15 results found
Farne H, Kumar K, Ritchie AI, et al., 2020, Repurposing existing drugs for the treatment of COVID-19, Annals of the American Thoracic Society, Vol: 17, Pages: 1186-1194, ISSN: 1546-3222
The rapid global spread and significant mortality associated with the coronavirus disease (COVID-19) caused by SARS-CoV-2 viral infection has spurred an urgent race to find effective treatments. Repurposing existing drugs is a particularly attractive approach as pharmacokinetic and safety data already exist, thus development can leapfrog straight to clinical trials of efficacy, generating results far more quickly than de novo drug development. This review summarizes the state of play for the principle drugs identified as candidates to be repurposed for treating COVID-19 grouped by broad mechanism of action: antiviral, immune enhancing, and anti-inflammatory or immunomodulatory. Patient selection, particularly with regard to disease stage, is likely to be key. To date only dexamethasone and remedesivir have been shown to be effective, but several other promising candidates are in trials.
Ritchie AI, Brill SE, Vlies BH, et al., 2020, Targeted retreatment of incompletely recovered COPD exacerbations with ciprofloxacin: a double-blind, randomised, placebo-controlled, multicentre phase III trial, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 549-557, ISSN: 1073-449X
RATIONALE: COPD exacerbations are prone to non-recovery but there are no data about the effectiveness of retreatment on these prolonged events. We examined whether further therapy with ciprofloxacin for incompletely resolved COPD exacerbations prolonged the time until the next event. METHODS: This multi-centre randomised double-blind placebo-controlled trial studied retreatment with oral ciprofloxacin 500mg or matched placebo twice daily for 7 days in patients with GOLD stage II - IV COPD with persistent symptoms and/or serum C-reactive protein (CRP) ≥8mg/L initiated 14 (+/- 3) days after an index COPD exacerbation. The primary outcome was the time to the next exacerbation within a 90-day period. RESULTS: Of 826 patients screened at 4 centres, 144 eligible participants with incomplete recovery were randomised to receive ciprofloxacin (n=72) or placebo (n=72). 57% of patients in the ciprofloxacin group had experienced 1 or more exacerbations, compared to 53% in the placebo group. The median time to the next exacerbation was 32.5 days (IQR 13-50) in the placebo arm and 34 days (IQR 17-62) in the ciprofloxacin arm, which was not significantly different (adjusted hazard ratio = 1.07, 95% CI 0.68-1.68; p=0.76). No significant differences were seen in quality of life scores or lung function between treatment groups. CONCLUSION: In patients with persistent symptoms and/or raised CRP 14 days following a COPD exacerbation, an additional course of ciprofloxacin resulted in no additional benefit compared to placebo. This suggests that non-recovered exacerbations are not driven by ongoing bacterial infection and may potentially be targeted with anti-inflammatory therapy.
Ritchie AI, Singanayagam A, 2020, Metagenomic Characterization of the Respiratory Microbiome A Piece de Resistance, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 321-322, ISSN: 1073-449X
Ritchie AI, Singanayagam A, 2020, Immunosuppression for hyperinflammation in COVID-19: a double-edged sword?, LANCET, Vol: 395, Pages: 1111-1111, ISSN: 0140-6736
Wedzicha JA, Ritchie AI, Martinez FJ, 2019, Can macrolide antibiotics prevent hospital readmissions?, American Journal of Respiratory and Critical Care Medicine, Vol: 200, Pages: 796-798, ISSN: 1073-449X
Edwards MR, Ritchie AI, Johnston SL, 2019, Exacerbations of chronic respiratory diseases, Rhinovirus Infections: Rethinking the Impact on Human Health and Disease, Pages: 137-168, ISBN: 9780128164174
Respiratory viral infections including human rhinovirus (RV) infection have been identified as the most important environmental trigger of exacerbations of chronic lung diseases. While well established as the most common viral infections associated with exacerbations of asthma and chronic obstructive pulmonary disease, RVs and other respiratory viruses are also now thought to be important in triggering exacerbations of cystic fibrosis and the interstitial lung diseases. Here, we summarize the epidemiological evidence the supports respiratory viruses including RV as triggers of exacerbations of chronic lung diseases. We propose that certain characteristics of RVs may explain why they are the most common trigger of exacerbations of chronic lung diseases. We further highlight the latest mechanistic evidence supporting how and why common respiratory viral infections may enhance and promote disease triggering exacerbation events, through their interactions with the host immune system, and may be affected by ongoing treatments. We also provide a commentary on how new treatments may better manage the disease burden associated with respiratory viral infections and the exacerbation events that they trigger.
Ritchie AI, Singanayagam A, Wiater E, et al., 2018, beta(2)-agonists enhance asthma-relevant inflammatory mediators in human airway epithelial cells, American Journal of Respiratory Cell and Molecular Biology, Vol: 58, Pages: 128-132, ISSN: 1044-1549
Abbara A, Chitty S, Roe JK, et al., 2017, Drug-induced liver injury from antituberculous treatment: a retrospective study from a large TB centre in the UK, BMC INFECTIOUS DISEASES, Vol: 17, ISSN: 1471-2334
Singanayagam A, Ritchie AI, Johnston SL, 2017, Role of microbiome in the pathophysiology and disease course of asthma, Current Opinion in Pulmonary Medicine, Vol: 23, Pages: 41-47, ISSN: 1070-5287
Purpose of review: The emergence of next-generation 16S rRNA sequencing techniques has facilitated a more detailed study of the body's microbiota and led to renewed interest in the association between microbial exposure and asthma inception. In this review, we evaluate the evidence that the respiratory tract and intestinal microbiota contribute to asthma pathogenesis and progression.Recent findings: Human studies have revealed associations between the presence of potentially pathogenic bacteria in the respiratory tract in early life and subsequent risk of allergic sensitization and asthma. Similarly, alterations in the intestinal microbiota of neonates have also been shown to precede the development of asthma. Emerging evidence suggests that the lung microbiota is dysregulated in asthma with specific changes in bacterial diversity and community composition according to severity and phenotype. Studies using germ-free mice have been invaluable in moving our understanding from correlation to causation by demonstrating a mechanistic link between the neonatal microbiota and the development of allergic airway inflammation.Summary: An expanding body of literature supports the hypothesis that early life microbial exposures and bacterial communities within the lung and/or intestine play an important role in shaping early immunological development. Perturbations in the microbiota may promote immune defects associated with the development of asthma and allergic sensitization.
Singanayagam A, Manalan K, Connell DW, et al., 2016, Evaluation of serum inflammatory biomarkers as predictors of treatment outcome in pulmonary tuberculosis, International Journal of Tuberculosis and Lung Disease, Vol: 20, Pages: 1653-1660, ISSN: 1815-7920
OBJECTIVE: To evaluate C-reactive protein (CRP), globulin and white blood cell (WBC) count as predictors of treatment outcome in pulmonary tuberculosis (PTB).METHODS: An observational study of patients with active PTB was conducted at a tertiary centre. All patients had serum CRP, globulin and WBC measured at baseline and at 2 months following commencement of treatment. The outcome of interest was requirement for extension of treatment beyond 6 months.RESULTS: There were 226 patients included in the study. Serum globulin >45 g/l was the only baseline biomarker evaluated that independently predicted requirement for treatment extension (OR 3.42, 95%CI 1.59–7.32, P < 0.001). An elevated globulin level that failed to normalise at 2 months was also associated with increased requirement for treatment extension (63.9% vs. 5.1%, P < 0.001), and had a low negative likelihood ratio (0.07) for exclusion of requirement for treatment extension. On multivariable analysis, an elevated globulin that failed to normalise at 2 months was independently associated with requirement for treatment extension (OR 6.13, 95%CI 2.23–16.80, P < 0.001).CONCLUSIONS: Serum globulin independently predicts requirement for treatment extension in PTB and outperforms CRP and WBC as a predictive biomarker. Normalisation of globulin at 2 months following treatment commencement is associated with low risk of requirement for treatment extension.
Rawson T, Abbara A, Kranzer K, et al., 2016, Factors which influence treatment initiation for pulmonary non-tuberculous mycobacterium infection in HIV negative patients; a multicentre observational study, Respiratory Medicine, Vol: 120, Pages: 101-108, ISSN: 1532-3064
BackgroundClinical, radiological and microbiological criteria inform diagnosis of pulmonary Non-Tuberculous Mycobacteria (NTM) disease and treatment decisions. This multicentre, review aims to characterise NTM disease meeting ATS/IDSA criteria and define factors associated with initiation of treatment.MethodsSputum samples growing NTM from 5 London hospitals between 2010 and 2014 were identified. Data for HIV-negative individuals meeting ATS/IDSA guidelines for pulmonary NTM disease were extracted. Associations between clinical variables and treatment decision were investigated using Chi-squared, Fishers-exact or Mann Whitney tests. Factors associated with treatment in univariate analysis (p < 0.150) were included in a multivariate logistic regression model.ResultsNTM were identified from 817 individuals' sputum samples. 108 met ATS/IDSA criteria. 42/108 (39%) were initiated on treatment. Median age was 68 (56–78) in the cohort.On multivariate analysis, factors significantly associated with treatment of pulmonary NTM infection were: Cavitation on HRCT (OR: 6.49; 95% CI: 2.36–17.81), presenting with night sweats (OR 4.18; 95% CI: 1.08–16.13), and presenting with weight loss (OR 3.02; 95% CI: 1.15–7.93).Of those treated, 18(43%) have completed treatment, 9(21%) remain on treatment, 10(24%) stopped due to side effects, 5(12%) died during treatment. Mortality was 31% (n = 13) in treated versus 21% (n = 14) in the non-treated cohort. Subgroup analysis of individual NTM species did not observe any differences in treatment initiation or outcomes between groups.DiscussionDecision to treat pulmonary NTM infection requires clinical judgement when interpreting clinical guidelines. Factors independently associated with decision to treat in this HIV-negative cohort include cavitation on HRCT and presenting with night sweats or weight loss.
Hewitt R, Farne H, Ritchie A, et al., 2016, The role of viral infections in exacerbations of chronic obstructive pulmonary disease and asthma, Therapeutic Advances in Respiratory Disease, Vol: 10, Pages: 158-174, ISSN: 1753-4666
Asthma and chronic obstructive pulmonary disease (COPD) are major causes of global morbidity and mortality worldwide. The clinical course of both asthma and COPD are punctuated by the occurrence of exacerbations, acute events characterized by increased symptoms and airflow obstruction. Exacerbations contribute most of the morbidity, mortality and excess healthcare costs associated with both asthma and COPD. COPD and asthma exacerbations are frequently associated with respiratory virus infections and this has led to an intense research focus into the mechanisms of virus-induced exacerbations over the past decade. Current therapies are effective in reducing chronic symptoms but are less effective in preventing exacerbations, particularly in COPD. Understanding the mechanisms of virus-induced exacerbation will lead to the development of new targeted therapies that can reduce the burden of virus-induced exacerbations. In this review we discuss current knowledge of virus-induced exacerbations of asthma and COPD with a particular focus on mechanisms, human studies, virus–bacteria interactions and therapeutic advances.
Ritchie AI, Jackson DJ, Edwards MR, et al., 2016, Airway epithelial orchestration of innate immune function in response to virus infection. A focus on asthma, Annals of the American Thoracic Society, Vol: 13 Suppl 1, Pages: S55-S63, ISSN: 2329-6933
Ritchie AI, Farne HA, Singanayagam A, et al., 2015, Pathogenesis of Viral Infection in Exacerbations of Airway Disease., Annals of the American Thoracic Society, Vol: 12, Pages: S115-S132, ISSN: 2329-6933
Chronic airway diseases are a significant cause of morbidity and mortality worldwide, and their prevalence is predicted to increase in the future. Respiratory viruses are the most common cause of acute pulmonary infection, and there is clear evidence of their role in acute exacerbations of inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease. Studies have reported impaired host responses to virus infection in these diseases, and a better understanding of the mechanisms of these abnormal immune responses has the potential to lead to the development of novel therapeutic targets for virus-induced exacerbations. The aim of this article is to review the current knowledge regarding the role of viruses and immune modulation in acute exacerbations of chronic pulmonary diseases and to discuss exciting areas for future research and novel treatments.
Finney LJ, Ritchie A, Pollard E, et al., 2014, Lower airway colonization and inflammatory response in COPD: a focus on Haemophilus influenzae, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 9, Pages: 1119-1132, ISSN: 1176-9106
Bacterial infection of the lower respiratory tract in chronic obstructive pulmonary disease (COPD) patients is common both in stable patients and during acute exacerbations. The most frequent bacteria detected in COPD patients is Haemophilus influenzae, and it appears this organism is uniquely adapted to exploit immune deficiencies associated with COPD and to establish persistent infection in the lower respiratory tract. The presence of bacteria in the lower respiratory tract in stable COPD is termed colonization; however, there is increasing evidence that this is not an innocuous phenomenon but is associated with airway inflammation, increased symptoms, and increased risk for exacerbations. In this review, we discuss host immunity that offers protection against H. influenzae and how disturbance of these mechanisms, combined with pathogen mechanisms of immune evasion, promote persistence of H. influenzae in the lower airways in COPD. In addition, we examine the role of H. influenzae in COPD exacerbations, as well as interactions between H. influenzae and respiratory virus infections, and review the role of treatments and their effect on COPD outcomes. This review focuses predominantly on data derived from human studies but will refer to animal studies where they contribute to understanding the disease in humans.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.