Clinical standards for the assessment, management and rehabilitation of post-TB lung disease.

BACKGROUND: Increasing evidence suggests that post-TB lung disease (PTLD) causes significant morbidity and mortality. The aim of these clinical standards is to provide guidance on the assessment and management of PTLD and the implementation of pulmonary rehabilitation (PR).METHODS: A panel of global experts in the field of TB care and PR was identified; 62 participated in a Delphi process. A 5-point Likert scale was used to score the initial ideas for standards and after several rounds of revision the document was approved (with 100% agreement).RESULTS: Five clinical standards were defined: Standard 1, to assess patients at the end of TB treatment for PTLD (with adaptation for children and specific settings/situations); Standard 2, to identify patients with PTLD for PR; Standard 3, tailoring the PR programme to patient needs and the local setting; Standard 4, to evaluate the effectiveness of PR; and Standard 5, to conduct education and counselling. Standard 6 addresses public health aspects of PTLD and outcomes due to PR.CONCLUSION: This is the first consensus-based set of Clinical Standards for PTLD. Our aim is to improve patient care and quality of life by guiding clinicians, programme managers and public health officers in planning and implementing adequate measures to assess and manage PTLD.

Latent tuberculous infection among foreign-born individuals applying to shelters in the metropolitan area of Milan.

SETTING: Screening for latent tuberculous infection (LTBI) of groups at high risk of active tuberculosis (TB) is a key component of the End TB Strategy. OBJECTIVE: To conduct a retrospective descriptive analysis of LTBI rates among foreign-born individuals applying to shelters in the metropolitan area of Milan, Italy. DESIGN: All foreign-born individuals registering for accommodation centres in the city of Milan from November 2009 to April 2017 were screened for active TB and LTBI. Individuals aged <36 years with a tuberculin skin test (TST) induration of >10 mm were offered confirmatory testing with QuantiFERON®-TB Gold In-Tube (QFT-GIT). RESULTS: Of the 2666 TST-positive migrants aged <36 years who underwent LTBI confirmation testing, 1322 (49.6%) tested negative, 1339 (50.2%) were positive and five (0.2%) had indeterminate results. In the multivariate analysis, TB incidence in the country of origin and age were significantly associated with QFT-GIT positivity. Although estimated TB incidence in Eritrea, Morocco and Romania was 100/100 000 person-years (py), the probability of being QFT-GIT-positive in individuals from these countries were not statistically significantly different from individuals from countries with TB incidence > 250/100 000 person-years. CONCLUSION: Our data showed a high proportion of LTBI among individuals coming from intermediate TB burden countries.

Tuberculosis-related stigma leading to an incomplete contact investigation in a low-incidence country.

A contact investigation following a case of infectious tuberculosis (TB) reported in a call centre in Milan (Italy) led to the identification of three additional cases that had occurred in employees of the same workplace during the previous 5 years, one of whom was the probable source case. Thirty-three latent infections were also identified. At the time of diagnosis, the source case, because of fear of stigma related to TB, claimed to be unemployed and a contact investigation was not performed in the workplace. Cases were linked through genotyping of Mycobacterium tuberculosis. TB stigma has been described frequently, mainly in high-incidence settings, and is known to influence health-seeking behaviours and treatment adherence. The findings in this report highlight that TB-associated stigma may also lead to incomplete contact investigations. Little is known about the causes and impact of TB-related stigma in low-incidence countries and this warrants further exploration. Research is also needed to evaluate the effectiveness of specific interviewing techniques and training interventions for staff in reducing feelings of stigma in TB patients. Finally, the outbreak emphasizes the importance of integrating routine contact investigations with genotyping.

Tuberculosis control in big cities and urban risk groups in the European Union: a consensus statement.

In low-incidence countries in the European Union (EU), tuberculosis (TB) is concentrated in big cities, especially among certain urban high-risk groups including immigrants from TB high-incidence countries, homeless people, and those with a history of drug and alcohol misuse. Elimination of TB in European big cities requires control measures focused on multiple layers of the urban population. The particular complexities of major EU metropolises, for example high population density and social structure, create specific opportunities for transmission, but also enable targeted TB control interventions, not efficient in the general population, to be effective or cost effective. Lessons can be learnt from across the EU and this consensus statement on TB control in big cities and urban risk groups was prepared by a working group representing various EU big cities, brought together on the initiative of the European Centre for Disease Prevention and Control. The consensus statement describes general and specific social, educational, operational, organisational, legal and monitoring TB control interventions in EU big cities, as well as providing recommendations for big city TB control, based upon a conceptual TB transmission and control model.

The spread of drug-resistant tuberculosis in children: an Italian case series.

Drug-resistant paediatric tuberculosis (TB) is an overlooked global problem. In Italy, the epidemiology of TB has recently changed and data regarding drug-resistant forms in the paediatric setting is scanty. The aim of this case series was to report the cases of drug-resistant TB, diagnosed between June 2006 and July 2010 in four Italian tertiary centres for paediatric infectious diseases, in children and adolescents living in Italy. Twenty-two children were enrolled, of these 17 were resistant to one or more drugs and five had multidrug-resistant TB. All but one child were either foreign born or had at least one foreign parent. Twenty-one patients completed their treatment without clinical or radiological signs of activity at the end of treatment, and one patient was lost to follow up. The outcomes were good, with few adverse effects using second-line anti-TB drugs. Although this series is limited, it might already reflect the worrisome increase of drug-resistant TB, even in childhood.

Isoniazid preventive treatment: predictors of adverse events and treatment completion.

SETTING: Villa Marelli Institute (VMI), Niguarda Ca'Granda Hospital, Milan, Italy. BACKGROUND: A recent report on the fatal side effects of isoniazid preventive therapy (IPT) from the United States has re-ignited discussion on the safety of this intervention. OBJECTIVE: To evaluate IPT feasibility, treatment completion and adverse events (AE) and their determinants under field conditions. METHODS: Data from consecutive subjects undergoing IPT at the VMI were recorded in an electronic database from 1992 to 2009. Logistic regression analysis was performed to detect completion and AE determinants. RESULTS: A total of 11,963 patients were included in the study. AE (odds ratio [OR] 2.70, 95%CI 2.22-3.28) and human immunodeficiency virus positive status (OR 5.20, 95%CI 2.10-12.93) were the main determinants of treatment interruption among Italians, while social weakness (no housing/job; OR 2.88, 95%CI 2.43-3.42), AEs (OR 1.33, 95%CI 1.15-1.53, 2.22-3.28) and screening in undocumented subjects (OR 1.20, 95%CI 1.01-1.44) prevailed among foreigners. Age was the main determinant of transaminase increase (OR 1.03, 95%CI 1.03-1.04), as were AEs of the gastrointestinal (OR 1.02, 95%CI 1.02-1.03), central nervous (OR 1.02, 95%CI 1.02-1.05) and peripheral nervous systems (OR 1.04, 95%CI 1.02-1.05). CONCLUSION: This analysis demonstrates the feasibility and safety of IPT, with determinants of interruption and AEs being predictable and addressable.

[Are targeted interventions needed in foreigner workers with latent tubercular infection? A study on anti-tubercular treatment compliance among health care workers]. / C'è esigenza di interventi mirati nei lavoratori stranieri affetti da infezione tubercolare latente? Uno studio sulla compliance alla terapia antitubercolare in operatori sanitari.

INTRODUCTION: Health care workers (HCWs) are at high risk of latent tubercular infection (LTBI). In this study predictors of anti-tubercular treatment interruption in HCWs with LTBI are evaluated. METHODS: 1056 HCWs with LTBI were followed up to register adverse events and predictors of treatment interruption. RESULTS: 289 workers did not complete the treatment. Predictors of treatment interruption were adverse events (OR 1.47; 95CI% 1.07-2.03) and to be born in South-America (OR 1.55; 95CI% 1.06-2.26). CONCLUSION: The higher risk in South-Americans supports the need of targeted formative interventions on these workers.

Clinical and operational value of the extensively drug-resistant tuberculosis definition.

Currently, no information is available on the effect of resistance/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB (MDR-TB) and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation during the period 1999-2006 were analysed. Drug-susceptibility testing for first- and second-line anti-TB drugs, quality assurance and treatment delivery was performed according to World Health Organization recommendations in all study sites. Out of 4,583 culture-positive TB cases analysed, 361 (7.9%) were MDR and 64 (1.4%) were XDR. XDR-TB cases had a relative risk (RR) of 1.58 to have an unfavourable outcome compared with MDR-TB cases resistant to all first-line drugs (isoniazid, rifampicin ethambutol, streptomycin and, when tested, pyrazinamide), and an RR of 2.61 compared with "other" MDR-TB cases (those susceptible to at least one first-line anti-TB drug among ethambutol, pyrazinamide and streptomycin, regardless of resistance to the second-line drugs not defining XDR-TB). The emergence of extensively drug-resistant tuberculosis confirms that problems in tuberculosis management are still present in Europe. While waiting for new tools which will facilitate management of extensively drug-resistant tuberculosis, accessibility to quality diagnostic and treatment services should be urgently ensured and adequate public health policies should be rapidly implemented to prevent further development of drug resistance.

Use of a T-cell-based test for detection of tuberculosis infection among immunocompromised patients.

The aim of this study was to compare the performance of the T-SPOT.TB test, a T-cell-based test, with the tuberculin skin test (TST) in the diagnosis of latent tuberculosis (TB) infection. The study was carried out in 138 immunosuppressed haematology patients who had been nosocomially exposed to a case of smear-positive TB. Overall, 44.2% of the contacts were positive by T-SPOT.TB test, and 17.4% by TST (concordance 67.8%). The apparent prevalence of infection fell from 25.9 to 14.5% with the TST with increasing immunosuppression, although this difference was not significant. In contrast, the apparent prevalence of infection with the T-SPOT.TB test was unaffected at 44.6 and 44.3%, respectively. The T-SPOT.TB test had an overall indeterminate rate of 4.3%, and this was also unaffected by the level of immunosuppression. This study suggests that the T-SPOT.TB test maintains its sensitivity and performance in immunocompromised patients, identifying a large number of truly infected patients anergic to the tuberculin skin test.

Comparison of tuberculin skin test and Quantiferon immunological assay for latent tuberculosis infection.

BACKGROUND: Correct identification of individuals with latent tuberculosis infection (LTBI) is a crucial element of the elimination strategy, allowing their adequate treatment. In addition to tuberculin skin test (TST), the Quantiferon test (QFT, based on whole blood gamma-interferon release) had been recently proposed. Aim of the study is to compare this test to TST for identification of LTBI in a non-selected population, in order to verify their value in identifying truly infected individuals (entitled to receive preventive chemotherapy), and to exclude from treatment those having a positive TST for other reasons (e.g. after BCG vaccination). METHODS: 136 consecutive persons (78 males, mean age 34 +/- 9 years) referred to the clinic for TST were recruited (78 born in low--or middle--income countries). Based on their history, the cases were divided into 4 groups: 1) recently traced contacts of whom 18 TST negative and 28 TST positive; 2) 22 screening subjects, all TST negative; 3) BCG vaccinated subjects (14); and 4) 54 subjects already undergoing treatment of LTBI for exposure to TB. RESULTS: The overall agreement between TST and QFT was 72% (64% in TST positive and 88.4% in TST negative subjects). The proportion of TST positive/QFT negative BCG vaccinated individuals was 23.1%. The K coefficient was 0.474 in recently traced contacts, 0.366 in BCG vaccinated individuals and 0.451 overall. CONCLUSIONS: The study results suggest that agreement between TST and QFT is lower in TST positive than in negative subjects, being lower in individuals treated for LTBI. Quantiferon does not seem to have brought significant improvement in the diagnosis of LTBI.

Management of multidrug-resistant tuberculosis in Italy.

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.

Prevalence of resistance to anti-tuberculosis drugs: results of the 1998/99 national survey in Italy.

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.

Microbiological confirmation of tuberculosis cases at diagnosis and at the end of treatment in Italy.

Microbiological findings at diagnosis and at the end of treatment are relevant for evaluating tuberculosis (TB) treatment programmes. The objectives of this study were to describe the microbiological findings at diagnosis and at the end of treatment in pulmonary and extrapulmonary TB patients treated under programme conditions in Italy. The study was a prospective monitoring activity based on the collection of standard recording and reporting forms from a representative sample of Italian TB Units. The forms with individual data were reviewed and analysed on a quarterly basis, 9 months after enrolment. The complete bacteriological profile of patients was analysed at diagnosis and at the completion of treatment. Individual data on 992 patients were analysed. At diagnosis 320 (32.2%) of cases were pulmonary sputum smear positive, 361 (36.4%) pulmonary smear negative or not done and 311 (33.4%) extrapulmonary; 424 (42.7%) of all TB cases were culture confirmed at diagnosis (368, 50.2%, of pulmonary cases); 575 (84.4%) of pulmonary cases had a culture done at diagnosis and 156 (22.9%) at the end of treatment (p < 0.001); 572 (84%) had a sputum smear done at diagnosis and 164 (24.1%) at the end of treatment (p < 0.001). Although the rate of bacteriologically confirmed cases is similar to that of other European countries, the bacteriological confirmation at diagnosis and, particularly, at the end of treatment, is sub-optimal. The importance of further disseminating national guidelines among physicians managing TB is emphasized, in order to achieve a higher proportion of TB cases bacteriologically confirmed at diagnosis and monitored at the end of treatment.

Circulating, Mycobacterium tuberculosis-specific lymphocytes from PPD skin test-negative patients with tuberculosis do not secrete interferon-gamma (IFN-gamma) and lack the cutaneous lymphocyte antigen skin-selective homing receptor.

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.

Hospital admission policy for tuberculosis in pulmonary centres in Italy: a national survey. AIPO Tuberculosis Study Group. Italian Association of Hospital Pulmonologists.

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.

Tuberculosis among immigrants from developing countries in the province of Milan, 1993-1996.

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.

The Italian AIPO study on tuberculosis treatment results, report 1995. National AIPO "Tuberculosis" Study Group.

In Italy, no national data on tuberculosis (TB) treatment results were available. 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 World Health Organization (WHO) and International Union against Tuberculosis and Lung Disease (IUATLD) recommendations. Data were collected from a nationwide network of 41 TB units, managing a significant proportion of all TB cases notified in Italy each year. The aim of this study was to analyse the case findings and treatment results for the year 1995. Seven hundred and seventy eight TB cases were reported (59% males; 21% immigrants), 640 (82%) being new cases. Of these cases, 517 (66%) were pulmonary, 239 (31%) extrapulmonary and 22 (3%) both pulmonary and extrapulmonary. The main risk factors for TB were a history of recent contact and alcohol abuse among native Italians and human immunodeficiency virus-seropositive status among immigrants. The majority of immigrants were from Africa and South America, and had been in Italy > 24 months before diagnosis of TB. Thirty-seven per cent of patients had a positive direct sputum smear examination for alcohol acid-fast bacilli; 20% were resistant to any drug (monoresistance to isoniazid 3.5%; multidrug resistance 5.2%). In 95% of cases, the duration of treatment was < 12 months. The overall success rate (cured plus treatment completed) was 81.1%. A significantly higher percentage of deaths was found in native Italians (being age-related), whereas immigrants had a higher default rate.