Worldwide Effects of Coronavirus Disease Pandemic on Tuberculosis Services, January-April 2020.

Coronavirus disease has disrupted tuberculosis services globally. Data from 33 centers in 16 countries on 5 continents showed that attendance at tuberculosis centers was lower during the first 4 months of the pandemic in 2020 than for the same period in 2019. Resources are needed to ensure tuberculosis care continuity during the pandemic.

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.

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.

Towards tailored regimens in the treatment of drug-resistant tuberculosis: a retrospective study in two Italian reference Centres.

BACKGROUND: The increased incidence of drug-resistant TB is a major challenge for effective TB control. Limited therapeutic options and poor treatment outcomes of DR-TB may increase drug-resistance rates. The objective of the study is to retrospectively compare MDR-TB and pre-XDR-TB treatment regimens and outcomes in two large TB reference centres in Italy from January 2000 to January 2015. METHODS: A retrospective, multicentre study was conducted at the Regional TB Reference Centre Villa Marelli Institute (Milan) and at the Reference Center for MDR-TB and HIV-TB, Eugenio Morelli Hospital (Sondalo). The supra-national Reference Laboratory in Milan performed DST. Inclusion criteria were: age ≥ 18 and culture-confirmed diagnosis of MDR- or pre-XDR TB. Chi-square or Fisher exact test was used to detect differences in the comparison between treatment outcomes, therapeutic regimens, and drug-resistances. Computations were performed with STATA 15. RESULTS: A total of 134 patients were selected. Median (IQR) age at admission was 33 (26-41) years and 90 patients (67.2%) were male. Pulmonary TB was diagnosed in 124 (92.5%) patients. MDR- and pre-XDR-TB cases were 91 (67.9%) and 43 (32.1%), respectively. The WHO shorter MDR-TB regimen could have been prescribed in 16/84 (19.1%) patients. Treatment success was not statistically different between MDR- and pre-XDR-TB (81.3% VS. 81.4%; P = 0.99). Mortality in MDR-TB and pre-XDR-TB groups was 4.4 and 9.3%, respectively (P = 0.2). Median duration of treatment was 18 months and a total of 110 different regimens were administered. Exposure to linezolid, meropenem, and amikacin was associated with a better outcome in both groups (P = 0.001, P < 0.001, and P = 0.004, respectively). CONCLUSIONS: Tailored treatment regimens based on DST results can achieve successful outcomes in patients with pre-XDR-TB.

First evaluation of QuantiFERON-TB Gold Plus performance in contact screening.

Identifying latently infected individuals is crucial for the elimination of tuberculosis (TB). We evaluated for the first time the performance of a new type of interferon-γ release assay, QuantiFERON-TB Plus (QFT-Plus), which includes an additional antigen tube (TB2), stimulating both CD4+ and CD8+ T-cells in contacts of TB patients.Contacts were screened for latent TB infection by tuberculin skin test, QFT-Plus and QuantiFERON-TB Gold in Tube (QFT-GIT).In 119 TB contacts, the overall agreement between QFT-Plus and QFT-GIT was high, with a Cohen's κ of 0.8. Discordant results were found in 12 subjects with negative QFT-GIT and positive QFT-Plus results. In analyses of markers of TB exposure and test results, the average time spent with the index case was the strongest risk factor for positivity in each of these tests. The difference in interferon-γ production between the two antigen tubes (TB2-TB1) was used as an estimate of CD8+ stimulation provided by the TB2. TB2-TB1 values >0.6 IU·mL-1 were significantly associated with proximity to the index case and European origin.QFT-Plus has a stronger association with surrogate measures of TB exposure than QFT-GIT in adults screened for latent TB infection. Interferon-γ response in the new antigen tube used an indirect estimate of specific CD8+ response correlates with increased Mycobacterium tuberculosis exposure, suggesting a possible role in identifying individuals with recent infection.

Effect of enalapril on exercise cardiopulmonary performance in chronic obstructive pulmonary disease: A pilot study.

BACKGROUND: Some studies suggest that the sympathetic nervous system and the renin-angiotensin system are activated in patients with chronic obstructive pulmonary disease (COPD), potentially resulting in negative cardiopulmonary and muscular effects. The aim of this pilot study was to evaluate the efficacy of an angiotensin converting enzyme (ACE) inhibitor on cardiopulmonary exercise performance in COPD patients. Primary outcome was the effect of treatment on the ventilatory response to exercise (VE/VCO(2) slope). Secondary outcomes were exercise variables evaluated by the cardiopulmonary exercise test, and pulmonary function according to ACE genotyping. METHODS: 4 weeks treatment with enalapril (10 mg od) or placebo was evaluated in 21 COPD patients (FEV(1) < 60%) and without cardiovascular disease in a double-blind, cross-over study. RESULTS: 18 patients completed the study. Enalapril did not exert a significant effect on exercise VE/VCO(2) slope or on peak O(2) consumption. However enalapril significantly improved peak O(2) pulse and work rate compared to placebo. A mild but significant worsening of the diffusion capacity of the lung was observed. ACE genotype did not significantly affect patients' response to treatment, except for a trend toward a more evident effect of treatment in patients with II ACE genotype in terms of O(2) pulse and gas diffusion. CONCLUSIONS: In this pilot study, ACE inhibition did not affect the ventilatory response to exercise in COPD patients. However, treatment resulted in improvement in work rate and O(2) pulse, suggesting that ACE inhibitor therapy warrants consideration and may provide beneficial effect on the cardiovascular response to exercise in COPD.

European Respiratory Society International Congress, Madrid, 2019: nontuberculous mycobacterial pulmonary disease highlights.

Once overlooked, awareness of nontuberculous mycobacterial pulmonary disease (NTM-PD) is rapidly rising, in line with increasing prevalence worldwide. The European Respiratory Society (ERS) International Congress 2019, held in Madrid, Spain, provided a platform for invigorating discussions and exciting new research in the field. This article explores approaches being taken to combat NTM-PD with a focus not only on novel prevalence and risk factor data, but also on emerging antimicrobials and their routes of delivery, and other potential treatment options in early clinical development.

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.

From the past, a long way to future challenges for a greater control of tuberculosis.

Tuberculosis (TB) and humans have coexisted for more than 40,000 years; however TB remains a global threat to human kind. The international community has developed new tools for early detection, but TB strains evolved acquiring resistance to first-line therapeutic drugs with increasing treatment challenges. Furthermore, TB has formed also an alliance with human immunodeficiency virus; in this way the poorest populations are most affected. The current vaccine planning activity includes 14 new vaccines against TB (11 of those in the phaseII/III) developed with different techniques. Now, more than ever, new anti-TB drugs and new anti-TB regimens are urgently required as well as universal health care and social protection in order to tackle down both hard to treat TB and the social determinants of TB. Coordinated actions and sharing of information are needed to aspire everywhere to the best clinical practices and improve quality of life of patients and their families.

Preliminary observations on IGRA testing for TB infection in patients with severe COVID-19 eligible for immunosuppressive therapy.

COVID-19, the novel coronavirus pandemic, has already spread around the globe affecting more than 18 million people. As previously observed with other coronaviruses, SARS-CoV-2 deeply dysregulate the immune system eliciting respiratory failure and a state of systemic hyperinflammation in severely ill individuals. Immunotherapy is often used to downgrade the detrimental effects of the disease sustained by high-level of cytokines. Those treatments, however, are known to undermine patients' ability to contain tuberculosis (TB) infection. This study aims to describe interferon-γ release assay (IGRA) results in severe COVID-19 patients eligible for immunosuppressive treatment. Aggregate data were gathered from five hospitals in Milan, Italy, from March 1 to May 15, 2020 and retrospectively analyses. Results were summarized using absolute frequencies and percentages and compared using a two-sided Chi-squared test. Overall, 462 COVID-19 patients were eligible for immunosuppressive therapy, among which 335 were tested using IGRA testing. More than one-third of them (122/335; 36.4%) had an indeterminate IGRA result because of insufficient immune response to mitogen control, 19 (5.7%) tested positive and 194 (57.9) negative. The majority of patients with lymphocytopenia (i.e., total lymphocyte count [TLC] below 1000 cells/mm3) had indeterminate IGRAs (81/155; 52.3%). The proportion becomes even higher in patients with severe lymphocytopenia (i.e., TLC<500 cells/mm3) (36/57; 63%). Our results suggest a possible negative impact of COVID-19 related immune dysregulation on TB infection assessment and management. Close monitoring of individuals with or without retesting of individuals with indeterminate IGRAs and further basic science investigations should to be sought to better comprehend their implication on TB epidemiology.

Real-life evaluation of clinical outcomes in patients undergoing treatment for non-tuberculous mycobacteria lung disease: A ten-year cohort study.

Outcome recognition is a crucial step in the management of non-tuberculous mycobacteria lung disease (NTM-LD). In order to explore NTM-LD outcomes in a real-life setting, an observational, retrospective study enrolling consecutive adults who received treatment for NTM-LD in Milan, Italy, from 2007 to 2017 was conducted. Among 170 patients (68.2% females; median age: 68 years), NTM-LD was mainly due to M. avium complex (MAC) (71.2%), M. kansasii (9.4%) and M. xenopi (7.1%). Along a median follow-up of 31 months, adverse events occurred in 37.6% of the patients. Treatment outcomes of the entire study population included an unsuccessful outcome in 35.3% of the patients, including treatment halted in 13.5%, recurrence in 11.2%, re-infection in 5.3%, treatment failure in 4.1% and relapse in 1.2%. The main reason for treatment halted was drug intolerance. No differences were detected between patients with MAC-LD vs. those with other NTM-LD in terms of unsuccessful outcome in general (35.5% vs. 34.7%). A significantly higher prevalence of patients who underwent treatment halted was found in patients with NTM-LD other than MAC in comparison to patients with MAC-LD (22.4% vs. 9.9%, p = 0.030). One third of adults undergoing treatment for a NTM-LD experiences an unsuccessful outcome with adverse events and treatment discontinuation being major challenges in patients' management.

Latent Tuberculosis Infection Treatment Completion while Shifting Prescription from Isoniazid-Only to Rifampicin-Containing Regimens: A Two-Decade Experience in Milan, Italy.

To tackle the tuberculosis (TB) epidemic, in 2014 the World Health Organization launched the End TB Strategy, which includes action to prevent latent TB infection (LTBI) reactivation. Available preventive treatments (PT) are based on either isoniazid (INH) alone or rifampicin (RIF)-containing regimens. This study aims to assess and compare PT completion rates, the occurrence of adverse events, and the time of dropout among those receiving INH-alone or RIF-containing regimens at Villa Marelli Institute, Milan, Italy, covering the period from 1992 to 2018. A total of 19670 subjects, belonging to various risk groups-mainly young (median age of 29 years), foreign-born (73.3%), and males (58.8%)-with presumed LTBI were prescribed PT (79.3% INH-alone and 20.7% RIF-containing regimens). The treatment completion rate was 79.4% on average, with higher rates among those receiving RIF-containing regimens (85.6%) compared to those that were prescribed INH-alone (77.8%) (p < 0.0001). Notably, some of the high-risk groups for progression of LTBI were more likely to complete PT from RIF-containing regimens. These groups included recent TB contact (89.9%, p < 0.0001), healthcare workers (93.5%, p < 0.0001), and homeless people (76.6%, p < 0.0001). Irrespectively of the chosen PT regimen, most of the dropouts occurred between the start of the treatment and the first follow-up visit (14.3%, 15.2% for those on INH-alone vs. 11.1% for those on RIF-containing regimens). Further shortening of the PT regimen is therefore an aim to ensure adherence, even though it might need further efforts to enhance the patient's attitude towards starting and carrying out PT.

Exertional hypoxemia in stable COPD is common and predicted by circulating proadrenomedullin.

BACKGROUND: The prevalence of exertional hypoxemia in unselected patients with COPD is unknown. Intermittent hypoxia leads to adrenomedullin (ADM) upregulation through the hypoxia-inducible factor-1 pathway. We aimed to assess the prevalence and the annual probability to develop exertional hypoxemia in stable COPD. We also hypothesized that increased ADM might be associated with exertional hypoxemia and envisioned that adding ADM to clinical variables might improve its prediction in COPD. METHODS: A total of 1,233 6-min walk tests and circulating proadrenomedullin (proADM) levels from 574 patients with clinically stable, moderate to very severe COPD enrolled in a multinational cohort study and followed up for 2 years were concomitantly analyzed. RESULTS: The prevalence of exertional hypoxemia was 29.1%. In a matrix derived from a fitted-multistate model, the annual probability to develop exertional hypoxemia was 21.6%. Exertional hypoxemia was associated with greater deterioration of specific domains of health-related quality of life, higher severe exacerbation, and death annual rates. In the logistic linear and conditional Cox regression multivariable analyses, both FEV1% predicted and proADM proved independent predictors of exertional hypoxemia (P < .001 for both). Adjustment for comorbidities, including cardiovascular disorders, and exacerbation rate did not influence results. Relative to using FEV1% predicted alone, adding proADM resulted in a significant improvement of the predictive properties (P = .018). Based on the suggested nonlinear nomogram, patients with moderate COPD (FEV1% predicted = 50%) but high proADM levels (> 2 nmol/L) presented increased risk (> 30%) for exertional desaturation. CONCLUSIONS: Exertional desaturation is common and associated with poorer clinical outcomes in COPD. ADM improves prediction of exertional desaturation as compared with the use of FEV1% predicted alone. TRIAL REGISTRY: ISRCTN Register; No.: ISRCTN99586989; URL: www.controlled-trials.com.

Bronchiectasis: an update.

BACKGROUND AND AIMS: Bronchiectasis is defined as an abnormal and irreversible dilatation of the bronchi, often associated with chronic productive cough, airway obstruction, and recurrent infections. METHODS: MEDLINE data from 1978 to November 2008 was analysed. Search was limited to randomized control trials, clinical trials, meta-analysis, reviews published in English, using the keyword bronchiectasis. RESULTS: The prevalence of bronchiectasis is unknown. However, prevalence seems to increase with age from 4.2 per 100 000 persons aged 18-34 years to 271.8 per 100 000 among those aged 75 years or older. Therapy is aimed to limit the cycle of infection and inflammation and to reduce the number of exacerbations, in order to improve quality of life. CONCLUSIONS: Bronchiectasis still remain a significant health problem. Further research is required to improve the management of this herterogeneous condition.