Clinical Focus

  • Pediatrics
  • PANS

Academic Appointments

Professional Education

  • Board Certification: American Board of Pediatrics, Pediatrics (2017)
  • Medical Education: Tufts University School of Medicine (2004) MA
  • Residency: Tufts Medical Center (2007) MA
  • PhD, Tufts University Sackler School of Biomedical Sciences, Immunology (2002)

Current Research and Scholarly Interests

Clinical research program focusing on children and adolescents with immune-mediated neuropsychiatric symptoms. Research team led by Dr Jennifer Frankovich.

All Publications

  • Chronic Fatigue Symptoms in Children with Abrupt Early-onset OCD And/or PANS Chan, A., Truong, A., Farhadian, B., Willett, T., Silverman, M., Tran, P., Thienemann, M., Frankovich, J. WILEY. 2020: 252–54
  • The Killer Immunoglobulin-like Receptor KIR3DL1 in Combination with HLA-Bw4 Is Associated with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Frankovich, J., Anderson, K., Montero-Martin, G., Chan, A., Thienemann, M., Farhadian, B., Willett, T., Mellins, E., Madden, A., Murphy, T., Swedo, S., Fernandez-Vina, M., Hollenbach, J. WILEY. 2020: 255–57
  • Familial Clustering of Immune-mediated Diseases in Children with Abrupt-onset OCD Chan, A., Phu, T., Farhadian, B., Willett, T., Silverman, M., Tran, P., Thienemann, M., Frankovich, J. WILEY. 2020: 250–52
  • Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome. Pediatric research Chan, A. n., Karpel, H. n., Spartz, E. n., Willett, T. n., Farhadian, B. n., Jeng, M. n., Thienemann, M. n., Frankovich, J. n. 2020


    Pediatric acute-onset neuropsychiatric syndrome (PANS) is an abrupt debilitating psychiatric illness. We anecdotally observed hypoferritinemia and iron deficiency in a subset of patients with PANS, prompting this study.In this IRB-approved prospective cohort study, we included patients seen at the Stanford PANS Clinic who met study criteria. The prevalence of hypoferritinemia (using cut-offs of 7 ng/ml in children ≤ 15 years and 18 ng/ml in adolescents > 15 years) and iron deficiency was estimated. Differences in patients with and without hypoferritinemia during PANS flare were explored.Seventy-nine subjects (mean age of PANS onset of 8.7 years) met study criteria. Hypoferritinemia was observed in 27% and three quarters occurred during a PANS flare. Compared to patients without hypoferritinemia during PANS flare, patients with hypoferritinemia had worse global impairment, more comorbid inflammatory diseases, and exhibited a chronic course of PANS illness. The estimated prevalence of iron deficiency was 3-8% in the PANS cohort, 1.4-2.0-fold higher than in the age- and sex-matched U.S.More stringent ferritin level cut-offs than the comparison CDC dataset were used.Hypoferritinemia and iron deficiency appear to be more common in PANS patients. More research is needed to confirm and understand this association.Our study suggests hypoferritinemia and iron deficiency are more common in patients with pediatric acute-onset neuropsychiatric syndrome (PANS) than in the sex- and age-matched US population.Hypoferritinemia was commonly observed during a disease flare but not associated with dietary or demographic factors. In patients with PANS and iron deficiency, clinicians should consider possibility of inflammation as the cause especially if iron deficiency cannot be explained by diet and blood loss.Future research should include larger cohorts to corroborate our study findings and consider examining the iron dynamics on MRI brain imaging in order to better understand the pathophysiology of PANS.

    View details for DOI 10.1038/s41390-020-1103-3

    View details for PubMedID 32746449

  • Familial Clustering of Immune-Mediated Diseases in Children with Abrupt-Onset Obsessive Compulsive Disorder. Journal of child and adolescent psychopharmacology Chan, A. n., Phu, T. n., Farhadian, B. n., Willett, T. n., Thienemann, M. n., Frankovich, J. n. 2020

    View details for DOI 10.1089/cap.2019.0167

    View details for PubMedID 32311283

  • The Burden of Caring for a Child or Adolescent With Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): An Observational Longitudinal Study. The Journal of clinical psychiatry Frankovich, J., Leibold, C. M., Farmer, C., Sainani, K., Kamalani, G., Farhadian, B., Willett, T., Park, J. M., Sidell, D., Ahmed, S., Thienemann, M. 2018; 80 (1)


    OBJECTIVE: To describe the longitudinal association between disease severity, time established in clinical treatment, and caregiver burden in a community-based patient population diagnosed with pediatric acute-onset neuropsychiatric syndrome (PANS).METHODS: The study included an observational longitudinal cohort design, with Caregiver Burden Inventories (CBIs) collected between April 2013 and November 2016 at the Stanford PANS multidisciplinary clinic. Inclusion criteria for this study were as follows: pediatric patients meeting strict PANS/pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) diagnostic criteria (n = 187), having a caregiver fill out at least 1 complete CBI during a disease flare (n = 114); and having family who lives locally (n = 97). For longitudinal analyses, only patients whose caregiver had filled out 2 or more CBIs (n = 94 with 892 CBIs) were included. In the study sample, most primary caregivers were mothers (69 [71.1%] of 97), the majority of PANS patients were male (58 [59.8%] of 97), and mean age at PANS onset was 8.8 years.RESULTS: In a patient's first flare tracked by the clinic, 50% of caregivers exceeded the caregiver burden score threshold used to determine respite need in care receiver adult populations. Longitudinally, flares, compared with quiescence, predicted increases in mean CBI score (6.6 points; 95% CI, 5.1 to 8.0). Each year established in clinic predicted decreased CBI score (-3.5 points per year; 95% CI, -2.3 to -4.6). Also, shorter time between PANS onset and entry into the multidisciplinary clinic predicted greater improvement in mean CBI score over time (0.7 points per year squared; 95% CI, 0.1 to 1.3). Time between PANS onset and treatment with antibiotics or immunomodulation did not moderate the relationship between CBI score and time in clinic.CONCLUSIONS: PANS caregivers suffer high caregiver burden. Neuropsychiatric disease severity predicts increased caregiver burden. Caregiver burden tends to decrease over time in a group of patients undergoing clinical treatment at a specialty PANS clinic. This decrease could be independent of clinical treatment.

    View details for PubMedID 30549499

  • Psychometric Properties of the Pediatric Acute-Onset Neuropsychiatric Syndrome Global Impairment Score in Children and Adolescents with Pediatric Acute-Onset Neuropsychiatric Syndrome JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Leibold, C., Thienemann, M., Farhadian, B., Willett, T., Frankovich, J. 2019; 29 (1): 41–49
  • Psychometric Properties of the Pediatric Acute-Onset Neuropsychiatric Syndrome Global Impairment Score in Children and Adolescents with Pediatric Acute-Onset Neuropsychiatric Syndrome. Journal of child and adolescent psychopharmacology Leibold, C., Thienemann, M., Farhadian, B., Willett, T., Frankovich, J. 2018


    OBJECTIVES: This study validates the caregiver-rated Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Global Impairment Score (GIS), a single-item, 0-100 scale, for use in PANS.METHODS: We collected longitudinal data from community patients meeting PANS criteria. We included 128 patients with 1926 GISs, each from a unique clinic visit. To assess discriminant validity, we compared GISs from patients with PANS with scores from a population of healthy controls. To evaluate external validity, we compared global impairment with a clinician-reported global measure-the Child Global Assessment Scale (CGAS)-using the Bland-Altman plots and correlation coefficients. Then, we evaluated associations between the PANS GIS and symptom-specific disease severity variables by fitting mixed models with repeated measures.RESULTS: The GIS shows excellent discriminant validity, distinguishing patients with PANS from healthy controls. The scores on the GIS show an acceptable level of agreement with the clinician-reported CGAS. The regression line in the Bland-Altman plot had a positive slope, indicating that parents tend to report higher disease severity than clinicians at higher levels of disease severity. Correlation was higher during disease remissions than during disease flares (r=-0.69 vs. r=-0.48). All disease severity scales predicted GIS in the expected direction.CONCLUSION: The GIS has excellent discriminant validity and acceptable construct validity.

    View details for PubMedID 30421965

  • Clinical Management of Pediatric Acute-onset Neuropsychiatric Syndrome (PANS): Part II – Use of Immunomodulatory Therapies Journal of Child and Adolescent Psychopharmacology Frankovich, J., Swedo, S., Murphy, T., Dale, R. C., Agalliu, D., Williams, K., Daines, M., Hornig, M., Chugani, H., Sanger, T., Muscal, E., Pasternack, M., Cooperstock, M., Gans, H., Zhang, Y., Cunningham, M., Bernstein, G., Bromberg, R., Willett, T., Brown, K., Farhadian, B., Chang, K., Geller, D., Hernandez, J., Sherr, J., et al 2017; 27 (7): 574-593

    View details for DOI 10.1089/cap.2016.0148

  • An effective second-generation outer surface protein A-derived Lyme vaccine that eliminates a potentially autoreactive T cell epitope PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Willett, T. A., Meyer, A. L., Brown, E. L., Huber, B. T. 2004; 101 (5): 1303–8


    The antigenic component of a common Lyme disease vaccine is recombinant outer surface protein A (rOspA) of Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Coincidentally, patients with chronic, treatment-resistant Lyme arthritis develop an immune response against OspA, whereas those with acute Lyme disease usually do not. Treatment-resistant Lyme arthritis occurs in a subset of Lyme arthritis patients and is linked to HLA.DRB1*0401 (DR4) and related alleles. Recent work from our laboratory identified T cell crossreactivity between epitopes of OspA and lymphocyte function-associated antigen 1alpha(L) chain (LFA-1alpha(L)) in these patients. We generated a form of rOspA, FTK-OspA, in which the LFA-1alpha(L)/rOspA crossreactive T cell epitope was mutated to reduce the possible risk of autoimmunity in genetically susceptible individuals. FTK-OspA did not stimulate human or mouse DR4-restricted, WT-OspA-specific T cells, whereas it did stimulate antibody responses specific for WT-OspA that were similar to mice vaccinated WT-OspA. We show here that the protective efficacy of FTK-OspA is indistinguishable from that of WT-OspA in vaccination trials, as both C3H/HeJ and BALB/c FTK-OspA-vaccinated mice were protected from Bb infection. These data demonstrate that this rOspA-derived vaccine lacking the predicted cross-reactive T cell epitope, but retaining the capacity to elicit antibodies against infection, is effective in generating protective immunity.

    View details for PubMedID 14742868

  • T cell epitope modified Lyme disease vaccine induces protective immunity. Willett, T. A., Meyer, A., Huber, B. T. FEDERATION AMER SOC EXP BIOL. 2002: A311
  • T-cell costimulatory blockade in experimental chronic cardiac allograft rejection - Effects of cyclosporine and donor antigen TRANSPLANTATION Chandraker, A., Russell, M. E., GlysingJensen, T., Willett, R. A., Sayegh, M. H. 1997; 63 (8): 1053–58


    Chronic rejection is a T cell-dependent process and blockade of the CD28-B7 T-cell costimulatory activation pathway by the fusion protein CTLA4Ig has been shown to prevent the development of accelerated graft arteriosclerosis in a rat model of chronic cardiac allograft rejection. The effectiveness of T-cell costimulatory blockade at preventing chronic allograft rejection in a clinically relevant model in combination with cyclosporine therapy has not been investigated. Using the well-established LEW into F334 heterotopic cardiac allograft model, we show that when cyclosporine is administered in combination with CTLA4Ig, it abrogates the previously demonstrated protective effect of CTLA4Ig in preventing chronic allograft rejection. Long-term surviving allografts from animals treated with a combination of cyclosporine and CTLA4Ig had a mean vascular luminal occlusion of 42.2%, affecting more than 90% of graft vessels due to accelerated arteriosclerosis. This was associated with up-regulation of intragraft expression of mRNA for CD4, the costimulatory molecule B7, the T-cell cytokine interferon-gamma, monocyte chemoattractant protein-1, and the fibrogenic growth factor transforming growth factor-beta; all have been previously shown to be associated with development of chronic rejection in this model. In comparison, the addition of donor splenocytes to the combination of CTLA4Ig and cyclosporine therapy protocol significantly reduced the amount of arteriosclerosis; mean vascular luminal occlusion was 11.3%, affecting approximately 50% of vessels. This was associated with decreased intragraft expression of CD4, B7, interferon-gamma, monocyte chemoattractant protein-1, and transforming growth factor-beta. These data indicate that the mechanism of action of CTLA4Ig in attenuating chronic rejection is cyclosporine sensitive, and that strategies implying combination of CTLA4Ig and cyclosporine may not be clinically desirable. Administration of donor antigen may be necessary if CTLA4Ig and cyclosporine are to be combined, to prevent the process of chronic rejection.

    View details for DOI 10.1097/00007890-199704270-00002

    View details for Web of Science ID A1997WW66000002

    View details for PubMedID 9133464

  • Mechanisms of indirect allorecognition in graft rejection - Class II MHC allopeptide-specific T cell clones transfer delayed-type hypersensitivity responses in vivo TRANSPLANTATION Chen, W. J., Murphy, B., Waaga, A. M., Willett, T. A., Russell, M. E., Khoury, S. J., Sayegh, M. H. 1996; 62 (6): 705–10


    Recent animal studies suggest that indirect T-cell recognition of alloantigen plays an important role in allograft rejection and tolerance. In this study, we generated T cell clones from Lewis (LEW, RT1(l)) rat lymph node cells that had been primed in vivo by immunization with immunogenic class II MHC allopeptide RT1.D(u)beta2, representing residues 20-44 of the polymorphic beta chain of RT1.Dbeta(u) (Wistar Furth [WF]). Using reverse transcriptase polymerase chain reaction transcript analysis with specific rat T cell receptor Vbeta primers, we show that six out of nine T cell clones specifically proliferated to RT1.D(u)beta2 and expressed Vbeta 9. One of these clones, clone 2F4, which specifically proliferated to RT1.D(u)beta2 in a dose-response fashion and produced interferon-gamma in response to restimulation by RT1.D(u)beta2, was selected for further studies. The beta-chains of RT1.D(l) and RT1.D(u) residues 20-44 differ by two amino acids at positions 30 and 38. We synthesized two peptides, each containing a single polymorphic site: RT1.D(u)beta 20-33 and RT1.D(u)beta 31-44. Both these peptides were immunogenic by LEW responders, since lymph node cells primed by immunization proliferated equally to the peptides in vitro. Interestingly, in vitro dose-response studies with clone 2F4 showed better proliferative response to peptide RT1.D(u)beta 20-33 than to peptide RT1.D(u)beta 31-44, indicating that this T cell clone preferentially recognizes a single amino acid difference on residue 30. Finally, it has been suggested that indirect allorecognition by CD4+ T cells mediate graft rejection by delayed-type hypersensitivity responses, although definitive studies are lacking. Systemic injection of the 2F4 clone to naive LEW rats elicited an antigen-specific delayed-type hypersensitivity response against RT1.D(u)beta2 peptide and WF splenocytes, confirming indirect presentation in vivo. These data demonstrate that Th1 cell clones generated by in vivo priming via the indirect pathway utilize specific T cell receptor Vbeta and recognize single amino acid differences in the allopeptide. More importantly,these Th1 clones are capable of mediating a specific immune response in vivo. These studies with MHC allopeptide-specific T cell clones further delineate the cellular mechanisms of indirect allorecognition and provide a potential strategy to study its role in acute and chronic rejection, and tolerance.

    View details for DOI 10.1097/00007890-199609270-00001

    View details for Web of Science ID A1996VK61100001

    View details for PubMedID 8824464

  • Chronic cardiac rejection in the LEW to F344 rat model blockade of CD28-B7 costimulation by CTLA41g modulates T cell and macrophage activation and attenuates arteriosclerosis JOURNAL OF CLINICAL INVESTIGATION Russell, M. E., Hancock, W. W., Akalin, E., Wallace, A. F., GlysingJensen, T., Willett, T. A., Sayegh, M. H. 1996; 97 (3): 833–38


    CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.

    View details for DOI 10.1172/JCI118483

    View details for Web of Science ID A1996UB65600033

    View details for PubMedID 8609241

    View details for PubMedCentralID PMC507122