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8/4/2019 Mike McKendrick
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Dpt. Infection and Tropical Medicine,Sheffield Teaching Hospitals
Clinical Aspects of Clinical Aspects of
TuberculosisTuberculosisProfessor Mike McKendrick
Lead Physician
Department of Infection and Tropical Medicine
Royal Hallamshire Hospital
Sheffield
Honorary Professor
Division of Genomic Medicine
University of Sheffield
8/4/2019 Mike McKendrick
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Dpt. Infection and Tropical Medicine,Sheffield Teaching Hospitals
Clinical aspects of TBClinical aspects of TB Pathogenisis
Clinical diagnosis Treatment and monitoring and control
New issues
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Dpt. Infection and Tropical Medicine,Sheffield Teaching Hospitals
Clinical Aspects of Clinical Aspects of
TuberculosisTuberculosis Pathogenesis of tuberculosis
± Infection versus disease
Host factors
Pathogen factors
8/4/2019 Mike McKendrick
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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
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Dpt. Infection and Tropical Medicine,Sheffield Teaching Hospitals
Pathogenesis
Pathogenesis
Organism factors e.g.
± Virulence factors
± [Drug resistance]
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Dpt. Infection and Tropical Medicine,Sheffield Teaching Hospitals
Pathogenesis
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 µseeding¶
Consequence of tuberculous infection
± Symptomatic illness ± disease (minority)
± immunological control (majority) with Ghon focus on Xray.Infection is µcontained¶ by granuloma but not eliminated
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8/4/2019 Mike McKendrick
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Dpt. Infection and Tropical Medicine,Sheffield Teaching Hospitals
Clinical featuresClinical features
Clinical illness
± Pulmonary ± Extrapulmonary
8/4/2019 Mike McKendrick
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Dpt. Infection and Tropical Medicine,Sheffield Teaching Hospitals
Clinical illnessClinical 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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Dpt. Infection and Tropical Medicine,Sheffield Teaching Hospitals
Clinical clues for TBClinical clues for TB Clinical symptoms ± usually µchronic¶ 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
TBTB ± ± guidelines for the clinicianguidelines for the clinician
Great mimicker
Low index of suspicion
Pulmonary TB usually easy to consider
Non pulmonary often requires µlateral
thinking¶
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Clinical TBClinical 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
What can the laboratory do toWhat can the laboratory do to
help the clinician?help the clinician? Awareness of TB e.g. in the patient with recurrent
sputum samples for µchronic bronchitis¶
µRapid¶ 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
What samples? Depends on clinicalWhat samples? Depends on clinical
scenarioscenario 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 whereit is likely to be helpful
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Induced sputumInduced 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Audit of induced sputum in Audit of induced sputum in
Department of Infection in SheffieldDepartment 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 casesmissed
- Bell et al. J Infection 2003: 47; 317-321
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Clinical casesClinical cases Cases of
± pulmonary infection
± Non pulmonary infection
± Examples of spectrum of disease produced by
TB
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Pulmonary and non pulmonaryPulmonary and non pulmonary
TB diseaseTB disease ± ± Sheffield 2005Sheffield 2005
Equal numbers of patients with pulmonary
and non pulmonary tuberculosis
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Clinical presentation 1Clinical 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Case 1Case 1 ± ± miliary tuberculosismiliary tuberculosis
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Pulmonary TB typically affectsPulmonary TB typically affects
the upper zones of the lungthe upper zones of the lung
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Case 1Case 1 Investigation
± FBC normal
± ESR 53
± U and E normal
± LFT ± albumen 31
± CRP 40
± Induced sputum ± smear negative
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Case 1Case 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Case 1Case 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Case 1Case 1 Cured after standard 6 months therapy
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Clinical presentation 2Clinical 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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8/4/2019 Mike McKendrick
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Clinical case 2Clinical case 2
What will happen if diagnosis or
treatment for TB spinalosteomyelitis is delayed?
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
What will happen if treatment delayed?What will happen if treatment delayed? ± ± gibbusgibbus
formation (acute angulation of spine with or formation (acute angulation of spine with or
without neurological damage)without neurological damage)
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
The physical appearanceThe physical appearance ± ± PottsPotts
disease of spinedisease of spine -- gibbusgibbus
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Clinical case 2Clinical 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Clinical case 2Clinical 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Skin and soft tissue
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
25 male African. Expanding non painful lesion25 male African. Expanding non painful lesion
in neckin neck -- Cervical lymph node TB progressing toCervical lymph node TB progressing to
abscessabscess (beware deep extension(beware deep extension ± ± collar studcollar studabscess)abscess)
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
TB node in neck with deepTB node in neck with deep
extensionextension
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
35 female African35 female African ± ± systemically wellsystemically well -- handhand
and foot lesions present for 6 monthsand foot lesions present for 6 months ± ± MTBMTB
grown on biopsy by plastic surgeonsgrown on biopsy by plastic surgeons (HIV neg)(HIV neg)
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Bony tuberculosis
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Astute radiologist should enable the Astute radiologist should enable the
appropriate further investigationappropriate further investigation
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Often associated with delay in diagnosisOften associated with delay in diagnosis ± ±
anyany chronic discharging lesion must bechronic discharging lesion must be
considered possibly TBconsidered possibly TB
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Abdominal Tuberculosis
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Renal tuberculosisRenal tuberculosis (may have few(may have few
or no symptoms) leading toor no symptoms) leading toautonephrectomyautonephrectomy
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
30 middle eastern asylum seeker 30 middle eastern asylum seeker -- abdo pain,abdo pain,
fever, sweatsfever, sweats ± ± CT scanCT scan -- peritoneal TBperitoneal TB
confirmed on biopsyconfirmed on biopsy ± ± may mimic malignancymay mimic malignancy
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Intracranial TB
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
miliary TB on MRI scanmiliary TB on MRI scan
tuberclomas on CT scantuberclomas on CT scan
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
meningitismeningitis ± ± diagnosis usually made ondiagnosis usually made on
clinical groundsclinical 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Treatment of TB
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
BTS guidelines ± 1999 Thorax 2000: 55; 210-218
NICE guidelines ± 2006
± Sensitive TB ± 4 drugs for 2 months2 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Problems of TB therapyProblems of TB therapy
Toxicity e.g. liver
Multiple therapy
Prolonged treatment
Drug interactions e.g. anti HIV drugs
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
ComplianceCompliance
± Treatment will not work if not taken
± DOTS (Directly Observed Therapy) if:
Likely poor compliance
MDRTB
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
OutcomeOutcome WHO target (1991)
± detect 70% infectious cases of TB and cure atleast 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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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. µlost to follow up¶
Lack of medical/nursing support
others
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
public healthpublic health -- avoidingavoiding
transmissiontransmission 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
New challenges in TBNew challenges in TB
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Challenges in TBChallenges 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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Challenges in TBChallenges in TB
What will be the place of
Quantiferon and Elispot type tests in clinical practice?
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Clinical need for new and
better anti TB drugs
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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Will there be new affordableWill there be new affordable
therapy for TB?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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Dpt. Infection and Tropical Medicine,
Sheffield Teaching Hospitals
Will there be new affordableWill there be new affordable
therapy for TB?therapy for TB? Moxifloxacin
TMC 207
OPC-67683
PA-824
LL3858
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Dpt. Infection and Tropical Medicine,
SummarySummary
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