Assessment of children in contact with sputum positive adult patients with respect to TB disease and latency
ORIGINAL RESEARCH
Correspondence: Dr. Rakesh Thamke, Department of Pediatrics, MGM Medical College Kamothe, Navi Mumbai-410209
Received: 20 Th August,2018, Reviewed:14th October 2018, Accepted:11 Th December 2018
Citation Of Article: Rakesh Thamke, Vijay kamale,Ragi Rajan Assessment of children in contact with sputum positive adult patients with respect to TB disease and latency; New Indian Journal Of Pediatrics 7:4
ORIGINAL RESEARCH
ABSTRACT: Introduction: Tuberculosis (TB) contacts are people who have close contact with patients with infectious TB. TB contacts should be investigated systematically and actively for TB infection and disease. Such interventions are called ‘tuberculosis contact investigations’. They contribute to early identification of active TB, thus decreasing its severity and reducing transmission of Mycobacterium tuberculosis to others, and identification of latent TB infection (LTBI), to allow preventive measures. The present study was undertaken to study epidemiological,socio-economic ,clinical factors in contact children of sputum positive cases. During study ,investigations were also carried out to differentiate stages of tubercular infection ,latency and disease. Aims & Objectives: 1. To identify children in contact with adult index case and to assess contact investigation according to WHO guidelines.2. Evaluate socioeconomic and Clinical parameters3. Investigate as per guidelines and perform IGRA. 4. To find proportion of infection, disease and latency in contact children. Materials and Methods Study Design: It was a prospective observational study, conducted in MGM Medical College and Hospital which is a tertiary care referral unit in Navi Mumbai, Raigad District of Maharashtra. Study Period: The study was performed over a period from April 2015 to October 2016. Sample Size: (80) SS = Z 2 x P x (1-P) 2 Z: value (1.96 for 95% CI) P: % of picking choice C: confidence interval. Sampling Technique: Selection of index cases: An index case was defined as a newly pulmonary tuberculosis case in DOTS OPD (confirmed by 3 consecutive sputum smears positive for acid-fast bacilli and/or positive culture).Selection of contacts: Children contacts were defined as a family members or living with the index case in the same house before the starting of tuberculosis treatment of index case. They were recruited into study, and consent was obtained from the parent/representatives to undertake the study.
Methodology: This was a prospective observational study consisting of 80 contact children, of smear positive PTB. The parents were interviewed using a standard questionnaire to obtain demographic and socio-economic information of the household and the health condition of the children. After the interview, children were examined by a clinician as well as nutritional assessment was done according to WHO Protocol and necessary laboratory tests (x-ray, induced sputum and gastric lavage) were done to rule out active TB. All children were given a TST and 3 ml of blood was obtained for laboratory tests for IGRA. Conclusion: Active tuberculosis (TB) and TB Infection is common among household contacts of index cases in India, especially among young children. Although all children with household exposure have a high risk of contracting the infection and disease, specific risk factors include severity of disease in cases and the intensity of exposure of the child.
Present study found that IGRAs is a good diagnostic tool for the diagnosis of latent tuberculosis infection as well as active disease.
Keywords: Active tuberculosis, Latent tuberculosis, IGRA, TST, Mantaux test
INTRODUCTION: Tuberculosis (TB) contacts are people who have close contact with patients with infectious TB. TB contacts should be investigated systematically and actively for TB infection and disease. Such interventions are called ‘tuberculosis contact investigations’. They contribute to early identification of active TB, thus decreasing its severity and reducing transmission of Mycobacterium tuberculosis to others, and identification of latent TB infection (LTBI), to allow preventive measures.
Contacts are commonly investigated in high-income countries with low TB burdens and in settings in which a TB elimination policy is implemented, in order to identify persons with early active TB or who have recently been infected. People identified as infected are then treated for LTBI with isoniazid for at least 6 months (usually 9 months) or with shorter combination regimens including isoniazid and rifampicin.
TB contact investigations are rarely and inconsistently carried out in resource-limited settings. In most low- and middle-income countries, it is included in the national policy to control and prevent TB; however, in the vast majority of countries, it is either not undertaken or is implemented on the basis of no or poor standards, because of the absence of clear definitions of index cases, contacts and procedures. Furthermore, the health personnel who should be involved are usually not clearly identified.
Information on the contribution of routine contact investigations to early TB case detection is scarce in these countries or is non-standardized, thus precluding an assessment of its impact on reducing transmission.
Many studies in countries with a high TB incidence have shown that the prevalence may reach 5% or more among contacts, particularly among household members. Other data suggest that contact investigations could be particularly useful for identifying childhood TB.
WHO estimates show that, worldwide, highly infectious, smear-positive pulmonary TB develops in over 4 million people annually. If we assume that each of these patients has at least three close contacts, such as in their household, and that the prevalence of active TB among the close contacts is 2.5%, the number of early TB cases that could be identified among close contacts is at least 300 000 per year.
Early identification means a better chance of cure and, especially, a reduction in further transmission. Furthermore, contact investigation allows identification of people who are latently infected and at high risk for active TB, who can be treated preventively.(1,2,3) The present study was undertaken to study epidemiological, socio-economic ,clinical factors in contact children of sputum positive cases. During study, investigations also carried out to differentiate stages of tubercular infection, latency and disease.
AIMS & OBJECTIVES:
1. To identify children in contact with adult index case and to assess contact investigation according to WHO guidelines.
3. Evaluate socioeconomic and Clinical parameters
4. Investigate as per guidelines and perform IGRA.
5. To find proportion of infection, disease and latency in contact children.
MATERIALS AND METHODS STUDY DESIGN: It was a prospective observational study, conducted in MGM Medical College and Hospital which is a tertiary care referral unit in Navi Mumbai, Raigad District of Maharashtra.
Study Period: The study was performed over a period from April 2015 to October 2016.
Sample Size: (80) SS = Z 2 x P x (1-P) 2 Z: value (1.96 for 95% CI) P: % of picking choice C: confidence interval.
Sampling Technique:
Selection of index cases: An index case was defined as a newly pulmonary tuberculosis case in DOTS OPD (confirmed by 3 consecutive sputum smears positive for acid-fast bacilli and/or positive culture).
Selection of contacts: Children contacts were defined as a family members or living with the index case in the same house before the starting of tuberculosis treatment of index case. They were recruited into study, and consent was obtained from the parent/representatives to undertake the study.
Inclusion Criteria: Contact children from 6 months to 15 yr.
Exclusion Criteria: Children with immunodeficiency.
Methodology: This was a prospective observational study consisting of 80 contact children, of smear positive PTB. The parents were interviewed using a standard questionnaire to obtain demographic and socio-economic information of the household and the health condition of the children. After the interview, children were examined by a clinician as well as nutritional assessment was done according to WHO Protocol and necessary laboratory tests (x-ray, induced sputum and gastric lavage) were done to rule out active TB. All children were given a TST and 3 ml of blood was obtained for laboratory tests for IGRA.
Tuberculin Skin Test: All the children received 2 TU of PPD RT 23 with Tween 80 injected on the volar aspect of arm using the Mantoux method on the day of the initial visit. TST readings were obtained using the palpation method where horizontal diameter of the induration to the long axis of the arm was measured (WHO, 2006b) at 48-72 hours by trained laboratory technicians and results were classified according to the degree of indurations as negative (<5 mm), intermediate (5 to 9 mm) and positive (≥ 10 mm).
IGRAs: The test was performed by drawing 1 ml of blood into one of each of the three manufacturer-precoated, heparinised tubes. Within 16 hours of blood collection, the tubes were incubated for another 16 to 24 hours at 37 °C. The plasma was harvested after centrifugation (tubes contain a gel plug that separates the plasma from the cells when centrifuged) and used to assess the concentration of IFN-γ by ELISA test.
ELISA assay(3)-Immunocheck TB Platinum(IGRA) Make-Immunocheck
– 50 μl of working conjugate added to each well, then 50 μl of plasma or standard was added.
– The covered plate was shaked for 1 minute, and then incubated for 120 minutes at room temperature.
– The plate was washed 6 times with washing buffer and 100 μl substrate was added & incubated for 30 minutes at room temperature.
– 50 μl stop solution was added and absorbance was read at 450 nm (620 ref) – IFN-γ values (IU/ml) for TB-specific antigens were corrected for background by subtracting the value obtained for the respective negative control.
As recommended by the manufacturer, the cut-off value for a positive test was IFN-γ ≥ 0.35 IU/ml.
Treatment: All active cases were treated with AKT according to RNTCP guidelines, rest children less than 6 years old with latent infection received INH chemoprophylaxis.
RESULTS: Most of the contacts were in between 5 to 10 years of age (57.5%). Rest 35% were <5 years and 7.5% were more than 10 years. Distribution of gender was done and out of total 80 contacts, 53.8% were males while 46.3% were females.
We had 43 index cases and 80 contact children related to them .The distribution of cases based on sputum grade out of 43 index cases 30.2% had +1 sputum positivity while 46.5% and 23.3% had +2 and +3 sputum positivity.
We assessed the relationship of index and contact cases. In most of the cases index case was either father (48.8%) or mother (18.8%).
We found in our study that BCG scar was absent in 18.8% contacts and was present in 81.3 %.The nutritional evaluation was based on WHO classification of malnutrition.57.5% were normal, 37.5% had chronic malnutrition and 2.5% had Acute and Acute on chronic malnutrition each.
Socio economic status was assessed by modified Kuppuswami scale. Most of the contacts were from lower (57.5%), middle (36.3%) and Upper (11.6%) socio-economic status respectively.
Out of 80 contact cases household size of </=4, 5-6 and > 6 was seen in 43.8%, 31.3% and 25% contacts respectively. Most of the children were asymptomatic; cough was present in (5.3%), weight loss (5%) and fever was seen in 2.5% cases. All the contacts underwent X ray examination of chest; however it is not advised according to RNTCP. Abnormal chest x-ray was seen 8.8% contacts.
Out of 80 contacts Mantoux test was positive in 13 (16.3%) contacts. Out of 80 contacts who were only MT (n=13) or had an abnormal x-ray (n=7) and both x-ray and MT positive (n=6) . Sputum or gastric lavage for AFB was done however we did not find sputum positive in any of the contacts suggesting they are non-infective. Distribution of cases based on Interferon-gamma release assay (IGRAs) results was done and out of 80 contacts IGRA was positive in 34(42.5%) contacts. The prevalence of active TB in contacts was in 7 (8.8%) contacts in our study while latent TB was seen in 27 (33.8%) contacts. All the contacts of active TB were started on AKT as per RNTCP guidelines, while Isoniazid chemoprophylaxis was given in 41 (51.3%).
A significant association was seen between incidences of Tb in contacts with the grade of sputum positivity of cases (p<0.05). The incidence of TB in sputum grade 1 and 2 and 3 was 7.7%, 2.6% and 25%.
In the present study there was no association seen between presence of BCG scar and incidence of TB in contacts (p-0.311), socio-economic status and incidence of TB in contacts (p-0.281) household size and incidence of TB in contacts (p-0.794). In our study there was no association seen between number of rooms and incidence of TB in contacts (p-0.141). A significant association was seen between incidences of Tb in contacts with malnutrition (p<0.01). The incidence of TB was 14.7% in children with malnutrition as compared to 4.3% in those with normal nutritional status.
In our study IGRA was positive in all the cases of active (n=7) and latent tuberculosis (n=27). Out of 80 contact children Abnormal chest x-ray findings was seen in all active TB cases (n=7). Out of 80 contacts Mantoux positivity (> 10 mm) was seen in 85.7% cases with active TB while it was positive in 25.9% cases with latent TB. A significant association was seen between IGRA and MT results (p<0.05). All the IGRA negative cases were negative on MT too while 38.2% cases with positive IGRA results were MT positive. The sensitivity and specificity of IGRA compared to MT in our study was 100% and 68.6% respectively. MT was positive in 85.7% cases with active TB (6/7) and 25.9% cases with latent TB (7/27) while IGRA was positive in all cases of active/ latent disease.
DISCUSSION: The present study was thus conducted to find the incidence of Tuberculosis Infection and active disease in children in contact with adult index case.
Incidence of TB Infection & Disease
The prevalence of active TB in contacts was 8.8% in present study while latent TB was seen in 33.8% contacts.
Studies conducted in the 1960s and 1970s showed that household contacts of individual with TB had higher risk of infection than individuals in the general population (4,5). This was confirmed in several recent studies conducted among children in New York City (6), Botswana (7), and Brazil (8 )in which contact with an individual with TB came out as the strongest risk factor for TB infection.
Guwatudde D et al. (9), Among the 1,206 household contacts, 76 secondary cases (6%) of tuberculosis were identified. The risk for secondary tuberculosis was greater among young children than adults (10% vs. 1.9%). In another study by Gessner et al. (10), Infection developed in 25% of the children and progressed to active disease in 9.6%. In another study by Songpol Tornee et al(11) prevalence of tuberculosis infection among household contacts to be 47.80%. In another study by Hiral H Shah et (12) 90(30%) out of 300 children were positive for the latent infection. In a similar study by Seddon et al. (13) ,4.7% children were classified as infected and 14.7% had TB disease. In a study by Kinikar et al. (14), in 15 (30%) of the 50 pediatric index cases, the household contained known TB contacts, 14 (86%) of whom were adults. Singh et al. 36, in their study observed the prevalence of tuberculosis infection and disease as 33.8% in children with household contacts of sputum positive cases.
Risk Factors
In present study a significant association was seen between incidences of Tb in contacts with malnutrition (p<0.01). The incidence of TB was 14.7% in children with malnutrition as 58 compared to 4.3% in those with normal nutritional status. However no association was seen between SES, household size and no. of rooms with incidence of TB in contacts (p>0.05). Seventy-eight percent of children have received a BCG vaccination according to NFHS-3 55. In our study we found that BCG scar was present in 81.3 percent contacts while BCG was not given in 18.8 percent.
It is now universally accepted that the risk of acquiring TB is directly proportional to the number of bacilli to which a subject is exposed (15). In the first place, it depends on the characteristics of the source case: contagiousness is generally limited to subjects with lung disease, and is greater among the patients with bacilleferous forms (i.e. those with positive microscopic test results), in whom the estimated transmission rate is about 35% as against the 17% observed among those with non-bacilleferous forms (16). Similarly, it is important to evaluate the time spent in an enclosed space with the source case.
The effect of the combination of these two variables has been clearly shown in studies of the contacts arising during air flights (17). Living together gives rise to the greatest exposure to TB: this has been documented in studies such as that of Singh et al. who evaluated the prevalence of TB in children living with adults with active TB and found a significant difference between those living with adults with microscopic positive or negative expectorate (respectively 68.4 and 31.6%) (18).
A recent meta-analysis (19) has shown that contact with expectorate positive TB patients is a factor indicating a similar risk of infection in both high income (odds ratio [OR] 3.3; 95% confidence interval [CI] 2.2–4.8) and low income countries (OR 3.3; 95% CI 2,2– 5.1). The risk of acquiring tuberculous infection is particularly high in children who live with expectorate-positive adults (relative risk [RR] 6.78; 95% CI 3.51–13.10) or adults with cavitating lesions revealed by chest X-ray (RR 2.45; 95% CI 1.60–3.76), or in those who have close contacts with drug users (RR 1.81; 95% CI 1.03–3.19)( 20,21). Children whose families include women with TB are exposed to an even higher risk (RR 1.34; 95% CI 1.34–3.14), probably because their contacts are more frequent than in the case of male relatives. One case-control study carried out in Thailand found that the risk of developing the disease was high in children having any kind of contact with TB patients (very close: OR 85.67; 95% CI 33–647.79; p < 0.001; close: OR 31.11; 95%CI 4.18–255.94; p = 0.001; not close: OR 32.70; 95% CI 4.18–255.94; p < 0.001).(22) In present study too, we observed a significant association between incidences of TB in contacts with the grade of sputum positivity of cases (p<0.05). The incidence of TB in sputum grade 1 and 2 and 3 was 7.7%, 2.6% and 25%. Living arrangements and housing conditions play an important role: a case-control study carried out in Bangladesh (23)found that co-dwellers were protected against transmission if there were < 2 people per bedroom (OR 0.29; 95% CI 1.79–6.03; p < 0.0001), if the kitchen was separated from the bedroom (OR 0.35; 95% CI 0.2–0.62; p = 0,001), and if the home was adequately ventilated (OR 0.25; 95% CI 0.13–0.49; p < 0.0001). The risk of transmission is also affected by overcrowding and the economic conditions of the family (OR 1.35; 95% CI 1.06–1.72; p < 0.017). 4 as well as by an inadequate supply of food (OR 1.52; 95% CI 1.15–2.02; p < 0.003) .(24)
Diagnosis
In present study Interferon-gamma release assay (IGRAs) was positive in 34 (42.5%) cases, out of which X-ray was abnormal in 7 cases (8.8%) showing presence of active disease. All the IGRA negative cases were also negative on TST too while only 13 out of 34 (38.2%) cases with positive IGRA results were also TST positive. Thus TST was positive in 85.7% cases with active TB (6/7) and 25.9% cases with latent TB (27/47).
A large number of studies have evaluated the efficacy of IGRAs in diagnosing LTBI (25-29). An IGRA is recommended by WHO, for subjects who have been vaccinated with BCG in order to confirm /exclude the presence of TB in subjects with a positive TST 21.
It is therefore recommended that these tests should not be used in individuals suspected of active pulmonary or extra-pulmonary TB, irrespective of their HIV status. This recommendation also applies to paediatric TB based on the generalisation of data from adults.” (30)
Management
The overall prevalence of active TB in contacts was 8.8% in present study while latent TB was seen in 33.8% contacts. All the cases of active TB were started on AKT as per RNTCP guidelines, while isoniazid chemoprophylaxis was given for LTBI cases .The rationale underlying the treatment of LTBI is based on the possibilityof eliminating dormant bacilli, thus reducing their activation and the development of active disease. A Cochrane review has shown that treating LTBI with isoniazid reduces the risk of pulmonary and extra-pulmonary TB and the related deaths, but there does not seem to be any significant difference in the efficacy of 6- and 9-month treatment.(31)
CONCLUSION: Active tuberculosis (TB) and TB Infection is common among household contacts of index cases in India, especially among young children. Although all children with household exposure have a high risk of contracting the infection and disease, specific risk factors include severity of disease in cases and the intensity of exposure of the child. Present study found that IGRAs is a good diagnostic tool for the diagnosis of latent tuberculosis infection as well as active disease. A significant association was seen between incidences of Tb in contacts with malnutrition (p<0.01). The incidence of TB was 14.7% in children with malnutrition as compared to 4.3% in those with normal nutritional status. In our study IGRA was positive in all the cases of active (n=7) and latent tuberculosis (n=27). Out of 80 contact children Abnormal chest x-ray findings was seen in all active TB cases (n=7). Out of 80 contacts Mantoux positivity (> 10 mm) was seen in 85.7% cases with active TB while it was positive in 25.9% cases with latent TB. A significant association was seen between IGRA and MT results (p<0.05). All the IGRA negative cases were negative on MT too while 38.2% cases with positive IGRA results were MT positive. The sensitivity and specificity of IGRA compared to MT in our study was 100% and 68.6% respectively. MT was positive in 85.7% cases with active TB (6/7) and 25.9% cases with latent TB (7/27) while IGRA was positive in all cases of active/ latent disease.
Declarations: Contribution of authors: – Rakesh Thamke-concept ,strategy,;Vijay kamale – supervision and revision of manuscript, guidance , Ragi Rajan -data collection,statistical analysis,,initial manuscript,
Conflict of interest – Nil
Funding source and its role in the study – No
References:
1) Recommendations for investigating contacts of persons with infectious tuberculosis in low- and middle-income countries..World Health Organization. ISBN 978 92 4 150449 2 (NLM classification: WF 205)
2) Global Tuberculosis Report 2018 ISBN 978-92-4-156564-6 © World Health Organization 2018
3)IGRA ASSAY- Immunocheck TB Platinum(IGRA) Make-Immunocheck product information sheet
4) Andersen S, Geser A. The distribution of tuberculous infection among households in African communities. Bull World Health Organ.1960;22 :39– 60
5) Grzybowski S, Barnett GD, Styblo K. Contacts of cases of active pulmonary tuberculosis. Bull Int Union Tuberc Lung Dis.1975;5 :90– 106.
6) Saiman L, San Gabriel P, Schulte J, Pimentel Vargas M, Kenyon T, Onorato I. Risk factors for latent tuberculosis infection among children in New York City. Pediatrics.2001;107:999– 1003.
7) Lockman S, Tappero JW, Kenyon TA, Rumisha D, Huebner RE, Binkin NJ. Tuberculin reactivity in a paediatric population with high BCG vaccination coverage. Int J Tuberc Lung Dis.1999;1 :23– 30.
8) Almeida LM, Barbieri MA, Da Paixao AC, Cueva LE. Use of purified protein derivative to assess the risk of infection in children in close contact with adults with tuberculosis in a population with high Calmette-Guerin bacillus coverage.Pediatr Infect Dis J.2001;20 :1061– 1065
9) Guwatudde D, Nakakeeto M, Jones-Lopez EC, Maganda A, Chiunda A, Mugerwa RD, Ellner JJ, Bukenya G, Whalen CC. Tuberculosis in household contacts of infectious cases in Kampala, Uganda. American Journal of epidemiology. 2003 Nov 1;158(9):887-98.
10) Gessner BD, Weiss NS, Nolan CM. Risk factors for pediatric tuberculosis infection and disease after household exposure to adult index cases in Alaska. The Journal of Pediatrics. 1998 Mar 31;132(3):509-13.
11) Songpol Tornee1, Jaranit Kaewkungwal1 risk factors for tuberculosis infection among household contacts in bangkok, thailand Vol 35 No. 2 June 2004
12) Hiral H Shah1, Halak J Vasavada1 study of transmission of tuberculous infection among children in contact with parents having tuberculosis Volume 3│Issue 3│July – Sept 2013
13) Seddon JA, Hesseling AC, Godfrey-Faussett P, Fielding K, Schaaf HS. Risk factors for infection and disease in child contacts of multidrug-resistant tuberculosis: a cross-sectional study. BMC infectious diseases. 2013 Aug 26;13(1):1.
14) Kinikar A, Adhav PS, Kamble S, Sahoo P, Koli H, Kanade S, Mave V, Suryavanshi N, Gupte N, Gupta A, Mathad J. Source Case Investigation for Children with TB Disease in Pune, India. Tuberculosis research and treatment. 2014;18(2):832-836.
15) Marais BJ, Gie RP, Schaarf HS, Hesseling AC, Obihara CC, Nelson LJ, et al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:278–85.
16) Erikens CGM, Kamphorst M, Abubakar I, Bothamley GH, Chemtob D, Haas W, et al. Tuberculosis contact investigation in low prevalence countries: a European consensus. Eur Respir J 2010;36:925–49.
17) Driver CR, Valway SE, Morgan WM, Onorato IM, Castro KG. Transmission of Mycobacterium tuberculosis associated with air travel. JAMA 1994;272:1031–5.
18) Singh M, Mynak ML, Kumar L, Mathew JL, Jindal SK. Prevalence and risk factors for transmission of infection among children in household contact with adults having pulmonary tuberculosis. Arch Dis Child 2005;90:624–8
19) Fox GJ, Barry SE, Britton WJ, Marks GB. Contact investigation for tuberculosis: a systematic review and meta-analysis. Eur Resp J 2013;41:140–56.
20) Nguyen TH, Odermatt P, Slesak G, Barennes H. Risk of latent tuberculosis infection in children living in households with tuberculosis patients: a cross sectional survey in remote northern Lao People’s Democratic Republic. BMC Infect Dis 2009;9:96.
21) Stout JE, Saharia KK, Nageswaran S, Ahmed A, Hamilton CD. Racial and ethnic disparities in pediatric tuberculosis in North Carolina. Arch Pediatr Adolesc Med 2006;160:631–7.
22) Tipayamongkholgul M, Podhipak A, Chearskul S, Sunakorn P. Factors associated with the development of tuberculosis in BCG immunized children. Southeast Asian J Trop Med Public Health 2005;36:145–50.
23) Karim MR, Rahman MA, Mamun SA, Alam MA, Akhter S. What cannot be measured cannot be done; risk factors for childhood tuberculosis: a case control study. Bangladesh Med Res Counc Bull 2012;38:27–32.
24) Tornee S, Kaewkungwal J, Fungladda W, Silachamroon U, Akarasewi P, Sunakorn P. The association between environmental factors and tuberculosis infection among household contacts. Southeast Asian J Trop Med Public Health 2005;36:221–4.
25) Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007; 146:340.
26) Pai M, Zwerling A, Menzies D. Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update. Ann Intern Med 2008; 149:177.
27) van Zyl-Smit RN, Zwerling A, Dheda K, Pai M. Within-subject variability of interferon-g assay results for tuberculosis and boosting effect of tuberculin skin testing: a systematic review. PLoS One 2009; 4:e8517.
28) Chang KC, Leung CC. Systematic review of interferon-gamma release assays in tuberculosis: focus on likelihood ratios. Thorax 2010; 65:271.
29) Magdorf K, Detjen AK. Proposed management of childhood tuberculosis in lowincidence countries. Eur J Pediatr 2008;167:927–38.
30. Use of tuberculosis interferon-gamma release assays (IGRAs) in low and middle income countries: Policy Statement, World Health Organization, Geneva 2011. Commercial serodiagnostic tests for diagnosis of tuberculosis: Policy Statement. Geneva, World Health Organization 2011.
31.Ongoing trials for treating TB infection include Short and ultra-short course treatment Treatment of MDR TB infectionTechnical Consultation on the Programmatic Management of Latent Tuberculosis Infection,Seoul, Republic of Korea, 31 August – 1 September 2017 WHO
Issue: October-December 2018 [Volume 7.4]