mike mckendrick

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




Clinical aspects of TBClinical aspects of TB Pathogenisis

Clinical diagnosis Treatment and monitoring and control

New issues




Clinical Aspects of Clinical Aspects of

TuberculosisTuberculosis Pathogenesis of tuberculosis

± Infection versus disease

Host factors

Pathogen factors




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




Pathogenesis

Pathogenesis

Organism factors e.g.

± Virulence factors

± [Drug resistance]




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




Clinical featuresClinical features

Clinical illness

± Pulmonary ± Extrapulmonary




Clinical illnessClinical illness Chest

± Pulmonary

± Pleural

± Mediastinal nodes ± pericardium

Extra pulmonary

± skin and soft tissues (including lymph nodes)

± Bone ± Abdominal

± Intra cranial

± other




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]



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¶





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!)





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





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





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





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





Clinical casesClinical cases Cases of

± pulmonary infection

± Non pulmonary infection

± Examples of spectrum of disease produced by

TB





Pulmonary and non pulmonaryPulmonary and non pulmonary

TB diseaseTB disease ± ± Sheffield 2005Sheffield 2005

Equal numbers of patients with pulmonary

and non pulmonary tuberculosis





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





Case 1Case 1 ± ± miliary tuberculosismiliary tuberculosis





Pulmonary TB typically affectsPulmonary TB typically affects

the upper zones of the lungthe upper zones of the lung





Case 1Case 1 Investigation

± FBC normal

± ESR 53

± U and E normal

± LFT ± albumen 31

± CRP 40

± Induced sputum ± smear negative





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





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





Case 1Case 1 Cured after standard 6 months therapy





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





Clinical case 2Clinical case 2

What will happen if diagnosis or

treatment for TB spinalosteomyelitis is delayed?





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)





The physical appearanceThe physical appearance ± ± PottsPotts

disease of spinedisease of spine -- gibbusgibbus





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





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?





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





Skin and soft tissue





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)





TB node in neck with deepTB node in neck with deep

extensionextension





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)





Bony tuberculosis





Astute radiologist should enable the Astute radiologist should enable the

appropriate further investigationappropriate further investigation





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





Abdominal Tuberculosis





Renal tuberculosisRenal tuberculosis (may have few(may have few

or no symptoms) leading toor no symptoms) leading toautonephrectomyautonephrectomy





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





Intracranial TB





miliary TB on MRI scanmiliary TB on MRI scan

tuberclomas on CT scantuberclomas on CT scan





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)





Treatment of TB





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)]





Problems of TB therapyProblems of TB therapy

Toxicity e.g. liver

Multiple therapy

Prolonged treatment

Drug interactions e.g. anti HIV drugs





ComplianceCompliance

± Treatment will not work if not taken

± DOTS (Directly Observed Therapy) if:

Likely poor compliance

MDRTB





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





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





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





New challenges in TBNew challenges in TB





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





Challenges in TBChallenges 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 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)





Will there be new affordableWill there be new affordable

therapy for TB?therapy for TB? Moxifloxacin

TMC 207

OPC-67683

PA-824

LL3858




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

mike mckendrick

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