Sean McGhee

All Publications

• GENETIC AND MECHANISTIC DIVERSITY IN PEDIATRIC HEMOPHAGOCYTIC LYMPHOHISITOCYTOSIS Eckstein, O. S., Chinn, I. K., Peckham-Gregory, E. C., Goldberg, B. R., Forbes, L. R., Nicholas, S. K., Mace, E. M., Vogel, T. P., Abhyankar, H. A., Diaz, M. I., Heslop, H. E., Krance, R. A., Martinez, C. A., Nguyen, T. C., Bashir, D. A., Goldman, J. R., Stray-Pedersen, A., Pedroza, L. A., Cecilia Poli, M., Aldave Becerra, J. C., McGhee, S. A., Al-Herz, W., Chamdin, A., Coban-Akdemir, Z. H., Jhangiani, S. N., Muzny, D. M., Cao, T. N., Hong, D. N., Gibbs, R. A., Lupski, J. R., Orange, J. S., McClain, K. L., Allen, C. E. WILEY. 2019: S11–S12

  View details for Web of Science ID 000449991100022

• Four cases of delayed onset systemic reaction to shellfish JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Huffaker, M., McGhee, S. 2018; 6 (2): 656–57

  View details for PubMedID 28734856

• Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Engelhardt, K. R., McGhee, S., Winkler, S., Sassi, A., Woellner, C., Lopez-Herrera, G., Chen, A., Kim, H. S., Lloret, M. G., Schulze, I., Ehl, S., Thiel, J., Pfeifer, D., Veelken, H., Niehues, T., Siepermann, K., Weinspach, S., Reisli, I., Keles, S., Genel, F., Kutuculer, N., Camcioglu, Y., Somer, A., Karakoc-Aydiner, E., Barlan, I., Gennery, A., Metin, A., Degerliyurt, A., Pietrogrande, M. C., Yeganeh, M., Baz, Z., Al-Tamemi, S., Klein, C., Puck, J. M., Holland, S. M., McCabe, E. R., Grimbacher, B., Chatila, T. A. 2009; 124 (6): 1289-1302

  Abstract

  The genetic etiologies of the hyper-IgE syndromes are diverse. Approximately 60% to 70% of patients with hyper-IgE syndrome have dominant mutations in STAT3, and a single patient was reported to have a homozygous TYK2 mutation. In the remaining patients with hyper-IgE syndrome, the genetic etiology has not yet been identified.We aimed to identify a gene that is mutated or deleted in autosomal recessive hyper-IgE syndrome.We performed genome-wide single nucleotide polymorphism analysis for 9 patients with autosomal-recessive hyper-IgE syndrome to locate copy number variations and homozygous haplotypes. Homozygosity mapping was performed with 12 patients from 7 additional families. The candidate gene was analyzed by genomic and cDNA sequencing to identify causative alleles in a total of 27 patients with autosomal-recessive hyper-IgE syndrome.Subtelomeric biallelic microdeletions were identified in 5 patients at the terminus of chromosome 9p. In all 5 patients, the deleted interval involved dedicator of cytokinesis 8 (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton. Sequencing of patients without large deletions revealed 16 patients from 9 unrelated families with distinct homozygous mutations in DOCK8 causing premature termination, frameshift, splice site disruption, and single exon deletions and microdeletions. DOCK8 deficiency was associated with impaired activation of CD4+ and CD8+T cells.Autosomal-recessive mutations in DOCK8 are responsible for many, although not all, cases of autosomal-recessive hyper-IgE syndrome. DOCK8 disruption is associated with a phenotype of severe cellular immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective T-cell activation and T(h)17 cell differentiation, and impaired eosinophil homeostasis and dysregulation of IgE.

  View details for DOI 10.1016/j.jaci.2009.10.038

  View details for Web of Science ID 000273071500022

  View details for PubMedID 20004785

• Potential costs and benefits of newborn screening for severe combined immunodeficiency JOURNAL OF PEDIATRICS McGhee, S. A., Stiehm, E. R., McCabe, E. R. 2005; 147 (5): 603-608

  Abstract

  Severe combined immunodeficiency (SCID) is a rare, treatable disorder of the immune system. The incidence is unknown but may be more common than published estimates because infants frequently die of infection before diagnosis. SCID is a candidate for universal newborn screening, so there is a need to determine under which circumstances screening would be cost-effective.We assumed a screening program for SCID would use T-cell lymphopenia as the screening criterion and performed a cost-utility analysis comparing universal screening with screening only those with a family history of SCID.Assuming society is willing to pay $50,000 for every quality-adjusted life-year saved, a SCID screening test that cost less than $5 with a false-negative rate of 0.9% and a false-positive rate of 0.4% would be considered cost-effective. A nationwide screening program would cost an additional $23.9 million per year for screening costs but would result in 760 years of life saved per year of screening. The cost to detect 1 case of SCID would be $485,000.SCID screening could result in a large benefit to detected individuals, making screening relatively cost-effective in spite of the low incidence of the disease. However, an adequate test is critical to cost-effectiveness.

  View details for DOI 10.1016/j.jpeds.2005.06.001

  View details for Web of Science ID 000233500000012

  View details for PubMedID 16291349

• Allergic Diseases and Immune-Mediated Food Disorders in Pediatric Acute-Onset Neuropsychiatric Syndrome PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY Rosa, J. S., Hernandez, J. D., Sherr, J. A., Smith, B. M., Brown, K. D., Farhadian, B., Mahony, T., McGhee, S. A., Lewis, D. B., Thienemann, M., Frankovich, J. D. 2018; 31 (3): 158–65

  View details for DOI 10.1089/ped.2018.0888

  View details for Web of Science ID 000445067100006

• Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis BLOOD Chinn, I. K., Eckstein, O. S., Peckham-Gregory, E. C., Goldberg, B. R., Forbes, L. R., Nicholas, S. K., Mace, E. M., Vogel, T. P., Abhyankar, H. A., Diaz, M. I., Heslop, H. E., Krance, R. A., Martinez, C. A., Nguyen, T. C., Bashir, D. A., Goldman, J. R., Stray-Pedersen, A., Pedroza, L. A., Poli, M., Aldave-Becerra, J. C., McGhee, S. A., Al-Herz, W., Chamdin, A., Coban-Akdemir, Z. H., Jhangiani, S. N., Muzny, D. M., Cao, T. N., Hong, D. N., Gibbs, R. A., Lupski, J. R., Orange, J. S., McClain, K. L., Allen, C. E. 2018; 132 (1): 89–100

  Abstract

  The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

  View details for PubMedID 29632024

  View details for PubMedCentralID PMC6034641

• Biologics in pediatric lung disease. Current opinion in pediatrics McGhee, S. A. 2018; 30 (3): 366–71

  Abstract

  PURPOSE OF REVIEW: Although biologic therapies can provide outstanding efficacy in the management of lung disease, especially asthma, most of these agents have been approved only for adults. Recent findings provide new strategies for using these agents in children.RECENT FINDINGS: Extensive evidence has consistently demonstrated the efficacy and safety of biologic therapy for asthma. In addition, some studies have documented potentially important secondary effects, such as improving response to respiratory virus infection in asthmatic patients. Additional strategies for improving asthma control using biologic therapy, such as seasonal administration, have been suggested, and may limit cost while still providing a high degree of efficacy.SUMMARY: Many of the current biologics are able to readily establish control even in asthmatic patients for whom inhaled steroid and long-acting beta agonist have failed. However, biologics currently have limited regulatory approval and availability in the pediatric age range, despite this age being disproportionately affected by asthma. In addition, successful biologics for asthma to date have largely been limited to the Th2-high endotype of asthma, and there is great need for similar medications to target the Th2-low endotype. Other pediatric lung disease might well benefit from the specificity allowed by biologic therapy.

  View details for PubMedID 29538045

• Anaphylaxis to invasive chlorhexidine administration despite tolerance of topical chlorhexidine use JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE Postolova, A., Bradley, J. T., Parris, D., Sherr, J., McGhee, S. A., Hernandez, J. D. 2018; 6 (3): 1067-+

  View details for PubMedID 29226805

• International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Nowak-Wegrzyn, A., Chehade, M., Groetch, M. E., Spergel, J. M., Wood, R. A., Allen, K., Atkins, D., Bahna, S., Barad, A. V., Berin, C., Whitehorn, T. B., Burks, A. W., Caubet, J., Cianferoni, A., Conte, M., Davis, C., Fiocchi, A., Grimshaw, K., Gupta, R., Hofmeister, B., Hwang, J. B., Katz, Y., Konstantinou, G. N., Leonard, S. A., Lightdale, J., McGhee, S., Mehr, S., Sopo, S. M., Monti, G., Muraro, A., Noel, S. K., Nomura, I., Noone, S., Sampson, H. A., Schultz, F., Sicherer, S. H., Thompson, C. C., Turner, P. J., Venter, C., Westcott-Chavez, A. A., Greenhawt, M. 2017; 139 (4): 1111-?

  Abstract

  Food protein-induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; high-quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence-based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available.

  View details for DOI 10.1016/j.jaci.2016.12.966

  View details for Web of Science ID 000398771800005

  View details for PubMedID 28167094

• Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Xia, M., Viera-Hutchins, L., Garcia-Lloret, M., Rivas, M. N., Wise, P., McGhee, S. A., Chatila, Z. K., Daher, N., Sioutas, C., Chatila, T. A. 2015; 136 (2): 441-453

  Abstract

  Traffic-related particulate matter (PM) has been linked to a heightened incidence of asthma and allergic diseases. However, the molecular mechanisms by which PM exposure promotes allergic diseases remain elusive.We sought to determine the expression, function, and regulation of pathways involved in promotion of allergic airway inflammation by PM.We used gene expression transcriptional profiling, in vitro culture assays, and in vivo murine models of allergic airway inflammation.We identified components of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells. PM, especially ultrafine particles, upregulated TH cytokine levels, IgE production, and allergic airway inflammation in mice in a Jag1- and Notch-dependent manner, especially in the context of the proasthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacologic antagonism of AhR or its lineage-specific deletion in CD11c(+) cells abrogated the augmentation of airway inflammation by PM.PM activates an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with proasthmatic alleles.

  View details for DOI 10.1016/j.jaci.2015.02.014

  View details for Web of Science ID 000359004900026

  View details for PubMedID 25825216

  View details for PubMedCentralID PMC4530027

• Long-term Sinonasal Outcomes of Aspirin Desensitization in Aspirin Exacerbated Respiratory Disease OTOLARYNGOLOGY-HEAD AND NECK SURGERY Cho, K., Soudry, E., Psaltis, A. J., Nadeau, K. C., McGhee, S. A., Nayak, J. V., Hwang, P. H. 2014; 151 (4): 575-581

  Abstract

  This study aimed to assess sinonasal outcomes in patients with aspirin exacerbated respiratory disease (AERD) undergoing aspirin desensitization following endoscopic sinus surgery (ESS).Case series with chart review.University hospital.A retrospective review of sinonasal outcomes was conducted for 30 AERD patients undergoing aspirin desensitization and maintenance therapy following ESS. Sinonasal outcomes were prospectively assessed by the Sinonasal Outcomes Test-22 (SNOT-22) and endoscopic polyp grading system. Data were collected preoperatively, 1 and 4 weeks postsurgery (before desensitization), and 1, 6, 12, 18, 24, and 30 months after aspirin desensitization.Twenty-eight of 30 patients (93.3%) successfully completed aspirin desensitization, whereas 2 of 30 (6.7%) were unable to complete desensitization due to respiratory intolerance. Of the 21 patients who successfully completed a minimum of 24 weeks of follow-up, 20 (95.2%) patients demonstrated sustained endoscopic and symptomatic improvement for a median follow-up period of 33 months. After surgical treatment but before desensitization, patients experienced significant reductions in SNOT-22 and polyp grade scores. In the first 6 months after aspirin desensitization, patients experienced further significant reductions in SNOT-22 scores, whereas polyp grade remained stable. The improvements in symptom endoscopic scores were preserved throughout the follow-up period after desensitization. No patients required additional sinus surgery. One patient had to discontinue aspirin therapy due to gastrointestinal side effects. No other adverse reactions to aspirin were noted.Aspirin desensitization following ESS appears to be a well-tolerated and effective adjunctive therapy for long-term control of nasal polyposis in patients with AERD.

  View details for DOI 10.1177/0194599814545750

  View details for Web of Science ID 000342982900008

• Long-term sinonasal outcomes of aspirin desensitization in aspirin exacerbated respiratory disease. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Cho, K., Soudry, E., Psaltis, A. J., Nadeau, K. C., McGhee, S. A., Nayak, J. V., Hwang, P. H. 2014; 151 (4): 575-581

  Abstract

  This study aimed to assess sinonasal outcomes in patients with aspirin exacerbated respiratory disease (AERD) undergoing aspirin desensitization following endoscopic sinus surgery (ESS).Case series with chart review.University hospital.A retrospective review of sinonasal outcomes was conducted for 30 AERD patients undergoing aspirin desensitization and maintenance therapy following ESS. Sinonasal outcomes were prospectively assessed by the Sinonasal Outcomes Test-22 (SNOT-22) and endoscopic polyp grading system. Data were collected preoperatively, 1 and 4 weeks postsurgery (before desensitization), and 1, 6, 12, 18, 24, and 30 months after aspirin desensitization.Twenty-eight of 30 patients (93.3%) successfully completed aspirin desensitization, whereas 2 of 30 (6.7%) were unable to complete desensitization due to respiratory intolerance. Of the 21 patients who successfully completed a minimum of 24 weeks of follow-up, 20 (95.2%) patients demonstrated sustained endoscopic and symptomatic improvement for a median follow-up period of 33 months. After surgical treatment but before desensitization, patients experienced significant reductions in SNOT-22 and polyp grade scores. In the first 6 months after aspirin desensitization, patients experienced further significant reductions in SNOT-22 scores, whereas polyp grade remained stable. The improvements in symptom endoscopic scores were preserved throughout the follow-up period after desensitization. No patients required additional sinus surgery. One patient had to discontinue aspirin therapy due to gastrointestinal side effects. No other adverse reactions to aspirin were noted.Aspirin desensitization following ESS appears to be a well-tolerated and effective adjunctive therapy for long-term control of nasal polyposis in patients with AERD.

  View details for DOI 10.1177/0194599814545750

  View details for PubMedID 25118195

• Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA-the journal of the American Medical Association Kwan, A., Abraham, R. S., Currier, R., Brower, A., Andruszewski, K., Abbott, J. K., Baker, M., Ballow, M., Bartoshesky, L. E., Bonilla, F. A., Brokopp, C., Brooks, E., Caggana, M., Celestin, J., Church, J. A., Comeau, A. M., Connelly, J. A., Cowan, M. J., Cunningham-Rundles, C., Dasu, T., Dave, N., De La Morena, M. T., Duffner, U., Fong, C., Forbes, L., Freedenberg, D., Gelfand, E. W., Hale, J. E., Hanson, I. C., Hay, B. N., Hu, D., Infante, A., Johnson, D., Kapoor, N., Kay, D. M., Kohn, D. B., Lee, R., Lehman, H., Lin, Z., Lorey, F., Abdel-Mageed, A., Manning, A., McGhee, S., Moore, T. B., Naides, S. J., Notarangelo, L. D., Orange, J. S., Pai, S., Porteus, M., Rodriguez, R., Romberg, N., Routes, J., Ruehle, M., Rubenstein, A., Saavedra-Matiz, C. A., Scott, G., Scott, P. M., Secord, E., Seroogy, C., Shearer, W. T., Siegel, S., Silvers, S. K., Stiehm, E. R., Sugerman, R. W., Sullivan, J. L., Tanksley, S., Tierce, M. L., Verbsky, J., Vogel, B., Walker, R., Walkovich, K., Walter, J. E., Wasserman, R. L., Watson, M. S., Weinberg, G. A., Weiner, L. B., Wood, H., Yates, A. B., Puck, J. M. 2014; 312 (7): 729-738

  Abstract

  Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births.To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments.Epidemiological and retrospective observational study.Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test.Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked.Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia.Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.

  View details for DOI 10.1001/jama.2014.9132

  View details for PubMedID 25138334

• Primary Immune Deficiency Treatment Consortium (PIDTC) report. journal of allergy and clinical immunology Griffith, L. M., Cowan, M. J., Notarangelo, L. D., Kohn, D. B., Puck, J. M., Pai, S., Ballard, B., Bauer, S. C., Bleesing, J. J., Boyle, M., Brower, A., Buckley, R. H., van der Burg, M., Burroughs, L. M., Candotti, F., Cant, A. J., Chatila, T., Cunningham-Rundles, C., Dinauer, M. C., Dvorak, C. C., Filipovich, A. H., Fleisher, T. A., Bobby Gaspar, H., Gungor, T., Haddad, E., Hovermale, E., Huang, F., Hurley, A., Hurley, M., Iyengar, S., Kang, E. M., Logan, B. R., Long-Boyle, J. R., Malech, H. L., McGhee, S. A., Modell, F., Modell, V., Ochs, H. D., O'Reilly, R. J., Parkman, R., Rawlings, D. J., Routes, J. M., Shearer, W. T., Small, T. N., Smith, H., Sullivan, K. E., Szabolcs, P., Thrasher, A., Torgerson, T. R., Veys, P., Weinberg, K., Zuniga-Pflucker, J. C. 2014; 133 (2): 335-347 e11

  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.

  View details for DOI 10.1016/j.jaci.2013.07.052

  View details for PubMedID 24139498

• Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: Results of the first 2 years JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Kwan, A., Church, J. A., Cowan, M. J., Agarwal, R., Kapoor, N., Kohn, D. B., Lewis, D. B., McGhee, S. A., Moore, T. B., Stiehm, E. R., Porteus, M., Aznar, C. P., Currier, R., Lorey, F., Puck, J. M. 2013; 132 (1): 140-U245

  Abstract

  Assay of T-cell receptor excision circles (TRECs) in dried blood spots obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID).We sought to report the first 2 years of TREC NBS in California.Since August 2010, California has conducted SCID NBS. A high-throughput TREC quantitative PCR assay with DNA isolated from routine dried blood spots was developed. Samples with initial low TREC numbers had repeat DNA isolation with quantitative PCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked.Of 993,724 infants screened, 50 (1/19,900 [0.005%]) had significant T-cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (n = 11), leaky SCID or Omenn syndrome (n = 3), or complete DiGeorge syndrome (n = 1). Survival to date in this group is 93%. Other T-cell lymphopenic infants had variant SCID or combined immunodeficiency (n = 6), genetic syndromes associated with T-cell impairment (n = 12), secondary T-cell lymphopenia (n = 9), or preterm birth (n = 8). All T-cell lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test, and 0.016% required lymphocyte phenotyping by using flow cytometry.TREC NBS in California has achieved early diagnosis of SCID and other conditions with T-cell lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes, and follow-up of T-cell lymphopenia in a large diverse population.

  View details for DOI 10.1016/j.jaci.2013.04.024

  View details for Web of Science ID 000321052300019

  View details for PubMedID 23810098

• Use and interpretation of diagnostic vaccination in primary immunodeficiency: A working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Orange, J. S., Ballow, M., Stiehm, E. R., Ballas, Z. K., Chinen, J., de la Morena, M., Kumararatne, D., Harville, T. O., Hesterberg, P., Koleilat, M., McGhee, S., Perez, E. E., Raasch, J., Scherzer, R., Schroeder, H., Seroogy, C., Huissoon, A., Sorensen, R. U., Katial, R. 2012; 130 (3): S1-S24

  Abstract

  A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research.

  View details for DOI 10.1016/j.jaci.2012.07.002

  View details for Web of Science ID 000308464300001

  View details for PubMedID 22935624

• Public health comes to immune deficiency BLOOD McGhee, S. A. 2012; 119 (11): 2433-2435

  View details for DOI 10.1182/blood-2011-12-397836

  View details for Web of Science ID 000301941700005

  View details for PubMedID 22422811

• How the practice of allergy shows the promise and challenge of personalized medicine MOLECULAR GENETICS AND METABOLISM McGhee, S. A. 2011; 104 (1-2): 3-6

  Abstract

  Personalized medicine seeks to stratify therapies according to individual characteristics, and by so doing improve effectiveness and reduce complications. However, there are not many models of care that is highly stratified within a single diagnosis in this manner. One potential model is the practice of allergy, in which care is tailored to specific allergens for individual patients within the broader context of care for rhinitis or asthma. Allergists have already confronted many of the same regulatory issues anticipated for personalized medicine. The history of allergy practice also anticipates some of the patient safety concerns that may arise from tracking and using highly personalized medical information. Finally, the therapy of allergy and asthma has been at the forefront of attempts to incorporate pharmacogenomics information into patient care. Individualized therapy has always been central to the practice of allergy, and so provides a useful proving ground for personalized medicine as a concept of care.

  View details for DOI 10.1016/j.ymgme.2011.07.017

  View details for Web of Science ID 000295151300002

  View details for PubMedID 21810545

• DOCK8 immune deficiency as a model for primary cytoskeletal dysfunction DISEASE MARKERS McGhee, S. A., Chatila, T. A. 2010; 29 (3-4): 151-156

  Abstract

  DOCK8 deficiency is a newly described primary immune deficiency resulting in profound susceptibility to cutaneous viral infections, elevated IgE levels, and eosinophilia, but lacking in the skeletal manifestations commonly seen in hyper IgE syndrome, which it otherwise resembles. Although little is known about the DOCK8 protein, it resembles other atypical guanine exchange factors in the DOCK family, and is known to bind to CDC42. This suggests that a likely role for DOCK8 is in modulating signals that trigger cytoskeletal reorganization. As a result, DOCK8 may also be related to other immune deficiencies that involve the cytoskeleton and Rho GTPase signaling pathways, such as Wiskott-Aldrich syndrome and Rac2 deficiency.

  View details for DOI 10.3233/DMA-2010-0740

  View details for Web of Science ID 000285458400005

  View details for PubMedID 21178274

• Immunologic reconstitution in 22q deletion (DiGeorge) syndrome IMMUNOLOGIC RESEARCH McGhee, S. A., Lloret, M. G., Stiehm, E. R. 2009; 45 (1): 37-45

  Abstract

  Adoptive transfer of mature T cells (ATMTC) through bone marrow (BM) transplantation, first attempted over 20 years ago, has recently emerged as a successful therapy for complete 22q deletion syndrome (22qDS). This provides a potential option to thymic transplantation (TT) for immune reconstitution in 22qDS. Compared to thymic transplant, ATMTC is an easier procedure to accomplish and is available at more centers. However, there are differences in the nature of the T-cell reconstitution that results. Predictably, more naïve T cells and recent thymic emigrants are present in patients treated with thymus transplant. There are no significant differences in mortality between the two procedures, but the number of patients is too limited to conclude that the procedures are equally effective. Adoptive transfer should be pursued as a reasonable treatment for 22qDS patients requiring immune reconstitution when thymus transplant is not available.

  View details for DOI 10.1007/s12026-009-8108-7

  View details for Web of Science ID 000269904000004

  View details for PubMedID 19238335

• Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Al Khatib, S., Keles, S., Garcia-Lioret, M., Koc-Aydiner, E. K., Reisli, I., Artac, H., Camcioglu, Y., Cokugras, H., Somer, A., Kutukculer, N., Yilmaz, M., Ikinciogullari, A., Yegin, O., Yueksek, M., Genel, F., Kucukosmanoglu, E., Baki, A., Bahceciler, N. N., Rambhatla, A., Nickerson, D. W., McGhee, S., Barlan, I. B., Chatila, T. 2009; 124 (2): 342-348

  Abstract

  The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation.To elucidate mechanisms underlying different forms of HIES.A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively.Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps.In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.

  View details for DOI 10.1016/j.jaci.2009.05.004

  View details for Web of Science ID 000268860400023

  View details for PubMedID 19577286

• Immunoglobulin Replacement Therapy in Children IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Garcia-Lloret, M., McGhee, S., Chatila, T. A. 2008; 28 (4): 833-849

  Abstract

  The benefit of immunoglobulin (IG) replacement in primary antibody deficiencies is unquestionable. Many of these congenital disorders present early in life and this therapy is often first implemented in the young. This article focuses on the indications of IG replacement in children, with an emphasis on the specific diagnostic problems encountered in this population. Also presented is an overview of the practical aspects of IG administration in the pediatric setting, including the recognition and management of adverse reactions. Finally, the advent of subcutaneous IG, a therapeutic IG modality with the potential to have a great impact on the quality of life of children with antibody deficiencies and their families, is discussed.

  View details for DOI 10.1016/j.iac.2008.07.001

  View details for Web of Science ID 000261161800010

  View details for PubMedID 18940577

• Representational oligonucleotide microarray analysis (ROMA) and comparison of binning and change-point methods of analysis: Application to detection of de122q11.2 (DiGeorge) syndrome HUMAN MUTATION Stanczak, C. M., Chen, Z., Nelson, S. E., Suchard, M., McCabe, E. R., McGhee, S. 2008; 29 (1): 176-181

  Abstract

  DiGeorge (del22q11.2) syndrome is estimated to occur in 1:4,000 births, is the most common contiguous-gene deletion syndrome in humans, and is caused by autosomal dominant deletions in the 22q11.2 DiGeorge syndrome critical region (DGCR). Multiple microarray methods have been developed recently for analyzing such copy number changes, but data analysis and accurate deletion detection remains challenging. Clinical use of these microarray methods would have many advantages, particularly when the possibility of a chromosomal disorder cannot be determined simply on the basis of history and physical examination data alone. We investigated the use of the microarray technique, representational oligonucleotide microarray analysis (ROMA), in the detection of del22q11.2 syndrome. Genomic DNA was isolated from three well-characterized cell lines with 22q11.2 DGCR deletions and from the blood of a patient suspected of having del22q11.2 syndrome, and analyzed using both the binning and change-point model algorithms. Though the 22q11.2 deletion was easily identified with either method, change-point models provide clearer identification of deleted regions, with the potential for fewer false-positive results. For circumstances in which a clear, a priori, copy-number change hypothesis is not present, such as in many clinical samples, change-point methods of analysis may be easier to interpret.

  View details for DOI 10.1002/humu.20593

  View details for Web of Science ID 000252143300024

  View details for PubMedID 17694540

• Long-term results of bone marrow transplantation in complete DiGeorge syndrome JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Land, M. H., Garcia-Lloret, M. I., Borzy, M. S., Rao, P. N., Aziz, N., McGhee, S. A., Chen, K., Gorski, J., Stiehm, E. R. 2007; 120 (4): 908-915

  Abstract

  Therapeutic options for DiGeorge syndrome (DGS) with profound T-cell deficiency are very limited. Thymic transplantation has shown promising results but is not easily available. Hematopoietic cell transplantation (HCT) has been successful in restoring immune competence in the short term.Present the long-term follow-up of 2 patients with complete DGS who received bone marrow transplants in the neonatal period from HLA-matched siblings, and perform a multicenter survey to document the status of other patients with DGS who have undergone HCT.Immune function assessment by immunophenotyping, lymphocyte proliferation, T-cell receptor excision circles, single nucleotide polymorphism mapping arrays, spectratyping, cytogenetics, and fluorescence in situ hybridization were used.Among reported patients with DGS receiving HCT, survival is greater than 75%. Our patients are in their 20s and in good health. Their hematopoietic compartment shows continuous engraftment with mixed chimerism, normal T-cell function, and humoral immunity. Circulating T cells exhibit a memory phenotype with a restricted repertoire and are devoid of T-cell receptor excision circles.These features suggest that T-cell reconstitution has occurred predominantly through expansion of the donors' mature T-cell pool. Although restricted, their immune systems are capable of providing substantial protection to infection and respond to vaccines. We conclude that bone marrow transplant achieves long-lived reconstitution of immune function in complete DGS and is a good alternative to thymic transplantation in patients with a suitable donor.Bone marrow transplant in complete DGS using an HLA-matched sibling donor provides long-lasting immunity and is a suitable and more available alternative to thymic transplantation.

  View details for DOI 10.1016/j.jaci.2007.08.048

  View details for Web of Science ID 000250157700027

  View details for PubMedID 17931564

• Genome-wide testing: Genomic medicine PEDIATRIC RESEARCH McGhee, S. A., McCabe, E. R. 2006; 60 (3): 243-244

  View details for DOI 10.1203/01.pdr.0000233116.85413.cd

  View details for Web of Science ID 000239861300001

  View details for PubMedID 16923947

• Two-tiered universal newborn screening strategy for severe combined immunodeficiency MOLECULAR GENETICS AND METABOLISM McGhee, S. A., Stiehm, E. R., Cowan, M., Krogstad, P., McCabe, E. R. 2005; 86 (4): 427-430

  Abstract

  Outcomes for infants with severe combined immunodeficiency (SCID) would be improved by universal newborn screening, but there are not yet screening tests of sufficient accuracy for the disorder. In a pilot study, we assessed the ability of a two-tiered strategy to improve accuracy. Dried blood samples from patients were assessed with two tests for lymphopenia: interleukin-7, a T-cell growth cytokine, and TRECs, a byproduct of T-cell receptor recombination. IL-7 screening has a specificity of 96.1% and TRECs have a specificity of 92.3%. Combining these tests in a two-tiered strategy increases specificity to 100% (97-100% CI). Sensitivity was 85% for IL-7 screening and 100% for TREC screening. A two-tiered strategy may be of sufficient accuracy to enable universal SCID screening, and should be assessed in a prospective trial.

  View details for DOI 10.1016/j.ymgme.2005.09.005

  View details for Web of Science ID 000234282500002

  View details for PubMedID 16260163

• Persistent parvovirus-associated chronic fatigue treated with high dose intravenous immunoglobulin PEDIATRIC INFECTIOUS DISEASE JOURNAL McGhee, S. A., Kaska, B., Liebhaber, M., Stiehm, E. R. 2005; 24 (3): 272-274

  Abstract

  We report a 16-year-old boy with no evidence of immunodeficiency who had a 2-year history of chronic fatigue, low grade fever and slapped-cheek rash associated with chronic parvovirus B19 viremia. Prolonged intravenous immunoglobulin therapy resulted in resolution of his symptoms and viremia. Intravenous immunoglobulin may be useful in the resolution of parvovirus viremia regardless of immune status.

  View details for DOI 10.1097/01.inf.0000155194.66797.20

  View details for Web of Science ID 000227567700017

  View details for PubMedID 15750469

• Role of nonspecific cross-reacting antigen, a CD66 cluster antigen, in activation of human granulocytes INFECTION AND IMMUNITY Klein, M. L., McGhee, S. A., Baranian, J., Stevens, L., Hefta, S. A. 1996; 64 (11): 4574-4579

  Abstract

  Nonspecific cross-reacting antigen (NCA) is the name of a family of highly glycosylated bacterial-binding receptors found on human granulocytes and other tissues. These glycoproteins are members of the immunoglobulin supergene family and are related structurally to carcinoembryonic antigen. In this study, we demonstrate that ligation of granulocyte NCA results in the activation of the cells, as measured by degranulation and the flux of intracellular calcium. These studies further the proposition that NCA has a function in the immune response of granulocytes against bacterial infections.

  View details for Web of Science ID A1996VP42800024

  View details for PubMedID 8890209

• PERMEABILIZATION, STAINING AND CULTURE OF LIVING DROSOPHILA EMBRYOS BIOTECHNIC & HISTOCHEMISTRY STRECKER, T. R., McGhee, S., Shih, S., Ham, D. 1994; 69 (1): 25-30

  Abstract

  The organic solvent octane has been used routinely to permeabilize the hydrophobic vitelline membrane surrounding the Drosophila embryo, thereby allowing the movement of small molecules into the egg. We present evidence that hexane is a more effective permeabilizing agent than octane and compare the effects of these solvents on uniformity of permeabilization and embryonic viability. The ability of each solvent to make the embryo accessible to a range of biological stains was compared. The effect of octane versus hexane permeabilization on subsequent embryonic viability was measured at seven different stages during early embryogenesis. We found that although hexane is a superior solvent for permeabilizing the vitelline membrane, it decreases the viability of embryos exposed between 0 and 3 hr of age. Older embryos treated with either hexane or octane are usually viable. We also showed that molecules with a molecular mass of 984 Daltons or more did not diffuse into the embryo following treatment with either hexane or octane. Results presented here challenge a phase-partition model that has been proposed previously to explain the molecular basis of permeabilization of the Drosophila egg. An alternative model is described as well as an optimized protocol for permeabilizing and staining Drosophila embryos at any stage during early embryogenesis while maintaining viability for subsequent culture.

  View details for Web of Science ID A1994MU12300004

  View details for PubMedID 7511938