Research Articles
Related Research Articles
Our team is involved in some excited research projects. Check out some of the research that we have been involved in lately.
Calaprice, D., Moon, Helvick M., Harvey, C., Tang, A., Aguirre, K., Tererri, R., Hunt, J., Whitty, C., Fitzgerald, M. (2026). Access to Care in Pediatric Acute-Onset Neuropsychiatric Syndrome: A Survey of Families’ Journeys to and Experiences with Intravenous Immunoglobulin Treatment. Journal of Child and Adolescent Psychopharmacology, doi.org/10.1177/1044546326
Abstract
Background: Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by abrupt-onset neuropsychiatric symptoms, often infection-triggered. Intravenous immunoglobulin (IVIG) is recommended by expert guidelines in select cases, yet insurance denials and high out-of-pocket costs have been barriers to access.
Methods: We surveyed 60 caregivers and adult PANS patients who pursued IVIG therapy, collecting data on insurance coverage, treatment protocols, financial strategies, and quality of life (QoL) before and after treatment.
Results: Most patients (88%) eventually received IVIG, 10% were still in pursuit, and 2% discontinued trying. Insurance approval without appeal occurred for 24%, often for patients with comorbidities for which IVIG is typically covered. Only 5% of those receiving IVIG for PANS alone were treated within a month of the doctor’s order compared with 38% of those receiving IVIG for comorbidities plus PANS; 14% waited ≥9 months. Financial strain was routine: at least one-third of families without “substantial” insurance coverage (≥70% of expenses) reported extreme stress (10 on scale of 1 to 10), 58% borrowed money, and 21% sold major assets. Even families with substantial insurance coverage commonly depleted savings or took on additional work. Before IVIG, patient QoL ratings were poor (means 2.1–2.9 across domains), with over one-third selecting the lowest possible overall QoL rating. During the 6 months following IVIG initiation, mean ratings rose to 6.2–6.8, with over 60% reporting “good” to “exceedingly good” overall outcomes. Caregivers reported parallel gains, with family QoL ratings rising from 2.4–4.0 pretreatment to 5.7–6.6 posttreatment.
Conclusions: Families pursuing IVIG for PANS reported prolonged delays, repeated denials, and financial strain, often resorting to loans, asset sales, and additional work. Despite these burdens, IVIG was correlated with marked improvements in perceived QoL for patients and caregivers.
part of their clinical toolkit
Moon, C., Helvick M., Calaprice, D., Pasupuleti, U., & Fitzgerald, M. (2025). Another Arrow in our Quiver: a Role for Anti-Inflammatory Therapies in Mental Health Treatment for Pediatric Patients. Medical Research Archives, 13(10). doi:10.18103/mra.v13i10.7017
Abstract
The prevalence of pediatric depression and anxiety has surged dramatically, particularly in the wake of the COVID-19 pandemic, exposing limitations in existing mental health treatments. Traditional therapies of psychotropics and psychotherapies often yield suboptimal results due to limited efficacy, tolerability concerns, poor adherence, and treatment resistance. Emerging evidence suggests that neuroinflammation may drive treatment-resistant psychiatric symptoms in youth, particularly in cases of sudden-onset symptoms and post-infectious presentations. In this select group of patients, anti-inflammatory therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, corticosteroids, and intravenous immunoglobulin (IVIG), show promise as adjunctive and/or alternative interventions, potentially providing symptom relief and improved tolerability compared with psychotropics. Though behavioral therapy and psychotropics like selective serotonin reuptake inhibitors (SSRIs) remain a mainstay of treatment, anti-inflammatory therapies represent a promising arrow in the quiver, especially in cases where antidepressants are insufficient or contraindicated. NSAIDs in particular may provide safe and rapid symptom relief. Further research is needed to establish treatment protocols and guide clinicians in providing personalized care for neuroimmune-linked psychiatric disorders in youth; however, we aim to help fuel this important conversation and encourage clinicians to begin considering anti-inflammatory therapies as part of their clinical toolkit.
Bhatia, A., Preiss, A. J., & N3C Consortium (including Megan Fitzgerald). (2025). Effect of nirmatrelvir/ritonavir (Paxlovid) on hospitalization among adults with COVID-19: An electronic health record-based target trial emulation from N3C. PLOS Medicine, 22(1), e1004493. https://doi.org/10.1371/journal.pmed.1004493
Abstract
Background
Nirmatrelvir with ritonavir (Paxlovid) is indicated for patients with Coronavirus Disease 2019 (COVID-19) who are at risk for progression to severe disease due to the presence of one or more risk factors. Millions of treatment courses have been prescribed in the United States alone. Paxlovid was highly effective at preventing hospitalization and death in clinical trials. Several studies have found a protective association in real-world data, but they variously used less recent study periods, correlational methods, and small, local cohorts. Their estimates also varied widely. The real-world effectiveness of Paxlovid remains uncertain, and it is unknown whether its effect is homogeneous across demographic strata. This study leverages electronic health record data in the National COVID Cohort Collaborative’s (N3C) repository to investigate disparities in Paxlovid treatment and to emulate a target trial assessing its effectiveness in reducing severe COVID-19 outcomes.
Methods and Findings
This target trial emulation used a cohort of 703,647 patients with COVID-19 seen at 34 clinical sites across the United States between April 1, 2022 and August 28, 2023. Treatment was defined as receipt of a Paxlovid prescription within 5 days of the patient’s COVID-19 index date (positive test or diagnosis). To emulate randomization, we used the clone-censor-weight technique with inverse probability of censoring weights to balance a set of covariates including sex, age, race and ethnicity, comorbidities, community well-being index (CWBI), prior healthcare utilization, month of COVID-19 index, and site of care provision. The primary outcome was hospitalization; death was a secondary outcome. We estimated that Paxlovid reduced the risk of hospitalization by 39% (95% confidence interval (CI) [36%, 41%]; p < 0.001), with an absolute risk reduction of 0.9 percentage points (95% CI [0.9, 1.0]; p < 0.001), and reduced the risk of death by 61% (95% CI [55%, 67%]; p < 0.001), with an absolute risk reduction of 0.2 percentage points (95% CI [0.1, 0.2]; p < 0.001). We also conducted stratified analyses by vaccination status and age group. Absolute risk reduction for hospitalization was similar among patients that were vaccinated and unvaccinate, but was much greater among patients aged 65+ years than among younger patients. We observed disparities in Paxlovid treatment, with lower rates among black and Hispanic or Latino patients, and within socially vulnerable communities. This study’s main limitation is that it estimates causal effects using observational data and could be biased by unmeasured confounding.
Conclusions
In this study of Paxlovid’s real-world effectiveness, we observed that Paxlovid is effective at preventing hospitalization and death, including among vaccinated patients, and particularly among older patients. This remains true in the era of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Omicron subvariants. However, disparities in Paxlovid treatment rates imply that the benefit of Paxlovid’s effectiveness is not equitably distributed.
Calaprice, D., Terreri, R., Whitty, C., Whitty, R., & Tona, J. (2024). The Flip Side of the Coin: Giftedness in Pediatric Acute-Onset Neuropsychiatric Syndrome. Children, 11(12), 1524. https://doi.org/10.3390/children11121524
Abstract
Background/Objectives: Individuals with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), an immune-modulated disorder, experience exacerbation-related neuropsychiatric symptoms, functional impairments, and high rates of developmental diagnosis. The literature describes links between giftedness and mental illness, and giftedness and autoimmune disorders. We sought to explore rates of giftedness among children with PANS as perceived by their caregivers, and to examine whether giftedness was related to PANS symptom severity, persistence, or duration. Methods: Data were extracted from a larger, 146-item survey, with 680 respondents meeting inclusion criteria of being a parent/guardian of a child with PANS and answering questions regarding perceived giftedness in empathy, social skills, verbal ability, reading, memory, math, creativity, or “other.” Results: In all, 604 respondents indicated some type of giftedness; the categories of giftedness were each endorsed by 30–57% of respondents. We found no significant associations between giftedness and severity of worst symptoms, persistence of symptoms, or length of time since symptom onset, once Bonferonni corrections were applied. Significantly more females than males were identified as gifted in creativity, but no other sex-related differences were seen. Thematic analysis of optional comments revealed three themes: (1) Elaboration on Types of Giftedness; (2) Objective Basis for Perceptions of Giftedness; and (3) Impact of PANS on Giftedness. Conclusions: The rate of giftedness reported by parents of PANS subjects in this study is much higher than would be expected in the general population, even when adjusting generously for potential overestimation. This study of the “flip side” of PANS should serve as impetus for future studies regarding giftedness in this population; a robust finding of exceptionally high rates of giftedness would have implications for diagnosis, interpretation of symptoms (for example, perfectionism and social challenges) and disease management.
Calaprice-Whitty, D., Tang, A., & Tona, J. (2023). Factors Associated with Symptom Persistence in PANS: Part I—Access to Care. Journal of Child and Adolescent Psychopharmacology, 33(9), 356–364. https://doi.org/10.1089/cap.2023.0022
Abstract:
Objective: Pediatric acute-onset neuropsychiatric syndrome (PANS) presents with abrupt neuropsychiatric symptoms, often after an immunologic trigger. A 2017 survey of 698 subjects found diagnostic delays to be associated with recurrences, suggesting that timely care impacts course. This secondary analysis explores the impact of barriers to care on symptom persistence.
Methods: A 146-question online survey gathered history, symptomatology, intervention, and outcome data from subjects with PANS. Multivariate analyses examined associations between symptom persistence over the entire reported disease course, measured as % days symptom-free over reporting periods averaging approximately 4 years, and access-to-care history, reflected in availability of medical expertise and affordability of care. The impacts of time from symptom onset to treatment and effectiveness of initial antibiotics were also examined.
Results: Among the 646 subjects analyzed, greater symptom persistence was associated with longer intervals between symptom onset and treatment (F = 4.43, p = 0.002). Thirty-four percent of subjects with the least symptom persistence (>75% symptom-free days), versus 13% of those with the most (symptoms every day), had been diagnosed by the first practitioner seen (likelihood ratio [L-R] χ2 = 36.55, p < 0.0001, for comparison across all groups). Diagnosis and treatment had not been impeded by lack of access to expertise for 52% of subjects with the least persistent symptoms, versus 22% of those with the most (L-R χ2 = 22.47, p < 0.0001). Affordability had not impacted diagnosis and treatment for 76% of subjects with the least persistent symptoms, versus 42% of those with the most (L-R χ2 = 27.83, p < 0.0001). The subjects whose PANS symptoms resolved with antibiotic treatment of the inciting infection experienced less symptom persistence than others (χ2 = 23.27, p = 0.0001). More persistently symptomatic subjects were more likely to have discontinued intravenous immunoglobulin (IVIG) treatment for access-to-care reasons.
Conclusions: Unimpeded access to care for PANS is associated with more symptom-free days over reporting periods averaging approximately 4 years. Difficulty reaching expert providers, missed opportunities for diagnoses, and financial limitations may worsen outcomes. Practitioners, particularly primary providers, should adhere to published diagnostic and treatment guidelines promptly upon presentation.
Calaprice-Whitty, D., Tang, A., & Tona, J. (2023). Factors Associated with Symptom Persistence in PANS: Part II—Presenting Features, Medical Comorbidities, and IVIG Treatment History. Journal of Child and Adolescent Psychopharmacology, 33(9), 365–377. https://doi.org/10.1089/cap.2023.0023
Abstract:
Objective: Individuals with Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) experience neuropsychiatric symptoms following an infection or other trigger. Although PANS is typically described as relapsing-remitting, a large community-based 2017 study revealed a range of courses. The present study examined clinical predictors of symptom persistence, measured as % days symptom-free, in this same sample.
Methods: A 146-question online survey gathered histories (infections and other triggers, medical and developmental comorbidities), symptomatology, interventions, and outcomes (including school functioning) of PANS patients. Multivariate analyses were applied to examine associations between these variables and % days symptom-free across the disease course.
Results: Among the 646 subjects included, significant relationships were found between greater symptom persistence and higher rates of medical comorbidities (especially rashes, headaches, chronic sinusitis, frequent diarrhea, and immune deficiencies), developmental diagnoses, and respondent-perceived developmental lags. Subjects with greater symptom persistence were significantly more likely to report PANS exacerbations associated with infections in close contacts, vaccinations, environmental triggers, and exacerbations of comorbidities and were more likely to report PANS recurrences triggered by Epstein Barr Virus, mycoplasma, and sinus infections. More persistent PANS was also associated with significantly higher frequencies of certain symptoms (sleep disturbance, urinary incontinence, muscle pain, brain fog, sensory defensiveness, irritability, and aggression-related symptoms), less effectiveness of intravenous immunoglobulin in combating symptoms, and more difficulty attending school.
Conclusions: Our results suggest high symptom persistence in PANS to be associated with more pervasive medical and neuropsychiatric symptoms. Differences in symptom persistence are associated with both intrinsic (e.g., immune competence) and extrinsic (e.g., infections, treatment) factors. Because extrinsic factors are potentially modifiable, it is critical that providers be aware of current guidelines on PANS evaluation and treatment.
Calaprice-Whitty, D., Whitty, R., Moon, C., Hidajat, N. (2023). Who Cares About Diversity in Clinical Trials. Journal for Clinical Studies, 15(1), 28–31.
Description: The imperative to obtain a diverse body of clinical trial participants has been stressed in public statements for decades; however, parties executing clinical trials have remained insufficiently effective in addressing it. Understanding the patterns unveiled in this study’s analyses can inform policies and programs designed to effectively encourage personnel to make diversity-oriented decisions.
Fitzgerald, M., et. al. (2024). A call from patient-researchers to advance research on long COVID. Cell, 187(20), 5499–5503. https://doi.org/10.1016/j.cell.2024.09.011
Description: Long COVID is a chronic and often disabling illness with long-term consequences. Although progress has been made in the clinical characterization of long COVID, no approved treatments exist and disconnects between patients and researchers threaten to hinder future progress. Incorporating patients as active collaborators in long COVID research can bridge the gap and accelerate progress toward treatments and cures.
Gross, R. S., Thaweethai, T., Kleinman, L. C., Snowden, J. N., Rosenzweig, E. B., Milner, J. D., Tantisira, K. G., Rhee, K. E., Jernigan, T. L., Kinser, P. A., Salisbury, A. L., Warburton, D., Mohandas, S., Wood, J. C., Newburger, J. W., Truong, D. T., Flaherman, V. J., Metz, T. D., Karlson, E. W., … Yurgelun-Todd, D. A. (Megan Fitzgerald) (2024). Characterizing long COVID in children and adolescents. JAMA, 330(7), 549–559. https://doi.org/10.1001/jama.2024.12747
Abstract
Importance Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.
Objective To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.
Design, Setting, and Participants Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.
Exposure SARS-CoV-2 infection.
Main Outcomes and Measures PASC and 89 prolonged symptoms across 9 symptom domains.
Results A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise–related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.
Conclusions and Relevance This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.
Moore Vogel, J., Fitzgerald, M., et.al. (2024). Designing and optimizing clinical trials for long COVID. Life Sciences, 355, 122970. https://doi.org/10.1016/j.lfs.2024.122970
Description: Long COVID is a debilitating, multisystemic illness following a SARS-CoV-2 infection whose duration may be indefinite. Over four years into the pandemic, little knowledge has been generated from clinical trials. We analyzed the information available on ClinicalTrials.gov, and found that the rigor and focus of trials vary widely, and that the majority test non-pharmacological interventions with insufficient evidence. We highlight promising trials underway, and encourage the proliferation of clinical trials for treating Long COVID and other infection-associated chronic conditions and illnesses (IACCIs). We recommend several guidelines for Long COVID trials: First, pharmaceutical trials with potentially curative, primary interventions should be prioritized, and both drug repurposing and new drug development should be pursued. Second, study designs should be both rigorous and accessible, e.g., triple-blinded randomized trials that can be conducted remotely, without participants needing to leave their homes. Third, studies should have multiple illness comparator cohorts for IACCIs such as myalgic encephalomyelitis (ME/CFS) and dysautonomia, and screen for the full spectrum of symptomatology and pathologies of these illnesses. Fourth, studies should consider inclusion/exclusion criteria with an eye towards equity and breadth of representation, including participants of all races, ethnicities, and genders most impacted by COVID-19, and including all levels of illness severity. Fifth, involving patient-researchers in all aspects of studies brings immensely valuable perspectives that will increase the impact of trials. We also encourage the development of efficient clinical trial designs including methods to study several therapies in parallel.
Soares, L., Assaf, G., McCorkell, L., Davis, H., Cohen, A., Moen, J., … & Fitzgerald, M. (2024). Long COVID and associated outcomes following COVID-19 reinfections: Insights from an International Patient-Led Survey. PrePrint.
Background: COVID-19 reinfections are common worldwide. Long COVID is a serious infection-associated chronic condition and a major public health concern. Using a patient-centered approach, we characterized the association between reinfections and Long COVID.
Methods: We developed and disseminated internationally a patient-centered online survey examining the outcomes of COVID-19 reinfections. The survey incorporated validated instruments on fatigue, post-exertional malaise, and physical function with questions about COVID-19 infection history, vaccination, and Long COVID symptoms, including symptoms related to immune and reproductive health. We tested whether the likelihood of Long COVID and related outcomes increases with COVID-19 infection numbers.
Results: Here we show that reinfections increase the likelihood of reporting Long COVID, which increased 2.1-fold from one to two infections. Among 3,382 participants, 22% reported never having had COVID-19, 42% experienced it once, and 35% reported reinfections. Relative to those who did not report infections or experienced COVID-19 once, reinfections were associated with increased likelihood of severe fatigue, post-exertional malaise, decreased physical function, poorer immune health, symptom exacerbation before menstruation, and multiple other Long COVID symptoms. While vaccinations and boosters prior to infection are associated with lower likelihood of Long COVID, reinfections diminish their protective effect. The probability of reporting Long COVID remission is generally low (11.5%-6.5%).
Conclusions: COVID-19 reinfections are associated with higher likelihood of Long COVID and related outcomes. These findings underscore the need for robust public health measures for COVID-19 infection prevention and the importance of considering reinfections in Long COVID research and clinical practice.
Vreeland, A., Calaprice, D., Or-Geva, N., Frye, R. E., Agalliu, D., Lachman, H. M., Pittenger, C., Pallanti, S., Williams, K., Ma, M., Thienemann, M., Gagliano, A., Mellins, E., & Frankovich, J. (2023). Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder. Developmental Neuroscience, 45(6), 361–374. https://doi.org/10.1159/000534261
Description: Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.