Tuberculosis

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History

• Died from or infected by Tb
  • John Keats (poet)
  • George O'well
  • Nelson Mandella

• Hippocrates description
  • Phthisis (to waste away, consumption)

• Robert Koch found the bacteria 1882

Epidemiology

est. case est. death all form 10mil 1.4mil HIV-ass 0.9 mil 208,000 MDR-Tb ≈558,000 ≈190,000

• 8 countries account for 2/3 of all worldwide Tb

1. India
2. China
3. Indonesia
4. the Phillippines
5. Pakistan
6. Nigeria
7. Bangladesh
8. South Africa

Transmission

• transmission-influencing factors
  • sputum status of index case
  • proximity - distance between each other
  • time
• susceptibility of person

• [math]\displaystyle{ R_0 \approx r \times c \times d }[/math]
  • [math]\displaystyle{ r }[/math] = transmissibility
    • to reduce [math]\displaystyle{ r }[/math]
      • ealier detection
      • rapid commencing of treatment
      • reduce aerolization (surgical masks on patients)
        • surgical masks on patients reduce infectivity by 56%
  • [math]\displaystyle{ c }[/math] = susceptibility of contacts
    • to reduce [math]\displaystyle{ c }[/math]
      • open windows
        • Tb airborne transmission risk: windows closed 97%, negative pressure room (ACH12) 39%, windows and doors fully open 33%
      • N95 respirator
      • ARTs for HIV patients
  • [math]\displaystyle{ d }[/math] = duration of infectivity
    • to reduce [math]\displaystyle{ d }[/math]
      • treat patients appropriately

Risk factors

• HIV
• malnutrition
  • Tb risk inversely correlates with BMI
• diabetes
  • diabetes and Tb are syndemic
  • diabetes and Tb pathophysiologically exacerbate each other even under treatment condition in terms of hepatotoxicity
• overcrowding
  • people per room vs Tb rate per 100,000 (in Canada)
    • 0.4-0.6 vs 18.9
    • 1.0-1.2 vs 113
• ....

Natural history

1. inhalation of M.tb containing droplets
2. macrophages phagocytosis
3. granuloma + lymphadenopathy
4. Ghon complex - primary infection
   1. 5% local progression/disseminated Tb
   2. 95% latent Tb
      1. 10% of latent Tb reactivates in lifetime - secondary Tb

Latent Tb

• 1/3 of the world's population have latent Tb
  • modelling approx. 1.7 bil. people
• 10% of those latent Tb people get reactivation in their lifetime

Symptoms

• cough ± sputum ± hemoptysis > 2weeks
• fever
• malaise
• weight loss

Various presentations

pulmonary

• • 80-85% of TB diagnosis are pulmonary

extra-pulmonary

lymphadenitis - hilar/other

• cold abscess
• more common in cervical and hilar
• possibly in axillar, inguinal and abdominal
• hilar adenitis DDx - sarcoidosis, lymphoma, histoplasmosis

pleural

• usually uni-lateral
• effusion high LDH, high protein, high lymphocyte

pericardial

• cardiac tamponade
• sequele - carcified pericardium
• very pauci-bacillary and bacterial investigation from pericardiocentesis is very much less sensitive

intestinal

• can mimic Crohn's disease
• most common in ileocecal

meningitis

• often involves 3rd and 6th cranial nerves
• meningeal irritation signs often unaccompanied

cerebral tuberculoma

• DDx primary CNS lymphoma

Pott's disease (vertebral destruction due to TB)

• kyphosis, gibbus formation
• sometimes extends to psoas muscle abscess;

arthritis

• synovial fluid does not necessarily contains enough TB bacteria; fluid culture may miss diagnosis
• IGRA could be clue

skin

• erythema nodosum
  • DDx - TB, cryptococcal, sarcoidosis, UC, oral contraceptive, ≈50% idiopathic
• lupus vulgaris

miliary TB

• massive lymphohematogenous dissemination
  • nodules diameter <10mm
• liver
• spleen
• bone marrow
• lungs
  • pulmonary miliary TB easily missed by chest X-ray
• meninges

Diagnosis

baseline investigation

blood

• full blood count
  • clues for TB - leukopenia, anemia, thrombocytopenia
• liver enzyme, renal function, electrolyte
  • for baseline to monitor Tx side effect or to adjust dose
• diabetes
• co-infection
  • HIV
  • Hep B - HBsAg
  • Hep C - HCV-Ab

imaging

• chest X-ray
• other targeted imaging

microbiological

smear/microscopy

• Ziehl-Neelsen of sputum
  • positive smear needs cavitation
  • children and HIV-positive tend not to cavitate
  • specificity 98%
• fluorescent

culture - 4-8weeks

• culture is definitive/reference standard
• Lowenstein-Jensen medium
• liquid medium 3 weeks

PCR TB DNA

• Gene Xpert
  • Xpert MTB/RIF
  • can detect resistance to rifampicin

histopathology

• tissue biopsy
  • caseating granuloma
    • multinucleated giant cells with nuclei arranged like a horseshoe

urinary LAM antigen detection

• mycobacterial cell wall glycolipid antigen lipoarabinomannan (LAM)
• marker of active TB
• specificity 98%
• sensitivity 40-70%

Manteau text/tuberculin skin test (TST)

• low value for diagnosis

Interferon gamma release assay (IGRA)

• T-SPOT/Quantiferon(QFT)
• cannot distinguish between latent/active/used be treated

Treatment

• needs prolonged Tx
• needs multiple drugs

1st line target

• cell wall synthesis
  • H - isoniazid (isoniotinic adid hydrozide)
  • E - ethanbutol
• DNA synthesis
  • R - rifampicin
• ?
  • Z - pyrazinamide

• 2RHZE+4RH
• 2RHZE+4(RH)₃

side effects

• hepatotoxicity - H, R, Z
• ocular toxicity - E
• peripheral neuropathy - H
  • add vitamin B6 (pyridoxin)
• gout - Z
• fever - Z
• lupus - H
• drug interaction related to CYP 450P - R
  • carbamazepine
  • oral contraceptive
  • methadone

interrupted Tx

• interrupted during intensive phase
  • interrupted for > 14 days - re-Tx from the beggining
  • interrupted for < 14 days - continue
• during continuing phase

spinal/bone TB

• needs 9 months

TB meningitis

• needs 12 months
• 2RHZE+10RH

latent TB

• some options

Management

paradoxical reaction

• inflammation after commencing Tx
• problematic in CNS, pericardial
• co-Tx with steroids
  • CNS/meningitis,tuberculoma - dexamethasone
  • pericardial - predonisolone

Directoly Observed Treatment, short course (DOTs)

• in high risk stuation
• in homeless/chaotic social circumstance
• in poor adherence/treatment failure

• Dr. Karlos Stybro

TB in pregnancy

• RHZE are safe
• supplementation with VitB6 (pyridoxine) recommended
  • hyperemesis gravidarum

TB in breastfeeding

• no contraindication
• rule out TB in baby

hepatotoxicity

• any GI complaint may represent hepatotoxicity
• suspend all TB drugs until lab test revealed
• risk
  • co-infection HIV, hepB/C
  • other chronic liver disease
  • alcohol
  • advanced age
• early - 2-3wks, R,H; good prognosis
• late - after 1mo, E; bad prognosis

Drug-resistant

mono-resistant

• H-resistant approx. 7%

• primary resistance
  • infected by resistant TB
• secondary resistance

multi-resistant MDR

• resistant to H and R
• risk
  • previous Tx
  • household contact with MDR
  • HIV
• resistance to R is a marker of MDR
  • 90% of R-resistance strains are also resistant to H → GeneXpert

extensively resistant XDR

• MDR + fluoroquinolone-resistant and at least one additional group A drug

pre-extensively resistant pre-XDR

• MDR + fluoroquinolone-resistant