1227CHAPTER 103 Congenital Immunodeficiency In addition to evaluating antibody quantity and quality, it is essential to determine whether patients have normal B cell num bers by evaluating lymphocyte[.]
CHAPTER 103 Congenital Immunodeficiency In addition to evaluating antibody quantity and quality, it is essential to determine whether patients have normal B-cell numbers by evaluating lymphocyte subsets The use of more detailed B-cell immunophenotyping to evaluate B-cell development, the presence of CD271 memory B cells, and the ability of memory B cells to undergo immunoglobulin class switching has become standard of care in many clinics, as it provides valuable diagnostic and prognostic information.105 Flow cytometry testing to assess the expression of specific proteins that are defective in B-cell and antibody deficiency disorders—including BTK, CD40 ligand, CD40, ICOS, CD27, BAFF receptor, and so on—can be performed in specialty laboratories and offer the ability to rapidly obtain a molecular diagnosis This is typically supplemented by sequencing of specific genes Diagnostic Testing: T Cells T-cell testing begins with determination of whether the absolute lymphocyte count is normal and assessment of lymphocyte subsets (CD41, CD81, CD561, CD162, CD191, Treg) Gross Tcell function can be ascertained beginning with T-cell proliferation assays Vaccine responses with tetanus or diphtheria can also be quantified Diagnosis of specific T-cell defects are usually made with flow cytometry to demonstrate alteration or absence of some lymphocyte protein or focused genetic testing Interrogation of specific T-cell subsets and activation can also be used to identify poorly functioning T-cell pathways Treatment of Immune System Disorders Treatment: Complement Patients with complement deficiency are susceptible to fulminant sepsis and other deep-seated infections caused by encapsulated organisms For this reason, patients should be given a letter, laminated card, medical alert bracelet/necklace, or Health Data “Me” app that they can keep with them at all times with contact information for their primary care physician and clinical immunologist and a message indicating that they have a complement deficiency The message should emphasize that there should be no delay in giving parenteral antibiotics should they be ill For patients who live at a distance from skilled medical care, consideration should be given to providing a dose of parenteral antibiotic, such as ceftriaxone, that can be administered by the patient or a family member when they become ill, before a lengthy trip to the hospital The efficacy of chronic prophylactic antibiotics to prevent infection in patients with complement deficiency is not well studied and remains a significant question in this group of disorders In addition to preparing for and treating infections, patients should also be regularly screened for autoimmunity by history, physical examination (i.e., blood pressure monitoring), and laboratory testing—including blood urea nitrogen, creatinine, and urinalysis—to monitor for signs of glomerulonephritis because this is a common autoimmune manifestation Treatment: Phagocytes As noted earlier, management of phagocytic disorders revolves around having a heightened suspicion for infections, aggressively treating acute infections using antibiotics and G-CSF as needed and developing a prophylaxis regimen that is both effective and 1227 reasonable from a patient standpoint At times, patients continue to have recurrent or severe infections despite these efforts and require more definitive therapy As indicated earlier, HSCT has been shown to be effective in many, but not all, phagocytic disorders Gene therapy has been attempted for both X-linked CGD106 and for LAD-I,107 but neither has been particularly successful thus far and at this point is considered to be experimental Ongoing research to address the challenges of gene therapy that are unique to these two disorders is underway Treatment: B Cells and Antibodies Immunoglobulin Replacement In patients with antibody deficiency, replacement of IgG is critical to maintaining health and preventing long-term complications associated with recurrent infections Immunoglobulin replacement therapy has been found to be effective when administered intravenously (IVIg), subcutaneously (SCIg), and intramuscularly (IMIg) US Food and Drug Administration–approved products support administration via any of these routes With that said, because of significant discomfort associated with IMIg administration, this route is rarely used in North America Most patients are maintained on either IVIg or SCIg depending on patient preference and provider recommendations related to each patient’s clinical need Because the half-life of IgG in the circulation is approximately 21 days under normal circumstances, IVIg is typically administered every to weeks, providing high peak levels followed by a decline over the ensuing weeks to a trough before the next infusion In contrast, SCIg is typically administered to times per week in smaller doses, providing a more steady-state level of IgG in the circulation IgG products are prepared from the pooled plasma collected from thousands of healthy donors and therefore contain a broad range of antibodies A reasonable starting dose of either IVIg or SCIg is 400 to 600 mg/kg per month This can be divided into the number of doses required to administer the necessary monthly volume (IgG preparations range in concentration from g/100 mL [5%] to 20 g/100 mL [20%]) In most patients, a trough IgG level of 600 mg/dL in the blood is a reasonable initial minimum target However, the dose should then be adjusted to achieve a trough IgG level that prevents both acute infections and development of progressive lung disease There is evidence that, at least for bacterial pneumonia, higher IgG trough levels are directly correlated with a decreased risk of infection.108 Supplemental IgG is generally effective at preventing lower respiratory tract infections (bronchitis and pneumonia), but the response of upper tract disease (particularly sinusitis) is more variable Some patients have persistent sinus symptoms that can be a significant clinical problem despite IgG therapy In these patients, the addition of prophylactic macrolide therapy or increasing the frequency or dose of IgG infusions may be beneficial Side effects with IVIg therapy are relatively common, occurring in up to 25% of treated patients.109 These include headaches, nausea, vomiting, chills, fatigue, fever, rash, and aseptic meningitis These can often be managed by changing the IgG product being used; pretreating with diphenhydramine, acetaminophen, and corticosteroids before infusion; by augmenting hydration; or slowing the rate of infusion Patients who have persistent symptoms despite these measures will often tolerate subcutaneous IgG supplementation Side effects with SCIg are rarer and consist mainly of transient local inflammatory reactions 1228 S E C T I O N X I Pediatric Critical Care: Immunity and Infection Prophylactic Antibiotics It has been increasingly recognized that in many patients with antibody deficiency, replacement of IgG (even to normal levels) may not prevent all clinically significant infections The addition of prophylactic antibiotics has been used as an adjunct to IgG therapy to try to improve control of infections and decrease morbidity Unfortunately, to date there have been no wellperformed studies that argue strongly either for or against the use of prophylactic antibiotics to improve outcomes Further studies are needed to clarify the role of prophylactic antibiotics and to define the optimal regimen stem cell sources have been tried, including matched bone marrow, matched peripheral blood, cord blood, and haploidentical Lastly, a variety of prophylactic immunosuppressive regimens have been used in the early posttransplant period to limit GVHD and prevent graft rejection Each option has advantages and disadvantages, which has led to the spectrum of transplant regimens that have been attempted for SCID Current efforts are underway to assess which regimens offer the best outcomes and lowest risk.110–113 Treatment: T Cells Amaya-Uribe L, Rojas M, Azizi G, Anaya JM, Gershwin ME Primary immunodeficiency and autoimmunity: A comprehensive review J Autoimmun 2019;99:52-72 Bonilla FA, Barlan I, Chapel H, et al International Consensus Document (ICON): Common Variable Immunodeficiency Disorders J Allergy Clin Immunol Pract 2016;4:38-59 Dotta L, Tassone L, Badolato R Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome Curr Mol Med 2011;11:317-325 Frank MM Complement deficiencies Pediatr Clin North Am 2000;47: 1339-1354 Hanna S, Etzioni A Leukocyte adhesion deficiencies Ann N Y Acad Sci 2012;1250:50-55 Hussain A, Yu L, Faryal R, et al TEC family kinases in health and disease–loss-of-function of BTK and ITK and the gain-of-function fusions ITK-SYK and BTK-SYK FEBS J 2011;278:2001-2010 Lee WI, Torgerson TR, Schumacher MJ, et al Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome Blood 2005;105:1881-1890 Mamcarz E, Zhou S, Lockey T, et al Lentiviral gene therapy combined with low-dose busulfan in infants with SCID-X1 N Engl J Med 2019;380:1525-1534 Notarangelo L, Casanova JL, Conley ME, et al Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005 J Allergy Clin Immunol 2006;117:883-896 Resnick ES, Moshier EL, Godbold JH, et al Morbidity and mortality in common variable immune deficiency over decades Blood 2012; 119:1650-1657 Rezaei N, Moazzami K, Aghamohammadi A, Klein C Neutropenia and primary immunodeficiency diseases Int Rev Immunol 2009;28: 335-366 Segal BH, Leto TL, Gallin JI, et al Genetic, biochemical, and clinical features of chronic granulomatous disease Medicine (Baltimore) 2000;79:170-200 Kuhns DB, Alvord WG, Heller T, et al Residual NADPH oxidase and survival in chronic granulomatous disease N Engl J Med 2010; 363:2600-2610 SCID was uniformly lethal in the first years of life until Good and colleagues successfully reconstituted an affected infant with a transplant of sibling bone marrow Experience in subsequent years has shown that patients with B-cell2positive SCID (IL2RG, JAK3, IL7RA, etc.) readily reconstitute their T-cell deficiency but may not develop significant B-cell chimerism The reasons for this are not entirely understood, but various hypotheses have been put forward From a practical standpoint, a lack of donor B-cell engraftment may lead to a chronic need for IgG replacement therapy even after transplant because patients may not be able to mount sufficient antibody responses Patients with B-cell2 negative SCID are more likely to have successful donor engraftment of both T- and B-cell lineages and more likely to recover full humoral immune function One of the most significant challenges in the treatment of SCID is that in the absence of family history, most patients come to attention because of infections These are most commonly PJ pneumonia and severe viral infections (see earlier discussion) PJ pneumonia can be treated but may lead to lung damage, whereas viral infections may or may not be controllable In addition, many SCID infants have significant diarrhea and weight loss by the time they reach a transplantation center Together, these complications increase the risk of adverse outcomes during transplantation for SCID and have been the major impetus for adding SCID to state newborn screening panels Initial management before transplantation involves aggressive supportive care, antimicrobials to treat any intercurrent infections (bacterial, viral, and fungal), antimicrobial prophylaxis to prevent future infections, and IgG replacement therapy There is significant debate about the best pretransplant conditioning regimen for patients with SCID to balance safety and efficacy In general, those patients that have a matched sibling donor receive no conditioning before receiving unmanipulated bone marrow For other patients, a variety of conditioning regimens have been tried, ranging from no conditioning to fully myeloablative regimens Similarly, a range of manipulated and unmanipulated Key References The full reference list for this chapter is available at ExpertConsult.com e1 References Notarangelo L, Casanova JL, Conley ME, et al Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005 J Allergy Clin Immunol 2006;117:883-896 Cossu F Genetics of SCID Ital J Pediatr 2010;36:76 Leiva LE, Zelazco M, Oleastro M, et al Primary immunodeficiency diseases in Latin America: the second report of the LAGID registry J Clin Immunol 2007;27:101-108 Frank MM Complement deficiencies Pediatr Clin North Am 2000;47:1339-1354 Hofer J, Janecke AR, Zimmerhackl LB, et al Complement factor H-related protein deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome Clin J Am Soc Nephrol 2013;8:407-415 Joseph C, Gattineni J Complement disorders and hemolytic uremic syndrome Curr Opin Pediatr 2013;25:209-215 Westra D, Vernon KA, Volokhina EB, et al Atypical hemolytic uremic syndrome and genetic aberrations in the complement factor H-related gene J Hum Genet 2012;57:459-464 Kawalec P, Holko P, Paszulewicz A, et al Administration of conestat alfa, human C1 esterase inhibitor and icatibant in the treatment of acute angioedema attacks in adults with hereditary angioedema due to C1 esterase inhibitor deficiency Treatment comparison based on systematic review results Pneumonol Alergol Pol 2013;81:95-104 Patel NS, Fung SM, Zanichelli A, et al Ecallantide for treatment of acute attacks of acquired C1 esterase inhibitor deficiency Allergy Asthma Proc 2013;34:72-77 10 Cole SW, Lundquist LM Icatibant for the treatment of hereditary angioedema Ann Pharmacother 2013;47:49-55 11 Walport MJ, Davies KA, Morley BJ, et al Complement deficiency and autoimmunity Ann N Y Acad Sci 1997;815:267-281 12 Figueroa JE, Densen P Infectious diseases associated with complement deficiencies Clin Microbiol Rev 1991;4:359-395 13 Hanna S, Etzioni A Leukocyte adhesion deficiencies Ann N Y Acad Sci 2012;1250:50-55 14 Farinha NJ, Duval M, Wagner E, et al Unrelated bone marrow transplantation for leukocyte adhesion deficiency Bone Marrow Transplant 2002;30:979-981 15 Thomas C, Le Deist F, Cavazzana-Calvo M, et al Results of allogeneic bone marrow transplantation in patients with leukocyte adhesion deficiency Blood 1995;86:1629-1635 16 Le Deist F, Blanche S, Keable H, et al Successful HLA nonidentical bone marrow transplantation in three patients with the leukocyte adhesion deficiency Blood 1989;74:512-516 17 Gulino AV, Moratto D, Sozzani S, et al Altered leukocyte response to CXCL12 in patients with warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome Blood 2004;104:444-452 18 Dotta L, Tassone L, Badolato R Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome Curr Mol Med 2011;11:317-325 19 McDermott DH, Liu Q, Ulrick J, et al The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome Blood 2011;118:4957-4962 20 Dale DC, Bolyard AA, Kelley ML, et al The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome Blood 2011;118:4963-4966 21 Krivan G, Erdos M, Kallay K, et al Successful umbilical cord blood stem cell transplantation in a child with WHIM syndrome Eur J Haematol 2010;84:274-275 22 Segal BH, Leto TL, Gallin JI, et al Genetic, biochemical, and clinical features of chronic granulomatous disease Medicine (Baltimore) 2000;79:170-200 23 Kuhns DB, Alvord WG, Heller T, et al Residual NADPH oxidase and survival in chronic granulomatous disease N Engl J Med 2010;363:2600-2610 24 Seger RA Hematopoietic stem cell transplantation for chronic granulomatous disease Immunol Allergy Clin North Am 2010; 30:195-208 25 Hussain A, Yu L, Faryal R, et al TEC family kinases in health and disease–loss-of-function of BTK and ITK and the gain-of-function fusions ITK-SYK and BTK-SYK FEBS J 2011;278:2001-2010 26 Dua J, Elliot E, Bright P, et al Pyoderma gangrenosum-like ulcer caused by Helicobacter cinaedi in a patient with X-linked agammaglobulinaemia Clin Exp Dermatol 2012;37:642-645 27 Cuccherini B, Chua K, Gill V, et al Bacteremia and skin/bone infections in two patients with X-linked agammaglobulinemia caused by an unusual organism related to Flexispira/Helicobacter species Clin Immunol 2000;97:121-129 28 Turvey SE, Leo SH, Boos A, et al Successful approach to treatment of Helicobacter bilis infection in X-linked agammaglobulinemia J Clin Immunol 2012;32:1404-1408 29 Kainulainen L, Nikoskelainen J, Vuorinen T, et al Viruses and bacteria in bronchial samples from patients with primary hypogammaglobulinemia Am J Respir Crit Care Med 1999;159:1199-1204 30 Katamura K, Hattori H, Kunishima T, et al Non-progressive viral myelitis in X-linked agammaglobulinemia Brain Dev 2002;24: 109-111 31 Misbah SA, Spickett GP, Ryba PC, et al Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review J Clin Immunol 1992;12:266-270 32 Quan PL, Wagner TA, Briese T, et al Astrovirus encephalitis in boy with X-linked agammaglobulinemia Emerg Infect Dis 2010;16: 918-925 33 Lee WI, Torgerson TR, Schumacher MJ, et al Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome Blood 2005;105:1881-1890 34 Cabral-Marques O, Schimke LF, Pereira PV, et al Expanding the clinical and genetic spectrum of human CD40L deficiency: the occurrence of paracoccidioidomycosis and other unusual infections in Brazilian patients J Clin Immunol 2012;32:212-220 35 Rodrigues F, Davies EG, Harrison P, et al Liver disease in children with primary immunodeficiencies J Pediatr 2004;145:333-339 36 Jo EK, Kim HS, Lee MY, et al X-linked hyper-IgM syndrome associated with Cryptosporidium parvum and Cryptococcus neoformans infections: the first case with molecular diagnosis in Korea J Korean Med Sci 2002;17:116-120 37 Isam H, Al-Wahadneh A Successful bone marrow transplantation in a child with X-linked hyper-IgM syndrome Saudi J Kidney Dis Transpl 2004;15:489-493 38 Duplantier JE, Seyama K, Day NK, et al Immunologic reconstitution following bone marrow transplantation for X-linked hyper IgM syndrome Clin Immunol 2001;98:313-318 39 Ferrari S, Giliani S, Insalaco A, et al Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM Proc Natl Acad Sci USA 2001;98:12614-12619 40 Imai K, Slupphaug G, Lee WI, et al Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination Nat Immunol 2003;4:1023-1028 41 Revy P, Muto T, Levy Y, et al Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyperIgM syndrome (HIGM2) Cell 2000;102:565-575 42 Resnick ES, Moshier EL, Godbold JH, et al Morbidity and mortality in common variable immune deficiency over decades Blood 2012;119:1650-1657 43 Bates CA, Ellison MC, Lynch DA, et al Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency J Allergy Clin Immunol 2004;114:415-421 44 Chase NM, Verbsky JW, Hintermeyer MK, et al Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID) J Clin Immunol 2013;33:30-39 45 Podjasek JC, Abraham RS Autoimmune cytopenias in common variable immunodeficiency Front Immunol 2012;3:189 e2 46 Warnatz K, Voll RE Pathogenesis of autoimmunity in common variable immunodeficiency Front Immunol 2012;3:210 47 van de Ven AA, Compeer EB, van Montfrans JM, et al B-cell defects in common variable immunodeficiency: BCR signaling, protein clustering and hardwired gene mutations Crit Rev Immunol 2011;31:85-98 48 Orange JS, Glessner JT, Resnick E, et al Genome-wide association identifies diverse causes of common variable immunodeficiency J Allergy Clin Immunol 2011;127:1360-1367 49 Bukowska-Strakova K, Kowalczyk D, Baran J, et al The B-cell compartment in the peripheral blood of children with different types of primary humoral immunodeficiency Pediatr Res 2009;66:28-34 50 de Greef JC, Wang J, Balog J, et al Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type Am J Hum Genet 2011;88:796-804 51 Moarefi AH, Chedin F ICF syndrome mutations cause a broad spectrum of biochemical defects in DNMT3B-mediated de novo DNA methylation J Mol Biol 2011;409:758-772 52 Arumugakani G, Wood PM, Carter CR Frequency of Treg cells is reduced in CVID patients with autoimmunity and splenomegaly and is associated with expanded CD21lo B lymphocytes J Clin Immunol 2010;30:292-300 53 Melo KM, Carvalho KI, Bruno FR, et al A decreased frequency of regulatory T cells in patients with common variable immunodeficiency PLoS ONE 2009;4:e6269 54 Genre J, Errante PR, Kokron CM, et al Reduced frequency of CD4(1)CD25(HIGH)FOXP3(1) cells and diminished FOXP3 expression in patients with common variable immunodeficiency: a link to autoimmunity? Clin Immunol 2009;132:215-221 55 Yu GP, Chiang D, Song SJ, et al Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease Clin Immunol 2009;131:240-253 56 Fevang B, Yndestad A, Sandberg WJ, et al Low numbers of regulatory T cells in common variable immunodeficiency: association with chronic inflammation in vivo Clin Exp Immunol 2007;147:521-525 57 Lilic D, Sewell WA IgA deficiency: what we should—or should not—be doing J Clin Pathol 2001;54:337-338 58 Bassett AS, McDonald-McGinn DM, Devriendt K, et al Practical guidelines for managing patients with 22q11.2 deletion syndrome J Pediatr 2011;159:332-339 59 McDonald-McGinn DM, Sullivan KE Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) Medicine (Baltimore) 2011;90:1-18 60 Tomita-Mitchell A, Mahnke DK, Larson JM, et al Multiplexed quantitative real-time PCR to detect 22q11.2 deletion in patients with congenital heart disease Physiol Genomics 2010;42A:52-60 61 Ciupe SM, Devlin BH, Markert ML, et al The dynamics of T-cell receptor repertoire diversity following thymus transplantation for DiGeorge anomaly PLoS Comput Biol 2009;5:e1000396 62 Markert ML, Devlin BH, Chinn IK, et al Thymus transplantation in complete DiGeorge anomaly Immunol Res 2009;44:61-70 63 Matsumoto T, Amamoto N, Kondoh T, et al Complete-type DiGeorge syndrome treated by bone marrow transplantation Bone Marrow Transplant 1998;22:927-930 64 Goldsobel AB, Haas A, Stiehm ER Bone marrow transplantation in DiGeorge syndrome J Pediatr 1987;111:40-44 65 Puck JM Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles J Allergy Clin Immunol 2012;129:607-616 66 Verbsky J, Thakar M, Routes J The Wisconsin approach to newborn screening for severe combined immunodeficiency J Allergy Clin Immunol 2012;129:622-627 67 Yamada K, Tsukahara T, Yoshino K, et al Identification of a high incidence region for retroviral vector integration near exon of the LMO2 locus Retrovirology 2009;6:79 68 Rans TS, England R The evolution of gene therapy in X-linked severe combined immunodeficiency Ann Allergy Asthma Immunol 2009;102:357-362 69 Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al LMO2associated clonal T cell proliferation in two patients after gene therapy for SCID-X1 Science 2003;302:415-419 69a Mamcarz E, Zhou S, Lockey T, et al Lentiviral gene therapy combined with low-dose busulfan in infants with SCID-X1 N Engl J Med 2019;380(16):1525–34 70 O’Shea JJ, Husa M, Li D, et al Jak3 and the pathogenesis of severe combined immunodeficiency Mol Immunol 2004;41:727-737 71 Roberts JL, Lengi A, Brown SM, et al Janus kinase (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation Blood 2004;103:2009-2018 72 Villa A, Notarangelo LD, Roifman CM Omenn syndrome: inflammation in leaky severe combined immunodeficiency J Allergy Clin Immunol 2008;122:1082-1086 73 Booth C, Gaspar HB Pegademase bovine (PEG-ADA) for the treatment of infants and children with severe combined immunodeficiency (SCID) Biologics 2009;3:349-358 74 Lee CR, McKenzie CA, Webster KD, et al Pegademase bovine: replacement therapy for severe combined immunodeficiency disease DICP 1991;25:1092-1095 75 Gaspar HB Gene therapy for ADA-SCID: defining the factors for successful outcome Blood 2012;120:3628-3629 76 Nekrep N, Fontes JD, Geyer M, et al When the lymphocyte loses its clothes Immunity 2003;18:453-457 77 d’Hennezel E, Bin Dhuban K, Torgerson T, et al The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome J Med Genet 2012;49:291-302 78 Torgerson TR, Ochs HD Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein mutations and lack of regulatory T cells J Allergy Clin Immunol 2007;120:744-750 79 Lucas KG, Ungar D, Comito M, et al Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX syndrome Bone Marrow Transplant 2007;39:55-56 80 Rao A, Kamani N, Filipovich A, et al Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning Blood 2007;109:383-385 81 Seidel MG, Fritsch G, Lion T, et al Selective engraftment of donor CD4125high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation Blood 2009;113:5689-5691 82 Ariga T Wiskott-Aldrich syndrome; an X-linked primary immunodeficiency disease with unique and characteristic features Allergol Int 2012;61:183-189 83 Cleland SY, Siegel RM Wiskott-Aldrich syndrome at the nexus of autoimmune and primary immunodeficiency diseases FEBS Lett 2011;585:3710-3714 84 Moratto D, Giliani S, Bonfim C, et al Long-term outcome and lineagespecific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study Blood 2011;118:1675-1684 85 Albert MH, Bittner TC, Nonoyama S, et al X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, longterm outcome, and treatment options Blood 2010;115:3231-3238 86 Boztug K, Schmidt M, Schwarzer A, et al Stem-cell gene therapy for the Wiskott-Aldrich syndrome N Engl J Med 2010;363: 1918-1927 87 Guggenheim R, Somech R, Grunebaum E, et al Bone marrow transplantation for cartilage-hair-hypoplasia Bone Marrow Transplant 2006;38:751-756 88 de Miranda NF, Bjorkman A, Pan-Hammarstrom Q DNA repair: the link between primary immunodeficiency and cancer Ann N Y Acad Sci 2011;1246:50-63 89 Al-Muhsen S, Casanova JL The genetic heterogeneity of Mendelian susceptibility to mycobacterial diseases J Allergy Clin Immunol 2008;122:1043-1051 90 Moilanen P, Korppi M, Hovi L, et al Successful hematopoietic stem cell transplantation from an unrelated donor in a child with interferon gamma receptor deficiency Pediatr Infect Dis J 2009;28:658-660 e3 91 Chantrain CF, Bruwier A, Brichard B, et al Successful hematopoietic stem cell transplantation in a child with active disseminated Mycobacterium fortuitum infection and interferon-gamma receptor deficiency Bone Marrow Transplant 2006;38:75-76 92 Filipovich AH The expanding spectrum of hemophagocytic lymphohistiocytosis Curr Opin Allergy Clin Immunol 2011;11:512-516 93 Casanova JL, Abel L, Quintana-Murci L Human TLRs and IL1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics Annu Rev Immunol 2011;29:447-491 94 Puel A, Cypowyj S, Marodi L, et al Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis Curr Opin Allergy Clin Immunol 2012;12:616-622 95 Kisand K, Lilic D, Casanova JL, et al Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications Eur J Immunol 2011;41:1517-1527 96 Puel A, Doffinger R, Natividad A, et al Autoantibodies against IL17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I J Exp Med 2010;207:291-297 97 Oliveira JB, Bleesing JJ, Dianzani U, et al Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop Blood 2010;116:e35-e40 98 Oliveira JB, Gupta S Disorders of apoptosis: mechanisms for autoimmunity in primary immunodeficiency diseases J Clin Immunol 2008;28(suppl 1):S20-S28 99 Teachey DT Autoimmune lymphoproliferative syndrome: new approaches to diagnosis and management Clin Adv Hematol Oncol 2011;9:233-235 100 Teachey DT, Greiner R, Seif A, et al Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome Br J Haematol 2009;145:101-106 101 Boxer LA How to approach neutropenia Am Soc Hematol Educ Program 2012;2012:174-182 102 Jirapongsananuruk O, Malech HL, Kuhns DB, et al Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay J Allergy Clin Immunol 2003;111:374-379 103 Vowells SJ, Sekhsaria S, Malech HL, et al Flow cytometric analysis of the granulocyte respiratory burst: a comparison study of fluorescent probes J Immunol Methods 1995;178:89-97 104 Orange JS, Ballow M, Stiehm ER, et al 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 J Allergy Clin Immunol 2012;130:S1-S24 105 Wehr C, Kivioja T, Schmitt C, et al The EUROclass trial: defining subgroups in common variable immunodeficiency Blood 2008;111: 77-85 106 Kang HJ, Bartholomae CC, Paruzynski A, et al Retroviral gene therapy for X-linked chronic granulomatous disease: results from phase I/II trial Mol Ther 2011;19:2092-20101 107 Bauer TR Jr, Hickstein DD Gene therapy for leukocyte adhesion deficiency Curr Opin Mol Ther 2000;2:383-388 108 Orange JS, Grossman WJ, Navickis RJ, et al Impact of trough IgG on pneumonia incidence in primary immunodeficiency: a metaanalysis of clinical studies Clin Immunol 2010;137:21-30 109 Pierce LR, Jain N Risks associated with the use of intravenous immunoglobulin Transfus Med Rev 2003;17:241-251 110 Teigland CL, Parrott RE, Buckley RH Long-term outcome of non-ablative booster BMT in patients with SCID Bone Marrow Transplant 2013;48:1050-1055 111 Buckley RH, Win CM, Moser BK, et al Post-transplantation B cell function in different molecular types of SCID J Clin Immunol 2013;33:96-110 112 Grunebaum E, Roifman CM Bone marrow transplantation using HLA-matched unrelated donors for patients suffering from severe combined immunodeficiency Hematol Oncol Clin North Am 2011;25:63-73 113 Roifman CM, Grunebaum E, Dalal I, et al Matched unrelated bone marrow transplant for severe combined immunodeficiency Immunol Res 2007;38:191-200 ... reconstitute their T-cell deficiency but may not develop significant B-cell chimerism The reasons for this are not entirely understood, but various hypotheses have been put forward From a practical... Similarly, a range of manipulated and unmanipulated Key References The full reference list for this chapter is available at ExpertConsult.com e1 References Notarangelo L, Casanova JL, Conley