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 Baby Teenage girl Old age HIV Gamma interferon SCID
Age e.g.

Immunity e.g.

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 skin and soft tissues (including lymph nodes) Bone Abdominal Intra cranial other
Extra pulmonary

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,
Sheffield Teaching Hospitals
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 2006
Thorax 2000: 55; 210-218
NICE guidelines
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 Tuberculosis

Professor Mike McKendrick

diagnosis  Treatment and monitoring and control  New issues

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Clinical Aspects of Tuberculosis

Infection versus disease  Host factors  Pathogen factors

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Host factors include

Virulence factors [Drug resistance]

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Mycobacteraemia with potential for seeding Consequence of tuberculous infection

Infection is contained by granuloma but not eliminated

Tuberculous disease is a consequence of:

natural Associated with immunosupression

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Clinical clues for TB

Clinical symptoms usually chronic rather than acute

Fever Sweats Weight loss Focal symptoms

[England, Wales & NI 2004

7,176 notifications, 414 children 70% foreign born population groups]

TB guidelines for the clinician

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

What can the laboratory do to help the clinician?

What samples? Depends on clinical scenario

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Audit of induced sputum in Department of Infection in Sheffield

114 procedures, 12 positive for TB

pulmonary infection Non pulmonary infection Examples of spectrum of disease produced by

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Pulmonary and non pulmonary TB disease Sheffield 2005

of patients with pulmonary and non pulmonary tuberculosis

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Case 1 miliary tuberculosis

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Pulmonary TB typically affects the upper zones of the lung

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

What about HIV testing? who to test?

What about testing for vitamin D?

destroy mycobacteria Vitamin D deficiency in ethnic populations in UK often low

after standard 6 months therapy

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

impinging on the cord

Biopsy and culture

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

The physical appearance Potts disease of spine - gibbus

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

symptoms mild leg weakness Repeat MRI changes similar

Weakness of legs Neurosurgery and internal splinting

Has she got HIV? Is her vitamin D level normal?

may affect any tissue of the body including:

peritoneum Kidneys Adrenal glands Lymph nodes

Skin and soft tissue

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

TB node in neck with deep extension

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Astute radiologist should enable the appropriate further investigation

diagnosis Treatment and monitoring and control New issues

Infection versus disease Host factors Pathogen factors

movement e.g. lost to follow up Lack of medical/nursing support others

Alliance for TB Drug Development TB development drug discovery research unit

links with pharma TB trials consortium (US CDC)

207 OPC-67683 PA-824 LL3858