Treatable traits and challenges in the clinical management of non-tuberculous mycobacteria lung disease in people with cystic fibrosis.

INTRODUCTION: Over the last ten years an increasing prevalence and incidence of non-tuberculous mycobacteria (NTM) has been reported among patients with cystic fibrosis (CF) Viviani (J Cyst Fibros, 15(5):619-623, 2016). NTM pulmonary disease has been associated with negative clinical outcomes and often requires pharmacological treatment. Although specific guidelines help clinicians in the process of diagnosis and clinical management, the focus on the multidimensional assessment of concomitant problems is still scarce. MAIN BODY: This review aims to identify the treatable traits of NTM pulmonary disease in people with CF and discuss the importance of a multidisciplinary approach in order to detect and manage all the clinical and behavioral aspects of the disease. The multidisciplinary complexity of NTM pulmonary disease in CF requires careful management of respiratory and extra-respiratory, including control of comorbidities, drug interactions and behavioral factors as adherence to therapies. CONCLUSIONS: The treatable trait strategy can help to optimize clinical management through systematic assessment of all the aspects of the disease, providing a holistic treatment for such a multi-systemic and complex condition.

Country-specific lockdown measures in response to the COVID-19 pandemic and its impact on tuberculosis control: a global study / Medidas de confinamento específicas de cada país em resposta à pandemia de COVID-19 e seu impacto no controle da tuberculose: um estudo global

ABSTRACT The objective of this study was to describe country-specific lockdown measures and tuberculosis indicators collected during the first year of the COVID-19 pandemic. Data on lockdown/social restrictions (compulsory face masks and hand hygiene; international and local travel restrictions; restrictions to family visits, and school closures) were collected from 24 countries spanning five continents. The majority of the countries implemented multiple lockdowns with partial or full reopening. There was an overall decrease in active tuberculosis, drug-resistant tuberculosis, and latent tuberculosis cases. Although national lockdowns were effective in containing COVID-19 cases, several indicators of tuberculosis were affected during the pandemic.

RESUMO O objetivo deste estudo foi descrever as medidas de confinamento específicas de cada país e os indicadores de tuberculose coletados durante o primeiro ano da pandemia de COVID-19. Dados referentes a confinamento/restrições sociais (uso obrigatório de máscaras faciais e higiene obrigatória das mãos; restrições a viagens internacionais e locais; restrições a visitas familiares e fechamento das escolas) foram coletados de 24 países em cinco continentes. A maioria dos países implantou múltiplos confinamentos, com reabertura parcial ou total. Houve uma redução geral dos casos de tuberculose ativa, tuberculose resistente e tuberculose latente. Embora os confinamentos nacionais tenham sido eficazes na contenção dos casos de COVID-19, vários indicadores de tuberculose foram afetados durante a pandemia.

Intestinal tuberculosis versus Inflammatory Bowel Diseases: a never-ending challenge.

Inflammatory Bowel Diseases (IBD) and intestinal tuberculosis (ITB) frequently share similar clinical, radiological, endoscopic and histologic features. The misdiagnosis of IBD can lead to worsening of ITB course, eventually with dissemination of Mycobacterium tuberculosis (MTB) due to immunosuppressive treatment. We herein report a challenging diagnosis of ITB, progressed from localized to disseminated, in a pregnant woman previously misdiagnosed with Crohn' disease (CD) on prolonged steroid treatment. Furthermore, we focus on three main issues: 1) the need for tuberculosis (TB) screening in pregnant women and in patients coming from TB endemic countries; 2) the effect of prolonged steroid treatment in misdiagnosed TB, particularly on its histological pattern; 3) the optimum clinical management of ITB.

A rare case of multi-focal human TB after BCG instillation for non-muscle-invasive bladder cancer.

OBJECTIVE: To describe a left epididymitis and para-aortical involvement caused by Mycobacterium tuberculosis hominis reactivation after bacillus Calmette-Guérin instillation for non-muscle-invasive bladder cancer. PATIENT AND METHODS: A Caucasian male, aged 76 years, exposed to bacillus Calmette-Guérin for a high-grade non-muscle-invasive bladder cancer in 2015, reported painful and progressive left scrotal swelling with purulent discharge from a cutaneous fistulous track that yielded, on liquid culture, a pan-susceptible Mycobacterium tuberculosis hominis strain. Moreover, after 6 months of anti-tuberculosis treatment, an abdominal peri-aortic mass, sized 4 cm, was found and a surgical biopsy showed necrotizing granulomas; however, although smear microscopy and Xpert MTB/Rif™ performed on fresh biopsy sample were positive, liquid cultures resulted negative, indicating treatment efficacy. RESULTS: Numerous peculiar and multi-organ involvement due to BCGitis after intravesical immunotherapy have been previously described, including 17 scientific articles about epididymitis, however, no reports so far showed reactivation of Mycobacterium tuberculosis hominis after bacillus Calmette-Guérin treatment. CONCLUSION: Although BCGitis is more prevalent in patients undergoing bacillus Calmette-Guérin instillation for non-muscle-invasive bladder cancer, tuberculosis by other species of Mycobacterium tuberculosis should be always ruled out by molecular and conventional microbiology in patients with a history of Mycobacterium tuberculosis hominis exposure.

Mycobacterium chimaera infections: An update.

Mycobacterium chimaera is a non-tuberculous mycobacterium belonging to the Mycobacterium avium complex, described for the first time in 2004. It acts as an opportunistic pathogen, with infections, usually respiratory illnesses, occurring more frequently in immunocompromised patients or in patients with underlying respiratory diseases. During the last decade Mycobacterium chimaera disseminated infections following cardiothoracic surgery, especially open-heart surgery, have been increasingly reported worldwide. From a pathogenic standpoint, Mycobacterium chimaera is acquired during cardiopulmonary bypass via bioaerosols emitted from contaminated heater-cooler units water systems. Due to non-specific symptoms and long latency, postoperative Mycobacterium chimaera infections may not be promptly diagnosed and treated, and may become life-threatening. The indication for revision surgery needs to be carefully evaluated on a case-by-case basis, and antibiotic therapy should be based on drug susceptibility testing results. Our review aims to provide an updated account of microbiological characteristics, clinical presentation, diagnosis, and management of Mycobacterium chimaera infections, with a special focus on those developing after cardiothoracic surgery.

Tuberculosis among asylum seekers in Milan, Italy: epidemiological analysis and evaluation of interventions.

In countries of the European Union, tuberculosis (TB) mainly affects marginalised people, including asylum seekers. Migratory flows from high-incidence countries to Italy have increased up to 2017, posing challenges to the national health system. This study sought to assess TB and latent TB infection (LTBI) prevalence among asylum seekers in Milan during the biennium 2016-2017 and to evaluate interventions in place.A two-level active surveillance and screening system was developed for both TB and LTBI. Asylum seekers underwent an initial screening with a tuberculin skin test (TST) and a questionnaire at the receiving sites. At the Regional TB Reference Centre, those with a positive result underwent chest radiography. People aged <35 years with negative chest radiography results underwent further testing by interferon-γ release assay. If results of the assay were positive, LTBI treatment was offered. TB and LTBI prevalence were compared with literature data.A total of 5324 asylum seekers, mostly young (10-39 years; 98%), male (84%) and from sub-Saharan Africa (69%), were enrolled in the study. 69 active TB cases were diagnosed and 863 LTBI-positive individuals were detected. TB prevalence was high (1236 per 100 000 population) and LTBI prevalence was 28%. Despite losses (41%) during the transition from initial screening sites and the diagnostic centre, a good TB cure rate (84%) and optimal LTBI treatment completion (94%) were achieved.Our study shows that TB incidence is high among asylum seekers in Milan and that well-coordinated screening measures are critical for early diagnosis and treatment. It also proves that rolling out successful at-scale interventions for both prophylaxis and disease management is feasible.

The Italian registry of pulmonary non-tuberculous mycobacteria - IRENE: the study protocol.

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.

Pulmonary disease by non-tuberculous mycobacteria - clinical management, unmet needs and future perspectives.

INTRODUCTION: The number of patients with pulmonary disease caused by non-tuberculous mycobacteria (NTM) is increasing globally. Poor resistance against infections, for example, due to pre-existing lung diseases, immune deficiency and immune-modulating treatment, predisposes the population to developing pulmonary NTM disease. The incidence of pre-existing lung diseases such as chronic obstructive pulmonary disease and bronchiectasis has also increased. NTM disease diagnosis is often delayed due to non-specific symptoms. The therapeutic arsenal is limited and adherence to treatment guidelines is often low since the treatment regimens are complex, lengthy and side effects are common. Thus, current disease management is far from satisfactory and needs to be improved. Areas covered: This review provides an overview of the current knowledge of NTM infections and includes pathogenesis, disease patterns, epidemiology, disease management, unmet needs and future perspectives. Expert commentary: NTM disease is becoming more prevalent, in part with our increased awareness and improved diagnostic methods. However, our understanding of the disease pathogenesis is limited and treatment decisions are challenging, with difficult to employ drug regimens. Optimal management requires collaboration between healthcare providers, patients and expert centers.

Characterizing Non-Tuberculous Mycobacteria Infection in Bronchiectasis.

Chronic airway infection is a key aspect of the pathogenesis of bronchiectasis. A growing interest has been raised on non-tuberculous mycobacteria (NTM) infection. We aimed at describing the clinical characteristics, diagnostic process, therapeutic options and outcomes of bronchiectasis patients with pulmonary NTM (pNTM) disease. This was a prospective, observational study enrolling 261 adult bronchiectasis patients during the stable state at the San Gerardo Hospital, Monza, Italy, from 2012 to 2015. Three groups were identified: pNTM disease; chronic P. aeruginosa infection; chronic infection due to bacteria other than P. aeruginosa. NTM were isolated in 32 (12%) patients, and among them, a diagnosis of pNTM disease was reached in 23 cases. When compared to chronic P. aeruginosa infection, patients with pNTM were more likely to have cylindrical bronchiectasis and a "tree-in-bud" pattern, a history of weight loss, a lower disease severity and a lower number of pulmonary exacerbations. Among pNTM patients who started treatment, 68% showed a radiological improvement, and 37% achieved culture conversion without recurrence, while 21% showed NTM isolation recurrence. NTM isolation seems to be a frequent event in bronchiectasis patients, and few parameters might help to suspect NTM infection. Treatment indications and monitoring still remain an important area for future research.

Lessons learnt from TB screening in closed immigration centres in Italy.

BACKGROUND: Between June 2012 and December 2013 Médecins Sans Frontières launched a pilot project with the aim of testing a strategy for improving timely diagnosis of active pulmonary TB among migrants hosted in four centres of identification and expulsion (CIE) in Italy. METHODS: This is a descriptive study. For active TB case finding we used an active symptom screening approach among migrants at admission in four CIE's. Here we describe the feasibility and the yield of this programme. RESULTS: Overall, 3588 migrants were screened, among whom 87 (2.4%) had a positive questionnaire. Out of 30 migrants referred for further investigations, three were diagnosed as having TB, or 0.1% out of 3588 individuals that underwent screening. Twenty-five (29%, 25/87) migrants with positive questionnaires were not referred for further investigation, following the doctors' decision; however, for 32 (37%, 32/87) migrants the diagnostic work-out was not completed. In multivariate analyses, being over 35 years (OR 1.7; 95% CI 1.1-2.6) and being transgender (OR 4.9; 95% CI 2.1-11.7), was associated with a positive questionnaire. CONCLUSIONS: TB screening with symptom screening questionnaires of migrants at admission in closed centres is feasible. However, to improve the yield, follow-up of patients with symptoms or signs suggestive for TB needs to be improved.

Risk Assessment of Tuberculosis in Contacts by IFN-γ Release Assays. A Tuberculosis Network European Trials Group Study.

RATIONALE: Latent infection with Mycobacterium tuberculosis is defined by a positive IFN-γ release assay (IGRA) result in the absence of active tuberculosis. Only few, mostly monocentric studies have evaluated the role of IGRAs to predict the development of tuberculosis in recent contacts in low-incidence countries of tuberculosis. OBJECTIVES: To analyze IGRA results and the effect of preventive chemotherapy on tuberculosis progression rates among recent contacts. METHODS: Results from contact investigations at 26 centers in 10 European countries including testing for latent infection with M. tuberculosis by the QuantiFERON-TB Gold In-Tube (QFT) test or the T-SPOT.TB (TSPOT) were prospectively collected and analyzed. MEASUREMENTS AND MAIN RESULTS: Among 5,020 contacts of 1,023 index cases, 25 prevalent secondary cases were identified at screening. Twenty-four incident cases occurred among 4,513 contacts during 12,326 years of cumulative follow-up. In those with a positive IGRA result, tuberculosis incidence was 0.2 (QFT) and 0 (TSPOT) per 100 patient-years when contacts received preventive chemotherapy versus 1.2 (QFT) and 0.8 (TSPOT) per 100 patient-years in those not treated (38 and 37 patients needed to be treated to prevent one case, respectively). Positive and negative predictive values were 1.9% (95% confidence interval [CI], 1.1-3.0) and 99.9% (95% CI, 99.7-100) for the QFT and 0.7% (95% CI, 0.1-2.6) and 99.7% (95% CI, 99.1-99.9) for the TSPOT. CONCLUSIONS: Tuberculosis rarely developed among contacts, and preventive chemotherapy effectively reduced the tuberculosis risk among IGRA-positive contacts. Although the negative predictive value of IGRAs is high, the risk for the development of tuberculosis is poorly predicted by these assays.

Comparison of a commercial and an in-house T cell-based assay for the diagnosis of Mycobacterium tuberculosis infection.

Identification of individuals with a tuberculosis infection is a very important element for the control of tuberculosis. The currently used tuberculin skin test has poor sensitivity and specificity. Recently, an important advance in tuberculosis diagnosis occurred with the development of in vitro T cell-based IFN-gamma release assays. The aim of this study was to compare a RD1-based in-house ELISPOT-IFN-gamma assay with a commercial (T-SPOT.TB) assay for the diagnosis of tuberculosis infection. The results showed an almost complete concordance between the two assays, confirming that our restricted but highly selected pool of peptides is sufficient to detect tuberculosis infection.

Use of T-SPOT.TB in latent tuberculosis infection diagnosis in general and immunosuppressed populations.

Immunosuppressed patients have a nine-fold greater risk of developing active tuberculosis (TB) disease given the latent TB infection than the general population. Few data are available on the predictivity of T-SPOT.TB in immunosuppressed patients. We had a T-SPOT.TB determination and a TST from 197 immunosuppressed haematological patients and 324 community contacts of infectious TB cases. In the general population, TST was positive in 275 (84.9%), T-SPOT.TB in 167 (51.5%) (p < 0.0001). In immunosuppressed patients, TST was positive in 34 (17.3%), T-SPOT.TB in 70 (35.5%). T-SPOT.TB is not influenced by immunosuppression and even an indeterminate result may yield useful information on patient's anergy.

An in-house RD1-based enzyme-linked immunospot-gamma interferon assay instead of the tuberculin skin test for diagnosis of latent Mycobacterium tuberculosis infection.

Identification of individuals infected with Mycobacterium tuberculosis is essential for the control of tuberculosis (TB). The specificity of the currently used tuberculin skin test (TST) is poor because of the broad antigenic cross-reactivity of purified protein derivative (PPD) with BCG vaccine strains and environmental mycobacteria. Both ESAT-6 and CFP-10, two secretory proteins that are highly specific for M. tuberculosis complex, elicit strong T-cell responses in subjects with TB. Using an enzyme-linked immunospot (ELISPOT)-IFN-gamma assay and a restricted pool of peptides derived from ESAT-6 and CFP-10, we have previously demonstrated a high degree of specificity and sensitivity of the test for the diagnosis of TB. Here, 119 contacts of individuals with contagious TB who underwent TST and the ELISPOT-IFN-gamma assay were consecutively recruited. We compared the efficacy of the two tests in detecting latent TB infection and defined a more appropriate TST cutoff point. There was little agreement between the tests (k = 0.33, P < 0.0001): 53% of the contacts with a positive TST were ELISPOT negative, and 7% with a negative TST were ELISPOT positive. Furthermore, respectively 76 and 59% of the ELISPOT-negative contacts responded in vitro to BCG and PPD, suggesting that most of them were BCG vaccinated or infected with nontuberculous mycobacteria. The number of spot-forming cells significantly correlated with TST induration (P < 0.0001). Our in-house ELISPOT assay based on a restricted pool of highly selected peptides is more accurate than TST for identifying individuals with latent TB infection and could improve chemoprophylaxis for the control of TB.

Comparison of an in-house and a commercial RD1-based ELISPOT-IFN-gamma assay for the diagnosis of Mycobacterium tuberculosis infection.

OBJECTIVE: To compare a RD1-based in-house ELISPOT-interferon-gamma (IFN-gamma) assay with a commercial (T-SPOT.TB) assay for the diagnosis of Mycobacterium tuberculosis (TB) infection and the efficacy of the tuberculin skin test (TST) and ELISPOT assay in detecting latent TB infection (LTBI). DESIGN: Eighty-six subjects (65 household contacts of contagious TB-infected patients, 13 subjects with active or previous TB infection, and 8 with suspected TB infection) were consecutively recruited in the context of a surveillance program. METHODS: Enrolled subjects underwent the Mantoux TST and two different ELISPOT-IFN-gamma assays: an in-house assay using a pool of selected M. tuberculosis peptides (MTP) and the commercial T-SPOT.TB assay. RESULTS: The in-house and commercial ELISPOT-IFN-gamma assays showed almost complete concordance (99%) in diagnosing acute or LTBI. When comparing the efficacy of the TST with the in-house ELISPOT assay in detecting TB infection, a small agreement was observed (k=0.344, P<0.0001): 36% of the subjects with a positive TST were ELISPOT-MTP negative and 12% with a negative TST were ELISPOT-MTP positive. Furthermore, 78% of the ELISPOT-MTP negative individuals were ELISPOT- Bacillus Calmette-Guérin (BCG) positive, most of whom had received BCG vaccination. CONCLUSION: Our in-house ELISPOT assay based on a restricted pool of highly selected peptides is equivalent to the commercial T-SPOT.TB assay, is cheaper and is probably not confounded, unlike the TST, by BCG vaccination in our setting.