• Pediatric Infection and Vaccine
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• v.9 no.2
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• pp.208-214
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• 2002

Purpose : The number of newborns vaccinated with BCG of Tokyo 172 strain, which has been claimed to cause lesser degree of local adverse events including scar, has recently been increasing. However, tuberculin response to this vaccine has inadequately been studied, especially with newborns cared at primary care clinics. We, therefore, performed a study in newborns vaccinated with BCG at private pediatric offices and evaluated the response to PPD 2TU or PPD 5TU following vaccination with percutaneous or intradermal BCG. Methods : Two hundred infants who had been cared at three private pediatric offices were retrospectively enrolled in the study. One hundred fifty one infants had received percutaneous BCG(Tokyo strain); 129 infants had had tuberuclin test with PPD 2TU and the rest of 22 infants with PPD 5TU. Forty nine infants had received intradermal BCG(28 infants Copenhagen strain, I infant French strain, 20 infants unknown); 35 infants had had tuberculin test with PPD 2TU, 14 infants(11%) with PPD 5TU. Results : In infants vaccinated with percutaneous BCG, the mean induration diameter in tuberculin test was significantly greater with PPD 5TU($12.4{\pm}3.5mm$) compared to PPD 2TU ($9.2{\pm}4.4mm$). In infants vaccinated with intradermal BCG, the mean induration diameters in tuberculin test were $5.7{\pm}5.1mm$ to PPD 2TU and $6.6{\pm}4.8mm$ to PPD 5TU, which were not significantly different. The tuberculin response to PPD 2TU was significantly greater in infants vaccinated with percutaneous BCG compared to those with intradermal BCG. The tuberculin response to PPD 5TU was also significantly greater in infants vaccinated with percutaneous BCG compared to those with intradermal BCG. Conclusion : Percutaneous BCG(Tokyo strain) seems to cause greater response to tuberculin compared to intradermal BCG and PPD 2TU induces weaker response compared to PPD 5TU. Acknowledging some discrepancies from the previously reported data, which might have been due to the different source of the study subjects, more studies are needed to establish the range of tuberculin response following BCG vaccination in order to differentiate from tuberculosis.

• Journal of Animal Science and Technology
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• v.56 no.8
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• pp.32.1-32.4
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• 2014

Though many alternative methods to tuberculin skin testing (TST) have been established and evaluated in recent years, sensitivities and specificities of most methods could not meet the requirements of golden standards. In this study, we sought to identify whether repeated TSTs could affect the immune responses in experimental monkeys. Nine natural tuberculosis (TB) monkeys receiving repeated TSTs biweekly were used to demonstrate the effect on TST responsiveness. Two healthy monkeys were administrated with repeated TSTs to analyze the immune response profiling. Intrapalpebral reactions in TB infections gradually weakened or presented intermittent positive reactions. The leukocyte counts, cytokine responses, and antibody responses to all antigens except Old tuberculin (OT) and MPT64L showed no specific changes for TB in healthy monkeys. Positive antibody responses to OT and MPT64L emerged during the first half experimental period, which may cause by their cross-reactivity with mycobacterial species. Results showed that repeated TSTs had no significant effects on immune responses in healthy monkeys but a progressive reduction in TST responsiveness in TB infections.

• Tuberculosis and Respiratory Diseases
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• v.47 no.1
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• pp.13-25
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• 1999

Background: Ineffective cell-mediated immune response in human tuberculosis is associated with a depressed Thl cytokine response and reduced production of IFN-$\gamma$. Most persons infected with Mycobacterium tuberculosis are healthy tuberculin reactors with protective immunity, but a minority with ineffective immunity develop extensive pulmonary tuberculosis. The cell-mediated immune response is an important aspect of host resistance to mycobacterial infection and is believed to be tightly regulated by a balance between Th1 cytokines including IFN-$\gamma$, IL-12, IL-18, regulated on activation, normal T cell expressed and secreted (RANTES) and Th2 counterparts such as IL-4, monocyte chemoattractant protein-l (MCP-l). Methods: Proliferation and mRNA expression of IFN-$\gamma$, RANTES and MCP-l by RT-PCR in peripheral blood mononuclear cells (PBMCs) in response to in vitro stimulation with mycobacterial antigens were compared in pulmonary tuberculosis patients with cured and treatment failure and in tuberculin-positive and tuberculin-negative healthy subjects. Results: Defective proliferative responsiveness to aqueous TSP antigen was involved with treatment failure tuberculosis patients. Aqueous TSP antigen-induced IFN-$\gamma$ and RANTES mRNA expression was decreased in treatment failure tuberculosis patients compared with healthy tuberculin reactors and cured tuberculosis patients (23.1 % versus 90.0% for IFN-$\gamma$ and 46.2% versus 70.0% versus 46.2% for RANTES). The frequency of MCP-l mRNA expression to aqueous TSP antigen in treatment failure tuberculosis patients was greater than in healthy tuberculin reactors and cured tuberculosis patients (76.9% versus 40.0%). Conclusion: The increasing expression of MCP-1 mRNA in response to aqueous TSP antigen might be predicted to favor Th1 responses and restricted Th1 responses in treatment failure of pulmonary tuberculosis.

• Tuberculosis and Respiratory Diseases
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• v.65 no.4
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• pp.269-276
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• 2008

Background: Although the prevalence of tuberculosis infections (PTBI) is one of the basic epidemiologic indices, no survey has been carried out since 1995 because the nation-wide tuberculosis prevalence survey was changed to a surveillance system. Subjects without a BCG scar are examined in a tuberculin survey. However, it is very difficult to select these subjects under high vaccination coverage. It is important to evaluate the impact of BCG vaccinations on the tuberculin response and estimate the PTBI regardless of the BCG vaccination status. Methods: A nation-wide, school-based cross-sectional tuberculin survey was carried out among first graders in elementary school in 2006. A total of 5,148 children in 40 schools were selected by quota sampling. Tuberculin testing with 0.1 ml of two tuberculin units of PPD RT23 was carried out on 4,018 children. The maximum transverse diameter of induration was measured 48 to 72 hours later. The presence of a BCG scar was checked separately. Results: There were no BCG scars in 6.3% of the subjects. The mean induration size of tuberculin testing was $3.7{\pm}4.4mm$, which included 1,882 (46.8%) subjects with an induration size of 0 mm. The PTBI was 10.9% (439 subjects) using a cut-off point of ${\geq}10mm$ (conventional method). The annual risk of tuberculosis infections (ARTI) was 1.9% when the mean age of the subjects was assumed to be 6 years. There was no difference in the PTBI according to the presence or absence of a BCG scar [11.2% vs 7.6% (OR: 1.54, 95% CI: 0.98~2.43)]. Using a mirror image technique with 16 mm as the cut-off point, the PTBI and ARTI had decreased to 2.4% and 0.4% respectively. Conclusion: PTBI and ARTI, as estimated by conventional methods, appear to be high among BCG vaccinated children. A mirror image technique is more suitable for estimating the indices in a country with an intermediate burden of tuberculosis than the conventional method.

• Clinical and Experimental Pediatrics
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• v.59 no.6
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• pp.256-261
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• 2016

Purpose: Latent tuberculosis infection (LTBI) in young children may progress to severe active tuberculosis (TB) disease and serve as a reservoir for future transmission of TB disease. There are limited data on interferon-${\gamma}$ release assay (IGRA) performance in young children, which our research aims to address by investigating the usefulness of IGRA for the diagnosis of LTBI. Methods: We performed a tuberculin skin test (TST) and IGRA on children who were younger than 18 years and were admitted to Chung-Ang University Hospital during May 2011-June 2015. Blood samples for IGRA were collected, processed, and interpreted according to manufacturer protocol. Results: Among 149 children, 31 (20.8%) and 10 (6.7%) were diagnosed with LTBI and active pulmonary TB, respectively. In subjects lacking contact history with active TB patients, TST and IGRA results were positive in 41.4% (29 of 70) and 12.9% (9 of 70) subjects, respectively. The agreement (kappa) of TST and IGRA was 0.123. The control group, consisting of non-TB-infected subjects, showed no correlation between age and changes in interferon-${\gamma}$ concentration after nil antigen, TB-specific antigen, or mitogen stimulation in IGRAs (P=0.384, P=0.176, and P=0.077, respectively). In serial IGRAs, interferon-${\gamma}$ response to TB antigen increased in IGRA-positive LTBI subjects, but did not change considerably in initially IGRA-negative LTBI or control subjects. Conclusion: The lack of decrease in interferon-${\gamma}$ response in young children indicates that IGRA could be considered for this age group. Serial IGRA tests might accurately diagnose LTBI in children lacking contact history with active TB patients.

• Tuberculosis and Respiratory Diseases
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• v.46 no.2
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• pp.175-184
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• 1999

Background: Bronchial asthma is characterized by chronic eosinophilic inflammatory airway disease associated with bronchial hyperresponsiveness and reversible airway obstruction. Bronchial inflammation in asthma may depend in part on the activation of T helper lymphocytes that elaborate proinflammatory cytokines. T helper (Th) lymphocytes can be divided into two categories; Th1 lymphocytes, which secrete IL-2, IL-12 and IFN-$\gamma$, and Th2 lymphocytes, which secrete IL-4, IL-5, IL-6 and IL-10. Th2 lymphocytes appear to induce allergic responses, whereas Th1 lymphocytes induce delayed-type hypersensitivity response. Some infections, such as tuberculosis, cultivate a Th1 immunological environment and inhibit Th2 lymphocytes function. The presence of such infections might inhibit Th2 immune responses and thus protect development of atopic diseases. Method: 15 patients with allergic bronchial asthma, 10 patients with intrinsic bronchial asthma, and 10 healthy volunteers were studied. The serum concentrations of IFN-$\gamma$, IL-12, IL-4, IL-5, and IL-10 were measured by ELISA method and tuberculin skin test was estimated in different groups. Results: The positive response rates of tuberculin test were 46.7% in patients with allergic asthma, 100% in patients with intrinsic asthma and 60% in normal controls. The positive response rates were significantly lower in patients with allergic asthma than those of in patients with intrinsic asthma (p<0.05). Degree of responses to tuberculin test were $12.0{\pm}9.6mm$ in patients with allergic asthma, $18.4{\pm}4.5mm$ in patients with intrinsic asthma and $10.9{\pm}8.8mm$ in normal controls. The degree of responses were significantly reduced in patients with allergic asthma than those of patients with intrinsic asthma (p<0.05). The serum levels of IL-5 in patients with allergic asthma were significantly higher than in patients with intrinsic asthma and normal controls (p<0.05), although it was insignificant. the serum levels of IL-4 and IL-10 in patients with allergic asthma were higher than that of intrinsic asthma and normal controls. The serum levels of IL-12 and IFN-$\gamma$ in patients with allergic asthma and intrinsic asthma were significantly lower than those in normal controls(p<0.05). The serum levels of total immunoglobulin E (IgE) and peripheral blood eosinophile counts in patients with allergic asthma were significantly higher than those in normal controls. Peripheral blood esinophil counts had a significant correlation with the serum levels of total IgE, IL-5 and IL-10 in patients with allergic asthma (p<0.05). Conclusion: These results have showed that Th1 lymphocyte functions were lowered and Th2 lymphocyte functions were elevated in patients with allergic asthma than those in normal controls. Suppression of Th1 lymphocyte functions by activation of Th2 lymphocyte might be one of the important aspects of pathogenesis in allergic bronchial asthma.

• Tuberculosis and Respiratory Diseases
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• v.62 no.4
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• pp.270-275
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• 2007

The QuantiFERON-TB Gold assay and tuberculin skin test (TST) have been useful test for diagnosing latent tuberculosis infections (LTBI). However, there are few reports on the efficacy of the QuantiFERON-TB Gold assay and TST in evaluating the response after the treatment of LTBI. This study examined the changes in the TST and QuantiFERON-TB Gold assay before and after a treatment for latent tuberculosis in health care workers (HCWs) at a local tertiary hospital. Methods: A cohort of volunteers working as nurses and doctors who underwent a TST and QuantiFERON-TB Gold assay was established. The volunteers positive for the QuantiFERON-TB Gold assay had been treated with 3 months of isoniazid (INH) and rifampin (RFP). After completing treatment, the TST and QuantiFERON-TB Gold assay were repeated. Results: Of the 48 participants (14 doctors, 34 nurses, M: F=11:37, mean $age=29.9{\pm}5.5$ years, mean employment $period=74.9{\pm}64.3$ months), 19 (39.6%) tested positive to the TST (mean induration=$19.1{\pm}9.7mm$) and 8 (16.7%) were QuantiFERON-TB Gold assay. Among them, one had active pulmonary tuberculosis. Seven volunteers were consistently positive to both the TST and QuantiFERON-TB Gold assay after being medicated with INH and RFP for 3 months. Conclusion: TST and QuantiFERON-TB Gold assay are unsuitable for evaluating the treatment response of LTBI because they were consistently positive both before and after the anti-tuberculosis medication.

• Tuberculosis and Respiratory Diseases
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• v.39 no.4
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• pp.334-342
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• 1992

Background: The activated T lymphocyte by inhalaed mycobacterial antigen may evoke cell-mediated immunity in patients with active pulmonary tuberculosis. These activated lymphocyte may influence the response of tuberculin-purified protein derivative (PPD) in skin test. But occasionally, anergy to PPD appear in patients with pulmonary tuberculosis in spite of active stage. Thus we evaluated the effect of change of subtypes of lymphocyte in bronchoalveolar lavage fluid (BAL) and peripheral blood on anergy to PPD in patients with active pulmonary tuberculosis. Method: We performed tuberculin skin test and flow-cytometry analysis of lymphocytes obtained from BAL fluid and peripheral blood in 11 healthy normal volunteers and 20 patients with active pulmonary tuberculosis. Results: 1) The composition of lymphocyte significantly increased in patients with active pulmonary tuberculosis when compared with that in healthy control ($25.2{\pm}4.8$ vs $6.5{\pm}1.3%$, p<0.01), but composition of monocyte significantly decreased ($69.6{\pm}5.7$ vs $89.2{\pm}1.4%$, p<0.05) in analysis of BAL fluid. 2) There were no differences in compositions of cells in BAL fluid between responders and no-responders to PPD. 3) The compositions of CD3 (+), CD4 (+), CD3 (+) IL-2R (+), CD3 (+) HLA-DR (+) significantly increased in BAL fluid when compared with those in peripheral blood in patients with active pulmonary tuberculosis. But the composition of CDS (+), CD4/CDS were not different between BAL fluid and peripheral blood. 4) There were no correlations between response to PPD and compositions of cells and lymphocyte subtypes in BAL fluid and peripheral blood in all patients with tuberculosis, responders, and no-responders, respectively. Conclusion: From these results, we suggest no direct relationship between compositions of inflammatory cells in bronchoalveolar lavage fluid and we could not rule out the possibility of compartmentalization of activated lymphocyte involving in anergy to PPD in skin test in patients with active pulmonary tuberculosis.

• Clinical and Experimental Pediatrics
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• v.51 no.9
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• pp.971-976
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• 2008

Purpose : Surveillance for detecting and managing latent tuberculosis infection (LTBI) is a key component of tuberculosis control. The classic surveillance tool, the tuberculin skin test (TST), may have some limitations when used in the Bacillus Calmette-$Gu{\acute{e}}rin$ (BCG)-vaccinated population. The object was to perform a blood test $QuantiFERON^{(R)}$-TB Gold In Tube (QFT-G IT) based on the detection of interferon-$\gamma$ ($IFN-{\gamma}$) released by T cells in response to Mycobacterium tuberculosis-specific antigens, and to compare the efficacy of this new diagnostic tool for LTBI with that of TST. Methods : For six months, between October 1, 2006 and April 30, 2007, data were collected from 111 patients under 15 years of age at Severance Children's Hospital. TST and QFT-G IT tests were performed with children with or without contact histories of tuberculosis. In addition to these tests, we examined comparative data from 29 adults who had tuberculosis, to detect false negative rates in the QFT-G IT method. Results : Thirty-three children had household contact histories. In this group, 15% and 42% of cases were found to be positive using the QFT-G IT assay and TST, respectively. Agreement was low between these two tests (${\kappa}=0.39$). In the adult active tuberculosis group, the QFT-G IT false negative rate defined as a positive culture and a negative QFT-G IT result was 12.5%. Conclusion : In diagnosing LTBI in children, the usefulness of a whole-blood $IFN-{\gamma}$ assay employing TB-specific antigens will be revealed only by examining additional longitudinal clinical data; this study serves as a starting point in that process.

• Pediatric Infection and Vaccine
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• v.5 no.1
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• pp.69-78
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• 1998

Purpose : The risk of severe tuberculous disease such as meningitis or miliary tuberculosis increases as younger is the child at the time of infection. Therefore, the early diagnosis and prompt treatment is mandatory for infants with tuberculosis. This study was undertaken to describe the epidemiology, clinical and radiographic manifestations, and response to therapy in infants with tuberculous disease. Methods : Medical records of 29 infants with tuberculosis diagnosed at the Seoul National University Children's Hospital from July, 1985, to April, 1997, were reviewed, retrospectively. A case of tuberculosis was confirmed if M. tuberculosis was isolated from any body site or if there was histologic proof of tuberculosis. Otherwise, the diagnoses were individualized considering history of contact with contagious adult case, clinical manifestations, chest X-ray findings, result of a Mantoux test reaction with 5 tuberculin unit of PPD, and the response to therapy. Results : The mean age at diagnosis was $7.00{\pm}2.65$ months (range, 3 to 12 months). Twelve cases had isolated pulmonary diseases, and the rest had pulmonary disease and meningitis, 5 cases; pulmonary disease and cervical lymphadenitis, 3; isolated meningitis, 3; and miliary tuberculosis, 6. Source case was identified in 19 cases, 7 of which were detected with retrograde manner. Twenty seven of 29 were symptomatic at their initial visit. The presenting symptoms were mainly respiratory or neurologic, and respiratory difficulty was accompanied in 7 cases. Physical examination revealed wheezing in 7 cases and decreased breath sounds in 9. Hepatomegaly or hepatosplenomegaly were frequent. Chest radiographs showed lung parenchymal disease with hilar lymphadenopathy in 18 cases, and focal or generalized emphysematous change in 7 cases. Conclusion : Most of the infants with tuberculosis are symptomatic at diagnosis, and many of infants with intrathoracic tuberculosis presented with symptoms of bronchial obstruction. When tuberculosis is suspected in an infant, the adult source case should be vigorously investigated to aid in diagnosis and for the prevention of further transmission of tuberculous disease. Almost half of infant tuberculosis are preventable if prophylaxis were given when adult cases were diagnosed.