Idiopathic pulmonary fibrosis (IPF) is a devastating condition that carries a prognosis worse than that of many cancers. A recent classification of the idiopathic interstitial pneumonias has ...redefined the diagnostic criteria necessary to determine a diagnosis of IPF. The present authors believe that this redefinition is incorrect, relying as it does on subtle histological differences for the definition of separate disease categories. A further issue affecting IPF research is the polarisation of views around two competing pathogenetic hypotheses. One argues for the primacy of inflammation as the trigger that initiates fibrosis, and the other proposes that fibrosis arises as a consequence of chronic epithelial injury and failure of repair due to aberrant epithelial-mesenchymal interactions. The present authors believe that this schism is hampering understanding of IPF and skewing research priorities. It is argued here, instead, that abnormalities in multiple pathways involved in wound healing and inflammation lead to the development of idiopathic pulmonary fibrosis, and it is suggested that a new rationale for clinical classification and pathogenesis may be more productive in driving the search for novel therapies in the future.
In idiopathic interstitial pneumonia (IIP), the significance of connective tissue disease (CTD) features in the absence of a specific CTD diagnosis remains unclear. We studied the clinical and ...prognostic utility of a diagnosis of undifferentiated CTD (UCTD) in patients with biopsy-proven IIP. IIP patients undergoing surgical lung biopsy (1979-2005) were studied (nonspecific interstitial pneumonia (NSIP), n = 45; idiopathic pulmonary fibrosis, n = 56). UCTD was considered present when serum autoantibodies were present and symptoms or signs suggested CTD. The relationship between UCTD and NSIP histology was evaluated. A clinical algorithm that best predicted NSIP histology was constructed using a priori variables. The prognostic utility of UCTD, and of this algorithm, was evaluated. UCTD was present in 14 (31%) NSIP and seven (13%) IPF patients. UCTD was not associated with a survival benefit. The algorithm predictive of NSIP (OR 10.4, 95% CI 3.21-33.67; p<0.0001) consisted of the absence of typical high-resolution computed tomography (HRCT) features for IPF and 1) a compatible demographic profile (females aged <50 yrs) or 2) Raynaud's phenomenon. In patients with an HRCT scan not typical for IPF, this algorithm predicted improved survival (hazard ratio 0.35, 95% CI 0.14-0.85; p = 0.02) independent of IIP severity. UCTD is associated with NSIP histology. However, the diagnostic and prognostic significance of UCTD in IIP patients remains unclear.
Pulmonary fibrosis has been identified as a main factor leading to pulmonary dysfunction and poor quality of life in post-recovery Severe Acute Respiratory Syndrome (SARS) survivor's consequent to ...SARS-Cov-2 infection. Thus there is an urgent medical need for identification of readily available biomarkers that in patients with SARS-Cov-2 infection are able to; (1) identify patients in most need of medical care prior to admittance to an intensive care unit (ICU), and; (2) identify patients post-infection at risk of developing persistent fibrosis of lungs with subsequent impaired quality of life and increased morbidity and mortality. An intense amount of research have focused on wound healing and Extracellular Matrix (ECM) remodelling of the lungs related to lung function decline in pulmonary fibrosis (PF). A range of non-invasive serological biomarkers, reflecting tissue remodelling, and fibrosis have been shown to predict risk of acute exacerbations, lung function decline and mortality in PF and other interstitial lung diseases (Sand et al. in Respir Res 19:82, 2018). We suggest that lessons learned from such PF studies of the pathological processes leading to lung function decline could be used to better identify patients infected with SARS-Co-V2 at most risk of acute deterioration or persistent fibrotic damage of the lung and could consequently be used to guide treatment decisions.
Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias with an estimated 5-year survival of approximately 20%. In the last two decades our ...understanding of disease pathogenesis has substantially evolved and novel compounds have been developed consequent to the increasing knowledge of the mechanisms underlying disease pathobiology. The disease appears to be driven - following chronic injury - by abnormal/dysfunctional alveolar epithelial cells that promote fibroblast recruitment and proliferation, resulting in scarring of the lung and irreversible loss of function. With very few exceptions, clinical trials evaluating novel potential therapies have provided disappointing results. More recently, pirfenidone and nintedanib, two compounds with pleiotropic mechanisms of action, have proven effective in slowing functional decline and disease progression in IPF patients with mild to moderate functional impairment, highlighting the importance of timely diagnosis and administration of treatment in early stages of disease. However, due to the complexity and uncertainties intrinsic to IPF, it is essential that each therapeutic strategy be tailored to the individual patient, after evaluation of potential benefits and risks. This article provides an overview of the most recent clinical trials in IPF and discusses how their results are going to change the clinical and clinical research landscape in IPF. A number of agents with high potential are currently being tested and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.
Idiopathic pulmonary fibrosis (IPF) is a progressive, and invariably fatal, condition that is believed to arise in genetically susceptible individuals as a consequence of an aberrant wound-healing ...response following repetitive alveolar injury. The exact triggers, which initiate the fibrotic process, remain unknown. Infectious agents, including both viruses and bacteria, have the capacity to cause alveolar-epithelial cell injury and apoptosis. Relatively few studies have examined the role of infection in IPF. Those that have, point to viruses playing a key role as cofactors in the initiation and progression of IPF. There is also some evidence to suggest that viral infection may be responsible for a proportion of acute exacerbations of IPF. The role played by bacteria in the pathogenesis of IPF is less clear cut. Studies from other respiratory diseases suggest that alterations in the lung microbiome are associated with disease and that these changes influence disease behaviour. Emerging molecular microbiological techniques are making the study of microbial communities in the lung easier. It is hoped that by combining such techniques with the careful longitudinal phenotyping of patients with IPF, it will be possible to elucidate the role played by bacteria and viruses in the pathogenesis of the disease. If infection plays a causal role in IPF then it is possible that therapeutic strategies, utilising currently available antiviral or antibiotic drugs, may be effective in modifying the course of this devastating condition.
Schizophrenia has a heritability of 60-80%
, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia ...and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.
Objective
To study the tocolytic action of nifedipine combined with sildenafil citrate (SC) and if the combination is superior to nifedipine alone in inhibiting threatened preterm labour (PTL).
...Design
Prospective randomised study.
Setting
An Egyptian university hospital.
Population
Women with threatened PTL who received either nifedipine with SC or nifedipine alone.
Methods
Patients were randomly allocated to receive either (1) nifedipine 20 mg orally (stat dose), followed by 10 mg orally every 6–8 hours at the same time as vaginal administration of SC (25 mg at 8‐hourly intervals) or (2) nifedipine alone. Medications were continued for 48–72 hours.
Main outcome measures
The percentage of women who remained undelivered during hospitalisation.
Results
From January 2015 to November 2016, 239 women were randomised. The baseline characteristics of participants were similar. Nifedipine combined with SC was associated with more women remaining undelivered (81.8 versus 68.6%; P = 0.018) during hospitalisation. Regarding secondary outcomes, the addition of SC was also associated with fewer deliveries within 7 days of admission (9.1 versus 20.3%; P = 0.014), prolonged latency (29 versus 7 days; P = 0.002), fewer admissions to neonatal intensive care units (31.4 versus 44.1%; P = 0.043), fewer very preterm deliveries (from 28 to <32 weeks, 20.7 versus 38.1%; P = 0.043), and increased neonatal birthweight (1900 versus 1500 g; P = 0.018).
Conclusions
Vaginal SC combined with nifedipine is an effective option for tocolytic therapy during threatened PTL.
Tweetable
Vaginal SC enhances the tocolytic effect of nifedipine.
Tweetable
Vaginal SC enhances the tocolytic effect of nifedipine.
IntroductionIdiopathic pulmonary fibrosis (IPF) is a debilitating, life-limiting fibrotic lung disease. Cough and breathlessness are among the most commonly reported symptoms and confer negative ...psychological burden, yet its exact relationship with anxiety and depression remains unknown. We aimed to determine the severity of mood disorders in individuals with IPF and assess the association with symptom burden.MethodsWe prospectively recruited incident cases of IPF into an observational study (ethics reference 20/EE/0261). Hospital Anxiety and Depression Scales were collected at baseline and repeated at 12 months (subscales for HADS-A and HADS-D, range 0–21; higher scores depicting worse quality of life). Dyspnoea-12 (range 0–36), Leicester Cough Questionnaires (LCQ, range 3–21) and cough visual analogue scales (VAS, range 0–100mm) were also recorded. Demographic data and lung function were collected.Results207 IPF patients were recruited, of whom 107 completed follow-up (table 1). Subjects were on average aged 74.5 years, predominantly male, with moderately impaired lung function (FVC 77.9% ± 14.2%, TLco 47.9% ± 13.6%). The prevalence of anxiety and depression at baseline (HADS > 8) were 29.0% and 29.5% respectively. On univariate analysis worse dyspnoea and cough scores were associated with greater anxiety and depression (P < 0.001). However, on multivariate analysis while the relationship with Dyspnoea-12 scores was preserved (P < 0.001), out of the cough measures only LCQ was associated with HADS-A (P = 0.03). Baseline lung function did not correlate with HADS.At follow up, both HADS-A and HADS-D increased in the cohort (mean change 0.79 and 0.70 respectively), but these changes were below the threshold for meaningful change.1 Deteriorating scores in both Dyspnoea-12 (r = 0.51 and 0.58 for HADS-A and HADS-D) and cough VAS (r = 0.29 and 0.42) correlated with worsening HADS scores. There was no difference in HADS score change between subjects with stable and progressive disease.ConclusionAnxiety and depression are common in patients with IPF. Dyspnoea and, to a lesser extent, cough play a central role.ReferenceKim, Jee Whang, et al. Psychometric properties of patient reported outcome measures in idiopathic pulmonary fibrosis. Chron Respir Dis. 2021 Jan 5;18:147997312110339.Abstract P222 Table 1Data are presented as mean ± SD or No. (%) unless otherwise indicated Baseline (n = 207) Variable Value Range Age 74.5 ± 7.2 51 – 91 Male sex 169 (81.6) - BMI 28.5 ± 4.9 17.9 – 47.4 Smoking history Current 1 (0.5) - Former 143 (69.1) - Never 63 (30.4) - Long-term oxygen therapy 26 (12.6) - ACEi therapy 45 (21.7) - Antidepressant therapy 18 (8.7) - Pulmonary function tests FVC% predicted 77.9 ± 14.2 39.7 – 123 TLCO% predicted 47.9 ± 13.6 20.5 – 106.1 HADS-A 5.31 ± 3.79 0 – 18 HADS-D 6.01 ± 3.92 0 – 18 Dyspnoea-12 13.5 ± 8.9 0 – 36 VAS 32.7 ± 24.6 0 – 91 LCQ 16.1 ± 2.7 8 – 21 Abbreviations: FVC = forced vital capacity; TLCO = diffusion capacity of the lung for carbon monoxide; HADS = Hospital Anxiety and Depression Scale; D-12 = Dyspnoea-12 Questionnaire; VAS = Cough Severity Visual Analogue Scale; LCQ = Leicester Cough Questionnaire.
Background
International guidelines recommend nintedanib (OFEV
®
) as an option for the treatment of idiopathic pulmonary fibrosis (IPF).
Objective
The objective of this study was to assess the cost ...effectiveness of nintedanib versus pirfenidone,
N
-acetylcysteine and best supportive care (BSC) for the treatment of IPF from a UK payer’s perspective.
Methods
A Markov model was designed to capture the changes in the condition of adults with IPF. Efficacy outcomes included mortality, lung function decline and acute exacerbations. Treatment safety (serious adverse events) and tolerability (overall discontinuation) were also considered. The baseline risk of these events was derived from patient-level data from the placebo arms of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). A network meta-analysis (NMA) was conducted to estimate the relative effectiveness of the comparator treatments. Quality of life and healthcare resource use data from the clinical trials were also incorporated in the economic model.
Results
Nintedanib showed statistically significant differences against placebo on acute exacerbation events avoided and lung function decline. In the cost-effectiveness analysis, the results were split between two treatments with relative low costs and modest effectiveness (BSC and
N
-acetylcysteine) and two that showed improved effectiveness (lung function) and higher costs (nintedanib and pirfenidone). All comparators were assumed to have similar projected survival and the difference in quality-adjusted life-years (QALYs) was driven by the acute exacerbations and lung function estimates. In the base-case deterministic pairwise comparison with pirfenidone, nintedanib was found to have fewer acute exacerbations and resulted in less costs and more QALYs gained.
Conclusions
Compared with BSC (placebo), nintedanib and pirfenidone were the only treatments to show statistical significance in the efficacy parameters. We found substantial uncertainty in the overall cost-effectiveness results between nintedanib and pirfenidone.
N
-Acetylcysteine was largely similar to BSC but with a worse survival profile.
INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477
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