Tuberculosis

Question 1

What are the risk factors for TB? (4)

Answer 1

Immigrants from countries with high rates of TB (Africa, South America, Asia)

Immunodeficiency - HIV, drugs (e.g. anti-TNFs, steroids), transplant, steroids

Chronic diseases: diabetes, CKD, Chronic liver (cirrhosis), chronic lung disease (silicosis, COPD), malnutrition, malignancy

Substance use: Smoking, alcohol, drug use

Question 2

TB - history?

Answer 2

P: symptoms, diagnosis date

Risk factors - contact, recent immigrant, ImmSx, chronic disease, substances, had BCG (at what age)?

I: How was it dx? CXR/CT, Mantoux/IGRA screening, TB sputum culture (having to give early morning sputum), Bronchoscopy/BAL

C: compliance - how is the drug administered (TB clinic - supervised vs. self)

M: Tx history - in detail. Doses, duration, previous treatments and resistance

C:

• complications of drugs - optic neuritis (eye pain), ototoxicity, hepatitis, renal impairment, PN,
• complications of disease (RF, ICU admissions)

Prognosis/current Progress

• Current state: symptoms, ET, frequency of FU, plan for the future.
• Insight into the disease - especially regarding public health
• How is patient affected - stigma, bothersome DOT, work/life...etc
• Public Health: does patient’s occupation involve a public health risk? - how is this handled? Did patient’s family & friends have screening? Is anyone else being treated?

Question 3

IGRA +ve means what?

Answer 3

It is a diagnostic test for latent TB infection.

It cannot distinguish between latent vs active TB disease.

Negative IGRA does not rule out active TB at any stage.

Question 4

What constitutes a positive tuberculin skin test (TST/Mantoux)?

Answer 4

≥5mm (High-Risk)

• Abnormal CXR consistent with prior TB
• Close contact with documented case
• ImmSx - transplant, HIV, pred ≥15mg/d

≥10mm (intermediate-risk) - all other at-risk groups, i.e.

• Health Care Workers
• From countries with high prevalence
• Pred <15mg/d
• Inmates, IVDU
• Diabetic (remember it is a risk factor for TB development)

≥15mm in all other patients.

Question 5

When would you choose IGRA (interferon gamma release assay) over TST?

Answer 5

When patient had BCG vaccination as they are less likely to return to have TST read.

Question 6

Rifampicin - usual daily dose and 3 side effects?

Answer 6

600mg/day.

RifamPicin

Red-orange urine

P450 inducer

Hepatitis

Question 7

Isoniazid - 3 side effects + daily dose

Answer 7

INH - 300mg (reduce the dose in CKD to 2-3 times per week)

Iron accumulation in mitochondria → sideroblastic anaemia

Neuropathy (peripheral) - give vitamin B6 (Pyridoxine)

Hepatitis

Question 8

Ethambutol usual dose and side effect (1)?

Answer 8

15mg/kg.

Ethambutol = Eye problems

Optic neuritis, decreased acuity + red/green discrimination

Question 9

Pyrazinamide usual dose and side effects (2)?

Answer 9

1.5 - 2g / day

PyRAZinamide - Raise uric acid - Gout

Hepatitis

Question 10

PAS (Para-Aminosalicylic Acid) - purpose, dose and 3 side effects?

Answer 10

12g.

Hepatitis

Diarrhoea

Hypersensitivity

Question 11

Streptomycin side effects (2) and dose?

Answer 11

StReptOmycin

Ototoxicity

Renal impairment

1g/day - contraindicated in pregnancy

Question 12

TB - exam finding to report?

Answer 12

General: Cachexia & wasting

Chest: upper-lobe coarse crackles/wheezes due to partial bronchial obstruction by lymphadenopathy

Amphoric breath sound (rare)

Extra-pulmonary (LN, Heart, Abdo, Renal, Bones)

Lymphadenopathy (especially in HIV patient) - most common

TB pericarditis - say no muffled breath sounds to suggest tamponade

Abdominal mass - say no evidence of TB peritonitis (severe tenderness)

Renal angle tenderness (GU involvement)

Pott’s - lumbar spine/Hips/Knees

Question 13

Positive TST (or IGRA) but no active disease on CXR and sputum for AFB. What is your management?

Answer 13

A careful approach to balancing the risk of disease vs. risk of treatment. Especially in elderly ≥65 (risk increases from 50) given risk of serious hepatotoxicity - there is linear relationship between the two.

Regime is usually INH for 9 months (90% never re-activate)

Question 14

Causes for false -ve TST? (4)

Answer 14

ImmuSx

Elderly (re-check after 3 weeks)

Miliary TB (50%)

Recent exposure (re-check after 12 weeks)

Question 15

Does QuntiFERON GOLD assay positivity always indicate TB infection? If IGRA -ve, does it mean that patient does not have TB?

Answer 15

No - false +ve can occur with other atypical mycobacteria. 98% specificity.

False -ve also occur, as sensitivity is only 80-85% (not a great NPV)

Question 16

What are the indications of testing for Latent TB infection (LTBI)? in which setting is TST preferred and why?

Answer 16

Individuals who are at risk of…

• New infection (contacts of patients with untreated, active TB, HCW at risk of exposure in regions with high TB incidence rate). HCWs in this setting require serial testing (at baseline then annual) - TST preferred for serial testing as IGRA is difficult to interpret in this setting.
• Progression from latent to active TB due to underlying conditions

Question 17

What is your approach to investigating a suspected active TB?

Answer 17

1. Obtain bodily secretions (3xmorning sputum, BAL, pleural fluid) or tissues (lung biopsy / LN biopsy)
   - Bronchoscopy/BAL should be reserved unless expectorated/induced sputum sample is not possible, or sputum is -ve, for alternative diagnosis or biopsy considered.
2. Send for AFB smear, culture, NAAT (nucleic acid amplification testing / PCR) and sensitivities to main TB drugs.
3. Send for Rpo gene if MDRTB suspected
4. IGRA or TST - not diagnostic, but supports dx if +Ve
5. CXR / CT chest (if not done already)
6. All should be tested for HIV and diabetes

Question 18

What are the risk factors for MDRTB? (3)

Answer 18

Prior TB treatment

Progression whilst receiving therapy

From a region (or contact with) with high prevalence of MDRTB (China, India, Russia - I would look this up)

Question 19

TB PCR/NAAT - What are caveats?

Answer 19

False-positive can occur (contamination/lab-error) hence should be interpreted in conjunction with AFB smear

Does not distinguish between dead / live organisms - so can remain +ve even after therapy. Therefore NAAT is only appropriate for initial diagnostic purposes but not for monitoring treatment

Must be confirmed by culture

Question 20

What is the 1st line drug regime for pulmonary & extra-pulmonary TB?

Answer 20

Pulmonary TB

RIPE - 4 drugs - Rifampicin, Isoniazid, Pyrazinamide, Ethambutol for 2 months, followed by 4 months of 2 drugs (usually rifampicin and INH).

Extra-pulmonary: same, except for

CNS (12 months + steroids for TB meningitis) or bone/joint (Pott’s - 9 months) disease.

Question 21

What is your approach to managing this patient with TB? (e.g. previously treated TB in transplant patient presenting with SOB/Cough)

Answer 21

Confirm previous dx: sputum/specimen/biopsy AFB cultures, histo, NAAT, sensitivities to drugs, and regimes patient received. Pulmonary vs. extra-pulmonary.

A:

• Investigate & treat exacerbating factors. Repeat sputum for above + work-up for non-TB pneumonia (including atypical / viral screen and blood cultures) + other alternative dx (CCF, PE, anaemia…etc).
• Investigate for complications: ABG, spirometry, extra-pulmonary TB guided by symptoms (CNS, Pott’s…etc)
• Screen for & treat depression

T: non-pharm (once confirmed)

• Educate: importance of adherence in preventing MDRTB, public health risk hence importance of contact traching. Written summary and web-site. Explain sideFX of treatments at each visits (hepatitis).
• All patient require individual case management with DOT (or video observed therapy) if adherence seems doubtful.
• Contact management: notify public health, GP, ID and if inpatient isolate in -ve pressure room, patient must be excluded from work-places/educational/childcare settings.
• Screen contacts to identify newly infected: any contacts with suspicious symptoms → need immediate review in TB clinic, asymptomatic contacts require TST/IGRA + CXR and referred to TB clinic to exclude active disease & consider treatment for LTBI

T: Pharm

• RIP(E-until sensitivity available) 2 months (intensive) then 4 months 2 drugs (continuation phase).
• If high-risk of MDR TB, consider addition of fluoroquinolones (e.g. moxifloxacin). Other choice includes streptomycin, amikacin, para-aminosalicylate (PAS). Seek ID advice.

Involve GP, Family, TB specialist for ongoing support and monitoring of adherence

Ensure F/U - monitor progress & screen for complicaitons

• Monthly sputum AFB + culture until 2 consecutive cultures are -ve
• At the end of 2 months of intensive phase of treatment - assess relapse risk (history, sputum, CXR) and determine total duration of therapy (if sputum still positive, need 7-9 months).
• If CXR has worsened, MDRTB / poor complaince / alternative dx should be suspected and managed as appropriate.

Question 22

Comment on below CXR (in context of patient with TB)?

Answer 22

Ghon focus is a small round area of shadowing that results from granulomatous inflammation. Classically found in the midzone (upper part of lower lobe or lower part of upper lobe).

If the Ghon focus also involves infection of adjacent lymph nodes / hilar lymph nodes - it is known as Ghons complex (or primary complex) - seen in the photo.

When it undergoes fibrosis/calcify (as part of healing) - it is called Ranke complex.

In contrast, TB reactivation/re-infection - cavitation occur & there is no lymphadenopathy.

Question 23

Patient was started on RIPE for TB. LFTs are derranged - what should you do?

Answer 23

This depends on the degree of derrangement.

Transaminitis up to 3 times ULN - no cause for concern and poorly correlates to significant hepatotoxicity.

Question 24

Newly dx TB patient. If a close contacts (e.g. household) relative or colleague have negative TST, what would you do?

Answer 24

Treat for 12 weeks and repeat the TST

Question 25

How would you decide whether this patient's anti-TB treatment is adequate and when it might be stopped? (4)

Answer 25

This depends on several factors. 1. Initial CXR (whether or not had cavitation) + progress CXR 2. Subsequent sputum AFB smear + cultures (especially at 2 months) 3. Symptoms 4. Side effects of drugs / tolerability **_Approach following 2 months of intensive phase_** * In most cases, the continuation phase should be 4 months * In HIV -ve patient, if initial CXR had no cavitation and AFB smear + culture -ve at 2 months **and** symptomatic and radiographic improvement → 2 months of continuation phase (total of 4 months) therapy is reasonable (aka culture-negative TB) * If at 2 months, if patient had cavitation on initial CXR **and** positive sputum culture → treatment should be extended to 7 months, especially if 1st regime did not contain pyrazinamide

Question 26

TB: In cases where the therapy was interrupted, how would you manage?

Answer 26

The decision need to be made whether to 1) extend the current therapy or 2) restart the treatment from the beginning. This would be based on the burden of disease, duration of the interruption, and time-point when it was interrupted. Consultation with an expert in TB is required

Question 27

How would you manage Hepatotoxicity whilst receiving RIPE therapy for TB?

Answer 27

Involve **expert TB physician** early Drug susceptibility data need to be reviewed carefully + identify drug (s) that has caused hepatotoxicity. All drugs in RIPE, except for Ethambutol can cause hepatotoxicity. **Principles**: 1. Rule out other causes of hepatitis or biliary obstructions 2. If bilirubin (\>45) or transaminases (\>3-5 times ULN) → anti-TB hepatotoxins need to be ceased 3. Once LFT returns to baseline (or \<2 x UNL) → start the drug 1 at a time whilst carefully monitoring LFTs 4. If interruption of therapy is not possible (e.g. progressive loss of pulmonary function / worsening active disease) → 3 second line drugs (e.g. ethambutol, moxifloxacin, streptomycin...etc) until LFT returns to baseline 5. Then restart one at a time 6. Once the causative agents are identified, Options are: Intolerance to INH → RPE regime for 6 months Intolerance to Rifampicin → IPE for 2 months, then IE for 12-18 months Intolerance to pyrazinamide → RIE for 9 months (stop E once susceptibility to iNH / Rifampicin demonstrated) Intolerant to all → ethambutol, moxifloxacin and other 2nd line agents

Question 28

What is your approach to manage newly dx TB in patient with HIV on ART?

Answer 28

Main issue is the drug interaction, especially with **Rifampin - p450 inducer.** Generally, patients with HIV already on ART → continue ART regime + initiate anti-TB asap. * If current ART regime is well tolerated, it should be continued ant anti-TB meds should be adjusted accordingly. * Use online interaction tool + expert ID advice regarding choice of anti-TB regime. * Key change is likely to involve using **Rifabutin** - that has fewer drug interactions, equally active as Ripampin (rifampicin) but less cost-effective. If patient is on PI, NNRTI, INSTI, switch to Rifabutin is likely needed. * Further refinement once susceptibility is available * May need to adjust ART to more rifabutin compatible regime (in consultation with ID)

Question 29

TB patient not on treatment yet was also diagnosed with HIV. What is your approach in managing this?

Answer 29

It is generally agreed that ART should not be delayed just to complete anti-TB therapy. The main aim is to prevent IRIS when ART is started. Approach depends on patient's CD4 counts. **CD4 \<50**: start **ART within 2 weeks** after starting TB treatment (1A) - risk of IRIS is higher, but lower combined risk of AIDS defining illness & death. **Give steroids for 4 weeks.** **CD4 ≥50**: ART **8 weeks after** starting TB treatment (1A) - this is to minimise risk of IRIS **CNS TB**: ART should be delayed for **8 weeks after** TB treatment, regardless of CD4 Give steroids for 1st 4 weeks after initiating ART if it was started within 30 days of commencing anti-TB