Rehabilitation, optimized nutritional care, and boosting host internal milieu to improve long-term treatment outcomes in tuberculosis patients.

BACKGROUND: The holistic management of tuberculosis (TB) patients can improve life expectancy and lost organ function. REHABILITATION: Chronic sequelae are very common among patients who survive TB, which can lead to a further decline in lung function. There is still no guidance for 'cured' patients with impaired lung function who need pulmonary rehabilitation. Additional tests for evaluation should be given after the end of treatment, as recent studies have shown the good effect of pulmonary rehabilitation for TB patients. OPTIMIZED NUTRITIONAL CARE: Malnutrition is very common among TB patients and is related to malabsorption. The latter can cause lower drug exposure, which may result in treatment failure, increasing the risk of death, and can lead to acquired drug resistance. Malnutrition should be assessed according to the Global Leadership Initiative on Malnutrition (GLIM) criteria and the diagnosis should lead to an individualized treatment plan, including sufficient proteins and preferably in combination with adequate training. PROTECTIVE IMMUNE RESPONSES: Under normal circumstances, most immune cells use a glucose-based mechanism to generate energy. Therefore the patient's nutritional status is a key factor in shaping immune responses. Disease-related malnutrition leads to proteolysis and lipolysis. In the end, the identification of individuals who will benefit from immune-modulatory strategies may lead to clinically relevant markers.

Precision and personalized medicine and anti-TB treatment: Is TDM feasible for programmatic use?

Therapeutic Drug Monitoring (TDM) is increasingly recommended to ensure the correct drug dose thereby minimizing adverse events and maximizing regimen efficacy. To facilitate implementation in TB programs, a framework for TDM is urgently needed. TDM is only useful for dose optimization if a patient is on an appropriate regimen guided by drug susceptibility testing. TDM using a targeted approach selecting patients with risk factors for suboptimal drug exposure (e.g. diabetes) or not responding to treatment for drugs with a clear concentration-response relationship may provide the best value for money. Semiquantitative point-of-care tests for detection of low or high drug concentration should be implemented at community level while quantitative assays can be performed at regional or central level. Expanding PK/PD research followed by clinical trials including both clinical outcome as well as cost-effectiveness will increase the level of evidence supporting TDM.

Effectiveness of pulmonary rehabilitation in severe asthma: a retrospective data analysis.

Background: Pulmonary Rehabilitation (PR) is a multimodal treatment that is still poorly investigated in severe asthma where respiratory symptoms remain "uncontrolled" despite intensive pharmacological therapy. Bronchiectasis and obstructive sleep apnea (OSAS) are common comorbidities which may worsen asthma control.Aim: Aim of the present study is to investigate the effectiveness of PR on functional exercise, dyspnea, and muscle fatigue in patients with severe asthma.Methods: A total of 317 patients affected from severe asthma according to GINA guidelines who underwent a multidisciplinary 3 weeks rehabilitation program with an adherence of >80% to PR and able to complete a Six Minute Walking Test (6MWT) were retrospectively included in the analysis. Pulmonary rehabilitation included endurance training, educational meetings, chest physiotherapy, breathing exercises, and psychological support. Six-minute walking distance and Borg scale for dyspnea and muscle fatigue were recorded before and after the rehabilitation.Results: A total of 371 patients were analyzed, 39 had bronchiectasis (10.5%), 163 (43.9%) OSAS and 17 had both (4.6%). PR significantly improved 6MWT distance, Borg dyspnea and muscle fatigue (p value < 0.0001 for all outcomes) and mean SpO2 recorded during 6MWT (p value < 0.0001). Median (IQR) delta 6 minute walking distance was 33 (14-60) m. 6MWT distance (p < 0.0001) and the oxygen saturation (p < 0.01) significantly improved in severe asthma with bronchiectasis and/or OSAS.Conclusions: Our study provides evidence for the first time on a large sample of patients with severe asthma that a multidisciplinary PR program is effective in terms of exercise capacity and symptoms. In addition, exercise capacity improved in the presence of bronchiectasis and/or OSAS.

Tuberculosis elimination and the challenge of latent tuberculosis.

Latent tuberculosis infection (LTBI) affects one third to one fourth of the human population and is the reservoir for a significant proportion of emerging active tuberculosis (TB) cases, especially in low incidence countries. The World Health Organization launched in 2015 the END-TB strategy that aims at TB elimination and promotes, for the first time ever, the management of LTBI. The preventive package, basically consisting of testing and treatment for LTBI in groups at high risk of reactivation, is a mainstay of the first pillar of the strategy, alongside prompt diagnosis and early treatment of both drug-susceptible and drug-resistant TB disease. Testing and treatment for LTBI should be pursued with a programmatic perspective. This implies strong political commitment, adequate funding and an effective monitoring and evaluation system. People living with HIV and children under five years of age who are household contact of a contagious TB cases are primarily targeted in all epidemiological setting. In high resource and low incidence setting, additional at risk populations should also be the target for systematic LTBI testing and treatment. Research is urgently needed to develop diagnostic tests with higher predictive value to identify individuals that progress from infection to disease. Similarly, shorter and safer treatment regimens are needed to make the trade-off between potential benefits and harms more favourable for an increasing proportion of infected individuals.

Applicability of the shorter 'Bangladesh regimen' in high multidrug-resistant tuberculosis settings.

In spite of the recent introduction of two new drugs (delamanid and bedaquiline) and a few repurposed compounds to treat multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB), clinicians are facing increasing problems in designing effective regimens in severe cases. Recently a 9 to 12-month regimen (known as the 'Bangladesh regimen') proved to be effective in treating MDR-TB cases. It included an initial phase of 4 to 6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol, followed by 5 months of moxifloxacin, clofazimine, pyrazinamide, and ethambutol. However, recent evidence from Europe and Latin America identified prevalences of resistance to the first-line drugs in this regimen (ethambutol and pyrazinamide) exceeding 60%, and of prothionamide exceeding 50%. Furthermore, the proportions of resistance to the two most important pillars of the regimen - quinolones and kanamycin - were higher than 40%. Overall, only 14 out of 348 adult patients (4.0%) were susceptible to all of the drugs composing the regimen, and were therefore potentially suitable for the 'shorter regimen'. A shorter, cheaper, and well-tolerated MDR-TB regimen is likely to impact the number of patients treated and improve adherence if prescribed to the right patients through the systematic use of rapid MTBDRsl testing.

Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.

Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference.Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.

Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines.

Despite concerted efforts over the past 2 decades at developing new diagnostics, drugs, and vaccines with expanding pipelines, tuberculosis remains a global emergency. Several novel diagnostic technologies show promise of better point-of-care rapid tests for tuberculosis including nucleic acid-based amplification tests, imaging, and breath analysis of volatile organic compounds. Advances in new and repurposed drugs for use in multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis have focused on development of several new drug regimens and their evaluation in clinical trials and now influence World Health Organization guidelines. Since the failure of the MVA85A vaccine 2 years ago, there have been no new tuberculosis vaccine candidates entering clinical testing. The current status quo of the lengthy treatment duration and poor treatment outcomes associated with MDR/XDR tuberculosis and with comorbidity of tuberculosis with human immunodeficiency virus and noncommunicable diseases is unacceptable. New innovations and political and funder commitment for early rapid diagnosis, shortening duration of therapy, improving treatment outcomes, and prevention are urgently required.

Tuberculosis comorbidity with communicable and non-communicable diseases: integrating health services and control efforts.

Recent data for the global burden of disease reflect major demographic and lifestyle changes, leading to a rise in non-communicable diseases. Most countries with high levels of tuberculosis face a large comorbidity burden from both non-communicable and communicable diseases. Traditional disease-specific approaches typically fail to recognise common features and potential synergies in integration of care, management, and control of non-communicable and communicable diseases. In resource-limited countries, the need to tackle a broader range of overlapping comorbid diseases is growing. Tuberculosis and HIV/AIDS persist as global emergencies. The lethal interaction between tuberculosis and HIV coinfection in adults, children, and pregnant women in sub-Saharan Africa exemplifies the need for well integrated approaches to disease management and control. Furthermore, links between diabetes mellitus, smoking, alcoholism, chronic lung diseases, cancer, immunosuppressive treatment, malnutrition, and tuberculosis are well recognised. Here, we focus on interactions, synergies, and challenges of integration of tuberculosis care with management strategies for non-communicable and communicable diseases without eroding the functionality of existing national programmes for tuberculosis. The need for sustained and increased funding for these initiatives is greater than ever and requires increased political and funder commitment.

Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis: epidemiology and control.

The emergence of multidrug-resistant (MDR)-TB and, more recently, of extensively drug-resistant (XDR)-TB is a real threat to achieve TB control and elimination. Over 400,000 new cases of MDR-TB occur each year and, although their number is currently unknown, XDR cases are recognized in every setting where there has been the capacity to detect them. The long-term vision for the full control of MDR-TB requires the scaling-up of culture and drug-susceptibility testing capacity, which is very limited in disease-endemic countries, and the expanded use of high-technology assays for rapid determination of resistance. MDR cases are treatable and well designed regimens, largely based on second-line anti-TB drugs, can considerably improve cure rates. However, treatment regimens need to be markedly improved through the introduction of less toxic and more powerful drugs, thus reducing duration of treatment and tolerability. This is of utmost importance for XDR-TB cases. The prevalence of MDR-TB and XDR-TB are inversely correlated with the quality of TB control and the proper use of second-line anti-TB drugs. Adherence to proper standards of care and control is imperative and a top priority of all TB control efforts. However, the risk of an uncontrollable epidemic of MDR- and XDR-TB is real considering current levels of financing and commitment to care.

Long-term moxifloxacin in complicated tuberculosis patients with adverse reactions or resistance to first line drugs.

STUDY OBJECTIVES: To test safety and tolerability of long-term moxifloxacin in resistant tuberculosis (TB) patients and patients with intolerance to first line anti-TB drugs. DESIGN: Clinical evaluation of adverse events (AEs) during prolonged moxifloxacin treatment. SETTING: TB Unit of the Regional TB Reference Center, Villa Marelli Institute, Niguarda Ca'Granda Hospital, Milan, Italy PATIENTS AND INTERVENTIONS: Patients treated with moxifloxacin, 400 mg orally once daily for TB in the Villa Marelli Institute from January 2001 to December 2003 were enrolled. RESULTS: Thirty-eight patients were treated with moxifloxacin at the Villa Marelli Institute in the study period, for multidrug resistant (MDR) TB (14, 36.8%), for intolerance to first line anti-TB drugs (9, 23.7%), for combined resistance and intolerance to first line anti-TB drugs (12, 31.6%), other reasons (3, 7.9%). The mean duration of moxifloxacin treatment was 6.3 +/- 5.2 months. Twelve (31.6%) patients reported at least an AE due to moxifloxacin, mostly gastrointestinal (8, 21.0%), general (5, 13.2%) and central nervous system (3, 7.9%) AEs. In 4 (10.5%) patients the drug was withdrawn for major AEs; no irreversible or fatal events were recorded. Most of the patients (31, 81.6%) reported a treatment success, even if the success rate was lower in MDR TB patients (8/14, 51.7%). CONCLUSIONS: Despite the fact that a large proportion of patients experienced at least an AE due to moxifloxacin, the drug resulted safe in the long-term administration for complicated TB cases.