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1.
HemaSphere ; 6:3515, 2022.
Article in English | EMBASE | ID: covidwho-2032161

ABSTRACT

Background: Diagnosis of AL amyloidosis requires demonstration of amyloid in affected tissues along with clonal plasma cells in bone marrow or presence of monoclonal light chains in blood. With increasing awareness among physicians and availability of proper diagnostics, more cases of AL amyloidosis are being diagnosed. Here we present our experience of AL amyloidosis diagnosis and treatment in the era of modern diagnostics and therapy with novel agents. Aims: We aimed to describe the clinical presentations, laboratory features and outcomes of patients with AL amyloidosis in a single center using standard diagnostic tests and treatment with novel agents. Methods: A retrospective analysis of AL amyloidosis patients, diagnosed in our hospital, a tertiary care center in India from January 2016 to December 2021. The data was collected from departmental database. All statistical analyses were done by SPSS version 17. Results: Diagnosis of AL amyloidosis was done in 27 patients. Median age of presentation was 59 years. 22 (81.5%) were males. Major symptoms were pedal edema (37%), shortness of breath (22.2%), frothy urine (11.1%) and fatigue (11.1%). Twenty two (81.5%) presented with ECOG PS ≥ 2. Most common system involved was renal in 16 (59.2%), followed by cardiac in 13 (48.1%) and gastro-intestinal in 9 (33.3%). Fifteen (55.6%) had two or more system involvement while 12 (44.4%) had single system involvement. Lambda monoclonal light chain was present in 22/27 (81.5%) and kappa monoclonal light chain was present in 5/27 (18.5%). Median Hb was 11.6 g/dl (range 6.7- 14.8 g/dl), median M-protein was 0.69 g/dL (range 0-2 g/dL) and median bone marrow plasma cells were 7% (range- 1-18%). Fourteen patients were treated;cyclophosphamide, bortezomib and dexamethasone (CyBORD) in 10/14 (71.4%) and bortezomib + dexamethasone in 4/14 (28.6%). Among 14 patients followed up with median follow up of 13 months (range 6-60 months), 5 expired;3 due to COVID, one due to cardiac arrhythmia (during first cycle) and one due to relapse and rest 9 were alive. Among the 9 patients who were alive 6 were in complete hematological response and 3 were in partial response after 6 cycles of therapy. Summary/Conclusion: Our study presents the spectrum of clinical manifestations, management and outcomes of primary amyloidosis in Indian context. There is a need to increase the awareness among the physicians about amyloidosis so that early diagnosis can be made and timely treatment can be done with novel agents to improve the dismal historical results.

2.
HemaSphere ; 6:293-294, 2022.
Article in English | EMBASE | ID: covidwho-2032133

ABSTRACT

Background: Patients with hematological malignancies (HM) infected with SARS-CoV-2 hae a higher risk of deeloping seere coronairus disease (COVID-19) with consequent death, due to immune system impairment. Anti-spike Neutralizing Monoclonal Antibodies (nMoAbs) are indicated for the treatment of paucisymptomatic COVID-19 patients, but eidence of safety and efficacy among HM subjects is still lacking. Aims: To assess the efficacy of different nMoAbs approed by Agenzia Italiana del Farmaco (AIFA) on HM patients affected by paucisymptomatic SARS-COV-2. Methods: Multicenter retrospectie obserational study at ten sites in Italy, which enrolled consecutie patients with SARS-CoV-2 infection and treated with nMoAbs from February 2020 to December 2021. Only HM subjects on treatment or in disease remission within 6 months from treatment discontinuation with paucisymptomatic SARSCOV- 2 infection were included. nMoAbs approed by AIFA include Bamlaniimab, Bamlaniimab/Eteseimab, Casiriimab/Imdeimab, Sotroimab, and Regdanimab. The primary endpoint was to assess the time to SARS-CoV- 2 molecular swab negatiization. A comparison to an historical control not receiing nMoAbs was assessed. Secondary endpoints consisted in ealuation of Hospitalization rate due to COVID-19, including intensie care unit (ICU) admission rate due to respiratory failure, and safety assessment. Results: Oerall 51 HM patients (median age 62 years;35% women) were ealuated. Seenteen of them had non- Hodgkin lymphomas, 9 multiple myeloma, 6 chronic lymphocytic leukemia, 6 acute myeloid leukemia, 3 Hodgkin lymphoma, 2 acute lymphoblastic leukemia, 2 myeloproliferatie neoplasm, 1 Waldenstrom macroglobulinemia and 5 had other HM diagnosis. Thirty-six patients were on actie treatment, whereas 11 had completed their therapies within 6 months from nMoAbs administration, for 4 patients data were missing. In 7 subjects the last treatment was chemotherapy, in 19 immunotherapy with or without chemotherapy, in 9 target therapy, in 4 autologous stem cell transplantation, in 2 allogeneic stem cell transplantation, for 4 patients data were missing. Detailed description of patients' characteristics is reported in table 1. Twenty-six patients were treated with Bamlaniimab/Eteseimab, 17 with Casiriimab/Imdeimab, 3 with Bamlaniimab, and 2 with Sotroimab, for 3 patients data were missing. Median time to SARS-CoV-2 molecular swab negatiization was ealuable in 41 subjects and was 17 days (min 5, IQR 12-26, max 174). This result compared well with the preious finding of 28 days reported in an historical group of HM patients not treated with nMoAbs. We did not find any subpopulation, according to age, diagnosis, period of infection or type of nMoAbs who achieed a major benefit from nMoAbs treatment. The rate of Hospitalization due to COVID-19 progression was 19% (10/51), with an extremely low percentage of patients requiring ICU admission due to seer COVID-19 (2%,1/51). Most frequent side effects included chills (8%), diarrhea (6%), headache (2%), nausea (2%) and omiting (2%). Summary/Conclusion: Among paucisymptomatic SARS-CoV-2 positie HM patients on actie treatment or in disease remission within 6 months from treatment discontinuation, the administration of nMoAbs substantially reduced the time to swab negatiization compared to an historical control of HM subjects. This treatment was also able to reduce the rate of Hospitalization and death due to COVID-19 progression in this high risk group. (Table Presented).

3.
HemaSphere ; 6:1038, 2022.
Article in English | EMBASE | ID: covidwho-2032104

ABSTRACT

Background: Vulnerability of patients (pts) with chronic lymphocytic leukemia (CLL) and their susceptibility to Covid-19 infection is documented in several studies with reported case fatality rates (CFRs) up to 40%, but there is still paucity of data on identifying risk factors of their adverse outcome. Aims: To evaluate demographic, patient-related, CLL-related and Covid-19 related risk factors in hospitalized pts with concurrent CLL and Covid-19. Methods: Total of 81 CLL pts were identified in medical records of three University centers in Belgrade: Clinical Hospital Center (CHC) Zemun, CHC Bezanijska kosa and CHC Zvezdara dedicated to treatment of Covid-19 pts during pandemic (from 15 March 2020 to 31 December 2021). Results: For all 81 pts CFR was 32.1%. Age (median age 68 yrs;range 45-90 yrs) and sex (apparent male prevalence: 61 male and 20 female;M:F=3.05) had no influence on outcome. Pts with Charlson comorbidity index >4 (29/81;35.8%) had significantly higher CFR (38% vs 9.5%, p=0,025). Concerning CLL-directed treatment: 26/81(32.1%) pts were on active treatment (5 pts were on Bruton tyrosine kinase inhibitor, 21pts receiving imunochemotherapy), 11/81(13.6%) pts were in remission on previous lines of therapy, while 44/81(54.3%) pts were treatment naive. CLL treatment history had no impact on CFR, as well as anemia (Hb<100g/l) that was present in 29/81(35.8%)pts, hipogammaglobulinemia (21/81;26%pts) and hiperferritinemia>450ng/mL (50/81;61.7%pts). Of evaluated laboratory parameters, high levels of lactate-dehydrogenase (LDH>2xUNL:6/81;7.4%pts), D-dimer (>1000ng/mL:36/81;44.4%pts), and C-reactive protein (CRP>100mg/L: 31/81;38.3%pts) proved to be associated with adverse outcome;p-values 0.002, 0.039 and <0.001, respectively. According to Covid-19 clinical course, the severe Covid-19 score had 35(43,2%)pts, and critical 19(23.5%)pts. Covid-19 infection was treated according to current National guidelines. Corticosteroids were administrated to 81.5% of pts, antiviral agents to 38.3%, IL-6 receptor inhibitor to 11.1%, antiviral monoclonal antibodies to 7.4% and intravenous immunoglobulin to 19.8% of pts. None of listed therapeutic approaches had impact on CFRs. Antibiotics were administrated to 43/81 (53.1%) of pts with documented or highly suspected concomitant bacterial infection (procaltitonin level>0.5ng/mL and/or chest X-Ray image corresponding to bacterial pneumonia), and the bacterial coinfection had adverse impact on CFR (51.2% vs.10.2%;p<0.001). Significantly higher mortality was documented in pts who needed supplemental oxygen (58/81;71%) (CFR 43.1 vs.4.3%;p<0.001), and intensive care unit (ICU) admission (25/81-30.9%;19/25 needed mechanical ventilation) (CFR 88% vs.7.1%;p<0.001). In multivariate analysis, bacterial coinfection and ICU admission proved to be the most significant adverse parameters influencing outcome (p=0.012). Summary/Conclusion: Our study proved the dismal outcome of CLL pts with concurrent Covid-19. That could be mainly attributed to the high proportion of bacterial coinfections reflecting their frailty and sucessibility to both viral and bacterial infections.

4.
Journal of Medical Cases ; 13(8):380-385, 2022.
Article in English | Scopus | ID: covidwho-2025721

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic emerged as a world crisis in 2019 and started a global search for optimal therapeutic regimen including vaccines, antiviral agents, and recently monoclonal antibody therapy. Clinical trials are currently underway for the efficacy of several neutralizing monoclonal antibodies against COVID-19. The evolution of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with immune evasion capacity has created a challenge for the healthcare workers with urgent need for prospective studies to determine functionality of monoclonal antibody therapy and their role in the reduction of hospitalization for disease severity. Herein, we report three cases of COVID-19 during the beginning of the spread of Omicron variants that were hospitalized after treatment with monoclonal antibody therapy in the emergency department. All the patients showed progression of the disease on imaging and were treated with dexamethasone, remdesivir and anticoagulation based on the symptoms and contraindications. Two of the patients recovered and were discharged with out-patient follow-up;however, one patient expired in the hospital. Monoclonal antibody therapy is a promising treatment to limit the progression of COVID-19 and reduce the hospital strain specifically in small community hospitals. Limited information is available about their efficacy in the new viral variants. These cases emphasize the need of future prospective study and randomized controlled trials to illustrate the utilization of monoclonal antibodies as a therapeutic modality in patients infected with the variants of SARS-CoV-2. © The authors ;Journal compilation J Med Cases and Elmer Press Inc™ ;www.journalmc.org This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited

5.
International Journal of Molecular Sciences ; 23(17):9674, 2022.
Article in English | ProQuest Central | ID: covidwho-2023747

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) infects piglets and causes serious diarrhea as well as vomiting, dehydration, and death. The trimeric S protein plays a crucial role in the induction of neutralizing antibodies, and many neutralizing monoclonal antibodies (mAbs) against PEDV S protein have been developed. However, these mAbs exclusively target the S1 protein. In this study, we obtained a neutralizing mAb, 5F7, against the S2 protein of PEDV, and this mAb could neutralize new variant genotype 2 PEDV strains (LNCT2), as well as a genotype 1 PEDV strain (CV777), in vitro. The core sequence of the epitope was found in amino acid sequence 1261 aa~1337 aa. These findings confirm that the S2 protein possessed neutralizing epitopes and provided knowledge to aid further research on this virus.

6.
International Journal of Molecular Sciences ; 23(17):9604, 2022.
Article in English | ProQuest Central | ID: covidwho-2023744

ABSTRACT

Understanding the biological mechanisms underlying the pH-dependent nature of FcRn binding, as well as the various factors influencing the affinity to FcRn, was concurrent with the arrival of the first recombinant IgG monoclonal antibodies (mAbs) and IgG Fc-fusion proteins in clinical practice. IgG Fc–FcRn became a central subject of interest for the development of these drugs for the comfort of patients and good clinical responses. In this review, we describe (i) mAb mutations close to and outside the FcRn binding site, increasing the affinity for FcRn at acidic pH and leading to enhanced mAb half-life and biodistribution, and (ii) mAb mutations increasing the affinity for FcRn at acidic and neutral pH, blocking FcRn binding and resulting, in vivo, in endogenous IgG degradation. Mutations modifying FcRn binding are discussed in association with pH-dependent modulation of antigen binding and (iii) anti-FcRn mAbs, two of the latest innovations in anti-FcRn mAbs leading to endogenous IgG depletion. We discuss the pharmacological effects, the biological consequences, and advantages of targeting IgG–FcRn interactions and their application in human therapeutics.

7.
Biomedicines ; 10(8):1861, 2022.
Article in English | ProQuest Central | ID: covidwho-2023145

ABSTRACT

Monoclonal antibodies (mAbs), the new revolutionary class of medications, are fast becoming tools against various diseases thanks to a unique structure and function that allow them to bind highly specific targets or receptors. These specialized proteins can be produced in large quantities via the hybridoma technique introduced in 1975 or by means of modern technologies. Additional methods have been developed to generate mAbs with new biological properties such as humanized, chimeric, or murine. The inclusion of mAbs in therapeutic regimens is a major medical advance and will hopefully lead to significant improvements in infectious disease management. Since the first therapeutic mAb, muromonab-CD3, was approved by the U.S. Food and Drug Administration (FDA) in 1986, the list of approved mAbs and their clinical indications and applications have been proliferating. New technologies have been developed to modify the structure of mAbs, thereby increasing efficacy and improving delivery routes. Gene delivery technologies, such as non-viral synthetic plasmid DNA and messenger RNA vectors (DMabs or mRNA-encoded mAbs), built to express tailored mAb genes, might help overcome some of the challenges of mAb therapy, including production restrictions, cold-chain storage, transportation requirements, and expensive manufacturing and distribution processes. This paper reviews some of the recent developments in mAb discovery against viral infections and illustrates how mAbs can help to combat viral diseases and outbreaks.

8.
Frontiers in Immunology ; 13, 2022.
Article in English | Web of Science | ID: covidwho-2022749

ABSTRACT

Class 1 and 2 monoclonal antibodies inhibit SARS-CoV-2 entry by blocking the interaction of the viral receptor-binding domain with angiotensin-converting enzyme 2 (ACE2), while class 3 antibodies target a highly conserved epitope outside the ACE2 binding site. We aimed to investigate the plasticity of the spike protein by propagating wild-type SARS-CoV-2 in the presence of class 3 antibody S309. After 12 weeks, we obtained a viral strain that was completely resistant to inhibition by S309, due to successively evolving amino acid exchanges R346S and P337L located in the paratope of S309. The antibody lost affinity to receptor-binding domains carrying P337L or both amino acid exchanges, while ACE2 binding was not affected. The resistant strain replicated efficiently in human CaCo-2 cells and was more susceptible to inhibition of fusion than the original strain. Overall, SARS-CoV-2 escaped inhibition by class 3 antibody S309 through a slow, but targeted evolution enabling immune escape and altering cell entry. This immune-driven enhancement of infectivity and pathogenicity could play an important role in the future evolution of SARS-CoV-2, which is under increasing immunological pressure from vaccination and previous infections.

9.
Appl Microbiol Biotechnol ; 2022 Aug 10.
Article in English | MEDLINE | ID: covidwho-2014103

ABSTRACT

To establish a rapid and specific antigen detection method for porcine circovirus type 2 (PCV2), monoclonal antibodies (mAbs) were produced against the PCV2 epidemic strains and a red latex microsphere immunochromatographic strip was established. A total of eight anti-PCV2b and four anti-PCV2d mAbs were produced, and seven mAbs were confirmed to react with PCV2a, PCV2b, and PCV2d strains using an immunoperoxidase monolayer assay. The results of micro-neutralization tests showed that the mAbs 2C8, 9H4, 10G7, 7B9, and 7C7 had good neutralizing activity, whereas the neutralizing activity of the mAbs 4B3, 4C9, 6H9, and 7E2 was lower than 50%. Three mAbs, 4B3, 7C7, and 9H4, and PCV2 pAb were selected for the establishment of a red latex microsphere immunochromatographic strip, and the combination of mAb 7C7 labeled with red latex microspheres and mAb 9H4 exhibited the greatest detection ability. The immunochromatographic strip had minimum detection limits of 102.5 TCID50/0.1 ml, 100.7 TCID50/0.1 ml, and 101.5 TCID50/0.1 ml for PCV2a/CL, PCV2b/MDJ, and PCV2d/LNHC, respectively. Furthermore, no cross-reactivity was found for African swine fever virus, classical swine fever virus, porcine respiratory and reproductive syndrome virus, porcine parvovirus, porcine pseudorabies virus, porcine circovirus type 1, transmissible gastroenteritis virus, porcine epidemic diarrhea virus, porcine rotavirus, or porcine deltacoronavirus using the immunochromatographic strip. Using PCR as a reference standard, the detection sensitivity, specificity, and overall coincidence rate of the immunochromatographic strip were 81.13%, 100%, and 90.00%. Additionally, the detection ability of the immunochromatographic strip was correlated with that of virus titration. The immunochromatographic strip was used to detect 183 clinical disease samples, and the average positive detection rate was 22.95%. In summary, this method has good sensitivity and specificity and is simple, convenient, and quick to operate. It has high application value for on-site diagnosis of PCV2 and virus quantification. KEY POINTS: • A red latex microsphere immunochromatographic strip for PCV2 detection was developed. • The method was not only simple to operate, but also takes less time. • The method had good sensitivity and specificity.

10.
Journal of Asthma and Allergy ; 15:1195-1203, 2022.
Article in English | EMBASE | ID: covidwho-2009779

ABSTRACT

Purpose: Patients with severe asthma (SA) are at an increased risk of asthma-related hospitalizations and exacerbations. Despite concerns that COVID-19 circulation would increase exacerbations of SA, anecdotal reports suggest that social distancing and exposure avoidance may have led to reduced exacerbations. Patients and methods: CHRONICLE is an ongoing noninterventional observational study of 3100 subspecialist-treated patients with SA. Eligible adults (≥ 18 years of age) have (1) current use of monoclonal antibody (ie, biologic) therapy for SA, (2) use of maintenance systemic corticosteroids (mSCS) or other systemic immunosuppressants for ≥ 50% of the prior 12 months for SA, or (3) persistently uncontrolled asthma while treated with high-dosage inhaled corticosteroids with additional controllers. For enrolled patients, electronic medical records were reviewed to record all exacerbations and asthma-related hospitalizations. Descriptive analyses were conducted of the monthly incidence of exacerbations, exacerbation-related visits to the emergency department (ED), and asthma hospitalizations from July 2018 through July 2021. Results: Exacerbations, exacerbation-related ED visits, and hospitalizations decreased since April 2020. Exacerbations in 2020 were 20% to 52% lower in April through August relative to the same months in 2019. Exacerbations remained lower than the prior year through May 2021. Similar results were observed by United States (US) census region, with an earlier decrease in exacerbation rates in the western US versus other regions. Across all months, exacerbation rates were lower among biologic recipients. Conclusion: In a clinical cohort of subspecialist-treated patients with SA, there was a meaningful reduction in exacerbations, exacerbation-related ED visits, and asthma hospitalizations following COVID-19–related stay-at-home orders and social distancing recommendations. Reasons for these reductions are likely multifactorial, including reduced viral infections due to less social contact and altered patient behavior.

11.
Journal of Clinical Oncology ; 40(16), 2022.
Article in English | EMBASE | ID: covidwho-2009634

ABSTRACT

Background: Maintaining relative dose intensity (RDI) of chemotherapy is important to ensure optimal patient outcomes in a variety of solid cancers. RDI < 85% significantly decrease therapy efficiency (including overall survival) in almost solid tumors (ST). Chemotherapy-induced neutropenia (CIN) is the most common adverse event (AE) leading to low RDI. Proper administration of primary G-CSF prophylaxis (PP) allows to achieve optimal therapy efficiency. There are several trials and meta-analyses have shown a superior efficiency prolonged G-CSF vs short G-CSF. This multicenter prospective observational post-registration study of prolonged G-CSF empegfilgrastim (Extimia) was designed to evaluate the RDI of the cytotoxic therapy course under PP by empegfilgrastim in patients (pts) with ST receiving myelosuppressive therapy in the routine clinical practice. Methods: 2000 pts with ST receiving cytotoxic therapy (4-8 cycles per course are allowed) under PP with empegfilgrastim by investigator choice in the routine clinical practice. RDI of therapy course was primary endpoint and presented here for pts who completed the planned regimen. For each agent, both the planned and actual dose intensity were calculated by dividing the total cumulative dose by treatment duration in days. RDI was calculated for each single agent in chemotherapy-based (CTb) regimen and for CTb regimen in total. These descriptive analyses and RDI calculations were performed for the whole CT based regimen (chemotherapeutic agents, molecular target agents, monoclonal antibodies). Funded by JSC Biocad;Defendor Clinical-Trials.gov No NCT04811443. Results: At the data cut-off 1074 pts from 31 Russian sites underwent ≥ one cycle of CTb regimens combined with empegfilgrastim. Distribution of all-cancer types was in line with epidemiology data in Russia. 526 pts completed the planned CT course. 352 (66,9%) of them have at least one of FN risk factor. RDI≥85% were achieved in 492 (93,5%) pts. RDI by key nosology is presented in Tab.1. 118 (22,4%) cases of interval prolongation and/or dose reduction was registered. The main reasons of RDI decrease were personal pts's issues 69 (13,1%), COVID-19 pandemic 26 (4,9%), holidays 9 (1,7%) and others. Neutropenia was in 6 (1,1%) cases as a reason of RDI decrease. Treatment-related AEs of grade 1-2 occurred 12 (2,3%) pts (back pain, ossalgia, myalgia). Conclusions: Thus, PP with prolonged G-CSF empefilgrastim allows effectively maintain RDI in different nosology and treatment groups in pts with ST in the routine clinical practice.

12.
Journal of Clinical Oncology ; 40(16), 2022.
Article in English | EMBASE | ID: covidwho-2009630

ABSTRACT

Background: Patients with hematologic malignancies have a lower vaccine response and higher rates for SARS CoV-2 morbidity and mortality. We present preliminary data focusing on humoral vaccine responses and correlates with disease subtype and treatment exposure. Methods: We analyzed data from 332 patients with a hematologic malignancy from May 1, 2021 - Jan 31, 2022 who received SARSCoV-2 vaccination and performed a prospective cohort serologic study with the Elecsys®Anti-SARSCoV-2-S test. Patients received homologous or heterologous vaccine combination of BNT162b2, mRNA1273, ChAdOx1 nCoV-19, and/or Ad26.COV2.S. Blood samples were obtained before any vaccination, 2-6 weeks after the second vaccine (2V), before third vaccine (3V), and 2-6 weeks after 3V. Results: The median age was 67 years (range 18-91years) with 41.9% female. At 2V, 11.5% and at 3V, 23.8% received heterologous vaccines. Treatment status at first vaccine dose significantly affected peak 2V antibody response (p < 0.05). Seropositive rate and median antibody titer after 2V for previously untreated patients were higher compared to patients on active therapy or had previously been treated. Treatment naïve (n = 60;seropositivity 85.1%;median titer 1306 U/mL;[Q1-Q3:11.4-> 2499]);first-line (1L) active therapy (n = 127;65.4%;41.25 U/mL;[ < 0.8-592.5]);second-line and beyond (2L+) active therapy (n = 56;60.7%;2.6U/mL;[ < 0.8-154]);previous treatment with 1L (n = 66;64.8%;118 U/mL;[ < 0.8-> 2499]);previous treatment with 2L+ (n = 23;59.1%;4U/mL;[ < 0.8-229.5]). Of 61 patients that were seronegative at 2V, 17 (27.9%) seroconverted after 3V. Anti-CD20 monoclonal antibody (mAb) containing therapy as the most recent treatment from 2V had the greatest impact on humoral response. Exposure to anti-CD20 mAb based regimens or as monotherapy revealed low antibody responses (n = 84;seropositivity 22.6%;median titer < 0.8 U/mL;Q1-Q3 [ < 0.8-< 0.8]). On analysis of indolent B-cell Non-Hodgkin Lymphomas whereby antiCD-20 mAb are often incorporated, treatment proximity to 2V impacted responses: < 3 months (n = 33;22%;< 0.8 U/ mL;[ < 0.8-< 0.8]) vs. 12-24 months (n = 4;60%;228 U/mL;[ < 0.8-232]). In contrast, tyrosine kinase inhibitor (n = 38;100%;858 U/mL;[221-> 2499]), proteosome inhibitor monotherapy (n = 4;100%;median titer 1520 U/mL;[462-> 2499]) were among the subgroups with the highest numerical responses, however, the addition of corticosteroids impacted vaccine response as seen in proteosome inhibitor with corticosteroids (n = 7;85.7%;6.6 U/mL;[1.8-115.2]). Conclusions: The humoral response from our single institution cohort identifies diminished responses depending on treatment status and the type of treatment including the proximity of treatment exposure to receipt of vaccination. Furthermore, vaccine boosters can induce antibody responses in patients who were previously seronegative.

13.
Transpl Infect Dis ; 24(4): e13901, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-2008758

ABSTRACT

BACKGROUND: Solid organ transplant recipients (SOTRs) are at high-risk for severe infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Anti-spike monoclonal antibodies are currently utilized under emergency use authorization to prevent hospitalization in high-risk individuals with coronavirus disease 2019 (COVID-19), including SOTRs. However, clinical data for bebtelovimab, the sole currently available anti-spike monoclonal antibody for COVID-19, is limited. METHODS: We conducted a retrospective cohort study of adult SOTRs diagnosed with mild-to-moderate COVID-19 from January 2022 through May 2022 who received either bebtelovimab or sotrovimab. The primary outcome was COVID-19-related hospitalization within 30 days of COVID-19 diagnosis. Data were analyzed with Fisher's exact test. RESULTS: Among 361 SOTRs, 92 (25.5%) received bebtelovimab and 269 (74.5%) received sotrovimab. The most common organ transplant was a kidney (42.4%). SOTRs who received bebtelovimab had a higher proportion who had received a booster SARS-CoV-2 vaccine dose and had received their last vaccination dose more recently. Eleven (3.0%) SOTRs were hospitalized, and rates of hospitalization were similar between monoclonal antibody groups (3.3% versus 3.0%; p > .99). Three patients required admission to an intensive care unit, all of who received sotrovimab. Four (1.1%) patients died within 30 days of COVID-19 diagnosis, two from each group. CONCLUSIONS: SOTRs with mild-to-moderate COVID-19 who received bebtelovimab had similar rates of COVID-19-related hospitalization as those who received sotrovimab. While differences in vaccination rates and viral subvariants could act as confounders, bebtelovimab appears to be of similar effectiveness as sotrovimab.


Subject(s)
COVID-19 , Organ Transplantation , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing , COVID-19/drug therapy , COVID-19 Testing , COVID-19 Vaccines , Humans , Organ Transplantation/adverse effects , Retrospective Studies , SARS-CoV-2 , Transplant Recipients
14.
Annals of the Rheumatic Diseases ; 81:1698, 2022.
Article in English | EMBASE | ID: covidwho-2009126

ABSTRACT

Background: Several studies suggested that SARS-CoV-2 infection may induce autoantibodies related to autoimmune rheumatic diseases (ARD). Objectives: To determine whether polyclonal antibodies from SARS-CoV-2 unin-fected patients with ARDs cross-react with SARS-CoV-2 and vice versa. Methods: 90 sera positive at high-titres for 23 common autoantibodies (all sera stored before 2018), were tested for reactivity against proteins of SARS-CoV-2 (spike protein S1, nucleocapsid NC etc) by ELISA and CMIA. Vice versa, 10 monoclonal antibodies against S1 protein (most of them against RBD) were tested for autoantibody reactivity by indirect immunofuorescence, ELISA, immunoblot and dot/line immunoassays coated with different antigens. Ten post-COVID sera with high titers of anti-Spike abs were tested by ELISAs for reactivity against various autoantigens related to ARDs. Results: 88 out of 90 samples (%), were totally unreactive to SARS-CoV-2 proteins;2 sera, one anti-CCP and one anti-CENP reacted against S protein. All sera tested negative for neutralized abs against SARS-CoV-2. None of 10 sera from SARS-CoV-2 infected patients reacted with different autoantigens by molecular assays. None of the 10 monoclonal abs against S1 protein reacted with 23 different self-antigens. On HEp2 cells as substrate for IIF, 3 of the 10 monoclonal abs gave a low-titre coarse speckled pattern. No reactivity was found by IIFL using tissue substrates. Conclusion: Our data do not suggest a dominant role for molecular mimicry and immunological cross reactivity as a trigger of autoantibodies related to ARDs.

15.
Annals of the Rheumatic Diseases ; 81:330, 2022.
Article in English | EMBASE | ID: covidwho-2008937

ABSTRACT

Background: Among immunocompromised patients with immune mediated infammatory diseases (IMIDs), those undergoing therapy with B cell depleting agents are among the most vulnerable to both severe COVID-19 disease and sub-optimal response to COVID-19 vaccines(1). Numerous studies have documented suppressed humoral, but relatively maintained cell mediated, responses to COVID-19 vaccines in these patients. However, the clinical signifcance of such immunity in terms of protection from infection and its sequelae are poorly understood. We have analyzed a large cohort of vaccinated IMIDs patients undergoing B cell depleting therapy for the presence of breakthrough infection and assessed their outcomes. Objectives: To defne the frequency and outcomes of COVID-19 breakthrough infection in fully or partially vaccinated IMIDs patients receiving B cell depleting therapies. To assess the characteristics and risk factors for severe outcomes and death. Methods: All pharmacy records from within a large health care system were electronically searched for patients undergoing B cell depleting therapies with approved monoclonal antibodies in 2020. Records with ICD codes for IMIDs but not malignancies were included;patients must also have had at least one documented COVID-19 vaccine. From this cohort all patients with breakthrough COVID-19 disease from time of 1st vaccination through December 15, 2021 were identifed;each record was hand-reviewed to extract clinical data including vaccine history, demographics, comorbidities, use of monoclonal antibodies, dose and timing of B cell depleting therapy, and outcomes as assessed by an 8 point NIH ordinal scale. Univariate and multivariable logistic/proportional-odds regression models were used to examine the risk factors for severe outcomes. Results: A total of 1677 IMIDs patients were identifed who received any B cell depleting monoclonal antibody and at least one COVID-19 vaccine in 2021. From this cohort 74 patients (4.4%) experienced a breakthrough COVID-19 infection. Among the breakthrough patients 34 (46%) had a rheumatic disease (RA 11, AAV 15, SLE 2), 34 (46%) had CNS infammatory disease (MS 32, 2 other), and 6 (8%) had immune hematologic/miscellaneous diseases. Four patients had a previous history of COVID-19 infection. Overall 24 (35%) were hospitalized with 11 patients requiring critical level care (15%) and 6 deaths (8 %). All fatal cases had rheumatic diseases. Monoclonal antibodies were given as outpatient therapy to 21 patients and among these only 1 patient was hospitalized without requiring O2 and none died. In univariate analysis only number of comorbidi-ties had a signifcant positive effect (p=.001) on severe outcomes (i.e. groups 1-4 vs. groups 5-8: Table 1) while monoclonal antibody therapy was associated with more favorable outcomes (p=.005 group 1-2 vs.3-8, Table 1). There were no associations between the dose, duration or timing of the B cell therapy, concomitant therapies including glucocorticoids, vaccine status (incomplete, complete, boosted) or date of vaccination with severe outcomes. Conclusion: In IMIDs patients treated with B cell depleting therapies breakthrough infections are common with many experiencing severe outcomes. Concomitant comorbidities were associated with risk of severe disease. Monoclonal antibody therapy was used in only 28% but was associated with enhanced clinical outcomes with only 1 in 21 requiring hospitalization and zero mortality. This population of immunocompromised patients remains vulnerable to COVID-19 disease despite vaccination. More aggressive use of outpatient management with monoclonal antibody therapy and other preventive and therapeutic measures are urgently needed.

16.
Annals of the Rheumatic Diseases ; 81:1859-1860, 2022.
Article in English | EMBASE | ID: covidwho-2008919

ABSTRACT

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy characterized by microangio-pathic haemolytic anemia, consumption thrombocytopenia and organ injury, particularly kidney failure and neurological manifestation1. Two forms are distinguished: the hereditary one, caused by a deficit of the metallopro-tease ADAMTS13, and the idiopathic one characterized by the presence of antibodies directed against ADAMTS13. The second one is the most common. There are various subgroups of acquired TTP associated with HIV infection, sepsis, pregnancy, autoimmune disease, disseminated malignancies and drugs. Antiphospholipid syndrome (APS) is a clinical immunological condition characterized by thromboembolic events, repe-tead miscarriages or stillbirth and thrombocytopenia;it can be a primary disorder or due to connective tissue disease, in particular systemic lupus erythematosus2. Objectives: We describe a case of TTP associated with a primary APS. The real clinical challenge lies in the differential diagnosis between TTP and anti-phos-pholipid antibody syndrome. Methods: A 37-year-old man presented to the emergency department for short-term episodes of anesthesia of the right upper limb and face with spontaneous resolution. In his past medical history, he suffered of antiphospholipid syndrome treated with warfarin. Upon admission, blood tests revealed severe thrombocytopenia, haemolytic anemia with schistocytes on peripheral blood smear, low thrombin time and prolongation in the prothrombin time. Neurological symptoms were assessed by electroencephalogram and CT brain, resulted negative, while a brain MRI revealed acute-subacute ischemic stroke. Based on these fndings we suspected a diagnosis of TTP, subsequently confrmed by reduced activity of ADAMTS-13 with borderline ADAMTS-13 inhibitory antibodies. Immunological testing confrmed positivity of antiphospholipid antibodies and antinuclear antibodies. Results: According to the last guidelines3 about management of acute episode of TTP, immediate therapy with high-dose corticosteroids (prednisone 1 mg/kg) and plasmapheresis was started and then we added infusion of ritux-imab (375 mg/m2/week for 4 times). Efficacy of treatment was evaluated by weekly dosage of ADAMTS13 activity, with a gradual rise in values (3 → 78%) and improvement in symptoms and laboratory examination. After persistent remission, we gradually reduced steroid therapy. Few months later, in February 2021, patient developed a bilateral comunitary pneumonia, that required hospitalization, oxygen-therapy (also with C-PAP) and endovenous antibiotics. After two weeks patient was discharged from hospital in good clinical health and he was subjected to periodic outpatients visits. Disease activity was in remission, so steroid therapy was reduced and recently we added hydroxychloroquine for APS. Some days ago patient developed covid-19 infection, despite vaccination, and he was treated with monoclonal antibodies, with good clinical response. Conclusion: We have described a rare clinical case of TTP, despite concomitant warfarin treatment for primary anti-phospholipid syndrome. A careful follow-up of these medical conditions is recommended for patient's fragility and for the risk of related serious clinical complications.

17.
Journal of Neuroimaging ; 32(4):767-768, 2022.
Article in English | EMBASE | ID: covidwho-2008752

ABSTRACT

Background and Purpose: Balo's concentric sclerosis (BCS) is a rare inflammatory demyelinating disorder of the central nervous system (CNS) characterized pathologically and radiologically by concentric lamella of alternating demyelinated and partially myelin-preserved white matter. Whether BCS is a variant of multiple sclerosis (MS) or a distinct entity remains debatable. Here, we report an unusual case of MS complicated by Balo's lesions, post-Coronavirus disease 2019 (COVID-19), focusing on the evolution ofMRI findings. Methods: Single-case study. Results: The patient is a 42-year-old woman with relapsing-remitting MS diagnosed at age of 19 who was treated with teriflunomide for the past 5 years. She developed a febrile illness and arthralgia for a week;however, COVID-19 testing was deferred. Two weeks later, she presented with vertigo followed by profound right-hemiparesis, gait impairment, and encephalopathy. Cerebrospinal fluid analysis revealed a protein of 56 mg/dl, increased immunoglobulinG(IgG) index, and>l10 unique oligoclonal bands. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG was detected in serum, but viral ribonucleic acid was absent in the CSF. BrainMRI demonstrated, for the first time, several Balo-like and tumefactive lesions, with contrast enhancement and restricted diffusion. She received plasma exchange alternating with pulse steroids, yet was left with ataxic hemiparetic gait. She was later switched to an anti-CD20 monoclonal antibody therapy. Followup brain MRIs showed continuous regression of the tumefactive and Balo-like lesions. Conclusion: This case adds to the emerging spectrum of COVID-19- associated radiological findings regarding inflammatory demyelination in the CNS. It remains unknown whether potential neurotropism of SARS-CoV-2 or parainfectious mechanisms might have contributed to the fulminant disease in our patient.

18.
Monoclonal antibodies in immunodiagnosis and immunotherapy ; 41(4):173-180, 2022.
Article in English | MEDLINE | ID: covidwho-2008502

ABSTRACT

Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, are the important tools both for the diagnosis and therapeutics of this infectious disease. The high-performance antibody against spike protein of SARS-CoV-2 is expected to inhibit the binding of viruses to their receptors on the surface of their target cells. In this study, we propose the novel screening method for mAbs against the pathogenic infectious virus using exosome. By this method, the exosome that artificially expresses SARS-CoV-2 spike protein was purified and used as a virus-like vesicle, which could bind to the viral receptor, angiotensin-converting enzyme 2 (ACE2). As a result, seven mAbs that could bind to the spike protein were obtained and six of these clones could strongly inhibit the binding to ACE2 of both the protein corresponding to the receptor binding domain (RBD) and the exosome expressing the spike protein. Interestingly, some of these antibodies seemed to share their epitopes in RBD, suggesting that highly antigenic sites exist in the spike protein. In view of the neutralizing activities on infection, five clones of these antibodies could inhibit the internalization of vesicular stomatitis virus-based pseudo viruses expressing various types of spike proteins derived from SARS-CoV-2 variants. In addition, these antibodies inhibited the infection of SARS-CoV-2 to cultured mammalian cells. These antibodies are expected to be utilized for both diagnosis and therapeutics of COVID-19.

20.
Medical Immunology (Russia) ; 24(3):629-640, 2022.
Article in Russian | EMBASE | ID: covidwho-2006567

ABSTRACT

The relevance of the current epidemic situation of a new coronavirus infection is determined by new strains of the virus and the registration of cases of re-infection in COVID-19 survivors earlier. In this regard, the questions about the expediency and nature of vaccination of those who have been ill attract close attention, moreover it has affected the formation of the concept of “hybrid immunity”. The aim of this study was to analyze changes in the parameters of the immune system, reflecting their regulatory and functional potential, in response to the introduction of the peptide vaccine EpiVacCorona to persons who have suffered from the new coronavirus infection. To study the features of the formation of hybrid immunity, a retrospective analysis of the observation of 43 study participants was carried out. The inclusion criteria were data confirming COVID-19 in mild and moderate forms of the course in the period from six months to a year ago, a low level or absence of antibodies to the nucleocapsid protein SARS-CoV-2, a negative PCR result for the presence of the SARS-CoV-2 virus, the absence of comorbid pathology. The subpopulation composition, regulatory and functional potential of the immune system were determined by flow cytofluorimetry using a set of monoclonal antibodies corresponding to the goals. 21 days after the administration of a single dose of EpiVacCorona, antibodies to the vaccine peptide antigens were registered in all study participants at the highest coefficient of positivity values for the SARS-CoV-2-IgG-Vector test system used. In addition, there was a fourfold increase in the number of specific IgG to the N protein. A specific immune response to recombinant SARS-CoV-2 antigens was accompanied by a decrease in the circulation of the number of monocytes expressing TLR4, T helper cells expressing the interaction coreceptor with antigen-presenting cells, unconnected B memory with an increase in the number of B lymphocytes expressing the CD40 T-B coreceptor interaction molecule. The remaining differences in the functioning of the immune system identified in patients with COVID-19 before the vaccination in comparison with the control data have not changed. The differences consist in a decrease in the proportion of monocytes expressing HLA-DR, an increase in the expression of interaction molecules on T and B lymphocytes, an increase in the number of Treg, B1 cells, activated B lymphocytes with a decrease in the proportion of suppressor Breg and B memory. The totality of the presented data demonstrates that the COVID-19 infection that preceded vaccination in mild and moderate clinical course contributes to the formation of immunological memory, which made it possible to form a secondary immune response even to a single injection of peptide antigens of the virus.

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