Tuberculosis Screening, Testing, and Treatment of US Health Care Personnel

e355 infection. The 2019 MMWR CDC/NTCA rec- Transitioning a TBgram for Screening Health Pro- Care Personnel Progression from LTBIease to (Reactivation TB TB) Dis- Educating HCP with LTBI Recommending Treatment Voluntary Testing forPotential Self-assessed Exposure Post-Exposure Testingations and Interpretation Consider- Serial Screening and Testing Annual Education Requirement Annual Symptom Reviewwith for LTBI HCP Treatment to prevent progressionTB to disease active (reactivationencouraged TB) for is allLTBI. HCP strongly diagnosed with HCP without LTBIroutine should serial TB notany screening undergo interval or after testing baseline at (eg, annually) The term healthreplaced by care HCP and worker refers tounpaid, all has paid and part been time,student temporary, and contract, full-time personshealth working in care settings. At the point of hire or transfer into aposition, clinical all HCP should havescreening baseline that TB includes anassessment, individual symptom evaluation risk and (for those without LTBI or TB disease) aM. test tuberculosis for Treatment and Education of Health Care Personnel with Positive Test Results Serial Screening, Testing and Education for HCP KEY POINTS –CDC/NTCA 2019 Recommendations MMWR ommendations shift the focusserial from routine testing toincreasing improving LTBI education treatment. and Identifying,the best to of our ability, theallows presence occupational of health LTBI practitionersencourage to treatment and prevent futuredisease. TB Efforts to eliminateworkforce LTBI support and workplacewhile moving us health closer to locally, a TB-free nation. TATEMENT S UIDANCE The sections to follow closely mirror This document offers the collective and/or Positive Symptom Review Considering Active TB Disease Compliance, Confidentiality,Communication and Overview Travel-Related Exposure Post-Offer/Pre-Placement (POPP) TB Risk AssessmentReview andTB Testing Symptom forPositive HCP Test Without Prior Regarding Reversions TB TestingPositive Test for HCPNewly Confirmed with Positive TB Prior Test Post-exposure TB Screening and Testing Introduction Background with Literature Review BaselineScreening and Testing (post-offer/pre-placement) arise and to offer strategies fortion. This implementa- ‘‘companion’’document was writ- ten tohealth support providers, the infectionpublic nation’s health preventionists, officers, occupational valued HCP,patients and we the serve. those of theRecommendations: 2019 MMWR CDC/NTCA on the role of occupational healthaging in encour- treatmenttuberculosis infection (LTBI) of to prevent pro- personsgressiontoactivedisease(reactivation)andto withpositively latent impact the public’s health. effort and experience of occupational health, infectious disease, and public health experts from major academic and public health institutions across thesection US. of It the 2019 expands Mortality andWeekly on Morbidity Report (MMWR) CDC/NTCA each Rec- ommendations toexplanations, provide and clarifications, beyond considerations the 2019 that MMWR CDC/NTCAommendations go rec- to answer questions that may annualtuberculosis(TB)testinginhealthcare personnel (HCP) and the increased emphasis ACOEM G 1 2019 MMWR Recommendations of US Health Care Personnel Mycobac- in Health-Care Set- lic health institutions sonnel-related sections and public health experts ons, and considerations that in Health-Care Settings, n issued new Recommenda- Lawrence Budnick, MD, MPH, Ellen Murray, RN, PhD, Ann Scarpita, BSN, MPH, Tuberculosis Screening, Testing, and Treatment Bobbi Jo Hurst, MBA, Sarah Foster-Chang, DNP, ANP-BC, Trini Mathew, MD, MPH, ACOEM and NTCA Joint Task Force on Implementation of the 2020 American College of Occupa- Wendy Thanassi, MD, MA, Amy J. Behrman, MD, Randall Reves, MD, Mark Russi, MD, MPH, ß Melanie Swift, MD, MPH, Jon Warkentin, MD, MPH, Ryo Miyakawa, MD, Donna Wegener, MA, Volume 62, Number 7, July 2020 In particular, both ACOEM and MaryAnn Gruden, MSN, COHN-S/CM, Julie Higashi, MD, PhD, and Thomas Warner Hudson III, MD 2 he American College ofand Occupational Environmental Medicine Elk Grove Village, IL 60007 ([email protected]). Environmental Medicine, Elk Grove, Illinois. article. Directprinted URL text and citationPDF is versions provided of appears this in article on insite the the (www.joem.org). HTML journal’s Web the and ACOEM, 25 Northwest Point Blvd, Suite 700, tional and Environmental Medicine (ACOEM) fully supportsof the implementation Unites States’s (US)ease Centers for Control Dis- andNational Tuberculosis Prevention Controllers Associa- (CDC)tion’s (NTCA) Recommendations for and Tuber- culosis Screening, Testing and Treatment of Health Care Personnel, United States, 2019. Copyright JOEM From the American College ofThe Occupational authors and declare noSupplemental conflicts digital of contents interest. are available for this Address correspondence to: Marianne Dreger, MA, personnel-related sections of the Guidelines for Preventing the Transmission of terium tuberculosis 2005. The new guidance updates the health care section of the 2019clarifications, explanati recommendations to provide go beyond the 2019questions that recommendations may to arise answer andimplementation. to offer strategies for T of the Guidelines for Preventing the Transmission of Mycobacterium tuberculosis tings, 2005. This companioncollective document effort offers the andhealth, experience infectious disease, of occupational from major academic and pub across the United States and expands on each On May 17, 2019,Control the and Prevention US and Centers NationalControllers for Tuberculosis Associatio Disease tions for Tuberculosis Screening, Testing, and Treat- ment of Health Care Personnel, United States, 2019, updating the health care per DOI: 10.1097/JOM.0000000000001904 NTCA endorse the discontinuation of routine Copyright © 2020 American College of Occupational and Environmental Medicine. Unauthorized reproduction of this article is prohibited Copyright © 2020 American College of Occupational and Environmental Medicine.

Downloaded from https://journals.lww.com/joem by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3JfJeJsayAVVA0tuPeWF8+fcCByaszlArA0/85mOoxJ79CzoKGQxNkw== on 07/08/2020 Downloaded from https://journals.lww.com/joem by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3JfJeJsayAVVA0tuPeWF8+fcCByaszlArA0/85mOoxJ79CzoKGQxNkw== on 07/08/2020 Thanassi et al JOEM Volume 62, Number 7, July 2020

attributed facility-based transmission to 200711 and the second for the 7-year period in the absence of known exposure or 12 evidence of ongoing TB transmission. administrative errors (inadequate infection 2010 to 2016. Both showed consistent HCP with untreated LTBI should receive a control policies), clinical errors (missed evidence of lower TB incidence rates yearly symptom review, TB education, and delayed diagnoses and delayed drug- among HCP compared with the national and treatment encouragement. resistance detection), and poor engineering population. The mean annual HCP TB rates The facility risk assessment, contained in 3,6,7 the 2005 MMWR CDC Guidelines controls (inadequate ventilation). HCP for the 5-year period 2003 to 2007 and the Appendix B,2 continues to be required tuberculin skin test (TST) conversions in 7-year period 2010 to 2016 were 4.2 and 2.5 annually for the assessment and the early 1990s ranged from less than 0.1% per 100,000 persons, respectively. During maintenance of environmental controls (Appendix 1, http://links.lww.com/JOM/ to 4.5% annually in hospitals in non-out- these study periods, the US annual TB rates A780). break settings, but were as high as 20% in declined from 5.1 to 4.4, and from 3.6 to After known exposure to potentially just 6 months in some institutions with 2.9, respectively (Table 1). In addition to infectious TB without adequate personal outbreaks.8 Annual TST conversions in TB rate comparisons, the national genotyp- protection, HCP should have a symptom evaluation and timely TB testing. hospitals with high TB admission rates ing data estimate the proportion of TB cases All HCP should receive TB education were over 4% in the early 1990s but due to recent transmission was only 10% in annually. Education should include dropped to less than 1% within years of HCP, compared with 14% in the population information on TB risk factors, the signs adopting improved administrative and engi- overall.12 and symptoms of TB disease, TB infection 6–9 control policies and procedures, and LTBI neering controls. The epidemiology of TB among treatment regimen options. Publications in this decade confirm HCP parallels the national pattern of pre- annual US HCP TST conversion rates well dominately occurring in non-US-born per- below 1%. At a Midwest tertiary care med- sons.11 Lambert et al11 also described the ical center, 39,280 HCP with a baseline features of TB disease over the 13-year BACKGROUND WITH negative TB test underwent nearly period of 1995 to 2007 that included fatal LITERATURE REVIEW 200,000 annual TSTs and only 123 outcomes among 3.1% of HCP reported TB In the 1920s, US researchers began (0.31%) conversions were detected over a cases, while fatal outcomes nationally were to recognize that HCP were at risk of con- 16-year period.10 Most of the TST conver- 10.9%. The relatively lower incidence and tracting TB from patients.3 By the 1950s, sions appear to have been false-positive mortality rate from TB disease in the HCP TB rates remained as high as 50 cases per TSTs attributed to a delayed boosting effect population is not unexpected considering 100,000 population and the increased risk since the positive TSTs occurred most fre- HCP are generally well-educated, of nosocomial TB in health care occupa- quently with the third TST placed during employed, tend to have adequate housing tions became more clear.3,4 Routine admis- employment. In addition, only 9% of the and nutrition, and are in the middle of the sion chest x-rays (CXR) were instituted and 123 conversions were associated with age spectrum. These studies provide further were shown to reduce TB risk among HCP.4 known workplace or community TB expo- evidence of very limited nosocomial or By the 1980s, when TB rates decreased by sure, 66% of these had negative interferon consequential transmission of TB to 80% to under 10 cases per 100,000 popula- gamma release assay (IGRA) results, and US HCP. tion, the utility of such routine admission no one developed active TB disease. These In this era of low TB incidence radiography was questioned.5 There were data, along with annual conversion rates of among US HCP, the high cost of maintain- occasional published reports of nosocomial less than 1% in HCP at medical centers that ing annual testing and the burden of false- transmission of TB to HCP from the 1960s care for patients with active TB disease, positive results has led to several revisions and 1980s, usually attributed to diagnostic illustrate that the efficacy of TB infection of recommendations for LTBI testing. The and/or treatment delays in environments control programs resulted in limiting the 2017 Clinical Practice Guidelines by Con- with inadequate ventilation.3 TB transmission to HCP.6,9 sensus of the American Thoracic Society, The TB resurgence of 1985 to 1992, In a remarkable turn of events, effec- Infectious Diseases Society of America, which mirrored the rise of human immuno- tive TB infection control has led to such a and the CDC recommend the use of IGRAs deficiency virus (HIV) in the US, resulted low probability of HCP exposure that the over TSTs in low-risk persons who undergo in a concurrent rise in nosocomial TB TB rate in US HCP has dropped below that mandatory testing.14 IGRAs require only a transmission to HCP in urban hospitals of the overall population. Two national single encounter, have higher specificity and again highlighted their occupational studies published by CDC compared with than the TST among individuals with prior risk. US TB rates increased from 9.3 to TB rates among HCP to the total US popu- bacille Calmette-Gue´rin (BCG) vaccina- 10.4 per 100,000. Numerous investigations lation, one for the 5-year period 2003 to tion,15,16 and are reported in many studies

TABLE 1. Mean Annual Numbers and Rates of Active TB Cases among Health Care Personnel (HCP) by Country of Birth during 2003–2007 and 2010–2016, Compared With the Total US Annual Numbers and Rates for 2005 and 2013

HCP USy Study Period US-born Non-US-born HCP Total US-born Non-US-born US Total

2003–2007 Rate 1.7 17.9 4.2 2.5 22.3 4.8 No. (%) 151 (35) 278 (65) 429 (100) 6,290 (45) 7,745 (55) 14,065 (100) 2010–2016 Rate 0.8 10.8 2.5 1.2 15.7 3.0 No. (%) 90 (28) 262 (72) 352 (100) 3,330 (34) 6,222 (68) 9,561 (100)

The mean annual numbers and rates for the 5- or 7-year periods were obtained from Lambert et al,11 Mongkolrattanothai et al,12 and via Lauren Lambert, personal communication. yThe comparison annual US numbers and rates for the two study periods are the data of 2005 and 2013, the mid-year of each study period when rates declined from 4.4 to 5.1 and 3.6 to 2.9, respectively.13

e356 ß 2020 American College of Occupational and Environmental Medicine

Copyright © 2020 American College of Occupational and Environmental Medicine. Unauthorized reproduction of this article is prohibited JOEM Volume 62, Number 7, July 2020 Tuberculosis Screening, Testing, and Treatment of US Health Care Personnel

to be more cost-effective than TST for Risk factors for progression to active TB serial screening.11,17–19 However, the spe- placement, and reduce the risk to patients disease (reactivation TB), such as and other health care personnel. The risk immune-suppressing medications, diabe- cificities of both approved IGRAs appear assessment and symptom evaluation help 23 lower than with TST when used for serial guide decisions when interpreting test tes, cancer, organ transplant, or HIV. testing of low risk populations who did not results. For example, health care Note that diabetes is not a risk factor for have BCG vaccination. personnel with a positive test who are acquiring TB, but having diabetes imparts asymptomatic, unlikely to be infected a 2 to 4-fold increased risk for LTBI A multicenter study comparing the with M. tuberculosis, and at low risk for 24 performance of serial TST and of both of progression on the basis of their risk progressing to active TB disease. the IGRAs then approved by the US Food assessment should have a second test Additionally, obtaining the individu- and Drug Administration (FDA) was con- (either an IGRA or TST) as recommended al’s TB history is important and could in the 2017 TB diagnostic guidelines of the include: ducted from 2008 to 2011 among HCP at American Thoracic Society, Infectious four US hospitals with annual TST conver- Diseases Society of America, and CDC. In sion rates of less than 1%. In this study, this example, the health care personnel Documentation of prior TB test results simultaneous TST, QuantiFERON1-TB- should be considered infected with M. (including dates and type of test where tuberculosis only if both the first and possible), Gold In Tube (QFT-GIT) (QFT, Qiagen second tests are positive.’’1 Inc.), and T-Spot1.TB (TSPOT, Oxford History of LTBI or active TB disease, Immunotec) were obtained at baseline and and repeated thrice at 6-month intervals. Treatment history for active TB disease Among over 2100 HCP with baseline neg- Summary or for LTBI including location of treat- ative tests, the cumulative number of con- The primary changes from the 2005 ment, length of treatment, medications versions was 21 (0.9%) for TST as expected MMWR CDC Guidelines specific to the taken (if known), whether treatment was but was 138 (6.1%) with QFT-GIT, and 177 post-offer pre-placement process are the completed, and any current symptoms (8.3%) using the T-Spot1.TB. There were addition of an individual TB risk assess- consistent with active TB disease. no known TB exposures at the institutions. ment with symptom review, and the recom- Only four HCP converted by both TST plus mendation to strongly encourage treatment The symptom review should include: one IGRA, and 17 converted by TST alone. of HCP with LTBI.2 Repeat tests found reversion to negative in Questions regarding the presence of pro- 65% of the TST converters and over 75% longed (more than 3 weeks), unex- for converters with either IGRA, demon- Post-Offer/Pre-Placement plained fever, prolonged cough or strating the low positive predictive value of (POPP) TB Risk Assessment and fatigue, hemoptysis, unintended weight TB tests in US HCP.20 These findings have Symptom Review loss, or drenching night sweats. been supported in other studies including a The 2019 MMWR CDC/NTCA Rec- 2018 report of a retrospective cohort anal- ommendation states that all HCP should The individual risk assessments, ysis of 40,142 tertiary care HCP who have a baseline POPP TB evaluation. An including the TB history and symptom review received a TST, showing 123 conversions updated list of employees who are desig- questions (screening questionnaire), can be over 16.4 years. Only nine (7%) of the nated as ‘‘HCP’’ is included in Appendix 2, administered electronically, on paper, or by converters had a suspected workplace TB http://links.lww.com/JOM/A781.2 For interview but should be standardized within exposure and none developed active TB. institutions where non-clinical new hires an institution. Screening questionnaires The majority (66%) of TST converters had are not screened for TB, those employees should be consistent with national guidelines, a negative QuantiFERON-TB test result at should enter the pre-placement TB screen- evolving best practices, state/local health the time of the TST conversion.21 ing process if they transfer into a clinical department requirements, and institutional In addition to reducing serial TB test- position. policies. Since the HCP responses will ing, the 2019 MMWR CDC/NTCA Recom- POPP TB screening is done in order include both health information and other mendations emphasize the need to increase to: (a) rule out active TB disease prior to protected personal information, completed efforts to encourage treatment of LTBI, placement; (b) identify LTBI and offer treat- TB screening questionnaires must be kept whether it was acquired in the community ment or consultation for treatment as appro- confidential. A licensed practitioner or quali- or in the workplace.22 The emphasis on LTBI priate; and (c) establish a baseline to guide fied occupational health professional should diagnosis, education, and treatment comple- interpretation of future tests in the event of a review screening questionnaires and docu- tion is an attempt to prevent reactivation and new exposure or new symptoms suggesting mentation of treatment. Clinical practices/ thereby reduce TB morbidity, mortality, and active TB disease. POPP TB screening will institutions may opt for a single integrated transmission to other HCP and patients. always include a risk assessment, TB history, screening questionnaire to streamline the and a symptom review; will usually include onboarding process, or may use the risk BASELINE (POST-OFFER/ assessment form included with the 2019 testing by IGRA or TST; and may include 1 PRE-PLACEMENT) SCREENING imaging or additional evaluation to rule out MMWR CDC/NTCA Recommendations, AND TESTING active TB disease and guide treatment rec- in combination with a TB history and symp- ommendations. tom review. A sample integrated question- 2019 MMWR CDC/NTCA Recommen- Individual risk assessments are nec- naire addressing all essential components of dation: ‘‘All US health care personnel essary for interpreting test results. These TB screening is appended and may be adapted should have baseline TB screening, should include: to meet institutional needs (Appendix 3, including an individual risk assessment, http://links.lww.com/JOM/A782). which is necessary for interpreting any test result. The 2005 guidelines state that Risk factors for exposure, such as known baseline test results provide a basis for exposure to person(s) with active TB TB Testing for HCP Without comparison in the event of a potential or disease or birth/residence in TB endemic Prior Positive Tests known exposure to M. tuberculosis, facilitate detection and treatment of LTBI or TB countries (see 2019 MMWR CDC/ Institutions may opt to accept recent, disease in health care personnel before NTCA Recommendations Risk Assess- documented negative TB test results from ment1). other employers or training programs. The

ß 2020 American College of Occupational and Environmental Medicine e357

decision to accept such results will vary Test results should be interpreted in specificity to be closer to 95%, while that based on reliability and remoteness of the the context of the individual’s TB risk of the TST is roughly 97% in those report, workers’ compensation consider- assessment and current guidelines.1,14 Usu- with no prior exposure to BCG.15 TST ations and facility policy. Institutions that ally, a single negative IGRA or a negative specificity is reduced to closer to 60% in accept prior negative IGRA or TST results two-step TST is sufficient for TB clearance those with a history of BCG vaccina- for POPP clearance should use a consistent of HCP without TB risk factors. A positive tion.15 For TSPOT, a negative result is approach considering time interval, expo- TST is defined by the combination of indu- returned when the number of spots sure risk, and medical history. ration and risk factors. For instance, a TST counted(range0to100s)is0to4in The initial TB test for HCP without a is considered positive at more than or equal the US and 0 to 6 in Europe, equating to a documented prior positive TB test can be to 5 mm for any person with either immu- 95% to 97% specificity.14,26 either an IGRA (preferred) or a TST.14 The nocompromising conditions (such as HIV Mathematically, when highly specific choice of test may be influenced by a health infection) or with known, recent, unpro- tests for low-prevalence diseases are used in care institution’s specific cost, staffing, and tected TB exposure. The TST is considered large populations that are at low-risk for the logistical considerations. A single test type positive with induration more than or equal disease, false-positive rates rise due to math- should be employed as much as possible in to 10 mm for HCP without immunocom- ematical principles of positive and negative order to maintain consistency in interpreta- promising conditions and without a known, predictive values. (PPV ¼ True positives/ tion. Current FDA-approved whole blood recent, unprotected TB exposure.30 Finally, (true positives þ false positives) 100. IGRA tests are the QuantiFERON1-TB more than or equal to 15 mm induration is NPV ¼ True negatives/(true negatives þ Gold Plus (QFT, Qiagen Inc.),25 an the positive ‘‘cut-off’’ for individuals (non- false negatives) 100). Therefore, positive enzyme-linked immunoassay (ELISA), HCP) without immunosuppression or iden- results in this setting represent an indirect and the TSPOT1.TB (TSPOT, Oxford tified TB exposure. Note that CDC’s posi- measurement of interferon-gamma release Immunotec),26 a ficoll-separation assay tive cut-off induration for HCP, despite low that may be just above the FDA-mandated (ELISPOT). Both tests utilize negative rates of TB in HCP and data showing that cut-off point, but actually reflect only a mini- and positive controls, and both use the most HCP do not have elevated risk com- mally higher likelihood that the infection is MTB-specific antigens ESAT-6 and CFP- pared with the general population, currently present. Further, when tests in large popula- 10. Both assays are indirect measures of remains at more than or equal to 10 mm.2 tions are repeated, a repeated result will tend interferon gamma release in response to Newly positive IGRA or TST results to more accurately represent the mean result the TB-specific antigens. IGRAs have in HCP who have been negative in the past of the entire population (known as regression advantages over the TST during the onboard- and are without risk factors for exposure to to the mean), which in the case of US HCP ing process, including greater specificity in TB (ie, those with a low probability of true and TB, is a negative result.37 Therefore, the BCG vaccinated and faster time-to- infection) should have a confirmatory/ repeating an unexpected test result in a popu- onboarding compared with the two-step repeat TB test prior to radiography. If the lation that has an overall low prevalence of the TST.27,28 Retesting indeterminate or repeat test is negative the result can, in the disease may yield a more accurate result than invalid (QFT) and borderline or invalid absence of clinical symptoms of TB, be the original test provided. (TSPOT1.TB) results is recommended. regarded as negative and accepted for The intradermal TST utilizes purified pro- employment placement without radio- TB Testing for HCP with Prior tein derivative (PPD) tuberculin antigen graphs.14,16 When the repeat test is difficult Positive TB Tests solution and is sold in the US under the trade to obtain, or when a significant delay may Documentation should be obtained names Tubersol1 (Sanofi Pasteur Ltd., occur, a negative chest radiograph can be whenever possible for previous TB test Toronto, Canada) and Aplisol1 (JHP Phar- used for hiring clearance with the repeat test results, imaging and TB treatment includ- maceuticals, LLC, Rochester, MI). placed or drawn at the same time. ing compliance. For those with LTBI that Intradermal TST placement and was untreated or partially treated, further reading require annual training and compe- Regarding Reversions testing may be indicated. HCP with a pre- tency. All tests should be placed consistent The recommendation to repeat posi- viously positive TB test who have not with CDC methodology and standards. tive tests for confirmation in HCP without completed treatment, or who report relevant Standardized training using validated known exposure to active TB has been a symptoms regardless of treatment history, resources is available (eg, CDC TST train- CDC recommendation since 2010 and has should undergo a focused physical exami- ing video29). Institutions using TSTs to been supported by extensive literature on nation to identify signs of TB disease screen newly hired HCP should use the serial testing of US HCP.14,16,31–35 This including examination of the lungs and both two-step methodology, with retesting ide- recommendation has both operational and cervical and supraclavicular lymph nodes. ally 1 to 3 weeks after the first TST.2 Two- mathematical premises. Obtaining a new TB test in individ- step TST is a recognized way of boosting an First, TST and both IGRAs are indi- uals with previously positive test results immune response that may have waned rect measures of infection based on a skin could be considered when additional test after a prior infection. HCP with a poorly induration or whole blood interferon results are likely to alter management. Key documented prior positive TST may also gamma response to TB-specific antigens: examples include: benefit from two-step TST to confirm prior they are not direct visualizations of the infection. A consistent approach for accept- mycobacteria. Second, both IGRAs have 1. HCP with prior positive TSTs who have ing documentation of prior TST results for cut-off values that were assigned by the previously declined LTBI treatment may either ‘‘step’’ should be adopted (recogniz- FDA to maximize specificity, so that the accept chemoprophylaxis to reduce the ing that the evidence basis for cut-offs is likelihood of a false-negative result is min- risk of progression to active TB disease limited). For instance, a policy might stip- imized. On a scale of 0 to 10 international when presented with confirmatory IGRA ulate that a documented TST within a year units per milliliter (IU/mL), the QFT is result.38–42 prior to onboarding is acceptable.2 The considered negative at less than 0.35 IU/ 2. HCP who have received BCG vaccina- two-step TST process is recommended mL, corresponding to 99% specificity.25,36 tion and have a prior positive TST may for clearance when more than 1 year has Subsequent research, some of it summa- benefit from the increased specificity of elapsed since the most recent TST.2 rized in a meta-analysis, has shown the QFT the IGRA.

e358 ß 2020 American College of Occupational and Environmental Medicine

3. HCP with an undocumented prior posi- counseled by a qualified provider regarding of mortality to the elderly, young and tive TST may benefit from a two-step further evaluation and management. A immune compromised. Most states require TST to confirm prior infection. TST is major tenet of the 2019 MMWR CDC/ prompt public health reporting of persons considered safe in HCP with a history of NTCA Recommendations is that the with suspected active TB disease, and con- positive TST results, except when a onboarding process provides a crucial firmed active TB is reportable to the local prior TST was associated with necrosis, 43 opportunity to offer counseling and to health department in all states. Public health blistering, ulceration, or anaphylaxis. strongly encourage treatment for LTBI departments are responsible for contact 4. HCP with low positive or unquantified (see section on ‘‘Education and Treatment screening in the community, for monitoring results by an older generation IGRA and of Health Care Personnel with Positive Test treatment of individuals with confirmed no history of TB treatment may benefit Results’’ for further information). active TB disease, and for providing clear- from retesting with a newer generation The medical history, previous TB ance for the treated employee to return to IGRA to clarify treatment recommenda- test results, identified TB exposures, and work. State and local public health depart- tions. any prior TB or LTBI treatment should be ments can also offer valuable insights and 5. HCP with IGRA results that are discordant evaluated to ascertain whether a positive resources for TB screening, diagnosis, and or suggest reversion may benefit from a test represents a new conversion or reflects treatment in circumstances when guidance TST. TSTs should be avoided in HCP with a remote exposure. A history of time spent from this companion document cannot be a history of necrotic, blistering, ulcerated, 43 in any TB endemic country may also be directly applied due to unique characteristics or anaphylactic reactions to TST. relevant to establishing an infection time- of the HCP, local regulations, or limited line. A thorough work and volunteer history available occupational health resources. Asymptomatic HCP with docu- can also establish possible exposures. This If imaging or clinical presentation mented prior positive TB tests (IGRA timeline is important because active TB suggests active pulmonary TB disease, fur- and/or TST) do not require imaging for disease is most common in the first 2 years ther evaluation is necessary for work clear- clearance if they have documentation of following exposure with conversion.44 ance. For HCP with possible infectious normal chest imaging after the prior posi- The medical history should also TB, occupational health clinicians should tive TB test. A normal CXR is one with no elicit factors that would predispose the arrange for appropriate isolation precautions radiographic evidence of TB disease or patient to progress to active TB disease when necessary. Of note, neither the TST, granuloma. Repeat imaging in the context such as HIV/AIDS, immune suppression IGRA, clinical examination, nor imaging of a normal baseline CXR is not recom- (eg, cancer, solid organ transplant, biologic alone can exclude active TB disease. mended by the CDC but may be required by medications), recent significant weight False-negative IGRAs and TSTs occur in local workers’ compensation or facility loss, diabetes, smoking, or fibrotic lung 10% to 30% of people with active TB disease guidelines. If repeat imaging in this context disease. CDC recommends screening adults and are more frequent among those with is conducted, the facility should be consis- with LTBI for HIV in health care settings,45 extra-pulmonary TB and those with immune tent in the documentation and time frame and the US Preventive Services Task Force suppression. Clinicians should not rely on requirements for prior CXR. recommends screening adults for diabe- these indirect tests for M. tuberculosis infec- Re-imaging during the POPP TB tes.46 Given the high risk of progression tion when active TB is suspected.48 evaluation can also be considered in HCP to active TB disease in patients with Chest radiography is a mainstay of with a prior positive TB test and a prior untreated comorbidities, this TB evaluation the initial evaluation for possible active normal CXR based upon review of their TB presents a logical opportunity to recom- pulmonary TB disease. While a single risk assessments: mend diabetes and HIV screening if not PA view is usually sufficient, adding a previously done. Symptoms of pulmonary lateral view may improve sensitivity, par- 1. When there has been known exposure to or extra-pulmonary TB should also ticularly in immune compromised HCP active TB since the prior image was be ascertained. whoaremorelikelytohaveatypicalradio- obtained or extended time spent in The physical examination should graphic presentations of active TB.49,50 regions with elevated TB rates, identify signs of active TB disease and Additional imaging, including computed 2. When prior imaging is not well docu- include auscultation of the lungs, and pal- tomography (CT) scanning may be indi- mented or is not normal, pation of both cervical and supraclavicular cated based on clinical assessment or dis- 3. When previous LTBI treatment was lymph nodes. Weighing the patient is useful cussion with the radiologist. HCP with incomplete, to document weight stability, loss or gain. incidental findings of clinical significance 4. When the HCP was not treated for LTBI All HCP with newly confirmed pos- on CXR should be counseled, given copies and has risk factors for progression to itive TB tests should be evaluated with a of their imaging, and confidentially active TB disease (reactivation TB). CXR. CXRs are reasonably sensitive for referred for appropriate care. active pulmonary TB, and the vast majority Note that CXRs are likely to be Newly Confirmed Positive TB of asymptomatic HCP with newly positive normal in HCP with extra-pulmonary TB Test and/or Positive Symptom TB tests can be cleared safely for work disease, so the absence of lung disease on Review placement based on a normal CXR alone. CXR does not prove absence of either For low-risk HCP (defined as those A single posterior-anterior (PA) view is active TB disease or of infectiousness. ‘‘who are asymptomatic, unlikely to be usually adequate for employment clearance Oropharyngeal and laryngeal TB are highly infected with M. tuberculosis, and at low in asymptomatic individuals without TB contagious, but not visible on CXR. Per- risk for progression on the basis of their risk risk factors. sonnel with suspected oropharyngeal, assessment,’’)1 a confirmed positive TB test laryngeal, or pulmonary TB should wear is a test that is positive and when repeated is Considering Active TB Disease a mask and be restricted from work until positive again. HCP with a history of Active pulmonary tuberculosis is a their disease is determined by experts not to necrotic, blistering, ulcerated, or anaphy- serious, contagious disease: between 5% be infectious. Extra-pulmonary TB disease lactic reactions to TST, if retested, should and 10% of people will die before or during in the mediastinum, bones, lymph nodes, be tested with an IGRA.43 All HCP with their treatment for TB disease.47 Active TB and abdomen is also not visible on confirmed positive TB tests should be disease poses a disproportionately high risk CXR, but is not contagious. HCP with these

ß 2020 American College of Occupational and Environmental Medicine e359

non-contagious conditions can remain at Appendix 4, http://links.lww.com/JOM/ occurred are similar to those with other work during evaluation and treatment. A783 contains a sample declination form. infectious diseases, including influenza Clearance to work for HCP with and the pandemic novel coronavirus. These possible infectious TB disease requires considerations include the infectiousness of direct testing for M. tuberculosis and expert POST-EXPOSURE TB SCREENING the patient, the location and duration of the consultation. Testing may include serial AND TESTING HCP relative to the infected person, the sputum smear collection with acid-fast activity being performed (eg, aerosol-gen- bacillus (AFB) staining, polymerase chain erating), and the environmental controls 2019 MMWR CDC/NTCA Recommen- reaction (PCR), nucleic acid amplification dation: ‘‘After known exposure to a person that are in practice (eg, PPE and ventila- testing (NAAT), or sputum culture. Such with potentially infectious TB disease tion). testing is sometimes completed in consul- without adequate personal protection, The 2019 MMWR CDC/NTCA Rec- tation with the facility’s infection control, health care personnel should have a ommendations update the 2005 MMWR timely symptom evaluation and additional 2 infectious diseases, or local public testing, if indicated. Those without CDC Guidelines in a few important ways: health services. documented evidence of prior LTBI or TB Return-to-work clearance is appro- disease should have an IGRA or TST 1. The definition of TB exposure is refined priate if initial smears or NAATare negative performed. Health care personnel with by adding the language ‘‘without use of documented prior LTBI or TB disease do on at least three high-quality sputum speci- not need another test for infection after adequate personal protection’’ to qual- mens, collected 8 to 24 hours apart with at exposure. These persons should have ify those who should be included in least one collection obtained early in the further evaluation if a concern for TB contact investigations. TB transmission morning, even though final culture results disease exists. Those with an initial generally requires prolonged exposure will not be available for several negative test should be retested 8 to in a closed air space, but there is no 2,51,52 10 weeks after the last exposure, weeks. Clinical judgment should preferably by using the same test type as static definition of what constitutes a always supersede test results. was used for the prior negative test.’’1 TB exposure event. Table 2 lists factors that should be considered when gauging Compliance, Confidentiality, and the clinical significance of an exposure. Communication Also included in the table are factors Information management require- that can mitigate M. tuberculosis trans- ments for occupational health practices that Overview mission. provide POPP TB screening and testing for While the US has one of the lowest 2. Contact investigations may be done HCP are complex. Minimum needs include: incidence rates of TB in the world at 2.8 with either IGRA or TST, though the cases per 100,000 persons (2018), HCP collaborative 2017 CDC/ATS/IDSA Ensuring that all newly onboarded HCP cases in the US continue to experience Diagnostic Guidelines recommended have met institutional policy require- exposures to persons with active pulmo- IGRA over TST for exposure investiga- ments for work clearance specifically nary TB.53 A contact investigation should tions.13 related to excluding active TB disease be conducted for HCP exposed to persons 3. HCP with documented prior LTBI do and documenting LTBI, with confirmed infectious TB disease or not need another test for infection after Ensuring that HCP with positive test aerosolized Mtuberculosisspecimens. exposure. This recommendation and results are aware of their TB/LTBI sta- The timing and extent of contact investi- exceptions to consider are explored tus, gation activities such as risk and exposure further below. Maintaining strict confidentiality of all assessment, symptom screening, and test- 4. The designation of a facility as medium medical and personal information, ing should be dictated by the specific risk, based on the 2005 MMWR CDC Ensuring that HCP have been educated characteristics of the exposure. For most Guidelines Facility Risk Assessment on signs and symptoms of TB disease health care settings in the US, investiga- Appendix B,2 no longer establishes a and are aware of when they should seek tions may simply document the lack of requirement for annual HCP TB testing. further medical evaluation, and significant exposure due to the appro- However, medium risk facilities will Communicating clearance status to hir- priate engineering and administrative continue to be guided by all of the ing managers without compromising controls or use of personal protective environmental, administrative, and protected health information. Occupa- equipment (PPE). The Guidelines for monitoring requirements that are out- tional health staff should restrict their the Investigation of Contacts of Persons lined. Appendices 1, http://links.lww. responses to the clearance status only, with Infectious Tuberculosis by CDC and com/JOM/A780 and 5, http://links. without revealing further testing needs. NTCA in 2005 contain information lww.com/JOM/A784 are the adapted regarding environmental controls, data versions of the 2005 MMWR CDC An overarching goal of the 2019 management, confidentiality, consent, Guidelines’ Appendices B and C,2 with MMWR CDC/NTCA Recommendations is and human resource considerations that minor, bolded changes that reflect the to accurately identify and encourage the are useful when structuring and opera- 2019 MMWR CDC/NTCA Recommen- treatment of LTBI in order to prevent the tionalizing investigations.54 dations’ guidance. devastating consequences that occur when TB experts are also available for HCP progress to active, infectious TB dis- consultation through jurisdictional public Travel-Related Exposure ease while working with vulnerable patients health agencies and consultation and col- Work, educational, and volunteer- and colleagues. To that end, onboarding laboration is encouraged. In most US juris- related travel to TB endemic areas of the HCP who are confirmed to have LTBIshould dictions, reporting and consultation with world merit special mention. The 2019 be strongly encouraged to undergo treat- the public health department is required MMWR CDC/NTCA Recommendations ment. Occupational health staff can docu- upon confirmation of a case of active TB identify any region other than Australia, ment treatment declination in the medical disease in a health care setting. Canada, New Zealand, and those countries record and should revisit the treatment dis- Many of the principles used to deter- in western or northern Europe as likely to cussion and education on an annual basis. mine whether a significant exposure have high rates of TB disease.1 Clinical

e360 ß 2020 American College of Occupational and Environmental Medicine

TABLE 2. Factors that Affect Risk of TB Transmission to Health Care Personnel (HCP)

Factors that Decrease Risk for TB Transmission to HCP

Patient Factors Environmental Factors Time and Intensity of Exposure

Early identification of possible TB disease Isolation room under negative air pressure Risk of transmission is directly of respiratory tract Removal of infectious droplet nuclei by proportional to time and intensity of Early/prompt transfer of patient into adequate air exchanges with exhaust to exposure respiratory isolation outside air Short exposure duration Early initiation of effective anti-TB Use of adequate ultraviolet germicidal Infrequent exposure regimen irradiation (UVGI) Absence of close physical contact Effective antibiotic treatment of 3 days or Employee using appropriate personal more protective equipment (PPE) (N95, Patient is not coughing powered air-purifying respirator Surgical mask is worn by patient [PAPR], or equivalent)

Factors that Increase Risk for TB Transmission to HCP

Patient Factors Environmental Factors Time and Intensity of Exposure

Incorrect, lack of, or short duration of TB Sharing small, enclosed spaces Prolonged cumulative duration of exposure treatment Inadequate local or general ventilation that Frequent exposure High concentrations of acid-fast bacillus results in insufficient dilution or Prolonged close physical proximity (AFB) on sputum smear removal of infectious droplets Intense exposure (eg, conducting Presence of cough Recirculation of air containing infectious aerosol-generating procedures) Cavitation on CXR droplet nuclei Oropharyngeal or laryngeal TB Inadequate cleaning and disinfection of Failure to cover the mouth and nose while medical equipment coughing (or not wearing a mask) Improper procedures for handling Undergoing cough-inducing or aerosol- specimens generating procedures (eg, bronchoscopy, sputum induction, autopsy) Culture or NAAT þ regardless of AFB smear positivity

Partially adapted from Centers for Disease Control and Prevention.2

rotations and overseas duties lasting a may decide that HCP can self-report a TB disease should be evaluated for active TB month or more in regions with high TB exposure concern and request a TB test with promptly. While this evaluation is ongoing, incidence (generally accepted to be more or without further inquiry by an occupa- they should be restricted from work, than 20 cases/100,000 people) may pose a tional health provider into the potentially instructed to avoid activities that could risk for TB exposure to HCP. The 1-month personal and private nature of that expo- expose others, and reported to the public timeframe derives from the 2018 California sure. Alternatively, occupational health can health department. Department of Health Risk Assessment,55 encourage such HCP to seek testing from IGRAs are preferred for post-expo- though studies regarding TB conversions in their primary care provider when such a sure testing of previously negative person- US HCP who travel for work are sparse. concern arises. If the option for voluntary nel because of the timeliness of the results, HCP who plan to engage in clinical or testing in the workplace is offered, notifi- the obviation of the need for two-step research activities with risk of exposure cation of that option should be included in testing, and for their higher sensitivity than to active TB disease should undergo pre- the annual education program. the TST in contact investigations.13,57–59 and post-travel symptom screening and The two-step TST procedure typically used testing (more than 8 weeks after return- Post-Exposure Testing during the pre-placement process (to pro- ing).1 Serial TB screening and testing Considerations and mote boosting for remote TB exposures) may be warranted for HCP who rotate on Interpretation should not be used in contact investiga- a regular basis to these regions. HCP who experienced unprotected tions.2 exposure to active pulmonary or oropha- If the HCP has a record of a previ- Voluntary Testing for Self- ryngeal TB should be enrolled in a contact ously positive TB test, the 2019 MMWR assessed Potential Exposure investigation, ideally within 4 weeks of the CDC/NTCA Recommendations state that Employees may become exposed to first exposure event. This includes screen- the HCP does not require post-exposure TB disease if incarcerated, experiencing ing for (1) symptoms and signs of TB; (2) testing. However, standard occupational homelessness, have a family member/ history of prior M. tuberculosis infection health practice is to conduct testing in some roommate from a high-risk country with and treatment; and (3) risk of progressing to of these personnel. A new TB test could a cough, or via other non-work-related sit- TB disease if infected with M. tuberculosis. prove useful in clarifying the pre-exposure uations, though the annual TB test conver- This initial set of evaluations is to establish status and protecting the worker in the event sion rate of less than 1% in US HCP a baseline in the event of a change in that the test is now negative. Untreated HCP supports that such conversions are uncom- symptoms or test conversion later. Persons with a previously positive TB test may mon.56 Nonetheless, facilities or sections with symptoms or signs suggestive of TB be considered for new baseline/initial

ß 2020 American College of Occupational and Environmental Medicine e361

TABLE 3. Management of HCP Exposed to Potentially Infectious Tuberculosis

HCP TB Status Prior to Known TB Exposure

Negative IGRA or Negative IGRA or TST Positive IGRA Positive TST <3 Months 3 Months Ago or Unknown or TST, IGRA or TST, Time Frame Clinical Management Ago or Unavailable Results Untreated Treated

As soon as TB exposure Step 1 TB symptom screen Yes Yes Yes Yes is identified, up to 4 weeks after first exposure Step 2 Obtain initial post-exposure Optionalz Yes Conditional§ No test (IGRA or TST)y Step 3 If initial post-exposure test is Yes Yes Yes Yes positive, or if TB symptoms are reported, obtain CXR and focused clinical examinationjj Step 4 Recommend LTBI treatment Yes Yes Yes Rare if initial post-exposure test is positive without evidence of active TB diseasejj At least 8 weeks after Step 5 TB symptom screen Yes Yes Yes Yes last exposure,{ Step 6 Obtain follow-up post- Yes Yes Yes§ No exposure test# if initial post-exposure test was negative or not obtained Step 7 Obtain CXR and perform Yes Yes Yes Yes focused clinical examination if symptom screen or post-exposure test is positivejj Step 8 Recommend LTBI treatment Yes Yes Yes Rare if this post-exposure test is positive without evidence of active TB diseasejj

Tests for TB infection obtained between 4 and 8 weeks after TB exposure serve neither as a valid baseline nor as a follow-up test, and are not recommended except, potentially, in the case of severe immunocompromised status or extenuating circumstance. If exposure identification was made after 4 weeks, commence with Steps 5 to 8 after 8 weeks using the last known test as the baseline. ySome references may call this first post-exposure test a new ‘‘baseline’’ result. An interferon-gamma release assay (IGRA) is preferred over tuberculin skin testing (TST) for use in contact investigations. If TST must be used, note that if the previous TST result is >12 months old, two-step TST testing would be ideal, if feasible, for the 1st post-exposure test. IGRA is strongly preferred because this is difficult to accomplish in a timely manner and delays in the two-step testing process can cause confusing results. zThe first post-exposure test may have limited value in HCP who had a negative IGRA or TST in the past 3 months, though it may be required by the facility or workers’ compensation; check local policy. An IGRA could be useful for use in individuals who have only had TSTs. §Obtain an IGRA for those with a previously positive test if (1) TST is the only test that was previously positive (particularly in BCG-vaccinated individuals) or (2) an earlier IGRA was positive on only one instance and not confirmed by a repeat test. If the LTBI diagnosis was confirmed, repeat testing is not necessary. jjIf there is any suspicion of active TB disease, expert consultation should be obtained. {HCP who are identified as TB contacts >8 weeks following last exposure to active TB disease should still be clinically managed as soon as possible as in Steps 5 to 8. #Using the same test method as the first post-exposure test (if obtained) is preferred. Those with prior TB treatment may benefit from re-treatment, depending on exposure history, post-exposure test results, and risk factors, such as HIV infection, solid-organ transplant or ongoing treatment with a TNF-alpha inhibitor. Consultation with a specialist or the public health department is recommended.

post-exposure TB test in a few situations, HCP has had treatment for LTBI or active result obtained less than 8 weeks after including but not limited to when: TB disease, testing may not be indicated exposure is considered unreliable for (Table 3). excluding infection due to the time 1. The HCP had a positive TST without a Management of contact investiga- needed for the body to mount a reliable confirmatory IGRA, particularly if tions and interpretation of results for immune response. BCG-vaccinated; HCP can be nuanced. Table 3 offers a A positive test result indicates that a 2. An older generation IGRA with poorer suggested workflow for such investigations. prior infection is likely. Evaluation and quality control or reliability was used; The interpretation of the initial test result treatment are recommended. A follow- 3. The TST or a single IGRA was positive (less than 4 weeks from first significant up TB test in more than 8 weeks is in an HCP without TB risk factors; and exposure) should be as follows: not indicated. 4. There is poor or absent documentation If the initial post-exposure TB test is of the previous positive TB result. A negative test result should be retested negative or is not obtained within 4 weeks In contrast, if it is determined during more than 8 weeks following cessation of the first exposure, contacts should the course of taking the history that the of suspected exposure. A negative test undergo TB testing no sooner than 8 to

e362 ß 2020 American College of Occupational and Environmental Medicine

10 weeks after the last exposure, or as soon should be individualized based upon crite- Health care personnel might have risks for as possible if this time window is missed. TB exposure that are not related to work in ria including: Re-testing with the same method as the the United States, or they might have risks initial test is recommended to minimize for TB progression after baseline testing that 1. The number of patients with infectious variability in results. Re-testing after at necessitate special consideration. If these pulmonary TB examined; risks are unrecognized, these health care least 8 weeks from the last exposure allows personnel might experience TB disease 2. Whether delays occurred in initiating the immune system time to mount a reliable and transmit TB to patients, coworkers, or airborne isolation; response to M. tuberculosis if sufficient other contacts. Therefore, health care 3. Whether environmental controls and exposure occurred. If either symptom facilities should educate all health care processes, such as patient masking personnel annually about TB, including screening or the TB test is positive, addi- risk factors, signs and symptoms; facilities and air handlers are in place and are tional steps (such as physical examination also should encourage health care functional; or and chest radiographs) are required to diag- personnel to discuss any potential 4. If prior serial testing has revealed nose LTBI or active TB disease. occupational or nonoccupational TB ongoing transmission. exposure with their primary care provider The interpretation of the follow-up and occupational health clinician. The When there is any concern or uncer- test result (more than 8 weeks after last decision to perform TB testing after tainty, consultation with public health is exposure) should be as follows: baseline should be based on the person’s recommended. Current state and local reg- risk for TB exposure at work or elsewhere 1 ulations may be in conflict with this new A negative TSTor IGRA test result more since that person’s last test.’’ federal guidance and may require routine than 8 weeks after the end of exposure TB testing for certain groups until such indicates that M. tuberculosis infection regulations change. is unlikely. A negative test result The 2019 MMWR CDC/NTCA A specific threshold number of obtained less than 8 weeks after expo- Recommendations state that the risk active TB cases that would trigger serial sure is considered unreliable for exclud- assessment for health care settings (found surveillance testing is not identified as it ing infection. in Appendices B and C in the Guidelines was in the 2005 MMWR CDC Guidelines A positive TSTor IGRA result more than (Appendix 5, http://links.lww.com/JOM/ for Preventing the Transmission of Myco- 2 8 weeks after the final exposure suggests bacterium tuberculosis in Health-Care A784). Instead, the recommendations that M. tuberculosis infection has Settings, 20052) no longer forms the basis advise that clinical staff involved in the occurred since prior testing (conver- for determining a TB testing regimen for direct care of patients with active pulmo- sion). HCP with newly diagnosed M. HCP, and that HCP without LTBI should nary TB on a regular and ongoing basis may tuberculosis infection should have a not undergo routine serial TB screening constitute personnel at increased risk. symptom review, CXR, and evaluation or testing at any interval after baseline (ie, Examples of such increased risk would for progression to active TB. For those annually) in the absence of known expo- include HCP in a TB clinic who encounter diagnosed with LTBI, treatment should sure or evidence of ongoing TB transmis- patients with TB before initiation of air- be encouraged. If the recommendation sion. This is part of the updated approach borne isolation, or individuals involved for treatment is not accepted initially, to TB elimination in US health care set- directly and frequently in cough-inducing annual symptom reviews should com- tings. Driving the new recommendation or aerosol generating procedures on mence, and annual education should are current TB rates among HCP match- patients with active pulmonary TB. Staff reinforce treatment options. The public ing those of the general population,11 the involved in autopsy examinations in an area health department should be notified of inherent limitations in predictive value of with high rates of TB, and laboratorians any suspected transmissions. screening tests administered among low manipulating specimens or cultures with a risk populations,60 and the public health large TB burden, may warrant further con- SERIAL SCREENING, TESTING, sideration for inclusion in serial screening imperative to be proactive and treat LTBI. 63–66 AND EDUCATION FOR HCP For more information regarding the sup- or testing programs. While there does porting data, refer to ‘‘Background with not appear to be current published evidence Literature Review’’ section of this docu- in the US of higher LTBI incidence among 2019 MMWR CDC/NTCA Recommen- those employees, such clinical settings have dation: ‘‘In the absence of known ment. exposure or evidence of ongoing TB been associated with occupational trans- transmission, US health care personnel (as missions in the past. Any extension of identified in the 2005 guidelines) without Serial Screening and Testing serial/annual testing to individual HCP LTBI should not undergo routine serial TB The 2019 MMWR CDC/NTCA Rec- should take into account the specific work- screening or testing at any interval after baseline (ie, annually). Health care ommendations instruct not to conduct rou- place clinical setting, its environmental and facilities might consider using serial TB tine serial TB screening or testing at any safety controls, and its volume of active TB screening of certain groups who might be interval after hire in the absence of known cases seen where such precautions have or at increased occupational risk of TB exposure, but state that health care facilities may fail. In situations where serial testing is exposure (eg, pulmonologists or respiratory therapists) or in certain ‘‘might consider’’ serial TB screening for considered, positive IGRA results should be settings if transmission has occurred in certain groups at increased occupational confirmed (repeated) given the higher rates the past (eg, emergency departments). risk (citing pulmonologists or respiratory of conversions and reversions compared Such determinations should be therapists as possible examples)61 or for with the TST.20,67 It is worth re-stating that individualized on the basis of factors that might include the number of patients with personnel working in settings with past there is a paucity of recent literature report- infectious pulmonary TB who are examined documented transmission. Additionally, ing occupational transmission of TB to in these areas, whether delays in initiating other HCP may have institutional or regu- any specific group of US hospital-based airborne isolation occurred, or whether latory requirements for serial testing, such personnel. prior annual testing has revealed ongoing as laboratory personnel performing micro- The second criterion, delays in transmission. Consultation with the local or 62,63 state health department is encouraged to biological specimen testing for TB. initiating airborne isolation, is largely assist in making these decisions. The new guidance further instructs that addressed within the recommendations any decision to extend such serial testing for post-exposure TB surveillance (see

ß 2020 American College of Occupational and Environmental Medicine e363

preceding section, ‘‘Post-Exposure Screen- based medical resources to access if understand which symptoms to monitor, ing and Testing’’). An instance in which symptoms develop. Staff should be whom to contact if symptoms of concern such a delay occurs for a patient with active reminded of the option for voluntary develop, and what LTBI treatment options TB disease should generally be regarded as TB testing if it is offered. Additional to consider. While there is a paucity of an exposure, triggering baseline, and fol- attention should be given to specific literature showing efficacy of annual symp- low-up TST or IGRA testing as per current knowledge required by HCP who have tom surveys to detect active TB disease, the guidance. Instances of delayed isolation untreated LTBI and to those who may required annual symptom screening can be should be identified and handled as spe- be at increased TB risk due to work- a useful point of contact to review the cific exposure events. Settings in which related or non-work-related factors (such HCP’s knowledge and understanding of such delays may be more likely and fre- as immune suppression70; see Appendix TB and to encourage treatment of LTBI quent would include patient care environ- 6, http://links.lww.com/JOM/A785). for those who have not previously accepted ments in regions of the world with high Importantly, the 2019 MMWR recommendations. rates of active TB, to which US HCP may CDC/NTCA Recommendations do not Importantly, the symptom assess- periodically rotate. Increased risk of TB include the recommendation to conduct ments among those with LTBI should be among HCP continues to be a substantial an annual individual risk assessment for carried out with an awareness of the possi- hazardinsuchsettings.68,69 We recom- HCP (eg, asking employees where they bly stigmatizing effect of singling out a mend that a clinical rotation to TB- traveled outside of work). The recommen- specific group of HCP for serial surveil- endemic regions of the world be considered dation to conduct the annual facility risk lance due to LTBI positivity. Medical cen- an increased risk for TB exposure and thus assessment (2005 MMWR CDC Guide- ter occupational health clinics have often warrant post-travel testing, and that serial lines Appendix B,2) does remain in relied upon communication with managers screening be considered for the HCP who place. Individuals with increased risk to enforce adherence to serial TB surveil- rotates on a regular basis to higher risk for occupational exposure (eg, engaging lance programs, but this strategy could international settings. Those who rotate in aerosolizing procedures in facilities have the unintended consequence of sug- only rarely or intermittently to such that routinely diagnose TB) should be gesting the presence of TB infection to an settings should be considered for post- identified by the facility risk assess- individual’s manager. To avoid this, adher- exposure TB surveillance upon return to ment, and may be considered for serial ence with annual symptom monitoring the US, regarding the time in the higher testing. Serial testing for targeted staff should be enforced to the extent possible risk setting as an interval of potential can also be appropriate when environ- through direct communication from occu- exposure. mental controls have been shown or are pational health to the HCP with LTBI The third criterion addresses settings strongly suspected to have failed, as rather than through the HCP’s manager in which the risk of TB exposure may be demonstrated by evidence of trans- or supervisor. Options include regular inadequately characterized but where past mission without knowledge of a specific mail, direct e-mail with a linked symptom experience in monitoring LTBI conversion exposure. survey, telephonic assessment, or in-per- among HCP has suggested enhanced risk Messages specifically directed at son interview. If communication with a (as evidenced by annual testing that those with untreated LTBI to be aware of manager to enhance adherence is deemed revealed ongoing transmission). Such set- symptoms suggestive of active disease and necessary, it should state only that the tings offer the opportunity to better under- to promptly report any such symptoms to employee has an occupational health stand and mitigate risk factors for TB occupational health should be folded into requirement to be addressed. transmission (ie, enhanced environmental generally targeted educational modules. controls), and may benefit from continued Annual education can help establish the serial surveillance in order to assess the knowledge base necessary to enhance per- Transitioning a TB Screening impact of risk factor mitigation efforts. sonal awareness of potential signs and Program for Health Care Encouragement in the new guidance to symptoms of TB. While such education Personnel consult with local or state health depart- could be accomplished with a widely The vast majority of health care ments prior to continuing any serial screen- directed teaching module, face-to-face facilities will be able to eliminate serial ing is sound, since ongoing screening is encounters with occupational health pro- TB testing thereby saving time and money likely to be based on local factors rather viders do add value by providing the oppor- that may be redirected to activities such as than the general trends recognized in recent tunity to teach, ask questions, and allay educating, identifying, tracking, and treat- years for US HCP. employee concerns. Most importantly, edu- ing LTBI. Some programs will have tran- cating untreated staff regarding short- sient impediments to getting to this future Annual Education Requirement course treatments that are equally effective, state that may include mandatory testing by With implementation of the new have much higher compliance rates and are localities and states, updating of hospital guidance, rigorous annual TB education generally well tolerated can result in both policies, contracts that specify TB testing, for HCP will take on greater importance. individual and public health benefits and general resistance to change. The tran- This is due both to the elimination of (Fig. 1). sition will require consistent, reassuring widespread serial surveillance testing communication that emphasizes that the and the intent of the guidance to encour- safety of HCPs and patients should be age more treatment of LTBI in HCP. Annual Symptom Review for improved by the pre-placement identifica- Educational programs should address HCP with LTBI tion and treatment of LTBI, and identifica- the range of TB-related issues with which The 2019 MMWR CDC/NTCA Rec- tion and monitoring of those exposed to all staff should be familiar: exposure risks ommendations do continue to support an active TB cases. It is worth reiterating that (both within and outside of the work- annual symptom evaluation for those with the decades of serial TB screening program place), what to expect if a workplace untreated LTBI1 (Appendix 7, http://links. results, in conjunction with improvements TB exposure is identified, signs and lww.com/JOM/A786). This symptom sur- in environmental controls, show the US symptoms of active disease, and which vey should include education to help the has had a substantial reduction in TB workplace-based and non-workplace- HCP with treated or untreated LTBI burden.

e364 ß 2020 American College of Occupational and Environmental Medicine

FIGURE 1. LTBI treatment options quick-reference guide, 2020. Rifapentine: 25.1 to 32.0 kg, 600 mg; 32.1 to 49.9 kg, 750 mg; more than or equal to 50.0 kg, 900 mg maximum. See Table 4 for list of abbreviation meanings.

TREATMENT AND EDUCATION Progression from LTBI to TB treatment, the importance of education can- OF HEALTH CARE PERSONNEL Disease (Reactivation TB) not be overstated. The goal is to teach HCP WITH POSITIVE The vast majority of TB disease in about their diagnosis, the risk of developing TEST RESULTS the US is caused by the progression from active TB disease, treatment options, and latent infection to active disease (reactiva- the benefits and risks of treatment. Once tion). Eighty-percent of the nearly 40,000 active TB disease is ruled out, the following active TB cases reported in the US between key concepts should be clearly conveyed: 2006 and 2008 were reactivation TB, 2019 MMWR CDC/NTCA Recommen- largely in non-US born persons.47 Over You have LTBI, not active TB disease. dation: ‘‘Health care personnel with a The BCG vaccine does not interfere with newly positive test result (with 60% of these persons progressed more than confirmation for those persons at low risk 4 years after they arrived in the United the accuracy of the TB blood tests. as described previously) should undergo a States.71 The rate of progression from LTBI When you have LTBI, it is not conta- symptom evaluation and chest radiograph to active TB disease was slightly higher gious so you cannot pass this to to assess for TB disease. Additional workup other people. might be indicated on the basis of those among non-US born than US born per- results. Health care personnel with a prior sons.72 Finding and treating LTBI, whether You can be at work. positive TB test and documented normal related to a contact investigation from an You are at risk of developing active TB chest radiograph do not require a repeat exposure or as identified during the POPP disease in the future. radiograph unless they are symptomatic or The risk of developing active TB starting LTBI treatment. The local public evaluation, both act to reduce the possibility health department should be notified of future cases. Preventing progression depends on your health status and how immediately if TB disease is suspected. from LTBI to active TB disease in HCP recently you were infected. Health care personnel with LTBI and no merits particular attention because active During the first 2 years after infection, prior treatment should be offered, and the risk starts at about 5%, but can be strongly encouraged to complete disease often goes unrecognized for weeks treatment with a recommended regimen, to months and exposes large numbers of much higher in some people. including short-course treatments, unless a colleagues, vulnerable patients, and their After the first 2 years the risk starts at contraindication exists. Health care families. Contact investigations associated about 1% per decade of life but can be personnel who do not complete LTBI much higher. treatment should be monitored with with HCP who progress to TB disease can annual symptom evaluation to detect cost millions of dollars, result in negative Conditions and medications that you early evidence of TB disease and to media attention and cause significant may have now or in the future could reevaluate the risks and benefits of LTBI harm.73 substantially increase that risk, including treatment. These health care personnel HIV infection, diabetes, cancer, lung also should be educated about the signs and symptoms of TB disease that should disease, tobacco use, and immune sup- prompt an immediate evaluation between Educating HCP about LTBI pression from medications and aging. screening visits.’’1 When HCPs with LTBI are evaluated If you develop active TB disease you at occupational health for consideration of may expose patients, coworkers, and

ß 2020 American College of Occupational and Environmental Medicine e365

FIGURE 2. NTCA provider guidance: using the Isoniazid/Rifapentine regimen to treat latent tuberculosis infection (LTBI). Source: Tuberculosis Controllers Association. NTCA provider guidance: using the Isoniazid/Rifapentine regimen to treat latent tuberculosis infection. November 2019; Revised April 2019. Available at: http://www.tbcontrollers.org/docs/resources/3hp/NTCA_Provider_- Guidance_3HP_11918.pdf.74

family. Some of these people may be at The use of IGRAs increased accep- and therefore may be more acceptable to high risk of developing active TB and tance of LTBI treatment compared with HCP. The consequences of active TB in serious complications of the disease TST. In one study, that acceptance rate HCP are potentially more serious than in including death. increased from 11% to 52% with positive the general population because they include Treatment of LTBI is safe, effective, and results.41 However, there is a concerning, not only personal illness but also costly and strongly recommended in most cases. consistent finding that HCP with LTBI are disruptive contact investigations, lost work Treatment of LTBI can be as short as less likely than non-HCP to accept LTBI time and an appreciable risk of exposing 1 day per week for 12 weeks (Fig. 2). treatment.38–40,42 Treatment acceptance medically vulnerable patients.80–84 Consid- rates vary but seem to cluster between eration of these factors may convince oth- Recommending Treatment 40% and 50% when all eligible HCP are erwise ambivalent HCP to accept treatment. Since more than 80% of active TB included.10,38,39,41,76,77 Acceptance rates as Occupational health programs cases in the US arise from previously high as 90% with adherence have been should utilize strategies to reduce barriers untreated LTBI,47 LTBI represents a reported with intensive clinic interventions to treatment and optimize treatment accep- unique opportunity to prevent a potentially including frequent follow-up visits. Selec- tance and completion. Such strategies may devastating infectious disease via early tion bias may limit the reproducibility of include: treatment. For this reason, treatment of these findings.77,78 LTBI is now a cornerstone of the nation’s The reasons for low HCP acceptance Offer treatment through an onsite occu- TB elimination strategy.75 Treatment is of treatment are unclear. Recent data sug- pational health clinic. now strongly recommended for HCP with gest that physicians and HCP from high TB Provide LTBI education appropriate to LTBI, unless risks of treatment outweigh burden countries may be less likely to the HCP’s knowledge base. the anticipated benefit for a particular accept and complete treatment compared Elicit and address the HCP’s beliefs patient. A CXR prior to the time of treat- with other HCP.76,79 One potential contrib- and concerns about LTBI and LTBI ment initiation is recommended by the utor may be greater familiarity with isonia- treatment. CDC; 3 to 6 months is a reasonable time- zid (INH) treatment-associated adverse Subsidize the cost of treatment. frame for needing to repeat a CXR prior events. Newer regimens afford not only Offer flexible, convenient mechanisms to treatment. shorter, but safer courses of treatment, for follow-up care.

e366 ß 2020 American College of Occupational and Environmental Medicine

have been shown to have equal or greater significant improvement in either HCP or TABLE 4. Abbreviations efficacy at preventing progression to active in-patient health. Policies that called for 3HP 3 months INH þ rifapentine TB, significantly higher completion rates, large-scale serial testing without attention (once weekly) and superior safety profiles when compared to preventive treatment also generated 88–90 4RIF 4 months rifampin (daily) with 9INH. Even shorter regimens many false-positive results and has resulted 6INH 6 months INH (daily) continue to be studied.91 When prescribing in additional unnecessary testing and treat- 9INH 9 months INH (daily) rifampin-based regimens, the potential for ment of people without TB. The waste and AFB Acid-fast bacillus drug–drug interactions should be carefully harm associated with tens of millions of AIDS Acquired Immunodeficiency considered and monitored. An LTBI treat- negative TB tests annually also contributes Syndrome ment comparison table is offered in Fig. 1, both enormous medical waste and a sub- BAMT Blood assay for M. tuberculosis and a 3HP user Guide is included in Fig. 2. stantial carbon footprint that negatively BCG Bacille Calmette-Gue´rin 95 CDC Centers for Disease Control Some HCP who initially decline impact the planet as a whole. and Prevention treatment may change their mind in subse- It is a true public health feat that the CXR Chest radiograph, ‘‘x-ray’’ quent years as medication regimens and US is on its way to elimination of a disease FDA Food and Drug Administration influences in their personal lives also that just 100 years ago killed one in seven HCP Health care personnel change. For those who decline or defer Americans, and still kills 1.6 million people HIV Human Immunodeficiency Virus treatment, a mechanism to periodically across the globe annually. The decline of IGRA Interferon gamma release assay reissue the offer and to educate them on TB in the US overall, and in HCP in INH Isoniazid new treatments as they become available is particular, is remarkable in a country as LTBI Latent tuberculosis infection MMWR Morbidity and Mortality Weekly recommended and could be embedded in large and as diverse as the US; the elimina- Report ongoing TB awareness education or respi- tion of TB disease by proactively treating NAAT Nucleic acid amplification testing ratory fit testing. Resources for LTBI diag- LTBI should be the US health care com- PA Posterior-anterior nosis, education, and treatment are munity’s next collective priority. These are PAPR Powered air purifying respirator available through CDC,92 and its four testaments to what we can do together when PCR Polymerase chain reaction regional TB Centers of Excellence for good science and good practice beget good POPP Post-Offer/Pre-Placement Training, Education, and Medical Consul- policy. PPD Purified protein derivative tation,93 as well as the NTCA.94 PPE Personal protective equipment 1 ACKNOWLEDGMENTS QFT-GIT QuantiFERON -TB-Gold In CONCLUSION Tube ACOEM and NTCA wish to thank the TB Tuberculosis The epidemiology of tuberculosis in section leaders for this document: Randall TNF Tumor necrosis factor the US is changing, and diagnostic tests and Reves, MD (Background with Literature TST Tuberculin Skin Test treatment regimens for TB are evolving. Review), Amy Behrman, MD (Baseline Occupational health providers should (post-offer/pre-placement) Screening and implement policies and protocols based Testing), Jon Warkentin, MD, MPH (Post- on the current science. The 2019 MMWR exposure Screening and Testing), Mark Follow up with HCP who do not accept CDC/NTCA Recommendations represent a Russi, MD, MPH (Serial Screening, Testing treatment initially. philosophy and approach that focuses on and Education for HCP), and Melanie Use a declination form to clearly educating all HCP and on treating HCP Swift, MD, MPH (Education and Treatment document the offer of treatment and identified with LTBI to minimize the pro- of HCP with Positive Test Results). They underscore the educational messages gression to active disease and infectious- also wish to thank the NTCA Board (Appendix 4, http://links.lww.com/ ness. In this companion document, we have members and Paul J. Papanek MD, MPH, JOM/A783). sought to provide practical context for the for their contribution as reviewers to Nine months of daily isoniazid recommendations. Occupational health this document. (9INH) has long been a standard regimen practitioners should bear in mind that the used in the US for the treatment of LTBI. 2019 MMWR CDC/NTCA Recommenda- REFERENCES Clinical studies have indicated it can be tions exist within the regulatory environ- 1. Sosa LE, Njie GJ, Lobato MN, et al. Tubercu- highly effective in preventing progression ment, and that some states or local losis Screening, Testing, and Treatment of US to active TB, but adherence rates are typi- governments may still have annual TB Health Care Personnel: recommendations from cally suboptimal. Six months of daily INH testing requirements for HCP. Over time, the National Tuberculosis Controllers Associa- tion and CDC, 2019. MMWR Morb Mortal Wkly (6INH) is another acceptable regimen, but the regulations will evolve and allow this Rep. 2019;68:439–443. again the high adherence rates required for ACOEM/NTCA Companion Guidance to 2. Centers for Disease Control and Prevention. optimal efficacy have been difficult to be used for occupational health practi- Guidelines for preventing the transmission of achieve. Both long course INH treatment tioners who will implement work-based Mycobacterium tuberculosis in health-care set- regimens are associated with rare compli- programs. tings, 2005. MMWR Morb Mortal Wkly Rep. cations including mild-to-severe hepatocel- In addition to promoting health and 2005;54:1–141. lular toxicity. 3. Sepkowitz KA. Tuberculosis and the health care preventing disease, the new recommenda- worker: a historical perspective. Ann Intern Currently, there are three short- tions should improve the efficiency and Med. 1994;120:71–79. course treatment regimens for LTBI that effectiveness of occupational health practi- 4. Jacobson G, Hoyt DD, Bogen E. Tuberculosis in are recommended over 6INH and 9INH: ces in health care facilities. The require- hospital employees as affected by an admission 12 weeks of once-weekly INH and rifapen- ment for routine, serial, untargeted annual chest x-ray screening program. Dis Chest. tine (3HP), 3 months of daily INH plus testing is no longer justified. This approach 1957;32:27–38. rifampin (3HR), and 4 months of daily has generated tens of millions of negative 5. Tape TG, Mushlin AI. The utility of routine chest radiographs. Ann Intern Med. 1986;104: rifampin alone (4R). Each of these short TB test results and has occupied hundreds 663–670. regimens are now preferred first-line thera- of thousands of hours of occupational 6. Blumberg HM, Watkins DL, Berschling JD, et al. pies, supplanting the long course INH health time, HCP time, and significant fis- Preventing the nosocomial transmission of tuber- options.85–87 The short-course therapies cal resources each year without providing culosis. Ann Intern Med. 1995;122: 658–663.

ß 2020 American College of Occupational and Environmental Medicine e367

7. Maloney SA, Pearson ML, Gordon MT, Del tuberculosis incidence in New York State. Am J interferon-gamma release assay testing. Infect Castillo R, Boyle JF, Jarvis WR. Efficacy of Infect Control. 2005;33:519–526. Control Hosp Epidemiol. 2013;34:625–630. control measures in preventing nosocomial 23. Benoit SR, Gregg EW, Jonnalagadda S, et al. 38. Colson PW, Hirsch-Moverman Y,Bethel J, et al. transmission of multidrug-resistant tuberculosis Association of diabetes and tuberculosis disease Acceptance of treatment for latent tuberculosis to patients and health care workers. Ann Intern among US-bound adult refugees, 2009–2014. infection: prospective cohort study in the United Med. 1995;122:90–95. Emerg Infect Dis. 2017;23:543–545. States and Canada. Int J Tuberc Lung Dis. 8. Fella P, Rivera P, Hale M, Squires K, Sepkowitz 24. Al-Rifai RH, Pearson F, Critchley JA, Abu- 2013;17:473–479. K. Dramatic decrease in tuberculin skin test Raddad LJ. Association between diabetes mel- 39. Gershon AS, McGeer A, Bayoumi AM, Raboud conversion rate among employees at a hospital litus and active tuberculosis: a systematic J, Yang J. Health care workers and the initiation in New York City. Am J Infect Control. review and meta-analysis. PLoS One. of treatment for latent tuberculosis infection. 1995;23:352–356. 2017;12:e0187967. Clin Infect Dis. 2004;39:667–672. 9. Welbel SF, French AL, Bush P, DeGuzman D, 25. QIAGEN. QuantiFERON1-TB Gold Plus 40. Horsburgh Jr CR, Goldberg S, Bethel J, et al. Weinstein RA. Protecting health care workers (QFT1-Plus) Package Insert. Germantown, Latent TB infection treatment acceptance and from tuberculosis: a 10-year experience. Am J MD; 2019. Available at: https://www.quantifer- completion in the United States and Canada. Infect Control. 2009;37:668–673. on.com/us/wp-content/uploads/sites/13/2019/ Chest. 2010;137:401–409. 10. Dobler CC, Farah WH, Alsawas M, et al. Tuber- 07/L1095849-R05-QFT-Plus-ELISA-IFU- 41. Sahni R, Miranda C, Yen-Lieberman B, et al. Does culin skin test conversions and occupational USCA.pdf. Accessed June 15, 2020. theimplementationofaninterferon-gammarelease exposure risk in US Healthcare Workers. Clin 26. Oxford Immunotec, Inc. T-SPOT1.TB Pack- assay in lieu of a tuberculin skin test increase Infect Dis. 2018;66:706–711. age Insert. Marlborough, MA; 2015. Available acceptance of preventive therapy for latent tuber- 11. Lambert LA, Pratt RH, Armstrong LR, Haddad at: http://www.tspot.com/wp-content/uploads/ culosis among healthcare workers? Infect Control MB. Tuberculosis among healthcare workers, 2012/01/PI-TB-US-v5.pdf. Accessed June Hosp Epidemiol. 2009;30:197–199. United States, 1995–2007. Infect Control Hosp 15, 2020. 42. Sandgren A, Vonk Noordegraaf-Schouten M, Epidemiol. 2012;33:1126–1132. 27. Foster-Chang SA, Manning ML, Chandler L. van Kessel F, Stuurman A, Oordt-Speets A, van 12. Mongkolrattanothai T, Lambert LA, Winston Tuberculosis screening of new hospital employ- der Werf MJ. Initiation and completion rates for CA. Tuberculosis among healthcare personnel, ees: compliance, clearance to work time, and latent tuberculosis infection treatment: a sys- United States, 2010–2016. Infect Control Hosp cost using tuberculin skin test and interferon- tematic review. BMC Infect Dis. 2016;16:204. Epidemiol. 2019;40:701–704. gamma release assays. Workplace Health Saf. 43. Centers for Disease Control and Prevention. TB 13. Centers for Disease Control and Prevention 2014;62:460–467. Elimination: Tuberculin Skin Testing. 2011. (CDC). Reported Tuberculosis in the United 28. Pai M, Denkinger CM, Kik SV, et al. Gamma Available at: https://www.cdc.gov/tb/publica- States, 2016. Atlanta, GA: US Department of interferon release assays for detection of Myco- tions/factsheets/testing/skintesting.htm. Health and Human Services, CDC; 2017. bacterium tuberculosis infection. Clin Micro- Accessed May 7, 2019. 14. Lewinsohn DM, Leonard MK, LoBue PA, et al. biol Rev. 2014;27:3–20. 44. Styblo K. Recent advances in epidemiological Official American Thoracic Society/Infectious 29. Centers for Disease Control and Prevention. TST research in tuberculosis. Adv Tuberc Res. Diseases Society of America/Centers for Dis- Training Video. Available at: https://tools.cdc.- 1980;20:1–63. ease Control and Prevention clinical practice gov/podcasts/media/mp4/mantoux.mp4. 45. Branson BM, Handsfield HH, Lampe MA, et al. guidelines: diagnosis of tuberculosis in adults Accessed June 15, 2020. Revised recommendations for HIV testing of and children. Clin Infect Dis. 2017;64:e1–e33. 30. National Center for HIV/AIDS, Viral Hepatitis, adults, adolescents, and pregnant women in 15. Diel R, Goletti D, Ferrara G, et al. Interferon- STD, and TB Prevention Division of Tuberculo- health-care settings. MMWR Recomm Rep. gamma release assays for the diagnosis of latent sis Elimination, Centers for Disease Control and 2006;55(RR–14):1–17. quiz CE11–14. Mycobacterium tuberculosis infection: a sys- Prevention. TB Elimination Targeted Tuberculo- 46. Siu AL, Force USPST. Screening for abnormal tematic review and meta-analysis. Eur Respir J. sis Testing and Interpreting Tuberculin Skin Test blood glucose and type 2 diabetes mellitus: US 2011;37:88–99. Results. Available at: https://www.cdc.gov/tb/ Preventive Services Task Force recommendation 16. Mazurek G, Jereb J, Vernon A, LoBue P, Gold- publications/factsheets/testing/skintestresults_- statement. Ann Intern Med. 2015;163:861–868. revised.pdf. December 2011. berg S, Castro K. Updated guidelines for using 47. Flood J, Barry PM. Mainstreaming latent tuber- interferon gamma release assays to detect 31. Zwerling A, van den Hof S, Scholten J, Cobe- culosis infection testing and treatment in the Mycobacterium tuberculosis infection — lens F, Menzies D, Pai M. Interferon-gamma United States: who and how. JAMA Intern Med. United States, 2010. MMWR Morb Mortal Wkly release assays for tuberculosis screening of 2017;177:1764–1765. Rep. 2010;59(RR05):1–25. healthcare workers: a systematic review. Tho- rax. 2012;67:62–70. 48. Kim YJ, Kang JY, Kim SI, Chang MS, Kim YR, 17. de Perio MA, Tsevat J, Roselle GA, Kralovic Park YJ. Predictors for false-negative Quanti- SM, Eckman MH. Cost-effectiveness of inter- 32. Thanassi W, Noda A, Hernandez B, Friedman FERON-TB Gold assay results in patients with feron gamma release assays vs tuberculin skin L, Dorman S, Yesavage J. Negative tuberculin extrapulmonary tuberculosis. BMC Infect Dis. tests in health care workers. Arch Intern Med. skin test and prediction of reversion of Quanti- 2018;18:457. 2009;169:179–187. FERON interferon gamma release assay in US 49. Eisenberg RL, Romero J, Litmanovich D, Boiselle 18. Linas BP, Wong AY, Freedberg KA, Horsburgh healthcare workers. Infect Control Hosp Epide- miol. 2016;37:478–482. PM, Bankier AA. Tuberculosis: value of lateral Jr CR. Priorities for screening and treatment of chest radiography in pre-employment screening of latent tuberculosis infection in the United 33. Thanassi W, Noda A, Hernandez B, et al. Delin- patients with positive purified protein derivative States. Am J Respir Crit Care Med. eating a retesting zone using receiver operating skin test results. Radiology. 2009;252:882–887. 2011;184:590–601. characteristic analysis on serial QuantiFERON 50. Meyer M, Clarke P, O’Regan AW. Utility of the 19. Wrighton-Smith P, Sneed L, Humphrey F, Tao tuberculosis test results in US healthcare workers. Pulm Med. 2012;2012:291294. lateral chest radiograph in the evaluation of X, Bernacki E. Screening health care workers patients with a positive tuberculin skin test with interferon-gamma release assay versus 34. Fong KS, Tomford JW, Teixeira L, et al. Chal- result. Chest. 2003;124:1824–1827. tuberculin skin test: impact on costs and adher- lenges of interferon-gamma release assay con- ence to testing (the SWITCH study). J Occup versions in serial testing of health-careworkers in 51. Luetkemeyer AF, Firnhaber C, Kendall MA, Environ Med. 2012;54:806–815. a TB control program. Chest. 2012;142:55–62. et al. Evaluation of Xpert MTB/RIF versus AFB smear and culture to identify pulmonary 20. Dorman SE, Belknap R, Graviss EA, et al. 35. Ringshausen FC, Nienhaus A, Torres Costa J, tuberculosis in patients with suspected tubercu- Interferon-gamma release assays and tuberculin et al. Within-subject variability of Mycobacte- losis from low and higher prevalence settings. skin testing for diagnosis of latent tuberculosis rium tuberculosis-specific gamma interferon Clin Infect Dis. 2016;62:1081–1088. infection in healthcare workers in the United responses in German health care workers. Clin States. Am J Respir Crit Care Med. Vaccine Immunol. 2011;18:1176–1182. 52. National TB Controllers Association (NTCA), 2014;189:77–87. Association of Public Health Laboratories 36. Mori T, Sakatani M, Yamagishi F, et al. Specific (APHL). Consensus statement on the use of 21. Dobler C, Farah W, Alsawas M, et al. Tubercu- detection of tuberculosis infection: an inter- Cepheid Xpert MTB/RIF1 assay in making lin skin test conversions and occupational expo- feron-gamma-based assay using new antigens. decisions to discontinue airborne infection iso- sure risk in US healthcare workers. Clin Infect Am J Respir Crit Care Med. 2004;170:59–64. lation in healthcare settings; 2016. Available at: Dis. 2018;66:706–711. 37. Daley CL, Reves RR, Beard MA, et al. A http://www.tbcontrollers.org/docs/resources/ 22. Driver CR, Stricof RL, Granville K, et al. Tuber- summary of meeting proceedings on addressing NTCA_APHL_GeneXpert_Consensus_State- culosis in health care workers during declining variability around the cut point in serial ment_Final.pdf. Accessed December 18, 2019.

e368 ß 2020 American College of Occupational and Environmental Medicine

53. Talwar A, Tsang CA, Price SF, et al. Tubercu- workers: conversions or unexplained variabil- ready? Infect Control Hosp Epidemiol. 2009; losis - United States, 2018. MMWR Morb Mor- ity? PLoS One. 2013;8:e54748. 30:80–82. tal Wkly Rep. 2019;68:257–262. 68. Apriani L, McAllister S, Sharples K, et al. 82. Nania JJ, Skinner J, Wilkerson K, et al. Expo- 54. National Tuberculosis Controllers Association, Latent tuberculosis infection in health care sure to pulmonary tuberculosis in a neonatal Centers for Disease Control and Prevention. workers in low and middle-income countries: intensive care unit: unique aspects of contact Guidelines for the investigation of contacts of an updated systematic review. Eur Respir J. investigation and management of hospitalized persons with infectious tuberculosis. Recom- 2019;53:1801789. neonates. Infect Control Hosp Epidemiol. mendations from the National Tuberculosis 69. Joshi R, Reingold AL, Menzies D, Pai M. 2007;28:661–665. Controllers Association and CDC. MMWR Tuberculosis among health-care workers in 83. Ohno H, Ikegami Y, Kishida K, et al. A contact Recomm Rep. 2005;54(RR–15):1–47. low- and middle-income countries: a systematic investigation of the transmission of Mycobac- 55. California Department of Public Health. California review. PLoS Med. 2006;3:e494. terium tuberculosis from a nurse working in a Adult Tuberculosis Risk Assessment and User 70. Murphy ME, Wilmore S, Satta G, et al. newborn nursery and maternity ward. J Infect Guide September; 2018. Available at: https:// Occupational tuberculosis despite minimal nos- Chemother. 2008;14:66–71. www.cdph.ca.gov/Programs/CID/DCDC/CDPH ocomial contact in a health care worker under- 84. Schepisi MS, Sotgiu G, Contini S, Puro V, %20Document%20Library/TBCB-CA-TB-Risk- going treatment with a tumor necrosis factor Ippolito G, Girardi E. Tuberculosis transmis- Assessment-and-Fact-Sheet.pdf. Accessed June inhibitor. Ann Am Thorac Soc. 2016;13:2275– sion from healthcare workers to patients and co- 15, 2020. 2277. workers: a systematic literature review and 56. Lobato MN, Hopewell PC. Mycobacterium meta-analysis. PLoS One. 2015;10:e0121639. tuberculosis infection after travel to or contact 71. Centers for Disease Control and Prevention with visitors from countries with a high preva- (CDC). Tuberculosis (TB): Data and Statistics; 85. McClintock AH, Eastment M, McKinney CM, lence of tuberculosis. Am J Respir Crit Care 2019. Available at: https://www.cdc.gov/tb/ et al. Treatment completion for latent tubercu- Med. 1998;158:1871–1875. statistics/default.htm. Accessed December 18, losis infection: a retrospective cohort study 2019. comparing 9 months of isoniazid, 4 months 57. Barcellini L, Borroni E, Brown J, et al. First 72. Shea KM, Kammerer JS, Winston CA, Navin of rifampin and 3 months of isoniazid and evaluation of QuantiFERON-TB Gold Plus per- rifapentine. BMC Infect Dis. 2017;17:146. formance in contact screening. Eur Respir J. TR, Horsburgh Jr CR. Estimated rate of reac- 2016;48:1411–1419. tivation of latent tuberculosis infection in 86. Menzies D, Adjobimey M, Ruslami R, et al. the United States, overall and by population Four months of rifampin or nine months of 58. Diel R, Loddenkemper R, Niemann S, Mey- subgroup. Am J Epidemiol. 2014;179:216– isoniazid for latent tuberculosis in adults. N wald-Walter K, Nienhaus A. Negative and pos- 225. Engl J Med. 2018;379:440–453. itive predictive value of a whole-blood interferon-gamma release assay for developing 73. Muckenfuss M. Health Warning: Loma Linda 87. Sterling TR, Njie G, Zenner D, et al. Guidelines active tuberculosis: an update. Am J Respir Crit VA Employee Treated for TB. Riverside, Calif: for the treatment of latent tuberculosis infection: Care Med. 2011;183:88–95. The Press-Enterprise; 2015. recommendations from the National Tuberculo- 74. Tuberculosis Controllers Association. NTCA Pro- sis Controllers Association and CDC, 2020. 59. Sester M, Sotgiu G, Lange C, et al. Interferon- MMWR Recomm Rep. 2020;69:1–11. gamma release assays for the diagnosis of active vider Guidance: Using the Isoniazid/Rifapentine tuberculosis: a systematic review and meta- Regimen to Treat Latent Tuberculosis Infection 88. Arguello Perez E, Seo S, Schneider W, Eisen- analysis. Eur Respir J. 2011;37:100–111. (LTBI). November 2019 (Revised April 2019). stein C, Brown A. Management of latent tuber- Available at: http://www.tbcontrollers.org/docs/ culosis infection among healthcare workers: 10- 60. Mullie GA, Schwartzman K, Zwerling A, N’Diaye resources/3hp/NTCA_Provider_Guidance_3HP_ year experience at a single center. Clin Infect DS. Revisiting annual screening for latent tuber- 11918.pdf. Accessed June 5, 2019. Dis. 2017;65:2105–2111. culosis infection in healthcare workers: a cost- effectiveness analysis. BMC Med. 2017;15:104. 75. Getahun H, Matteelli A, Abubakar I, et al. 89. Stagg HR, Zenner D, Harris RJ, Munoz L, Management of latent Mycobacterium tubercu- Lipman MC, Abubakar I. Treatment of latent 61. Malasky C, Jordan T, Potulski F, Reichman L. losis infection: WHO guidelines for low tuber- tuberculosis infection: a network meta-analysis. Occupational tuberculous infections among culosis burden countries. Eur Respir J. Ann Intern Med. 2014;161:419–428. pulmonary physicians in training. Am Rev 2015;46:1563–1576. Respir Dis. 1990;142:505–507. 90. Sterling TR, Villarino ME, Borisov AS, et al. 62. Association of Public Health Laboratories 76. Lee H, Koo GW, Min JH, et al. Factors associ- Three months of rifapentine and isoniazid for (APHL). Mycobacterium Tuberculosis: Assess- ated with non-initiation of latent tuberculosis latent tuberculosis infection. N Engl J Med. ing Your Laboratory. Silver Spring, MD; 2019. treatment among healthcare workers with a 2011;365:2155–2166. Available at: https://www.aphl.org/abou- positive interferon-gamma releasing assay. Sci 91. Swindells S, Ramchandani R, Gupta A, et al. tAPHL/publications/Documents/ID-2019Apr- Rep. 2019;9:61. One Month of Rifapentine plus Isoniazid to TB-Toolkit.pdf. Accessed February 28, 2020. 77. Lal A, Al Hammadi A, Rapose A. Latent tuber- prevent HIV-related tuberculosis. N Engl J 63. Miller JM, Astles R, Baszler T, et al. Guidelines for culosis infection: treatment initiation and com- Med. 2019;380:1001–1011. safe work practices in human and animal medical pletion rates in persons seeking immigration 92. Centers for Disease Control and Prevention. diagnostic laboratories. Recommendations of a and health care workers. Am J Med. Deciding When to Treat Latent TB Infection.; CDC-convened, Biosafety Blue Ribbon Panel. 2019;132:1353–1355. 2018. Available at: https://www.cdc.gov/tb/ MMWR Suppl. 2012;61:1–102. 78. Shukla SJ, Warren DK, Woeltje KF, Gruber CA, topic/treatment/decideltbi.htm. Accessed June 64. de Vries G, van Hunen R, Meerstadt-Rombach Fraser VJ. Factors associated with the treatment 15, 2020. FS, et al. Analysing tuberculosis cases among of latent tuberculosis infection among health- 93. Centers for Disease Control and Prevention. TB healthcare workers to inform infection control care workers at a midwestern teaching hospital. Centers of Excellence for Training, Education, and policy and practices. Infect Control Hosp Epi- Chest. 2002;122:1609–1614. Medical Consultation.; 2018. Available at: https:// demiol. 2017;38:976–982. 79. Swift MD, Molella RG, Vaughn AIS, et al. www.cdc.gov/tb/education/tb_coe/default.htm. 65. Holden KL, Bradley CW, Curran ET, et al. Determinants of latent tuberculosis treatment Accessed June 15, 2020. Unmasking leading to a healthcare worker acceptance and completion in healthcare per- 94. National Tuberculosis Controllers Association. Mycobacterium tuberculosis transmission. J sonnel. Clin Infect Dis. 2019;ciz817. https:// State, Big City, and Territory TB Program Hosp Infect. 2018;100:e226–e232. doi.org/10.1093/cid/ciz817. Contacts. Available at: http://www.tbcontroller- 66. Seidler A, Nienhaus A, Diel R. Review of 80. Ahn JG, Kim DS, Kim KH. Nosocomial expo- s.org/community/statecityterritory/#.Xadvbeh- epidemiological studies on the occupational sure to active pulmonary tuberculosis in a neo- KiM9. Accessed October 16, 2019. risk of tuberculosis in low-incidence areas. natal intensive care unit. Am J Infect Control. 95. Gluaser W, Petch J, Pendharkar S. Are disposable Respiration. 2005;72:431–446. 2015;43:1292–1295. hospital supplies trashing the environment? In: 67. Zwerling A, Benedetti A, Cojocariu M, et al. 81. Fraser TG, Kowalczyk J, Schmitt S, et al. Active Healthy Debate; 2016. Available at: https://health- Repeat IGRA testing in Canadian health tuberculosis in a healthcare worker: are you ydebate.ca/2016/08/topic/hospital-medical-waste.

ß 2020 American College of Occupational and Environmental Medicine e369