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1.
J Infect Dis ; 2022 Jun 29.
Article in English | MEDLINE | ID: covidwho-1978234

ABSTRACT

We examined the relationship between placental histopathology and transplacental antibody transfer in pregnant patients following SARS-CoV-2 infection. Differences in plasma concentrations of anti-Receptor Biding Domain (RBD) Immunoglobulin (Ig) G antibodies in maternal and cord blood were analyzed according to presence of placental injury. Median [IQR] anti-RBD IgG concentrations in cord blood with placental injury (n = 7) did not differ significantly from those without injury (n= 16) [(2.7 [1.8,3.6] vs 2.7[2.4, 2.9], p= 0.59). However, they were associated with lower transfer ratios (median [IQR] 0.77[0.61, 0.97] vs. 0.97[0.80, 1.01], p = 0.05) suggesting that SARS-CoV-2 placental injury mediates reduced maternal-fetal antibody transfer.

2.
Ann Diagn Pathol ; 60: 152019, 2022 Aug 03.
Article in English | MEDLINE | ID: covidwho-1966324

ABSTRACT

BACKGROUND: From 2008 to 2017, 28.8 % fewer United States allopathic medical students (MD seniors) applied to pathology residency in the Main Residency Match (MRM) and 27.5 % fewer matched. This study is a 5-year follow-up. METHODS: MRM data from 2018 to 2022 were reviewed to determine the numbers of MD seniors that applied and matched to pathology residency and other major medical specialties. RESULTS: From 2018 to 2022, the number of MD seniors applying to pathology increased 4.6 % from 237 to 248, while MD seniors matching to pathology increased 5.0 % from 220 to 231. For the 4 years from 2018 to 2021, there was a slight decline in MD seniors filling pathology positions, followed by a substantial 16.7 % spike in 2022. For the entire 5-year interval, because the number of filled pathology residency positions increased by 9.0 %, the percentage of filled positions taken by MD seniors declined from 38.7 % to 37.3 %. Of the 15 major medical specialties evaluated, pathology now has the 14th lowest percentage of filled positions taken by MD seniors. CONCLUSIONS: The number of MD seniors applying and matching to pathology residency increased over the past 5-years, in contrast to the timespan of 2008 to 2017. However, the percentage of pathology residency positions taken by MD seniors continued to decline and remains low compared to other major medical specialties. MRM data should be continually monitored to study trends in MD seniors filling pathology residency positions in the context of new recruitment efforts and the pandemic.

3.
Biomedicines ; 10(7)2022 Jul 18.
Article in English | MEDLINE | ID: covidwho-1963712

ABSTRACT

The development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target patient population receiving the drug, the antigen-specific immune response underlying the development of anti-drug antibodies often remains difficult to define. This is especially true for patients with hemophilia A who, following exposure, develop antibodies against the coagulation factor, factor VIII (FVIII). Models capable of studying this response in an antigen-specific manner have been lacking. To overcome this challenge, we engineered FVIII to contain a peptide (323-339) from the model antigen ovalbumin (OVA), a very common tool used to study antigen-specific immunity. FVIII with an OVA peptide (FVIII-OVA) retained clotting activity and possessed the ability to activate CD4 T cells specific to OVA323-339 in vitro. When compared to FVIII alone, FVIII-OVA also exhibited a similar level of immunogenicity, suggesting that the presence of OVA323-339 does not substantially alter the anti-FVIII immune response. Intriguingly, while little CD4 T cell response could be observed following exposure to FVIII-OVA alone, inclusion of anti-FVIII antibodies, recently shown to favorably modulate anti-FVIII immune responses, significantly enhanced CD4 T cell activation following FVIII-OVA exposure. These results demonstrate that model antigens can be incorporated into a therapeutic protein to study antigen-specific responses and more specifically that the CD4 T cell response to FVIII-OVA can be augmented by pre-existing anti-FVIII antibodies.

4.
J Infect Dis ; 2022 Jul 25.
Article in English | MEDLINE | ID: covidwho-1961056

ABSTRACT

Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is essential for diagnosis, treatment, and infection control. Polymerase chain reaction (PCR) fails to distinguish acute from resolved infections, as RNA is frequently detected after infectiousness. We hypothesized that nucleocapsid in blood marks acute infection with the potential to enhance isolation and treatment strategies. In a retrospective serosurvey of inpatient and outpatient encounters, we categorized samples along an infection timeline using timing of SARS-CoV-2 testing and symptomatology. Among 1860 specimens from 1607 patients, the highest levels and frequency of antigenemia were observed in samples from acute SARS-CoV-2 infection. Antigenemia was higher in seronegative individuals and in those with severe disease. In our analysis, antigenemia exhibited 85.8% sensitivity and 98.6% specificity as a biomarker for acute coronavirus disease 2019 (COVID-19). Thus, antigenemia sensitively and specifically marks acute SARS-CoV-2 infection. Further study is warranted to determine whether antigenemia may aid individualized assessment of active COVID-19.

5.
Blood ; 139(21): 3222-3225, 2022 May 26.
Article in English | MEDLINE | ID: covidwho-1896318
7.
Obstet Gynecol ; 138(2): 189-197, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1364849

ABSTRACT

OBJECTIVE: To characterize maternal immune response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and quantify the efficiency of transplacental antibody transfer. METHODS: We conducted a prospective cohort study of pregnant patients who tested positive for SARS CoV-2 infection at any point in pregnancy and collected paired maternal and cord blood samples at the time of delivery. An enzyme-linked immunosorbent assay (ELISA) and neutralization assays were performed to measure maternal plasma and cord blood concentrations and neutralizing potency of immunoglobulin (Ig)G, IgA, and IgM antibodies directed against the SARS-CoV-2 spike protein. Differences in concentrations according to symptomatic compared with asymptomatic infection and time from positive polymerase chain reaction (PCR) test result to delivery were analyzed using nonparametric tests of significance. The ratio of cord to maternal anti-receptor-binding domain IgG titers was analyzed to assess transplacental transfer efficiency. RESULTS: Thirty-two paired samples were analyzed. Detectable anti-receptor-binding domain IgG was detected in 100% (n=32) of maternal and 91% (n=29) of cord blood samples. Functional neutralizing antibody was present in 94% (n=30) of the maternal and 25% (n=8) of cord blood samples. Symptomatic infection was associated with a significant difference in median (interquartile range) maternal anti-receptor-binding domain IgG titers compared with asymptomatic infection (log 3.2 [3.5-2.4] vs log 2.7 [2.9-1.4], P=.03). Median (interquartile range) maternal anti-receptor-binding domain IgG titers were not significantly higher in patients who delivered more than 14 days after a positive PCR test result compared with those who delivered within 14 days (log 3.3 [3.5-2.4] vs log 2.67 [2.8-1.6], P=.05). Median (range) cord/maternal antibody ratio was 0.81 (0.67-0.88). CONCLUSIONS: These results demonstrate robust maternal neutralizing and anti-receptor-binding domain IgG response after SARS-CoV-2 infection, yet a lower-than-expected efficiency of transplacental antibody transfer and a significant reduction in neutralization between maternal blood and cord blood. Maternal infection does confer some degree of neonatal antibody protection, but the robustness and durability of protection require further study.


Subject(s)
Antibody Formation , COVID-19/immunology , Maternal-Fetal Exchange , Pregnancy Complications, Infectious/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Neutralizing , Asymptomatic Infections , Female , Humans , Pregnancy , Prospective Studies , Young Adult
8.
Transfusion ; 61(6): 1740-1748, 2021 06.
Article in English | MEDLINE | ID: covidwho-1243668

ABSTRACT

BACKGROUND: While convalescent plasma (CP) may benefit patients with COVID-19, fundamental questions remain regarding its efficacy, including the components of CP that may contribute to its therapeutic effect. Most current serological evaluation of CP relies on examination of total immunoglobulin or IgG-specific anti-SARS-CoV-2 antibody levels. However, IgA antibodies, which also circulate and are secreted along the respiratory mucosa, represent a relatively uncharacterized component of CP. STUDY DESIGN AND METHODS: Residual samples from patients and CP donors were assessed for IgM, IgG, and IgA anti-SARS-CoV-2 antibody titers against the receptor-binding domain responsible for viral entry. Symptom onset was obtained by chart review. RESULTS: Increased IgA anti-SARS-CoV-2 antibody levels correlated with clinical improvement and viral clearance in an infant with COVID-19, prompting a broader examination of IgA levels among CP donors and hospitalized patients. Significant heterogeneity in IgA levels was observed among CP donors, which correlated weakly with IgG levels or the results of a commonly employed serological test. Unlike IgG and IgM, IgA levels were also more likely to be variable in hospitalized patients and this variability persisted in some patients >14 days following symptom onset. IgA levels were also less likely to be sustained than IgG levels following subsequent CP donation. CONCLUSIONS: IgA levels can be very heterogenous among CP donors and hospitalized patients and do not necessarily correlate with commonly employed testing platforms. Examining isotype levels in CP and COVID-19 patients may allow for a tailored approach when seeking to fill specific gaps in humoral immunity.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Convalescence , Immunoglobulin A/blood , SARS-CoV-2/immunology , Antibodies, Viral/blood , Blood Donors , Down Syndrome/complications , Down Syndrome/immunology , Down Syndrome/therapy , Female , Heart Septal Defects/complications , Heart Septal Defects/immunology , Heart Septal Defects/therapy , Humans , Immunity, Humoral/immunology , Immunization, Passive/methods , Immunoglobulin A/analysis , Immunoglobulin G/blood , Immunoglobulin M/blood , Infant , Retrospective Studies , Serologic Tests , United States
11.
J Clin Microbiol ; 59(4)2021 03 19.
Article in English | MEDLINE | ID: covidwho-1166354

ABSTRACT

Accurate diagnosis of acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is critical for appropriate management of patients with this disease. We examined the possible complementary role of laboratory-developed class-specific clinical serology in assessing SARS-CoV-2 infection in hospitalized patients. Serological tests for immunoglobulin G (IgG), IgA, and IgM antibodies against the receptor binding domain (RBD) of SARS-CoV-2 were evaluated using samples from real-time reverse transcription-quantitative PCR (qRT-PCR)-confirmed inpatient coronavirus disease 2019 (COVID-19) cases. We analyzed the influence of timing and clinical severity on the diagnostic value of class-specific COVID-19 serology testing. Cross-sectional analysis revealed higher sensitivity and specificity at lower optical density cutoffs for IgA in hospitalized patients than for IgG and IgM serology (IgG area under the curve [AUC] of 0.91 [95% confidence interval {CI}, 0.89 to 0.93] versus IgA AUC of 0.97 [95% CI, 0.96 to 0.98] versus IgM AUC of 0.95 [95% CI, 0.92 to 0.97]). The enhanced performance of IgA serology was apparent in the first 2 weeks after symptom onset and the first week after PCR testing. In patients requiring intubation, all three tests exhibit enhanced sensitivity. Among PCR-negative patients under investigation for SARS-CoV-2 infection, 2 out of 61 showed clear evidence of seroconversion IgG, IgA, and IgM. Suspected false-positive results in the latter population were most frequently observed in IgG and IgM serology tests. Our findings suggest the potential utility of IgA serology in the acute setting and explore the benefits and limitations of class-specific serology as a complementary diagnostic tool to PCR for COVID-19 in the acute setting.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , Cross-Sectional Studies , Humans , Immunoglobulin M , Sensitivity and Specificity
12.
Front Pediatr ; 8: 616731, 2020.
Article in English | MEDLINE | ID: covidwho-1033060

ABSTRACT

Most children with COVID-19 have asymptomatic or mild illness. Those who become critically ill suffer from acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI). The rapid deterioration of lung function has been linked to microangiopathic and immune-mediated processes seen in the lungs of adult patients with COVID-19. The role of complement-mediated acute lung injury is supported by animal models of SARS-CoV, evaluation of lung tissue in those who died from COVID-19 and response of COVID-19 ARDS to complement inhibition. We present a summary of a child with COVID-19 disease treated with convalescent plasma and eculizumab and provide a detailed evaluation of the inflammatory pathways.

13.
Transfusion ; 61(4): 1029-1034, 2021 04.
Article in English | MEDLINE | ID: covidwho-969728

ABSTRACT

BACKGROUND: Recent data suggests an association between blood hyperviscosity and both propensity for thrombosis and disease severity in patients with COVID-19. This raises the possibility that increased viscosity may contribute to endothelial damage and multiorgan failure in COVID-19, and that therapeutic plasma exchange (TPE) to decrease viscosity may improve patient outcomes. Here we sought to share our experience using TPE in the first 6 patients treated for COVID-19-associated hyperviscosity. STUDY DESIGN AND METHODS: Six critically ill COVID-19 patients with plasma viscosity levels ranging from 2.6 to 4.2 centipoise (cP; normal range, 1.4-1.8 cP) underwent daily TPE for 2-3 treatments. RESULTS: TPE decreased plasma viscosity in all six patients (Pre-TPE median 3.75 cP, range 2.6-4.2 cP; Post-TPE median 1.6 cP, range 1.5-1.9 cP). TPE also decreased fibrinogen levels in all five patients for whom results were available (Pre-TPE median 739 mg/dL, range 601-1188 mg/dL; Post-TPE median 359 mg/dL, range 235-461 mg/dL); D-dimer levels in all six patients (Pre-TPE median 5921 ng/mL, range 1134-60 000 ng/mL; Post-TPE median 4893 ng/mL, range 620-7518 ng/mL); and CRP levels in five of six patients (Pre-TPE median 292 mg/L, range 136-329 mg/L; Post-TPE median 84 mg/L, range 31-211 mg/L). While the two sickest patients died, significant improvement in clinical status was observed in four of six patients shortly after TPE. CONCLUSIONS: This series demonstrates the utility of TPE to rapidly correct increased blood viscosity in patients with COVID-19-associated hyperviscosity. Large randomized trials are needed to determine whether TPE may improve clinical outcomes for patients with COVID-19.


Subject(s)
Blood Viscosity , COVID-19 , Plasma Exchange , SARS-CoV-2/metabolism , Adult , Aged , COVID-19/blood , COVID-19/therapy , Humans , Male , Middle Aged
15.
Cell Rep Med ; 1(3): 100040, 2020 06 23.
Article in English | MEDLINE | ID: covidwho-549041

ABSTRACT

SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating worldwide pandemic, and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.

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