Emerging drugs for idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal lung disorder of unknown etiology. The disease is characterized by alveolar epithelial cell injury, formation of activated fibroblasts/myofibroblasts foci and finally by the exaggerated accumulation of extracellular matrix with the subsequent destruction of the lung architecture. The long-term survival is distinctly poor, with only a 20-30\% survival 5 years after the time of diagnosis. Actually, regardless of extensive research, no current therapy has been shown to either reverse or stop the progression of this disease. AREAS COVERED: The authors searched the Medline database from January 1990 to December 2010 using search terms 'pulmonary fibrosis', 'fibrosing alveolitis' and 'usual interstitial pneumonia'. Several subsets were included: definition and epidemiology, risk factors, clinical behavior, pathogenesis and therapy. For the section of IPF treatment, the authors examined all relevant studies including randomized controlled trials, cohort studies, case-control studies and cross-sectional studies. In this review, the authors describe the current therapeutic approaches, the ongoing clinical trials and some future options based on stem cells, lung bioengineering and microRNAs. EXPERT OPINION: The treatment of IPF represents one of the greatest challenges confronting respiratory medicine and, currently, there is no effective therapeutic option for IPF. Perhaps some of the drugs that are under evaluation in clinical trials will slow the decline of the pulmonary function tests or hopefully stabilize some patients. Nonetheless, it appears clear that new therapeutic approaches are urgently needed

Differing severities of acute exacerbations of idiopathic pulmonary fibrosis (IPF): Insights from the INPULSIS\uae trials

Background: Given the broad definition of an acute exacerbation of IPF, it is likely that acute exacerbations are heterogeneous in their aetiology, severity and clinical course. We used pooled data from the INPULSIS\uae trials of nintedanib versus placebo to investigate whether acute exacerbations reported as serious adverse events were associated with higher mortality than those reported as non-serious adverse events and to assess the effect of nintedanib on these types of events. Methods: Adverse events considered by an investigator to be an acute exacerbation were adjudicated as a confirmed acute exacerbation, suspected acute exacerbation, or not an acute exacerbation. Time to first investigator-reported acute exacerbation or confirmed/suspected acute exacerbation reported as a serious adverse event or non-serious adverse event over the 52-week treatment period was assessed post-hoc. Deaths were assessed based on data collected over the 52-week treatment period. Results: Of 63 patients who had 651 investigator-reported acute exacerbation, 48 (76.2%) had a first acute exacerbation reported as a serious adverse event. Thirty-six (3.4%) patients had 651 confirmed/suspected acute exacerbation, of whom 31 had a first event reported as a serious adverse event. Investigator-reported acute exacerbations reported as serious adverse events occurred in 23 patients in the nintedanib group and 26 in the placebo group. Confirmed/suspected acute exacerbations reported as serious adverse events occurred in 10 and 21 patients in these groups, respectively. Nintedanib significantly reduced the risk of a first acute exacerbation reported as a serious adverse event (HR 0.57 [95% CI: 0.32, 0.99]; p = 0.0476) and the risk of a first confirmed/suspected acute exacerbation reported as a serious adverse event (HR 0.30 [95% CI: 0.14, 0.64]; p = 0.0019) versus placebo. A higher proportion of patients with investigator-reported acute exacerbations reported as serious adverse events died than patients with acute exacerbations reported as non-serious adverse events (61.2% versus 7.1%). Conclusion: Different severities of acute exacerbation of IPF may exist. Acute exacerbations reported as serious adverse events in the INPULSIS\uae trials were associated with high mortality. Nintedanib significantly reduced the risk of acute exacerbations reported as serious adverse events. Trial registration: ClinicalTrials.gov NCT01335464 and NCT01335477

Digital lung auscultation: Will early diagnosis of fibrotic interstitial lung disease become a reality?

Non

Clinical use of Levofloxacin in the long-term treatment of drug resistant tuberculosis.

Multidrug-resistant (MDR) tuberculosis (TB) is a form of TB that is resistant to some of the first-line drugs used for the treatment of the disease. It is associated both with a higher incidence of treatment failures and of disease recurrence, as well as with higher mortality than forms of TB sensitive to first-line drugs. Levofloxacin (LFX) represents one of the few second-line drugs recently introduced in the therapeutic regimens for MDR TB. We report our experience concerning in vitro activity and clinical safety of LFX in long term second-line regimens for MDR TB. IN VITRO ACTIVITY ON MYCOBACTERIA: The in vitro activity of ciprofloxacin, ofloxacin and LFX was studied on 28 strains belonging to different species of Mycobacteria. In Dubos medium, LFX inhibited the growth of both library and MDR clinical Mycobacteria strains in a range of 0.25-1 mcg/ml. In International Union Tuberculosis Medium (IUTM) the minimum inhibitory concentrations (MIC) were slightly higher, but LFX activity was not affected by the higher complexity of the medium. CLINICAL EXPERIENCE: Four patients with MDR TB were treated with a second-line regimen comprising oral LFX 500 mg twice daily, for at least 9 months. Two isolates obtained from the patients reported here showed multi resistance to isoniazid and rifampin, one to rifampin and streptomycin and one to isoniazid and ethambutol. During therapy, no significant alteration of either liver function tests, blood tests or any other described side effect of the fluoroquinolone class was observed. The 3 patients with pulmonary MDR TB showed radiologic and clinical improvement. CONCLUSION: We confirm the higher in vitro activity of LFX compared to older fluoroquinolones. Furthermore, in a limited number of MDR TB patients, second-line regimens comprising LFX 500 mg b.i.d. administered in a range of 9-24 months were well tolerated and safe

Reply to Moodley and to Ravaglia et al

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Efficacy of hormonal suppression in a patient with chyluria due to lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare lung disease affecting almost exclusively young women, characterised by abnormal proliferation of atypical smooth muscle cells. We describe a young woman presenting with chyluria secondary to the presence of a large retroperitoneal lymphangioleiomyoma. Immunohistochemical analysis revealed HMB45-negative LAM cells (HMB45 staining is absent only in rare cases) expressing low levels of estrogen receptors. Estrogen suppressive treatment with triptoreline, a synthetic analogue of Gn-RH, resulted in dramatic reduction of the retroperitoneal mass size. The role of estrogens in the pathogenesis of LAM remains poorly understood, and hormonal therapy is still debated, but this case suggests that at least in some LAM patients, possibly those with HMB45-negative disease and estrogen receptor expression, hormonal therapy may be effective in controlling the disease process

Performance of commerical blood tests for the diagnosis of latent tuberculosis infection in children and adolescents

BACKGROUND: The accurate diagnosis of latent tuberculosis infection reduces the risk of progression to severe disseminated disease. However, in young children, a major limitation of the standard tuberculin skin test is that false-negative results cannot be detected. The new interferon-gamma release assays QuantiFERON-TB Gold (Cellestis Carnegie Victoria, Australia), QuantiFERON-TB In-Tube (Cellestis), and T-SPOT.TB (Oxford Immunotec, Abingdon, United Kingdom) show promise of greater accuracy, but they may also be affected by impaired cellular immunity, resulting in indeterminate results (ie, insufficient response in positive-control wells).OBJECTIVE:To evaluate the impact of age on the performance of interferon-gamma release assays when used in a routine hospital setting among children tested for suspected active or latent TB infection.METHODS:We retrospectively studied 496 children 0 to 19 years of age who had been tested with the tuberculin skin test and at least 1 interferon-gamma release assay: 181 with QuantiFERON-TB Gold and 315 with QuantiFERON-TB In-Tube. In 154 of the children, paired interferon-gamma release assay testing was available: 87 with QuantiFERON-TB Gold/T-SPOT.TB and 67 with QuantiFERON-TB In-Tube/T-SPOT.TB.RESULTS:Compared with T-SPOT.TB, the rates of indeterminate results were significantly higher for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube. QuantiFERON-TB Gold and QuantiFERON-TB In-Tube also gave indeterminate results more frequently in children /=4 years of age. Indeterminate results were associated with younger age for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube but not for T-SPOT.TB. Considering age as a binary variable (/=4 years of age), a significantly higher concentration of phytohaemagglutinin-produced interferon-gamma was observed in older children with both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube.CONCLUSIONS:Different blood tests for the diagnosis of latent tuberculosis infection in children seem to perform differently, because both QuantiFERON-TB tests were more likely than T-SPOT.TB to give indeterminate results in children <4 years of age

Effects of nintedanib in patients with idiopathic pulmonary fibrosis by GAP stage

We conducted a post hoc analysis to assess the potential impact of GAP (gender, age, physiology) stage on the treatment effect of nintedanib in patients with idiopathic pulmonary fibrosis. Outcomes were compared in patients at GAP stage I versus II/III at baseline in the INPULSIS\uae trials. At baseline, 500 patients were at GAP stage I (nintedanib 304, placebo 196), 489 were at GAP stage II (nintedanib 296, placebo 193) and 71 were at GAP stage III (nintedanib 38, placebo 33). In nintedanibtreated patients, the annual rate of decline in forced vital capacity (FVC) was similar in patients at GAP stage I and GAP stage II/III at baseline (-110.1 and -116.6 mL.year-1, respectively), and in both subgroups was lower than in placebo-treated patients (-218.5 and -227.6 mL.year-1, respectively) (treatment-by-time-by-subgroup interaction p=0.92). In the nintedanib group, the number of deaths was 43.8% of those predicted based on GAP stage (35 versus 79.9). In the placebo group, the number of deaths was 59.8% of those predicted based on GAP stage (33 versus 55.2). In conclusion, data from the INPULSIS\uae trials suggest that nintedanib has a similar beneficial effect on the rate of FVC decline in patients at GAP stage I versus II/III at baseline

Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS® trials

AbstractBackground and purposeThe Phase II TOMORROW trial and two Phase III INPULSIS® trials investigated the efficacy and safety of nintedanib versus placebo in patients with idiopathic pulmonary fibrosis (IPF). To obtain an overall estimate of the treatment effect of nintedanib 150 mg twice daily (bid), pooled and meta-analyses of data from these three trials were conducted.MethodsPooled and meta-analyses were conducted for annual rate of decline in forced vital capacity (FVC), time to first acute exacerbation, change from baseline in St George's Respiratory Questionnaire (SGRQ) total score and mortality over 52 weeks.Results1231 patients (nintedanib n = 723, placebo n = 508) were included in the pooled analysis. Adjusted annual rate of decline in FVC was −112.4 mL/year with nintedanib and −223.3 mL/year with placebo (difference: 110.9 mL/year [95% CI: 78.5, 143.3]; p < 0.0001). The hazard ratio for time to first acute exacerbation was 0.53 (95% CI: 0.34, 0.83; p = 0.0047). Adjusted mean change from baseline in SGRQ score at week 52 was 2.92 with nintedanib and 4.97 with placebo (difference: −2.05 [95% CI: −3.59, −0.50]; p = 0.0095). Hazard ratios for time to all-cause and on-treatment mortality were 0.70 (95% CI: 0.46, 1.08; p = 0.0954) and 0.57 (95% CI: 0.34, 0.97; p = 0.0274), respectively, in favour of nintedanib. The meta-analysis was generally consistent with the pooled analysis. Diarrhoea was the most frequent adverse event in the nintedanib group (61.5% of patients treated with nintedanib versus 17.9% of patients treated with placebo).ConclusionNintedanib has a beneficial effect on slowing disease progression in patients with IPF