p ractical c onsiderations of l atent t uberculosis i nfection susan even, md university of missouri...

PRACTICAL CONSIDERATIONS OF LATENT TUBERCULOSIS INFECTION

Susan Even, MD University of Missouri

Sharon McMullen, RN, BSN University of Pennsylvania

Brenda Johnston, RN, MSN Oklahoma City University

Tim Crump, RN, MSN, FNP University of Portland

DISCLAIMERThe presenters have NO actual or

potential conflict of interest in relation to this educational activity or presentation

Even-McMullen-Johnston-Crump, ACHA, 6.2.2011

CAMPUS CASE 22 yo Vietnamese female graduate student Tested during fall orientation Risk factor – country with high TB incidence Symptom review – negative QFT-GIT positive


CASE MANAGEMENT

Partnered with local health department

Smears negative

Culture positive for M. tuberculosis, pan-sensitive

Contact investigation - roommates negative initially and 8 weeks

Completed 9 month treatment (3 drugs) May 2011


TUBERCULOSIS IS A VERY ANCIENT DISEASE


Evidence of tubercular decay has been found in Egyptian Mummies.

3000-2400 BCE


Recently, discoveries in the submerged village of Atlit-Yam suggest Tuberculosis was present 7000 BCE


Atlit-Yam was a village that now is submerged just off the coast of Israel.

The village dates from the very dawn of Neolithic times, earliest agricultural settlements.

Both skeletal and DNA evidence demonstrate TB in a woman and an infant buried together.


TB already established at dawn of agricultural settlements.

DNA supports that human TB was not from Bovine TB.


In the 17th and 18th Centuries, Tuberculosis caused up to 25% of all Deaths in Europe


In 1854, Herman Brehmer proposed TB was a curable disease.

Established the Sanitorium movement.


TB ESTABLISHED AS INFECTIOUS DISEASE

In 1882, Robert Koch discovered the bacteria that caused TB

In 1900, he isolated tuberculin from tubercle bacilli, which became the basis of the ppd.


ROBERT KOCH


BCG

In 1921, the BCG Vaccine was first used in humans, though widespread use did not occur till after WWII.


BCG

Most effective against TB Meningitis and Miliary TB.

Most useful in pediatric age group. Efficacy Varies. Studies in UK consistently

have shown protective effect of 60-80%. Closer to equator, benefit appears less. Causes false positive TST results.


BCG: METHOD OF ADMINISTRATION

TST administered prior to BCG; positive TST contraindicates BCG administration.

Positive TST does not imply immunity, only that there is high probability of severe local reaction.

Intradermal administration. BCG Leaves a Characteristic Scar, often used

as proof of prior immunization.


EFFECT OF BCG ON TST

The effect on TST of BCG received in infancy is minimal, especially > 10 years after vaccination

BCG received after infancy produces more frequent, more persistent and larger TST reactions.


MEDICATIONS TO TREAT TUBERCULOSIS

In 1946, Streptomycin was introduced as the first antibiotic to be effective against TB.

In 1952, Isoniazid (INH) was introduced. Originally an antidepressant.

While initial results were dramatic, resistance was soon noted to develop.

As other TB antibiotics were discovered, it was noted that combination therapy prevented or slowed the development of resistance.


SELMAN WAKSMAN


BURDEN OF TUBERCULOSIS

In 2008, WHO estimated that 1/3 of the global population is infected with TB.

In 2005, 1.6 million people died of TB. The emergence of drug-resistant organisms

threatens to make TB once again an incurable disease.


“High Incidence” Countries

are defined as areas with reported or estimated incidence of

≥20 cases per 100,000 population


Afghanistan, Algeria, Angola, Argentina, Armenia, Azerbaijan, Bahrain, Bangladesh, Belarus, Belize, Benin, Bhutan, Bolivia (Plurinational State of), Bosnia and Herzegovina, Botswana, Brazil, Brunei Darussalam, Bulgaria, Burkina Faso, Burundi, Cambodia, Cameroon, Cape Verde, Central African Republic, Chad, China, Colombia, Comoros, Congo, Cook Islands, Côte d'Ivoire, Croatia, Democratic People's Republic of Korea, Democratic Republic of the Congo, Djibouti, Dominican Republic, Ecuador, El Salvador, Equatorial Guinea, Eritrea, Estonia, Ethiopia, French Polynesia, Gabon, Gambia, Georgia, Ghana, Guam, Guatemala, Guinea, Guinea-Bissau, Guyana, Haiti, Honduras, India, Indonesia, Iraq, Japan, Kazakhstan, Kenya, Kiribati, Kuwait, Kyrgyzstan, Lao People's Democratic Republic, Latvia, Lesotho, Liberia, Libyan Arab Jamahiriya, Lithuania, Madagascar, Malawi, Malaysia, Maldives, Mali, Marshall Islands, Mauritania, Mauritius, Micronesia (FederatedStates of), Mongolia, Montenegro, Morocco, Mozambique, Myanmar, Namibia, Nepal, Nicaragua, Niger, Nigeria, Pakistan, Palau, Panama, Papua New Guinea, Paraguay, Peru, Philippines, Poland, Portugal, Qatar, Republic of Korea, Republic of Moldova, Romania, Russian Federation, Rwanda, Saint Vincent and the Grenadines, Sao Tome and Principe, Senegal, Serbia, Seychelles, Sierra Leone, Singapore, Solomon Islands, Somalia, South Africa, Sri Lanka, Sudan, Suriname, Swaziland, Syrian Arab Republic, Tajikistan, Thailand, The former Yugoslav Republic of Macedonia, Timor-Leste, Togo, Tonga, Trinidad and Tobago, Tunisia, Turkey, Turkmenistan, Tuvalu, Uganda, Ukraine, United Republic of Tanzania, Uruguay, Uzbekistan, Vanuatu,Venezuela (Bolivarian Republic of), Viet Nam, Yemen, Zambia, Zimbabwe


“Low Incidence” Countries

are defined as areas with reported or estimated incidence of

<20 cases per 100,000 population


Albania, Andorra, Antigua and Barbuda, Australia, Austria, Bahamas, Barbados, Belgium, British Virgin Islands, Canada, Chile, Costa Rica, Cuba, Cyprus, Czech Republic, Denmark, Dominica, Egypt, Fiji, Finland, France, Germany, Greece, Grenada, Hungary, Iceland, Iran (Islamic Republic of), Ireland, Israel, Italy, Jamaica, Jordan, Lebanon, Luxembourg, Malta, Mexico, Nauru, Netherlands, New Zealand, Norway, Oman, Puerto Rico, Saint Kitts and Nevis, Saint Lucia, Samoa, Saudi Arabia, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Arab Emirates, United Kingdom, United States of America, West Bank and Gaza Strip


SCREENING OUR STUDENTS

ACHA Recommendations Screening vs. Testing


Increased Risk For Tuberculosis Infection (Population risks):

• Foreign-born persons who have immigrated within the last 5 years from countries with high incidence of TB disease

• Persons with a history of travel to/in areas with a high incidence of TB disease

• Persons with signs and symptoms of active TB disease

• Close contacts of a person known or suspected to have TB disease

• Employees, residents, and volunteers of high-risk congregate settings (e.g., correctional facilities, nursing homes, homeless shelters, hospitals, and other health care facilities)

• Some medically underserved, low income populations as defined locally

• High-risk racial or ethnic minority populations defined locally as having an increased prevalence of TB disease

• Persons who inject illicit drugs or other groups of high-risk substance users (e.g., crack cocaine)


WHAT ARE SCHOOLS DOING?

Informal study via SHS Some schools following ACHA Guidelines and

screening all students and testing appropriately. Some schools are testing certain higher risk

populations who are easily mandated for testing (International, health-care, education students).

Some schools do not require asymptomatic testing.


WHY SHOULD WE CARE ABOUT TUBERCULOSIS SCREENING?


IDENTIFY, TREAT, AND MINIMIZE TRANSMISSION OF ACTIVE TB


ALSO IMPORTANT: IDENTIFY AND TREAT LATENT TB

10% of persons with Latent TB will develop Active TB at some point in their life.

80% of Active TB in the US is from reactivation of previous disease.

Nearly all of those cases could have been prevented by prior administration of prophylactic treatment of latent infection.


TUBERCULIN SKIN TESTAlso known as PPD (Purified Protein Derivative)

Or

Mantoux Test


I’M PREACHING TO THE CHOIR


PURPOSE OF THE TST

PPD (Mantoux) is indicated for the detection of a delayed hypersensitivity reaction to tuberculin as an aid in the detection of infection with Mycobacterium tuberculosis


HISTORY OF THE TB SKIN TEST

Test created in 1907 by Charles Mantoux in France, modified in 1939 in USSR

Used worldwide, largely replacing Tine test Tuberculin is a glycerol extract of the tubercle

bacillus PPD is precipitate of molecules obtained from

filtrates of sterilized concentrated cultures


INDICATIONS FOR USE

Immigrants from countries where prevalence of TB is high

Risk of reactivation due to impaired immunity Healthcare workers Travelers at risk from travel in high-endemic

countries Staff members in correctional facilities


METHODOLOGY OF TST

0.1 ml (5 TU) Injected intradermally with ¼ to ½” needle,

usually anterior surface of forearm Requires producing wheal of 6 to 10 mm Read at 48-72 hours


WHY AND HOW DOES THIS TEST WORK?

After initial exposure with M. Tuberculosis, sensitization occurs primarily in regional lymph nodes

T lymphyocytes proliferate in response to the antigenic stimulus

Subsequent re-stimulation by PPD evokes a local reaction mediated by these cells

Incubation of 2 to 12 weeks usually necessary after exposure to TB in order for result to be positive.


TWO-STEP TESTING

Not a test of dance skills!

2-step used to detect individuals with past TB infection who now have diminished skin test reactivity

Reduces the likelihood that a boosted reaction is later interpreted as a new infection

2-step testing is indicated as initial test for persons who will be retested periodically, such has health profession workers. (not indicated if IGRA available)

Method: A second TST is placed 7 days after first Abbreviated method: first test read 7 days after

placing it and 2nd test administered during same visit.


INTERPRETATION Read at 48-72 hours Induration is produced through vasodilatation,

edema, fibrin deposition and other inflammatory cells

Measure induration transversely across the forearm

Result is positive if:

>5mm in immunocompromised persons or those who have had recent close contact with active TB

>10 mm if born in countries in Asia, Africa, Caribbean, Latin America or high-risk communities. Also healthcare workers

>15 mm if general population with no other risk factors


FALSE NEGATIVES

Can be caused by: Viral infections such as MMR, chickenpox and

HIV Live virus vaccinations given within 1 month Active TB Immunosuppressive agents Malignancy


DOCUMENTATION

Document:Date, brand, lot number, expiration date, result in mm

Provide patient with documentation of date and result in mm

Do not accept documentation stating “positive” or “negative”

Most Universities do not accept testing beyond 1 year


VARIABLES

A history of BCG vaccine may cause a positive result persisting for years.

Clinical Infectious Disease 2000 Sept; 31 Suppl 3:S71-4

“Those who were vaccinated with BCG after the first year of life or had more than 1 dose of vaccine have the greatest likelihood of persistent positive results vs. those who were vaccinated as infants.”

Readings beyond 72 hours may underestimate the size of response.


RISKS AND LIMITATIONS

Sensitive test, but poor at predicting reactivation TB

Very slight risk of severe reaction including redness, swelling, blistering

Live bacteria is NOT used, so no chance of getting disease from TST.

Untrained and even trained persons providing results may read incorrectly.

Serum not stored properly may not provide accurate results.

Specificity of TST in BCG-vaccinated populations is low and highly variable


ADVANTAGES TO TST

Inexpensive Experienced persons can provide and read

accurately Colleges have a “captive audience” that

must return for readings due to option to place “holds” on accounts

Still a valid screening tool for latent TB Specificity in non-BCG vaccinated

populations high = 97%


A LITTLE TB ART LESSON


ABOUT THE HISTORY OF THE POSTER

The Federal Art Project (FAP) was the visual arts arm of the Great Depression-era New Deal Works Progress Administration (WPA) program in the U.S.

FAP operated from August 1935, until June 1943.

Artists created more than 200,000 separate posters, murals and paintings

The City of Chicago Sanitarium was one of the largest TB hospitals in the nation and the world.


INTERFERON GAMMA RELEASE ASSAY (IGRA)Blood test for TB infection (TTBI)

1 visit 2-step not requiredLess reader bias and errorMore specific, with less cross-reaction

with most non-TB mycobacteria and BCG than TST


WHY TARGETED TESTING IS IMPORTANT

A low probability of infection increases the likelihood of a false-

positive result


↑ RISK FOR PROGRESSION TO ACTIVE TB

HIV infection Children under 5 years Therapeutically immunosuppressed Recently infected with M. tb Untreated or inadequately treated active TB Silicosis, diabetes, chronic renal failure, leukemia,

lymphoma, or cancer of the head, neck, or lung Gastrectomy or jejunoileal bypass

<90% of ideal body weight Smokers and persons who abuse drugs or alcohol Populations defined locally ↑incidence of active TB


WHICH TEST?

Despite the indication of a preference, the use of an alternative test (IGRA or TST) is

“acceptable medical and public health practice.” Even-McMullen-Johnston-Crump, ACHA,

6.2.2011

WHAT ABOUT USING BOTH?

“An IGRA may be used in place of (but not in addition to)

a TST in all situations” where testing for TB infection is

indicated.

HOWEVER…


3 SITUATIONS WHEN TESTING WITH BOTH MAY BE CONSIDERED

1. If the initial test is indeterminate, borderline, or invalid AND a reason for testing persists

2. If the initial test is negative*

3. If the initial test is positive*

*under certain circumstances…


WHEN THE INITIAL TEST (TST OR IGRA) IS NEGATIVE AND:

1) the risk for infection, progression, and poor outcome are increased

OR 2) clinical suspicion exists for active TB

and confirmation of infection is desired.


WHEN THE INITIAL TEST (TST OR IGRA) IS POSITIVE:

1) In healthy persons with LOW risk for infection/progression

OR2) To encourage compliance

(BCG)


FALSE POSITIVE TST?

If TST <15mm AND history of BCG

AND no increased risk for poor outcome if infected

AND –IGRA,

THEN false positive


NEITHER IGRA NOR TST CAN DISTINGUISH LTBI FROM ACTIVE TB

The Point?

Treating active TB (often 4 antibiotics) with an LTBI regimen (1 antibiotic)

can lead to drug-resistant TB


MEDICAL MANAGEMENT AFTER +TTBI (TEST FOR TB INFECTION)

Diagnoses are not based on test results alone and should include:

epidemiologic contextmedical historyclinical information


Required after +TTBI:TB Symptom CheckChest x-ray

Both negative? → patient clearedEither positive? → follow-up required

Treatment for LTBI is encouraged, not required


TREATMENT OF LATENT TB

Why careful treatment decisions are essential

Drug resistance Treatment failure


Always rule out active TB!


LTBI -TO TREAT OR NOT TO TREAT?

Risk of developing active TB vs.Risks of treatment


RISK FOR PROGRESSION TO ACTIVE TB

Advanced, untreated HIV infection (RR=10) Close contact infectious TB (RR=6) X-ray old, fibrotic untreated TB (RR=5)

NEJM; “Latent Tuberculosis Infection in the US”, Horsburgh and Rubin, April 14, 2011


MORE RISKS FOR PROGRESSION

Conditions with suppressed immunity -

Prednisone over 15 mg per day (RR=2.8) Chronic renal failure, treatment with TNF-

alpha inhibitor (RR=2.4) Poorly controlled diabetes (RR=1.7) Underweight >10% below normal (RR=1.6) Smoking (RR=1.5)

NEJM; “Latent Tuberculosis Infection in the US”, Horsburgh and Rubin, April 14, 2011


LTBI TREATMENT OPTIONS

Endorsed by ATS, CDC, IDSA

INH -daily 9 months (preferred) -daily 6 months

Rifampin – daily 4 months


INH –9 MONTHS

Daily for 9 months or 270 doses 90% effectiveness Recommended in HIV infection and old

fibrotic changes on x-ray Dosing

Daily - 5 mg per kg (max 300 mg) Twice weekly-15 mg per kg (max 900 mg)


INH – 6 MONTHS

Daily for 6 months or 180 doses 60 to 80% protection

Consider Unable or unwilling to do 9 months Nonadherent, can’t take rifampin


RIFAMPIN – 4 MONTHS

Treatment trial underway to evaluate May offer less hepatotoxicity and greater

treatment completion rate Consider

o when INH resistance is known or suspected o when unable to tolerate INH


RIFAMPIN

10 mg per kg (600 mg) daily for 4 months in adults

Not recommended as monotherapy in HIV infection

increased rates of resistance drug interactions with many

antiretrovirals


ANY OTHER OPTIONS?

INH and Rifampin for 3 months (UK)o not first-lineo may be option in selected cases

Rifampin and PZA for 2 months –

eliminated due to significant hepatotoxicity


RISKS OF TREATMENT HEPATOTOXICITY

Serious potential side effect of both INH andRifampin


TO MINIMIZE RISKS

Proper drug selection and dose Education Appropriate clinical monitoring


HEPATOTOXICITY WITH INH

0.1 to 1.0% risk of hepatotoxicity Increases with chronic liver disease

(alcoholism, viral hepatitis and older age) Clinical symptoms of hepatitis Can be severe, even fatal


INH-INDUCED NEUROPATHY

Use Pyridoxine (Vit B6) with INH to reduce risk Alcoholism, preexisting neuropathy Diabetes, pregnancy, Uremia, malnutrition HIV Underlying seizure disorderDaily dose - 25-50 mg


INH – OTHER ADVERSE EFFECTS(LOW INCIDENCE)

Rheumatologic – lupus like syndrome Dermatologic – hives, rash GI – abdominal pain, nausea, vomiting Seizures, optic neuritis Bone marrow suppression Toxic psychosis Idiosyncratic drug-induced reactions


INH MONOAMINE TOXICITY

Flushing may occurAvoid foods with high

levels of monoamines (tyramines)

Aged cheeses Cured sausages Wines, beer


RISKS OF RIFAMPIN

Hepatotoxicity

Interference with metabolism of many drugs-oral contraceptives-anti-retroviral drugs used in HIV

disease-methadone


OTHER ADVERSE EFFECTS OF RIFAMPIN

Bone marrow suppression

Immune reactions Pruritis Orange

discoloration of body fluids


MONITORING ADVERSE EFFECTS

No data from prospective studies available

Baseline testing – check liver enzymes Underlying liver disease HIV infection Substantial alcohol consumption During pregnancy through 3 months after

delivery Medications with hepatotoxic potential


MONITORING GUIDELINES

Monthly testing of liver enzymes only in those whose baseline levels are elevated

Monthly monitoring for clinical signs and symptoms of hepatitis or adverse reactions Particularly if pre-existing liver disease and

higher risk for hepatoxicity


DISCONTINUE TREATMENT

No symptoms - when LFT’s exceed 5 times upper normal limit

WITH symptoms - when LFT’s exceed 3 times upper normal limit


ADHERENCE TO REGIMEN

Important determinant of effectiveness of treatment

Side effects - small percent of low completion rates

Shorter regimens increase completion rates—45 - 60% completion in 9 month INH55 - 57% with 6 month INH

69 - 78% with 4 month daily rifampin


CHALLENGES OF TREATMENT ADHERENCE

Access to care Interpretation of wellness Financial burden Attitude, knowledge and beliefs about

treatment Laws and immigration status Patient characteristics Family, community, household influences


DOCUMENT COMPLETION OF TREATMENT

Provide relevant details of treatmentLTBI diagnosis with specific test method MedicationNumber of treatmentsTime interval of therapy

Contact information

Appropriate signatures


DECLINING THERAPY

Consider documenting that treatment for LTBI was recommended

Identify student’s reason Another educational opportunity

-review signs and symptoms of active TB Leave the door open to future treatment


Treatment for Latent Tuberculosis Infection Declination Form

I have been identified as having latent tuberculosis infection (LTBI). My healthcare provider has recommended a course of treatment with Isoniazid (INH). Treatment with this drug will prevent active TB disease in most persons.

Without treatment, approximately 10% of persons with normal immune systems who have LTBI will develop active TB disease during their lifetime. Some medical and other conditions increase the risk of LTBI progressing to active TB disease, such as: HIV infection, certain chronic medical conditions i.e. diabetes and end-stage kidney disease, becoming infected with TB within the past two years, and injecting illicit drugs.

I understand the tuberculin skin and/ or tuberculin blood test should not be repeated, as they will always likely remain positive. I also understand routine chest x-rays are not recommended for persons with LTBI unless signs or symptoms of active TB disease occur.

I confirm I do not have any signs or symptoms of active TB disease. I understand I am to seek immediate medical attention and inform my provider I have LTBI if I develop any of the following signs or symptoms of active TB disease:

Fatigue Cough lasting three (3) weeks or longerNight sweatsCoughing up blood or sputumChillsWeakness

Loss of appetite Unexplained fever Unexplained weight loss Chest pain Respiratory Difficulty

I have read the information given to me about LTBI and treatment of LTBI. I believe I understand the benefits and risks of taking the recommended treatment. I have had the opportunity to have my questions regarding LTBI and LTBI treatment answered to my satisfaction.I have chosen not to take the recommended treatment for LTBI at this time. The MU Student Health Center has offered to provide me with the medication and nursing supervision at no cost. I understand if, in the future, I decide to take the medication, the TB Nurse at the Student Health Center will be available to advise me on this matter (phone (573) 882-9240).

Reason For Declining Treatment:

Signature Date

Provider/Nurse Signature Date


CDC/ACHA SURVEYIMMUNIZATION AND TB

How do US colleges and universities handle immunization requirements and TB Screening with their international student population?

Do they use ACHA’s Prematriculation Immunization and TB Screening and Testing Guidelines?

Help by completing the survey this Fall!


QUESTIONS?


REFERENCES ACHA Guidelines: Tuberculosis Screening and Targeted Testing of College and University

students: http://www.acha.org/Publications/docs/ACHA_Tuberculosis_Screening_Apr2011.pdf CDC: Fact Sheet: BCG Vaccination:

http://www.cdc.gov/tb/publications/factsheets/prevention/BCG.htm CDC. Core Curriculum on Tuberculosis. Third Edition. 1994 CDC.gov/tb Dyer, Carol. Tuberculosis (Biographies of Disease). Santa Barbara, CA: Greenwood Press. Farhat, Greenaway, Pai, and Menzies, “False-positive tuberculin skin tests: what is the absolute

effect of BCG and non-tuberculous mycobacteria,” Int J Tuberc Lung Dis 2006; 10: 1192-1204. Horsburgh, C., & Rubin, E. (2011). Latent tuberculosis infection in the United States. The New

England Journal of Medicine, 3674(15), 1441-1448. Inge and Wilson, “Update on Treatment of Tuberculosis,” American Family Physician, August

15, 2008 Kik SV, Franken WP, Mensen M., et al. Predictive value for progression to tuberculosis by IGRA

and TST in immigrant contacts. Eur Respir J 2010; 35: 1346-53 Madhukar P, Zwerling A, Menzies D. Annals of Internal Medicine 2008; 149: 177-184 Mazurek, G. H., Jereb, J. A., Vernon, A., LoBue, P., Goldberg, S., Castro, K. G., . . . Centers for

Disease Control and Prevention (US). (2010). Updated guidelines for using interferon gamma release assays to detect mycobacterium tuberculosis infection, united states, 2010 Dept. of Health and Human Services, Centers for Disease Control and Prevention

Menzies. What Does Tuberculin Reactivity after Bacille Calmette-Guerin Vaccination Tell Us? Clinical Infectious Diseases 2010;31 (Suppl 3) S71-4

Munro et al., “Patient Adherence to Tuberculosis Treatment: a Systematic Review of Qualitative Research;” PLoSMed. 2007, 4 (7):e238

TB: an Overview: http://www.emedicinehealth.com/tuberculosis/article_em.htm World Health Organization: Incidence of Tuberculosis by Country: http://apps.who.int/ghodata/?

vid=510#Even-McMullen-Johnston-Crump, ACHA, 6.2.2011

p ractical c onsiderations of l atent t uberculosis i nfection susan even, md university of missouri...

Documents