Tuberculosis 101Tuberculosis 101

John Bernardo, M.D.John Bernardo, M.D.

Pulmonary CenterPulmonary CenterBoston University School of MedicineBoston University School of Medicine

Massachusetts Department of Public HealthMassachusetts Department of Public HealthDivision of TB Prevention and ControlDivision of TB Prevention and Control

2009

Brontes

Vivian Leigh

TB Luminaries

TB Luminaries

Stevenson

Keats

TB - The Problem:TB - The Problem:A World-Wide EpidemicA World-Wide Epidemic

• 1/3 of world’s population infected 1/3 of world’s population infected

• 10% develop active disease10% develop active disease

• 2 million die each year from TB2 million die each year from TB

• TB increasing world-wide:TB increasing world-wide:• 1997: 8.0 million new TB cases (WHO) 1997: 8.0 million new TB cases (WHO)

• 2006: 9.2 million new cases2006: 9.2 million new cases

• Rise due largely to a 20% increase in Rise due largely to a 20% increase in African countries affected by HIV/AIDSAfrican countries affected by HIV/AIDS

• Lack of necessary resources/infrastructure Lack of necessary resources/infrastructure

Estimated TB incidence rate, 2006

Estimated new TB cases (all forms) per 100 000 population

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2006. All rights reserved

No estimate

0-24

50-99

300 or more

25-49

100-299

2008: 12,904 cases (4.2/100,000 pop) 2.9% decr. vs 2007

TB Case Rates, United States and Massachusetts, 1986-2008

0

2

4

6

8

10

12

14

16

86 88 90 92 94 96 98 2000 02 04 06 08

US MA

Cas

e R

ate

Per

100

,000

YEAR

2008: MA 261 US 12,904

TB Cases by Primary Site of Disease

Massachusetts, 2008

Pulmonary, 181, 69%

Bone and or/Joint, 8, 3%

Lymphatic: Cervical, 18, 7%

Miliary, 17, 7%

Peritoneal, 8, 3%

Other*, 17, 7%

Pleural, 12, 5%

*Other:Other Site: 8, 3%Lymphatic:Intrathoracic: 1, <1%Meningeal: 1, <1%Lymphatic:Other: 3, 1%Genitourinary: 4, 2%

n = 261

Barnstable, 4, 2%

Worcester, 29, 11%

Essex, 23, 9%Middlesex, 68,

26%

Other*, 7, 3%

Bristol, 20, 8%

Norfolk, 22, 8%

Plymouth, 14, 5%

Suffolk, 74, 28%

TB Cases by County Massachusetts, 2008

*Other Counties Include: Dukes<1%Hampshire 1%Hampden 1%0 TB cases reported in Berkshire, Dukes, Franklin, Nantucket Countiesn = 261

TB Cases by Race/Ethnicity Massachusetts, 2008

White/Non-Hispanic, 53,

20%

Black/Non-Hispanic, 71,

27%

Asian/Pacific Islander, 94,

36%

Other, 2, <1%Hispanic, 41,

16%

n = 261

Trends in TB Cases in Non-US Born Persons, Massachusetts, 1995 - 2008

0

50

100

150

200

250

300

95 96 97 98 99 2000 01 02 03 04 05 06 07 08

Pe

rce

nt o

f Ca

se

s

0

10

20

30

40

50

60

70

80

90

Number of Cases Percent of Cases

YEAR

Nu

mb

er o

f C

ases

What is TB?What is TB?and and

How does one get it???How does one get it???

Sputum Stain for AFB

Primary TB in a Child

Latency of M. tuberculosis

• Environment of granuloma favors altered metabolism:• Low pO2

• Reduced CHO• High Fat

• Replication time >>> 20hr.• Loss of acid fast staining properties• Mechanism(s) unknown

• genetic switch?

• Lifetime risk of Reactivation

AFB

Reading the Skin TestReading the Skin Test

• Read @ 48-72 hours• Must be measured by a

professional TRAINED to read TB Skin Tests

• Size of the “bump” is measured

10mm

5mm

15mm

Tuberculin Skin Test in HIVTuberculin Skin Test in HIV

• Insensitive in low-prevalence populations• Reactivity varies with level of immunosuppression

– In early HIV, reactivity is maintained– Smaller or no reaction in advanced HIV (CD4 <200)

• Cut point is reduced • Positive reaction ( 5mm; U.S. standard) should

raise suspicion for TB infection• Anergy testing generally is unreliable

BCG - Bacille Calmette Guerin

• Derived from a strain of M. bovis• Not accepted/recognized in U.S. as

protection against TB• Not standardized vaccine• Efficacy studies range from 0-80% • Can confound Tuberculin skin test

– But consider patient to be TB infected if PPD-positive

Interferon-gamma Release Interferon-gamma Release Assays (IGRA)Assays (IGRA)

• in vitro assays for Cell-Mediated Immunity to M. tuberculosis antigens– Utilize whole blood– Measure release of IFNγ by circulating T lymphocytes

following stimulation with TB antigens (specific)

• QuantiFERON-TB approved by FDA in 2001 as “… an aid to the diagnosis of TB infection.”

• QFT-Gold test US FDA approved in 2005• QFT-Gold in-Tube test approved 2007• T Spot-TB test approved 2008

Heparinised whole bloodHeparinised whole blood

ESAT-6ESAT-6 CFP-10CFP-10 MitogenMitogenControlControl

Transfer undiluted whole bloodTransfer undiluted whole bloodinto wells of a culture plateinto wells of a culture plate

and add antigensand add antigens

Culture overnight at 37Culture overnight at 37ooCC

TB infected individuals TB infected individuals respond by secreting IFN-respond by secreting IFN-

Harvest Plasma from above Harvest Plasma from above settled cells and incubate settled cells and incubate

120 min in ‘Sandwich’ 120 min in ‘Sandwich’ ELISAELISA

Wash, add Substrate, Wash, add Substrate, incubate 30 minincubate 30 min

then stop reactionthen stop reaction

TMBTMB

COLORCOLOR

Measure OD andMeasure OD anddetermine IFN-determine IFN- levels levels

Stage 1 Whole Blood CultureStage 1 Whole Blood Culture

Stage 2 IFN-Stage 2 IFN- ELISA ELISA

QuantiFERONQuantiFERON®®-TB GOLD Method-TB GOLD Method

NilNilControlControl

IFN-IFN- IU/ml IU/ml

OD

45

0n

mO

D 4

50

nm

Standard CurveStandard Curve

ESAT-6/CFP-10ESAT-6/CFP-10

ESAT-6, CFP-10, TB7.7ESAT-6, CFP-10, TB7.7

NilNil MitogenMitogen

QFT Advantages

• Single patient visit• Does not “boost” subsequent test responses• Less likely positive in BCG-vaccinated• Objective read-out• Results available in < 24 hr.• Cost benefits (??)• Culture- and ethnic-naïve

QFT Limitations

• Time constraints (to get blood to lab)• Immunocompromised

– HIV-infected individuals?– Chronic corticosteroids?– Recipients of TNF- inhibitors,

immunomodulators?– Children?

• Conversions/Reversions?• Likely more specific, but less sensitive ???

CDC: MMWR 54, 12/16/2005

Most Tuberculosis in Massachusetts Results from

Reactivation of Latent Infection

Little evidence to support significant local transmission

CDC Genotyping Network

Preventing TB: Treatment of Latent TB Infection

• Significant (“positive”) TST or IGRA test• Rule out active disease

– History, examination, CXR

• Consider coincident co-morbidities/medications – As affecting risks/benefits of treatment

• Treatment– Isoniazid (INH) 300mg/d x 9 mos (standard), or– Rifampicin 600mg/d x 4 mos– PZA+Rif x 2 mos NO LONGER RECOMMENDED

• Monitor at least monthly (clinically/lab)– Adherence, toxicity (esp. hepatotoxicity)

• Reduces risk of disease by >90%

CDC: MMWR 49 (RR06), 6/9/2000

TBTC Study 26

• CDC-sponsored study of TLTBI in high-risk persons– Close contacts, recent converters, HIV, >2cm nodule

• 9 mos INH (270 doses; self-administered) vs 3 mos INH + Rifapentine once a week (12 doses; by DOT)– Safety and efficacy

• Ongoing at 23 TBTC sites, US, Canada, and overseas– 8,000 subjects enrolled; 2 year follow-up– Still enrolling children (<5y/o); HIV+

• Can we extrapolate findings to other groups?

2009

How to Diagnose and Treat TB Disease?

DOT?

Nursing Case Management!

A Typical Case

• 48 y/o homeless male with hx IDDM, chronic bronchitis, EtOH– Presents with “4-5 wk” hx cough, with increased sputum production,

sweats at night, weight loss

• Diabetes has been in fair control– Recent HbA1c 7; BS 160-200 range

• Past history of contact to TB case, with positive TST (1997)– Treated with 6 mos INH, self administered

• Physical examination– Looked disheveled; coughing– Temp: 99.0o – Chest: diffuse ronchi and scattered, coarse wheezes bilaterally

Initial Course

• Admitted to respiratory isolation• Sputum AFB – positive• Started on treatment for presumed TB

– INH, rifampin, ethambutol, pyrazinamide daily, by DOT

to come later: • How to confirm diagnosis?

– Sputum cultures grew M. tuberculosis at 14 days (susceptible to all first-line medications)

• Sooner?– MTD test positive for MTb complex the next day

Screening

• Contacts identified in shelter– Symptom/medical history (incl HIV), and TST screening

• Close friend with stable, mild asthma – TST-negative (<5mm); CXR not done– No treatment indicated

• Non-friend, but slept in next bed 4 nights, known hepatitis C– TST-positive; exam and CXR neg– Previously 0mm TST at shelter 2 yr prior– Started on INH x 9 mos; monthly monitoring

Dormitory, Pine Street Inn

UV Lights

Counselor - bed list - cough log

Bed Number

One Month Later

• Staff identified as possible contact; not screened; presents to MD w 2 wk hx dry cough, scant sputum, sob – Exam: wheezing with good air movement

• Diagnosis: asthmatic bronchitis• Treatment: Levaquin; albuterol

• 1 week later: slightly better, but still coughing – no change in treatment

• 2 wk later: cough persists; new L pleuritic chest pain

CXR:

Subsequent Course• Clinical re-evaluation

– Exam: dullness at L base– TST now 12mm (originally 0mm)– Sputum AFB smear-negative

• Next steps?– Thoracentesis?– Pleural biopsy?– Bronchoscopy?

• Treatment???– Respiratory isolation– Started 4 drug therapy for presumed TB (INH/R/Z/E)– Sputum subsequently culture-pos (21 days)

Subsequent Course

• Index patient received standard 4-drug regimen– Clinically improved within 5 days

• Clinically monitored for side effects of drugs monthly

• Sputum at 1 mos smear/cult-positive• Sputum at 2 mos smear/cult-negative• EMB was stopped at 4 wk (after susceptibilities

known); PZA was stopped at 8 wk

• Patient successfully completed 24 wk (6 mos) course – INH + Rifampin for final 4 mos

Diagnosis of TB2009

• Symptoms– Specific to system involved

• e.g., cough (pulmonary), chest pain (pericardial), …

– Nonspecific (constitutional)• e.g., fever, wt loss, night sweats, fatigue, …

– May be absent

• Epidemiology– Where is the person from?– Is he/she a “Contact” to a known case?

• Chest radiograph• Laboratory studies (smear, culture, molecular)

– Sputum/respiratory secretions– Tissue

• Initial diagnosis usually is Clinical – based on Suspicion

Diagnosis of TuberculosisDiagnosis of Tuberculosis

Suspicion !

Suspicion !!

Suspicion !!!Suspicion !!!

Diagnosis of Tuberculosis:Diagnosis of Tuberculosis:Risks, Massachusetts, 2009Risks, Massachusetts, 2009

• Homeless

• Non-US Born – from TB-endemic countries

• Immunosuppressed

• Hx of past TB

• PPD+ contact of case

• PPD+ child (< 4 yr)

Percent of TB Cases with Substance Abuse, Massachusetts, 1994 - 2008

0

2

4

6

8

10

12

14

16

94 96 98 2000 02 04 06 08Year

US born*Non-US Born Substance User

Substance User - person reported with excessive use of alcohol, injecting or non-injecting drugs within 1 year of diagnosis.

Per

cen

t o

f C

ases

*US Born cases includes those born in U.S. territories

Conditions that Favor Progression of Conditions that Favor Progression of TB Infection to DiseaseTB Infection to Disease

• Recent infection (PPD/QFT-G +) • 2-5%/yr for first 2 yr following infection

• HIV/AIDS• 7 - 10%/year for co-infected persons

• Other medical co-morbidities• IDDM, steroid therapy, rapid weight loss,

ESRD, lymphatic/hematolologic malignancies

• Age (4 yr; elderly)

Cough Log

• Pine Street Inn– Counselors in dorms observe guests

at night

• Coughing for 3 days in a row– Triggers physical evaluation, CXR

PSI TB ClinicPSI TB Clinic

Chest Radiograph

• Time: minutes to hours (days)• Sensitivity: excellent (but there are exceptions)• Specificity: poor• Advantage: inexpensive screening of

potentially active pulmonary cases• Disadvantages: cost (who pays?)

– requires skilled interpretation

TB is a Clinical Diagnosis (most of the time)

• TB is a Clinical Diagnosis– Most clinicians will initiate multi-drug therapy

if the disease is suspected on clinical grounds– But many cases go undiagnosed until a

laboratory reports a positive culture

• How is that diagnosis confirmed?– In the Laboratory

Diagnosis of TuberculosisDiagnosis of Tuberculosis

• Secretions or tissue - subjected to laboratory Secretions or tissue - subjected to laboratory techniques techniques to identify organismto identify organism– AFB SmearAFB Smear– CultureCulture– Nucleic Acid Amplification (sputum/resp. secretions)Nucleic Acid Amplification (sputum/resp. secretions)

• Can be done as outpatient or inpatientCan be done as outpatient or inpatient

• For outpatients, consider possible risk to publicFor outpatients, consider possible risk to public

• For inpatients, use respiratory isolation if risk of For inpatients, use respiratory isolation if risk of transmission to otherstransmission to others

Heliotherapy (sun therapy)Heliotherapy (sun therapy)Valley EchoValley Echo, April, 1927 , April, 1927

Treatment of TuberculosisTreatment of Tuberculosis

FUNDAMENTAL RESPONSIBILITY AND

APPROACH The provider (or program) is responsible for

prescribing an appropriate regimen AND ensuring that treatment is completed successfully

Direct observation of treatment (DOT) with individualized case-management is the approach of choice

EFFECTS OF ANTITUBERCULOSIS

CHEMOTHERAPY

• Rapid killing of tubercle bacilli

• Minimize potential for organisms to develop drug resistance: Combination chemotherapy

• Sterilize host tissues: Sufficient length of treatment

• Patient is cured with very small likelihood of relapse

DRUGS IN CURRENT USE

First-line Second-lineIsoniazid Cycloserine Ethambutol Levofloxacin*Rifampin Ethionamide Rifabutin* Moxifloxacin* Rifapentine PAS Pyrazinamide Gatifloxacin*

Amikacin/Kanamycin*CapreomycinStreptomycin

*Not approved by FDA for use in tuberculosis 2009

• Nursing Case Management is a care delivery system that promotes the coordination of necessary medical, nursing, outreach, and social services to assure that all suspected and confirmed cases of tuberculosis are appropriately and effectively treated– You get what you pay for …

Massachusetts’ Nursing Case Massachusetts’ Nursing Case Management ModelManagement Model

Massachusetts’ Nursing Case Massachusetts’ Nursing Case Management ModelManagement Model

Principles:Principles: Relationship between patient and nurse is built Relationship between patient and nurse is built

upon trust - with a common understandingupon trust - with a common understanding of of issues of culture, lifestyle, and languageissues of culture, lifestyle, and language

• Patients have the right to exercise Patients have the right to exercise choicechoice in their treatment in their treatment planplan

• Nurse is responsible for Nurse is responsible for identifying behaviors identifying behaviors that predict that predict nonadherence and for nonadherence and for developing strategies developing strategies that address that address these behaviors and assure treatment completionthese behaviors and assure treatment completion

Process • Each case of confirmed or suspected TB is assigned a PHN affiliated

with the local BOH– This nurse becomes the patient’s Case-Manager

• Case managers, working with patients’ physicians, are responsible for all aspects care for their patients and contacts– Medical

• Treatment administration (including DOT); Clinical Monitoring– Non-medical

• Education, social issues– Contact investigation, education

• Case Managers receive oversight from designated TB Surveillance Area (TSA) Nurse-Specialists (MDPH)– Assist local BOH Case-Managers to coordinate patient care and contact

investigation

• Nurses recognize factors that create nonadherence– Design interventions, may include admit to TTU at Shattuck Hospital

Completion of Therapy (COT)• COT determined by total number of doses

– Not by duration (months) of treatment• Document number of doses for each medication• Self-administered Therapy (SAT)

– Estimate based on # doses/week x # weeks, less any reported missed doses/weeks

• Directly Observed Therapy (DOT) – Use DOT log to document each dose given– Use recorded doses from log to calculate COT

The Bottom Line --> 90% complete treatment in MA 00% Secondary Drug Resistance

Worth It??

Come and Get Me!!