Professional Documents
Culture Documents
Clinical Practice
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence
supporting various strategies is then presented, followed by a review of formal guidelines, when they exist.
The article ends with the authors’ clinical recommendations.
A 36-year-old man comes to establish care with a primary care clinician. He has no From the Johns Hopkins University
chronic medical conditions and takes no medications. He was born and lived in School of Medicine and the Baltimore
City Health Department — both in Balti-
India until 1 year ago, when he came to the United States. He reports never having more (M.S.); and the Medical University
had tuberculosis or tuberculosis testing, although when the patient was a child, of South Carolina, Charleston, and the
his father was treated for tuberculosis disease. The patient received bacille South Carolina Department of Health
and Environmental Control, Columbia
Calmette–Guérin vaccine as an infant. He reports no cough, fever, night sweats, or (S.E.D.). Dr. Dorman can be contacted at
weight loss. Should testing for Mycobacterium tuberculosis infection be performed dorman@musc.edu or at the Medical
and, if so, how? If testing shows evidence of M. tuberculosis infection, how should University of South Carolina, 135 Rutledge
Ave., Rm. 1207, Charleston, SC 29425.
this patient be treated?
N Engl J Med 2021;385:2271-80.
DOI: 10.1056/NEJMcp2108501
The Cl inic a l Probl em Copyright © 2021 Massachusetts Medical Society.
O
ne fourth of the world’s population is infected with Mycobac- CME
at NEJM.org
terium tuberculosis, the causative agent of tuberculosis.1 From a clinical-
management perspective, two states of M. tuberculosis infection are recog-
nized — latent tuberculosis infection (LTBI) and active tuberculosis disease — although
infection and immunologic control exist across a spectrum. LTBI is a state of
persistent immune response to stimulation by M. tuberculosis antigens without
evidence of clinically manifested active tuberculosis and with bacillary replica-
tion absent or below some undefined threshold as a result of immunologic
An audio version
control. Most persons with LTBI never become sick with tuberculosis; however,
of this article
approximately 5 to 15% have progression to tuberculosis disease.2-5 Tuberculosis is available at
disease results from bacterial replication and includes tissue damage and in- NEJM.org
flammation, which lead to clinical manifestations. Common signs and symp-
toms include fever, sweats, fatigue, and weight loss, as well as cough if the lungs
are affected. Tuberculosis disease can involve any tissue and organ system, with
diverse manifestations.
Prevention of progression from LTBI to tuberculosis disease is an important
individual and public health goal because persons with LTBI are a reservoir for
incident tuberculosis disease. Two principles form the basis for guidance about
whom to test for LTBI and whom to treat for LTBI. First, infection with M. tuber-
culosis requires previous exposure to someone with tuberculosis disease, and there-
fore asking about known exposure and epidemiologic risk factors for exposure is
important. Second, for a person infected with M. tuberculosis, the risk of progres-
sion to tuberculosis disease is determined by their immune competence and the
time since initial infection; therefore, eliciting biologic risk factors for progression
is important.
Screening (through interview, questionnaire, and medical history review) to assess for
risk factors for infection with M. tuberculosis and risk factors for progression
to active tuberculosis if infection with M. tuberculosis is present
Perform additional tests to evaluate No evidence of active Assess potential benefits vs. potential risks of
for active tuberculosis disease tuberculosis disease LTBI treatment
Biologic risk factors for progression from
Microbiologic or LTBI to active tuberculosis disease
clinical diagnosis of active Drug–drug interaction
tuberculosis disease Risk of hepatotoxic effects
Pregnancy testing
Figure 1. Algorithm for Deciding Whom to Test and Whom to Treat for Latent Tuberculosis Infection (LTBI).
This algorithm is intended for use in asymptomatic persons and is not intended for use in the evaluation of persons who present for
medical care with signs or symptoms of active tuberculosis disease. High-priority risk factors are household or other close contact with
someone with infectious active tuberculosis disease; birth, residence, or prolonged travel (>1 mo) in a setting in which tuberculosis dis-
ease is common; other circumstances based on local epidemiology (e.g., corrections facilities and homeless shelters); and immunosup-
pression. Biologic risk factors for progression of LTBI to active tuberculosis disease are immunosuppression; diabetes mellitus; chronic
kidney disease; leukemia or lymphoma; cancer of the head or neck; chronic malabsorption, gastrectomy, or intestinal bypass; a body-
mass index (the weight in kilograms divided by the square of the height in meters) of 20 or less; silicosis; current or former smoking sta-
tus; or an age of 5 years or younger.
Table 1. Risk-Based Approach for Latent Tuberculosis Infection (LTBI) Testing and Treatment.*
* This table is based on recommendations from the National Society of Tuberculosis Clinicians.6 HIV denotes human immunodeficiency virus,
and TNF-α tumor necrosis factor α.
† Tuberculin skin test (TST) results are interpreted at the listed positivity thresholds on the basis of epidemiologic or host risk and to improve
test positive and negative predictive values. Interferon-γ release assays currently have absolute thresholds for positivity without incorpora-
tion of host or epidemiologic risk.
‡ The TST positivity threshold is 5 mm or more.
§ The TST positivity threshold is 10 mm or more.
¶ Children 5 years of age or younger are at high risk for rapid progression to active tuberculosis disease after infection, and severe forms of
tuberculosis (including disseminated and central nervous system tuberculosis) are more likely to develop in such children than in older
children or in adults.
specific than tuberculin skin testing for the de- The T-SPOT.TB and QuantiFERON-TB Gold Plus
tection of M. tuberculosis infection. Vaccination IGRAs have sensitivities of approximately 90%,
against bacille Calmette–Guérin (BCG) can cause whereas that of tuberculin skin tests is approxi-
a positive tuberculin skin test owing to shared mately 80%.13,14,16 Host immunocompromise, in-
antigenic components with purified protein de- cluding that arising from tuberculosis disease
rivative, although the effect on the tuberculin itself, can be associated with false negative skin
skin test of BCG received in infancy is minimal, tests and IGRAs.17,18 For IGRAs and tuberculin skin
especially 10 years or more after vaccination.12 testing, there are positive associations between
IGRA results are unaffected by previous BCG the risk of progression to tuberculosis disease
vaccination, because stimulatory antigens that and test quantitative results, but this popula-
are used in these assays are absent from BCG tion-level observation is not readily translatable
vaccines. In settings of low tuberculosis preva- to the individual patient because immunocom-
lence, the specificity of IGRAs is more than promise can cause low quantitative results in a
95%; the specificity of tuberculin skin tests is person at high risk for tuberculosis disease.19,20
also more than 95% in populations without BCG
vaccination but is lower in populations in which Evaluation of Persons with Positive Test Results
BCG vaccines are administered.13,14 Nevertheless, A diagnosis of LTBI requires the ruling out of
IGRAs can yield false positive results, particu- tuberculosis disease by assessment for signs and
larly when used in low-risk populations.15 symptoms of tuberculosis disease plus chest ra-
Estimated sensitivities of tuberculin skin tests diography. Findings suggestive of tuberculosis
and IGRAs have relied on the assessment of per- disease should trigger individualized evaluation
formance in patients with tuberculosis disease that usually includes obtaining sputum speci-
as a reference standard and have varied widely. mens for mycobacterial culture and performing
smear microscopy and nucleic acid amplification regimen had similar efficacy to the 9-month
testing and that may include further imaging, regimen (0.10 and 0.11 cases of active tubercu-
bronchoscopy, and biopsy of affected tissues. losis disease per 100 person-years, respectively)
and was associated with a higher completion
Antimicrobial Treatment for LTBI rate (78.8% and 63.2%, respectively; P<0.001),
Identification of Appropriate Candidates for Treatment fewer overall adverse events, and fewer hepa-
Randomized, controlled trials have shown that totoxic effects (0.3% and 1.8%, respectively;
antimicrobial treatment of LTBI is effective in P<0.001).31 Retrospective observational studies
preventing progression to tuberculosis disease involving patients at public health clinics in
overall and in children and persons living with North America had similar findings.32-34 A regi-
HIV and reducing mortality among adults with men of 3 months of once-daily isoniazid plus
HIV infection.21-25 Decisions about whether to rifampin has been shown to have an efficacy
recommend LTBI treatment are based on risks of and safety that are similar to those of daily iso-
adverse effects from treatment (discussed below) niazid administered for 6 to 12 months.35
weighed against the risk of development of tu- Rifampin and rifapentine-containing LTBI
berculosis disease. Persons with LTBI who are treatment regimens are less commonly associ-
at increased risk for progression to tuberculosis ated with hepatotoxic effects than is isonia-
disease (Table 1) generally should be offered zid.26,31,34,36 However, rifampin and rifapentine
LTBI treatment to prevent illness and death asso- induce cytochrome P450 enzymes and transport-
ciated with tuberculosis disease.6 All persons with ers, causing reductions in the plasma concentra-
LTBI should undergo testing for HIV infection. tions of certain drugs (Table 2). Rifamycins can
cause neutropenia or thrombocytopenia as well
Rifamycin-Containing Regimens (Preferred) as a flulike systemic drug reaction that rarely
Rifamycin-based treatments are now the pre- includes hypotension and syncope41 (Table 2).
ferred approach for LTBI treatment because they
have similar or better efficacy and higher com- Isoniazid Monotherapy (Alternative)
pletion rates than isoniazid monotherapy. The Isoniazid monotherapy has long been used for
randomized, controlled PREVENT TB trial com- LTBI treatment. However, given its longer treat-
pared 3 months of once-weekly rifapentine plus ment duration, lower completion rates, and high-
isoniazid, administered by directly observed ther- er rates of hepatotoxic effects as compared with
apy, with 9 months of participant-administered rifamycin-based regimens, isoniazid monother-
daily isoniazid in 7731 persons at high risk for apy is no longer considered in U.S. guidelines to
tuberculosis disease. In the trial, a 3-month course be a preferred LTBI treatment.6 Isoniazid de-
of rifapentine and isoniazid was noninferior to creases the risk of tuberculosis disease among
a 9-month course of isoniazid with respect to persons with a positive tuberculin skin test, in-
the cumulative rate of tuberculosis disease (0.19% cluding adults and children without HIV infec-
vs. 0.43%) and was associated with a higher rate tion and adults with HIV infection.21-23 A pre–
of treatment completion (82.1% vs. 69.0%, HIV era trial that involved approximately 28,000
P<0.001) and a lower rate of drug-related hepa- persons at high risk for progression to tuber-
totoxic effects (0.4% vs. 2.7%, P<0.001).26 Effi- culosis disease showed that treatment with 12
cacy similar to that of longer isoniazid regi- months or 6 months of isoniazid was more ef-
mens, a high completion rate, and a good safety fective than treatment for 3 months (75%, 65%,
profile were confirmed in studies involving chil- and 21% lower incidence of tuberculosis disease,
dren 2 years of age or older and in studies in- respectively, than with placebo), thereby estab-
volving adults with HIV infection.27-29 A phase 4 lishing 6 to 12 months as the target duration.39,40
randomized trial showed a similarly high rate of The effectiveness of isoniazid monotherapy is
completion of a participant-administered 3-month diminished by completion rates of 50% or less
course of rifapentine and isoniazid in the United in clinical practice.42 Isoniazid can cause clini-
States and elsewhere.30 cally significant hepatotoxic effects, which oc-
A multinational, randomized, controlled trial curred in 2 to 3% of persons receiving isoniazid
that involved more than 6000 adults compared LTBI treatment in clinical trials26,31,36 (Table 2).
4 months of once-daily rifampin with 9 months In a retrospective cohort of all persons starting
of isoniazid for LTBI treatment.31 The 4-month isoniazid LTBI treatment in Quebec, Canada,
Phlebotomy Phlebotomy
Intradermal inoculation
of PPD into volar
aspect of forearm
Whole blood
Whole blood
PBMCs Add blood to
tubes precoated
Centrifugation with nil control, M.
tuberculosis antigens
(tubes TB1 and
Wait 48–72 hr. TB2), and mitogen
Nil TB1 TB2 Mitogen positive control.
Plate 250,000 cells into
each of four wells per Incubate 16–24 hr. Add aliquot
patient. of stimulated plasma to wells
of ELISA plate that contains
interferon-γ antibodies.
Add nil control, M.
tuberculosis antigens
(×2), and mitogen
positive control.
Incubate for 16–20 hr.
0 1 2 3 4 5 6 7
Interferon-γ antibodies
Tuberculin Skin Test Ruler capture interferon-γ as it A secondary enzyme-
is released from cells. A linked antibody is added
secondary enzyme-labeled and binds to interferon-γ.
Measure and record antibody is added and binds A detection reagent is
diameter of induration. to captured interferon-γ. A added, and absorbance at
detection reagent is added, resulting in spots that 450 nm is measured. Con-
are a footprint of the location where the inter- centration of interferon-γ
feron-γ was released by a cell. Spots are counted. is calculated on the basis
of a standard curve.
Two patient encounters required to One patient encounter sufficient to obtain result
obtain result
Interpretation subjective; positivity Interpretation less subjective to not Interpretation not subjective; positivity
thresholds are risk-stratified subjective; positivity thresholds fixed thresholds fixed
Cross-reacts with BCG (PPD consists Does not cross-react with BCG on the basis of
of many components) selection of stimulation antigens
A previous tuberculin skin test can boost A previous IGRA does not boost a subsequent
a subsequent such test or IGRA tuberculin skin test or IGRA
Table 2. Dose, Frequency, and Prescribing Information for Recommended Regimens for Treatment of LTBI.*
guidelines, and its efficacy and safety have not performed to evaluate for tuberculosis disease,
been established beyond the studied population and he should undergo testing for HIV infection.
of adults and adolescents living with HIV mostly Clinical assessment should elucidate coexisting
in settings with a high incidence of tuberculo- conditions that increase the risk of progression
sis.46 The roles of new drugs for LTBI treatment from LTBI to tuberculosis disease, if this infor-
(ClinicalTrials.gov number, NCT03568383) and of mation has not already been gathered. We would
vaccines for preventing infection and progression assess AST and ALT levels and perform a com-
(NCT04453293 and NCT03512249) are being in- plete blood count before initiating therapy, al-
vestigated.47,48 Inclusion of children and pregnant though these studies are not strictly recommend-
persons in LTBI treatment trials is essential for ed in current guidelines for persons without
informing safety and efficacy in these populations coexisting conditions or risk factors for hepato-
and accelerating their access to new regimens.49 toxic effects. If there is no evidence of tubercu-
losis disease and aminotransferase levels are nor-
mal, then LTBI treatment should be initiated with
Guidel ine s
one of the preferred rifamycin-based regimens,
Guidelines for the evaluation and management given their similar or greater efficacy and higher
of LTBI have been issued by the WHO and re- completion rates as compared with isoniazid
gional entities.45 Recommendations differ some- monotherapy. Our practice would be to recom-
what across guidelines, reflecting regional dif- mend 3 months of once-weekly rifapentine plus
ferences in tuberculosis epidemiology and health isoniazid; an alternative would be 4 months of
systems. Recommendations in this article are daily rifampin. Monthly clinical follow-up is war-
concordant with Centers for Disease Control and ranted to assess for medication adverse effects
Prevention guidelines.6,10,37,38 and adherence and for any signs or symptoms
that could indicate progression to tuberculosis
disease. If pretreatment aminotransferase results
C onclusions a nd
R ec om mendat ions were normal for a person taking a rifamycin-
containing preferred regimen, our practice would
The asymptomatic patient in the vignette has be to check aminotransferase levels and perform
epidemiologic risk factors for M. tuberculosis in- a complete blood count after 1 month of treat-
fection, and testing for M. tuberculosis infection is ment and, if findings were normal, thereafter
indicated. Use of an IGRA is preferred over tu- monitor clinically without laboratory testing un-
berculin skin testing and has specificity advan- less there were new symptoms of an adverse
tages in this person who received a BCG vaccine. drug reaction.
If testing indicates M. tuberculosis infection, chest Disclosure forms provided by the authors are available with
radiography and clinical assessment should be the full text of this article at NEJM.org.
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