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Simple Estimates for Local Prevalence of Latent Tuberculosis Infection, United States, 2011-2015.

Approximately 25% of the world's population is latently infected with Mycobacterium tuberculosis. Latent tuberculosis infection (LTBI) is an asymptomatic equilibrium between the immune response of the host and the infectious process. Although not infectious, LTBI can be activated years later as infectious tuberculosis (TB), which is why diagnosing and treating LTBI in high-risk populations is a key component of the World Health Organization End TB Strategy (1-4).

Most countries have established systems for surveillance of active TB. Public health interventions to control TB include timely detection and treatment of active cases and prompt investigations of persons with recent contact with someone who has infectious TB. However, few jurisdictions have estimates of local LTBI prevalence. Having such estimates could help direct TB prevention efforts for persons with the highest risk for infection, highest risk for progression to TB, and greatest benefit from treatment to prevent progression (2-4). We describe a simple method that uses genotyping results from active TB cases to derive a population estimate of untreated LTBI prevalence for any jurisdiction.

The Study

The US National TB Surveillance System contains 48,955 verified TB cases for 2011-2015. In the subset of 37,723 (77.1%) cases that were confirmed by culture, 36,104 (95.7%) had an M. tuberculosis isolate genotyped by the National TB Genotyping Service by using spacer oligonucleotide typing and 24-locus mycobacterial interspersed repetitive unit-variable number tandem repeat methods. The 50 US states and the District of Columbia are divided into 3,143 local jurisdictions (typically called counties). We used the US Census 2010 population denominator, annual TB incidence averaged during 2008-2015, and 2 assumptions for each county to derive an estimated prevalence of LTBI among residents.

For the 1,360 counties with no genotyped TB cases, which corresponded to 8% of the US population, we estimated local LTBI prevalence as <1%. For other counties, we assumed that all genotyped TB cases not attributed to recent M. tuberculosis transmission arose from preexisting LTBI (i.e., were reactivation TB). We used the previously field-validated plausible source-case method (5-7) to attribute cases to recent transmission (i.e., plausible source case within 10 miles within previous 2 years having infectious TB and a matching genotype result) for the District of Columbia and 49 US states. All cases diagnosed in non-US-born persons within 100 days of entry into the United States were excluded because the presumption was that these persons did not represent infection acquired in the United States. Because some cases in Oklahoma were missing geographic identifiers for identifying the 10-mile radius, a modification for these cases in this analysis was that the plausible source case could have occurred anywhere in the same county. Our second assumption was that the same recent transmission versus reactivation TB proportions for genotyped cases would apply to nongenotyped TB cases in each county (8).

Based on the estimate of Shea et al. (8) of [approximately equal to] 0.084 cases of reactivation TB/100 person-years among US residents with LTBI, we applied a uniform population-level 0.10% annual risk for progression to active disease to derive an estimated number of county residents with LTBI. As sensitivity analyses, we examined how LTBI prevalence estimates would decrease with a higher 0.14% uniform annual risk and how estimates would increase with a lower 0.06% uniform annual risk. We present estimates as uncertainty limits and provide the formula and examples of this method (Table 1).

We estimated that 3.1% (uncertainty limits 2.2%-5.2% based on higher or lower risk progression assumptions) of the US population, corresponding to 8.9 (6.3-14.8) million persons, were latently infected with M. tuberculosis during 2011-2015. County-level estimates varied widely: estimated LTBI prevalence of <1% in 1,981 counties, 1% -<3% in 785 counties, and [greater than or equal to] 3% in 377 counties (Figure). As defined by the US Census Bureau Small Area Income and Poverty Estimates, poverty in >20% of the population was a characteristic of 146 (72%) of the 202 rural counties and 62 (35%) of the 175 metropolitan counties that had an estimated LTBI prevalence >3% (Table 2).

Conclusions

Preventing TB is a growing focus of TB control strategies in the United States and internationally. As governments, public health departments, and private sector partners intensify TB prevention activities, having a tool to understand local variations in LTBI prevalence could help prioritize resources (2-4).

We used routinely collected TB surveillance and genotyping data to derive untreated LTBI prevalence estimates for all US counties. This method was designed to be simple (Table 1). By excluding the contribution of any TB cases attributed to recent transmission, our estimates disregard the comparatively smaller number of recent infections and instead draw attention to more longstanding LTBI prevalence. Because time since initial M. tuberculosis infection was unknown, a uniform population-level 0.10% annual risk for progression to active disease was assumed. Changing that uniform risk to 0.14% would have decreased the number of counties with an estimated LTBI prevalence [greater than or equal to] 3% to 113 counties. A change to 0.06% would have increased the number of counties with an estimated LTBI prevalence [greater than or equal to] 3% to 516 counties.

A more sophisticated approach to estimate local longstanding LTBI prevalence might consider individual characteristics and differentiate risk for progression based on HIV status, age group, and possibly geographic region, place of birth, and recent migration (8). For example, a person receiving a TB diagnosis soon after arrival in a county would increase the LTBI prevalence estimates for that county, even if the TB was caused by an infection that had been acquired in another jurisdiction. Conversely, our overall estimate that 2.2%-5.2% of the US population is infected is similar to estimates from the 2011-2012 National Health and Nutrition Examination Survey (9).

For the United States, the last published nationwide county-level estimates of LTBI prevalence are based on 1958-1965 data, when 275,558 men 17-21 years of age who had lived their entire lives in 1 county were examined as they entered the US Navy (10). Men from poor counties in the southwestern United States and the Appalachian Mountains were more likely to have positive tuberculin skin test results (10). Compared with estimates from 5 decades ago, our estimates show a more diffuse pattern of higher LTBI prevalence counties (Figure). However, poverty remains a frequent characteristic of counties that we estimated as having a higher LTBI prevalence.

This method has limitations. We applied the proportion of genotyped TB cases in the county estimated to arise from preexisting LTBI to all nongenotyped TB cases in that county, which could overestimate the prevalence of LTBI in counties with many pediatric TB cases, which tend to be more difficult to confirm by culture techniques (i.e., cannot be genotyped), yet are sentinel events for recent transmission. Conversely, the genotyping methods used during 2011-2015 might have overestimated recent TB infections (i.e., underestimated LTBI prevalence) in certain localities with longstanding genotyping clusters; this limitation should decrease as the National TB Genotyping Service transitions to universal whole-genome sequencing in 2018.

This method also has several advantages. It could be applied in jurisdictions without TB genotyping services, given an assumption or range of assumptions about the proportion of active TB cases arising from LTBI in the jurisdiction. Rather than relying on costly and imperfect LTBI screening methods, its starting point is verified cases of TB that are already routinely reported to established TB surveillance systems. If deemed applicable, an adjustment for underreported TB cases could be made. In addition, these cases represent infected persons who have the greatest risk for progression to active TB and are the populations most likely to benefit from interventions to prevent TB in the future.

Acknowledgments

We thank the clinicians, laboratory personnel, and public health staff who reported cases and contributed data to the US National TB Surveillance System and L. Allen, A.M. France, A. Langer, S. Marks, R. Miramontes, K. Schmit, B. Silk, and J. Wortham for providing helpful discussions about the analysis. N.R.G. is supported by the National Institute of Allergy and Infectious Disease, National Institutes of Health (grant 1K24AI114444). K.G.C. is supported by an existing US Agency for International Development Intergovernmental Personnel Act agreement with Emory University.

Ms. Haddad is an epidemiologist at the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, and a doctoral candidate at Emory University, Atlanta, GA. Her research interests include the history and social determinants of tuberculosis in North America.

References

(1.) Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med. 2016;13:e1002152. http://dx.doi.org/10.1371/ journal.pmed.1002152

(2.) World Health Organization. Latent TB infection: updated and consolidated guidelines for programmatic management. Geneva: The Organization; 2018.

(3.) Bibbins-Domingo K, Grossman DC, Curry SJ, Bauman L, Davidson KW, Epling JW Jr, et al.; US Preventive Services Task Force. Screening for latent tuberculosis infection in adults: US Preventive Services Task Force recommendation statement. JAMA. 2016;316:962-9. http://dx.doi.org/10.1001/jama.2016.11046

(4.) Taylor Z, Nolan CM, Blumberg HM; American Thoracic Society; Centers for Disease Control and Prevention; Infectious Diseases Society of America. Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2005;54:1-81.

(5.) France AM, Grant J, Kammerer JS, Navin TR. A field-validated approach using surveillance and genotyping data to estimate tuberculosis attributable to recent transmission in the United States. Am J Epidemiol. 2015;182:799-807. http://dx.doi.org/ 10.1093/aje/kwv121

(6.) Yuen CM, Kammerer JS, Marks K, Navin TR, France AM. Recent transmission of tuberculosis--United States, 2011-2014. PLoS One. 2016;11:e0153728. http://dx.doi.org/10.1371/ journal.pone.0153728

(7.) Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2016. Atlanta: The Centers; 2017.

(8.) Shea KM, Kammerer JS, Winston CA, Navin TR, Horsburgh CR Jr. Estimated rate of reactivation of latent tuberculosis infection in the United States, overall and by population subgroup. Am J Epidemiol. 2014;179:216-25. http://dx.doi.org/10.1093/aje/kwt246

(9.) Miramontes R, Hill AN, Yelk Woodruff RS, Lambert LA, Navin TR, Castro KG, et al. Tuberculosis infection in the United States: prevalence estimates from the National Health and Nutrition Examination Survey, 2011-2012. PLoS One. 2015;10:e0140881. http://dx.doi.org/10.1371/journal.pone.0140881

(10.) Edwards LB, Acquaviva FA, Livesay VT, Cross FW, Palmer CE. An atlas of sensitivity to tuberculin, PPD-B, and histoplasmin in the United States. Am Rev Respir Dis. 1969;99(Suppl):1-132.

Address for correspondence: Maryam B. Haddad, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Mailstop US12-4, Atlanta, GA 30329-4027, USA; email: mhaddad@cdc.gov

Author affiliations: Centers for Disease Control and Prevention, Atlanta, Georgia, USA (M.B. Haddad, K.M. Raz, A.N. Hill, J.S. Kammerer, C.A. Winston, T.R. Navin); Emory University, Atlanta (M.B. Haddad, T.L. Lash, A.N. Hill, C.A. Winston, K.G. Castro, N.R. Gandhi)

DOI: https://doi.org/10.3201/eid2410.180716

Caption: Figure. Estimated prevalence of latent tuberculosis infection, by county, United States, as derived from genotyped cases of tuberculosis reported to the US National Tuberculosis Surveillance System, 2011-2015. County equivalents (i.e., Alaska boroughs, District of Columbia, Louisiana parishes, and Virginia independent cities) are also shown. A modified method for analyzing data for Oklahoma is found in the text. Prevalence estimates for Alaska are aggregated by region.
Table 1. Formula and examples of method for estimating prevalence
of latent TB infection, United States, 2011-2015 *

Variable                 a                 b                 c

Jurisdiction        Population      Average annual     Proportion of
                                     no. active TB       TB cases
                                                        attributed
                                                         to recent
                                                       transmission

Example X            Any size           0 cases             NA
Example Y             150,000              1                 0
Example Z            2,000,000            50                0.2

Variable                 d                 e                 f

Jurisdiction        Annual no.       Estimated no.       Estimated
                       cases           infected        prevalence of
                   attributed to     residents if      infection if
                  reactivation TB    0.10% annual      0.10% annual
                                       risk for          risk for
                                      progression     progression, %

Example X                0                NA                <1
Example Y                1               1,000              0.7
Example Z               40              40,000              2.0

Variable                 g                 h

Jurisdiction      Sensitivity analysis for
                  estimated prevalence of
                  latent infection, %

                       Lower             Upper
                    uncertainty       uncertainty
                  limit based on    limit based on
                   0.14% annual      0.06% annual
                     risk for          risk for
                    progression       progression

Example X               NA                NA
Example Y               0.5               1.1
Example Z               1.4               3.3

* Let a = jurisdiction population, b = average annual no. TB cases
in that jurisdiction, and c = proportion of TB cases attributed to
recent transmission (i.e.,

[1-c] = proportion attributed to latent TB infection). Then if b =
0, d = 0, and f <1%, otherwise d = b x (1-c) and e = d/0.0010 if
one assumes a 0.10% annual risk and f = e/a (x 100 to express as a
percentage) or (d/0.0014/a for lower uncertainty limit and h =
d/0.0006/a for upper uncertainty limit. NA, not applicable; TB,
tuberculosis.

Table 2. Characteristics of 1,976 rural and 1,167 metropolitan
counties, by estimated prevalence of latent TB infection, United
States, 2011-2015 *

                                               1,976 rural counties
                                                  1,454 with
                                                  estimated
Characteristic                                  prevalence <1%

US Census 2010 data
  Combined population of counties                 28,727,127
  Median county population, rounded                 13,000
  to thousands

Estimated prevalence of Mycobacterium tuberculosis infection
  Estimated no. infected in all counties            126,140
  Estimated median no. infected/county                 0
County population living in poverty, % ([dagger])
  <10                                               95 (7)
  10-15.5                                          564 (39)
  15.6-19.9                                        378 (26)
  [greater than or equal to] 20                    417 (29)

Race/ethnic group in county with largest no. active TB cases reported
  Black non-Hispanic                               81 (15)
  White non-Hispanic                               241 (45)
  Hispanic                                          74 (14)
  Alaska Native/Native American or                  36 (7)
  Pacific Islander
  Asian                                             43 (8)
  No predominant race/ethnic group                 979 (67)

                                               1,976 rural counties

                                                   320 with
                                                   estimated
Characteristic                                 prevalence 1%-<3%

US Census 2010 data
  Combined population of counties                 11,750,121
  Median county population, rounded                 32,000
  to thousands

Estimated prevalence of Mycobacterium tuberculosis infection
  Estimated no. infected in all counties            191,707
  Estimated median no. infected/county                500
County population living in poverty, % ([dagger])
  <10                                               13 (4)
  10-15.5                                           78 (24)
  15.6-19.9                                         95 (30)
  [greater than or equal to] 20                    134 (42)

Race/ethnic group in county with largest no. active TB cases reported
  Black non-Hispanic                                42 (13)
  White non-Hispanic                               109 (34)
  Hispanic                                          58 (18)
  Alaska Native/Native American or                  14 (4)
  Pacific Islander
  Asian                                             24 (8)
  No predominant race/ethnic group                  73 (23)

                                               1,976 rural counties

                                              202 with estimated
                                           prevalence [greater than
Characteristic                                  or equal to] 3%

US Census 2010 data
  Combined population of counties                  5,816,158
  Median county population, rounded                 23,000
  to thousands

Estimated prevalence of Mycobacterium tuberculosis infection
  Estimated no. infected in all counties            329,547
  Estimated median no. infected/county               1,112
County population living in poverty, % ([dagger])
  <10                                                2 (1)
  10-15.5                                           29 (14)
  15.6-19.9                                         25 (12)
  [greater than or equal to] 20                    146 (72)

Race/ethnic group in county with largest no. active TB cases reported
  Black non-Hispanic                                60 (30)
  White non-Hispanic                                34 (17)
  Hispanic                                          60 (30)
  Alaska Native/Native American or                  15 (7)
  Pacific Islander
  Asian                                              8 (4)
  No predominant race/ethnic group                  24 (12)

                                                  1,167 metropolitan
                                                    counties

                                                   527 with
                                                   estimated
Characteristic                                   prevalence <1%

US Census 2010 data
  Combined population of counties                 37,414,210
  Median county population, rounded                 38,000
  to thousands

Estimated prevalence of Mycobacterium tuberculosis infection
  Estimated no. infected in all counties            212,563
  Estimated median no. infected/county                124
County population living in poverty, % ([dagger])
  <10                                              112 (21)
  10-15.5                                          221 (42)
  15.6-19.9                                        124 (24)
  [greater than or equal to] 20                     70 (13)

Race/ethnic group in county with largest no. active TB cases reported
  Black non-Hispanic                                45 (14)
  White non-Hispanic                               142 (44)
  Hispanic                                          25 (8)
  Alaska Native/Native American or                   8 (2)
  Pacific Islander
  Asian                                             48 (14)
  No predominant race/ethnic group                 259 (49)

                                                 1,167 metropolitan
                                                    counties

                                                   465 with
                                                  estimated
Characteristic                                 prevalence 1%-<3%

US Census 2010 data
  Combined population of counties                 115,341,399
  Median county population, rounded                 144,000
  to thousands

Estimated prevalence of Mycobacterium tuberculosis infection
  Estimated no. infected in all counties           2,300,435
  Estimated median no. infected/county               2,376
County population living in poverty, % ([dagger])
  <10                                               63 (14)
  10-15.5                                          171 (37)
  15.6-19.9                                        144 (31)
  [greater than or equal to] 20                     87 (19)

Race/ethnic group in county with largest no. active TB cases reported
  Black non-Hispanic                                86 (18)
  White non-Hispanic                               110 (24)
  Hispanic                                          82 (18)
  Alaska Native/Native American or                   8 (2)
  Pacific Islander
  Asian                                            118 (25)
  No predominant race/ethnic group                  61 (13)

                                                 1,167 metropolitan
                                                    counties

                                              175 with estimated
                                           prevalence [greater than
Characteristic                                  or equal to] 3%

US Census 2010 data
  Combined population of counties                 109,697,523
  Median county population, rounded                 291,000
  to thousands

Estimated prevalence of Mycobacterium tuberculosis infection
  Estimated no. infected in all counties           5,772,136
  Estimated median no. infected/county              12,388
County population living in poverty, % ([dagger])
  <10                                               25 (14)
  10-15.5                                           30 (17)
  15.6-19.9                                         58 (33)
  [greater than or equal to] 20                     62 (35)

Race/ethnic group in county with largest no. active TB cases reported
  Black non-Hispanic                                57 (33)
  White non-Hispanic                                17 (10)
  Hispanic                                          43 (25)
  Alaska Native/Native American or                   3 (2)
  Pacific Islander
  Asian                                             46 (26)
  No predominant race/ethnic group                   9 (5)

* Values are no. (%) unless otherwise noted. County equivalents
(i.e., Alaska boroughs, District of Columbia, Louisiana parishes,
and Virginia independent cities) are also shown. US Department of
Agriculture 2013 Rural-Urban Continuum Codes were dichotomized
(i.e., codes 4-9 were considered rural and codes 0-3 were
considered metropolitan).

([dagger]) County all-ages poverty level in 2011 determined by US
Census Bureau Small Area Income and Poverty Estimates.
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Title Annotation:DISPATHCES
Author:Haddad, Maryam B.; Raz, Kala M.; Lash, Timothy L.; Hill, Andrew N.; Kammerer, J. Steve; Winston, Car
Publication:Emerging Infectious Diseases
Date:Oct 1, 2018
Words:2999
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