Intracutaneous tuberculin test using the Mendel-Mantoux technique. Tuberculin reactivity among inpatients in a pneumology department

Detection of latent tuberculosis infection is an important step in the control of tuberculosis. The tuberculin skin test is the only proven method for identifying tuberculosis infection in patients who do not have tuberculosis disease. The prevalence of tuberculosis infection among hospitalized patients in a pneumological department of an inner-city hospital was evaluated, using the intradermal tuberculin skin test (Mantoux technique). Interpretation of the Mantoux test was based on the size of induration in millimeters and the individual risk profile of the patients, according to the guidelines of the American Thoracic Society and the Centers for Disease Control, revised in 1989. Of 697 tested patients, 252 showed test results consistent with tuberculosis infection (36.2%). 55 of these 697 patients had active tuberculosis disease or a prior history of tuberculosis (7.9%). A positive tuberculin skin test was found in 197 of 642 patients (30.7%) with a diagnosis different from tuberculosis (COPD, pneumonia, cancer and others). In our study, the sensitivity of the tuberculin skin test for active tuberculosis infection was 95%. The present study revealed a high prevalence of tuberculosis infection among hospitalized patients in a pneumological department. Further studies are needed to assess the usefulness of routine tuberculin skin testing in hospitalized populations.     

Effectiveness of isoniazid chemoprophylaxis for HIV-infected drug users at high risk for active tuberculosis.

OBJECTIVE: To define the effectiveness of chemoprophylaxis, outside of a clinical trial setting, in preventing tuberculosis among tuberculin-reactive and anergic HIV-infected drug users at high risk of developing active tuberculosis. DESIGN: An observational cohort study. SETTING: Methadone maintenance treatment program with on-site primary care. PARTICIPANTS: Current or former drug users enrolled in methadone treatment. INTERVENTIONS: Annual skin testing for tuberculosis infection and anergy was performed, and eligible patients were offered daily isoniazid for 12 months and followed prospectively. MAIN OUTCOME MEASURE: The development of active tuberculosis. RESULTS: A total of 155 persons commenced chemoprophylaxis. Among tuberculin reactors, tuberculosis rates were 0.51 and 2.07/100 person-years in those completing 12 months versus those not taking prophylaxis [rate ratio 0.25, 95% confidence interval (CI) 0.06-1.01]. Among anergic individuals, comparable rates were 0 and 1.44/100 person-years. Lower tuberculosis rates among completers were not attributable to differences in immune status between the treated and untreated groups. CONCLUSION: The completion of isoniazid chemoprophylaxis was associated with a marked reduction in tuberculosis risk among tuberculin reactors and anergic persons in this high-risk population. These data support aggressive efforts to provide a complete course of preventative therapy to HIV-infected tuberculin reactors, and lend weight to the findings of others that isoniazid can reduce the rate of tuberculosis in high-risk anergic HIV-infected persons.     

The influence of a history of a previous test on the prevalence and size of reactions to tuberculin.

Ten millimeters of more of induration to the Mantoux tuberculin test indicates present or past infection with Mycobacterium tuberculosis in the overwhelming majority of cases. Because a number of patients gave a history of a previous positive reaction that was not confirmed on retesting, we carefully evaluated, as part of a large tuberculin testing survey, 1,428 persons who claimed to have had a previous positive test. Of these, 606 (42.4 per cent) had a positive reaction on retesting. When compared to subjects with no history of a previous tuberculin test, this group had only a slightly higher percentage of large reactions (greater than 24 mm). The difference was not significant. This discrepancy between history and test results cannot be assumed to be due to technique or to anergy in the current testing because of appropriate controls. It probably reflects variability in the use of antigens, technique at the previous testing, or faulty recollection of the subject. Because presumption of tuberculosis infection may lead to further diagnostic or therapeutic decisions, it is recommended that all skin test histories be documented or confirmed by retest before consideration of further examinations or therapy. In those with a history of a previous reaction, very large reactions (greater than 24 mm) were only slightly more frequent (but not to a significant degree) than those without such a history; thus, a previous reaction history should not be sufficient to preclude retesting.     

The immune spectrum in patients with pulmonary tuberculosis

The immune response to mycobacterial antigens of 65 patients with pulmonary tuberculosis was studied using delayed skin test reactions and enzyme-linked immunosorbent antibody assays. Evidence for a spectrum of immune response was found. Six of 35 patients studied during the first month of therapy had tuberculin skin test anergy. Anergy was not related to state of nutrition or extent of disease, but it may have been associated with radiographically acute disease. The 6 anergic patients had somewhat higher antibody titers to mycobacterial protein, but not polysaccharide antigens, than did nonanergic patients.     

The Mantoux reaction in pulmonary tuberculosis

The Mantoux test was done on 181 tuberculous patients, of which 124 were sputum-positive. In 102 (93%) sputum positive cases the tuberculin reaction was between 10 and 19 mm. and in only 2 cases was the reaction less than 6 mm. In the sputum negative cases 7 (12%) were Mantoux negative and 5 (9%) had reactions of less than 10 mm. In some of the sputum-negative cases the diagnosis of tuberculosis may have been incorrect.     

Tuberculosis, tuberculin reactivity, and delayed cutaneous hypersensitivity in nursing home residents

When all residents of a 460-bed nursing home were tuberculin tested after discovery of a fatal case of pulmonary tuberculosis, 34% reacted, including 6% who gave boosted reactions. Twenty-four of 262 (9.2%) nonreactors converted to tuberculin reactors 6 months after exposure. Six of the convertors were among the 21% of the residents who were originally considered anergic on the basis of negative Candida and Trichophyton skin tests. These results confirm the observation that aged nursing home residents have lower rates of tuberculin reactivity than earlier in their lives, and that tuberculosis is a nosocomial infection in nursing homes. However, generalized immune senescence cannot be invoked as a reason for apparent susceptibility because the very marker of infection--the development of tuberculin reaction--is evidence of some degree of immune competence. Furthermore, the presence of cutaneous anergy as clinically determined does not predict inability to develop an immune response to the tubercle bacillus.     

Evaluation of DPPD, a single recombinant Mycobacterium tuberculosis protein as an alternative antigen for the Mantoux test.

Although the tuberculin test has aided in the diagnosis of tuberculosis for more than 85 years, its interpretation is difficult particularly because sensitization with non-tuberculous mycobacteria leads to false positive tests. Using the guinea pig model of tuberculosis, we have recently described a recombinant antigen (DPPD) that could circumvent this problem. The DPPD gene is unique to the M. tuberculosis complex organisms and is absent in the organisms representative of all other members of the Mycobacterium genus. Moreover, DPPD induced strong DTH in 100% of the guinea pigs infected with M. tuberculosis and in none of the guinea pigs immunized with nine different species of Mycobacterium. Here we present results of a clinical investigation using DPPD. Mantoux test using both PPD and DPPD was initially performed in 26 patients with confirmed pulmonary tuberculosis and in 25 healthy PPD negative individuals. The results indicated that both PPD and DPPD elicited DTH in 24 out of the 26 patients. No DTH was observed in any of the PPD negative individuals. In addition, a small clinical trial was performed in a population of 270 clinically healthy and randomly selected individuals. DPPD produced a bimodal histogram of skin reaction size and PPD produced a skewed histogram. Because the DPPD gene is not present in non-tuberculous bacilli, these results suggest that this molecule can be an additional tool for a more specific diagnosis of tuberculosis.     

Tuberculosis vaccination versus isoniazid preventive therapy: a decision analysis to determine the preferred strategy of tuberculosis prevention in HIV-infected adults in the developing world.

SETTING: The developing world. OBJECTIVE: To compare the strategy of TB vaccination with that of tuberculin skin-testing in conjunction with isoniazid (INH) in preventing tuberculosis in HIV-infected persons. For any clinical scenarios in which immunization would be more effective than INH preventive therapy, to determine the minimum necessary vaccine safety and effectiveness required. DESIGN: Decision analysis. A hypothetical cohort of 10000 HIV-infected persons, 65% of whom were tuberculin positive, living in the developing world, was studied. Probability estimates were based on BCG vaccine for the baseline analysis, and it was assumed that the vaccine cannot protect if given after infection. RESULTS: Under the probability estimates and assumptions of the analysis, tuberculin skin testing/INH preventive therapy would prevent 458 more cases of TB and 45 more deaths due to TB than TB vaccination. One- and two-way sensitivity analyses revealed no thresholds at which TB vaccination would be the preferred strategy. Vaccine safety did not impact the outcome of the analysis. Three-way sensitivity analysis revealed that if the prevalence of anergy were 35% and the risk of progression to active TB among anergic persons 12.2 cases per 100 person-years, a vaccine would have to be at least 87% effective to be preferred over INH preventive therapy. CONCLUSIONS: Under the conditions of the analysis, which did not account for cost or logistics, tuberculin skin testing/INH preventive therapy would be more effective than TB vaccination in preventing TB among HIV-infected persons. The hypothesized TB vaccine would prevent more TB than INH preventive therapy only in areas where the prevalence of anergy and risk of active TB if anergic were high, and vaccine effectiveness exceeded 87%.     

Pulmonary tuberculosis in Kigali, Rwanda. Impact of human immunodeficiency virus infection on clinical and radiographic presentation.

The aim of the present study was to compare the clinical and radiographic presentation as well as the therapeutic outcome of pulmonary tuberculosis (PT) in adult patients with and without human immunodeficiency virus type 1 (HIV-1) infection in Kigali, Rwanda. Over a 17-month period 59 consecutive patients with bacteriologically and/or histopathologically documented PT were enrolled. Of these, 48 (81%) patients were HIV seropositive. Among these, 35 fit the WHO clinical criteria for AIDS (WHOCCA) at the time of admission. Significant differences were found between the HIV-seropositive and HIV-seronegative groups of patients: fever (85 versus 36%; p less than 0.001), tuberculin skin test anergy (69 versus 0%; p less than 0.01), mediastinal and/or hilar adenopathies (31 versus 0%; p = 0.05), and pleural effusion (43 versus 9%; p less than 0.05) were more frequently encountered in the HIV-seropositive group, and upper lobe infiltrates (55 versus 16%; p less than 0.02) and cavitation (91 versus 39%; p less than 0.003) were more often seen in the HIV-seronegative group. However, HIV-seropositive patients not meeting WHOCCA were less frequently anergic (0 versus 100%; p less than 0.001) and feverish (53 versus 97%; p less than 0.01) and more often had cavitation (69 versus 28%; p less than 0.02) and less often mediastinal and/or hilar adenopathies (7 versus 40%; p less than 0.04) compared with HIV-seropositive patients meeting WHOCCA. Under antituberculosis treatment, clearance of fever was slower in HIV-seropositive compared with HIV-seronegative patients, and among the HIV-seropositive group it was slower in those fitting WHOCCA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalence of positive ppd in a cohort of rheumatoid arthritis patients

The main objective of this study is to determine the prevalence of positive and anergic tuberculin skin test (ppd) in a rheumatoid arthritis cohort of patients (RA) and assess the association among ppd results and clinical and treatment variables. Patients with RA diagnosis were included. The ppd was done by Mantoux method. Positive result was considered when indurations were equal or greater than 5 mm. Anergic reaction was defined when the indurations was 0 mm. We included 105 patients (N = 105). The prevalence of positive ppd was 12.4% (n = 13), while the 87.6% (n = 92) presented a negative result. The 69.5% (n = 73) of the population were anergic to ppd. Patients with negative result received higher steroids dosages than patients with positive ppd (p < 0.04). In the multivariable model, the steroids dosage was a significant and independent predictor of negative ppd (p = 0.021, OR 0.72, 95% CI 0.55–0.95). Anergic and non-anergic patients were separated in groups, and a new analysis was done. The higher dosage of methotrexate was associated to tuberculine anergy (p = 0.025). In the multivariable model, the methotrexate dosage was a significant and independent predictor of tuberculine anergy (p = 0.005, OR 1.14, 95% CIs 1.04–1.24). In conclusion, in our cohort, the prevalence of positive ppd was lower than others studies. Among analyzed variables, the high steroid dose was a significant and independent predictor of negative ppd. The methotrexate treatment and dose were associated with ppd anergy.     

Symptoms of pulmonary tuberculosis in consecutive smear-positive cases treated in Ethiopia

The purpose of the study was to define in detail the usually accepted respiratory and non-respiratory symptoms of newly discovered smear-positive pulmonary tuberculosis in a group of Ethiopians. There were 163 consecutive patients referred to the weekly Chest Clinic at the Tuberculosis Demonstration and Training Centre in Addis Ababa.The results showed that more than 5% of pulmonary tuberculosis cases had respiratory symptoms of less than 2 weeks. Some symptoms such as haemoptysis, chest pain and dyspnoea prompted early reporting while there was a delay in reporting other symptoms such as cough, in spite of cough being present in all patients. Most of the non-respiratory (constitutional) symptoms were reported fairly early.A history of tuberculosis contact was relevant in this group of patients. A negative Mantoux test was noted in 20% of patients.     

Pulmonary tuberculosis in the Republic of Ireland: an epidemiological profile from a single unit

We present a retrospective epidemiological analysis of 1011 adults with a first time diagnosis of pulmonary TB seen between 1980-1985. Most (98.7%) were from the Republic of Ireland and 68.4% were male. Both males and females showed a bimodal age distribution with 37.6% of females and 18.8% of males aged younger than 30 years. More than half (58.6%) of patients smoked cigarettes and 63.7% consumed alcohol. Two patients indulged in the use of hard drugs. Only 5% of patients were asymptomatic and 0.9% of patients had symptoms for longer than 1 year. Radiologically, 54.7% of patients had bilateral disease; 58.5% had cavities and 10% had pleural effusions. Mantoux testing was positive to 1 tuberculin unit Mantoux in 76%; to 10 tuberculin units Mantoux in 15.3%; to 100 tuberculin units Mantoux in 3.7%; and negative to 100 tuberculin units in 5.0%. Primary drug resistance occurred in 0.9% of patients. Ninety (9.0%) of patients died before completing antituberculous treatment and in 40 patients tuberculosis was the principle or main cause of death.     

Two-step tuberculin testing of passengers and crew on a commercial airplane

OBJECTIVES: We investigated the risk of tuberculosis transmission from a person with highly infectious pulmonary tuberculosis to fellow passengers and crew members on a 14-hour commercial flight. The 2-step tuberculin testing was used to minimize the effects of the booster phenomenon. METHODS: Passengers and flight crew members identified from airline records were contacted by letter, telephone, or both to notify them of their potential exposure to Mycobacterium tuberculosis. The subjects were advised to undergo Mantoux tuberculin skin testing within the required time period to assess a conversion. In addition, information regarding tuberculosis history and other sources of potential exposure was solicited by means of a questionnaire. RESULTS: Of the 277 passengers and crew members on the aircraft, 225 (81.2%) responded. Of these, 173 (76.9%) had positive tuberculin results on the first test (induration > 10 mm). Thirteen subjects with negative results refused further testing; 11 (28%) of the remaining 39 exhibited the booster phenomenon on the second test. Subjects who exhibited the booster phenomenon were significantly more likely to have received previous BCG vaccination. Nine contacts with negative results on the initial test had positive results on a third test administered at 12 weeks after the flight exposure Of these, 6 contacts had previous BCG vaccination, old tuberculosis, or a family member with tuberculosis; the remaining 3 reported on other risk factors for positive reactions. None of these 3 contacts had sat in the same section of the plan as the index patient. CONCLUSIONS: The 2-step tuberculin testing procedure is an effective tool for minimization of the booster effect, thus allowing accurate monitoring of subsequent tuberculin conversion rates. Moreover, the clustering of tuberculin skin test conversions among passengers in this study demonstrates the possible risk of M tuberculosis transmission during air travel.     

Evaluation of DPPD, a single recombinant Mycobacterium tuberculosis protein as an alternative antigen for the Mantoux test

Although the tuberculin test has aided in the diagnosis of tuberculosis for more than 85 years, its interpretation is difficult particularly because sensitization with non-tuberculous mycobacteria leads to false positive tests. Using the guinea pig model of tuberculosis, we have recently described a recombinant antigen (DPPD) that could circumvent this problem. The DPPD gene is unique to the M. tuberculosis complex organisms and is absent in the organisms representative of all other members of the Mycobacterium genus. Moreover, DPPD induced strong DTH in 100% of the guinea pigs infected with M. tuberculosis and in none of the guinea pigs immunized with nine different species of Mycobacterium. Here we present results of a clinical investigation using DPPD. Mantoux test using both PPD and DPPD was initially performed in 26 patients with confirmed pulmonary tuberculosis and in 25 healthy PPD negative individuals. The results indicated that both PPD and DPPD elicited DTH in 24 out of the 26 patients. No DTH was observed in any of the PPD negative individuals. In addition, a small clinical trial was performed in a population of 270 clinically healthy and randomly selected individuals. DPPD produced a bimodal histogram of skin reaction size and PPD produced a skewed histogram. Because the DPPD gene is not present in non-tuberculous bacilli, these results suggest that this molecule can be an additional tool for a more specific diagnosis of tuberculosis.     

Clinico-immunological studies of pulmonary tuberculosis in the elderly

We studied tuberculin reactivity and clinical course after starting chemotherapy in patients with active pulmonary tuberculosis divided by four age-groups less than 29, 30-49, 50-69 and 70 years and more. The skin test to tuberculin purified protein derivative (PPD) was examined in 178 cases of active pulmonary tuberculosis, 120 cases of lung cancer, 25 cases of atypical mycobacteriosis and 466 cases of the other respiratory diseases. The average size of tuberculin reaction in pulmonary tuberculosis decreased with age, but significantly higher than that in patients with other nontuberculous pulmonary diseases of the same age-group. The size of PPD skin test in the group of 70 years and more was significantly lower than other age-groups in pulmonary tuberculosis. We compared the time required for negative conversion of sputum by culture after primary chemotherapy among the different age-groups in pulmonary tuberculosis. It revealed that the time for negative conversion tended to be longer with age, and the time in the group 70 years and more was significantly longer than that of the group less than 29 years of age, although no significant differences in the radiographic severity and conditions of chemotherapy were observed. Finally, the PPD-induced lymphocyte proliferation test in vitro was done in newly diagnosed patients with pulmonary tuberculosis. The patients were divided into two groups by the size of PPD skin test (high responder more than 16 mm and low responder less than 15 mm of erythema induced by PPD).(ABSTRACT TRUNCATED AT 250 WORDS)     

The significance of the tuberculin skin test in elderly persons

Study of 49,467 persons over age 50 in Arkansas nursing homes afforded insight into the significance of the tuberculin skin test in the elderly. Whereas only 15% to 20% of persons showed a significant (10 mm or more) reaction to tuberculin on admission, 2% to 3% of these developed tuberculosis. Persons having no reactions comprised two subsets: a small group who died at an increased rate and were probably anergic, and a larger group who survived as well as persons who had reactions. Minor increases in reaction size with repeated testing appeared to be due to immunologic recall. However, conversions of 12 mm or more from a documented negative result indicated spread of infection. When not treated preventively, 7.6% (women) to 12.7% (men) of definite converters developed tuberculosis. The increase in number of persons showing positive reactions after entry may have been due to rapid demise of the anergic subset, improvement in nutrition of survivors, or unsuspected spread of tuberculous infection.     

Tuberculin reaction is not attenuated in patients with rheumatoid arthritis living in a region with intermediate burden of tuberculosis

Tuberculin reactions in patients with immunocompromised conditions have been reported to be attenuated compared with healthy controls. In the case of rheumatoid arthritis (RA), several studies have reported conflicting results. We performed this study to evaluate the tuberculin reaction in patients with RA in a region with intermediate burden of tuberculosis. Eighty-one RA patients and 104 age- and sex-matched controls who underwent tuberculin skin test (TST) at Severance Hospital in Seoul, South Korea were reviewed. TST was carried out using the Mantoux method. Indurations larger than 10 mm were considered positive. Information about risk factors for latent tuberculosis infection was acquired. The mean age of the patients with RA was 48 ± 14 years, and the median disease duration was 9 (1–203) months. The mean DAS28 was 5.22 ± 0.13. The control group consisted of healthy living donors for liver transplantation and the patients with diseases not related with immunosuppression. BCG vaccination, close contact history with active tuberculosis, and history of pulmonary tuberculosis were not different between the two groups. The positive rate of TST (34.6% vs. 38.5%) and the median skin induration size (5 mm vs. 6 mm) of the two groups were similar. Medications and DAS28 were not associated with the TST result. The tuberculin reaction of patients with RA is not attenuated compared with that of controls in South Korea.     

Tuberculin conversions in Indochinese refugees. An assessment of boosting and anergy

Indochinese refugees entering the United States have a high rate of tuberculosis and tuberculin reactivity. In addition, several investigators have noted that a large number of refugees with initial tuberculin tests that are "not significant" change to "significant" reactions when retested within 8 wk. This "conversion" phenomenon has been reported in 21 to 43% of refugees and has been unexplained by antigen, testing, demographic, or exposure risk factors. A prospective evaluation of 218 refugees, conducted to assess the role of anergy and boosting, confirmed earlier findings, with 52% of 118 persons with initial tuberculin reactions that were "not significant" developing "significant" reactions on subsequent testing. Anergy, as measured by nonreactivity to mumps and candida skin tests, was not found to be a contributing factor, as few refugees were anergic and as rates of anergy did not differ significantly among refugees with different responses to tuberculin. Boosting, however, played a major role in explaining the "conversions," as 59% of persons who changed to "significant" tuberculin tests did so when retested with tuberculin at 1 to 3 wk. "Delayed" boosting rather than incubating disease or anergy appeared to be the most likely explanation for the remaining "conversions" that occurred on a third PPD test conducted at approximately 8 wk. If the "conversion" phenomenon is due to boosting, it remains to be seen whether the boosting is a result of previous exposure to Mycobacterium tuberculosis or to other, nontuberculous mycobacteria.     

Tuberculin reaction in pulmonary tuberculosis in the Asir Region of Saudi Arabia

The Mantoux test was performed on 75 Saudi and Yemeni patients with pulmonary tuberculosis using 2TU of PPD-RT23; 82.7% of these patients had a positive skin test. It was also noted that, contrary to findings in the West, old age does not seem to affect the Mantoux reaction adversely. 9 patients had a non-significant reaction and using the 3-step ‘boosting’, 8 of the 9 (88.9%) non-reactors converted to positive. Despite the low number of patients included in our study, we recommend 3-step ‘boosting’ when doing tuberculin skin testing in Third World Countries in order to bring out the true tuberculin ‘reactors’.     

High incidence of anergy in inflammatory bowel disease patients limits the usefulness of PPD screening before infliximab therapy.

BACKGROUND & AIMS: Reports of tuberculosis (TB) in patients administered infliximab prompted the Food and Drug Administration to recommend that all patients being considered for this therapy be evaluated for the risk for latent TB infection by means of a tuberculin skin test (TST). The aim of this study is to evaluate the utility of a TST as an adequate screen for TB exposure in patients with inflammatory bowel disease (IBD). METHODS: Eighty-two consecutive patients with IBD (Crohn's disease, 70 patients; ulcerative colitis, 4 patients; indeterminate colitis, 8 patients) seen at Cedars-Sinai Medical Center IBD Center (Los Angeles, CA) being treated with or considered for infliximab therapy underwent a standard intradermal purified protein derivative (PPD) TST before or between infusions of infliximab. One or more control antigens (Candida, tetanus, and/or mumps) were concurrently placed on 69 of these patients. Skin tests were read for induration at 48-72 hours after placement, and results were recorded. RESULTS: None of 82 patients had a positive PPD TST result. Overall, 71% of patients (49 of 69 patients) with controls placed failed to react to any antigen. Eighty-three percent of patients (40 of 48 patients) who were administered corticosteroids and/or immunosuppressive medications, not including infliximab, for at least 1 month were anergic compared with 43% of patients (9 of 21 patients; P < 0.002) who were not administered those medications. CONCLUSIONS: Given the high prevalence of anergy, a negative TST result in patients with IBD administered infliximab is an unreliable indicator for TB exposure. Evaluation for TB risks should include not only a TST, but also a detailed history of travel, TB exposures, and such symptoms as chronic cough and weight loss, and a chest radiograph should be considered.