Transcript TB - What`s New in Medicine

Tuberculosis
Scott Lindquist MD MPH
Washington State Communicable
Disease Epidemiologist
Estimated TB Global Incidence 2012
A Brief History of Tuberculosis (TB)
- Tuberculosis (phthisis) described since the
time of Hippocrates (460 BC - 370 BC)
- 1689: Doctor Richard Morton used the term
“consumption” to denote TB.
- Second half of the 17th century: high death
rates from TB in Europe.
- 1722: Doctor Benjamin Marten proposed
that TB could be transmitted in the air and
described TB as being caused by
“wonderfully minute living creatures”
- End of 19th century to the start of 20th
century: Principal cause of death in Europe
was TB.
- The romantic Era of TB
“Queen Guinevere” painted by William Morris
A Brief History of Tuberculosis (TB)
- 1865 Jean-Antoine Villemin: confirmed that
TB is contagious.
- Robert Koch:
- 1882: Isolated and cultured M. tuberculosis.
- 1890: Announced the discovery of tuberculin.
- Developed staining methods used to identify the
bacteria.
- 1905: Received the Nobel Prize
- Bacteriologist Paul Ehrlich developed ZiehlNeelsen staining.
- Late 1800’s: Edward Livingston Trudeau
established “Adirondack Cottage
Sanatorium”, first TB sanatorium in the US.
Visualization of M. tuberculosis
using the Ziehl-Neelsen stain
Tuberculosis
• 1882 – Robert Koch – “one seventh of all human beings die
of tuberculosis and… if one considers only the productive
middle-age groups, tuberculosis carries away one-third and
often more of these…”
A Brief History of Tuberculosis (TB)
- 1896 Theobald Smith demonstrated that bovine
TB is caused by M. bovis.
- 1908 Albert Calmette and Camille Guérin isolated
M. bovis and grew it in ox bile.
- Identified a morphological variant of M.
bovis found to be avirulent, conferred
immunity against M. tuberculosis.
– Lead to the BCG vaccine (bacilli CalmetteGuérin).
- Development of antibiotics to combat infection:
– 1947: streptomycin, 1952: isoniazid
– The majority of drugs used to combat
infection were identified between 1945 and
1967.
– No new drugs developed since the 1980’s
- Reoccurrence of TB for two main reasons:
1)HIV/AIDS pandemic
2)Development of drug resistance
M. bovis
Reported TB Cases
United States, 1982–2012*
30,000
No. of Cases
25,000
20,000
15,000
10,000
5,000
0
*Updated as of June 10, 2013.
Year
TB Morbidity
United States, 2007–2012
Year
No.
Rate*
2007
13,282
4.4
2008
12,895
4.2
2009
11,520
3.8
2010
11,163
3.6
2011
10,517
3.4
2012
9,945
3.2
*Cases per 100,000. Updated as of June 10, 2013.
TB Case Rates,* United States, 2012
D.C.
< 3.2 (2012 national average)
>3.2
*Cases per 100,000.
Map of U.S.-Affiliated Pacific Islands
by TB Case Rates,* 2012
Northern
Mariana Islands
Guam
Marshall
Islands
Palau
Federated
States of
Micronesia
≤9.9
*Cases per 100,000
10–49.9
American
Samoa
≥50
TB Case Rates,* U.S.-Affiliated
Pacific Islands, 2012
0
50
211.7
Marshall Islands
United States overall
*Cases per 100,000
250
42.5
Guam
Hawaii
200
162.5
Federated States of Micronesia
American Samoa
150
40.9
Northern Mariana Islands
Palau
100
9.5
1.8
8.4
3.4
TB Case Rates* by Age Group
United States, 1993–2012
Cases per 100,000
20.0
15.0
10.0
5.0
0.0
0 - 14
* Updated as of June 10, 2013.
15 -24
25 - 44
45 - 64
≥65
TB Case Rates by Age Group and Race/Ethnicity,*
United States, 2012
60
Hispanic or Latino
Cases per 100,000
50
American Indian or
Alaska Native
40
30
Asian
20
Black or African
American
10
Native Hawaiian or
Other Pacific
Islander
0
Under 5
5 - 14
15 - 24
24 - 44
45-64
≥65
*All races are non-Hispanic. Persons reporting two or more races accounted for less than 1% of all cases.
Number of TB Cases in
U.S.-born vs. Foreign-born Persons,
United States, 1993–2012*
No. of Cases
20,000
15,000
10,000
5,000
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
U.S.-born
*Updated as of June 10, 2013
Foreign-born
Trends in TB Cases in Foreign-born Persons,
United States, 1992 – 2012*
No. of Cases
Percentage
10,000
9,000
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
70
60
50
40
30
20
10
0
Number of Cases
*Updated as of June 10, 2013
Percentage of Total Cases
Reported TB Cases by Origin and Race/Ethnicity,*
United States, 2012
Foreign-born**
U.S.-born
White
(35%)
Hispanic or
Latino
(19%)
American
Indian or
Alaska
Native
(4%)
Black or
African
American
(14%)
White
(5%)
Asian
(3%)
Native
Hawaiian
or Other
Pacific
Islander
(1%)
Black or
African
American
(37%)
Asian
(45%)
*All races are non-Hispanic. Persons reporting two or more races accounted for less than 1% of all cases.
** American Indian or Alaska Native and Native Hawaiian or Other Pacific Islander accounted for less than 1% of
foreign-born cases and are not shown.
Hispanic or
Latino
(33%)
TB Case Rates in U.S.-born vs. Foreign-born Persons,
United States, 1993 – 2012*
40.0
Cases per 100,000
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
U.S. Overall
*Updated as of June 10, 2013.
U.S.-born
Foreign-born
Estimated HIV Coinfection in Persons
Reported with TB, United States, 1993 – 2012*
70
% Coinfection
60
50
40
30
20
10
0
Aged 25-44
All Ages
*Updated as of June 10, 2013
Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group
Percent of Foreign-born with TB by Time of Residence
in U.S. Prior to Diagnosis, 2012
100
80
60
40
20
0
Mexico
Philippines
Unknown*
<1 year
India
1-4 years
All Other Foreign-born
≥5 years
*Foreign-born TB patients for whom information on length of residence in the U.S. prior to diagnosis is unknown or
missing
TB Cases by Residence in Correctional Facilities, Age
≥15, United States, 1993-2012*
1200
6.0%
1000
5.0%
800
4.0%
600
3.0%
400
2.0%
200
1.0%
0
0.0%
No. of Cases
*Updated as of June 10, 2013
Note: Resident of correctional facility at time of TB diagnosis
Percent of Total Cases
TB Cases Reported as Homeless in the
12 Months Prior to Diagnosis,
Age ≥15, United States, 1993-2012*
1600
8.0%
1400
7.0%
1200
6.0%
1000
5.0%
800
4.0%
600
3.0%
400
2.0%
200
1.0%
0
0.0%
No. of Cases
*Updated as of June 10, 2013
Note: Homeless within past 12 months of TB diagnosis
Percent of Total Cases
Transmission of M. tuberculosis



M. tb spread via airborne
particles called droplet
nuclei
Expelled when person with
infectious TB coughs,
sneezes, shouts, or sings
Transmission occurs when droplet nuclei inhaled and reach
the alveoli of the lungs, via nasal passages, respiratory tract,
and bronchi
Pathogenesis of TB Infection
Droplet nuclei containing tubercle
bacilli are inhaled, enter the lungs, and
travel to the alveoli.
Tubercle bacilli multiply in the alveoli.
Pathogenesis of TB Infection
A small number of tubercle bacilli
enter the bloodstream and spread
throughout the body. The tubercle
bacilli may reach any part of the
body, including areas where TB
disease is more likely to develop
(such as the brain, larynx, lymph
node, lung, spine, bone, or
kidney).
TB – A Multi-system Infection
Probability TB Will Be Transmitted





Susceptibility of the exposed person
Infectiousness of person with TB (i.e., number of bacilli TB
patient expels into the air)
Environmental factors that affect the concentration of M. tb
organisms
Proximity, frequency, and duration of exposure (e.g., close
contacts)
Can be transmitted from children, though less likely
Latent TB Infection (LTBI) or TB Infection




Granulomas may persist (LTBI), or may break down to
produce TB disease
2 to 8 weeks after infection, LTBI can be detected via TST or
interferon-gamma release assay (IGRA)
The immune system is usually able to stop the multiplication
of bacilli
Persons with LTBI are not infectious and do not spread
organisms to others
Natural History of TB Infection
Exposure to TB
No infection
(70-90%)
Infection
(10-30%)
Latent TB
(90%)
Never develop
Active disease
Die within 2 years
Active TB
(10%)
Untreated
Survive
Treated
Die
Cured
LTBI Progression to Active TB Disease
• LTBI
– 10% lifetime risk of active TB disease
– 90% lifetime risk of no active TB
5% First Year
2-3% Second Year
– 30% lifetime risk if diabetic
– 10% risk per year if HIV +
@ 0.1% per year
thereafter
TB Disease




In some, the granulomas break down, bacilli escape and
multiply, resulting in TB disease
Can occur soon after infection, or years later
Persons with TB disease are usually infectious and can
spread bacteria to others
Positive M. tb culture confirms TB diagnosis
Latent TB vs. Active TB
Latent TB (LTBI) (Goal = prevent future active disease)
= TB Infection
= No Disease
= NOT SICK
= NOT INFECTIOUS
Active TB (Goal = treat to cure, prevent transmission)
= TB Infection which has
progressed to TB Disease
= SICK (usually)
= INFECTIOUS if PULMONARY (usually)
= NOT INFECTIOUS if not PULMONARY (usually)
LTBI vs. TB Disease
Person with LTBI (Infected)
Person with TB Disease (Infectious)
Has a small amount of TB bacteria in his/her
body that are alive, but inactive
Has a large amount of active TB bacteria in
his/her body
Cannot spread TB bacteria to others
May spread TB bacteria to others
Does not feel sick, but may become sick if the
bacteria become active in his/her body
May feel sick and may have symptoms such as a
cough, fever, and/or weight loss
Usually has a TB skin test or TB blood test
reaction indicating TB infection
Usually has a TB skin test or TB blood test
reaction indicating TB infection
Radiograph is typically normal
Radiograph may be abnormal
Sputum smears and cultures are negative
Sputum smears and cultures may be positive
Should consider treatment for LTBI to prevent Needs treatment for TB disease
TB disease
Does not require respiratory isolation
May require respiratory isolation
Not a TB case
A TB case
Identifying Who Is At Risk
For Infection or Disease
• Infection
–
–
–
–
Foreign Born
Age greater than 65 y/o (usually LTBI)
Homeless
Alcohol use
• Disease
– Age (very young)
– Anything that lowers the immune system
Initial TB Testing

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
Two methods for detecting M. tb infection: TST and IGRAs
TST and IGRAs help differentiate persons with M. tb
infection from those not infected
Negative reaction to either does not exclude diagnosis of TB
or LTBI
TST versus IGRA
Initial TB Testing
Tuberculin Skin Test (TST)
• Pro’s and Con’s
–
–
–
–
Cheap
2 visits
Human error/bias
Variable sensitivity and
specificity
– Reacts with BCG and
MOTTS
– Shortage of supplies
Interferon Gamma Release
Assay (IGRA)
• Pro’s and Con’s
– Initial expense higher
– Single visit
– Positive and negative
control
– Better sensitivity and
specificity
– Does not react with BCG
and most other MOTTS
Sorting Out TB Infection/Disease
• Epidemiology profile
– develop a high index of suspicion
• TB Test (IGRA or TST) is least helpful
• Radiograph
• Sputum for AFB smear and culture
• Hi Tech diagnostics have a role but only after the above have
been considered
Targeting High Risk Patients with High Tech Tools
• This is the partnership between the lab and clinician
• Clinician has a high index of suspicion for TB
• Laboratorian makes sure tools are available and proficiency
is assured
– Automated NAA testing
– Molecular Drug Susceptibility Testing
– Interferon Gamma Release Assays
Automated NAA Test
GeneXpert (Cepheid)
•
•
•
•
New platform for TB NAAT
Platform used for other diseases
Technically simple
Performance is excellent
– very high specificity
– very high sensitivity for smear positive
• Provides rapid rifampin susceptibility
GeneXpert
Xpert MTB/RIF assay & GeneXpert instrument
Xpert MTB/RIF assay & GeneXpert
Xpert MTB/RIF assay & GeneXpert
Sensitivity and specificity
Compared to culture
• Sensitivity for AFB+/culture+ 98.2%
• Sensitivity for AFB-/culture+ 72.5%
• Specificity
99.2%
Rifampin resistance detection
• Sensitivity – 98%
• Specificity – 99%
Universal Genotyping
• All TB cultures are now sent to CDC sponsored labs for
“fingerprinting” from each state
• Goal is to detect clusters
Number and Percent of Unique* and
County-GENType Clustered** Cases,
United States, 2010–2012
17,669
(79%)
4,585
(21)%
Unique
*Unique
Clustered
case is a case with a spoligotype and 24-locus locus MIRU-VNTR (GENType) that does not match any other case in that county during the
specified 3-year time period
** Two or more cases with matching spoligotype and 24-locus locus MIRU-VNTR (GENType) within a county during the specified 3-year time period
Molecular Detection of Drug Resistance
• CDC offers a semi-automated rapid detection of drug
resistance in isolates
• Using conventional PCR and DNA sequencing
• Looks for common mutations associated with drug
resistance
• The resistance testing will define MDR and XDR
Molecular Detection of Drug Resistance
• Drug Resistance Testing
– INH
– Rifampin
– FQ
– KAN
– AMK
– CAP
% Resistant
10
Primary Anti-TB Drug Resistance,
United States, 1993 – 2012*
5
0
Isoniazid
MDR TB
*Updated as of June 10, 2013.
Note: Based on initial isolates from persons with no prior history of TB. Multidrug resistant TB (MDR TB) is defined
as resistance to at least isoniazid and rifampin
Primary Isoniazid Resistance in
U.S.-born vs. Foreign-born Persons,
United States, 1993 – 2012*
14
12
% Resistant
10
8
6
4
2
0
U.S.-born
*Updated as of June 10, 2013.
Note: Based on initial isolates from persons with no prior history of TB.
Foreign-born
Primary MDR TB in
U.S.-born vs. Foreign-born Persons
United States, 1993 – 2012*
% Resistant
3
2
1
0
U.S.-born
Foreign-born
*Updated as of June 10, 2013.
Note: Based on initial isolates from persons with no prior history of TB. MDR TB defined as resistance to at least
isoniazid and rifampin.
XDR TB Case Count Defined on Initial DST*
by Year, 1993 – 2012**
12
Case Count
10
8
6
4
2
0
Year of Diagnosis
* Drug susceptibility test
** Updated as of June 10, 2013.
Note: Extensively drug-resistant TB (XDR TB) is defined as resistance to isoniazid and rifampin, plus resistance to any fluoroquinolone and at
least one of three injectable second-line anti-TB drugs
Major Goals of TB Treatment

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Cure patient, minimize risk of death/disability, prevent
transmission to others
Provide safest, most effective therapy in shortest time
Prescribe multiple drugs to which the organisms are
susceptible
Never treat with a single drug or add single drug to failing
regimen
Ensure adherence and completion of therapy
Current Anti-TB Drugs
10 drugs FDA-approved for treatment of TB
Isoniazid (INH)
 Rifampin (RIF)
 Pyrazinamide (PZA)
 Ethambutol (EMB)
 Rifapentine (RPT)

Streptomycin (SM)
 Cycloserine
 Capreomycin
 ρ-Aminosalicylic acid
 Ethionamide

Current Anti-TB Drugs (cont.)
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Four first-line drugs considered standard treatment:
 Isoniazid (INH)
 Rifampin (RIF)
 Pyrazinamide (PZA)
 Ethambutol (EMB)
Rifabutin and rifapentine also considered first-line drugs in
some circumstances
Streptomycin (SM) formerly first-line drug, but now less
useful owing to increased SM resistance
Treatment
Antibacterial chemotherapy:
- Combination of first and second line drugs for the first 2
months which could include:
-
Isoniazid
Rifampicin
Pyrazinamide
Streptomycin or Ethambutol
- Next 4 months, combination of:
- Isoniazid
- Rifampicin
- Early resistance to isoniazid: other first-line drugs
such as ethambutol, streptomycin, pyrazinamide and
fluoroquinolones can be added to drug arsenal.
- These drugs are relatively effective in killing the bacteria,
however, they also produce a wide variety of side effects.
Drug Resistance and Tuberculosis
- M. tuberculosis: naturally resistant to certain
antibiotics due to presence of:
- Drug-modifying enzymes
- Drug-efflux systems
- Hydrophobic cell wall
- Mycobacteria undergo natural mutations
which can lead to development of drug
resistance.
- TB is treated by administration of
combination chemotherapy: decreases
probability of development of drug
resistance.
- Development of increasingly resistant strains
mainly due to: Patient non-compliance
MDR and XDR Tuberculosis
MDR: Multidrug-resistant strains:
-
Strains of tuberculosis resistant at least to rifampicin and isoniazid.
Mortality rate: 40-60%
Estimated that 50 million people are infected with MDR-TB.
MDR-TB is approximately 125 times more expensive to treat than drug
susceptible TB.
XDR: Extensively-drug resistant strains:
- Strains of tuberculosis resistant to rifampicin,
isoniazid and at least three of the following
classes of second-line drugs: aminoglycosides,
polypetides, fluoroquinolones, thioamides,
cycloserine and para-aminosalicylic acid.
MDR and XDR Tuberculosis
- Emergence due to lack of patient compliance during TB treatment and
inappropriate administration of TB drugs.
- Results in more aggressive forms of TB.
- Drug resistance does not increase infectiousness.
- MDR and XDR-TB: uncommon in developing nations lacking TB drugs
(high drug-susceptible TB rates)
- MDR and XDR-TB rates are higher in developed nations with access to
anti-TB drugs.
Mode of Treatment Administration
in Persons Reported with TB,
United States, 1993 – 2010*
Percentage**
100
80
60
40
20
0
DOT only
DOT + SA
SA only
*Updated as of June 10, 2013. Data available through 2010 only.
**Percentage of total cases in persons alive at diagnosis, with an initial regimen of one or more drugs prescribed, and excluding cases with
unknown mode of treatment administration.
Directly observed therapy (DOT); Self-administered therapy (SA)