Introduction to Clinical Tuberculosis

Introduction to Clinical Tuberculosis

James T. Noble, M.D., FACP Infectious Diseases Section

Concord Hospital

Medical Director, Infection Prevention & Control

State of New Hampshire TB Conference 2011

“TB 101 – Back to the Basics”

November 18, 2011

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My Introduction

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Aspects of Clinical Tuberculosis

• Pathogenesis

• Clinical disease + epidemiology

• Treatment and monitoring

• New issues

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Aspects of Clinical Tuberculosis

• Pathogenesis of tuberculosis

– Infection versus disease

• Host factors

• Pathogen factors

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Pathogenesis – Host Factors

• Host factors include – Social e.g.

• Poverty

• alcoholism

– Age e.g. • Baby

• Teenage girl

• Old age

– Immunity e.g. • HIV

• Impaired IFN-gamma production, TNF inhibition

• SCID

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Pathogenesis – Organism Factors

• Organism factors include

– Virulence factors

• Mycolic acid in cell wall (antiphagocytic)

• Inhibition of intracellular killing

• Ability to induce granuloma formation

– Drug resistance

• INH resistant TB

• Multidrug Resistant (MDR) TB

• Extensively/Extremely Resistant (XDR) TB

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Pathogenesis – Primary Infection

• MTB into lungs (or to cervical nodes or abdo. nodes)

• Replication of organisms

• Primary complex (lung and mediastinal lymph nodes)

• Mycobacteremia with potential for foci of infection, especially in high-pO2 areas (apices, renal cortex)

• Consequence of tuberculous infection – Symptomatic illness – disease (minority)

– immunological control (majority). Infection is ‘contained’ by granuloma but not eliminated. May see Ghon complex on CXR.

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Pathogenesis – Development of Disease

• Tuberculous disease is a consequence of:

–Primary infection either in childhood or as a result of

exposure later in life. Primary progressive TB < 2 years

of age, less common later in childhood

–Reactivation

• Spontaneous or “natural”

• Associated with immunosupression

–Re-infection

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Tuberculosis - Clinical disease

• Clinical illness

– Pulmonary

– Extrapulmonary

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Tuberculosis - Clinical disease

• 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 signs and symptoms of TB

• Clinical signs/symptoms – usually ‘chronic’ rather than acute

– Fever

– Sweats

– Weight loss

– Focal symptoms • Pulmonary (cough, hemoptysis, laryngeal involvement)

• GU (sterile pyuria, infertility)

• Lymph node enlargement (scrofula)

• GI (Asymptomatic LFT elevation, chronic IBS picture)

• Hematopoetic (anemia, pancytopenia)

• CNS (“Aseptic” meningitis, focal brain lesions)

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Clinical disease due to TB – points to remember

• Great mimicker

• Low index of suspicion in many cases

• Pulmonary TB usually easy to consider

• Non pulmonary often requires high index of suspicion

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Clinical TB Diagnosis

• Laboratory samples

– Due to emergence of resistance, it is critical to obtain adequate samples likely to lead to a microbiological diagnosis before treatment is started. Emphasize need for fresh tissue/nonbacteriostatic saline/NO FORMALIN for 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 – now used for rapid diagnosis at NHPHL

– Gamma interferon based tests (Quantiferon Gold)

– Other (Gene Xpert MTB/RIF, etc)

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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 first AM urine or gastrics? - should be done selectively where it is likely to be helpful – but not for smears.

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Induced sputum

• Hypertonic saline nebuliser in negative pressure room with HEPA filter and well trained respiratory therapist

– 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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TB Epidemiology - USA

• Diagnostic Factors – History of TB, HIV

– Country of origin, recent travel/work

– Contact with TB case – at any age

11,182 US Cases 2010, 10 from NH (16 in 2009)

64% ages 25-64, 20% > age 65, 11% ages 15-24, 6% ages 0-14

29% Hispanic, 28% Asian, 24% Black, 16% White.

598 (7.9%) INH [R], 88 (1.2%) INH + RIF [R]

XDR TB – 1 case 2009, 0 cases 2010

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Pulmonary and extrapulmonary TB

disease USA 2010

• 67.9% Pulmonary TB only

• 21.8% Extrapulmonary TB only

• 10% Both Pulmonary and Extrapulmonary TB (299 miliary cases included, 2.7% of total)

• Of Extrapulmonary sites, 40.1% lymphatic, 16.1% pleural, 10.3% bone/joint, 5.6% peritoneal, 5.5% meningeal, 4.6% GU, 17.7% “other”.

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Clinical cases

• Cases of

– Pulmonary tuberculosis

– Extrapulmonary tuberculosis

– Examples of spectrum of disease produced by TB

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Clinical case 1

• 19 yo woman with productive cough x 2 weeks,

increasing SOB x 2 days, T=102.5F

• Born in Liberia, arr. USA 2006 after stay in refugee camp

Ghana

• PPD = 12mm on arrival in US, CXR negative

• Took INH “on and off” x 6 months in 2006-7

• Past history of “bronchitis”, on + off antibiotics

• CXR = RUL, RML infiltrate

• WBC 8100, 80% PMN

• Pneumococcal, Legionella Ag negative

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Clinical case 1 CXR

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Clinical case 1 Chest CT

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Clinical case 1

• CT scan = Dense RUL infiltrate with

cavitation

• Gram stain – normal flora

• AFB stain + with >1 AFB/hpf

• Started INH+EMB+PZA+RIF

• Subsequently, culture + M. tuberculosis

complex [S] to all drugs tested

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Clinical case 1

• Suffered massive PE day 8

• Transferred to MGH, ECMO support

• While on ECMO, amikacin+moxi+rifampin

• Recovered, transferred back to Concord

• DOT managed in FHC, referred CRVNA

8/2/11 to complete DOT

• Completed 6 months Rx October 2011

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Clinical case 2

• 47 year old Rwandan female with backache for 6 weeks, prior history of HIV.

• HIV RNA <48 copies, CD4+ 455 (33%, 0.80)

• Diagnosed initially as non-specific

• Developed fever – no obvious cause

• Investigation with MRI scan (Initially disapproved by Medicaid, “has not failed conservative therapy”, 4 week delay)

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Clinical case 2 - MRI

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Clinical case 2

• MRI Result

– “destruction in the right lamina at L4. There is an associated fluid collection, which extends from the epidural space into the interspinous process between L4 and L5. The fluid collection measures approximately 3.7 x 1.6 x 0.9 cm. This causes mass effect upon the thecal sac and enhances avidly on administration of contrast.”

• Workup

• Biopsy and culture

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Diagnostic Studies

• Bacterial cultures negative @ 21 days

• Fungal cultures negative at 6 weeks

• Cryptococcal antigen negative (serum)

• Histoplasma capsulatum serology negative

• AFB studies on next slide

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AFB Studies – Case 2

• Results from NH Public Health Lab:

– Fluorochrome Smear negative

– Gene probe + Mycobacterium avium

– ID as MAC 6/12/09, retracted 6/16/09

– Organism isolated: M. tuberculosis complex

probe +

– Only resistance streptomycin 2.0 mcg.

– M. tuberculosis complex confirmed @ NJMRC

by HPLC and culture.

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Course of Therapy, case 2

• INH+EMB+PZA+RBU

• Continue AZT+3TC+NVP

• Avoid PI therapy because of interactions with RBU

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Clinical case 2

• Course:

– Rapid improvement in fever

– Developed severe arthralgias and hyperbilirubinemia

– Discontinued rifabutin, month 4

– External support (brace)

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Clinical case 2

• Further course

• Slow improvement in pain symptoms

• Rapid improvement in arthralgias after RBU stopped

• Completed 12 months Rx 6/2010

• Still has minor back complaints, considered cured

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Clinical case 2

What can happen if diagnosis or treatment

for TB spinal osteomyelitis is delayed?

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The physical appearance – Potts

disease of spine - gibbus

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Clinical Case 3

• 35 year old African woman 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 3 – miliary tuberculosis

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Clinical Case 3

• Course

– 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

Cured after 6 months standard therapy

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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 draining 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 scan

Tuberculomas on CT scan

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TB 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

• 138 cases in 2010, USA

• CSF – Cell count 50-500 (50% lymphs, 50% polys)

– High protein ++

– Low glucose

– Micro often negative (PCR/culture important)

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TB Meningitis is bacterial meningitis in slow motion – each

day is worse than the day before- Louis Weinstein

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Treatment of TB

Almost always initiated as empiric Rx

USA 2010 7.9% Isoniazid resistant, 1.2% MDR TB

(R to Isoniazid and rifampin), no cases XDR TB

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CDC/ATS/IDSA Rx Guideline (2003)

• All patients start with 4 drugs for 2 months

• Several options for extension, 4-7 months

• Core recommendation for sensitive

strains:

INH+RIF+PZA+EMB x 2 months

INH+RIF x 4 months, unless remains

culture + @ 2 months = extend to 7

months

Dosing Recommendations vary for DOT

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Algorithm for Active TB

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Algorithm for Culture Negative/Inactive TB

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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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Adherence

– Treatment will not work if not taken

– DOT (Directly Observed Therapy) if:

• Likely poor adherence

• MDRTB

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Recommendations for DOT

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Why failure?

• Patient nonadherence/poor adherence

– 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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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 @ CDC

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Will there be new affordable

therapy for TB?

• Moxifloxacin

• Bedaquiline (TMC-207)

• Delamanid (OPC-67683)

• PA-824 (?aerosol therapy)

• Sudoterb (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 regimens

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