Introduction: Severe Combined Immunodeficiency (SCID) is a life-threatening immunodeficiency caused by several pathogenic genetic variants, and it is characterized by profound defects in T-cell numbers and immune function. First performed in the late 1960's, hematopoietic stem cell transplantation remains the standard treatment for most cases of SCID. There is a growing number of post-transplant SCID patients, and it is imperative to assess the long-term outcomes of these patients. We have reported here the longest follow-up of a post-transplant SCID patient who, to our knowledge, bears the first gamma chain (γc) variant to show intact IL-21 signaling. Case Presentation: The patient presented at 5 months of age with recurrent thrush and Pneumocystis jiroveci pneumonia. In 1971, at the age of 11 months, he received an unconditioned, matched, related donor transplant comprising whole, unprocessed bone marrow. He is now 48 years old without significant illness and has never required immunoglobulin replacement. He exhibits T-dependent vaccine responses. He does suffer from chronic warts and bacterial infections that have worsened in recent years. We confirmed a known pathogenic variant in the IL2RG gene showing a hemizygous variant NM_000206.2:c.675C>A, resulting in p.Ser225Arg. His chimerism studies revealed donor T cells, host B cells, host myeloid cells, and mixed NK cells. Lymphocyte enumeration revealed normal numbers and distribution of B cells. The host B cells carry the pathogenic variant in IL2RG, but, when stimulated with IL-21, they demonstrated intact, γc-dependent signaling. Conclusions: Even with host B cells, reconstitution with donor T cells can be sufficient to allow over four decades of survival when B-cell function is intact. Our case demonstrates that satisfactory B-cell function can arise as a consequence of both intact IL-21 signaling due to a hypomorphic γc variant, and close HLA matching with the donor to allow for effective T-cell help.

SAD is frequently associated with chronic and recurrent rhinosinusitis (CRS) and is defined as inadequate post-vaccination percentage of protective (≥1.3 ug/mL) pneumococcal antibody serotypes /total tested serotypes (post-pPA). Although <70% post-pPA has been used commonly as the criterion for SAD, we sought to evaluate the clinical outcome of a different definition of SAD. 204 patients aged 6 to 70 years with CRS were classified by pre- and post-pPA by two different criteria. First, 70% is used as the threshold for adequate PA (pneumococcal antibody) response: Group A (adequate pre-pPA), Group B (inadequate pre-pPA, adequate post-pPA), Group C (inadequate pre-pPA, inadequate post-pPA, SAD). Second, 50% is used as the threshold for the identical classification: Group A', B' and C'. These 6 groups were compared for clinical features. The prevalence of SAD was 24% by 70% criterion (Group C) and 7% by 50% criterion (Group C') (P = .17). Among 120 patients with pre-pPA<50% and post-pPA ≥50% (Group B'), 94 patients with post-pPA of ≥70% (Group B'B) would have been classified as vaccine responders by the 70% criterion. However, 27 patients with post-pPA, 50% - 69% (Group BC'), were classified as SAD by the 70% criterion. The recurrence rates of sinusitis in the following one year among Group B'B were significantly less compared to Group B'C (28% vs. 73%, P <.001) Patients with ≥70% pPA compared to <70% pPA experienced decreased recurrence of sinusitis in the next year. 70% pPA criterion is recommended for screening and vaccination.

SAD is common among patients with recurrent respiratory infections and is defined by the degree of inadequate response to polysaccharide pneumococcal vaccines. We sought to determine the risk factors associated with SAD. 313 patients aged 6 to 70 years with symptoms of recurrent respiratory infections, especially rhinosinusitis, were classified by pre- and post-pPA (post-vaccination percentage of protective (≥1.3 ug/mL) pneumococcal antibody serotypes / total tested serotypes): Group A (adequate pre-pPA), Group B (inadequate pre-pPA, adequate post-pPA, responders), Group C (inadequate pre-pPA, inadequate post-pPA, consistent with SAD). Immunity against Streptococcus pneumoniae was defined as adequate when the pPA was ≥70%. Each group was analyzed for demographics, history of sinusitis, recurrent sinusitis in the following year, and allergic conditions, levels of immunoglobulins, and individual pneumococcal serotype titers for discernible characteristics. The prevalence of SAD was 20% (62/313) in the total patients and 26% (37/143) among patients with CRS. The lower the pre-pPA is, the higher is the probability of SAD. Lower pre-pPA, inadequate pneumococcal antibody titers to certain serotypes, increased age, and lower IgG level were significantly associated with SAD SAD should be considered among patients with recurrent respiratory infections, especially CRS. These patients would benefit from careful assessment of the risk factors of SAD and vaccination if pre-pPA is <70%.

Background Specific antibody deficiency (SAD) is highly associated with chronic rhinosinusitis (CRS) and is defined by inadequate post-vaccination percentage of protective (≥1.3 ug/mL) pneumococcal antibody serotypes divided by total tested serotypes (post-pPA). Objective Although < 70% post-pPA has been used commonly as the criterion for SAD, we sought to evaluate the clinical outcome of a different definition of SAD. Methods 203 patients aged 6 to 70 years with CRS were classified, retrospectively by pre-vaccination pPA (pre-pPA) and post-pPA by two different criteria. Using 70% as the threshold for adequate pneumococcal antibody (PA) response, patients were classified as: Group A (adequate pre-pPA), Group B (inadequate pre-pPA, adequate post-pPA), Group C (inadequate pre-pPA, inadequate post-pPA, SAD). Using 50% as the threshold, patients were similarly classified as: Group A’, B’ and C’. Results The recurrence rate of sinusitis during the next one year in Group A (pre-pPA ≥70%) was significantly less than that of Group A’ (pre-pPA ≥50%) (10% vs. 34%, P = .03). Group A had lower incidence of sinusitis than Group B (pre-pPA < 70%, post-pPA ≥70%) (10% vs. 34%, P = .025). Among Group B’ patients, the recurrence rate of sinusitis was significantly less among those with post-pPA of ≥70% than those with 50%–69% (28% vs. 69%, P < .01). Conclusion Employment of a 70% pPA threshold for SAD in comparison to a 50% threshold would decrease the incidence of sinusitis in the next one year by vaccinating patients in 51–69% pPA range. Pre-existing PAs (Group A) yielded a higher protection against sinusitis than vaccine-acquired antibodies (Group B).

Background Inadequate titers of pneumococcal antibody (PA) are commonly present among patients with recurrent respiratory infections. Objective We sought to determine the effect of the degree of inadequacy in baseline PA titers on the subsequent polysaccharide vaccine response, the incidence of sinusitis, and allergic conditions. Methods A total of 313 patients aged 6 to 70 years with symptoms of recurrent respiratory infections were classified by baseline-pPA (percentage of protective [≥1.3 µg/mL] PA serotypes/total tested serotypes) and postvaccination pPA (post-pPA): Group A (adequate baseline-pPA), Group B (inadequate baseline-pPA, adequate post-pPA, responders), and Group C (inadequate baseline-pPA, inadequate postpPA, nonresponders, specific antibody deficiency [SAD]). Immunity against Streptococcus pneumoniae was defined as adequate when the pPA was ≥70%. Each group and combined groups, Group AB (inadequate baseline-pPA), and Group BC (adequate post-pPA) were analyzed for demographics, history of sinusitis, recurrent sinusitis in the following year, allergic conditions, and association with inadequate individual serotype titers. Results Over 80% of patients with respiratory symptoms had inadequate baseline-pPA. Baseline-pPA and SAD prevalence are inversely related (odds ratio = 2.02, 95% CI: 1.15–3.57, P = .01). Inadequate serotype 3 antibody titer is highly associated with SAD (odds ratio = 2.02, 96% CI: 1.61–5.45, P < .01). The groups with inadequate pPA (Group B and C, or BC) had significantly higher percentage of patients with chronic rhinosinusitis (P < .001), allergic sensitization, and allergic rhinitis (P < .05). Group A contained higher percentage of patients with recurrent upper airway infections (P < .001). Conclusion Low baseline-pPA and low antibody titers to serotype 3 are highly associated with SAD, increased incidence of respiratory infections including CRS and allergic conditions.

Domino hematopoietic stem cell transplantation (HSCT) is a treatment in which an HSCT recipient serves as the donor for an HLA-identical recipient (Fig 1, A). A potential advantage of domino HSCT over other transplantation strategies is induction of T-cell tolerance toward recipient HLA in the primary recipient, resulting in decreased risk of graft-versus-host-disease (GvHD) in a secondary HLA-identical (domino) recipient.1Goebel W.S. Nelson R.P. Brahmi Z. Gowan D.J. Towell P.J. Robertson K.A. et al.Serial transplantation resulting in tolerance to an unrelated cord blood graft.Transplantation. 2006; 81: 1596-1599Crossref PubMed Scopus (4) Google Scholar Several successful cases have been reported,1Goebel W.S. Nelson R.P. Brahmi Z. Gowan D.J. Towell P.J. Robertson K.A. et al.Serial transplantation resulting in tolerance to an unrelated cord blood graft.Transplantation. 2006; 81: 1596-1599Crossref PubMed Scopus (4) Google Scholar, 2Cohen J.M. Rogers V. Gaspar H.B. Jones A. Davies E.G. Rao K. et al.Serial transplantation of mismatched donor hematopoietic cells between HLA-identical sibling pairs with congenital immunodeficiency: in vivo tolerance permits rapid immune reconstitution following T-replete transplantation without GVHD in the secondary recipient.Blood. 2006; 108: 2124-2126PubMed Google Scholar, 3Stiehm E.R. Roberts R.L. Hanley-Lopez J. Wakim M.E. Pallavicini M.G. Cowan M.J. et al.Bone marrow transplantation in severe combined immunodeficiency from a sibling who had received a paternal bone marrow transplant.N Engl J Med. 1996; 335: 1811-1814Crossref PubMed Scopus (14) Google Scholar, 4Buckley R.H. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes.Immunol Res. 2011; 49: 25-43Crossref PubMed Scopus (133) Google Scholar yet systematic analysis of the outcome of domino HSCT is lacking. Here we report the first international multicenter study on the outcome of domino HSCT in human recipients. Through a retrospective survey within the European Group for Blood and Marrow Transplantation and the Primary Immune Deficiency Treatment Consortium networks, we identified 12 domino HSCT cases performed by 9 different centers between 1992 and 2016. Each domino recipient was matched to 3 control recipients of a nondomino HSCT based on age, disease, and year of transplantation by using covariate value matching. Detailed information is provided in Table I1Goebel W.S. Nelson R.P. Brahmi Z. Gowan D.J. Towell P.J. Robertson K.A. et al.Serial transplantation resulting in tolerance to an unrelated cord blood graft.Transplantation. 2006; 81: 1596-1599Crossref PubMed Scopus (4) Google Scholar, 2Cohen J.M. Rogers V. Gaspar H.B. Jones A. Davies E.G. Rao K. et al.Serial transplantation of mismatched donor hematopoietic cells between HLA-identical sibling pairs with congenital immunodeficiency: in vivo tolerance permits rapid immune reconstitution following T-replete transplantation without GVHD in the secondary recipient.Blood. 2006; 108: 2124-2126PubMed Google Scholar, 3Stiehm E.R. Roberts R.L. Hanley-Lopez J. Wakim M.E. Pallavicini M.G. Cowan M.J. et al.Bone marrow transplantation in severe combined immunodeficiency from a sibling who had received a paternal bone marrow transplant.N Engl J Med. 1996; 335: 1811-1814Crossref PubMed Scopus (14) Google Scholar, 4Buckley R.H. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes.Immunol Res. 2011; 49: 25-43Crossref PubMed Scopus (133) Google Scholar and in Table E1 in this article's Online Repository at www.jacionline.org.Table IDetailed characteristics of primary and secondary (domino) transplantationsCase no.TxRecipientSexAge at Tx (y)DonorStem cell sourceGraft manipulationHLA matchTNC (108/kg)CD34 (106/kg)ConditioningGvHD prophylaxisOutcomeRetransplantationSurvivalSurvival after HSCT (yrs)Acute GVHD (grade)Reference1 = Primary2 = DominoDiseaseTypeChimerism11SCIDFemale1Haplo∗Domino donor received 2 transplants from the same donor; depicted are numbers and outcomes for first/second transplantations.BMTCD3/61.3/1.59NRNoneYesR/mixed∗Domino donor received 2 transplants from the same donor; depicted are numbers and outcomes for first/second transplantations.BoosterAlive27.1No3Stiehm E.R. Roberts R.L. Hanley-Lopez J. Wakim M.E. Pallavicini M.G. Cowan M.J. et al.Bone marrow transplantation in severe combined immunodeficiency from a sibling who had received a paternal bone marrow transplant.N Engl J Med. 1996; 335: 1811-1814Crossref PubMed Scopus (14) Google Scholar2SCIDFemale0MSDBMNone4.8NRNoneYesMixedBoosterAlive21.4No21SCIDMale0HaploBMTCD3/66.55.8NoneNoMixedNoYesNRYes (IV)4Buckley R.H. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes.Immunol Res. 2011; 49: 25-43Crossref PubMed Scopus (133) Google Scholar2SCIDMale0SYNBMNoneNRNRNoneNoMixed†Full chimerism in T-cell compartment.DLIYes21.4No31SCIDMale1MUDCBNone4/60.90.4MAYesDNoYes14.6Yes (III)1Goebel W.S. Nelson R.P. Brahmi Z. Gowan D.J. Towell P.J. Robertson K.A. et al.Serial transplantation resulting in tolerance to an unrelated cord blood graft.Transplantation. 2006; 81: 1596-1599Crossref PubMed Scopus (4) Google Scholar2SCIDMale0MSDBMNone2.09.9NMAYesMixedNoYes9.3No41SCIDMale1MUDBMTCD9/100.9NRMAYesDNoYes19.9Yes (II)2Cohen J.M. Rogers V. Gaspar H.B. Jones A. Davies E.G. Rao K. et al.Serial transplantation of mismatched donor hematopoietic cells between HLA-identical sibling pairs with congenital immunodeficiency: in vivo tolerance permits rapid immune reconstitution following T-replete transplantation without GVHD in the secondary recipient.Blood. 2006; 108: 2124-2126PubMed Google Scholar2SCIDMale0MSDBMNone3.54.9NoneNoMixed†Full chimerism in T-cell compartment.NoYes16.1No51SCIDFemale0HaploBMTCD5/10NRNRMAYesMixedNoYes21.4Yes (II)—2SCIDMale0MSD/haploBMNone‡Combined graft of CD34+-selected cells from initial adult donor and unfractionated domino donor cells.2.24.0/13.8MAYesDNoYes8.9No61LADFemale1HaploBMNR6/81.1NRMAYesNRNoYes24.5Yes (II)—2LADMale0MSDBMNone7.0NRMAYesMixedNoNo7.1No71MST1Female4MMRDBMCD345/60.0303.2MANoDNoYes7.2No—2MST1Female15MSDBMNone1.12.3MAYesDNoNo0.45Yes (II)81WASMale4MMSDBMNone9/10NRNRMAYesNRNoYes19.3Yes (II)—2WASMale2MSDBMNone5.87.7MAYesMixedYesYes17.6No91WASMale1HaploPBCD345/10NR36.5MAYesMixed/D§Low mixed chimerism after first transplantation; full donor chimerism after second transplantation from the same donor.YesYes17.1No2Cohen J.M. Rogers V. Gaspar H.B. Jones A. Davies E.G. Rao K. et al.Serial transplantation of mismatched donor hematopoietic cells between HLA-identical sibling pairs with congenital immunodeficiency: in vivo tolerance permits rapid immune reconstitution following T-replete transplantation without GVHD in the secondary recipient.Blood. 2006; 108: 2124-2126PubMed Google Scholar2WASMale3SYNBMNR2.44.8NMAYesRYesYes15.6No101XLPMale12MUDPBNRNRNR3.9NMAYesDNoYes5.1Yes (II)—2XLPMale7MSD/haploBMNone‡Combined graft of CD34+-selected cells from initial adult donor and unfractionated domino donor cells.NR2.0/3.54MAYesRYesYes3.4No111HurlerMale1MUDCBNone5/61.51.5MAYesDNoYes7.3No—2HurlerMale0MSDBMNone6.0NRMAYesMixedNoYes5.7No121FAFemale11MUDCBNone4/60.590.02MAYesDNoYes2.3No—2FAMale8MSDBMNone4.14.9MAYesMixedYesYes0.7NoBM, Bone marrow; CB, cord blood; CD34, CD34+ selection; D, >95% donor; DLI, donor lymphocyte infusion; FA, Fanconi anemia; Haplo, haploidentical donor; LAD, leukocyte adhesion deficiency; MA, myeloablative; MMRD, mismatched related donor; MMSD, mismatched sibling donor; MRD, matched related donor; MSD, matched sibling donor; MST1, mammalian sterile 20-like protein 1 deficiency; MUD, matched unrelated donor; NMA, nonmyeloablative; NR, not reported; PB, peripheral blood; R, >95% recipient; SYN, syngeneic twin; TCD, T-cell depletion; TNC, total nucleated cells; Tx, transplantation; WAS, Wiskott-Aldrich syndrome; XLP, X-linked lymphoproliferative syndrome.∗ Domino donor received 2 transplants from the same donor; depicted are numbers and outcomes for first/second transplantations.† Full chimerism in T-cell compartment.‡ Combined graft of CD34+-selected cells from initial adult donor and unfractionated domino donor cells.§ Low mixed chimerism after first transplantation; full donor chimerism after second transplantation from the same donor. Open table in a new tab BM, Bone marrow; CB, cord blood; CD34, CD34+ selection; D, >95% donor; DLI, donor lymphocyte infusion; FA, Fanconi anemia; Haplo, haploidentical donor; LAD, leukocyte adhesion deficiency; MA, myeloablative; MMRD, mismatched related donor; MMSD, mismatched sibling donor; MRD, matched related donor; MSD, matched sibling donor; MST1, mammalian sterile 20-like protein 1 deficiency; MUD, matched unrelated donor; NMA, nonmyeloablative; NR, not reported; PB, peripheral blood; R, >95% recipient; SYN, syngeneic twin; TCD, T-cell depletion; TNC, total nucleated cells; Tx, transplantation; WAS, Wiskott-Aldrich syndrome; XLP, X-linked lymphoproliferative syndrome. Indications for domino HSCT were immune deficiency (n = 10, 5 of which had severe combined immunodeficiency [SCID]), inborn errors of metabolism (n = 1), and hereditary bone marrow failure (n = 1). For the primary transplantation, donors were HLA-mismatched relatives in 7 (58%) cases and unrelated donors in 5 (42%) cases. Stem cell sources for the primary transplantation were bone marrow (n = 7, 58%), peripheral blood (n = 2, 17%), or cord blood (n = 3, 25%). Nine (75%) primary recipients received myeloablative conditioning. For the secondary (domino) HSCT, donors and recipients were HLA-identical siblings in 10 (83%) cases; in 2 (17%) cases they were syngeneic twins. All domino HSCTs used marrow as a stem cell source (some combined grafts were explored, Table I). The median interval between the primary HSCT and the domino HSCT was 2.1 years (range, 1.5-15.7 years). Domino HSCT recipients received a median CD34+ cell dose of 5.8 × 106/kg (range, 2.3-17.8 × 106/kg) and a median total nucleated cell dose of 4.5 × 108/kg (range, 1.1-7.0 × 108/kg). Nine domino HSCT recipients received conditioning, with 7 (78%) receiving myeloablative conditioning. GvHD prophylaxis was used in 10 (83%) recipients. At a median follow-up of 10 years, overall survival of domino HSCT recipients was 80% (55% to 100%; 10/12 cases), and event-free survival (defined as survival without retransplantation) was 49% (20% to 78%), which tended to be poorer than that of the primary recipients (overall survival, 100% [P = .15]; event-free survival, 92% [P = .08]) but similar to that of matched control subjects (Fig 1). Two domino HSCT recipients died, both of infection after successful engraftment: 1 underwent transplantation for mammalian sterile 20-like protein 1 deficiency deficiency, with neutrophil engraftment on day 21 of 100% donor origin. Several infectious complications ensued, leading to lethal varicella-zoster encephalitis. The other recipient underwent successful transplantation for leukocyte adhesion deficiency (recipient 6) but had neuroblastoma and succumbed to bacterial pneumonia (for details, see Table I and Table E2 in this article's Online Repository at www.jacionline.org). Four domino HSCT recipients required retransplantation, all for reasons related to graft failure (see Table E3 in this article's Online Repository at www.jacionline.org). The time between domino HSCT and retransplantation ranged from 3 to 190 months. All retransplantations resulted in successful engraftment. Notably, despite fulfilling our criteria for successful engraftment, 2 domino HSCT recipients required additional donor cell infusions to maintain adequate lymphocyte counts. The remaining 4 recipients demonstrated long-term adequate graft function, for a median duration of follow-up of 109 months after HSCT. Remarkably, only 1 (8%) domino HSCT recipient had acute GvHD compared with 58% of primary recipients (P = .01) and 22% (7% to 35%) of control subjects (P = .41; Fig 1, G). We next addressed potential causes of nonengraftment by comparing transplantation characteristics of successfully engrafted domino recipients and those who later required a retransplantation. We did not find any difference in administered cell doses (median CD34+ dose, 6.1 × 106/kg vs 5.4 × 106/kg; P = .74; see Fig E1 in this article's Online Repository at www.jacionline.org), donor age, or conditioning (myeloablative vs nonmyeloablative and myeloablative/nonmyeloablative vs none) or in the interval between first HSCT and domino HSCT. Four domino donors were mixed chimeric at the time of donation, yet this did not affect the outcome of their recipients. Because all domino HSCT recipients showed initial donor neutrophil engraftment, we were able to compare the time until neutrophil recovery between recipients requiring retransplantation versus those who did not, yet did not find any difference (median, 18 vs 21 days; P = .45). The outcome of domino HSCT recipients undergoing transplantation for SCID trended to be better than that of those undergoing transplantation for other indications (Table I). In conclusion, our results indicate that serial transplantation of human hematopoietic stem cells (HSCs) can result in long-term donor engraftment. In addition, the low incidence of GvHD in the domino recipients supports the concept of tolerance induction in the primary recipient.3Stiehm E.R. Roberts R.L. Hanley-Lopez J. Wakim M.E. Pallavicini M.G. Cowan M.J. et al.Bone marrow transplantation in severe combined immunodeficiency from a sibling who had received a paternal bone marrow transplant.N Engl J Med. 1996; 335: 1811-1814Crossref PubMed Scopus (14) Google Scholar According to this concept, T cells from the initial donor are tolerized to recipient HLA in the primary recipient, resulting in nonreactivity when transplanted into a secondary HLA-identical domino recipient (Fig 1, A). Nevertheless, a substantial proportion of domino recipients require retransplantation or additional cell doses. Potential explanations include dilution, replicative stress, and/or functional decrease of the transplanted HSCs.5Kamminga L.M. van Os R. Ausema A. Noach E.J.K. Weersing E. Dontje B. et al.Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging.Stem Cells. 2005; 23: 82-92Crossref PubMed Scopus (113) Google Scholar, 6Allsopp R.C. Cheshier S. Weissman I.L. Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells.J Exp Med. 2001; 193: 917-924Crossref PubMed Scopus (154) Google Scholar, 7Harrison D.E. Astle C.M. Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure.J Exp Med. 1982; 156: 1767-1779Crossref PubMed Scopus (232) Google Scholar In the future, detailed studies on graft composition and maintenance of stemness are needed to support this theory. In addition, host-versus-graft immune reactivity might contribute to the loss of stem cell activity. Although domino HSCT can induce tolerance in the graft-versus-host direction, there might still be alloreactivity in the host-versus-graft direction, resulting in immune-mediated destruction of donor HSCs. In this respect it is interesting to note that the patients with SCID, who were less likely to have host-versus-graft immunity tended to have better outcomes. Finally, one could hypothesize that some graft-versus-host alloreactivity is required for adequate homing,8Pavlu J. Szydlo R.M. Goldman J.M. Apperley J.F. Three decades of transplantation for chronic myeloid leukemia: what have we learned?.Blood. 2011; 117: 755-763Crossref PubMed Scopus (82) Google Scholar which in the case of domino HSCT, can be hampered by the tolerance induction in the primary recipient. Of note, although domino recipients tended to have poorer outcome than their donors, these comparisons need to be interpreted with caution because they are likely biased by selection of donors with adequate graft function. In addition to biological questions, domino HSCT also raises ethical issues. In 9 domino HSCT pairs, the primary recipient underwent transplantation from an adult donor, suggesting the existence of at least 1 alternative donor. The ethical and psychosocial effect of choosing a domino donor or reusing the original donor versus searching a new donor (if available) are beyond the scope of this study yet need to be taken into account. Despite being the first and largest cohort thus far, our study is limited by the scarcity of domino HSCT and by lack of its registration in transplantation databases. Identification of additional cases will be essential to increase the robustness of our findings. Therefore any physician who has performed a domino HSCT is invited to contact the authors. Altogether, our data indicate that domino HSCT is feasible and can result in long-term engraftment, especially in patients with immune deficiency. Nonetheless, there is a substantial risk of retransplantation and/or need for additional cell boosts. Therefore domino HSCT can be considered in comparison with other transplantation strategies. BM, Bone marrow; CB, cord blood; PB, peripheral blood; TNC, total nucleated cell. VZV, Varicella-zoster virus. CB, Cord blood; MA, myeloablative; MSD, matched sibling donor; MUD, matched unrelated donor; NMA, nonmyeloablative.

UpToDate is an online resource of synthesized medical information, consisting of nearly 10,000 topic reviews. The mission of UpToDate is to improve the quality and effectiveness of health care by answering clinical questions quickly at the point of care. UpToDate is used by medical personnel in their offices and clinics and in the inpatient wards of most major US medical centers.1-3 Use of UpToDate has grown steadily in the United States and around the world, and in 2016, the program passed a milestone of more than 1 million topic views per day.

Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted. (J Allergy Clin Immunol 2017; 139: S1-46.)

Background We reported on six infants between 5 and 11 months old, with transient hypogammaglobulinemia of infancy and severe refractory atopic dermatitis, who were treated with open-label immunoglobulin (Ig) after conventional therapy failed. All six infants had an IgG level of <225 mg/dL, elevated eosinophil and IgE levels, and no urine or stool protein losses, but they did exhibit hypoalbuminemia. Objective To evaluate the utility of open-label immunoglobulin in infants with severe atopic dermatitis for whom conventional therapy failed. We reviewed the clinical utility of intravenous immunoglobulin in the treatment of severe atopic dermatitis, the most recent research in the field, and suggested mechanisms for its benefit. Methods The six infants were identified from a retrospective chart review at the University of California Los Angeles Allergy and Immunology outpatient pediatric clinic. Results All six patients were treated with 400 mg/kg/month of intravenous immunoglobulin and had normalization of their IgG and albumin levels, and all but one had clinically improved atopic dermatitis. Conclusion Infants with severe atopic dermatitis who did not respond to conventional therapy avoidance may benefit from intravenous immunoglobulin therapy.

The recognition of neutralizing, opsonizing, and autoaggressive antibodies in the serum, the development of vaccines to induce their production and of techniques to isolate and enrich these proteins and formulate safe preparations for the treatment of primary immunodefeicny disorders (PIDD) has taken a bit more than one hundred years. While immunoglobulin replacement therapy for primary and secondary immunodeficiencies is now well established, it is also used for the prevention and treatment of established infections and for immune modulation of many autoimmune, inflammatory, and neurological disorders. New indications and improved products will result in its greatly expanded use both in developed and developing countries, possibly leading to shortages and the need for stricter allocations.

Mutations in IL2RG are the recognized cause of X-SCID, a disorder that presents in infancy with overwhelming infection and fatal if untreated. Rare phenotypes of IL2RG mutations were identified in patients presenting later in life with history of severe recurrent infections. We report novel IL2RG mutation in young adult presenting with diffuse cutaneous lesions and immune dysfunction in absence of systemic infections. Flow Cytometry, Serum-Immunoglobulin Measurements, Lymphocyte Proliferation studies, Skin Biopsies, Whole-Exome Sequencing 18-year-old-male presents with five-year history of diffuse red-purple plaques on face/extremities and pink, confluent macules/patches on chest. Laboratory findings were suggestive of combined immunodeficiency: IgG-133mg/dL, IgA-54mg/dL, IgM-10mg/dL, CD4-159cells/ul, CD8-480cells/ul, CD19-148cells/ul, NK-5cells/ul, no lymphocyte proliferative response to mitogens/antigens. He had no significant sinopulmonary or systemic infections. Skin biopsies of lesions: cutaneous granulomas and epidermodysplasia verruciformis(EDV). EDV is associated with cutaneous Human Papillomavirus infection in immunodeficiency syndromes. Intravenous immunoglobulin was started at replacement doses as well as antibiotics(later discontinued when infectious cause for granulomas was ruled out). Granulomatous lesions responded well to systemic steroids. EDV lesions were refractory to topical-5%-imiquimod and remained unchanged. Due to unusual presentation, whole-exome sequencing was performed showing novel mutation of IL2RG (Val152Ala) affecting extracellular-domain of gamma-chain. Unforeseen finding of novel IL2RG mutation indicates that spectrum of disorders associated with this type of defect is not limited to severe impairment in host defenses. It is important to consider combined immunodeficiency evaluation and possibility of IL2RG mutation in patients with diffuse cutaneous granulomas and EDV even in absence of history of systemic infectious complications.

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.

IMPORTANCENewborn 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.OBJECTIVESTo 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.DESIGNEpidemiological and retrospective observational study.SETTINGRepresentatives 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.MAIN OUTCOMES AND MEASURESInfants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked.RESULTSScreening 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.CONCLUSIONS AND RELEVANCENewborn 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.

Bare lymphocyte syndrome is a rare form of combined immunodeficiency characterized by complete or partial lack of major histocompatability complex (MHC) expression. Defects in MHC class II result in early onset bacterial, viral, fungal, and protozoal infections. Here we describe a patient with MHCII deficiency born in California with normal newborn screening results. Chromosomal microarray analysis was performed by the UCLA Clinical Microarray Core. The patient was admitted at 9 months of age with intractable diarrhea, FTT, thrush, and candidal diaper rash. At admission, he had profound hypogammaglobulinemia: IgG <8mg/dL, IgA <7mg/dL, and IgM <5mg/dL. Total T and B lymphocyte counts were conserved with a relative deficiency of the CD4+ subset (CD3 2634, CD4 525, CD8 1887, CD19 1881, CD16/56 331) and inverted CD4/8 ratio of 0.28. Stool was positive for Norovirus, and respiratory studies were positive for Coxsackie/Echovirus. Flow cytometry showed no HLA-DR expression on monocytes and lymphocytes consistent with MHCII deficiency. Allogenic stem cell transplant (SCT) was performed at 11 months of age. Despite initial clinical improvement, norovirus-positive diarrhea and coxsackie/echovirus respiratory infection persisted. He died 91 days post SCT of progressive intestinal and pulmonary complications. Although not traditionally classified as a form of SCID, MHCII deficiency follows a similar clinical course and arguably should be included in the classification. We here present the first evidence that TREC numbers in MHCII deficiency, although below the mean values for immunocompetent neonates, are well above the current cutoff that is considered abnormal.