Faculty Bibliography

BACKGROUND:The complex relationship between clinical manifestations of SARS-CoV-2 and individual immune responses is not fully elucidated. OBJECTIVE:To examine phenotypes of symptomatology and their relationship with positive anti-SARS-CoV-2 IgG antibody responses. METHODS:An observational study was performed of adults (≥18 years) from 5 US states. Participants completed an electronic survey and underwent testing to anti-SARS-CoV-2 nucleocapsid protein IgG antibody between May-July 2020. Latent Class Analysis was used to identify characteristic symptom clusters. RESULTS:Overall, 9,507 adults (mean±SD age: 39.6±15.0 years) completed the survey; 6,665 (70.1%) underwent antibody testing for anti-SARS-CoV-2 IgG. Positive SARS-CoV-2 antibodies were associated with self-reported positive SARS-CoV-2 nasal swab (bivariable logistic regression; OR [CI95]: 5.98 [4.83, 7.41]), household with ≥6 members (1.27 [1.14, 1.41]) and sick contact (3.65 [3.19, 4.17]), and older age (50-69 years: 1.55 [1.37, 1.76]); ≥70 years: 1.52 [1.16, 1.99]), but inversely associated with female sex (0.61 [0.55, 0.68]). Latent class analysis revealed 8 latent classes of symptoms. Latent classes-1 (all symptoms) and 4 (fever, cough, muscle ache, anosmia, dysgeusia, and headache) were associated with the highest proportion (62.0% and 57.4%) of positive antibodies, whereas classes-6 (fever, cough, muscle ache, headache) and 8 (anosmia, dysgeusia) had intermediate proportions (48.2% and 40.5%), and classes-3 (headache, diarrhea, stomach pain) and 7 (no symptoms) had the lowest proportion (7.8% and 8.5%) of positive antibodies. CONCLUSION/CONCLUSIONS:SARS-CoV-2 infections manifest with substantial diversity of symptoms, which are associated with variable anti-SARS-CoV-2 IgG antibody responses. Prolonged fever, anosmia and receiving supplemental oxygen therapy had strongest associations with positive SARS-CoV-2 IgG.

Unbiased antibody profiling can identify the targets of an immune reaction. A number of likely pathogenic autoreactive antibodies have been associated with life-threatening SARS-CoV-2 infection; yet, many additional autoantibodies likely remain unknown. Here we present Molecular Indexing of Proteins by Self Assembly (MIPSA), a technique that produces ORFeome-scale libraries of proteins covalently coupled to uniquely identifying DNA barcodes for analysis by sequencing. We used MIPSA to profile circulating autoantibodies from 55 patients with severe COVID-19 against 11,076 DNA-barcoded proteins of the human ORFeome library. MIPSA identified previously known autoreactivities, and also detected undescribed neutralizing interferon lambda 3 (IFN-λ3) autoantibodies. At-risk individuals with anti-IFN-λ3 antibodies may benefit from interferon supplementation therapies, such as those currently undergoing clinical evaluation.

Importance:Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seroprevalence in the United States are still emerging. Objective:To elucidate SARS-CoV-2 seroprevalence and symptom onset in a culturally linked community across 5 states in the United States. Design, Setting, and Participants:This cross-sectional study included adults (aged ≥18 years) recruited from the orthodox Jewish community across 5 states (California, Connecticut, Michigan, New Jersey, and New York) in 3 geographically distinct areas of the United States between May 13 and July 6, 2020. Participants completed an online survey and underwent SARS-CoV-2 antibody testing. Main Outcomes and Measures:Seroprevalence and date of symptom onset of SARS-CoV-2. Results:Overall, 9507 adults (mean [SD] age, 39.6 [15.0] years; 3777 [39.7%] women) completed the SARS-CoV-2 survey, of whom 6665 (70.1%) had immunoglobin G anti-SARS-CoV-2 antibody levels assessed. A high seroprevalence of SARS-CoV-2 antibodies was observed across all communities, with the highest proportion of positive testing observed in New Jersey (1080 of 3323 [32.5%]) and New York (671 of 2196 [30.6%]). Most individuals with a positive SARS-CoV-2 immunoglobin G antibody test reported a date of symptom-onset between March 9 and March 31, 2020 (California: 135 of 154 [87.7%]; Connecticut: 32 of 34 [94.1%]; Michigan: 44 of 50 [88.0%]; New Jersey: 964 of 1168 [82.5%]; New York: 571 of 677 [84.3%]). This start date was coincident with the Jewish festival of Purim, celebrated March 9 to 10, 2020, with extensive intracommunity spread in the weeks following (mean and mode of peak symptom onset, March 20, 2020), occurring in the absence of strong general and culture-specific public health directives. Conclusions and Relevance:This cross-sectional study of orthodox Jewish adults across the US found that socioculturally bound communities experienced early parallel outbreaks in discrete locations, notably prior to substantive medical and governmental directives. Further research should clarify optimal national, local, community-based, and government policies to prevent outbreaks in social and cultural communities that traditionally gather for holidays, assemblies, and festivals.

Diamond Blackfan anemia (DBA) is a heterogeneous genetic disorder characterized by red cell aplasia, congenital anomalies, and a predisposition to cancer. Although incompletely understood, the erythroid failure in DBA appears to result from the accelerated apoptosis of affected erythroid progenitors/precursors. One of what appears to be multiple DBA genes, coding for a ribosomal protein RPS 19, has been cloned. Even within multiplex families individuals may vary dramatically as to the degree of anemia, response to treatment and the presence of congenital anomalies. The Diamond Blackfan Anemia Registry (DBAR), a comprehensive database of pediatric and adult patients with DBA who are enrolled after informed consent, was designed to overcome two significant obstacles encountered in the study of a rare disease; the reporting bias inherent in the literature and the lack of an active patient database. To enroll, patients, their families and their physicians complete a detailed questionnaire. A review of medical records and telephone interviews are performed to complete and clarify the information provided. As of May 1, 2005, 420 patients have been enrolled in the DBAR. Epidemiological, clinical, and laboratory data have been collected and analyzed. The DBAR has provided new information on the clinical presentation, outcome and genetics of DBA as well as a better description of congenital malformations and cancer predisposition. This has resulted both in improved clinical care of patients with DBA as well as providing new insights into the pathophysiology of this complex disorder.