Transcript TB - New England TB Consortium

Tuberculosis 101
John Bernardo, M.D.
Pulmonary Center
Boston University School of Medicine
Massachusetts Department of Public Health
Division of TB Prevention and Control
2009
TB Luminaries
Stevenson
Brontes
Vivian Leigh
Keats
TB - The Problem:
A World-Wide Epidemic
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1/3 of world’s population infected
10% develop active disease
2 million die each year from TB
TB increasing world-wide:
• 1997: 8.0 million new TB cases (WHO)
• 2006: 9.2 million new cases
• Rise due largely to a 20% increase in
African countries affected by HIV/AIDS
• Lack of necessary resources/infrastructure
Estimated TB incidence rate, 2006
Estimated new TB cases (all
forms) per 100 000 population
No estimate
0-24
25-49
50-99
100-299
300 or more
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
2008: 12,904 cases (4.2/100,000 pop)
2.9% decr. vs 2007
TB Case Rates, United States and
Massachusetts, 1986-2008
16
Case Rate Per 100,000
14
12
10
8
6
4
2
0
86
88
90
92
94
96
98
2000
02
04
06
08
YEAR
US
MA
2008: MA 261
US 12,904
TB Cases by Primary Site of Disease
Massachusetts, 2008
Pleural, 12, 5%
Bone and
or/Joint,
8, 3%
Other*, 17, 7%
Peritoneal, 8, 3%
Miliary, 17, 7%
Lymphatic:
Cervical, 18, 7%
Pulmonary,
181, 69%
*Other:
Other Site: 8, 3%
Lymphatic:Intrathoracic: 1, <1%
Meningeal: 1, <1%
Lymphatic:Other: 3, 1%
Genitourinary: 4, 2%
n = 261
TB Cases by County
Massachusetts, 2008
Other*, 7, 3%
Plymouth, 14,
5%
Bristol, 20, 8%
Barnstable, 4,
2%
Suffolk, 74,
28%
Norfolk, 22,
8%
Essex, 23, 9%
Middlesex, 68,
26%
Worcester, 29,
11%
n = 261
*Other Counties Include:
Dukes<1%
Hampshire 1%
Hampden 1%
0 TB cases reported in
Berkshire, Dukes, Franklin,
Nantucket Counties
TB Cases by Race/Ethnicity
Massachusetts, 2008
Other, 2, <1%
Hispanic, 41,
16%
Asian/Pacific
Islander, 94,
36%
White/NonHispanic, 53,
20%
Black/NonHispanic, 71,
27%
n = 261
Trends in TB Cases in Non-US Born
Persons, Massachusetts, 1995 - 2008
300
90
80
250
70
60
50
150
40
100
30
20
50
10
0
0
95
96
97
98
99
2000
01
02
03
Number of Cases
04
05
06
07
Percent of Cases
YEAR
08
Percent of Cases
200
What is TB?
and
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 Test
• Read @ 48-72 hours
• Must be measured by
a professional
TRAINED to read TB
Skin Tests
• Size of the “bump” is
measured
5mm
10mm
15mm
Tuberculin 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
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
QuantiFERON®-TB GOLD Method
Stage 1 Whole Blood Culture
ESAT-6/CFP-10
Nil ESAT-6 CFP-10 Mitogen
Control
Control
Stage 2 IFN-g ELISA
Nil
Mitogen
Transfer
undiluted whole blood
into wells of a culture plate
and add
antigens
ESAT-6,
CFP-10,
TB7.7
COLOR
TMB
Harvest Plasma from above
settled cells and incubate
120 min in ‘Sandwich’
ELISA
Wash, add Substrate,
incubate 30 min
then stop reaction
Culture overnight at 37oC
TB infected individuals
respond by secreting IFN-g
Standard Curve
OD 450nm
Heparinised whole blood
IFN-g IU/ml
Measure OD and
determine IFN-g levels
QFT Advantages
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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
UV Lights
Bed Number
Dormitory, Pine Street Inn
Counselor
- bed list
- cough log
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 TB
2009
• 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 Tuberculosis
Suspicion !
Suspicion !!
Suspicion !!!
Diagnosis of Tuberculosis:
Risks, Massachusetts, 2009
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Homeless
Non-US Born – from TB-endemic countries
Immunosuppressed
Hx of past TB
PPD+ contact of case
PPD+ child (< 4 yr)
Percent of Cases
Percent of TB Cases with Substance
Abuse, Massachusetts, 1994 - 2008
16
14
12
10
8
6
4
2
0
94
96
98
2000
02
Year
US born*
Non-US Born Substance User
04
06
08
Substance User - person reported
with excessive use of alcohol,
injecting or non-injecting drugs
within 1 year of diagnosis.
*US Born cases includes those born
in U.S. territories
Conditions that Favor Progression of
TB Infection to Disease
• Recent infection (PPD/QFT-G +)
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2-5%/yr for first 2 yr following infection
• HIV/AIDS
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7 - 10%/year for co-infected persons
• Other medical co-morbidities
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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 Clinic
Chest Radiograph
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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 Tuberculosis
• Secretions or tissue - subjected to laboratory techniques
to identify organism
– AFB Smear
– Culture
– Nucleic Acid Amplification (sputum/resp. secretions)
• Can be done as outpatient or inpatient
• For outpatients, consider possible risk to public
• For inpatients, use respiratory isolation if risk of
transmission to others
Treatment of Tuberculosis
Heliotherapy (sun therapy)
Valley Echo, April, 1927
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
Isoniazid
Ethambutol
Rifampin
Rifabutin*
Rifapentine
Pyrazinamide
Second-line
Cycloserine
Levofloxacin*
Ethionamide
Moxifloxacin*
PAS
Gatifloxacin*
Amikacin/Kanamycin*
Capreomycin
Streptomycin
*Not approved by FDA for use in tuberculosis
2009
Massachusetts’ Nursing Case
Management Model
• 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
Management Model
Principles:
Relationship between patient and nurse is built
upon trust - with a common understanding of
issues of culture, lifestyle, and language
• Patients have the right to exercise choice in their treatment
plan
• Nurse is responsible for identifying behaviors that predict
nonadherence and for developing strategies that address
these 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!!