A tuberculin screening and isoniazid preventive therapy program in an inner-city population

As tuberculosis transmission decreases, case rates decline and an increasing proportion of cases arises from the pool of persons with latent infection. Elimination of tuberculosis will require preventing disease from developing in infected persons. From 1994 to 1996 the Atlanta TB Prevention Coalition conducted a community-based tuberculin screening and isoniazid preventive therapy project among high-risk inner-city residents of Atlanta, Georgia. We established screening centers in outpatient waiting areas of the public hospital serving inner-city residents, the city jail, clinics serving the homeless, and with outreach teams in neighborhoods frequented by drug users. All services were provided free. A total of 7,246 persons participated in tuberculin testing; 4,701 (65%) adhered with skin test reading, 809 (17%) had a positive test, 409 (50%) fit current guidelines for isoniazid preventive therapy, 84 (20%) we intended to treat completed therapy. The major limitations of this community-based tuberculin screening and preventive therapy project were the low proportion of infected individuals who were eligible for isoniazid preventive therapy and the poor adherence with a complete regimen among those we intended to treat. For community-based programs to be efficacious, preventive therapy regimens that are of shorter duration and safe for older persons will need to be implemented.     

5 years'' experience in complex percutaneous transluminal coronary angioplasty]

SETTING: A residential program in Barcelona for drug addicts (therapeutic community) admitted between November 1988 and March 1992, and followed until September 1994. OBJECTIVE: To study the incidence of tuberculosis as related to the presence of tuberculosis infection and/or human immunodeficiency virus (HIV) infection, and to evaluate the protective effect of chemoprophylaxis with isoniazid. DESIGN: Prospective cohort study. Incidence rates were compared using the Chi-square test for cohort studies. The effectiveness of chemoprophylaxis was evaluated by the Kaplan-Meier method at the univariate level, and by logistic regression models and proportional risks analysis at the multivariate level. RESULTS: During the study of 361 individuals without previous known tuberculosis or history of anti-tuberculosis chemoprophylaxis, 25 developed tuberculosis, an overall incidence rate of 1.79/100 person-years. For HIV-positive persons, the incidence rate was 3.25/100 person-years, compared with 0.30/100 in those who were HIV-negative (P < 0.05). The highest incidence rates occurred among HIV-positive persons who did not receive chemoprophylaxis and who were either anergic (HIV-positive, purified protein derivative [PPD]-negative, Multitest-negative) or who were infected with Mycobacterium tuberculosis (PPD+), 10.0/100 person-years and 4.64/100 person-years, respectively. Of the 53 persons who received chemoprophylaxis, three developed tuberculosis, an incidence rate of 1.4/100 person-years. In comparison, in the group of 51 patients who were designated to receive chemoprophylaxis but where none was actually taken, 17 developed tuberculosis, an incidence rate of 5.7/100 person-years (P = 0.03). CONCLUSION: HIV-infected intravenous drug users, particularly those who are anergic or who are PPD positive, are at increased risk of developing tuberculosis. Anti-tuberculosis chemoprophylaxis proved effective in this population.     

A prospective study of the risk of tuberculosis among HIV-infected patients

OBJECTIVE: To evaluate the risk of developing active tuberculosis (TB) in a cohort of HIV-1-infected patients. METHODS: Prospective longitudinal follow-up of 839 HIV-infected patients, of whom 505 (60%) were parenteral drug users and 269 (32%) homosexual men. Tuberculin skin tests were performed at baseline and annually thereafter. Prophylaxis with isoniazid (300 mg daily for 9 months) was offered to those with a positive tuberculin test (induration > or = 5 mm). Diagnosis of TB was accepted if it could be confirmed microbiologically (acid-fast bacilli seen in Ziehl-Neelsen stains or grown in Lowenstein-Jensen cultures) or pathologically (presence of caseating granulomas) and patients had consistent clinical manifestations. RESULTS: Active TB developed in 23 out of the 733 (3.1%) patients with a negative tuberculin skin test after a mean follow-up of 16 +/- 11 months (range, 2-52 months), with an estimated cumulative probability of 1.5 and 7% after 1 and 3 years, respectively (or 2.4 per 100 patient-years). None of the 87 patients with a negative tuberculin test but a positive Multitest developed TB. Conversely, 106 patients had a positive tuberculin skin test (97 at baseline and nine who converted during follow-up). Active TB developed in seven out of the 26 not receiving prophylaxis or in whom prophylaxis had to be discontinued (16.2 per 100 patient-years), in four out of 61 patients 3-27 months after having completed 9 months of prophylaxis with isoniazid (8.9 per 100 patient-years) and in none of the 19 still receiving isoniazid. When TB was diagnosed, the mean CD4 lymphocyte count of the 34 patients who developed it during follow-up was 77 +/- 103 x 10(6)/l (range, 1-400 x 10(6)/l). CONCLUSIONS: Among HIV-infected patients in whom the tuberculin skin test is negative, the risk of developing active TB is sufficient to consider prophylaxis if the CD4 count falls below 400 x 10(6)/l, at least in those patients with skin anergy living in high-risk geographical areas such as Spain. When the tuberculin skin test was positive, isoniazid (9 months) provided a 45% protection beyond the period of its administration.     

Tuberculin skin testing of hospitalized patients

OBJECTIVES: We sought to define the prevalence of tuberculin skin test (TST) positivity in a group of newly hospitalized patients, to identify risk factors for positive tests, and to examine the impact of testing on infection control practices. DESIGN: Unblinded cohort study over 5 days in July 1992. SETTING: A 1,000-bed university-affiliated hospital. PATIENTS: All patients admitted (excluding obstetric patients and newborns) were interviewed. Patients without a history of tuberculosis (TB) or a positive TST were offered a TST with Candida and tetanus controls. RESULTS: Of 346 patients offered the test, 21 (6%) had a prior history of TB or a positive TST, and 36 (10%) declined to participate; 279 of the remaining 289 completed the study. Anergy was demonstrated in 94 (33.7%) of 279 patients. New positive TSTs were identified in 19 (10.3%) of 185 nonanergic patients. Of the 19 TST-positive patients, 6 (32%) had infiltrates on chest radiographs and were evaluated for active TB. One patient was treated empirically for active TB, and five received isoniazid prophylaxis. Risk factors for a new positive TST included age (odds ratio [OR], 1.56 per decade of life; P = .021), African American race (OR, 4.81; P = .008), alcohol abuse (OR, 5.53; P = .005), and peptic ulcer disease (OR, 4.53; P = .017). Risk factors for anergy included admission to a surgical service (OR, 2.1; P = .006), current use of steroids (OR, 2.65; P = .005), and human immunodeficiency virus (HIV) infection (OR, undefined; P = .034). CONCLUSIONS: Despite a high rate of anergy, routine tuberculin skin testing identified a substantial number of patients with TB infection who might otherwise have gone unrecognized.     

Inhibin-B: the physiologic basis of the clomiphene citrate challenge test for ovarian reserve screening

Disseminated tuberculosis was diagnosed at the autopsy of a 65-day-old premature infant who died in a 52-bed neonatal intensive care unit (NICU). Both parents and one sibling had previously had positive tuberculin skin tests (TSTs); none had active pulmonary tuberculosis, but a second sibling had hilar adenopathy. Congenital transmission was confirmed by isolation of Mycobacterium tuberculosis from the mother's endometrium and the infant's lung tissue. Both strains were identical by DNA restriction fragment analysis. TSTs were performed on 14 neonates, 27 NICU visitors, 11 contacts of the family, and 260 health care workers. TST conversion occurred in two nurses (0.8%); both had normal chest radiographs and received isoniazid therapy. Exposed neonates had negative chest radiographs, had negative gastric aspirates for acid-fast bacilli, and received isoniazid preventive therapy. Diagnosis of congenital tuberculosis requires a high index of suspicion. Transmission of tuberculosis in the NICU setting is unusual but can occur.     

Comparison of three composite compliance indices in a trial of self-administered preventive therapy for tuberculosis in HIV-infected Ugandan adults. Uganda-Case Western Reserve University Research Collaboration

Compliance with tuberculosis preventive therapy in a randomized placebo-controlled trial in 2736 HIV-infected Ugandans was measured using urinary isoniazid metabolite testing, clinic attendance, and self-report. Overall, 77% of urine tests were positive, subjects kept 85% of their scheduled visits while on therapy, and 69% reportedly never forgot to take their medication. Different strategies were used for constructing three composite compliance indices in active arms: (1) an unweighted index of the summed scores on scaled compliance measures; (2) a weighted index using weights obtained from a survey of experts on tuberculosis; and (3) a statistically weighted index using principal components analysis. Composite indices were evaluated for reliability, validity, and practical utility. Understanding of the regimen, study arm, subsequent follow-up, tuberculosis status, and urine spot-check result were associated with composite compliance scores. The unweighted index in this study performed as well as the weighted indices.     

Protection from Mycobacterium avium complex disease in human immunodeficiency virus-infected persons with a history of tuberculosis

Risk of Mycobacterium avium complex disease was examined in human immunodeficiency virus (HIV)-infected patients with and without a history of tuberculosis. Information was obtained by retrospective review of charts of patients in HIV clinics in 10 US cities. Among 1363 patients with <200 CD4 cells/mm3 seen at Grady Memorial Hospital (GMH), 11 (17%) of 66 with a history of a positive purified protein derivative (PPD) skin test acquired M. avium infection, while 29 (16%) of 185 who were PPD-negative (but not anergic) did not (P = .85). Only 4 (8%) of 49 GMH patients with a history of tuberculosis acquired M. avium infection compared with 252 (19%) of 1314 GMH patients without a history of tuberculosis (P = .05). Proportional hazards analysis of risk factors for M. avium infection among 441 persons with and 8702 persons without a history of tuberculosis in 9 other cities confirmed protection from M. avium infection in persons with a history of tuberculosis (relative risk, 0.52; 95% confidence interval, 0.36-0.76; P < .001). Prior tuberculosis provides protection against M. avium infection in HIV-infected persons, possibly by stimulation of antimycobacterial immunity.     

Patient's self-interpretation of tuberculin skin tests

BACKGROUND: In the outpatient use of tuberculin skin testing (purified protein derivative [PPD]), it is at times inconvenient to have a patient revisit for interpretation. Therefore, we assessed patients' ability to self-interpret these test results. METHODS: In keeping with prior custom, patients were seen by an experienced nurse, who performed skin testing with PPD intermediate strength as well as mumps and Candida anergy control tests in some cases, and explained the procedure. The patients were asked to return 48 to 72 h later, at which time one of the researchers recorded their test interpretations before they were again evaluated by the nurse. RESULTS: Sixty-eight patients were studied, of whom 59 returned at appropriate interval. Eighteen patients had a positive PPD test reaction of 10 to 20 mm induration, which only one patient correctly identified as a positive test result. However, positive anergy control tests were correctly interpreted in 10 of 27 cases. CONCLUSION: The small number of positive PPD test result recognition by these patients may be partially attributed to their lack of education, as well as foreign birth and denial of illness. PPD results should be checked by an experienced professional.     

Adrenal gland incidentaloma in the oncologic patient: is its histologic study obligatory?

We evaluated the performance of an automatic polymerase chain reaction (PCR) detection system for identification of Mycobacterium tuberculosis in respiratory specimens. Six hundred and two respiratory specimens, including 557 sputa and 45 bronchial washing samples, were analyzed using the COBAS AMPLICOR Mycobacterium tuberculosis (MTB) test. The results were compared with those obtained from acid-fast microscopy, conventional culture, and clinical history. In cases of discrepancy between the results of the COBAS AMPLICOR MTB test and culture, the medical history of the patient was reviewed, the COBAS AMPLICOR MTB test was repeated, and the gene encoding M. tuberculosis superoxide dismutase was screened using PCR (SOD-PCR). Fourteen samples were excluded because the internal control test result was negative. Of 57 specimens that were culture positive for Mycobacterium species, 40 appeared to have growth of M. tuberculosis and 21 were smear positive for acid-fast bacteria. The sensitivity, specificity, and positive and negative predictive values for the COBAS AMPLICOR MTB test evaluated at our laboratory were 85.0% (34/40), 99.3% (544/548), 89.5% (34/38), and 98.9% (544/550), respectively. Three specimens that were culture positive for M. tuberculosis but negative by COBAS AMPLICOR MTB test were positive when rechecked by both COBAS AMPLICOR MTB test and SOD-PCR. Among the four specimens with positive reactions on both COBAS AMPLICOR MTB test and SOD-PCR that were culture negative, two were from patients who had been receiving antituberculosis treatment, one was from a patient who had been treated for tuberculosis for 1 year, and the other was from a patient who died of sepsis with adult respiratory distress syndrome. In more than 70% of smear-negative and culture-positive specimens and 86.4% of smear-positive specimens, M. tuberculosis was identified by the COBAS AMPLICOR MTB test within 10 hours after receipt of the specimens. Our data show that the COBAS AMPLICOR MTB test provides rapid and accurate detection of M. tuberculosis in respiratory specimens.     

Amelioration of collagen-induced arthritis and suppression of interferon-gamma, interleukin-12, and tumor necrosis factor alpha production by interferon-beta gene therapy

Human Vgamma9Vdelta2 T cells contribute to immunity against intracellular pathogens and recognize nonpeptidic antigens, such as the mycobacterial phosphoantigen TUBAg. HIV infection is associated with a polyclonal decrease of peripheral Vgamma9Vdelta2 T cells and we previously reported that the remaining cells show a proliferative anergy to stimulation with Mycobacterium tuberculosis in 60% of patients. Because of alterations in the Th1/Th2 cytokine balance reported in HIV infection, we analyzed, at the single-cell level, the influence of exogenous IL-4, IL-10, IL-12 and IL-15 on the response to mycobacterial phosphoantigens of gammadelta T cells from HIV-infected patients and healthy donors. We report that the strong gammadelta T cell response to TUBAg is characterized by the rapid and selective production of the Th1/proinflammatory cytokines IFN-gamma and TNF-alpha in responder HIV-infected donors. In addition, a positive regulation by IL-12 and IL-15 of the production of these cytokines by Vgamma9Vdelta2 T cells in response to nonpeptidic ligands was observed, whereas IL-4 and IL-10 had no effect. In contrast, Vgamma9Vdelta2 T cells from the anergic HIV-infected donors had lost the ability to produce Th1 cytokines and were not shifted towards a Th2 profile. Furthermore, neither IL-12 nor IL-15 could reverse this functional anergy. The consequences of these observations are discussed in the context of HIV pathogenesis.     

Seropositive rheumatoid arthritis with interstitial lung disease in giant cell arteritis

Unusually high mortality rates have been recorded among HIV-infected tuberculosis patients in urban Africa 6 and 12 months after initiation of tuberculosis treatment--a trend that impedes efforts to achieve the 85% cure rate target set by the World Health Organization. This study investigated tuberculosis treatment outcomes in relation to HIV serostatus in a rural district of Malawi (Ntcheu). All 205 smear-positive pulmonary tuberculosis patients newly diagnosed in the district in 1995 received 2 months of daily supervised streptomycin, rifampicin, isoniazid, and pyrazinamide in the hospital followed by 6 months of isoniazid and thiacetazone at home. HIV testing, offered to all tuberculosis patients, was accepted by 110 (54%), 73 (66%) of whom were HIV-positive. By the end of treatment, 126 patients (61%) had been cured and 56 (27%) had died. Significantly fewer HIV-positive patients or patients who declined HIV testing were cured (59% and 55%, respectively) than those who agreed to testing and were HIV-negative (84%). The mortality rate was 29% among patients who tested HIV-positive, 8% among those with a negative test result, and 34% among patients who declined HIV testing. Acceptance of HIV testing improved over the course of the study period in response to changes in counseling techniques, especially clarification that blood taken for HIV testing would not be used for transfusions. Overall, these findings suggest that, in areas where HIV infection is prevalent, an 85% tuberculosis cure rate may be unrealistic.     

The importance of early erythematous reaction in purified protein derivative skin testing

We attempted to assess the diagnostic value of the early erythematous reaction observed at the sixth hour after the application of purified protein derivative (PPD) skin testing. For this purpose, 64 children with pulmonary tuberculosis and 49 healthy age-matched controls were PPD skin tested. Our results showed that the erythematous reaction of 5 mm or greater at the sixth hour was able to detect patients with active tuberculosis with 76% sensitivity, 85% specificity, 87% positive predictivity and 73% negative predictivity. Among 113 subjects, 6 h erythematous reaction of 5 mm or greater in size had 83% sensitivity to detect the ones who subsequently developed 10 mm or greater induration reaction at 48 h. We concluded that the sixth hour early erythematous reaction is just as helpful as the 48 h induration of 10 mm or greater in detecting patients with pulmonary tuberculosis.     

Isoniazid preventive therapy in human immunodeficiency virus-infected persons. Long-term effect on development of tuberculosis and survival

BACKGROUND: Although the short-term benefit of isoniazid prophylaxis in patients coinfected with human immunodeficiency virus (HIV) and tuberculosis has been shown, long-term benefits are unknown. METHODS: Historical cohort study in an acquired immunodeficiency syndrome unit at a tertiary referral hospital. A sample of 121 HIV-infected patients with positive results on a purified protein derivative test were followed up for development of active tuberculosis and survival. Patients who received isoniazid prophylaxis were compared with patients who did not receive prophylaxis. RESULTS: Of the 121 patients examined, 29 (24%) completed a 9- to 12-month course of isoniazid prophylaxis (median follow-up, 89 months), and 92 (76%) did not receive the drug (median follow-up, 60 months). Active tuberculosis developed in 46 patients (38%). The incidence of tuberculosis was higher among patients with no prophylaxis (9.4 per 100 patient-years) than among patients with isoniazid prophylaxis (1.6 per 100 patient-years) (P = .006). Risk for development of tuberculosis was associated with the absence of isoniazid prophylaxis (relative risk [RR], 6.55; 95% confidence interval [CI], 2.02-21.19). Death during the period of study was more frequent in patients who did not receive isoniazid (50/92 or 54%) than in patients who received isoniazid (7/29 or 24%) (P = .008). Median survival was more than 111 months in patients who received isoniazid compared with 75 months in patients who did not receive isoniazid (P < .001). In a proportional hazards analysis, the development of tuberculosis (RR, 1.88; 95% CI, 1.09-3.27), the absence of isoniazid prophylaxis (RR, 2.68; 95% CI, 1.16-6.17), and a CD4+ cell count lower than 0.20 x 10(9)/L (RR, 3.03; 95% CI, 1.39-6.61) were independently associated with death. Patients who received isoniazid had a longer survival after stratifying for the CD4+ cell count. CONCLUSIONS: Preventive therapy with isoniazid confers long-term protection against tuberculosis and significantly increases survival in patients dually infected with HIV and Mycobacterium tuberculosis.     

Direct evidence for suppression of recombination within two pericentric inversions in humans: a new sperm-FISH technique

The tuberculin reaction following the intradermal injection of PPD appears 48-72 hours after injection. The positivity is shown by an > 5 mm area of induration of the skin. Tuberculin reaction is an invaluable instrument of epidemiologic investigation. Clinically, the value of tuberculin test, though remarkable, is limited by the fact that its positivity is not necessarily a sign of active tuberculosis. The three control strategies of tuberculosis are: prompt identification and correct management of cases, vaccination, prophylaxis. The latter, that in most cases is performed with isoniazid (300 mg/daily for 12 months) is indicated in the following situations: subjects with > 5 mm tuberculin test; recent contacts with patients with infective tuberculosis; chest X-ray indicative for old fibrotic lesions, HIV infection; subjects with > 10 mm tuberculin test: HIV-negative drug-addicts; clinical conditions at high risk for tuberculosis (e.g. silicosis, hematologic malignancy, iatrogenic immunosuppression).     

Characterization of an inhibitory seric factor from tuberculosis anergic patients that acts on non-adherent PPD reactive cells

Non-adherent cells from PPD+ tuberculosis patients (TBP PPD+) and from healthy individuals treated with whole tuberculosis anergic immune sera or with its protein A-Sepharose IgG fraction, or with sera fraction separated by PPD-Sepharose chromatography, were submitted to immunofluorescence assays. Anti-human IgG or IgM FITC-conjugate were used to reveal the assays, and results were expressed by a fluorescence percentage or fluorescence index. The presence of IgG over the surface of PPD+ non-adherent cells was detected. High fluorescence percentages were observed only in those PPD+ cells treated with whole anergic serum or with its IgG fraction. Positive fluorescence index values were obtained only in those PPD+ cells treated with anergic serum, meanwhile fluorescence index was always negative when non-bound fractions from PPD-Sepharose were used. Results suggest that non-adherent population are the cell targets for the serum inhibitory factor, which previously has been detected to inhibit antigen response in PPD reactive cells and, point out the specific behavior of this factor, since it was eliminate by PPD-Sepharose chromatography. The IgG nature of the factor was demonstrated by SDS-PAGE and immunoelectrophoresis.     

Close contact with tuberculosis in childhood

In a 1-year prospective study 83 children, who had been in close contact with 52 adults who had tuberculosis, were examined. Thirty-six of the index cases had culture positive tuberculosis and 16 of these had smear positive tuberculosis. All the children had been BCG-vaccinated at birth. Forty-one (49%) of the children were PPD negative on examination with the Mantoux test. Of these 83 children, one 14-year-old boy was diagnosed as having primary tuberculosis and was treated. Twenty-one children received INH therapy, 12 because of their age (under 2 years of age or at puberty), nine because of a strong positive reaction to the first Mantoux test or because of the conversion of a negative test result to positive during the follow-up period. Seven of the latter nine children had been in contact with persons whose disease was culture- and smear-positive. It is concluded that as the frequency of tuberculosis declines, the practice of examining all children who have been in close contact with tuberculous adults is possible. The children who have been in contact with smear-positive index cases are at special risk of contracting tuberculosis.     

The role of anergy in peripheral T cell unresponsiveness

When a T cell's encounter with specific antigen results in good signaling through the T cell antigen receptor yet does not lead to a proliferative response, the T cell enters a state of nonresponsiveness, or anergy. Anergy induction can result from a number of different situations, including antigen presentation by costimulation-deficient or "non-professional" antigen presenting cells, pharmacological blocking of T cell proliferation, or chronic stimulation of the T cell receptor by antigen. Anergy is a long-lived but temporary state characterized by a profound inability of the T cell to produce IL-2. Other effector functions may be affected to variable degrees. Anergy has been characterized most carefully under in vitro conditions, but several experimental models have demonstrated that T cells can also become anergic in vivo. This mechanism for tolerance induction may help to ensure that any mature autoreactive T cells which escape thymic deletion are unable to respond to host tissues. Furthermore, an understanding of the mechanism of anergy induction will most certainly lead to beneficial clinical applications, including improving graft acceptance and avoiding such deleterious immune responses as autoimmunity and allergy.     

Infection of sheep with adult and larval Ostertagia circumcincta: gastrin

OBJECTIVE: To determine the prevalence, incidence and risk factors for Mycobacterium tuberculosis infection, as well as to assess TB knowledge and attitudes, among a group of known drug users in a city with low TB incidence (11.3 per 100,000 in 1995). METHODS: Patients of an urban drug treatment facility enrolled in opioid substitution, opioid antagonist and other drug treatment programs were screened for TB, including tuberculin skin testing and standardized data collection on TB risk factors. A subsample of clients was interviewed about TB knowledge and attitudes. RESULTS: Between 1 June 1995 and 31 May 1996, 1055 individuals were screened. The prevalence of infection was 15.7% (CI: 13.2-18.2%). PPD positivity was associated with older age (per annum, OR = 1.08, CI: 1.05-1.11), non-white race (OR = 2.81, CI: 1.72-4.60), foreign birth (OR = 4.24, CI: 2.35-7.62) and a history of injecting drug use (OR = 1.89, CI: 1.14, 3.12). The incidence of infection was 2.9 per 100 person-years (CI: 1.8-4.7). Thirty-two per cent of 79 drug users interviewed about TB knowledge and attitudes thought TB could be prevented by bleaching or not sharing needles/syringes. Fifty-one per cent thought anyone with a positive TB skin test was contagious. CONCLUSION: M. tuberculosis infection was common in this population and associated with injecting drugs and several demographic factors. The incidence of new infection was relatively low. In this non-endemic environment, the detection and treatment of latent infection are important aspects of TB control. Misconceptions about TB transmission were also widespread in this population. Drug treatment programs can play a key role by undertaking screening programs that educate about TB and identify infected subjects who would benefit from preventive therapy.