Screening and Treatment Recommendations for Persons Exposed to MDR TB

Screening and Treatment Recommendations for Persons Exposed to MDR TB Although all persons at increased risk of tuberculosis (TB) infection should be screened for TB infection per USPTF/CDC guidelines [1, 2], this document provides specific guidance for all persons who have been identified through public health investigations as having been exposed to multidrug-resistant (MDR) TB. The initial screening should occur as soon as possible following exposure to a person with infectious TB disease. A repeat screening at least 8 weeks after the last exposure may also be necessary. Step 1: Initial Screening A. Obtain a medical history including prior TB screening and TB treatment information Determine if the patient has any immunocompromising conditions or other conditions that put the patient at an increased risk of progression from latent TB infection (LTBI) to active TB disease. For purposes of TB screening, the following are immunocompromising conditions of concern: HIV infection with CD4 count <200 Stem cell or solid organ transplant recipients receiving immunosuppressive medications Daily treatment with moderate/high dose corticosteroid (equivalent to prednisone 15 mg) Treatment with a TNF-alpha antagonist Poorly controlled diabetes (most recent hemoglobin A1c >9%) Receiving dialysis or has uremia Leukemia or lymphoma Cancer of head, neck, or lungs Receiving chemotherapy for any neoplasm Nephrotic syndrome Protein losing enteropathy Protein energy malnutrition Age <5 years Other (non-immunocompromising) conditions that increase risk of progression to active TB include: Controlled diabetes Silicosis Gastrectomy or jejunal bypass Tobacco use 9/6/2017 1

B. Screen for the following TB symptoms: Screen for the following TB symptoms: cough 3 weeks, hemoptysis, shortness of breath, night sweats, fevers or chills, or unintentional weight loss. If the symptom screen is done <8 weeks from the date of last exposure to TB, the symptom screen must be repeated at least 8 weeks after the date of last exposure (ideally 8 10 weeks after last exposure). Patients reporting cough of <3 weeks duration at the time of screening should have follow-up to determine if the cough has resolved. If they have a persistent cough for 3 weeks, further evaluation is indicated. C. Obtain a TB screening test (i.e., interferon-gamma release assay [IGRA] or tuberculin skin test [TST]) if the person has no documented prior positive IGRA or TST. An IGRA (QuantiFERON -TB Gold [QFT-G], or T-SPOT TB test [T-Spot]) is the preferred test for contacts who originate from areas where they likely received BCG vaccine or are unlikely to return for reading of a TST. A TST result of 5 mm of induration is considered positive for persons exposed to infectious TB cases. A TST should be performed for children <5 years old. If the TB screening test is negative and was performed <8 weeks from the date of last exposure to TB, a screening test must be repeated at least 8 weeks after the date of last exposure (ideally 8 10 weeks after last exposure). Contacts with prior positive TST or IGRA results DO NOT need a new TST or IGRA performed. Instead, they should be considered to have a positive TB screening test. In the event a person with a past positive TST or IGRA has a new TST or IGRA performed and it is negative, the significance of the new screening test is uncertain, please contact MDH (651-201- 5414) to discuss these discrepant results with a physician or nurse in the TB control unit. D. Determine if a chest x-ray is needed, as follows: For contacts who were clients of the Hmong senior center where documented MDR TB transmission occurred, and for any other types of exposures that MDH or local public health determine to represent very high risk settings for MDR TB transmission, obtain a chest x-ray, regardless of TB screening test or symptom screening results. If uncertain if a patient falls into this category, contact MDH (651-201-5414) or your local public health department. All contacts who have a previously documented positive IGRA or TST, or a history of LTBI or active TB, regardless of treatment history, require a chest x-ray. For all other contacts, obtain a chest x-ray if the TB screening test is positive, the person is immunocompromised or < 5 years old, or if the person has any of the TB symptoms listed in step 1B. Step 2: Rule out Active Disease A. Determine if a provider visit is needed The following contacts should be directly evaluated by a provider as soon as possible (i.e., do not wait until the results of repeat assessments performed 8 10 weeks after last TB exposure if any the following criteria are identified at the initial screening): 9/6/2017 2

Any person with symptoms compatible with TB Any person with a prior or new positive IGRA or TST Any person with an abnormal chest x-ray compatible with TB Any person with a history of LTBI or active TB, regardless of treatment history Any person with an immunocompromising condition or a child < 5 years old B. Physical exam and testing to evaluate for active TB For patients that require a provider visit, perform a thorough review of systems and physical exam to assess for abnormalities including extrapulmonary sites of infection. The following patients must be tested for active pulmonary TB: Symptomatic patients (defined as cough lasting 3 weeks, or hemoptysis, or 2 of the other symptoms listed in step 1B) regardless of TB screening test result. Patients with chest x-ray abnormalities that could be consistent with active pulmonary TB disease, regardless of medical history or TB screening test result. C. Test for active pulmonary TB Obtain 3 sputum samples for AFB smear and AFB culture, and, for 2 of the 3 samples, Mycobacterium tuberculosis PCR. Notify MDH (651-201-5414) whenever ordering sputum samples for TB testing. Patients should stay in home isolation while waiting for smear and PCR results. Continued avoidance of public settings will be made on a case-by-case basis while awaiting culture results. D. Negative sputum testing does not necessarily rule out active TB. If a patient has symptoms or radiological findings concerning for TB, consult with a TB expert before fully ruling out active TB. Additional testing may be required to rule out active disease, including, but not limited to, chest CT or other imaging, bronchoscopy, or further assessment for extrapulmonary TB. If active disease is diagnosed, refer patient to a TB expert for treatment. If active disease has been ruled out, proceed to step 3. Step 3: Determine Diagnosis After active disease has been ruled out, place patient into one of the following five categories and follow the management guidance listed. Category 1. History of inadequately treated LTBI or active TB. See steps 4A, 4B, and 4C. Category 2. History of adequately treated LTBI or active TB. See step 4D. 9/6/2017 3

Category 3. Newly detected LTBI (i.e., new positive TB screening test) See steps 4A, 4B, and 4C. Category 4. No evidence of LTBI (i.e. negative TB screening test) If not immunocompromised: no further follow-up needed if most recent TB screening test and symptom screen were obtained >8 weeks after last known TB exposure (if not, repeat TB screening test and symptom screen 8-10 weeks after last exposure). If immunocompromised or contact is a child <5 years old: call MDH to consult with an MDR TB expert because these patients may need window prophylaxis and likely should be treated as outlined in steps 4A, 4B, and 4C. Category 5. TB screening test indeterminate Repeat TB screening test. If repeat TB screening test remains indeterminate, call MDH to consult with an MDR TB expert. Step 4: LTBI Treatment or 2-year Monitoring Before starting a patient on treatment for LTBI, ensure active TB disease has been ruled out as described above (step 2) and screen for factors that increase the risk of adverse events (step 5). A. Administer 9 months of treatment for presumed MDR LTBI For persons 15 years old: Moxifloxacin 400 mg by mouth daily For persons <15 years old: Levofloxacin 15 20 mg/kg by mouth daily (not to exceed 750 mg daily) B. If patient unable to tolerate Moxifloxacin due to side effects (e.g., headache, dizziness, nausea, vomiting, diarrhea, abdominal pain, tendonitis, peripheral neuropathy, arthralgias, etc.) Switch to Levofloxacin For persons 18 years old: Levofloxacin 500mg by mouth daily if 45.5kg; 750 mg by mouth daily if >45.5kg For persons <18 years old: Levofloxacin 15 20 mg/kg by mouth daily (not to exceed 750 mg daily) Renal failure/dialysis: Levofloxacin 750 1000 mg/dose 3 times weekly for creatinine clearance <30 ml/min If unable to tolerate both Moxifloxacin and Levofloxacin: discontinue treatment and monitor for the next 2 years as outlined in step 4C. 9/6/2017 4

C. If patient refuses treatment or is unable to take fluoroquinolones due to other medical reasons Monitor patient for 2 years. (The period of follow-up is based on the date of the first chest x-ray after the last date of TB exposure, aka baseline chest x-ray. Patients may require to be monitored for more than 2 years if they were re-exposed to MDR TB after starting monitoring). At 3 months after baseline chest x-ray: Provider visit with symptom screen and physical exam. At 6, 12, 18, and 24 months after baseline chest x-ray: Chest x-ray and provider visit to include symptom screen and physical exam. Educate patient about the need to notify their medical provider if the patient becomes symptomatic at any time during the 2-year follow-up period. Initiate evaluation for active TB immediately if symptoms or chest x-ray abnormalities develop during the follow-up period. D. For those who have previously completed treatment for either drug resistant or pan-susceptible LTBI or active TB. The need for treatment of MDR LTBI should be made on an individual basis. In general: For immunocompromised patients or patients with comorbidities associated with increased risk of TB reactivation, and/or patients with history of completed treatment for either active TB or LTBI 10 years ago Encourage treatment with MDR LTBI regimen as outlined in steps 4A and 4B. If patient refuses treatment or is unable to take fluoroquinolones due to other medical reasons, monitor them for the next 2 years as outlined in step 4C. If not immunocompromised and no comorbidities associated with increased risk of TB reactivation, and active TB treatment/ltbi treatment was completed <10 years ago Treatment for MDR LTBI is likely unnecessary. Monitor for the next 2 years as outlined in step 4C. Step 5: Screening for Adverse Events While on treatment patients should be evaluated every month using the MDH MDR LTBI Treatment Monitoring Flow Sheet to ensure adequate screening for side effects at each monthly medical visit. Fluoroquinolones can lower blood glucose, cause tendinitis, peripheral neuropathy, and prolong the QTc interval which, rarely, can lead to life-threating arrhythmias. Screen patients for medical conditions and for potential medication interactions that could increase the risk of adverse events associated with Moxifloxacin and Levofloxacin before starting MDR LTBI treatment. Persons with congenital prolonged QT syndromes should not be offered a fluoroquinolone; they should be monitored for 2 years. 9/6/2017 5

For persons with electrolyte abnormalities, bradycardia, ischemic heart disease, intracranial disease, HIV infection, hepatic impairment, connective tissue diseases with anti-ro/ssa antibodies, and persons who are taking a medication known to prolong the QTc interval, obtain a baseline ECG before starting MDR LTBI treatment and a repeat ECG 1 2 weeks after starting treatment. For a list of QTc prolonging medications go to the Credible Meds website (https://www.crediblemeds.org/) Take a complete history of all patients medications at each monthly clinic visit. If the patient reports a new QTc prolonging medication, continue the fluoroquinolone and obtain an ECG at time of first report of the new medication and then again in 1-2 weeks. If the QTc is longer than normal ( 0.44 seconds among children 1 15 years old, 0.43 seconds among males >15 years, or 0.45 seconds among females >15 years, or if the QTc increases by >25% during the course of treatment), consult with a cardiologist before starting or continuing MDR LTBI treatment. While taking MDR LTBI treatment, patients should be instructed to promptly report any new palpitations or fainting which may be signs of QTc prolongation. Patients should be educated on the small risk of tendinitis related to fluoroquinolone use and that the concomitant use of corticosteroids with fluoroquinolones may increase the risk for tendinopathy. The risk of tendinitis may also be increased among patients with kidney failure and rheumatoid arthritis Patients taking medications to lower blood glucose, especially oral hypoglycemic agents, should be notified to check their blood sugar closely while taking a fluoroquinolone and to contact their primary care provider immediately if blood glucose levels are measuring lower than normal so oral hypoglycemic dosage(s) can be adjusted. Moxifloxacin and levofloxacin may worsen muscle weakness among patients with myasthenia gravis. Persons with renal insufficiency require dosing adjustment for levofloxacin, but not for Moxifloxacin as outlined in step 4B. Although the risk of liver damage with fluoroquinolones is low, all patients should be notified to stop taking the fluoroquinolone if they develop jaundice. References 1. Kahwati LC, Feltner C, Halpern M, Woodell CL, Boland E, Amick HR, Weber RP, Jonas DE. Primary Care Screening and Treatment for Latent Tuberculosis Infection in Adults Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2016; 316(9):970 983. doi:10.1001/jama.2016.10357 2. Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley CL, Desmond E, Keane J, Lewinsohn DA, Loeffler AM, Mazurek GH, O'Brien RJ, Pai M, Richeldi L, Salfinger M, Shinnick TM, Sterling TR, Warshauer DM, Woods GL. Clinical Infectious Diseases, Volume 64, Issue 2, 15 January 2017, Pages 111 115, https://doi.org/10.1093/cid/ciw778 9/6/2017 6

TB Screening Flow Diagrams for Contacts of Infectious MDR TB Disease Part A: High transmission risk groups (e.g., Hmong Senior Center Attendees) 9/6/2017 7

Part B: All other contacts 9/6/2017 8

Footnotes MDR TB EXPOSURE SCREENING AND TREATMENT RECOMMENDATIONS a IGRAs are the preferred test for persons who originate from areas where they likely have received BCG vaccine. TST should be done for children <5 years old. TST result of 5 mm of induration is considered positive for persons exposed to infectious TB cases. Persons with previous positive TST or IGRA do not need a repeat TST or IGRA and instead should be considered TST/IGRA positive. b Cough lasting 3 weeks, hemoptysis, shortness of breath, night sweats, fevers or chills, or unintentional weight loss. If the symptom screen is done <8 weeks from the date of last exposure to TB, the symptom screen must be repeated at least 8 weeks after the date of last exposure. c Medical history includes prior TB screening and treatment, immunocompromising conditions (see footnote d) and other conditions that increase risk of progression from latent TB infection to active TB disease (i.e., controlled diabetes mellitus, silicosis, gastrectomy, jejunal bypass, and tobacco use). d Immunocompromising conditions include the following: HIV infection with CD4 count <200, stem cell or solid organ transplant recipients receiving immunosuppressive medications, daily corticosteroid use equivalent to prednisone 15 mg, use of TNF-alpha antagonist, poorly controlled diabetes mellitus with Hgb A1c >9%, dialysis, uremia, leukemia, lymphoma, cancer of head, neck, or lungs, currently receiving chemotherapy, nephrotic syndrome, protein losing enteropathy, protein energy malnutrition, age <5 years. For immunocompromised persons, consult with TB experts. e Additional testing may include induced sputum collection, other chest imaging (e.g., CT scan), bronchoscopy, or imaging or specimen collection to assess for extrapulmonary TB. f Immunocompetent contacts with a history of completed treatment for susceptible LTBI (INH x 6-9 months, rifampin x 4 months, or INH + rifapentine x 3 months) within the past 10 years likely do not require MDR LTBI treatment if they don t have other comorbidities associated with increased risk of TB activation, but still require monitoring for active TB disease for 2 years following last known MDR TB exposure. g Baseline chest x-ray is defined as the first chest x-ray after the last date of TB exposure Minnesota Department of Health Tuberculosis Prevention and Control Program PO Box 64975 St. Paul, MN 55164-0975 651-201-5414 www.health.state.mn.us/tb To obtain this information in a different format, call 651-201-5414. Printed on recycled paper. 9/6/2017 9