Tuberculosis

Question 1

Microbiology of tuberculosis infection:

Answer 1

• TB caused by members of the M.tuberculosis complex - M. tuberculosis, M. bovis, M. africanum, M. micronoti, M.canetti, M. caprae
• Aerobic, thin curved rod
• Cell envelope is distinguishing characteristic
• Gram positive on staining. Ziehl-Neelson stain or fluorescent dye (auramine) to identify AFB (though does not distinguish from non-tuberculous mycobacteria) - sensitivity on non-sputum samples generally lower. Generally consider smear negative patients non-infectious (if subsequent positive culture)
• Growth - slow, requires 3-4 weeks. M. tuberculosis reduces nitrate allowing it to be distinguished from other mycobacterial species

Question 2

What are the 4 potential outcomes of inhalation aerosol droplets of M. tuberculosis:

Answer 2

1. Immediate clearance
2. Primary disease - immediate onset of active disease
3. Latent infection
4. Reactivation disease - onset of active disease many years following a period of latent infection
   
   1. If no underlying medical problems - 5-10% of latent infections will reactivate. Increased risk with HIV

Question 3

Notes on TB Primary Disease

Answer 3

• 5-10% infected develop active disease - 50% within 2-3 years following infection
• Bacilli → droplets → alveolar space → proliferate inside alveolar macrophages → migrate from lungs to other tissues
• Lungs: develop granulomatous structure called tubercle → enlarges (Ghon focus). Bacilli enter local draining lymph nodes → lymphadenopathy (lymph node enlargement/calcification + Ghon focus = Ranke complex)
• Cell-mediated immune response develops within 2-10 weeks (CMI). Failure to amount effective CMI → progressive destruction of lung and caseating necrosis
• Unchecked growth = disseminated TB
  
  • Miliary TB, bacilli can spread mechanically by erosion of caseating lesions into airways (host becomes infectious). Death in 80% without treatment

Question 4

Disorders that cause caseating necrosis:

Answer 4

• TB
• Syphilis
• Histoplasmosis
• Cryptococcus
• coccidioidomycosis

Question 5

Notes on reactivated TB

Answer 5

• Proliferation of previously latent bacteria seeded at the time of the primary infection
• Reactivation A/W immunosuppresion:
  
  • HIV, CKD, DM, lymphoma, corticosteroids, TNF-a inhibitors, cigarette smoking, diminution in cell-mediated immunity associated with age
• Tends to be localised - little regional lymph node involvement and less caseation
• Lesion typically at lung apices - disseminated disease unusual unless severely immunocompromised
• Latent TB confers some protection against subseqeunt TB infection, prior TB disease A/W increased risk of subseqeunt TB disease

Question 6

Risk factors for TB

Answer 6

Host factors:

• Immunosuppression - HIV, glucocorticoids, DM, TNF inhibitors, transplant
• Substance abuse - drug (plus epidemiological factors A/W this e.g. homelessness), tobacco, alcohol
• Systemic disease - silicosis, malignancy (haematological, and head and neck cancers), DM, CKD, cirrhosis, COPD, gastric resection for PUD
• Nutritional status - underweight, vitamin D deficiency

Social/Environmental factors

• Household contacts
• Birth in a TB endemic area → Philippines, Vietnam, China, India
• Low socioeconomic static - crowding, poor nutrition, poor access to medical care, unemployment, low education

Question 7

Investigations for pulmonary tuberculosis:

Answer 7

• CXR
• Sputum - 3 x early morning sputum for AFB and culture
  
  • Induced sputum preferred - more sensitive than bronchoscopy in dx pulmonary TB in subjects who are AFB negative
  • If bronchoscopy required - BAL produces better yeild than “bronchial washings’

Question 8

CXR findings in TB:

Answer 8

• Features of active pulmonary disease (need to be followed up with sputum):
  
  • Patchy consolidation or infiltration
  • Definite infiltration/consolidation/cavitation
• Features of inactive/fibrotic changes with high probablity progession (need to send sputum)
  
  • Minor lobar scarring, large focal areas of scarring, patchy/definite lobar consolidation/infiltration
• Features of previous TB with low probability of reactivation (do not need sputum testing unless immunosuppressed)
  
  • Calcified lymph node or pleura, minor apical pleural thickening, single calcified granuloma <10mm
• Cavity formation uncommon in primary TB
• Miliary - evenly distributed nodules - disseminated TB
• Pleural and mediastinal lymph node disease are classified as extra-pulmonary TB

Question 9

Investigations for suspected pleural TB:

Answer 9

• Pleural biopsy more sensitive than pleural fluid TB culture
• ADA (adenosine deaminase) - useful in diagnosis suspected TB pleural effusion

Question 10

Notes on CNS tuberculosis:

Answer 10

• Chronic presentation - malaise, headache, mental change, meningism and focal neurological signs - presentation can be broad (headache → coma)
• May be no evidence of pulmonary disease
• Investigations:
  
  • CT/MRI - r/o raised ICP, posterior fossa disease, obstructive hydrocephalus
  • CSF (large volume): leucocytosis (lymphocyte predominant), raised protein, low glucose, send CSF for NAAT, AFB found <20% cases, 45% with suspected TB meningitis have negative CSF cultures
• Moxifloxacin better CNS penetration than ethambutol

Question 11

Other abnormalities of blood tests/routine blood tests that should be done in TB:

Answer 11

• CBC - leucoctosis, of leukopaenia
• Anaemia
• Pancytopaenia if extensive bone marrow involvement
• Hyponatraemia - production of ADH like hormone in diseased tissue
• Hypercalcaemia - mild and usually responds to TB treatment
• Mild LFT derangement
• Hypoalbuminaemia
• All patients with suspected TB should have HIV test

Question 12

Standard treatment regimens for pulmonary tuberculosis

Answer 12

• 2RZHE/4RH
• Intensive phase:
  
  • 2 months of rifampicin, isoniazid, ethambutol and pyrazinamide
• Continuation phase:
  
  • 4 months isoniazid and rifampicin

Update 2022

4 month regimen now supported by WHO

8 weeks rifapentine, isoniazid, pyrazinamide, moxifloxacin, then 9 weeks rifapentin, isoniazid, moxifloxacin

Problems with international supply of rifapentine

Question 13

Standard treatment regimens for extrapulmonary tuberculosis

Answer 13

• Generally same 6 month regimen except for meningeal TB, intracranial TB, and TB of bones and joints
• Meningeal TB = 12 months therapy
  
  • 2RHZE/10RH
• Intracerebral TB = 18 months
  
  • 2RZHE/16RH
• If disseminated TB treat for 9 months and look for CNS involvement and extend treatment accordingly
• 9-12 months for bone and joint TB (given difficulties in assessing treatment response)
• Longer duration of treatment also recommended in the presence of severe disease, extensive disease, drug resistance or clinical or radiological improvement that is slower than expected

Question 14

Predictors of drug-resistant TB:

Answer 14

1. Previous TB treatment
2. Progressive clinical and/or radiographic findings while on TB treatment
3. Origin from, history of residence in or frequent travel to a region/country with high rates of drug resistance
4. Exposure to an individual with infectious drug-resistant TB

Question 15

Treatment of drug resistant tuberculosis:

Answer 15

Isoniazid resitant tuberculosis:

• 6REZM (isoniazid replaced with moxifloxacin)

Rifampicin resistant tuberculosis

• Very uncommon, should raised suspicion of MDR-TB. Requires longer duration of treatment if loss of rifampicin from regimen

Pyrazinamide resistant tuberculosis

• M. bovis naturally resistant to this
• 2RHE/7RH. Add moxifloxacin if extensive disease

Question 16

Notes on multidrug-resistant TB

Answer 16

• TB that is resistant to rifampicin and isoniazid
• Pre-XDR TB (extensively resistant) → resistance to rifampicin + isoniazid + fluroquinolones
• XDR TB → Above + at least one additional Group A drug
• Therapy for 18 months with at least 5 drugs that are likely to be effective - work way through groups as below (note Bangladesh regimen allows 9 months of therapy only)
• Daily DOT mandatory for all patients with MDR-TB
• Elective partial lung resection may be used alongside a recommended MDR-TB regimen

Question 17

Role for corticosteroids in tuberculosis

Answer 17

• Recommended in first eight weeks for:
  
  • TB meningitis
  • TB pericarditis
  • Possible benefit in life-threatening cases of TB
    
    • Miliary TB on CXR
    • To reduce mass effects and obstructive complications from mediastinal lymphadenopathy
    • In HIV immune reconstitution syndrome resulting in worsening of clinical status in a patient with active TB

Question 18

Notes on tuberculous pericarditis

Answer 18

• Almost always fatal without treatment - 40% mortality rate with treatment
• Constrictive pericarditis can be early or late complication of TB
• Corticosteroids unlikely to stop progression to constrictive pericarditis but do improve survival and reduce need for surgery

Question 19

Other considerations in management of TB:

Answer 19

• Smoking cessation - smoking A/W increased rates TB, increased risk transmission, faster progression and poorer prognosis
• Nutrition - malnutrition A/W increased risk mortality and relapse of active tb

Question 20

Notes on isoniazid

Answer 20

• Should take pyridoxine 10-25mg/day esp. if at risk of peripheral neuropathy for other reasons (DM, CKD, malnourishment, alcoholism, HIV)
• Adverse effects;
  
  • Hepatotoxicity
  • Peripheral neuropathy, optic neuritis
  • Rash

Question 21

Notes on rifampicin

Answer 21

• Take on empty stomach - peak serum concentration reduced by ⅓ if taken with fatty meal
• Only free rifampicin (not plasma-protein bound rifampicin) is available to interact with mycobacteria
• Excreted in urine, sweat, tears, other bodily fluids - colours them orange
• Adverse effects:
  
  • Gastrointestinal disturbances, LFT derangement
  • Acute haemolytic anaemia, thrombocytopaenia, leukopaenia
  • Drug induced lupus
  • Cutaneous syndrome may occur with flushing and/or itch without rash

Question 22

Notes on pyrazinamide

Answer 22

• Adverse effects:
  
  • GI, hyperuricaemia → precipitation of gout
  • Of all the TB drug → most common cause of rash
  • Hepatitis

Question 23

Notes on ethambutol

Answer 23

• Adverse effects:
  
  • Optic neuropathy (dose related) - should have baseline visual acuity and red-green colour vision assessment prior to starting
  • Peripheral neuropathy

Question 24

TB drugs that cause rash:

Answer 24

• Pyrazinamide most common
  
  • Also causes facial flushing and transient pruritus
• Isoniazid - isolated rash in 2%
• Can get a mild rash with rifampicin
• Photosensitivity - pyrazinamide and fluoroquinolones

Question 25

Hepatotoxic TB drugs

Answer 25

Occurs in about 5% treatment courses Risk factors * Pre-existing liver disease, alcohol * Increased age * HCV, HBV, HIV co-infection * Pregnancy → 3rd trimester * Other medications ALT 2-5 x ULN and asymptomatic → monitor closely \>5 X ULN with symptoms → stop If can't safely stop then use: amikacin, ethambutol, moxifloxacin Once ALT near baseline restart with drug challenge → up to 75% of patients will tolerate re-introduction of isoniazid and rifampicin Pyrazinamide \> isoniazid \>\> rifampicin (Same as the skin ones)

Question 26

Notes on aminoglycoside toxicity

Answer 26

**Auditory and vestibular** * Half of aminoglycoside hearing impairment irreversible, vestibular dysfunction sometimes reversible * Independent of nephrotoxicity * Risk factors: * Older age * High trough serum levels * Duration of administration * Total dose * High fever and bacteraemia * Dehydration and prior renal or ear disease **Nephrotoxicity** * Relates to dose, duration of treatment and age * More likely if pre-existing renal impairment, dehydration or liver disease * Loopd diuretics nad other nephrotoxics also increase risk

Question 27

Notes on interferon-gamma release assays for diagnosis of latent TB infection

Answer 27

* Quanteferon Gold * If a person is infected with M.tuberculosis, T lymphocytes circulating will produce IGN-gamma if re-exposed to TB antigens in vitro * They use antigens that are more specific than Mantoux - so not confounded by prior BCG vaccination - preferred testing tool with prior BCG vaccination * Specificty 98% for low TB populations with no risk factors * Sensitivity 80% → can't be used as a test to exclude active TB * Can stay positive after sucessful TB treatment → cannot be used to assess treatment outcome * May be negative in active disease * Settings where Quant Gold is preferred over Mantoux: * BCG vaccination * High risk patient won't return to read their Mantoux * The patient has had LTBI or TB previously * Healthcare workers

Question 28

Who should be screened for latentTB:

Answer 28

* High-priority contacts of pulmonary TB cases * People with HIV * People starting TNF-alpha inhibitors or undergoing solid organ transplant * People potentially exposed to TB and are at increased risk of developing active disease due to impaired immunity * Health care workers with an exposure history

Question 29

Tests used to diagnose latent TB - Mantoux

Answer 29

* Mantoux * Intradermal injection of 5 tuberculin units of purified protein derivative (PPD) - derived from cultures of M.tuberculosis * If prior M tuberculosis infection patient will develop a delayed type hypersensitivity reaction * High sensitivity in immunocompetant individuals * Potential for confounding of the test result by prior BCG vaccine and exposure to non-tuberculous mycobacteria

Question 30

Notes on treatment of latent TB (who)

Answer 30

* Note: final diagnosis depends on absence of radiological or other signs of active or inactive TB disease - need a CXR before starting treatment for LTBI * Generally hold off on treating LTBI in pregnancy and breastfeeding women until after delivery * Caution in liver disease * Hepatitis B e antigen positivity → important risk factor for severe isoniazid hepatitis * Caution with concurrent meds that cause hepatotoxicity * Caution in alcohol abuse

Question 31

Treatment regimens for LTBI

Answer 31

* WHO recommendation options: * 9 months isoniazid → up to 15% world's TB resistant, severe hepatotoxicity in \<2% but increases with age * 4 months rifampicin → note drug interactions, higher completion rates and less hepatotoxic * Prevent TB trial: 9H vs 3 months of weekly H and rifapentine → higher completion rates, less hepatotoxic, higher rates of hypersensitivity, non-inferior

Question 32

Notes on GeneXpert (Xpert MTB/RIF)

Answer 32

* Automated molecular test for MTB and resistance to rifampin * PCR assay * For smear positive TB - sensitivity is 98%

Question 33

Notes on bedaquiline and delamanid

Answer 33

Newer drugs for TB (multi-drug resistant) **Bedaquiline** Oral diarylquinolone; targets ATP synthase 1ST drug with novel mechanism approved by FDA for TB since 1971 **Delamanid** Nitroimidazole class; inhibits mycolic acid synthesis

Question 34

WHO update May 2022 on treatment of drug resistant TB

Answer 34