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Introduction Coronavirus disease 2019 (COVID‐19) adversely affects patients who are older, multimorbid, and from Black, Asian or minority ethnicities (BAME). We assessed whether being from BAME is independently associated with mortality in end‐stage kidney disease (ESKD) patients with COVID‐19. Methods Prospective observational study in a single UK renal center. A study was conducted between March 10, 2020 and April 30, 2020. Demographics, socioeconomic deprivation (index of multiple deprivation), co‐morbidities (Charlson comorbidity index [CCI]), and frailty data (clinical frailty score) were collected. The primary outcome was all‐cause mortality. Data were censored on the 1st June 2020. Findings Overall, 191 of our 3379 ESKD patients contracted COVID‐19 in the 8‐week observation period; 84% hemodialysis, 5% peritoneal dialysis, and 11% kidney transplant recipients (KTR). Of these, 57% were male and 67% were from BAME groups (43% Asian, 17% Black, 2% mixed race, and 5% other). Mean CCI was 7.45 (SD 2.11) and 3.90 (SD 2.10) for dialysis patients and KTR, respectively. In our cohort, 60% of patients lived in areas classified as being in the most deprived 20% in the United Kingdom, and of these, 77% of patients were from BAME groups. The case fatality rate was 29%. Multivariable cox regression demonstrated that BAME (hazard ratio [HR]: 2.37, 95% CI: 1.22–4.61) was associated with all‐cause mortality after adjustment for age, deprivation, co‐morbidities, and frailty. Associations with all‐cause mortality persisted in sensitivity analyses in patients from South Asian (HR: 2.52, 95% CI: 1.24–5.12) and Black (HR: 2.43, 95% CI: 1.04–5.67) ethnic backgrounds. Discussion BAME ESKD patients with COVID‐19 are just over twice as likely to die compared to White patients, despite adjustment for age, deprivation, comorbidity, and frailty. This study highlights the need to develop strategies to improve BAME patient outcomes in future outbreaks of COVID‐19.

Background Patients with chronic kidney disease (CKD) are more prone to severe infection. Vaccination is a key strategy to reduce this risk. Some studies suggest vaccine efficacy may be reduced in patients with CKD, despite preserved maintenance of long-term responses to some pathogens and vaccines. Here, we investigated immune responses to 2 vaccines in patients with CKD to identify predictors of immunological responsiveness. Methods Individuals >65 years old, with or without nondialysis CKD (n = 36 and 29, respectively), were vaccinated with a nonadjuvanted seasonal influenza vaccine (T-dependent) and Pneumovax23 (23-valent pneumococcal polysaccharide [PPV23], T-independent). Humoral responses were measured at baseline, day 28, and 6 months. Lymphocyte subset and plasma cell/blast analyses were performed using flow cytometry. Cytomegalovirus (CMV) serotyping was assessed by enzyme-linked immunosorbent assay. Results Only modest responsiveness was observed to both vaccines, independent of CKD status (25% adequate response in controls vs. 12%–18% in the CKD group). Unexpectedly, previous immunization with PPV23 (median 10-year interval) and CMV seropositivity were associated with poor PPV23 responsiveness in both study groups (P < .001 and .003, respectively; multivariable linear regression model). Patients with CKD displayed expanded circulating populations of T helper 2 and regulatory T cells, which were unrelated to vaccine responses. Despite fewer circulating B cells, patients with CKD were able to mount a similar day 7 plasma cell/blast response to controls. Conclusion Patients with nondialysis CKD can respond similarly to vaccines as age- and sex-matched healthy individuals. CKD patients display an immune signature that is independent of vaccine responsiveness. Prior PPV23 immunization and CMV infection may influence responsiveness to vaccination. Clinical Trials Registration. NCT02535052, Patients with nondialysis Chronic Kidney Disease (CKD) can mount similar responses to vaccination as controls. Subtle changes in lymphocyte phenotype are seen in CKD when controlled for effect of Cytomegalovirus (CMV). Latent CMV infection and previous PPV23 vaccination are associated with poorer vaccine responses.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections have a devastating effect on patients receiving hemodialysis. To what extent infection-induced antibody responses are maintained, or protective, is unknown. This study describes the evolution of antibodies against the SARS-CoV-2 spike protein in a cohort of 990 patients on hemodialysis. During the first wave of the pandemic, 26% of patients had developed antispike SARS-CoV-2 antibodies. Fewer PCR-confirmed second-wave infections were observed in patients with pre-existing antibodies (4.2%) than those without antibodies (11.4%). This study shows that SARS-CoV-2 antibodies in patients on hemodialysis are well maintained and associate with reduced risk of subsequent SARS-CoV-2 infection.

Since their inception in March 1972, Keystone Symposia on Molecular and Cellular Biology have brought together scientists from across the globe to discuss key biological topics. Now in its 40th year, it is a completely independent, nonprofit organization devoted solely to providing outstanding scientific conferences in all areas of the biological and biomedical sciences. Towards the end of May 2011, over 200 virologists and immunologists came to Hong Kong, an appropriate setting given the emergence of H5N1, to discuss influenza virus and host interactions. The meeting, expertly organized by Siamon Gordon (University of Oxford, Oxofrd, UK), Malik Peiris (University of Hong Kong, Hong Kong, China) and Kanta Subbarao (NIAID, NIH, MD, USA), took place in the aftermath of the first pandemic in 40 years and provided great insight into both pandemic H1N1 and H5N1. This article focuses on some of the recurring themes that were discussed during the week.

Lung viral infections continue to kill millions of people worldwide. Virus-specific properties, replication kinetics and longevity affect the subsequent vigour of innate and adaptive immunity, which contribute to clinical manifestations. The point at which lung innate immunity activates is different between individuals and is determined by age, genetics, underlying conditions and infection history. On resolution of virus-induced lung disease an 'altered state of homeostasis' exists that in turn affects the next antigenic challenge. The last two years has produced a plethora of studies on the resolution of inflammatory lung disease; highlighting potential for immune modulation. In the future a more precise etiological diagnosis, combined with a knowledge of co-morbidities and an immune signature will lead to the development of more specifically targeted therapeutics.

The lung is exposed to a myriad of innocuous antigens on a daily basis and must maintain a state of immune ignorance or tolerance to these harmless stimuli to retain pulmonary homeostasis and to prevent potentially fatal immunopathology. Here, we examine how, in the lower airways, resident cell populations contribute to the immune regulatory strategies that restrain inflammation. During influenza infection, these suppressive signals must be overcome to elicit a protective immune response that eliminates the virus. We also discuss how, after resolution of infection, the lung does not return to the original homeostatic state, and how the induced altered state can persist for long periods, which leaves the lung more susceptible to other infectious insults.

Respiratory syncytial virus (RSV) causes bronchiolitis, the main cause of infantile hospitalization. Immunity against reinfection is poor, and there is great interest in boosting vaccine responses using live vectors expressing host cytokines. We therefore constructed a recombinant RSV expressing murine interleukin 18 (RSV/IL-18), a cytokine capable of inducing strong antiviral immune responses.In vitroRSV/IL-18 replicated at wild-type levels and produced soluble IL-18. In naïve BALB/c mice, RSV/IL-18 infection significantly increased both IL-18 mRNA and protein and attenuated the peak viral load 3-fold. Despite a reduced viral load, RSV/IL-18 infection caused a biphasic weight loss at days 2 and 6 postinfection that was not seen in wild-type infection. Day 2 disease was associated with enhanced pulmonary natural killer (NK) cell numbers and activity and was prevented by NK cell depletion during infection; day 6 disease was correlated with CD8 T-cell recruitment and was enhanced by NK cell depletion. IL-18 expression during priming also enhanced RSV-specific antibody responses and T-cell responses on secondary RSV infection. Therefore, while IL-18 boosted antiviral immunity and reduced the viral load, its coexpression worsened disease. This is the first recombinant RSV with this property, and these are the first studies to demonstrate that NK cells can induce pathology during pulmonary viral infections.

Benzodiazepines increase vulnerability to infection through α1 subunit dependent Υ-amino-butyric-type-A (GABAA) signalling. Immune cell expression of GABAA receptors and the effect of diazepam on influenza infection was investigated. In patients with pneumonia, α1 GABAA subunits were expressed on alveolar macrophages and blood monocytes. In mice, influenza induced dynamic changes in immune cell GABAA subunit expression: α1 subunits decreased on alveolar macrophage, but increased on monocytes, CD4+ and CD8+ T cells. Following influenza viral infection, diazepam delayed weight loss on day 3 but later increased weight loss. Viral load was unaffected but increased bacterial superinfection was noted on day 10.

The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to α-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves. IMPORTANCE Although most people infected with the 2009 pandemic influenza virus had mild or unapparent symptoms, some suffered severe and devastating disease. The reasons for this variability were unknown, but the numbers of severe cases increased during successive waves of human infection in the United Kingdom. To determine the causes of this variation, we studied genetic changes in virus isolates from individual hospitalized patients. There were no consistent differences between these viruses and those circulating in the community, but we found multiple evolutionary changes that in combination over time increased the virus's ability to infect human cells. These adaptations may explain the remarkable ability of A(H1N1)pdm09 virus to continue to circulate despite widespread immunity and the apparent increase in severity of influenza over successive waves of infection.

ObjectivesBenzodiazepines are used for treating anxiety, epilepsy, muscle spasm, alcohol withdrawal, palliation, insomnia, and sedation as they allosterically modulate γ-amino-butyric acid type A (GABAA) receptors. Despite widespread use, the importance and mechanism of their immune side-effects are poorly understood. Herein we sought to elucidate the impact and mechanism of benzodiazepine-induced susceptibility to infection at anxiolytic doses in mice.DesignAnimal randomized controlled trial.SettingLaboratory.SubjectsAdult female C57BL/6 and BALB/c mice.InterventionsThe effect of a subsedative, anxiolytic dose of diazepam (2 mg kg intraperitoneal) was investigated in a murine Streptococcus pneumoniae pneumonia model.Measurement and main resultsMortality, bacterial and cytokine load, cell recruitment, and intracellular pH were measured. Diazepam treatment did not affect immune homeostasis in the lung. However, diazepam increased mortality and bacterial load from S. pneumoniae pneumonia. The increases in mortality and bacterial load were reversed by a GABAA antagonist, bicuculline, indicating dependence on GABAA receptor signaling. While cell recruitment was unaltered by diazepam, the cytokine response to infection was affected, suggesting that local responses to the pathogen were perturbed. Macrophage and monocytes expressed benzodiazepine sensitive (α1-γ2) GABAA receptors. Interestingly macrophage GABAA receptor expression was regulated by bacterial toll-like receptor agonists and cytokines indicating an endogenous role in the immune response. Functionally diazepam appeared to counteract the endogenous down-regulation of GABAA signaling during infection. Consistent with augmented GABAA signaling, diazepam provoked intracellular acidosis in macrophage, leading to impaired cytokine production, bacterial phagocytosis and killing. In contrast, selective benzodiazepines that do not target the α1 GABAA subunit did not affect macrophage function ex vivo or increase susceptibility to pneumonia in vivo.ConclusionsOur data highlight the regulation of macrophage function by GABAA receptor signaling and the potential harm of benzodiazepine exposure during pneumonia. Therapeutically, selective drugs may improve the safety profile of benzodiazepines.

Animal models of viral respiratory disease often use weight loss as a marker of disease severity; however, this may relate to dehydration and malnutrition that would be corrected clinically. We tested whether parenteral fluid therapy improved weight loss from influenza infection. BALB/c and C57BL/6 mice were infected with A/X31 (H3N2) influenza and randomized to intraperitoneal fluid therapy. Blood glucose was also measured post-viral infection on day 3 and 6 in BALB/c mice and on day 6 in C57BL/6 mice. Parenteral fluids did not alter weight loss or the immunological response to infection, and glucose levels were not abnormal.

Background. Previous studies have shown that the interaction of CD200R, a myeloid inhibitory receptor, with its ligand, CD200, is critical in the control of innate immune activation in the lung. Methods and Results. Using a mouse model of bacterial superinfection following influenza, we show that an absence of CD200R (a negative regulator highly expressed by macrophages and dendritic cells), restricts commensal and exogenous bacterial invasiveness and completely prevents the mortality observed in wild-type mice. This benefit is due to a heightened innate immune response to influenza virus in cd200r knockout mice that limits immune pathogenesis and viral load. In wild-type mice, apoptotic cells expressing CD200 that we believe contribute to the suppressed innate immune response to bacteria dominate during the resolution phase of influenza-induced inflammation. We also show for the first time the presence of a variety of previously unidentified bacterial species in the lower airways that are significantly adjusted by influenza virus infection and may contribute to the pathophysiology of disease. Conclusions. The interaction of CD200 with CD200R therefore contributes to the hyporesponsive innate immune state following influenza virus infection that predisposes to secondary bacterial infection, a phenomenon that has the potential for immune modulation.

A number of acute and chronic immunopathological diseases are driven by excessive Th1 cytokine responses. During influenza infection, Th1 cells and CTL dominate in the lungs. Whilst important for viral clearance, these cells may also cause damaging immune pathology. We now show for the first time that a newly-described cytokine, IL-33, drives Th2 cell polarization during influenza infection, and may be used to counter excessive pathology caused by Th1 cells. We show a change in expression of both endogenous IL-33 and its receptor, ST2L, in the influenza-inflamed lung. IL-33 administration improves resolution of disease and reduces the number of TNF-α and IFN-γ-secreting CD4 and CD8 T cells in the airways of influenza-infected animals. Critically, this reduction in anti-viral T cell number does not impair viral clearance nor alter the recall response. Surprisingly, IL-33 treatment during influenza infection also promotes Th17 cell development. Our data suggest that IL-33 mediates these effects via respiratory epithelium-derived TSLP. This interaction drives a Th17-promoting cytokine cascade involving IL-23 and IL-21. Though viral-induced illness is lessened by IL-33 treatment alone, further improvements are observed when IL-33 is given in combination with IL-17A depletion. These results have important implications for pathologies associated with both Th1 and Th17 cytokine profiles and may explain how an increase of IL-33 correlates with a worsening of disease.

In our murine model of influenza, significant weight loss occurs up to day 7 post-infection [1]. We sought to determine whether weight loss from influenza could be altered by rehydration and whether this affects pulmonary immune responses.