Disclosures. Learning objectives. Case 1

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1 Disclosures Newborn screening for immune deficiency disorders: what have we learned so far? Anthony J. Infante, MD, PhD Professor, Pediatrics (Immunology & Infectious diseases) and Microbiology & Immunology, UTHSCSA No connections with commercial ventures relevant to this topic Consulting immunologist, Texas DSHS Newborn Screening Programs Learning objectives Case 1 Review the rationale for implementation of newborn screening for SCIDS Summarize the results of adding SCIDS to state newborn screening (NBS) panels Discuss whether newborn screening for other immune deficiency disorders may be warranted 7 mo. old boy, recently emigrated from India, parents contracted to work at large local business Presented to ER with fever, deltoid abscess, axillary lymphadenopathy Returned to ER with inability to bear weight on left leg Laboratory CBC ALC: 216 cells/mm 3 Lymphocyte subsets CD3: 6 cells/mm 3 ; CD4: 2; CD8: 0; CD19: 1, CD16/56: 189 HIV1/2 Negative Immunoglobulins IgA undetectable, IgM undetectable, IgG 140 mg/dl CSF 83 WBCs/mm 3, 50% PMNs, 42% MNCs, 2% L; protein 48 mg/dl; glucose 49 mg/dl Imaging Chest x ray Brain & spine MRI Chest, abdomen, pelvis CT Normal 8 mm lesion in right cerebral peduncle; prominent abnormal T2 weighted signal at cord T11 level on the left; additional abnormal signal and contrast enhancement of several nerve roots Enlarged lymph nodes: left supraclavicular, left axilla, retroperitoneal 1

2 MRI Microbiology Blood CSF Stool No bacterial growth at 48 hrs.; later positive for AFB identified as M. bovis/bcg Negative bacterial meningitis screen and gram stain; negative fungal smear and culture; negative PCR for HSV 1 and 2, CMV Enterovirus isolated; identified as ivdpv1 Lymph node FNA AFB stain positive; identified as M. bovis/bcg Case 1 Genetic diagnosis of RAG 1 deficient SCIDS Vaccine associated paralytic polio (VAPP) BGG osis Family history of consanguinity and early infant death After meeting with several consultants and ethics committee, parents decided to withdraw life support India declared free of endemic polio in 2012; can expect VDPP cases with continued OPV use SCIDS: Definition Clinical Presentations Severe Fatal if untreated Combined Reduced numbers and/or function of both T and B cells Immune Deficiency Very reduced or absent immune function Opportunistic and other serious infections Syndromes Multiple genetic defects Opportunistic infections CMV retinitis Pneumocystis jirovecii pneumonia Viral pneumonia Infections derived from live viral vaccines Oral thrush Skin rash Potentially due to maternal engrafted T cells Failure to thrive +/ diarrhea Family history 2

3 Definitive Diagnosis Survival benefit from early treatment Clinical history, especially opportunistic infection Lymphocyte subsets by flow cytometry Low or absent T cells (typically <300) Genetic analysis for candidate gene mutations Buckley, JACI 2012 Impact of age largely a result of pre existing infections Cost savings of early treatment Pai, et al. N Engl J Med, 2014 Buckley, JACI 2012 Newborn screening options for SCIDS CBC and diff Flow cytometry PCR & sequencing of candidate genes More than a dozen at last count RT PCR for TRECs Byproduct of TCR gene rearrangement Stable, episomal DNA Absent or reduced in most genetic forms of SCIDS 3

4 TRECs: T Cell Receptor Excision Circles TRECs performance from Guthrie cards Guthrie cards from infants later found to have SCIDS Puck, JACI 2012 Puck, JACI 2012 You Should Take the Following Actions: Contact family to inform them of the positive SCID screening results, ascertain clinical status, and refer to an immunologist. If the infant has any signs of illness, refer to a pediatric hospital right away for evaluation. Well infants may stay at home safely during preliminary diagnostic testing as they have some protection from maternal antibodies. Infants with congenital or neonatal infections should be immediately evaluated by an immunologist (see attached list). Avoid exposing patient to illness pending completion of testing. If the infant requires transfusion of any blood products, be sure that only leukoreduced, irradiated products that are negative for cytomegalovirus (CMV) are used. The Primary Care Physician should obtain: CBC with differential and chest x ray TX SCIDS ACT Form DO NOT give live attenuated rotavirus vaccine, which could cause serious diarrhea in a baby with SCID. This vaccine is to be given only after an immunology specialist confirms that the baby s immune system is normal. Consult with a specialist in pediatric immunodeficiency diseases (a pediatric immunologist) who will assist with further testing. Provide the family with basic information about SCID and T cell lymphopenia Repeat newborn screen if second screen has not been done. Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States Antonia Kwan, PhD, MRCPCH 1,2 ; Roshini S. Abraham, PhD 3 ; Robert Currier, PhD 4 ; Amy Brower, PhD 5 ; Karen Andruszewski, BS 6 ; Jordan K. Abbott, MD 7 ; Mei Baker, MD 8,9 ; Mark Ballow, MD 10 ; Louis E. Bartoshesky, MD 11 ; Francisco A. Bonilla, MD, PhD 12,13 ; Charles Brokopp, DrPH 14 ; Edward Brooks, MD 15 ; Michele Caggana, ScD 16 ; Jocelyn Celestin, MD 17 ; Joseph A. Church, MD 18,19 ; Anne Marie Comeau, PhD 20,31 ; James A. Connelly, MD 21 ; Morton J. Cowan, MD 1,2 ; Charlotte Cunningham Rundles, MD 22 ; Trivikram Dasu, PhD 23 ; Nina Dave, MD 24 ; Maria T. De La Morena, MD 25 ; Ulrich Duffner, MD 26 ; Chin To Fong, MD 27 ; Lisa Forbes, MD 28,29 ; Debra Freedenberg, MD 30 ; Erwin W. Gelfand, MD 7 ; Jaime E. Hale, BS 20 ; I. Celine Hanson, MD 28,29 ; Beverly N. Hay, MD 31 ; Diana Hu, MD 32 ; Anthony Infante, MD, PhD 15 ; Daisy Johnson, BSN 30 ; Neena Kapoor, MD 18,19 ; Denise M. Kay, PhD 16 ; Donald B. Kohn, MD 33 ; Rachel Lee, PhD 30 ; Heather Lehman, MD 10 ; Zhili Lin, PhD 34 ; Fred Lorey, PhD 4 ; Aly Abdel Mageed, MD, MBA 26 ; Adrienne Manning, BS 35 ; Sean McGhee, MD 36,37 ; Theodore B. Moore, MD 33 ; Stanley J. Naides, MD 38 ; Luigi D. Notarangelo, MD 12,13 ; Jordan S. Orange, MD 28,29 ; Sung Yun Pai, MD 12,13 ; Matthew Porteus, MD, PhD 36,37 ; Ray Rodriguez, MD, JD, MPH, MBA 24 ; Neil Romberg, MD 39 ; John Routes, MD 40 ; Mary Ruehle, MS 41 ; Arye Rubenstein, MD 42 ; Carlos A. Saavedra Matiz, MD 16 ; Ginger Scott, RN 30 ; Patricia M. Scott, MT 43 ; Elizabeth Secord, MD 41 ; Christine Seroogy, MD 44 ; William T. Shearer, MD, PhD 28,29 ; Subhadra Siegel, MD 45 ; Stacy K. Silvers, MD 46 ; E. Richard Stiehm, MD 33 ; Robert W. Sugerman, MD 46 ; John L. Sullivan, MD 31 ; Susan Tanksley, PhD 30 ; Millard L. Tierce IV, DO 41 ; James Verbsky, MD, PhD 40 ; Beth Vogel, MS 16 ; Rosalyn Walker, MD 24 ; Kelly Walkovich, MD 21 ; Jolan E. Walter, MD, PhD 47,48 ; Richard L. Wasserman, MD, PhD 46 ; Michael S. Watson, MS, PhD 5 ; Geoffrey A. Weinberg, MD 27 ; Leonard B. Weiner, MD 49 ; Heather Wood, MS 6 ; Anne B. Yates, MD 24 ; Jennifer M. Puck, MD 1,2 JAMA. 2014;312(7): doi: /jama Results Infants born from January 2008 through 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. 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 4

5 Conclusions Case 2 SCIDS is about twice as frequent as previously estimated (guessed) TRECs forms the basis for robust NBS No subsequent SCIDS cases diagnosed in states implementing screening Screening allows realization of expected survival advantage of early detection 10 month old boy transferred for neuro rehab PMH S. pneumo meningitis age 4 mos., recovered S. pneumo meningitis age 9 mos., devastated Immunizations up to date Hypogammaglobulinemia noted Very low B cells in blood BTK mutation detected Dx: X linked agammaglobulinemia (XLA) Quantitative Immunoglobulins IgG: 132 mg/dl ( ) IgA: <1 mg/dl (16 83) IgM: <5 mg/dl (39 142) Flow Cytometry WBC: th/mm 3 Lymph%: 34.1 (L) 44 74% Lymph #: 3410 (L) /mm 3 CD3%: (H)55 82% CD3#: 3101 (L) /mm3 CD3/8%: CD3/8#: /mm3 CD3/4%: (H)49 55% CD3/4#: 2350 (L) /mm3 CD4:CD8 Ratio: CD16+56%: % CD16+56# /mm3 CD19% 0.2 (L) 11 45% CD19# 7 (L) /mm3 A Devastating Outcome in Undiagnosed X Linked Agammaglobulinemia A Call for Earlier Screening Karen E. Bruner, MD 1, Anthony J. Infante, MD, PhD 2 1 Wilford Hall Ambulatory Surgical Center, Joint Base San Antonio, 2 University of Texas Health Sciences Center San Antonio Trainee poster award, 2 nd place, ACAI, 2014 Severe bacterial infections (pneumonia, sepsis, meningitis, osteomyelitis) may occur in a normal child, a second occurrence should alert the physician to possible immunodeficiency. Conley & Stiehm, Immunologic Disorders in Infants & Children, 4 th edition, Effects of vaccination Should this advice be modified in the era of highly effective bacterial vaccines for H. influenzae, S. pneumoniae, N. meinigitidis? 5

6 Delay in diagnosis common in XLA XLA in children hospitalized for community acquired pneumonia 254 subjects (131 males) median age 4.5 years Screened for hypogammaglobulinemia 2 boys found to have genetically confirmed XLA Proposal: screen all boys <5 yo with CAP Vancikova, et al. Klin Padiatr, 2013 NBS for XLA? Techniques for NBS in XLA Avoid rare but devastating outcomes Prevent bronchiectasis Reduce hospitalizations for CAP? Ig levels Flow cytometry Candidate gene mutation analysis RT PCR based assay KRECs: B cell equivalent of TRECs 6

7 Multiplex RT PCR for TRECs and KRECs Summary Statewide newborn screening has been successfully implemented for SCIDS Expected results of early SCIDS detection appear to be realized XLA can have adverse consequences when diagnosis is delayed Newborn screening for XLA is feasible and may be warranted Borte, et al. Blood, 2012 References Clinic referrals SCIDS Polio Trimble, et al. MMWR Weekly 2014; 63(33): SCIDS NBS Kwan, et al. JAMA 2014; 312(7): SCIDS BMT outcomes Pai, et al. N Engl J Med 2014; 371: XLA in CAP Vancikova, et al. Klin Pediatr 2013; 225(6); NBS for T & B disorders Borte, et al. Blood 2012; 119(11); Immune deficiency, incl. newborn screen evals University Hospital Pediatrics Hematology/Oncology & Infusion Center, 10 th floor, Horizon Tower, Rheumatology UHS Robert B. Green Clinic, 6 th floor, 358 KIDS (5437) UTHSCSA Office