Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood. Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness. Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVID stable patients), patients with COVID-19 requiring ICU admission (COVID ICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAP ICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated. Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVID ICU patients could be clearly differentiated from COVID stable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAP ICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission ( P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution ( P < 0.0001). Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.

Background Multimorbidity, defined as the co-existence of two or more chronic conditions, presents significant challenges to patients, healthcare providers and health systems. Despite this, there is ongoing uncertainty about the most effective ways to manage patients with multimorbidity. This review updated and narrowed the focus of a previous Cochrane review and aimed to determine the effectiveness of interventions designed to improve outcomes in people with multimorbidity in primary care and community settings, compared to usual care. Methods We searched eight databases and two trials registers up to 9 September 2019. Two review authors independently screened potentially eligible titles and selected studies, extracted data, evaluated study quality and judged the certainty of the evidence (GRADE). Interventions were grouped by their predominant focus into care-coordination/self-management support, self-management support and medicines management. Main outcomes were health-related quality of life (HRQoL) and mental health. Meta-analyses were conducted, where possible, but the synthesis was predominantly narrative. Results We included 16 RCTs with 4753 participants, the majority being older adults with at least three conditions. There were eight care-coordination/self-management support studies, four self-management support studies and four medicines management studies. There was little or no evidence of an effect on primary outcomes of HRQoL (MD 0.03, 95% CI −0.01 to 0.07, I2 = 39%) and mental health or on secondary outcomes with a small number of studies reporting that care coordination may improve patient experience of care and self-management support may improve patient health behaviours. Overall, the certainty of the evidence was graded as low due to significant variation in study participants and interventions. Conclusions There are remaining uncertainties about the effectiveness of interventions for people with multimorbidity, despite the growing number of RCTs conducted in this area. Our findings suggest that future research should consider patient experience of care, optimising medicines management and targeted patient health behaviours such as exercise.

The 'Journal of Comorbidity' is changing its name to the 'Journal of Multimorbidity and Comorbidity'. This may seem redundant, as many see 'comorbidity' and 'multimorbidity' as interchangeable terms. We believe it is important to highlight the distinction given the differences in how healthcare systems view patients with multiple chronic conditions (MCCs), and the important differences that arise in research and intervention development for these patients.In 1970, Feinstein first coined the term 'comorbidity' to describe 'Any distinct additional entity that has existed or may occur during the clinical course of a patient who has the index disease under study'. 1 From 1976, 2,3 the term 'multimorbidity' was increasingly used by health researchers to describe patients with MCCs. Due to the growing ambiguity around the use of the terms comorbidity and multimorbidity, in 1996 van den Akker et al. suggested clear definitions for both terms. 4 They suggested that comorbidity be defined according to Feinstein's original definition and multimorbidity be defined as 'the cooccurrence of multiple chronic or acute diseases and medical conditions within one person'. 4 In 2010, Boyd and Fortin provided a simpler definition of multimorbidity: 'the co-existence of two or more chronic conditions, where one is not necessarily more central than the others'. 5

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