Tuberculosis

Question 1

Mycobacterium

Answer 1

• Meaning fungus-bacterium because of the way the tubercle bacillus grows as mold-like particles on the surface of liquid media.
• Aerobic, non-spore forming, non-motile rods
• Cell wall contains mycolic acids , that provide a hydrophobic permeability barrier
• Acid and alcohol fast

Question 2

Mycobacterium Classification

Answer 2

• *M.tuberculosis *(MTB) complex (Typical)
  
  • All phenotypically and genotypically similar
  • Can all cause tuberculosis
• Non-Cultivatable Mycobacterium
  
  • M.leprae
• ​MOTT (mycobacteria other than TB) - Atypical or Non-tuberculous mycobacterium (NTM)
  
  • Runyon Clasification
    
    • I - Photochromogens
    • II - Scotochomogens
    • II - Nonphotochromogens
    • IV - Rapid Growers
      
      • Chromogens
      • Non-chromogens

Question 3

MTB Complex

Answer 3

• M.tuberculosis
• M.bovis (inc. BCG)
• M.africanum
• M.microti
• M.canetti
• M.caprae
• M.pinnipedii

Question 4

Mycobacterium Tuberculosis

Answer 4

• Human pathogen
• Transmitted by respiratory droplet (infectious dose: 1-10 bacilli)
• Adapted to intracellular survival within the human macrophage
  
  • Latency/dormant/non-replicating persistence
  • Allows lifelong infection

Question 5

Tuberculosis Infection - Natural History

Answer 5

• Exposure to MTB
  
  • No infection
  • Infection ==>
    
    • Primary TB in the first 1-2 years after infection - 5% - re-exposed to MTB
    • Latent TB infection 95% ==>
      
      • Long-term immune control==>
        
        • Reactivation TB - 5% - re-exposed to MTB
        • Lifelong Containment - 90%

Question 6

Tuberculosis - Factors That Promote Progression To Active Disease

Answer 6

• HIV
  
  • At all CD4 counts
  • More extrapulmonary disease manifestation
• Immunosuppressive drugs:
  
  • High dose steroids
  • Infliximab (anti-TNAalpha)
• Age: very young; very old
• Poor nutrition
• Homelessness/alcohol/IVDA/poverty

Question 7

Tuberculosis - Control

Answer 7

• Diagnose & treat people with active disease, especially infectious pulmonary tuberculosis
• Vaccination
  
  • Limited and variable efficacy (UK not-useful vs India where prevents dissemination)
  • Age 12-14, or at birth if parents are from high risk groups
• Diagnose people with latent tuberculosis infection and give preventative therapy
  
  • 1 infectious case infects 10 other people, of whom 1 will develop TB
  • Tuberculin skin test (Heaf): cross-reactivity of PPD with BCG
    
    • Focus on high-risk groups at risk of progression to active TB:
      
      • Recent contacts of TB cases
      • Recent immigrants
      • HIV infected
      • Children - especially <5 years old
      • Concomitant illness: renal failure, diabetes, haematological malignancies etc.
      • Iatrogenic immunosuppression: steroids, organ transplants, methorexate, anti-TNFalpha
  • Contact tracing
  • New arrivals from high prevalence areas
  • Child contacts

Question 8

Tuberculosis - Diagnosis

Answer 8

• Specimens:
  
  • Sputum, gastric washings (for children who swallow sputum - acid fast bacterium so survives in stomach), bronchoalveolar lavage
  • Early morning urines
  • Biopsies
• Procedures:
  
  • Microscopy (result within 24h; not all AFBs are TB)
    
    • Ziehl-Neelsen
    • Auramine
  • Culture (crucially important, but often negative)
    
    • Solid phase: Lowenstein-Jensen medium
    • Liquid phase: uptake & release of radiolabelled carbon
    • Drug sensitivities
  • Histology
    
    • Granulomata with central caseous necrosis

Question 9

Guidelines For Tuberculin Screening And Treatment For Latent TB Infection

Answer 9

• Focus on high risk-groups who are at increased risk of progression to active TB:
  
  • Recent contacts of TB cases
  • Recent immigrants
  • HIV
  • Children, especially < 5yrs old
  • Concomitant illnesses: renal failure, diabetes, haematological malignancies etc
  • Iatrogenic immunosuppression
    
    • Steroids
    • Organ transplants
    • Methotrexate
    • anti-TNF

Question 10

Tuberculosis - Mantoux Test - Mechanism

Answer 10

• Purified protein derivative (PDD) is a glycerol extract from cultured tubercele bacilli
• Injected intradermally (2U of 0.1-mL)
• Result is measured 2-3 days later:
  
  • Mantoux negative - Induration less than 6 mm
  • Mantoux positive - Induration 6 mm or greater
  • Mantoux strongly positive - Induration 15 mm or greater
    
    • ​​A positive result implies previous exposure to tuberculin protein - thus it could represent previous BCG exposure = type IV hypersensitivity reaction
• Formerly used Heaf test same principle but less accurate

Question 11

Tuberculosis - Mantoux Test - Drawbacks

Answer 11

• Poor specificity: antigenic cross-reactivity of PPD with BCG and environmental mycobacteria
• Poor sensitivity: 75-90% in active disease (lower in disseminated TB and HIV infection; unknown for latent infection)
• Operational drawbacks:
  
  • ​Need for return visit
  • Operator variability (inoculation & reading)
  • Standardisation of reagent
  • Painful inflammation & scarring

Question 12

Tuberculosis - ELISPOT Test

Answer 12

• T-SPOT.TB is a type of ELISPOT assay used for tuberculosis diagnosis:
  
  • Non-radioactive
  • Sterile tissue culture facilites not required
• High affinity antibodies to IFN-gamma capture amounts emmitted by T-cells they are incubated with overnight
  
  • The amounts are then revealed by dye showing spots proportional the amount of individual effector-memory anti-mycobacterial T-cells
    
    • This reveals the prescence of infection with Mycobacterium tuberculosis including latent infection
• Advantages over tuberculin skin tests are:
  
  • Fast - results within 24 hours
  • Less influenced by BCG vaccination - uses relatively* Mycobacterium tuberculosis* specific antigens (peptides ESAT-6 and CFP-10) which are absent from BCGs (which use a different antigen) and most nontuberculus mycobacteria

Question 13

Tuberculosis - Treatment

Answer 13

• Standard of 2 months isoniazind + rimpicin + pyrazinamide + ethambutol
  
  • Followed by:
    
    • ​Conventional active respitatory (lung/pleura/mediastinal nodes/larynx) TB
    • Bone and joint TB
    • Lymph node TB
    • Disseminated including miliary (unless evidence of meningeal involvement)
    • Other sites NOS
      
      • 4 months of isoniazid + rifampicin
    • Meningeal TB = 10 months* isoniazid + rifampicin* plus prednisolone (20-40mg or 1-2mg/kg per day)
    • Pericardial TB = **4 **months of* isoniazid + rifampicin* plus predinoslone (60mg or 1mg/kg per day)

Question 14

Tuberculosis - Multi-Drug Resistant

Answer 14

• MDR-TB (Multidrug Resistant TB) describes strains of tuberculosis that are resistant to at least the two main first-line TB drugs - isoniazid and rifampicin.
• XDR-TB, or Extensive Drug Resistant TB (also referred to as Extreme Drug Resistance) is MDR-TB that is also resistant to three or more of the six classes of second-line drugs (aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine and terizidones)
• In 2000–2004, of 17,690 TB isolates referred to international network of TB laboratories, 20% were MDR and 2% were XDR.

Question 15

Tuberculosis - Multi-Drug Resistance - Causes and Risk Factors

Answer 15

• Resistance in populations is largely due to poorly managed TB care - incorrect prescribing, poor quality drugs, erratic supply and patient non adherence
• Risk factors for diagnosis include:
  
  • History of prior TB drug treatment; prior TB treatment failure
  • Contact with a known case of drug-resistant TB
  • Birth in a foreign country, particularly high-incidence countries
  • HIV infection
  • Residence in London
  • Age profile - with highest rates between ages 25 and 44
  • Male gender