Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals Clinical Aspects of Tuberculosis Professor Mike McKendrick Lead Physician Department.

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals

Clinical Aspects of Clinical Aspects of TuberculosisTuberculosis

Professor Mike McKendrick

Lead PhysicianDepartment of Infection and Tropical Medicine

Royal Hallamshire HospitalSheffield

Honorary ProfessorDivision of Genomic Medicine

University of Sheffield


Clinical aspects of TBClinical aspects of TB

PathogenisisClinical diagnosisTreatment and monitoring and controlNew issues


Clinical Aspects of Clinical Aspects of TuberculosisTuberculosis

Pathogenesis of tuberculosis– Infection versus disease

Host factors Pathogen factors


PathogenesisPathogenesis

Host factors include– Social e.g.

Poverty alcoholism

– Age e.g. Baby Teenage girl Old age

– Immunity e.g. HIV Gamma interferon SCID



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 ‘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



Tuberculous disease is a consequence of:– Primary infection e.g. in baby

– Reactivation ‘natural’ Associated with immunosupression

– Re infection


Clinical features Clinical 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 ‘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 clinicianTB – guidelines for the clinician

Great mimickerLow index of suspicionPulmonary TB usually easy to considerNon pulmonary often requires ‘lateral

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 to What can the laboratory do to help the clinician?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 What 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

where it 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 cases

missed - 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 pulmonary Pulmonary and non pulmonary TB disease – Sheffield 2005TB disease – Sheffield 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 unwellNight sweatsWeight loss 4 poundsNo history of contact with TBCXR


Case 1 – miliary tuberculosisCase 1 – miliary tuberculosis


Pulmonary TB typically affects Pulmonary 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 1Progress

– 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 specificDeveloped fever – no obvious causeID opinion soughtInvestigation with MRI scan


Clinical case 2Clinical 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 Clinical case 2

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


What will happen if treatment delayed? – gibbus What will happen if treatment delayed? – gibbus formation (acute angulation of spine with or formation (acute angulation of spine with or

without neurological damage)without neurological damage)


The physical appearance – Potts The physical appearance – Potts disease of spine - gibbusdisease of spine - gibbus


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 2Further 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 lesion 25 male African. Expanding non painful lesion in neck - Cervical lymph node TB progressing to in neck - Cervical lymph node TB progressing to abscess abscess (beware deep extension – collar stud (beware deep extension – collar stud abscess)abscess)


TB node in neck with deep TB node in neck with deep extensionextension


35 female African – systemically well - hand 35 female African – systemically well - hand and foot lesions present for 6 months – and foot lesions present for 6 months – MTB MTB

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 diagnosis – Often associated with delay in diagnosis – anyany chronic discharging lesion must be chronic discharging lesion must be

considered possibly TBconsidered possibly TB


Abdominal Tuberculosis


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

autonephrectomyautonephrectomy


30 middle eastern asylum seeker - abdo pain, 30 middle eastern asylum seeker - abdo pain, fever, sweats – CT scan - peritoneal TB fever, sweats – CT scan - peritoneal TB

confirmed on biopsy – may mimic malignancy confirmed on biopsy – may mimic malignancy


Intracranial TB


miliary TB on MRI scanmiliary TB on MRI scantuberclomas on CT scantuberclomas on CT scan


meningitismeningitis – diagnosis usually made on – diagnosis 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 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 therapyProblems of TB therapy

Toxicity e.g. liverMultiple therapyProlonged treatmentDrug 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 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?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 supportothers


public health - public health - avoiding avoiding

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 affordable Will there be new affordable therapy for TB?therapy for TB?

Global Alliance for TB Drug DevelopmentTB development drug discovery research

unit– Astra Zenica– Glaxo SmithKline– Novartis

WHO links with pharmaTB trials consortium (US CDC)


Will there be new affordable Will there be new affordable therapy for TB?therapy for TB?

MoxifloxacinTMC 207OPC-67683PA-824LL3858


SummarySummary

TB is a challenging disease for the clinicianMust have microbiology before starting

treatment – more rapid lab tests?Need to encourage complianceNeed for multidisciplinary approach to

diagnosis and management and controlNeed shorter, better, cheap anti TB regimes

Dpt. Infection and Tropical Medicine, Sheffield Teaching Hospitals Clinical Aspects of Tuberculosis Professor Mike McKendrick Lead Physician Department.

Documents

infection slide

primary infection

tb clinical symptoms

lateral thinking slide

tb england

awareness of tb

pulmonary skin

cervical nodes