Serologic response and safety after third dose of the COVID-19 BNT162b2 vaccine in patients with Inflammatory Bowel Diseases

Background: Vaccines are pivotal for control of the ongoing coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF)-alpha have lower serologic response after two COVID-19 vaccine doses. Data regarding a 3rd vaccine are scarce. Method(s): Aim: To assess immune responses to, and safety of COVID-19 vaccines in patients with IBD, stratified according to therapy, and compared to healthy controls (HC). Subjects were recruited before the 1st vaccine (BNT162b2, Pfizer) and prospectively evaluated after the 2nd and 3rd vaccine doses. Evaluation included: Disease activity, anti-spike (S) and nucleocapsid (N), anti-TNFalpha drug levels and adverse events (AE) Results: Of 198 subjects having the 3rd vaccine dose, 125 had IBD: average age: 39.1+/-14.8 years;40.8% females;82-Crohn's disease (CD), 33 ulcerative colitis (UC), 6 pouch, 3 IBD-U. There were 73 HC: average age 39.4+/-12.5 years, 69.9% females. Among patients with IBD: 51 and 74 (40.8%, 59.2%)) were treated or not with anti-TNFalpha, respectively. A month after the 3rd vaccine dose IBD activity was comparable in all patients regardless of treatment, and no increase in C-reactive protein or white blood cells was observed. Higher but not significant AE rate was registered in all subjects after the 3rd compared to 2nd vaccine dose (81% vs. 76%, respectively). AE rate in IBD and HC was comparable. No serious AE detected. There was a significant increase in anti-S levels one month after compared to pre 3rd vaccine dose in all participants. Furthermore, increase was 2-3 folds higher than that observed one month after the 2nd dose. Importantly, patients treated with anti-TNFalpha compared to non-anti-TNFalpha treated had significantly lower responses: 9219 (6347-13390) vs 16955 (13721-20951) (GMC (95%CI)), p<0.05. Serologic response did not correlate with anti-TNFalpha drug levels, antibodies or interval between drug and vaccine administration. During extended follow-up post 3rd dose, we found that lower serologic response predicts infection over time. Conclusion(s): This prospective study shows that a 3rd dose of BNT162b2 vaccine is effective and safe in patients with IBD. Furthermore, patients treated with anti-TNFalpha had significantly lower serologic responses compared to anti-TNFalpha untreated ones. Lack of correlation between anti-TNFalpha drug levels and immune responses suggests there is no need to modify vaccination timing relatively to anti-TNFalpha administration. The significantly steeper increase in anti-S levels between 2nd and 3rd doses, suggests the 3rd dose is crucial in anti-TNFalpha treated patients, specifically due to the fact that higher serologic response predicts better defense from infection.

The Thresholds of Caprini Score Associated With Increased Risk of Venous Thromboembolism Across Different Specialties: A Systematic Review.

OBJECTIVE: Estimation of the specific thresholds of the Caprini risk score (CRS) that are associated with the increased incidence of venous thromboembolism (VTE) across different specialties, including identifying the highest level of risk. BACKGROUND: Accurate risk assessment remains an important but often challenging aspect of VTE prophylaxis. One well-established risk assessment model is CRS, which has been validated in thousands of patients from many different medical and surgical specialties. METHODS: A search of MEDLINE and the Cochrane Library was performed in March 2022. Manuscripts that reported on 1) patients admitted to medical or surgical departments and 2) had their VTE risk assessed by CRS and 3) reported on the correlation between the score and VTE incidence, were included in the analysis. RESULTS: A total of 4562 references were identified, and the full text of 202 papers was assessed for eligibility. The correlation between CRS and VTE incidence was reported in 68 studies that enrolled 4,207,895 patients. In all specialties, a significant increase in VTE incidence was observed in patients with a CRS of ≥5. In most specialties thresholds of ≥7, ≥9, and ≥11-12 were associated with dramatically increased incidences of VTE. In COVID-19, cancer, trauma, vascular, general, head and neck, and thoracic surgery patients with ≥9 and ≥11-12 scores the VTE incidence was extremely high (ranging from 13% to 47%). CONCLUSION: The Caprini score is being used increasingly to predict VTE in many medical and surgical specialties. In most cases the VTE risk for individual patients increases dramatically at a threshold CRS of 7-11.

Full-Blown Nephrotic Syndrome in a Fully Vaccinated Woman Following COVID-19 Infection

Introduction: There have been a few cases of nephrotic syndrome reported after vaccination for COVID-19. When GFR is well-preserved, the majority of these patients have Minimal Change Disease (MCD). Here, we present a case of full-blown nephrotic syndrome in a fully vaccinated woman developing 6 weeks after she had a COVID-19 infection Case Description: A 66-year-old woman with a 6 year history of well-controlled type 2 DM but no history of retinopathy, proteinuria, or kidney disease received the Pfizer-BioNTech vaccine x 2 in April 2021 and Pfizer booster in October 2021. She had an exuberant local reaction each time she had a vaccine. In January 2022, she suffered a COVID-19 infection and about 6 weeks later, she noted the onset of peri-orbital edema followed by progressive leg edema. At the time of evaluation 5 weeks later, she had pitting edema to the abdomen and sacral edema. Overall, she gained 30 pounds of edema. She had not used any new medications including NSAIDs. Labs showed serum [albumin] of 2.2 g/ dL and serum [creatinine] of 0.92 mg/dL. A full serological work-up including serum free light chains and anti-PLA2R antibody was negative. Urine [albumin]:[creatinine] ratio increased from <30 mg/g in May 2021 to >22,000 mg/g in April 2022. A kidney biopsy was scheduled and the results are pending at the time of this writing. Discussion(s): A number of glomerulopathies have been reported in vaccinated patients and those with COVID-19 infection. The majority of post-vaccination cases have been due to MCD, almost always developing within 10 days of receiving the vaccine. Although our patient had a severe local reaction to the 2 vaccines she received in April 2021, she did not have proteinuria in May 2021 and did not present with nephrotic syndrome until 6 weeks after a COVID-19 infection in January 2022. The kidney biopsy results are pending, but given her presentation and the few similar cases reported, it seems most likely she will have MCD triggered by immune dysfunction, dysregulation, or a circulating permeability factor affecting the podocytes. Of course, it is also possible that the development of her nephrotic syndrome was not related to her COVID vaccinations or infection.

Serologic Response and Safety after Third Dose of the Covid-19 Bnt162b2 Vaccine in Patients with Inflammatory Bowel Diseases

Introduction: Vaccines are pivotal for control of the ongoing coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF)-alpha have significantly lower serologic response after two COVID-19 vaccine doses. Data regarding a 3rd vaccine are scarce. Aims & Methods: We conducted a prospective observational multi-center Israeli study aiming to assess immune responses to, and safety of mRNAbased COVID-19 vaccines in patients with IBD, stratified according to therapy, and compared to healthy controls (HC). Subjects were recruited before the 1st vaccine (BNT162b2, Pfizer) and were prospectively evaluated one and six months after the 2nd vaccine dose, as well as one month after the 3rd vaccine dose. Disease activity was assessed using accepted clinical scores and biomarkers. COVID-19 spike (S) and nucleocapsid (N) antibodies concentrations were analyzed using ELISA. Anti- TNFalpha drug levels were measured using ELISA. Adverse events (AE) were registered. Result(s): Of 198 subjects having the 3rd vaccine dose, 125 had IBD: average age: 39.1+/-14.8 years;40.8% females;82- Crohn's disease (CD), 33 ulcerative colitis (UC), 6 pouch, 3 IBD-U. There were 73 HC: average age 39.4+/-12.5 years, 69.9% females. IBD treatment: 51 (40.8%) patients were treated with anti-TNFalpha: monotherapy 35, concomitant immunomodulators 7, 5ASA 5, steroids 3 and ustekinumab 1. In 74 non-TNFalpha treated patients 5ASA were received by 19, vedolizumab 18, ustekinumab 9, immunomodulators 2, steroids 2, tofacitinib 4, no medication 19 patients. The 3rd vaccine dose was administered 201 (187-216) (median [IQR]) days after the 2nddose and 267 (250-278) days after the 1st dose. A month after the 3rd vaccine dose IBD activity was comparable in all patients regardless of treatment, and no increase in C-reactive protein or white blood cells was observed. Higher but not significant AE rate was registered in all subjects after the 3rd compared to 2nd vaccine dose (81% vs. 76%, respectively). AE proportion in IBD and HC was comparable, mostly local pain. No serious AE detected. Significant increase in anti-S levels one month after compared to pre 3rd vaccine dose was observed in IBD and HC. Furthermore, increase was 2-3 folds higher than that observed one month after the 2nd dose. Importantly, patients treated with anti-TNFalpha compared to non-anti-TNFalpha treated had significantly lower responses: 9219 (6347-13390) vs 16955 (13721- 20951) (GMC (95%CI)), p<0.05. Anti-N levels reflecting infection were positive in only 4 subjects- all with IBD, 2 treated with anti-TNFalpha, 1 ustekinumab, 1 untreated. Serologic response did not correlate with anti-TNFalpha drug levels, antibodies or interval between drug and vaccine administration (p=0.616, p=0.697 and p=0.6, respectively). Conclusion(s): In this prospective study we show that a 3rd dose of BNT162b2 vaccine is effective and safe in patients with IBD, however, patients treated with anti-TNFalpha had significantly lower serologic responses compared to anti-TNFalpha untreated ones. Lack of correlation between anti-TNFalpha drug levels and immune responses suggests there is no need to modify vaccination timing relatively to anti-TNFalpha administration. The significantly steeper increase in anti-S levels between 2nd and 3rd doses, suggests the 3rd dose is crucial in anti-TNFalpha treated patients. Their significantly lower anti-S levels compared to anti-TNFalpha untreated ones may suggest the advantage of a 4th vaccine dose.

WITHIN 6 MONTHS FROM COVID-19 BNT162B2 VACCINE PATIENTS WITH INFLAMMATORY BOWEL DISEASES TREATED WITH ANTI-TNFα HAVE SIGNIFICANTLY LOWER SEROLOGIC RESPONSES

Background: While vaccines against COVID-19 are effective in healthy individuals, we reported significantly lower serologic responses to BNT162b2 in patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF) α agents. As this was apparent already 4 weeks post vaccination, vaccine longevity is concerning. Aim: to assess long-term serologic responses to BNT162b2 in patients with IBD stratified according to medical treatment. Methods: A prospective, observational multi-center Israeli study. Patients with IBD (anti-TNFα treated versus non-anti-TNFα treated) and healthy controls (HC) were followed from before the 1st BNT162b2 dose until 6 months after vaccination. COVID-19 spike (S) and nucleocapsid (N) antibodies (Abs) concentrations were analyzed by ELISA, followed by neutralization studies. Specific anti-receptor binding domain (RBD) memory Bcells response, serologic responses against variants of concern (VOCs), Beta, Gamma and Delta, immunoglobulin levels and lymphocyte cell subsets were evaluated as well. Safety was assessed using questionnaires, clinical and laboratory data. Results: Of 193 subjects, 130 had IBD (45 and 85 in the anti-TNFa and non-anti-TNFα groups, respectively), 63 HC. Serologic response assessed 176 (median) days (IQR 166-186) and compared to 4 weeks after 1st dose significantly declined in all three groups, but was lowest in the anti- TNFα group: 6 months anti-S Abs titer geometric means: 193 (95%CI: 128-292), 703 (520- 951), and 1253 (1023-1534) in anti-TNFα, non- anti-TNFα and HC groups, respectively, p<0.001, Figure 1. This was further supported by neutralization and inhibition studies. Importantly, significantly decreased memory B-cell response towards RBD was detected only in the anti-TNFα group, with the most significant reduction in response to Beta VOC (p<0.0008 and p<0.0001, vs. non-anti-TNFα and HC, respectively). Older age was an additional predictor of lower serologic response. Immunoglobulin levels and lymphocyte cell subsets were comparable between the study groups. Infection rate reflected by anti-N Abs was ~1% in all groups. Safety was comparable in all groups. Conclusion: The 6-months serologic response to BNT162b2 vaccine, evaluated prospectively, decreased in all subjects, most prominently in patients with IBD treated with anti-TNFα. Importantly, the latter also had the sharpest decline in serologies, the lowest functional activity and lowest RBD specific memory B-cells. Older age is an additional predictor of decreased serologic response. Altogether, waning of COVID-19 serologic and functional response over 6 months, specifically in patients with IBD treated with anti-TNFα, supports the need for an early third vaccine dose. (Figure Presented)

Within, 6 months from COVID-19 BNT162b2 vaccine patients with Inflammatory Bowel Diseases treated with Anti-TNFα have significantly lower serologic responses

Background: While vaccines against COVID-19 are effective in healthy individuals, we reported significantly lower serologic responses to BNT162b2 in patients with inflammatory bowel diseases (IBD) treated with anti-tumor necrosis factor (TNF) α agents. As this was apparent already, 4 weeks post vaccination, vaccine longevity is concerning. Aim: to assess long-term serologic responses to BNT162b2 in patients with IBD stratified according to medical treatment. Methods: A prospective, observational multi-center Israeli study. Patients with IBD (anti-TNFα treated versus non-anti-TNFα treated) and healthy controls (HC) were followed from before the, 1st BNT162b2 dose until, 6 months after vaccination. COVID-19 spike (S) and nucleocapsid (N) antibodies (Abs) concentrations were analyzed by ELISA, followed by neutralization studies. Specific anti-receptor binding domain (RBD) memory B-cells response, serologic responses against variants of concern (VOCs), Beta, Gamma and Delta, immunoglobulin levels and lymphocyte cell subsets were evaluated as well. Safety was assessed using questionnaires, clinical and laboratory data. Results: Of, 193 subjects, 130 had IBD (45 and, 85 in the anti-TNFα and non-anti-TNFα groups, respectively), 63 HC. Serologic response assessed, 176 (median) days (IQR, 166-186) and compared to, 4 weeks after, 1st dose significantly declined in all three groups, but was lowest in the anti- TNFα group:, 6 months anti-S Abs titer geometric means:, 193 (95%CI:, 128-292), 703 (520-951), and, 1253 (1023-1534) in anti-TNFα, nonanti- TNFα and HC groups, respectively, p<0.001, Figure, 1. This was further supported by neutralization and inhibition studies. Importantly, significantly decreased memory B-cell response towards RBD was detected only in the anti-TNFα group, with the most significant reduction in response to Beta VOC (p<0.0008 and p<0.0001, vs. non-anti-TNFα and HC, respectively). Older age was an additional predictor of lower serologic response. Immunoglobulin levels and lymphocyte cell subsets were comparable between the study groups. Infection rate reflected by anti-N Abs was ∼1% in all groups. Safety was comparable in all groups. Conclusion: The, 6-months serologic response to BNT162b2 vaccine, evaluated prospectively, decreased in all subjects, most prominently in patients with IBD treated with anti-TNFα. Importantly, the latter also had the sharpest decline in serologies, the lowest functional activity and lowest RBD specific memory B-cells. Older age is an additional predictor of decreased serologic response. Altogether, waning of COVID- 19 serologic and functional response over, 6 months, specifically in patients with IBD treated with anti-TNFα, supports the need for an early third vaccine dose. (Figure Presented).

Predictors of mortality in ICU patients with severe COVID-19 and renal failure-the Lahey experience

Rationale: Coronavirus disease 2019 (COVID-19) is currently the third leading cause of death in the United States. During the Spring of 2020, the Commonwealth of Massachusetts, USA experienced a surge of COVID-19 ICU cases. Many of these patients developed acute renal failure (ARF) requiring renal replacement therapy (RRT) with hemodialysis (HD) or continuous veno-venous hemofiltration (CVVH) which taxed our hospital's supply of equipment and staff. The goal of our study was to identify predictors of mortality in ICU patients requiring RRT in the setting of COVID-19, should rationing of ICU care became necessary. Methods: Between March 2020 and April 2020, we prospectively collected data on patients admitted to the Lahey ICUs with severe COVID-19 who required RRT and assessed patient characteristics and mortality. Results: Thirty ICU patients were identified with severe COVID-19 requiring RRT. Twenty-seven patients (90%) required acute initiation of CVVH, while three (10%) only utilized intermittent HD during their hospitalization. Only ten (33%) survived their hospitalization. No significant difference was found between survivors and patients who died with respect to age, comorbidities (BMI, CKD, HTN, DM, alcohol use, heart disease, malignancy, COPD, asthma) or baseline creatinine. All 30 patients (100%) required mechanical ventilation (MV) and 25 (83%) developed shock requiring vasopressors prior to initiation of RRT. Seventy percent of survivors (7/10) had been on either an ACE-inhibitor (ACEI) or an Angiotensin Receptor Blocker (ARB) prior to hospitalization, compared to only 20% (4/20) who died (p=0.0147) Survivors were treated with hydroxychloroquine (HC) significantly more frequently (10/10 vs 8/20;p=0.0016) and treated with systemic corticosteroids (CS) significantly less frequently (5/10 vs 20/20;p=0.0018) than those who died. There was no difference in survival between those who received Vancomycin or Tocilizumab and those who did not. The median hospital stay was significantly longer for survivors (46 days) than for those who died (19 days;p =0.0003). Conclusion: The need for RRT in ICU patients with COVID-19 was associated with significant mortality (66%) and a significant need for MV (100%) and vasopressors (83%). The use of an ACEI or ARB prior to admission was significantly associated with improved survival, the use of CS was associated with higher mortality, and the use of HC was associated with improved survival. These latter findings go against current theories of COVID pathophysiology and may be a result of the small number of patients in our study.

Outpatient evaluation of transient ischemic attack and minor, non-disabling stroke during the COVID-19 pandemic

Introduction: Reductions in hospital visits for stroke have been seen during the COVID-19 pandemic, partly reflecting perceived risks of in-hospital care. We recently implemented an evidence-based protocol for outpatient rapid evaluation of transient and minor, non-disabling stroke symptoms for patients seeking care 24 hours after symptom onset. We present our early experience through the pandemic. Methods: We conducted a retrospective review of patients evaluated in the RESCUE-TIA (Rapid Evaluation of minor Stroke and CerebrovascUlar Events including TIA) clinic from December 2019- August 2020. The clinic sees patients with TIA symptoms or with fixed, non-disabling deficits seeking care > 24 hours after symptom onset. We introduced telemedicine in March 2020. Magnetic resonance brain and vascular imaging is available within 24 hours of visit. We summarized patient characteristics and quality data with standard descriptive statistics. Results: A total of 21 patients were seen in the RESCUE-TIA clinic, including 15 patients during the height of the pandemic in NY;67% were seen by telemedicine. The median age was 75 years (interquartile range [IQR], 61-82), and 71% were women. The median NIH Stroke Score for patients with minor stroke was 0 (IQR, 0-1), and the median ABCD score for TIA patients was 3 (IQR, 2-3). Median time from symptom onset to evaluation was 3 days (IQR, 2.5-17.5). Median time from evaluation to laboratory diagnostics was 8 hours (IQR, 2-21), and to completion of imaging was 1 day (IQR, 0-5). Outpatient telemetry commenced in a median of 5 days (IQR, 1-9), and echocardiography was completed in a median of 8 days (IQR, 0-10). One patient was referred to the emergency room for a carotid occlusion. Final diagnoses were TIA (n=12), ischemic stroke (n=5), transient global amnesia (n=2), migraine (n=1), and non-aneurysmal, distal subarachnoid hemorrhage (n=1). Secondary prevention was initiated or optimized in 94% of TIA and stroke patients. Recurrent TIA occurred in 1 patient after 67 days, and ischemic stroke occurred in 1 patient 55 days after TIA. Conclusion: Timely outpatient evaluation of patients with recent TIA and minor, non-disabling stroke is feasible and may be useful during the pandemic, especially during emergency room crowding.