Management of tuberculosis(TB, purpose only

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Management of

tuberculosis(TB,結核 )

KY Yuen 2011

Burden (負擔)of the problem of TB

• Global population: 1/3 infected

• New cases: >8 million/yr

• Location: 95% in developing countries

• Mortality: 2 million/yr

• China: 1.35 billion/6.97 billion: 19.3%/yr

(>1.6 million new case, 0.4 million deaths)

• Hong Kong: 90 per 100,000 population,

about 6000 new cases/yr, 200 deaths/yr

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Restricted for teaching purpose only-Preparatory Course for Macau SAR Medical Graduates

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J Hosp Infect. 2006 Oct;64(2):100-14.

Sneezing/coughing: Produce as many as 40 000 droplets of 0.5 -12

µm expelled at a velocity of 100 m/s

N Engl J Med. 2004 Apr 22;350(17):1710-2.

Emerg Infect Dis. 2006 Nov;12(11):1657-62.

20 µm

6 µm

≤ 5 µm

Arbitrary cut-off for

the size of the

droplet

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Airborne transmission

M. tuberculosis

Varicella zoster virus

Measles

Droplet transmission

Invasive H.influenzae type b

Invasive N. meningitidis

Diphtheria (pharyngeal)

Adenovirus

Influenza virus

Parvovirus B19

Mumps & Rubella

Mycoplasma pneumonia

Streptococcal pharyngitis

Pertussis

Pneumonic plague

Contact transmission

Colonization with

MDR bacteria

Norovirus / rotavirus

Clostridium difficile

RSV / PIF enterovirus

Skin infections of highly contagious

Viral hemorrhagic conjunctivitis

Viral hemorrhagic infections

Transmission-based precautions(傳輸為基礎的預防措施)

3 Airborne 2 Droplets 1 Contact

Rationale Aerosols < 5 um Particles > 5 um and Direct / indirect settle within 1 m contact with patients and formites (inanimate objects)

Agents Tuberculosis Influenza, adenovirus MRSA Chickenpox Parvovirus B19 VRE Measles Mumps Enteric pathogens Rubella Scabies Meningococcus

Methods Higher air change All precautions of 1 Isolation area Negative pressure room Private single room Glove, gown Closed door Surgical mask Dedicate use of non- Respirators critical patient care items to a single patient Hand hygiene

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Perform

hand hygiene

before putting

on a respirator

Entry to alveolar macrophage by

complement receptors,

mannose receptor, DC-SIGN,

Fc receptors;

Survival strategies:

1. Block phagolysosomal fusion

by eukaryotic-like signaling

kinases & phosphatases &

activation of eukaryotic Ca2+-

dependent signaling

molecules eg. Calcineurin

2. Produce modulators of

macrophage activation eg.

KatG (ROI),mycobacterial

proteasome(RNI), LAM,

manLAM (block activation of

MAPK downstream interferon

induced macrophage

activation)

Pathogenesis of damage

1. Produce CMI inducers:

ESAT6, CFP10

(inactivated[dead/caseous] & activated by

IFNg, IL12 produced by T lymphocytes)

Growth of MTB:

103-104 at 2-12

wk; CMI/DTH

mounted with

mantoux+

Before 2 wk: innate

immune response of

chemokines recruit

inflammatory cells

(先天免疫 )

巨噬細胞

肉芽腫反應

淋巴細胞 Restric

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停止吞噬體與溶酶體融合融合

Airborne transmission of MTB &

progression to active TB

• Droplet nuclei (飛沫核<0.5 um) suspended in air for long time: sneezing, singing, talking, aerosol generating medical procedure

• Risk of infection: concentration of MTB in the air, length of exposure, & immune status of exposed person

• Risk: amount of contaminated air breathed, not direct contact with index case

• Mantoux(TST) conversion: 50% if 8 hours per day for 6 months with index patient

• Lifetime risk of progression to active TB:10% (5% within first 2 yrs after infection)

• Risk of progression to active TB in HIV cases: 5% to 10% per year

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Risk factors for endogenous reactivation of tuberculosis: aging (50% of all TB), diabetes

mellitus(3X), malignancies, chronic renal failure(10X), chemotherapy & steroids,

silicosis(3X), alcoholism(3X), malnutrition, smoking(2X), male(2X, 64%) & post-gastrectomy

Unlike progressive primary infection

& exogenous reinfection (<5 yr after

exposure, 20% of all cases),

endogenous reactivation not affected

by DOT

CHP, DH: Chest Manual

矽肺病

CHP, DH: Chest Manual

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Ways of making a Diagnosis of

tuberculosis

• Clinical: symptoms & signs; urinalysis

• Radiological: CXR-PA, lateral, CT scan (sensitive but not specific)

• Microbiolgical (Gold standard): early morning sputum, gastric

aspirate, BAL, early morning urine, stool,

pleural/pericardial/peritoneal/joint fluid, CSF, tissue biopsy (pleura,

lymph node, marrow, liver) taken for Microscopy: AFB smear (Ziehl-

Neelsen/Auromine O fluorescent stain) & Mycobacterial Culture with

drug sensitivity testing (Lowentein Jensen/Middlebrook culture

medium for mycobacteria; 藥敏試驗)

• PCR: rapid, specific but have false negative in smear negative

specimens

• Histology of tissue biopsy (needle biopsy or open biopsy)

• Host enzymes (Adenosine deaminase[ADA] in CSF/pleural fluid)

• Tuberculin skin test (結核菌素皮膚試驗)

• Gamma interferon release assay (γ干擾素釋放試驗) from Ex vivo

peripheral blood mononuclear cells

Clinical symptoms & signs

• Primary TB(原發性肺結核): TST/GIRA-, subpleural lesion mid/lower lobe & regional lymph node: ILI, pneumonitis, lobar collapse, bronchiectasis, pleural effusion in 10% who progress; hypersensitivity phenomenon: erythema nodosum/induratum(結節性紅斑), phlyctenular conjunctivitis & dactylitis;

• Serious progression to Miliary (粟粒性肺結核): hematogenous spread to lungs, kidneys, bone marrow, CNS & anywhere; CXR: diffuse micronodular shadows; fever, prostration, dry cough, dyspnea, choroidal tubercles.

• Postprimary pulmonary TB(90%): MT/GIRA+, Apical lesions, chronic cough/hemoptysis, evening fever, night sweating, weight loss;

• Postprimary extrapulmonary(肺外)TB(10%): pleuritis(effusion, man); lymphadenitis(women); urinary(sterile pyuria/haematuria), genito-: epididymo-orchitis, infertility, pelvic pain, dysmenorrhea; arthritis & skeletal deformity; pericarditis(effusion); meningitis/myelitis; intestinal(diarrhea) peritonitis(ascites), abdominal mass; granulomatous hepatitis; adrenalitis;

• Cryptic TB: hematogenous, eldelry; fever, weight loss, dissemination in RES: bone marrow, hepatosplenomegaly, CNS

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Shadows on CXR: edema, infection(acute bacterial/viral, chronic mycobacterial/fungal/parasitic), haemorrhage, cancer/tumor, alveolar proteinosis;

Progressive SOB for 6/12

Alveolar proteinosis

AML with fever

Pneumonia

M/14

Mental retardation;

Refuse to eat;

Foul breath;

Weight loss in last 3 weeks;

Low grade fever; high ESR; WBC: 9.7

Increasing shortness of breath;

AFB smear of sputum negative

Pleural effusion tapped:

Turbid with WBC+++ * Restric

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*

CT scan: pericardial & extrapleural collection due to chicken bone in oesophagus

Laboratory Dx of TB:

AFB smear: 22 to 78% sensitivity(AFB/ml: 103 to 104); NOT

specific for MTB;

AFB culture: 10 to 100 AFB/ml; I/D specific; takes 4 to 6 weeks

(slow growth: divide once/day)

TB PCR: 100% for smear positive; 70% for smear negative; very

specific

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Nucleic acid amplification(PCR, RT-

PCR): slow/difficult to grow microbes

In vitro reproduction of

one TB bacterium (not

visible on microscopy)

1010-11 organisms

One visible colony on

solid culture medium

In vitro reproduction of

one short segment of

specific DNA/RNA

1012 copies

Readily visible band of

defined size on gel

electrophoresis

One cycle 18–24 h

Time taken 4–6 weeks

One cycle 2 min

Time taken 2 h

Cheng VC, et al, Yuen KY. Clinical evaluation of the polymerase chain reaction for the rapid diagnosis of tuberculosis. J Clin Pathol 2004;57:281–285.

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M/32, doctor

Fever 39 Celsius for

2 days & subsided

with IV ceftriaxone;

Erythema nodosum

over legs two months

later;

No cough/sputum;

Normal CBP, ESR,

L/RFT

Transbronchial biopsy of RMZ lesion: granuloma with one AFB seen; no culture/ST;

Rx: 2 HRZ+(E/S)/4 HR

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Tree-in-Bud sign

Endobronchial TB

small airway infection

M/49, chronic

smoker;

PH of TB Rx at

Chest Clinic in

1997;

c/o cough 2 mths;

Night sweating &

weight loss 5 lb;

CXR: apical

scars

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Sputum & BAL smear and

culture negative but TB PCR

positive on BAL;

Only the needle biopsy is

histologically positive for AFB

Retreatment: 3HRZES/6HRE

Postprimary active tuberculosis in a patient with a chronic cough Tree-in-bud appearance

The tree-in-bud pattern on CT scan correlates well with histopathological changes of :

1. bronchiolar luminal impaction with mucus, pus, or fluid,

2. Dilated & thickened walls of the peripheral airways and peribronchiolar inflammation and

therefore visible bronchioles which are affected

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Principles of anti-TB Rx

• Directly Observed Therapy short-course (DOTS直接觀察短期治療) • Modification according to drug sensitivity test results, disease severity,

underlying illness, organ dysfunction, drug side effects, response to Rx

• Notification for contact tracing & health education;

• Baseline CBP, LFT, RFT, HBsAg; educate on warning signs of hepatoxicity, allergic reaction, visual & hearing impairment

• Usual duration of Rx: 6 months; extension to 9 to 12 or more mths for relapse, cavitation, persistent culture positivity at 2 mths, drug resistance,

• 4 drugs (HRZ+E/S) for initial phase of 2 months to reduce the microbial load & prevent emergence of resistant mutants; 2 drugs (HR) for continuation phase of 4 months for the slow grower; daily or thrice weekly DOTS

• The initial phase can be extended to 3 to 4 months if suboptimal clinical, radiological or microbiological response

• Monitor symptoms, side effects, AFB smear & culture blood tests & imaging;

• H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambutol; S: streptomycin; O: levofloxacin/ofloxacin

.

Parenchymal postprimary tuberculosis

M/55, known silicosis put on isoniazid for 6 months 7 years ago, cough for a year,

occasional blood streaked morning sputum, no fever but night sweating,Sputum AFB

smear – /PCR+; culture positive with isoniazid resistance;

Rx regimen for

Isoniazid Resistance:

2SRZE/7RZE

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Bilateral upper lobes disease, RUL infiltrates, LUL cavities

M/17, recent immigrant from Mainland, occasional blood streak sputum; evening fever & night

sweating; poor performance at school, poor appetite, weight loss; sputum AFB smear+++;

4 HRZE/5 HR

Extension of both initial &

continuation phase

because of

1. Cavitory disease,

systemic upsets

2. Persistent culture

positive at 2 months

M/44, computer engineer, routine check up for a new job; no symptoms; Radiologist report: RUL cavity, posterior segment; early morning sputum AFB smear: occasional+; HBsAg positive, ALT146; HBV viral load: >105

Put on SMO & entecavir

When LFT normalize,

reintroduce H & R; off S;

Total duration of Rx: 9 with 6

months of HR

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Upper lobes calcification with new infiltrates

Lymphadenopathy(left hilum & right paratracheal) in a patient with primary tuberculosis.

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Right pleural effusion

Raised right diaphragm - subpulmonary effusion for lateral decubitus & USG aspiration/pleural biopsy

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F/62, systemic lupus erythematosis on maintenance prednisolone 15mg/D & mycophenolate; recent fatigue and weight loss; sputum AFB smear –; Miliary shadows on CXR; BAL PCR and AFB culture positive;

Miliary TB:

3HRZ+(E/S)

/9HRE

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CXR at last

admission of a

45 yr old nurse

with XDR-TB

XDR-TB

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Modification of basic DOTS anti-TB regimen

• New case: 2 HRZ+(E/S)/4 HR

• Retreatment: 3HRZES/6HRE

• Isoniazid R: 2SRZE/7RZE

• TB meningitis: 3HRZES/9HRE

• Miliary TB: 3HRZ+(E/S) /9HRE

• TB bone & joint: 2 HRZ+(E/S) /10 HR

• Diabetes/Immunosuppressed hosts: 2 HRZ+(E/S)/9 HR

• Pregnancy/poor hearing: No S

• Children/poor vision: No E

• Silicosis & TB: 2HRZ+(E/S)/7HR

• Elderly >65 for dose reduction: H(200mg); pyrazinamide(1gm) to decrease hepatotoxicity; add pyridoxine;

• Poor liver function & shown not tolerating HRZ: 12 SMO

• Poor renal function: H(200mg), add pyridoxine; adjust E according to creatinine clearance

Rx of LTBI(latent 潛伏 TB infection)

Initial clinical evaluation and Dx of LTBI (usually household contacts)

Use of TST and definition of positivity (cut-off value depends on risk level and purpose)

• In Hong Kong: 2TU of PPD-RT23

• • 15 mm in general population or conversion

• • 10 mm in silicotic patients/ patients receiving anti-TNF

• • 5 mm in HIV+ve patients/ infants aged below 1

Before Rx of LTBI

• Clients who have past Rx for TB or LTBI are generally not candidates for further Rx of LTBI

• Rule out active TB by CXR,

• Discuss with client the pros & cons

• Choose regimen: drug tolerance, index case INH-resistance, duration

During Rx

• monitor for side effects of drugs, adherence, and possible development of active TB

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Andersen P, Munk ME, Pollock JM, Doherty TM. Specific immune-based diagnosis of tuberculosis. Lancet 2000;356:1099–1104.

Interferon- release assays (IGRA) specific

for Mycobacterium tuberculosis

ESAT6 & CFP10 specific for MTB

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Pai M, Riley LW, Colford JM Jr.

Interferon-gamma assays in the

immunodiagnosis of tuberculosis:

a systematic review. Lancet

Infect Dis 2004;4:761–776.

Sensitivity

• QFT-IT 81-84%

• T-SPOT.TB 88-89%

• MT 70%

Specificity

• QFT-IT 99%

• T-SPOT.TB 86%

• MT 60-97%

(depends on previous

BCG vaccination)

Chest; 137: 4; April 2010

Most useful for the diagnosis of

Latent tuberculosis infection;

Quantiferon & T spot tests are more

specific in areas with BCG

vaccination;

But the sensitivity is not markedly

better; false negative in

immunosuppressed host

Comparison between Quantiferon, T spot &

Mantoux skin test with microbiologically

documented TB as Gold Standard

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Thank you

Current evidence: ELISPOT vs

TST • Diagnosis of active TB More sensitive

(healthy and HIV+,

children and adult)

• Diagnosis of LTBI More sensitive and specific

• Contact tracing Stronger correlation with

exposure

• Prior BCG vaccination Minimal effect

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Interfering with Host Cell Signaling by hijacking the

Calcineurin Pathway: activated calcineurin in inhibiting

phagosome-lysosome fusion

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Management of tuberculosis(TB, purpose only

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