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Flashcards in 43. Tuberculosis Deck (18):
1

high risk groups for TB?

close contact, foreign born, HIV+, homeless, incarcerated

2

risk factors for TB disease?

extremities of age

HIV+ (5-10% risk of reactivation per year)

recently infected

immunocompromised

genetic defic (IFN-g or IL-12)

Diabetes (30% risk of reactivation over the lifetime)

Vit D defic

malnutrition

lung disease (silicosis)

3

Mtb complex?

M.tuberculosis + M.bovis +
M.africanum

4

Mtb epidemiology?

2nd leading cause of death from infectious disease
-1/3 of the world w/latent TB
- if exposed, 30% infection
- if primary TB, 90% containment (latent TB)
- if progression to TB disease and not treated, 50% death
- if latent TB, 10% reactivation risk per lifetime for normal ppl, 5-10% risk per year for HIV pts

5

Mtb transmission?

Inhalation (droplets can remain suspended in air for several hours)

RFs:
Case (degree of infectiousness: lung cavities, bact burden, freq/strength of cough, virulence of mtb strain)

Env’t (ventilation, space, air circulation, exposure to UV light)

Contact (immune status: innate resistance, immunosupp, genetics)

Exposure (duration, frequency, proximity)

6

mtb peptidoglycan?

maintains cell integrity

differs from classic peptidoglycans: 3-3 cross linnked and glycosylation of NAM residues and amidation of peptide side chain

enzymes involved in assembly are possible therapeutic drug targets (L, D transpeptidase = Ldt)

7

mtb arabinogalactan?

highly branched polysaccharide that connects peptidoglycan to outer mycolic acid layer

enzymes involved in synth eval as therapeutic Rx

8

mycobacterial cell wall?


Mycobacterial cell wall is a complex structure required for cell growth, resistance to antibiotics, and virulence. It is composed of three distinct macromolecules: a peptidoglycan which is covalently attached to arabinogalactans which in turn are attached to mycolic acids. This cell wall core is referred to as the mycolyl arabinogalactan-peptidoglycan complex (mAGP). This cell wall core is surrounded by an outer membrane (mycomembrane) which is composed of free lipids, lipoglycans, and proteins. These lipids/proteins/lipoglycans are considered the signaling effector molecules while the mAGP core is essential for cell viability.

9

mtb mucolic acids and "free lipids"?

cell wall core is surrounded by an outer membrane of free lipids and lipoglycans (mycomembrane)

forms characteristic thick waxy coat and contributes to impermeability of the cell wall

responsible for "acid fastness"

responsible for cord formation (trehalose dimycolate = cord factor)

mediate interaction w/phagocytic cells (APCs)

implicated in impairing phagosomal mautraiont

key targets of anti-TB drugs like isoniazid and ethionamide

10

molecules of the mycomembrane?

signaling effector molecules, outer membrane surrounds cell wall core

- lipoarabinomannan (LAM) = virulence factor and interacts w/APCs impairing phagosomal maturation
- phosphatidylinositol mannosides (PIM) mediates attachment of Mtb to APCs and granuloma formation
- mannosylated LAM (manLAM) inhibits production of TNFa and IL-12 by APCs, impairs phagolysosome fusion

11

TB pathogenesis?

Early (week 1)
- droplet nuclei enter alveoli, bacilli ingestied by APCs
- Mtb antigens bind host receptors
- activation of alveolar macrophages and gen of pro-inflamm cytokines (IL-12, IFNg, TNFa), chemokines, and ROS…should kill (mediated through 1,25(OH)2D3 and cathelcidin) BUT
- Mtb can subvert initial innate immune response by: impairing phago-lysosome fusion (manLAM, cord factor, detox NO and ROS, inhibiting pro-apoptotic pathway and promoting necrosis, type 1 secretion system and phagosomal escape/recruitment of uninfected macrophages(ESX-1)

Week 2
- bacilli multiply in APCs, APCs to LNs, active of Th1 CD4 cells

Weeks 3-4
- CD4 cells to site of infection, restimulated & activate macrophages (through IFNg & TNFa)

Weeks 4-6
- granuloma develop w/activated macrophages and CD4 Th1 cells, center can become caseous
- granulomas limit Mtb growth (restrict O2 and nutrients) *reduced O2 tension induces latency, so pts often at high altitudes for tx
- need IFNg and TNFa
- = CD4s, CD8s, giant cells, neutrophils, APCs, B cells
Tissue damage in TB is due to host immune response vs Mtb – no known toxins or enzymes assoc w/tissue damage

12

key cytokines in TB pathogenesis?

IFNg: rel by Mtb APCs and T cells, activates macrophages, induces autophagy, maintains granulomas, humans w/deficiencies in IFNg-R and redisposed to mycobacterial infection

TNFa: rel by both Mtb APCs and T cells, activates macrophages, granuloma maintenance

IL-12: secreted by Mtb APCs, indivs w/IL-12R defic are more susceptible to Mtb

13

Mtb morphology?

- nonmotile, non-spore forming, aerobic bacillus
- slow-growing
- GP but not gram stain-able, instead acid fast stain procedure

14

TB disease?

Primary
- primary lesion = Ghon focus and assoc lymph node = Ghon complex
- heals w/calcification
- occurs in childhood in endemic regions
Latent (LTBI)
- persistent asymptomatic infection
- dormant bacteria contained w/in granuloma
- not detectable by smear or cx
- can persist for lifetime without illness
- can convert to active replication when immune defense breaks down
Active TB
- bacteria can be identified and/or clinical sxs present
- occurs just after 1st exposure = progressive primary TB
- can be due to reactivation of latent TB: post-primary = reactivation TB
- can be pulmonary (cough, hemoptysis, fevers, night sweats, weight loss anorexia, crackles/decreased breath sounds) or extrapulmonary (CNS = basilar meningitis, tuberculoma, Pott’s disease – anterior portion of vertebral body (gibbus formation), military TB = mult organs, etc

15

TB diagnosis?

LTBI
- screen pts at increased risk
- TST /PPD = Type IV delayed-type hypersensitivity rxn re: Th1 cells (low sens 70% and spec, >5 if high risk, >10 if intermediate risk, >15 if average, low risk; Anergy testing w/control antigen (candida) to r/o TN vs FN)
- IGRA (pts w/h/o BCG vacc or low likelihood of followup; measures amt of IFNg rel re: Mtb Ag stim; uses Ags present in Mtb but absent in BCG and non-TB mycobacteria, higher specificity >95% but similar sens 70-80%; quantiferon gold or TB-elispot)
- r/o active TB (normal cxr, asymptomatic, negative sputum sample)
- assess risk/benefit of tx (side effects, toxicity, adherence)
- monitor pt w/chosen tx

Active

Pulm:
-  sxs
- apical lung involvement, cavitary lesion (primary is confluent and lobar, well defined consolidation, hilar adenopathy may be present, reactivation in apices or fibrosis)
- AFB smear (3 sputum samples), Zeihl Neelsen stain (acid fast) or auramine-rhodamine fluorescent stain
- culture (Lowenstein Jensen, liquid culture/MGIT more rapid, MODS assay fastest and simultaneously detects resistance)
- NAAT (nucleic acid amplification test) targeting rpoB in MTB

Extrapulm:
- subacute (headaches, fevers, altered mental status)
- CSF w/ lymphocytic pleiocytosis, high protein, low glucose
- Mtb DNA PCR from CSF positive 80% (NAAT)
- millet seed cxr re: military TB

16

TB treatment?

LTBI
(give w/vit B6)
- isoniazid qd X 9 mos
- isoniazid dq x 6 mos
- isoniazid + rifapentine qweek X 3 mos (DOT) (not in kids or HIV+)
- rifampin qd x 4 mos
- monitor side effects (N/V, RUQ abd pain, dark urine, rash, paresthesias re: B6, fever) and adherence
- discontinue INH if >5-fold increase in transaminases or >3-fold and symptomatic

Active
- airborne precaution w/negative pressure room
- stop AI if 3 sputum smears are AFB negative or if 1 sample obtained from BAL is negative
- no longer infectious p 2 weeks of therapy and smear negative and clinical response
- INH+ RIF + PZA + ETH qd X 2 mos
- then INH + RIF dq x 4 mos w/B6
- TB meningitis: FQ instead of EMB
- spinal TB: 6-9 mos of tx
- if HIV+, potential drug-drug interactions so ART started 8 weeks after TB therapy started unless CD4

17

side effects of TB drugs?

INH: hepatitis, peripheral neutopathy (if don't have B6)

rifampin: hepatitis, orange fluids

pyrazinamide: GI upset, hepatitis

ethambutol: optic neuritis, impaired color vision

streptomycin: renal, auditory, vestibular toxicity (aminoglycoside)

18

BCG

Attenuated live M. bovis strain
Given at birth in TB endemic countries
Most efficacious for prevention of disseminated TB and TB meningitis in childhood
TST (PPD) test cannot distinguish reaction to BCG vaccine from reaction to TB infection; however, BCG induced response wanes over time
IGRA testing can distinguish prior immunization from TB infection
Newer vaccines are in clinical trials