The evolution of a neglected disease: tuberculosis discoveries in the centuries.

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.

Epidemiology and treatment outcome of MDR and pre-XDR TB in international migrants at two reference centers in the North of Italy: a cross-sectional study coordinated by Stop TB Italia Onlus.

OBJECTIVE: We evaluated the epidemiology and treatment outcomes of multi-drug-resistant (MDR) and pre-extensively-resistant (pre-XDR) tuberculosis (TB) in migrants at two TB reference centers in Italy. STUDY DESIGN: Patient selection criteria for the present study were as follows: age ≥18 years, international migrants (i.e., person who lives in a country other than his/her country of origin), MDR or pre-XDR-TB based on drug-susceptibility test findings, full availability of microbiological, radiological and clinical data. Non-intersecting populations between the two centers were selected. The primary outcome was the proportion of patients with a successful (i.e., cured and treatment completed) treatment outcome. METHODS: A retrospective cross-sectional study was conducted, from 01/Jan/2000 to 01/Jan/2015, at the Regional TB Reference Centre of Lombardy Region, Villa Marelli Institute/ASST Niguarda Ca' Granda (Milan, Italy) and at the Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital ASST (Sondalo, Italy). All data were made anonymous. Qualitative and quantitative variables were collected in an ad hoc electronic database. The statistical software used for all computations was STATA version 15 (StataCorp, Texas, USA). RESULTS: Overall, 116 MDR-TB and pre-XDR-TB cases were recorded: 82 (70.7%) MDR-TB and 34 (29.3%) pre-XDR-TB patients, respectively. The majority (53.5%) were from the World Health Organization European Region (excluding EU/EEA) and 75 (64.5%) were male. Median (interquartile range) age was 32 (26-39) years. TB/HIV coinfection was found in 12 (10.3%) patients. Pulmonary TB was diagnosed in 107/116 (92.2%) patients. Resistance to fluoroquinolones and second-line injectables was detected in 22/116 (19.0%) and 12/107 (11.2%) patients, respectively. Overall treatment success was reached in 95/116 (81.9%) cases. CONCLUSION: Pre-XDR-TB in migrants coming from high-endemic countries represents a matter of concern; therefore, prevention and control activities targeted to high-risk populations are needed to progress toward TB elimination.

The never-ending story of the fight against tuberculosis: from Koch's bacillus to global control programs.

Tuberculosis (TB) is one of the oldest diseases known to affect humanity, and is still a major public health problem. It is caused by the bacillus Mycobacterium tuberculosis (MT), isolated in 1882 by Robert Koch. Until the 1950s, X rays were used as a cheap method of diagnostic screening together with the tuberculin skin sensitivity test. In the diagnosis and treatment of TB, an important role was also played by surgery. The late Nineteenth century saw the introduction of the tuberculosis sanatorium, which proved to be one of the first useful measures against TB. Subsequently, Albert Calmette and Camille Guérin used a non-virulent MT strain to produce a live attenuated vaccine. In the 1980s and 1990s, the incidence of tuberculosis surged as a major opportunistic infection in people with HIV infection and AIDS; for this reason, a combined strategy based on improving drug treatment, diagnostic instruments and prevention was needed.

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.

A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis.

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.

Three-port lens-sparing vitrectomy for aggressive posterior retinopathy of prematurity: early surgery before tractional retinal detachment appearance.

PURPOSE: Aggressive posterior retinopathy of prematurity (APROP) may suddenly develop into tractional retinal detachment (TRD), often resulting in poor vision if untreated. The aim of the current study is to examine the anatomic results and complications of lens-sparing vitrectomy (LSV) for stage 3 APROP, before TRD appearance. METHODS: A retrospective, noncomparative, consecutive case series of 13 eyes of 9 patients (mean gestational age 24.1+/-0.9 weeks [range: 23-25 weeks], mean birthweight of 725.8+/-107.9 grams [range: 598-897 grams]) with stage 3 APROP was carried out. The eyes did not respond to at least one session of retinal laser photocoagulation, showing signs of disease progression. All eyes underwent 20-gauge LSV before retinal detachment appearance. RESULTS: All eyes underwent 20-gauge three-port LSV and intraoperative additional laser photocoagulation. At the end of the surgery, five eyes were tamponaded with air; in eight eyes, a balanced salt solution was left in the vitreous cavity. After 13.5+/-5.3 months of follow-up (range: 4-22), the retina was completely attached in all eyes, without any signs of progression. The authors did not observe any intraoperative or postoperative complications. CONCLUSIONS: Surgical approach to stage 3 APROP refractory to laser photocoagulation could be effective and safe in order to avoid the progression of the disease.

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.

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.

Intravitreal triamcinolone acetonide: valuation of retinal thickness changes measured by optical coherence tomography in diffuse diabetic macular edema.

PURPOSE: The authors studied the efficacy of intravitreal triamcinolone acetonide in a case series of patients with diffuse diabetic macular edema without evidence of vitreous-macular traction refractory to laser photocoagulation. METHODS: Six eyes with clinically diffuse diabetic macular edema that failed to respond to at least two previous sessions of laser photocoagulation were included. The mean age of selected patients was 72.5+/-13.8 years, with a preoperative best-corrected visual acuity reduced to 1.48+/-0.18 logMar and a mean baseline intraocular pressure (IOP) of 15.17+/-2.64 mmHg. The authors also studied macular thickness measured by optical coherence tomography (OCT 2000 scanner, Humphrey Instruments, San Leandro, CA) - in the preoperative period it was 640.8+/-171.1 microm - and the fluorangiographic (Heidelberg Retina Angiograph, Heidelberg Engineering GmbH, Heidelberg, Germany) patterns, which showed pooling in tardy phases and leakage. Mean follow-up was 4 months. RESULTS: In each patient the authors observed a significant improvement, both functionally and anatomically. Mean best-corrected visual acuity increased in the postoperative period to 0.94+/-0.53 logMar. No patient showed decline of visual acuity at the end of follow-up. Base line macular thickness was reduced in the postoperative period to 312.2+/-157.65 microm measured by OCT and fluorangiographic patterns showed a reduction of pooling and of leakage. The most common complications described in the literature were not observed and the increase of mean IOP in the postoperative period to 18.76+/-5.72 mmHg was not significant. CONCLUSIONS: Intravitreal triamcinolone acetonide may decrease macular edema and improve visual acuity in eyes with diffuse diabetic macular edema.

Intravitreal triamcinolone acetonide: valuation of retinal thickness changes measured.

PURPOSE: The authors studied the efficacy of intravitreal triamcinolone acetonide in a case series of patients with diffuse diabetic macular edema without evidence of vitreous-macular traction refractory to laser photocoagulation. METHODS: Six eyes with clinically diffuse diabetic macular edema that failed to respond to at least two previous sessions of laser photocoagulation were included. The mean age of selected patients was 72.5 13.8 years, with a preoperative best-corrected visual acuity reduced to 1.48 0.18 logMar and a mean baseline intraocular pressure (IOP) of 15.17 2.64 mmHg. The authors also studied macular thickness measured by optical coherence tomography (OCT 2000 scanner, Humphrey Instruments, San Leandro, CA) in the preoperative period it was 640.8 171.1 m and the fluorangiographic (Heidelberg Retina Angiograph, Heidelberg Engineering GmbH, Heidelberg, Germany) patterns, which showed pooling in tardy phases and leakage. Mean follow-up was 4 months. RESULTS: In each patient the authors observed a significant improvement, both functionally and anatomically. Mean best-corrected visual acuity increased in the postoperative period to 0.94 0.53 logMar. No patient showed decline of visual acuity at the end of follow-up. Base line macular thickness was reduced in the postoperative period to 312.2 157.65 m measured by OCT and fluorangiographic patterns showed a reduction of pooling and of leakage. The most common complications described in the literature were not observed and the increase of mean IOP in the postoperative period to 18.76 5.72 mmHg was not significant. CONCLUSIONS: Intravitreal triamcinolone acetonide may decrease macular edema and improve visual acuity in eyes with diffuse diabetic macular edema. (Eur J Ophthalmol 2004; 14: 321-4).

Monitoring the quality of laboratories and the prevalence of resistance to antituberculosis drugs: Italy, 1998-2000.

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.

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.

Surveillance of anti-tuberculosis drug resistance: results of the 1998/1999 proficiency testing in Italy. SMIRA (Italian Multicentre Study on Antituberculosis Drug Resistance) Study Group.

OBJECTIVE: To determine the accuracy of drug-susceptibility testing (DST) for isoniazid, rifampicin, ethambutol and streptomycin in a provisional network of 22 regional laboratories in Italy. METHODS: Methods, definitions and reference Mycobacterium tuberculosis strains were derived from the WHO/IUATLD Global Project on Anti-tuberculosis Drug Resistance Surveillance. The laboratories were selected based on technical skills required by the project, the number of DST performed annually and geographic localisation. The results (sensitive/resistant strain) were compared with the gold standard (global project results). Sensitivity (ability to detect true resistance), specificity (ability to detect true susceptibility), positive predictive values for resistance and susceptibility, efficiency and reproducibility were calculated in two rounds. RESULTS: Eighteen of 22 laboratories completed the first round of proficiency testing for the four drugs. Sensitivity was 76.6%, specificity 97.2%, predictive value of a resistant test 89.8% and of a susceptible test 86.8%, efficiency 87.8% and reproducibility 92.8%. A second round was performed by all those laboratories that did not achieve > or = 90% agreement with the results of the Global Project. Overall, after the second round, all the parameters except specificity improved, exceeding 90%. CONCLUSIONS: A network of 15 regional laboratories that fulfil the quality criteria for determining the susceptibility of M. tuberculosis to the four primary antituberculosis drugs was established in Italy.

Effectiveness of infection control measures in controlling a nosocomial outbreak of multidrug-resistant tuberculosis among HIV patients in Italy.

SETTING: Between October 1992 and February 1994, 33 cases of multidrug-resistant tuberculosis (MDR-TB) were diagnosed among patients infected by the human immunodeficiency virus (HIV) and hospitalised in an HIV ward in Milan, Italy. This outbreak was part of a much larger outbreak, begun in another hospital and probably transferred through a patient. OBJECTIVE: To evaluate risk factors for transmission and the effectiveness of infection control measures. DESIGN: 1) Active follow-up of exposed patients, 2) cohort study among HIV-infected patients exposed to MDR-TB cases before and after the implementation of control measures, 3) screening of close contacts of MDR-TB cases, and 4) molecular typing by restriction fragment length polymorphism (RFLP) analysis. RESULTS: The risk of MDR-TB was higher in patients with lower CD4+ lymphocyte percentages and longer duration of exposure. No difference in the daily risk was observed for in-patients vs day-hospital patients or by room distance from an infectious case. Of the 90 patients exposed before the implementation of infection control measures (i.e., October 1992-June 1993) 26 (28.9%) developed MDR-TB, whereas none of the 44 patients exclusively exposed after implementation developed MDR-TB, despite the continuing presence of infectious MDR-TB cases in the ward. CONCLUSION: Simple control measures were effective in significantly reducing nosocomial transmission among patients.