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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. Clinical aspects of TB. Pathogenisis Clinical diagnosis

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clinical aspects of tuberculosis
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
Clinical aspects of TB
  • Pathogenisis
  • Clinical diagnosis
  • Treatment and monitoring and control
  • New issues

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical aspects of tuberculosis3
Clinical Aspects of Tuberculosis
  • Pathogenesis of tuberculosis
    • Infection versus disease
      • Host factors
      • Pathogen factors

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

pathogenesis
Pathogenesis
  • Host factors include
    • Social e.g.
      • Poverty
      • alcoholism
    • Age e.g.
      • Baby
      • Teenage girl
      • Old age
    • Immunity e.g.
      • HIV
      • Gamma interferon
      • SCID

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

pathogenesis5
Pathogenesis
  • Organism factors e.g.
    • Virulence factors
    • [Drug resistance]

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

pathogenesis6
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

pathogenesis7
Pathogenesis
  • Tuberculous disease is a consequence of:
    • Primary infection e.g. in baby
    • Reactivation
      • ‘natural’
      • Associated with immunosupression
    • Re infection

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical features
Clinical features
  • Clinical illness
    • Pulmonary
    • Extrapulmonary

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical illness
Clinical illness
  • Chest
    • Pulmonary
    • Pleural
    • Mediastinal nodes
    • pericardium
  • Extra pulmonary
    • skin and soft tissues (including lymph nodes)
    • Bone
    • Abdominal
    • Intra cranial
    • other

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical clues for tb
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]

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical tb
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!)

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

what can the laboratory do to help the clinician
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

what samples depends on clinical scenario
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

induced sputum
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

audit of induced sputum in department of infection in sheffield
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical cases
Clinical cases
  • Cases of
    • pulmonary infection
    • Non pulmonary infection
    • Examples of spectrum of disease produced by TB

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

pulmonary and non pulmonary tb disease sheffield 2005
Pulmonary and non pulmonary TB disease – Sheffield 2005
  • Equal numbers of patients with pulmonary and non pulmonary tuberculosis

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical presentation 1
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

case 1 miliary tuberculosis
Case 1 – miliary tuberculosis

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

pulmonary tb typically affects the upper zones of the lung
Pulmonary TB typically affects the upper zones of the lung

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

case 123
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

case 124
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

case 125
Case 1
  • Cured after standard 6 months therapy

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical presentation 2
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical case 2
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical case 228
Clinical case 2

What will happen if diagnosis or treatment for TB spinal osteomyelitis is delayed?

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide29
What will happen if treatment delayed? – gibbus formation (acute angulation of spine with or without neurological damage)

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

the physical appearance potts disease of spine gibbus
The physical appearance – Potts disease of spine - gibbus

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical case 231
Clinical case 2
  • Progress
    • Increasing back pain and neurological symptoms – mild leg weakness
    • Repeat MRI – changes similar
  • Treatment
    • Continue therapy
    • consider surgical decompression

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

clinical case 232
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?

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide33
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, Sheffield Teaching Hospitals

slide34
Skin and soft tissue

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide35

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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

tb node in neck with deep extension
TB node in neck with deep extension

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide37
35 female African – systemically well - hand and foot lesions present for 6 months – MTB grown on biopsy by plastic surgeons(HIV neg)

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide38
Bony tuberculosis

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

astute radiologist should enable the appropriate further investigation
Astute radiologist should enable the appropriate further investigation

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide40
Often associated with delay in diagnosis – any chronic discharging lesion must be considered possibly TB

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide41
Abdominal Tuberculosis

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide43
30 middle eastern asylum seeker - abdo pain, fever, sweats – CT scan - peritoneal TB confirmed on biopsy – may mimic malignancy

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide44
Intracranial TB

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

miliary tb on mri scan tuberclomas on ct scan
miliary TB on MRI scantuberclomas on CT scan

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

meningitis diagnosis usually made on clinical grounds
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)

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide47
Treatment of TB

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide48
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)]

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

problems of tb therapy
Problems of TB therapy
  • Toxicity e.g. liver
  • Multiple therapy
  • Prolonged treatment
  • Drug interactions e.g. anti HIV drugs

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

compliance
Compliance
  • Treatment will not work if not taken
  • DOTS (Directly Observed Therapy) if:
    • Likely poor compliance
    • MDRTB

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

outcome
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

why failure
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

public health avoiding transmission
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

new challenges in tb
New challenges in TB

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

challenges in tb56
Challenges in TB

What will be the place of Quantiferon and Elispot type tests in clinical practice?

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide57
Clinical need for new and better anti TB drugs

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

slide58
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

will there be new affordable therapy for tb
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)

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

will there be new affordable therapy for tb60
Will there be new affordable therapy for TB?
  • Moxifloxacin
  • TMC 207
  • OPC-67683
  • PA-824
  • LL3858

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

summary
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

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals