Clinical Aspects of Tuberculosis

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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

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Clinical aspects of TB

• Pathogenisis
• Clinical diagnosis
• Treatment and monitoring and control
• New issues

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Clinical Aspects of Tuberculosis

• Pathogenesis of tuberculosis
• Infection versus disease
• Host factors
• Pathogen factors

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Pathogenesis

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

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Pathogenesis

• Organism factors e.g.
• Virulence factors
• Drug resistance

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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

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Pathogenesis

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

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Clinical features

• Clinical illness
• Pulmonary
• Extrapulmonary

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Clinical illness

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

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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

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TB guidelines for the clinician

• Great mimicker
• Low index of suspicion
• Pulmonary TB usually easy to consider
• Non pulmonary often requires lateral thinking

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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!)

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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

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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

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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

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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

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Clinical cases

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

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Pulmonary and non pulmonary TB disease
Sheffield 2005

• Equal numbers of patients with pulmonary and non
  pulmonary tuberculosis

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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

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Case 1 miliary tuberculosis
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Pulmonary TB typically affects the upper zones of
the lung
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Case 1

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

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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

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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

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Case 1

• Cured after standard 6 months therapy

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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

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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

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Clinical case 2

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

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What will happen if treatment delayed? gibbus
formation (acute angulation of spine with or
without neurological damage)
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The physical appearance Potts disease of spine
- gibbus
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Clinical case 2

• Progress
• Increasing back pain and neurological symptoms
  mild leg weakness
• Repeat MRI changes similar
• Treatment
• Continue therapy
• consider surgical decompression

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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?

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• 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

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• Skin and soft tissue

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25 male African. Expanding non painful lesion in
neck - Cervical lymph node TB progressing to
abscess (beware deep extension collar stud
abscess)
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TB node in neck with deep extension
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35 female African systemically well - hand and
foot lesions present for 6 months MTB grown on
biopsy by plastic surgeons (HIV neg)
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• Bony tuberculosis

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Astute radiologist should enable the appropriate
further investigation
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Often associated with delay in diagnosis any
chronic discharging lesion must be considered
possibly TB
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• Abdominal Tuberculosis

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Renal tuberculosis (may have few or no symptoms)
leading to autonephrectomy
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30 middle eastern asylum seeker - abdo pain,
fever, sweats CT scan - peritoneal TB confirmed
on biopsy may mimic malignancy
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• Intracranial TB

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miliary TB on MRI scantuberclomas on CT scan
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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)

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• Treatment of TB

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• 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)

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Problems of TB therapy

• Toxicity e.g. liver
• Multiple therapy
• Prolonged treatment
• Drug interactions e.g. anti HIV drugs

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Compliance

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

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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

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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

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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

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New challenges in TB

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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

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Challenges in TB

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

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• Clinical need for new and better anti TB drugs

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• 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

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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)

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Will there be new affordable therapy for TB?

• Moxifloxacin
• TMC 207
• OPC-67683
• PA-824
• LL3858

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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