New perspectives on difficult-to-treat tuberculosis based on old therapeutic approaches

Tuberculosis (TB) is an important clinical and public health issue worldwide. Despite improved treatment success rates following the introduction of antibiotics in daily clinical practice, the expected decline in incidence has been hampered by HIV epidemics and multi- and extensively drug-resistant TB. During the pre-antibiotic era, TB therapies were mainly based on improving hygiene conditions, strengthening the immune system, and targeting the rest of the affected lungs with invasive techniques. Detailed knowledge of old non-pharmacological therapies might support physicians and researchers in the identification of new solutions for difficult-to-treat patients. We performed a narrative literature review on the main old therapeutic options prescribed for patients with TB. The main recommendations and contraindications of sanatorium therapies (i.e., bed rest, fresh air, sunlight) and pulmonary collapse techniques are reviewed, evaluating their physiological basis and their impact on patient outcomes. We report studies describing new interventional pulmonary and surgical techniques and assess new perspectives based on old medical and surgical treatments, whose potential implementation could help complicated patients. Keywords: Tuberculosis, Collapse therapy, Hemoptysis, Sanatorium, Sunlight, Vitamin D, Surger

Prulifloxacin: a brief review of its potential in the treatment of acute exacerbation of chronic bronchitis

Exacerbations of chronic bronchitis (AECB) are a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), and their impact on public health is increasing. The new fluoroquinolones have an excellent spectrum providing cover for the most important respiratory pathogens, including atypical and “typical” pathogens. Not surprisingly, different guidelines have inserted these agents among the drugs of choice in the empirical therapy of AECB. The pharmacokinetic and dynamic properties of the new fluoroquinolones have a significant impact on their clinical and bacteriological efficacy. They cause a concentration-dependent killing with a sustained post-antibiotic effect. This review discusses the most recent data on the new fluoroquinolone prulifloxacin and critically analyses its activity and safety in the management of AECB

Tiotropium is less likely to induce oxygen desaturation in stable COPD patients compared to long-acting β2-agonists

SummaryIn a three-way crossover pilot study, the acute effects of tiotropium 18μg inhalation on the respiratory function and arterial blood gas tensions of 30 patients with stable chronic obstructive pulmonary disease (COPD) were compared with those of salmeterol 50μg and formoterol 12μg. In each study day, lung function and arterial blood gas analyses were performed before and up to 180min after inhalation. All treatments significantly improved lung function, increased DLco, decreased PaO2, and increased P(A-a)O2, with no change in PaCO2. The effects of salmeterol and tiotropium on PaO2 were slower in onset and more prolonged than those of formoterol but PaO2AUC0–180min was significantly greater for formoterol and salmeterol than for tiotropium. It is likely that the significant but small decreases in PaO2 and increases in P(A-a)O2 have been caused by pulmonary vasodilator effects. Since the three agents were similar in inducing bronchodilation, we believe that tiotropium is preferable in patients with hypoxemia caused by stable COPD because it seems to carry a smaller risk of worsening systemic hypoxemia

Effects of pulmonary rehabilitation on exercise capacity in patients with COPD: A number needed to treat study

BACKGROUND: Pulmonary rehabilitation (PR) is recognized as an evidence-based treatment in improving dyspnea and quality of life in patients with COPD. We evaluated the number needed to treat (NNT) to achieve an increase in physical capacity, as defined by a significant improvement in the six-minute walk test (6MWT) in patients with COPD undergoing PR. METHODS: The study enrolled 284 patients aged 41 to 86 years (mean age 69.4 years) divided into two groups: a study group (222 patients) undergoing a PR program, and a control group (62 patients) treated only with drugs. The study group included patients with COPD divided in four subgroups according to GOLD stages. RESULTS: In the study group, 142 out of 222 patients (64%) had an increase of at least 54 m in the 6MWT following PR versus 8 out of 62 patients (13%) in the control group after the same time interval. The NNT in the overall study group was 2; the same NNT was obtained in GOLD stages 2, 3, and 4, but was 8 in stage 1. CONCLUSIONS: PR is highly effective in improving the exercise capacity of patients with COPD, as demonstrated by a valuable NNT, with better results in patients with a more severe disease

Huge Tracheal Diverticulum in a Patient with Mounier-Kuhn Syndrome

Tracheal diverticulum is a rare benign entity. Tracheobronchomegaly (TBM), also known as Mounier-Kuhn syndrome, is a rare disorder characterized by marked dilation of the trachea and main bronchi, associated with thinning or atrophy of the elastic tissue. Because of the weakened trachea and increased intraluminal pressure related to chronic cough, some patients may develop mucosal herniation leading to tracheal diverticulosis. We report the case of a patient with TBM with a huge tracheal diverticulum, diagnosed by bronchoscopy and computed tomography with three-dimensional reconstruction. To our knowledge this is the largest tracheal diameter described in a patient affected by this syndrome

Haemoptysis and fever in a young refugee from Somalia

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A dose-ranging study of indacaterol in obstructive airways disease, with a tiotropium comparison

SummaryThis dose-ranging study assessed the bronchodilator efficacy and tolerability of indacaterol, a novel once-daily inhaled β2-agonist, in subjects clinically diagnosed with COPD. Comparative data with tiotropium were collected.In the double-blind, core period of the study, 635 subjects with COPD (prebronchodilator FEV1⩾40% of predicted and ⩾1.0L; FEV1/FVC <70%) were randomized to receive indacaterol 50, 100, 200 or 400μg or placebo via multi-dose dry powder inhaler, or indacaterol 400μg via single-dose dry powder inhaler, once daily for 7 days. After completing double-blind treatment and washout, a subset of subjects from each treatment group entered an open-label extension and received tiotropium 18μg once daily for 8 days. The primary efficacy variable was the trough bronchodilator effect: standardized area under the FEV1 curve between 22 and 24h post-dose (FEV1 AUC22–24h) on Day 1.Clinically relevant improvements versus placebo in FEV1 AUC22–24h were seen for 400 and 200μg doses on Day 1 and all doses on Day 7. All indacaterol doses significantly (P<0.05) increased FEV1 from 5min to 24h post-dose; the 400 and 200μg doses were most effective. All doses were well tolerated. Indacaterol trough FEV1 levels compared favorably with the improvement seen by Day 8 in subjects treated with tiotropium in the open-label extension.The results confirm that indacaterol has a 24-h duration of bronchodilator effect and a fast onset of action in COPD and suggest that indacaterol could be an effective once-daily inhaled β2-agonist bronchodilator. Indacaterol demonstrated a good overall safety and tolerability profile

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)

Background: Dysregulated systemic inflammation is the primary driver of mortality in severe coronavirus disease 2019 (COVID-19) pneumonia. Current guidelines favour a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg daily. A comparative randomised controlled trial (RCT) with a higher dose and a longer duration of intervention was lacking. Methods: We conducted a multicentre, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg once daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. The primary outcome was reduction in 28-day mortality. Secondary outcomes were mechanical ventilation-free days at 28 days, need for intensive care unit (ICU) referral, length of hospitalisation, need for tracheostomy, and changes in C-reactive protein (CRP) levels, arterial oxygen tension/inspiratory oxygen fraction (P aO2 /F IO2 ) ratio and World Health Organization Clinical Progression Scale at days 3, 7 and 14. Results: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35 (10.4%) versus 41 (12.1%); p=0.49) nor in median mechanical ventilation-free days (median (interquartile range (IQR)) 23 (14) versus 24 (16) days; p=0.49). ICU referral was necessary in 41 (12.2%) versus 45 (13.2%) (p=0.68) and tracheostomy in 8 (2.4%) versus 9 (2.6%) (p=0.82). Survivors in the methylprednisolone group required a longer median (IQR) hospitalisation (15 (11) versus 14 (11) days; p=0.005) and experienced an improvement in CRP levels, but not in P aO2 /F IO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified time-points. Conclusion: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared with conventional dexamethasone in COVID-19 pneumonia

Benralizumab in Patients With Severe Eosinophilic Asthma With and Without Chronic Rhinosinusitis With Nasal Polyps: An ANANKE Study post-hoc Analysis

Background: Severe eosinophilic asthma (SEA) in the presence of chronic rhinosinusitis with nasal polyps (CRSwNP) indicates the presence of a more extensive eosinophilic inflammation. Post-hoc analyses from a pivotal clinical trial have demonstrated the enhanced efficacy of benralizumab on asthma outcomes in patients with CRSwNP as a comorbidity. Methods: This is a post-hoc analysis from the Italian multi-center observational retrospective ANANKE study. Patients were divided into two groups based on self-reported CRSwNP. Baseline clinical and laboratory features in the 12 months prior to benralizumab prescription were collected. Data of change over time of blood eosinophils, annualized exacerbations rates (AER), asthma control, lung function, oral corticosteroids (OCS) use, and benralizumab discontinuation were collected during the observation period. Results: At baseline, the 110 patients with CRSwNP were less frequently female (50.9% vs 74.2%) and obese (9.1% vs. 22.6%) with higher eosinophils (605 vs. 500 cells/mm3) and OCS use when compared to patients without CRSwNP. Similar reductions of AER were seen (-95.8% vs. -91.5% for any exacerbation and -99.1% vs. -92.2% for severe exacerbations in patients with and without CRSwNP, respectively). During benralizumab treatment, comorbid SEA+CRSwNP was associated with a lower risk of any exacerbation (p = 0.0017) and severe exacerbations (p = 0.025). After a mean ± SD exposure of 10.3 ± 5.0 months, half of the SEA+CRSwNP patients eliminated OCS use. No discontinuation for safety reasons was recorded. Conclusions: This study helped to confirm the baseline clinical features that distinguish patients with and without CRSwNP being prescribed benralizumab. Numerically enhanced OCS reduction and lower exacerbation risk were observed in patients with SEA and comorbid CRSwNP treated with benralizumab

ChAracterization of ItaliaN severe uncontrolled Asthmatic patieNts Key features when receiving Benralizumab in a real-life setting: the observational rEtrospective ANANKE study

Background: Data from phase 3 trials have demonstrated the efficacy and safety of benralizumab in patients with severe eosinophilic asthma (SEA). We conducted a real-world study examining the baseline characteristics of a large SEA population treated with benralizumab in clinical practice and assessed therapy effectiveness. Methods: ANANKE is an Italian multi-center, retrospective cohort study including consecutive SEA patients who had started benralizumab therapy ≥ 3&nbsp;months before enrolment (between December 2019 and July 2020), in a real-world setting. Data collection covered (1) key patient features at baseline, including blood eosinophil count (BEC), number and severity of exacerbations and oral corticosteroid (OCS) use; (2) clinical outcomes during benralizumab therapy. We also conducted two post-hoc analyses in patients grouped by body mass index and allergic status. Analyses were descriptive only. Results: Of 218 patients with SEA enrolled in 21 Centers, 205 were evaluable (mean age, 55.8 ± 13.3&nbsp;years, 61.5% females). At treatment start, the median BEC was 580 cells/mm3 (interquartile range [IQR]: 400-850); all patients were on high-dose inhaled controller therapy and 25.9% were on chronic OCS (median dose: 10&nbsp;mg/die prednisone-equivalent [IQR: 5-25]); 92.9% experienced ≥ 1 exacerbation within the past 12&nbsp;months (annualized exacerbation rate [AER] 4.03) and 40.3% reported ≥ 1 severe exacerbation (AER 1.10). During treatment (median duration: 9.8&nbsp;months [IQR 6.1-13.9]; ≥ 12&nbsp;months for 34.2% of patients), complete eosinophil depletion was observed; exacerbation-free patients increased to 81% and only 24.3% reported ≥ 1 severe event. AER decreased markedly to 0.27 for exacerbations of any severity (-&nbsp;93.3%) and to 0.06 for severe exacerbations (-&nbsp;94.5%). OCS therapy was interrupted in 43.2% of cases and the dose reduced by 56% (median: 4.4&nbsp;mg/die prednisone-equivalent [IQR: 0.0-10.0]). Lung function and asthma control also improved. The effectiveness of benralizumab was independent of allergic status and body mass index. Conclusions: We described the set of characteristics of a large cohort of patients with uncontrolled SEA receiving benralizumab in clinical practice, with a dramatic reduction in exacerbations and significant sparing of OCS. These findings support benralizumab as a key phenotype-specific therapeutic strategy that could help physicians in decision-making when prescribing biologics in patients with SEA. Trial registration ClinicalTrials.gov Identifier: NCT04272463