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PRACTICAL CONSIDERATIONS OF LATENT TUBERCULOSIS INFECTION Susan Even, MD University of Missouri Sharon Mc. PRACTICAL CONSIDERATIONS OF LATENT TUBERCULOSIS INFECTION Susan Even, MD University of Missouri Sharon Mc. Mullen, RN, BSN University of Pennsylvania Brenda Johnston, RN, MSN Oklahoma City University Tim Crump, RN, MSN, FNP University of Portland

DISCLAIMER The presenters have NO actual or potential conflict of interest in relation to DISCLAIMER The presenters have NO actual or potential conflict of interest in relation to this educational activity or presentation Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

CAMPUS CASE 22 yo Vietnamese female graduate student Tested during fall orientation Risk factor 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

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CASE MANAGEMENT Partnered with local health department Smears negative Culture positive for M. tuberculosis, 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

TUBERCULOSIS IS A VERY ANCIENT DISEASE Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 TUBERCULOSIS IS A VERY ANCIENT DISEASE Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Evidence of tubercular decay has been found in Egyptian Mummies. 3000 -2400 BCE Even-Mc. Evidence of tubercular decay has been found in Egyptian Mummies. 3000 -2400 BCE Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

 Recently, discoveries in the submerged village of Atlit-Yam suggest Tuberculosis was present 7000 Recently, discoveries in the submerged village of Atlit-Yam suggest Tuberculosis was present 7000 BCE Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Atlit-Yam was a village that now is submerged just off the coast of Israel. 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

TB already established at dawn of agricultural settlements. DNA supports that human TB was TB already established at dawn of agricultural settlements. DNA supports that human TB was not from Bovine TB. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

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 In the 17 th and 18 th Centuries, Tuberculosis caused up to 25% In the 17 th and 18 th Centuries, Tuberculosis caused up to 25% of all Deaths in Europe Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

In 1854, Herman Brehmer proposed TB was a curable disease. Established the Sanitorium movement. In 1854, Herman Brehmer proposed TB was a curable disease. Established the Sanitorium movement. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

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TB ESTABLISHED AS INFECTIOUS DISEASE In 1882, Robert Koch discovered the bacteria that caused 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

ROBERT KOCH Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 ROBERT KOCH Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

BCG In 1921, the BCG Vaccine was first used in humans, though widespread use BCG In 1921, the BCG Vaccine was first used in humans, though widespread use did not occur till after WWII. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

BCG Most effective against TB Meningitis and Miliary TB. Most useful in pediatric age 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

BCG: METHOD OF ADMINISTRATION TST administered prior to BCG; positive TST contraindicates BCG administration. 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

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EFFECT OF BCG ON TST The effect on TST of BCG received in infancy 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

MEDICATIONS TO TREAT TUBERCULOSIS In 1946, Streptomycin was introduced as the first antibiotic to 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

SELMAN WAKSMAN Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 SELMAN WAKSMAN Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

BURDEN OF TUBERCULOSIS In 2008, WHO estimated that 1/3 of the global population is 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

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“High Incidence” Countries are defined as areas with reported or estimated incidence of ≥ “High Incidence” Countries are defined as areas with reported or estimated incidence of ≥ 20 cases per 100, 000 population Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Afghanistan, Algeria, Angola, Argentina, Armenia, Azerbaijan, Bahrain, Bangladesh, Belarus, Belize, Benin, Bhutan, Bolivia (Plurinational 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-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 (Federated States of), Mongolia, Montenegro, Morocco, Mozambique, Myanmar, Namibia, Nepal, Nicaragua, 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

“Low Incidence” Countries are defined as areas with reported or estimated incidence of <20 “Low Incidence” Countries are defined as areas with reported or estimated incidence of <20 cases per 100, 000 population Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Albania, Andorra, Antigua and Barbuda, Australia, Austria, Bahamas, Barbados, Belgium, British Virgin Islands, Canada, 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

SCREENING OUR STUDENTS ACHA Recommendations Screening vs. Testing Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 SCREENING OUR STUDENTS ACHA Recommendations Screening vs. Testing Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Increased Risk For Tuberculosis Infection (Population risks): • Foreign-born persons who have immigrated within 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) Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

WHAT ARE SCHOOLS DOING? Informal study via SHS Some schools following ACHA Guidelines and 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

WHY SHOULD WE CARE ABOUT TUBERCULOSIS SCREENING? Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 WHY SHOULD WE CARE ABOUT TUBERCULOSIS SCREENING? Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

IDENTIFY, TREAT, AND MINIMIZE TRANSMISSION OF ACTIVE TB Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 IDENTIFY, TREAT, AND MINIMIZE TRANSMISSION OF ACTIVE TB Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

ALSO IMPORTANT: IDENTIFY AND TREAT LATENT TB 10% of persons with Latent TB will 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

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TUBERCULIN SKIN TEST Also known as PPD (Purified Protein Derivative) Or Mantoux Test Even-Mc. TUBERCULIN SKIN TEST Also known as PPD (Purified Protein Derivative) Or Mantoux Test Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

I’M PREACHING TO THE CHOIR Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 I’M PREACHING TO THE CHOIR Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

PURPOSE OF THE TST PPD (Mantoux) is indicated for the detection of a delayed 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

HISTORY OF THE TB SKIN TEST Test created in 1907 by Charles Mantoux in 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

INDICATIONS FOR USE Immigrants from countries where prevalence of TB is high Risk of 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

METHODOLOGY OF TST 0. 1 ml (5 TU) Injected intradermally with ¼ to ½” 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

WHY AND HOW DOES THIS TEST WORK? After initial exposure with M. Tuberculosis, sensitization 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

TWO-STEP TESTING Not a test of dance skills! 2 -step used to detect individuals 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 2 nd test administered during same visit. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

INTERPRETATION Read at 48 -72 hours Induration is produced through vasodilatation, edema, fibrin deposition 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: >5 mm 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

FALSE NEGATIVES Can be caused by: Viral infections such as MMR, chickenpox and HIV 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

DOCUMENTATION Document: Date, brand, lot number, expiration date, result in mm Provide patient with 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

VARIABLES A history of BCG vaccine may cause a positive result persisting for years. VARIABLES A history of BCG vaccine may cause a positive result persisting for years. Clinical Infectious Disease 2000 Sept; 31 Suppl 3: S 71 -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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

RISKS AND LIMITATIONS Sensitive test, but poor at predicting reactivation TB Very slight risk 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

ADVANTAGES TO TST Inexpensive Experienced persons can provide and read accurately Colleges have a 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% Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

A LITTLE TB ART LESSON Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 A LITTLE TB ART LESSON Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

ABOUT THE HISTORY OF THE POSTER The Federal Art Project (FAP) was the visual 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

INTERFERON GAMMA RELEASE ASSAY (IGRA) Blood test for TB infection (TTBI) 1 visit 2 INTERFERON GAMMA RELEASE ASSAY (IGRA) Blood test for TB infection (TTBI) 1 visit 2 -step not required Less reader bias and error More specific, with less cross-reaction with most non-TB mycobacteria and BCG than TST Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

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WHY TARGETED TESTING IS IMPORTANT A low probability of infection increases the likelihood of WHY TARGETED TESTING IS IMPORTANT A low probability of infection increases the likelihood of a false-positive result Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

↑ RISK FOR PROGRESSION TO ACTIVE TB HIV infection Children under 5 years Therapeutically ↑ 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

WHICH TEST? IGRA Preferred TST Preferred IGRA or TST • Low • Recent likelihood WHICH TEST? IGRA Preferred TST Preferred IGRA or TST • Low • Recent likelihood contacts of • Children • Periodic returning <5 years testing of for TST old HCWs reading • Hx of BCG Despite the indication of a preference, the use of an alternative test (IGRA or TST) is “acceptable medical and public health practice. ” Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

WHAT ABOUT USING BOTH? “An IGRA may be used in place of (but not 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… Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

TESTING WITH BOTH MAY BE CONSIDERED 1. If the initial test is indeterminate, borderline, 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… Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

WHEN THE INITIAL TEST (TST OR IGRA) IS NEGATIVE AND: 1) the risk for 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. Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

WHEN THE INITIAL TEST (TST OR IGRA) IS POSITIVE: 1) In healthy persons with WHEN THE INITIAL TEST (TST OR IGRA) IS POSITIVE: 1) In healthy persons with LOW risk for infection/progression OR 2) To encourage compliance (BCG) Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

FALSE POSITIVE TST? If TST <15 mm AND history of BCG AND no increased FALSE POSITIVE TST? If TST <15 mm AND history of BCG AND no increased risk for poor outcome if infected AND –IGRA, THEN false positive Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

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NEITHER IGRA NOR TST CAN DISTINGUISH LTBI FROM ACTIVE TB The Point? Treating active 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

AFTER +TTBI (TEST FOR TB INFECTION) Diagnoses are not based on test results alone AFTER +TTBI (TEST FOR TB INFECTION) Diagnoses are not based on test results alone and should include: epidemiologic context medical history clinical information Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Required after +TTBI: TB Symptom Check Chest x-ray Both negative? → patient cleared Either Required after +TTBI: TB Symptom Check Chest x-ray Both negative? → patient cleared Either positive? → follow-up required Treatment for LTBI is encouraged, not required Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

TREATMENT OF LATENT TB Why careful treatment decisions are essential Drug resistance Treatment failure TREATMENT OF LATENT TB Why careful treatment decisions are essential Drug resistance Treatment failure Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Always rule out active TB! Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 Always rule out active TB! Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

LTBI -TO TREAT OR NOT TO TREAT? Risk of developing active TB vs. Risks LTBI -TO TREAT OR NOT TO TREAT? Risk of developing active TB vs. Risks of treatment Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

RISK FOR PROGRESSION TO ACTIVE TB Advanced, untreated HIV infection (RR=10) Close contact infectious 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

MORE RISKS FOR PROGRESSION Conditions with suppressed immunity Prednisone over 15 mg per day 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

LTBI TREATMENT OPTIONS Endorsed by ATS, CDC, IDSA INH -daily 9 months (preferred) -daily LTBI TREATMENT OPTIONS Endorsed by ATS, CDC, IDSA INH -daily 9 months (preferred) -daily 6 months Rifampin – daily 4 months Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

INH – 9 MONTHS Daily for 9 months or 270 doses 90% effectiveness Recommended 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) Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

INH – 6 MONTHS Daily for 6 months or 180 doses 60 to 80% 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

RIFAMPIN – 4 MONTHS Treatment trial underway to evaluate May offer less hepatotoxicity and RIFAMPIN – 4 MONTHS Treatment trial underway to evaluate May offer less hepatotoxicity and greater treatment completion rate Consider when INH resistance is known or suspected o when unable to tolerate INH o Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

RIFAMPIN 10 mg per kg (600 mg) daily for 4 months in adults Not 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

ANY OTHER OPTIONS? INH and Rifampin for 3 months (UK) o not first-line o ANY OTHER OPTIONS? INH and Rifampin for 3 months (UK) o not first-line o may be option in selected cases Rifampin and PZA for 2 months –eliminated due to significant hepatotoxicity Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

RISKS OF TREATMENT HEPATOTOXICITY Serious potential side effect of both INH and Rifampin Even-Mc. RISKS OF TREATMENT HEPATOTOXICITY Serious potential side effect of both INH and Rifampin Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

TO MINIMIZE RISKS Proper drug selection and dose Education Appropriate clinical monitoring Even-Mc. Mullen-Johnston-Crump, TO MINIMIZE RISKS Proper drug selection and dose Education Appropriate clinical monitoring Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

HEPATOTOXICITY WITH INH 0. 1 to 1. 0% risk of hepatotoxicity Increases with chronic 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

INH-INDUCED NEUROPATHY Use Pyridoxine (Vit B 6) with INH to reduce risk Alcoholism, preexisting INH-INDUCED NEUROPATHY Use Pyridoxine (Vit B 6) with INH to reduce risk Alcoholism, preexisting neuropathy Diabetes, pregnancy, Uremia, malnutrition HIV Underlying seizure disorder Daily dose - 25 -50 mg Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

INH – OTHER ADVERSE EFFECTS (LOW INCIDENCE) Rheumatologic – lupus like syndrome Dermatologic – 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

INH MONOAMINE TOXICITY Flushing may occur Avoid foods with high levels of monoamines (tyramines) INH MONOAMINE TOXICITY Flushing may occur Avoid foods with high levels of monoamines (tyramines) Aged cheeses Cured sausages Wines, beer Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

RISKS OF RIFAMPIN Hepatotoxicity Interference with metabolism of many drugs -oral contraceptives -anti-retroviral drugs RISKS OF RIFAMPIN Hepatotoxicity Interference with metabolism of many drugs -oral contraceptives -anti-retroviral drugs used in HIV disease -methadone Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

OTHER ADVERSE EFFECTS OF RIFAMPIN Bone marrow suppression Immune reactions Pruritis Orange discoloration of OTHER ADVERSE EFFECTS OF RIFAMPIN Bone marrow suppression Immune reactions Pruritis Orange discoloration of body fluids Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

MONITORING ADVERSE EFFECTS No data from prospective studies available Baseline testing – check liver 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

MONITORING GUIDELINES Monthly testing of liver enzymes only in those whose baseline levels are 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

DISCONTINUE TREATMENT No symptoms - when LFT’s exceed 5 times upper normal limit WITH DISCONTINUE TREATMENT No symptoms - when LFT’s exceed 5 times upper normal limit WITH symptoms - when LFT’s exceed 3 times upper normal limit Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

ADHERENCE TO REGIMEN Important determinant of effectiveness of treatment Side effects - small percent 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 INH 55 - 57% with 6 month INH 69 - 78% with 4 month daily rifampin Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

CHALLENGES OF TREATMENT ADHERENCE Access to care Interpretation of wellness Financial burden Attitude, knowledge 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

DOCUMENT COMPLETION OF TREATMENT Provide relevant details of treatment LTBI diagnosis with specific test DOCUMENT COMPLETION OF TREATMENT Provide relevant details of treatment LTBI diagnosis with specific test method Medication Number of treatments Time interval of therapy Contact information Appropriate signatures Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

DECLINING THERAPY Consider documenting that treatment for LTBI was recommended Identify student’s reason Another 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

Treatment for Latent Tuberculosis Infection Declination Form I have been identified as having latent 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 longer Night sweats Coughing up blood or sputum Chills Weakness 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 Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

CDC/ACHA SURVEY IMMUNIZATION AND TB How do US colleges and universities handle immunization requirements CDC/ACHA SURVEY IMMUNIZATION 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! Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

QUESTIONS? Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011 QUESTIONS? Even-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011

REFERENCES ACHA Guidelines: Tuberculosis Screening and Targeted Testing of College and University students: http: REFERENCES ACHA Guidelines: Tuberculosis Screening and Targeted Testing of College and University students: http: //www. acha. org/Publications/docs/ACHA_Tuberculosis_Screening_Apr 2011. 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. , Lo. Bue, 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) S 71 -4 Munro et al. , “Patient Adherence to Tuberculosis Treatment: a Systematic Review of Qualitative Research; ” PLo. SMed. 2007, 4 (7): e 238 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-Mc. Mullen-Johnston-Crump, ACHA, 6. 2. 2011