Tuberculosis

Question 0

What are the risk factors of tuberculosis?

Answer 0

Poverty and overcrowding which increases inter patient spread, resulting in the inhalation of aerosolised droplets by coughing, sneezing or talking

Medical risk factors like diabetes, conditions requiring long term high dose CS, immunosuppressant patents,

Homelessness, IV drug users, alcohol misusers

Malnutrition (deficiency of vitamin A and D)

HIV- the single most important factor determining the increased incidence of TB in the last 10 years
HIV weakens the immune system and increases likelihood of infection with TB bascilli
TB is the Leading cause of death among people who are HIV positive (13% of AIDS death worldwide)

Question 1

What is the epidemiology of tuberculosis?

Answer 1

Kills more people than any other single infectious agent
~1/3 if the worlds population is infected
1/3 of 40million people living with HIV are co infected with TB
Infection rates and risk of TB differ markedly between affluent and poorer areas of the world
Asia has the largest burden of disease
India and china are responsible for 35% of all cases worldwide
3million people die each year from the disease
There are 400 cases per year in NZ
2/3 of cases are pulmonary and 1/3 of cases are extrapulmonary
There is a 16x increased rate in maori than in Europeans

Question 2

What are the microbiological characteristics of TB?

Answer 2

Aerobic bacilli.
Complexes include M. Tuberculosis, M. Bovis, M. Microti, M africanum.
Predominant pathogen in humans is M. Tuberculosis.

Produces β lactamase enzymes: intrinsic resistance to penicillin.
Acid fastness: resistance to decolourisation by acid. Hence, acid fast bacilli

Question 3

What is the Pathogenesis of TB?

Answer 3

Primary infection initiated by alveolar implantation of organisms in droplet nuclei which are small enough to reach the alveolar surface (~1-5mm)
Ingestion and inoculation are rarer ways of getting TB infection.

Question 4

What are the main causative organisms of primary TB infection?

Answer 4

M. Tuberculosis
M. Bovis
M. Micro tri
M. Canetti
M. Africanum

Question 5

What are the main disease stages of TB?

Answer 5

Immediate clearance of organisms
Latent infection
Primary disease
Re activation of disease

Question 6

What does the progression of TB disease depend on?

Answer 6

The number of bacteria inhaled or ingested
The virulence of bacteria
The cell mediated immune response of the host

Question 7

What is primary TB infection?

Answer 7

Occurs within first 2-3 years after infection
Accounts for half of TB cases
Caused by inhaled TB bacilli reaching alveoli and infecting alveolar macrophages to induce n immune response with attraction of other inflammatory cells

Question 8

What is the immune response to primary TB infection?

Answer 8

CD4+ lymphocytes activate macrophages to engulf and kill mycobacteria. This forms a tubercle.
T lymphocytes destroy macrophages which are unable to kill invaders.
Depletion of T lymphocytes in HIV = inadequate defences against M. TB
If macrophages can kill the bacterial the infection is aborted.
If macrophages cannot kill bacteria, the bacteria multiplies within the macrophages.
If the bacteria cannot be contained, the macrophages rupture and release it which is then taken up by other macrophages to continue the process.

Question 9

What are the two mechanisms of immune evasion exhibited by M. TB?

Answer 9

Inhibition of lysosomes to phagosome fusion

Lopoarabinomamnan

Question 10

What is inhibition of lysosomes to phagosome fusion?

Answer 10

This prevents the destructive enzymes found in lysosomes from getting to the bacilli captured in hit he phagosomes.
This allows the M. TB to escape into the cytoplasm where it is able to multiple in the macrophage cytoplasm

Question 11

What is lipoarabinomanan?

Answer 11

This induces immunosuppressive cytokines, blocks macrophage activation, scavenges oxygen and therefore prevents attacks by superoxide anions, hydrogen peroxide and hydroxyl radicals

Question 12

What are the two ways which describe how is TB eradicated?

Answer 12

cell mediated immunity

delayed type hypersensitivity

Question 13

What is cell mediated immunity?

Answer 13

Where CD4+ T lymphocytes are presented with M. TB antigen

This stimulates macrophages to become bactericidal via interferonγ to target the mycobacterium and control the infection

Question 14

What is delayed type hypersensitivity?

Answer 14

This also develops through activation and multiplication of T lymphocytes.
This kills the infected macrophages and release the mycobacterium which is then killed by activated macrophages.

Question 15

Which hypersensitivity produces a positive TB test?

Answer 15

The delayed type hypersensitivity where T lymphocyte activation and multiplication kills infected macrophages to release the bacterium which can then be eradicated by active macrophages

Question 16

What are the the possible implications for people who have had primary TB ?

Answer 16

90% have no further clinical manisfestation
5% get progressive primary disease at site of infection leading to meningitis and often to involvement of upper lobes of the lung.
10% develope activation disease which occurs years later

Question 17

What sorts of patients typically make up the 5% who get progressive primary disease after the initial infection?

Answer 17

Children, elderly or the immunocompromised

Question 18

What is the usual site of primary TB infection?

Answer 18

The lower lobes

Question 19

What is progressive primary TB?

Answer 19

This occurs in 5-10% of cases and arises due to an inadequate immune system,
Patient develops both pulmonary and constitutional symptoms
May occur in 50% of HIV patients

Question 20

What is miliary TB?

Answer 20

Chronic TB infection where original primary infection is spread via lymphatic system.
Immunocompromised patients are more at risk
Treat with INH, rifampacin, ethambutol and other antibiotics

Question 21

What is latent TB infection?

Answer 21

Patient has TB but infection is not clinically apparent.
No active disease due to presence of live, dormant and non-reproducing M. TB
Disease may occur if host’s immune defences are impaired.
Chest X-ray either normal or trivial/stable evidence of past TB
5% of individuals with latent TB develop active disease within 2 years
Another 5% develop after 2 years

Question 22

What is post primary infection?

Answer 22

This occurs if the individual becomes reinfected or the primary disease is reactivated

Question 23

What is inactive TB?

Answer 23

Chest X-rat is not trivial
Patients have annual risk of developing active disease at least 2.5x greater than patients with latent TB
Patient is likely to have more dominant TB organisms than a patient with Mantoux conversion and a normal chest X-ray

Question 24

How is pulmonary TB clinically presented?

Answer 24

Persistent productive cough (>2 weeks) Pleuritic chest pain Shortness of breath Haemoptysis (coughing up blood) X-ray shows apical (upper lobe) consolidation + cavity formation Pulmonary cavity favours bacterial multiplication to very high levels Patients usually sputum smear positive and highly infectious

Question 25

How is CNS clinically presented?

Answer 25

Most serious clinical manisfestation Results in meningitis or space occupying lesions of the brain. Meningitis usually presents as headache, neck stiffness + fever Alteration in mental status is common. Cranial nerve palsies may occur Severe form of sudden onset of meningitis may occur with rapid progression to coma

Question 26

What is different about clinical presentations of TB in HIV patients?

Answer 26

Usually prevents atypically. HIV patients: Less likely to have Positive skin tests, cavitary lesions or fever Higher incidence of extrapulmonary TB More likely to present with progressive primary disease

Question 27

What is different about the clinical presentations of TB in elderly patients?

Answer 27

TB in elderly is easily confused with other respiratory diseases TB in elderly is less likely to present in skin tests, fevers, night sweats, sputum production or haemoptysis

Question 28

Whatis the preliminary diagnosis of TB based on?

Answer 28

Patient symptoms and signs Tuberculin reaction Radiographic appearance

Question 29

What are the clinical tests for TB?

Answer 29

Mantoux test | Interferon γ release assay test

Question 30

What is the Mantoux test?

Answer 30

Individuals in whom TB is suspected are given 0.1mL of 100units/ml interdermal tuberculin purified protein derivative injection. This causes a hypersensitivity reaction in patients exposed to TB, BCG and other mycobacteria as they will have the antibody against it. After 48-72 hours, result is measured based on the size of the welt formed on the skin.

Question 31

How is latent TB interpreted using the Mantoux test?

Answer 31

Size of the welt is correlated with future risk of developing TB

Question 32

How is recent TB infection interpreted using the Mantoux test?

Answer 32

Shown by the conversion of the Mantoux from negative to positive due to infection non with TB or non TB mycobacteria which includes the BCG vaccination

Question 33

What are the limitations of the Mantoux test?

Answer 33

Time consuming Requires great skill to administer Has poor positive predictive value for current active disease as there is no correlation between size of welt and likelihood of active disease. Diagnosis of disease depends on isolation of organism HIV/aids, and other immunosuppressive illnesses can give false negative Mantoux results

Question 34

What is considered a positive result for the Mantoux test?

Answer 34

If the size of the welt is >/=10mm for normal patient | Or >/=5 mm for immunosuppressed patients e.g. On prednisone etc

Question 35

What is the interferon γ release assay test?

Answer 35

3 test tubes are used One is a nil tube which acts as the control One is the nitogen tube and contains phytothemagglutinin which acts as the positive control One is the TB antigen coated tube which is the test tube. Blood from the infected patient is added to each tube. An immune response is triggered if patient is infected, releasing interferon γ from the T cells indicating tuberculosis

Question 36

What is the advantage of the interferon γ release assay test?

Answer 36

It is moire specific than the Mantoux test

Question 37

What are the desired outcomes of TB?

Answer 37

TB is a Notifiable disease. As stated by the TB act 1948 a medical officer needs to be notified to identify the source case and educated contacts about TB in order to rapidly identify new cases of TB. Also requires isolation of patient to prevent spread Collection of appropriate samples for sears and cultures Prompt resolution of signs and symptoms of disease after initiation of treatment Achievement of non infectious state in order to stop the isolation Promote adherence to treatment Cure patient ASAP usually with at least 6 months treatment

Question 38

What is the aim of pharmacological treatment of TB?

Answer 38

Reduce bacterial population as rapidly as possible and prevent the emergence of drug resistant bacteria.

Question 39

What is the fundamental treatment principle with TB?

Answer 39

A single drug should never be attempted | A single drug should never be added to a failing regimen

Question 40

What are the first line drugs for TB treatment?

Answer 40

``` Rifampicin Isoniazid Pyrazinamide Ethambutol Streptomycin ```

Question 41

What are the second line drugs for TB treatment?

Answer 41

Aminoglycosides (amikacin, streptomycin) Quinolones (ciprofloxacin) Macrolides (clarithromycin, azithromycin) Rifabutin (structurally related to rifampicin)

Question 42

What is rifampicin?

Answer 42

Bactericidal drug that should be given on an empty stomach

Question 43

What is the mechanisms of rifampicin?

Answer 43

Inhibits DNA dependent RNA polymerase in bacterial cells by binding to its β subunit to prevent transcription to RNA and subsequent translation to protein

Question 44

What is a benefit of the lipophilic nature of rifampacin?

Answer 44

Makes it a good candidate to treat meningitis forms of TB as this requires distribution of the drug to the CNS and penetration through the bbb. A lipophilic drug gains access to the bbb easier

Question 45

When would rifabutin be used?

Answer 45

It is a less potent enzyme inhibitor, it is better tolerated by HIV patients and their multi drug therapy.

Question 46

What are the adverse effects of rifabutin?

Answer 46

``` Hepatitis Cutaneous reactions like flushing, rash, redness GI reactions Flu like symptoms Staining of secretions Thrombocytopenia ```

Question 47

What is isoniazid?

Answer 47

Highly specific, readily absorbed drug and should be taken on an empty stomach

Question 48

Why is acetylator status important in TB?

Answer 48

Isoniazid is metabolised by n acetyl transferase, so patients known to be fast acetylators may require a higher dose Patients known to be slow acetylators require close monitoring

Question 49

What is a significant side effect with isoniazid?

Answer 49

LFTs will rise within the first weeks, isoniazid can cause peripheral neuropathy (often dose related) need to co administer pyridoxine (vitamin B6) ``` Other side effects include Hepatitis, cutaneous reactions, Hypersensitivity Peripheral neuropathy ```

Question 50

What is the mechanism of isoniazid?

Answer 50

Inhibits synthesis of my colic acid required for mycobacterial cell wall synthesis

Question 51

Why is isoniazid co administered with pyroxidine?

Answer 51

The main adverse effect from isoniazid use is peripheral neuropathy This mechanisms involves inhibition of pyridoxine activity which causes a decreased production of several neurotransmitters including dopamine, noradrenaline, serotonin and GABA However this can be prevented by adding pyridoxine (vitamin B6) to the regimen. Avoid high doses of pyridoxine as this may interfere with antibacterial action

Question 52

What is pyrazinamide?

Answer 52

Largely bacteriostatic drug but can be bactericidal on actively TB bacteria

Question 53

How does pyrazinamide work?

Answer 53

Acts as a substrate for the pyrazinamidase enzyme in M. TB. This gets converted into pyrazinoic acid in acidic conditions. Accumulation of pyrazinoic acid disrupts the membrane potential, interfering with energy production which is necessary for the survival of M. TB at an acidic site of action

Question 54

What are the adverse effects of pyrazinamide?

Answer 54

``` Anorexia Nausea Vomiting Hepatitis Arthralgia (pain in a joint) Hyperuricaemia Cutaneous hypersensitivity ```

Question 55

What is ethambutol?

Answer 55

Drug which is bacteriostatic against actively growing TB bacilli

Question 56

When is ethambutol used?

Answer 56

If isoniazid resistance is suspected or if patient has been in a high risk TB country

Question 57

How does ethambutol work?

Answer 57

Obstructing the formation of the cell wall by inhibiting the arabinosyl transferase enzyme and hence, the production of arabinogalactan. This prevents my colic acids from attaching onto the arabinogalactan residues to form the mycolyl-arabinogalactan peptidoglycan complex in the cell wall. The result is increased permeability of the cell wall.

Question 58

What are the adverse effects of ethambutol?

Answer 58

``` Retrobulbar neuritis (changes in eye vision, see green) Arthralgia ```

Question 59

What is streptomycin?

Answer 59

Bactericidal antibiotic. | This is given as IM to reduce drug resistance

Question 60

How does streptomycin work?

Answer 60

Binds to 30S ribosome subunit and interferes with binding of formyl-methionyl-tRNA to the 30S subunit Leads to inhibition of protein synthesis and death of microbial cells

Question 61

What are the adverse effects of streptomycin?

Answer 61

Vestibular ototoxicity (nausea, vomiting, vertigo), paraesthesia (numbness) of face Rash

Question 62

What is rifinah?

Answer 62

Combination pill of isoniazid and rifampicin (2 tablets/day) Reduces risk of patients inadvertently receiving monotherapy for TB with assoc. risks of resistances Aids compliance Evidence suggests incidence of side effects are lower

Question 63

Why are 6 month regimens of rifampacin, isoniazid, pyrazinamide and sometimes, ethambutol necessary?

Answer 63

TB bacteria grow relatively slowly and dormant bacteria only divide when threatened by antibiotic therapy so 6 month treatment regimens are necessary to ensure all active and dormant organisms are killed

Question 64

What are the two main phases of TB treatment?

Answer 64

Initial phase- bacterialcidal phase | Continuous phase- sterilisation phase

Question 65

What is require in the initial or bactericidal phase?

Answer 65

At least 3 drugs used concurrently for 2 months (usually Rifampacin, isoniazid and pyrazinamide) or rifampacin, ethambutol and pyrazinamide if isoniazid resistance is suspected Or all 4 if patient has been suspected to have been in a high risk country Treatment should be continued until two consecutive smear results come back negative even if this exceeds 2 months

Question 66

What happens in the continuous or sterilisation phase of TB treatment?

Answer 66

The treatment is continued for a further 4 months, usually with isoniazid and rifampacin Longer treatment is necessary with meningitis and resistant organisms

Question 67

When should a smear test be done in the TB treatment regime?

Answer 67

Once every week or twice weekly. If patient has 2 negatives in a row, then the treatment is good. If the smear test comes back as positive, drug susceptibility tests need to be conducted.

Question 68

When is streptomycin used?

Answer 68

It may be used in the initial phase of treatment if resistance to isoniazid has been established before therapy has been commenced

Question 69

What is the recommended dosage for standard 6 month treatment of TB?

Answer 69

Rifampacin for 6 months: Adult 50kg: 600mg daily Child 15mg/kg daily (max 450mg if under 50kg, max 600mg if over 50kg) Isoniazid for 6 months Adult 300mg daily, child 10mg/kg daily (300mg max) Pyrazinamide for 2 months initial phase Adult. 50kg: 2g daily Child. 35mg/kg daily (max 1.5g daily if under 50kg, max 2g daily if over 50kg) Ethambutol for 2 months initial phase Adult 15mg/kg daily Child 20mg/kg daily

Question 70

Which TB drug cannot be used in pregnancy?

Answer 70

Streptomycin

Question 71

Can the standard TB treatment regimen be used in breastfeeding?

Answer 71

Yes

Question 72

What is dot?

Answer 72

``` Direct observational therapy Where health care workers watch patients swallow the medication for all doses during the course of TB treatment to ensure that patient optimises therapy via checking they are taking: -the correct drug -the correct dose - at the correct time. This prevents resistance. ```

Question 73

When should dot therapy be used?

Answer 73

``` When there is resistance to rifampicin, Multi drug resistance Relapse/reactivation Clear inability to self medicate Poor adherence despite close monitoring ```

Question 74

What is the largest cause of treatment failure in TB?

Answer 74

Non adherence by the patient

Question 75

What are the main reasons for non adherence by the patient?

Answer 75

They feel better and do not appreciate the need to continue with medication They have received a lack of clarity of instructions Adverse effects of the drugs Increased number of tablets to take

Question 76

What is primary drug resistance and secondary drug resistance ?

Answer 76

Primary: organisms transmitted have existing resistance and continue to develop mutations spontaneous Secondary: resistance develops on medication

Question 77

Can TB be cured?

Answer 77

Yes, provided that an adequate treatment regimen is prescribed and the patient complies to it.

Question 78

How can patient adherence be improved?

Answer 78

Dispense OD using as few tablets as possible. Advise rifampacin and isoniazid to be taken on an empty stomach, 1 hour before food generally before breakfast (absorbed better) Cue the tablet taking to regular activity such as brushing teeth Use of combination preparations

Question 79

What factors should be considered regarding patient education of TB?

Answer 79

Offer written instruction to support verbal counselling Emphasise disease is curable but requires months of treatment and compliance Warn and explain the side effects and when to refer to health professionals Offer instructions in other languages, pictorial material and dosage sheets

Question 80

What are the main counselling points for patients with TB?

Answer 80

Rifampacin causes harmless discolourisarion or urine and other bodily fluids like sweat and tears The staining of soft contacts by tears is permanent- warn patient Should use other non hormonal type contraception for the duration of rifampacin treatment and for 8 weeks afterwards Stop medication and report to doctor if there are any changes in vision e.g. Reduction in visual activity or changes to colour vision. This may be reversible upon discontinuation, but may also be permanent if the medication is not stopped.