TB and NTM infection - RCP London

TB and NTM infection

GIM StR teaching 11.9.19

Dr Jim Macfarlane

Respiratory Physician RVI

North of Tyne TB Service lead

What I will cover• Couple of illustrative cases• Quick recap on TB/NTM basics• TB/NTM issues that you could encounter on the

acute medical take• Questions

What I will not cover!

• MDR TB

Case 1

• 35 year old Caucasian lady

• Ex-partner treated for pulmonary TB 12 yrsago – CXR normal on contact tracing

• Smoker, unemployed, 3 children

• Cough + night sweats for 2/12, left-sided chest pain. Normally thin but weight stable

• Seen in TB clinic 2 days after CXR

Case 1 progress

• Pleural fluid aspirated – lymphocytic, no growth

• ESR 79

• HIV -ve

• Sputum x 3 at home AFB smear negative

• CT scan and bronchoalveolar lavage (BAL) of left upper lobe

Case 1 progress

• BAL of left upper lobe AFB smear +ve (3+)

PULMONARY TB

• Commenced on standard anti-TB treatment:– Rifampicin (R)

– Isoniazid (H)

– Ethambutol (E)

– Pyrazinamide (Z)

– (+ Pyridoxine – vit B6)

Auramine-rhodaminestain

Ziehl-Nielson stain

Rifinah

Case 1 progress

• BAL rapid liquid culture - Mycobacterium tuberculosiscomplex

• Whole genome sequencing (WGS) – Mycobacterium tuberculosis confirmed, fully sensitive to first line TB drugs

• 6/12 standard TB treatment completed

• Contact tracing – no active/latent TB cases identified

• CXR + clinic review at 3 and 6 months post-treatment

4 months of treatment

6 months – treatment completed

Case 2

• 60 year old Caucasian man

• Long term smoker, excess EtOH

• Moderate COPD/emphysema, IHD, PVD

• 4 months weight loss, night sweats

• Productive cough, intermittent haemoptysis

• Seen in chest clinic

CT thorax

Case 2 progress

• HIV negative

• Bloods normal except ESR 50, CRP 70

• Clinically well, low grade To, O2 sat’n 96% ra

• Sputum – routine culture negative

• AFB smear positive (2+)

• Next test?

Case 2 progress

• M tb complex PCR (Cepheid Xpert® MTB/RIF)– Nucleic acid amplification test– Identifies Mycobacterium tuberculosis

complex DNA and predicts resistance to rifampicin

– Less than 2 hours– On primary sputum/CSF/tissue/BAL

fluid samples or on smear positive/culture positive samples

– Result = NEGATIVE

Case 2 progress

• Severe cavitatory non tuberculous mycobacterial (NTM) pulmonary disease complicating COPD/emphysema

• Commenced on empirical NTM treatment:– Rifampicin– Ethambutol– Macrolide (azithromycin/clarithromycin)– IV amikacin nebulised amikacin both later added in

• Whole genome sequencing of mycobacterium:– Mycobacterium avium, macrolide sensitive

• Remains on treatment 2 years later, still smoking, some clinicoradiological improvement, still culture positive

Before treatment Improving…

• 2014: 9.6 million new cases, 1.5 million deaths.

• Over 95% of TB deaths occur in low- and middle-income countries

• 480 000 MDR-TB, 10% XDR-TB

• WHO ‘End TB’ Strategy – reduce TB deaths and new cases by 90%

between 2015 and 2035

• PHE/NHSE TB Collaborative Strategy 2015-2020 – to reduce TB

incidence in UK year on year with aim of eradicating TB

• TB incidence in 2018 in England 9.6/100,000 (below low incidence

threshold). North East 5.8/100,000, Newcastle+Middlesborough higher18

A few key facts about TB

TB – the organism

• The clinical syndrome of ‘tuberculosis’ in humans is caused by members of the Mycobacterium tuberculosis complex

• Genetically similar organisms

– M. tuberculosis - commonest

– M. bovis – ~30 cases in UK/year

– M. africanum – 40% of pulm TB in central/west Africa

– (M. carnettii) – rare, opportunistic

– (M. microti) – rare, Horn of Africa

– (M. caprae) – rare, Spanish domestic animals

TB – the organism

• M. tb complex with no threat to humans:M. pinnipedii

Seals

M. suricattae

Kalahari meerkats

M. mungi

Botswanan mongooses

• Mycobacteria are slow-growing acid-fast bacilli– High lipid content in cell wall

TB – infection and spread

• Airborne droplet nuclei – coughing, singing, communal smoking

• Can remain suspended in air for hours

• Overcrowded living, prisons

• Oropharyngeal/intestinal deposition

TB spread – key facts to remember• 20-30% close household contacts of infectious (ie smear

+ve) case will become infected• Most primary TB infections resolve:

– 1 in 20 (5%) will develop active disease within 2 yrs– 1 in 20 (5%) will develop active disease in later life– If infected in infancy, adolescence or old age more likely to

progress– Treating latent TB in recent contacts probably reduces risk by

2/3

• Immunosuppressed eg HIV, up to 10% per year• Untreated Sm+ve Pulm TB – 70% mortality in 10 yrs• Untreated Sm-ve pulm TB – 20% mortality in 10 yrs• Key to control of infectivity is therefore early detection,

diagnosis and treatment completion

NTM – the organisms

• Environmental mycobacteria found in water and soil, > 180 species

• Any mycobacterium not in M tb complex (TB) or M. leprae/lepromatosis (leprosy)

• Can cause NTM-pulmonary disease, skin infections, sinus, nodal disease, catheter related, CNS infection or disseminated infection in susceptible individuals

NTM pulmonary disease

Transient, intermittent or permanent isolation in sputum without NTM-PD

2 broad types of NTM-PD:

1. Fibro-cavitary disease– Often resembles pulmonary TB/malignancy– Smokers/ex smokers– Often smear positive

2. Nodular bronchiectatic disease– Commonly women, no structural lung

disease– Often smear negative

Fibro-cavitary

Nodular bronchiectatic

More common NTMs causing PD

Slow-growing Rapid-growingM. avium complex (M. avium, intracellulare, chimaera)

M. abscessus family

M. kansasii M. chelonae

M. malmoense M. fortuitum

M. xenopi

NTM susceptibility

Lung disease

?Genetic Immunodeficiencies Medications

COPD Lady Windermere syndrome

HIV/AIDS Corticosteroids

CF Macrophage /dendritic cell dysfunction

Anti-TNF therapy

Non CF bronchiectasis

IFNγ-IL12 disorders Organ transplantimmunosupression

Asthma Chemotherapy

Pneumoconiosis

ABPA ?Azithromycin

Diagnosing NTM-PD

• CLINICAL FEATURES– Respiratory symptoms, nodular/cavitary opacities

on CXR or CT

– Exclusion of other diagnoses

• MICROBIOLOGICAL– ≥ 2 positive sputum cultures OR

– ≥ 1 positive “targeted deep sample” ie BAL OR

– Compatible lung biopsy histology + positive culture

Treating NTM-PD

• Most NTM-PD responds to:– Rifampicin– Ethambutol– Macrolide (azithromycin/clarithromycin) or if not

tolerated, fluoroquinolone (cipro/moxi)+/- IV amikacin up to 3 months as tolerated followed by nebulised amikacin

• Continue for at least 12 months after culture conversion (sputum or repeat BAL)

• Typically 18-24 months +• Difficult to cure in smokers and multifocal fibrocavitory

disease

GIM on-call scenario 1

• A+E SHO rings you on evening shift 9pm:

• “19 year old student, lives alone, originally from Zimbabwe has self-presented with 2/12 weight loss, night sweats, minimally productive cough, swelling on neck, ?CAP r/o TB. Normal observations, clinically well. Please admit”

The infection control nurse is standing over you looking very serious. Do

you….?

1. Admit to negative pressure side room, get CT scan and arrange sputums for AFBs

2. Admit to male bay on Medical Admissions as few respiratory symptoms and arrange sputumsfor AFB, consider bronchoscopy

3. See patient in A+E, move to single room, arrange sputums for AFBs and if well discharge home and arrange urgent chest/TB clinic appt within 24-48 hours

4. Admit to side room, start oral antibiotics for CAP and obtain sputums for routine/TB culture

The infection control nurse is standing over you looking very serious. Do

you….?

1. Admit to negative pressure side room, get CT scan and arrange sputums for AFBs

2. Admit to male bay on Medical Admissions as few respiratory symptoms and arrange sputumsfor AFB, consider bronchoscopy

3. See patient in A+E, move to single room, arrange sputums for AFBs and if well discharge home and arrange urgent chest/TB clinic appt within 24-48 hours

4. Admit to side room, start oral antibiotics for CAP and obtain sputums for routine/TB culture

TB infection control – NICE guidelines 2016

• Do not admit people with confirmed/suspected infectious laryngeal/pulmonary TB (ie smear positive) to hospital for diagnostic tests or care unless there is a clear clinical or public health need

• If admission unavoidable, isolate in single room until at least 2 weeks of standard treatment completed if:– No risk factors for MDR-TB or– Mtb/RIF PCR predicts no rifampicin resistance or this

is confirmed on culture whole genome sequencing

Scenario 1 continued:

• The TB team are all away, so you admit the patient to a single room. Sputum is AFB smear +ve (1+), M tb complex PCR positive, no rifampicin resistance.

• You start on standard TB treatment. Patient is tolerating the medication well, cough improving, still feels fine but is bored and wants to go home on day 3

Consider de-escalating isolation and discharge prior to 2 weeks if:

• No ongoing clinical or PH need

• Tolerant and adherent to medication

• Cough improving, temperature settling

• No immunosuppressed individuals in same accommodation

• Low initial smear grade (ie ≤ 2)

• No laryngeal TB

• TB not extensive

GIM on-call scenario 2

• TB clinic running late on Thurs afternoon. Biochemistry lab phones you on-call at 8 pm. Patient with confirmed fully sensitive mediastinal lymph node TB (extrapulmonary) 2 weeks into standard TB treatment has an ALT of 350, bilirubin normal, both normal before treatment.

Do you….?

1. Phone the patient, check they are well, advise them to stop taking all their TB medication and contact the TB team to arrange LFT monitoring

2. Phone the patient and advise admission for liver USS and liver screen, inform TB team

3. Phone the patient and advise them to stop rifampicin and isoniazid, inform TB team

4. Phone the patient and advise them to stop pyrazinamide and ethambutol, inform TB team

Do you….?

1. Phone the patient, check they are well, advise them to stop taking all their TB medication and contact the TB team to arrange LFT monitoring

2. Phone the patient and advise admission for liver USS and liver screen, inform TB team

3. Phone the patient and advise them to stop rifampicin and isoniazid, inform TB team

4. Phone the patient and advise them to stop pyrazinamide and ethambutol, inform TB team

DILI = Drug-induced liver injury –general principles

• Exclude infectious aetiology (Hep virus screen)

• Rifampicin, isoniazid, pyrazinamide all hepatotoxic –Pyrazinamide most likely– Acute hepatitis, cholestasis or granulomatous hepatitis

• Often asymptomatic – or abdo pain, jaundice, fatigue, N+V, itching

• If ALT > 3 x ULN (with symptoms), or > 5 x ULN (without symptoms), or if bilirubin rises – STOP all treatment

• Unless patient so sick they need treatment– Non-hepatotoxic regimen

Baseline

Day 13

5 weeksTB meds stopped

9 weeks

10 weeksTB meds restarted

Treatment reintroduction (NICE guidelines)for DILI or cutaneous reaction

80

Ethambutol + rifampicin FULL DOSE

Isoniazid (+pyridoxine)FULL DOSE

• Twice weekly bloods for 2 weeks then every 2 weeks

GIM on-call scenario 3

• GP admission to MAU of 70 year old man with lethargy, vomiting, dizziness on standing

• Started on standard treatment for pulmonary TB 6 weeks ago

• PMHx – DM on metformin, PMR on 20 mg pred maintenance

• BP 95/60 with postural drop. Na 121, K 5.9

Do you….

1. Stop TB treatment, investigate hyponatraemiawith osmolalities/urinary Na and cortisol, give 0.9% NaCl

2. Continue TB treatment, investigate hyponatraemia, give IV hydrocortisone and fluids, increase daily prednisolone for PMR whilst on TB medication

3. Stop rifampicin, treat with fluids and increased dose of steroids, continue other TB medication

4. Refer to falls and syncope team and see another patient

Do you….

1. Stop TB treatment, investigate hyponatraemiawith osmolalities/urinary Na and cortisol, give 0.9% NaCl

2. Continue TB treatment, investigate hyponatraemia, give IV hydrocortisone and fluids, increase daily prednisolone for PMR whilst on TB medication

3. Stop rifampicin, treat with fluids and increased dose of steroids, continue other TB medication

4. Refer to falls and syncope team and see another patient

TB drug interactionsMain problem is rifampicin (liver enzyme inducer)

• Oestrogens – alternative methods of contraception must be advised, preferably use of an intra-uterine device and condoms, continuing for 4 weeks after stopping the rifampicin.

• Corticosteroids – normal prednisolone/dexamethasone doses must be doubled whilst on rifampicin.

• Blood phenytoin levels will be significantly reduced, so regular doses will need to be titrated up using phenytoin levels.

• Sulphonylureas eg gliclazide. BM control in diabetics may deteriorate and adjustments need to be made

• Anticoagulants – warfarin, dabigatran, abixaban, rivaroxaban. Increased INR monitoring at initiation of therapy. Manufacturers of newer anticoagulants recommend monitoring for signs of thrombosis.

• Use TB drug monographswww.tbdrugmonographs.co.uk

GIM on-call scenario 4

• GP admission – 23 year old Serbian man with 3 months of breathlessness, low grade fevers, right sided chest ache. No cough

• CRP 33, Hb 101, MCV 74, ESR 31, plts 590

• HIV -ve

Do you…

1. Treat empirically as CAP with amox/clarithromycin and arrange CT scan

2. Ask respiratory team to assist you with diagnostic pleural aspirate for routine/TB culture, pH, biochem, cytology

3. Ask respiratory team to assist you with diagnostic pleural aspirate and biopsies for both culture and cytology/histology

4. Insert chest drain, drain effusion to dryness and send off samples for cytology/micro

Do you…

1. Treat empirically as CAP with amox/clarithromycin and arrange CT scan

2. Ask respiratory team to assist you with diagnostic pleural aspirate for routine/TB culture, pH, biochem, cytology

3. Ask respiratory team to assist you with diagnostic pleural aspirate and biopsies for both culture and cytology/histology

4. Insert chest drain, drain effusion to dryness and send off samples for cytology/micro

Pleural TB

• Pleural fluid typically lymphocytic (can use automated cell count/profile aka. ascitic fluid as quick test)

• Pleural fluid only culture positive in 20% cases• Pleural biopsies (blind or USS/CT guided) are 70-80% +ve on

histology and microbiology if clinical suspicion is high• Intercostal drain insertion often not required (lung often

trapped due to pleural thickening)• Adjunctive oral corticosteroids can help if effusion enlarges

and becomes more symptomatic on TB treatment• Pleural fluid ADA (adenosine deaminase) levels v. useful

diagnostically in high TB incidence countries. Not available easily in UK.

• Standard 6/12 treatment regimen

GIM on-call scenario 5

• A+E admission

• 65 year old man, smoker, excess EtOH, emphysema, IHD + previous NSTEMI, high cholesterol on treatment

• 3 months into treatment for fibrocavitaryNTM-PD (M. intracellulare)

• 2 weeks of proximal muscle aches, generalisedweakness and fatigue, dark urine, oliguria

• CK 240,000. Ur 46 Cr 833, K 5.5

Cause of his rhabdomyolysis is…?

1. Statin

2. Statin interaction with clarithromycin

3. Disseminated NTM infection

4. Alcohol abuse

Cause of his rhabdomyolysis is…?

1. Statin

2. Statin interaction with clarithromycin

3. Disseminated NTM infection

4. Alcohol abuse

Summary

• TB/NTM-PD basics• Inpatient infection control issues – avoid

admission unless clear clinical/PH indication. Early discharge if improving. Communicate well with your local TB nurse/drs

• Treatment complications – DILI and reintroduction regimen

• Drug interactions – rifampicin, isoniazid, macrolides

• Pleural biopsies for suspected pleural TB very helpful

Thanks – any questions?