Anca-Associated but Not Vasculitis

Background/Aims A 72-year-old lady presented in primary care with complaints of generalised body aches, bilateral leg weakness and constitutional symptoms following a first dose of COVID-19 vaccine. Blood tests showed slightly raised inflammatory markers. She was initially diagnosed with polymyalgia rheumatica and was started on 40mg prednisolone with minimal improvement. Methods The examination in the rheumatology clinic was unremarkable. Investigations revealed raised white cell count, consistent with high dose steroid treatment, and elevated monocytes. There was mild improvement in inflammatory markers. The working diagnosis was of self-limiting viral illness. Further testing discovered strongly positive MPO ANCA (115 IU/ml), and the patient received three pulses of 500mg methylprednisolone for suspected vasculitis arranged by the medical team. There was no evidence of renal involvement. The diagnosis made at this point was autoimmune inflammatory disorder with unclear aetiology. At the subsequent clinic visit she reported mild shortness of breath, but no other symptoms suggestive of either vasculitis or connective tissue disease. Repeat ANCA showed significant reduction in MPO titre following pulse steroid treatment. CT of chest, abdomen and pelvis demonstrated a localised lobular/ nodular deformity of the liver. Viral hepatitis screen was negative. CA19-9 was raised at 100 U/ml. Liver biopsy was reported as poorly differentiated carcinoma without specific localising immunohistochemical features. Results The patient underwent hemi-hepatectomy for histologically confirmed pT2pNXM0R0 liver cholangiocarcinoma in a tertiary centre followed by adjuvant chemotherapy with capecitabine. With treatment, her MPO ANCA and CA19-9 levels declined. An interval CT scan of chest, abdomen and pelvis performed ten months after the surgery, showed no recurrence of malignancy. Given the fact that the patient's MPO ANCA fell following the treatment of cholangiocarcinoma, it is likely that positive MPO ANCA is associated with underlying malignancy rather than an active vasculitis. Conclusion This unusual case describes an evolution of the diagnostic process guided by non-specific symptoms and ANCA positivity, arriving at an unexpected diagnosis of malignancy. Although ANCA is a sensitive and specific marker of vasculitides, it can be positive in other conditions particularly hepatitis B, inflammatory bowel disease and autoimmune liver disorders. Malignancy can also be associated with ANCA in the absence of vasculitis. In one study, of 118 ANCA positive patients without ANCA-associated vasculitis, four were found to have malignancy. In a study of 1024 patients who had ANCA tested, 61 patients were found to have malignancy, predominantly haematological and lung cancers. However, after adjustment for sex, age and time of blood draw, no association was found between ANCA status and incidence of cancer. Interestingly, paraneoplastic vasculitis such as polyarteritis nodosa (PAN) has been described in the context of underlying cholangiocarcinoma, and is associated with ANCA rise. Moreover, patients with raised ANCA and PAN also have raised CA 19- 9.

Title: Effect of COVID-19 on Mental Health: The perspectives

The year 2020 saw the emergence of a novel, highly contagious, coronavirus disease (COVID-19) that originated in the Wuhan province of China and spread across the globe. This led to a worldwide pandemic. The World Health Organisation (WHO), within a month of cases being detected, declared the illness as a -public health emergency of international concern". COVID-19 caused by SARS-CoV-2 not only affected the public health resulting in neurological manifestations (headache, dizziness, or cerebrovascular symptoms), but also initiated a plethora of mental health issues like anxiety, depression and suicidal tendencies. Having spread to over 200 countries, this virus has been a dire cause of concern for primarily two reasons: the threat they possess to the physiological and psychosocial health of the individuals;and the fear, anxiety and panic that has arisen as a result of the pandemic. Most nations, including India, underwent a complete lockdown with stringent norms of social distancing, self-isolation, and quarantine (for infected patients). As the nation tried to manage the situation, guidelines were set up for all its citizens by providing personal protective equipment (PPE), instilling practices like wearing a protective mask, gloves and frequent sanitisation in order to curb the spread of disease and safeguard public health. This review discusses the influence of COVID-19 on the mental health of the general population, focusing on the adolescent, pregnant and elderly;its proposed mechanism of action, and possible strategic interventions to protect the people, offer supportive measures to enhance quality of life, and prevent the spread.Copyright © 2020 Ubiquity Press. All rights reserved.

Additional Dose of SARS-CoV-2 Vaccine Increases Neutralization Capacity in Solid Organ Transplant Recipients

Purpose: Solid organ transplant recipients (SOTR) develop weak antibody responses after SARS-CoV-2 vaccination. Published data on neutralizing activity of plasma, a better measure of protection, in SOTR following an additional dose of SARSCoV- 2 vaccine is limited. Method(s): Plasma was longitudinally collected from SOTR following initial COVID- 19 vaccination. Neutralizing activity against SARS-CoV-2 was assessed using the cPass Neutralization Antibody Detection Kit (GenScript, Biotech). ELISAs were performed against SARS-CoV-2 proteins (S1, N, RBD), CMV (glycoprotein B), Influenza A H1N1 (nucleoprotein), HSV-1, EBV glycoprotein (gp350), and tetanus toxoid for comparison. Result(s): Demographic and clinical characteristics are summarized in table 1. No participants had evidence of COVID-19 infection as IgG titers to SARS-CoV-2 N protein were low. Neutralizing activity against SARS-CoV-2 RBD was observed in 39.6% of individuals (N=21/53) ~93 days after initial vaccination. Participants with neutralizing activity were more likely to have received a liver transplant (47.6% vs 6.25%, p=0.001), and less likely to be on an anti-metabolite (52.4% vs. 87.5%, p=0.009) or triple immunosuppression (14.3% vs. 53.1%, p=0.008). After an additional vaccine dose, 78.1% (N=25/32) of participants developed neutralizing activity with significant increases in viral neutralization (figure 1, median 36.8% [95%CI 18.9-64.6] to 97.2% [95%CI 74.0-98.9], p<0.0001). Participants with low neutralizing activity demonstrated adequate antibody titers to other microbial antigens (figure 2). Conclusion(s): An additional dose of SARS-CoV-2 vaccine increased the number of SOTR with neutralizing activity and the magnitude of the seroresponse. SOTR with low neutralizing activity maintain humoral responses to other microbial antigens suggesting the diminished seroresponse might be related to inhibition of new B cell responses.

Immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CART cell therapy

Introduction: Patients with hematologic malignancies are at an increased risk of morbid/mortality from COVID-19. Our prospective clinical study evaluated immune responses to COVID-19 mRNA vaccines in patients with B-cell lymphoma who had received CD19-directed chimeric antigen receptor (CAR) T cell therapy. Methods: We measured SARS-CoV-2 neutralizing activity of plasma from 18 patients and 4 healthy controls (HC) and antibody titers against viral spike proteins (S1, S2, RBD) including their delta variants using an enzyme-linked immunoassay (ELISA). We measured B cell subpopulations in the patients' blood using flow cytometry. Results: We found that the peripheral blood plasma from 3/4 HCs showed substantial SARS-CoV-2 neutralizing activity already at 4 weeks after the first dose of COVID-19 mRNA vaccine while none of the CD19 CART patients evidenced any antibody-mediated neutralizing activity at the same point in time. At 4 weeks after receiving the second dose of the vaccine, all 4 HCs showed complete neutralizing activity. In marked contrast, only 1 of 14 CART patients evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity. Assessing whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CART patients, we found that IgG antibody levels against common microbial and viral antigens like influenza, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and tetanus toxoid, were comparable to those observed in HCs. However, while at 4 weeks post second dose of the vaccine the HCs showed high levels of vaccine-induced IgG antibody titers against all the viral spike proteins (S1, S2, RBD), including the delta variants of the S1 and RBD proteins, the vast majority of our CART patients did not evidence any SARS-CoV-2-specific antibodies. Importantly, a third booster vaccination did not lead to an improvement in the antiviral immunity in the 4 CART patients analyzed. When we assessed B cell subpopulations in the blood of patients and HCs, we found that prior treatments had completely eradicated all CD19+/CD20+ B cells in the patients while numbers of long-lived memory plasma cells were comparable to those of HCs. Conclusions: In this study, 17 of 18 patients with lymphoma who received CD19 CART therapy had very poor immunoreactivity to 1-3 doses of mRNA-based COVID-19 vaccines. Importantly, antibody responses to common recall antigens were preserved, suggesting impaired immune response primarily against novel antigens like SARS-COV-2. This lack of immunoreactivity against novel antigens was probably based on the eradication of earlier-stage B cell subpopulations after treatment with anti-CD19 and anti-CD20 immunotherapies.

Removing the Roadblocks in Equitable Global Access to COVID-19 Vaccine through IPR Waiver

In October 2020, South Africa and India proposed a plan to protect developing nations' interests and ensure a seamless supply of COVID-19 vaccinations. While rich countries have made rapid progress with their immunization programmes, many poor and underdeveloped countries have been left behind to fend for themselves due to patent protection. With the frightening rate at which COVID-19 cases have been emerging, the global population requires immediate and equitable access to life-saving vaccines. In this paper a methodological systematic review of IPR waiver related journal papers and newsletters published from 2019-2021 was performed. Search was conducted through significant scientific databases for relevant publications for this systematic review. This paper discusses to waive IPR in the COVID-19 pandemic, which has received both criticism and praise. Some opponents oppose the IPR waiver because it eliminates rewards for pharmaceutical corporations' R & D efforts. Vaccine development necessitates specialized requirements which cost a lot of money. Along with this, pharmaceutical corporations will be hesitant to take the lead in the future if a situation similar to COVID-19 arises. However, those in favour believe that an IPR waiver can reduce the barriers to countries producing their own vaccines, particularly for the lowest-income nations. Whether the reasoning is correct or incorrect, the timely & equitable distribution of COVID-19 immunizations is critical to the abolition of this pandemic. © 2022, National Institute of Science Communication and Information Resources. All rights reserved.

ADVICE LINE . OF DUTY

Background/Aims Advice lines in Rheumatology services are well established and supported by NICE to provide specialist support and advice to rheumatology patients. During COVID-19 the demand on this service greatly increased due to disruption in appointments, confusion regarding national advice, concerns and fears regarding condition and medication. Although patients were encouraged to refer to national guidance, many found it difficult to interpret therefore continued to access the advice line. Our advice line service largely follows the RCN 2006 guidance regarding service provision. Despite this during COVID-19 the volume of calls increased to up to 100 calls per day during the first lockdown. Support was required to effectively manage these calls with reduced clinical staff. Methods A retrospective review of calls to the advice line compared to the previous year was undertaken from the call log database. A further review of the nature of calls was undertaken for April 2020 and January 2021 where the numbers of calls were at their peak. Data is recorded including time of call, nature of call, advice given and time call returned. Results There was a 130% increase in calls during the first lockdown. This reduced by the early 2021 lockdown to 72%. The majority of calls in April 2020 were related to shielding and risk status (53%). A further 19% of calls were related to medication, these included queries regarding homecare deliveries and delays. 6% were appointment enquiries and they were passed to the administrative team. In January 2021 the majority of calls were related to medication (30%). 19% of calls were regarding the COVID-19 vaccine. There were still 8% of calls regarding shielding. 9% of calls were related to appointments. Pressure on the nursing team was increased due to staff redeployment. Conclusion The analysis of calls during the COVID-19 pandemic highlighted that although there was extensive national guidance produced, many patients still required the support and guidance of their specialist teams to interpret these according to their condition. We believe there is a duty of care for the specialist teams to maintain this level of service during any future events and this should be factored into any decisions regarding redeployment of staff. Appointments and homecare delivery enquiries continued despite directions to alternate numbers, therefore impacted on workload for the clinical nursing team. In order to streamline the service we introduced 'options' to select: option 1 for appointments, option 2 for homecare and option 3 for advice line queries. Option 1 and 2 then directed to the relevant team. Future developments include audit to assess the impact of introducing telephone options;reviewing the funding and scope of the service, which has extended beyond medication and flare advice;and further exploration of text and email platforms.

Long-term outcomes of patients with large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel: Results from the us lymphoma CAR-T cell consortium

Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 27.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 39% progression free survival (PFS) at 2 years post-infusion (Locke, Lancet Onc 2019). We previously reported outcomes of axi-cel patients treated with standard of care therapy at a median follow up of 12.9 months, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 32.4 months, as well as late outcomes of interest including cytopenias, infections and secondary malignancies. Methods and Results: The US Lymphoma CAR-T Consortium comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After median follow-up of 32.4 months (95% CI 31.1 - 34.3), median OS was not reached (95% CI 25.6 - not evaluable) (Figure 1A) with 1-, 2- and 3-year OS of 68.5% (95% CI 62.6-73.7), 56.4% (95% CI 50.1-62.2) and 52.2% (95% CI 45.7-58.2%), respectively. Median PFS was 9 months (95% CI 5.9-19.6) (Figure 1B);1-, 2- and 3-year PFS was 47.4% (95% CI 41.4-53.2), 41.6% (95% CI 35.6-47.5) and 37.3% (95% CI 31.3-43.2), respectively. Twenty-seven PFS events occurred at or after 1 year post infusion;19 events were progressive lymphoma, with the latest relapse observed 28 months after axi-cel infusion. Eight patients died while in remission from their lymphoma: 4 from secondary malignancy, 3 from infection, and 1 from unknown causes. Results of multivariable modeling were similar to our prior analysis: factors associated with both a shorter PFS and shorter OS included male sex, elevated pre-lymphodepletion LDH, and poor ECOG status. Complete blood count and B- and T-cell recovery data were collected at 1 and 2-years post-infusion, excluding patients who had relapsed or been treated for secondary malignancy at time of collection (Table 1). Rates of neutropenia (absolute neutrophil count ≤1000) at 1- and 2- years were 9.2% (10/109) and 11.2% (9/80) and rates of CD4 count ≤200/ul were 62% (23/37) and 27% (7/26). Recovery of B cells was seen in 54% (15/28) and 57% (13/23) at 1-and 2-years post infusion. Infections were reported in 31.2% (34/109) patients between 6- and 12-months post infusion, and 17% (18/109) were severe, requiring either hospitalization and/or IV antibiotics. Twenty-one patients (24%, 21/89) had an infection between 1- and 2- years, 11% of which were severe. Twenty percent (10/49) of patients between 2- and 3-years had an infection and 4 (8%) were severe. Neutropenia, low CD4 counts, and IgG levels were not associated with infection, though patients with infection between 6-12 months were more likely to have received IVIG (p<0.001). No patient in this cohort died of COVID-19. Twenty-two of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=12), AML (n=1), CMML (n=1));other malignancies included squamous cell carcinoma of skin (n=3);sarcoma (n=1);endometrial (n=1);lung (n=1);mesothelioma (n=1) and AITL (n=1). Patients with myeloid malignancy had a median age of 62 at axi-cel apheresis (IQR 56-67), 64% were male and median lines of prior therapy was 4 (IQR 3-6), including 36% with a prior autologous stem cell transplant. Eleven patients were in remission from lymphoma at myeloid malignancy diagnosis, while 3 were diagnosed after progression and interval therapy. Conclusion: This multi-center retrospective study showed similar long-term results to the ZUMA-1 trial, despite including patients who did not meet ZUMA-1 eligibility criteria ba ed on comorbidities. Sixteen percent of PFS events were seen after 1 year, largely due to disease progression. Late infection was common but was not explained by persistent neutropenia or low CD4 counts. Subsequent malignancy, including MDS, occurred in 8% of patients and require further study to better identify patients at risk. (Figure Presented).

Impaired mRNA Based COVID-19 Vaccine Response in Patients with B-Cell Malignancies after CD19 Directed CAR-T Cell Therapy

Introduction: Patients with hematologic malignancies are at an increased risk of morbidity and mortality from COVID-19 disease (Vijenthira, Blood 2020). This is likely a result of combination of immunodeficiency conferred by the disease and the therapeutics. The immunogenicity of the COVID-19 vaccines in patients with exposure to CD19 directed Chimeric Antigen Receptor (CAR)-T cell therapy is not established. CD19 CAR-T cell therapies cause B-cell aplasia, which in turn can affect humoral immune response against novel antigens. Herein, we present results from our prospectively conducted clinical study to evaluate immune responses against mRNA based COVID-19 vaccines in patients with lymphoma who have received CD19 directed CAR-T cell therapy. Methods: All patients and healthy controls were enrolled in a prospective clinical study evaluating immune responses against commercial COVID-19 RNA vaccines in patients with hematologic malignancies. Plasma samples were generated from heparinized peripheral blood of 4 heathy controls (HCs) receiving the same vaccines and 19 B cell lymphoma patients treated with CD19 CAR- T cells. Samples from ~4 weeks post second dose of the vaccine (d56) were available for 14 CAR-T patients, for 5 CAR-T patients samples were available from ~4 weeks after the first dose (d28). Plasma samples were analyzed in an enzyme-linked immunosorbent assay (ELISA) using different full-length recombinant SARS-CoV-2 proteins and control proteins. Neutralizing activity was measured using the cPass Neutralization Antibody Detection Kit (GenScript Biotech). Results: Results from 4 healthy controls and 19 patients (12 males and 7 females) with lymphoma are reported. Median age for the lymphoma patients is 65 years. Eleven patients had large B cell lymphoma, 5 had follicular lymphoma and 3 had mantle cell lymphoma as primary diagnoses. Seventeen patients had advance stage disease (III/IV stage) and had received a median of 3 prior lines of therapy. All patients received CD19 directed CAR-T cell therapy. Ten patients received Moderna vaccine and 9 received Pfizer vaccine. Median time between CAR-T infusion and first COVID-19 vaccine was 258 days. While the peripheral blood plasma from 3/4 HCs already showed substantial SARS-CoV-2 neutralizing activity at ~4 weeks after the first dose of COVID-19 mRNA vaccine, none of the 5 CD19 CAR-T patients analyzed evidenced any antibody-mediated neutralizing activity in their blood at the same point in time (Figure 1A). Around 4 weeks after receiving the second dose of the vaccine, all 4 HCs tested evidenced complete or almost complete neutralizing activity (Figure 1B). In marked contrast, only 1 out of 14 CAR-T patients analyzed evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity in their blood (Figure 1B). Interestingly, when we asked whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CAR-T patients, we found that that was clearly not the case since anti-Flu, -TT, and -EBV responses were equivalent to the ones observed in HCs (Figure 2A). However, while at ~4 weeks post second dose of the vaccine the HCs showed marked antibody titers against all the viral spike proteins including their “delta” variants (Figure 2B), that was not the case for our CAR-T patients. The vast majority of our CAR-T patients did not evidence IgG antibody responses against any of the SARS-CoV-2 proteins analyzed such as S1, S1 delta, RBD, RBD delta, or S2 (Figure 2B). Conclusion: In this prospectively conducted clinical study, 18 of 19 patients with lymphoma who have received CD19 CAR-T therapy had poor immunogenicity against mRNA based COVID-19 vaccines as measured by neutralization assays and antibody titers. The antibody titers against B.1.617.2 (delta variant, S1 and RBD protein) were also demonstrably poor. The antibody response to common pathogens (flu, EBV, TT) were preserved, suggesting impaired immune response against novel antigens. Long-term follow-up of this study is ongoin . APR and DJ contributed equally [Formula presented] Disclosures: Dahiya: Kite, a Gilead Company: Consultancy;Atara Biotherapeutics: Consultancy;BMS: Consultancy;Jazz Pharmaceuticals: Research Funding;Miltenyi Biotech: Research Funding. Hardy: American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees;InCyte: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees.

LESSONS FROM INTERNET USE AND PERFORMANCE DURING COVID-19

When COVID-19 hit, many people began working, going to school, and living much of their lives from home. The Internet was a gateway to the world. This article uses data from Internet speed tests, consumer complaints, search engine optimization tools, and logs of Internet use from public libraries to understand the effects of the pandemic on Internet use and performance. Despite reports that the Internet handled the surge in traffic well, we find that complaints about Internet speed nearly tripled, and performance was degraded. Downstream data rates changed little, but median upstream data rates at midday dropped by about a third. When discussing Internet performance, people typically focus on downstream. This focus should shift. Internet service providers and policymakers should reduce the asymmetry by changing how infrastructure is designed, how Internet services are advertised, how regulators write transparency rules, and how government defines "broadband" in subsidy programs intended to reduce the digital divide. We also find significant increases in the use of many important categories of online content, including those used for work communications, education, grocery shopping, social media, news, and job searches. This shows the importance of the Internet during the crisis. Many people without Internet at home turned to public Wi-Fi hotspots during the pandemic. We find that this occurred disproportionately in neighborhoods with more students. Future distance learning initiatives should consider the challenges some students face in obtaining Internet access.

Role of blockchain in forestalling pandemics

The unexpected development and quick;however, the uncontrolled overall spread of the Coronavirus shows us the disappointment of existing human services observation frameworks to convenient handle general wellbeing crises. In spite of the fact that upgrades in medicinal services observation have been understood, these still miss the mark in forestalling commotion. Absence of important advances taken to guarantee control and following of the infection have bothered the circumstance. Blockchain innovation has progressively been referenced as an instrument to help with different parts of various applications. This paper highlights the role of blockchain in forestalling the future of pandemics. Various use cases of blockchain technology that can help in the battle against the COVID-19 are also highlighted in this paper. © 2020 IEEE.

ROLE OF COVID AS A CATALYST IN INCREASING ADOPTION OF OTTS IN INDIA: A STUDY OF EVOLVING CONSUMER CONSUMPTION PATTERNS AND FUTURE BUSINESS SCOPE

COVID-19 is an unprecedented global pandemic which has changed the way audience consume media. An undeniable trend surfaced in this period- adoption of OTTs. There are many reports which point to the growing market and consumer appetite for content of choice available on OTT platforms. OTTs offer a never before consumer advantage- choice of content, ease of access, choice of device / mediums (hand phone, laptop, tablet or TV screen). Gone are the days when family members fought for screen time of choice on family’s singular home device i.e. TV. With this study, the researchers studied the evolution of OTT space in India and reviewed the dynamic OTT space - evaluate some firsts like big banner movie releases on platforms like Amazon and Netflix, return of old content like Mythological programmes from the DD era on Hotstar etc. To complete the study, it was imperative to evaluate the impact of growing content consumption on psychographics across generations (children, adults and elderlies) as there is limited censorship in the OTT space. With this background, the researchers workedon the objectives and tried to evaluate the role played by the pandemic in evolving OTT media consumption trends;a qualitative mapping of increase in OTT adoption - Pre and Post COVID 19 in India;study underlying trends around increasing consumer appetite for the medium and analyse psychographic impact on children, adults and elderlies - listing pros and cons for freely available content with minimal censorship. The researchers adopteda combined qualitative and quantitative approach to extrapolate the data. A survey was also conducted to do audience mapping and analysis.In addition to primary data, content from news articles, industry research reports, international journals for accumulation of key trends were analysed. © 2020. All Rights Reserved.