Age: 1.1
Sex: F
Vaccine: MMR, VARCEL
Symptoms: Natural killer cell count, Nerve compression, Neutrophil count decreased, Pneumonia, Polymerase chain reaction
Clinical narrative: Information has been received from the author (unspecified healthcare professional) of a published article refers to a 13 month old female patient with severe combined immune deficiency (SCID) and neutropenia. Her past medical history included respiratory syncytial virus (RSV) bronchiolitis at 2 months of age with persistent chronic cough, hand-foot-mouth disease at 3 months of age, chronic oral mucositis since 3 months of age and recurrent episodes of acute otitis media requiring myringotomy tube placement at 9 months of age. Family history was negative for consanguinity, immune disorders, and early childhood death and disease. During a routine paediatric visit, including scheduled vaccinations at 12 months of age, a complete blood count was obtained and revealed neutropenia with absolute neutrophil count (ANC) = 100/mm^3. A bone marrow aspirate was not diagnostic and showed normocellular marrow with granulocytic hyperplasia and left shift. Anti-neutrophil antibody was not detected. Despite an unclear aetiology for neutropenia, granulocyte colony-stimulating factor (G-CSF) therapy was initiated and demonstrated a modest, short-lived response to G-CSF. On unknown dates, at 12 months of age, the patient was vaccinated with of M-M-R II and VARIVAX (Merck) (reported as "varicella zoster virus" vaccine) (strength, dose, dose number, route, application site and lot # were not reported). Concomitant medication was not reported. On an unknown date, 3 weeks after receipt of VARIVAX (Merck) and M-M-R II vaccines, the patient presented with cutaneous varicella infection. By 3 weeks following live viral vaccinations, vesicular lesions erupted surrounding her live viral vaccine injection site, which progressed to a diffuse vesicular rash on face, neck, trunk, extremities and eyelids. Disseminated varicella zoster virus (VZV) infection without hepatitis or pneumonitis was diagnosed, and intravenous (i.v.) acyclovir was initiated. T cell studies demonstrated CD4+ T lymphocyte deficiency with poor T cell mitogen responses, and a SCID-like disease was suspected. Assessment of viral pathogens identified RSV-B via polymerase chain reaction (PCR) in a nasal wash and picornavirus-like particles in stool, suggesting the persistence of RSV and hand-foot-mouth infections from earlier in life. PCR for HIV, Epstein-Barr virus (EBV) and cytomegalovirus (CMV) was negative. A skin biopsy documented positive immunohistochemistry for VZV within lesions, with multi-nucleated keratinocytes in epidermis. On single-agent anti-viral therapy with acyclovir, her lesions progressed, and VZV viraemia was documented subsequent to initiation of acyclovir. Although multiple specimens for plasma VZV PCR were obtained while maintained on acyclovir monotherapy, the analyses were unsuccessful and not reported. Foscarnet and subsequently cidofovir were administered, as plasma VZV copies increased rapidly. The patient's clinical course deteriorated, and VZV meningoencephalitis was diagnosed. During disease progression, the maximum VZV measured by PCR in plasma was 751 000 copies/ml (106 copies/ml) and in cerebrospinal fluid (CSF) 977 000 copies/ml. She had clinical signs of nerve entrapment and Bell's palsy associated with VZV meningoencephalitis and became symptomatic from isolated RSV. Varicella and rubella infections were determined to be vaccine-associated. Despite exposure to measles and mumps through the MMR vaccination, these viruses were never isolated from CSF, nasal wash or urine. Although intravenous immunoglobulin (IVIG) supplementation was given, patient VZV-specific IgG levels remained low after IVIG administration. Varicella zoster immunoglobulin (VZIG) was obtained as an investigational new drug, and 29 doses were delivered during her clinical course (including during myeloablation and HSCT). Due to the lack of clinical symptoms, no additional therapy was targeted to rubella. Persistent RSV infection, which was associated with chronic cough and pneumonia, was treated with palivizumab and i.v. as well as inhaled ribavirin. Ribavirin therapy was halted during myeloablation for transplant and then reinitiated during the post-transplant course. Following HSCT, acyclovir was continued as prophylaxis for 6 months and then discontinued upon documentation of donor cell engraftment and no further shedding of RSV, VZV or rubella. Initial analyses of lymphocyte subsets revealed lymphopenia with virtually undetectable CD4+ and CD45RN (naive) T lymphocytes, age-appropriate percentage yet decreased absolute number of CDS+ T lymphocytes, age-appropriate percentage and absolute number of CD19+ lymphocytes and decreased percentage yet age-appropriate absolute number of NK cells. Proliferative T cell responses to mitogens (PHA, ConA and PWM) and antigens (Candida, tetanus and diphtheria) were very low, suggestive of very poor T cell function. NK cell function by 51 Cr release assay was normal. Although serum IgG was elevated and IgM and IgA levels were normal for age, antibody titres to vaccines demonstrated five of 14 protective Spn serotypes detectable and lack of protection to tetanus toxoid and diphtheria toxin. VZV-specific IgG and IgM were negative, despite active VZV infection. Retrospective analysis of archived newborn screening specimens collected at birth and 2 weeks of age showed absence of TREC. A clinical diagnosis of SCID was made based on severe vaccine-acquired viral infection, CD4+ T lymphocyte deficiency and poor T cell function. Donor umbilical cord blood stem cells were identified with a 6/6 match by histocompatibility leucocyte antigen (HLA) testing. Full myeloablative conditioning for haematopoietic stem cell transplantation (HSCT) included busulfan (16 mg/kg total dose), cyclophosphamide (200 mg/kg total dose) and fludarabine (160 mg/m2 total dose). Donor engraftment was documented 1 month post-HSCT as determined by demonstration of STRs of donor origin only. Chimerism analysis by STRs was completed in monocytes and granulocytes cell lines, and this patient has demonstrated 100% engraftment in both cell lines since this initial evaluation. Anti-viral therapy was discontinued 9 months post-HSCT, and VZIG was discontinued on day +197 post-HSCT. Currently, the patient has no evidence of active disease or shedding of VZV, rubella or RSV. T, B and NK cell reconstitution with gradual improvement of CD4+ cells and normal lymphocyte proliferative response to mitogen stimulation with a minimally decreased proliferative response to Candida antigen. An IFN-y ELISPOT performed on days +63 and +85 post HSCT revealed weak but detectable T cell activity against RSV (14 and 30 SFC/1 x 106 PBMCs, respectively). VZV directed T cell immunity by ELISPOT was assessed on days + 176 and + 182 post-HSCT, which revealed weak but detectable activity in peripheral blood and in once-stimulated ex-vivo expanded T cells. B cell restoration gradually demonstrated improvement with IgA class switch at 4 and 12 months post-HSCT and IgG class switch at 12 months post HSCT. B cell challenge with killed bacterial vaccine antigens demonstrated a robust response, with protective antibody titres detected to tetanus toxoid, diphtheria toxin and 11 of 14 Spn serotypes at day +547 post-HSCT. Her resolved HSCT complications included autoimmune haemolytic anaemia and autoimmune thrombocytopenia, and she no longer requires IVIG, with the last administration at day +307 post-HSCT. Post-HSCT assessment documented normal renal and hepatic function. Formal neurodevelopment evaluation has not been completed to date. However, upon routine assessment by the paediatrician and bone marrow transplantation team, this patient had achieved age-appropriate developmental milestones 19 months post-HSCT. In discussion, the reporter stated that this patient also had vaccine-strain rubella (RA27 /3) infection, which has not been reported previously. There was no known effective treatment for rubella infection, yet our patient did not have significant signs and symptoms consistent with this infection. Given that the isolated rubella was an attenuated vaccine-strain virus, this might account for the lack of overt signs of rubella infection in our patient, yet treatment with multiple anti-viral medications and IVIG might have played a role in reducing viral load. The author consequently concluded that this child with disseminated vaccine-strain VZV and rubella infections was the first SCID case reported with an intragenic copy number variants (CNV) and reversion mutation in the IL7R gene. Due to delayed SCID diagnosis, this patient received live viral vaccines, which would have otherwise been avoided. In this case, the retrospective analysis of TREC demonstrates how early detection of T cell abnormalities by NBS was an essential tool in preventing morbidity. Through the combination of chromosomal microarray (CMA) and whole exome sequencing (WES), this patient was found to have IL-7Ra deficiency and was compound heterozygous for the following two deleterious IL7R gene variants: a single nucleotide variant (SNV) located within exon 3 and a copy number variants (CNV) deletion involving entire exon 3 of the IL7R gene. Maternal engraftment, somatic revertant mosaicism or both phenomena may explain the immunophenotype and delayed disease onset in this patient. This case demonstrated that the combination of newer genetic diagnostic tools, such as WES combined with CMA, can identify novel genetic aetiologies of SCID and broaden our knowledge of PIDD immunophenotypes. It also re-emphasizes the importance of avoiding live viral vaccination in SCID patients and the value of NBS for SCID. The outcome of events was not reported. The reporter considered events to be related to M-M-R II and VARIVAX (Merck). Upon internal review, VZV meningoencephalitis was considered to be medical significant event. Additional information has been requested.