Real-world effectiveness of steroids in severe COVID-19: a retrospective cohort study.

INTRODUCTION: Randomised controlled trials have shown that steroids reduce the risk of dying in patients with severe Coronavirus disease 2019 (COVID-19), whilst many real-world studies have failed to replicate this result. We aim to investigate real-world effectiveness of steroids in severe COVID-19. METHODS: Clinical, demographic, and viral genome data extracted from electronic patient record (EPR) was analysed from all SARS-CoV-2 RNA positive patients admitted with severe COVID-19, defined by hypoxia at presentation, between March 13th 2020 and May 27th 2021. Steroid treatment was measured by the number of prescription-days with dexamethasone, hydrocortisone, prednisolone or methylprednisolone. The association between steroid > 3 days treatment and disease outcome was explored using multivariable cox proportional hazards models with adjustment for confounders (including age, gender, ethnicity, co-morbidities and SARS-CoV-2 variant). The outcome was in-hospital mortality. RESULTS: 1100 severe COVID-19 cases were identified having crude hospital mortality of 15.3%. 793/1100 (72.1%) individuals were treated with steroids and 513/1100 (46.6%) received steroid ≤ 3 days. From the multivariate model, steroid > 3 days was associated with decreased hazard of in-hospital mortality (HR: 0.47 (95% CI: 0.31-0.72)). CONCLUSION: The protective effect of steroid treatment for severe COVID-19 reported in randomised clinical trials was replicated in this retrospective study of a large real-world cohort.

Clinical features and management of human monkeypox: a retrospective observational study in the UK.

BACKGROUND: Cases of human monkeypox are rarely seen outside of west and central Africa. There are few data regarding viral kinetics or the duration of viral shedding and no licensed treatments. Two oral drugs, brincidofovir and tecovirimat, have been approved for treatment of smallpox and have demonstrated efficacy against monkeypox in animals. Our aim was to describe the longitudinal clinical course of monkeypox in a high-income setting, coupled with viral dynamics, and any adverse events related to novel antiviral therapies. METHODS: In this retrospective observational study, we report the clinical features, longitudinal virological findings, and response to off-label antivirals in seven patients with monkeypox who were diagnosed in the UK between 2018 and 2021, identified through retrospective case-note review. This study included all patients who were managed in dedicated high consequence infectious diseases (HCID) centres in Liverpool, London, and Newcastle, coordinated via a national HCID network. FINDINGS: We reviewed all cases since the inception of the HCID (airborne) network between Aug 15, 2018, and Sept 10, 2021, identifying seven patients. Of the seven patients, four were men and three were women. Three acquired monkeypox in the UK: one patient was a health-care worker who acquired the virus nosocomially, and one patient who acquired the virus abroad transmitted it to an adult and child within their household cluster. Notable disease features included viraemia, prolonged monkeypox virus DNA detection in upper respiratory tract swabs, reactive low mood, and one patient had a monkeypox virus PCR-positive deep tissue abscess. Five patients spent more than 3 weeks (range 22-39 days) in isolation due to prolonged PCR positivity. Three patients were treated with brincidofovir (200 mg once a week orally), all of whom developed elevated liver enzymes resulting in cessation of therapy. One patient was treated with tecovirimat (600 mg twice daily for 2 weeks orally), experienced no adverse effects, and had a shorter duration of viral shedding and illness (10 days hospitalisation) compared with the other six patients. One patient experienced a mild relapse 6 weeks after hospital discharge. INTERPRETATION: Human monkeypox poses unique challenges, even to well resourced health-care systems with HCID networks. Prolonged upper respiratory tract viral DNA shedding after skin lesion resolution challenged current infection prevention and control guidance. There is an urgent need for prospective studies of antivirals for this disease. FUNDING: None.

Mandatory reporting and improvements in diagnosing Clostridium difficile infection: an incompatible dichotomy?

Toxin enzyme immunoassays (EIAs) are inadequate for the diagnosis of Clostridium difficile infection (CDI) when used alone. In September 2010 we replaced toxin EIA with a two-step algorithm, testing first with glutamate dehydrogenase and confirming with polymerase chain reaction for toxin B gene. We compared this to the gold standard of toxigenic culture, observing a positive predictive value of 96% (laboratory prevalence of 4.7%). There was no deterioration in turnaround time but there was a decrease of 11% in repeat specimens sent from the same patients. The improved performance of the algorithm increased the laboratory positivity rate from 2.2% to 5.6%. This led to an increase in our Trust CDI rate reported under the Health Protection Agency's mandatory surveillance scheme. We investigated whether the change was due to increasing nosocomial transmission, environmental contamination or consumption of antimicrobials, but found no evidence of this. We conclude that it probably resulted from the change in testing algorithm. Although we have improved testing and enhanced patient safety, we are likely to be unfairly financially penalised because of our apparent (but not real) increase in CDI rates. Assessment of CDI rates should take testing methodology into account and national policies should be revised to reflect this.

Multinucleate giant cells release functionally unopposed matrix metalloproteinase-9 in vitro and in vivo.

Multinucleated giant cells (MGCs) are characteristic of granulomatous inflammation. Matrix metalloproteinase (MMP)-9, the major monocyte-derived matrix metalloproteinase, is key in inflammatory tissue damage. At 72 h, MGCs secrete 153 +/- 2.5 ng/mL MMP-9, compared with 115 +/- 3.8 ng/mL during macrophage differentiation (P<.05). In contrast, the level of MGC secretion-specific tissue inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1, is lower (P<.05). Mature MGCs secrete constitutively greater concentrations of MMP-9 than do monocytes or macrophages (P<.05). MGCs in tuberculous lymph-node biopsy samples express high MMP-9 levels adjacent to areas of necrosis, whereas TIMP-1 is not detected. Thus, MGCs are potentially important sources of MMP-9 secretion and may contribute to inflammatory tissue damage in human tuberculosis.

Unopposed matrix metalloproteinase-9 expression in human tuberculous granuloma and the role of TNF-alpha-dependent monocyte networks.

Tuberculosis is characterized by granuloma formation and caseous necrosis, but the factors causing tissue destruction are poorly understood. Matrix metalloproteinase (MMP)-9 (92-kDa gelatinase) secretion from monocytes is stimulated by Mycobacterium tuberculosis (M. tb) and associated with local tissue injury in tuberculosis patients. We demonstrate strong immunohistochemical MMP-9 staining in monocytic cells at the center of granuloma and adjacent to caseous necrosis in M. tb-infected patient lymph nodes. Minimal tissue inhibitor of MMPs-1 staining indicated that MMP-9 activity is unopposed. Because granulomas characteristically contain few mycobacteria, we investigated whether monocyte-monocyte cytokine networks amplify MMP-9 secretion. Conditioned medium from M. tb-infected primary human monocytes or THP-1 cells (CoMTB) stimulated MMP-9 gene expression and a >10-fold increase in MMP-9 secretion by monocytes at 3-4 days (p < 0.009, vs controls). Although CoMTB stimulated dose-dependent MMP-9 secretion, MMP-1 (52-kDa collagenase) was not induced. Anti-TNF-alpha Ab but not IL-1R antagonist pretreatment decreased CoMTB-induced MMP-9 secretion by 50% (p = 0.0001). Anti-TNF-alpha Ab also inhibited MMP-9 secretion from monocytic cells by 50%, 24 h after direct M. tb infection (p = 0.0002). Conversely, TNF-alpha directly stimulated dose-dependent MMP-9 secretion. Pertussis toxin inhibited CoMTB-induced MMP-9 secretion and enhanced the inhibitory effect of anti-TNF-alpha Ab (p = 0.05). Although chemokines bind to G protein-linked receptors, CXCL8, CXCL10, CCL2, and CCL5 did not stimulate monocyte MMP-9 secretion. However, the response to cholera toxin confirmed that G protein signaling pathways were intact. In summary, MMP-9 within tuberculous granuloma is associated with tissue destruction, and TNF-alpha, critical for antimycobacterial granuloma formation, is a key autocrine and paracrine regulator of MMP-9 secretion.