David Sc Hui

miR-29 Inhibits Bleomycin-induced Pulmonary Fibrosis in Mice

Loss of microRNA-29 (miR-29) is known to be a mechanism of transforming growth factor-β (TGF-β)-mediated pulmonary fibrosis, but the therapeutic implication of miR-29 for pulmonary fibrosis remains unexplored. The present study investigated whether miR-29 had therapeutic potential for lung disease induced by bleomycin in mice. In addition, the signaling mechanisms that regulated miR-29 expression were investigated in vivo and in vitro. We found that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis.

Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives

Influenza A H1N1 2009 virus caused the first pandemic in an era when neuraminidase inhibitor antiviral drugs were available in many countries. The experiences of detecting and responding to resistance during the pandemic provided important lessons for public health, laboratory testing, and clinical management. We propose recommendations for antiviral susceptibility testing, reporting results, and management of patients infected with 2009 pandemic influenza A H1N1. Sustained global monitoring for antiviral resistance among circulating influenza viruses is crucial to inform public health and clinical recommendations for antiviral use, especially since community spread of oseltamivir-resistant A H1N1 2009 virus remains a concern. Further studies are needed to better understand influenza management in specific patient groups, such as severely immunocompromised hosts, including optimisation of antiviral treatment, rapid sample testing, and timely reporting of susceptibility results.

Viral clearance and inflammatory response patterns in adults hospitalized for pandemic 2009 influenza A(H1N1) virus pneumonia.

BACKGROUND Little is known about the virological and inflammatory responses of severe pandemic 2009 influenza A(H1N1) virus pneumonia during antiviral treatment. METHODS In a prospective observational study, we recruited consecutive adults hospitalized with confirmed pandemic 2009 H1N1 infection during a 16-week period. Nasopharyngeal aspirate and non-respiratory samples (blood, stool and urine) were collected at presentation, and serial nasopharyngeal flocked swabs (NPFS) and tracheal aspirates (TA) were collected after initiating oseltamivir treatment for quantitative viral RNA assay, using real-time reverse transcriptase-PCR. Serial plasma samples were collected for cytokine/chemokine assay using cytometric bead array. Patients with severe pneumonia (lung infiltrates and hypoxaemia) were compared to those with milder illnesses. RESULTS A total of 66 patients were studied (mean age 43 ±20 years); 28 (42%) developed severe pneumonia, of whom 10 (15%) required intubation. Severe pneumonia was associated with older age, dyspnoea, delayed presentation >2 days from onset, extrapulmonary virus detection (13-28%) and higher viral concentration despite late-presentation (multiple linear regression, β=0.94, 95% confidence interval 0.15-1.74; P=0.02). Patients with severe pneumonia exhibited slow viral clearance with oseltamivir treatment, particularly in the lower respiratory tract (median [interquartile range] durations of RNA positivity after antiviral initiation were NPFS 6.0 days [3.0-8.0], TA 11.0 days [7.8-14.3] versus milder illness group NPFS of 2.0 days [1.0-3.0] days; P<0.01). High viral load in lower respiratory tract despite upper-tract RNA negativity and viral rebound after stopping treatment were noted in some patients. H275Y mutation was absent. High plasma levels of interleukin (IL)-6, CXCL-8 (IL-8), CCL2 (monocyte chemoattractant protein-1) and soluble tumour necrosis factor receptor-1 were observed, which correlated with the extent and progression of pneumonia in hospital. CONCLUSIONS In severe 2009 H1N1 pneumonia, viral clearance is slow with treatment, particularly in the lower respiratory tract. A more sustained antiviral regime appears warranted.

Effect of early pulmonary rehabilitation on health care utilization and health status in patients hospitalized with acute exacerbations of COPD.

Background and objective:  Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) incur heavy utilization of health‐care resources for patients who require hospitalization. We evaluated whether an early outpatient pulmonary rehabilitation programme (PRP) after hospitalization for AECOPD could reduce acute health‐care utilization over the succeeding year.

Adjunctive therapies and immunomodulatory agents in the management of severe influenza

Abstract In addition to neuraminidase inhibitors and other drugs that directly target viral replication, a number of adjunctive and immunomodulatory therapies are currently under evaluation for the treatment of influenza. These novel treatments, which focus either on pathophysiological aspects of influenza virus infection or the neutralization of virus with antibodies, are the subject of this review. Cytokine dysregulation has been observed in patients with severe influenza, such as avian influenza A (H5N1) and pandemic 2009 influenza A (H1N1pdm09) virus infections, but the role of immunomodulatory therapy is unclear, due to lack of data from randomized controlled trials (RCTs). Convalescent plasma appears to be useful as an adjunctive therapy for the treatment of H5N1 and H1N1pdm09 infections. Until lately, data interpretation was limited to case reports and studies of non-randomized design, but a recent RCT found that patients with severe influenza A (H1N1pdm09) who were treated with hyperimmune immunoglobulin from persons who had survived the same disease had a lower peak viral load and lower mortality than controls, providing treatment was begun within 5days of symptom onset. The efficacy of agents with potential immunomodulating effects, including intravenous immunoglobulin, N-acetylcysteine, acute use of statins, macrolides, peroxisome proliferator-activated receptors agonists, celecoxib and mesalazine, and the role of plasmapheresis and hemoperfusion as rescue therapy, deserve more investigation and where feasible, studies by RCTs. Prospective observational studies have shown that systemic corticosteroids increase morbidity (e.g., secondary infections) and mortality in H1N1pdm09 influenza. This article forms part of a symposium in Antiviral Research on “Treatment of influenza: targeting the virus or the host.”

Measurement of tumor necrosis factor-α, leukotriene B4, and interleukin 8 in the exhaled breath condensate in patients with acute exacerbations of chronic obstructive pulmonary disease

Background Assessment of airway inflammation in the clinical course of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) may advance our understanding of the pathogenesis and treatment. Objectives To assess airway inflammation in patients during the course of AECOPD by serial analyses of their exhaled breath condensates (EBC). Methods Twenty-six patients with AECOPD (22 males, mean[SD] percentage predicted forced expiratory volume in one second (FEV1) 44.8 [14.3]), 11 with stable COPD, and 14 age and sex-matched healthy controls were studied. Patients with AECOPD were treated with systemic steroid and antibiotic for 7 days. EBC was collected from each patient with AECOPD on Day 5, 14, 30, and 60 post-hospitalization using EcoScreen (VIASYS Healthcare, USA) during tidal breathing over 10 minutes. Concentrations of tumor necrosis factor-α (TNF-α), leukotriene B4 (LTB4), and interleukin-8 (IL-8) were measured by enzyme-linked immunosorbent assay. Results The median (IQR) of TNF-α level on Day 5 was 5.08 (3.80–6.32) pg/ml, which was lower than on Day 14 (5.84 [4.91–9.14] pg/ml, p = 0.017), Day 30 (6.14 [3.82–7.67] pg/ml, p = 0.045), and Day 60 (5.60 [4.53–8.80] pg/ml, p = 0.009). On Day 60, subjects receiving inhaled corticosteroid (ICS) had a lower level of TNF-α than those who were not (4.82 [4.06–5.65] vs 7.66 [5.48–10.9] pg/ml, p = 0.02). EBC LTB4 level did not change significantly during recovery from AECOPD whereas IL-8 was mostly undetectable. Conclusions EBC TNF-α level was low in patients receiving systemic steroid and antibiotic therapy for AECOPD. These findings suggest a potential role for serial EBC TNF-α for non-invasive monitoring of disease activity.

Dexamethasone in community-acquired pneumonia.

Sabine Meijvis and colleagues (June 11, p 2023) investigated the role of adjuvant dexamethasone in community-acquired pneumonia. The primary outcome was median length of hospital stay, which was reported to be signifi cantly shorter in the dexamethasone group (6·5 days) than in the placebo group (7·5 days). However, Meijvis and col leagues do not show clinical or radiological cure rates with or without adjuvant dexamethasone therapy. In light of the poor clinical effi cacy of steroids for pneumonia in previous studies, a median diff erence of 1 day in length of hospital stay could easily be attributed to confounders such as variations in clinician behaviour and family assess ment of a patient’s readiness for discharge. Meijvis and colleagues should also have provided some absolute measures of treatment eff ect. We calculated the absolute risk reduction and number needed to treat to benefi t, along with 95% CIs, for the outcome of hospital admission (webappendix). Data were derived from fi gure 2 of the published study. We found that the absolute risk of remaining in hospital was 15% and 12% lower in the dexamethasone group than in the placebo group at days 8 and 12, respectively. Furthermore, we found that seven and eight patients with communityacquired pneumonia would need to be treated with adjuvant dexamethasone therapy (versus placebo) to result in early discharge of one additional patient on days 8 and 12 of hospital admission, respectively. Notably, a signifi cantly higher rate of hyperglycaemia was shown in the dexamethasone group (43%) than in the placebo group (23%; p<0·0001). Again for ease of clinical interpretation, we calculated the number needed to treat to harm, and it was 5 (95% CI 3–9). This fi nding indicates that, for every fi ve patients treated with dexamethasone (versus placebo), one additional patient would have hyperglycaemia. Overall, in terms of risk–benefi t assessment, the estimated ratio between the number needed to harm and number needed to benefi t (5/7 or 5/8) of less than unity does not fully support Meijvis and colleagues’ claims of clinical meaningfulness of adjuvant dexamethasone therapy in community-acquired pneumonia.

Advancements in the battle against severe acute respiratory syndrome.

Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease with a significant morbidity and mortality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache and dyspnoea. Respiratory failure is the major complication of SARS and ∼ 20% of patients may progress to acute respiratory distress syndrome requiring invasive mechanical ventilatory support. However, the severity is much milder in infected young children. Treatment of SARS was empirical in 2003 due to our limited understanding of this new disease. Protease inhibitors (lopinavir/ritonavir) in combination with ribavirin may play a role as antiviral therapy in the early phase, whereas the role of IFN and systemic steroid in preventing immune-mediated lung injury deserves further investigation. Knowledge of the genomic sequence of the SARS coronavirus has facilitated the development of rapid diagnostic tests. In addition, other antiviral treatment, RNA interference, monoclonal antibody, synthetic peptides, and vaccines are being developed. This paper provides a review of the epidemiology, clinical features and possible treatment strategies of SARS.

Development and validation of a clinical risk score for predicting drug-resistant bacterial pneumonia in older Chinese patients.

Health care‐associated pneumonia (HCAP) and drug‐resistant bacterial pneumonia may not share identical risk factors. We have shown that bronchiectasis, recent hospitalization and severe pneumonia (confusion, blood urea level, respiratory rate, low blood pressure and 65 year old (CURB‐65) score ≥3) were independent predictors of pneumonia caused by potentially drug‐resistant (PDR) pathogens. This study aimed to develop and validate a clinical risk score for predicting drug‐resistant bacterial pneumonia in older patients.

Exhaled air dispersion during coughing with and without wearing a surgical or N95 mask.

Objectives We compared the expelled air dispersion distances during coughing from a human patient simulator (HPS) lying at 45° with and without wearing a surgical mask or N95 mask in a negative pressure isolation room. Methods Airflow was marked with intrapulmonary smoke. Coughing bouts were generated by short bursts of oxygen flow at 650, 320, and 220L/min to simulate normal, mild and poor coughing efforts, respectively. The coughing jet was revealed by laser light-sheet and images were captured by high definition video. Smoke concentration in the plume was estimated from the light scattered by smoke particles. Significant exposure was arbitrarily defined where there was ≥ 20% of normalized smoke concentration. Results During normal cough, expelled air dispersion distances were 68, 30 and 15 cm along the median sagittal plane when the HPS wore no mask, a surgical mask and a N95 mask, respectively. In moderate lung injury, the corresponding air dispersion distances for mild coughing efforts were reduced to 55, 27 and 14 cm, respectively, p < 0.001. The distances were reduced to 30, 24 and 12 cm, respectively during poor coughing effort as in severe lung injury. Lateral dispersion distances during normal cough were 0, 28 and 15 cm when the HPS wore no mask, a surgical mask and a N95 mask, respectively. Conclusions Normal cough produced a turbulent jet about 0.7 m towards the end of the bed from the recumbent subject. N95 mask was more effective than surgical mask in preventing expelled air leakage during coughing but there was still significant sideway leakage.