43. Tuberculosis Flashcards
high risk groups for TB?
close contact, foreign born, HIV+, homeless, incarcerated
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)
Mtb complex?
M.tuberculosis + M.bovis +
M.africanum
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
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)
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)
mtb arabinogalactan?
highly branched polysaccharide that connects peptidoglycan to outer mycolic acid layer
enzymes involved in synth eval as therapeutic Rx
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.
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
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
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
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
Mtb morphology?
- nonmotile, non-spore forming, aerobic bacillus
- slow-growing
- GP but not gram stain-able, instead acid fast stain procedure
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
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
