Publications by authors named "Mark Drayson"

207 Publications

SARS-CoV-2-specific IgG1/IgG3 but not IgM in children with Pediatric Inflammatory Multi-System Syndrome.

Pediatr Allergy Immunol 2021 Mar 16. Epub 2021 Mar 16.

Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT, U.K.

There is a low rate of symptomatology associated with SARS-CoV-2 infection in children and a substantially lower risk of death than in adults . Nevertheless, in rare cases some children present with features of a multisystem inflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome .
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http://dx.doi.org/10.1111/pai.13504DOI Listing
March 2021

Health Care Professionals' Confidence and Preferences for Diagnostic Assays for SARS-CoV-2: A Global Study.

Front Public Health 2021 26;9:569315. Epub 2021 Feb 26.

Clinical Immunology Service, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.

The COVID-19 pandemic has led to an urgent requirement for novel diagnostic tests that determine infection with SARS-CoV-2 and the development of an immune response against it. The perspective of end users on the characteristics and clinical use of these assays has not been previously considered. We surveyed 17,186 health care professions (HCPs) in 29 countries to gauge opinion on the design, use, diagnostic impact and diagnostic accuracy of COVID-19 tests. Results were correlated with national statistics on the burden of disease and testing in individual countries. HCPs overwhelmingly recognized the importance of COVID-19 tests but 37.1% were unsure of the appropriate timing of investigations relative to disease symptoms. Confidence in the diagnostic accuracy of assays varied inversely with COVID-19-related mortality in individual countries but had no relationship with the total number of tests performed. There was global consensus that the most important impact of positive antigen and antibody testing was confidence in returning to work following recovery. Saliva was the preferred sampling fluid for COVID-19 diagnostic tests in all groups surveyed. HCP input can ensure novel assays are fit for purpose in varied global health care settings, but HCPs may require support to effectively use novel diagnostics thus minimizing waste when supplies are limited.
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http://dx.doi.org/10.3389/fpubh.2021.569315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952327PMC
March 2021

Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial.

PLoS Med 2021 Jan 11;18(1):e1003454. Epub 2021 Jan 11.

Perlmutter Cancer Center, NYU Langone Health, New York, New York, United States of America.

Background: Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.

Methods And Findings: The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.

Conclusions: The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.

Trial Registration: ClinicalTrials.gov ISRCTN49407852.
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http://dx.doi.org/10.1371/journal.pmed.1003454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799846PMC
January 2021

Autologous stem cell transplantation is safe and effective for fit older myeloma patients: exploratory results from the Myeloma XI trial.

Haematologica 2020 12 3;Online ahead of print. Epub 2020 Dec 3.

Perlmutter Cancer Center, NYU Langone, New York.

Autologous stem cell transplant (ASCT) remains standard of care for consolidation after induction therapy for eligible newly diagnosed myeloma patients. In recent clinical trials comparing ASCT to delayed ASCT, patients aged over 65 were excluded. In real-world practice stem cell transplants are not restricted to those aged under 65 and clinicians decide on transplant eligibility based on patient fitness rather than a strict age cut off. Data from the UK NCRI Myeloma XI trial, a large phase III randomised controlled trial with pathways for transplant-eligible (TE) and ineligible (TNE) patients, was used in an exploratory analysis to examine the efficacy and toxicity of ASCT in older patients including analysis using an agematched population to compare outcomes for patients receiving similar induction therapy with or without ASCT. Older patients within the TE pathway were less likely to undergo stem cell harvest at the end of induction than younger patients and of those patients undergoing ASCT there was a reduction in PFS associated with increasing age. ASCT in older patients was well tolerated with no difference in morbidity or mortality between patients aged.
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http://dx.doi.org/10.3324/haematol.2020.262360DOI Listing
December 2020

Copy number evolution and its relationship with patient outcome-an analysis of 178 matched presentation-relapse tumor pairs from the Myeloma XI trial.

Leukemia 2020 Dec 1. Epub 2020 Dec 1.

Division of Molecular Pathology, The Institute of Cancer Research, London, UK.

Structural chromosomal changes including copy number aberrations (CNAs) are a major feature of multiple myeloma (MM), however their evolution in context of modern biological therapy is not well characterized. To investigate acquisition of CNAs and their prognostic relevance in context of first-line therapy, we profiled tumor diagnosis-relapse pairs from 178 NCRI Myeloma XI (ISRCTN49407852) trial patients using digital multiplex ligation-dependent probe amplification. CNA profiles acquired at relapse differed substantially between MM subtypes: hyperdiploid (HRD) tumors evolved predominantly in branching pattern vs. linear pattern in t(4;14) vs. stable pattern in t(11;14). CNA acquisition also differed between subtypes based on CCND expression, with a marked enrichment of acquired del(17p) in CCND2 over CCND1 tumors. Acquired CNAs were not influenced by high-dose melphalan or lenalidomide maintenance randomization. A branching evolution pattern was significantly associated with inferior overall survival (OS; hazard ratio (HR) 2.61, P = 0.0048). As an individual lesion, acquisition of gain(1q) at relapse was associated with shorter OS, independent of other risk markers or time of relapse (HR = 2.00; P = 0.021). There is an increasing need for rational therapy sequencing in MM. Our data supports the value of repeat molecular profiling to characterize disease evolution and inform management of MM relapse.
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http://dx.doi.org/10.1038/s41375-020-01096-yDOI Listing
December 2020

Serological responses to SARS-CoV-2 following non-hospitalised infection: clinical and ethnodemographic features associated with the magnitude of the antibody response.

medRxiv 2020 Nov 16. Epub 2020 Nov 16.

Objective: To determine clinical and ethnodemographic correlates of serological responses against the SARS-CoV-2 spike glycoprotein following mild-to-moderate COVID-19.

Design: A retrospective cohort study of healthcare workers who had self-isolated due to COVID-19.

Setting: University Hospitals Birmingham NHS Foundation Trust, UK (UHBFT).

Participants: 956 health care workers were recruited by open invitation via UHBFT trust email and social media.

Intervention: Participants volunteered a venous blood sample that was tested for the presence of anti-SARS-CoV-2 spike glycoprotein antibodies. Results were interpreted in the context of the symptoms of their original illness and ethnodemographic variables.

Results: Using an assay that simultaneously measures the combined IgG, IgA and IgM response against the spike glycoprotein (IgGAM), the overall seroprevalence within this cohort was 46.2% (n=442/956). The seroprevalence of immunoglobulin isotypes was 36.3%, 18.7% and 8.1% for IgG, IgA and IgM respectively. IgGAM identified serological responses in 40.6% (n=52/128) of symptomatic individuals who reported a negative SARS-CoV-2 PCR test. Increasing age, non-white ethnicity and obesity were independently associated with greater IgG antibody response against the spike glycoprotein. Self-reported fever and fatigue were associated with greater IgG and IgA responses against the spike glycoprotein. The combination of fever and/or cough and/or anosmia had a positive predictive value of 92.3% for seropositivity.

Conclusions And Relevance: Assays employing combined antibody detection demonstrate enhanced seroepidemiological sensitivity and can detect prior viral exposure even when PCR swabs have been negative. We demonstrate an association between known ethnodemographic risk factors associated with mortality from COVID-19 and the magnitude of serological responses in mild-to-moderate disease. The combination of cough, and/or fever and/or anosmia identifies the majority of individuals who should self-isolate for COVID-19.
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http://dx.doi.org/10.1101/2020.11.12.20230763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685342PMC
November 2020

Renal outcome in patients with newly diagnosed multiple myeloma: results from the UK NCRI Myeloma XI trial.

Blood Adv 2020 11;4(22):5836-5845

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

Renal injury is a common complication of multiple myeloma (MM) and is associated with adverse outcome. Despite this, the natural history of renal injury in patients with MM remains uncertain especially in the context of intensive therapy and novel therapies. To address the lack of data, we evaluated the renal function of 2334 patients from the UK National Cancer Research Institute Myeloma XI trial at baseline and at 12 months to assess renal function over time and the factors associated with change. Patients who had severe acute kidney injury or a requirement for dialysis were excluded. At 12 months of the 1450 evaluable patients planned for autologous transplantation; 204 (14%) patients had a decline in estimated glomerular filtration rate (eGFR) ≥25% from baseline, 341 (23.5%) had an improvement and 905 (62%) had no significant change in eGFR. Renal outcome at 12 months for the 884 evaluable patients who were not planned for transplant was similar. Improved renal function was more likely if patients were <70 years old, male, had an average eGFR <60 mL per minute per 1.73 m2 and a higher baseline free light chain level >1000 mg/L, and/or a free light chain response of >90%. It did not correlate with monoclonal-protein response, transplantation, or use of a bortezomib-based regimen. We show that with current therapies the proportion of patients who have a significant decline in renal function in the first 12 months is small. The greatest relative improvement in eGFR is seen in patients with high free light chain at baseline and a high light chain response. This trial was registered at http://www.isrctn.com as #49407852.
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http://dx.doi.org/10.1182/bloodadvances.2020002872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686889PMC
November 2020

Anti-bacterial antibodies in multiple myeloma patients at disease presentation, in response to therapy and in remission: implications for patient management.

Blood Cancer J 2020 11 4;10(11):114. Epub 2020 Nov 4.

Institute of Immunology and Immunotherapy, Clinical Immunology Service, University of Birmingham, Birmingham, UK.

Multiple myeloma (MM) is associated with increased risk of infection, but little is known regarding antibody levels against specific bacteria. We assessed levels of polyclonal immunoglobulin and antibacterial antibodies in patients recruited to the TEAMM trial, a randomised trial of antibiotic prophylaxis at the start of anti-myeloma treatment. Polyclonal IgG, IgA and IgM levels were below the reference range in 71%, 83% and 90% of 838 MM patients at diagnosis. Anti-vaccine targeted tetanus toxoid antibodies were protective in 95% of 193 healthy controls but only 41% of myeloma patients. In healthy controls, protective antibodies against 6/12 pneumococcal serotypes, haemophilus and meningococcus A were present in 67%, 41% and 56% compared to just 15%, 21% and 17% of myeloma patients. By 1 year, myeloma patients IgG levels had recovered for 57% of patients whilst the proportion with protective levels of IgG against thymus-dependent protein antigen tetanus toxoid had changed little. In contrast the proportions of patients with protective levels against thymus independent polysaccharide antigens pneumococcus, haemophilus and meningococcus had fallen from 15 to 7%, 21 to 0% and 17 to 11%. Findings highlight the need for strategies to protect patients against bacterial infections during therapy and vaccination programmes during remission.
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http://dx.doi.org/10.1038/s41408-020-00370-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642409PMC
November 2020

Salivary free light chains as a new biomarker to measure psychological stress: the impact of a university exam period on salivary immunoglobulins, cortisol, DHEA and symptoms of infection.

Psychoneuroendocrinology 2020 12 15;122:104912. Epub 2020 Oct 15.

Institute of Immunology and Immunotherapy, University of Birmingham, UK. Electronic address:

Introduction: Measurement of immunoglobulin free light chains (FLCs) in saliva can serve as a non-invasive biomarker in health and behavioural research. FLCs have been explored in relation to physiological stress but FLC responses to psychological stress and their relationship with infections remain unknown. This study aimed to investigate the impact of exam period stress on salivary FLCs alongside other established biomarkers of stress and whether FLCs relate to symptoms of infection.

Methods: 58 healthy adults studying at university completed saliva samples and questionnaires in a period without exams (baseline), and again prior to the start of an exam period. Saliva samples were assessed for FLCs, IgA, cortisol and dehydroepiandrosterone (DHEA). Measures of life events stress, perceived stress, anxiety and depression were completed. Students also reported incidence and severity of symptoms of infection and rated general well-being at baseline, prior to, during and after the exam period. Exercise, sleep and alcohol consumption were also assessed at both timepoints.

Results: FLCs secretion rates were significantly lower at the exam period compared to baseline (p < .01), with reductions of 26% and 25% for κ FLC and λ FLC, respectively. In agreement, salivary IgA secretion rate was lower at exams (non-significant trend, p = .07). Cortisol concentration significantly increased at exams (p < .05) while DHEA did not change, leading to an increase in the cortisol:DHEA ratio (p = .06). Depression (p < .05) and anxiety increased from baseline to exams and life stress reported in the build up to the exam period was higher compared with baseline (p < .001). Well-being significantly decreased from baseline to exams (p < .01). The proportion of participants reporting infection symptoms (70%) was unchanged between baseline and prior to exams. No significant relationships were found between FLCs or other saliva parameters and infection symptoms, well-being or stress/psychological measures. Changes in saliva parameters between timepoints were independent of health behaviours.

Conclusions: Salivary FLCs are responsive to life events stress and corroborate with IgA. This preliminary study highlights the potential utility of FLCs as a new salivary biomarker in stress research.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104912DOI Listing
December 2020

Immunoglobulin Free Light Chains as Inflammatory Biomarkers of Atrial Fibrillation.

Circ Arrhythm Electrophysiol 2020 11 5;13(11):e009017. Epub 2020 Oct 5.

Department of Medicine, University of Utah Medical Center, Salt Lake City (J.W.M.).

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http://dx.doi.org/10.1161/CIRCEP.120.009017DOI Listing
November 2020

Sensitive Detection of SARS-CoV-2-Specific Antibodies in Dried Blood Spot Samples.

Emerg Infect Dis 2020 12 24;26(12):2970-2973. Epub 2020 Sep 24.

Dried blood spot (DBS) samples can be used for the detection of severe acute respiratory syndrome coronavirus 2 spike antibodies. DBS sampling is comparable to matched serum samples with a relative 98.1% sensitivity and 100% specificity. Thus, DBS sampling offers an alternative for population-wide serologic testing in the coronavirus pandemic.
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http://dx.doi.org/10.3201/eid2612.203309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706975PMC
December 2020

SARS-CoV-2 seroprevalence and asymptomatic viral carriage in healthcare workers: a cross-sectional study.

Thorax 2020 12 11;75(12):1089-1094. Epub 2020 Sep 11.

Clinical Immunology Service, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK

Objective: To determine the rates of asymptomatic viral carriage and seroprevalence of SARS-CoV-2 antibodies in healthcare workers.

Design: A cross-sectional study of asymptomatic healthcare workers undertaken on 24/25 April 2020.

Setting: University Hospitals Birmingham NHS Foundation Trust (UHBFT), UK.

Participants: 545 asymptomatic healthcare workers were recruited while at work. Participants were invited to participate via the UHBFT social media. Exclusion criteria included current symptoms consistent with COVID-19. No potential participants were excluded.

Intervention: Participants volunteered a nasopharyngeal swab and a venous blood sample that were tested for SARS-CoV-2 RNA and anti-SARS-CoV-2 spike glycoprotein antibodies, respectively. Results were interpreted in the context of prior illnesses and the hospital departments in which participants worked.

Main Outcome Measure: Proportion of participants demonstrating infection and positive SARS-CoV-2 serology.

Results: The point prevalence of SARS-CoV-2 viral carriage was 2.4% (n=13/545). The overall seroprevalence of SARS-CoV-2 antibodies was 24.4% (n=126/516). Participants who reported prior symptomatic illness had higher seroprevalence (37.5% vs 17.1%, χ=21.1034, p<0.0001) and quantitatively greater antibody responses than those who had remained asymptomatic. Seroprevalence was greatest among those working in housekeeping (34.5%), acute medicine (33.3%) and general internal medicine (30.3%), with lower rates observed in participants working in intensive care (14.8%). BAME (Black, Asian and minority ethnic) ethnicity was associated with a significantly increased risk of seropositivity (OR: 1.92, 95% CI 1.14 to 3.23, p=0.01). Working on the intensive care unit was associated with a significantly lower risk of seropositivity compared with working in other areas of the hospital (OR: 0.28, 95% CI 0.09 to 0.78, p=0.02).

Conclusions And Relevance: We identify differences in the occupational risk of exposure to SARS-CoV-2 between hospital departments and confirm asymptomatic seroconversion occurs in healthcare workers. Further investigation of these observations is required to inform future infection control and occupational health practices.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462045PMC
December 2020

Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial.

Br J Haematol 2021 Mar 15;192(6):997-1005. Epub 2020 Aug 15.

Department of Haematological Medicine, King's College Hospital NHS Trust, London, UK.

Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression.
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http://dx.doi.org/10.1111/bjh.17044DOI Listing
March 2021

Optimising the value of immunomodulatory drugs during induction and maintenance in transplant ineligible patients with newly diagnosed multiple myeloma: results from Myeloma XI, a multicentre, open-label, randomised, Phase III trial.

Br J Haematol 2021 Mar 12;192(5):853-868. Epub 2020 Jul 12.

Perlmutter Cancer Center, NY Langone Health, New York, NY, USA.

Second-generation immunomodulatory agents, such as lenalidomide, have a more favourable side-effect profile than the first-generation thalidomide, but their optimum combination and duration for patients with newly diagnosed transplant-ineligible myeloma (ND-TNE-MM) has not been defined. The most appropriate delivery and dosing regimens of these therapies for patients at advanced age and frailty status is also unclear. The Myeloma XI study compared cyclophosphamide, thalidomide and dexamethasone (CTDa) to cyclophosphamide, lenalidomide and dexamethasone (CRDa) as induction therapy, followed by a maintenance randomisation between ongoing therapy with lenalidomide or observation for patients with ND-TNE-MM. CRDa deepened response but did not improve progression-free (PFS) or overall survival (OS) compared to CTDa. However, analysis by age group highlighted significant differences in tolerability in older, frailer patients that may have limited treatment delivery and impacted outcome. Deeper responses and PFS and OS benefits with CRDa over CTDs were seen in patients aged ≤70 years, with an increase in toxicity and discontinuation observed in older patients. Our results highlight the importance of considering age and frailty in the approach to therapy for patients with ND-TNE-MM, highlighting the need for prospective validation of frailty adapted therapy approaches, which may improve outcomes by tailoring treatment to the individual.
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http://dx.doi.org/10.1111/bjh.16945DOI Listing
March 2021

Characterising the impact of pneumonia on outcome in non-small cell lung cancer: identifying preventative strategies.

J Thorac Dis 2020 May;12(5):2236-2246

Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Background: Infections remain a part of the natural course of cancer, and lung cancer patients often present with some form of respiratory infection that can lead to their ultimate demise.

Methods: Data was gathered concerning all unplanned hospital admissions (UHAs) to our centre from three separate patient cohorts; non-small cell lung cancer (NSCLC) patients (cohort 1), "other cancer" patients (breast, prostate, colon) (cohort 2) and all non-cancer patients (cohort 3).

Results: Across the three cohorts, there were 455, 1,190 and 54,158 individual patient UHAs to our centre respectively. Within the NSCLC cohort, 164 UHAs were as a direct result of pneumonia (36.0%), compared to 1.3% and 2.2% in the other two cohorts (P<0.0001). In-hospital mortality and length of hospital stay were significantly higher in the pneumonia sub-group of NSCLC patients only compared with the other two patient cohorts (P<0.0001 and P=0.011 respectively). Within the NSCLC cohort, Patient age, pneumococcal vaccination status, pneumonia admission, smoking status and specific tumour stages were identified as significant independent risk factors for in-hospital mortality. Odds ratios of 0.160 for positive vaccination status and 9.522 for pneumonia admission indicate that for NSCLC patients admitted to hospital with a pneumonia without previous pneumococcal vaccination in the last 5 years, the odds of death were almost 60-fold higher.

Conclusions: Vigilance for infection, early diagnosis with adequate assessment and efforts to identify a culprit organism should be a priority when faced with these patients. Infection prevention strategies should be further explored to address this high mortality risk in NSCLC.
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http://dx.doi.org/10.21037/jtd.2020.04.49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330320PMC
May 2020

Detection of antibodies to the SARS-CoV-2 spike glycoprotein in both serum and saliva enhances detection of infection.

medRxiv 2020 Jun 18. Epub 2020 Jun 18.

Background: Detecting antibody responses during and after SARS-CoV-2 infection is essential in determining the seroepidemiology of the virus and the potential role of antibody in disease. Scalable, sensitive and specific serological assays are essential to this process. The detection of antibody in hospitalized patients with severe disease has proven straightforward; detecting responses in subjects with mild disease and asymptomatic infections has proven less reliable. We hypothesized that the suboptimal sensitivity of antibody assays and the compartmentalization of the antibody response may contribute to this effect.

Methods: We systemically developed an ELISA assay, optimising different antigens and amplification steps, in serum and saliva from symptomatic and asymptomatic SARS-CoV-2-infected subjects.

Results: Using trimeric spike glycoprotein, rather than nucleocapsid enabled detection of responses in individuals with low antibody responses. IgG1 and IgG3 predominate to both antigens, but more anti-spike IgG1 than IgG3 was detectable. All antigens were effective for detecting responses in hospitalized patients. Anti-spike, but not nucleocapsid, IgG, IgA and IgM antibody responses were readily detectable in saliva from non-hospitalized symptomatic and asymptomatic individuals. Antibody responses in saliva and serum were largely independent of each other and symptom reporting.

Conclusions: Detecting antibody responses in both saliva and serum is optimal for determining virus exposure and understanding immune responses after SARS-CoV-2 infection.

Funding: This work was funded by the University of Birmingham, the National Institute for Health Research (UK), the NIH National Institute for Allergy and Infectious Diseases, the Bill and Melinda Gates Foundation and the University of Southampton.
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http://dx.doi.org/10.1101/2020.06.16.20133025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310662PMC
June 2020

Serology confirms SARS-CoV-2 infection in PCR-negative children presenting with Paediatric Inflammatory Multi-System Syndrome.

medRxiv 2020 Jun 7. Epub 2020 Jun 7.

Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT, U.K.

Background: During the COVID-19 outbreak, reports have surfaced of children who present with features of a multisystem inflammatory syndrome with overlapping features of Kawasaki disease and toxic shock syndrome - Paediatric Inflammatory Multisystem Syndrome- temporally associated with SARS-CoV-2 pandemic (PIMS-TS). Initial reports find that many of the children are PCR-negative for SARS-CoV-2, so it is difficult to confirm whether this syndrome is a late complication of viral infection in an age group largely spared the worst consequences of this infection, or if this syndrome reflects enhanced surveillance.

Methods: Children hospitalised for symptoms consistent with PIMS-TS between 28 April and 8 May 2020, and who were PCR-negative for SARS-CoV-2, were tested for antibodies to viral spike glycoprotein using an ELISA test.

Results: Eight patients (age range 7-14 years, 63% male) fulfilled case-definition for PIMS-TS during the study period. Six of the eight patients required admission to intensive care. All patients exhibited significant IgG and IgA responses to viral spike glycoprotein. Further assessment showed that the IgG isotypes detected in children with PIMS-TS were of the IgG1 and IgG3 subclasses, a distribution similar to that observed in samples from hospitalised adult COVID-19 patients. In contrast, IgG2 and IgG4 were not detected in children or adults. IgM was not detected in children, which contrasts with adult hospitalised adult COVID-19 patients of whom all had positive IgM responses.

Conclusions: Strong IgG antibody responses can be detected in PCR-negative children with PIMS-TS. The low detection rate of IgM in these patients is consistent with infection having occurred weeks previously and that the syndrome onset occurs well after the control of SARS-CoV-2 viral load. This implies that the disease is largely immune-mediated. Lastly, this indicates that serology can be an appropriate diagnostic tool in select patient groups.
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http://dx.doi.org/10.1101/2020.06.05.20123117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302282PMC
June 2020

Early relapse after high-dose melphalan autologous stem cell transplant predicts inferior survival and is associated with high disease burden and genetically high-risk disease in multiple myeloma.

Br J Haematol 2020 Jun 10. Epub 2020 Jun 10.

The Institute of Cancer Research, London, UK.

Predicting patient outcome in multiple myeloma remains challenging despite the availability of standard prognostic biomarkers. We investigated outcome for patients relapsing early from intensive therapy on NCRI Myeloma XI. Relapse within 12 months of autologous stem cell transplant was associated with markedly worse median progression-free survival 2 (PFS2) of 18 months and overall survival (OS) of 26 months, compared to median PFS2 of 85 months and OS of 91 months for later relapsing patients despite equal access to and use of subsequent therapies, highlighting the urgent need for improved outcome prediction and early intervention strategies for myeloma patients.
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http://dx.doi.org/10.1111/bjh.16793DOI Listing
June 2020

Correction to: Immunoglobulin free light chains: an inflammatory biomarker of diabetes.

Inflamm Res 2020 08;69(8):719

The University of Birmingham, Birmingham, UK.

In the original publication of this paper contains some typographical errors in Table 1.
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http://dx.doi.org/10.1007/s00011-020-01367-5DOI Listing
August 2020

Lenalidomide before and after ASCT for transplant-eligible patients of all ages in the randomized, phase III, Myeloma XI trial.

Haematologica 2020 06 4. Epub 2020 Jun 4.

Perlmutter Cancer Center, NYU Langone Health, New York, USA.

The optimal way to use immunomodulatory drugs as components of induction and maintenance therapy for multiple myeloma is unresolved. We addressed this question in a large phase III randomized trial, Myeloma XI. Patients with newly diagnosed multiple myeloma (n = 2042) were randomized to induction therapy with cyclophosphamide, thalidomide, and dexamethasone (CTD) or cyclophosphamide, lenalidomide, and dexamethasone (CRD). Additional intensification therapy with cyclophosphamide, bortezomib and dexamethasone (CVD) was administered before ASCT to patients with a suboptimal response to induction therapy using a response-adapted approach. After receiving high-dose melphalan with autologous stem cell transplantation (ASCT), eligible patients were further randomized to receive either lenalidomide alone or observation alone. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The CRD regimen was associated with significantly longer PFS (median: 36 vs. 33 months; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.75-0.96; P = 0.0116) and OS (3-year OS: 82.9% vs. 77.0%; HR, 0.77; 95% CI, 0.63-0.93; P = 0.0072) compared with CTD. The PFS and OS results favored CRD over CTD across all subgroups, including patients with International Staging System stage III disease (HR for PFS, 0.73; 95% CI, 0.58-0.93; HR for OS, 0.78; 95% CI, 0.56-1.09), high-risk cytogenetics (HR for PFS, 0.60; 95% CI, 0.43-0.84; HR for OS, 0.70; 95% CI, 0.42-1.15) and ultra high-risk cytogenetics (HR for PFS, 0.67; 95% CI, 0.41-1.11; HR for OS, 0.65; 95% CI, 0.34-1.25). Among patients randomized to lenalidomide maintenance (n = 451) or observation (n = 377), maintenance therapy improved PFS (median: 50 vs. 28 months; HR, 0.47; 95% CI, 0.37-0.60; P < 0.0001). Optimal results for PFS and OS were achieved in the patients who received CRD induction and lenalidomide maintenance. The trial was registered with the EU Clinical Trials Register (EudraCT 2009-010956-93) and ISRCTN49407852.
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http://dx.doi.org/10.3324/haematol.2020.247130DOI Listing
June 2020

Immunoglobulin free light chains as an inflammatory biomarker of heart failure with myocarditis.

Clin Immunol 2020 08 30;217:108455. Epub 2020 May 30.

University of Utah Medical Center, Salt Lake City, USA.

Background: In this study, we measured immunoglobulin free light chains (FLC), a biomarker of inflammation in the sera of patients with heart failure due to myocarditis.

Methods: FLC kappa and FLC lambda were assayed in stored serum samples from patients with heart failure with myocarditis from the US myocarditis treatment trial by a competitive-inhibition multiplex Luminex® assay.

Results: The median concentration of circulating FLC kappa/lambda ratio was significantly lower in the sera from patients with heart failure with myocarditis than in healthy controls, and FLC kappa/lambda ratio had good diagnostic ability for identification of heart failure with myocarditis. Further, FLC kappa/lambda ratio was an independent prognostic factor for overall survival, and allowed creation of three prognostic groups by combining with N-terminal pro-B-type natriuretic peptide.

Conclusions: This study suggests that FLC kappa/lambda ratio is a promising biomarker of heart failure with myocarditis.
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http://dx.doi.org/10.1016/j.clim.2020.108455DOI Listing
August 2020

Thrombosis in patients with myeloma treated in the Myeloma IX and Myeloma XI phase 3 randomized controlled trials.

Blood 2020 08;136(9):1091-1104

Freeman Hospital, University of Newcastle, Newcastle Upon Tyne, United Kingdom.

Newly diagnosed multiple myeloma (NDMM) patients treated with immunomodulatory drugs are at high risk of venous thromboembolism (VTE), but data are lacking from large prospective cohorts. We present thrombosis outcome data from Myeloma IX (n = 1936) and Myeloma XI (n = 4358) phase 3 randomized controlled trials for NDMM that treated transplant-eligible and transplant-ineligible patients before and after publication of thrombosis prevention guidelines. In Myeloma IX, transplant-eligible patients randomly assigned to cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) induction had higher risk of VTE compared with patients treated with cyclophosphamide, thalidomide, and dexamethasone (CTD) (22.5% [n = 121 of 538] vs 16.1% [n = 89 of 554]; adjusted hazard ratio [aHR],1.46; 95% confidence interval [95% CI], 1.11-1.93). For transplant-ineligible patients, those randomly assigned to attenuated CTD (CTDa) induction had a higher risk of VTE compared with those treated with melphalan and prednisolone (MP) (16.0% [n = 68 of 425] vs 4.1% [n = 17 of 419]; aHR, 4.25; 95% CI, 2.50-7.20). In Myeloma XI, there was no difference in risk of VTE (12.2% [n = 124 of 1014] vs 13.2% [n = 133 of 1008]; aHR, 0.92; 95% CI, 0.72-1.18) or arterial thrombosis (1.2% [n = 12 of 1014] vs 1.5% [n = 15 of 1008]; aHR, 0.80; 95% CI, 0.37-1.70) between transplant-eligible pathways for patients treated with cyclophosphamide, lenalidomide, and dexamethasone (CRD) or CTD. For transplant-ineligible patients, there was no difference in VTEs between attenuated CRD (CRDa) and CTDa (10.4% [n = 95 of 916] vs 10.7% [n = 97 of 910]; aHR, 0.97; 95% CI, 0.73-1.29). However, arterial risk was higher with CRDa than with CTDa (3.1% [n = 28 of 916] vs 1.6% [n = 15 of 910]; aHR, 1.91; 95% CI, 1.02-3.57). Thrombotic events occurred almost entirely within 6 months of treatment initiation. Thrombosis was not associated with inferior progression-free survival (PFS) or overall survival (OS), apart from inferior OS for patients with arterial events (aHR, 1.53; 95% CI, 1.12-2.08) in Myeloma XI. The Myeloma XI trial protocol incorporated International Myeloma Working Group (IMWG) thrombosis prevention recommendations and compared with Myeloma IX, more patients received thromboprophylaxis (80.5% vs 22.3%) with lower rates of VTE for identical regimens (CTD, 13.2% vs 16.1%; CTDa, 10.7% vs 16.0%). However, thrombosis remained frequent in spite of IMWG-guided thromboprophylaxis, suggesting that new approaches are needed.
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http://dx.doi.org/10.1182/blood.2020005125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453153PMC
August 2020

Immunoglobulin free light chains: an inflammatory biomarker of diabetes.

Inflamm Res 2020 Aug 18;69(8):715-718. Epub 2020 May 18.

The University of Birmingham, Birmingham, UK.

Objective: Inflammation is increasingly understood as playing an important role in type 2 diabetes mellitus (T2D) development. A critical mechanism of the inflammatory cascade in developing T2D is nuclear factor-kappa B (NF-kB) activation. As immunoglobulin free light chains (FLC) could be a biomarker of activation of NF-kB, we measured FLC in patients with T2D.

Subjects: The age range of the 77 patients with T2D and the 75 healthy control participants were 45-87 years (median 60) and 25-72 years (median 51), respectively.

Methods: Serum FLC kappa and lambda were assayed by a competitive-inhibition multiplex Luminex assay.

Results: The concentration of circulating FLC the kappa/lambda ratio was lower in patients with T2D than in healthy volunteers. The area under the receiver operating curve (ROC-AUC) of the FLC kappa/lambda ratio showed the largest ROC-AUC compared with other FLC variables and hemoglobin A1c (HbA1c). The diagnostic performance for distinguishing between T2D and healthy control was a sensitivity of 0.96 and a specificity of 1. The odds ratio was 0.000018.

Conclusions: These results suggest that FLC kappa/lambda may be more specific and sensitive for the diagnosis of T2D than HbA1c, and thus represents a potentially promising biomarker of inflammation.
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http://dx.doi.org/10.1007/s00011-020-01357-7DOI Listing
August 2020

Post-transplant Monoclonal Gammopathy of Renal Significance: A Case Series.

Transplant Proc 2020 Apr 3;52(3):857-864. Epub 2020 Mar 3.

Department of Renal Medicine, University Hospitals Birmingham, Birmingham, United Kingdom.

Monoclonal gammopathy of renal significance (MGRS) is a new concept with evolving evidence for treatment. MGRS in the transplant kidney is a rare cause of renal transplant dysfunction that can lead to graft loss. Most cases of post-transplant MGRS are due to recurrent disease. Clone-specific chemotherapy is required to target the underlying clone, and this may improve graft survival; however, this can be challenging, as most patients are elderly with age-related comorbidities and may have complications associated with increasing immunosuppression. Here, we report 3 cases of renal allograft MGRS, and each case highlights different challenges in the diagnosis and management of this condition.
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http://dx.doi.org/10.1016/j.transproceed.2019.12.040DOI Listing
April 2020

The benefits of physical exercise for the health of the pancreatic β-cell: a review of the evidence.

Exp Physiol 2020 04 13;105(4):579-589. Epub 2020 Mar 13.

Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

New Findings: What is the topic of this review? This review discusses the evidence of the benefits of exercise training for β-cell health through improvements in function, proliferation and survival which may have implications in the treatment of diabetes. What advances does it highlight? This review highlights how exercise may modulate β-cell health in the context of diabetes and highlights the need for further exploration of whether β-cell preserving effects of exercise translates to T1D.

Abstract: Physical exercise is a core therapy for type 1 and type 2 diabetes. Whilst the benefits of exercise for different physiological systems are recognised, the effect of exercise specifically on the pancreatic β-cell is not well described. Here we review the effects of physical exercise on β-cell health. We show that exercise improves β-cell mass and function. The improved function manifests primarily through the increased insulin content of the β-cell and its increased ability to secrete insulin in response to a glucose stimulus. We review the evidence relating to glucose sensing, insulin signalling, β-cell proliferation and β-cell apoptosis in humans and animal models with acute exercise and following exercise training programmes. Some of the mechanisms through which these benefits manifest are discussed.
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http://dx.doi.org/10.1113/EP088220DOI Listing
April 2020

Levofloxacin prophylaxis in patients with myeloma - Authors' reply.

Lancet Oncol 2020 02;21(2):e69

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

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http://dx.doi.org/10.1016/S1470-2045(20)30020-6DOI Listing
February 2020

The prevalence and significance of monoclonal gammopathy of undetermined significance in acute medical admissions.

Br J Haematol 2020 06 30;189(6):1127-1135. Epub 2020 Jan 30.

Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

Monoclonal gammopathy of undetermined significance (MGUS) affects 3·2% of adults aged >50 years. MGUS carries a life-long risk of progression to multiple myeloma and causes complications including infection and renal impairment; common causes of hospital admission. This study aimed to assess MGUS prevalence in emergency medical hospital admissions. Patients were recruited from unselected emergency medical admissions in a hospital in the United Kingdom. Serum protein electrophoresis was performed, with immunofixation of abnormal results. Reason for admission and routine test results were recorded. After education about MGUS and myeloma, patients chose whether they wished to be informed of new diagnoses. A total of 660 patients were tested and 35 had a paraprotein suggestive of MGUS. The overall rate of MGUS was 5·3%. MGUS prevalence in those aged >50 years was 6·94%, higher than the previously published rate of 3·2% (P < 0·0005). There were higher rates in those with chronic kidney disease (13·75% vs. 4·14%, P = 0·002), heart failure (14% vs. 4·59%, P = 0·012), anaemia (8·96% vs. 3·41%, P = 0·003) or leucocytosis (9·33% vs. 3·04%, P = 0·002). In all, 96% of patients wished to be informed of their screening results. The prevalence of MGUS in emergency hospital admissions is higher than expected based on previous population-based rates. This may suggest a selected population for screening.
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http://dx.doi.org/10.1111/bjh.16487DOI Listing
June 2020

The role of B lymphocytes in the immuno-biology of non-small-cell lung cancer.

Cancer Immunol Immunother 2020 Mar 4;69(3):325-342. Epub 2020 Jan 4.

Institute of Immunology and Immunotherapy (III), College of Medical and Dental Sciences, University of Birmingham, Vincent Drive, Birmingham, B15 2TT, UK.

Tumour-infiltrating immune cells have been widely implicated to play a significant role in carcinogenesis, through both pro- or anti-tumour effects. The multi-faceted effects of lung cancer associated T lymphocytes have been extensively studied, and yet, the role of B lymphocytes remains an area less studied. In this review, we will describe the current understanding of the role of tumour-infiltrating B lymphocytes in NSCLC, discuss their prognostic significance, their functionality within the tumour microenvironment and ultimately how we might harness B-cell biology to develop B-cell therapeutic strategies in cancer.
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http://dx.doi.org/10.1007/s00262-019-02461-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044257PMC
March 2020