tuberculosis (TB)

see also:

• infectious diseases
• mycobacteria
• the persistent cough
• back pain in the ED
• World Health Organisation (WHO) guide and updates on TB
• NZ govt TB literature
• EMedicine article on TB
• Western Health policies (intranet accessible only):
  • TB (pdf)
  • TB - General information for staff (pdf)

• tuberculosis is caused by the bacterial organism Mycobacterium tuberculosis (MTB) causing a generally slowly progressive chronic infection mainly of the lungs but in some cases may spread to other organs, or in severe cases mainly in immunocompromised people may have disseminated disease causing miliary TB and systemic spread
• drug resistant forms are increasing problematic
• an infectious case will typically infect up to ten other people in a year

• acid fast, slowly replicating, aerobic intracellular organism
• direct sunlight will kill the bacillus in a few minutes but it can live in dark and dusty areas up to 20 years
• virulence factors determine its ability to escape killing by macrophages

• following lung infection, multiplication and dissemination of the organism is contained once cell-mediated immunity develops at 2-12 weeks, but progress to primary active TB disease depends upon bacterial load and immune system status
• 5-8% will develop active TB disease within 5-7 years of contact, most of these are within first 1-2 years
• a further 2-5% will develop active TB disease later in life (“reactivation”) during a period of immunosuppression or further exposure.
• the remaining 90% will never develop active TB and are said to have latent “TB infection”, are asymptomatic and not contagious but at risk of reactivation.

• new term for latent TB
• asymptomatic immunologically dynamically contained infection but likely to still harbour viable organisms
  • ensuring the Mycobacteria remain contained seems to at least partly be due to TNF producing ROS in alveolar macrophages
• such patients are at very low risk of transmitting TB
• a period of immunocompromise in these patients may result in “active reactivation TB”
  • a healthy individual without immunocompromise has a 0.1% annual risk of developing reactivation TB
  • high risk of reactivation (> 6x risk of healthy individuals) include those with major immunocompromising conditions (see below eg. HIV, certain malignancies, immunosuppressant Rx), and those with radiologic fibronodular changes of healed “inactive TB”
  • mod. risk of reactivation (3-6x risk of healthy individuals) include diabetics and patients on corticosteroids
  • mild risk of reactivation (1-3x risk of healthy individuals) include those who are malnourished, smokers, or CXR shows small granulomas
• treatment of TBI can reduce the chance of later reactivation by up to 90%

• new term for active TB
• may be newly acquired TB or re-activation of TBI
• high risk of transmitting TB

• 33% of World's population is infected (approx. 1 billion people) - “the most successful pathogenic parasite of mankind”
• 8 million new clinical cases per year with 3 million deaths per year
  • 22 countries are high burden countries for TB
    • eg. Indonesia has 0.5 million new cases each year and 175,000 deaths per year putting TB in the top 2 causes of deaths of adults¹⁾
• re-emergence of TB in the 1990's:
  • ? poverty, malnutrition, HIV
  • rates in Australia:
    • still very low: 5.78 per 100,000 (was 48 in late 1940s before national TB control program instituted & ceased in mid-1980's)
    • 75% of new cases arise in people born overseas, usually in high risk countries
    • Aboriginals have much higher rates than general population
• MDR-TB = multi-drug resistant TB = resistance to at least isoniazid and rifampicin, the 2 main 1st line drug Rx
  • in 2000-2004, 20% of isolates from 49 countries were MDR-TB and 2% were XDR-TB
• XDR-TB = MDR-TB + resistance to any flouroquinolone AND resistane to at least 1 of 3 injectable 2nd line drugs: capreomycin, kanamycin, amikacin
  • mainly Latvia, South Korea, South Africa

• family members or close contacts of a patient with open TB accounts for ~42% of cases in NZ
• advanced HIV patients exposed to a pt with TB even if not open TB accounts for ~1% of TB cases in NZ and 8% of global TB cases.
• health care workers have ~7.5 x relative risk of being infected & accounts for ~6% of cases in NZ
  • particularly respiratory therapy workers and emergency department staff in high prevalence regions
• over-crowding eg. gay bars, prisoners (esp. in Russia)
• on an individual case basis depends on inhaled or ingested bacillus dose which depends upon:
  • bacillus strain hardiness & virulence
  • concentration of bacilli in sputum
  • mainly in patients with cavitating lung lesions “open TB”
  • declines with duration of TB drug Rx
  • paradoxically, end-stage HIV patients with low CD4+ counts usually have LOWER concentrations of bacilli in sputum as they tend not to have cavitating lesions
  • frequency of coughing
    • a case of TB laryngitis may be more infectious than a child with measles
    • ~50% of TB pts who developed a cough, do so within 10 weeks of infection (earlier disease is more likely if child or low CD4+ count)
  • proximity to patient or unfiltered air flow from patient
  • time exposed:
    • usually it takes many hours or days to transmit an infectious dose, but casual or short exposures may lead to transmission if the case is sufficiently infectious and environmental air conditions are favourable (eg. nightclubs)
  • air flow in room:
    • if room air is exchanged 12x per hour then concentration after a single cough is reduced by 99% after 35min
  • your immunologic status:
    • HIV +ve people with low CD4+ counts may become infected even from sputum -ve TB cases.

• NB. compared to healthy person with TBI and normal CXR, no risk factors ²⁾
• AIDS > 100x
• HIV >50x relative risk
  • TB notification rates in Kenya mirrored HIV rates with a lag time of 5yrs
• solid organ transplantation >20x
• silicosis ~30x
• chronic renal failure requiring haemodialysis 10-25x
• carcinoma (especially head and neck carcinoma 16x)
• TBI within past 2yrs 15x
• apical fibronodular changes on CXR (not just granuloma) > 6x
• immunosuppressive therapies eg. TNF-alpha inhibitors 2-9x
• corticosteroid Rx - 3-8x
  • risk is with supraphysiological daily doses of 7.5mg/d or more for over 1 month duration ³⁾
  • high dose inhaled steroids (eg. 1000μg/d fluticasone = 10mg oral prednisolone in steroid suppression effects) seems to double the risk when not taking oral steroids but seems to not have substantive additive effect when taking oral steroids ⁴⁾
• diabetes 2-3.5x
• age ⁵⁾
  • infancy age < 4yrs when infected 2-5x
  • 40-50% of infants with TBI progress to disease if untreated
  • 25% of 1-2 yr olds with TBI progress to disease if untreated
  • up to 10% of 2-12 yr olds with TBI progress to disease if untreated
  • 10-15% of adolescents with TBI progress to disease if untreated
  • 5-10% of adults with TBI progress to disease if untreated
• smoking 2-3x (accounts for 60% of deaths from TB in non-HIV patients)
• malnutrition and low body weight (less than 10% less than ideal body weight ie. BMI < 18) 2-3x
• alcoholism and risk of TB deaths despite starting Rx: population-attributable fraction (PAF) = 80%
• unemployment and risk of TB deaths despite starting Rx: PAF = 77%
• socioeconomic deprivation 60x relative risk compared to affluent sectors
• CXR with solitary granuloma 2x
• gastrectomy or jejunoileal bypass surgery
• role of BCG vaccination:
  • whilst not preventing infection, vaccination does markedly reduce advanced disease rates.
• age > 70yrs - mortality rate from TB is 6x that of TB mortality rates in infected patients at other ages.

• the Ghon complex - calcified scars in peripheral lung & in hilar LN:
  • acquired mainly via respiratory droplets from “open” TB patient
  • Taken up by alveolar macrophages in phagosomes without being killed.
  • Transported to hilar lymph nodes where:
    • MTB multiply in naive macrophages which are then lysed so that MTB can infect other macrophages & sometimes disseminate in blood stream.
  • After a few weeks, T cell-mediated immunity develops that is demonstrable by a +ve PPD test & involves MTB-activated T cells interacting with macrophages in 2 ways:
    • 1) CD4+ TH cells secrete IFN-gamma which activates macrophages to kill IC MTB via nitrogen dependant means (NO, NO2 & nitric oxide) which is associated with clearance of MTB & formation of epithelioid cell granulomas;
    • 2) CD8+ T suppressor cells kill MTB-infected macrophages (type IV HS) resulting in caseating granulomas.
    • NB. MTB do not survive in acidic, hypoxic EC medium in necrotic centres;

• Due to either:
  • re-infection
  • reactivation of dormant TB
  • dissemination from primary phase
• granulomas (esp. apex lung) fail to control TB & cause tissue damage by type IV HS.
• two complications of pulmonary TB granulomas:
  • 1) rupture of granuloma into blood vessel
    • ⇒ distant disemmination
    • ⇒ isolated end-organ disease as MTB destroyed elsewhere:
      • eg. meningitis, Cx LNs (scrofula), kidneys, adrenals, bones, Fallopian tubes, epididymis.
    • ⇒ miliary TB (millet seed size)
    • certain organs relative resistant to MTB → spread rare in these (heart,skel. muscle, thyroid & pancreas)
  • 2) rupture of granuloma into an airway
    • ⇒ “open” TB

• see also HIV / AIDS
• can take 3 forms:
  • 1) the usual pattern as above.
  • 2) if CD4+ TH cells < 200/cu.mm then:
    • decreased TH activation of macrophages
    • decreased response of HIV & MTB infected macrophages
    • relative increase in CD8+ Tcells may further deplete macrophage #s
      • ⇒ less well formed granulomas & are more frequently necrotic
      • ⇒ granulomas contain more MTB
      • ⇒ only 33% are reactive to PPD test
      • ⇒ extrapulmonary disease in 70%
  • 3) opportunistic MAIS infection if CD4+ < 60:
    • mostly originate in GIT but some begin in lung
    • ⇒ wide dissemination → enlarged, yellow LN's, liver & spleen
    • ⇒ yellow color due to 10^10 MTB per gram of tissue !!
    • granulomas, lymphocytes & tissue destruction are rare!

• 30-40% of clinical cases represent recent infection.

• cough, sputum, haemoptysis, fevers, weight loss over wks-months

• Primary TB (wks)
• post-primary (wks)
• latent (yrs)
• reactivated (yrs)

• risk of developing disease after infection is high ~40%, esp. in infancy
• disease can develop within weeks of infection
• Mantoux takes up to 8wks after infection to become positive.
• do not get renal TB (this is only in adults over aged 15yrs)
• children rarely present with infectious TB and often have smear and culture negative TB even with severe forms such as meninigitis or miliary TB.

• tuberculin skin test (TST)
  • intradermal injection then trained worker to assess size of the skin response at 48-72hrs
  • sensitivity for TB (as determined in those who are culture positive) = 80%
  • false-positive results likely if prior BCG vaccination or sensitization to nontuberculous mycobacteria
  • false-negative results are mainly in those with immunosuppression
  • if positive:
    • if low risk, consider IGRAs to confirm
    • if high risk, exclude active TB and Rx for TBI
  • if negative, assess for possible Rx of TBI
• interferon-gamma release assays (IGRAs)
  • unlike TST, prior BCG vaccination does not give false positive results but may still give false-negative results in those with immunosuppression
  • may give indeterminate results which require re-testing +/- TST
  • sensitivity for TB (as determined in those who are culture positive) = 80% but lower in those with HIV with low CD4 counts, and it is poor in children, especially under age 2yrs;
    • sensitivity is also reduced in TB disease due to temporary anergy of the acute illness, and immune-based tests cannot distinguish between active disease and latent infection
  • have a specificity for TB of > 95%
  • if positive, exclude active TB and Rx for TBI
  • if negative, assess for possible Rx of TBI
  • eg.QuantiFERON-TB Gold
    • Wikipedia - Quantiferon-TB gold
    • single interferon gamma blood test but must be processed with 12hrs of collection while WBC's are still viable
    • results within 24hrs
    • does not distinguish between latent or active TB, thus only advisable for screening of latent TB
    • utility not confirmed for:
      • paediatric patients
      • immonocompromised states such as HIV / AIDS
      • persons recently exposed to M. tuberculosis
      • current treatment with immunosuppressive drugs
      • selected haematological disorders, specific malignancies, diabetes, silicosis, and chronic renal failure).
• before testing, need to estimate the pre-test probability because if this is very low a positive test result may be more likely a false positive than a true positive and risk unnecessary risky Rx
  • risk is very low for those born in Western countries after 1960 who do not have a known exposure or high risk occupation or condition
  • if very high risk, consider doing both TST and IGRAs

• NB. over half do not have clinical features of TB disease (fever, cough, weight loss, night sweats), hence a CXR is needed to rule out asymptomatic TB disease
• CXR looking for features of TB:
  • see Wikipedia - TB radiology
  • opacification in upper lobe or superior segment of lower lobe
  • pleural effusion
  • hilar lymphadenopathy
  • NB. isolated granuloma or scarring are not regarded as consistent with TB disease
  • if CXR abnormal and consistent with TB disease:
    • 3x early morning sputum for acid fast bacilli smear and mycobacterial culture
      • NB. in low TB prevalence regions, check culture to distinguish between nontuberculous mycobacteria and TB
      • the gold standard
      • usually need two negative cultures to exclude TB (except in children who are often culture negative)
        • culture negative adults with CXR changes but no symptoms would suggest old, healed disease
          • HOWEVER, if culture negative but there are clinical features of TB disease or there are progressive CXR changes c/w TB, then consider Rx as per TB disease
      • consider also 3x urine early morning for AFB culture if > 15yrs age
    • TB PCR
      • NAAT PCR:
        • respiratory samples more reliable
        • sens 92%, spec 99%
    • if sputum are negative, consider bronchoscopy or tissue biopsy
• see also Wikipedia - TB diagnosis

• see also antibiotics used to treat TB

• manage with respiratory precautions as per open TB
• 3 x sputum cultures for AFB (as per above)
• sputum TB PCR
• D/W respiratory team regarding Mx of exacerbation of COPD - in general, a short course of oral corticosteroids eg. 37.5mg/d prednisolone initially, and quickly tapering, followed by inhaled steroids would probably be indicated
• other usual COPD Mx ?viral ?bacterial infection, etc.