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Summary Despite notable progresses in the recent decades, tuberculosis (TB) continues to remain a public health concern even in Europe. TB prevention and care should be people-centred, improving ambulatory models across countries, in order to expand access to diagnosis and treatment for both TB infection and disease. Even more, during emergencies such as the current pandemic, when seeking of TB care has been replaced by the fear of coronavirus disease 2019 (COVID-19), TB patient’s care is fundamental. In this short communication, we document how was possible to implement a TB outpatient service meanwhile a local outbreak of SARS-CoV-2 transmission was ongoing.

Journal of Preventive Medicine and Hygiene, Vol. 61 No. 1s1 (2020): Tuberculosis. The Never Ending Story: past, present and Future Challeng (Parte I)

Purpose: To study and compare the efficacy of different therapeutic options for the treatment of central serous chorioretinopathy (CSCR). Methods: This is a nonrandomized, international multicentre study on 1719 patients (1861 eyes) diagnosed with CSCR, from 63 centres (24 countries). Reported data included different methods of treatment and both results of diagnostic examinations [fluorescein angiography and/or optical coherent tomography (OCT)] and best-corrected visual acuity (BCVA) before and after therapy. The duration of observation had a mean of 11 months but was extended in a minority of cases up to 7 years. The aim of this study is to evaluate the efficacy of the different therapeutic options of CSCR in terms of both visual (BCVA) and anatomic (OCT) improvement. Results: One thousand seven hundred nineteen patients (1861 eyes) diagnosed with CSCR were included. Treatments performed were nonsteroidal anti-inflammatory eye drops, laser photocoagulation, micropulse diode laser photocoagulation, photodynamic therapy (PDT; Standard PDT, Reduced-dose PDT, Reduced-fluence PDT), intravitreal (IVT) antivascular endothelial growth factor injection (VEGF), observation and other treatments. The list of the OTHERS included both combinations of the main proposed treatments or a variety of other treatments such as eplerenone, spironolactone, acetazolamide, beta-blockers, anti-anxiety drugs, aspirin, folic acid, methotrexate, statins, vitis vinifera extract medication and pars plana vitrectomy. The majority of the patients were men with a prevalence of 77%. The odds ratio (OR) showed a partial or complete resolution of fluid on OCT with any treatment as compared with observation. In univariate analysis, the anatomical result (improvement in subretinal fluid using OCT at 1 month) was favoured by age 500 μm (p = 0.03). The OR for obtaining partial or complete resolution showed that anti-VEGF and eyedrops were not statistically significant; whereas PDT (8.5), thermal laser (11.3) and micropulse laser (8.9) lead to better anatomical results with less variability. In univariate analysis, the functional result at 1 month was favoured by first episode (p = 0.04), height of subretinal fluid >500 μm (p

Summary Tuberculosis (TB) and humans have coexisted for more than 40,000 years. The word “tuberculosis” derives from “tubercle”, the histological lesion which appears in the organs, described by Pott in the late Eighteenth century and found, by molecular biology, in human skeletons dating back to 5000 BC. Early description of TB can be found in the writings of ancient India and China and in the Bible. In ancient Greece tuberculosis was not considered contagious, but Aristotle recognized the contagious nature of the pig’s and ox’s scrofula. The suspicion that phthisis is a contagious disease and that isolation can reduce the risk of transmission was expressed for the first time by the Arabian Avicenna, in his work “The canon of medicine”. In 1699, the Health Council of the Republic of Lucca founded the “sanatorium” concept as place of care and isolation. In 1865 Villemain inoculated tubercular material from a human lymph node into a rabbit, obtaining for the first time the typical tubercular lesions. Some years later, on March 24, 1882, Robert Koch announced to the Berlin Society of Physiology the discovery of Mycobacterium tuberculosis. In the same period Virchow improved awareness of risk factors and correct behaviours among the general population. In 1952 Waksman won the Nobel Prize for the discovery of the first active drug against TB: streptomycin. Nevertheless, drug resistance appeared rapidly some years later and it is still a great challenge in TB fight nowadays.

Background A substantial increase in pulmonary and extra-pulmonary diseases due to non-tuberculous mycobacteria (NTM) has been documented worldwide, especially among subjects suffering from chronic respiratory diseases and immunocompromised patients. Many questions remain regarding the epidemiology of pulmonary disease due to NTM (NTM-PD) mainly because reporting of NTM-PD to health authorities is not mandated in several countries, including Italy. This manuscript describes the protocol of the first Italian registry of adult patients with respiratory infections caused by NTM (IRENE). Methods IRENE is an observational, multicenter, prospective, cohort study enrolling consecutive adult patients with either a NTM respiratory isolate or those with NTM-PD. A total of 41 centers, including mainly pulmonary and infectious disease departments, joined the registry so far. Adult patients with all of the following are included in the registry: 1) at least one positive culture for any NTM species from any respiratory sample; 2) at least one positive culture for NTM isolated in the year prior the enrolment and/or prescribed NTM treatment in the year prior the enrolment; 3) given consent to inclusion in the study. No exclusion criteria are applied to the study. Patients are managed according to standard operating procedures implemented in each IRENE clinical center. An online case report form has been developed to collect patients’ demographics, comorbidities, microbiological, laboratory, functional, radiological, clinical, treatment and outcome data at baseline and on an annual basis. An IRENE biobank has also been developed within the network and linked to the clinical data of the registry. Conclusions IRENE has been developed to inform the clinical and scientific community on the current management of adult patients with NTM respiratory infections in Italy and acts as a national network to increase the disease’s awareness. Trial registration Clinicaltrial.gov: NCT03339063.

No information is currently available on the influence of injectable second-line drugs on treatment outcomes of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) patients. To investigate this issue, a large series of MDR- and XDR-TB cases diagnosed in Estonia, Germany, Italy and the Russian Federation (Archangels Oblast) between 1999 and 2006 were analysed. All study sites performed drug susceptibility testing for first- and second-line anti-TB drugs, laboratory quality assurance and treatment delivery according to World Health Organization recommendations. Out of 4,583 culture-confirmed cases, 240 MDR- and 48 XDR-TB cases had a definitive outcome recorded (treatment success, death, failure). Among MDR- and XDR-TB cases, capreomycin resistance yielded a higher proportion of failure and death than capreomycin-susceptible cases. Resistance to capreomycin was independently associated with unfavourable outcome (logistic regression analysis: odds ratio 3.51). In the treatment of patients with multidrug-resistant and extensively drug-resistant tuberculosis, resistance to the injectable drug capreomycin was an independent predictor for therapy failure in this cohort. As Mycobacterium tuberculosis drug resistance is increasing worldwide, there is an urgent need for novel interventions in the fight against tuberculosis.

In 1998 a network of 20 regional tuberculosis (TB) laboratories (the Italian Multicentre Study on Resistance to Antituberculosis drugs (SMIRA) network) was established in Italy to implement proficiency testing and to monitor the prevalence of drug resistance nationwide. The network managed 30% of all TB cases reported in Italy each year. The aim of the present report is to describe: 1) the accuracy of drug-susceptibility testing in the network; 2) the prevalence of drug resistance for the period 1998-2000. Data were collected from the network laboratories. Sensitivity to streptomycin and ethambutol increased from the first survey (1998-1999) to the second survey (2000) from 87.7 to 91.9%. Specificity, predictive values for resistance and susceptibility, efficiency and reproducibility were consistent in both surveys. In previously untreated cases, the prevalence of multidrug-resistance was the same in both surveys (1.2%), while a slight decrease from the first to the second survey was observed for monoresistance to rifampicin (from 0.8 to 0.4%) and isoniazid (from 2.9 to 2%). The significant association found between isoniazid resistance and immigration is a useful indicator for both clinicians managing individual tuberculosis cases and public health services planning control strategies.

Linezolid is used to treat patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-tuberculosis (TB) cases, although clinical data on its safety, tolerability and efficacy are lacking. We performed a retrospective, nonrandomised, unblinded observational study evaluating the safety and tolerability of linezolid at 600 mg q.d. or b.i.d. in MDR/XDR-TB treatment in four European countries. Efficacy evaluation compared end-points of 45 linezolid-treated against 110 linezolid-nontreated cases. Out of 195 MDR/XDR-TB patients, 85 were treated with linezolid for a mean of 221 days. Of these, 35 (41.2%) out of 85 experienced major side-effects attributed to linezolid (anaemia, thrombocytopenia and/or polyneuropathy), requiring discontinuation in 27 (77%) cases. Most side-effects occurred after 60 days of treatment. Twice-daily administration produced more major side-effects than once-daily dosing (p = 0.0004), with no difference in efficacy found. Outcomes were similar in patients treated with/without linezolid (p = 0.8), although linezolid-treated cases had more first-line (p = 0.002) and second-line (p = 0.02) drug resistance and a higher number of previous treatment regimens (4.5 versus 2.3; p = 0.07). Linezolid 600 mg q.d. added to an individualised multidrug regimen may improve the chance of bacteriological conversion, providing a better chance of treatment success in only the most complicated MDR/XDR-TB cases. Its safety profile does not warrant use in cases for which there are other, safer, alternatives.

To the Editor: Twenty-three countries have reported >1 case of extensively drug-resistant tuberculosis (XDR TB) (1); however, information about XDR TB is still incomplete. In particular, the response of XDR TB to treatment in countries with low incidence is not known. We compared mortality rates from XDR TB with those from multidrug-resistant (MDR) TB. We analyzed data from all culture-confirmed TB cases diagnosed during 2003–2006 by the TB clinical reference centers in Italy (Sondalo, Milan, Rome) and Germany (Borstel, Grosshansdorf, Bad-Lippspringe) and reviewed original clinical records. Drug susceptibility testing for first- and second-line anti-TB drugs was performed according to World Health Organization (WHO) recommendations by quality-assured laboratories and retested at WHO Supranational Reference Laboratories (Rome/Milan; Borstel) (2–4). XDR TB was defined as resistance to at least rifampin and isoniazid (MDR TB definition) in addition to any fluoroquinolone and >1 of 3 injectable anti-TB drugs (capreomycin, kanamycin, amikacin) (3). Characteristics of MDR TB and XDR TB cases were compared by χ2 test (categorical variables), Student t test (admission days), and Kaplan-Maier curve (sputum smear, culture conversion), where appropriate. Of 2,888 culture-positive TB cases analyzed (Italy 2,140, Germany 748), 126 (4.4%) were MDR (Italy 83, Germany 43) and 11 (0.4%) were XDR (Italy 8, Germany 3). We estimate that the TB cases analyzed represent 24% of culture-positive cases reported in Italy (69.7% of MDR) and 4.2% of those reported in Germany (12.6% of MDR). XDR TB was diagnosed in each year of the study. All 11 XDR TB patients were receiving retreatment, and of the 126 MDR TB patients, 74 (58.7%) were receiving retreatment. All XDR TB patients were HIV seronegative; and of 109 MDR TB patients tested for HIV, 10 (9.2%) were HIV seropositive. Details about previous treatment regimens, drug resistance, and duration of treatment of XDR TB patients are summarized in the Appendix Table. XDR TB patients were significantly more likely than MDR TB patients to be resistant to all first-line drugs (8/11 vs. 36/126, p

Even 125 yrs after Robert Koch discovered the tuberculosis (TB) bacillus and 63 yrs since the discovery of streptomycin, the first anti-TB drug, TB, the “white plague”, still causes ∼9 million incidents of illness and claims >1.6 million lives annually. Yet, little attention has been paid to TB by decision-makers, the media or the general public, contributing to a lack of political will and public action to solve this global health emergency. With the recent rekindling of media and popular interest in the emerging threat of extensively drug-resistant TB (XDR-TB), the health community has a critical opportunity to leverage more coordinated and purposeful communications as an important weapon in the fight against TB. Data gathered through the study described below are a starting point for developing a communications strategy and key messages to strengthen Europe's response to the TB epidemic. TB traditionally receives little media attention; coverage is often limited to large exposures ( e.g. cases in schools and workplaces) and dramatic events, such as the high-mortality XDR-TB outbreak among HIV-positive individuals in South Africa 1. At the start of 2007, Le Iene (the Ienas 2; a popular evening television broadcast with a high market share in Italy) reviewed coverage of various health issues and “discovered” that the media had in the past given priority and much more relevance to hot-button issues, such as severe acute respiratory syndrome, avian flu and HIV/AIDS (without mentioning its association with TB), than to TB. The Ienas journalists charged one of the Italian national television channels with having forgotten TB, with the effect of raising discussion on this previously neglected disease. At around the same time, the European Respiratory Journal published a paper describing the threat of XDR-TB 1. In March 2007, following the publication of a scientific report on 11 XDR-TB cases in Europe (three …

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.

SMIRA (Italian Study on Anti-Tuberculosis Drug Resistance) network, 46 major clinical units and 22 laboratories nationwide in Italy.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.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 P0.05).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; P0.05) and treatment foror = 12 months (OR 5.03; 95% CI 1.65-15. 31; P0.05). Immigration and HIV infection were the main risk factors among new MDR-TB cases.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.

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 was12 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.

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.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.A 26-point questionnaire mailed to 203 PCs.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.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 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 Italy24 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 was12 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.

Although in developing countries the treatment of tuberculosis (TB) cases is among the most cost-effective health interventions, few studies have evaluated the cost-effectiveness of TB control in low-prevalence countries. The aim of the present study was to carry out an economic analysis in Italy that takes into account both the perspective of the resource-allocating authority (i.e. the Ministry of Health) and the broader social perspective, including a cost description based on current outcomes applied to a representative sample of TB patients nationwide (admission and directly observed treatment (DOT) during the initial intensive phase of treatment); a cost-comparison analysis of two alternative programmes: current policy based on available data (scenario 1) and an hypothetical policy oriented more towards outpatient care (scenario 2) (both scenarios included the option of including or not including DOT outside hospital admission, and incentives) were compared in terms of cost per case treated successfully. Indirect costs (such as loss of productivity) were included in considerations of the broader social perspective. The study was designed as a prospective monitoring activity based on the supervised collection of forms from a representative sample of Italian TB units. Individual data were collected and analysed to obtain a complete economic profile of the patients enrolled and to evaluate the effectiveness of the intervention. A separate analysis was done for each scenario to determine the end-point at different levels of cure rate (50-90%). The mean length of treatment was 6.6 months (i.e. patients hospitalized during the intensive phase; length of stay was significantly higher in smear-positive patients and in human immunodeficiency virus (HIV) seropositive patients). Roughly six direct smear and culture examinations were performed during hospital admission and three during ambulatory treatment. The cost of a single bed day was US$186.90, whereas that of a single outpatient visit ranged, according to the different options, from US$2.50 to US$11. Scenario 2 was consistently less costly than scenario 1. The cost per case cured for smear-positive cases was US$16,703 in scenario 1 and US$5946 in scenario 2. The difference in cost between the cheapest option (no DOT) and the more expensive option (DOT, additional staff, incentives) ranged from US$1407 (scenario 1, smear-negative and extrapulmonary cases) to US$1814 (scenario 2, smear-positive cases). The additional cost to society including indirect costs ranged from US$1800 to US$4200. The possible savings at the national level were in the order of US$50 million per year. In conclusion, cost-comparison analysis showed that a relatively minor change in policy can result in significant savings and that the adoption of DOT will represent a relatively modest economic burden, although the real gain in effectiveness resulting from DOT in Italy requires further evaluation.