Cellular mechanisms associated with sub-optimal immune responses to SARS-CoV-2 bivalent booster vaccination in patients with Multiple Myeloma.

BACKGROUND: The real-world impact of bivalent vaccines for wild type (WA.1) and Omicron variant (BA.5) is largely unknown in immunocompromised patients with Multiple Myeloma (MM). We characterize the humoral and cellular immune responses in patients with MM before and after receiving the bivalent booster, including neutralizing assays to identify patterns associated with continuing vulnerability to current variants (XBB1.16, EG5) in the current post-pandemic era. METHODS: We studied the humoral and cellular immune responses before and after bivalent booster immunization in 48 MM patients. Spike binding IgG antibody levels were measured by SARS-CoV-2 spike binding ELISA and neutralization capacity was assessed by a SARS-CoV-2 multi-cycle microneutralization assays to assess inhibition of live virus. We measured spike specific T-cell function using the QuantiFERON SARS-CoV-2 (Qiagen) assay as well as flow-cytometry based T-cell. In a subset of 38 patients, high-dimensional flow cytometry was performed to identify immune cell subsets associated with lack of humoral antibodies. FINDINGS: We find that bivalent vaccination provides significant boost in protection to the omicron variant in our MM patients, in a treatment specific manner. MM patients remain vulnerable to newer variants with mutations in the spike portion. Anti-CD38 and anti-BCMA therapies affect the immune machinery needed to produce antibodies. INTERPRETATION: Our study highlights varying immune responses observed in MM patients after receiving bivalent COVID-19 vaccination. Specifically, a subgroup of MM patients undergoing anti-CD38 and anti-BCMA therapy experience impairment in immune cells such DCs, B cells, NK cells and TFH cells, leading to an inability to generate adequate humoral and cellular responses to vaccination. FUNDING: National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), NCI Serological Sciences Network for COVID-19 (SeroNet) and The Icahn School of Medicine at Mount Sinai.

Mission, Organization, and Future Direction of the Serological Sciences Network for COVID-19 (SeroNet) Epidemiologic Cohort Studies.

Background: Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies. Methods: In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders). Results: Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes. Conclusions: In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

SARS-CoV-2 Antibody Response among Women Infected during Pregnancy.

OBJECTIVES: Novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus has been declared a pandemic by the World Health Organization as of March 11, 2020. Pregnant women naturally have a reduced immune system due to immunological changes and decreased lung capacity due to respiratory adaptations, making them more susceptible to coronavirus complications. Within the Mount Sinai Health system, more than 15,000 deliveries are performed annually. We began to care for pregnant women with known COVID-19 infections in late March of 2020. In early April 2020, a policy was implemented to perform universal COVID-19 testing for all women planning to deliver within the Mount Sinai Health system. We examined the antibody response of postpartum women who delivered at Mount Sinai Hospital with a SARS-CoV-2 infection between the study intervals during March 15, 2020, through April 30, 2020. STUDY DESIGN: This was a prospective observational study examining the immune response of pregnant women who delivered at Mount Sinai Hospital with a polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Women with a SARS-CoV-2 infection were contacted via phone to discuss participation in the study. Patients who consented were scheduled for a phlebotomy visit to assess their antibody titer levels to COVID-19. The COVID-19 enzyme-linked immunosorbent assay (ELISA) immunoglobulin (Ig)-G antibody test was used to evaluate the patients' antibody titers. The assay detects IgG antibodies for the detection of IgG seroconversion in patients following a known recent SARS-CoV-2 infection. RESULTS: A total of 120 patients were identified with a documented SARS-CoV-2 infection who delivered within the prespecified time frame. Of those patients, 25 women agreed to participate and were included. Of them, 64.00% were Caucasian with a mean age of 35 years. The mean body mass index (BMI) was 30 kg/m2 and the majority of patients had commercial insurance (88.00%). The majority of women were asymptomatic for COVID-19 at the time of admission (80.00%) and the average gestational age of delivery and diagnosis of COVID-19 was 39 weeks' gestation. The later the gestational age at the time of diagnosis, the lower the antibody titer response. When examining the interval from diagnosis to antibody titer analysis, patients with the highest titers (2,880) tended to have a shorter interval between their COVID-19 diagnosis and the time at which the titer level was drawn. Patients with symptoms on admission had similar antibody titer levels when compared with women who were asymptomatic. CONCLUSION: The antibody response among women infected with COVID-19 during pregnancy appears to be greater when the patients are diagnosed at an earlier gestational age. KEY POINTS: · COVID-19 antibody status appears to be greater when diagnosed at an earlier gestational age.. · Asymptomatic and symptomatic pregnant women had similar antibody responses.. · Patients with the highest titers tended to have a shorter interval between their COVID-19 diagnoses..

The success of behavioral economics in improving patient retention within an intensive primary care practice.

BACKGROUND: A minority of the U.S. population comprises a majority of health care expenses. Health system interventions for high-cost populations aim to improve patient outcomes while reducing costly over-utilization. Missed and inconsistent appointments are associated with poor patient outcomes and increased health care utilization. PEAK Health- Mount Sinai's intensive primary care clinic for high-cost patients- employed a novel behavioral economics-based intervention to reduce the rate of missed appointments at the practice. Behavioral economics has accomplished numerous successes across the health care field; the effect of a clinic-based behavioral economics intervention on reducing missed appointments has yet to be assessed. METHODS: This was a single-arm, pre-post trial conducted over 1 year involving all active patients at PEAK Health. The intervention consisted of: a) clinic signage, and b) appointment reminder cards containing behavioral economics messaging designed to increase the likelihood patients would complete their subsequent visit; appointment cards (t1) were transitioned to an identical EMR template (t2) at 6 months to boost provider utilization. The primary objective, the success of scheduled appointments, was assessed with visit adherence: the proportion of successful over all scheduled appointments, excluding those cancelled or rescheduled. The secondary objective, the consistency of appointments, was assessed with a 2-month visit constancy rate: the percentage of patients with at least one successful visit every 2 months for 1 year. Both metrics were assessed via a χ2 analysis and together define patient retention. RESULTS: The visit adherence rate increased from 74.7% at baseline to 76.5% (p = .22) during t1 and 78.0% (p = .03) during t2. The 2-month visit constancy rate increased from 59.5% at baseline to 74.3% (p = .01) post-intervention. CONCLUSIONS: A low-resource, clinic-based behavioral economics intervention was capable of improving patient retention within a traditionally high-cost population. A renewed focus on patient retention- employing the metrics described here- could bolster chronic care efforts and significantly improve the outcomes of high-cost programs by reducing the deleterious effects of missed and inconsistent appointments.

Neutralizing Antibody Responses in COVID-19 Convalescent Sera.

Passive transfer of antibodies from COVID-19 convalescent patients is being used as an experimental treatment for eligible patients with SARS-CoV-2 infections. The United States Food and Drug Administration's (FDA) guidelines for convalescent plasma initially recommended target antibody titers of 160. We evaluated SARS-CoV-2 neutralizing antibodies in sera from recovered COVID-19 patients using plaque reduction neutralization tests (PRNT) at moderate (PRNT50) and high (PRNT90) stringency thresholds. We found that neutralizing activity significantly increased with time post symptom onset (PSO), reaching a peak at 31-35 days PSO. At this point, the number of sera having neutralizing titers of at least 160 was approximately 93% (PRNT50) and approximately 54% (PRNT90). Sera with high SARS-CoV-2 antibody levels (>960 enzyme-linked immunosorbent assay titers) showed maximal activity, but not all high-titer sera contained neutralizing antibody at FDA recommended levels, particularly at high stringency. These results underscore the value of serum characterization for neutralization activity.

Humoral response and PCR positivity in patients with COVID-19 in the New York City region, USA: an observational study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The proportion of infected individuals who seroconvert is still an open question. In addition, it has been shown in some individuals that viral genome can be detected up to 3 months after symptom resolution. We investigated both seroconversion and PCR positivity in a large cohort of convalescent serum donors in the New York City (NY, USA) region. METHODS: In this observational study, we ran an outreach programme in the New York City area. We recruited participants via the REDCap (Vanderbilt University, Nashville, TN, USA) online survey response. Individuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via ELISA for presence of anti-SARS-CoV-2 spike antibodies. One-way ANOVA and Fisher's exact test were used to measure the association of age, gender, symptom duration, and days from symptom onset and resolution with positive antibody results. FINDINGS: Between March 26 and April 10, 2020, we measured SARS-CoV-2 antibody titres in 1343 people. Of the 624 participants with confirmed SARS-CoV-2 infection who had serologies done after 4 weeks, all but three seroconverted to the SARS-CoV-2 spike protein, whereas 269 (37%) of 719 participants with suspected SARS-CoV-2 infection seroconverted. PCR positivity was detected up to 28 days from symptom resolution. INTERPRETATION: Most patients with confirmed COVID-19 seroconvert, potentially providing immunity to reinfection. We also report that in a large proportion of individuals, viral genome can be detected via PCR in the upper respiratory tract for weeks after symptom resolution, but it is unclear whether this signal represents infectious virus. Analysis of our large cohort suggests that most patients with mild COVID-19 seroconvert 4 weeks after illness, and raises questions about the use of PCR to clear positive individuals. FUNDING: None.

Robust neutralizing antibodies to SARS-CoV-2 infection persist for months.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic with millions infected and more than 1 million fatalities. Questions regarding the robustness, functionality, and longevity of the antibody response to the virus remain unanswered. Here, on the basis of a dataset of 30,082 individuals screened at Mount Sinai Health System in New York City, we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust immunoglobulin G antibody responses against the viral spike protein. We also show that titers are relatively stable for at least a period of about 5 months and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggest that more than 90% of seroconverters make detectable neutralizing antibody responses. These titers remain relatively stable for several months after infection.

COVID-19: Staging of a New Disease.

Coronavirus disease 2019 (COVID-19), like cancer, is a complex disease with clinical phases of progression. Initially conceptualized as a respiratory disease, COVID-19 is increasingly recognized as a multi-organ and heterogeneous illness. Disease staging is a method for measuring the progression and severity of an illness using objective clinical and molecular criteria. Integral to cancer staging is "metastasis," defined as the spread of a disease-producing agent, including neoplastic cells and pathogens such as certain viruses, from the primary site to distinct anatomic locations. Staging provides valuable frameworks and benchmarks for clinical decision-making in patient management, improved prognostication, and evidence-based treatment selection.

Residency Practice Transformation: Implementation of Team-Based Care in an Academic Continuity Clinic.

BACKGROUND: Team-based primary care has the potential to improve care delivery. However, residency scheduling and precepting models make creating functional ambulatory teams challenging. OBJECTIVE: We describe the team-based care transformation at a large academic internal medicine residency practice. METHODS: On July 1, 2016, the program transitioned to a 6+2 schedule and the clinic was divided into teams. Residents were precepted by 2 team preceptors, social work and care coordination needs were met by team-specific staff, and front desk staff were trained on maintaining primary care physician (PCP) and team continuity. Weekly team meetings provided opportunities for proactive patient and panel management, and preclinic huddles incorporated staff into team functions. Pre-transformation (June 2016) and post-transformation (June 2017) surveys were distributed to residents (n = 131), faculty (n = 14), and staff (n = 65) to assess team functioning. Patient-PCP continuity was monitored on a quarterly basis. RESULTS: Three hundred sixty-two of 420 surveys were returned (86%). The intervention was associated with significant improvements in resident satisfaction (from 3.05 baseline to 4.07 of 5, P < .001) and perceptions of teamwork (4.14 to 4.61 of 6, P < .001), with moderate to large effect sizes. Patient-PCP continuity significantly increased (45% to > 70%). While domain-specific improvements were seen for faculty and staff, no overall changes were noted in their perceptions of teamwork or team-based care. CONCLUSIONS: Team-based care was implemented with significant improvements in continuity and resident satisfaction and perceptions of teamwork; however, the impact on faculty and staff was limited.

Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new human disease with few effective treatments1. Convalescent plasma, donated by persons who have recovered from COVID-19, is the acellular component of blood that contains antibodies, including those that specifically recognize SARS-CoV-2. These antibodies, when transfused into patients infected with SARS-CoV-2, are thought to exert an antiviral effect, suppressing virus replication before patients have mounted their own humoral immune responses2,3. Virus-specific antibodies from recovered persons are often the first available therapy for an emerging infectious disease, a stopgap treatment while new antivirals and vaccines are being developed1,2. This retrospective, propensity score-matched case-control study assessed the effectiveness of convalescent plasma therapy in 39 patients with severe or life-threatening COVID-19 at The Mount Sinai Hospital in New York City. Oxygen requirements on day 14 after transfusion worsened in 17.9% of plasma recipients versus 28.2% of propensity score-matched controls who were hospitalized with COVID-19 (adjusted odds ratio (OR), 0.86; 95% confidence interval (CI), 0.75-0.98; chi-square test P value = 0.025). Survival also improved in plasma recipients (adjusted hazard ratio (HR), 0.34; 95% CI, 0.13-0.89; chi-square test P = 0.027). Convalescent plasma is potentially effective against COVID-19, but adequately powered, randomized controlled trials are needed.

Role of House Calls in the Care of Patients With Pulmonary Disease.

As the population ages, and more patients with chronic pulmonary diseases become frail and functionally impaired, the prevalence of homebound patients grows. Homebound patients have higher disease burden, inpatient utilization rates, and mortality than nonhomebound patients. Vulnerable homebound patients with pulmonary disease benefit from pulmonary expertise to evaluate and optimize their complex medication regimens; evaluate equipment such as nebulizers, home oxygen, ventilators, and suction machines; and coordinate services. We review the need and benefits of house calls for these patients, and illustrate these needs with cases. We also explore the logistics of making house calls part of pulmonary practice, including supplies needed, safety in the home, and reimbursement. Reimbursement has grown for house calls, and we review how to bill for visits, advance care planning, and care management that is often required when caring for patients with advanced illness. In addition, house calls can often be beneficial for patients who may be identified as high risk and are part of value-based agreements with payers.

Empanelment in a Resident Teaching Practice: A Cornerstone to Improving Resident Outpatient Education and Patient Care.

BACKGROUND: Improving continuity is challenging in residency training practices. Studies have shown that empanelment enables high-performing primary care and is foundational to improve accountability and continuity. OBJECTIVE: An empanelment process was created in a large, urban, residency training practice as an effective approach to enhancing continuity among residents and their patients. METHODS: In 2016, we formed an empanelment committee that included stakeholders from the department of medicine, the internal medicine residency program, and hospital and IT leadership. This committee set goal panel sizes, selected an empanelment algorithm, determined which patients needed re-empanelment, and facilitated medical record integration. Empanelment was followed and reassessed quarterly for 2 years. We measured anticipated visit demand using visits in the prior year and continuity using the continuity for physician formula. RESULTS: Of 18 495 active patients in July 2016, 8411 (45%) were assigned a new PCP in the empanelment process. At baseline, panel sizes and expected visit demand were highly variable among residents (from 40 to 107 and 120 to 480, respectively). Empanelment led to more equivalent panel sizes and expected visit demand across same year residents (eg, PGY-3: 80-100 and 320-440, respectively). Continuity for all PCPs in the practice improved from 63% before empanelment to over 80% after empanelment, and improved from 55% to 72% for individual residents. CONCLUSIONS: In a large and complex practice environment, we were able to empanel resident clinic patients to improve continuity and maintain it over 2 years.

Hospital at Home-Plus: A Platform of Facility-Based Care.

OBJECTIVES: To describe the evolution of a hospital at home (HaH) program to a HaH with a 30-day posthospitalization transition period (HaH-Plus) and results of a retrospective review of cases. DESIGN: After launching HaH-Plus, we used the same interdisciplinary clinical team to provide acute home-based care for a broader range of home-based acute-level services than originally conceived in the Hospital at Home model. These included a palliative care unit at home (PCUaH), an observation unit at home (OUaH), a post-acute care rehabilitation at home (RaH), and a program for the hospital averse - those patients needing to be in the hospital but who refuse. SETTING: Urban health system. PARTICIPANTS: Individuals 18 years or older residing in specified catchment area with Medicare fee-for-service or accepted Medicare/Medicaid Advantage plans requiring facility-based care. INTERVENTION: Provision of facility-based acute-level care at home to 685 participants. MEASUREMENTS: Length of stay, readmission, and mortality. RESULTS: HaH-Plus cared for 685 individuals. The PCUaH had the oldest participants (mean age 87), and all groups were predominantly female and dually eligible for Medicare and Medicaid. Diagnoses and length of stay were similar in all groups except that those in RaH had a larger group of diagnoses, than those accepted in to HaH-Plus and those in OUaH had a shorter stay. Rate of readmission was highest for RaH (19%). Mortality during the active treatment episode was highest for PCUaH and hospital averse as compared to HaH-Plus, OUaH and RaH. CONCLUSION: Providing a broader range of facility-based care in the home has significant advantages for patients and increases the scalability of HaH. Developing a spectrum of services was possible by leveraging a robust, 24-hour HaH team. Community- and home-based care could become a greater part of the U.S. healthcare system if a platform of HaH services along with advances in technology and payment models were developed. J Am Geriatr Soc 67:596-602, 2019.