Mike McKendrick

Clinical Aspects of
Tuberculosis
Professor Mike McKendrick
Lead Physician
Department of Infection and Tropical Medicine
Royal Hallamshire Hospital
Sheffield
Honorary Professor
Division of Genomic Medicine
University of Sheffield
Dpt. Infection and Tropical Medicine,

Sheffield Teaching Hospitals
Clinical aspects of TB
 Pathogenisis
 Clinical diagnosis
 Treatment and monitoring and control
 New issues

Clinical Aspects of
Tuberculosis
 Pathogenesis of tuberculosis
– Infection versus disease
 Host factors
 Pathogen factors

Pathogenesis
 Host factors include
– Social e.g.
 Poverty
 alcoholism
– Age e.g.
 Baby
 Teenage girl
 Old age
– Immunity e.g.
 HIV
 Gamma interferon
 SCID
Pathogenesis
 Organism factors e.g.
– Virulence factors
– [Drug resistance]

Pathogenesis
 MTB into lungs (or to cervical nodes or abdo. nodes)
 Replication of organisms
 Primary complex (lung and mediastinal lymph nodes)
 Mycobacteraemia with potential for ‘seeding’
 Consequence of tuberculous infection

– Symptomatic illness – disease (minority)
– immunological control (majority) with Ghon focus on Xray.
Infection is ‘contained’ by granuloma but not eliminated

Pathogenesis
 Tuberculous disease is a consequence of:
– Primary infection e.g. in baby
– Reactivation
 ‘natural’
 Associated with immunosupression
– Re infection

Clinical features
 Clinical illness
– Pulmonary
– Extrapulmonary

Clinical illness
 Chest
– Pulmonary
– Pleural
– Mediastinal nodes
– pericardium
 Extra pulmonary
– skin and soft tissues (including lymph nodes)
– Bone
– Abdominal
– Intra cranial
– other
Clinical clues for TB
 Clinical symptoms – usually ‘chronic’ rather than acute
– Fever
– Sweats
– Weight loss
– Focal symptoms
 Epidemiology
– History of TB, HIV
– Country of origin, recent travel/work
– Contact with TB
[England, Wales & NI 2004
 7,176 notifications, 414 children
 70% foreign born population groups]

TB – guidelines for the clinician
 Great mimicker
 Low index of suspicion
 Pulmonary TB usually easy to consider
 Non pulmonary often requires ‘lateral
thinking’

Clinical TB
 Laboratory samples
– In the current era every effort must be made to
obtain adequate samples likely to lead to a
microbiological diagnosis before treatment is
started (sometimes difficult with surgical
specimens!)

What can the laboratory do to
help the clinician?
 Awareness of TB e.g. in the patient with recurrent
sputum samples for ‘chronic bronchitis’
 ‘Rapid’ diagnosis of infection and resistance

– Culture and sensitivities – the clinician wants answers
immediately if possible
– PCR – further opportunities for development
– Gamma interferon based tests??
– other
What samples? Depends on clinical
scenario
 Chest
– Sputum – if productive
– Induced sputum
– Bronchoscopic alveolar lavage (BAL)
– Pleural biopsy
– Pleural fluid
 Other
– E.g. Lymph node, aspiration of abscess, mesenteric
biopsy, stool, bone marrow etc.
– What about EMSU? - should be done selectively where
it is likely to be helpful
Induced sputum
 Hypertonic saline nebuliser in negative
pressure room with HEPA filter and well
trained physiotherapist
– Study of 27 confirmed positive patients
 13 +ve induced sputum only
 1 +ve bronchoscopy only
 13 +ve induced sputum and bronchoscopy

McWilliams T et al Thorax 2002: 57; 1010-1014

Audit of induced sputum in
Department of Infection in Sheffield
– Criteria for procedure
– Past history TB or contact with TB in last year
– Respiratory symptoms of one or more of:
• Non-productive cough
• Fever, Night sweats, weight loss
• Haemoptysis
114 procedures, 12 positive for TB
– Cohort followed up for 12 months, no cases
missed
- Bell et al. J Infection 2003: 47; 317-321

Clinical cases
 Cases of
– pulmonary infection
– Non pulmonary infection
– Examples of spectrum of disease produced by
TB

Pulmonary and non pulmonary
TB disease – Sheffield 2005
 Equal numbers of patients with pulmonary
and non pulmonary tuberculosis

Clinical presentation 1
 35 year old African lady with fever and dry
cough for 3 weeks.
 Mildly unwell
 Night sweats
 Weight loss 4 pounds
 No history of contact with TB
 CXR
Case 1 – miliary tuberculosis

Pulmonary TB typically affects
the upper zones of the lung

Case 1
 Investigation
– FBC normal
– ESR 53
– U and E normal
– LFT – albumen 31
– CRP 40
– Induced sputum – smear negative

Case 1
 Progress
– Clinical diagnosis of TB
 4 drug treatment
 Clinical improvement
– TB culture
 positive at week 3
 fully sensitive (week 5)
 Modified anti TB drug regime in light of lab results

Case 1
 What about HIV testing? – who to test?
– Strong association between HIV and TB
– Universal testing or selective testing?
 What about testing for vitamin D?

– Vitamin D has role in activating macrophages to
destroy mycobacteria
– Vitamin D deficiency in ethnic populations in UK often
low
Case 1
 Cured after standard 6 months therapy

Clinical presentation 2
 28 year old African lady with backache for
6 weeks
 Diagnosed initially as non specific
 Developed fever – no obvious cause
 ID opinion sought
 Investigation with MRI scan

Clinical case 2
 Diagnosis
– Vertebral osteomyelitis with soft tissue mass
impinging on the cord
 Investigation
 Biopsy and culture
 Treatment
– 4 anti TB drugs and antibiotic therapy

Clinical case 2
What will happen if diagnosis or

treatment for TB spinal
osteomyelitis is delayed?

What will happen if treatment delayed? – gibbus
formation (acute angulation of spine with or
without neurological damage)

The physical appearance – Potts
disease of spine - gibbus

Clinical case 2
 Progress
– Increasing back pain and neurological
symptoms – mild leg weakness
– Repeat MRI – changes similar
 Treatment
– Continue therapy
– consider surgical decompression

Clinical case 2
 Further progress
 Weakness of legs
 Neurosurgery and internal splinting
 Other considerations - clinical
 Has she got HIV?
 Is her vitamin D level normal?
 Other considerations - epidemiological
 From where has she got infection?
 To whom might she have given it?
 TB may affect any tissue of the body
including:
– Skin and soft tissue
– Lymph nodes
– Bones and joints
– Intra abdominal structures including
 peritoneum
 Kidneys
 Adrenal glands
 Lymph nodes
– Central nervous system
 Tuberculoma
 meningitis Dpt. Infection and Tropical Medicine,

Skin and soft tissue

25 male African. Expanding non painful lesion in
neck - Cervical lymph node TB progressing to
abscess (beware deep extension – collar stud
abscess)

TB node in neck with deep
extension

35 female African – systemically well - hand and
foot lesions present for 6 months – MTB grown on
biopsy by plastic surgeons (HIV neg)

Bony tuberculosis

Astute radiologist should enable the
appropriate further investigation

Often associated with delay in diagnosis –
any chronic discharging lesion must be
considered possibly TB

Abdominal Tuberculosis

Renal tuberculosis (may have few
or no symptoms) leading to
autonephrectomy

30 middle eastern asylum seeker - abdo pain,
fever, sweats – CT scan - peritoneal TB
confirmed on biopsy – may mimic malignancy

Intracranial TB

miliary TB on MRI scan
tuberclomas on CT scan

meningitis – diagnosis usually made on
clinical grounds
 Clinical
 Acute or subacute
 Prognosis related to severity of disease at onset of treatment
 Commonly delay between presentation and diagnosis
 Common in children
 c100 cases per year in England
 CSF
– Cell count 50-500 (50% lymphs, 50% polys)
– High protein ++
– Low glucose
– Micro often negative (PCR/culture important)
Treatment of TB

 BTS guidelines – 1999 Thorax 2000: 55; 210-218
 NICE guidelines – 2006
– Sensitive TB – 4 drugs for 2 months

2 drugs for 4 months
– Resistant TB - 6 drugs for 24 months (second

line drugs are not so effective)
[Eng, Wales & NI 2004, 6.8% Isoniazid resistant, 1%
MDR TB (R to Isoniazid and rifampicin)]
Problems of TB therapy
 Toxicity e.g. liver
 Multiple therapy
 Prolonged treatment
 Drug interactions e.g. anti HIV drugs

Compliance
– Treatment will not work if not taken
– DOTS (Directly Observed Therapy) if:

 Likely poor compliance
 MDRTB

Outcome
 WHO target (1991)
– detect 70% infectious cases of TB and cure at
least 85% by 2005
 Eng, Wales and NI

– Probably detect 70% cases infectious TB
– Cure rate uncertain
 Among all TB patients with a known outcome the
proportion of cases that have completed treatment
– 79% in 2003
– 78% in 2002
– 79% in 2001 CDR 23 March 2006

Why failure?
 Patient non compliance
– Deliberate
– Failure to understand e.g. language, culture
– Social e.g. alcohol
 Patient movement e.g. ‘lost to follow up’
 Lack of medical/nursing support
 others

public health - avoiding
transmission
 TB is statutorily notifiable disease
 Multidisciplinary approach – medical, TB nurses,
CCDC etc.
 Identify and manage possible sources of infection and contacts
 Considerations
 treat as OP where possible
 multi occupancy housing, social deprivation
 negative pressure rooms in hospitals (limited facility)
 beware transmission in OP setting e.g. waiting area

New challenges in TB

Challenges in TB
 Anti TNF therapy (Eg infliximab, etanercept)
– May promote breakdown of granulomas and
reactivation of TB
– How to screen
 Clinical history
 CXR (? With induced sputum)
 Skin testing
 ?? Value of gamma interferon tests

Challenges in TB
What will be the place of

Quantiferon and Elispot
type tests in clinical practice?

Clinical need for new and
better anti TB drugs

 Objective - to lead to more effective shorter
course regimen
– Better pharmacokinetics
 longer half life
 better penetration to cavities
– Better activity
 kill TB in dormant phase
 Active against resistant strains
– Safer and easier

 Lack of interaction with anti HIV therapy
 Less toxic
– Low cost

Will there be new affordable
therapy for TB?
 Global Alliance for TB Drug Development
 TB development drug discovery research
unit
– Astra Zenica
– Glaxo SmithKline
– Novartis
 WHO links with pharma
 TB trials consortium (US CDC)
Will there be new affordable
therapy for TB?
 Moxifloxacin
 TMC 207
 OPC-67683
 PA-824
 LL3858

Summary
 TB is a challenging disease for the clinician
 Must have microbiology before starting
treatment – more rapid lab tests?
 Need to encourage compliance
 Need for multidisciplinary approach to
diagnosis and management and control
 Need shorter, better, cheap anti TB regimes


Mike McKendrick

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Clinical Aspects of

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

 Mycobacteraemia with potential for ‘seeding’

 Consequence of tuberculous infection

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

 ‘Rapid’ diagnosis of infection and resistance

 1 +ve bronchoscopy only

 13 +ve induced sputum and bronchoscopy

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

 fully sensitive (week 5)

 Modified anti TB drug regime in light of lab results

Dpt. Infection and Tropical Medicine,

 What about testing for vitamin D?

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

What will happen if diagnosis or

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

 meningitis Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

 NICE guidelines – 2006

– Sensitive TB – 4 drugs for 2 months

– Resistant TB - 6 drugs for 24 months (second

Dpt. Infection and Tropical Medicine,

– Treatment will not work if not taken

– DOTS (Directly Observed Therapy) if:

Dpt. Infection and Tropical Medicine,

 Eng, Wales and NI

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

Dpt. Infection and Tropical Medicine,

What will be the place of

Dpt. Infection and Tropical Medicine,