Outcomes of Anti-Spike Monoclonal Antibody Therapy in Pregnant Women with Mild to Moderate COVID-19

ObjectiveTo evaluate the efficacy and safety of anti-spike monoclonal antibodies (MAb) in the treatment of mild to moderate COVID-19 in high-risk patients who are pregnant. MethodsThe database of patients treated with monoclonal antibodies in the Mayo Clinic Midwest region was reviewed for patients who were pregnant at the time of infusion. Manual chart review was performed to collect demographic details as well as COVID course for both the mother and the infant if delivered. The data are presented using descriptive methods. ResultsWe identified fifty-one pregnant patients with mild to moderate COVID-19 who were treated with MAb (4 with bamlanivimab monotherapy, 3 with bamlanivimab-etesevimab combination, and 44 with the casirivimab-imdevimab combination). No adverse effects were reported, and no patient required COVID-19 related hospitalization. Twenty-nine patients delivered healthy babies, there was one case of intrauterine fetal demise secondary to a congenital Ebstein anomaly (not related to MAb treatment), and twenty-one were uncomplicated pregnancies. ConclusionMAb infusions were well tolerated in pregnant patients considered at high risk for COVID-19 complications, with no observed adverse effects to mother or fetus. Although preliminary data suggest MAb therapy in pregnancy is safe, further research is recommended to fully assess safety and efficacy in pregnancy. TEACHING POINTSO_LIAnti-spike monoclonal antibody therapy is well tolerated in high-risk pregnant patients with mild to moderate COVID-19 C_LIO_LINo adverse effects of anti-spike monoclonal antibody administration were observed in either the mother or fetus. C_LI

COVID-19 vaccines dampen genomic diversity of SARS-CoV-2: Unvaccinated patients exhibit more antigenic mutational variance

Variants of SARS-CoV-2 are evolving under a combination of immune selective pressure in infected hosts and natural genetic drift, raising a global alarm regarding the durability of COVID-19 vaccines. Here, we conducted longitudinal analysis over 1.8 million SARS-CoV-2 genomes from 183 countries or territories to capture vaccination-associated viral evolutionary patterns. To augment this macroscale analysis, we performed viral genome sequencing in 23 vaccine breakthrough COVID-19 patients and 30 unvaccinated COVID-19 patients for whom we also conducted machine-augmented curation of the electronic health records (EHRs). Strikingly, we find the diversity of the SARS-CoV-2 lineages is declining at the country-level with increased rate of mass vaccination (n = 25 countries, mean correlation coefficient = -0.72, S.D. = 0.20). Given that the COVID-19 vaccines leverage B-cell and T-cell epitopes, analysis of mutation rates shows neutralizing B-cell epitopes to be particularly more mutated than comparable amino acid clusters (4.3-fold, p < 0.001). Prospective validation of these macroscale evolutionary patterns using clinically annotated SARS-CoV-2 whole genome sequences confirms that vaccine breakthrough patients indeed harbor viruses with significantly lower diversity in known B cell epitopes compared to unvaccinated COVID-19 patients (2.3-fold, 95% C.I. 1.4-3.7). Incidentally, in these study cohorts, vaccinated breakthrough patients also displayed fewer COVID-associated complications and pre-existing conditions relative to unvaccinated COVID-19 patients. This study presents the first known evidence that COVID-19 vaccines are fundamentally restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2. The societal benefit of mass vaccination may consequently go far beyond the widely reported mitigation of SARS-CoV-2 infection risk and amelioration of community transmission, to include stemming of rampant viral evolution.

The Female Predominant Persistent Immune Dysregulation of the Post COVID Syndrome: A Cohort Study

ObjectiveTo describe the clinical data from the first 107 patients seen in the Mayo Clinic Post COVID-19 Care Clinic (PCOCC). Patients and MethodsAfter IRB approval, we reviewed the charts of 107 patients seen between January 19, 2021 and April 29, 2021 in the Mayo Clinic Post COVID Care Clinic (PCOCC) in order to describe the first 107 patients treated through the Mayo Clinic PCOCC. Data was abstracted from the electronic medical record into a standardized database to facilitate analysis. Phenotypes of patients seen in the PCOCC clinic were identified by expert review of predominant symptom clusters. ResultsThe majority of patients seen in our clinic were female (75%, 80/107), and the median age at presentation was 47 years (interquartile range [IQR] 37, 55). All had Post Acute Sequelae of SARS-CoV-2 infection (PASC) with six clinical phenotypes being identified - fatigue predominant (n=68), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women (84%, p=0.006) and the dyspnea-predominant phenotype was more common in men (52%, p=0.002). IL-6 was elevated in 61% of patients (69% of women, p=0.0046) which was statistically discordant with elevation in CRP and ESR which was identified in 17% and 20% of cases respectively (p<0.001). Four PASC phenotypes (fatigue-predominant, myalgia-predominant, orthostasis predominant, and headache-predominant) were associated with central sensitization (CS), and higher IL-6 levels than those phenotypes not associated with CS (p=0.013). Patients with CS phenotypes after COVID-19 infection (post COVID syndrome) were predominantly female (80%, p=0.0085). ConclusionIn our post COVID clinic, we observed several distinct clinical phenotypes. Fatigue-predominance was the most common presentation and was associated with elevated IL-6 levels and female gender. Dyspnea-predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were significantly elevated in patients with PASC and discordant with ESR and CRP, particularly in those with central sensitization phenotypes.

Antigenic minimalism of SARS-CoV-2 is linked to surges in COVID-19 community transmission and vaccine breakthrough infections

The raging COVID-19 pandemic in India and reports of "vaccine breakthrough infections" globally have raised alarm mandating the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed 1.57 million SARS-CoV-2 genomes from 187 countries/territories and performed whole-genome viral sequencing from 53 COVID-19 patients, including 20 vaccine breakthrough infections. We identified 89 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a three-month window. Deletions in the Spike protein N-terminal domain (NTD) are highly enriched for these surge-associated mutations (Odds Ratio = 41.8, 95% CI: 6.36-1758, p-value = 7.7e-05). In the recent COVID-19 surge in India, an NTD deletion ({Delta}F157/R158) increased over 10-fold in prevalence from February 2021 (1.1%) to April 2021 (15%). During the recent surge in Chile, an NTD deletion ({Delta}246-253) increased rapidly over 30-fold in prevalence from January 2021 (0.86%) to April 2021 (33%). Strikingly, these simultaneously emerging deletions associated with surges in different parts of the world both occur at an antigenic supersite that is targeted by neutralizing antibodies. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences and identified deletions within this NTD antigenic supersite in a patient with vaccine breakthrough infection ({Delta}156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of Spike protein deletions throughout the pandemic and their association with case surges and vaccine breakthrough infections point to antigenic minimalism as an emerging evolutionary strategy for SARS-CoV-2 to evade immune responses. This study highlights the urgent need to sequence SARS-CoV-2 genomes at a larger scale globally and to mandate a public health policy for transparent reporting of relevant clinical annotations (e.g. vaccination status) in order to aid the development of comprehensive therapeutic strategies.

PROMIS scales for assessment of the impact of post-COVID syndrome: A Cross-Sectional Study

The post-COVID syndrome is estimated to occur in up to 10% of patients who have had COVID-19. This condition manifests as lingering symptoms which persist for weeks to months after resolution of the acute illness. The syndrome is poorly understood and efforts are just beginning to appropriately characterize the symptoms expressed by this population. We present a population of patients with persistent symptoms as measured by a select number of PROMIS surveys (i.e. fatigue, sleep, pain, physical functioning, and social roles). We believe this to be the first use of the PROMIS survey data collected in this population and one of the first to attempt to measure social dysfunction secondary to the post-COVID syndrome. Our patient population is notably younger (30.9% were between 40-59 years of age), with a majority being female (60.5%). They also reported deficits in social roles (34.5%), and greater fatigue (14.7%), and pain (15.9%); along with a variety of disease severity ranging from asymptomatic to requiring admission. Despite this increased heterogeneity of population, the symptomatology of the post-COVID syndrome is preserved. These findings differ significantly from previously published data that demonstrated that outpatients can have duration of post-COVID syndrome similar to those who were hospitalized.

Augmented curation of clinical notes of COVID-19 and influenza patients reveals that long-term neuropsychiatric and coagulopathic symptoms are more associated with COVID-19

After one year of the COVID-19 pandemic, over 130 million individuals worldwide have been infected with the novel coronavirus, yet the post-acute sequelae of COVID-19 (PASC), also referred to as the long COVID syndrome, remains mostly uncharacterized. We leveraged machine-augmented curation of the physician notes from electronic health records (EHRs) across the multi-state Mayo Clinic health system to retrospectively contrast the occurrence of symptoms and diseases in COVID-19 patients in the post-COVID period relative to the pre-COVID period (n=6,413). Through comparison of the frequency of 10,039 signs and symptoms before and after diagnosis, we identified an increase in hypertensive chronic kidney disease (OR 47.3, 95% CI 23.9-93.6, p=3.50x10-9), thromboembolism (OR 3.84, 95% CI 3.22-4.57, p=1.18x10-4), and hair loss (OR 2.44, 95% CI 2.15-2.76, p=8.46x10-3) in COVID-19 patients three to six months after diagnosis. The sequelae associated with long COVID were notably different among male vs female patients and patients above vs under 55 years old, with the hair loss enrichment found primarily in females and the thromboembolism enrichment in males. These findings compel targeted investigations into what may be persistent dermatologic, cardiovascular, and coagulopathic phenotypes following SARS-CoV-2 infection.