BACKGROUND:

New guidelines support using interferon-γ release assays (IGRAs) in children ≥2 years for diagnosis of latent tuberculosis infection (LTBI). However, lack of experience in young children and concern that IGRAs are less sensitive than tuberculin skin tests (TSTs) limit their use. Our aim was to identify active tuberculosis (TB) cases among high risk children <5 years and tested for LTBI with an IGRA.

METHODS:

. Retrospective review of domestic TB screening data from California’s Refugee Health Electronic Information System for children <5 years old who resettled in California between October, 2013 and December, 2016. Children were crossmatched with the California TB registry to identify cases of TB disease between October 2013 and December 2018.

RESULTS:

A total of 3371 children <5 years were identified; the majority were born in countries with high TB incidence (>150 cases per 100 000). Half received IGRAs (n = 1878; 56%), a quarter received TSTs (n = 811; 24%); 1.4% of children were IGRA-positive (n = 26) and 13% were TST-positive (n = 106). Twenty-two IGRA results were indeterminate (1.2%). Sixteen children had both tests; 9 were discrepant (positive TST with negative IGRA). No cases of TB disease were identified during 10 797 person-years of follow-up.

CONCLUSIONS:

IGRA positivity was less than TST positivity in high risk children <5 years old. Despite fewer LTBI diagnoses in the IGRA-tested population, no cases of TB disease among children who tested negative were identified, suggesting IGRA is valuable tool for identifying LTBI in this population.

What’s Known on This Subject:

Interferon-γ release assays (IGRAs) are the preferred tests for identification of tuberculosis (TB) infection among non–US-born people because of superior specificity among BCG-vaccinated individuals. Testing and treatment of TB infection in young children limits the severe sequela of TB disease.

What This Study Adds:

IGRAs are a valuable tool for identifying TB infection among children <5 years old. IGRA identified latent TB infection with greater precision, fewer indeterminates, and without missing children who went on to develop TB disease in subsequent years.

Each year, ∼1 million children globally develop tuberculosis (TB) disease, and >180 000 die of TB.1  Children <5 years old are at increased risk of developing TB disease, including more severe forms of disease.2  To limit the devastating consequences of TB in young children, identification and treatment of latent tuberculosis infection (LTBI) is essential. Although new diagnostics and shorter treatment regimens provide opportunities for maximizing TB prevention, progress in young children is hampered by concerns regarding sensitivity of interferon-γ release assay (IGRA) tests in this population.

IGRA has advantages over the tuberculin skin test (TST), including being more closely associated with TB exposure and having improved specificity for TB.3  In particular, studies have revealed that using an IGRA instead of TST in non–US-born children 2 to 14 years old would reduce the number of children diagnosed with LTBI by 75% to 80% in the United States.4,5  Prospective cohort studies have not revealed inferior sensitivity of the IGRA compared to the TST for LTBI diagnosis. A study in San Francisco revealed that among ∼1000 children <15 years old who were not treated for LTBI on the basis of a negative IGRA result, none developed active TB over ∼5500 person-years of follow-up.6  A national study revealed that among 533 untreated children <15 years old with a positive TST result but negative IGRA result, none progressed to TB disease.7  These studies suggest that using IGRAs to narrow the defined LTBI population in children does not result in missed cases of TB disease.

The American Academy of Pediatrics updated guidelines in early 2018 to encourage the use of IGRAs in children as young as 2 years old.8  Although some experts use IGRAs among children <2 years old, hesitation regarding use persists because of few studies with large populations in this age group and reports of high indeterminate results. Indeterminate results in children <2 years old range from 0% to 40%; however, the largest study in which authors looked at this included >5000 IGRA test results in children <2 years old, and the authors found <1% of results were indeterminate.9 

The purpose of our study was to identify TB cases among children <5 years old who resettled in California, were at high risk of TB exposure, and who were screened for LTBI after resettlement with an IGRA or TST. Refugee children are thought to be at increased risk for TB given their harsh living conditions, overcrowding, malnutrition, lack of health services in their home country, and elevated risk of TB in many of their home countries.10  Our primary outcome was to determine the negative predictive value of the 2 tests. We assumed the children’s TB exposure occurred before resettlement because all refugee arrivers, including adult family members, undergo the same health assessment with TB screening. We hypothesized that by managing the children for a minimum of 2 years after their initial domestic health assessment for reports of TB disease, we would identify false-negative TB tests because many TB cases in children occur within 2 years of exposure. Secondary outcomes included the predictors of IGRA positivity and the proportion of indeterminate results stratified by age.

We performed a retrospective review of all refugee children who resettled to California who were included in the Refugee Health Electronic Information System (RHEIS) database during October, 2013 to December, 2016 and who were <5 years old at the time of their health assessment in the United States. Children had to have started a domestic health assessment through the Refugee Health Assessment Program to be eligible for inclusion. This health assessment includes a standardized medical history interview and physical examination, along with laboratory studies, as indicated; BCG vaccine receipt is not elicited. Health assessments are performed and recorded by health care providers working at designated refugee health clinics. Decisions to test with IGRA or TST were based on clinic-specific guidelines and availability of tests; treatment was determined by the provider. We analyzed TB-related medical information in addition to demographic and arrival information, including TB test and chest radiograph (CXR) results that were collected by using the California Refugee Health Assessment form after arrival in the United States. The RHEIS database records participant data only up to 90 days after US arrival, at which time patient care is transferred to a primary care provider.

Positive TST results were defined as induration 5 mm or larger among children in close contact to known TB case-patients, with suspicion for TB disease, or with known immunocompromising conditions. For all other children, a result of 10 mm or larger was considered a positive result. QuantiFERON-TB-Gold (QFT) IGRAs were considered positive if values were >0.35 per the manufacturer’s guideline. LTBI and TB disease were defined according to the Centers for Disease Control and Prevention’s TB Classification System and were determined by the clinician performing the refugee health assessment.11 

We matched study participants to the robust California TB registry, which includes all suspected and confirmed cases of TB in California; confirmed cases include both bacteriologically confirmed case-patients and clinically diagnosed case-patients who received TB treatment. We sought to identify TB cases among children who were diagnosed during October 2013 to December 2018. This analysis was determined by the California Health and Human Services Agency’s Committee for the Protection of Human Subjects to be an evaluation of a public health program and as part of the California Department of Public Health’s mandate to routinely collect and analyze surveillance data for public health purposes.

The χ2 test and the Fisher exact test were used to compare proportions, and P < .05 was considered statistically significant. Analyses were performed by using SAS software version 9.4 (SAS Institute, Inc, Cary, NC).

We identified 3710 children <5 years old who resettled in California during the study period; 3399 (92%) children attended a medical assessment examination after their arrival, but 28 (0.8%) of these children reported moving out of California during their medical assessment. Our final sample size for inclusion was 3371. Demographic information for the cohort is presented in Table 1. Children <2 years old accounted for 36% (n = 1204) of the cohort. Most children had entered the United States with either a refugee or a Special Immigrant Visa (n = 3220; 96%). Birth country was known for 3360 (>99%) children; most children (n = 1996; 59%) were from countries with high TB incidence (>150 cases per 100 000 persons). Half of the cohort arrived from Afghanistan (n = 1743; 51.7%).

TABLE 1

Demographic Characteristics of Arrivers <5 Years of Age Who Initiated Domestic Health Assessment

n or N (%)
Total cohort 3371 (100) 
≤5 y of age  
 Sex  
  Male 1744 (52) 
  Female 1627 (48) 
 Age, moa  
  <12 475 (14) 
  12–24 729 (22) 
  24–36 777 (23) 
  36–48 693 (21) 
  48–60 696 (21) 
 Visa type  
  Special Immigrant Visa 1749 (52) 
  Refugee 1471 (44) 
  Asylee 112 (3) 
  Other 39 (1) 
 Birth country TB rateb  
  <5 7 (<1) 
  5–<50 1071 (32) 
  50–<150 286 (8) 
  ≥150 1996 (59) 
n or N (%)
Total cohort 3371 (100) 
≤5 y of age  
 Sex  
  Male 1744 (52) 
  Female 1627 (48) 
 Age, moa  
  <12 475 (14) 
  12–24 729 (22) 
  24–36 777 (23) 
  36–48 693 (21) 
  48–60 696 (21) 
 Visa type  
  Special Immigrant Visa 1749 (52) 
  Refugee 1471 (44) 
  Asylee 112 (3) 
  Other 39 (1) 
 Birth country TB rateb  
  <5 7 (<1) 
  5–<50 1071 (32) 
  50–<150 286 (8) 
  ≥150 1996 (59) 

Age = follow-up evaluation date – refugee child date of birth.

a

One child did not have a date of birth reported.

b

TB cases per 100 000 population. Birth country missing (n = 11).

One child was identified as having active TB during the initial health assessment. The child was from a country with high TB incidence. During evaluation, the child had a positive IGRA result and a CXR result that was consistent with TB disease. The child was admitted to a local hospital for gastric aspirate collection and was found to be culture-positive for TB. The child was counted as a prevalent TB case and therefore was excluded from the follow-up analysis.

IGRAs were performed on 1878 children (56%); all tests were QFT. Results were positive for 26 children (1.4%) overall, including 3 children <2 years old. Results were indeterminate for 22 children (1.2%); no indeterminate results were reported for 166 children <12 months of age. IGRAs were performed with greater frequency among children ≥24 months of age (n = 1443; 67%) compared with children <24 months of age (n = 434; 36%). The proportion of children with a positive IGRA result was similar across age groups, although there were no positive results among 268 children tested between 12 and <24 months of age. The highest number of positive IGRA results were reported among children from countries with high TB incidence (Table 2), but this finding was not statistically significant. A slightly higher proportion of children with a positive IGRA result was found among children with visa types (eg, refugees, asylees, paroles, and victims of trafficking) other than Special Immigrant Visas (Table 3).

TABLE 2

IGRA and TST Results by Age and Birth County TB Rate

IGRA ResultTST Result
Total, nPositive, n or n (%)aNegative, n or n (%)aIndeterminate, n or n (%)aTotal, nPositive, n or n (%)aNegative, n or n (%)aIndeterminate, n or n (%)a
Age, total, mo 1878 26 1830 22 811 106 675 30 
 <12 166 3 (11) 163 (9) 0 (0) 106 15 (14) 86 (13) 5 (17) 
 12–<24 268 0 (0) 262 (14) 6 (27) 240 24 (23) 209 (31) 7 (23) 
 24–<36 502 7 (27) 486 (27) 9 (41) 154 28 (26) 120 (18) 6 (20) 
 36–48 482 9 (35) 471 (26) 2 (9) 146 20 (19) 119 (18) 7 (23) 
 48–60 459 7 (27) 447 (24) 5 (23) 165 19 (18) 141 (20) 5 (17) 
Birth country TB rate,b total 1871 26 1823 22 806 105 671 30 
 <5 0 (0) 2 (<1) 0 (0) 0 (0) 2 (<1) 0(0) 
 5–<50 551 6 (23) 539 (29) 6 (27) 385 46 (44) 325 (48) 14 (47) 
 50–<150 161 2 (8) 158 (9) 1 (5) 77 6 (6) 69 (10) 2 (6) 
 ≥150 1157 18 (69) 1124 (61) 15 (68) 342 53 (50) 275 (41) 14 (47) 
IGRA ResultTST Result
Total, nPositive, n or n (%)aNegative, n or n (%)aIndeterminate, n or n (%)aTotal, nPositive, n or n (%)aNegative, n or n (%)aIndeterminate, n or n (%)a
Age, total, mo 1878 26 1830 22 811 106 675 30 
 <12 166 3 (11) 163 (9) 0 (0) 106 15 (14) 86 (13) 5 (17) 
 12–<24 268 0 (0) 262 (14) 6 (27) 240 24 (23) 209 (31) 7 (23) 
 24–<36 502 7 (27) 486 (27) 9 (41) 154 28 (26) 120 (18) 6 (20) 
 36–48 482 9 (35) 471 (26) 2 (9) 146 20 (19) 119 (18) 7 (23) 
 48–60 459 7 (27) 447 (24) 5 (23) 165 19 (18) 141 (20) 5 (17) 
Birth country TB rate,b total 1871 26 1823 22 806 105 671 30 
 <5 0 (0) 2 (<1) 0 (0) 0 (0) 2 (<1) 0(0) 
 5–<50 551 6 (23) 539 (29) 6 (27) 385 46 (44) 325 (48) 14 (47) 
 50–<150 161 2 (8) 158 (9) 1 (5) 77 6 (6) 69 (10) 2 (6) 
 ≥150 1157 18 (69) 1124 (61) 15 (68) 342 53 (50) 275 (41) 14 (47) 
a

Percent values are column percent.

b

TB cases per 100 000 population.

TABLE 3

IGRA and TST Results by Visa Status

IGRA ResultTST Result
Total, nPositive, n (%)Negative, n (%)Indeterminate, n (%)Total, nPositive, n (%)Negative, n (%)Indeterminate, n (%)
Total 1878 26 (1.4) 1830 (97.4) 22 (1.2) 811 106 (13) 675 (83) 30 (4) 
Special Immigrant Visa 1013 12 (1.2) 988 (97.5) 13 (1.3) 275 48 (17) 214 (78) 13 (5) 
Other visa types 865 14 (1.6) 842 (97.3) 9 (1) 536 58 (11) 461 (86) 17 (3) 
IGRA ResultTST Result
Total, nPositive, n (%)Negative, n (%)Indeterminate, n (%)Total, nPositive, n (%)Negative, n (%)Indeterminate, n (%)
Total 1878 26 (1.4) 1830 (97.4) 22 (1.2) 811 106 (13) 675 (83) 30 (4) 
Special Immigrant Visa 1013 12 (1.2) 988 (97.5) 13 (1.3) 275 48 (17) 214 (78) 13 (5) 
Other visa types 865 14 (1.6) 842 (97.3) 9 (1) 536 58 (11) 461 (86) 17 (3) 

TSTs were performed on 811 children (24%). The results were positive for 106 children (13%); 30 children (4%) did not return for a TST reading. There was no significant difference in the proportion of children with TSTs performed or in the proportion who had a positive result when the children were stratified by age. TST positivity was highest among children born in countries with high TB rates (Table 2), but this difference was not statistically significant. In contrast to findings for IGRA, TST positivity was higher among children with Special Immigrant Visa status (Table 3). A comparison of TST- versus IGRA-positive results by age can be found in Fig 1.

FIGURE 1

IGRA and TST result positivity by age.

FIGURE 1

IGRA and TST result positivity by age.

Close modal

Only 16 children had both a TST and IGRA performed; tests were concordant for 7 children (3 had both test results positive) but discordant (positive TST and negative IGRA) for 9 children. Among the 9 children with positive TST and negative IGRA results, 8 (88.9%) had TB classification recorded, none were classified as having LTBI or TB disease, and none received LTBI treatment from the refugee health provider. No children had positive IGRA results but negative TST results.

CXRs were performed on 151 children (4%), including among 23 of the 26 children (88%) who had positive IGRAs. Among these 23 children, 1 child (4%) had an abnormal finding consistent with TB; this is the child noted earlier who was later diagnosed with active TB.

A final TB classification was assigned to 2679 children (79%) at assessment completion. The majority of the children were determined to be TB uninfected or unexposed (n = 2584; 96%). Ninety-four children (4%) were classified as having LTBI. Among children with LTBI, 15 had a positive QFT result (16%) and 73 had a positive TST result (78%); 3 children had both test results positive (3%), and 3 children had either inconclusive or negative test results (3%). Approximately 50% of children (n = 43) started LTBI treatment. Approximately half reported LTBI treatment completion (n = 22; 51%). However, by the time treatment decisions and completion would be reported, many children had already transferred to a primary care provider or timed out of the 90-day period; whether preventive therapy was started or completed for these children is unknown. Only the 1 child previously discussed was classified as having active disease.

Among 1830 children with negative IGRA results, including 425 children <2 years old, no cases of TB were reported during the follow-up period. Table 4 reveals the median years of follow-up by age group with a median of 3 years of follow-up (range 1.7–5 years). No cases of TB were identified among the cohort during 10 797 person-years of follow-up.

TABLE 4

TB Test Result Negative: Children by Age and Study Follow-up

Test ResultTotal, NMedian Years of Follow-up (Range)Age <12 mo, nMedian Years of Follow-up (Range)Age 12-<24 mo, nMedian Years of Follow-up (Range)Age 24-<36 mo, nMedian Years of Follow-up (Range)Age 36–<48 mo, nMedian Years of Follow-up (Range)Age 48–60 mo, nMedian Years of Follow-up (Range)
Negative QFT 1828 3.1 (2.0–5.2) 163 3.1 (2.0–5.1) 262 2.9 (2.0–5.2) 486 3.1 (2.0–5.2) 471 3.1 (2.0–5.2) 446 3.1 (2.0–5.2) 
Negative TST 674 3.5 (2.0–5.2) 86 3.2 (2.0–5.2) 209 3.5 (2.1–5.2) 120 3.5 (2.0–5.2) 119 3.6 (2.0–5.2) 140 3.6 (2.0–5.2) 
Test ResultTotal, NMedian Years of Follow-up (Range)Age <12 mo, nMedian Years of Follow-up (Range)Age 12-<24 mo, nMedian Years of Follow-up (Range)Age 24-<36 mo, nMedian Years of Follow-up (Range)Age 36–<48 mo, nMedian Years of Follow-up (Range)Age 48–60 mo, nMedian Years of Follow-up (Range)
Negative QFT 1828 3.1 (2.0–5.2) 163 3.1 (2.0–5.1) 262 2.9 (2.0–5.2) 486 3.1 (2.0–5.2) 471 3.1 (2.0–5.2) 446 3.1 (2.0–5.2) 
Negative TST 674 3.5 (2.0–5.2) 86 3.2 (2.0–5.2) 209 3.5 (2.1–5.2) 120 3.5 (2.0–5.2) 119 3.6 (2.0–5.2) 140 3.6 (2.0–5.2) 

Because no cases of TB disease were identified during the follow-up period, we were precluded from reporting sensitivity, specificity, and positive and negative predictive values for IGRA and TST. We are able to report the proportion of children with an IGRA negative result among those tested as 98.6%, and the proportion with a TST negative result among those tested as 86.4%.

The findings from this study suggest that using IGRA to define LTBI in a high-risk population of children, including >400 children <2 years old, did not lead to missed cases of TB during 10 797 person-years of follow-up. TST positivity in our study was 9 times higher than IGRA positivity (13.1% vs 1.4%), which resulted in more children getting a CXR, LTBI diagnosis, and treatment. Use of IGRA to define LTBI allowed for a narrower focus on children with LTBI without missing children who might go on to develop active TB. The one child who had active TB had a positive IGRA result on initial health assessment.

We found an IGRA positivity of 1.4% among refugee children <5 years old. This is lower than previously reported in the literature. San Francisco found an IGRA positivity rate of 4% among non–US-born children <5 years old6 ; authors of a national study in the United States reported an IGRA positivity of 1% for children <2 years old and 4.3% among children 2 to 4 years old.7  In a study of Australian refugees, authors found an IGRA positivity of 0% for children <2 and 21% for children 2 to 4 years old.12  These studies included children primarily from African or Asian countries where TB incidence is higher than in the countries of origin represented by the majority of our cohort. In other studies of refugee populations, authors have found similarly higher rates of LTBI (7%–9%), but the authors of these studies have either used TST to diagnose LTBI13  or included adult patients,14  who typically have higher LTBI rates than younger children. The lower IGRA positivity in our cohort might be explained by the large number of children who arrived with Special Immigrant Visas, mostly from Afghanistan. These visas are primarily given to families whose parents assisted in the United States’ war effort; many families have high social status and live in cities as opposed to refugee camps before US arrival, which might be protective against TB exposure. Additionally, reported TB incidence in the home countries of the children might not be reliable given the instability. Overall, we found a lower proportion of IGRA-positive results among children with Special Immigrant Visas children compared with children with other visa types.

Because far fewer children had positive IGRA results and no subsequent cases of TB were diagnosed among children with negative IGRA results during the follow-up period, we find that IGRA use allows clinicians to focus on fewer children at elevated risk for LTBI. Many non–US-born children receive BCG vaccine at birth, which can cause false-positive TST results. Young children in particular are thought to have the highest risk for false-positive results because of the short time frame since BCG vaccination, although it is suggested in our data that TST positivity is similar up to 5 years old. We did not have a record of BCG vaccination among our cohort. It is possible that many children did not receive BCG vaccine at birth because it was not available through the medical system in their country of origin.

Risk factors for LTBI that we were able to evaluate included age at time of entry to the United States and TB rate in country of birth. Overall, our results revealed that there were similar proportions of children with positive IGRA and TST results across age groups, although we would have expected increased positivity with age because older age allows more time for TB exposures to occur. If the BCG vaccine was given at birth, we might have seen fewer positive TST results with increasing time from BCG vaccination, but BCG vaccination might not have been given in a timely manner in overseas refugee populations. Because we looked across a 5-year time period and found low TB test result positivity, we might not have been able to capture these trends.

One hesitation in using IGRAs in young children is the concern regarding indeterminate results, which are thought to be higher in younger children. The proportion of children with indeterminate IGRAs was low overall (1.4%), with no indeterminate results among 167 children <12 months of age and 2% indeterminate results among children 12 to <24 months of age. These results are comparable to those from a recent large analysis of IGRA results in South Africa9  and several smaller studies in which an indeterminate result of <1% among young children was reported.1517  These studies and others suggest that young children have a sufficient interferon-γ response to TB antigen, and mitogen responses are sufficient among children <2 years old.1823  Some differences in indeterminate results among young children might be explained by varying phlebotomy and laboratory practices. In a recent study performed in a tertiary pediatric hospital with a high proportion of immunocompromised and young patients, authors found a low proportion of indeterminate results (1.1%), which were attributed to expert pediatric phlebotomy and quick incubation and testing at an on-site laboratory.24  On the basis of our study, indeterminate findings were more frequent among young children who had a TST placed than an IGRA (3.7% vs 1.2%) because many children never returned for TST interpretation. Therefore, our study suggests that concern for indeterminate TB testing results should encourage the use of IGRA in place of TST, especially in populations who might not return for TST interpretation.

Our study had several limitations. First, the RHEIS database captures screening data of children for only up to 90 days after arrival in the United States. Because data were not collected beyond that period, we were unable to assess testing or treatment that occurred once children were referred outside of the Refugee Health Assessment Program to a primary care provider. We were unable to comment on TB classification and treatment outcomes among children with positive TB test results who had missing information in the RHEIS database. We also assumed that most of the children remained in California, and the TB registry we used to identify active TB cases among our cohort is restricted to cases reported in California. It is possible that some children moved to another state during the follow-up period. Finally, we assumed that the TB rates in the refugee camps would be similar to the TB rates in the affected countries in which the refugee children were born, but this assumption might not be accurate.

With our now stagnant TB rates in the United States, our TB elimination strategies have shifted to identifying and treating LTBI before it progresses to active TB and becomes communicable. In children, identifying LTBI is of particular importance because the risk of developing active TB and the severity of disease are both greater among young children. Use of IGRA for LTBI diagnosis among high-risk refugee children, including children <2 years old, appears to be effective in identifying children with LTBI without missing children who go on to develop TB disease. The use of IGRAs in our study resulted in fewer indeterminate test results than TST and allowed providers to identify risk for LTBI in a single visit. Additionally, IGRA appeared more specific for LTBI, allowing more focused diagnostics and treatment of children at risk for TB disease. On the basis of our findings, IGRA appears to be a valuable tool for identifying LTBI among children, even those <2 years old.

Dr Wendorf conceptualized and designed the study and drafted the initial manuscript; Mr Lowenthal conceptualized and designed the study, conducted the initial data analyses, created the figures and the tables, and critically reviewed the draft manuscript and revised critically for important intellectual content and data interpretation; Ms Feraud contributed to the conception and design of the project and assisted with creating figures and tables, review and interpretation of data elements, and overall formatting and other critical edits to the draft manuscript; Ms Cabanting acquired the initial data, assisted with understanding and correct use of the initial data and data analysis, and provided critical revisions of the manuscript to ensure correct interpretation of the data elements and provision of additional literature references in her specialty area; Dr Murto provided interpretation of data analysis and critically reviewed the draft manuscript to ensure correct interpretation of the data elements and analysis; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

     
  • CXR

    chest radiograph

  •  
  • IGRA

    interferon-γ release assay

  •  
  • LTBI

    latent tuberculosis infection

  •  
  • QFT

    QuantiFERON-TB-Gold

  •  
  • RHEIS

    Refugee Health Electronic Information System

  •  
  • TB

    tuberculosis

  •  
  • TST

    tuberculin skin test

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.