Lung ultrasound as a tool for monitoring the interstitial changes in recently hospitalised patients with COVID-19 pneumonia - The COVIDLUS study.

Background Long-term respiratory effects can occur after COVID-19 pneumonia (CP). The COVID Lung Ultrasound Study (COVIDLUS) aimed to investigate the utility of serial lung ultrasound (LUS) to track functional and physiological recovery after hospitalisation in patients with CP. Methods Between April 2021 and April 2022, 21 patients were recruited at discharge (D0). LUS was performed on D0, day 41 (D41) and day 83 (D83). CT Thorax was performed on D83. Lymphocyte count, Ferritin, Lactate Dehydrogenase, Troponin, CRP, and D-dimers were measured at D0, D41 and D83. 6 minute walking test (6MWT) was performed on D83 and quality of life questionnaires and spirometry completed on D41 and D83. Results 19 subjects completed the study (10 males [52%]; mean age: 52 years [range:37-74]). 1 patient died. LUS scores were significantly higher at D0, compared to D41 and D83 (Mean score:10.9 [D0]/2.8 [D41]/1.5 [D83]; p < 0.0001). LUS scores correlated poorly with CT at D83 (Pearson r2 = 0.28). Mean lymphocyte counts were lower at D0 but increased at D41 and D83. Mean serum Ferritin was significantly lower at D41 and D83, as compared to D0. The mean 6MWT distance was 385 m (130-540 m). Quality of life measures did not differ at D41 and D83. Lung function increased between D41 and D83 with mean increase in FEV1 and FVC of 160 ml and 190 ml respectively. Conclusion LUS can monitor the early recovery of lung interstitial changes from CP. The utility of LUS to predict development of subsequent lung fibrosis post-COVID deserves further study.

Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.

We previously reported that human CD4+ Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3). We now show that following stimulation by allergen, IL-10-secreting Tregs inhibit cytokine secretion by allergen-specific Th2 cells in an IL-10-dependent manner. A proportion of patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, and their asthma is characterized as glucocorticoid resistant (SR, abbreviation derived from "steroid resistant"). Dexamethasone does not enhance secretion of IL-10 by their CD4+ T cells. Addition of vitamin D3 with dexamethasone to cultures of SR CD4+ T cells enhanced IL-10 synthesis to levels observed in cells from glucocorticoid-sensitive patients cultured with dexamethasone alone. Furthermore, pretreatment with IL-10 fully restored IL-10 synthesis in these cells in response to dexamethasone. Vitamin D3 significantly overcame the inhibition of glucocorticoid-receptor expression by dexamethasone while IL-10 upregulated glucocorticoid-receptor expression by CD4+ T cells, suggesting potential mechanisms whereby these treatments may overcome poor glucocorticoid responsiveness. We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients.

A potential role for sildenafil in the management of pulmonary hypertension in patients with parenchymal lung disease.

BACKGROUND: Sildenafil offers potential to treat patients with pulmonary hypertension by selectively inhibiting phosphodiesterase type five pathways in the lung. It is recommended for selected patients with pulmonary arterial hypertension, but its role in the management of pulmonary hypertension associated with parenchymal lung disease is unclear. PATIENTS AND METHODS: Seven patients (68-86 years) with end stage chronic obstructive pulmonary disease (COPD, 4) and idiopathic pulmonary fibrosis (IPF, 3) were referred to our unit. All patients had a long-term history of chronic lung disease and were on maximal appropriate therapy prescribed by their referring pulmonologist. Thromboembolic disease was excluded by pulmonary angiography and all patients had had high resolution thoracic CT scan. At assessment right heart catheterisation, 2D echocardiography and 6-min walk test were performed prior to commencement of sildenafil 50mg tds. Their medication was otherwise unchanged. After 8 weeks treatment, right heart catheterisation, 2D echocardiography and 6-min walk test were repeated. RESULTS: The pulmonary vascular resistance was reduced in six patients (from 13, 3, 3, 6.5, 3.5 and 10.5 wood units to 9.7, 2.5, 2.8, 4.4, 2.5 and 5.4 wood units, respectively). Six-minute walk test increased in six patients (from 110 m, 210 m, 80 m, 30 m, 210 m and 80 m to 130 m, 312 m, 120 m, 82 m, 244 m and 100 m, respectively). One patient with COPD did not demonstrate a favourable response although their cardiac output increased on sildenafil therapy. 2D echocardiography showed a reduction in estimated PA pressure in six patients with an improvement in right ventricular systolic function in two COPD patients. CONCLUSION: Our results suggest that sildenafil may have a role for selected patients with COPD and IPF who have pulmonary hypertension.

Clinical and molecular aspects of glucocorticoid resistant asthma.

This paper is an overview of the diagnosis, differential diagnosis and cellular and molecular mechanisms of glucocorticoid resistant asthma. It addresses the clinical definition and rationale for the diagnosis of therapy resistant asthma. It purports that, since glucocorticoid resistant asthmatics are not globally physiologically glucocorticoid resistant, then the phenomenon is most likely acquired, probably in immune cells (and most probably in T cells and monocyte/macrophages), as a result of local inflammatory and environmental influences. The molecular mechanisms which have been uncovered to date which could account for glucocorticoid resistance are discussed, in particular the roles of AP-1 and p38 MAP kinase signaling, the role of the beta-isoform of the glucocorticoid receptor and the role of histone proteins and DNA folding. Finally, there are suggestions for clinical management of these patients based on accumulated evidence.

Do expandable metallic airway stents have a role in the management of patients with benign tracheobronchial disease?

BACKGROUND: With increasing availability many centers are deploying expandable metallic stents to manage patients with diverse endobronchial disorders. Although these devices have an important role in malignant disease their usefulness in benign large airway disorders is less defined. METHODS: Between 1997 and 2005, 31 patients aged 34 to 83 years with benign large airway compromise secondary to tracheomalacia (n = 7), posttracheostomy stricture (n = 8), posttracheostomy rupture (n = 2), postpneumonectomy bronchopleural fistula (n = 2), stricture after lung transplantation (n = 3), lobectomy, tuberculosis, traumatic injury to right main bronchus (n = 1 patient each), and external compression of the airway secondary to achalasia, multinodular goiter, aortic aneurysm, right brachiocephalic artery aneurysm, right interrupted aortic arch, and dissecting aneurysm (n = 1 patient each) who were medically unfit for formal surgical intervention were treated by Ultraflex stent deployment. The range of follow-up was 1 week to 96 months. Stents were deployed under anesthesia using rigid bronchoscopy. RESULTS: Complications included granulation tissue formation (n = 11) treated with Nd: YAG laser ablation, stent migration (n = 1; stent removed, another deployed), metal fatigue (n = 1), stent removal (n = 1), mucus plugging (n = 2), and halitosis (n = 6) difficult to treat despite antibiotics. Thirteen patients died of unrelated causes between 1 week and 15 months after stent deployment. CONCLUSIONS: Endobronchial metallic stents should be considered only for selected patients with large airway compromise secondary to benign airway diseases for whom other medical comorbidities contraindicate formal airway surgery. Once deployed, they are difficult to remove, are associated with significant complications, and require prospective bronchoscopic surveillance and often further therapeutic intervention.

Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients.

BACKGROUND: Overexpression of the transcriptional regulatory factor activator protein 1 might contribute to T-cell glucocorticoid (GC) refractoriness in GC-resistant asthma. OBJECTIVE: We sought to address the hypothesis that clinically GC-resistant asthma is accompanied by failure of systemic GCs to inhibit phosphorylation of c-jun and c-jun N-terminal kinase (JNK) in bronchial mucosal cells. METHODS: We performed enumeration of total (CD45+) leukocytes and cells expressing c-fos and total and phosphorylated c-jun and JNK in bronchial biopsy sections from 9 GC-sensitive and 17 GC-resistant asthmatic patients taken before and after oral prednisolone (40 mg/1.72 m(2) body surface area daily for 14 days) using specific antibodies, immunohistochemistry, and image analysis. RESULTS: At baseline, mean total (CD45+) mucosal leukocytes, total cells expressing phosphorylated c-jun and JNK, and mean percentages of cells in which these molecules were phosphorylated were similar in both groups, whereas mean total numbers of c-fos-immunoreactive cells were increased in the GC-resistant asthmatic subjects (P = .04). After prednisolone, the mean total cells expressing phosphorylated c-jun and JNK and the mean percentages of cells in which these molecules were phosphorylated were significantly reduced in the GC-sensitive (P < or = .02) but not the GC-resistant asthmatic subjects. Mean total CD45+ leukocytes and c-fos-immunoreactive cells were not significantly altered in either group. CONCLUSION: Clinical GC responsiveness in asthma is accompanied by reduced phosphorylation of bronchial mucosal c-jun and JNK, a phenomenon not seen in resistant patients. CLINICAL IMPLICATIONS: Dysregulation of activator protein 1 activation leading to clinical GC resistance might reflect identifiable environmental influences and is a target for future therapy.

Glucocorticoid-resistant asthma.

Glucocorticoids are currently the most effective anti-inflammatory therapy for asthma. However, a small subset of asthma sufferers do not respond to clinically relevant doses of glucocorticoids and are termed "glucocorticoid resistant." These patients are characterized by increased bronchial hyperreactivity, lower morning peak expiratory flow rates, and a longer total duration of symptoms. The definition of glucocorticoid resistance is arbitrary, and a dosage and duration of oral glucocorticoid therapy that represent a completely adequate therapeutic trial have yet to be established. For research purposes, glucocorticoid-resistant asthma is defined on the basis of a lack of improvement in airway obstruction (FEV1) following a 2-week course of oral glucocorticoid therapy. Glucocorticoid resistance is associated with in vivo and in vitro alterations in cellular responses to exogenous glucocorticoids. We have implicated abnormal regulation of the activator protein I in the molecular mechanism of glucocorticoid resistance, a phenomenon that may be confined to T cells and monocytes. The identification of an alternatively spliced isoform of the glucocorticoid receptor (GR beta) has sparked interest in the functional role of this isoform and its potential involvement in the pathology of glucocorticoid resistance. Alternative therapies for this condition will have to await a better understanding of the mechanisms of glucocorticoid action.