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Objectives: Patients with immune-mediated diseases achieve lower seroconversion rates to COVID19 vaccines compared to healthy controls. The aim of this study was to assess the SARS-CoV-2-specific humoral and T-cell responses after a two-dose regimen of SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA). Method(s): Observational study. Patients with RA, >=18 years of age, who were vaccinated according to the Argentine National Health Ministry's vaccination strategy were included. Anti-SARS-CoV-2 IgG antibodies, neutralizing activity and specific T-cell responses were assessed after the first and second doses. Result(s): A total of 120 RA patients were included. Mostly, homologous regimens were used, including Gam-COVID-Vac (27.5%), ChAdOx1 (24.2%), BBIBP-CorV (22.5%) and BNT162b2 (0.8%), while the most frequent combination of vaccines was Gam-COVID-Vac/mRNA-1273 (21.7%). After the second dose 81.7% presented anti-SARS-CoV-2 antibodies, 70.0% neutralizing activity and 65.3% specific T-cell response. The use of BBIBP-CorV, treatment with abatacept (ABA) and rituximab (RTX) were associated with undetectable antibodies and no neutralizing activity after two doses of vaccine. BBIBP-CorV was also associated with the absence of T-cell response. The total incidence of adverse events was 357.1 events/1000 doses: significantly lower with BBIBP-CorV (166.7 events/1000 doses, p alpha 0.02). Conclusion(s): In this cohort of patients with RA who received 2 doses of COVID-19 vaccine, according to the Argentine strategic vaccination planwhich included homologous and heterologous regimens, two of ten did not develop IgG anti-SARS-CoV-2, 70% presented neutralizing activity and 65% specific T-cell response. The use of BBIBP-CorV was associated with deficient humoral and cellular response, while treatment with ABA and RTXaffected the development of IgG anti-SARS-CoV-2 and neutralizing activity.
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Objectives: To evaluate the humoral immune response to the third dose (booster) of vaccine against SARS-CoV-2 in patients with autoimmune rheumatic diseases who were seronegative after a two-dose regimen. Method(s): Observational study. Patients with autoimmune rheumatic diseases who had not achieved seroconversion after a two-dose vaccine schedule against SARS-CoV-2 were included. To assess the humoral immune response, anti-RBD IgG (S protein receptor binding domain) neutralizing antibody titers were determined by ELISA (cutoff titer 200). The determination was made between 30 to 45 days after the third dose. Result(s): From 66 patients who received SARS-CoV-2 vaccination, 18 patients (29.5%) were seronegative after a two-dose schedule. 61% had SLE, 77% had comorbidities (61% with hypertension, p = 0.03). Patients were on treatment: 10 with prednisone (8 with doses greater than 10 mg/d, p = 0.01), 10 with hydroxychloroquine, one with methotrexate, one with leflunomide, four with azathioprine, five with my cophenolatemofetil and five with rituximab (they are the total number of non-responders on biological treatment, p = 0.03). Regarding the primary vaccination regimen, 11 received BBIBP-CorV (p = 0.01), 5 AZD1222, 1 Gam-COVID-Vac and 1 mRNA1273/Gam-COVID-Vac heterologous scheme. Of these 18 non-responders, 14 received a third dose;nine patients (62%) presented anti-RBD IgG detectable. Of the five patients who did not respond to the booster vaccination, three had received BBIBP-CorV as the initial schedule and the vaccines applied as a third dose were Ad5-nCoV (1), BNT162b2 (1), AZD 1222 (2) and Gam-COVID-Vac (1). They were being treated with: rituximab (2), azathioprine (2) and mycophenolate mofetil (1). Treatment with higher doses of prednisone was the only factor associated with non-seroconversion to the third dose (8 +/- 4.5;p 0.02). Conclusion(s): The third dose of SARS-CoV-2 vaccine allowed to improve the serological response to vaccination, achieving a seroconversion of 62% in this group of patients.
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Background/Aims Patients with immune-mediated rheumatic diseases (IMRD) are commonly treated with immunosuppressors and are prone to infections. Recently introduced mRNA SARS-Cov2 vaccines have demonstrated extraordinary efficacy across all ages. Immunosuppressed patients were excluded from phase III trials with SARS-We aim to fully characterize B and T cell immune responses elicited by mRNA SARS-Cov2 vaccines in patients with rheumatic diseases under immunotherapies, and to identify which drugs reduce vaccine's immunogenicity. Methods Humoral, CD4 and CD8 immune responses were investigated in 147 SARS-Cov2-naive patients with selected rheumatic diseases under immunosuppression after a two-dose regimen of SARS-Cov2 mRNA vaccine. Responses were compared with age, gender, and diseasematched IMRD patients not receiving immunosuppressors and with healthy controls Results IMRD patients showed decreased seroconversion rates (63% vs 100%, p=0.04) and cellular immune responses (59% vs 100%, p=0.007). Patients on methotrexate achieved seroconversion in 62% of cases and cellular responses in 80% of cases. Abatacept deeply affected humoral and cellular responses. Rituximab (31% responders) and belimumab (50% responders) showed severely impaired humoral responses but cellular responses were often preserved. Antibody titers were reduced with mycophenolate and azathioprine but preserved with leflunomide. Conclusion IMRD patients exhibit impaired SARS-CoV-2 vaccine-immunogenicity, variably reduced with immunosuppressors. Among commonly used therapies, abatacept and B-cell depleting therapies show the most deleterious effects, while anticytokines preserved immunogenicity. The effects of cumulative methotrexate and glucocorticoid doses on immunogenicity should be considered. Humoral and cellular responses are weakly correlated, but CD4 and CD8 tightly correlate. Seroconversion alone might not reflect the vaccine's immunogenicity.
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Objectives: The use of glucocorticoids (GC) has been associated with increased risk of hospitalization for coronavirus infection and reduced immunogenicity of SARS-CoV-2 vaccines in immune-mediated diseases (IMD) patients. However, there is still controversy of which dose of GC is correlated with impaired vaccine response on each of the diverse COVID-19 vaccines available, as well as the possible influence of other concurrent immunosuppressants. This study aimed at evaluating the effect of GC on serological response after two doses of BNT162b2 (Pfizer/BioNTech), CoronaVac (inactivated SARS-CoV-2 Vaccine) and ChadOx1 (AstraZeneca) and after the booster dose in patients with IMD. Method(s): The data were extracted from a multicenter longitudinal observational Brazilian cohort (SAFER: Safety and Efficacy on COVID19 Vaccine in Rheumatic Disease). Patients >18 years of age with IMD were evaluated after 2 doses of the same vaccine against COVID-19 and after a booster vaccine, applied according to Brazilian National Immunization Program. All patients underwent clinical examination and collected blood samples for immunogenicity tests. Serological response was evaluated by Anti-RBD titers (IgG) at baseline and 4 weeks after each vaccine dose. Result(s): Among the 1009 patients evaluated, 301 were using GC (196/401 SLE, 52/199 RA and 27/74 vasculitis). Patients using GC were younger (38.2 vs 40,8 years, p = 0,002), had higherBMI (27,6 vs 26,4 p = 0,008), higher prevalence of kidney disease (3,3% vs 0,5%, p = 0,001) and of thrombosis (11,6% vs 5,9%, p = 0,002) than non-users. Regarding the type of vaccine, most of the GC users received CoronaVac (61.7%), while only 31.9%of non-users received this vaccine (p alpha 0.001). Although there were similar rates of pre-vaccination infections among them, patients with GC tended to have a higher incidence of confirmed COVID-19 infection after the 2nd dose of the vaccine compared to non-users (4.5% vs 2.0% p = 0.054). The antibody titers after the 1st dose of COVID-19 vaccines were similar between groups, but there was a worse response in the GC group after the 2nd dose (p = 0.039). However, this difference was not statistically significant after the 3rd dose (Figure). Conclusion(s): GC use may compromise vaccine-induced immunogenicity after a 2-dose regimen;however, this effect does not remain significant after the booster dose. Multivariate analysis is still pending to assess the potential difference in the impact of GC on the immune response depending on GC dose, type of vaccine and associated drugs.
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Introduction: SARS-CoV-2 affected millions of lives globally and led to devastating impact on public health. India had also witnessed the dreadful effect of SARS-CoV-2 pandemic. Within a short span of time, various SARS-CoV-2 vaccines were developed using different platforms across the world. India has also developed one such indigenous whole-virion inactivated SARSCoV-2 vaccine named as BBV152 (Covaxin). The Covaxin has been found to be immunogenic and second most widely used vaccine in India. Recent studies have also shown significant increase in the humoral and neutralizing antibody response post the administration of booster dose against Omicron variant. Apparently, there is limited data on the long-term persistence of the immune response against the Covaxin in Indian context. Method(s): We evaluated an effectiveness of the Covaxin and comparing its specific immune responses in two categories through prospective cohorts recruited at the vaccination centre, Pune during June 2021 to March 2022. We defined the study population in two groups who were COVID-19 naive individuals (group-1) and COVID-19 recovered individuals (group-2) prior to the immunization with Covaxin. The two cohorts and the study participants were decided considering the baseline antibody titres against SARS-CoV-2, the COVID-19 positivity rate, sample power and loss to follow up. The study population was assessed during three follow-ups at second dose, one and six months post second dose to determine the immune response and effectiveness using S1-RBD IgG ELISA and neutralizing antibody response (NAbs) by plaque reduction neutralization test (PRNT). Result(s): We enrolled participants between age group of 18-80 year (median 32 years). In group-1 and group-2, we recruited 118 and 128 participants respectively. The cohort retention was found to be> 85%,>70% and>40% in 1st, 2nd and 3rd follow up respectively. Loss to the 3rd follow up was coincided with third wave with omicron variant. A rise in geometrical mean titre (GMT) of S1-RBD IgG were observed amongst the participants of both the groups at one-month post immunization (Group 1: S1-RBD: 154.4 to 446.3, Group 2 S1- RBD: 918 to 1127). However, the GMTs at six months post vaccination found to be slightly raised in Group 1 compared to one-month follow-up. Considering the hybrid immunity in group 2 participants, the GMTs of NAbs were higher than group 1 participants at each follow-up against B.1, Delta, Omicron BA.1 and BA.2. Both the groups had shown significant reduction in the levels of NAbs against Delta, Omicron BA.1 and BA.2 compared to B.1. The lowest GMTs of NAbs was observed against BA.1 variant. The IgG and NAbs persisted till six months in 90% participants in both categories except BA.1 variant. Breakthrough cases were reported at one-month (n = 1) and six-months (n = 2) post vaccination respectively from group 1. While reinfection cases (n = 3) were detected at six months post vaccination from group 2 due to Omicron BA.1 variant. Conclusion(s): A two-dose regimen of the Covaxin vaccine enhanced humoral immune response in adults with/without past COVID-19 infection and protected more than 90% adults against SARSCoV-2 infection. Additionally, IgG and NAb responses persisted for six months postvaccination.
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The pharmacokinetic (PK) drug-drug interactions (DDIs) of nelfinavir and cepharanthine combination is limited information in human. In addition, the dosage regimen of this combination is not available for COVID-19 treatment. The objective of this study was to perform in silico simulations using GastroPlusTM software to predict physicochemical properties, PK parameters using the physiologically based pharmacokinetic (PBPK) model of healthy adults in different dosage regimens. The DDIs analysis of nelfinavir and cepharanthine combination was carried out to optimize the dosage regimens as a potential against COVID-19. The Spatial Data File (SDF) format of nelfinavir and cepharanthine structures obtained from PubChem database were used to carry out in silico predictions for physicochemical properties and PK parameters using several aspects of modules such as ADMET Predictor, Metabolism and Transporter, PBPK model. Subsequently, all data were utilized in the DDIs simulations. The dynamic simulation feature was selected to calculate and investigate the Cmax, AUC0-120, AUC0-inf, Cmax ratio, AUC0-120 ratio, and AUC0-inf ratio. The victim or nelfinavir dosage regimens were used four oral administration regimens of 500 mg and 750 mg in every 8 and 12 hours for simulations. The perpetrator or cepharanthine oral dosage regimens were used in several regimens from 10 mg to 120 mg in every 8, 12, and 24 hours. From all predicted results, the dosage regimen as a potential combination against COVID-19 was nelfinavir 500 mg every 8 hours and cepharanthine 10 mg every 12 hours.Copyright © 2023 by Faculty of Pharmacy, Mahidol University, Thailand is licensed under CC BY-NC-ND 4.0. To view a copy of this license, visit https://www.creativecommons.org/licenses/by-nc-nd/4.0/.
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Background: Few studies demonstrating the involvement of the complement system in COVID-19 pathogenesis have been published, suggesting its role in pulmonary symptoms and endothelial permeability, which is known to be crucial in the origin of Hereditary Angioedema (HAE).1 Post-morten tissue of COVID-19 patients reported depots of complement, activated by the lectin pathway, in type I and II alveolar epithelial cells.2 After this evidence and the link that infectious processes have as triggers of angioedema episodes, in patients with HAE, we propose to study the implication of both the infection and de doses of the COVID vaccine, in the appearance of episodes of angioedema in our population with a diagnos is of HAE. Method(s): Telemedicine interventions (telephone consultations) were carried out by trained Allergists from Hospital Universitario de Canarias, reaching out patients with a confirmed diagnosis of HEA by Skin Allergy Unit (SAU) within the local health district. Result(s): A total of 17 (11 females) were finally screened, and 2 (11.76%) passed a confirmed COVID-19 disease in January 2022 associating no acute attacks or need for rescue medication. Both subjects were fully vaccinated (3 doses-schedule) prior to the infection and suffered from a COVID-19 mild disease only. Only an individual dose of COVID-19 vaccination (Vaxzevria, Astra-Zeneca) -out of 40 overall given doses in 15 subjects and 3 different brands-was associated to an acute episode of abdominal swelling demanding immediate self-administered rescue therapy (icatibant) thus, preventing the patient from rushing to the Emergency Department. The subsequent 2 doses of the COVID-19 vaccination were safely scheduled in the same patient. Conclusion(s): In accordance with former reports4, only mild COVID-19 symptoms were associated in subjects with a confirmed diagnosis of HAE.
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Case report Background: With the continued rise of COVID-19 hospitalizations due to variants, breakthrough infections and vaccine hesitancy, current treatment regimens must be evaluated. Corticosteroids (CS) have been shown to decrease mortality in patients who require oxygen, especially those on invasive mechanical ventilation [Pinzo et al. 2021]. Steroids also lower intubation rates and transfer to intensive care units [Ahmad et al. 2021]. Methylprednisolone (MP) and dexamethasone (DEX) have been used for the treatment of COVID-19 patients with varied data on outcomes. Having obtained the patient's consent, the case below aims to highlight the use of both MP and DEX in the management of COVID-19 ARDS. Case: A 61-year- old male with a history of prostate cancer in remission presented with fever for 2 weeks and cough and dyspnoea for 2 days. He denied any gastrointestinal or neurological symptoms. He was unvaccinated to COVID-19 and reported recent exposure. On examination his oxygen saturation was 89% on room air and on auscultation, decreased air entry and crepitations were noted bilaterally. COVID-19 infection was confirmed by a positive nasopharyngeal swab. Lab investigations revealed an elevated C-Reactive Protein (CRP) of 26 mg/L, with a normal leukocyte count and renal function. Chest radiograph showed scattered consolidations bilaterally. A diagnosis of ARDS was made and non-invasive ventilation via dual oxygen therapy was initiated. He was later admitted to the High Dependency Unit (HDU) for continuous positive airway pressure ventilation. A tapering dose of MP was administered starting with a loading dose of 1g intravenously (IV) followed by 250 mg IV daily for 3 days and then 1 mg/kg twice daily until discharged from the HDU. MP was then switched to DEX 8mg IV daily and continued until supplemental oxygen was no longer needed. Serial blood draws noted a gradual decline in the CRP value. He was subsequently discharged and followed up in an outpatient setting. Conclusion(s): Current guidelines recommend fixed dosing regimens of CS in COVID-19 ARDS. This case demonstrates the effectiveness of using tapered MP followed by DEX in the management of COVID-19 ARDS. As such CS should not be a fixed dose regimen but rather tailored to the patient's requirements with dose adjustments guided by supplemental oxygen demand and CRP values. Further research is required on CS potency and dosing in COVID-19 associated pulmonary disease.
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Symposium title: Addressing chronic pain and the opioid epidemic using auricular neuromodulation Symposium description: Our proposed symposium integrates a diverse group of scientist and clinician experts (Drs. Cunningham, Wilkes, Khodaparast, Badran) who have committed to exploring the anti-nociceptive and opioid sparing effects of auricular neuromodulation to progress toward non-opioid interventions for chronic pain and opioid use disorders. The demand for chronic pain therapies has increased at an unprecedented rate over the last several decades, contributing in part to a surge in prescription and illicit opioid demand. Countless patients were escalated to prolonged, high-dose opioid regimens over years of treatment. By 2014, 5.4% of U.S. adults were estimated to use prescription opioids on a long-term basis. As the harms of opioid proliferation became increasingly clear, a dramatic paradigm shift occurred in which these drugs are now perceived as more dangerous than beneficial for chronic pain. New clinical guidelines highlight the risks of high-dose regimens as well as the limited benefits, particularly insufficient analgesia and hyperalgesia, associated with long-term use. According to this new perspective, the preferred therapeutic modality for many patients is to safely taper, or even completely stop, using opioids. Transcutaneous auricular neurostimulation (tAN) is a novel therapeutic paradigm that includes stimulation of both the auricular branch of the vagus nerve and auriculotemporal nerve (branch of trigeminal). tAN therapy results in clinically significant reductions in opioid withdrawal symptoms associated with opioid detoxification and tapering. Either adjunctive vagal or trigeminal stimulation modulates pain transmission suggesting overlapping common effector pathways, possibly targeting the endogenous opioid system, which could lead to a synergistic therapeutic benefit for pain. This symposium will explore the scientific basis for this hypothesis across targeted and interconnected topics, including fundamental neuropharmacological mechanisms underlying pain and opioids, clinical challenges of tapering opioids, managing opioid withdrawal symptoms with tAN, and the prospects for tAN to deliver a safe alternative treatment option for pain disorders. The United States is experiencing an epidemic for prescription and non-prescription opioids, which have continued to rise since the 1990s. During 2015, approximately 2.1 million people were severely dependent on prescription opioids, and 513,000 on heroin. In 2020, the Centers for Disease Control reported 93,331 substance use overdose deaths. The continuing increase in opioid-related deaths from 2015 (18%) to 2020 (60%) is partly attributed to the mental health crisis during the Covid-19 pandemic. Aside from pain mitigation, individuals with opioid use disorder (OUD) may be motivated to continue drug-seeking by both the positive reinforcement of the euphoric effects of opioids and the negative reinforcement of opioid withdrawal symptoms due to cessation. Alternative approaches for OUD are a major priority for government agencies given the substantial impact on health, social, and economic welfare. Transcutaneous auricular neurostimulation (tAN) is a non-invasive form of vagus and trigeminal neuromodulation that was recently proven to be an efficacious non-pharmacologic based treatment for reducing opioid withdrawal symptoms. In 2021, tAN therapy received FDA clearance as an adjunctive treatment for opioid withdrawal symptoms in adults. tAN therapy was also proven safe and effective in reducing symptoms of neonatal opioid withdrawal syndrome (NOWS) in neonates. tAN as an adjuvant was safe, well-tolerated, while facilitating the successful rapid weaning of oral morphine and decreasing length of stay in the neonatal ICU. Based on these preliminary findings, tAN therapy is currently in two NIH-funded pivotal clinical trials to: 1) evaluate the long-term effects of tAN on opioid use relapse prevention and cravings in adults with OUD, and 2) determine f tAN therapy can reduce withdrawal symptoms and reduce morphine length of treatment for neonates with NOWS. Lastly, we will explore how tAN could be utilized as neuromodulatory approach for opioid sparing, and ultimately pain mitigation. Research Category and Technology and Methods Clinical Research: 12. Vagus Nerve Stimulation (VNS) Keywords: Vagus Nerve Stimulation, Opioid Use Disorder, Pain, NeurostimulationCopyright © 2023
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Background: Coagulopathy-associated thrombotic events, leading to venous and arterial thromboembolism are highly prevalent among COVID-19 patients. While pharmacologic thromboprophylaxis are the mainstays of treatment, the consideration for an escalated therapeutic dose anticoagulation in the non-critically ill remained a highly debated issue. Objective(s): This meta-analysis sought to evaluate whether therapeutic dose anticoagulation among hospitalized non-critically ill COVID-19 patients reduce the composite primary efficacy outcome (VTE, ATE or death), and the secondary outcomes of major bleeding risk and progression to intubation and mechanical ventilation compared to prophylactic dose anticoagulation. Methodology: After extensive search, screening based on predefined inclusion and exclusion criteria and critical appraisal by 3 independent reviewers 3 eligible open label RTCs with a total of 1492 patients were included in the study. The event rates of the primary and secondary outcomes were assessed after 21-30 days of hospitalization. Result(s): The Risk Ratio for VTE, ATE and death is higher in the prophylactic dose anticoagulation (RR 1.42;95% CI 1.08-1.86), p-value <0.05) compared to therapeutic dose anticoagulation. The risk for major bleeding (RR 0.70;95% CI 0.30-1.62, p-value >0.05) and progression to intubation and mechanical ventilation (RR of 1.13;95% CI 0.93-1.38, p-value >0.05) were not significantly different between the dosing regimens. Conclusion(s): Therapeutic-dose regimen among non-critically ill admitted COVID-19 patients conferred lower risk for the composite primary outcome of VTE, ATE and death with similar risk for bleeding compared to prophylactic dose regimen. Due to this outcome advantage, therapeuticdose anticoagulation can be considered as initial regimen in the noncritically ill COVID-19 patients in the absence of contraindications.
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Introduction: The optimal anticoagulant treatment regimen in hospitalized COVID-19 patients is debated amid studies investigating the effectiveness of different dosing strategies. Aims and Objectives: The aim of this study was to compare the rates of disease progression and mortality in patients treated with LMWH according to a protocol based on baseline D-dimer levels (prophylactic dose when level is below 1000 ng/mL, intermediate dose between 1000 and 3000 ng/mL, therapeutic dose when levels exceed 3000 ng/mL)(on-protocol) and those treated with a fixed-dose regimen (off-protocol). Method(s): This was a retrospective analysis of all patients admitted to a university hospital for COVID-19 pneumonia during a one-year period. Out of a total of 384 patients (mean age 61.5+/-15.9y, 216 male), 294 patients with complete data composed the study group. Result(s): 174 patients were treated on-protocol and 120 patients were off-protocol. The on-protocol group had higher CRP, ferritin, LDH and D-dimer levels and lower SpO2/FiO2 levels at admission. Disease progression developed in 44 out of 174 on-protocol patients (25.3%) vs 53 of 120 off-protocol patients (44.2%) during the follow-up (p=0.001) and 29 (16.7%) vs 32 (26.7%), respectively, died in hospital (p=0.041). Logistic regression analysis was performed and included age, presence of comorbidities, LMWH regimen, baseline SpO2/FiO2, CRP and LDH levels as independent variables. The presence of cardiac comorbidity, age and LDH levels, but not LMWH treatment regimen, were associated with both disease progression and mortality. Conclusion(s): A d-dimer-driven LMWH treatment protocol is not associated with better clinical outcomes in hospitalized COVID-19 patients.
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Objective Encouraged by reports of favorable outcomes following the use of corticosteroids in patients with moderate-to-severe coronavirus 2019 (COVID-19) pneumonia, we aimed to present our experience with early short-term corticosteroid use at our center in pediatric patients with COVID-19 pneumonia. Methods One hundred and twenty-nine pediatric patients were included in the study. Patients were divided into four groups according to the type and dose of corticosteroids given: Group 1 (those receiving dexamethasone 0.15 mg/kg/d);Group 2 (those receiving methylprednisolone 1 mg/kg/d);Group 3 (those receiving methylprednisolone 2 mg/kg/d);and Group 4 (those receiving pulse methylprednisolone 10-30 mg/kg/d). Results Of 129 patients, 19 (14.7%) patients were assigned to Group 1, 30 (23.3%) patients to Group 2, 30 (23.3%) patients to Group 3, and 50 (38.8%) patients to Group 4. Thirty-two (24.8%) patients were followed in the pediatric intensive care unit (PICU), of whom 13 (10%) required mechanical ventilation, and 7 (%5.4) died. In Group 4, the hospitalization length was significantly longer than in other groups (p < 0.001, p < 0.001). No significant difference was found among the groups in terms of mortality (p = 0.15). The most common comorbidity was obesity (33%). A significant association was found between the presence of comorbidity and mortality (p < 0.001). All patients who died had an underlying disease. Cerebral palsy was the most common underlying disease among the patients who died. Worsening of lymphopenia was significant in patients with severe COVID-19 pneumonia at the time of transfer to the PICU (p = 0.011). Conclusion Although children usually have a milder course of COVID-19 than adults, underlying diseases and obesity increase the severity of disease manifestations also in children. Further studies are needed to define the exact role of corticosteroids in COVID-19 patients. © 2022. Thieme. All rights reserved.
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Lysosomal acid lipase deficiency (LALD) has two clinical phenotypes: an infantile-onset form - Wolman disease (WD) presented by severe malabsorption, cholestasis, malnutrition, hepatosplenomegaly and early death, and a later-onset form - cholesteryl ester storage disorder (CESD) with hepatosplenomegaly, dyslipidemia, malabsorption and variable disease severity manifestation. Enzyme replacement therapy (ERT) with sebelipase alfa was approved by the Brazilian Health Regulatory Agency (ANVISA) in 2017. We report the deleterious effect of ERT interruption in a CESD patient. Male, 16y, diagnosed at 7y, positive familiar history with mother, grandfather and three siblings affected. He was enrolled in the phase 3 clinical trial from age 9-12y under the 3 mg/Kg dose regimen. Then he enrolled in the post-study donation program under the same dose. Due to personal, importation and supply issues, and the COVID-19 pandemic restrictions, he had a progressive decrease in treatment adherence rate: 68% at 12y, 27% at 13y, 30% at 14y and after that he had an interruption of 1 entire year. At 15y he presented with generalized edema, severe fatigue, tachycardia, was hospitalized, diagnosed low serum iron, albumin and protein, acute anemia (hemoglobin: 6.2 g/dL - normal range of 12,5-13,5), and received blood transfusion. In the next year, still without ERT, he was hospitalized again due to generalized edema, acute anemia (Hemoglobin = 6.9 g/dL) and worsening of hypoalbuminemia and iron deficiency, and received blood transfusion. Although our patient has the CESD phenotype, the ERT interruptions did not worsen the liver involvement nor the dyslipidemia, but caused a severe malabsorption which is classically described in WD phenotype. In conclusion, this case serves as an alert that when ERT is interrupted, there is a rapid clinical deterioration. Acknowledgements: to IGEIM, and Drs Felippe Raphael e Oliveira Previdi and Ana Eduarda Saraiva Pereira Campos for clinical assistance of the patient.
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Patients with immune mediated rheumatic and musculoskeletal diseases (RMD), including lupus, may develop more severe COVID 19 infection than the general population. Several medicines used in treatment of systemic lupus erythematosus (SLE), such as glucocorticoid, increases the risk of Covid 19 infection, especially at dose higher than 10 mg. The use of immunosuppression may have a role in altering the immune response to infection, therefore the experts recommend to use the good but safe alternatives, if available. However in manage acute or critical condition, established therapies may be more beneficial then alternatives to control the disease activity. Evidence for discontinuing immunosuppressants in RMD patients with COVID-19 is low, but the experts strongly recommended discontinuing them and weakly recommended to re-introduce them at least 2 weeks after recovery from acute COVID-19, but this may need to be individualized based on the clinical scenario and the judgment of physician. Lupus patients are recommended to receive SARS-CoV- 2 vaccine, as long as they do not have an allergy to vaccine components. Several studies revealed that there was no significant change in lupus disease activity after vaccination, however a study using BNT162b2 COVID-19 vaccine reported mild local reactogenicity in SLE and RA patients, such as redness and swelling. More frequent systemic reactogenicity, such as fever, fatigue, headache, chills, muscle and join pain, and vomiting, however, not more severe compared to healthy controls. This study adds to the notion that the vaccine is safe and well tolerated in patients with SLE and RA. Neutralizing antibody levels after COVID-19 vaccination were significantly lower than control population. The risk factors for reduced immunogenicity included older age and treatment with glucocorticoids, mycophenolate, rituximab and abatacept, and type of vaccines. Adjusting the immunosuppression dosage schedule was suggested and considered an individual condition. A COVID-19 vaccine booster is encouraged for patients with autoimmune inflammatory rheumatic disease, including lupus. If they have completed the primary COVID vaccine series of 3 doses and are expected to have mounted an inadequate vaccine response, they should receive supplemental doses (e.g., >=2 additional boosters, for a total of five doses) as recommended by the CDC for immunocompromised individuals.
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Heat shock proteins of 90 kDa (HSP90) have been proposed as adjuvants in the design of new vaccine formulations. In our laboratory, two cytosolic isoforms of plant HSP90 (AtHsp81.2 from Arabidopsis thaliana and NbHsp90.3 from Nicotiana benthamiana) demonstrate to have adjuvant properties against parasitic infections such as Toxoplasmosis and Neosporosis. We showed that plant HSP90 fused or mixed with the antigen of interest can enhance and modulate the immune response. To evaluate the adjuvant properties of plant HSP90 in other infectious diseases poorly characterized, we proposed to use the receptor binding domain (RBD) of the Spike protein of SARS-CoV2, and the main candidate in the design of subunit vaccines. Initially, we evaluated the humoral response against RBD using the strategy protein mixture (Adjuvant + Antigen). Thirty C57 mice (male and female) were randomly separated into 7 groups and intramuscularly immunized with AtHsp81.2, NbHsp90.3 or RBD as control groups, rRBD + rAtHsp81.2, rRBD + rNbHsp90.3 or rRBD + Alum as vaccinated groups. A PBS group immunized with PBS 1x buffer was also included. Mice received a two-dose schedule delivered in 21-day intervals, and the sera were obtained at 0, 21-, 42-, 63-and 84-days post-immunization (dpi). The analysis of the humoral response showed a significant increase in anti-RBD IgGt, which persisted between 21 and 42 dpi. In addition, the RBD + AtHsp81.2 group showed a Th2 profile with a significant increase of anti-RBD IgG1 like the control RBD + Alum group. By contrast, the RBD + NbHsp90.3 group showed a significant increase in anti-RBD IgG2b towards a Th1 profile. Finally, we evaluated the capacity of the sera to neutralize lentiviral vectors pseudotyped with Spike glycoprotein. Serum-neutralizing antibody titers were determined by the 50% inhibitory dilution. The sera obtained at 42 dpi from mice immunized with rRBD + rAtHsp81.2 and rRBD + rNbHsp90.3 showed the potential to neutralize viral infection. In addition, the differential profile of both isoforms in the triggered humoral response offers an advantage of rapid and safe response in pandemic situations such as those experienced by SARS-CoV2. Neurosciences.
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The great use of telecommunication technology propels new healthcare system of telemedicine through which diagnosis as well as treatment can be done in the remote areas. The ancient Greek language explain the terminology of telemedicine in the phrase of distance healing. As per WHO, Telemedicine is the delivery of health-care services, where distance is a critical factor, by all health-care professionals using information and communications technologies for the exchange of valid information for diagnosis, treatment and prevention of disease and injuries, research and evaluation, and the continuing education of health-care workers, with the aim of advancing the health of individuals and communities. Historically the concept of teleconsultation was evolved in the first half of twentieth century when the data of ECG was communicated through telephone lines, this can be traced as first evidence of this unique healthcare system. Further the introduction of electrical system of telegraph as well as evolution of telephone revolutionized this system of healthcare. when the Technology of telemedicine help both patients as well as service providers in multiple ways involving physicians, surgeons, pharmacists, paramedical staff, IT and electronics engineers, government, hospitals and end user public Location is now a days no problem and therefore there is no limitation of the availability of healthcare facilities to such location or remote location. The biggest role in such development is played by the communication technology which may provide healthcare services to every nook and corner of the location. It can decrease the health staff pressure because in India WHO guidelines ask to maintain the ratio 1:1000 of doctor and Indian public compared to present 0.62:1000 ratio of doctor and public. The great advantage of this system is that in case of epidemic or pandemic like COVID 19 Telemedicine can keep the health staff are well general public free from contagious infection (COVID-19). There are a number of networking communication modes that can be applied, which may improve the patient compliance,dosage regimen can be managed in better fashion thus increase the longevity of person life. Disasters management during pandemics present unique challenges which can be addressed effectively as happened during the lockdown. This technology-based practice can break the infectivity chain of the transmission of communicable diseases This chapter incorporates basic concept of telemedicine, its origin and types, communication technologies, services by telemedicine, types of telemedicine, tools of telemedicine, telemedicine software's and guidelines related to practicingtelemedicine in reference to Indian context. Copyright © RJPT All right reserved.
ABSTRACT
BACKGROUND: The Covid-19 infection has become a pandemic now. The rapidly changing morphology of the virus is a great challenge for accurate diagnosis management and for making effective preventive strategies. Understanding the development of neutralizing antibodies after vaccination in different subgroups of the population is important to curb the disease more so in CKD-HD group which is known for blunted immune response. As of now we have limited data regarding covid vaccinated CKD patient's protection status against SARS-COV-2 Virus. The recently published COVID-FRIAT study has presented a worrisome conclusion for CKD patients. It says that the antibody levels in patients on dialysis declining more rapidly than previously reported for the general population. AIM OF THE STUDY: AIM - This study is done to assess the development of covid neutralizing antibodies their adequacy and sustainability after vaccination in CKD-HD patients. Have analyzed the immune response according to the patient'S age, sex, comorbidities, adequacy of dialysis, and types of vaccine. METHOD(S): Material and method - Stage 5 CKD Patients who were on regular hemodialysis are selected for the study. Patients and vaccines related to various factors were recorded. Antibody level was checked by VIDAS II (9COG) kit which detects IgG specific for SARS COVID 2 Receptor Binding Domain (RBD) of the spike protein by ELFA (Enzyme-linked fluorescent assay) technique. The most patient had received either COVAXIN or COVISHIELD RESULTS: Result -The study confirms that CKD-HD patients are showing good responses after vaccination. The extraneous variables like gender, comorbidities didn't significantly affect the COVID-19 IGG antibodies formation The peak antibody level is seen around an average of 125 +- 25 days (4 months). The significant declining trend is seen around 225 +- 25 days (8 months). The robust response seen when the gap is around 100 days between 2 doses. Nonresponders were 66% in the no-vaccinated group, 23% in the single dose, and 5.88% in the double-dose group. CONCLUSION(S): Conclusion-Two dose regimen is helping in mounting better antibody response, but there is no significant effect on declining trend when compared to single vaccinated cohort. Both indigenously developed vaccines, Covaxin and Covishield are showing good and comparable efficacy.
ABSTRACT
Background. Worldwide, attempts to understand the neonatal response and the benefits of immunity conferred by the mother to continue preventing COVID-19 infection in vulnerable groups. Therefore, research on the efficacy of vaccination against SARS-CoV-2 in pregnancy remains as an important tool to prevention of complications. Methods. Cross-sectional study in which blood samples from 379 neonates taken from the umbilical cord. The inclusion criteria were: newborns of mothers with a history of vaccination against SARS-CoV-2 during pregnancy. Infants whose mothers had COVID-19 infection at birth, or receiving any immunosuppressive treatment during pregnancy were excluded. Results. 379 neonates were studied for their antispike IgG levels. The majority were full-term female neonates were of adequate weight for their gestational age and without complications during their birth, 28 neonates required NICU care for their. Antispike IgG levels were obtained in 94.9% . Mothers received first dose at first trimester in 28.4%, second trimester in 51.9% and in the third trimester 19.6). A total of 318 mothers (87.8%) completed the two-dose schedule receiving the same vaccine, six (1.6%) received another anti-COVID vaccine, and the remaining 39 (10.7%) received only one dose of vaccine. 64.9% were vaccinated with the BNT162b2 vaccine, were higher leves when received two vaccine doses compared to only one. Vaccines that stimulated highest levels were mRNA-1273 and BNT162b2, lowest levels were found in the CoronaVac and Ad5-nCoV vaccines. Finally, it should be noted that only four neonates presented levels below 0.8 BAU/ mL (non-positive). Conclusion. This study provides evidence on timing of maternal anti-COVID vaccination, antibody production, and transplacentary transfer ensuring maternal and neonatal protection through vaccination is key to encourage women to be vaccinated against COVID-19 during pregnancy. Follow-up studies in infants are needed to understand the persistence of placental-transferred antispike IgG and the role of breast milk antibodies in maximizing the protection of infants at this stage of risk of severe SARS-Cov-2 disease. These findings have implications for determining new public health and vaccination strategies for pregnant women.
ABSTRACT
Background. Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses. Methods. Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir. PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK). Results. The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results. Conclusion. The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days.