Household Contacts Of Tuberculosis Patients Research Articles

In silico analysis of potential human T Cell antigens from Mycobacterium tuberculosis for the development of subunit vaccines against tuberculosis

In silico analysis was used to predict MHC class I and class II promiscuous epitopes and potential antigens, from 24 novel T cell antigens of Mycobacterium tuberculosis. Majority of the antigens (16/24) had high affinity peptides to both MHC class I and class II alleles and higher population coverage compared to well-proven T cell antigens ESAT-6, CFP-10 and Ag85B. Among these, highest population coverage were calculated for three novel T cell antigens Rv0733 (97.24%), Rv0462 (96.9%) and Rv2251 (96.3%). The prediction results were experimentally tested by in vitro stimulation of these novel T cell antigens with blood drawn from QuantiFERON-TB Gold In-Tube (QFT-IT) positive healthy household contacts of tuberculosis patients and pulmonary TB patients. Significantly higher level interferon-γ (IFN-γ) was observed, with these novel T cell antigens, in healthy household contacts compared to pulmonary TB subjects (p = 0.0001). In silico analysis also resulted in prediction of 36 promiscuous epitopes from the novel 24 T cell antigens. Population coverage for 4 out of the 36 promiscuous epitopes was >90% [67 VVLLWSPRS (Rv1324), 42 VVGVTTNPS (Rv1448c), 178 MRFLLSAKS (Rv0242c) and 842 IRLMALVEY (Rv3800c)]. Our results shows that these novel antigens and promiscuous epitopes identified from our analysis can further be investigated for their usefulness for subunit vaccine development.

Active case finding of sputum positive pulmonary tuberculosis in household contacts of tuberculosis patients in Karachi, Pakistan

Background: Pakistan holds rank 8 th among the world countries in which high prevalence of tuberculosis (TB) is present. There is evidenced that up to 30% of close contacts of TB patients become infected and at least half of them progress to active disease. The aim of this study was to screen active contacts of sputum positive pulmonary TB (SS +ve PTB) among household contacts (HHCs) of TB patients in Karachi, Pakistan. Materials and Methods: Cross-sectional study, which was conducted at chest clinics of Karachi. Total 750 HHCs were screened out of which 135 diagnosed smear positive TB patients was registered as index cases (ICs) from July 2012 till March 2013. Logistic regression analysis was carried out to estimate the odds ratio (OR) of different associated factors. Results: Prevalence among males (6.1%) compared with female (5.6%). The crude OR for age less than 15 years was 0.28 (95% confidence interval (CI) 0.14-0.55). Eighty-eight HHCs (11.73%) were found to have SS +ve TB. Disease frequency was significantly higher in HHCs who were smokers (adjusted OR 36.41; 95% CI 12.07, 109.79), had age less than 12 years (adjusted OR 3.63; 95% CI 1.68, 7.86), and who lived in houses less than 80 square yards (adjusted OR 3.77; 95% CI 1.27, 6.05). Conclusion: The IC with positive sputum smear constitutes great risk for TB infection and disease in HHC. There is needed for contact tracing strategy in the high-risk population.

Genotypic characteristics of Mycobacterium tuberculosis isolated from household contacts of tuberculosis patients in the Philippines

BackgroundThe Philippines has an extremely high rate of tuberculosis but little is known about M. tuberculosis genotypes and transmission dynamics in this country. The aim of this study was to determine the proportion of household contacts who develop active TB due to direct transmission from an index case in that household.MethodsMycobacterium tuberculosis isolates from household contacts of tuberculosis patients in the Philippines were characterized using restriction-fragment-length polymorphism analysis, spoligotyping, and mycobacterial interspersed repetitive units – variable number tandem repeats typing (12-loci) to determine their utility in elucidating transmission in an area of high tuberculosis prevalence. Drug susceptibility patterns for these isolates were also determined.ResultsSpoligotyping and MIRU-VNTR typing results matched in 10 (62.5%) of 16 index patient-household contact pairs while IS6110 fingerprints matched in only six (37.5%) pairs. Only 3/16 (18.8%) index patient-household contact pairs had identical drug susceptibility results.ConclusionsStrain typing of M. tuberculosis isolates from household contacts in the Philippines indicates that transmission of strains does not necessarily occur directly from the index patient living in close proximity in the same household but rather that community-based transmission also frequently occurs. Accurate susceptibility testing of all isolates is necessary to insure optimal care of both the index patients and any culture-positive household contacts.

TUBERCULOUS PATIENTS;

Objective: This study was designed to analyze the BCG vaccination status and compare the immune globulins levels in thehousehold contacts of tuberculous patients with non contacts of unexposed healthy peoples. Place: Gulab Devi Hospital, Post GraduateMedical Institute and Defense Housing Authority Lahore. Study design: Cross sectional study. Materials and Methods: Investigationslike ESR were done and the sera of 200 persons included in the study were tested for anti tuberculous antibodies by ELISA. BCGvaccination present or absent and scars were positive or negative in both groups were included. Results: The combined serologicalpositivity of the household contacts was 65.8% and for non-contacts was 34.1%. BCG scars were mostly absent in the householdcontacts as well as in non-contacts; But statistically IgG and IgA were present significantly by higher number in the household contacts ascompared to non-contacts, where as no significant difference in the IgM levels. These immunoglobulins status were compared with BCGscars in both study and control groups. The results were analyzed by SPSS version 14. Conclusions: Household contacts of tuberculosispatients are more susceptible to tuberculosis as compared to the non-contacts, as shown by positive and negative status ofantituberculous antibodies in the house hold contacts. More over BCG vaccination has no significant role in humoral evaluation.

Reply to Herzmann et al

To The Editor—We thank Herzmann and colleagues for their interest, comments, and description of findings related to our proposed definition for the early and asymptomatic disease state “incipient tuberculosis (TB)” [1]. Herzmann et al describe a study in which 5 of 25 individuals who were household contacts of TB patients had an interferon-gamma release assay (IGRA) result that was negative testing peripheral blood and positive testing bronchoalveolar lavage (BAL) fluid. They propose including localized immune responses in the category of “incipient TB” by expanding our definition to encompass the “presence of measurable localized M. tuberculosis specific immune responses in the absence of a generalized M. tuberculosis specific immune response” [ref Herzmann]. The intent of our characterization of a state of incipient TB was to identify, among asymptomatic immunocompetent individuals with TB exposure, a group of individuals with radiographically minimal disease who are at greater risk for progression to active TB, compared with those without radiographic abnormalities. A localized immune response, while reflecting infection after exposure, does not necessarily imply either disease or a high likelihood of progression to disease. While we acknowledge that the radiographic abnormalities in our proposed definition for incipient TB lack specificity for M. tuberculosis infection, they still suggest evidence of early disease in a person exposed to TB and are associated with histopathological changes [2]. We deliberately used the term “incipient” since it connotes “an initial stage” of something “beginning to happen or develop” (Oxford English Dictionary) to distinguish early TB from latent M. tuberculosis infection. Further, the observations substantiating the prognostic impact of radiographic abnormalities for the development of culture-positive “proven,” “active” TB have been extensively demonstrated in both isoniazid prophylaxis trials [3] and treatment trials for culture-negative TB [4]. The rationale for the diagnostic category of “culture-negative TB” in patients with compatible chest radiographic findings is based on the observed high rate of progression, radiographically and microbiologically, to culture-positive disease in the absence of treatment [5]. In both situations, the greater the radiographic abnormality, the greater the risk of progression to culture-positive disease. In conclusion, although the observations of Herzmann et al are important and very interesting, they do not provide guidance on whether to “treat or not treat.” It remains to be learned whether their observation of a localized IGRA response by pulmonary alveolar mononuclear cells from TB-exposed patients in the absence of a systemic IGRA response confers a higher or a lower likelihood of progression to active TB, compared with those without such responses. Plausibly, a vigorous local immune response, as evidenced by a locally positive IGRA result, might be protective. Furthermore, Herzmann et al do not provide data whether the localized IGRA response was associated with any radiographic abnormalities or on the local IGRA response in the remaining 15 of 40 patients with systemic positive IGRA results. For these reasons, we feel that a pulmonary M. tuberculosis–specific immune response in the absence of a systemic M. tuberculosis–specific immune response, while certainly a sign of infection, cannot be considered indicative of early TB. We look forward to follow-up clinical data on these immunologically well-characterized TB-exposed individuals from Herzmann et al and the “TB or not TB” Consortium so that we may better learn the prognostic attributes that would justify early antituberculous treatment.

Risk Factors Associated with Positive QuantiFERON-TB Gold In-Tube and Tuberculin Skin Tests Results in Zambia and South Africa

IntroductionThe utility of T-cell based interferon-gamma release assays for the diagnosis of latent tuberculosis infection remains unclear in settings with a high burden of tuberculosis.ObjectivesTo determine risk factors associated with positive QuantiFERON-TB Gold In-Tube (QFT-GIT) and tuberculin skin test (TST) results and the level of agreement between the tests; to explore the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST.MethodsAdult household contacts of tuberculosis patients were invited to participate in a cross-sectional study across 24 communities in Zambia and South Africa. HIV, QFT-GIT and TST tests were done. A questionnaire was used to assess risk factors.ResultsA total of 2,220 contacts were seen. 1,803 individuals had interpretable results for both tests, 1,147 (63.6%) were QFT-GIT positive while 725 (40.2%) were TST positive. Agreement between the tests was low (kappa = 0.24). QFT-GIT and TST results were associated with increasing age (adjusted OR [aOR] for each 10 year increase for QFT-GIT 1.15; 95% CI: 1.06–1.25, and for TST aOR: 1.10; 95% CI 1.01–1.20). HIV positivity was less common among those with positive results on QFT-GIT (aOR: 0.51; 95% CI: 0.39–0.67) and TST (aOR: 0.61; 95% CI: 0.46–0.82). Smear positivity of the index case was associated with QFT-GIT (aOR: 1.25; 95% CI: 0.90–1.74) and TST (aOR: 1.39; 95% CI: 0.98–1.98) results. We found little evidence in our data to support our hypotheses.ConclusionQFT-GIT may not be more sensitive than the TST to detect risk factors associated with tuberculous infection. We found little evidence to support the hypotheses that positivity in QFT-GIT is more related to recent infection and less affected by HIV than the TST.

Reactividad de la prueba de tuberculina en contactos intradomiciliarios de pacientes con tuberculosis en Huánuco, Perú

Objectives. To determine the frequency and epidemiological factors related with the tuberculin test reactivity in household contacts of tuberculosis patients in four hospitals of the Andean city of Huanuco (Peru). Material and methods. An analytical cross-sectional study was carried out since April 2006 to January 2007 with 390 household contacts were considered. The tuberculin test was performed with induration reading at 48 hours, the Mantoux test was used. Patients with negative readings (induration < 10 mm) were subjected to another test four weeks later. Bivariate and multivariate associations were explored, tuberculin test reactivity was the outcome. Results. The reactivity frequency to the tuberculin test in the four hospitals amounted to 64.6% among household contacts. Only the presence of pulmonary TB [OR = 2.6 (95% CI = 1.35 - 4.84) p = 0.004], age ≥ 25 years [OR = 3.5 (95% CI = 2.15 – 5.67) p < 0.001] and time living together ≥ 1 year [OR = 1.9 (95% CI = 1.11 – 3.33) p = 0.020] were related to tuberculin test reactivity. Conclusions. The frequency of the tuberculin test reactivity in household contacts in four hospitals of the city of Huanuco was 64.6%. Independently related factors were pulmonary TB, age ≥ 25 years, and time living together ≥ 1 year.

IFNγ Response to Mycobacterium tuberculosis, Risk of Infection and Disease in Household Contacts of Tuberculosis Patients in Colombia

ObjectivesHousehold contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNγ produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNγ levels in HHCs correlate with tuberculosis development.MethodsA cohort of 2060 HHCs was followed for 2–3 years after exposure to a tuberculosis case. Besides TST, IFNγ responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination.ResultsUsing TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNγ response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNγ responders to CFP-10 (HR 1.82 95% CI 0.79–4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNγ producers was observed (trend Log rank p = 0.007).DiscussionCFP-10-induced IFNγ production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprohylaxis to child contacts regardless of BCG vaccination.

Dose–response relationship between treatment delay of smear-positive tuberculosis patients and intra-household transmission: a cross-sectional study

In order to document the effect of treatment delay on tuberculosis (TB) latent infection among the household contacts of TB patients, a cross-sectional TB infection prevalence survey was conducted among household contacts in Yunnan Province, southern China. In total, 1360 household contacts of 393 smear-positive pulmonary TB patients were enrolled, together with 308 household contacts of 90 non-TB patients. Using the contacts of non-TB patients as the baseline of TB infection, there was a dose-response relationship between household infection and delay of TB treatment (TB infection prevalence 9.7, 7.8, 19.9, 25.7 and 26.9% for non-TB case, TB case with delay < or =30 d, 30-60 d, 60-90 d and >90 d, respectively). Older age, TB index patient with lung cavitation, and sleeping in the same bedroom with a TB patient were all associated with an increased risk of being tuberculin-skin-test positive. In conclusion, 30 d delay in treatment seems to be the turning point at which a significant increase in risk for TB infection occurs. Apart from conventional indicators, magnitude of treatment delay should be considered as a performance indicator for TB control programmes in high-TB-burden countries. Measures for the detection of early cases should be intensified.

The 6-Kilodalton Early Secreted Antigenic Target-Responsive, Asymptomatic Contacts of Tuberculosis Patients Express Elevated Levels of Interleukin-4 and Reduced Levels of Gamma Interferon

It is well known that the majority of healthy individuals exposed to Mycobacterium tuberculosis do not become clinically ill. We have previously shown that in recently exposed healthy contacts of tuberculosis (TB) patients, a strong immune response to the M. tuberculosis 6-kDa early secreted antigenic target (ESAT-6) virulence factor correlated with a higher risk of subsequent disease, although the mechanism was unclear at that time. Inspired by recent reports that elevated expression of interleukin-4 (IL-4) in health care workers exposed to M. tuberculosis also correlated with a higher risk of their subsequently developing disease, we examined expression of IL-4, its competitive antagonist IL-4delta2, and gamma interferon (IFN-gamma) in healthy household contacts of TB patients from Ethiopia. We then compared cytokine expression to their recognition of ESAT-6 (which is largely restricted to members of the tuberculosis complex and which serves as a reliable marker of infection) or to Ag85A (an antigen that is conserved among the mycobacteria and serves as a nonspecific control). Our study shows that in these recently exposed individuals, there is a correlation between a strong response to ESAT-6 and elevated expression of IL-4. Further, elevated expression of IL-4 is associated with lower expression of its antagonistic splice variant IL-4delta2 and with the Th1 cytokine IFN-gamma, suggesting that in these at-risk individuals, immunity is skewed away from a protective Th1 response, even before the development of clinical symptoms.

Relative lack of clinical disease among household contacts of tuberculosis patients compared to leprosy households

The incidence of clinical tuberculosis and clinical leprosy among household members of tuberculosis and leprosy patients in Sri Lanka was studied. The study period was approximately 20 years (January 1981 to December 2001) and the total number of patients and contacts were 325 and 968 for tuberculosis and 726 and 3066 for leprosy, respectively. While none of the tuberculosis patient households had more than 1 patient nor any contacts who developed clinical disease during the observation period, 20% (148/726) of the leprosy patients had more than 1 patient in the family and 0.9% (13/1403) of their contacts who were followed-up developed clinical leprosy during the observation period. Although the tuberculosis patient household contacts did not develop clinical disease, in 79% (88/112) of contacts who were tested by Western blot analysis, there was serologic evidence of Mycobacterium tuberculosis infection. These data show that in populations of comparable socio-economic, environmental and geographic locations, tuberculosis and leprosy show very different transmission patterns. In general, in tuberculosis household contacts, in spite of exposure, infection did not proceed to clinical disease. In contrast, a significant number of leprosy household contacts developed clinical leprosy. These findings have implications in the design and implementation of control programmes for these two diseases.

Immune responses to the Mycobacterium tuberculosis-specific antigen ESAT-6 signal subclinical infection among contacts of tuberculosis patients.

Diagnosis of latent Mycobacterium tuberculosis infection is considered essential for tuberculosis control but is hampered by the lack of specific reagents. We report that strong recognition of tuberculosis complex-specific antigen ESAT-6 by healthy household contacts of tuberculosis patients correlates with the subsequent development of active tuberculosis during a 2-year follow-up period.

The impact of human immunodeficiency virus type 1 on infectiousness of tuberculosis: a meta-analysis.

To assess if the relative infectiousness of patients with tuberculosis is enhanced by coinfection with human immunodeficiency virus type 1 (HIV-1), data from 6 studies of 1240 health care workers who had contact with tuberculosis patients were analyzed. Overall rates of tuberculin skin test conversion were similar regardless of HIV-1 positivity of tuberculosis patients (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.23-1.84). However, when only 3 studies during nosocomial outbreaks of multidrug-resistant Mycobacterium tuberculosis were analyzed, rates of skin test conversion were higher among contacts of HIV-1-positive index cases (OR, 2.85; 95% CI, 1.85-3.85; P=.0002). A second meta-analysis included data from 11 studies of 10,714 household contacts of tuberculosis patients. Prevalence of both skin test positivity (OR, 0.45; 95% CI, 0.20-1.03) and active disease (OR, 1.17; 95% CI, 0.78-1.56) were similar regardless of HIV-1 positivity of index cases. These data suggest that tuberculosis patients with HIV-1 infection are not intrinsically more infectious to their contacts than are HIV-1-negative tuberculosis patients.

Tuberculosis Transmission in the Family

Objective: To evaluate the risk of tuberculosis (TB) transmission from family members with infectious TB to other family members, and to examine whether household contact investigations had an impact on tuberculosis patterns.Design: Under the direction of the Taipei Municipal Chronic Disease Hospital, 12 full-time public health nurses recruited the household contacts of TB patients. Chest X-ray examination was recommended for adult contacts. Child contacts received the Mantoux tuberculin skin test, and radiography was recommended if the results were positive.Setting: Family contacts of all TB index patients who attended one of 29 hospitals in Taipei, from July 1993 through June 1996. The medical records of index patients were obtained from the National Tuberculosis Registry.Results: During the study period, the families of 3903 index patients, comprising 11873 contacts, were investigated. Among these, 4595 received radiography, for a response rate of 38.7%. Of these, 284 had active pulmonary disease: 188 (66.3%) had minimal disease, 79 (27.8%) had moderately advanced disease, and only 17 (5.9%) had far advanced disease. Overall, the index patients had more advanced TB: only 1261 (32.3%) had minimal disease, while 2022 (51.8%) had moderately advanced disease and 620 (15.9%) had far advanced disease.Conclusions: These data show a relatively high risk of intrafamily TB transmission. Our findings also show that family contact investigations may help to diagnose TB in earlier stages. Such an approach should greatly reduce the number of new TB cases and speed eradication of the disease.