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Tuberculosis Infection in the US Military

LTC Jamie Mancuso, MD, MPH, DrPHJuly 2012

Program Director, Preventive Medicine ResidencyWalter Reed Army Institute of Research

http://213.121.208.204/servlet/ViewWork?workid=10482

Edward Munch.

The Sick Child. (1885)

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Outline

• Active vs. Latent TB• Active TB diagnosis and treatment• LTBI diagnosis and treatment• Military screening policies• Other issues

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Notable TB Patients

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Case Study

• SPC Snuffy, a 24 year old male Soldier, comes in after a 12 month deployment with the 101st. His paperwork says “positive PPD.” o What is your first priority?o What more do you want to know from the history?o What does “positive PPD” mean? o Physical exam?o Other tests necessary?o Treatment options?

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Evaluation of SPC Snuffy

• Symptoms?o Sputum X 3 (Smear and Culture)o 1 NAAT

• Exposures?o Foreign born?o Contact with known ACTIVE TB case?o Other risk factors? (Occupation, activities, medical history)

• TB test (TST or IGRA) results?o How many mm?o Previous positive (or previous 9 mm RXN)?o Previous BCG vaccine?o Use of Quantiferon Gold-in-tube or T-SPOT.TB?

• CXR?• Treatment?

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Global Burden of Tuberculosis

• 9.2 million cases and 1.7 million deaths yearly• Associated with co-pandemic of HIV• Drug-resistance increasingly common• 1/3 of the world’s population estimated to be infected

with LTBIo Focus on identification and treatment of active TB (DOTS)o LTBI not a well-known concept outside the USo Increasing efforts to extend LTBI treatment to HIV populations

Which of the following forms of TB is/are considered infectious from person-to-person?

Latent T

B infe...

Active

TB—Pulm...

Active

TB—Lymp...

Active

TB—Lary...

25% 25%25%25%

a) Latent TB infection (LTBI)b) Active TB—Pulmonaryc) Active TB—Lymphaticd) Active TB—Laryngeal

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TB Pathophysiology• Spread person-to-person through the air• Droplet nuclei may remain in the air• Primary infection

o Inhale tubercle bacillio Reach alveoli, engulfed by macrophageso Some multiply intracellularly and releasedo Immune system (cell-mediated) prevents progression

• Activationo Tubercle bacilli overcome immune systemo “5% risk in 2 years, 10% lifetime”

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Active TB

• Chronic granulomatous infection caused by M. tuberculosis complex

• Contagious • Lung disease is the most common

manifestation (80%)• Extrapulmonary (20%)

• Lymphadenitis (scrofula)• Meningitis

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Diagnosis of TB

• Clinical symptoms and signs• CXR (not confirmatory)• AFB Smear (sensitivity 50%)• Culture• NAATs• Sensitivity testing

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Symptoms of TB

• Fever• Chronic cough• Night sweats• Hemoptysis• Weight loss (unplanned)• Fatigue

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CXR

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AFB Smear

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Treatment

• “4 for 2 and 2 for 4”• INH, RIF, PYR, EMB X 2 months• INH, RIF X 4 months

• DOT is standard of care• Check bacteriologic response monthly• HIV test• Drug susceptibility vs. adherence for persistent

cases• “Never add a single drug to a failing regimen”

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When are they non-infectious?

• On adequate therapy• Clinical response• 3 consecutive negative sputum smears

from sputum collected on different days

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Infection Control

• Administrative controls • Primary strategy for infection control! *****• “Develop policies and protocols to ensure the rapid

identification, isolation, diagnostic evaluation, and treatment of persons likely to have TB”

• Engineering controls (ventilation)• Isolation• Negative pressure rooms

• Personal respiratory protection (N95)

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HIV and TB

• 10% risk of progression per year• Atypical presentations, anergy• Leading cause of death in HIV patients• MDR and XDR TB• Drug interactions • Reconstitution syndrome

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MDR and XDR

• MDR=INH, RIF resistance• XDR=MDR+

• Any fluoroquinolone; AND• 1 of 3 injectable second line drugs

• Capreomycin• Kanamycin• Amikacin

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LTBI vs. Pulmonary TB Disease

Latent Tuberculosis Infection

TST* or IGRA† positive

• Negative chest radiograph

• No symptoms or physical findings suggestive of TB disease

Pulmonary TB Disease• TST or IGRA usually positive

• Chest radiograph may be abnormal

• Symptoms may include one or more of the following: fever, cough, night sweats, weight loss, fatigue, hemoptysis, decreased appetite

• Respiratory specimens may be smear or culture positive

* Tuberculin Skin Test (TST)† Interferon Gamma Release Assay (IGRA) are blood tests to detect M. tuberculosis infection.

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Notable TB Patients

When you see a patient, what do you define as a positive TB test?

5 mm

10 mm

15 mm

It depends o

n ...

25% 25%25%25%a) 5 mmb) 10 mmc) 15 mmd) It depends on the

epidemiological characteristics and degree of TB exposure of the patient

22CDC. MMWR 2000;49:1-51.

CDC MMWR 2004;53:683-686.

Note: includes patients taking

TNF-α antagonists

Do you treat every patient that has a positive PPD?

Yes No

50%50%a) Yesb) No

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Decision to treat

• “A decision to test is a decision to treat”o Don’t ignore a positive testo However, don’t test low-risk populations!

• Must rule out active TB firsto Symptoms of active TBo Chest x-rayo If symptoms3 sputum smear & cx, at least 1 NAAT test

• Look at criteria to determine cutoff• Assess risks & benefits for each individual patient

o Medical history (esp. liver disease, alcohol abuse)o Pregnancyo Allergieso How close and how recent was contact with active TB case

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CDC Guidelines Call for Targeted Testing Only

• Targeted testing: • “…targeted tuberculin testing programs should be

conducted only among groups at high risk and discouraged in those at low risk.” (MMWR 2000)

• All military services conduct universal testing at accession• CDC clearly considers high-risk:

• Hospitals and health care settings (MMWR 2005)• Prisons (MMWR 2006)• HIV-infected, homeless, contacts of active case, etc.

(MMWR 2000, 2005)• Military not considered high-risk

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Testing for M. tuberculosis Infection

Mantoux tuberculin skin test (TST)Skin test that produces delayed-type hypersensitivity

reaction in persons with M. tuberculosis infection

Interferon Gamma Release Assays (IGRAs)Blood tests that measure and compare amount of interferon-

gamma (IFN-) released by blood cells in response to antigens.

These include:1. Quantiferon® Gold-in-tube (QFT-GIT)2. T-SPOT®.TB

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The TB Skin Test

• Cell-free purified protein fraction extracts obtained from a human strain of M. tuberculosis

• History and significance• 100 years of use with known endpoints of active TB

disease• Problems with TST

• Positive predictive value is low if prevalence of infection is low

• Errors and variability in administration• False negatives and false positives

• Pseudoepidemics of TST reactions in hospitals and prisons

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Administering the TST

• Inject 0.1 ml of 5 TU PPD tuberculin solution intradermally on volar surface of lower arm using a 27-gauge needle

• Produce a wheal 6 to 10 mm in diameter

CDC. MMWR (Appendix F) 2005;54(RR-17):138-9.

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Reading the TST

• Measure reaction in 48 to 72 hours

• Measure induration, not erythema

• Record reaction in millimeters, not “negative” or “positive”

• Ensure trained health care professional measures and interprets the TST

CDC. MMWR (Appendix F) 2005;54(RR-17):138-9.

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Boosting and two-step testing

• Boostingo May have an initially negative test due to waning

responsivenesso First test may stimulate immune response for second

testo Second test positive=boosted reaction

• Two-step testingo Standard of care when doing repeated testingo Differentiates boosted reaction from recent infectiono Patient still is positive even if on second test and

should be evaluated

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Notable TB Patients

Which of the following is true of the interferon-gamma release assays (IGRAs), the Quantiferon® Gold-in-

tube and T-SPOT®.TB?

They may be us..

.

They are alway...

They both have...

Use of a

n IGRA...

25% 25%25%25%a) They may be used as a

diagnostic aid for both active and latent TB infection

b) They are always preferred over the TB skin test (TST) for LTBI screening in US civilian and military guidelines

c) They both have a higher sensitivity than the TST

d) Use of an IGRA avoids the problem that the TST has had of having many false positives in low-prevalence populations such as the US military

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The Interferon Gamma Release Assay (IGRA)

• Measures interferon-gamma released from lymphocytes in whole blood samples incubated with antigens to MTBo Unknown progression of

positives to active TBo Better specificity, but

concerns with sensitivityo Lack of “gold standard”

• Not a panacea

Andersen P et al. Lancet 2000;356:1099.

In which population is the IGRA preferred for TB testing over the TST?

Children < 2 y...

Post-deploymen...

Milit

ary acce

s...

BCG vacci

nated

25% 25%25%25%a) Children < 2 years b) Military post-

deploymentc) Military accessiond) BCG vaccinated

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When should I use the IGRA?

• Depends who you talk to o CDC guidelines: may be used to replace TST, but

don’t do botho UK, many other European countries: use IGRA as

confirmatory testo Military policies conform with CDC, but Navy Great

Lakes is using it as a confirmatory test• Evolving issue, not resolved yet

o More datao Evolving technology

• IGRA preferred among BCG vaccinated

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Notable TB Patients

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What is your service policy for TB screening/testing?

• Army • Navy • Air Force

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What do the US Military Services Do?

• Over 250,000 tests per year among recruits• Accessions: all services do universal screening

o Army (DA PAM 40-11; 20 Oct 2008)o Navy (BUMED Instruction 6224.8A; 12 Feb 2009)o Air Force (AFI 48-105; 1 Mar 2005)

• Prevalence of TST reactors o Navy: 5%o Army: 3%o Air Force: 1.5%o Depends on proportion of foreign-born

• Deployment-related screening

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Recent Deployment TB Epidemiology

• Outbreaks on Navy ships—common in the 1960so USS Wasp (1998): 21 infected from failure to diagnose index case o USS Ronald Reagan (2003): 1 case reactivated despite prior INH

Rx • Active TB: lower rate of disease than in the US population • TST reactors during deployment

o Risk of TST conversion: about 1-2% per testo Problems with false positives and pseudo-outbreaks of TST

conversions

Lamar. Mil Med 2003; 168(7):523-7.

CDC. MMWR. 2007;55:1381-2.

Camarca MM and Krauss MR. Mil Med 2001;166(5):452-6

Mancuso J. AJRCCM 2008:177:1285-9.

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Pseudoepidemics of TST conversions in the US Army and their attributed causes, 1983-2005

Year Population Location

Pre-investigation estimate

of % conversions

Post-investigation estimate of % conversions

% of conversions with negative repeat test

Active TB cases identifie

d

Primary attributed cause(s) of outbreak

2005 Aviation unit Afghanistan

15% (30 of 198)

4.3% (16 of 374)

81% (13 of 16)

0 Test administration and reading; use of Aplisol; prior positives not documented; foreign birth

2005 Army National Guard

TF Falcon, Kosovo

5% (75 of 1500)

2.5% (37 of 1500)

95% (38 of 40)

0 Test administration and reading; use of Aplisol

2003 Army National Guard

TF Eagle, Bosnia

1.6% (19 of 1222)

0.5% (6 of 1222)

-- 0 68% (13 of 19) were prior reactors; conversion rate was not elevated

1996 Hospital Staff

TF Eagle, Bosnia

1.3% (1 of 80)

1.3% (1 of 80)

-- 1 Conversion rate not elevated

1996 Prisoners and prison guards

Ft. Leavenworth, KS

2.5% (34 of 1345)

-- 30% (9 of 30) 0 Use of Aplisol

1995 Military Police

Guantanamo Bay, Cuba

6.3% (81 of 1280)

3.6% (46 of 1280)

100% (6 of 6) 0 33% (25 of 75) were prior reactors; foreign birth

1984 Prisoners and prison guards

Ft. Leavenworth, KS

9.1% (191 of 2106)

-- 36% (62 of 172)

0 Increased surveillance, variability in test administration and reading; ethnic group and region of birth

1983 Medical students

Ft. Benning, GA

7.7% (5 of 65)

3.1% (2 of 65)

-- 0 60% (3 of 5) had dominant reactions to PPD-B, indicating cross-reactions with non-tuberculous mycobacteria (NTM)Mancuso JD. Am J Resp Crit Care Med 2008;177:1285

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What about guidelines for travelers?

• US Guidelines (CDC Yellow Book): both pre- and post-travel testing for those with “prolonged exposure to tuberculosis…e.g. [routine contact with] hospital, prison, and homeless shelter populations”

• IDSA Guidelines: TST “should be performed for those with anticipated exposure to TB or long-term stays in developing areas or when requested by the traveler because of concern about exposure”

• TRAVAX: “travelers to countries with high risk (i.e., > 100 cases per 100,000) should have pre-departure testing if staying for > 1 month; travelers to countries with moderate risk (approximately 25-100 cases per 100,000) should have pre-departure testing if they plan on staying for > 3 months”

• Canadian Guidelines: a single, post-travel test based on duration of travel as well as TB incidence in the country visited.

1. MF Iademarco. Tuberculosis. In: Health Information for International Travel 2008. Atlanta, GA: CDC, 2008.2. Hill et al. CID 2006;43:1514.3. Shoreland. Tuberculosis. Available at www.travax.com, Accessed 6 June 2009.4. W Wobeser et al. Surveillance and screening in tuberculosis control. In: Canadian tuberculosis standards: Public

Health Agency of Canada, 2007.

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Hmmm…so what does the US military do for “travelers” (deployers)?

• Air Force moved to targeted testing after deployment in ’05 (AFI 48-105)

• Army• Used to test before deployment, after deployment, and then

again 3-6 months after deployment (3 tests per deployment)• In 2008, moved to targeted testing after deployment using DD

2796 (OTSG Memo, 25 Sept 2008) • Navy

• Used to test operational units yearly with TST• Now targets testing during PHA with questionnaire

(BUMEDINST 6224.8A, 12 Feb 2009)• Policies available at:

http://www.pdhealth.mil/tuberculosis.asp#nm

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Air Force

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Navy (NAVMED 6224/8, Aug 08)

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Army (DD 2796, Jan 2008)

From service member section, page 4:

From provider assessment section, page 6:

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Notable TB Patients

Which of the following is the preferred first line drug combination to treat LTBI?

Weekly

Isoniaz..

.

Twice w

eekly R...

Daily Iso

niazi...

Weekly

Rifampi...

Daily Iso

niazi...

20% 20% 20%20%20%a) Weekly Isoniazid and Rifapentine for 3 months

b) Twice weekly Rifampin and Pyrazinamide for 2 months

c) Daily Isoniazid for 9 months

d) Weekly Rifampin for 4 months

e) Daily Isoniazid for 6 months

48CDC. MMWR 2003;52:736.

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• 900 mg (15 mg/kg) INH• 900 mg Rifapentine (RPT)• Weekly directly observed therapy (DOT)• 12 week duration of therapy• “Equal alternative to the 9 month INH regimen”• Not recommended

o Children < age 2o HIV receiving ARTso Pregnant womeno INH or RIF resistance

INH/RPT DOT Regimen

CDC. MMWR 2011;60:1650-1653.

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LTBI Treatment Myths

• Must be under 35 years old to treato Liver disease is the more important factor

• Patients with BCG vaccination should not be treatedo 10 mm or greater reaction should be considered for therapy

regardless of BCG• Serial liver enzyme tests should be performed for all

LTBI patientso Liver enzymes are not routinely done (see next slides)o Clinical monitoring monthly

• 6 month therapy is the standard regimeno 9 months of INH (isoniazid) is the preferred regimen

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Patient Instructions

• Rash• Anorexia, nausea, vomiting, or abdominal pain in

right upper quadrant• Fatigue or weakness• Dark urine• Persistent numbness in hands or feet

No alcohol!

Instruct patient to report signs or symptoms of adverse drug reactions:

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Monthly Clinical Monitoring

• Rationale for treatment• Adherence with therapy• Symptoms of adverse drug reactions• Plans to continue treatment

Monthly visits should include a brief physical exam and a review of:

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Baseline Laboratory Monitoring

Baseline liver function tests (e.g., AST, ALT, and bilirubin) are not necessary except for patients with the following risk factors:

• HIV infection

• History of liver disease

• Alcoholism

• Pregnancy or in early postpartum period

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Continued Laboratory Monitoring

Repeat laboratory monitoring if patient has:

• Abnormal baseline results • Current or recent pregnancy• High risk for adverse reactions• Symptoms of adverse reaction• Liver enlargement or tenderness during examination

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Adverse Effects of Medications: Isoniazid (INH)

• 10-20% have elevated liver enzymesoUp to 5 times normaloUsually return to normal even if rx is

continued• Clinical hepatitis in 0.1%• Peripheral neuropathy in 0.2%

oMore common with liver disease, diabetesoRx with Vitamin B6 (Pyridoxine)

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Adverse Effects of Medications: Rifampin (RIF)

• Hepatotoxicity in 0.6%• Cutaneous reactions in 6% • GI symptoms rarely severe• Orange discoloration of body fluids• Drug interactions (warfarin, OCPs, phenytoin)• Contraindicated in HIV-infected individuals on

certain PIs or NNRTIso Substitute with Rifabutin

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Notable TB Patients

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Adherence

• LTBI therapy not compulsory (active TB is)• Adherence is abysmal (up to 50% complete

therapy)o Therapeutic allianceo Don’t treat (or test!) low-risk patients

• Ways to improve adherenceo Improve access for patiento Good information and educationo 270 doses in 365 days for INHo Alternate regimens (intermittent, RIF)o Ensure continuity of care through PCSo Treat as soon as possible (during deployments, in

basic training)

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Who handles these cases?

• Civilian: public health/primary care partnershipo Most county health departments offer therapy free of

charge• Military: Usually referred to Preventive Medicine

o Can be ID, pulmonology, or primary careo Public health nurses usually do monthly clinical

follow-up• In the field (e.g. predeployment test is positive)

o Many elect to defer therapy until after deploymento Depends on comfort level, available resources, and

closeness of contact

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Other LTBI Testing Issues

• Must maintain good quality testing program, whether TST or IGRAo Both are difficult in the fieldo Should only be performed for contact investigationso Useful QA/QC guidelines for TST quality control in

Appendix F of: CDC.MMWR 2005;54(RR-17):138-9.• Tubersol® is the only TST that should be used

o False positives with Aplisol® o HA Policy 08-012 (29 Sept 08)

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Contact Investigations

• Concentric circles of contacts• Need to retest 8-10 weeks after

last contact with case• Garrison

o Refer to Preventive Medicineo CDC.MMWR 2005;54(RR-15).

• Deploymento Refer to Preventive Medicine

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Other important management issues

• Directly observed therapy (DOT)o Standard of care for Active TBo May be used for LTBI, but uncommono Refer to Preventive Medicine

• Disease reportingo Active TB is a reportable disease, LTBI is noto Positive TST or IGRA must be documented in an

electronic registry (ALTHA, MEDPROS, etc)o Reportable diseases are reported to Preventive

Medicine both in Garrison and Deployment

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“Inferior doctors treat the patient’s disease; mediocre doctors treat the patient as a person; superior doctors treat the community as a whole.”

— Huang Lee, 2600 BCE

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