Development of specific T-cell responses to Candida and tetanus antigens in partial DiGeorge syndrome

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1 Development of specific T-cell responses to Candida and tetanus antigens in partial DiGeorge syndrome Carla M. Davis, MD, a Vikas S. Kancherla, MD, a Ashwini Reddy, MD, a Wenyaw Chan, PhD, b Hung-Wen Yeh, PhD, c Lenora M. Noroski, MD, a Howard Rosenblatt, MD, a,d William T. Shearer, MD, PhD, a and Javier Chinen, MD, PhD a Houston and Austin, Tex, and Kansas City, Kan Background: Partial DiGeorge syndrome (pdgs) presents with thymic hypoplasia and a variable decrease in T-cell numbers. Although lymphocyte proliferation to mitogens is generally preserved, it is uncertain whether the development of specific cellular immunity in pdgs is similarly preserved. Objective: We sought to study the development of antigenspecific T-cell responses in patients with pdgs with regard to their initial CD3 T-cell counts. Methods: A retrospective review of 93 patients with pdgs followed at Texas Children s Hospital Allergy and Immunology Clinic from 1991 to 2006 was performed. Serial lymphocyte proliferation to Candida and tetanus antigens was longitudinally analyzed. Antigen-specific lymphoproliferation was compared with initial patient CD3 T-cell counts of less than the 10th percentile (n 5 63), the 10th to 50th percentile (n 5 20), and greater than the 50th percentile (n 5 10) of age-matched normal control values. Tetanus-specific IgG levels and the number of tetanus immunizations were also studied. Results: The median CD3 T-cell counts at baseline in all 3 groups were as follows: 10th percentile, 1188 cells/mm 3 (range, cells/mm 3 ); 10th to 50th percentile, 2816 cells/mm 3 (range, cells/mm 3 ); greater than 50th percentile, 4246 cells/mm 3 (range, cells/mm 3 ). Thirty-one (46%) of 68 patients with pdgs who received at least 3 tetanus vaccines had persistent Candida and tetanus-specific cellular immunity, and 24 (35%) did not have immunity to either antigen. Most (22/24) of these patients had CD3 T-cell counts at presentation of less than the 10th percentile of normal values. Protective tetanusspecific IgG titers (>0.10 IU/mL) were detected in all patients tested from the age of 2 to 85 months (n 5 72). Conclusion: Some patients with pdgs with low CD3 T-cell counts might not have specific Candida and tetanus cellular immunity. (J Allergy Clin Immunol 2008;122: ) Key words: Partial DiGeorge syndrome, 22q11 deletion, velocardiofacial syndrome, T-cell deficiency, tetanus immunity, Candida species immunity From a the Department of Pediatrics, Allergy and Immunology Section, Baylor College of Medicine, Houston; b the Division of Biostatistics, School of Public Health, University of Texas Health Science Center at Houston; c the Department of Biostatistics, the University of Kansas Medical Center, Kansas City; and d the Allergy and Immunology Service, Dell Children s Hospital, Austin. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. Received for publication April 28, 2008; revised June 13, 2008; accepted for publication June 17, Available online September 16, Reprint requests: Carla M. Davis, MD, Allergy and Immunology Section, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, MC FC , Houston, TX cmdavis@texaschildrenshospital.org /$34.00 Ó 2008 American Academy of Allergy, Asthma & Immunology doi: /j.jaci Abbreviations used ConA: Concanavalin A cpm: Counts per minute DGS: DiGeorge syndrome DTaP: Diphtheria, tetanus, and pertussis LPA: Lymphocyte proliferation assay pdgs: Partial DiGeorge syndrome PHA: Phytohemagglutinin DiGeorge syndrome (DGS) is one of the most common chromosomal disorders, with an estimated prevalence of 1 in 4000 to The syndrome arises from a defect in the differentiation of the third and fourth pharyngeal pouches during embryologic development. The resulting clinical features include conotruncal cardiac abnormalities, hypoparathyroidism, velopharyngeal insufficiency, craniofacial dysmorphism, and thymic hypoplasia. In published reports of large patient cohorts, the molecular defect has been identified in 90% to 95% of cases as a hemizygous deletion of chromosome 22q11. 2 Approximately 5% to 10% of patients do not have the deletion, and in some cases, deletions of chromosome 10p have been identified. 2 The immune defect component of this syndrome is variable, ranging from the absence of T cells to normal T-cell numbers. This defect is thought not to involve an intrinsic T-cell dysfunction. The term complete DiGeorge anomaly is used to describe less than 1% of patients with DGS who are athymic and have minimal circulating T cells (<50 cells/ml). 3 Patients with partial Di- George syndrome (pdgs) have thymic hypoplasia, as evidenced by the presence of circulating T cells and a spectrum of proliferative responses. 2 Clinically, 40% of patients are as well as their healthy counterparts, and 60% have episodes of recurrent sinusitis, otitis media, bronchitis, and pneumonia. 4 In addition to immunologic dysfunction, anatomic abnormalities, including bronchomalacia and aspiration, can contribute to this increased frequency of respiratory tract infections. With the variability of T-cell counts reported in patients with pdgs, there is currently no consensus regarding the minimum T-cell number or function needed for safe delivery of live viral vaccines. The Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency developed by the Joint Council of Allergy, Asthma, and Immunology recommends that no live viral vaccine be administered to patients with severely impaired specific immunity. 5 Similarly, the guidelines of the American Academy of Pediatrics ( Red Book ) state live viral vaccines are contraindicated for partial defects of T-cell function, which might include pdgs. 6 Retrospective studies of patients with pdgs with minimal-to-moderate compromise in T-cell production suggest that those with CD4 T-cell counts of greater than 1194

2 J ALLERGY CLIN IMMUNOL VOLUME 122, NUMBER 6 DAVIS ET AL cells/ml can safely receive the measles-mumps-rubella live attenuated viral vaccine. 7-9 The natural history of lymphocyte numbers in pdgs has been described in several studies, and lymphocyte responses to mitogens have largely been studied in cross-sectional analyses However, the development of cellular immune function to specific antigens has not been well documented. We sought to longitudinally describe T-cell responses to antigens in our cohort of patients with pdgs. METHODS Patients We reviewed the medical records of 93 children with a diagnosis of pdgs followed from 1991 to 2006 by the Allergy and Immunology Section at Texas Children s Hospital in Houston, Texas, with approval of the Institutional Review Board of Baylor College of Medicine. We based the diagnosis of DGS on clinical criteria, molecular criteria, or both (22q11.2 or 10p13-14 deletion). The clinical diagnosis of pdgs required the presence of a cardiac anomaly, hypoparathyroidism with hypocalcemia, and diminished T-cell counts. Those with complete DGS (CD3 T-cell counts <50 cells/mm 3 and phytohemagglutinin [PHA] proliferation <10,000 counts per minute [cpm], n 5 4) were excluded. The ages of the patients at the time of the most recent evaluation ranged from 1 to 210 months. Laboratory tests Genetic studies for chromosome 22q11.2 and 10p13-14 deletion were performed at the Kleberg Genetic Clinic at Baylor College of Medicine. Immunophenotyping and lymphocyte proliferation assays (LPAs) were performed by the Allergy and Immunology Laboratory at Texas Children s Hospital using flow cytometry (Cytomics FC 500; Coulter Corp, Hialeah, Fla). Age-matched normal values for phenotyping were obtained from previously published values. 14 Lymphocyte proliferation was measured to PHA (at 10 mg/ml) and concanavalin A (ConA; at 50 mg/ml) by using the tritiated thymidine incorporation assay. Specific antigen proliferation was measured to tetanus (0.08 flocculation units/ml) and Candida albicans (10 mg/ml). Lymphocyte cultures were pulsed with mitogens after 72 hours and harvested after 96 hours. Cultures were pulsed with the antigens after 5 days and harvested on day 6. The proliferation assays were performed in triplicate. LPAs were also performed on healthy adults with each assay (n 5 257). Children presenting with normal immunity are expected to have cellular immune responses to both Candida and tetanus antigens, as a result of natural exposure and vaccine administration, respectively. A standard definition for adequate cellular immunity to antigens is not available in the literature. Based on our laboratory historical data, we considered that a normal cellular specific immune response must include LPA to both Candida and tetanus antigens, with a stimulation index (SI) of greater than 3 and a cpm value of greater than Serum immunoglobulin levels and specific antibody titers to tetanus toxin were performed by Texas Children s Hospital Pathology and Specialty Laboratories, Inc. Low immunoglobulin levels were defined as less than 2 SDs below the mean for age. Protective antibody titers to tetanus were defined as greater than 0.10 IU/mL, according to the various certified clinical laboratories. Statistical analysis Initial T-cell subset counts and percentages, LPA cpm values, and SIs were analyzed for the entire cohort. Because our patient population presented at different ages, the data were analyzed based on the age at first immune evaluation. Patients with pdgs were stratified into one of 3 groups based on CD3 T-cell counts at initial presentation (<10th percentile, 10th-50th percentile, and >50th percentile). The percentiles used for this classification were based on published lymphocyte subset norms. 14 Longitudinal data were analyzed by means of generalized estimation equations (reported as cpm) or linear mixed models (continuous outcomes of SI). The values were log transformed before analysis by using the mixed model. In this retrospective study TABLE I. Clinical characteristics of the cohort of patients with pdgs at Texas Children s Hospital, Houston, Texas ( ) Clinical characteristic Patients (n 5 93) Sex Male 52 (56%) Female 41 (44%) Chr 22q11.2 deletion 78 (84%) Cardiac defect 81 (87%) Hypocalcemia 68 (73%) patients were observed at differing clinical intervals (age in months), and the numbers of observations were not the same among all patients. Therefore these models were used to account for the correlated nature of each outcome variable within the subject and to adjust for the weight difference caused by an unequal number of observations between subjects. RESULTS Patient characteristics Further data on patient characteristics are shown in Table I. Our patient cohort had a balanced sex distribution, and 84% presented with the 22q11.2 deletion. None of our patients had the 10p13-14 deletion. More than 85% of our patients had cardiac anomalies and hypocalcemia. Fig 1 shows the distribution of absolute CD3 T-cell counts at initial presentation to our clinic: of all patients, 68% (n 5 63) were in less than the 10th percentile, 22% (n 5 20) were in the 10th to 50th percentile, and 10% (n 5 10) were in greater than the 50th percentile. The median age at presentation was 4.4 months (range, months). Fifty-eight (62%) patients presented before 12 months of age, and 85 (91%) presented before 60 months of age. CD3 T-cell counts decreased mildly with age (P <.001), which is consistent with previous reports (Fig 2, A). 10,15 The CD3 T-cell percentages trended toward an increase over time (Fig 2, B), and the percentages of CD4 T-cells were relatively stable over time, with no statistically significant decrease (data not shown). Mitogen proliferation according to initial CD3 T-cell count is preserved Ninety (95%) patients had lymphocyte responses to PHA greater than 100,000 cpm (Fig 3). LPAs to PHA ranged from 17,184 to 368,065 cpm (median, 178,068 cpm) and did not statistically change over time. Only 4 patients had persistent proliferation of less than 100,000 cpm. Three of these 4 patients had a baseline CD3 T-cell count of less than the 10th percentile of normal values, and 1 had a CD3 T-cell count of greater than the 50th percentile. Of the 4 patients with proliferation of less than 100,000 cpm, 1 patient had poor responses to both Candida antigen and tetanus, 1 had a variable response to Candida antigen and tetanus (the patient intermittently had responses and then lost both), and 2 had adequate responses. Lymphocyte proliferation to ConA also did not statistically change over time (median, 95,797 cpm; range, ,023 cpm; data not shown). Fig 4 shows that the 3 groups defined according to initial CD3 T-cell counts show similar stability in lymphocyte proliferation to PHA. PHA proliferation at baseline for all 3 groups was greater than 160,000 cpm. The group with CD3 T-cell absolute counts of greater than the 50th percentile of healthy control subjects had the highest cpm values, up to 400,000 cpm. All groups maintained good proliferative responses to PHA over the 14-year

3 1196 DAVIS ET AL J ALLERGY CLIN IMMUNOL DECEMBER 2008 FIG 1. CD3 T-cell absolute counts at baseline presentation. Diamonds represent individual values. Lines represent values for age-matched healthy control subjects, as indicated. FIG 3. Conserved mitogen (PHA) stimulated lymphocyte proliferation (cpm) progress over time after baseline presentation. Available results obtained from all 93 patients are presented (438 points). Points per patient range from 1 to 19. Available results obtained from all patients are presented. The red line represents overall trend, according to the multiple mixed linear model. FIG 4. Conserved mitogen (PHA) stimulated lymphocyte proliferation (cpm) trends over time after baseline presentation in patient groups stratified by baseline CD3 lymphocyte counts (<10th percentile [dashed line], 10th-50th percentile [dotted line], and >50th percentile [solid line] of published normal values). FIG 2. Slow decrease of CD3 T-cell counts over time. All obtained values (456 points) from 93 patients with pdgs are plotted. Data points per patient range from 1 to 21. The red line represents the overall trend calculated by using the multiple mixed linear model. A, CD3 T-cell absolute counts (in cells per cubic millimeter). B, CD3 T-cell percentages (CD3 T-cell count/total lymphocyte number). period of observation. Lymphoproliferation to ConA also showed stability over time, with only a slight decrease, although one in the normal range (>50,000 cpm, data not shown). Development of lymphocyte proliferation response to Candida antigen and tetanus There was a significant increase in both the lymphocyte proliferation to Candida antigen based on absolute cpm (P <.04) and SI (P <.01) values for patients with pdgs (Fig 5, A and B). Increase of lymphocyte proliferation to tetanus was also significant (P <.005; SI, P <.001; Fig 5, C and D). Fourteen (15%) patients in our cohort had 1 or 2 assays with absent lymphocyte responses to Candida antigen stimulation, which became positive later. Six of these patients were tested within the first 7 months of life, when it is possible that specific cellular immune responses were still developing and optimal exposure for adequate sensitization had not yet been achieved. In this pdgs cohort the development of specific immunity to Candida antigen occurred between 3 and 42 months of age. Although the specific cellular responses to Candida antigen and tetanus, followed over a 14-year period, were adequate in most patients of our cohort, we sought to determine whether cellular function developed differentially in patients with lower CD3 cell absolute counts at presentation. The initial median SI of all 3 groups ranged from 2 to 4 (Fig 6, A). Candida antigen specific cellular function increased most markedly in the patients with pdgs who had initial CD3 absolute counts greater than the 50th percentile for age. The SI increased on average more than 25-fold in this group. Of note, Candida antigen specific cellular function also developed for those who had CD3 counts initially less than the 10th and between

4 J ALLERGY CLIN IMMUNOL VOLUME 122, NUMBER 6 DAVIS ET AL 1197 FIG 5. Increasing antigen-specific stimulated lymphocyte proliferation over time. All obtained values (443 points) from 93 patients are plotted. Data points per patient range from 1 to 19. The red line represents overall trend, according to the multiple mixed linear model. A, Candida antigen stimulated lymphocyte proliferation (cpm). B, Candida antigen stimulated lymphocyte proliferation (SI). C, Tetanus-stimulated lymphocyte proliferation (cpm). D, Tetanus-stimulated lymphocyte proliferation (SI). the 10th and 50th percentiles. Interestingly, increase of tetanus lymphocyte proliferation SIs was more marked in the pdgs group with initial CD3 absolute counts of less than the 10th percentile (Fig 6, B). Initial tetanus lymphocyte proliferation increased over the 14-year period to an SI of greater than 10 for those with the lowest CD3 absolute count at presentation. The other 2 groups had a more modest increase in proliferation to tetanus with an SI increase to greater than 6. When the data were analyzed by using the generalized estimation equations and linear mixed models, there was no significant difference between the CD3 T cell count stratified groups and proliferation responses to mitogens or antigens over time. Most patients with pdgs had sustainable cellular immunity to Candida antigen and tetanus by 4 years of age A progressive increase in immunity was noted in patients who received at least 3 tetanus vaccinations and had more than 1 LPA. We studied those patients who had evidence of receiving at least 3 tetanus immunizations to evaluate individual development of cellular immunity after antigen exposure. These patients had LPAs ranging from the ages of 2 to 210 months. Of a total of 68 tetanus-immunized patients, 31 (46%) patients with pdgs initially had inadequate immunity and subsequently had immunity at the age of 6 to 199 months (ideal immunity group). The development of ideal immunity occurred in 21 (69%) of these 31 patients by 4 years of age (Fig 7, A). Thirteen (19%) patients had evidence of immunity to Candida, tetanus, or both that was not detected subsequently (transient immunity group). In the ideal and transient immunity groups, 65% (20/31) and 54% (7/13) had baseline CD3 counts of less than the 10th percentile, respectively. Twenty-four (35%) of the tetanus-vaccinated patients (n 5 68) did not show lymphocyte responses to Candida, tetanus, or both (incomplete immunity group; Fig 7, B). These 24 patients had adequate lymphocyte proliferative responses to PHA (range, 108, ,065 cpm), and 22 (92%) patients had an initial CD3 T-cell count of less than 10% of normal control values. However, only 7 of these patients have been followed up to 4 years of age. In this incomplete immunity group 16% had poor LPA responses to only Candida antigen, 37% had poor responses to tetanus, and 47% had poor responses to both antigens. Ten (16%) of the 63 patients with CD3 T-cell counts of less than 10% of normal values had absent antigen-specific responses to both Candida and tetanus. Nine of these 10 patients were less than 4 years old when the last LPA was performed. Thirty (32%) patients in our 93-patient cohort received live viral vaccines. Sixteen (11%) of the 63 patients with pdgs with CD3 counts of less than the 10th percentile received live viral vaccines, and none had adverse reactions. Nine (50%) of those 16 patients had LPAs that revealed immunity to both tetanus and Candida. Two were only Candida species immune, and 2 were only immune to tetanus. Four (25%) of the 16 live viral vaccinated patients inadvertently received live viral vaccines and did not have documented immunity to either tetanus or Candida antigen. Even though there were no complications from live viral vaccines

5 1198 DAVIS ET AL J ALLERGY CLIN IMMUNOL DECEMBER 2008 FIG 7. Development of cellular immunity to Candida antigen and tetanus after 3 tetanus immunizations. A, Cumulative percentage of vaccinated patients having immunity to antigens. B, Percentage of vaccinated patients with lymphocyte proliferation to antigens (SI >3 and cpm >1000). Ideal indicates persistent immunity, transient indicates the development of antigen immune responses with subsequent loss, and incomplete indicates the lack of development of immunity. FIG 6. Increasing antigen-specific stimulated lymphocyte proliferation (SI) trends over time after baseline presentation in patient groups stratified by baseline CD3 lymphocyte counts (<10th percentile [dotted line], 10th-50th percentile [dashed line], and >50th percentile [solid line] of published age-matched normal values). A, Candida antigen specific lymphoproliferative response. B, Tetanus-specific lymphoproliferative response. in these patients, no conclusions can be made given the low number of these patients. Correlation of cellular and humoral immunity to tetanus Specific antibody to tetanus was measured in 72 patients, and all patients had protective antibody titers to tetanus. Sixty-eight patients received at least 3 tetanus vaccinations, and the other 4 patients received less than 3. Protective antibody titers for tetanus were occasionally documented in early measurements, likely reflecting maternally transferred humoral immunity to specific antigens or adequate antibody response to early tetanus vaccination beginning at 2 months of age. The age of detection of the tetanus protective IgG titer ranged from 2 to 85 months, with a median age of 22 months. We obtained immunization records with documentation of complete diphtheria, tetanus, and pertussis (DTaP) vaccine series delivery (6 vaccinations) in 43 patients. Of patients with pdgs with complete tetanus vaccination, 36 (83.7%) had protective tetanus IgG titers after 4 DTaP immunizations (Table II). Seven patients required 5 or 6 tetanus immunizations before development of protective antibody titers. Eleven of 43 fully vaccinated patients with pdgs demonstrated transient or absent LPA results to tetanus (8/11 had T-cell counts <10th percentile at baseline presentation). DISCUSSION In this cohort of patients with pdgs with surveillance of lymphocyte proliferative response to the mitogens PHA and ConA and the antigens Candida species and tetanus over a period of greater than 14 years, we confirm previous observations of the slow decrease of absolute T-cell counts and preservation of response to mitogens. Our patients presented with a wide range of T-cell counts, with two thirds of our cohort having CD3 T-cell counts of less than 10% of the age-matched normal range. Neither initial CD3 T-cell count nor LPA result to mitogens predicted the ability of cellular immunity to specific antigens in tetanus-immunized patients to develop. Almost all patients with incomplete antigen-specific cellular immunity had baseline CD3 T-cell counts of less than the 10th percentile of normal values. Not all patients with pdgs with initial CD3 T-cell counts of less than the 10th percentile of normal values had specific cellular immunity to Candida species or tetanus antigen. Patients with pdgs with higher T-cell counts generally did have specific cellular immunity to both antigens. When examining only patients with full tetanus immunization series, our data suggest that although tetanus-specific humoral responses were able to develop in all patients, a subset of them (7/ 43, 16.3%) required booster doses 5 and 6 to achieve protective antibody titers. In contrast, the development of persistent cellular specific immunity to tetanus did not occur in about one fourth of these patients without an obvious correlation with development of protective antitetanus antibody titers or the initial CD3 T-cell number. However, most of these patients did have low initial CD3 T-cell numbers. It is also conceivable that some of these patients might have specific cellular immunity at a later age, suggesting the need of increased antigen exposure. Currently, the use of live attenuated viral vaccines in patients with pdgs is controversial because there are no specific guidelines. The development of humoral immunity to vaccines has been documented in patients with pdgs and is consistent with our reported findings of tetanus serologic response. 16 The evidence

6 J ALLERGY CLIN IMMUNOL VOLUME 122, NUMBER 6 DAVIS ET AL 1199 TABLE II. Cumulative percentage of patients according to the number of tetanus vaccinations received before documentation of protective tetanus IgG titers No. of DTaP vaccinations Patients (n 5 43) 3 47% 4 84% 5 95% 6 100% that specific cellular immunity to antigens develops in these patients is important for the management and education of the patients and their families. In our cohort most patients receiving live viral vaccines had adequate immunity to tetanus or Candida species. Even though there were no complications from live viral vaccines in these patients, including those with no antigen-specific cellular immunity, the low number of patients evaluated limits definite conclusions regarding the safety of live viral vaccines in this patient population. Previous studies have suggested adequate immunity based on T-cell counts and lymphocyte proliferative responses to mitogens. 17 Azzari et al 8 described a smaller cohort of patients with pdgs receiving measles vaccines without serious adverse effects who had preservation of lymphocyte proliferation to PHA despite a low number of T cells. It is noted that these studies had limited numbers of immunized patients that might not have allowed detection of those who might have severe viral disease or reactivation of latent infection. 7,18 However, concerns exist that even in the face of good lymphocyte proliferative responses to mitogens, decreased diversity of the T-cell receptor repertoire in patients with pdgs might impair the immune response to infectious agents, such as those present in live viral vaccines. An altered T- cell repertoire has been reported in patients with pdgs by means of analysis of their spectratyping variable b chain profiles. 19,20 These concerns are illustrated by the case of a 13-month-old patient with pdgs with a CD4 T-cell count of 320 cell/ml and adequate lymphocyte proliferative response to PHA who was recently reported with a fatal viral (measles was highly suggested) pneumonia after inadvertent measles-mumps-rubella and varicella vaccine delivery. The specific antigen cellular function of this patient was not reported. 18 A biased T-cell repertoire might help to explain the lack of immunity to pathogens while demonstrating acceptable responses to mitogens, as seen in some of our pdgs cohort. In summary, we report that the development of cellular immunity to specific antigens was generally robust in our cohort of patients with pdgs, with a large majority having low initial CD3 absolute counts. We also show that there is development of specific humoral immune responses to tetanus accompanying the increase in cellular tetanus responses. In the majority of patients who had immunity to both Candida species and tetanus and received the standard schedule of immunization for tetanus, this complete immune response was accomplished by 4 years of age. Although our observations support the capacity of most patients with pdgs to have specific cellular immunity, patient evaluation of T-cell counts and mitogen proliferative responses did not identify those patients who would not have adequate antigen-specific cellular responses. In our cohort the majority of patients receiving live viral vaccines had adequate immunity to tetanus or Candida species. Therefore our data argue for continuing the recommendation of avoidance of live viral vaccines in patients with pdgs, with emphasis in those patients presenting with CD3 T-cell counts of less than the 10th percentile of age-matched normal values and without evidence of humoral or cellular responses to specific antigens. We thank Dr Celine Hanson for critical review of this manuscript; Betty Brown, Nirmi Parikh, and Pratima Patel for their excellent work in the clinical immunology laboratory; and the patients and their families. Clinical implications: This study demonstrates that specific cellular immunity to antigens is not predicted by CD3 T-cell counts at presentation in patients with pdgs, which has implications for providing recommendations for live vaccine administration in these patients. REFERENCES 1. Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, et al. 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