Tuberculosis

Scott Lindquist MD MPHWashington 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 Ziehl- Neelsen 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…”

- 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 Calmette-Guérin).

- 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

A Brief History of Tuberculosis (TB)

M. bovis

Reported TB Cases United States, 1982–2012*

*Updated as of June 10, 2013.

19821984

19861988

19901992

19941996

19982000

20022004

20062008

20102012

0

5,000

10,000

15,000

20,000

25,000

30,000

No.

of C

ases

Year

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 MorbidityUnited States, 2007–2012

TB Case Rates,* United States, 2012

*Cases per 100,000.

< 3.2 (2012 national average)

>3.2

D.C.

≥5010–49.9

≤9.9

Map of U.S.-Affiliated Pacific Islands by TB Case Rates,* 2012

*Cases per 100,000

Federated States of

Micronesia

Marshall Islands

Northern Mariana Islands

American Samoa

Guam

Palau

Northern Mariana Islands

Federated States of Micronesia

Guam

Marshall Islands

Palau

American Samoa

Hawaii

United States overall

0 50 100 150 200 250

40.9

162.5

42.5

211.7

9.5

1.8

8.4

3.4

TB Case Rates,* U.S.-Affiliated Pacific Islands, 2012

*Cases per 100,000

TB Case Rates* by Age Group United States, 1993–2012

* Updated as of June 10, 2013.

Cas

es p

er 1

00,0

00

Age Group (years)

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

20112012

0.0

5.0

10.0

15.0

20.0

0 - 14 15 -24 25 - 44 45 - 64 ≥65

TB Case Rates by Age Group and Race/Ethnicity,*United States, 2012

*All races are non-Hispanic. Persons reporting two or more races accounted for less than 1% of all cases.

Cas

es p

er 1

00,0

00

Under 5 5 - 14 15 - 24 24 - 44 45-64 ≥650

10

20

30

40

50

60

Hispanic or Latino

American Indian or Alaska Native

Asian

Black or African American

Native Hawaiian or Other Pacific Is-lander

White

Number of TB Cases inU.S.-born vs. Foreign-born Persons,

United States, 1993–2012*

*Updated as of June 10, 2013

No.

of C

ases

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 20120

5,000

10,000

15,000

20,000

U.S.-born Foreign-born

Trends in TB Cases in Foreign-born Persons,United States, 1992 – 2012*

*Updated as of June 10, 2013

No. of Cases Percentage

19921993

19941995

19961997

19981999

20002001

20022003

20042005

20062007

20082009

20102011

20120

1,0002,0003,0004,0005,0006,0007,0008,0009,000

10,000

0

10

20

30

40

50

60

70

Number of Cases Percentage of Total Cases

Reported TB Cases by Origin and Race/Ethnicity,* United States, 2012

*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(19%)

American In-dian or

Alaska Native(4%)

Asian(3%)

Black or African American

(37%)

Native Hawaiian or Other Pacific

Islander(1%)

White(35%)

Hispanic or Latino

(33%)

Asian(45%)

Black or African Ameri-

can(14%)

White(5%)

U.S.-born Foreign-born**

TB Case Rates in U.S.-born vs. Foreign-born Persons, United States, 1993 – 2012*

*Updated as of June 10, 2013.

Cas

es p

er 1

00,0

00

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

20112012

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

U.S. Overall U.S.-born Foreign-born

Estimated HIV Coinfection in Persons Reported with TB, United States, 1993 – 2012*

*Updated as of June 10, 2013Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group

% C

oinf

ectio

n

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

20112012

0

10

20

30

40

50

60

70

Aged 25-44 All Ages

Percent of Foreign-born with TB by Time of Residence in U.S. Prior to Diagnosis, 2012

*Foreign-born TB patients for whom information on length of residence in the U.S. prior to diagnosis is unknown or missing

Mexico Philippines India All Other Foreign-born0

10

20

30

40

50

60

70

80

90

100

Unknown* <1 year 1-4 years ≥5 years

TB Cases by Residence in Correctional Facilities, Age ≥15, United States, 1993-2012*

*Updated as of June 10, 2013Note: Resident of correctional facility at time of TB diagnosis

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

20112012

0

200

400

600

800

1000

1200

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

No. of Cases Percent of Total Cases

TB Cases Reported as Homeless in the 12 Months Prior to Diagnosis,

Age ≥15, United States, 1993-2012*

*Updated as of June 10, 2013Note: Homeless within past 12 months of TB diagnosis

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

20112012

0

200

400

600

800

1000

1200

1400

1600

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

No. of Cases Percent of Total Cases

Transmission of M. tuberculosis

M. tb spread via airborneparticles called dropletnuclei

Expelled when person withinfectious 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%)

Active TB(10%)

Untreated

Die within 2 years Survive

Treated

Die Cured

Never develop Active disease

LTBI Progression to Active TB Disease

• LTBI– 10% lifetime risk of active TB disease– 90% lifetime risk of no active TB

– 30% lifetime risk if diabetic– 10% risk per year if HIV +

5% First Year 2-3% Second Year @ 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 DiseasePerson 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 TB disease

Needs treatment for 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

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

• Pro’s and Con’s– Cheap– 2 visits– Human error/bias– Variable sensitivity and

specificity– Reacts with BCG and

MOTTS– Shortage of supplies

• 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

Tuberculin Skin Test (TST)Interferon Gamma Release Assay

(IGRA)

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 TestGeneXpert (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

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%

Xpert MTB/RIF assay & GeneXpert Sensitivity and specificity

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* andCounty-GENType Clustered** Cases,

United States, 2010–2012

17,669 (79%)

4,585 (21)%

Unique Clustered*Unique 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

Primary Anti-TB Drug Resistance,United States, 1993 – 2012*

*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

% R

esis

tant

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

20112012

0

1

2

3

4

5

6

7

8

9

10

Isoniazid MDR TB

Primary Isoniazid Resistance in U.S.-born vs. Foreign-born Persons,

United States, 1993 – 2012*

*Updated as of June 10, 2013.Note: Based on initial isolates from persons with no prior history of TB.

% R

esis

tant

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

20112012

0

2

4

6

8

10

12

14

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.

Primary MDR TB in U.S.-born vs. Foreign-born Persons

United States, 1993 – 2012*

% R

esis

tant

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

20112012

0

1

2

3

U.S.-born Foreign-born

XDR TB Case Count Defined on Initial DST* by Year, 1993 – 2012**

* 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

Case

Cou

nt

Year of Diagnosis1993

19941995

19961997

19981999

20002001

20022003

20042005

20062007

20082009

20102011

20120

2

4

6

8

10

12

Major Goals of TB Treatment

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

Isoniazid (INH) Rifampin (RIF) Pyrazinamide (PZA) Ethambutol (EMB) Rifapentine (RPT)

10 drugs FDA-approved for treatment of TB

Streptomycin (SM) Cycloserine Capreomycin ρ-Aminosalicylic acid Ethionamide

Current Anti-TB Drugs (cont.)

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

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

Treatment

- 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.

- 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

Drug Resistance and 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.

MDR and XDR Tuberculosis

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.

- 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.

MDR and XDR Tuberculosis

Mode of Treatment Administration in Persons Reported with TB,United States, 1993 – 2010*

*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)

Perc

enta

ge**

19931994

19951996

19971998

19992000

20012002

20032004

20052006

20072008

20092010

0

20

40

60

80

100

DOT only DOT + SA SA only