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tuberculosis (TB)

Introduction

  • 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

incidence

  • 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

risk factors for becoming infected with TB

  • 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
  • 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.

risk factors for developing TB disease

  • HIV ~6x relative risk
  • TB notification rates in Kenya mirrored HIV rates with a lag time of 5yrs
  • silicosis ~3x relative risk
  • smoking (accounts for 60% of deaths from TB in non-HIV patients)
  • 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
  • diabetes and incidence of TB: PAF = 25%
  • chronic renal failure / haemodialysis
  • immunosuppressive therapies
  • gastrectomy or jejunoileal bypass surgery
  • carcinoma (especially head and neck carcinoma)
  • malnutrition and low body weight (less than 10% less than ideal body weight ie. BMI < 18)
  • infancy
  • 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.

natural history of infection

  • 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 depends upon bacterial load and immune system status
  • 5-8% will develop active TB within 5-7 years of contact, most of these are within first 1-2 years
  • a further 2-5% will develop active TB 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, are asymptomatic and not contagious but at risk of reactivation.

Mycobacterium tuberculosis

  • 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:
    • cord factor - a surface glycolipid that causes MTB to grow in serpentine cords in vitro.
    • Injection of cord factor causes characteristic granulomas;
    • sulphatides - S-containing surface glycolipids that prevent fusion of lysosomes to phagosomes
    • LAM - a major heteropolysaccharide similar in structure to endotoxin of Gram -ve bacteria
      • ⇒ inhibits macrophage activation by IFN-gamma
      • ⇒ induces macrophages to secrete:
        • TNF-alpha which causes fever, weight loss & tissue damage
        • IL-10 which suppresses MTB-induced T cell proliferation
    • MTB heat shock protein:
      • a highly immunogenic protein similar to human HSP
    • uptake by macrophages via CR3 receptor without triggering metabolic burst.

Pathogenesis:

Primary phase

  • the Ghon complex - calcified scars in peripheral lung & in hilar LN:
    • Spread 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;

Secondary & disseminated TB:

  • 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.
  • 2 special features:
    • 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 (millet seed size) TB
      • certain organs relative resistant to MTB → spread rare in these (heart,skel. muscle, thyroid & pancreas)
    • 2) rupture of granuloma into an airway
      • ⇒ “open” TB

HIV +ve patients & 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!

Clinical Features:

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

Commonest presentations:

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

Clinical stages:

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

children under 5yrs age:

  • 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.

Diagnosis

CXR

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 hematological disorders, specific malignancies, diabetes, silicosis, and chronic renal failure).

NAAT PCR

  • respiratory samples more reliable
  • sens 92%, spec 99%

culture

  • the gold standard
  • usually need two negative cultures to exclude TB (except in children who are often culture negative)
  • Sputum x3 early morning for AFB m/c
  • Urine x3 early morning for AFB culture if > 15yrs age

screening for latent TB

  • the Australian National TB Advisory Committee as at 2010, recommends:
    • tuberculin skin test as the standard test for latent TB infection, with,
    • Quantiferon Gold when high specificity is required or when ability to read tuberculin tests is not available
  • these tests have no role in initial investigations for active TB because negative results do not exclude disease and positive results may not necessarily indicate disease.

Treatment

tb.txt · Last modified: 2020/04/20 17:53 by gary1