of strep pneumo and N meningitidis rarely cause major disease S pneumo >50% otitis media in children (encapsulated vs encapsulated?) unencapsulated strains of H influenzae are frequently responsible for: - otitis media in children - sinusitis - pneumonia in adults

Answer 35

children <6yo who are most susceptible to disease respond very poorly to T cell independent antigens such as capsular polysaccharides the protective Ab may come from an immune response normal flora antigens which cross-react (have similar antigenic structure) with he capsules of virulent specimens genes for resistance do NOT need to be on mobile genetic elements to be transmitted world wide

Answer 36

Hib (alone) Hib in combination w/ DTaP (Diptheria-Tetanus-acellular pertussis) vaccine Hib in combination w/ recombinant hepatitis (HBV) vaccine Who should receive vaccine: - children <5yo starting at 2 mo - 3-4 boosters needed Who should NOT: - children < 6 weeks - previous life-threatening allergic rxn to Hib

Answer 37

Pneumovax® polysaccharide vaccine. - It is composed of high molecular weight polysaccharides purified from 23 of the more than 80 S. pneumoniae Serotypes - It is typically called the “pneumonia” vaccine” which is a misnomer. It has efficacy against IPD, but there has been significant controversy regarding its protection against non-bacteremic pneumococcal pneumonia - It was mainly given only to persons >60 yrs and those from 2 yrs – 60yrs who may have some higher risks factors (e.g. HIV, leukemia, kidney failure, asthma). - This vaccine is not immunogenic in children <2 yrs. Prevnar vaccine: -A conjugated vaccine made from 13 capsule types of Streptococcus pneumoniae that are linked to a diphtheria toxoid called CRM197 It was tested extensively (by Kaiser Permanente) for vaccinating young children against the 13 most common types of S. pneumoniae. Prevnar 7 has been licensed since 2000. The 13 capsule type vaccine was approved in 2010 13-valent pneumococcal conjugate vaccine for adults: - Approval of PCV13 for adults was based on immunogenicity studies that compared antibody responses to PCV13 with antibody responses to 23-valent pneumococcal polysaccharide vaccine (Pneumovax, polysaccharide only) - PCV13 elicited phagocytic antibody responses that were comparable to, or higher than, those elicited by PPSV23 for the 13 serotypes. For 10 of 12 serotypes in common, the PCV13 responses were significantly greater than the PPSV23 responses. - Initial vaccination with PCV13 with a booster PCV13 gave higher and more sustained responses than initial vaccination with PPSV23 and a booster with PCV13. - The safety of the PCV13 for 6000 vaccinees >50 yrs was the same at it was for the polysaccharide only, PPSV23 vaccine.

Answer 38

``` obligate aerobe (requires O₂) requires Vit D/ sunlight very slow growing bug (18-24 hrs) -3-6 weeks for primary isolation -the whole process of isolating, Identifying, and treating TB takes months ``` hallmark of mycobacteria: acid- fast stain - very thick cell wall (15% lipid) - able to resistant staining procedures - thick wall functionally acts like an outer membrane in GN's- gives it resistance to detergents, other toxic molec's that are normally a problem for GP's - has an additional unique Arabinogalactan, which is a target of Ethambutol anti-TB drug - Mycolic acids are attached to Arabinogalactan layer- target of isoniazid (another TB drug; specific to mycobacteria) also has LAM and PIM on the outside important for interacting w/ immune system

Answer 39

human-human transmission via resp droplets/aerosol infectious particle for TB= droplet nuclei - droplets generated from cough, sneeze, speech, singing - evaporate to droplet nuclei (1-3 microns) - capable of reaching alveolus - remain suspended in air up to 1 hr - one cough --> 500 droplets - avg TB generates 75k droplets/day - 25 droplets/day after 2 weeks of tx Probability that TB will be transmitted depends on: - infectiousness of pt w/ TB - environment of exposure (outside vs inside) - length of exposure - virulence (strength) of tubercle bacilli best way to stop transmission: - isolate infectious persons - provide effective tx to infectious pts ASAP - open windows

Answer 40

Initial infection → no symptoms or mild flu-like disease Cell-mediated immunity develops at 2-6wks, dominated by Th1s. Control of infection is via cell-mediated immunity. Antibodies do not play a major role in recovery or prevention. Antigen-specific CD4+ Th cells secrete IFN- ɣ which attracts and activates macrophages The macrophages kill intracellular bacteria (think TB) or at least slow their growth IFN-γ and TNF-α (released by macrophages) are super important in controlling TB. -If you inhibit them with drugs for other conditions, you increase the risk of reactivation from latent infection. When the macrophages die, bacilli are released and travel through lymph to bloodstream and can get to the rest of the body → liver, spleen, kidney, bone, brain, meninges and lung again. Granulomas: where the bacteria are confined, made up of epithelioid cells, giant cells, & lymphocytes. -As they grow, their centers become necrotic (caseous necrosis). Ghon complex: the combination of a single lesion in the lung + a draining bronchial lymph node. In healthy people, the lesions heal and become calcified which can be seen on CXR. Sometimes the bacilli can persist within the granuloma for decades → latent TB infection.

Answer 41

initial encounter: - reach alveoli - phagocytosed by alveolar macrophages - replicate in macrophages - carried by macrophages and dendritic cells to draining lymph nodes - lymphatics --> blood --> other organs macrophages' general mech of defense is to produce oxidative stress, which has almost no effect on TB - NO can't kill TB but can stop its growth - PIM and LAM surface molecs that manipulate the intracellular macrophage environment - PIM causes endosomal compartments to fuse w/ phagosome and deliver nutrients - LAM is signaling not to fuse so bad things aren't imported into bug, and produces an enzyme that degrades PIP3 enzyme? TB granuloma (tubercle) formation: - essential for TB propagation - allows host to form a big lesion and to cough - most conserved genes of bacteria are the ones that attract macrophages and force a granuloma formation - TB enters naive macrophages - necrotic tissue in the middle where TB can survive - T cells and foamy macrophages come in too, and it grows, until eventually you cough out the bacteria Healing: -fibrosis, calcification, bone formation

Answer 42

70% of exposed pts are able to clear TB with non-immunologic defenses (catch in mucus) 30% pts develop infection - 95% of these infected pts develop latent infection - --95% chance of remaining latent whole life - --5% chance of reactivating at some point in life --> post primary (secondary reactivation) disease; immune responses aren't able to contain the latent infection (immunocompromised, age, HIV, anti-TNFalpha therapy) -5% of the infected pts go on to early progression/primary disease fate of uncontrolled primary infection: - middle/lower lungs destroyed - caseous necrosis latent infection: - dormant bacteria, not metabolically active - 1/3 of population - live bacteria in body - postive skin test - normal CXR - sputum smears and cultures are neg - no symptoms reactivation: - upper lobe of lung (good supply of O₂) - bacteria can grow rapidly - form large cavities - can be coughed out - most contagious

Answer 43

initial encounter: - reach alveoli - phagocytosed by alveolar macrophages - replicate in macrophages - carried by macrophages and dendritic cells to draining lymph nodes - lymphatics --> blood --> other organs macrophages' general mech of defense is to produce oxidative stress, which has almost no effect on TB - NO can't kill TB but can stop its growth - PIM and LAM surface molecs that manipulate the intracellular macrophage environment - PIM causes endosomal compartments to fuse w/ phagosome and deliver nutrients - LAM is signaling not to fuse so bad things aren't imported into bug, and produces an enzyme that degrades PIP3 enzyme? TB granuloma (tubercle) formation: - essential for TB propagation - allows host to form a big lesion and to cough - most conserved genes of bacteria are the ones that attract macrophages and force a granuloma formation - TB enters naive macrophages - necrotic tissue in the middle where TB can survive - T cells and foamy macrophages come in too, and it grows, until eventually you cough out the bacteria Healing: - fibrosis, calcification, bone formation - body starts to build a bone around the lesion over time (are hollow, can become sterile, can see easily on CXR)

Answer 44

Stop the transmission cycle: TB control strategies - #1- prompt ID and tx of TB cases or suspects - rapid ID of contacts to infectious cases - tx of high-risk individuals with presumed or documented latent TB infection - reduce the risk of exposure to droplet nuclei

Answer 45

pulmonary TB symtoms: - cough (>3 weeks)* - chest pain - hemoptysis* - fever - chills - night sweats - appetite loss - weight loss* (suggests subacute-chronic) - easy fatiguability - upper-lobe predominant opacities high risk conditions: - HIV infection - transplant or other immunosuppression - medical conditions - injection drug users - recent arrivals from endemic countries - contacts to infectious cases - health care workers - other workers exposed to TB cases

Answer 46

``` TB screening flow chart: at-risk pt -TB skin test/IGRA + symptom review -neg = tx not indicated -positive --> CXR -nl CXR= potential candidate for Rx of latent TB -Abnl CXR = evaluate for active TB ``` TB skin test: Mantoux Method - 5 TU of PPD (pure protein derivative) injected subdermally 48-72 hrs later - read across arm; measuring what you palpate, not the redness - cut-off rate depending on your risk: - >=5mm for: HIV infection, contact to active TB, abnl CXR, immunosuppression - >=10mm for: recent immigrants, IV drug users, children, high-risk med conditions, residents/employees of jails, nursing homes, hospitals - >=15mm for no risk (but shouldn't be screening them anyway- going to get false positives) TB skin test: false positives: - reader error - presence of cross-reacting antigens - --nontuberculous mycobacteria - --recent BCG vaccination - --don't want to tx false positive pts w/ a potentially toxic drug In vivo and in vitro diagnostic tests: - an infected pt will have APC present mycobacteria antigens to a memory T cell - we can now measure blood cytokines due to specific antigens that are only found in TB complex and not found in BCG vaccine (ESAT-6 and CFP-10) - 2 Interferon-gamma release assays that are available: QFT-IT and T-SPOT.TB - stimulate pt blood with these antigens, and you measure interferon conc - strength in these tests is w/ the BCG vaccination (otherwise similar to skin test)

Answer 47

``` **NEVER treat active TB w/ a single drug** Treat Active TB with all 4: -Rifampicin RIF -Isoniazid INH -Pyrazinamide PZA -Ethambutol EMB -2 mo initial phase: INH, RIF, PZA, EMB -4 mo continuation phase: INH, RIF ``` Treat LTBI: one of these - INH for 6-9 QD months - Rifampin +/- INH QD for 3-4 months - INH +/- Rifapentine QW for 3 months - shorter regimens increases completion objectives of antituberculosis therapy: - rapid killing of multiplying bacilli (bactericidal effect)--- INH - achievement of relapse-free cure (sterilizing effect)--- RIF, PZA - protection against acquisition of drug resistance--- INH, RIF, EMB TB drug resistance: acquire drug resistance through mutation not from other organisms -katG mutation confers resistance to INH factors contributing to drug resistance: - long tx course provides opportunity for drug resistance to develop - inadequate tx regimens - previous tx of TB - progressive disease despite TB therapy - origin from, history of residence in, or frequent travel to region/country w/ high rates of MDRTB - exposure to an individual w/ infectious drug-resistant TB

Answer 48

``` only currently available vaccine for TB: BCG -live attenuated organism from cow -different countries use different strains -vaccine efficacy is all over the board ``` overall feeling: - BCG is not effective in tx adult TB and does not help prevent transmission - BCG seems to promote the immune system enough to lessen severity of disease in very young

Answer 49

Nontuberculous mycobacteria: - over 170 species of NTM - less than 80 have been reported in diagnostic specimens in humans - AKA: atypical mycobacteria, mycobacteria other than tuberculosis (MOTT), environmental mycobacterial - not transmissible from human to human (not considered contagious) - high levels of in vitro drug resistance (hard to treat; more of a lifelong infection) - most common presentation: lung - can be rapid or slow growing - several can make up complexes (MAC) NTM rates are increasing quickly - highest in hot/humid climates - TB rates are going down Dx NTM infections: - same diagnostic pathway w/ same culture media as TB,b but you have 170 species to sift through - Dx can take 8-12 weeks - treatment response can even depend on a subspecies Risk factors: - underlying conditions (CFTR/CF, AAT, COPD, systemic illnesses, TNF alpha antagonists) - significant exposure group (aerosolized water/soil, residence in endemic area) - Innate host issues (postmenopausal women; thin F w/ pectus excavatum; chronically suppress the normal cough reflex)--> Lady Windermere Syndrome goal of therapy: - cure, bacteriologic conversion, relief of symptoms, and prevent progression - cure rates vary, but are generally a lot lower 25-80% both have: -cough, fatigue, and weight loss

Answer 50

systemic disease w/ multi-organ involvement NTM infections can form complexes: -MAC= mycobacterium Avium Complex - slow growing - reservoir in hot water systems, natural water, and soil - cause disseminated > pulmonary > cutaneous 3 most common pathogens for lung disease: - M avium - M chimaera - M intracellulare - different species, but they're called MAC- part of MAC complex MAC is the most common cause of lung disease from a slow-grower -(most common cause of lung disease from a rapid grower is M abscesses) Lady Windermere Syndrome: - postmenopausal, thin F w/ pectus excavatum - chronically suppresses normal cough reflex 2 varieties of disease from pulmonary NTM: - nodular bronchiectatic- small nodules (Lady Windermere) - fibrocavitary (looks like TB cavitary; in M w/ lung disease) Can present anywhere: - lungs - wisdom tooth extraction - hands - LE ulcers from a pedicure

Answer 51

- transmitted via nasal discharge - usually a clinical diagnosis - world's oldest recorded disease - very slow growing (20 day doubling time) - affects peripheral nerves, skin, and mucosa (prefers low temp's) - infects monocytes (doesn't grow extracellular; can't grow in vitro) - humans and armadillos are the only known natural hosts (cannot be cultured in vitro) who is at risk: - can affect all ages and both sexes - 95% of people who are exposed don't develop disease - mainly affects skin, eyes, peripheral nerves, mucosa of upper resp tract - painless lesions

Answer 52

- caused by Mycobacterium ulcerans - source: contaminated water in tropics - produces mycolactone toxin: induces necrotic cell death (painless- killing nerve cells) - surgery often required treatment is based on WHO's disease category - 1= single, non-ulcerated nodules: Rifampin + streptomycin x4 weeks + surgical excision - 2= plaques and ulcers, any lesions on head/neck: Rifampin + streptomycin x8 weeks (w/ surgical excision if not healing) - 3= Rifampin + streptomycin x8 weeks (w/ surgical debridement if necessary)

Answer 53

Lepromatous: (classic; out of control) - progressive disease - nodular skin lesions - abdundant bacilli in lesions - CD8+ suppressor T cells - IL-4 and IL-10 suppress healing - high humor immunity Tuberculoid: (controlled) - non-progressing disease - macular skin lesions - few bacilli in lesions - CD4+ helper T cells - IL-2, IFN-gamma, and IL-12 promote healing - high cell mediated immunity

Answer 54

MOA: - inhibits inhA in Mycolic acid synthesis and shortens FA chains - not active until it interacts with katG - bacteriostatic for resting organisms - bactericidal for growing mycobacteria - high selective toxicity (Mycolic acids are found in mycobacterial cell walls) Bacterial resistance mechanisms: - Prodrug - resistance develops rapidly through alterations in target modification: inhA and katG Pharmacokinetics: - oral - well distributed - Metabolized- I in CRIMES - good at accessing caseous lesions in lung Drug-host interaction: - Low/medium - Vit B6 deficiency-peripheral and optic neuritis - Hepatic damage (acetylator status is important- slow acetylators are at risk for dose toxicity) - EtOH Spectrum of activity and usage: - Mycobacteria only(TB and M. Ka) - Intracellular activity

Answer 55

MOA: - inhibits transcription by binding to the RNA polymerase - bactericidal Bacterial resistance mechanisms: -mutations in RNAP Pharmacokinetics: - oral - well distributed- colors fluids orange - metabolized- R in CRIMES - potent inducer of CYP450s, so will metabolize other drugs more quickly Drug-host interaction: - Low/medium - hepatic damage - drug interactions; HIV, steroids, etc. Spectrum of activity and usage: - Mycobacteria and Gram pos - intracellular activity - TB, endocardidits - H flu meningitis prophylaxis

Answer 56

MOA: - inhibits arabinosyl transerfase in cell wall synthesis - bacteriostatic (bactericidal in MAC?) Bacterial resistance mechanisms: -mutations in EMB genes Pharmacokinetics: - oral - well distributed; lungs, CSF - renal excretion Drug-host interaction: - low/medium - optic neuritis not for children <6yo or in pregnancy (red-green color blindness) - gout Spectrum of activity and usage: - mycobacteria only (TB, M Ka, MAC) - poor intracellular activity

Answer 57

MOA: - uncertain - prodrug - depletes E reserves of cell-membrane effects - better in acidic environment - bactericidal Bacterial resistance mechanisms: -PCNA gene Pharmacokinetics: - oral - well distributed; lungs, CSF - renal excretion Drug-host interaction: - Medium/high - hepatic damage- monitor SGOT levels - Gout - Not in pregnancy (US) Spectrum of activity and usage: - mycobacteria only - semi-dormant bacteria in caseous lesions (acidic environment) - variable intracellular activity

Answer 58

MOA: - protein synthesis inhibition - 30s ribosomal subunit - bactericidal Bacterial resistance mechanisms: Pharmacokinetics: - POOR oral abs; give IV/IM - distribute to TBW - accumulate in kidney and ear - renal excretion Drug-host interaction: - high toxicity - vestibular and auditory toxicity - nephrotoxicity Spectrum of activity and usage: - Medium spectrum gram neg aerobes (E. coli, Pseudomonas) - limited gram positive - TB- alternative 1st line tx - not intracellular

Answer 59

sometimes years of therapy ``` Dapsone: -oral; bacteriostatic -PABA antagonist- antimetabolite -hemolytic anemia (w/ G6PD deficiency) + Rifampin +/- Clofazimine (phenazine dye that binds to DNA; bactericidal; acts slowly) ```

Answer 60

``` MAC: Multi-drug treatments incl: Macrolides (Clarithromycin > Azithromycin) + Ethambutol +/- Rifabutin (~Rifamycin) Fluoroquinolone's Clofazimine (also for leprosy) Amikacin ``` MAC prophylaxis in AIDS: Macrolide + Ethambutol or Rifabutin M kansasii: Isoniazid + Rifampin + Ethambutol M fortuitum: Fluoroquinolone + Doxycycline

Answer 61

Bed aquiline inhibits ATP synthase -active against many other mycobacteria reserved for MDR TB oral good distribution metabolized (hepatotoxicity) nausea, hyperuriciemia, arthralgia cardiac issues- prolonged QT -3-fold higher deaths compared to placebo

Answer 62

opportunistic: -infections caused by organisms that do not normally cause disease in healthy or immunocompetent individuals nosocomial: -infections that occur in an institutional healthcare setting. iatrogenic: infections originating directly from something that health care workers do.

Answer 63

Biofilm is polysaccharide goo secreted by various organisms - Catheters, in particular, seem to attract things that like to secrete biofilms (S. epidermidis) - Pseudomonas biofilms like to stick to mucus in the lungs of CF patients, catheters, drains of hot tubs, etc. - Pseudomonas secretes alginate to combine with the mucus in CF lungs to form a kind of jelly. - The PMNs can't get to the bugs through the biofilm.

Answer 64

Granulocytopenia (low PMNs) - chemotherapy, radiation therapy, burns - GN and staph - #1 risk factor for pseudomonas Cellular immune dysfunction - AIDS, age, smoking, T cell defects - intracellular pathogens (Salmonella), Mycobacterium TB and avium, Listeria, shingles, Legionella Humoral immune dysfunction - Agammaglobulinemia - Splenectomy (responsible for protecting against encapsulated bugs) - Encapsulated pathogens- S pneumoniae and meningococci Foreign body - IV or urinary catheter - bone implants (not vascularized/not connected to immune sys) - GN and staph Surgery!!! -staph, E coli, pseudomonas

Answer 65

E. coli is probably the most common Pseudomonas: - associated with the highest mortality rate (on average, 40-50%) - Strongly associated with cystic fibrosis (CF). - Also associated with burn infections, puncture wounds, hot tubs, etc. - lives in moist soil; so puncture wounds from stepping on nails, etc in the dirt are often associated with it.

Answer 66

Endotoxin also known as LPS, is located in the cell walls of Gram (-). - Endotoxin contains Lipid A, which is the pathogenic portion of the toxin - released when the bacterium is lysed - Some bugs shed endotoxin, which can travel to distant parts of the body (systemic effects) - Lipid A activates macrophages - macrophages release IL-1 and TNF-α (a pyrogen and a vasodilator, respectively) - mediates fever and septic shock. (Septic shock also requires lots of other factors, many of which are also activated by endotoxin: clotting factors, bradykinins, etc.) - Endotoxin can also cause DIC, largely through the same pro-coagulant mechanisms. 1) similarity in clinical manifestations between infection and administration of LPS to man or animals. 2) common pattern of hematologic changes following LPS administration and infection. 3) generation of kinins and activation of Hageman factor in clinical infection and following LPS administration to animals. 4) Consumption of complement 5) antibody against core glycolipid antigens of LPS protects man and experimental animals against sequelae of shock.

Answer 67

The exotoxin, Exotoxin A, prevents protein synthesis The delivery mechanism interacts with different receptors and has slightly different antigenicity. Cornyebacterium diphtheriae only invades superficial tissue in the pharynx and skin Pseudomonas gets into the blood and deep tissues. cell receptors are different: diptheria toxin receptor = epidermal growth factor precursor. Exotoxin A receptor = a2 macroglobulin receptor. Think ETEC and Cholera: same toxin effect, different targeting, which is why Cholera can kill you and ETEC will just make you unhappy.

Answer 68

High innate resistance through lots of efflux pumps to get rid of antibiotics, and Tends to form biofilms. The biofilm likes to attach to mucus in lungs, which is one reason why it's almost impossible to get rid of in cystic fibrosis patients Some strains have an antiphagocytic capsule that helps it adhere to target cells Other virulence factors: Endotoxin/Lipid A, as mentioned. Phospholipases, proteases.

Answer 69

Nearly all bacteria require iron for growth (except lactobacilli and Treponema). Generally, iron in the plasma is bound to transferrin or lactoferrin, both to deny free iron to microorganisms and to avoid creating free radicals from the hyperferremia. Upon invasion by microorganisms, iron begins to get shunted into storage rather than floating around in the plasma. It gets stored in hemosiderin laden macrophages. You decrease absorption from the gut as well. Overcoming mechanisms of limited host Fe availability: They have proteins with high affinity for iron (siderophores), to wrest it away from the binding proteins. They can also either synthesize products to take iron out of transferrin/lactoferrin or just absorb lactoferrin whole and degrade it apart. Toxins that destroy cells also release lots of iron.

Answer 70

URT viruses: - rhinovirus (exception: Rhinovirus C) - Coronavirus - Parainfluenza virus - Respiratory - Syncytial virus - Influenza virus - Adenovirus - Herpes Simplex Virus - EBV LRT viruses: - Parainfluenza virus - Respiratory syncytial virus - Influenza virus - Adenovirus - Cytomegalovirus Common causes of syndromes: - Bronchiolitis: RSV - Common Cold: Rhinovirus, Coronavirus - Croup: Parainfluenza viruses - Influenza-like illness: Influenza viruses - Pneumonia: Influenza viruses, RSV, Adenoviruses

Answer 71

Patterns of viral replication: "come and go" acute infection w/ replication confined to respiratory mucosal surface: -Paramyxovirus (parinfluenza 1,2,3 and respiratory syncyticial virus) -Orthomyxovirus (Influenza A,B,C) -Coronavirus -Picornavirus (rhinovirus) ``` "come and stay" persistent replication on respiratory mucosal surface: -EBV -Adenovirus -Papillomavirus ``` systemic replication after primary replication on respiratory mucosal surface: - Paramyxovirus (mumps, measles) - Varicella Zoster - HHV6 - CMV - Rubella - Bunyaviruses - Arenavirus - Parvovirus - Picornavirus (poliovirus) - Poxviruses - Reoviruses

Answer 72

Respiratory viruses are transmitted via respiratory droplets - extend up to 3 feet - reach respiratory tract via aerosol or fomites (any virus contaminated object) - once virus is to fingers, it may be transferred to nasal and conjunctival mucosa by auto inoculation (rub eyes/nose) - as little as 1 plaque-forming unit can cause infection - (you cannot change your behavior but you can wash your hands!) - primary interaction occurs at epithelial surface - infection of epithelial cells results in release of cytokines which trigger many symptoms assoc w/ viral infection (fever, aches, etc) - temp difference between URT and LRT may influence virus' preferences (33 near pharynx vs 37 lower in lungs)

Answer 73

Replication: - envelope carries 2 types of protruding spike viral proteins: Neuraminidase NA (9 subtypes); Hemagglutinin HA (13 subtypes) - variation in HA and NA genes lead to designation of Influenza subtypes for A (B and C are mainly human pathogens) - surface glycoproteins of A have greater availability than B and C - Vaccines target A and B, not C - virus binds to target cell w/ glycoproteins - gets nucleic acid into nucleus of cell for replication - (-) RNA has to become (+) RNA to work - release of virus via neuraminidase (sialidase) Prevention: - vaccine-preventable disease - flu vaccine can prevent illness from A and B - C infections cause mild respiratory illness and are not thought to cause epidemics - seasonal flu vaccine is trivalent and prevents against circulating 2 seasonal A strains and 1 B virus - 2 types of influenza vaccine: - --attenuated - --killed virus vaccine - vaccines need to be updated yearly to match the circulating strains of influenza Pathogenesis: - aerosol inoculation of virus - virus gets into RT, replicates in LRT - desquamation of mucus-secreting and ciliated cells - strong immune response (antibodies, T cell responses for future protection mainly, and interferon induction) - influenza syndrome - 2ndary bacterial infection (high mortality pneumonia) - primary viral pneumonia - CNS, muscle involvement - antigenic drift: HA/NA point mutations in A,B, or C that alter antigenic sites such that they're no longer recognized by host's immune system - antigenic shift: occurs only in Influenza A; caused by a more radical change in HA/NA - cells can be infected by more than 1 virus; leads to reassortment because of segmented genome; can cause pandemic (via infecting humans and being easily spread among humans) Diseases caused by Influenza Virus: - classic influenza syndrome (fever, chills, muscle aches, HA, prostration, anorexia) - CNS involvement - muscle involvement- aches - primary viral pneumonia - 2ndary bacterial pneumonia Diagnosis: - RT-PCR assays are standard for dx - clinical dx based on fever, HA, myalgia, and cough during flu season has 60-85% accuracy - testing is necessary to know if a pt would benefit from influenza antiviral tx Treatment: - Neuraminidase inhibitors: Zanamivir, Oseltamivir, Peramivir for Influenza A,B - M2 inhibitors: amantadine and rimantadine for Influenza A - when given within 48 hrs, decreases symptoms by 1 day Key facts: - anywhere from 3-9:1 infections:clinical case (very infectious) - can spread virus in absence of symptoms! - virus replicates in the ciliated epithelial cells of the URT - --necrosis of these cells results in usually symptoms of acute respiratory infection - normally self-limited infection usually lasts 3-7 days - death from primary influenza infection is very rare and appears to be determined by host factors rather than "virulence" of virus - damage to respiratory epithelium predisposes to 2ndary bacterial infections which accounts for most deaths today (note the 1918 pandemic, though) - virus is NOT systemic (rarely/never have GI symptoms) - vaccinate-preventable disease

Answer 74

Replication: - replicate in cytoplasm of cell - receptors determine tropism (CD46 for measles, ex) Prevention: Pathogenesis: - both RSV and PIV can cause repeated infections throughout life - HPIV are spread from respiratory secretions through close contact w/ infected persons or contact w/ contaminated surfaces - HPIVs are ubiquitous and infect most people during childhood - different HPIV serotypes differ in their clinical features and seasonality Diagnosis: -epidemiology, nasal swab tests to detect RSV antigen and histology of cells Treatment: - No RSV vaccine available - RSV Hyperimmunoglobulin: RespiGam and Palivizumab approved for the prevention of RSV DISEASE in children <2yo w/ a chronic lung disease called bronchopulmonary dysplasia or a Hx of premature birth

Answer 75

Myxoviruses are made of orthomyxoviruses and Paramyxoviruses Orthomyxovirus: - one genus: Influenzavirus A,B,C - only RNA virus that replicate in nucleus of cell! - Segmented (-) sense RNA genome! - Enveloped Paramyxoviridae: - 3 genrea: - --Paramyxovirus: mumps, parainfluenzavirus 1-4 - --Morbillivirus: measles - --Pneumovirus: respiratory syncytial virus - --Henipavirus: Hendra and Nipah - cytoplasmic replication! - Non-segmented (-) sense RNA genome! - Enveloped - has F glycoprotein SPIKES - most common causes of respiratory illness in young children

Answer 76

Replication: - replicate in cytoplasm - non-segmented genome Pathogenesis: - one of the most infectious diseases known; highly contagious - near universal infection of all children in absence of vaccination - respiratory transmission - replication in nasopharynx and regional lymph nodes - primary viremia 2-3 days post-exposure - 2ndary viremia 5-7 days after exposure w/ spread to tissue - after 10-12 day incubation period: dry cough, sore throat, high fever, conjunctivitis (virus may be excreted during this phase) - followed by characteristic red, maculopapular rash and Koplik's spots (raised red spots w/ white centers in mouth) - near the end of disease: there is extensive, generalized virus infection in lymphoid tissue and skin - (rash has no role in virus transmission, vs chickenpox or pox virus) Measles and pregnancy can result in: - premature labor - spontaneous abortion - low birth weight infants Treatment: - Measles virus targeted for elimination - 2000 endemic measles eliminated from US - vaccine for prevention

Answer 77

Pathogenesis: - humans believed to be only natural reservoir for the virus - transmission via saliva and resp secretions (less infectious than measles/chickenpox- more adult cases) - primary replication of the virus in epithelial cells of the URT and local lymph nodes - viremia - typically causes painful swelling of parotid glands 16-18 days after infection - virus multiplies in ductal epithelial cells - local inflammation causes marked swelling - --children: usually self-limited - --adults: orchitis (-->M sterility), meningitis, encephalitis, pancreatitis, myocarditis, nephritis - --pancreas: may be assoc w/ onset of juvenile diabetes Prevention: - one invariant serotype therefore vaccines are viable - both formalin-inactivated and live attenuated exist - live attenuated is now widely used

Answer 78

Measles, Mumps, Rubella children should get 2 doses of MMR vaccine: - 1st dose 12-15 months of age - 2nd dose 4-6 years of age (may be given earlier, if at least 28 days after 1st dose) - 1 study shows link between MMR vaccine and Down Syndrome- falsified data

Answer 79

Rubella virus: - AKA Germal Measles - ss + RNA virus - member of Togavirus family (not a myxovirus) - causes rash, arthritis, and mild fever pregnant F w/ rubella: -could have a miscarriage or baby could have serious birth defects

Answer 80

virus nuclei acid antigens virus virus-specific antibody

Answer 81

ELISA follow up test is Western Blot the HIV ELISA and WB both detect HIV-specific antibody in the clinical specimen

Answer 82

collect throat washings placed into transport media antibiotics added to prevent growth of bacteria/fungi specimens inoculated onto tissue culture cells evaluated for cytopathic effects (CPE): rounding up of cells, cell fusion and cell lysis (evidence of virus) CPE in tissue culture cells provides evidence of infectious virus in the pt sample that infected the cells in culture and caused the cytopathic effects if cells appear normal 7 days after inoculation means either virus may not produce CPE in these cells or there is no virus present next,d o a Hemadsorption test to see if RBCs stick -positive test tells you some of the cells treated w/ the pt specimen are infected w/ a virus now find out what type of virus is present: - perform Hemadsoprtion inhibition test w/ different antibodies - the inhibition test where the RBCs DO NOT bind means that specific anti-virus antibody is effectively binding to the infected cell, and you have that virus so now you know what's present, but you need to know if it was the cause of the illness Serological confirmation that the isolated virus was assoc w/ the pt's disease - Hemadsorption Inhibition test - Hemagglutination Inhibition test

Answer 83

uninfected cells: - No RBC binding - Hemadsorption negative infected cells: - RBC binding - Hemadsorption positive - viral proteins are expressed on the surface of the cells to bind the RBC surface - lots of brown spots in a blue background - useful for some non-cytopathic viruses Hemadsprption Inhibition test: - infected cells: add Abs to the cells - add RBCs to cells - wash - the antibody will block the ability of the RBCs to bind to the infected cells - no binding Agglutination Inhibition test: - mix virus and RBCs--> hemagglutination "network formation" - mix RBCs and virus and antibody to see if the antibody prevents agglutination; a way to screen for antiviral antibodies - mix RBCs, virus, and pt serum to test for presence of virus-specific antibody - Hemaglutination: extensive network formation "mat" formation - Hem inhibition: sedimentation of RBCs by gravity "dot" formation

Answer 84

Rapid antigen tests - 15 min - broad range of sensitivities Direct fluorescent antibody assay DFA - 2 hrs - used to directly detect influenza virus infected cels from nasopharynx specimens - requires highly skilled technical expertise molecular assays RT-PCR - 20min-8 hrs - high specificity and sensitivity - requires skilled technical expertise and expensive equipment NOTE: virus isolation (inoculation of cell cultures) is still necessary -Influenza virus isolates are essential for determining the match b/w circulating influenza virus and those contained in the vaccine, for aiding in the selection of new vaccine strains, and for determining antiviral resistance

Answer 85

enveloped, positive-strand RNA virus -family Togaviridae genus Rubivirus humans are only natural host and reservoir spread predominantly by resp secretions infants w/ congenital rubella may shed infectious virus in urine and other body fluids for months one serotype vaccine: attenuated usually given in combo w/ measles and mumps virus: causes mild febrile rash syndrome which is self limited without sequelae -if a primary infection occurs during 1st trimester, can infect placenta and spread to fetus -can affect many tissues of developing baby- "congenital rubella syndrome"- eyes, ears, heart, brain, and other organs test for Anti-Rubella virus IgM to see if illness is due to acute and convalescent sera- acute/recent infection order a Rubella virus-specific hemagglutination inhibition test w/ serum collected from mother at time of first visit -want the mother to exhibit pre-existing anti-rubella antibody in her serum to say she's not susceptible to Rubella to determine if baby was infected w/ rubella virus: order Anti-Rubella virus IgM ELISA - IgG ELISA is the mom's antibodies - the IgM antibodies don't come from mother - F who have little/no anti-rubella antibody are advised to have live attenuated rubella vaccine well before becoming pregnant

Answer 86

each well is coated w/ virus antigen pt's sample is added to well it may or may not have Abs specific for antigen in the well enzyme-linked anti-human IgM or IgG added to well enzyme substrate is added if enzyme is present, it produces a color change

Answer 87

Zika virus sexual transmission ongoing Zika activity in Mexico TORCH pathogens: microorganisms that are assoc w/ congenital disease Toxcoplamsa gondii Other (Listeria, Trepanoma, VZV, HIV, Parvovirus B19, Zika?) Rubella CMV HSV-1 and HSV-2 Zika? to determine if this pt recently infected w/ Zika virus: order ZIKA virus IgM ELISA and Zika Virus RT-PCR (to look for nucleic acid) to detect a recent zika virus infection positive test results so you order close monitoring of developing fetus, but don't order test to evaluate ZIKV infection of the fetus because it's invasive- amniocentesis is risky and not recommended prior to 14 weeks gestation -sensitivity and specificity on amniotic fluid is unknown -meaning of positive result is not clear- not known if the baby with develop a disease -instead, do US monitoring and close consultation -microcephaly is a major manifestation in Zika fetus

Answer 88

flavivirus antigen in brain neurons -West Nile virus in Georgia w/ mosquitos and birds additional tests to confirm WNV infection: RT-PCR for WNV nucleic act in the brain and/or isolation of WNV in cell culture -pt can be negative for IgM and IgG because he might be immunocompromised ``` RT-PCR: Reverse transcriptase WNV single stranded positive sense RNA: use reverse transcriptase to create an RNAcDNA hybrid melt them apart single stranded RNA and DNA use WNV-specific primer 2 and DNA polymerase to synthesize 2nd strand cDNA then get double stranded DNA -can be melted and amplified -detect on a gel/band ``` WNV can be transmitted: bite from infected mosquito blood transfusion transplanted organ

Answer 89

virus-specific IgM or IgG capture ELISA- developed to enhance sensitivity/specificity of assay 1-first coat the well with anti-human IgM or IgG (different than normal ELISA that could give you a false positive) - pt sample is added to well - All IgM Ab's are bound in the well - virus antigen added to well - enzyme-linked anti-virus nation Ab added t well - enzyme substrate added - if enzyme is present, produces a color change

Answer 90

how do you test if the organ donor had been infected w/ WNV? - RT-PCR for viral RNA, ELISA for WNV-specific antibody, etc - serum and plasma samples fluorescence: cells in a monolayer well add pt sample to those cells if there's a virus present, some of the cells will become infected you can detect the infected cells w/ the anti-WNV Ab binding to infected cells use 2ndary Ab to detect the first stuck antibody (anti-IgG ab) it's conjugated to a fluorophore label to look for color on fluorescence staining -results show that the blood contains infectious WNV (the virus is present in the sample and infects the cells in that dish, which can be detected by antibodies) assay used to screen donated blood for presence of WNV: RT-PCR to detect viral nucleic acid (using IgM would miss dx if donor was immunosuppressed, or if the infection happened really recently and doesn't have any detectable WNV antibody yet) -pooling samples dilutes virus and could make it seem negative for WNV

Answer 91

virus nucleic acids viral antigens virus virus specific antibody

Answer 92

- paramyxoviruses differs from orthomyxoviruses genetically - --non-segmented negative sense ss RNA genome - --little genetic variation family is divided into 3 subfamilies: - paramyxovirinae - ---parainfluenzavirus 1-4; mumps - --morbillivirus: measles - Pneumovirinae - --Respiratory syncytial virus (RSV) - --Metapneumovirus - Henipavirinae - --Hendra virus (isolated from horses and humans) - --Nipah virus (isolated from pigs and humans)

Answer 93

Structure: - HMPV is an developed virus w/ a non-segmented negative-sense RNA genome - HMPV is most closely related to avian metapneumovirus (APV) - 4 subtypes, all common in circulation Transmission: - likely direct/close contact w/ contaminated secretions - large particle aerosols, droplets, or fomites - nosocomial infections reported - transmission to family members very common (est 5 day interval) Disease: - causes both URT and LRT infections - usually ascot w/ mild, self-limited infections in children/adults - incubation 5-6 days - typical duration 1 week - some require hospitalization (bronchiolitis, asthma exacerbation, severe pneumonia) - severe LRT disease- wheezing

Answer 94

``` RNA: orthomyxo paramyxo corona picorna ``` DNA: aden herpes papilloma

Answer 95

- dsDNA virus - icosohedral - non-enveloped - 100 serotypes, 47 can infect humans - different serotypes assoc w/ different diseases - widespread in nature, infecting birds, many mammals, and man - infections are common; most are asymptomatic - virus can be isolated from removed tonsils/adenoids (indicates latent infections) - not known how long virus can persist or if ti can reactivate - virus is reactivated during immunosuppression (AIDS, ex) - virus can be spread for long periods after infection diseases: - acute respiratory disease and pneumonia - conjunctivitis - acute hemorrhagic cystitis - gastroenteritis (daycare; rotavirus is still more common) - myocarditis Prevention and treatment: - frequent hand washing - vaccine against types 4 and 7 for US military - tx: supportive care (more serious clinically in immunocompromised)

Answer 96

- member of picornavirus family - small + RNA virus w/ naked capsid structure - most common cause of URI ("cold") - generally self-limiting infection of URT - replicates best at 33 degrees - acid labile (cannot pass through stomach), but resistant to drying and many detergents (vs other picornavirus: poliovirus-fecal:oral transmission) - >100 serotypes (immunity following 1 serotype infection does not prevent infection w/ other serotypes) - transmitted by fomites and aerosols Diseases: - linked to otitis media (bacterial) - linked to exacerbations of chronic pulm disease, asthma development, severe bronchiolitis in infants/children, fatal pneumonia in elderly and immunocompromised

Answer 97

- largest + RNA virus - have large glycoprotein spikes sticking out of their envelope (corona = crown) - major site of replication is epithelial cells of resp tract - ~1/3 of colds are caused by coronaviruses - symptoms are similar to rhinovirus colds (runny nose, sore throat, cough, HA, fever, chills, etc) - incubation time 3 days - viral spread is limited by the immune response of most pts, but immunity is short-lived - symptoms may last about 1 week w/ considerable variation between pts - often no apparent symptoms but pt still sheds infectious virus - enveloped, and rather unstable in environment (vs non-enveloped rhinoviruses) - transmission: nasal secretions (aerosols caused by sneezes) - viruses that infect epithelial cells of enteric tract cause diarrhea (neonates) - infections are usually local, but can spread - implicated in otitis media infections, some pneumonias in immunosuppressed pts, and myocarditis diseases: -cause resp and enteric disease in variety of animals

Answer 98

Severe Acute Respiratory Syndrome - viral respiratory illness caused by a coronavirus (SARS-CoV) - illness quickly spread in 2003 symptoms: - begin w/ high fever (>100.4) - HA - overall discomfort - body aches - mild resp symptoms at outset - 10-20% have diarrhea - after 2-7 days may develop a dry cough - most pts develop pneumonia - another virus MERS (middle eastern respiratory syndrome) from camels - example of "emerging virus" most likely introduced due to spillover from wildlife reservoir (bats or palm civets) to human host

Answer 99

spillover: - an epidemiological concept about viruses that can spill over from animal reservoirs into humans - AKA pathogen spillover and spillover event - occurs when a reservoir population w/ a high pathogen prevalence comes into contact w/ a novel host population - infection is transmitted fro reservoir population and may/may not be transmitted within the host population - influenza virus has the potential to cause large pandemics but needs spillover and a genetic change to allow person to person spread - other newly discovered respiratory viruses: Hendra, Nipah, SARS, MERS

Answer 100

Acute infection w/ replication confined to respiratory mucosal surface: - paramyxovirus (parainfluenza 1,2,3 and respiratory syncyticial virus) - orthomyxovirus (influenza A,B,C) - coronavirus - Picornavirus (rhinovirus) persistent replication on respiratory mucosal surface - EBV - Adenovirus - Papillomavirus ``` Systemic replication after primary replication on respiratory mucosal surface: -Paramyxovirus (mumps, measles) -Varicella Zoster -HHV6 -CMV Rubella -Bunyaviruses -Arenavirus -Parvovirus -Picornavirus (poliovirus) -Poxviruses -Reoviruses ```

Answer 101

atypical organisms (other than Strep pneumo, H influenzae, and moraxella catarrhalis) includes infections caused by other bacteria, viruses, fungi, and protozoa - atypical presentation: - only moderate amounts of sputum, no consolidation, only small increases in white cell counts, and no alveolar exudate - diffuse peribronchial pulmonary infiltrates

Answer 102

Mycoplasma: - lack a cell wall - not resistant to osmotic lysis - growth requirements; get cholesterol from host to make their cell walls - takes 2-3 weeks to grow - impervious to cell wall antibiotics (Penicillins and vanco) - Eaton agent- thought to be a virus because it went through the pores of a filter - grown on PPLO media (nutrient-rich) with selective antibiotic agents to inhibit faster growing contaminants - most mycoplasmas- double raised dot ring - exception: M pneumoniae: single craters - Resp tract syndromes assoc w/ M pneumoniae: atypical pneumonia, tracheobronchitis (chest cold), wheezing in infants, pharyngitis, rhinitis - Infection most commonly results in: trachobonchitis, pharyngitis, malaise, fever, cough, HA - Pathogenesis: - --transmitted via airborne droplets from person to person - --exclusively human pathogen - --extracellular pathogen that evolved specialized attachment organelle for resp epithelial cells - --damages the resp epithelial cells at the base of cilia, activating the innate immune response and producing local cytotoxic effects - --CARDS toxin that aids in colonization and inflammatory response to establish infection - Scanning EM: arrowheads indicate terminal attachment structure (to cilia) - P1- major adhesion also involved in sliding motility PCR target for diagnostics - Produces a novel toxin: - --called community acquired resp distress syndrome toxin (CARDS toxin) - --has AA sequence homology w/ S1 subunit of pertussis toxin - --induces cytopathic effects and vacuolization in mammal cells, and causes slowing and disorganized ciliary movement - --pts develop antibodies against CARDS - --CARDS toxin appears to be significant virulence factor for Mycoplasma pneumoniae - --PCR test for diagnostic - timecourse: by the time resp symptoms and fever/HA/malaise show up, the pt has already been significantly cultured

Answer 103

respiratory culture respiratory PCR serologic studies

Answer 104

Legionella: - soil and water microorganism - intercellular pathogen- within macrophages - majority of infections come from serotype 1 and 6 - 4th leading cause of community acquired pneumonia - difficult to dx - gram stain: GN bacilli; requires special buffered charcoal yeast extract and cysteine to grow; gram stains very poorly in sputum samples - CXR: diffuse infiltrates in middle lobes, and progresses has large white blobs infiltrating the lungs - histo: lung is massively infiltrated with macrophages Clinical clues suggestive of Legionnaires' disease: - high fever >104 - numerous neutrophils but no organisms revealed by gram staining of resp secretions - hyponatremia - failure to respond to beta lactam drugs and amino glycoside antibiotics - occurence of illness in environment in which potable water supply is known to be contaminated w/ Legionella - onset of symptoms within 10 days after discharge from hospital - 1-5% attack rate - 2-10 day incubation - symptoms: fever, cough, myalgia, chills, HA, chest pain, sputum, diarrhea, confusion - lung: pneumonia, pleural effusion - other organs affected, incl kidney, liver, GI, nervous sys - 15-20% fatality Pontiac Fever caused by legionella Pneumophila: - 95% attack rate - incubation 1-2 days - symptoms: fever, cough, myalgia, chills, HA, chest pain, confusion - lung: pleurites, no pneumonia - no other affected organ systems - no fatalties Legionella hs 2 different ways of being phagocytized: - coiling phagocytosis (characteristic for Legionella) - regular phagocytosis Pathogenesis: - phagocytosis - transient mito fusion - intercepts ER exit vesicles and forms an ER-derived vesicle - legionella-containing vacuole LCV - does this via type 4 secretion system- master manipulator of macrophage; inhibits apoptosis; manipulates stress response; recruits ER; does poly-ubiquiniation - persists for a very long time on CXR- take a long time to resolve Sources: - potable water (showers, tap water faucets, resp care equipment) - non-potable water (cooling towers and evaporative condensers, whirlpool baths, decorative fountains, ultrasonic mist machines)

Answer 105

Fluorescent antibody staining: -dark green with bright green mini-worms Lab tests to dx Legionnaires' disease: - Culture (sputum, transtracheal aspirate) - direct fluorescent antibody staining of sputum - urinary antigen testings (most common) - antibody serology

Answer 106

diffuse endothelial injury: - activation of coagulation and decreased fibrinolytic pathway - increased inflammation and oxidant stress - -> organ failure - acidosis, pulmonary dysfunction, encephalopathy, hepatic failure, kidney failure, heart failure --> death at the root, it's a vascular disease (endothelial damage)

Answer 107

``` hospitalizations have doubled 9.3% of US deaths 18-25% mortality ICU admission >50% costly for hospitals ``` mortality trends among pts have decreased microorganisms that have it in for us tend to be bystanders - it is our response that makes the disease - "shambles" - --shambles can be hyperactivaiton (w/ very little hypo activation) - --shambles can be hypo activation in elderly or in pts w/ chronic disease (DM, ESRF, CAP) ``` primary sepsis mediators: -IL-1, TNFalpha, ROS, RNS, lipids secondary mediators: -NO, PAF, PG, LT, IL, kinins) Vicious cycle of hypoperfsion, ischemia, microcirculatory shunts, and acidosis MODS Death ```

Answer 108

organisms cultured in sepsis: - Gram Neg 62% - Gram pos 46% - community acquired resistant bacteria (GP) is going up Non bacterial infectious causes: - influenzae/H1N1 - Emerging viral infections: incl Ebola, SARS - 1/3 of pts using current techniques, an infectious organism is never found!!! Non-infectious mimics of sepsis: 7 A's - Acute MI - Acute PE - Acute pancreatitis - Acute GI bleeding - Adverse drug rxn - Accidents: major trauma - (A)blaze: severe burns ``` Alternative mnemonics: • Doing – Drug rxn • My - MI • Best - Burns • To - Trauma • Prevent – Pulm embolism • Grave – GI bleeds • Prognoses – Pancreatitis ``` Most common sites: - respiratory - bacteremia - GU Mortality by site: - bacteremia - respiratory - endocarditis - CNS Effective immune response: - contained infection - rapid bacterial clearance - limited system immune activation - no organ failure - --can sometimes be worse than the disease itself Host response in severe sepsis: - Pro-inflammatory response: - --excessive inflammation causing collateral damage (tissue injury) - --leukocyte activation, complement activation, coagulation activation, necrotic cell death - --TNFalpha, IL-1 beta, IL-10 - Anti-inflammatory response: - --immunosuppression w/ enhanced susceptibility to 2ndary infections - ---neuroendocrine regulation, impaired function of immune cells, inhibition of prolinflammatory gene transcription early cellular and molecular events during infection: - vasodilation and endothelial activation - leukocyte recruitment and activation - coagulation and NET formation - ruins microcirculation - decrease in capillaries causes inability to extract oxygen due to compression of capillaries and clogged capillary lumen - tissues move away from aerobic metabolism and shift towards anaerobic metabolism; metabolism of lactate to generate high E equivalents; desperately trying to hold the body together when you have alterations in microcirculatory blood flow Energy metabolism crisis in sepsis: - mitochondrial "dysoxia" or cytopathic hypoxia: oxygen utilization is dysfunctional, but oxygen delivery is preserved - failed maintenance of the transmtiocondrial membrane gradient w/ uncoupling of ATP synthase - E depletion Immune paresis in late sepsis: - well after the bacteria is killed, the mitochondrial have abnormalities - apoptotic depletion of immune cells ``` SIRS: systemic inflammatory Response Syndrome: -Temp >38 HR >90 RR >20 PaCO2 <32 + infection = sepsis ```

Answer 109

Surviving Sepsis Campaign: - Routine Sepsis screening - Blood and respiratory Cx - Broad spectrum Abx - IV N/S - Normalize serum lactate - Vasopressors - Quantitative Resuscitation targets

Answer 110

systemic inflammatory response syndrome - related to sepsis - characterized by dysregulated inflammatory response to an infectious or noninfectious process - 2 or more of the following criteria: - --HR >90 - --Temp <36 or >38 - --WBC <4000 or >12000 or 10% bandemia - --RR >20 or PaCO2 <32

Answer 111

life-threatening organ dysfunction caused by dysregulated host response to an infection Organ dysfunction: - change in total sequential organ failure assessment score (SOFA) of >=2 points or more due to infection - RR >=22 - Altered mentation - SBP <=100 Risk factors for sepsis: - bacteremia - advanced age - diabetes - cancer - immunosuppression Severe sepsis: -meets sepsis criteria AND has evidence of organ dysfunction, hypotension, or hypo perfusion Septic shock: - subset of sepsis where pt has hypotension refractory to fluid resuscitation - pts require vasopressors to maintain MAP >=65 - have a serum lactate >2mmol/L (18mg/dL) - these findings occur despite adequate fluid resuscitation - caused by peripheral vasodilation --> severe drop in systemic vascular resistance - --flushed, warm skin (vs hypovolemic shock pts w/ cool skin due to peripheral vasoconstriction) Sepsis Lab findings: - positive cultures - elevated lactic acid - increased BUN/creatinine ratio - elevated liver enzymes - leukocytosis or leukopenia Septic shock (vs hypovolemic shock): - cardiac index: increased - MVO2: increased - Afterload: decreased - PCWP: normal or decreased impaired cellular metabolism and dysregulation of the microcirculation (eg AV shunts that bypass capillaries) in septic shock lead to impaired O₂ extraction and delivery --> elevated mixed venous O₂ saturation (MVO2) and increased blood lactate, despite in the presence of an increased cardiac index and circulatory volume sepsis and septic shock dx based on clinical assessment: - fever or hypothermia - tachycardia - tachypnea - altered mental status blood, sputum, or urine samples for culture and gram staining are important to dx sepsis and admin appropriate Ab's - take samples BEFORE empiric Ab therapy - 2/3 of sepsis cases in US are caused by GP bacteria - --Staph aureus is most common - 1/4 caused by GN - --E coli is most common - 1/10 are fungal - --Candida albicans most common Hospital-acquired sepsis: - MRSA - Pseudomonas - E coli Early and aggressive tx: - Broad spectrum Ab's - IV fluids - Pressors NE is 1st line vasopressor in septic shock -vasopressors generally reserved for pts who remain hypotensive even after IV fluid admin Start pts on empiric Ab's immediately until specific pathogen is identified

Answer 112

Diphtheria- - can vaccinate and eradicate, but will come back if you stop vaccinating - --vaccinate w/ toxoid - thought to be only transmitted by humans - clinical signs of diphtheria: - --diphtheritic membrane- only found in URT; never goes to blood or lungs; pseudomembranous pharyngitis (grayish-white membrane) w/ LAD, myocarditis, and arrhythmias - --swollen glands w/ drawing of bac into lymph nodes- "Bull neck" - GP rods- reminds people of Chinese calligraphy (??) - can get skin lesion diphtheria: highly transmissible, but uncommon Corynebacterium ulcerans: - causes zoonotic infections (diphtheria and extra-pharyngeal infections) - diphtheria-like disease - ability to make toxin is in environment, so it may be around forever (do not discontinue vaccination) C. diphtheriae - only has 1 major virulence determinant: - diphtheria toxin - --immunize against toxin, not the bacteria - --toxin attacks heart, peripheral nerves, and kidneys, even though organism doesn't invade beyond URT/skin - -1 toxin molec is sufficient to kill euk cell via modifying EF-2 protein synthesis - --if you have anti-toxin in your blood, you are protected Diphtheria toxin bound to euk wall - bacteriophage and low iron are required for expression of diphtheria toxin - endocytosed - inhibits protein synthesis - cell dies Dx: - test for toxin production - --agar plate + anti-serum to see if strain makes toxin - --PCR detection by contacting CDC ASAP Tx: - report to CDC to retrieve antitoxin - tx pt w/ equine antitoxin - --antibiotics are not used as primary tx for diphtheria (used to prevent carriage and its spread) - -----Azithromycin - F/U w/ possible contacts

Answer 113

Bordatella pertussis - causes Whooping Cough - vaccine exists - --dropped, but then went back up in 2012 to 48K cases and not evading much - --vaccine in use since the 1990s is not as effective as the previously used Whole Cell Vaccine - -----Whole Cell Vaccine- virulent, but not live, IM injected; not given to anyone older than 7yo - -----switched because it was assoc w/ seizures and inconsolable crying in kids - --acellular vaccines for teens and adults became available, then the rates really shot up - babies get severe disease because they can't be immunized until 6mo; get it from a community member who isn't immunized - complications - --cerebral hemorrhage and death Pertussis in adults: - myth: pertussis infection provides lifelong immunity - truth: - --seroloigc and epidemiological studies confirm reinfection - --attach rate in naturally "immune" individuals is 50% - --immune wanes after 15 yrs Bordatella species: -aerobic GN coccobacilli Dx: - swab nose while pt is coughing - --3-4 days to culture - fluorescent Ab assay - PCR, but costly - toxin testing is NOT done for pertussis - positive culture is only 60% effective even early in disease; during paroxysmal stage- you have high number of lymphocytes (usually assoc w/ viral, not bac, infection) Stages: - Catarrhal: - --7-10 days - --Coryza, low-grade fever, mild chills, cold-like symptoms - Paroxysmal: - --1-6 weeks - --paroxysmus of numerous, rapid cough due to difficulty expelling thick mucus - --whoop, cyanosis, vomiting, and exhaustion - Convalescent: - --7-10 days - --gradual recovery, decrease in persistent coughs Adhesion molecs and multiple toxins Bordatella pertussis isolates that do not cover pertactin are increasing in regions where acellular pertussis vaccines have been used for >7yo pts. -No major clinical differences were found between infants <6yo infected by PRN-positive or PRN-negative isolate vaccinate mother in 3rd trimester to protect child in early life

Answer 114

salient features of zoonotic diseases: - can be caused by any type of organism incl bac, viral, or protozoan - caused by direct or indirect contact w/ animals - dx requires great clinical acuity - --disease are rare, may mimic other presentations, and can die quickly

Answer 115

modes of acquisition: - cutaneous contact, incl bites (dogs, cats) - arthropod vector - inhalation - ingestion

Answer 116

in contact w/ animals (human-vertebrae transmission) - farmers - pet owners - Abbatoir workers (slaughter houses) - Veterinarians/ lab workers - Hunters/trappers/fishermen

Answer 117

PLAGUE historical origins: ---"black death" through Europe ---foods (and rats w/ fleas) traveled through Asian trade routes to Europe microbiology: ---caused by Yersinia pestis ---nasal transmission epidemiology: ---enzootic plague: stable rodent-flea infection cycle ---Epizootic plague: when plague bacilli are introduced into rodent or small mammal populations that are mod-highly susceptible to lethal effects ---zootic plague: transmission from animals to humans ---demic plague: human to human transmission (Pneumonic Plague) -Types of Plague: ---Bubonic (lymph gland swelling from flea bite 2-5 days earlier- 60-90% mortality untreated) ---Septicemic (invasion of almost all organs; no sig evidence of prior disease; death 12-24 hrs) ---Pneumonic (primary or 2ndary lung infection which is highly infectious and 100% fatal untreated) -Clinical features: ---Bubonic pague: "bubo" lump in lymph (inguinal, axillary); pus if full or organism; Giemsa stain shows "bipolar safety pin" (Yersinia pestis); ecchymoses and petechiae on skin - dx: - Tx: prevention: TULAREMIA: historical origins: microbiology:: epidemiology: Clinical features: dx: Tx: prevention: BRUCELLOSIS: historical origins: microbiology:: epidemiology: Clinical features: dx: Tx: prevention: LYME DISEASE: historical origins: microbiology:: epidemiology: Clinical features: dx: Tx: prevention:

Answer 118

Ehrliche and anaplamsa: - obligate intracellular - infect phagocytic cells - multiply inside vacuoles - clinical: - --fever, HA, malaise, NO RASH, but similar to rickettsial infection - heme abnormalities: - --leukopenia - --thrombocytopenia - elevations in hepatic aminotransferases Ehrlichiosis: - E chaffeensis and E erwingii: human monocytic ehrlichiosis (HME) - Anaplasma phagocytophilia: Anaplasmosis - reservoir: deer - transmission: bite of hard (HME) or soft (Anaplasmosis) ticks - distributions in SE and NE/N US - No rash - inclusion bodies (morula) in leukocytes! - tx: Tetracycline for HME; Doxycycline for anaplasmosis Seasonal incidences: -between May and Sep, when people are outside Pathogenesis: - entry requires lipid rafts - prevent fusion w/ lysosomes - downregulates reactive oxygen species generation - inhibits host cell apoptosis - subverts autophagy Clinical presentation: - common symptoms incl fever, HA, malaise, sometimes N/V - most rickettsioses are accompanied by maculopapular, vesicular, or petechial rash, and/or eschar at site of tick bite - many cause mild disease - epidemic typhus and RMSF can be quite severe and may be fatal in 20-60% of untreated cases Dx: - PCR - immunohistologic detection - isolation of a rickettsial agent by culture during acute stage of illness - dx confirmed by obtaining acute and convalescent-phase serum from pt, looking for at least a 4-fold change Tx: -tetracycline class (doxycycline) Prevention: - no vaccines or drugs are available for preventing infection - minimize exposure to fleas, ticks, and animal reservoirs - use insect repellants, avoid vector-infested areas, and wearing protective clothing reduce risks

Answer 119

oxygen is toxic for anaerobes: - direct oxidation of cellular components - production of H2O2 and O₂- - strict anaerobes typically lack catalase and SOD (superoxide dysmutase) - anaerobes typically assoc w/ disease: - --may be aerotolerant - --may produce catalase and/or SOD (virulence factors) - special precautions are required for collection, transport, and cultivation

Answer 120

anaerobes are THE predominant component of human microbial flora - oral cavity = bacteriodes - colon = bacteriodes, clostridium - Female genital tract - skin humans encounter anaerobes from environment: - Clostridia (spore formers) - --clostridium botulinum: soil and water - --clostridium tetani: man, animal, soil, water - --clostridium perfringens: man, animal, soil, water - --clostridium difficile: man, fomites Anaerobic gram neg rod and anaerobic cocci: - normal microbial flora - aerotolerant - disease follows utoinfecitong into normally sterile sites (trauma, aspiration, bowel perforation) - hallmark: abscess formatin - --"mixed" polymicrobial infection w/ anaerobes plus facultative or aerobic organisms formation of anaerobic abscess: - acute stage: - --aerobes and facultative organisms predominate - --febrile, hypotensive - chronic stage: - --formation of fibrin-encased abscesses - --anaerobes predominate; polymicrobial Bacteriodes fragilis: - a frequent isolate from anaerobic abscesses - minor component of gut flora - isolated from 80% of abdominal abscesses - virulence factors: - --aerotolerant (produces catalase and SOD) - --extracellular enzymes (phospholipase, collagenase) - --capsule- abscess formation

Answer 121

Clostridium: - Gram positive spore-forming anaerobes - C tetani--> tetanus - C botulinum--> botulism - C perfringens--> tissue infections; food poisoning - C difficile--> antibiotic-associated diarrhea; pseudomembranous colitis

Answer 122

Clostridium: - Gram positive spore-forming anaerobes - C tetani--> tetanus - C botulinum--> botulism - C perfringens--> tissue infections; food poisoning - C difficile--> antibiotic-associated diarrhea; pseudomembranous colitis C tetani: - tennis racquets - widely distributed in feces, soil, part of normal flora - at risk: unvaccinated, agrarian society, poor hygiene, maternal and neonatal tetanus - spores introduced into puncture wounds - --germinate in devitalized tissue - --infection is often minor - --locally produced tetanospasmin transported to CNS via retrograde axonal transport along peripheral motor neurons - --blocks release of inhibitory NTs (GABA, glycine) - -----spastic paralysis - disese is preventable by immunization w/ tetanus toxoid - --death often occurs by diaphragm paralysis

Answer 123

Clostridium: - Gram positive spore-forming anaerobes - C tetani--> tetanus - C botulinum--> botulism - C perfringens--> tissue infections; food poisoning - C difficile--> antibiotic-associated diarrhea; pseudomembranous colitis C tetani: - tennis racquets - widely distributed in feces, soil, part of normal flora - at risk: unvaccinated, agrarian society, poor hygiene, maternal and neonatal tetanus - spores introduced into puncture wounds - --germinate in devitalized tissue - --infection is often minor - --locally produced tetanospasmin transported to CNS via retrograde axonal transport along peripheral motor neurons - --blocks release of inhibitory NTs (GABA, glycine) - -----spastic paralysis - disese is preventable by immunization w/ tetanus toxoid - --death often occurs by diaphragm paralysis maternal and Neonatal tetanus: - easily preventable - immunize of women w/ TT vaccine for protection against Tetanus - hygienic birth practices - proper cord care Clostridium botulinum: - spores are ubiquitous in soil and water - commonly contaminate food and wounds - pressure sterilization is required to kill spores - --toxin is heat-labile and is destroyed by cooking - botulism is mediated by action of botulinum toxin - toxin blocks ACh transmission at NMJ - --flaccid paralysis - foodborne botulism: - --spores contaminate food to be preserved by canning - --canning protocol insufficient to kill spores - --most outbreaks can be traced to HOME-CANNED foods - --spores germinate, grow, produce toxin - --there may not be signs of spoilage - --food/toxin is consumed uncooked - --toxin is destroyed by cooking - --bloodstream --> synapses at NMJ's - --overall, ingestion of pre-formed toxin - Infant botulism: - --unpasteurized honey and some corn syrups - --swallowing microscopic dust particles that carry the spores - --spores and therefore toxin are growing in the local gut of infant - wound botulism: - --most frequently assoc w/ black-tar heroin injection - tx: - --supportive measures to reduce resp failure - --anti-toxin, but will prevent future damage

Answer 124

inhalation botulism -potent, lethal, ease of production, intensive care needed for tx likely use is as an aerosolized toxin (not organisms) -absorption across lung mucosa to blood toxin may be used to deliberately contaminate food

Answer 125

inhalation botulism -potent, lethal, ease of production, intensive care needed for tx likely use is as an aerosolized toxin (not organisms) -absorption across lung mucosa to blood toxin may be used to deliberately contaminate food

Answer 126

- Zoonotic pool is very large- many opportunities for new human infections - --2 pandemics in history were caused by zoonotic viruses (Influenza; HIV/AIDS) factors that contribute to emergence or re-emergence of viral diseases: - globalization; rapid air travel - altered ecosystems - microbial evolution - expanding populations; "mega-cities;" poverty - environmental changes - improved detection and dx - human susceptibility to infection - changes in populations of reservoir hosts or vectors

Answer 127

Rabies: - transmit from animals to humans only (via bite or saliva of rabid animal) - global distribution - without tx: uniformly fatal - >99% from dog bite injury - immunization and post-exposure prophylaxis make this completely preventable (incl in pets) - family Rhabdoviridae - bullet-shaped vision - non-segmented neg-sense RNA - lipid envelope - post-exposure prophylaxis is effective against all strains of Rabies virus - --each host harbors a unique Rabies virus variant - Clinical manifestations: - --prolonged incubation phase (1-3 months; administer post-exposure prophylaxis!) - --2 major forms: both begin w/ fever, HA, N) - -----Furious (encephalitic) form: 80% (dysphagia, hydrophobia, hallucination, hyper salivation, brain stem dysfunc, coma, death) - -----Paralytic form: 20% (lack of major features; quadriparxsis; multiple organ failure; death) - Pathogenesis: - --virus replicates initially at site of wound - --infects neurons innervating site of wound - --infection spreads retrograde through axons to the CNS; no Viremia - --behavioral changes/symptoms develop Hantaviruses: - genus Bunyaviridae - segmented x3, neg sense, ssRNA - human infection primarily due to exposure to aerosols of rodent urine - causative agents of 2 major diseases in humans: Hemorrhagic Fever w/ renal syndrome HFRS; and Hantavirus pulmonary syndrome HPS - transmission: all have specific rodent reservoirs; cause persistent infection - --absence of overt disease in the host rodents - --horizontally transmitted from rodent to rodent - ex. Sin Nobre in North America: causes HPS; from a deer mouse - Hantavirus Pulmonary Syndrome HPS: - --prodromal phase 3-7 days: fever, chills, myalgia - --clinical recognition of HPS prodrome: pain in legs and back can be very severe; presence of productive cough at onset of illness is NOT consistent w/ HPS; CBC shows low plts, neutrophilia, elevated LDH, and AST; rodent exposure (deer mouse) - --Disease progression: prodrome to resp failure is rapid 12-24 hrs; tachypnea; tachycardia; pulm edema and inflamm; crackles; hypotension/shock; intubation and mechanical vent; death - --Tx: no specific anti-viral or vaccines available; supportive, assisted respiration, blood oxygen in severe cases

Answer 128

PEP: - tx of animal wounds; wash w/ detergent and water - Human Rabies Virus Immunoglobulin (HRIG): passive immunization around area of wound- neutralize virus - Rabies virus vaccine: inactivated vaccine, admin IM at different site than HRIG; additional doses at 3,7, and 14 Preventing Rabies: - public health resources and access to preventive tx - diagnostic faciliteit and rabies surveillance - educate those at risk; seek proper tx following possible exposure - vaccinate dogs

Answer 129

these viruses: -transmit from animals to humans and cause limited cycles of human-human transmission Ebola virus: - Family Filoviridae (also Marburg virus); 5 species - --non-segmented, neg sense RNA - --filamentous morphology - --nucleocapsid - --matrix protein - --envelope (derived fro host PM) - --membrane glycoprotein - Africa in 2014; began in Guinea - close contact between body fluids and other person (Blood, urine, saliva, sweat, feces, vomit, semen) - ---droplet transmission is possible (not airborne) - early symptoms: 2-21 days after exposure (fever, HA, fatigue, diarrhea, vomiting, weakness, stomach pain, lack of appetite, unexplained bleeding, MSK aches) - tx: tx symptoms as they appear - --supportive care and pt immune response - --IV fluids and electrolytes - --O₂ status and BP maintenance - --tx other infections if they occur - --rVSV-EBOV vaccine under trial testing - recovering from Ebola can develop joint and vision problems Nipah virus: Monkeypox:

Answer 130

Arbovirus: - virus maintained in nature in cycles involving hematophagous arthropod vectors and susceptible vertebrate hosts- nearly all have RNA genomes - have geographic and ecological limitations imposed by their vectors and natural reservoirs - >500 known arboviruses Most arboviruses fall into 3 taxonomic families: - Bunyaviridae - Flaviviridae - Togaviridae Major global arboviruses: - Yellow Fever Virus - Japanese Encephalitis Virus - Dengue viruses - WNV - Zkia virus - Chikungunya virus other US viruses: - St louis encephalitis virus - La Crosse virus - Eastern equine encephalitis virus - West Nile is most common arboviral disease cause in US

Answer 131

Humans are dead end hosts for most arboviruses: - No sig role in maintenance of virus in nature or amplification during outbreaks - --Ex West Nile Virus - --Exceptions: Dengue, Yellow Fever, Zika Major outcomes of human infection: - 75-90% asymptomatic in Dengue/WNV/Zika - Febrile illness (fever, chills, muscle pain) - Neurologic disease (encephalitis, meningitis, AFP, fatal or long-term neuro sequelae) - arthritis/MSK - hemorrhagic fever (damage to vascular system, loss of plt function; bleeding under skin, internal organs, shock, seizures, mortality) - congenital disease (Zika Congenital Syndrome)

Answer 132

Arthropod vectors: - primarily mosquitos, but also ticks, biting flies - infected vectors transmit virus to vertebrate hosts during feeding Vertebrate hosts: -may serve as main reservoir (may/not develop disease); or may have overt disease but not reservoir Role of mosquito in arbovirus transmission: - female mosquito ingests blood from viremic vertebrate - virus réplication in mosquito midgut - systemic spread in mosquito - virus replicates and accumulates in salivary glands - mosquito injects saliva/virus into skin during next blood meal Humans are dead end hosts for most arboviruses: - No sig role in maintenance of virus in nature or amplification during outbreaks - --Ex West Nile Virus - --Exceptions: Dengue, Yellow Fever, Zika

Answer 133

Non-vector transmission of ZIKV: - sexually transmissible (unique to ZIKV among flaviviruses) - persists in M reproductive tract (188 days post symptom onset in semen) Non-vector transmission of WNV: -solid organ transplant -blood transfusion -

Answer 134

Dengue viruses: - 4 serotypes; part of Flavivirus genus of Flaviviridae - cause 2 syndromes: Dengue Fever DF (mild) and Dengue hemorrhagic fever/Dengue shock syndrome DHF/DSS - --DF: acute febrile illness w/ HA, MSK pain, rash - --DHF/DSS: thrombocytopenia, capillary leakage, damage to liver; fluid los in tissue spaces --> hypovolemic shock/death - unique in that it is maintained in human-mosquito-human transmission cycle General Risk factors: - high temp, precipitation - proximity to low-income urban centers - lack of mosquito control - not blocking transmission cycle (no buildings, air conditioning) - low per capita income - piped water - window/patio screens Risk factors for DHF/DSS: - a second dengue infection of a different serotype! - <15 yo - host genetic background - viral genotype (each of the 4 serotypes is composed of several genotypes) - disease severity is determined by a combination of host and viral factors - --pre-existing immunity and virus genetics are critical determinants!! Hypothesis: Antibody-dependent enhancement (ADE) of disease severity

Answer 135

Developing a Dengue vaccine: -complications incl antibodies that play both protective and pathologic role; and need to provide lasting responses to all 4 serotypes; needs to be safe for all ages incl infants - non-protective, pre-existing immunity can promote more severe disease: - --individuals that are seronegative at the time of vaccination may be at high risk of hospitalization during their primary natural dengue infection - --limit vaccination to seropositive individuals? - --add immunological screening program before vaccination? - DENGVAXIA Prevention/Tx of arboviral disease: - vaccines - --YFV (effective live-attenuated vaccine) - --JEV (effective inactivated vaccines; effective chimeric live-attenuated and live-attenuated vaccines) - --TBEV (effective inactivated vaccines) - --Dengue (newly approved human vaccine) No specific anti-viral or other therapies exist Vector control: - insecticides, reduction of container habitats, improved water supply, and waste management - prevention and edu programs (repellents, clothes, avoid dawn/dusk, H2o management) - research to prevent mosquito sting and lifespan

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"that which bends up" "painful weakening of the joints" acute: 1-3 weeks - Sudden fever, arthralgia, arthritis, rash - Wrists, ankles, phalanges (commonly up to 16 joints) - Atypical presentations are rare (0.5%) - Treatment: Symptomatic with pain killers and NSAIDS - --Corticosteriods associated with severe rebound of arthritis and tenosynovitis Post-acute (3 weeks – 3 months) ▪ Persistent joint pain, arthritis, tenosynovitis ▪ > 50% of patients ▪ Treatment: pain killers and NSAIDS continued for several weeks Absence of anti-inflammatory treatment has severe consequences for recovery Chronic (> 3 months) ▪ Similar to post-acute stage ▪ 10-50% of patients ▪ Musculoskeletal disorders (95%) – managed as in post-acute stage ▪ Chronic Inflammatory Rheumatisms (5%) – ex. Post-CHIKV RA

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* Infection: asymptomatic (80%) to fever, muscle/joint pain, conjuctivitis (20%) * Now linked to severe fetal disease and Guillain-Barre Syndrome in adults Zika Congenital syndrome: - microcephaly - replicates in neural tissues in vitro and causes injury - likely severe when infection occurs during 1st trimester - variety of outcomes: - --microcephaly, CNS injury, intrauterine growth restriction, ocular abnormalities, placental insufficiency