Managing severe warm autoimmune haemolytic anaemia after the SARS-Cov- 2 vaccine with emergency splenectomy and eculizumab

Autoimmune haemolytic anaemia (AIHA) is rare but described after the SARS-CoV- 2 Pfizer-BioNTech vaccine. We present a case of severe refractory warm AIHA after this vaccine, managed with emergency splenectomy and complement inhibition with eculizumab. A male in his teens with a history of liver transplant for biliary atresia (aged 2 years) and AIHA (aged 6 years) presented to his district general hospital with jaundice, dark urine, fatigue and chest discomfort 48 h after the first dose of SARS-CoV- 2 Pfizer-BioNTech vaccine (BNT162b2 mRNA). Investigations revealed haemoglobin (Hb) of 70 g/L and bilirubin of 98 mumol/L, which was treated as AIHA. The patient initially responded to prednisolone (1 mg/kg, 60 mg) but subsequently deteriorated and failed to respond to second-line rituximab (375 mg/m2) and two units of packed red blood cells (PRBC). By day 29 the patient had developed life-threatening anaemia culminating in a Hb of 35 g/L (after transfusion), lactate dehydrogenase (LD) of 1293 units/L and bilirubin of 228 mumol/L. This necessitated an immediate transfer to our tertiary centre for specialist support. Further investigations revealed a haptoglobin <0.1 g/L and direct antiglobulin test (DAT) strongly positive for IgG (4+) and negative for C3d. The peripheral blood film showed severe anaemia, nucleated red cells, anisocytosis and spherocytes with no autoagglutination, schistocytes or platelet clumps. Thrombocytopaenia (platelets 49 +/- 109/L) was present. Differentials were ruled out, such as paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopaenia. HIV and hepatitis serology were negative, as were adenovirus, cytomegalovirus and Epstein-Barr virus PCR assays. A CT showed splenomegaly of 15.5 cm. Urinalysis found urobilinogen and bilirubin at high concentrations and negative urinary haemosiderin. Together, the investigations were consistent with warm AIHA. On day 29, four units of PRBC were transfused alongside 100 mg methylprednisolone and 1 g/kg IVIG. On day 30 the patient deteriorated despite the escalated treatment: Hb had only increased to 54 g/L, bilirubin was 200 mumol/L and LD was rising. Considering this life-threatening fulminant haemolysis, an emergency splenectomy was performed. This slowed haemolysis but did not completely ameliorate it: by day 33 the patient had received 15 units of PRBC. Thus, eculizumab, a terminal complement pathway inhibitor, was trialled to arrest intravascular haemolysis, alongside rituximab, repeat IVIG 1 g/kg, prednisolone 40 mg and tacrolimus 2 mg. This showed a favourable response, requiring less frequent transfusions and settling haemolysis. This case highlights the rare complication of warm AIHA with the SARS-CoV- 2 Pfizer-BioNTech vaccine, the use of emergency splenectomy for disease control, and the potential of eculizumab for refractory cases.

Factors affecting blood culture contamination rates and effective reduction measures

Blood culture collection is a crucial procedure used universally in hospital settings to identify bloodstream infections. A false positive culture arises when contamination occurs during culture collection or when handling the culture in the laboratory. These contaminated cultures cause inaccurate diagnoses resulting in longer hospital stays, increased cost, and unnecessary antimicrobial treatments. It is therefore vital to limit the rate of blood culture contamination. Here we discuss various factors that play roles in blood culture contamination rates. The roles of phlebotomy teams, the coronavirus disease 2019 pandemic, blood draw location, and hospital department on blood culture contamination rates will be discussed. Potential methods that can be deployed to decrease blood culture contamination rates will be compared. Copyright (C) 2022 Wolters Kluwer Health, Inc. All rights reserved.

Global uncertainty in the diagnosis of neurological complications of SARS-CoV-2 infection by both neurologists and non-neurologists: An international inter-observer variability study.

INTRODUCTION: Uniform case definitions are required to ensure harmonised reporting of neurological syndromes associated with SARS-CoV-2. Moreover, it is unclear how clinicians perceive the relative importance of SARS-CoV-2 in neurological syndromes, which risks under- or over-reporting. METHODS: We invited clinicians through global networks, including the World Federation of Neurology, to assess ten anonymised vignettes of SARS-CoV-2 neurological syndromes. Using standardised case definitions, clinicians assigned a diagnosis and ranked association with SARS-CoV-2. We compared diagnostic accuracy and assigned association ranks between different settings and specialties and calculated inter-rater agreement for case definitions as "poor" (κ ≤ 0.4), "moderate" or "good" (κ > 0.6). RESULTS: 1265 diagnoses were assigned by 146 participants from 45 countries on six continents. The highest correct proportion were cerebral venous sinus thrombosis (CVST, 95.8%), Guillain-Barré syndrome (GBS, 92.4%) and headache (91.6%) and the lowest encephalitis (72.8%), psychosis (53.8%) and encephalopathy (43.2%). Diagnostic accuracy was similar between neurologists and non-neurologists (median score 8 vs. 7/10, p = 0.1). Good inter-rater agreement was observed for five diagnoses: cranial neuropathy, headache, myelitis, CVST, and GBS and poor agreement for encephalopathy. In 13% of vignettes, clinicians incorrectly assigned lowest association ranks, regardless of setting and specialty. CONCLUSION: The case definitions can help with reporting of neurological complications of SARS-CoV-2, also in settings with few neurologists. However, encephalopathy, encephalitis, and psychosis were often misdiagnosed, and clinicians underestimated the association with SARS-CoV-2. Future work should refine the case definitions and provide training if global reporting of neurological syndromes associated with SARS-CoV-2 is to be robust.

Speaking of Online Learning: Alternative Practice-Based Learning Experiences for Speech Pathologists in Australia, Ghana and Hong Kong

Speech Pathology programs usually send students to workplaces to learn clinical skills necessary for practice. During COVID-19, programs needed to respond quickly to ensure that students continued to gain the necessary experiences and skills required to progress through their program and graduate as clinicians, while simultaneously complying with COVID-19 requirements. Case studies from seven different universities in Australia, Ghana and Hong Kong described the diverse ways in which placements were adapted to be COVID-safe, taking into account local needs. Some practices which had been included in placement education prior to the pandemic, such as telepractice and simulation-based learning, were extended and developed during this time. Educators, students, clinicians and clients responded to the rapidly changing needs of the time with flexibility and innovation, utilising a variety of technologies and tools to support case-based and virtual learning opportunities. Feedback from these diverse stakeholders about the experiences was positive, despite inevitable limitations and less-than-ideal circumstances. The positive findings provided insights for consideration in the future: could strategies implemented in response to the pandemic continue to be incorporated into placement experiences, enhancing current practices and maintaining student performance outcomes? Exceptional circumstances prompted exceptional responses;flexibility and innovation were accelerated in response to the pandemic and may transform future placement-based learning opportunities. © 2022 Jemma Skeat, Josephine Ohenewa Bampoe, Susan Booth, Emily Brogan, Maya Conway, Rachel Davenport, Simone Howells, Peggy Kan, Michelle Krahe, Sally Hewat, Abigail Lewis, Alex Little, Joanne Walters, Gwendalyn Webb, & Nikki Worthington. This Open Access article is distributed under the terms of the Creative Commons Attribution Attribution-Non-Commercial No Derivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited and is unaltered.

Supporting a statewide policy consideration: Virtual advancing educational leadership training during COVID-19

COVID-19 pandemic was and continues to be a shock and a challenge to the entire world. This health and safety challenge found its way into the world of higher education, even in programs that were already delivered in online environments. In this study, we examined the perceptions of 79 developing principals enrolled in a Master of Education Degree program in Educational Administration at Texas A&M University in the United States as they processed the efficacy of a virtual professional development (VPD) leadership for a state certificate in Advancing Educational Leadership (AEL). The state agency has required AEL as a 3-day state-mandated face-to-face training which is a basic requirement for school leaders who evaluate teachers. In fact, per state policy, AEL was delivered in a face-to-face format since it began in 2015, but was transformed to a VPD format in 2020, for the first time, as a response to safety concerns resulting from the COVID-19 pandemic. The Texas Education Agency indicated that the training would go back to a face-to-face format after Fall 2021;however, recently the Agency determined that virtual training could continue, along with face-to-face. Initially, this study was conducted to add information to the policy consideration as to whether to leave the option open for university principal preparation programs to offer the AEL virtually or face-to-face;however, with the alteration of the policy and with the findings of the study, we now provide empirical support, based on a a concurrent triangulation mixed methods design, for the Agency's policy action. This study might be the first published in support of this AEL training policy.

A DIFFUSIVE SEIR MODEL FOR COMMUNITY TRANSMISSION OF COVID-19 EPIDEMICS: APPLICATION TO BRAZIL

A mathematical model incorporating diffusion is developed to describe the spatial spread of COVID-19 epidemics in geographical regions. The dynamics of the spatial spread are based on community transmission of the virus. The model is applied to the outbreak of the COVID-19 epidemic in Brazil. © 2022 Mathematics in Applied Sciences and Engineering. All rights reserved.

Global variability in admission to intensive care units for patients with chronic liver disease and COVID-19: International registry data

Background: The COVID-19 pandemic has provided a unique opportunity to evaluate global intensive care unit (ICU) admission practices. Patients with chronic liver disease (CLD) and cirrhosis may have limited or variable access to ICU. We aimed to describe international ICU admission rates and outcomes in critically-ill patients with CLD and COVID-19. Methods: Data were combined from two international registries (SECURE-Liver and COVID-Hep) for patients with CLD and lab-confirmed COVID-19 deemed sick enough to require ICU admission by the reporting clinician. Rates of ICU admission or decline, and respective outcomes were compared by country. We performed a secondary analysis comparing ICU admissions/declines and outcomes from the United States (US) and United Kingdom (UK), the two greatest contributing countries. Results: Between 25 March 2020 and 3 February 2021, 319 patients with CLD and COVID-19 from 27 countries were deemed to require ICU care. There was considerable country-level variability in ICU decline rates (Figure 1A), although mortality following ICU admission was similar by country (Figure 1B). Rates of ICU admission differed significantly between the US (75/79, 95%) and UK (22/77, 29%) (p<0.001). However, there were no differences in the US and UK in mortality after ICU admission (42/75 [56%] vs. 10/22 [45%];p=0.468;Figure 1B) or mortality after invasive ventilation (29/59 [49%] vs. 9/17 [53%];p=1.000). Both in those requiring ICU admission and admitted to the ICU, there were no differences in age, sex, Charlson Comorbidity Index or Child Pugh Score. Only four US patients were declined ICU admission of whom 2 (50%) died compared to 55 UK patients declined ICU admission of whom 51 (93%) died. Baseline factors associated with being declined ICU admission in the UK were older age, alcohol-related liver disease, and Child B/C cirrhosis. In both US and UK cohorts, the reason for not admitting patients to ICU was due to this being deemed inappropriate (futile) by the responsible clinician, except for one case in both countries in which no ICU bed was available. Information relating to patient goals of care, longterm outcomes in survivors, and granular detail regarding organ support requirements were not available. Conclusion: Patients with CLD and critical COVID-19 were over 3-times more likely to be admitted to ICU in the US than the UK despite having similar baseline characteristics. However, the rates of mortality following ICU admission were comparable between the two countries. ICU bed availability was not a key factor in decline rates. The differing thresholds for escalation to ICU with similar post admission outcomes warrants further discussion.

Fxr as a new therapeutic target for COVID-19

Background: Despite recent advances, the management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. Modifying the expression of the SARS-CoV-2 entry receptor ACE2 could prevent viral infection and limit disease progression. Here, we identify that ACE2 expression is controlled by the transcription factor farnesoid X receptor (FXR) and demonstrate that ACE2 downregulation through FXR antagonism, using approved drugs, such as ursodeoxycholic acid (UDCA), could represent a novel therapeutic strategy to complement current approaches. Methods: Primary cholangiocyte, pulmonary and intestinal organoids were propagated using established protocols. Marker expression was assessed using singlecell RNA sequencing, QPCR, immunofluorescence and flow cytometry. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Viral load was measured via QPCR. Human livers not used for transplantation were perfused ex-situ using the metra (OrganOx) normothermic perfusion device. Serum ACE2 activity was measured with commercial kits. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching. Results: FXR activation directly upregulated ACE2 transcription in organoids from COVID19 affected tissues, including the biliary, gastrointestinal and respiratory systems. Conversely, FXR antagonism with z-guggulsterone or UDCA, had the opposite effect. Importantly, both drugs reduced susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. Furthermore, systemic administration of UDCA in human organs perfused ex-situ downregulated ACE2 and reduced SARS-CoV-2 infection ex-vivo. Oral UDCA rapidly reduced serum ACE2 in vivo. Registry data showed a correlation between UDCA administration and better clinical outcomes in COVID19 patients, including hospitalisation, ICU admission, mechanical ventilation and death. Conclusion: We discovered FXR as a novel therapeutic target against SARS-CoV-2 and we identified approved FXR inhibitors which could be repurposed to potentially treat COVID19, paving the road for future clinical trials to validate these results.

Intensive care unit (icu) escalation more likely among liver transplant (lt) recipients with sarscov-2 compared to patients with decompensated cirrhosis

Background: A number of factors can inform ICU escalation decisions, including the likelihood of survival and patient co-morbidities. This study examined prior liver transplant (LT) recipients and patients with chronic liver disease (CLD) diagnosed with SARS-CoV-2, and compared the rate of ICU admission and decline amongst those who were sick enough to require ICU care. Methods: Patient data from 12 March 2020 to 6 May 2021 was extracted using two international reporting registries (SECURE-Liver and COVID-Hep). Patients had a history of LT or CLD, laboratory-confirmed SARS-CoV-2, and were deemed ill enough to require ICU care. Patients were either admitted to the ICU, or declined admission due to inadequate capacity or because ICU escalation was deemed inappropriate. We compared patient characteristics by ICU decline, and compared ICU decline rates by LT and CLD categories with unadjusted and multivariable logistic regression. Results: 173 LT recipients were admitted to the hospital with SARS-CoV-2 (transplant year 1986-2020, median age 63, 74% male), and 66 (38.2%) were deemed unwell enough to require ICU care. Among those sick enough to require ICU care, 55 (83.3%) were admitted to the ICU and 11 (16.7%) were declined admission. Compared to those admitted to the ICU, patients declined ICU admission were significantly older (median 69 yrs vs 62 yrs, p=0.01) but otherwise similar in other characteristics. ICU decline rates in prior LT recipients (16.7%) were similar to patients with non-cirrhotic CLD (16.1%, p=0.96), but substantially lower than patients with Child A cirrhosis (31.8%, p=0.03), Child B cirrhosis (37.1%, p=0.006) and Child C cirrhosis (38.7%, p=0.004). Differences in ICU decline between LT recipients and Child B or C cirrhosis remained statistically significant after adjustment for age, sex and major co-morbidities. Among patients admitted to the ICU, mortality was higher in LT recipients compared to non-cirrhotic CLD (OR 0.31, 95% CI 0.14-0.71) but lower in LT recipients compared to Child C cirrhosis (OR 3.85, 95% CI 1.47-10.11) after adjustment for age, sex and co-morbidities (see Figure 1). Conclusion: ICU decline was less likely in LT recipients compared to patients with decompensated cirrhosis. LT recipients may be seen as gaining more benefit from ICU care, given the higher mortality amongst patients with decompensated cirrhosis. This is in line with prior data showing decompensated cirrhosis is a predictor of higher mortality in patients with SARS-CoV-2. Moreover, large investment of resources in LT recipients may make them more likely to be admitted to the ICU.

Fxr antagonists as new agents for COVID19

Introduction The management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. The viral receptor ACE2 is an ideal target as it is required for SARS-CoV-2 entry in host cells. Modifying ACE2 expression could prevent infection and/or limit disease progression. Nevertheless, the mechanisms controlling ACE2 expression remain elusive. Aims To identify pathways controlling the transcriptional regulation of ACE2, and exploit them to reduce SARS-CoV-2 infection. Methods Organoids from primary biliary, intestinal and pulmonary epithelia were derived and cultured as previously described. Single-cell RNA sequencing, QPCR, immunofluorescence and flow cytometry were used to assess marker expression. Chromatin immunoprecipitation was used to assess FXR binding on DNA. Bronchoalveolar lavage SARS-CoV-2 patient isolates were used for infection experiments. Human livers not used for transplantation were connected to the metra (OrganOx) normothermic perfusion device and perfused ex-situ using therapeutic doses of UDCA for 12 hours. ACE2 activity was measured following manufacturer's instructions. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching for sex, age and Child-Turcotte-Pugh score. Results We first demonstrated that cholangiocytes are susceptible to SARS-CoV-2 infection in vivo and in organoid culture. We then used cholangiocyte organoids to identify FXR as a transcriptional regulator of ACE2. We validated our results in pulmonary and intestinal organoids, showing that ACE2 regulation by FXR represents a broad mechanism present in multiple COVID19-affected tissues. We then demonstrated that approved FXR inhibitors, such as ursodeoxycholic acid (UDCA) and z-guggulsterone (ZGG), decrease ACE2 levels and reduce viral infection in vitro in primary biliary, intestinal and pulmonary organoids. We interrogated the impact of systemic UDCA administration in human livers perfused ex-situ, demonstrating reduced ACE2 levels and SARS-CoV-2 infection. Furthermore, we showed that commencing UDCA treatment lowers ACE2 levels in primary biliary cholangitis (PBC) patients. Finally, we identified a correlation between UDCA treatment and better clinical outcome in COVID-19 patients, including hospitalisation, ICU admission, mechanical ventilation and death, using registry data. Conclusion We identified FXR as a novel master regulator of ACE2 expression. Using a bench-to-bedside approach we combined in vitro, ex-vivo and patient data to demonstrate the efficacy of ACE2 downregulation against SARS-CoV-2 infection and identified approved and inexpensive drugs (UDCA, ZGG) which could be repurposed as prophylactic and therapeutic agents against SARS-CoV-2 infection, paving the road for future clinical trials.

ANALYSIS OF A REACTION–DIFFUSION EPIDEMIC MODEL WITH ASYMPTOMATIC TRANSMISSION

We develop a dynamic model of an evolving epidemic in a spatially inhomogeneous environment. We analyze the model, as a system of reaction–diffusion partial differential equations, to predict the outbreak and spatio-temporal spread of the disease. The model features both an asymptomatic infectious stage and symptomatic infectious stage, with both the asymptomatic and the symptomatic infected populations dispersing through the susceptible population. We prove the existence and uniform boundedness of solutions, and investigate their long-time behavior. We apply the spatially homogeneous version of the model to the current COVID-19 epidemic in Brazil.

Predicting the number of reported and unreported cases for the COVID-19 epidemics in China, South Korea, Italy, France, Germany and United Kingdom.

We model the COVID-19 coronavirus epidemics in China, South Korea, Italy, France, Germany and the United Kingdom. We identify the early phase of the epidemics, when the number of cases grows exponentially, before government implementation of major control measures. We identify the next phase of the epidemics, when these social measures result in a time-dependent exponentially decreasing number of cases. We use reported case data, both asymptomatic and symptomatic, to model the transmission dynamics. We also incorporate into the transmission dynamics unreported cases. We construct our models with comprehensive consideration of the identification of model parameters. A key feature of our model is the evaluation of the timing and magnitude of implementation of major public policies restricting social movement. We project forward in time the development of the epidemics in these countries based on our model analysis.

A COVID-19 epidemic model with latency period.

At the beginning of a COVID-19 infection, there is a period of time known as the exposed or latency period, before an infected person is capable of transmitting the infection to another person. We develop two differential equations models to account for this period. The first is a model that incorporates infected persons in the exposed class, before transmission is possible. The second is a model that incorporates a time delay in infected persons, before transmission is possible. We apply both models to the COVID-19 epidemic in China. We estimate the epidemiological parameters in the models, such as the transmission rate and the basic reproductive number, using data of reported cases. We thus evaluate the role of the exposed or latency period in the dynamics of a COVID-19 epidemic.