Correlation between levels of anti-cytokine antibodies, recombination activity of the mutant RAG proteins and clinical phenotype in patients with RAG deficiency

RAG mutations cause various phenotypes: SCID, Omenn syndrome (OS), leaky SCID (LS) and combined immunodeficiency (CID). We had previously reported autoantibodies targeting IFN-alpha, IFN-omega in patients with RAG deficiency. However, how the presence of such antibodies correlated with the severity of the clinical phenotype and with the recombination activity of the mutant proteins was unknown. To address this, we have studied anti-cytokine antibodies in 118 patients with RAG defects (SCID, n = 28;OS, n = 29;LS, n = 29;CID, n = 32), and in 42 controls (protocols NCT03394053 and NCT03610802). RAG mutant proteins associated with CID and LS retained 35.6 +/- 4.3 (mean +/- SE) and 29.8 +/- 5.1% recombination activity respectively, compared to wildtype protein, which was significantly higher than the recombination activity of the mutant RAG proteins associated with OS (4.1 +/- 1.5%) and SCID (5.7 +/- 2.1%) (p < 0.0001). Among 32 CID patients, 24 tested positive for anti-IFN-alpha and 21 for anti-IFN-omega antibodies. Among 29 LS patients, 15 had high levels of anti-IFN-alpha and 13 of anti-IFN-omega antibodies. A minority of the CID and LS patients had also high levels of anti-IFN-beta and anti-IL-22 antibodies. By contrast, none of the OS patients tested positive for anti-cytokine antibodies. High levels of anti-IFN-alpha and anti-IFN-omega antibodies correlated with their neutralizing activity as demonstrated in vitro by analysis of STAT1 phosphorylation upon stimulation of healthy donor monocytes in the presence of the appropriate cytokine and patient's or control plasma. Severe viral infections were recorded in 26/41 patients with CID and LS who tested positive and in 7/20 who tested negative for anti-IFN-alpha and/or anti-IFN-omega antibodies (p <0.05). Among those with anti-IFN antibodies, EBV (n = 8), CMV (n = 6), HSV (n = 5), VZV (n = 4) and adenovirus (n = 4) infections were more common. Two patients had COVID-19, which was fatal in one. Presence of the rubella virus was documented in 5 patients with anti-type I IFN antibodies. These results demonstrate that high levels of neutralizing anti-IFN-alpha and anti-IFN-omega antibodies are common in patients with RAG mutations manifesting as CID and LS, but not in those with OS, and that their presence is associated with a high risk of serious viral infections.Copyright © 2023 Elsevier Inc.

Development of warm autoimmune hemolytic anemia after initiation of Ruxolitinib in a patient with STAT1 gain-of-function mutation

Introduction: STAT1 gain-of-function (GOF) disease is associated with chronic mucocutaneous candidiasis (CMC) and a broad spectrum of infectious, inflammatory, and vascular manifestations. The Janus Kinase inhibitor ruxolitinib has been used successfully for CMC and autoimmune phenomena. We describe a case of warm autoimmune hemolytic anemia (WAIHA) in a patient with STAT1 GOF disease after initiating ruxolitinib. Case report: A 36-year-old man with STAT1 c.850G>A (p.Glu284Lys) mutation presented with CMC as well as recurrent viral and bacterial infections, lymphadenopathy, enteritis, nodular regenerative hyperplasia (NRH) and splenomegaly. Immune workup confirmed a combined immunodeficiency with hypogammaglobulinemia and T-cell lymphopenia. Ruxolitinib was initiated at 5 mg twice daily (due to pre-existing thrombocytopenia) with up titration over 3 months to 20 mg twice daily. He improved with weight gain, increased energy, resolution of chronic anemia, and improved lymphadenopathy and splenomegaly on imaging. Serum CXCL9 only minimally decreased from 4660 pg/ml to 3990 pg/ml. Soon after reaching ruxolitinib 20 mg twice daily, he developed JC viremia, prompting dose reduction to 15 mg BID. Within two weeks, he developed a non-COVID upper respiratory tract infection followed by fatigue, shortness of breath with ambulation, and dark urine. Emergency evaluation revealed warm antibody positive hemolytic anemia with a hemoglobin of 5 g/dL, and worsened thrombocytopenia. He was treated with blood transfusions, pulse steroids, and high-dose IVIG with stabilization but continued hemolysis. Due to the JC viremia, there was concern to give rituximab with increased PML risk. Bone marrow showed trilineage hematopoiesis, a mild increase in megakaryocytes and RBC precursors, and a loss of B-cell progenitors with retention of mature B cells. His B and T lymphocyte numbers had increased since prior to ruxolitinib, with a predominance of Tfh1-cells (58.7% of total Tfh-cells). He was started on sirolimus with a slow taper of prednisone with continued stable hemoglobin and platelets, and resolution of hemolysis after 3 months. Conclusion(s): To our knowledge, this is the first case of a STAT1 GOF patient developing WAIHA while receiving ruxolitinib therapy. Treatment choices were complicated by the risks of PML. Sirolimus combined with ruxolitinib allowed wean of corticosteroid and subsequent resolution of hemolysis.Copyright © 2023 Elsevier Inc.

Pims-Ts: The Psychological Needs of Families Admitted to Intensive Care

Background Paediatric Inflammatory Multisystem Syndrome (PIMS-TS) is a rare inflammatory condition affecting children and young people (CYP) weeks after infection with the COVID-19 virus. The aim of this study was to understand the potential psychological needs of these families. Methods PIMS-TS patients and their parents admitted to the hospital between April 2020 and May 2021 were reviewed by a psychologist 6-8 weeks post discharge as part of their clinical care. Young people over the age of 7 were asked to complete 2 measures for psychological distress and PTSD symptoms (CRIES-13 and PIED) and their parent/carer completed a measure of PTSD symptoms (IES-R). Ethical approval was not required for this study. Results 118 CYP and parents/carers who were admitted to GOSH were screened 6-8 weeks post discharge. 85 of the 118 CYP were aged 8 or over. 76.8% (n=91) of parents/carers completed the IES-R 78% (n=66) of CYPs completed the PIED and CRIES. 15% (n=10) of CYPs scores on the PIED suggested they were at risk of anxiety and depression. 24% (n=16) of CYPs reported clinically significant difficulties for PTSD on the CRIES-13 placing them in high probability of for a diagnosis of PTSD. 35% of parents/carers met the threshold for clinical concern on IES-R with 23% (n=21) scoring in the range for a likely diagnosis of PTSD. Discussion The findings of both the self-report screening questionnaires, indicate that significant number for CYP and their parent/carers are at risk of developing symptoms of psychological distress and trauma in 6-8 week period post discharge after PIMS-TS admission. Conclusion The result of this study clearly show identification of high levels of trauma and emotional distress for the CYP and their parents and carers and a potential need for ongoing psychological support to be provided as part of ongoing care.

Evaluation of a Creative Photography Workshop for Children and Young People Following a Diagnosis of Pims-Ts

Background Paediatric Multisystem Inflammatory Syndrome Temporally Associated with SARS-CoV-2 (PIMS-Ts) is a rare inflammatory condition affecting children and young people (CYP). Many CYP report behavioural/mood changes concentration difficulties and increased isolation which for some occurred following an admission to intensive care. This workshop aimed to reduce CYPs' experiences of isolation using a strength-based Narrative Therapy group approach. Methods The workshop was co-facilitated by a photography artist psychologists and ID clinical team in local gallery to create a safe therapeutic space. The workshop involved activities to allow CYP to explore their identity through the use of photography and to enable them to share their stories of their PIMS-TS experiences with their peers. The participants completed pre and post outcome evaluation measures and a free text feedback form. Two weeks following the workshop parents/carers and CYP were contacted to participate in a semi structured interview to evaluate the impact of the workshop on CYP relationship to their health condition and hospital experience. Results The workshop was attended by 9 CYP (aged 8-11 years). Participants indicated that the workshop had led to increased comfort and confidence in talking about their health condition and that they had appreciated the opportunity to meet other CYP. Discussion Feedback suggests that an arts-based workshop was an effective peer support-based psychological intervention. Conclusion These findings suggest that there are psychological benefits to narrative therapy-based arts group for CYP post discharge to share and reflect on their health and hospital experiences with those who have lived through similar experiences. Given that treatment protocols are still being refined for PIMS-TS the findings of this project suggest that CYP and families may benefit from follow-up interventions to better understand and identify their psychological needs post diagnosis.

Flipping the model: A novel approach to expand access and increase capture of ovarian cancer patients for genetic testing

Background Genetic testing for ovarian cancer patients is essential to consideration of PARP inhibitor therapy. To improve access, we piloted a Genetic Testing Station (GTS) which allowed patients to have a drop-in, same-day genetic testing visit facilitated by Genetic Counselor Assistants (GCAs) under the supervision of Genetic Counselors (GCs). Methods The GTS was implemented in December 2018 and operated through February 2020. Gynecologic Oncologist offered ovarian cancer patients a same-day GTS visit with a GCA, where the patient received education via videos designed by GCs. The patient also provided consent, a brief family history, and a sample for a standardized 133-gene panel. Results were provided by a telehealth or clinic visit with a GC. We compared uptake of genetic testing post-GTS, and also time from referral to delivery of testing results. Patients were retrospectively identified by querying the medical record for ovarian cancer patients seen 12 months prior to and 18 months after GTS implementation. Results A total of 482 patients pre-GTS were compared to 625 patients post-GTS. Genetic testing increased from 68.5% to 75.66665% (p = 0.012) after implementation of the GTS, with the majority of the increase in patients with epithelial histologies (80% vs 89% in pre-GTS vs post-GTS, p = 0.005). Time from referral to genetic testing to obtaining results was evaluated in the post-GTS cohort, comparing patients who had traditional counseling to those who utilized the GTS. The time to obtaining results was shorter in the GTS group at 21 days (95% CI [10, 34]) compared to 56 days (95% CI [41,76]) in the traditional genetic counseling group. Discussion The GTS reduces barriers to care and facilitates discussion of precision treatment and prevention strategies with patients and their families in a timely fashion while optimizing Genetic Counselor clinic time. Post-COVID, access improvement remains integral to improving uptake of genetic testing.

NeuroSAFE PROOF. Update on a multi-centre, pragmatic, RCT for men undergoing robot-assisted radical prostatectomy: Trial in progress

Introduction & Objectives: Robot-assisted Radical Prostatectomy (RARP) is an effective cure for organ confined prostate cancer but is associated with considerable post-operative functional toxicity. The NeuroSAFE technique (intra-operative frozen section analysis of the neurovascular structure adjacent margin) may help improve functional outcomes by promoting optimal nerve-sparing (NS) RARP without compromising on oncological outcomes. NeuroSAFE technique has reported favourably in retrospective, single-centre studies but has never been evaluated prospectively by a randomised study. The NeuroSAFE PROOF Feasibility Study has succeeded in demonstrating feasibility and has been succeeded by the fully powered, definitive NeuroSAFE PROOF Randomized Controlled Trial (RCT) (NCT03317990). Materials & Methods: Potent men (IIEF-5>21) with localised prostate cancer at 4 regional uro-oncology centres in the UK (UCLH, Bristol, Sheffield and Glasgow) are eligible. Participants are randomised 1:1 to RARP with NS decision guided by standard of care (clinical information, DRE and pre-operative mpMRI surgical plan) vs. RARP with NS decision guided by standard of care information and the NeuroSAFE technique. The primary outcome is erectile function (EF) recovery assessed by IIEF-5 score at 12-months. Important secondary outcomes include detailed peri-operative outcomes, histological outcomes, post-operative complications, biochemical recurrence rates, urinary continence (assessed by ICIQ), health related quality of life (assessed by Rand-36 and EQ-5D-5L), and health economics. In order to demonstrate a difference of 15% in EF recovery rates between the arms, a total of 404 men will be randomised and treated. Patient follow-up will continue for 5 years after RARP. Results: At the time of writing, 160 men have been recruited and treated with RARP as per random allocation at 4 participating sites. The independent DMC has met twice to ensure the oncological safety of the trial and will continue to review the data at intervals. Covid-19 has led to significant challenges, including suspension of recruitment and difficulties performing follow-up. The trial team have developed new methods of recruitment, consent and follow-up to ensure conduct of the study remains in line with the highest standards of trial conduct, including electronic remote consent processes and remote collection of PROMs. Conclusions: The NeuroSAFE technique has been reported as a method to optimise outcomes for men undergoing RARP for over a decade, but, in the absence of Level 1 evidence, equipoise remains. Despite the Covid-19 pandemic recruitment continues to be favourable. We hope that our

COVID-19 risk perception: a longitudinal analysis of its predictors and associations with health protective behaviours in the United Kingdom. (Special Issue: COVID-19 one year on.)

In this study, we present results from five cross-sectional surveys on public risk perception of COVID-19 and its association with health protective behaviours in the UK over a 10-month period (March 2020 to January 2021). Samples were nationally balanced on age, gender, and ethnicity (total N = 6,281). We find that although risk perception varies between the time points surveyed, it is consistently, significantly, and positively correlated with the reported adoption of protective health behaviours, such as wearing face masks or social distancing. There is also an increase in reported health protective behaviours in the UK between March 2020 and January 2021. The strength of the association between risk perception and behaviour varies by time point, with a stronger relationship in January 2021 compared to March and May 2020. We also assess the stability of the psychological determinants of risk perception over time. People's prosocial tendencies and individualistic worldviews, experience with the virus, trust in government, science, and medical professionals, as well as personal and collective efficacy all emerged as significant predictors. With few exceptions, these predictors remained consistent in their relationship with risk perception over time. Lastly, we find that psychological factors are more predictive of risk perception than an objective measure of situational severity, i.e. the number of confirmed COVID-19 cases at the time of data collection. Implications for risk communication are discussed.

Cardiopulmonary exercise testing to evaluate exercise limitation and shortness of breath in long COVID

S25 Table 1Preliminary CPET data for patients with persistent symptoms following non-hospitalised SARS-CoV2 infection, demonstrating reduced levels of aerobic fitness compared to% predicted, as assessed by oxygen uptake at peak exercise, oxygen uptake at anaerobic threshold (AT) and O2 pulse.Patient number Peak oxygen uptake as% predicted Peak AT as% of peak oxygen uptake O2 pulse as% predicted VEVCO2 slope Breathing reserve (litres/minute) 1 110 69 101 26.9 59 2 70 31 76 22.6 138 3 91 45 80 31.4 36 4 108 63 93 28.1 84 5 81 46 78 27.7 31 6 81 44 82 26.4 71 7 111 47 106 25.4 69 8 61 33 70 27.5 96 9 64 43 78 29.6 40 ConclusionsCPET provided an objective measure of functional limitation in our preliminary patient cohort, profound deconditioning was apparent. Given that our patient has normal cardiac function, it is possible that the reduction in O2 pulse reflects an intrinsic impairment in muscle oxygen utilisation. We have demonstrated similar patterns of exercise limitation in cancer patients undergoing chemotherapy, and subsequent improvements in their exercise training capacity following a 12 week personalised exercise training program.1 Exercise intervention studies are needed in these patients to determine optimal rehabilitation strategies.ReferenceWest, et al. Br J Anaesth. 2015;114(2):244–5.

Neurosafe proof: A multi-centre, pragmatic, RCT for men undergoing robot-assisted radical prostatectomy. update on a trial in progress

INTRODUCTION AND OBJECTIVE: Robot-assisted Radical Prostatectomy (RARP) is an effective cure for organ confined prostate cancer but is associated with considerable post-operative functional toxicity. The NeuroSAFE technique (intra-operative frozen section analysis of the neurovascular structure adjacent margin) may help improve functional outcomes by promoting safe nerve-sparing (NS) RARP without compromising on oncological outcomes. NeuroSAFE technique has reported favourably in retrospective, single-centre studies but has never been evaluated prospectively by a randomised study. The NeuroSAFE PROOF Feasibility Study has succeeded in demonstrating feasibility and has facilitated opening of the full-scale, definitively powered NeuroSAFE Randomized Controlled Trial (RCT) (NCT03317990). We report on the design and progress of the full NeuroSAFE PROOF RCT. METHODS: Potent men (IIEF-5>21) with localised prostate cancer at 4 regional uro-oncology centres in the UK (UCLH, Bristol, Sheffield and Glasgow) are eligible. Participants are randomised 1:1 to RARP with NS decision guided by standard of care (clinical information, DRE and pre-operative mpMRI surgical plan) vs. RARP with NS decision guided by standard of care information and the NeuroSAFE technique. The primary outcome is erectile function recovery assessed by IIEF-5 score >15 at 12-months. Important secondary outcomes include detailed peri-operative outcomes, histological outcomes, post-operative complications, biochemical recurrence rates, urinary continence (assessed by ICIQ), and health related quality of life (assessed by Rand-36 and EQ-5D-5L). Aiming to demonstrate a difference of 15% in erectile function recovery rates between the arms, a total of 404 men will need to be randomised and treated. Patients will continue to be followed for outcomes until 5 years after treatment. RESULTS: At the time of writing, 159 men have been recruited and treated with RARP as per random allocation at the 4 participating sites. The independent DMC has met thrice to ensure the oncological safety of the trial and will continue to review the data at intervals. Covid-19 has led to significant challenges, including suspension of recruitment and difficulties performing follow-up. The trial team have developed new methods of recruitment, consent and follow-up to ensure conduct of the study remains in line with the highest standards of trial conduct. CONCLUSIONS: The NeuroSAFE technique has been reported as a method to optimise outcomes for men undergoing RARP for over a decade, but, in the absence of level 1 evidence, equipoise remains. We hope that our full trial (the first RCT of the NeuroSAFE technique in the world) will provide the evidence to establish whether what has long been a promising technique truly improves outcomes for men undergoing RP.

EOSINOPHILS AND IL-5 RECEPTOR IN COVID-19 POSTMORTEM LUNG TISSUE

TOPIC: Chest Infections TYPE: Original Investigations PURPOSE: Severe COVID-19 infections have been associated with alterations in blood eosinophil counts and elevated blood interleukin (IL)-5 levels [1,2]. The aim of this study was to explore whether eosinophils and IL-5 receptors are observed in post-mortem lung tissue from patients with COVID-19 pneumonia. METHODS: Hematoxylin & eosin (H&E) and immunohistochemical staining (major basic protein [MBP], eosinophil-derived neurotoxin [EDN], interleukin-5 receptor alpha [IL-5Rα] + neutrophil elastase duplex, IL-5Rα + tryptase duplex, and basophils [2D7]) were performed on post-mortem lung tissue samples from 10 patients with COVID-19 pneumonia, 5 patients with non-COVID-19 viral pneumonia, and 5 patients without pneumonia. RESULTS: Low to moderate numbers of eosinophils were identified in H&E-stained samples of post-mortem lung tissue from patients with COVID-19 and non-COVID-19 pneumonia. There was also moderate to marked immunohistochemical expression of IL-5Rα in both pneumonia groups, and some IL-5Rα–expressing cells also expressed neutrophil elastase. IL-5Rα expression did not generally colocalize with tryptase expression, but rare colocalization was also observed in all groups. CONCLUSIONS: Eosinophils and eosinophil activation products are present in COVID-19 lung disease, suggesting that eosinophils may play a role in the pathogenesis of viral pneumonias. Co-expression of IL-5Rα and neutrophil elastase suggests that, within pathological contexts including viral pneumonia, IL-5Ra-dependent processes may influence neutrophil function. CLINICAL IMPLICATIONS: Eosinophil-depleting therapies such as benralizumab may be potential therapeutic agents for COVID-19 disease and other viral pneumonias. REFERENCEs 1. Lucas C, Wong P, Klein J, et al. Longitudinal analyses reveal immunological misfiring in severe COVID-19. Nature. 2020;584(7821):463–9. 2. Rodriguez L, Pekkarinen PT, Lakshmikanth T, et al. Systems-level immunomonitoring from acute to recovery phase of severe COVID-19. Cell Rep Med. 2020;1(5):100078. DISCLOSURES: Employee relationship with AstraZeneca Please note: 7.5 years Added 04/30/2021 by Jennifer Cann, source=Web Response, value=stock grants No relevant relationships by David Chain, source=Web Response Employee relationship with AstraZeneca Please note: 15/06/2020 Added 04/30/2021 by Ron Chen, source=Web Response, value=Salary No relevant relationships by Karma Dacosta, source=Web Response No relevant relationships by Adrian Freeman, source=Web Response Employee relationship with AstraZeneca Please note: 1996 to date Added 04/29/2021 by Andrew Jones, source=Web Response, value=Salary Stock Owner relationship with AstraZeneca Please note: 1996 to date Added 04/29/2021 by Andrew Jones, source=Web Response, value=Stock Owner Employee relationship with astrazeneca Please note: current Added 04/30/2021 by Rohit Katial, source=Web Response, value=Salary Employee relationship with AstraZeneca Please note: July 2019-present Added 04/29/2021 by Allen McAlexander, source=Web Response, value=Salary Employee relationship with AstraZeneca Please note: Jul 1999 to present Added 04/29/2021 by Christopher McCrae, source=Web Response, value=Salary Employee relationship with AstraZeneca Please note: Jul 1999 to present Added 04/29/2021 by Christopher McCrae, source=Web Response, value=Ownership interest No relevant relationships by Hitesh Sanganee, source=Web Response No relevant relationships by WEIGUANG ZHAO, source=Web Response

Risk factors for persistent abnormality on chest radiographs at 12-weeks post hospitalisation with PCR confirmed COVID-19.

BACKGROUND: The long-term consequences of COVID-19 remain unclear. There is concern a proportion of patients will progress to develop pulmonary fibrosis. We aimed to assess the temporal change in CXR infiltrates in a cohort of patients following hospitalisation for COVID-19. METHODS: We conducted a single-centre prospective cohort study of patients admitted to University Hospital Southampton with confirmed SARS-CoV2 infection between 20th March and 3rd June 2020. Patients were approached for standard-of-care follow-up 12-weeks after hospitalisation. Inpatient and follow-up CXRs were scored by the assessing clinician for extent of pulmonary infiltrates; 0-4 per lung (Nil = 0, < 25% = 1, 25-50% = 2, 51-75% = 3, > 75% = 4). RESULTS: 101 patients with paired CXRs were included. Demographics: 53% male with a median (IQR) age 53.0 (45-63) years and length of stay 9 (5-17.5) days. The median CXR follow-up interval was 82 (77-86) days with median baseline and follow-up CXR scores of 4.0 (3-5) and 0.0 (0-1) respectively. 32% of patients had persistent CXR abnormality at 12-weeks. In multivariate analysis length of stay (LOS), smoking-status and obesity were identified as independent risk factors for persistent CXR abnormality. Serum LDH was significantly higher at baseline and at follow-up in patients with CXR abnormalities compared to those with resolution. A 5-point composite risk score (1-point each; LOS ≥ 15 days, Level 2/3 admission, LDH > 750 U/L, obesity and smoking-status) strongly predicted risk of persistent radiograph abnormality (0.81). CONCLUSION: Persistent CXR abnormality 12-weeks post COVID-19 was common in this cohort. LOS, obesity, increased serum LDH, and smoking-status were risk factors for radiograph abnormality. These findings require further prospective validation.

Effect of Information about COVID-19 Vaccine Effectiveness and Side Effects on Behavioural Intentions: Two Online Experiments

The success of mass COVID-19 vaccination campaigns rests on widespread uptake. However, although vaccinations provide good protection, they do not offer full immunity and while they likely reduce transmission of the virus to others, the extent of this remains uncertain. This produces a dilemma for communicators who wish to be transparent about benefits and harms and encourage continued caution in vaccinated individuals but not undermine confidence in an important public health measure. In two large pre-registered experimental studies on quota-sampled UK public participants we investigate the effects of providing transparent communication-including uncertainty-about vaccination effectiveness on decision-making. In Study 1 (n = 2097) we report that detailed information about COVID-19 vaccines, including results of clinical trials, does not have a significant impact on beliefs about the efficacy of such vaccines, concerns over side effects, or intentions to receive a vaccine. Study 2 (n = 2217) addressed concerns that highlighting the need to maintain protective behaviours (e.g., social distancing) post-vaccination may lower perceptions of vaccine efficacy and willingness to receive a vaccine. We do not find evidence of this: transparent messages did not significantly reduce perceptions of vaccine efficacy, and in some cases increased perceptions of efficacy. We again report no main effect of messages on intentions to receive a vaccine. The results of both studies suggest that transparently informing people of the limitations of vaccinations does not reduce intentions to be vaccinated but neither does it increase intentions to engage in protective behaviours post-vaccination.

Comparisons in early and late presentation to Hospital in covid-19 patients

Background The clinical presentation and disease severity in SARS-Cov-2 infection ranges from asymptomatic carriage to death. There is little data regarding the timeframe of symptom onset to presentation to hospital, and disease outcomes. Therefore, we aim to investigate differences between 'early presenters' (< 7 days of symptom onset) and 'late presenters' (>7 days) and their clinical and radiological outcomes. Methods In this retrospective cohort study, symptom onset, epidemiological, and clinical characteristics were collected from patient electronic medical records at University Hospital Southampton Foundation Trust with laboratory confirmed SARS-Cov-2 infection. Logistical regression models were used to explore the relationships between these data and time of presentation to hospital. Results Between March and July 2020, symptom onset data was collected for 626 SARS-Cov-2 positive patients, 574 of whom had chest radiographs (CXR). Early presenters comprised 388 (62%) and 238 (38%) were late presenters. Early presenters were significantly older (p<0.001), more likely to have significant comorbidities-hypertension, thromboembolic and renal disease (p<0.001)- A nd also significantly less likely to report cardinal symptoms of Covid-19;fever, cough, SOB, myalgia, fatigue/malaise, headache (p<0.001). In the cohort overall, the presence of infiltrates was not predictive of adverse outcome (ICU admission, ventilation or death) (p=0.214). Although early presenters were less likely to have infiltrates on their CXR (58% vs 76.8%), (p<0.001), the presence of CXR infiltrates in early presenters demonstrated an increased risk of adverse outcome (OR 1.90, 95% CI 1.11, 3.25). Conclusion We have demonstrated that SARS-Cov-2 infection presents in an heterogenous manner that varies with symptom duration. Atypical presentation of SARS-Cov-2 infection is more common earlier on in disease course, where viral shedding is likely to be higher, and this finding is of note in the context of national criteria for self-isolation and testing. Late presentation is more likely to be associated with radiological change, but this does not reflect an increased likelihood of adverse outcome. Patients who present early in their illness with radiological changes are at increased risk of adverse clinical outcome, suggesting that symptom onset and detection of CXR infiltrates are important for clinical assessment of severity at presentation to hospital in Covid-19.

S3 Comparisons in early and late presentation to hospital in COVID-19 patients

BackgroundThe clinical presentation and disease severity in SARS-Cov-2 infection ranges from asymptomatic carriage to death. There is little data regarding the timeframe of symptom onset to presentation to hospital, and disease outcomes. Therefore, we aim to investigate differences between ‘early presenters’ (< 7 days of symptom onset) and ‘late presenters’ (>7 days) and their clinical and radiological outcomes.MethodsIn this retrospective cohort study, symptom onset, epidemiological, and clinical characteristics were collected from patient electronic medical records at University Hospital Southampton Foundation Trust with laboratory confirmed SARS-Cov-2 infection. Logistical regression models were used to explore the relationships between these data and time of presentation to hospital.ResultsBetween March and July 2020, symptom onset data was collected for 626 SARS-Cov-2 positive patients, 574 of whom had chest radiographs (CXR). Early presenters comprised 388 (62%) and 238 (38%) were late presenters. Early presenters were significantly older (p<0.001), more likely to have significant comorbidities – hypertension, thromboembolic and renal disease (p<0.001) – and also significantly less likely to report cardinal symptoms of Covid-19;fever, cough, SOB, myalgia, fatigue/malaise, headache (p<0.001). In the cohort overall, the presence of infiltrates was not predictive of adverse outcome (ICU admission, ventilation or death) (p=0.214). Although early presenters were less likely to have infiltrates on their CXR (58% vs 76.8%), (p<0.001), the presence of CXR infiltrates in early presenters demonstrated an increased risk of adverse outcome (OR 1.90, 95% CI 1.11, 3.25).ConclusionWe have demonstrated that SARS-Cov-2 infection presents in an heterogenous manner that varies with symptom duration. Atypical presentation of SARS-Cov-2 infection is more common earlier on in disease course, where viral shedding is likely to be higher, and this finding is of note in the context of national criteria for self-isolation and testing. Late presentation is more likely to be associated with radiological change, but this does not reflect an increased likelihood of adverse outcome. Patients who present early in their illness with radiological changes are at increased risk of adverse clinical outcome, suggesting that symptom onset and detection of CXR infiltrates are important for clinical assessment of severity at presentation to hospital in Covid-19.