Sex: M
Vaccine: MMRV
Symptoms: Lymphadenopathy, Lymphocyte count increased, Meningitis, Monocyte count normal, Neisseria test positive
Clinical narrative: He had pancytopenia, decreased fibrinogen levels, increased ferritin levels, and increased circulating levels of soluble IL-2 receptor, meeting the clinical criteria for hemophagocytic lymphohistiocytosis (HLH); Meningitis caused by vaccine-strain mumps was confirmed; he was hospitalized with fever, cough, and emesis occurring 7 days after vaccination with the measles, mumps, rubella, and varicella vaccines;   This literature marketed report has been received from the author of a published article referring to a 12-month-old male patient.  The patient was a nonconsanguineous boy with normal newborn screening results for severe combined immune deficiency (T-cell receptor excision circles, more than 252 copies/mL), was hospitalized 5 times in the first year of life with dehydration caused by common viral illnesses, including respiratory syncytial virus, norovirus, and coxsackie virus. At 12 months of age, he was hospitalized with fever, cough, and emesis occurring 7 days after vaccination with the measles, mumps, rubella, and varicella vaccines (manufacturer unknown) (strength, dose, frequency, route, lot# and expiration date were not reported) for prophylaxis (Contraindicated product administered). He rapidly had respiratory insufficiency and abdominopelvic ascites accompanied by diffuse adenopathy. Laboratory evaluation did not suggest a cellular or humoral immunodeficiency. He had pancytopenia, decreased fibrinogen levels, increased ferritin levels, and increased circulating levels of soluble IL-2 receptor, meeting the clinical criteria for hemophagocytic lymphohistiocytosis (HLH). Meningitis caused by vaccine-strain mumps was confirmed by means of PCR of cerebral spinal fluid. High-dose intravenous immunoglobulin (IVIG) treatment (2 g/kg) has been reported to be useful in the management of a STAT2-deficient patient with severe viral infections. Treatment of the patient with high-dose IVIG led to prompt resolution of HLH, with defervescence and normalization of ferritin levels and cell counts. He was subsequently started on IVIG (0.5 g/kg) every 3 weeks and avoids all live viral vaccines. The patient was 2 years old and had not had any further infections, hospitalizations, or episodes of HLH. Targeted next-generation sequencing of the patient's genomic DNA for 207 genes associated with primary immunodeficiency identified a novel homozygous splice donor variant in STAT2. His parents were heterozygous for the variant. No mutations were identified in other genes associated with primary HLH or primary immune deficiency. RT-PCR was performed on mRNA from EBV-transformed B-lymphoblastoid cell lines (BLCLs) from control subjects and the patient to determine whether the mutation affected STAT2 splicing. The 533-bp fragment surrounding the mutation site was identified in the control subject. In contrast, a lower molecular weight band of approximately 437 bp was identified in cDNA from the patient's BLCLs. Sanger sequencing demonstrated abnormal splicing in the patient's cDNA amplicon, resulting in deletion of exon 13 and in-frame splicing of exons 12 and 14. Immunoblotting of lysates from BLCLs demonstrated abrogation of STAT2 protein expression in the patient without expression of any truncated protein products. STAT2 deficiency in human subjects and mice is characterized by defective type I interferon signaling. The infection and subsequent transformation of B cells with EBV activates STAT2 and upregulates expression of interferon-stimulated genes, including IFIT1, ISG15, and IRF7, which are further increased after exposure to type I interferons. Expression of IFIT1, ISG15, and IRF7 was severely decreased in the patient's BLCLs compared with those from control subjects. Furthermore, the patient's BLCLs did not upregulate IFIT1, ISG15, and IRF7 after IFN-a stimulation, indicating a lack of STAT2-driven signaling in response to type I interferons. Lab test result included: White blood cell (WBC)s (unknown date, 12 months of age): 3.71 thousand cells/micro-L; WBCs (unknown date, 14 months of age): 13.06 thousand cells/micro-L; Neutrophils (unknown date, 12 months of age): 0.91 thousand cells/micro-L ;Neutrophils (unknown date, 14 months of age): 4.35 thousand cells/micro-L ;Lymphocytes (unknown date, 12 months of age): 2.36 thousand cells/micro-L ;Lymphocytes (unknown date, 14 months of age): 6.99 thousand cells/micro-L; Monocytes (unknown date, 12 months of age): 0.20 thousand cells/micro-L; Monocytes (unknown date, 14 months of age): 0.46 thousand cells/micro-L; Hemoglobin (unknown date, 12 months of age): 7.9 thousand cells/micro-L ;Hemoglobin (unknown date, 14 months of age): 10.2 thousand cells/micro-L ;Hematocrit (unknown date, 12 months of age) 23.6 thousand cells/micro-L; Hematocrit (unknown date, 14 months of age)29.8 thousand cells/micro-L; IgG (unknown date, 12 months of age) 884 mg/dL ;IgG (unknown date, 14 months of age) 1386 mg/dL; IgM (unknown date, 12 months of age) 80 mg/dL ;IgM (unknown date, 14 months of age) 87 mg/dL ;IgA (unknown date, 12 months of age) 52 mg/dL ;IgA (unknown date, 14 months of age) 28mg/dL; Tetanus (unknown date, 14 months of age) 5,530cpm;Platelets (unknown date, 12 months of age): 89 thousand per microlitre; Platelets (unknown date, 14 months of age): 474 thousand per microlitre;CD3+ (unknown date, 12 months of age): 804 thousand cells/micro-L  ;CD3+ (unknown date, 14 months of age): 3,651 thousand cells/micro-L ;CD3+CD4+ (unknown date, 12 months of age): 261 thousand cells/micro-L ;CD3+CD4+ (unknown date, 14 months of age): 1070 thousand cells/micro-L ;CD45RA+CCR7+ (unknown date, 12 months of age): 66.8 %CD4+; CD45RA+CCR7+ (unknown date, 14 months of age): 52.4% CD4+; CD45RA-CCR7+ (unknown date, 12 months of age): 22.6 % CD4+; CD45RA-CCR7+ (unknown date, 14 months of age): 28.2% CD4+; CD45RA-CCR7- (unknown date, 12 months of age): 9.5 % CD4+; CD45RA-CCR7- (unknown date, 14 months of age): 18.1% CD4+; CD45RA+CCR7- (unknown date, 12 months of age): 0.9 % CD4+; CD45RA+CCR7- (unknown date, 14 months of age): 15% CD4+;CD3+CD8+ (unknown date, 12 months of age): 505 thousand cells/micro-L; CD3+CD8+ (unknown date, 14 months of age): 2,328thousand cells/micro-L; CD45RA+CCR7+ (unknown date, 12 months of age): 55.9 % CD8+; CD45RA+CCR7+ (unknown date, 14 months of age): 70.4% CD8+; CD45RA-CCR7+ (unknown date, 12 months of age): 6.5% CD8+ ; CD45RA-CCR7+ (unknown date, 14 months of age): 1.5% CD8+; CD45RA-CCR7- (unknown date, 12 months of age): 9.5 % CD8+; CD45RA-CCR7- (unknown date, 14 months of age): 13.2% CD8+; CD45RA+CCR7- (unknown date, 12 months of age): 14% CD8+ ; CD45RA+CCR7- (unknown date, 14 months of age): 15% CD8+; CD19+ (unknown date, 12 months of age): 465 thousand cells/micro-L; CD19+ (unknown date, 14 months of age): 2,375thousand cells/micro-L; CD27-IgD+ (unknown date, 12 months of age): ND ; CD27-IgD+ (unknown date, 14 months of age) :90.9 % CD19+; CD27-+IgD+ (unknown date, 12 months of age): not determined (ND); CD27-+IgD+ (unknown date, 14 months of age): 4.5 % CD19+; CD27+IgD- (unknown date, 12 months of age): ND ; CD27+IgD- (unknown date, 14 months of age): 2.7 % CD19+; CD3-CD56+ (unknown date, 12 months of age): 216 thousand cells/micro-L; CD3-CD56+ (unknown date, 14 months of age): 1,136 thousand cells/micro-L; Concanavalin A (unknown date,14 months of age):34503cpm; PHA (unknown date,14 months of age): 229096cpm; Anti-CD3 (unknown date,14 months of age)76757cpm; T-cell mitogen background (unknown date,14 months of age) 264cpm; Candida (unknown date,14 months of age) 25,213cpm; T-cell antigen background (unknown date,14 months of age) 3,502cpm.  The outcome of haemophagocytic lymphohistiocytosis and meningitis was reported as recovered. The reporter considered haemophagocytic lymphohistiocytosis and meningitis to be related to measles, mumps, rubella, and varicella vaccines (manufacturer unknown).  Upon internal review, haemophagocytic lymphohistiocytosis and meningitis were considered to be medically significant.  A copy of the published article is attached as further documentation of the patient's experience.