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Setting: SMIRA (Italian Study on Anti-Tuberculosis Drug Resistance) network, 46 major clinical units and 22 laboratories nationwide in Italy., Objectives: To determine the main features, adherence to WHO guidelines and the outcomes of multidrug-resistant tuberculosis (MDR-TB) patients enrolled from January 1995 to December 1999., Design: Observational study, preceded by proficiency testing, according to WHO recommendations. Results were stratified by appropriate and inappropriate regimens (< three active drugs). Analysis of the outcomes was performed according to adequacy of treatment. Analysis of risk factors and factors predicting treatment outcomes was performed using univariate and multivariate analysis (level of significance P < 0.05)., Results: One hundred and twenty-seven MDR patients were diagnosed. The overall success rate was low (39%). Seventy per cent of cases were treated with at least three active drugs. Factors predicting treatment success were new MDR-TB cases (OR 3.45; 95% CI 1.22-9.78; P < 0.05) and treatment for > or = 12 months (OR 5.03; 95% CI 1.65-15. 31; P < 0.05). Immigration and HIV infection were the main risk factors among new MDR-TB cases., Conclusion: The best available treatment should be provided to all newly diagnosed MDR-TB patients, avoiding the use of poorly modified regimens. MDR-TB patients should be referred to highly specialised centres.

Mycobacterium lentiflavum is a recently described nontuberculous mycobacterium that has mainly clinical importance in young children with cervical lymphadenitis and in immunocompromised patients. We describe a case of chronic pulmonary infection in an immunocompetent patient. Our observation confirms clinical, diagnostic, and treatment difficulties in the management of M. lentiflavum infection.

Objective: To determine the prevalence of resistance to the main anti-tuberculosis drugs in newly and previously treated tuberculosis patients in Italy and to evaluate the contribution of foreign-born and human immunodeficiency virus (HIV) positive cases to drug resistance., Methods: Methods and definitions were derived from the WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. Univariate and multivariate analysis was used to study prevalence rates of drug resistance in risk groups., Results: In a national survey in Italy, 810 initial isolates of Mycobacterium tuberculosis (683 from new cases, 115 from retreatment cases and 12 from patients whose treatment history was unknown/dubious) were analysed. Low prevalence of drug and multidrug resistance was found in the new cases (isoniazid 2.9%; rifampicin 0.8%; multidrug resistance 1.2%; any drug resistance 12.3%). The prevalence of resistance to isoniazid and rifampicin was significantly higher in immigrants and HIV-positive subjects, respectively. A high prevalence of drug resistance was found in cases with previous treatment failure or default (isoniazid 5.2%; rifampicin 4.3%; multidrug resistance 36.5%; any drug resistance 61.7%)., Recommendations: Special efforts are necessary to monitor trends in drug resistance and to ensure favourable treatment outcomes among immigrants and HIV-positive tuberculosis cases.

In geographical areas with a low incidence of tuberculosis, recurrent tuberculosis is generally due to reactivation of the disease. However, the relative contribution of tuberculosis reinfection increases in parallel with the incidence of disease and is likely to depend on the epidemiological context: factors such as the spread of multidrug resistance, human immunodeficiency virus (HIV) infection, and immigration from developing countries could modify disease transmission in areas at low risk for tuberculosis. A molecular epidemiology study was performed in Lombardy, Northern Italy, where the incidence of tuberculosis is 17.5 cases per 100,000 persons. A total of 2,452 cases of culture-confirmed tuberculosis in 2,127 patients were studied. A group of 32 patients (1.5%), each of whom had two episodes of tuberculosis with cure as the outcome of the first episode and with more than 6 months between the two episodes, were studied by means of restriction fragment length polymorphism DNA fingerprinting analysis. For 5 of the 32 patients (16%), the DNA fingerprinting patterns of Mycobacterium tuberculosis strains responsible for the second episode did not match those of the corresponding isolates of the first episode, indicating exogenous reinfection. Two of these patients developed multidrug-resistant tuberculosis during the second episode, and in three cases the isolates belonged to clusters of M. tuberculosis strains spreading in the community. A fourfold-increased risk for reinfection was observed in immigrant patients compared to Italian subjects. In contrast, a higher risk of relapse rather than reinfection was evidenced in HIV-positive subjects and in patients infected with multidrug-resistant tuberculosis. Episodes of tuberculosis reinfection in areas with a low incidence of tuberculosis are rare compared to those in high-incidence geographical regions. In populations that have immigrated from high-risk areas, reinfection may represent a considerable contributor to the rate of recurrent tuberculosis. This finding emphasizes the importance of containing the spread of epidemic strains in close communities, in order to prevent changes in global tuberculosis trends for developed countries.

Individuals with a negative intradermal reaction to tuberculin PPD have long been described in the Mycobacterium tuberculosis exposed, immune-competent population. Here, we studied PPD-specific blood T lymphocytes from these subjects for phenotypic markers relevant to skin migration, including the expression of the skin-selective homing receptor, the cutaneous lymphocyte-associated antigen (CLA). Out of 82 patients with active tuberculosis we identified four subjects who were repeatedly PPD skin test-negative. CD4 T lymphocytes specific to mycobacterial antigens were derived from these individuals, which (i) proliferated in vitro to M. tuberculosis antigens comparably to those from PPD+ patients; (ii) secreted comparable amounts of IL-2 but lower amounts of IFN-gamma; (iii) were confined within the CLA-negative T cell subset. We conclude that the negative tuberculin reaction in a small subset of patients exposed to mycobacteria is associated with impaired production of IFN-gamma by circulating PPD-specific T cells that are lacking CLA expression. On this basis in vitro proliferation to PPD can discriminate bona fide non-responders from infected patients with a deficit in the margination of M. tuberculosis-specific T lymphocytes.

Setting: A national survey including 203 pulmonary centres (PCs) (144 hospital PCs with beds dedicated to TB patients and 59 out-patient PCs) managing tuberculosis cases in Italy during 1995., Objectives: To evaluate: 1) hospitalisation practices (criteria for admission/discharge; duration of hospitalisation) as primary end-points; and 2) as secondary end-points the availability of beds, the preventive measures adopted to reduce the spread of infection, the sources of referral for hospitalisation and the procedures adopted to follow up TB patients after discharge., Design: A 26-point questionnaire mailed to 203 PCs., Results: Of 167 PCs that responded to the questionnaire (82.3%), 159 questionnaires were considered valid for the analysis (110 from hospitals PCs and 49 from out-patient PCs). The criteria adopted by PCs to admit TB patients were: all TB cases 47%, only smear-positive pulmonary TB 14%, TB cases with clinical problems 39%. Hospital PCs hospitalised significantly more cases of smear-negative, extra-pulmonary TB. On average 71.6% of all cases were hospitalised (88.2% by hospital and 28% by out-patient PCs). The median hospital stay was 34 days for sputum smear-positive, 20 for sputum smear-negative and 21.5 for extra-pulmonary TB cases. Sputum conversion was considered the mandatory criterion to allow discharge from 61% of hospital PCs., Conclusion: A switch from the present policy (majority of cases hospitalised for a long period) to an outpatient oriented policy needs the co-ordinated educational effort of scientific societies and health authorities.

In Italy no national data have been available on tuberculosis (TB) treatment results. In 1995 the AIPO (Italian Association of Hospital Pneumologists) TB Study Group, in collaboration with the Istituto Superiore di Sanità (technical branch of the Ministry of Health) started a prospective monitoring activity based on the recommendations of the World Health Organization and the International Union Against Tuberculosis and Lung Disease. The aim of this study was to analyse the case findings and treatment results during 1997. Data were collected from a representative network of TB units nation-wide, managing a significant proportion of all TB cases notified in Italy each year. A total of 715 TB cases were reported (56% males; 24% immigrants), of which 635 (89%) were new cases. Of these cases 493 (69%) were pulmonary, 187 (26%) extra-pulmonary cases and 35 (5%) both pulmonary and extrapulmonary. The main risk factors for TB were history of recent contact and diabetes among native Italians, human immunodeficiency virus-seropositive status and a history of recent contact among immigrants. The majority of immigrants came from Africa and Central and South America, and stayed in Italy for more than 24 months before the diagnosis of TB was made. Thirty-six per cent of patients had a positive direct sputum smear examination for alcohol acid-fast bacilli and 27% were resistant to any drug (monoresistance to isoniazid: 2.4%; multi-drug resistance: 7.5%). In 97% of cases the duration of treatment was < 12 months. The overall success rate (cured plus treatment completed) was 78.1%. A significantly higher percentage of deaths, which was age related, was found in native Italians, while immigrants had a higher default rate. In conclusion, case finding and treatment results in Italy in 1997 are similar to those described in 1995 and 1996.

Setting: The Province of Milan, which has high rates of immigration from developing countries, and the Villa Marelli Institute (VMI), Reference Centre for Tuberculosis Control of Lombardy., Objective: To describe epidemiology and clinical patterns of tuberculosis among immigrants from developing countries (IDCs) in the Province from 1993 to 1996., Design: Retrospective analysis of the registries of the Regional Bureau for Public Health and of the VMI concerning immigrant patients with active TB living in the Province. Restriction fragment length polymorphism (RFLP) analysis of the available strains to detect recent transmission among immigrants., Results: IDCs represented 22.8% of all TB cases. The standardised incidence rate was eight times higher in IDCs compared to Italians. Of 596 cases notified in IDCs, 524 (87.9%) had been referred at least once to the VMI. Of these, 77.2% were diagnosed within 5 years of arrival, and 86.6% were brought to medical attention because of symptoms. RFLP fingerprinting demonstrated that the mean period of stay in Italy was significantly higher in clustered than in non clustered patients (61.5 versus 37.3 months). Spread to the native population was episodic., Conclusions: The incidence of TB is higher among more recent immigrants (i.e., Peruvians). TB cases are largely due to reactivation of infection occurring in the country of origin. Preventive measures for early diagnosis of disease or chemoprophylaxis of dormant infection are not regularly performed, but should be implemented for those immigrants at high risk.

We retrospectively evaluated a group of human immunodeficiency virus (HIV)-negative adult patients with hilar and/or mediastinal tubercular adenopathy to assess their epidemiological, clinical and radiological features. Out of 3,003 intrathoracic tuberculosis (TB) cases (of which 745 were immigrants from various developing countries) observed in our Institute from 1986-1996, 8 Italians and 52 immigrants were selected. Case history analysis, and standard chest radiography were performed in all cases, while other investigations such as a tuberculin test, sputum and culture examination for Mycobacterium tuberculosis, computed tomography (CT) scanning and biopsy were performed in the majority of patients. Less frequently, bronchoscopy, mediastinoscopy, and echography were also performed. Right paratracheal adenopathy was found most frequently (29 cases), as previously described. CT scanning showed a central necrosis pattern in 31 cases, while normo/hyperdensity occurred in 11 cases. M. tuberculosis was detected in sputum smear and/or culture in only 16 patients. Our study confirms that, when HIV-positive patients are excluded, this peculiar TB location occurs more frequently in immigrants than in the indigenous Italian population (7.0 versus 0.3%, p < 0.001). People from the Indian subcontinent and Senegal are the most frequently involved nationalities among the immigrants present in Milan.

Setting: Villa Marelli Institute, Lombardy Regional Reference Centre for Tuberculosis., Objective: To evaluate acceptance of and adherence to isoniazid preventive treatment (IPT) of close contacts of contagious tuberculosis (TB) cases (CC); comparison of Italian and immigrant patients., Methods: A retrospective study of a consecutive series of 692 subjects (474 Italians and 218 immigrants from developing countries) exposed to contagious TB cases, who were offered IPT after tuberculin skin testing and chest X-ray, according to the Lombardy Regional Protocol for TB control., Results: Of 692 CCs, 36 (5.2%) subjects refused IPT, 522 (75.5%) completed the treatment as prescribed, 23 (3.3%) suspended IPT because of adverse effects, 14 (2.0%) spontaneously discontinued IPT against our advice, 93 (13.4%) were lost to follow up, and seven (0.6%) were still in treatment when the present data were evaluated. Italian CCs had a completion rate significantly higher than the immigrants (81.0% vs 63.3%, P < 0.01)., Conclusion: The rate of acceptance and completion of IPT in our population proved higher than many previously reported data, and the better results among Italian subjects reflect the importance of a complete comprehension of IPT that may not always be achieved with immigrant patients.

Sensitization to environmental allergens in nasal polyposis was evaluated in an in vitro study conducted on 90 patients undergoing polypectomy by measuring total and specific IgE for a panel of common allergens and levels of IgG, IgA and albumin in serum, and nasal secretions (NSe). Fifty healthy individuals were chosen as a control group. Total IgE concentrations were higher in patients with nasal polyps than in controls. RAST was positive in serum in 34 (38%), in NSe in 29 (32%), and exclusively in NSe in 10 patients (11%). Allergens most frequently involved were mites and cat dander. No differences were found between the study and control groups for serum and NSe IgA, albumin, and serum IgG, whereas IgG in NSe were significantly higher in patients with nasal polyps. Subjects with positive RAST only in NSe had significantly lower secretory IgA than did controls. Our data indicate that in nasal polyposis: 1) sensitization to aeroallergens is relatively common; 2) a local production of specific IgE may occur, especially for perennial allergens; 3) prolonged exposure to these allergens gives rise to chronic nasal inflammation, with altered local production of immunoglobulins.

Twenty-eight subjects affected by perennial asthma were selected in order to investigate the possibility of inducing or relieving an asthmatic attack by means of suggestion. Twenty-five were positive to methacholine challenge test and, among them, eleven reacted to an ultrasonic nebulized distilled water test. The effect of suggestion on airway response was assessed by eight inhalations of normal saline at 32 degrees C alternately presented as a bronchoconstrictor or as a bronchodilator drug. Eight inhalations of the same diluent without any psychic stimulus were used as control test. Seven patients reacted with bronchoconstriction to both positive and negative suggestion and to control test. Further, this group of patients showed a lower methacholine PD20 when compared with the other subjects. In this study, the effects of suggestion on bronchial reactivity were not observed and bronchoconstriction belonged to an individual hyperreactivity of the airways.

Venom immunotherapy provides clinical protection against hymenoptera stings in almost all treated allergic patients. Venom specific IgG antibodies often rise during immunotherapy and some studies found an association between their levels and clinical protection in subjects treated with Yellow Jacket venom. It is interesting to report that, among IgG subclasses, venom specific IgG4 show the most significant increase but IgG1 could represent a relevant immunological mechanism, exerting a regulatory function on venom specific IgE levels. We observed in patients submitted to Honey Bee venom immunotherapy a significant increase of venom specific IgG1 and IgG4 antibodies, while IgG2 showed an insignificant increase only in some patients. Persistent high levels of IgG4 with respect to decreasing levels of IgG1 were observed only after prolonged treatment.

T-lymphocyte subsets in peripheral blood, bronchoalveolar lavage fluid, and prescalenic lymph nodes from eight patients with sarcoidosis were evaluated with monoclonal antibodies. Both in lung and lymph nodes significant increases in helper T cells were demonstrated, except in patients with stage III pulmonary disease or with unaffected lymph nodes. A good statistical correlation was observed between the activity of the disease (expressed by an increased ratio of helper to suppressor/cytotoxic T cells) in bronchoalveolar fluid and in lymph node cell suspensions from each patient. A three-step immunoperoxidase staining reaction, performed on lymph node frozen sections, showed a prevalence of helper T cells both inside and around the granulomas. These findings confirm that sarcoidosis is characterized by increased activity of cell-mediated immunity in its different localizations.

Previous studies have shown that suggestion may modify bronchial reactivity to both inactive diluents and pharmacologically bronchoconstrictor or dilator substances. In our study, 14 patients were subjected to two methacholine challenge tests presented, respectively, as a bronchoconstrictor or as a bronchodilator drug. Forced expiratory volumes in one second were recorded and a PD20 was determined. No significant differences were reported in PD20 values of each patient after the two kinds of suggestion.

To determine the diagnostic value and precision of the quantitative skin test (QST), RAST, specific nasal (NPT) and conjunctival (CPT) provocation tests, we studied 91 patients, suffering from allergic rhinoconjunctivitis with positive skin prick tests (SPT) to common allergens, among whom sixty-nine of them had symptoms related to the positive SPT, and 22 had no clinical correspondence. In these two groups, by comparing the threshold of positivity, we investigated whether there was any parallelism between responses to the tests considered. We also compared the level of specific IgE (RAST) to the wheal-areas evoked by preliminary SPT for the corresponding allergen in order to detect any quantitative relationship between these investigations. Increasing concentrations of standardized allergen extracts (from 10 to 100,000 BU/ml) were used in all in vivo tests. NPT was evaluated on the basis of multiple recordings of nasal resistances by anterior passive rhinomanometry. QST proved to correlate well with RAST and its easier method ensures it a major role in assessing the levels of allergic sensitization. SPT wheal-areas and RAST vales correlated well only for grass and birch, presumably because of better standardization of these allergen extracts. When provocation tests, especially NPT, were positive, patients were almost always symptomatic for the allergen tested (high positive predictive value). Likewise, 21 out of the 22 asymptomatic subjects had negative NPT (high specificity). These results suggested the utility of standardized provocation tests in order to restrict diagnosis to the truly causative allergens in patients with multiple positive SPT results.

A double-blind study was carried out in 65 patients with seasonal rhinitis to compare the effectiveness and tolerance of terfenadine and dexchlorpheniramine. Patients were allocated at random to receive treatment for 1 week with either 60 mg terfenadine twice daily or 2 mg dexchlorpheniramine maleate 3-times daily. Before and after treatment, patients underwent RAST and skin prick tests for reactivity to pollen and those who were positive also had rhinomanometric measurements made of nasal resistance. Diary cards were used by patients to record the severity of nasal obstruction, rhinorrhoea, sneezing, watery, irritated and red eyes, itching of the nose, throat and eyes, and cough. Details were also kept of the frequency and severity of any side-effects. Pollen counts were taken daily during the treatment period. The results showed that both terfenadine and dexchlorpheniramine produced good or excellent relief of the main symptoms in 78% and 73% of the patients, respectively. There was no significant correlation between the pollen count and reduced symptom severity. Both drugs produced a reduction in total nasal resistance but this was not significantly different from initial values, neither was there a significant difference between treatment. Terfenadine was well tolerated and side-effects incidence was significantly lower (p less than 0.01) than in patients treated with dexchlorpheniramine, particularly so with reference to drowsiness.