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Objective To assess adaptive immunity to SARS-CoV-2 in anti-CD20 treated individuals with mRNA vaccination. Background Anti-CD20 therapies attenuate humoral responses to vaccines. However, their effect on T cell responses is less clear. We examined B and T cell responses following COVID-19 vaccination in patients receiving anti-CD20 therapy for multiple sclerosis (MS) and other autoimmune inflammatory neurologic diseases (AINDs, e.g., autoimmune encephalitis, stiff person syndrome, etc.). Design/Methods MS and AIND patients on anti-CD20 therapies were prospectively enrolled for longitudinal analysis of antibody and T cell responses after a 3rd COVID-19 vaccination. Serum antibodies against the receptorbinding domain of the S1 spike protein (RBD-S1 IgG), neutralizing antibodies, and SARS-CoV-2 CD8 T cell responses, using activationinduced markers (AIM) and INF-gamma release assays (EUROIMMUN, Germany), were measured at various time points including prevaccination, post initial vaccination series, and 4 and 12 weeks after 3rd dose. Results Thirty-four MS and AIND participants are enrolled. Results for these patients (mean age 52 years-old, 79% female, 21 Pfizer, 13 Moderna) demonstrated attenuated RBD IgG antibody responses. However, a robust CD8 T cell response was observed, following a two-dose series, compared to non-immunosuppressed, age-matched vaccinated controls or unvaccinated with severe SARS-CoV-2 infection (p = 0.01). T cell response was sustained long-term (>12 weeks post 3rd dose) in all 11 anti-CD20 patients analyzed thus far. Collections are completed for all participants at 12 weeks and analysis to be completed by 05/15/22. Further analysis includes correlation of the INF- gamma release assay compared to RBD-CD8 T cell response detected by AIM assay. Conclusions Results suggest that patients treated with anti-CD20 therapy generate a robust CD8 T cell response to SARS-CoV-2 mRNA after three doses but remain with attenuated humoral immune responses. Our observational study will provide important data to guide vaccine management in patients on or anticipating anti-CD20 therapy.
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Objective: To assess adaptive immunity to SARS-CoV-2 in anti-CD20 treated individuals with mRNA vaccination as it relates to spike binding IgG, neutralizing antibody titers, and T cell response. Background: Anti-CD20 therapies attenuate humoral responses to vaccines. Their effect on T cell responses is unclear. We examined B and T cell responses with COVID-19 vaccination in patients receiving anti-CD20 therapy for multiple sclerosis (MS) and other autoimmune inflammatory neurologic diseases (AINDs). Design/Methods: Patients on anti-CD20 therapies were prospectively enrolled for longitudinal analysis of antibody and T cell responses before and after COVID-19 vaccination. Serum antibodies against the receptor-binding domain of the S1 spike protein (RBD-S1 IgG), neutralizing antibodies, and SARS-CoV-2 CD4 and CD8 T cell levels responses using activation-induced markers and INF-gamma release assay were measured at various time points including pre-vaccination, less than 12 weeks and greater than 12 weeks post initial vaccination series, and 4 and 12 weeks after 3rd “booster” vaccination. Results: Twenty-five MS and AIND participants are enrolled as of 10/11/21 with projected enrollment complete by December 2021 (50-60 total). Preliminary results for 17 of these patients (mean age 44 years-old, 83% female, 16 Pfizer, 1 Moderna) demonstrated attenuated RBD IgG antibody responses. However, CD8 T cell response is robust compared to non-immunosuppressed, age-matched controls (n=22) less than 12 weeks after two dose series (p value = 0.0069) and sustained long-term (>12 weeks) in all eight anti-CD20 patients tested thus far. Additional analysis will include comparison between pre and post 3rd vaccination at 4- and 12-week timepoints. Conclusions: Early results suggest that patients treated with anti-CD20 therapy generate a robust CD8 T cell response to SARS-CoV-2 mRNA post initial series of vaccination but remain with attenuated humoral immune responses. Our observational study will provide important data to guide vaccine management in patients on or anticipating anti-CD20 therapy.
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Objective: To evaluate the frequency of infusion-related reactions (IRRs) and PROs following administration of ocrelizumab (OCR) as a 2-hour home infusion. Background: Home-based infusion of multiple sclerosis (MS) drugs may be a safe and convenient treatment during the SARS-CoV-2 pandemic. Design/Methods: 100 MS patients from Rocky Mountains MS Center who fulfill these criteria: 18-55 years;relapsing or primary progressive MS;completed first 600-mg dose of OCR;had neurologist-approved-therapy-monitoring labs;resided in area with 911 access;completed PROs in English;and no >/Grade 3 IRR in prior infusions. Patients completed majority of study visits in home or via telehealth. Primary outcome is IRRs with common terminology criteria for adverse events (CTCAE) collected at the infusion visit, 24 hours post-infusion, and 2 weeks post infusion via telehealth. Patients were asked to compare their home infusion vs last OCR infusion using PROs measuring infusion experience, nurse responsiveness and confidence in receiving a home infusion. Standard statistical methods were used for proportions and change scores. Results: Currently 51/100 patients have received a home infusion. Mean age of 42.5 years (SD +/ - 8.34);73% female;89% white;96% with relapsing MS;mean MS duration 8.8 years;3.3 years on OCR. Only 15.70% (95% CI: (7.02%, 28.59%) experienced an IRR, all classified as Grade 1. CTCAEs were self-reported in 82.35% of patients. Most common by occurrence were fatigue (n=21), itching (n=19), headache/migraine (n=10) and tingling (n=9). No SAEs were reported. These PROs showed improvements pre vs post home infusion (range 1-5, higher is better): nurses explained things clearly (pre=3.78, post=3.94;p=0.01);confidence in nurses administering infusion (pre=4.40, post=4.67;p=0.02);felt safe and respected during infusion (pre=4.45, post=4.69;p=0.03);felt comfortable in surroundings (pre=3.98;post=4.65;p<0.0001);worries about safety and AEs decreased (pre=3.75;post=4.16;p=0.008). Conclusions: Interim analysis of OCR home infusion safety and experience is encouraging.
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Background. Although CRE are a global threat, data in low- and middle-income countries are scarce. Colonization data are vital for informing antibiotic resistance strategies. We characterized the colonization prevalence of CRE in various settings in Botswana. Methods. This study was conducted in 3 districts in Botswana (1 hospital and 2 clinics per district). Adult inpatients and clinic patients were randomly selected for enrollment. Community subjects were enrolled by inviting each enrolled clinic subject to refer up to 3 adults. Each adult clinic or community subject was also asked to refer their children. All subjects had rectal swabs obtained and inoculated on selective chromogenic media for preliminary identification of CRE. Final identification and susceptibility testing were performed using MALDI-TOF MS and VITEK-2, respectively. CRE underwent genotyping for carbapenemase genes. Results. Subjects were enrolled from 1/15/20-9/4/20 with a pause from 4/2/20-5/21/20 due to a countrywide COVID lockdown. Of 5,088 subjects approached, 2,469 (49%) participated. Enrollment by subject type was: hospital - 469 (19%);clinic - 959 (39%);community adult - 477 (19%);and community child - 564 (23%). Of 2,469 subjects, the median (interquartile range) age was 32 years (19-44) and 1,783 (72%) were female. 42 (1.7%) subjects were colonized with at least one CRE;10 subjects were colonized with multiple strains. E. coli (n=17), K. pneumoniae (n=20), and E. cloacae complex (n=11) were most common. CRE colonization prevalence was 6.8% for hospital subjects, 0.7% for clinic subjects, 0.2% for adult community subjects, and 0.5% for child community subjects (p< 0.001)). CRE prevalence varied across regions (Figure 1) and was significantly higher pre- vs post-lockdown (Figure 2). VIM and NDM were the most common carbapenemase genes (Figure 3). Conclusion. CRE colonization was significantly higher in hospital vs community settings in Botswana. CRE prevalence varied by region and decreased significantly following a countrywide lockdown. With CRE prevalence still modest, elucidating risk factors for CRE colonization holds promise in developing strategies to curb further emergence of CRE. Additional investigation of the CRE isolates without identified resistance genes is warranted.
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Background. Although ESCrE are a global challenge, data on ESCrE in low- and middle-income countries are limited. In particular, colonization data are critical for larger antibiotic resistance efforts. We characterized the colonization prevalence of ESCrE in various settings in Botswana. Methods. This study was conducted in 3 hospitals and 6 clinics located in 3 districts in Botswana. In each hospital, we conducted surveillance of adult patients. Adult clinic patients were also randomly selected for participation. Finally, we enrolled community subjects by inviting each enrolled clinic subject to refer up to 3 adults. Each adult clinic or community subject was also allowed to refer their children. All subjects had rectal swabs obtained which were inoculated onto chromogenic media for preliminary identification of ESCrE. Final identification and susceptibility testing were performed using MALDI-TOF MS and VITEK-2, respectively. Genotyping was done for identification of extended-spectrum beta-lactamase (ESBL) genes. Results. Enrollment occurred from 1/15/20-9/4/20 but paused from 4/2/20-5/21/20 due to a countrywide COVID lockdown. Of 5,088 subjects approached, 2,469 (49%) participated. Enrollment by subject type was: hospital - 469 (19%);clinic - 959 (39%);community adult - 477 (19%);and community child - 564 (23%). Of 2,469 subjects, the median (interquartile range) age was 32 years (19-44) and 1,783 (72%) were female. 759 (31%) subjects were colonized with at least one ESCrE;130 subjects were colonized with multiple strains. E. coli (n=663) and K. pneumoniae (n=121) were most common. ESCrE colonization prevalence was 43% for hospital subjects, 31% for clinic subjects, 24% for adult community subjects, and 26% for child community subjects (p< 0.001)). ESCrE prevalence varied significantly across regions (Figure 1) and was significantly higher pre-lockdown vs post-lockdown (Figure 2). CTX-M was the most common ESBL gene (Figure 3). Conclusion. ESCrE colonization was common in both healthcare and community settings in Botswana. Colonization prevalence varies by region and clinical setting and decreased following a countrywide lockdown. These findings provide important clues regarding potential drivers of ESCrE that might serve as targets for intervention.
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Introduction: Viral infections may trigger diabetes. Clinical data suggest infection with the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), may impact glucose homeostasis in patients. Notably, cases of new-onset diabetes upon SARS-CoV-2 infection have been reported. However, experimental evidence of pancreatic infection is still controversial. Aims & Methods: Here, we employ cadaveric human pancreatic islets, as well as pancreatic tissue from deceased COVID-19 patients to investigate the impact of SARS-CoV-2 on the pancreas. Results: We show that human β-cells express viral entry proteins ACE2 and TMPRSS2, making them susceptible to SARS-CoV-2 infection and replication. Our data further demonstrates that SARS-CoV-2 infects and replicates in ex vivo cultured human islets and infection. This infection is associated with morphological, transcriptional and functional changes, such as reduction of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 post-mortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 in all patients investigated. Conclusion: Taken together, our data define the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection might contribute to the metabolic dysregulation observed in patients with COVID- 19.
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Background: The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), mainly affects the lung, but may also result in extrapulmonary manifestations such as lesions in kidneys, heart, brain, gastrointestinal and endocrine organs. Clinical data suggest that a SARS-CoV-2 infection disturbs glucose homeostasis, and cases of new-onset diabetes mellitus after SARS-CoV-2 infection have been reported. However, experimental evidence that SARS-CoV-2 can infect pancreatic tissue is lacking. We here explored whether pancreatic tissue is susceptible to SARS-CoV-2 infection. Methods: We analyzed healthy human pancreas tissue and cells for ACE2 and TMPRSS2 expression by immunohistochemistry. We exposed human Langerhans islets to SARS-CoV-2 ex vivo and determined viral infection by staining for SARS-CoV-2 spike and nucleoprotein. Viral replication was monitored by detection of released viral RNA by qPCR and infectious titers by TCID50 titration. In addition, infection and the impact of SARS-CoV-2 on cell morphology was examined by electron microscopy. Consequential changes in cell functionality were analyzed by determining insulin secretion and performing transcriptomics. Finally, we performed immunohistochemistry staining of pancreatic sections of four COVID-19 deceased individuals for the presence of SARS-CoV-2 nucleoprotein. Results: Our results show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human β-cells express ACE2 and TMPRSS2, and support SARS-CoV-2 replication. The infection was associated with morphological, transcriptional and functional changes, including reduced numbers of insulin secretory granules in β-cells, upregulation of antiviral gene expression, and impaired glucose-stimulated insulin secretion. Finally, all four analyzed full body autopsies of COVID-19 patients showed SARSCoV-2 nucleoprotein in pancreatic cells, including those that stain positive for the β-cell marker NKX6.1. Conclusion: Our data demonstrate that the human pancreas is a target of SARS-CoV-2 ex vivo and in vivo and suggest that β-cell infection may contribute to pancreatic dysregulation observed in COVID-19 patients.
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INTRODUCTION: The COVID-19 pandemic has resulted in cancellation of medical peer meetings. The Chest Wall Injury Society Annual Summit was scheduled for April 2020. Due to safety concerns, the Society altered the meeting to an online format. The purpose of this paper is to describe how this was accomplished and also to highlight its outcomes. METHODS: An online survey of participants was carried out to assess their views on the educational yield and technical difficulties encountered as compared to in-person meetings. RESULTS: Sixty two of 275 (23%) registered participants filled out the survey. Eighty four percent felt that the educational quality was excellent/good. Seventy five percent and 95% felt in-person meetings are better for education and for networking, respectively. Eighty seven percent preferred in-person meetings in the future but would attend a virtual meeting again. Thirteen percent had technical difficulties accessing the meeting. CONCLUSION: Online meetings are feasible but in-person meetings have more educational and networking value.
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BACKGROUND: The COVID-19 pandemic has major ramifications for global health and the economy, with growing concerns about economic recession and implications for mental health. Here we investigated the associations between COVID-19 pandemic-related income loss with financial strain and mental health trajectories over a 1-month course. METHODS: Two independent studies were conducted in the U.S and in Israel at the beginning of the outbreak (March-April 2020, T1; N = 4 171) and at a 1-month follow-up (T2; N = 1 559). Mixed-effects models were applied to assess associations among COVID-19-related income loss, financial strain, and pandemic-related worries about health, with anxiety and depression, controlling for multiple covariates including pre-COVID-19 income. FINDINGS: In both studies, income loss and financial strain were associated with greater depressive symptoms at T1, above and beyond T1 anxiety, worries about health, and pre-COVID-19 income. Worsening of income loss was associated with exacerbation of depression at T2 in both studies. Worsening of subjective financial strain was associated with exacerbation of depression at T2 in one study (US). INTERPRETATION: Income loss and financial strain were uniquely associated with depressive symptoms and the exacerbation of symptoms over time, above and beyond pandemic-related anxiety. Considering the painful dilemma of lockdown versus reopening, with the tradeoff between public health and economic wellbeing, our findings provide evidence that the economic impact of COVID-19 has negative implications for mental health. FUNDING: This study was supported by grants from the National Institute of Mental Health, the US-Israel Binational Science Foundation, Foundation Dora and Kirsh Foundation.