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1.
AACE Clin Case Rep ; 10(3): 84-88, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38799040

RESUMO

Background/Objective: Ectopic cosecretion of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) in silent (ie, non-catecholamine-secreting) pheochromocytoma is a rare cause of Cushing syndrome. Case Report: A 57-year-old woman rapidly developed hypercortisolism, clinically manifesting as fatigue, muscle weakness, weight gain, and worsening hypertension and biochemically characterized by hypokalemia and marked increases in the serum cortisol and plasma ACTH levels. This acute presentation suggested a diagnosis of ectopic ACTH syndrome (EAS). Imaging studies revealed a right adrenal mass that enhanced after administration of the radioisotope gallium-68-DOTATATE. Plasma metanephrines were normal in 2 separate measurements. The possibility of a silent pheochromocytoma was considered. After controlling her hypercortisolism with metyrapone and surgical preparation with alpha blockade, the patient underwent elective right adrenalectomy. Pathology revealed a pheochromocytoma that stained focally for ACTH and CRH. Postoperatively, the cortisol levels normalized, the hypothalamic-pituitary-adrenal axis was not suppressed, and clinical symptoms from hypercortisolism abated. Discussion: Patients who exhibit a rapid progression of ACTH-dependent hypercortisolism should be screened for EAS. The use of functional imaging radioisotopes (eg, gallium DOTA-peptides) improves the detection of ACTH-secreting tumors. Preoperative treatment with steroidogenesis inhibitors helps control clinical and metabolic derangements associated with severe hypercortisolemia, whereas alpha blockade prevents the onset of an adrenergic crisis. Conclusion: We present a rare case of EAS due to a silent pheochromocytoma that cosecreted ACTH and CRH. Pheochromocytoma should be considered in patients with EAS who have an adrenal mass even in the absence of excessive catecholamine secretion.

2.
Open Forum Infect Dis ; 11(5): ofae207, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38813260

RESUMO

Background: Syphilis diagnosis in the emergency department (ED) setting is often missed due to the lack of ED-specific testing strategies. We characterized ED patients with high-titer syphilis infections (HTSIs) with the goal of defining a screening strategy that most parsimoniously identifies undiagnosed, untreated syphilis infections. Methods: Unlinked, de-identified remnant serum samples from patients attending an urban ED, between 10 January and 9 February 2022, were tested using a three-tier testing algorithm, and sociodemographic variables were extracted from ED administrative database prior to testing. Patients who tested positive for treponemal antibodies in the first tier and positive at high titer (≥1:8) for nontreponemal antibodies in the second tier were classified as HTSI. Human immunodeficiency virus (HIV) status was determined with Bio-Rad enzyme-linked immunosorbent assay and confirmatory assays. Exact logistic regression and classification and regression tree (CART) analyses were performed to determine factors associated with HTSI and derive screening strategies. Results: Among 1951 unique patients tested, 23 (1.2% [95% confidence interval, .8%-1.8%]) had HTSI. Of those, 18 (78%) lacked a primary care physician, 5 (22%) were HIV positive, and 8 (35%) were women of reproductive age (18-49 years). CART analysis (area under the curve of 0.67) showed that using a screening strategy that measured syphilis antibodies in patients with HIV, without a primary care physician, and women of reproductive age would have identified most patients with HTSI (21/23 [91%]). Conclusions: We show a high prevalence of HTSI in an urban ED and propose a feasible, novel screening strategy to curtail community transmission and prevent long-term complications.

3.
Microbiol Spectr ; 11(6): e0218323, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-37811983

RESUMO

IMPORTANCE: Despite the evolution of SARS-CoV-2 variants of concern and ongoing transmission, COVID-19 hospitalization and mortality rates continue to decline. Both the percent seropositive and antibody levels have risen over the past 3 years. Here, we observe more than 90% seropositivity as well as more than a hundred-fold increase in spike IgG levels in a tertiary hospital clinical immunology laboratory setting. Antibody effector functions (such as neutralization, opsonization, and complement activation) and cell-mediated immunity all contribute to protection from COVID-19 progression to hospitalization, and all correlate to the total SARS-CoV-2 antibody levels. We recommend therapeutic COVID-19 convalescent plasma be restricted to the top 20% of potential donors to maintain activity against ongoing SARS-CoV-2 variant evolution.


Assuntos
COVID-19 , Laboratórios Hospitalares , Humanos , Laboratórios Clínicos , SARS-CoV-2/genética , Soroterapia para COVID-19 , Anticorpos Antivirais , Centros de Atenção Terciária , Anticorpos Neutralizantes
4.
Pract Lab Med ; 33: e00307, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36660178

RESUMO

Objectives: The objectives were to characterize the liver kidney microsome (LKM) antibody profile of a 14-month-old girl with autoimmune hepatitis and analyze the laboratory prevalence of LKM positivity. Design and methods: This is retrospective analysis of the LKM antibody immunofluorescence tests performed by the Immunology Laboratory of Johns Hopkins Hospital from September 8, 2020 to July 31, 2022. LKM positive sera were also tested by an ELISA for LKM1 antibodies, which recognize the cytochrome P450 2D6 antigen. In silico analysis of 2D6 mRNA expression across anatomical sites was performed using Bgee and GTEx Portal databases. Results: Of the total of 1598 patients (893 F, 705 M, ages 0.8-94 years) tested for LKM antibodies, 3 were positive, yielding a 0.2% period prevalence. The clinical diagnosis was autoimmune hepatitis in the index case, acute viral hepatitis in a 3-yo male, and hepatocellular carcinoma in a 54-yo male. LKM antibodies yielded the classical homogenous staining pattern in the liver cytosol and proximal kidney tubular cells. The first two patients were also positive for LKM1 antibodies, whereas the third was negative. 2D6 mRNA was expressed highly in the liver, moderately in the duodenum, and minimally in other tissues. Conclusions: Overall, LKM antibodies are rare. They contribute to establish a diagnosis of autoimmune hepatitis, although they are also found in other liver diseases. The cytochrome P450 2D6 is one of the antigens recognized by LKM antibodies, but other antigens are likely targeted considering that 2D6 is minimally expressed in the kidney and yet LKM antibodies bind to kidney tubuli.

5.
Transfusion ; 63(1): 23-29, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36268708

RESUMO

BACKGROUND: It is important to maintain the safety of blood products by avoiding the transfusion of units with known and novel viral pathogens. It is unknown whether COVID-19 convalescent plasma (CCP) may contain pathogenic viruses (either newly acquired or reactivated) that are not routinely screened for by blood centers. METHODS: The DNA virome was characterized in potential CCP donors (n = 30) using viral genome specific PCR primers to identify DNA plasma virome members of the Herpesviridae [Epstein Barr Virus (EBV), cytomegalovirus (CMV), human herpesvirus 6A/B, human herpesvirus 7] and Anelloviridae [Torque teno viruses (TTV), Torque teno mini viruses (TTMV), and Torque teno midi viruses (TTMDV)] families. In addition, the RNA plasma virome was characterized using unbiased metagenomic sequencing. Sequencing was done on a HiSeq2500 using high output mode with a read length of 2X100 bp. The sequencing reads were taxonomically classified using Kraken2. CMV and EBV seroprevalence were evaluated using a chemiluminescent immunoassay. RESULTS: TTV and TTMDV were detected in 12 (40%) and 4 (13%) of the 30 study participants, respectively; TTMDV was always associated with infection with TTV. We did not observe TTMV DNAemia. Despite CMV and EBV seroprevalences of 33.3% and 93.3%, respectively, we did not detect Herpesviridae DNA among the study participants. Metagenomic sequencing did not reveal any human RNA viruses in CCP, including no evidence of circulating SARS-CoV-2. DISCUSSION: There was no evidence of pathogenic viruses, whether newly acquired or reactivated, in CCP despite the presence of non-pathogenic Anelloviridae. These results confirm the growing safety data supporting CCP.


Assuntos
Anelloviridae , COVID-19 , Infecções por Citomegalovirus , Infecções por Vírus de DNA , Infecções por Vírus Epstein-Barr , Torque teno virus , Humanos , Estudos Soroepidemiológicos , Herpesvirus Humano 4/genética , COVID-19/terapia , Soroterapia para COVID-19 , SARS-CoV-2/genética , Anelloviridae/genética , Torque teno virus/genética , Citomegalovirus/genética , DNA , DNA Viral/genética
6.
J Gerontol A Biol Sci Med Sci ; 78(2): 227-235, 2023 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35914953

RESUMO

Aging and age-related diseases represent a compelling therapeutic goal for senolytics and drugs targeting inflammatory or metabolic pathways. We compared MyMD-1, a synthetic derivative of the alkaloid myosmine capable of suppressing TNF-α production, to rapamycin, the best characterized drug endowed with antiaging properties. In vivo, a longitudinal cohort of 54 C57BL/6 mice, 19-month-old at the start, was randomized to receive MyMD-1, high-dose (126 ppm) rapamycin, or low-dose (14 ppm) rapamycin plus metformin. Each treatment arm included 18 mice (10 females and 8 males) and was followed for 16 months or until death. Life span was significantly longer in MyMD-1 than rapamycin (p = .019 vs high-dose and .01 vs low-dose) in a Cox survival model that accounted for sex and serum levels of IL-6, TNF-α, and IL-17A. MyMD-1 also improved several health span characteristics, resulting in milder body weight loss, greater muscle strength, and slower progression to frailty. In vitro, MyMD-1 and rapamycin were compared using a panel of 12 human primary cell systems (BioMAP Diversity PLUS), where a total of 148 biomarkers were measured. MyMD-1 possessed antiproliferative, anti-inflammatory, and antifibrotic properties. Many were shared with rapamycin, but MyMD-1 was more active in the inhibition of proinflammatory and profibrotic biomarkers. Overall, MyMD-1 emerges as a new compound that, even when begun at an advanced age, induces beneficial effects on health and life span by modulating inflammation and tissue remodeling.


Assuntos
Alcaloides , Longevidade , Masculino , Feminino , Camundongos , Animais , Humanos , Longevidade/fisiologia , Sirolimo/farmacologia , Fator de Necrose Tumoral alfa , Camundongos Endogâmicos C57BL , Alcaloides/farmacologia , Biomarcadores
7.
J Immunother Cancer ; 10(12)2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36521928

RESUMO

BACKGROUND: The response of solid tumors such as papillary thyroid cancer (PTC) to immune checkpoint inhibitors (ICIs) is highly variable. The biological basis of this variability remains unknown. METHODS: To test the hypothesis that preconditioning of the immune system modulates the therapeutic effect of ICIs, we used a murine model where PTC and iodine exacerbated thyroiditis (IET) can be induced in a temporally predictable fashion. A total of 122 mice were divided into 3 experimental groups. In the first one, named concomitant IET and PTC (No.=40), IET, and PTC were induced at the same time; in the second one, named pre-existing IET (No.=44), IET was induced prior to the induction of PTC; in the third one, named no IET (No.=38), only PTC was induced. Following disease induction, mice of each group were treated with anti-PD-1 antibody, anti-lymphocyte activation gene 3 antibody (anti-Lag3), anti-T-cell immunoglobulin and mucin domain 3 antibody (anti-Tim3), or IgG control. Ten weeks after the initial ICI injection, mice were sacrificed to collect the thyroid gland for histological analysis, to quantify the incidence and burden of PTC, and to perform high-throughput single-cell RNA sequencing of infiltrating CD45+ cells. RESULTS: In the concomitant IET and PTC group, ICI treatment reduced PTC incidence (p=0.002 comparing treatment with any ICI vs control), while it had no effect in the pre-existing IET and no IET groups. Single-cell sequencing of thyroidal CD45+ cells showed that the different ICIs tested had both specific and shared effects on all the components of the thyroidal immune cell infiltrate. The shared effect of the tested ICIs was dependent on the presence of pre-existing versus concomitant IET. In the context of concomitant IET, ICI treatment resulted in the modulation of a greater number of pathways related to both innate and adaptive immunity. CONCLUSIONS: Response to ICIs depends on the status of the immune system of the treated individual. Modulation of the immune system should be explored as a tool to improve response to ICIs in patients with PTC or other forms of cancer.


Assuntos
Inibidores de Checkpoint Imunológico , Neoplasias da Glândula Tireoide , Camundongos , Animais , Câncer Papilífero da Tireoide/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Sistema Imunitário/patologia , Neoplasias da Glândula Tireoide/patologia
8.
Microbiol Spectr ; 10(5): e0204622, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36190405

RESUMO

SARS-CoV-2 antibody levels wane following two-doses of mRNA vaccination. An mRNA booster dose provides increased protection against hospitalization and death. We demonstrated that a booster dose provides a significant increase in the neutralization of the Beta, Delta and Omicron variants in addition to an increased neutralization of the vaccine strain. The total spike IgG measurements, obtained by using commercial kits that target the spike protein from the vaccine strain, may not reflect serum neutralization against variants of concern. IMPORTANCE This study found little to no neutralizing capability following a 2-dose mRNA vaccine series against the omicron variant, and neutralizing capacity to any variant strain tested was lost by 8-months post 2-dose series. However, the mRNA booster dose eliminated the immune escape observed by the Omicron variant, following the 2-dose series. Even more, the neutralizing titers were significantly higher for all variants post-boost, compared to the titers from the post-two-dose series. Our data are unique, using paired samples that eliminate potential confounders that may impact vaccine response. Notably, as seen after the primary two-dose vaccine series, total antibody levels did not correlate perfectly with variant neutralization activity, suggesting that simply testing titers as a measure of protection may not be a long-term solution. Therefore, it is important to reassess the utility of SARS-CoV-2 antibody testing, as current vaccine strain-based testing may not reliably detect reactive antibodies to Omicron or other variants of concern.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Humanos , Testes de Neutralização , Glicoproteína da Espícula de Coronavírus/genética , SARS-CoV-2/genética , COVID-19/prevenção & controle , Anticorpos Antivirais , Imunoglobulina G , RNA Mensageiro/genética , Anticorpos Neutralizantes , Vacinas de mRNA
9.
Cancers (Basel) ; 14(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36077831

RESUMO

Papillary thyroid cancer (PTC) often co-occurs with Hashimoto's thyroiditis, an association that has long been reported in clinical studies, remaining controversial. Experimental evidence has recently shown that pre-existing thyroiditis has a beneficial effect on PTC growth and progression by a distinctive expansion of effector memory CD8 T cells. Although the link between inflammation and PTC might involve different components of the immune system, a deep characterization of them which includes T cells, B cells and tertiary lymphoid structures, Mye-loid cells, Neutrophils, NK cells and dendritic cells will be desirable. The present review article considers the role of the adaptive and innate immune response surrounding PTC in the context of Hashimoto's thyroiditis. This review will focus on the current knowledge by in vivo and in vitro studies specifically performed on animals' models; thyroid cancer cells and human samples including (i) the dual role of tumor-infiltrating lymphocytes; (ii) the emerging role of B cells and tertiary lymphoid structures; (iii) the role of myeloid cells, dendritic cells, and natural killer cells; (iv) the current knowledge of the molecular biomarkers implicated in the complex link between thyroiditis and PTC and the potential implication of cancer immunotherapy in PTC patients in the context of thyroiditis.

10.
Immunity ; 55(6): 1051-1066.e4, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35649416

RESUMO

Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for detecting exposure and response to microbial protein products. We designed and constructed a library of 95,601 56-amino acid peptide tiles spanning 14,430 proteins with "toxin" or "virulence factor" keyword annotations. We used PhIP-Seq to profile the antibodies of ∼1,000 individuals against this "ToxScan" library. In addition to enumerating immunodominant antibody epitopes, we studied the age-dependent stability of the ToxScan profile and used a genome-wide association study to find that the MHC-II locus modulates bacterial epitope selection. We detected previously described anti-flagellin antibody responses in a Crohn's disease cohort and identified an association between anti-flagellin antibodies and juvenile dermatomyositis. PhIP-Seq with the ToxScan library is thus an effective tool for studying the environmental determinants of health and disease at cohort scale.


Assuntos
Bacteriófagos , Biblioteca de Peptídeos , Sequência de Aminoácidos , Anticorpos , Formação de Anticorpos , Bacteriófagos/genética , Estudo de Associação Genômica Ampla , Humanos , Epitopos Imunodominantes , Prevalência , Fatores de Virulência/genética
11.
PLoS One ; 17(6): e0264298, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35679259

RESUMO

The association between COVID-19 symptoms and antibody responses against SARS-CoV-2 is poorly characterized. We analyzed antibody levels in individuals with known SARS-CoV-2 infection to identify potential antibody-symptom associations. Convalescent plasma from 216 SARS-CoV-2 RNA+ individuals with symptomatology information were tested for the presence of IgG to the spike S1 subunit (Euroimmun ELISA), IgG to receptor binding domain (RBD, CoronaCHEK rapid test), and for IgG, IgA, and IgM to nucleocapsid (N, Bio-Rad ELISA). Logistic regression was used to estimate the odds of having a COVID-19 symptom from the antibody response, adjusting for sex and age. Cough strongly associated with antibodies against S1 (adjusted odds ratio [aOR] = 5.33; 95% CI from 1.51 to 18.86) and RBD (aOR = 4.36; CI 1.49, 12.78). In contrast, sore throat significantly associated with the absence of antibodies to S1 and N (aOR = 0.25; CI 0.08, 0.80 and aOR = 0.31; 0.11, 0.91). Similarly, lack of symptoms associated with the absence of antibodies to N and RBD (aOR = 0.16; CI 0.03, 0.97 and aOR = 0.16; CI 0.03, 1.01). Cough appeared to be correlated with a seropositive result, suggesting that SARS-CoV-2 infected individuals exhibiting lower respiratory symptoms generate a robust antibody response. Conversely, those without symptoms or limited to a sore throat while infected with SARS-CoV-2 were likely to lack a detectable antibody response. These findings strongly support the notion that severity of infection correlates with robust antibody response.


Assuntos
COVID-19 , Faringite , Anticorpos Antivirais , Formação de Anticorpos , COVID-19/terapia , Tosse , Humanos , Imunização Passiva , Imunoglobulina G , RNA Viral , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Soroterapia para COVID-19
12.
Blood Adv ; 6(12): 3678-3683, 2022 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-35443020

RESUMO

The ongoing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. COVID-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The Food and Drug Administration currently allows outpatient CCP for the immunosuppressed. Viral-specific antibody levels in CCP can range 10- to 100-fold between donors, unlike the uniform viral-specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-δ/pre-ο donor units obtained before March 2021, 20 post-δ COVID-19/postvaccination units, and 1 pre-δ/pre-ο hyperimmunoglobulin preparation for variant-specific virus (vaccine-related isolate [WA-1], δ, and ο) neutralization correlated to Euroimmun S1 immunoglobulin G antibody levels. We observed a two- to fourfold and 20- to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to δ or ο, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-δ COVID-19/postvaccination units and the hyperimmunoglobulin effectively neutralized all 3 variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais , COVID-19/terapia , Humanos , Imunização Passiva , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Estados Unidos , Soroterapia para COVID-19
13.
J Clin Oncol ; 40(23): 2578-2587, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35417260

RESUMO

PURPOSE: Thyroid autoimmunity has been associated with differentiated thyroid cancer although multiple potential biases might have influenced the results of previous studies. METHODS: We conducted a case-control study nested within the cohort of US active-duty personnel 1996-2014 to assess the association between thyroid autoimmunity, defined by serology, and thyroid cancer diagnosis. The primary exposure was thyroid peroxidase (TPO) antibody status 7-10 years before the thyroid cancer index date. We also assessed whether diagnosis of thyroid autoimmunity mediated any associations identified and if thyroid cancer features differed by autoimmunity status. RESULTS: Among 451 incident cases of papillary thyroid cancer and matched controls (median age 36 years, 61.4% men), TPO antibody positivity (v negative) 7-10 years prediagnosis was associated with thyroid cancer (odds ratio [OR] 1.90 [95% CI, 1.33 to 2.70]). Exploratory analyses suggested an increasing risk of thyroid cancer with higher TPO antibody titer (TPO antibody 550-1,399 IU/mL: OR 2.95 [95% CI, 1.37 to 6.36]; and ≥ 1,400 IU/mL: OR 3.91 [95% CI, 1.66 to 9.24]). Positive TPO antibody status remained associated with thyroid cancer after those with diagnosed autoimmunity were excluded, and the association was not mediated by diagnosis of thyroid autoimmunity. Among the cases with diagnosed autoimmunity, 58% thyroid cancers were ≤ 10 mm diameter. CONCLUSION: Longstanding prior thyroid autoimmunity up to 10 years before thyroid cancer diagnosis was associated with papillary thyroid cancer risk. The results could not be fully explained by diagnosis of thyroid autoimmunity although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage.


Assuntos
Autoimunidade , Neoplasias da Glândula Tireoide , Adulto , Anticorpos , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/epidemiologia
14.
medRxiv ; 2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35262085

RESUMO

The ongoing evolution of SARS-Co-V2 variants to omicron severely limits available effective monoclonal antibody therapies. Effective drugs are also supply limited. Covid-19 convalescent plasma (CCP) qualified for high antibody levels effectively reduces immunocompetent outpatient hospitalization. The FDA currently allows outpatient CCP for the immunosuppressed. Viral specific antibody levels in CCP can range ten-to hundred-fold between donors unlike the uniform viral specific monoclonal antibody dosing. Limited data are available on the efficacy of polyclonal CCP to neutralize variants. We examined 108 pre-delta/pre-omicron donor units obtained before March 2021, 20 post-delta COVID-19/post-vaccination units and one pre-delta/pre-omicron hyperimmunoglobulin preparation for variant specific virus (vaccine-related isolate (WA-1), delta and omicron) neutralization correlated to Euroimmun S1 IgG antibody levels. We observed a 2-to 4-fold and 20-to 40-fold drop in virus neutralization from SARS-CoV-2 WA-1 to delta or omicron, respectively. CCP antibody levels in the upper 10% of the 108 donations as well as 100% of the post-delta COVID-19/post-vaccination units and the hyperimmunoglobulin effectively neutralized all three variants. High-titer CCP neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants. Key points: All of the post-delta COVID-19/post vaccination convalescent plasma effectively neutralizes the omicron and delta variants.High-titer CCP and hyperimmunoglobulin neutralizes SARS-CoV-2 variants despite no previous donor exposure to the variants.

15.
Healthcare (Basel) ; 10(3)2022 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35327055

RESUMO

Early in the COVID-19 pandemic (March−July 2020 in Baltimore), emergency department (ED) healthcare workers (HCWs) were considered to be at greater risk of contracting SARS-CoV-2. Limited data existed, however, on the prevalence of SARS-CoV-2 infection and its impact in this workforce population. We enrolled 191 ED HCWs from a tertiary academic center, administered baseline and weekly surveys, and tested them twice (July and December 2020) for serum antibodies against SARS-CoV-2 spike protein. Approximately 6% (11 of 191, 5.8%) of ED HCWs had spike antibodies in July, a prevalence that doubled by December (21 of 174, 12.1%). A positive PCR test was self-reported by 15 of 21 (71%) seropositive and 6 of 153 (4%) seronegative HCWs (p < 0.001). Of the total 27 HCWs who had antibodies and/or were PCR positive, none required hospitalization, 18 (67%) had a self-perceived COVID-19 illness, and 12 of the 18 reported symptoms. The median number of missed workdays was 8.5 (ranging from 2 to 21). While most seropositive ED HCWs who reported symptoms took work absences, none required hospitalization, indicating that COVID-19's impact on staffing prior to vaccination was not as great as feared.

16.
medRxiv ; 2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35132427

RESUMO

Recognizing that anti-SARS-CoV-2 antibody levels wane over time following the 2-dose SARS-CoV-2 mRNA series, the FDA approved a booster dose for people greater than 12 years old. Limited data exist on whether a booster dose of the mRNA vaccine results in greater antibody protection than the primary series. We examined total and neutralizing antibodies to the spike protein of SARS-CoV-2, and neutralizing antibodies against Washington-1 (WA-1) and variants of concern (VOC) including Beta, Delta and Omicron in a longitudinal cohort. Healthcare workers (HWs) were included in the analysis if serum was collected 1) within 14-44 days post-dose2 of an mRNA SARS-CoV-2 vaccine (Timepoint 1, TP1), or 2) at least 8 months post-dose2 (Timepoint 2, TP2), or 3) within 14-44 days following mRNA booster (Timepoint 3, TP3). HWs with prior covid-positive PCR were excluded. We found that there is little to no neutralizing capability following a 2-dose mRNA vaccine series against the omicron variant, and neutralizing capacity to any variant strain tested has been lost by 8-months post two-dose vaccination series. However, the mRNA booster series eliminates the immune escape observed by the omicron variant with the two-dose series. Neutralizing titers were significantly higher for all variants post-boost compared to the titers post two-dose series. The longitudinal nature of our cohort facilitated the analysis of paired samples pre and post boost, showing a greater than 15-fold increase in neutralization against omicron post-boost in these paired samples. An mRNA booster dose provides greater quantity and quality of antibodies compared to a two-dose regimen and is critical to provide any protection against the omicron variant.

17.
medRxiv ; 2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35169815

RESUMO

The association between COVID-19 symptoms and antibody responses against SARS-CoV-2 is poorly characterized. We analyzed antibody levels in individuals with known SARS-CoV-2 infection to identify potential antibody-symptom associations. Convalescent plasma from 216 SARS-CoV-2 RNA+ individuals with symptomatology information were tested for the presence of IgG to the spike S1 subunit (Euroimmun ELISA), IgG to receptor binding domain (RBD, CoronaCHEK rapid test), and for IgG, IgA, and IgM to nucleocapsid (N, Bio-Rad ELISA). Logistic regression was used to estimate the odds of having a COVID-19 symptom from the antibody response, adjusting for sex and age. Cough strongly associated with antibodies against S1 (adjusted odds ratio [aOR]= 5.33; 95% CI from 1.51 to 18.86) and RBD (aOR=4.36; CI 1.49, 12.78). In contrast, sore throat significantly associated with the absence of antibodies to S1 and N (aOR=0.25; CI 0.08, 0.80 and aOR=0.31; 0.11, 0.91). Similarly, lack of symptoms associated with the absence of antibodies to N and RBD (aOR=0.16; CI 0.03, 0.97 and aOR=0.16; CI 0.03, 1.01). Cough appeared to be correlated with a seropositive result, suggesting that SARS-CoV-2 infected individuals exhibiting lower respiratory symptoms generate a robust antibody response. Conversely, those without symptoms or limited to a sore throat while infected with SARS-CoV-2 were likely to lack a detectable antibody response. These findings strongly support the notion that severity of infection correlates with robust antibody response.

18.
EBioMedicine ; 75: 103747, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34922324

RESUMO

BACKGROUND: Comprehensive characterization of exposures and immune responses to viral infections is critical to a basic understanding of human health and disease. We previously developed the VirScan system, a programmable phage-display technology for profiling antibody binding to a library of peptides designed to span the human virome. Previous VirScan analytical approaches did not carefully account for antibody cross-reactivity among sequences shared by related viruses or for the disproportionate representation of individual viruses in the library. METHODS: Here we present the AntiViral Antibody Response Deconvolution Algorithm (AVARDA), a multi-module software package for analyzing VirScan datasets. AVARDA provides a probabilistic assessment of infection with species-level resolution by considering sequence alignment of all library peptides to each other and to all human viruses. We employed AVARDA to analyze VirScan data from a cohort of encephalitis patients with either known viral infections or undiagnosed etiologies. We further assessed AVARDA's utility in associating viral infection with type 1 diabetes and lupus. FINDINGS: By comparing acute and convalescent sera, AVARDA successfully confirmed or detected encephalitis-associated responses to human herpesviruses 1, 3, 4, 5, and 6, improving the rate of diagnosing viral encephalitis in this cohort by 44%. AVARDA analyses of VirScan data from the type 1 diabetes and lupus cohorts implicated enterovirus and herpesvirus infections, respectively. INTERPRETATION: AVARDA, in combination with VirScan and other pan-pathogen serological techniques, is likely to find broad utility in the epidemiology and diagnosis of infectious diseases. FUNDING: This work was made possible by support from the National Institutes of Health (NIH), the US Army Research Office, the Singapore Infectious Diseases Initiative (SIDI), the Singapore Ministry of Health's National Medical Research Council (NMRC) and the Singapore National Research Foundation (NRF).


Assuntos
Viroma , Viroses , Anticorpos Antivirais , Antígenos Virais , Epitopos , Humanos , Estados Unidos , Viroses/diagnóstico
20.
Thyroid ; 31(12): 1839-1849, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34598661

RESUMO

Background: The pathogenesis of thyroiditis caused by immune-checkpoint inhibitors (ICIs) such as antiprogrammed death receptor-1 (PD-1) and anticytotoxic T lymphocyte antigen-4 (CTLA-4) is incompletely understood. To gain mechanistic insights, we developed a mouse model of ICI-related thyroiditis and assessed the clinical, hormonal, and cytokine profiles. Methods: Forty NOD-H2h4 mice, 112 days old at the start of the experiments, were divided into two sequential cohorts. In the first one (No. = 21), mice were injected with both anti-PD-1 and anti-CTLA-4 checkpoint inhibitors while drinking either regular water or iodine-supplemented water. In the second cohort (No. = 19), mice were injected with either anti-PD-1 or anti-CTLA-4 while drinking iodine-supplemented water. Mice were sacrificed two months after the initial injection to collect thyroid gland for histopathology (to assess thyroiditis severity) and flow cytometry (to identify immune cell subsets and tissue-resident memory T cell markers). Mice were also studied before sacrifice to determine thyroid area and structure (by ultrasound), thyroid function (serum total thyroxine, thyrotropin, thyroid antibodies), and cytokine profile (by bead-based Luminex technology). Results: Thyroiditis was more severe upon PD-1 than CTLA-4 blockade (p = 0.01) and significantly correlated with the number of CD45+ cells infiltrating the thyroid (cumulative odds ratio [OR] 1.2 [95% confidence interval, CI 1.1-1.3], p < 0.001, that is 20% greater odds of a higher severity score for every 170-unit increase in CD45 infiltrating cells). Thyroiditis was instead more prevalent (100% vs. 63%, p < 0.01) in the anti-CTLA-4 mice, which also showed a larger thyroid area (17 ± 8.2 mm) than those treated with anti-PD-1 (11 ± 4.2 mm) and controls (p < 0.01). Serum IL-6 was markedly increased upon PD-1 blockade (40 pg/mL at baseline, 198 pg/mL on day 172), an increase not seen in the anti-CTLA-4 group (p = 0.01). IL-6 mirrored thyroiditis severity, with highest serum values found in greatest histopathology scores (cumulative OR 1.1 [CI 1.02-1.15], p = 0.009). GM-CSF and MIP1ß increased more in the anti-CTLA-4 group (p < 0.001 for both), whereas the other cytokines did not differ among the treatment groups. Conclusions: The study reports a mouse model of thyroiditis induced by PD-1 blockade and, comparing it to the anti-CTLA-4 model, uncovers distinctive histopathological, sonographic, hormonal, and immunological features, offering biomarkers, such as serum IL-6, that could be used in the clinical setting.


Assuntos
Antígeno CTLA-4/antagonistas & inibidores , Citocinas/sangue , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tireoidite Autoimune/imunologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos Endogâmicos NOD
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