Altered immune response to vaccination in patients with plasma cell premalignancy

Introduction Patients with hematological malignancies, including multiple myeloma (MM), experience suboptimal responses to SARS-CoV-2 vaccination. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) are precursors to MM and exhibit altered immune cell composition and function. The SARS-CoV-2 pandemic and the subsequent population-wide vaccination represent an opportunity to study the real-life immune response to a common antigen. Here, we present updated results from the IMPACT study, a study we launched in November 2020 to characterize the effect of plasma cell premalignancy on response to SARS-CoV2 vaccination (vx). Methods We performed: (i) ELISA for SARS-CoV-2-specific antibodies on 1,887 peripheral blood (PB) samples (237 healthy donors (HD), and 550 MGUS, 947 SMM, and 153 MM patients) drawn preand post-vx;(ii) single-cell RNA, T cell receptor (TCR), and B cell receptor (BCR) sequencing (10x Genomics) on 224 PB samples (26 HD, and 20 MGUS, 48 SMM, and 24 MM patients) drawn preand post-vx;(iii) plasma cytokine profiling (Olink) on 106 PB samples (32 HD, and 38 MGUS and 36 SMM patients) drawn pre- and post-vx;and (iv) bulk TCR sequencing (Adaptive Biotechnologies) on 8 PB samples from 4 patients (2 MGUS, 2 SMM) drawn pre- and post-vx. Results Patients with MGUS and SMM achieved comparable antibody titers to HD two months post-vx. However, patient titers waned significantly faster, and 4 months post-vx we observed significantly lower titers in both MGUS (Wilcoxon rank-sum, p=0.030) and SMM (p=0.010). These results indicate impaired humoral immune response in patients with MGUS and SMM.At baseline, the TCR repertoire was significantly less diverse in patients with SMM compared to HD (Wilcoxon rank-sum, p=0.039), while no significant difference was observed in the BCR repertoire (p=0.095). Interestingly, a significant increase in TCR repertoire diversity was observed post-vx in patients with SMM (paired t-test, p=0.014), indicating rare T cell clone recruitment in response to vaccination. In both HD and patients, recruited clones showed upregulation of genes associated with CD4+ naive and memory T cells, suggesting preservation of the T cell response in SMM, which was confirmed by bulk TCR-sequencing in 4 patients.Lastly, by cytokine profiling, we observed a defect in IL-1beta and IL-18 induction post-vx in patients with SMM compared to HD (Wilcoxon rank-sum, p=0.047 and p=0.015, respectively), two key monocyte-derived mediators of acute inflammation, suggesting an altered innate immune response as well. Conclusion Taken together, our findings highlight that despite the absence of clinical manifestations, plasma cell premalignancy is associated with defects in both innate and adaptive immune responses. Therefore, patients with plasma cell premalignancy may require adjusted vaccination strategies for optimal immunization.

Die Auswirkungen der COVID-19 Pandemie führten zu signifikanten Veränderungen der Operations- und Liegezeiten bei Patienten nach Cholezystektomie The COVID-19 pandemic had significant impact on duration of surgery and hospitalization time for patients after cholecystectomy

Hintergrund Die COVID-19 Pandemie (Pandemie) hat erhebliche Veränderungen der medizinischen Versorgung notwendig gemacht. Ziele dieser Studie waren herauszufinden, welchen Einfluss die Pandemie auf den perioperativen Verlauf bei Patienten mit Cholezystektomie (CHE) hatte und mögliche bleibende Schlussfolgerungen aufzuzeigen. Methodik Vom 01.07.2018 bis 31.12.2021 wurden 735 Patienten mit CHE analysiert. Dabei wurden die Patienten bis zum 21.03.2020 als reguläre Patientengruppe (Reg, n = 430), die Patienten danach (1. Lockdown 22.03.2020) als Cov19-Patientengruppe (Cov19, n = 305) bezeichnet und miteinander verglichen. Ergebnisse Das Durchschnittsalter aller Patienten betrug 59 Jahre, 63 % der Patienten waren Frauen. Die durchschnittliche Krankenhausverweildauer (KrVD, Zeitraum zwischen Operation und Entlassung) betrug 4,4 Tage. Die Patientengruppen Reg und Cov19 unterschieden sich nicht bez. Alter, Geschlecht oder KrVD. Die Gesamtzahl der durchgeführten CHE hat sich durch Cov19 um 21,4 % reduziert. Dies betraf gleichermaßen elektive sowie auch notfallmäßige CHE. Die Operationsdauer stieg in der Gruppe Cov19 signifikant von 64 min (SD 34 min) auf 71 min (SD 38 min) an (p < 0,05). Die Anzahl der Kurz- und Langlieger (KrVD 2 bzw. > 4 Tage) stieg in der Cov19-Gruppe signifikant von 4 % auf 20 % (Kurzlieger, p < 0,01) bzw. von 23 % auf 27 % (Langlieger, p < 0,01) an. Dies war vor allem bei über 70-jährigen Patienten mit einem Anstieg der Langlieger von 43 % auf 56 % in der Cov19-Gruppe zu beobachten. Diskussion Die COVID-19-Pandemie führte zu einer deutlichen Abnahme der CHE sowohl bei Elektiv- als auch bei Notfalleingriffen. Des Weiteren konnte eine signifikante Verlängerung der Operations- und Liegedauer bei älteren Patienten beobachtet werden. Bleibende Konsequenzen der Pandemie könnten Liegezeitverkürzungen nach unkomplizierten CHE und mehr interventionelle Therapieverfahren in komplexen Fällen sein.

[The COVID-19 pandemic had significant impact on duration of surgery and hospitalization time for patients after cholecystectomy]. / Die Auswirkungen der COVID-19 Pandemie führten zu signifikanten Veränderungen der Operations- und Liegezeiten bei Patienten nach Cholezystektomie.

BACKGROUND: The COVID-19 pandemic made substantial changes in medical care necessary. The aims of this study were to find out what influence the pandemic had on the perioperative course in patients with cholecystectomy (CHE) and to highlight possible residual consequences. METHOD: From 1 July 2018 to 31 December 2021 a total of 735 patients with CHE were analyzed. Up to 21 March 2020 patients were assigned to the regular patient group (Reg, n = 430), patients after this date (first lockdown 22 March 2020) to the Cov19 patient group (Cov19, n = 305) and the 2 groups were compared. RESULTS: The average age of all patients was 59 years and 63% were women. The average length of hospitalization (KrVD, time period between surgery and discharge) was 4.4 days. The patient groups Reg and Cov19 did not differ with respect to age, gender or KrVD. The total number of CHEs carried out was reduced by 21.4% in the Cov19 group. This affected elective and emergency CHE to the same extent. The length of surgery significantly increased in the Cov19 group from 64 min (SD 34 min) to 71 min (SD 38 min). The number of short and long hospital stays (KrVD 2 or >4 days) significantly increased in the Cov19 group from 4 % to 20 % (short stay, p < 0.01) and from 23 % to 27 % (long stay, p < 0.01). This was particularly observed for patients >70 years old with an increase in long stays from 43 % to 56 % in the Cov19 group. CONCLUSION: The COVID-19 pandemic led to a clear reduction in CHE both for elective and emergency interventions. Furthermore, a significant lengthening of the surgery and hospitalization times could be observed for older patients. The residual consequences of the pandemic could be shortened hospitalization times after uncomplicated CHE and more interventional treatment procedures in complex cases.

Humoral SARS-CoV-2 response in asymptomatic precursor plasma cell dyscrasia patients: IMPACT study results

Introduction: Patients with hematologic malignancies, including multiple myeloma (MM), experience worse SARS-CoV-2 infection outcomes and sub-optimal vaccine responses. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) precede MM and affect ∼5% of individuals age >=50. We previously showed that individuals with MGUS and SMM exhibit immune dysregulation. Here, we investigate the immune response to SARS-CoV-2 vaccination in these asymptomatic but potentially immunocompromised individuals. Methods: The IMPACT study (IRB #20-332) is a prospective study at Dana-Farber Cancer Institute in collaboration with MMRF, which enrolled individuals nationwide with a diagnosed plasma cell dyscrasia and healthy individuals. As of October 2021, 3,005 individuals completed a questionnaire regarding prior infection or vaccination. We obtained 1,350 blood samples from 628 participants and analyzed anti-SARS-CoV-2 IgG antibody titer by ELISA. Results: 2,771 (92%) participants were fully vaccinated (2 doses BNT162b2 or mRNA-1273;1 dose Ad26.COV2.s), 269 (9%) had received a 3rd mRNA vaccine dose, and 234 (8%) were unvaccinated. 1,387 (46%) and 1,093 (36%) participants received mRNA vaccines (BNT162b2 and mRNA-1273), and 139 (5%) participants received an adenovirus vector vaccine (Ad26.COV2.S). 34 (1%) individuals reported SARS-CoV-2 infection after full vaccination. We measured antibody titers in 201 MGUS, 223 SMM, 40 smoldering Waldenstrom macroglobulinemia (SWM), 64 MM, and 100 healthy controls. Multiple linear regression model estimated the association between various clinical variables and post-vaccination antibody titers. As previously reported, having MM was associated with low antibody titer (p < 0.001). Of note, having SMM, regardless of risk stratification by 2/20/20 criteria, was also associated with low antibody titers, indicating that even low-risk SMM patients have a poor response to vaccination. MGUS and SWM diagnoses were not significantly associated with antibody titers. Additionally, male sex (p < 0.010), elapsed time after vaccination (p < 0.001), and BNT162b2 vaccine (p < 0.001) were associated with low antibody titers. SARS-CoV-2 infection prior to vaccination was associated with high antibody titers. We identified 25 patients (6 MGUS, 10 SMM, 2 SWM, 7 MM) who submitted blood samples after both the 2nd and 3rd dose. In these patients we observed a significant increase in antibody titer after a 3rd dose (p = 0.002). We also observed that antibody titers of patients after a 3rd dose (13 MGUS, 12 SMM, 2 SWM, 31 MM) were comparable to that of healthy individuals after a 2nd dose (p = 0.833). Conclusion: Our data indicates that suboptimal response to SARS-CoV-2 does not only occur with MM and cancer patients receiving therapy but also in precursor asymptomatic patients including low-risk SMM.

Single-cell RNA-sequencing for immune profiling of SARS-CoV2 vaccine response in healthy individuals and patients with precursor plasma cell malignancies

Introduction: Patients with hematological malignancies exhibit inferior response to SARS-CoV2 vaccination, compared to healthy individuals, however little is known about patients with precursor hematological malignancies and the cellular underpinnings of vaccination response. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Myeloma (SMM) are plasma cell premalignancies that precede Multiple Myeloma (MM) and exhibit signs of immune dysregulation;they affect approximately 5% of the population over 50 years of age, who remain largely undiagnosed, due to lack of screening. In November 2019, we launched the IMPACT study to characterize the immune response to SARS-CoV2 vaccination in patients with plasma cell dyscrasias and healthy individuals. Methods: We performed single-cell RNA-sequencing on 224 peripheral blood mononuclear cell samples drawn from 118 IMPACT (IRB #20-332) participants with MGUS (n=20), SMM (n=48), or MM (n=24), as well as healthy individuals (n=26). Samples were collected before vaccination and after 2 doses of BNT162b2 (Pfizer-BioNtech) (n=123), mRNA-1273 (Moderna) (n=83) or 1 dose of Ad26.COV2.S (Janssen) (n=14). Results: Overall, we sequenced 2,025,611 cells from 224 samples of 118 patients with MGUS, SMM, MM and healthy individuals pre- and post-vaccination for SARS-CoV2, and profiled 553,082 T-cells, 95,392 B-cells, 74,394 NK cells, 195,371 Monocytes, and 35,236 Dendritic cells (DC). We identified activated clusters of B-cells, NK cells and DCs expressing genes such as CD83, CD69, CXCR4, and genes related to the NF-kB and AP-1 pathways. We compared cell type abundances pre- and post-vaccination within each participant population and found that activated CD83+ cells significantly increased post-vaccination in healthy individuals and patients with MGUS (paired t-test, q < 0.1), but not in patients with SMM or overt MM. At baseline, patients with SMM and MM had significantly fewer memory B-cells and significantly more cytotoxic T-cells and NK cells, compared to healthy individuals (Wilcoxon, q < 0.1), which could partly explain the differences observed post-vaccination. Patients with MM also had significantly higher levels of tolerogenic IL-10-expressing DCs (DC10) at baseline (Wilcoxon, q < 0.1), which could be dampening antigen-specific T-cell responses. Conclusion: We identified a significant expansion of activated B-cell, NK cell and DC subpopulations expressing CD83, CD69 and CXCR4, following vaccination in healthy individuals and patients with MGUS, but less so in patients with SMM and overt MM. Our results provide insight into the cellular mechanisms of immune response to SARS-CoV2 vaccination in healthy individuals and patients with precursor plasma cell malignancies and suggest that asymptomatic individuals with SMM may exhibit inferior response to vaccination.

The publics of public health: learning from COVID-19

This commentary reflects on what has been learnt from government and public health responses to COVID-19, suggesting a tension between ‘business as usual’ forms of public health in the face of crisis, and the possibilities for a step-change towards a ‘healthy publics’ approach. We set out a range of ways that diverse, multiple publics have been implicated or brought into being during the COVID-19 pandemic, and we argue that these have generally been ignored or erased by agents or agencies of public health, keen to preserve certainty in their messaging and public confidence in their authority. We conclude with five principles for re-organising pandemic responses around a richer, more context-dependent and diverse account of ‘the public’.

Gargle pool PCR testing in a hospital during medium and high SARS-CoV-2 incidence.

BACKGROUND: Hospitals need to be protected from SARS-CoV-2 infections to protect vulnerable patients. Thus, a safe, efficient, and cost-effective SARS-CoV-2 testing system for hospitals, in addition to standard hygiene measures and vaccination of staff, is necessary. Here we report on the feasibility and performance of a pool real-time reverse-transcriptase polymerase-chain-reaction (rRT-PCR) test system at, medium and high incidence. METHODS: We implemented a testing concept based on gargling at home and pooling of samples in the hospital before PCR testing in the laboratory. We used two PCR systems (point of care and standard 96-well plate system) to adapt to challenges in the hospital setting and respond to a rising incidence in the Omicron wave. FINDINGS: During our 10-week study period, we performed 697 pool PCRs (8793 tests in total) and identified 65 asymptomatic staff members by pool PCR and 94 symptomatic staff members by positive individual PCR. Virus loads in those detected by pool testing were significantly lower (P<0.001). The test system remained workable even during the peak of the Omicron wave and no outbreaks occurred in any specific area of the hospital during the study period. Unvaccinated individuals were over-represented in the positively tested (37% vs 22% positive tests, P=0.04). The test procedure was well accepted by a majority of the hospital staff (84%). CONCLUSION: Repeated gargle pool rRT-PCR testing can be implemented quickly in hospitals and is an effective, easily adaptable and well-accepted test system for hospitals, even during phases with very high infection rates.

Oxygenation and Inflammatory Markers after Early Covid-19 Convalescent Plasma: A Comparison of Survivors and Non-Survivors

Background Acute respiratory distress syndrome (ARDS) is a major complication in patients with severe coronavirus disease in 2019 (COVID-19). COVID-19 convalescent plasma (CCP) has been proposed as a specific therapy for patients with COVID-19. Our goal is to assess changes in oxygenation and inflammatory markers in patients after receiving CCP. Methods This is a retrospective, health system-based, a case-control study comparing hospitalized patients with COVID-19 who received CCP and were discharged (survivors) to patients who died after receiving CCP (non-survivors). We analyzed the severity of ARDS, oxygenation, and inflammatory markers of 295 patients, comparing 202 survivors to 93 non-survivors with COVID-19 who received CCP. Demographic information and laboratory data were collected on the day of the admission (initial), the day of the plasma infusion (D1), and post-infusion days 3, 7, 15, and 30 (when available). Results Survivors were younger (52.48 y versus 64.02 y;p<0.001) with no pre-existing conditions (25.2% versus 13.9%;p=0.03) compared to non-survivors. Severe ARDS (PaO2/FiO2 <100) was predictive of increased mortality after CCP in non-survivors (p<0.001). Survivors with mild (20%) or moderate (46%) ARDS on D1 had a 54% resolution of ARDS on D7 after CCP (p<0.001). After 72 hours of transfusion, supplemental oxygen requirements decreased by 63% of the survivors, compared to 33% of non-survivors (p<0.001). Inflammatory markers, including white blood cells, absolute neutrophils, platelets, C-reactive protein (CRP), lactate dehydrogenase (LDH), and creatinine, improved within three days in survivors after CCP (p<0.05). Baseline findings associated with a poor prognosis on D1 include a lower platelet count (219.02 versus 281.64, p<0.001), higher blood urea nitrogen (BUN) (35.41 versus 21.48, p<0.001), higher creatinine (2.24 versus 1.26, p<0.001), higher D-dimer (5.88 versus 2.46, p<0.001) and elevated lactate dehydrogenase (LDH) (698.3 versus 464.51, p<0.001) when comparing non-survivors to survivors, respectively. After 72 hours post-transfusion, the following changes were remarkable: normalization of creatinine with a mean of 1.07 in survivors versus 1.92 in non-survivors (p<0.001), a significant decrease in CRP improving from 129.27 to 84.25 in survivors versus 139.11 to 130.0 in non-survivors (p<0.001), and lower lactate dehydrogenase (LDH) in survivors (459.47) versus non-survivors (674.56, p<0.001). Conclusion In this retrospective, health system-based, case-control study, we found that the improvement in oxygenation, resolution of ARDS, and reduced inflammatory markers are seen in survivor patients after early COVID-19 convalescent plasma transfusion. These parameters can be used to assess response to COVID-19 convalescent plasma after 72 hours of the transfusion and could help physicians in the decision-making when administering CCP, especially if resources are scarce. [Formula presented] Disclosures: No relevant conflicts of interest to declare.

Early cross-coronavirus reactive signatures of humoral immunity against COVID-19

The introduction of vaccines has inspired hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against SARS-CoV-2, thus we profiled the earliest humoral signatures in a large cohort of acutely ill (survivors and nonsurvivors) and mild or asymptomatic individuals with COVID-19. Although a SARS-CoV-2-specific immune response evolved rapidly in survivors of COVID-19, nonsurvivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibodies. Given the conservation of S2 across 0-coronaviruses, we found that the early development of SARS-CoV-2-specific immunity occurred in tandem with preexisting common I3-coronavirus OC43 humoral immunity in survivors, which was also selectively expanded in individuals that develop a paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.

Management, screening and follow-up of COVID-19 patients in a dedicated Ambulatory Center, Val-de-Marne, April-June 2020

In response to the COVID-19 crisis, and in absence of dedicated structures, an ambulatory medical centre dedicated to patients suspected of being infected with SARS-CoV-2 was created by a group of general practitioners (GP). Objective was to take care of patients under hygienic conditions satisfactory to physicians and patients. Ten days were needed to set up the center in a gymnasium. The center allowed complete medical management of patients (consultation, sampling and diagnosis, follow-up) in adequate hygienic conditions (patient and caregiver circuits with "forward walking", dedicated rooms, hygiene equipment, waste management, etc.). The objectives of the article are to describe the organization of the COVID-19 center, to present the epidemiological and clinical characteristics of suspected COVID-19 patients tested for SARS-CoV-2 and confirmed cases for patients who consulted between the April 7 and May 15, 2020. From April 1 to June 12, 2020, 824 consultations were carried out and 11 patients were hospitalized. Patients were referred to the center by their general practitioner (58%), hospital doctors or the Samu-Center 15, the French emergency call center (15%). The consultations were 70% initial and 30% follow-up consultations, especially after hospitalization. The proportion of patients tested for SARS-CoV-2 has increased over time (from 39%, week 15 to 66%, week 20) and the positive rate of samples has decreased (from 28% to 0%). The most frequently tested patients were those with criteria of severity, those in contact with fragile people, healthcare professionals (HCP) and those who consulted from week 18 to 20. The most frequently positive patients for SARS-CoV-2 were women, those aged 60 years and over, HCP and those with ageusia, those with seriousness criteria and those who consulted from week 15 to 17. No cases of COVID-19 have been reported among professionals due to their activities in the center. Situated between community and hospital care, the COVID-19 center provided an emergency response to an unprecedented epidemic caused by a contagious infectious agent. Such an organization would deserve to be supported by professionalized structures with financial resources that could be mobilized urgently.