Hospital mortality and resource implications of hospitalisation with COVID-19 in London, UK: a prospective cohort study

Background. Coronavirus disease 2019 (COVID-19) had a significant impact on the National Health Service in the United Kingdom (UK), with over 35 000 cases reported in London by July 30, 2020. Detailed hospital-level information on patient characteristics, outcomes, and capacity strain is currently scarce but would guide clinical decision-making and inform prioritisation and planning. Methods. We aimed to determine factors associated with hospital mortality and describe hospital and ICU strain by conducting a prospective cohort study at a tertiary academic centre in London, UK. We included adult patients admitted to the hospital with laboratory-confirmed COVID-19 and followed them up until hospital discharge or 30 days. Baseline factors that are associated with hospital mortality were identified via semiparametric and parametric survival analyses. Results. Our study included 429 patients: 18% of them were admitted to the ICU, 52% met criteria for ICU outreach team activation, and 61% had treatment limitations placed during their admission. Hospital mortality was 26% and ICU mortality was 34%. Hospital mortality was independently associated with increasing age, male sex, history of chronic kidney disease, increasing baseline C-reactive protein level, and dyspnoea at presentation. COVID-19 resulted in substantial ICU and hospital strain, with up to 9 daily ICU admissions and 41 daily hospital admissions, to a peak census of 80 infected patients admitted in the ICU and 250 in the hospital. Management of such a surge required extensive reorganisation of critical care services with expansion of ICU capacity from 69 to 129 beds, redeployment of staff from other hospital areas, and coordinated hospital-level effort. Conclusions. COVID-19 is associated with a high burden of mortality for patients treated on the ward and the ICU and required substantial reconfiguration of critical care services. This has significant implications for planning and resource utilisation

Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to Streptococcus pneumoniae.

Both intracellular immune sensing and extracellular innate immune sensing have been implicated in initiating macrophage proinflammatory cytokine responses to Streptococcus pneumoniae The S. pneumoniae capsule, a major virulence determinant, prevents phagocytosis, and we hypothesized that this would reduce activation of host innate inflammatory responses by preventing activation of intracellular proinflammatory signaling pathways. We investigated this hypothesis in human monocyte-derived macrophages stimulated with encapsulated or isogenic unencapsulated mutant S. pneumoniae Unexpectedly, despite strongly inhibiting bacterial internalization, the capsule resulted in enhanced inflammatory cytokine production by macrophages infected with S. pneumoniae Experiments using purified capsule material and a Streptococcus mitis mutant expressing an S. pneumoniae serotype 4 capsule indicated these differences required whole bacteria and were not due to proinflammatory effects of the capsule itself. Transcriptional profiling demonstrated relatively few differences in macrophage gene expression profiles between infections with encapsulated S. pneumoniae and those with unencapsulated S. pneumoniae, largely limited to reduced expression of proinflammatory genes in response to unencapsulated bacteria, predicted to be due to reduced activation of the NF-κB family of transcription factors. Blocking S. pneumoniae internalization using cytochalasin D had minimal effects on the inflammatory response to S. pneumoniae Experiments using murine macrophages indicated that the affected genes were dependent on Toll-like receptor 2 (TLR2) activation, although not through direct stimulation of TLR2 by capsule polysaccharide. Our data demonstrate that the early macrophage proinflammatory response to S. pneumoniae is mainly dependent on extracellular bacteria and reveal an unexpected proinflammatory effect of encapsulated S. pneumoniae that could contribute to disease pathogenesis.IMPORTANCE Multiple extra- and intracellular innate immune receptors have been identified that recognize Streptococcus pneumoniae, but the relative contributions of intra- versus extracellular bacteria to the inflammatory response were unknown. We have shown that intracellular S. pneumoniae contributes surprisingly little to the inflammatory responses, with production of important proinflammatory cytokines largely dependent on extracellular bacteria. Furthermore, although we expected the S. pneumoniae polysaccharide capsule to block activation of the host immune system by reducing bacterial internalization and therefore activation of intracellular innate immune receptors, there was an increased inflammatory response to encapsulated compared to unencapsulated bacteria, which is likely to contribute to disease pathogenesis.This work was supported by grants from the Medical Research Council, UK: MR/K00168X/1 (to J.P.), G0700569 (to T.P.), G0600410 (to E.C.), and G0801211 (to G.T.) and Wellcome Trust grant WT076442 (to S.C.). C.H. received support from the Astor Foundation and GlaxoSmithKline through the University College London MBChB program. This work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centre’s funding scheme

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

Abstract: The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

Abstract: The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients

Pneumonia

Pneumonia is a common lung infection that causes significant mortality and morbidity worldwide, particularly in children and elderly individuals. The diagnosis is confirmed by radiographic evidence of new consolidation. Pneumonia can be caused by a variety of microorganisms, with the dominant pathogens varying across the globe and between community- or hospital-acquired infections. Bacterial causes are usually acquired by microaspiration of organisms colonizing the nasopharynx. Microbes reaching the distal airways and alveoli induce local and systemic inflammatory responses and can disseminate beyond the lung. Although most cases of pneumonia occur in the community, a significant subset develop in hospital, often caused by multidrug-resistant bacteria, which are associated with higher mortality. Microbiological investigations are required to identify the pathogenic organism but lack sensitivity. Severity scoring systems can be used to predict outcome and identify patients who can be safely managed in outpatient settings. The mainstay of treatment is early antibiotics and, if appropriate, supportive therapies such as oxygen and intravenous fluids. Large vaccination programmes have proven effective in reducing the incidence of some of the causative organisms; however, the overall incidence of pneumonia remains high, and further research is required to improve care in at-risk groups such as the elderly

Opportunistic bacterial, viral and fungal infections of the lung

Respiratory opportunistic infections are a major cause of morbidity and mortality in severely immunocompromised patients, such as those treated with biological therapies, chemotherapy and solid organ or stem cell transplants, and those with haematological malignancy, aplastic anaemia or HIV infection. The type and degree of immune defect dictates the profile of potential opportunistic pathogens; T-cell-mediated defects increase the risk of viral (cytomegalovirus, respiratory viruses) and Pneumocystis jirovecii infections, whereas neutrophil defects are associated with bacterial pneumonia and invasive aspergillosis. However, patients often have combinations of immune defects, and a wide range of other opportunistic infections can cause pneumonia. Importantly, conventional non-opportunistic pathogens are also frequently encountered in immunocompromised hosts and should not be overlooked. The radiological pattern of disease (best assessed by computed tomography) and speed of onset help identify the likely pathogen(s); this can then be supported by targeted investigation including early use of bronchoscopy in selected patients. Rapid and expert clinical assessment can help identify the most likely pathogens, allowing timely appropriate therapy

Pulmonary immune response to Streptococcus pneumoniae

Streptococcus pneumoniae is a common cause of respiratory infection associated with significant morbidity and mortality. The immune response to S. pneumoniae is complex, multi-layered and incompletely understood. The lung has non-specific defence mechanisms that include cellular and secreted components. The initial response to bacteria that adhere to or breach the epithelium is mediated by the innate immune system and recognition of non-specific motifs common to many pathogens. This stimulates the inflammatory response and subsequently the development of the more specific adaptive immune system. Better understanding of the immune response to S. pneumoniae will underpin future progress in both the prevention of infection and adjuvants to existing treatments