Publications

Borrelia miyamotoi disease (BMD), also known as hard-tick relapsing fever, is an emerging tick-borne illness caused by the bacterium Borrelia miyamotoi. This pathogen is transmitted primarily by Ixodes ticks, also known as deer ticks or black-legged ticks. BMD poses significant public health concerns because of its potential to cause severe hemodynamic and hematologic disturbances, particularly in vulnerable populations such as pregnant individuals. BMD often presents with symptoms like other tick-borne infections, including fever, chills, headache, and muscle aches, but often lacks the characteristic rash seen in Lyme disease and does not typically have a greater-than-24-hour tick attachment period for transmission. A high index of suspicion in the late spring and summer months in the Northern hemisphere is essential for early diagnosis of BMD and treatment to prevent maternal and neonatal morbidity and mortality.

IMPORTANCE: Classification of persons with long COVID (LC) or post-COVID-19 condition must encompass the complexity and heterogeneity of the condition. Iterative refinement of the classification index for research is needed to incorporate newly available data as the field rapidly evolves.

OBJECTIVE: To update the 2023 research index for adults with LC using additional participant data from the Researching COVID to Enhance Recovery (RECOVER-Adult) study and an expanded symptom list based on input from patient communities.

DESIGN, SETTING, AND PARTICIPANTS: Prospective, observational cohort study including adults 18 years or older with or without known prior SARS-CoV-2 infection who were enrolled at 83 sites in the US and Puerto Rico. Included participants had at least 1 study visit taking place 4.5 months after first SARS-CoV-2 infection or later, and not within 30 days of a reinfection. The study visits took place between October 2021 and March 2024.

EXPOSURE: SARS-CoV-2 infection.

MAIN OUTCOMES AND MEASURES: Presence of LC and participant-reported symptoms.

RESULTS: A total of 13 647 participants (11 743 with known SARS-CoV-2 infection and 1904 without known prior SARS-CoV-2 infection; median age, 45 years [IQR, 34-69 years]; and 73% were female) were included. Using the least absolute shrinkage and selection operator analysis regression approach from the 2023 model, symptoms contributing to the updated 2024 index included postexertional malaise, fatigue, brain fog, dizziness, palpitations, change in smell or taste, thirst, chronic cough, chest pain, shortness of breath, and sleep apnea. For the 2024 LC research index, the optimal threshold to identify participants with highly symptomatic LC was a score of 11 or greater. The 2024 index classified 20% of participants with known prior SARS-CoV-2 infection and 4% of those without known prior SARS-CoV-2 infection as having likely LC (vs 21% and 5%, respectively, using the 2023 index) and 39% of participants with known prior SARS-CoV-2 infection as having possible LC, which is a new category for the 2024 model. Cluster analysis identified 5 LC subtypes that tracked quality-of-life measures.

CONCLUSIONS AND RELEVANCE: The 2024 LC research index for adults builds on the 2023 index with additional data and symptoms to help researchers classify symptomatic LC and its symptom subtypes. Continued future refinement of the index will be needed as the understanding of LC evolves.

IMPORTANCE: A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain.

OBJECTIVE: To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)-Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection.

EXPOSURE: Self-reported sex (male, female) assigned at birth.

MAIN OUTCOMES AND MEASURES: Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity.

RESULTS: Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants.

CONCLUSIONS AND RELEVANCE: In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. These results reclassify HDP clinical phenotypes into two distinct molecular subtypes, placental-associated or immune-associated. Validation performance for placental-associated HDP yields an AUC of 0.88 in the advanced maternal age population without pre-existing high risk factors. Molecular subtypes create new opportunities to apply precision-based medicine in maternal health.

IMPORTANCE: The US Preventive Services Task Force (USPSTF) guidelines on preeclampsia risk assessment and aspirin prophylaxis (AP) have not been evaluated for clinical utility.

OBJECTIVE: To evaluate which characteristics in the USPSTF guidelines identify risk status and the association of preeclampsia risk with AP recommendations.

DESIGN, SETTING, AND PARTICIPANTS: This observational cohort study enrolled from July 2020 to March 2023 with data analysis performed from October to December 2024. Enrollment occurred at 11 centers throughout the US or via direct-to-participant recruitment. Pregnant participants aged 18 years or older with a singleton pregnancy less than 22 weeks' gestation were selected via convenience sampling.

EXPOSURE: The exposures were clinical factors abstracted from medical records by research coordinators, which were stratified according to USPSTF definitions of low, moderate (parity, advanced maternal age [AMA], race, and body mass index), and high (chronic hypertension, prior preeclampsia, type 1 or 2 diabetes, kidney disease, and/or autoimmune conditions) risk.

MAIN OUTCOMES AND MEASURES: Data collected included AP recommendation, presence of USPSTF-defined moderate risk factors or high risk factors, and any preeclampsia diagnosis. Effect sizes and relative risk (RR) were calculated within risk strata.

RESULTS: Of 5684 participants (median [IQR] age, 30.9 [26.4-34.6] years; 267 [4.1%] Asian; 1191 [21.0%] Black; 990 Hispanic [17.4%]; 2764 [48.6%] White; and 472 [8.3%] with other race or ethnicity), 5046 (88.8%) were at increased risk of preeclampsia (3996 [70.3%] at moderate risk and 1050 [18.5%] at high risk). A total of 2438 participants (43.1%) received an AP recommendation. The overall preeclampsia rate was 12.1% (685 participants). The PE rates specific to USPSTF categories were 3.0% for those at low risk (19 of 638 participants), 10.5% for those at moderate risk (419 of 3996 patients), and 23.5% for those at high risk (247 of 1050 participants). Among individuals with 2 or more moderate risk factors but without any high risk factor, nulliparity was associated with significantly increased risk of preeclampsia (RR, 1.48; 95% CI, 1.35-1.62; P < .001), while AMA was associated with decreased risk (RR, 0.79; 95% CI, 0.65-0.96; P = .02); there was no association with obesity (RR, 1.11; 95% CI, 1.01-1.22; P = .048) or Black race (RR, 0.95; 95% CI, 0.80-1.14; P = .63). Of 1044 participants with any high risk factors, 856 (82.0%) were recommended AP and of 634 at low risk, 538 (85.9%) were not recommended AP. In contrast, of 1942 participants with 1 moderate risk factor, 463 (23.8%) were recommended AP, and of 2032 with 2 or more moderate risk factors, 1024 (50.4%) were recommended AP.

CONCLUSIONS AND RELEVANCE: In this prospective cohort study of 5684 singleton pregnancies, 89% of the population was assessed as having increased risk (moderate or high) of preeclampsia by USPSTF criteria. These findings suggest that moderate risk factors in the absence of high risk factors show no or low value for estimating the risk of developing preeclampsia, leading to nonspecific recommendations of AP in the moderate risk category.

Messenger RNA (mRNA) vaccines were highly effective against the ancestral SARS-CoV-2 strain, but the efficacy of bivalent mRNA boosters against XBB variants was substantially lower. Here, we show limited durability of neutralizing antibody (NAb) responses against XBB variants and isotype switching to immunoglobulin G4 (IgG4) responses following bivalent mRNA boosting. Bivalent mRNA boosting elicited modest XBB.1-, XBB.1.5-, and XBB.1.16-specific NAbs that waned rapidly within 3 months. In contrast, bivalent mRNA boosting induced more robust and sustained NAbs against the ancestral WA1/2020 strain, suggesting immune imprinting. Following bivalent mRNA boosting, serum antibody responses were primarily IgG2 and IgG4 responses with poor Fc functional activity. In contrast, a third monovalent mRNA immunization boosted all isotypes including IgG1 and IgG3 with robust Fc functional activity. These data show substantial immune imprinting for the ancestral spike and isotype switching to IgG4 responses following bivalent mRNA boosting, with important implications for future booster designs and boosting strategies.

A new highly mutated Omicron subvariant BA.2.87.1 has recently been identified with over 30 amino acid mutations in the Spike protein compared with BA.2, BA.5, XBB.1.5, and JN.1 variants. Mutiple mutations in BA.2.87.1 are located in the N-terminal domain (NTD) rather than in the receptor binding domain (RBD) of the Spike protein. We evaluated neutralizing antibody (NAb) responses to BA.2.87.1 because of its highly mutated sequence and its unique NTD region. Our data show that NAb responses to BA.2.87.1 were lower than to BA.2 but higher than to JN.1, suggesting that BA.2.87.1 is not a further antibody escape variant compared with other currently circulating variants. Moreover, XBB.1.5 mRNA boosting increased NAb titers to all variants tested including BA.2.87.1.

Prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is typically measured by nucleocapsid serology assays. In this study, we show that the Simoa serology assay and T-cell intracellular cytokine staining assay are more sensitive than the clinical Elecsys assay for detection of nucleocapsid-specific immune responses. These data suggest that the prevalence of prior SARS-CoV-2 infection in the population may be higher than currently appreciated.