Sex: M
Vaccine: PPV
Symptoms: Epstein-Barr virus test, Failure to thrive, Hepatosplenomegaly, Measles antibody negative, Monocyte count normal
Clinical narrative: Boosting with polysaccharide pneumococcal vaccine resulted in poor responses; This literature marketed report has been received from the author of a published article referring to a 48-year-old male patient.  The patient had a family history that included the infantile deaths of three maternal uncles. He presented at 5 months of age with recurrent oral thrush and Pneumocystis jiroveci pneumonia. He later developed Candida esophagitis and failure to thrive. The patient received an unconditioned transplant at 11 months of age in 1971 that comprised whole, unprocessed bone marrow. Human leukocyte antigen (HLA) compatibility with his 11-year-old sister, the donor, was determined by HLA serotyping andmixed leukocyte culture. The immediate post-transplant course was complicated by acute Graft vs. Host Disease (GvHD) with rash, fever, hepatosplenomegaly, and respiratory distress that resolved after treatment with prednisone. In the first 10 years post-transplant, he developed chronic dry eyes, a few cases of pneumonia, and one episode of cellulitis. He was lost to follow-up at age 17.  He was referred back to an Immunology department three decades later because of the failure of four corneal transplants. The patient reported living a "normal life" working as a plumber. He had never required immunoglobulin (Ig) replacement or nutritional support. He had recurrent dental infections, and one skin carcinoma had been removed. He developed cutaneous, oropharyngeal, and genital warts that relapsed and remitted but had worsened in recent years (numerous, confluent cutaneous warts on palmar surface of hand). In the prior 5 years, he had three pneumonias, chronic sinusitis (Computed tomography (CT) sinuses showing turbinate edema and maxillary sinus mucosal thickening with layering fluid), and a skin infection due to Methicillin-resistant Staphylococcus aureus (MRSA). The IL2RG gene was sequenced from patient's buccal mucosal cells, and this revealed a hemizygous variant on Chromosome X at location g.70329160 (based on build GRCh37/hg19), NM_000206.2:c.675C greater than A, resulting in p.Ser225Arg. The investigators diagnosed the patient with X-linked severe combined immunodeficiency (X-SCID).   Lymphocyte enumeration showed normal numbers of T and B cells but low numbers of Natural killer (NK) cells. A predominantly memory phenotype was seen for both CD4+ and CD8+ T cells. T-Cell Receptor Excision Circles (TREC)s were absent. Lymphocytes responded with modest proliferation after stimulation with mitogens phytohemag-glutinin (PHA), pokeweed mitogen (PWM), and concanavalin A (ConA). There was a minimal proliferative response to either tetanus antigen or Candida. The response to Staph enterotoxin B stimulation was robust. Foxp3+ Tregs comprised 2.7% of circulating CD4+ T cells (normal). The diversity of the patient's T cells was examined by assessing the frequency of usage of 24 TCR Vbeta regions in T cells by flow cytometry. The investigators found 31.1% of his T cells were Vbeta3+, 22.5% of his T cells were Vbeta1+, and 5.7% of his T cells were Vbeta16+, while proportions of 15 other Vbeta regions were lower than normal. Thus, while T-cell numbers were normal, the patient's T cells had a diminished repertoire.  In vitro assays revealed that NK-cell-dependent cytotoxicity was impaired in the patient. The investigators examined killing after normalizing for numbers of NK cells and offered a range of erythroblastoid target cell concentrations, but killing was less than 2% and was not accentuated by pre-incubation with the gc cytokines IL-2 or IL-15. This result suggested that his NK cells were poorly functional.  HLA typing was performed by sequencing DNA isolates from the patient's buccal mucosal cells, confirming a 12-out-of-12 match with the donor. To assess engraftment and the origins of specific hematopoietic lineages, the investigators performed chimerism studies on sorted cells by short-tandem repeats. As expected, myeloid cells were entirely from the recipient, and T cells were entirely from the donor. However, B cells were 93% from the recipient and 7% from the donor, and the degree of uncertainty in this test did not preclude the possibility that 100% of the B cells are from the recipient. NK cells were 69% from recipient. To further understand the origins of these cells, we rigorously purified T cells, B cells, and monocytes by flow sorting and analyzed each population with whole exome sequencing. None of the T cells showed rare variants in Interleukin 2 Receptor Subunit Gamma (IL2RG), while 100% of the monocytes and B cells showed the pathogenic variant of IL2RG. Thus, a somatic reversion mutation was not responsible for the resiliency of the patient's B cells nor were any of the B cells derived from the donor.  Thirty percent of the patient's B cells had a memory phenotype, and 5% were of the switched memory subtype. These proportions were normal for his age. His serum immunoglobulin levels were normal to elevated across all isotypes, and he had never been on Ig replacement. B-cell function, as measured by antibody titers, showed measurable titers to tetanus, cytomegalovirus (CMV), and herpes simplex virus (HSV)-1 but no protective titers for Streptococcus pneumoniae, polio, or HiB. He had absent titers to Epstein-Barr virus (EBV) and HSV-2. Boosting with Pneumococcal Vaccine, Polyvalent (23-valent) (PNEUMOVAX23) (reported as PNEUMOVAX, also reported as polysaccharide pneumococcal vaccine) (dose, route, lot# and expiration date were not reported) for prophylaxis resulted in poor responses (Therapy partial responder). These studies suggested a specific antibody defect to polysaccharide antigens but otherwise relatively intact B-cell function.   To better delineate the patient's B-cell function, the investigators studied the response of his lymphocytes to cytokines that signal through the gamma-c receptor. The investigators found the patient's T cells showed normal gamma-c signaling (IL-2, IL-4, and IL-21 stimulation in CD4+ T cells in control, sister (donor) and patient, as measured by pSTAT5, pSTAT6, and pSTAT3, respectively). When the investigators tested B-cell responses to gamma-c-dependent cytokines, they found that B cells stimulated with IL-21 showed normal phosphorylation of STAT3 (IL-4 and IL-21 stimulation of B cells in control, sister (donor), and patient as measured by pSTAT6 and pSTAT3). This result suggested that the genomic variant gamma-c, which is present in the B cell population, retains normal IL-21 signaling. Most NK cells showed normal gamma-c signaling (IL-2 and IL-15 stimulation in NK cells in control and patient as measured by pSTAT5), corresponding to the degree of chimerism. Finally, the investigators found that IL-4 stimulation showed normal phosphorylation of STAT6 in B cells and monocytes.   The laboratory results on unknown dates included: CD3+ was 1515 cells/micro-L; CD4+ was 511 cells/micro-L; CD8+ was 1116 cells/micro-L; CD56+/CD16+ was 17 cells/micro-L; CD19+ was 230 cells/micro-L; CD4:CD8 was 0.52. Memory B cells (CD27+ of CD19+) was 30%; Switched memory B cells (IgD-IgMof CD19+CD27+) was 5%; Immature B cells (CD21 low of CD19+) was 8%; CD4 Naive (CD45RA+CD62L+ of CD4+) was 4%; CD4 Effector memory (CD45RA-CD62L- of CD4+) was 65%; CD4 Central memory (CD45RA-CD62L+ of CD4+) was 26%; CD4 TEMRA (CD45RA+CD62L- of CD4+) was 5%; CD8 Naive (CD45RA+CD62L+ of CD8+) was 6%; CD8 Effector memory (CD45RA-CD62L- of CD8+) was 42%; CD8+ Central memory (CD45RA-CD62L+ of CD8+) was 10%; CD8 TEMRA (CD45RA+CD62L- of CD8+) was 41%. Immunoglobulin G (IgG) was 1370 mg/dL; Immunoglobulin A (IgA) was 527 mg/dL; Immunoglobulin M (IgM) was 292 mg/dL; Immunoglobulin E (IgE) was 6 kIU/L. Pre-pneumovax Streptococcal pneumonia titers (unit: micro-g/mL) (unknown date): Serotype 1 (1) was less than 0.3; Serotype 2 (2) was 1.6; Serotype 3 (3) was less than 0.3; Serotype 4 (4) was less than 0.3; Serotype 5 (5) was 0.7; Serotype 8 (6) was 0.8; Serotype 9 (9N) was less than 0.3; Serotype 12 (12F) was 2.0; Serotype 14 (14) was 1.4; Serotype 17 (17F) was less than 0.3; Serotype 19 (19F) was 2.6; Serotype 20 (20) was 0.3; Serotype 22 (22F) was less than 0.3; Serotype 23 (23F) was 16.1; Serotype 26 (6B) was 0.7; Serotype 34 (10A) was less than 0.3; Serotype 43 (11A) was 5.1; Serotype 51 (7F) was less than 0.3; Serotype 54 (15B) was less than 0.3; Serotype 56 (18C) was less than 0.3; Serotype 57 (19A) was less than 0.3; Serotype 68 (9V) was less than 0.3; Serotype 70 (33F) was less than 0.3. There was 26% protective pre-pneumovax. Post-pneumovax Streptococcal pneumonia titers (unit: micro-g/mL) (unknown date): Serotype 1 (1) was 0.3; Serotype 2 (2) was 1.2; Serotype 3 (3) was less than 0.3; Serotype 4 (4) was less than 0.3; Serotype 5 (5) was 0.8; Serotype 8 (6) was 1.1; Serotype 9 (9N) was less than 0.3; Serotype 12 (12F) was 1.1; Serotype 14 (14) was 0.4; Serotype 17 (17F) was less than 0.3; Serotype 19 (19F) was 4.2; Serotype 20 (20) was 0.4; Serotype 22 (22F) was less than 0.3; Serotype 23 (23F) was 2.9; Serotype 26 (6B) was 1.0; Serotype 34 (10A) was less than 0.3; Serotype 43 (11A) was less than 0.3; Serotype 51 (7F) was less than 0.3; Serotype 54 (15B) was less than 0.3; Serotype 56 (18C) was less than 0.3; Serotype 57 (19A) was less than 0.3; Serotype 68 (9V) was less than 0.3; Serotype 70 (33F) was less than 0.3. There was 9% protective post-pneumovax. Tetanus IgG was 3.7 IU/mL (Protective); HiB IgG was 0.1 micro-g/mL (Not protective); EBV DNA PCR was negative; EBNA-1 IgG was negative; EBV-VCA IgM was negative; CMV Ab was positive; CMV DNA PCR was not detected; HSV 1 type specific IgG (index) was 10.03 (unit unspecified) (positive); HSV 2 type specific IgG (index) was less than 0.90 (unit unspecified) (Not detected); HSV 1 DNA PCR was negative; HSV 2 DNA PCR was negative; Poliovirus type I was less than 1:10 (Not detected); Poliovirus type III was less than 1:10 (Not detected); Varicella IgG (IV) was 75 (unit unspecified) (negative); Measles Ab immune status was negative.  The outcome of the event was unknown. The reporter considered the event to be related to Pneumococcal Vaccine, Polyvalent (23-valent) (manufacturer unknown).    A copy of the published article is attached as further documentation of the patient's experience.