The impact of immunosuppressive therapy on secondary infections and antimicrobial use in COVID-19 inpatients: a retrospective cohort study.

BACKGROUND: Immunosuppressive therapies have become a cornerstone of the management of severe COVID-19. The impact of these therapies on secondary infections and antimicrobial prescribing remains unclear. We sought to assess antimicrobial use and the incidence of bacterial and fungal infections in patients with severe COVID-19, and to explore their associations with receipt of immunosuppressive therapies. METHODS: Our retrospective cohort study included 715 hospitalised, adult patients with severe COVID-19 admitted to St George's Hospital, London, UK, during the first UK pandemic wave (1st March-10th June 2020). Co-infections (occurring within 48 h of admission) and secondary infections (≥ 48 h) were defined as a positive microbiological culture with supporting clinical, radiological or laboratory data to suggest true infection. Cox regression models with time-dependent covariates were used to explore the association between immunosuppressant use and secondary infection. RESULTS: Microbiologically confirmed co-infection occurred in 4.2% (n = 30) and secondary infection in 9.3% (n = 66) of the cohort (n = 715) and were associated with in-hospital mortality (48% vs 35%, OR 1.8, 95%CI 1.1-2.7, p = 0.01). Respiratory (n = 41, 39%) and bloodstream infections (n = 38, 36%) predominated, with primarily Gram-negative pathogens. 606 (84.7%) patients received an antimicrobial, amounting to 742 days of therapy per 1000 patient-days (DOTs). In multivariable models, receipt of high-dose steroids (≥ 30 mg prednisolone or equivalent) or tocilizumab was significantly associated with increased antimicrobial consumption (+ 5.5 DOTs, 95%CI 3.4-7.7 days) but not secondary infection (HR 0.56, 95%CI 0.26-1.18). CONCLUSIONS: Bacterial and fungal infections in severe COVID-19 were uncommon. Receipt of steroids or tocilizumab was independently associated with antimicrobial consumption despite its lack of association with secondary infection. These findings should galvanise efforts to promote antimicrobial stewardship in patients with COVID-19.

Increased risk of death in COVID-19 hospital admissions during the second wave as compared to the first epidemic wave: a prospective, single-centre cohort study in London, UK.

BACKGROUND: The second coronavirus disease (COVID-19) epidemic wave in the UK progressed aggressively and was characterised by the emergence and circulation of variant of concern alpha (VOC 202012/01). The impact of this variant on in-hospital COVID-19-specific mortality has not been widely studied. We aimed to compare mortality, clinical characteristics, and management of COVID-19 patients across epidemic waves to better understand the progression of the epidemic at a hospital level and support resource planning. METHODS: We conducted an analytical, dynamic cohort study in a large hospital in South London. We included all adults (≥ 18 years) with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who required hospital admission to COVID-19-specific wards between January 2020 and March 2021 (n = 2701). Outcome was COVID-19-specific in-hospital mortality ascertained through Medical Certificate Cause of Death. RESULTS: In the second wave, the number of COVID-19 admissions doubled, and the crude mortality rate dropped 25% (1.66 versus 2.23 per 100 person-days in second and first wave, respectively). After accounting for age, sex, dexamethasone, oxygen requirements, symptoms at admission and Charlson Comorbidity Index, mortality hazard ratio associated with COVID-19 admissions was 1.62 (95% CI 1.26, 2.08) times higher in the second wave. CONCLUSIONS: Although crude mortality rates dropped during the second wave, the multivariable analysis suggests a higher underlying risk of death for COVID-19 admissions in the second wave. These findings are ecologically correlated with an increased circulation of SARS-CoV-2 variant of concern 202012/1 (alpha). Availability of improved management, particularly dexamethasone, was important in reducing risk of death.

Does Sildenafil produce a sustained benefit in patients with pulmonary hypertension associated with parenchymal lung and cardiac disease?

BACKGROUND: Sildenafil may be of benefit for selected patients with pulmonary hypertension associated with parenchymal lung and cardiac diseases. However the medium term benefits of this treatment for such patients is unclear. PATIENTS AND METHODS: 16 consecutive patients with secondary pulmonary hypertension who had been on maximal appropriate therapy received Sildenafil 50 mg tds following assessment which included right heart catheter, 2D echocardiography and six minute walk test. Right heart catheterisation, 2D echocardiography and six minute walk test were performed after eight weeks treatment, at 12 months and at six monthly intervals thereafter. Baseline medications were continued. RESULTS: 16 patients with pulmonary hypertension associated with inoperable chronic pulmonary thromboembolism (6 patients), valvular heart disease (4), chronic obstructive pulmonary disease (3), idiopathic pulmonary fibrosis (2), and obstructive sleep apnoea (1) were studied. The age range was 42 to 81 (median 68) years and the period of follow up was 12 to 51 (median 22) months. Six minute walk increased significantly, p=0.002, from baseline to long term follow up. The improvement in 14 patients ranged from 14 m to 300 m with a percentage increase of 5% to 567% increase. In one patient there was no change and in one patient the six minute walk test fell as a consequence of progression of known arthritis. The mean pulmonary artery pressure was significantly reduced at long term follow up (p=0008). The pulmonary vascular resistance (PVR) fell in eleven patients, this reduction ranged from 0.2 woods units to 8.7 woods units (mean reduction 3.3 woods units). The percentage reduction in PVR ranged from 7% to 71% with a mean reduction of 43%. In five patients the pulmonary vascular resistance increased. 2D echocardiography showed a sustained improvement in right ventricular function in 11 patients. There were no deaths during follow up. CONCLUSION: Sildenafil may have a role for selected patients with pulmonary hypertension associated with cardiac and pulmonary diseases. The medication seems well tolerated and for some patients is effective within 8 weeks and results in a sustained long term improvement in haemodynamics and exercise capacity.

Anti-IgE (omalizumab) inhibits late-phase reactions and inflammatory cells after repeat skin allergen challenge.

BACKGROUND: Anti-IgE (omalizumab) inhibited early and late asthmatic reactions and infiltration of inflammatory cells in asthmatic bronchial biopsies at baseline. The effect of chronic allergen exposure on these outcomes is unknown. Repeat allergen challenge in human skin represents a suitable model to address this question. OBJECTIVE: To study the effect of anti-IgE (omalizumab) on early-phase (EPR) and late-phase (LPR) skin reactions and cellular infiltration by using a repeat skin allergen challenge designed to imitate chronic allergen exposure. METHODS: Twenty-four atopic allergic volunteers received omalizumab or placebo for 12 weeks. Paired intradermal challenges of allergen (30 biological units) and diluent control were administered on 9 occasions at 2-week intervals. Early-phase and late-phase skin reactions and cellular infiltration in skin biopsies (using immunohistochemistry and in situ hybridization) were measured at intervals. RESULTS: Compared with placebo, omalizumab-treated patients had a progressive reduction in the LPR that was significantly greater than its effect on the EPR (median, --63% vs--24% respectively; P=.009). In addition, significant reduction of the LPR was reached within 2 weeks of commencing treatment, compared with 8 weeks for the EPR. There was a priming effect of repeated allergen challenge on infiltration of eosinophil, neutrophil, T(H)2 (CD3(+)/IL-4(+)), and total FcepsilonRI(+) cells in patients on placebo that was abrogated in those receiving omalizumab. CONCLUSION: The more marked effect of omalizumab on the LPR and prevention of the repeat-dose priming effect on several inflammatory cell types support a role for anti-IgE treatment in conditions associated with chronic allergic inflammation.

Early haemodynamic benefit of sildenafil in patients with coexisting chronic thromboembolic pulmonary hypertension and left ventricular dysfunction.

Sildenafil, a phosphodiesterase type-5 inhibitor, offers potential to treat pulmonary hypertension associated with a variety of conditions. We assessed the early impact of sildenafil on a cohort of patients referred to our unit who had severe pulmonary hypertension secondary to chronic thromboembolic disease which was not amenable to pulmonary thromboendarterectomy and who also had coexisting left ventricular dysfunction. Six patients were studied. Diagnosis of pulmonary embolic disease was made by ventilation perfusion scanning and/or CT pulmonary angiography. All patients were anticoagulated with oral coumarin derivatives and none were considered suitable for pulmonary thromboendarterectomy. Pulmonary hypertension was diagnosed by right heart catheterisation and each patient had Medical Research Council (MRC) dyspnoea score and New York Heart Association (NYHA) class noted and 2D echocardiography prior to commencement of sildenafil 50 mg three times a day. After 6 weeks of sildenafil therapy, right heart catheterisation and 2D echocardiography were repeated, and MRC dyspnoea score, NYHA class and exercise capacity were recorded. All patients demonstrated an improvement in mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, MRC dyspnoea score, NYHA class and gas transfer. No adverse effects of sildenafil were noted. Our data suggests that sildenafil is an effective and well-tolerated therapy for patients with severe pulmonary hypertension associated with pulmonary thromboembolic disease and impaired left ventricular function, producing beneficial effects as early as 6 weeks.

Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin.

Anti-IL-5 monoclonal antibody (mepolizumab) reduces baseline bronchial mucosal eosinophils and deposition of extracellular matrix proteins in the reticular basement membrane in mild asthma. Here we report the effect of anti-IL-5, in the same patients, on allergen-induced eosinophil accumulation, tenascin deposition (as a marker of repair and remodelling) and the magnitude of the late-phase allergic cutaneous reaction. Skin biopsies were performed in 24 atopic subjects at allergen- and diluent-injected sites before 6 and 48 h after, three infusions of a humanized, monoclonal antibody against IL-5 (mepolizumab) using a randomized double-blind, placebo-controlled design. Anti-IL-5 significantly inhibited eosinophil infiltration in 6 h and 48 h skin biopsies as well as the numbers of tenascin immunoreactive cells at 48 h. In contrast, anti-IL-5 had no significant effect on the size of the 6 or 48 h late-phase cutaneous allergic reaction. This study (a) suggests that eosinophils are unlikely to cause the redness, swelling, and induration characteristic of the peak (6 h) late-phase cutaneous allergic reaction and (b) shows that decreases in tenascin positive cells at 48 h correlates with reduction of eosinophils, so providing further evidence of involvement in remodelling processes associated with allergic inflammation.

The relationship between allergen-induced tissue eosinophilia and markers of repair and remodeling in human atopic skin.

Several in vitro studies suggest that eosinophils may play a role in fibrosis, remodeling, and repair processes associated with IgE-mediated hypersensitivity. However, the relationship in vivo, between allergen-induced tissue eosinophilia and markers of repair has yet to be established in human atopic subjects. Using the allergen-induced cutaneous late-phase reaction as a model of allergic inflammation, we have tested the hypothesis that eosinophil-derived TGF-beta1 and IL-13 are temporarily associated with myofibroblast formation and deposition of tenascin and procollagen I. Biopsies were taken from atopic volunteers at 1, 3, 6, 24, 48, and 72 h after intradermal allergen challenge and were examined by immunohistochemistry. Following the peak of the late-phase reaction (6 h) there were persisting TGF-beta1(+) eosinophils, alpha-smooth muscle actin(+) myofibroblasts, tenascin immunoreactivity, and procollagen-I(+) cells 24-48 h postchallenge. Direct evidence of generation of repair markers was obtained by coculture of eosinophils and fibroblasts. This resulted in alpha-smooth muscle actin immunoreactivity that was inhibitable by neutralizing Abs to TGF-beta as well as production of tenascin transcripts and protein product. TGF-beta1 and IL-13 also induced tenascin expression. We conclude that TGF-beta1 and IL-13, provided partially by eosinophils, contribute to repair and remodeling events in allergic inflammation in human atopic skin.