Kathleen E Sullivan

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States

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Publications (218)1093.62 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine–derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.
    The Journal of allergy and clinical immunology 04/2014; 133(4):961–966. DOI:10.1016/j.jaci.2013.11.043 · 11.48 Impact Factor
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    ABSTRACT: Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies.
    Journal of Clinical Immunology 03/2014; 34(4). DOI:10.1007/s10875-014-0003-x · 3.18 Impact Factor
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    ABSTRACT: Background/Purpose:miRNAS are responsible for post-transcriptional gene silencing and typically regulate multiple targets. Our goal was to study the miRNA pattern of lupus nephritis (LN) in order to better understand its pathogenesis.Methods:A retrospective cohort study was performed on a large single-center cohort of children exposed to anti-Ro and/or anti-La antibodies on whom prospective data has been collected since 1984. Inclusion criteria were: 1) first child born from a woman positive for anti-Ro and/or anti-La antibodies with a diagnosis of cutaneous lupus, systemic lupus erythematosus, Sjogren's syndrome, dermatomyositis or rheumatoid arthritis, 2) the mother underwent fetal echocardiography screening during pregnancy and/or the child had a postnatal ECG and 3) the child was ≥6 months old as of October 2013. We used Bayesian analysis for the association between prenatal use of AM and NLE.Results:A kidney LN miRNA signature was identified, which, according to Ingenuity pathway analysis, mainly reflected cell proliferation (p = 3.3E-23-0.049). miR-26a, miR-30b and miR-4286 were significantly decreased in LN (p = 0.002; p = 0.005; p = 0.002). The levels of miR-26a and miR-30b were also decreased in the urine of LN patients when compared to controls (p = 0.03; p = 0.02). The genes significantly up-regulated in the knockdowns of miR-26a, miR-30b and miR-4286 when compared to controls were related to mitosis (p = 1.06E-10). These results were validated by qRT-PCR, including the increase on the expression of genes associated with cell cycle (CCNE2, E2F8, MAD2L1, MYBL1 and POLQ).Based on these results, we examined HER2 expression, a protein that regulates miR-26a and miR-30b levels in breast cancer cell lines. We found that it was highly increased in the glomeruli and tubular compartment of LN patients and not in other mesangioproliferative diseases. Moreover, the average of HER2+ cells in the glomeruli of NZM2410 mice was higher than in B6 or Balb/c mice (p < 0.0001; p = 0.009) and it was associated with proteinuria (p = 0.001). Finally, HER2 expression was increased in mesangial cells by α Ninterferon exposure (p = 0.02) and IRF-1 transfection (p = 0.0009).Conclusion:The kidneys of LN patients have a miRNA pattern characterized by a significant decrease of miR-26a, miR-30b and miR-4286, which is predicted to be associated with increased proliferation. In addition, miR-26a and miR-30b are also decreased in the urine of LN patients, which makes them interesting candidates as biomarkers. It was previously shown that trastuzumab, an antibody against HER2, produces therapeutic actions by up-regulating miR-26a and miR-30b in breast cancer cell lines. Since we demonstrated that HER2 was highly increased in the kidneys of LN patients and NZM2410 mice, blocking HER2 may be a new promising pathway to decrease cell proliferation and damage in this disease.
    Arthritis and Rheumatology 03/2014; 66(S11). DOI:10.1002/art.38571
  • Lihua Shi · Li Song · Michael Fitzgerald · Kelly Maurer · Asen Bagashev · Kathleen E Sullivan
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    ABSTRACT: Noncoding RNAs have been implicated in the regulation of expression of numerous genes; however, the mechanism is not fully understood. We identified bidirectional, long noncoding RNAs upstream of the TNF gene using five different methods. They arose in a region where the repressors LRRFIP1, EZH2, and SUZ12 were demonstrated to bind, suggesting a role in repression. The noncoding RNAs were polyadenylated, capped, and chromatin associated. Knockdown of the noncoding RNAs was associated with derepression of TNF mRNA and diminished binding of LRRFIP1 to both RNA targets and chromatin. Overexpression of the noncoding RNAs led to diminished expression of TNF and recruitment of repressor proteins to the locus. One repressor protein, LRRFIP1, bound directly to the noncoding RNAs. These data place the noncoding RNAs upstream of TNF gene as central to the transcriptional regulation. They appear to serve as a platform for the assembly of a repressive complex.
    The Journal of Immunology 02/2014; 192(7). DOI:10.4049/jimmunol.1302063 · 4.92 Impact Factor
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    ABSTRACT: Common variable immunodeficiency (CVID) has recently been associated with a dramatic increase in total copy number variation burden, the cause of which is unclear. In order to further explore the origin and clinical relevance of this finding, we quantified the total genomic copy number variation (CNV) burden in affected patients and evaluated clinical details in relationship to total CNV burden. No correlation was found between total CNV burden and either patient age or time elapsed since symptom onset, and higher total burden did not correlate with incidence of malignancy nor other subphenotypes. These findings suggest that the increased CNV burden is static and intrinsic to CVID as a disease.
    Clinical & Experimental Immunology 12/2013; 177(1). DOI:10.1111/cei.12255 · 3.04 Impact Factor
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    ABSTRACT: We report a 45-year old female adult patient with terminal deletion of chromosome 11q resulting in clinical phenotype of late-onset combined immunodeficiency. We describe the clinical phenotype and discuss the similarities between our patient and those with chromosome 22q11.2 deletion syndrome. Immunological evaluation included immunoglobulin levels, vaccine responses, number and function of T, NK and B cell subsets and comparative genomic hybridization test of blood and fibroblasts. The patient suffered from recurrent pneumococcal pneumonia and genital and cutaneous condylomas. She had a history of learning difficulties, dysmorphic features, autoimmune thyroiditis, chronic thrombocytopenia and severe asthma. We found Paris-Trousseau type thrombocytopenia, B-, T- and NK-lymphopenia, T cell oligoclonality and IgG hypogammaglobulinemia with inability to respond to pneumococcal polysaccharide, tetanus and diphtheria vaccines. A terminal deletion of chromosome 11q compatible with partial Jacobsen syndrome was found. This confirms Jacobsen syndrome as a chromosome deletion syndrome able to cause combined immunodeficiency.
    Journal of Clinical Immunology 11/2013; 34(1). DOI:10.1007/s10875-013-9966-2 · 3.18 Impact Factor
  • Acta Haematologica 11/2013; 131(3):167-169. DOI:10.1159/000353758 · 1.12 Impact Factor
  • Solrun Melkorka Maggadottir · Kathleen E. Sullivan
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    ABSTRACT: A 2-year-old boy with chromosome 22q11.2 deletion syndrome was referred for recurrent sinopulmonary infections. He was diagnosed shortly after birth by a fluorescence in situ hybridization test that was performed due to interrupted aortic arch type B. He had no hypocalcemia, and his recovery from cardiac repair was uneventful. He had difficulty feeding and gained weight slowly, but, otherwise, there were no concerns during his first year of life. At 15 months of age, he began to develop significant otitis media and bronchitis. He was hospitalized once for pneumonia at 18 months of age and has never been off antibiotics for more than 1 week since then. He has not had any previous immunologic evaluation. Recurrent sinopulmonary infections in a child with chromosome 22q11.2 deletion syndrome can have the same etiologies as in any other child. Atopy, anatomic issues, cystic fibrosis, and new environmental exposures could be considered in this setting. Early childhood can be problematic for patients with chromosome 22q11.2 deletion syndrome due to unfavorable drainage of the middle ear and sinuses. Atopy occurs at a higher frequency in 22q11.2 deletion syndrome, and these children also have a higher rate of gastroesophageal reflux and aspiration than the general population. As would be appropriate for any child who presents with recurrent infections at 2 years of age, an immunologic evaluation should be performed. In this review, we will highlight recent findings and new data on the management of children and adults with chromosome 22q11.2 deletion syndrome.
    11/2013; 1(6):589–594. DOI:10.1016/j.jaip.2013.08.003
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    ABSTRACT: The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.
    The Journal of allergy and clinical immunology 10/2013; 133(2). DOI:10.1016/j.jaci.2013.07.052 · 11.48 Impact Factor
  • Patrícia Costa-Reis · Lehn K Weaver · Edward M Behrens · Kathleen E Sullivan
    Joint, bone, spine: revue du rhumatisme 09/2013; 81(2). DOI:10.1016/j.jbspin.2013.08.005 · 2.90 Impact Factor
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    ABSTRACT: To examine the effect of chemotherapy for ovarian cancer on immunologic function and to define the effect on the serologic response to the influenza vaccine. Under IRB approved protocols, patients with ovarian cancer were administered seasonal trivalent killed influenza vaccines. Peripheral blood was collected for immunologic assessments. Serum was analyzed for hemagglutination inhibition (HAI) antibody titers. Peripheral blood mononuclear cells were isolated to characterize T and B cell populations and function. Thirty-one patients were recruited: 13 in remission receiving a dendritic cell vaccine with or without a single dose of low-dose cyclophosphamide, 3 in remission not receiving treatment, and 15 undergoing standard therapy. Significant effects on T cell and B cell subset distributions were seen. Functional effects were also seen. Few patients were able to mount a 4-fold HAI antibody response. A 4-fold response was observed for H1N1 in 20%, for H3N2 in 26%, and for influenza B in 6%. Pre-existing exposure to influenza was predictive of responders. Despite CDC recommendations that patients undergoing chemotherapy receive influenza vaccine, there is little evidence to support its serologic effectiveness in this population. Patients with ovarian cancer are almost uniformly unable to mount a meaningful antibody response. These findings have serious implications for future resource allocation for both seasonal and novel pandemic influenza outbreak and understanding the immunologic deficits as a result of chemotherapy may improve patient care.
    Vaccine 09/2013; 31(46). DOI:10.1016/j.vaccine.2013.09.001 · 3.62 Impact Factor
  • Patrícia Costa-Reis · Kathleen E Sullivan
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    ABSTRACT: Genetics unquestionably contributes to systemic lupus erythematosus (SLE) predisposition, progression and outcome. Nevertheless, single-gene defects causing lupus-like phenotypes have been infrequently documented. The majority of the identified genetic SLE risk factors are, therefore, common variants, responsible for a small effect on the global risk. Recently, genome wide association studies led to the identification of a growing number of gene variants associated with SLE susceptibility, particular disease phenotypes, and antibody profiles. Further studies addressed the biological effects of these variants. In addition, the role of epigenetics has recently been revealed. These combined efforts contributed to a better understanding of SLE pathogenesis and to the characterization of clinically relevant pathways. In this review, we describe SLE-associated single-gene defects, common variants, and epigenetic changes. We also discuss the limitations of current methods and the challenges that we still have to face in order to incorporate genomic and epigenomic data into clinical practice.
    Current Rheumatology Reports 09/2013; 15(9):369. DOI:10.1007/s11926-013-0369-4 · 2.87 Impact Factor
  • Soma Jyonouchi · Jordan Orange · Kathleen E Sullivan · Ian Krantz · Matthew Deardorff
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    ABSTRACT: Objectives: Cornelia de Lange syndrome (CdLS) is a genetic syndrome with multisystem abnormalities. Infections are a significant cause of morbidity and mortality. The goals of our study were to identify the frequency and types of infections in CdLS and to determine if underlying immunodeficiency contributes to the clinical spectrum of this syndrome. Methods: We assessed infectious histories in 45 patients with CdLS and evaluated conventional immunologic screening tests in 27 patients. Among these 27 subjects, additional phenotypic enumeration of T-cell subsets, expression of activation markers in T cells, and production of cytokines in response to T-cell stimulants were studied in 12 CdLS subjects compared with 12 normal case control subjects. Results: Recurrent infections were reported at high frequency in CdLS patients and included chronic ear infections (53%), chronic viral respiratory infections (46%), pneumonia (42%), sinus infections (33%), oral candidiasis (13%), sepsis (6%), and bacterial skin infections (4%). Full immune evaluation in 27 subjects led to identification of 9 cases of antibody deficiency syndrome in patients with severe forms of CdLS. Subjects with CdLS had decreased percentages of T regulatory cells and T follicular helper cells compared with normal control subjects (P < .05). Conclusions: This study identified for the first time a high frequency of antibody deficiency in CdLS subjects, indicating a critical need for screening and management of immunodeficiency in CdLS patients with a history of well-documented severe or recurrent infections. Furthermore, our results indicate that impaired T-cell populations may be associated with antibody deficiency in CdLS.
    PEDIATRICS 07/2013; 132(2). DOI:10.1542/peds.2012-3815 · 5.47 Impact Factor
  • Patrícia Costa-Reis · Kathleen E Sullivan
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    ABSTRACT: Chronic recurrent multifocal osteomyelitis is a rare auto-inflammatory condition that primarily affects children and adolescents. It presents with recurrent episodes of pain related to the presence of foci of sterile bone inflammation. The long bones of the lower extremities are more frequently affected and the spine can also be involved. Imaging studies, including whole-body magnetic resonance, are important for diagnosis and detection of asymptomatic lesions. Bone biopsies may be necessary to exclude other diseases, including malignancy and infections. Non-steroidal anti-inflammatory drugs cause relief of symptoms in the majority of cases. Bisphosphonates and TNF-α blockers are alternatives for patients who do not respond or who have spinal involvement.
    Journal of Clinical Immunology 05/2013; 33(6). DOI:10.1007/s10875-013-9902-5 · 3.18 Impact Factor
  • Solrun Melkorka Maggadottir · Kathleen E. Sullivan · Jennifer Heimall
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    ABSTRACT: A 13 year old female presented 2 years ago with episodic CUA, marginally responsive to corticosteroids. Extensive workup was negative for hereditary angioedema, different autoimmune, rheumatological, malignant and infectious conditions. Her CUA initially responded to high dose antihistamines and LTRA but worsened, required hospitalization and was unresponsive to doxepin, accolate, dapsone, cyclosporine, methotrexate and omalizumab. Workup for sinusitis revealed CVID and after 3 IVIG infusions her angioedema resolved. A 16 year old boy with recurrent sinusitis was diagnosed with CVID at age 11 and started IVIG. 4 years later he developed CUA. Extensive workup, as for the girl, was negative. During 2 months of refractory angioedema and ICU care he did not respond to high dose antihistamines, LTRA, corticosteroids, immunomodulatory IVIG doses, icatibant, FFP, omalizumab or berinert. His flares of angioedema continue and he has a tracheostomy for airway protection.The increased incidence of autoimmune disease in CVID is well established. CUA, a common diagnosis, can occur in CVID without relation to the immunodeficiency. 25-50% of CUA patients have auto-antibodies to the high affinity IgE-receptor, however this was not found in our patients. Possibly CVID patients, being prone to autoimmune conditions, have IgG auto-antibodies triggering mast cell and/or basophil activation.
    2013 Clinical Immunology Society Annual Meeting; 04/2013
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    ABSTRACT: Human DOCK8 deficiency is associated with diffuse warts, combined immunodeficiency and malignancy. NK cells serve as an innate defense against virally infected cells and function in tumor surveillance. NK cell cytotoxicity requires reorganization of actin at the lytic NK cell immunologic synapse (IS) formed with target cells. Since DOCK8-deficient patients have severe cutaneous viral infections and malignancy, we hypothesized that NK cell function was abnormal. Ten patients with biallelic DOCK8 mutations as well as NK cell lines with stably reduced DOCK8 expression were evaluated experimentally using in vitro NK cell cytotoxicity, F-actin quantification, and high-resolution analyses of the NK cell IS. Cytolytic function was decreased in DOCK8-deficient patients and cell lines and was not corrected by IL-2 stimulation. Importantly, DOCK8 deficiency did not affect total NK cell filamentous actin content, but abrogated filamentous actin accumulation at the lytic IS. DOCK8 deficiency impairs NK cell function by blocking formation of a mature lytic IS owing to ineffective synaptic actin accumulation. This previously unappreciated defective host defense mechanism may explain the unusual susceptibility to viral infections and related cancers in DOCK8-deficient patients.
    2013 Clinical Immunology Society Annual Meeting; 04/2013
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    ABSTRACT: Dyskeratosis congenita (DC) is a multisystem disease caused by genetic mutations that result in defective telomere maintenance. Herein, we describe a 17-year-old patient with severe DC, manifested by bone marrow failure, severe immunodeficiency, and enterocolitis requiring prolonged infliximab therapy, who developed fatal hepatic failure caused by an aggressive, infiltrating hepatic angiosarcoma. Although DC patients have known increased risk of developing liver failure and multiple types of malignancy, this report is the first to describe angiosarcoma in a DC patient. Malignancy should thus be considered in the differential diagnosis of progressive liver dysfunction in DC patients.
    Journal of Pediatric Hematology/Oncology 04/2013; 36(4). DOI:10.1097/MPH.0b013e318286d4d4 · 0.90 Impact Factor
  • Solrun Melkorka Maggadottir · Kathleen E. Sullivan · Jennifer Heimall
    Journal of Clinical Immunology 04/2013; 33(3):687-687. · 3.18 Impact Factor
  • Journal of Clinical Immunology 04/2013; 33(3):671-671. · 3.18 Impact Factor
  • Kathleen E. Sullivan · Lihua Shi · Li Song
    Journal of Clinical Immunology 04/2013; 33(3):671-672. · 3.18 Impact Factor

Publication Stats

5k Citations
1,093.62 Total Impact Points


  • 1994–2015
    • The Children's Hospital of Philadelphia
      • • Division of Rheumatology
      • • Department of Pediatrics
      • • Division of Human Genetics and Molecular Biology
      Filadelfia, Pennsylvania, United States
  • 1998–2014
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1998–2011
    • University of Pennsylvania
      • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 2003
    • Westat
      Maryland, United States
  • 1993–1997
    • Johns Hopkins University
      • Department of Pediatrics
      Baltimore, Maryland, United States