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Prevalence of Latent Mycobacterium Tuberculosis Infection (LTBI) in Saudi Arabia; Population based survey
Accepted Manuscript Title: Prevalence of Latent Mycobacterium Tuberculosis Infection (LTBI) in Saudi Arabia; Population based survey Authors: Hanan H. Balkhy, Kamel El Beltagy, Aiman El-Saed, Badr Aljasir, Abdulhakeem Althaqafi, Adel F. Alothman, Mohammad Alshalaan, Hamdan Al-Jahdali PII: DOI: Reference:
S1201-9712(17)30109-1 http://dx.doi.org/doi:10.1016/j.ijid.2017.03.024 IJID 2913
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
13-12-2016 22-3-2017 31-3-2017
Please cite this article as: Balkhy Hanan H, El Beltagy Kamel, El-Saed Aiman, Aljasir Badr, Althaqafi Abdulhakeem, Alothman Adel F, Alshalaan Mohammad, AlJahdali Hamdan.Prevalence of Latent Mycobacterium Tuberculosis Infection (LTBI) in Saudi Arabia; Population based survey.International Journal of Infectious Diseases http://dx.doi.org/10.1016/j.ijid.2017.03.024 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Prevalence of Latent Mycobacterium Tuberculosis Infection (LTBI) in Saudi Arabia; Population based survey Running title: Prevalence of latent TB in Saudi Arabia
Hanan H. Balkhya,b,c, Kamel El Beltagyc,d, Aiman El-Saedc,e, Badr Aljasira,f, Abdulhakeem Althaqafia,c, Adel F. Alothmana,g, Mohammad Alshalaana,h, Hamdan Al-Jahdali a,g.
King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Kingdom of Saudi Arabiaa King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Kingdom of Saudi Arabiab Infection Prevention and Control Department, King Abdulaziz Medical City, National Guard Health Affairs, Saudi Arabiac; Public health & Community Medicine Department, Faculty of Medicine, Tanta University, Egyptd; Public health & Community Medicine Department, Faculty of Medicine, Mansoura University, Egypt e, Preventive Medicine Department, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Saudi Arabiaf Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Saudi Arabiag Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Saudi Arabiah
Corresponding Author: Hanan H. Balkhy King Saud bin Abdulaziz University for Health Sciences Mail Code: 2134 P.O. Box 22490 11426 Riyadh City Saudi Arabia Tel: +966 11 80 43761 Fax : +966 11 80 43733 Email: [email protected]
1
HIGHLIGHTS
The overall prevalence of LTBI was 9.3% using TST and 9.1% using QFT-GIT
The prevalence rates were variable by several sociodemographic characteristics
ARTI data in Saudi Arabia has not been updated since 1993
The overall ARTI was 0.36% using TST and 0.35% using QFT-GIT
The current prevalence of LTBI and ARTI are much lower than reported before
ABSTRACT BACKGROUND: The annual risk of tuberculosis infection (ARTI) data in Saudi Arabia has never been updated since 1993. OBJECTIVES: To estimate the prevalence of latent TB infection (LTBI) and ARTI in a population-based sample in Saudi Arabia using Tuberculin skin test (TST) and QuantiFERON TB Gold in tube (QFT-GIT) test. METHODS: A populationbased cross sectional study was conducted between July 2010 and March 2013. Participants were randomly selected from the population served by the primary healthcare centers of the Ministry of National Guard Health Affairs in Riyadh, Jeddah, Alhassa and Dammam, Saudi Arabia. RESULTS: A total 1369 participants were included. The overall prevalence of LTBI was similar using TST and QFT-GIT (9.3% and 9.1% respectively, p=0.872) but stratified prevalence rates were variable in all sociodemographic groups except marital status. Additionally, the prevalence rates of LTBI using either test alone showed significant differences by several sociodemographic and behavioral characteristics. The overall ARTI was 0.36% using TST and 0.35% using QFT-GIT. CONCLUSIONS: We are reporting much lower estimates for the prevalence of LTBI and the ARTI in a population-based sample in Saudi Arabia relative to the data that have been used for more than two decades.
2
KEYWORDS: Latent Tuberculosis Infection, Prevalence, QuantiFERON TB Gold test, Tuberculin Skin Test, Saudi Arabia
INTRODUCTION Tuberculosis (TB) continues to be a global health problem. It is a leading cause of morbidity and mortality in several parts of the world.1 World Health Organization (WHO) estimated that onethird of the world population is currently infected with the TB bacillus, with approximately 5% to 10% of them has been or will get sick or infectious at some point during their life.2 Latent tuberculosis infection (LTBI) is defined as lack of clinically manifested active TB in a person who has persistent immune response to stimulation by Mycobacterium tuberculosis antigens.3 LTBI is detected either by tuberculin skin testing (TST) or by QuantiFERON Gold in tube (QFT-GIT) test. This detection provides an opportunity to treat LTBI and prevent progression of TB infection to active TB disease.4 The annual risk of tuberculosis infection (ARTI) which is defined as the probability of acquiring new tuberculosis infection or re-infection over a period of one year, is a sensitive indicator of the extent of transmission of tubercule bacilli as well as the effeciency of case finding and treatment programs.5-7 Monitoring TB infection overtime is challenged by several factors including the varaibility of Bacillus Calmette–Guérin (BCG) vaccination, lack of large scale surveys, and limitations of reporting systems.1 8 As ARTI is the most reliable indicator for trending tuberculosis infection,810
there is a need for updated population based estimates of LTBI prevelance. In Saudi Arabia,
such data is clearly outdated as the last community-based survey of the epidemiology of LTBI was conducted in 1993.7 11 12 Obviously, this data did not reflect the major changes that have happened in socioeconomic standards and TB management in Saudi Arabia in the last three decades. Additionally, the impact of using QFT-GIT in estimating LTBI prevalence and ARTI 3
has never been adequately examined in a population-based sample in Saudi Arabia.13-15 The objective of the current study was to calculate recent estimates of the prevalence of LTBI and ARTI in a Saudi population-based sample. METHODS Setting: The study was conducted in primary care centers of the Ministry of National Guard Health Affairs (MNGHA). There are over 27 primary care centers serving a population greater than one million, distributed in the three main regions in Saudi Arabia; Central, Western and Eastern regions. Eleven primary health care centers in Riyadh, Jeddah, Alhassa & Dammam served as primary study sites for enrollment of study participants from their catchment areas. Design: A population-based cross-sectional study was conducted between July 2010 and March 2013. The study was approved by the institutional review board (IRB) of King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia. Population: The study was conducted among the population eligible to receive healthcare services at one of the selected primary care centers of the MNGHA. Inclusion criteria included Saudi Nationals aged five years or older who were able to frequent one of the study sites. Exclusion criteria included children below five years of age (to exclude the BCG vaccination effect on the results of the study as it is given routinely at birth for all newborns in Saudi Arabia), those with current or previous active pulmonary TB disease, those with diagnosis of TB infection and on anti TB prophylaxis, and those with immunocompromised disease or a condition such as patients with leukemia, lymphoma, other cancers under chemotherapy, hemodialysis, organ transplantation, chronic steroid or immunosuppressive therapy, or HIV (self-reported). Recruitment: Stratified random sampling technique with age and gender proportional to the distribution of the served primary care population was used to randomly choose the participants. 4
The study coordinator contacted the selected participants, explained the aim of the study and invited them to join. Study objectives and testing details were explained to each subject or one of his/her parents (in cases of children). Informed consent was obtained before filling out the study questionnaire, which included questions about the participant’s socio-demography (age, gender, marital status, education, occupation, family income, and residence), behavior (cigarette smoking and hookah “shisha” smoking), medical history (to ensure absence of exclusion criteria), and family history (tuberculosis). LTBI testing: From each subject a 3-ml blood sample was collected by venipuncture for the QFT-GIT assay then TST (0.1 mL of tuberculin PPD using 5 unit ampoules) was injected intradermally into the volar aspect of the forearm, and the transverse induration diameter was measured 48-72 hours later. The positive interpretation of a TST is an area of induration of ≥10 mm in diameter. QFT-GIT was conducted by the central laboratory of the MNGHA. The cut-off for QFT was TB antigen tube value minus the Nil tube value ≥0.35 IU/mL. Statistical analysis: All categorical variables were presented as frequencies and percentages while continuous variables were presented as means and standard deviations. The prevalence of LTBI was defined as the percentage of positive TST or QFT-GIT relative to those who were tested. McNemar test was used to compare the prevalence of LTBI between TST and QFT-GIT within each sociodemographic and behavioral group. Chi-square test was used within each test alone to compare the prevalence of LTBI between the levels of sociodemographic and behavioral groups. ARTI was calculated using the standard formula R = 1−(1−Prevalence) 1/A +0.5 where R is the probability of being infected in any one year and A is the mean age.6 Because the age (in full years) of each child at their last birthday was used, 0.5 was added to the mean age for the calculation of ARTI. P-value <0.05 was considered significant. SPSS software (release 20.3, Armonk, NY: IBM Corp) was used for all statistical analyses. 5
RESULTS Out of 1745 contacted, 1443 Saudi participants accepted to be included in the study, with response rate of 82.7%. Out of 1443 participants, 74 (5%) were excluded from the study because of unavailability of QFT-GIT results (as a result of poor handling and transport of the blood sample, 38 participants), indeterminate results of QFT-GIT (27 participants), unavailability of TST readings (due to not showing back within 72 hours, 5 participants) and age less than 5 years (3 participants). The data of the rest of the participants (1369) with complete testing information was used for analysis. As shown in Table 1, 597 (43.6%) out of the 1369 participants included were males and 772 (56.4%) were females. The mean age was 26.3±19.0 years, with the majority (80%) below 45 years; 43.2% were 5-14 years old and 36.7% were 15-44 years. More than half (57.6%) of the participants were single while 40% were married. Approximately 90% of the participants had secondary education or lower, with 13.2% were illiterate. More than half (57.6%) of the participants were students while only 15.3% were military employees and 13.4% were housewives. The median monthly family income was SR 8000 ($2133), with the most frequently reported income between SR 6000 ($1600) and SR 9000 ($2400). The mean household family size was 8 members, with the most frequently reported family size between 6 and 10 family members. Approximately 55.7% of the included participants were from Central region, 22.9% from Eastern region and 21.4% from Western region of Saudi Arabia. The great majority of study participants had never smoked cigarettes (90%) or never smoked shisha (94.8%) while only 10% and 5.2% were either current or previous smokers of cigarette and/or shisha, respectively. The overall prevalence of LTBI was 9.3% using TST and 9.1% using QFT-GIT (Table 2). While the overall prevalence of LTBI was not different between the two tests (p=0.872), there were significant differences in the prevalence rates between TST and QFT-GIT after stratifying 6
by the levels of all sociodemographic and behavioral groups, except marital status. Additionally, the prevalence rates of LTBI using either test alone showed significant differences across the levels of several sociodemographic and behavioral characteristics. For example as shown in Table 2 and Figure 1, the highest prevalence of LTBI was observed among those aged ≥45 years using TST (19.2% in those aged 45-64 years and 18.1% in those ≥65 years) and ≥65 years using QFT-GIT (40.3%). The prevalence decreased with decreasing age using both tests and the lowest prevalence was observed in children aged 5-14 years (2.9% by TST and 3.6% by QFT-GIT). Males showed a higher prevalence than females using TST (12.9% vs 6.5%) but not using QFTGIT (9.2% vs 8.9%). In both tests, divorced/widowed had the highest prevalence while singles had the lowest prevalence (30.3% vs 4.2% using TST and 42.4% vs 5.1% using QFT-GIT). Illiterates using both testes (12.0% by TST and 18.9% by QFT-GIT) and those with University and above education using TST (16.4%) had the highest prevalence while primary education had the lowest prevalence (4.3% using TST and 5.5% using QFT-GIT). Retired (40.0% using TST) and unemployed (28.3% using QFT-GIT) had the highest prevalence while students had the lowest prevalence (3.3% using TST and 4.9% using QFT-GIT). Using TST, the prevalence was higher among those living in the Eastern region and current/previous smokers with no significant differences by family income and size. Using QFT-GIT, the prevalence was higher among those with bigger family size with no significant differences by family income, residence, and smoking status. The overall ARTI was 0.36% using TST and 0.35% using QFT-GIT (Figure 2). ARTI was higher among males than females (0.46% vs 0.32%) using TST and among females than males (0.38% vs 0.27%) using QFT-GIT.
7
DISCUSSION The current study is considered the first population-based survey examining the epidemiology of tuberculosis infection in Saudi Arabia in more than two decades and the first study ever to examine LTBI using both TST and QFT-GIT in a population-based sample. The last populationbased survey was published by Al-Kassimi et al in 1993 based on data from 7721 participants aged 5 to 65 years who were screened using TST only.11 Overall as well as age- and genderstratified prevalence of LTBI in Al-Kassimi et.al was much higher than those reported in the current TST rates. For example, the overall prevalence was 33.2% in the Al-Kassimi study compared with 9.3% in the current study. Additionally, the prevalence of LTBI among males and children aged 5-14 were 43% and 5.6% (respectively) in the Al-Kassimi study compared with 12.9% and 2.9% (respectively) in the current study. However, in both Al-Kassimi and current studies the prevalence of LTBI was higher in older age group, in males, and extremes of educational status. The discrepancy in infection rates between the current and previous studies
11 12
can be
explained by the significant decrease in the prevalence of the TB disease during the last three decades. For example, the WHO and official estimates of the prevalence of TB in Saudi Arabia showed a decrease from 86 per 100,000 in 1990 to 55 per 100,000 in 2004 to 10.6 per 100,000 in 2015 compared to global average of 133 per 100,000.16 17 The observed significant difference in the prevalence of LTBI using TST and QFT-GIT has been reported in several studies.13
15 18
However, explaining such differences is difficult as both tests do not measure the same components of the immunologic response and the concordance was shown to be only fair to moderate. 19 The higher prevalence in old age is generally reflecting accumulated exposure over previous decades. However, the clearer association with old age using QFT-GIT compared with TST may reflect that the high TST false negative results in old age 9, the lower concordance of 8
both tests in older population,19 and the probable higher waning of the T-cell mediated immune response to TST than to QFT
20
. Similar to the current finding, the higher prevalence of LTBI
using TST in males irrespective of BCG vaccination has been reported in Saudi Arabia and was attributed to the higher risk of exposure.11 The higher prevalence of LTBI in illiterates, divorced/widowed , and retired participants in our study using both tests may reflect the fact that the majority of them were aged 45 years or older. Additionally, all retired participants were males. However, the higher prevalence of LTBI using TST among those who had University degree cannot be explained on the basis of age or gender distribution (after subgroup analysis) and should be interpreted with caution given the small number of this group. The ARTI was estimated at 0.35% to 0.36% in the current study, using TST and QFT-GIT. We did not present the ARTI estimates by different sociodemographic characteristic of the study participants (as we did of the prevalence of LTBI), as the ARTI is a population-based tool that was primarily designed to model the changes in transmission patterns by serial estimations of the disease risk over a given period of time rather than comparing the risk in specific groups of the population.6 Since we did not have serial estimations of ARTI, we compared our ARTI with previously available Saudi estimates of ARTI that were based on TST survey done between 1987-1988.7 In that data, the ARTI was estimated among participants less than 35 years; ranging between 0.5% in children 5 to 8 years and 4.7% in adults 24 to 34 years.7 Obviously the current ARTI estimates were much lower; this may be due to the different methods used in calculation of ARTI and non-inclusion of individuals above 35 years in El-Kassimi study. Similar to the prevalence of LTBI, the lower ARTI in the current study can be explained by the significant decrease in the incidence of TB disease in Saudi Arabia during the last three decades; from 50 per 100,000 in 1990 to 40 per 100,000 in 2004 to 12 per 100,000 in 2014.1 17 This decrease may reflect better local management of cases and a global trend of decreasing incidence and 9
prevalence of TB.21
22
However, there is still a wide international variability in the ARTI
estimates which range between 4.2% in South Africa and 0.03% in the United States. Considering Saudi incidence rates, more work needs to be done to move from the moderate burden countries to low burden countries (incidence less than 10 per 100,000) with much lower ARTI. The ARTI can also used to estimate the load of new sputum smear-positive cases in the community by using Styblo’s formula.10 Therefore, the estimated 0.36% ARTI in the current study is equivalent to approximately 18 new smear positive case per 100,000 population per year.10 Given the current ARTI estimates (0.36%) and the reported estimates of Saudi population (21,130,000 during 2015),16 the expected number of new smear-positive cases is 3803 plus the additional cases among other 7.1 million expatriates in Saudi Arabia. Interestingly, a total of 3346 TB (pulmonary and extra-pulmonary) cases were actually reported to the Saudi Ministry of health in 2015. The slight difference between the current estimates and the case reported may reflect the estimated 16% missing case detection rate.1 The major strengths of the current study were the stratified random sampling technique used in recruitment, the relatively large number of study participants, and the inclusion of the main three geographic regions in Saudi Arabia, the use of both TST and QFT-GIT in testing for LTBI, and the calculation of both prevalence and ARTI. Nevertheless, we acknowledge a number of limitations; the cross-sectional design does not detect causal relationship with risk factors. The current findings should be generalized cautiously to other populations in Saudi Arabia as the National Guard population is not identical to typical Saudi population. For example, the study population had higher percentage of military personnel, children <15 years, students, and females. Additionally, they were exclusively Saudi nationals with no history of TB diagnosis or treatment. Additionally, since we did not have serial estimations of ARTI in our 10
population which probably had also a changing LTBI prevalence, we could not estimate the changes in TB transmission in our population. However, we believe that the current ARTI estimates may serve as recent baseline estimates for future comparisons by similar populations. In conclusion, we are reporting much lower estimates for the prevalence of LTBI and the ARTI in a Saudi community compared with the data that has been used for more than two decades. While this may indicate improved TB care over the last two decades, there is still a potential for more improvement.
Funding : by King Abdullah International Medical Research Center (KAIMRC), grant number RC-09-093, Ministry National Guard Health Affairs, Kingdom of Saudi Arabia. Ethical approval: IRB of KAIMRC approved the current study
Conflict of interest: no conflict of interest
Acknowledgment: We greatly appreciate the contributions of all data collectors, which made this study possible
11
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Al Jahdali H, Ahmed AE, Balkhy HH, Baharoon S, Al Hejaili FF, Hajeer A, et al. Comparison of the tuberculin skin test and Quanti-FERON-TB Gold In-Tube (QFT-G) test for the diagnosis of latent tuberculosis infection in dialysis patients. J Infect Public Health 2013;6:166-72.
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Al Wakeel JS, Makoshi Z, Al Ghonaim M, Al Harbi A, Al Suwaida A, Algahtani F, et al. The use of Quantiferon-TB gold in-tube test in screening latent tuberculosis among Saudi Arabia dialysis patients. Ann Thorac Med 2015;10:284-8.
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Nienhaus A, Schablon A, Diel R. Interferon-gamma release assay for the diagnosis of latent TB infection--analysis of discordant results, when compared to the tuberculin skin test. PLoS One 2008;3:e2665.
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14
30% Male
Prevalence of LTBI using TST
Female
22.5%
21.4%
20% 16.9%
16.1%
15.9%
10% 5.7% 3.6% 1.5% 0% <15
15-44
45-64
≥65
Age and gender groups
Male
Prevalence of LTBI using QFT-GIT
50%
50.0%
Female
34.1%
25%
19.4% 16.2%
3.0% 3.9%
6.7%
8.5%
0% <15
15-44
45-64
≥65
Age and gender groups
Figure 1: Prevalence of LTBI using TST and QFT-GIT by age and gender groups The prevalence of LTBI was significantly different by age groups in both tests and in both genders (p<0001 in each). The prevalence of LTBI was significantly different by gender, only in age group 15-44 years using TST (p<0001).
15
TST 0.5%
QFT-GIT
0.46%
ARTI estimates
0.38%
0.36% 0.35%
0.32% 0.27% 0.3%
0.0% Male
Female
Total
Gender groups
Figure 2: Annual risk of tuberculosis infection (ARTI) using TST and QFT-GIT by gender groups ARTI was not significantly different by gender using TST nor QFT-GIT.
16
Table 1: Sociodemographic characteristics of the study participants Characteristics Age (years) Mean ± SD <15 15-44 45-64 ≥65 Gender Male Female Marital status Single Married Divorced/widowed Education Illiterate Primary school Mid/high school University and above Occupation Military Civilian Housewife Student Unemployed Retired Family income Median & IQR, SR Median & IQR, $ ≤ SR 6,000 (≤ $1600) SR 6,001-9,000 ($1600-2400) > SR 9,000 (> $2400) Family size Median & IQR ≤5 6-10 >10 Geographic region Central region Eastern region Western region Cigarette smoking Never Current &/previous Hookah (shisha) smoking Never Current&/previous
Value* 26.3±19.0 591 (43.2%) 502 (36.7%) 204 (14.9%) 72 (5.3%) 597 (43.6%) 772 (56.4%) 782 (57.6%) 543 (40.0%) 33 (2.4%) 175 (13.2%) 559 (42.3%) 455 (34.4%) 134 (10.1%) 183 (15.3%) 67 (5.6%) 161 (13.4%) 691 (57.6%) 53 (4.4%) 45 (3.8%) SR 8,000 (5,500-10,000) $ 2133 (1467-2667) 178 (33.6%) 194 (36.6%) 158 (29.8%) 8 (6-10) 261 (22.0%) 691 (58.2%) 235 (19.8%) 763 (55.7%) 313 (22.9%) 293 (21.4%) 1220 (90.0%) 136 (10.0%) 1282 (94.8%) 70 (5.2%)
* Number (percentage) unless mentioned otherwise. SD, standard deviation; IQR, inter-quartile range
17
Table 2: Prevalence of LTBI using TST and QFT-GIT by the characteristics of the study participants QFT-GIT p-value* % N % 1369 9.3% 124 9.1% 0.872 Overall P<0.001 P<0.001 Age (years) <15 591 17 2.9% 21 3.6% 0.523 15-44 502 57 11.4% 38 7.6% 0.040 45-64 204 40 19.6% 36 17.6% 0.618 ≥65 72 13 18.1% 29 40.3% <0.001 P<0.001 P=0.860 Gender Male 597 77 12.9% 55 9.2% 0.023 Female 772 50 6.5% 69 8.9% 0.027 P<0.001 P<0.001 Marital status Single 782 33 4.2% 40 5.1% 0.410 Married 543 83 15.3% 68 12.5% 0.151 Divorced/widowed 33 10 30.3% 14 42.4% 0.125 P<0.001 P<0.001 Education Illiterate 175 21 12.0% 33 18.9% 0.036 Primary school 559 24 4.3% 31 5.5% 0.281 Mid/high school 455 54 11.9% 40 8.8% 0.103 University and above 134 22 16.4% 11 8.2% 0.043 P<0.001 P<0.001 Occupation Military 183 33 18.0% 11 6.0% <0.001 Civilian 67 16 23.9% 6 9.0% 0.013 Housewife 161 16 9.9% 22 13.7% 0.263 Student 691 23 3.3% 34 4.9% 0.108 Unemployed 53 8 15.1% 15 28.3% 0.039 Retired 45 18 40.0% 11 24.4% 0.092 P=0.116 P=0.311 Family income ≤ SR 6,000 (≤ $1600) 178 29 16.3% 23 12.9% 0.362 SR 6,001-9,000 ($1600-2400) 194 32 16.5% 16 8.2% 0.011 > SR 9,000 (> $2400) 158 15 9.5% 15 9.5% >0.95 P=0.076 P=0.004 Family size ≤5 261 34 13.0% 14 5.4% 0.001 6-10 691 57 8.2% 58 8.4% >0.95 >10 235 25 10.6% 32 13.6% 0.324 P<0.001 P=0.157 Geographic region Central region 763 66 8.7% 77 10.1% 0.242 Eastern region 313 56 17.9% 20 6.4% <0.001 Western region 293 5 1.7% 27 9.2% <0.001 P<0.001 P=0.103 Cigarette smoking Never 1220 94 7.7% 114 9.3% 0.088 Current/previous 136 29 21.3% 7 5.1% <0.001 P<0.001 P=0.587 Hookah (shisha) smoking Never 1282 103 8.0% 116 9.0% 0.298 Current/previous 70 18 25.7% 5 7.1% 0.002 * p-values in the right-sided column indicate the differences in LTBI between TST and QFT-GIT while p-values in the fourth and sixth columns (Italic font) indicate the differences within each test alone between the groups defined by the characteristics of the studyparticipants Characteristics
Tested
TST N 127
18
S1201-9712(17)30109-1 http://dx.doi.org/doi:10.1016/j.ijid.2017.03.024 IJID 2913
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
13-12-2016 22-3-2017 31-3-2017
Please cite this article as: Balkhy Hanan H, El Beltagy Kamel, El-Saed Aiman, Aljasir Badr, Althaqafi Abdulhakeem, Alothman Adel F, Alshalaan Mohammad, AlJahdali Hamdan.Prevalence of Latent Mycobacterium Tuberculosis Infection (LTBI) in Saudi Arabia; Population based survey.International Journal of Infectious Diseases http://dx.doi.org/10.1016/j.ijid.2017.03.024 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Prevalence of Latent Mycobacterium Tuberculosis Infection (LTBI) in Saudi Arabia; Population based survey Running title: Prevalence of latent TB in Saudi Arabia
Hanan H. Balkhya,b,c, Kamel El Beltagyc,d, Aiman El-Saedc,e, Badr Aljasira,f, Abdulhakeem Althaqafia,c, Adel F. Alothmana,g, Mohammad Alshalaana,h, Hamdan Al-Jahdali a,g.
King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Kingdom of Saudi Arabiaa King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Kingdom of Saudi Arabiab Infection Prevention and Control Department, King Abdulaziz Medical City, National Guard Health Affairs, Saudi Arabiac; Public health & Community Medicine Department, Faculty of Medicine, Tanta University, Egyptd; Public health & Community Medicine Department, Faculty of Medicine, Mansoura University, Egypt e, Preventive Medicine Department, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Saudi Arabiaf Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Saudi Arabiag Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Saudi Arabiah
Corresponding Author: Hanan H. Balkhy King Saud bin Abdulaziz University for Health Sciences Mail Code: 2134 P.O. Box 22490 11426 Riyadh City Saudi Arabia Tel: +966 11 80 43761 Fax : +966 11 80 43733 Email: [email protected]
1
HIGHLIGHTS
The overall prevalence of LTBI was 9.3% using TST and 9.1% using QFT-GIT
The prevalence rates were variable by several sociodemographic characteristics
ARTI data in Saudi Arabia has not been updated since 1993
The overall ARTI was 0.36% using TST and 0.35% using QFT-GIT
The current prevalence of LTBI and ARTI are much lower than reported before
ABSTRACT BACKGROUND: The annual risk of tuberculosis infection (ARTI) data in Saudi Arabia has never been updated since 1993. OBJECTIVES: To estimate the prevalence of latent TB infection (LTBI) and ARTI in a population-based sample in Saudi Arabia using Tuberculin skin test (TST) and QuantiFERON TB Gold in tube (QFT-GIT) test. METHODS: A populationbased cross sectional study was conducted between July 2010 and March 2013. Participants were randomly selected from the population served by the primary healthcare centers of the Ministry of National Guard Health Affairs in Riyadh, Jeddah, Alhassa and Dammam, Saudi Arabia. RESULTS: A total 1369 participants were included. The overall prevalence of LTBI was similar using TST and QFT-GIT (9.3% and 9.1% respectively, p=0.872) but stratified prevalence rates were variable in all sociodemographic groups except marital status. Additionally, the prevalence rates of LTBI using either test alone showed significant differences by several sociodemographic and behavioral characteristics. The overall ARTI was 0.36% using TST and 0.35% using QFT-GIT. CONCLUSIONS: We are reporting much lower estimates for the prevalence of LTBI and the ARTI in a population-based sample in Saudi Arabia relative to the data that have been used for more than two decades.
2
KEYWORDS: Latent Tuberculosis Infection, Prevalence, QuantiFERON TB Gold test, Tuberculin Skin Test, Saudi Arabia
INTRODUCTION Tuberculosis (TB) continues to be a global health problem. It is a leading cause of morbidity and mortality in several parts of the world.1 World Health Organization (WHO) estimated that onethird of the world population is currently infected with the TB bacillus, with approximately 5% to 10% of them has been or will get sick or infectious at some point during their life.2 Latent tuberculosis infection (LTBI) is defined as lack of clinically manifested active TB in a person who has persistent immune response to stimulation by Mycobacterium tuberculosis antigens.3 LTBI is detected either by tuberculin skin testing (TST) or by QuantiFERON Gold in tube (QFT-GIT) test. This detection provides an opportunity to treat LTBI and prevent progression of TB infection to active TB disease.4 The annual risk of tuberculosis infection (ARTI) which is defined as the probability of acquiring new tuberculosis infection or re-infection over a period of one year, is a sensitive indicator of the extent of transmission of tubercule bacilli as well as the effeciency of case finding and treatment programs.5-7 Monitoring TB infection overtime is challenged by several factors including the varaibility of Bacillus Calmette–Guérin (BCG) vaccination, lack of large scale surveys, and limitations of reporting systems.1 8 As ARTI is the most reliable indicator for trending tuberculosis infection,810
there is a need for updated population based estimates of LTBI prevelance. In Saudi Arabia,
such data is clearly outdated as the last community-based survey of the epidemiology of LTBI was conducted in 1993.7 11 12 Obviously, this data did not reflect the major changes that have happened in socioeconomic standards and TB management in Saudi Arabia in the last three decades. Additionally, the impact of using QFT-GIT in estimating LTBI prevalence and ARTI 3
has never been adequately examined in a population-based sample in Saudi Arabia.13-15 The objective of the current study was to calculate recent estimates of the prevalence of LTBI and ARTI in a Saudi population-based sample. METHODS Setting: The study was conducted in primary care centers of the Ministry of National Guard Health Affairs (MNGHA). There are over 27 primary care centers serving a population greater than one million, distributed in the three main regions in Saudi Arabia; Central, Western and Eastern regions. Eleven primary health care centers in Riyadh, Jeddah, Alhassa & Dammam served as primary study sites for enrollment of study participants from their catchment areas. Design: A population-based cross-sectional study was conducted between July 2010 and March 2013. The study was approved by the institutional review board (IRB) of King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia. Population: The study was conducted among the population eligible to receive healthcare services at one of the selected primary care centers of the MNGHA. Inclusion criteria included Saudi Nationals aged five years or older who were able to frequent one of the study sites. Exclusion criteria included children below five years of age (to exclude the BCG vaccination effect on the results of the study as it is given routinely at birth for all newborns in Saudi Arabia), those with current or previous active pulmonary TB disease, those with diagnosis of TB infection and on anti TB prophylaxis, and those with immunocompromised disease or a condition such as patients with leukemia, lymphoma, other cancers under chemotherapy, hemodialysis, organ transplantation, chronic steroid or immunosuppressive therapy, or HIV (self-reported). Recruitment: Stratified random sampling technique with age and gender proportional to the distribution of the served primary care population was used to randomly choose the participants. 4
The study coordinator contacted the selected participants, explained the aim of the study and invited them to join. Study objectives and testing details were explained to each subject or one of his/her parents (in cases of children). Informed consent was obtained before filling out the study questionnaire, which included questions about the participant’s socio-demography (age, gender, marital status, education, occupation, family income, and residence), behavior (cigarette smoking and hookah “shisha” smoking), medical history (to ensure absence of exclusion criteria), and family history (tuberculosis). LTBI testing: From each subject a 3-ml blood sample was collected by venipuncture for the QFT-GIT assay then TST (0.1 mL of tuberculin PPD using 5 unit ampoules) was injected intradermally into the volar aspect of the forearm, and the transverse induration diameter was measured 48-72 hours later. The positive interpretation of a TST is an area of induration of ≥10 mm in diameter. QFT-GIT was conducted by the central laboratory of the MNGHA. The cut-off for QFT was TB antigen tube value minus the Nil tube value ≥0.35 IU/mL. Statistical analysis: All categorical variables were presented as frequencies and percentages while continuous variables were presented as means and standard deviations. The prevalence of LTBI was defined as the percentage of positive TST or QFT-GIT relative to those who were tested. McNemar test was used to compare the prevalence of LTBI between TST and QFT-GIT within each sociodemographic and behavioral group. Chi-square test was used within each test alone to compare the prevalence of LTBI between the levels of sociodemographic and behavioral groups. ARTI was calculated using the standard formula R = 1−(1−Prevalence) 1/A +0.5 where R is the probability of being infected in any one year and A is the mean age.6 Because the age (in full years) of each child at their last birthday was used, 0.5 was added to the mean age for the calculation of ARTI. P-value <0.05 was considered significant. SPSS software (release 20.3, Armonk, NY: IBM Corp) was used for all statistical analyses. 5
RESULTS Out of 1745 contacted, 1443 Saudi participants accepted to be included in the study, with response rate of 82.7%. Out of 1443 participants, 74 (5%) were excluded from the study because of unavailability of QFT-GIT results (as a result of poor handling and transport of the blood sample, 38 participants), indeterminate results of QFT-GIT (27 participants), unavailability of TST readings (due to not showing back within 72 hours, 5 participants) and age less than 5 years (3 participants). The data of the rest of the participants (1369) with complete testing information was used for analysis. As shown in Table 1, 597 (43.6%) out of the 1369 participants included were males and 772 (56.4%) were females. The mean age was 26.3±19.0 years, with the majority (80%) below 45 years; 43.2% were 5-14 years old and 36.7% were 15-44 years. More than half (57.6%) of the participants were single while 40% were married. Approximately 90% of the participants had secondary education or lower, with 13.2% were illiterate. More than half (57.6%) of the participants were students while only 15.3% were military employees and 13.4% were housewives. The median monthly family income was SR 8000 ($2133), with the most frequently reported income between SR 6000 ($1600) and SR 9000 ($2400). The mean household family size was 8 members, with the most frequently reported family size between 6 and 10 family members. Approximately 55.7% of the included participants were from Central region, 22.9% from Eastern region and 21.4% from Western region of Saudi Arabia. The great majority of study participants had never smoked cigarettes (90%) or never smoked shisha (94.8%) while only 10% and 5.2% were either current or previous smokers of cigarette and/or shisha, respectively. The overall prevalence of LTBI was 9.3% using TST and 9.1% using QFT-GIT (Table 2). While the overall prevalence of LTBI was not different between the two tests (p=0.872), there were significant differences in the prevalence rates between TST and QFT-GIT after stratifying 6
by the levels of all sociodemographic and behavioral groups, except marital status. Additionally, the prevalence rates of LTBI using either test alone showed significant differences across the levels of several sociodemographic and behavioral characteristics. For example as shown in Table 2 and Figure 1, the highest prevalence of LTBI was observed among those aged ≥45 years using TST (19.2% in those aged 45-64 years and 18.1% in those ≥65 years) and ≥65 years using QFT-GIT (40.3%). The prevalence decreased with decreasing age using both tests and the lowest prevalence was observed in children aged 5-14 years (2.9% by TST and 3.6% by QFT-GIT). Males showed a higher prevalence than females using TST (12.9% vs 6.5%) but not using QFTGIT (9.2% vs 8.9%). In both tests, divorced/widowed had the highest prevalence while singles had the lowest prevalence (30.3% vs 4.2% using TST and 42.4% vs 5.1% using QFT-GIT). Illiterates using both testes (12.0% by TST and 18.9% by QFT-GIT) and those with University and above education using TST (16.4%) had the highest prevalence while primary education had the lowest prevalence (4.3% using TST and 5.5% using QFT-GIT). Retired (40.0% using TST) and unemployed (28.3% using QFT-GIT) had the highest prevalence while students had the lowest prevalence (3.3% using TST and 4.9% using QFT-GIT). Using TST, the prevalence was higher among those living in the Eastern region and current/previous smokers with no significant differences by family income and size. Using QFT-GIT, the prevalence was higher among those with bigger family size with no significant differences by family income, residence, and smoking status. The overall ARTI was 0.36% using TST and 0.35% using QFT-GIT (Figure 2). ARTI was higher among males than females (0.46% vs 0.32%) using TST and among females than males (0.38% vs 0.27%) using QFT-GIT.
7
DISCUSSION The current study is considered the first population-based survey examining the epidemiology of tuberculosis infection in Saudi Arabia in more than two decades and the first study ever to examine LTBI using both TST and QFT-GIT in a population-based sample. The last populationbased survey was published by Al-Kassimi et al in 1993 based on data from 7721 participants aged 5 to 65 years who were screened using TST only.11 Overall as well as age- and genderstratified prevalence of LTBI in Al-Kassimi et.al was much higher than those reported in the current TST rates. For example, the overall prevalence was 33.2% in the Al-Kassimi study compared with 9.3% in the current study. Additionally, the prevalence of LTBI among males and children aged 5-14 were 43% and 5.6% (respectively) in the Al-Kassimi study compared with 12.9% and 2.9% (respectively) in the current study. However, in both Al-Kassimi and current studies the prevalence of LTBI was higher in older age group, in males, and extremes of educational status. The discrepancy in infection rates between the current and previous studies
11 12
can be
explained by the significant decrease in the prevalence of the TB disease during the last three decades. For example, the WHO and official estimates of the prevalence of TB in Saudi Arabia showed a decrease from 86 per 100,000 in 1990 to 55 per 100,000 in 2004 to 10.6 per 100,000 in 2015 compared to global average of 133 per 100,000.16 17 The observed significant difference in the prevalence of LTBI using TST and QFT-GIT has been reported in several studies.13
15 18
However, explaining such differences is difficult as both tests do not measure the same components of the immunologic response and the concordance was shown to be only fair to moderate. 19 The higher prevalence in old age is generally reflecting accumulated exposure over previous decades. However, the clearer association with old age using QFT-GIT compared with TST may reflect that the high TST false negative results in old age 9, the lower concordance of 8
both tests in older population,19 and the probable higher waning of the T-cell mediated immune response to TST than to QFT
20
. Similar to the current finding, the higher prevalence of LTBI
using TST in males irrespective of BCG vaccination has been reported in Saudi Arabia and was attributed to the higher risk of exposure.11 The higher prevalence of LTBI in illiterates, divorced/widowed , and retired participants in our study using both tests may reflect the fact that the majority of them were aged 45 years or older. Additionally, all retired participants were males. However, the higher prevalence of LTBI using TST among those who had University degree cannot be explained on the basis of age or gender distribution (after subgroup analysis) and should be interpreted with caution given the small number of this group. The ARTI was estimated at 0.35% to 0.36% in the current study, using TST and QFT-GIT. We did not present the ARTI estimates by different sociodemographic characteristic of the study participants (as we did of the prevalence of LTBI), as the ARTI is a population-based tool that was primarily designed to model the changes in transmission patterns by serial estimations of the disease risk over a given period of time rather than comparing the risk in specific groups of the population.6 Since we did not have serial estimations of ARTI, we compared our ARTI with previously available Saudi estimates of ARTI that were based on TST survey done between 1987-1988.7 In that data, the ARTI was estimated among participants less than 35 years; ranging between 0.5% in children 5 to 8 years and 4.7% in adults 24 to 34 years.7 Obviously the current ARTI estimates were much lower; this may be due to the different methods used in calculation of ARTI and non-inclusion of individuals above 35 years in El-Kassimi study. Similar to the prevalence of LTBI, the lower ARTI in the current study can be explained by the significant decrease in the incidence of TB disease in Saudi Arabia during the last three decades; from 50 per 100,000 in 1990 to 40 per 100,000 in 2004 to 12 per 100,000 in 2014.1 17 This decrease may reflect better local management of cases and a global trend of decreasing incidence and 9
prevalence of TB.21
22
However, there is still a wide international variability in the ARTI
estimates which range between 4.2% in South Africa and 0.03% in the United States. Considering Saudi incidence rates, more work needs to be done to move from the moderate burden countries to low burden countries (incidence less than 10 per 100,000) with much lower ARTI. The ARTI can also used to estimate the load of new sputum smear-positive cases in the community by using Styblo’s formula.10 Therefore, the estimated 0.36% ARTI in the current study is equivalent to approximately 18 new smear positive case per 100,000 population per year.10 Given the current ARTI estimates (0.36%) and the reported estimates of Saudi population (21,130,000 during 2015),16 the expected number of new smear-positive cases is 3803 plus the additional cases among other 7.1 million expatriates in Saudi Arabia. Interestingly, a total of 3346 TB (pulmonary and extra-pulmonary) cases were actually reported to the Saudi Ministry of health in 2015. The slight difference between the current estimates and the case reported may reflect the estimated 16% missing case detection rate.1 The major strengths of the current study were the stratified random sampling technique used in recruitment, the relatively large number of study participants, and the inclusion of the main three geographic regions in Saudi Arabia, the use of both TST and QFT-GIT in testing for LTBI, and the calculation of both prevalence and ARTI. Nevertheless, we acknowledge a number of limitations; the cross-sectional design does not detect causal relationship with risk factors. The current findings should be generalized cautiously to other populations in Saudi Arabia as the National Guard population is not identical to typical Saudi population. For example, the study population had higher percentage of military personnel, children <15 years, students, and females. Additionally, they were exclusively Saudi nationals with no history of TB diagnosis or treatment. Additionally, since we did not have serial estimations of ARTI in our 10
population which probably had also a changing LTBI prevalence, we could not estimate the changes in TB transmission in our population. However, we believe that the current ARTI estimates may serve as recent baseline estimates for future comparisons by similar populations. In conclusion, we are reporting much lower estimates for the prevalence of LTBI and the ARTI in a Saudi community compared with the data that has been used for more than two decades. While this may indicate improved TB care over the last two decades, there is still a potential for more improvement.
Funding : by King Abdullah International Medical Research Center (KAIMRC), grant number RC-09-093, Ministry National Guard Health Affairs, Kingdom of Saudi Arabia. Ethical approval: IRB of KAIMRC approved the current study
Conflict of interest: no conflict of interest
Acknowledgment: We greatly appreciate the contributions of all data collectors, which made this study possible
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30% Male
Prevalence of LTBI using TST
Female
22.5%
21.4%
20% 16.9%
16.1%
15.9%
10% 5.7% 3.6% 1.5% 0% <15
15-44
45-64
≥65
Age and gender groups
Male
Prevalence of LTBI using QFT-GIT
50%
50.0%
Female
34.1%
25%
19.4% 16.2%
3.0% 3.9%
6.7%
8.5%
0% <15
15-44
45-64
≥65
Age and gender groups
Figure 1: Prevalence of LTBI using TST and QFT-GIT by age and gender groups The prevalence of LTBI was significantly different by age groups in both tests and in both genders (p<0001 in each). The prevalence of LTBI was significantly different by gender, only in age group 15-44 years using TST (p<0001).
15
TST 0.5%
QFT-GIT
0.46%
ARTI estimates
0.38%
0.36% 0.35%
0.32% 0.27% 0.3%
0.0% Male
Female
Total
Gender groups
Figure 2: Annual risk of tuberculosis infection (ARTI) using TST and QFT-GIT by gender groups ARTI was not significantly different by gender using TST nor QFT-GIT.
16
Table 1: Sociodemographic characteristics of the study participants Characteristics Age (years) Mean ± SD <15 15-44 45-64 ≥65 Gender Male Female Marital status Single Married Divorced/widowed Education Illiterate Primary school Mid/high school University and above Occupation Military Civilian Housewife Student Unemployed Retired Family income Median & IQR, SR Median & IQR, $ ≤ SR 6,000 (≤ $1600) SR 6,001-9,000 ($1600-2400) > SR 9,000 (> $2400) Family size Median & IQR ≤5 6-10 >10 Geographic region Central region Eastern region Western region Cigarette smoking Never Current &/previous Hookah (shisha) smoking Never Current&/previous
Value* 26.3±19.0 591 (43.2%) 502 (36.7%) 204 (14.9%) 72 (5.3%) 597 (43.6%) 772 (56.4%) 782 (57.6%) 543 (40.0%) 33 (2.4%) 175 (13.2%) 559 (42.3%) 455 (34.4%) 134 (10.1%) 183 (15.3%) 67 (5.6%) 161 (13.4%) 691 (57.6%) 53 (4.4%) 45 (3.8%) SR 8,000 (5,500-10,000) $ 2133 (1467-2667) 178 (33.6%) 194 (36.6%) 158 (29.8%) 8 (6-10) 261 (22.0%) 691 (58.2%) 235 (19.8%) 763 (55.7%) 313 (22.9%) 293 (21.4%) 1220 (90.0%) 136 (10.0%) 1282 (94.8%) 70 (5.2%)
* Number (percentage) unless mentioned otherwise. SD, standard deviation; IQR, inter-quartile range
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Table 2: Prevalence of LTBI using TST and QFT-GIT by the characteristics of the study participants QFT-GIT p-value* % N % 1369 9.3% 124 9.1% 0.872 Overall P<0.001 P<0.001 Age (years) <15 591 17 2.9% 21 3.6% 0.523 15-44 502 57 11.4% 38 7.6% 0.040 45-64 204 40 19.6% 36 17.6% 0.618 ≥65 72 13 18.1% 29 40.3% <0.001 P<0.001 P=0.860 Gender Male 597 77 12.9% 55 9.2% 0.023 Female 772 50 6.5% 69 8.9% 0.027 P<0.001 P<0.001 Marital status Single 782 33 4.2% 40 5.1% 0.410 Married 543 83 15.3% 68 12.5% 0.151 Divorced/widowed 33 10 30.3% 14 42.4% 0.125 P<0.001 P<0.001 Education Illiterate 175 21 12.0% 33 18.9% 0.036 Primary school 559 24 4.3% 31 5.5% 0.281 Mid/high school 455 54 11.9% 40 8.8% 0.103 University and above 134 22 16.4% 11 8.2% 0.043 P<0.001 P<0.001 Occupation Military 183 33 18.0% 11 6.0% <0.001 Civilian 67 16 23.9% 6 9.0% 0.013 Housewife 161 16 9.9% 22 13.7% 0.263 Student 691 23 3.3% 34 4.9% 0.108 Unemployed 53 8 15.1% 15 28.3% 0.039 Retired 45 18 40.0% 11 24.4% 0.092 P=0.116 P=0.311 Family income ≤ SR 6,000 (≤ $1600) 178 29 16.3% 23 12.9% 0.362 SR 6,001-9,000 ($1600-2400) 194 32 16.5% 16 8.2% 0.011 > SR 9,000 (> $2400) 158 15 9.5% 15 9.5% >0.95 P=0.076 P=0.004 Family size ≤5 261 34 13.0% 14 5.4% 0.001 6-10 691 57 8.2% 58 8.4% >0.95 >10 235 25 10.6% 32 13.6% 0.324 P<0.001 P=0.157 Geographic region Central region 763 66 8.7% 77 10.1% 0.242 Eastern region 313 56 17.9% 20 6.4% <0.001 Western region 293 5 1.7% 27 9.2% <0.001 P<0.001 P=0.103 Cigarette smoking Never 1220 94 7.7% 114 9.3% 0.088 Current/previous 136 29 21.3% 7 5.1% <0.001 P<0.001 P=0.587 Hookah (shisha) smoking Never 1282 103 8.0% 116 9.0% 0.298 Current/previous 70 18 25.7% 5 7.1% 0.002 * p-values in the right-sided column indicate the differences in LTBI between TST and QFT-GIT while p-values in the fourth and sixth columns (Italic font) indicate the differences within each test alone between the groups defined by the characteristics of the studyparticipants Characteristics
Tested
TST N 127
18