Overexpression of TSLP in the Lungs Or Skin Also Promoted Peripheral Basophilia. This Systemic Basophilia Resulted from TSLP-Tri

overexpression of TSLP in the lungs or skin also Classification of Diseases, Ninth Revision, codes indicative of promoted peripheral basophilia. This systemic basophilia immunodeficiency or recurrent infection. resulted from TSLP-triggered expansion of bone marrow METHODS. This was a retrospective chart review. Patients precursor cells through a mechanism independent of IL-3 were classified with PID if they met published diagnostic signaling. Basophils were present in TSLP-deficient mice, criteria and were diagnosed with immunodeficiency. indicating that TSLP was not essential for normal basophil Those with PID were evaluated for the presence of warning development. In comparison with classical basophils signs and categorized as those who met 1 or more of the induced by IL-3, TSLP-elicited basophils expressed higher warning signs (WS1) and those who did not (WS2). levels of TH2-skewing cytokines and proinflammatory mediators. Furthermore, basophils obtained from patients RESULTS. Twenty-three percent of patients were diagnosed with eosinophilic esophagitis, a disease associated with with PID. Of those with PID, ,70% met 1 or more criteria aberrant TSLP production, were phenotypically distinct set forth in the warning signs. The most common warning from those found in healthy controls. signs met were recurrent otitis media, recurrent sinusitis, and need for intravenous antibiotics. Sensitivity of the CONCLUSIONS. Abnormal TSLP production at 1 barrier sur- warning signs was 63% and specificity was 23%. face may promote development of allergic inflammation at other sites by increasing the number and altering the CONCLUSIONS. “10 Warning Signs of Primary Immunodefi- function of circulating basophils. ciency” were found to have low specificity and relatively low sensitivity. Study numbers were too small to draw REVIEWER COMMENTS. It is well known that patients with 1 conclusions regarding the utility of specific warning signs. allergic disorder are likely to develop others, but the mechanisms for this “atopic march” remain obscure. REVIEWER COMMENTS. The primary pediatrician’s question of Here, the authors show an important role for the cyto- when to refer a patient for workup of PID is a challenging kine TSLP, which has been shown to be highly expressed one. The study suggests that this widely used screening in animal and human tissues with active allergen-driven tool has relatively low sensitivity and, therefore, the po- inflammation. The ability of TSLP to expand and alter tential to miss PID cases. When clinical suspicion is high, the phenotype of peripheral basophils may promote the immune evaluation should be considered even if a patient development of allergic disease at other barrier surfaces does not meet .1 of these 10 warning signs. Further and could explain why patients with atopic dermatitis studies are needed to develop a more optimal screening frequently go on to develop asthma or food allergy. In toolandtoevaluatewhichspecific signs are most relevant. addition to contributing to our understanding of the URL: www.pediatrics.org/cgi/doi/10.1542/peds.2012–2183EEEE biology of allergic diseases, these studies also identify TSLP as a potentially important target for pharmacological Caroline Hobbs, MD Wesley Burks, MD blockade in vulnerable patients. Chapel Hill, NC URL: www.pediatrics.org/cgi/doi/10.1542/peds.2012–2183DDDD Timothy P. Moran, MD, PhD The Wisconsin Approach to Newborn Screening Brian P. Vickery, MD for Severe Combined Immunodeficiency Durham, NC Versky J, Thakar M, Routes J. J Allergy Clin Immunol. 2012;129(3):622–627 PRIMARY IMMUNODEFICIENCY PURPOSE OF THE STUDY. Severe combined immunodeficiency (SCID) is a life-threatening disease of infants that is curable Clinical Characteristics of Pediatric Patients with hematopoietic cell transplantation if detected early, Evaluated for Primary Immunodeficiency whereas the outcome is less favorable if treatment is McGinnitie A, Aloi F, Mishra S. Pediatr Allergy Immunol delayed. The study evaluated outcomes of a screening 2011:22(7):671–674 program in Wisconsin. PURPOSE OF STUDY. To investigate clinical characteristics of STUDY POPULATION. Newborns in Wisconsin over a 3-year children evaluated for primary immunodeficiency (PID) period. and address the utility of the “10 Warning Signs of Pri- mary Immunodeficiency” developed in 1994 by expert METHODS. Population-based screening for SCID by using consensus and published by the Jeffry Modell Founda- the T-cell receptor excision circle (TREC) assay applied tion (http://www.jfmworld.com). to samples obtained from routine newborn screening (Guthrie) cards has been underway in the state of STUDY POPULATION. The study included 141 children (birth to Wisconsin since 2008. 21 years) evaluated in the Allergy/Immunology clinic at Children’s Hospital of Pittsburgh for possible PID in RESULTS. Five infants with SCID or other forms of severe 2004–2005. Patients were identified by International T-cell lymphopenia (TCL) have been detected out of a total

S50 BEST ARTICLES RELEVANT TO PEDIATRIC ALLERGY AND IMMUNOLOGY Downloaded from www.aappublications.org/news by guest on September 28, 2021 of 207 696 infants screened between January 1, 2008, and STUDY POPULATION. This is a single-center retrospective cohort December 31, 2010. Based on these data, the specificity of study of 11 children with a diagnosis of CGD, a history of this screening assay is 99.98% with a false-positive rate of at least 1 invasive infection, and 70% meeting parameters 0.018%. In addition, the positive predictive value of this indicative of high-risk disease. Nine children had X-linked test as applied for identifying a severe TCL due to any CGD, 1 had autosomal recessive CGD, and 1 did not have cause was 45.83%. Among 9 infants without other an identifiable mutation. Nine of the 11 patients were secondary causes for the TCL, 5 had reversible TCL, and boys, and mean age at transplantation was 3.8 years 4 had 22q11.2 microdeletion (DiGeorge) syndrome. (range: 11 months to 13 years). Importantly, it appears that no infants with SCID have METHODS. been missed during this screening period. Of the 11 patients studied, 4 received HSCT from 6/6 HLA-MRDs (siblings); 7 received HSCT from 10/10 CONCLUSIONS. TREC assay screening as part of routine HLA-genoidentical MUDs. All patients underwent newborn screening detects infants with severe TCL in busulfan-based myeloablation (with addition of cy- a cost-effective fashion and should be adopted as a part of clophosphamide, cytarabine, or fludarabine) and graft- routine newborn screening as currently recommended by versus-host disease (GvHD) prophylaxis with cyclo- the US Department of Health and Human Services. sporine A. Time to engraftment was defined as time from . REVIEWER COMMENTS. This report provides the cumulative transplantation to time of neutrophil count 500 cells/ experience of newborn screening by using the TREC mL for 3 consecutive days. B- and T-cell recovery was fl assay over a 3-year period in Wisconsin, proving that it is measured by ow cytometry, and lymphoproliferative an effective means of identifying newborns with severe responses were measured by response to mitogens and TCL associated with immune deficiencies including SCID antigens. Chimerism was measured in each patient. and complete DiGeorge syndrome. Importantly, this RESULTS. Nine patients achieved full donor chimerism, experience also proved that the TREC assay is unreliable whereas 2 had stable mixed chimerism. A neutrophil in premature infants such that their current practice is to count of .500 cells/mL was reached at a median of 18 repeat the TREC assay until an infant reaches an adjusted days for the cohort. Time to engraftment was not signif- gestational age of 37 weeks at which time it is viewed as icantly different between MRD and MUD recipients, as reliable. One clear conclusion from these data is that an measured by recovery of neutrophils, platelets, CD31 and infant with severe TCL identified by an abnormal TREC CD41 T cells, and T-cell proliferative responses. Oxidative assay should undergo a complete immunologic evaluation burst was normal by day 100 in all patients. Grade I acute managed by an experienced clinical immunologist. An- GvHD of the skin occurred in 4 of 11 patients, 3 of whom other unanticipated finding from this experience is the fact received MUD transplants. One patient had a relapse of that there are rare newborns with TCL but normal T-cell Aspergillus-associated pneumonia initially acquired before function, and as more of these infants are identified it engraftment. Patients were followed for a mean of 4 years will become clearer as to how they should best be managed. (range: 1–8 years), and all are well with significant It should be noted that the results of an abnormal TREC assay improvements in quality of life, including the ability to are available early enough to prevent immunizations with attend school with no special care requirements. live viral vaccines and exposure to unirradiated blood products until the immune status of the infant is clarified, CONCLUSIONS. The study reveals 100% survival at mean a situation that should prevent unnecessary complications follow-up time of 4 years, no severe or chronic GvHD, no from these agents. graft failure, and only 1 incidence of recurrent infection before engraftment for MRD and MUD transplant URL: www.pediatrics.org/cgi/doi/10.1542/peds.2012–2183FFFF recipients. The authors suggest that both MRD and Thomas A. Fleisher, MD MUD HSCT should be considered early in the course of Bethesda, MD CGD in children with severe invasive infection.

REVIEWER COMMENTS. Where previously HSCT was recom- Excellent Survival After Sibling or Unrelated mended only in patients with HLA-MRDs, these results Donor Stem Cell Transplantation for Chronic suggest that earlier HSCT with related or unrelated Granulomatous Disease donor stem cells provides good outcomes and low Martinez CA, Shah S, Shearer WT, et al. J Allergy Clin complication rates, and this may lead to improved Immunol. 2012;129(1):176–183 survival and quality of life in patients with CGD as well as less end-organ damage. PURPOSE OF THE STUDY. To determine outcomes and survival in patients with chronic granulomatous disease (CGD) URL: www.pediatrics.org/cgi/doi/10.1542/peds.2012–2183GGGG after hematopoietic stem cell transplantation (HSCT) in Allison Burbank, MD both HLA-matched related (MRD) and unrelated donor Stacie M. Jones, MD (MUD) transplants. Little Rock, AR

PEDIATRICS Volume 130, Supplement 1, October 2012 S51 Downloaded from www.aappublications.org/news by guest on September 28, 2021 The Wisconsin Approach to Newborn Screening for Severe Combined Immunodeficiency Thomas A. Fleisher Pediatrics 2012;130;S50 DOI: 10.1542/peds.2012-2183FFFF

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 The Wisconsin Approach to Newborn Screening for Severe Combined Immunodeficiency Thomas A. Fleisher Pediatrics 2012;130;S50 DOI: 10.1542/peds.2012-2183FFFF

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