Abstracts of the UK PIN Meeting December 2013 Oral Presentations O.01 Next-generation sequencing for the molecular diagnosis of primary immune deficiencies Bibi, Shahnaz1; Drury, Suzanne2; Loughlin, Sam2; Cullup, Thomas2; Boustred, Christopher2; Gilmour, Kimberly C3; Davies, Graham3; Cale, Catherine M3; Jenkins, Lucy2; Lench, Nicholas2 1

NE Thames Regional Genetics Service, Great Ormond Street Hospital NHS Foundation Trust, UK; 2Regional Molecular Genetics Laboratory, Great Ormond Street Hospital NHS Trust, UK; 3Department of Immunology, Great Ormond Street Hospital NHS Foundation Trust, UK

Primary immunodeficiencies (PIDs) represent a rare, life-threatening group of illnesses. They include severecombined immune deficiency (SCID), characterised immunologically by a lack or complete absence of T-cell lymphocytes, and diseases of immune dysregulation, including defects of apoptosis resulting in autoimmune lymphoproliferative syndrome (ALPS). Phenotypes can be clinically indistinct, presenting a challenge to accurately diagnose. Identifying the molecular basis of the disorder is important to guide therapy and to counsel family members. Until recently, molecular testing has been by the sequential sequencing of genes. It is not uncommon for more than five genes to be tested, a lengthy and costly procedure. Next generation sequencing (NGS) enables the simultaneous screening of multiple genes and samples. Following on from an initial SureSelect XT custom capture panel of 34 SCID and ALPS genes, for which average coverage was 99% and where we identified mutations in 8/40 (20%) patients, we have now expanded the design to include 72 genes associated with PID and have started to introduce NGS into our diagnostic service. To date, 23 patients have been tested with this more comprehensive approach. 96% of the PID exons are covered at a depth of 30x or more. Pathogenic mutations have been identified in ten patients (43%), in a total of 8 genes, with NGS expanding the repertoire and expediting the diagnosis for these patients. These preliminary results indicate NGS is a

more time and cost-effective analysis method for detecting novel and known mutations in identified PID genes. Of the 72 PID genes, 27 are also associated with veryearly onset inflammatory bowel disease (VEO-IBD), a differential diagnoses for PID, and an additional 26 genes associated with early-onset bowel disease are included on the panel, thus analysis can be extended to a total of 98 genes for cases presenting with overlapping disease features, expanding the clinical utility of this assay.

O.02 The health of carriers of X-linked chronic granulomatous disease Battersby, Alexandra1; Pearce, Mark2; Cale, Catherine3; Goldblatt, David4; Gennery, Andrew1 1

Institute of Cellular Medicine, Newcastle University, UK; 2Institute of Health and Society, Newcastle University, UK; 3Clinical Immunology, Great Ormond Street Hospital, UK; 4Institute of Child Health, University College London, UK

Background: X-linked Chronic Granulomatous Disease (CGD), a rare primary immunodeficiency due to a CYBB mutation leading to defective gp91PHOX, one of the NADPH oxidase complex subunits, results in decreased or absent oxidative burst. X-linked carriers have a high incidence of discoid lupus; other symptoms are anecdotally reported. Aim: To establish the presence of medical problems in carriers of X-linked CGD Methods: X-linked CGD carriers, recruited from the Great North Children’s Hospital, Newcastle and Great Ormond Street and Royal Free Hospitals, London, are completing detailed questionnaires about medical history, presence of symptoms and psychological health. Neutrophil oxidative burst and autoantibody panel are performed on enrolment. Results: 80 Families identified, 42 Carriers recruited to date (2 deceased)

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



10 had significant gastrointestinal symptoms necessitating investigation; 4 were diagnosed with inflammatory bowel disease (IBD). 21 described photosensitivity, 9 exhibited signs of discoid lupus. 22 suffered recurrent joint pain and swelling 7 had Lupus-Like Syndrome (clinical features but negative autoantibodies), 2 of whom died. 5 were hypothyroid requiring treatment 12 reported excessive fatigue not accounted for by an alternative diagnosis Conclusion: This is the largest cohort of X-linked CGD carriers studied in the UK to date. Significant medical problems are more common and diverse than previously considered. The overlap with IBD has not been previously described further highlighting the association between CGD colitis and IBD. Symptoms do not appear to correlate with neutrophil oxidative burst result, or presence of autoantibodies. These preliminary results suggest a burden of disease in carriers, hitherto undiscovered, suggesting greater awareness of the potential medical problems of these carriers is required. The study is ongoing. O.03 Hypomorphic, Homozygous Mutations In Phosphoglucomutase-3 Impair Immunity And Increase Serum IgE Levels Sassi, Atfa1; Lazaroski, Sandra2; Wu, Gang3; Haslam, Stuart M.4; Mellouli, Fethi5; Patiroglu, Turkan6; Jouhadi, Zineb7; Khadir, Khadija7; Pfeifer, Dietmar8; Jakob, Thilo9; Khemiri, Monia10; Ben-Mustapha, Imen1; Asplund, Charlotta11; Gustafsson, Manuela11; Lundin, Karin11; Falk-Sörqvist, Elin12; Moens, Lotte12; Unal, Ekrem5; Ozdemir, Mehmet Akif5; Gungor, Hatice Eke6; Engelhardt, Karin13; Dziadzio, Magdalena13; Stauss, Hans13; Fleckenstein, Bernhard14; Fliegauf, Manfred2; Meier, Rebecca2; Ben-Khemis, Leila1; Kraus, Helene2; Nadifi, Sellama15; Eibel, Hermann2; Nilsson, Mats12; Bejaoui, Mohamed4; Schäffer, Alejandro16; Smith, Edvard11; Dell, Anne3; Barbouche, Mohamed-Ridha1; Grimbacher, Bodo2 1

Laboratory of Immunopathology, Vaccinology and Molecular Genetics, Pasteur Institute of Tunis and University Tunis, Tunisia; 2Centre of Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Germany; 3Department of Life Sciences, Imperial College London, United Kingdom; 4Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia; 5Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey; 6Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Turkey;



Department of Pediatric Infectious Diseases, Hassan II University, Casablanca, Morocco; 8Department of Hematology and Oncology, University Medical Center Freiburg, Germany; 9Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, Germany; 10Pediatrics Department A, Children’s Hospital of Tunis, Tunisia; 11Clinical Research Center, Department of Laboratory Medicine, Karolinska Institute, Sweden; 12Department of Immunology, Genetics and Pathology, Uppsala University, Sweden; 13Royal Free Hospital, Departmernt of Immunology, University College London, United Kingdom; 14Institute of Virology, Friedrich-Alexander-University Erlangen-Nürnberg, Germany; 15Department of Genetics, Hassan II University, Casablanca, Morocco; 16Department of Health and Human Services, NCBI, NIH, Maryland, USA

Background: Recurrent bacterial and fungal infections, eczema and elevated serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes are mutations in STAT3 and DOCK8, involved in signal transduction. We performed mutational analysis to identify the genetic cause in HIES patients who do not carry mutations in STAT3 or DOCK8. Methods: SNP-chip genotyping and homozygosity mapping were performed in HIES patients to establish a linkage interval. Mutations were detected with selectorbased, high-throughput sequencing and standard sequence analyses. Protein expression was analyzed by Western blotting and glycosylation was profiled by mass spectrometry. Results: Mutational analysis of candidate genes in a 11.9 Mb linkage region on chromosome 6 shared by two multiplex families identified two homozygous mutations in PGM3 which segregated with the disease status and recessive inheritance. The mutations predict amino acid changes in Phosphoglucomutase-3; PGM-3 (E340del and L83S). A third homozygous mutation (D502Y) and the L83S variant were identified in two other affected families, respectively. PGM-3 catalyzes the reversible conversion of GlcNAc-6-P to GlcNAc-1-P, which is essential for UDP-GlcNAc synthesis. In protein glycosylation, the formation of mono-/bi-/tri- and tetraantennary branched N-gycans is dependent on the supply of the common substrate, UDP-GlcNAc. Consistently, glycomic analyses demonstrated aberrant glycosylation patterns in PGM3-mutant leukocytes with markedly reduced levels of tri- and tetra-antennary N-glycans. Discussion: Glycosylation defects have previously not been described in HIES. We show that biallelic hypomorphic PGM3 mutations are associated with impaired glycosylation and a hyper-IgE-like syndrome and thus cause a novel primary (inborn) immune defect.

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36


Poster Presentations Clinical P.01 Depletion of circulating mucosal-associated T cells in patients with common variable immunodeficiency correlates with autoimmune complications Arduini, Serena1; Doherty, Derek2; Feighery, Con3 1

Division of Immunology, School of Medicine, Trinity College Dublin, Room 1.02, Trinity Centre for Health Sciences, Dublin, Ireland; 2Division of Immunology, School of Medicine, Trinity College Dublin, Ireland; 3 Department of Immunology, St. James’s Hospital, Ireland

Background: Common Variable ImmunoDeficiency (CVID) is the most commonly diagnosed primary immunodeficiency, clinically heterogeneous but always characterized by abnormally low immunoglobulin titres and recurrent infections. Aim: Since T cell help is required for B cell differentiation and immunoglobulin production, we investigated if circulating T and innate subpopulations are numerically or phenotypically altered in CVID. Methods: Blood was obtained from 28 healthy controls and 21 CVID patients attending St. James’s Hospital, Dublin. Using flow cytometry we determined the frequencies and absolute numbers of plasmablasts, naive and switched memory B cells, CD4+ and CD8+ T cells, Natural Killer (NK) cells, γδ T cell subsets, invariant Natural Killer T (iNKT) cells and Mucosal-Associated Invariant T (MAIT) cells. Clinical data were collected from patient records. Results: B cell maturation was skewed in patients, with significantly increased frequencies of naive B cells and decreased switched memory B cells and plasmablasts. NK cells and γδ T cell subsets were normal, however iNKT and MAIT cells were depleted in patients (p < 0.0001 and p < 0.01, respectively). MAIT cells also exhibited an atypical CD4/CD8 distribution, and their frequencies were particularly low in patients with CVID complicated by autoimmunity (p < 0.005). Conclusions: Circulating MAIT and iNKT cells were found to be depleted in CVID patients. iNKT cells can influence B cell differentiation and antibody production. MAIT cells require B cells to expand and could, like iNKT cells, affect B cell function. Their reduction in patients with autoimmune complications moreover suggests they have regulatory functions in peripheral tissues.

P.02 Eczema is not a consistent finding of autosomaldominant Hyper-IgE syndrome: case report Bernatoniene, Jolanta1; Manyika, Florence2; Hutchison, Lizzie2; Hamilton-Ayres, Michelle3; Finn, Adam4 1

Paediatric Infectious Disease & Immunology, Bristol Royal Hospital for

Children, UHBristol Education Centre, Upper Maudlin Street, Bristol, UK; 2Paediatric Infectious Disease & Immunology, Bristol Royal Hospital for Children, UK; 3Paediatric, Gloucester Hospitals NHS Foundation Trust, UK; 4Schools of Clinical Sciences & Cellular & Molecular Medicine, University of Bristol, UK

Background: Autosomal dominant hyper-IgE syndrome (ADHIES) is caused by mutations in signal transducer and activator of transcription 3 (STAT3) gene and is responsible for the majority of the known HIES cases. ADHIES is a rare primary immunodeficiency characterized by recurrent sinopulmonary infections, elevated serum IgE, connective tissue and skeletal abnormalities. Most studies claim 100% prevalence of eczema in ADHIES patients. Aim: We report an unusual case of ADHIES who was identified to have a novel STAT3 variant in the SH2 domain but had no history of eczema or atopic dermatitis. Case presentation: A 12 year old girl presented with long standing history of recurrent respiratory tract infections, deep seated abscesses, multiple fractures and characteristic facies, but no history of eczema. The disease course was further complicated by severe episodes of mediastinal abscesses associated with vascular complications and right paratracheal diverticulum. Her NIH clinical score at the initial presentation was 45 points. These manifestations were accompanied by markedly elevated IgE level and reduced IL-17 CD3 + CD4 + T cells. The repeat genetic analysis identified de novo mutation in the STAT3 gene. The severe infections, including the pulmonary complications have been successfully managed with immunoglobulin replacement therapy. Discussion: Mutations in STAT3 have been found to account for most cases; however, pathogenesis of the varied features of ADHIES remains poorly defined. Eczema should not be a definitive variable for the diagnosis of HIES. Further understanding of how STAT3 results in the diverse manifestations of HIES is needed to develop more specific therapies for many HIES manifestations.

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



P.03 Functional antibody impairment in myeloma persists after apparent haematopoietic reconstitution Birtwistle, Jane; Richter, Alex; Hart, Miebaka; Giles, Lynda; Whitelegg, Alison; Drayson, Mark Clinical Immunology Service, University of Birmingham, UK

Background: Multiple myeloma is characterised by a variable level of immunosuppression. The risk of infection is high, especially in the first 12 weeks following diagnosis. We present functional antibody data from the MRC myeloma IX trial for the younger/fitter cohort of patients which were randomised to receive induction therapy followed by high dose melphalan therapy plus autologous stem cell transplantation(SCT). Methods: Functional antibodies and total immunoglobulins were measured at presentation and 100 days post autologous stem cell transplant, using a 19plex luminex assay. Data was compared between responders and non responders.

Serotype Pn1 (geomean) Pn3 Pn4 Pn5 Pn6v Pn7f Pn9v Pn14 Pn18c Pn19a Pn19f Pn23f MenA MenC MenW135 MenY Tetanus Diptheria HiB

Presention (good responders)

Presentation (poor responders)

100 days (good responders)

100 days (poor responders)

p value (presentation v 100 days all groups)

0.039 0.122 0.065 0.114 0.113 0.151 0.350 0.253 0.194 0.490 0.417 0.130 0.956 0.023 0.073 0.038 0.119 0.011 0.088

0.034 0.109 0.051 0.069 0.097 0.112 0.085 0.231 0.175 0.459 0.319 0.135 0.1210 0.019 0.032 0.036 0.132 0.012 0.08

0.026 0.075 0.053 0.091 0.112 0.115 0.288 0.329 0.219 0.361 0.283 0.133 0.908 0.035 0.060 0.062 0.197 0.014 0.076

0.024 0.070 0.040 0.046 0.061 0.084 0.065 0.186 0.186 0.278 0.195 0.085 0.987 0.021 0.030 0.043 0.177 0.010 0.066

100 adult patients via medical records (past 2 years), patient self-completion questionnaires and centre interviews. Results: Early results suggest that HAE costs the NHS £2million per year excluding hospital drug costs. HAE patients admitted to hospitals in England, for any reason, in the past 2 years (n = 1,022) incurred average £1,202 higher per-patient-per-year secondary care costs (excluding drug costs) than matched controls (age, gender, locality) (£1,985 vs. £782), equating to a total additional NHS cost of £1,713,099. In primary care, the 251 HAE patients identified incurred average £293 higher per-patient-per-year primary care cost than their matched controls (£982 vs. £689; total additional NHS cost of £378,297). Discussion: This is the first comprehensive UK HAE burden of illness study. Although rare, HAE causes a high burden on the NHS, related both to increased secondary and primary care costs relative to controls. These findings will be further investigated with results of the primary patient research.


P.17 Activity, severity and impact of respiratory disease in primary antibody deficiency syndromes Hurst, John1; Workman, Sarita2; Garcha, Davinder3; Seneviratne, Suranjith2; Haddock, Jamanda2; Grimbacher, Bodo3 1

UCL Medical School, Royal Free Campus, London, UK; 2Royal Free

London NHS Foundation Trust, UK; 3UCL Medical School, UK

Background: Some patients with primary antibody deficiency (PAD) develop bronchiectasis. In immunocompetent bronchiectasis, key clinico-pathophysiological relationships exist between exacerbation frequency, lung function, health-status, infection and inflammation. It is not known whether such relationships are present in PAD. It is also not known how local and systemic inflammation in PAD compares with that in non-PAD bronchiectasis patients. Method: We assessed symptoms, exacerbation frequency, health-status, lung function, CT, airway and systemic inflammation and infection in 33 PAD and 20 immunocompetent subjects with bronchiectasis. Results: Despite less severe airflow obstruction, PAD patients had similar health-status impairment and greater airway (sputum log10 IL-6 2.71 vs. 1.81 pg/ml, p = 0.001) and systemic inflammation than immunocompetent controls (serum log10 CRP 0.77 vs. 0.36 mg/l, p = 0.001). In PAD, cross-sectional markers of disease severity (CT and lung function) did not relate to inflammatory markers of disease activity, however there was a relationship between FEV1 decline and systemic inflammation (IL-6; r = 0.42, p = 0.036) and the magnitude of the systemic inflammatory response was related to that in the airway. Correlation between generic SF36 and respiratory SGRQ questionnaires (r = −0.79, p < 0.001) suggests that much health-status impairment in PAD relates to respiratory involvement. Health-status was associated with dyspnoea (rho = 0.77, p < 0.001), respiratory infection frequency (rho = 0.48, p = 0.016), lung function (FEV1: r = −0.60, p = 0.001) and lung function decline (r = 0.41, p = 0.047). Conclusion: In patients with PAD, cross-sectional markers of disease severity such as lung function and CT do not reflect disease activity as assessed by inflammation. In addition, there is a relationship between the rate of progression of lung disease and the severity of the systemic inflammatory response. Much of the quality of life impact in PAD relates to respiratory involvement, specifically the severity of airflow obstruction, exacerbation frequency and dyspnoea. Finally, patients with PAD had greater airway and systemic inflammation than a control population with non-PAD bronchiectasis which may suggest a dysregulated airway immune response.

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36


P.18 Undefined immunodeficiency presenting with autoimmune cytopenias, hypogammaglobulinaemia and chronic cryptosporidiosis: a case report Miller, Joanne1; Dhalla, Fatima1; Ferry, Berne L2; Collier, Jane3; Chapel, Helen M1; Patel, Smita Y1 1

Department of Clinical Immunology, John Radcliffe Hospital, Oxford,

UK; 2Department of Clinical Immunology Laboratory, Churchill Hospital, Oxford, UK; 3Department of Gastroenterology, John Radcliffe Hospital, Oxford, UK

We discuss the case of a Caucasian male who presented at the age of 30 with recurrent sino-pulmonary infections, immune thrombocytopenia purpura (ITP), and hypogammaglobulinaemia, (IgG 1.1 g/L, IgA 0.1 g/L, IgM 0.3 g/L). Further immunological testing revealed low specific antibodies to polysaccharide and protein antigens with normal levels of T (CD4+ and CD8+), B and NK cells. CD40 ligand expression was normal and he was HIV negative. He was commenced on immunoglobulin replacement therapy but continued to have recurrent sinus and chest infections and was diagnosed with bronchiectasis aged 45. He had further relapses of ITP and subsequently developed autoimmune haemolytic anaemia requiring steroid and Rituximab therapy. Aged 46 he was diagnosed with cutaneous non-Hodgkin lymphoma and received R-CHOP chemotherapy. A striking feature in this gentleman’s case was his predisposition to recurrent Cryptosporidium infection. Over the past 20 years he suffered from intermittent diarrhoea, with C. hominis and C. parvum isolated in stool specimens on multiple occasions. Over the past 3 years his diarrhoea became severe, chronic and resistant to treatment with Paromomycin. He developed sclerosing cholangitis and malabsorption secondary to chronic cryptosporidiosis and required long-term parenteral feeding. Sadly the patient died in April 2013 from a hospital acquired pneumonia. In his family history 2 of his sisters had died during early childhood from unknown haematological conditions. Loss of function mutations in the IL-21 receptor have recently been described in patients with Cryptosporidium infections associated with chronic cholangitis. Post-mortem molecular analysis of this gene is being arranged. P.19 Persistent Polyclonal B Cell Lymphocytosis (PPBL) with infections and antibody deficiency. Mutlu, Leman1; Goddard, Sarah2; Drayson, Mark3; Huissoon, Aarnoud1 1

West Midlands Immunodeficiency Centre, Birmingham Heartlands Hospital, UK; 2Immunology Department, North Staffordshire University Hospital, UK; 3School of Immunity and Infection, University of Birmingham, UK

Background and Method: PPBL is a rare entity characterised by chronic lymphocytosis, binucleated lymphocytes, polyclonal increase in IgM and cytogenetic abnormalities on chromosome 3. Most patients are asymptomatic. Immunodeficiency has not been reported as a feature. Here, we present 2 cases of PPBL with recurrent infections and evidence of defective immunity. Results: Patient 1 is a 46-year-old woman, a smoker, who presented with recurrent upper and lower respiratory tract infections requiring antibiotics. CT chest showed evidence of bronchiectasis. Vaccination testing showed poor response to polysaccharide. She was found to have polyclonal CD27+ve B cell lymphocytosis (2.4 x 109/L) and polyclonally elevated IgM (10.7 g/L). Patient 2 is a 61-year-old asthmatic woman, a non-smoker, who suffered from recurrent chest infections and sinusitis. She also had arthralgia and myalgia, and PMR was suspected. She was found to have low IgG, normal IgA but increased IgM at 7.2 g/L with persistent B cell lymphocytosis (2.5 x 109/L). She did not generate antibody responses to Pneumovax but had protective levels of anti- Hib and tetanus toxoid antibodies. Infection rates in both cases improved with immunoglobulin replacement. Discussion: PPBL is a well described condition but associated defective immunity is not well reported. It may be that infection history is not given due attention and immune defects are not sought. These cases suggest that antibody deficiency may be part of the clinical syndrome of PPBL in some patients, and identification and treatment of this defect may benefit the patient.

P.20 Stratifying the underlying primary immunodeficiency when warts are a predominant clinical manifestation Ramakrishnan, Ananth1; Gao, Yifang2; Eren, Efrem3; Saul, Faust4; Anthony, Williams2 1

Cancer Sciences Division, University of Southampton, MP824, University Hospital Southampton, Southampton, UK; 2Cancer Sciences Division, University of Southampton, UK; 3Department of Clinical Immunology, University Hospital Southampton NHS FT, UK; 4Clinical and Experimental Sciences Division, University of Southampton, UK

Background: Severe, recurrent or recalcitrant warts may sometimes indicate an underlying immunodeficiency. We present our experience of investigating two patients with warts Results A 69-year-old man presented with a 20 year history of warts involving hands, feet and lower torso, with no susceptibility to other infections. These had been resistant to laser therapy, Diphencyprone and immunotherapy. Routine investigations revealed a normal FBC, immunoglobulins, specific antibodies to pneumococcus and tetanus. Lymphocyte subsets

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



revealed a normal T cell count with absent B cells and low NK cells. His phenotype was consistent with a GATA2 mutation. Sequencing of GATA2 did not reveal any significant exonic mutations and an intronic mutation reported to cause haploinsufficiency was also not present. However allelic expression using cDNA amplification of GATA2 SNP was consistent with GATA2 haploinsufficiency and the novel molecular cause is under investigation. A 48 year old female presented with a history of repeated lower respiratory tract infections in infancy, liver abscess resection in childhood and recurrent warts from early adulthood. She had recently completed an 18 month treatment for MAI and had started IVIG for specific antibody deficiency. Her phenotype was consistent with Warts, Hypogammaglobulinemia, Immunodeficiency and Myelokathesis (WHIM) syndrome. Evaluation of dendritic cell (DC) numbers showed reduced myeloid and absent plasmacytoid DCs. Type I interferon production to selective TLR ligands was impaired. Sequencing of the CXCR4 gene confirmed a previously reported premature stop codon pR334X mutation. Discussion: Clinical phenotype and careful consideration of targeted investigations can direct gene sequencing in patients with recalcitrant warts.

P.21 DCML deficiency presenting with hepatitis – a novel presentation Richter, Alex1; Bigley, Venetia2; Hirschfield, Gideon3; Drayson, Mark4

P.22 Perforin deficiency presenting as isolated pancytopenia in childhood Robertson, Nic1; Moses, Samuel2; Abinun, Mario1; Barge, Dawn3; Cant, Andrew1; Savic, Sinisa4; Gilmour, Kimberly5; Gennery, Andrew1; Hambleton, Sophie1 1


Clinical Immunology Service, University of Birmingham, Edgbaston, Birmingham, UK; 2Institute of Cellular Medicine, Newcastle University, UK; 3School of Immunity and Infection, University of Birmingham, UK; 4 Clinical Immunology Service, University of Birmingham, UK

Background: Heterzygous mutation in GATA2 transcription factor results in a complex haematopoietic disorder characterised by failure of mononuclear cell development. Early onset myelodysplastic syndrome (MDS) with progression to AML are common associated with other extra-haematopoietic features. Presentation ranges from child to adulthood with lymphoedema, sensorineural deafness, pulmonary alveolar proteinosis and infections including non tuberculous mycobacterial and human papilloma virus infection. Equally healthy family members are found with the mutation. Case: A 32 year old lady, referred from the liver unit in 2012, had a history of EBV hepatitis aged 21 followed by atypical autoimmune hepatitis with iron overload, MDS and neurological damaged following progressive multifocal leukoencephalopathy due to JC virus infection. Further questioning revealed a history of primary


lymphoedema (age 5) and family history of bladder cancer (3 close family). She was suffering recurrent sepsis and had persistent oropharyngeal and vaginal thrush. Cervical/vaginal intraepithelial neoplasia 3 and then squamous cell carcinoma was diagnosed. Transplant was not undertaken due to multiple co-morbidities. The family declined genetic testing. Peripheral blood phenotyping revealed low monocytes and dendritic cells. T cell numbers were within the normal range but there was B and NK cell lymphopaenia. Bone marrow analysis showed absolute loss of multilymphoid and granulocyte macrophage progenitor. Serum Flt-3 ligand, trophic factor for progenitors and DCs, was markedly elevated all in keeping with DCML. Sequencing confirmed a GATA2 mutation (R361C). Liver transaminitis was associated with elevated IgG 32.88 g/l (IgG1 30.55), IgA 0.94 g/l, IgM 2.18 g/l. ANA weakly positive (1:40), with negative LKM, MT and SM antibodies. Conclusions: The clinical phenotype of DCML is heterogeneous and this is the first time presumed autoimmune hepatitis, albeit antibody negative, is described in association.

Great North Children’s Hospital, RVI, Newcastle-Upon-Tyne, UK; Newcastle HPA Molecular Laboratory, RVI, Newcastle-Upon-Tyne, UK; 3 Regional Immunology Laboratory, RVI, Newcastle-Upon-Tyne, UK; 2


Department of Clinical Immunology, St James’s University Hospital, Leeds, UK; 5Camelia Botnar Laboratories, Great Ormond Street Hospital, London, UK

Background: Hemophagocytic lymphohistiocytosis (HLH) is a multisystem inflammatory disorder. In 1999, deficiency of the cytotoxic protein perforin became the first monogenic cause of HLH to be described; children without functional perforin typically develop fever, lymphadenopathy and hepatosplenomegaly in the first months of life. Several other monogenic forms of the HLH syndrome have since been described, as well as secondary causes where triggers include malignancy and infection. Adults without functional perforin occasionally present with aplastic anaemia, but childhood presentation with isolated pancytopenia has not been previously described. Methods: We now report the first known case of a child who presented with transient pancytopenia and was found to be deficient of perforin on investigation. We

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36


reviewed the literature to identify patients with similar mutations. Results: Our patient is the first child of distantly related parents. He had initially normal development and no adverse response to routine vaccinations. He presented with fever at the age of four after developing chicken pox and was found to be pancytopenic. He recovered but presented again two years later with systemic illness and was found to be deficient of perforin. The same mutation with a different presentation has previously been reported. Discussion: This patient is particularly interesting given the overlap between HLH syndromes and x-linked proliferative disorder (XLP1) caused by deficiency of SLAMassociated protein (SAP, encoded by SH2D1A). Aplastic anaemia is a rare but recognised presenting feature of XLP1, whereas HLH is both the most common presenting feature and the most common feature present at any time. P.23 Cytomegalovirus (CMV) re-activation in the bowel is associated with severe enteropathy in Common Variable Immunodeficiency (CVID). Seneviratne, Suranjith1; Verma, Nisha2; Rodriguez-Justo, Manuel3; Patterson, Jennifer3; Dziadzio, Magdalena2; Mai, Annabelle2; Harper, Jennifer2; Ambrose, Lyn2; Chee, Ronnie2; Burns, Siobhan2; Clarke, Ian2; Paul, Griffiths2; Webster, David2 1

Clinical Immunology, Royal Free Hospital, UK; 2Royal Free Hospital, UK; 3UCL Advanced Diagnostics, UK

Background: Severe chronic diarrhoea occurs in about 5% of CVID patients, the majority having colitis on histology, and the rest having extensive small bowel disease. Having previously found that many of these patients had a persistent robust T cell response to CMV, we postulated that this was driven by active viral replication in the bowel. Methods: We identified CMV exposed patients and estimated the magnitude of the CD8+ T cell response with a CMV Quantiferon kit and used a sensitive immunohistology technique to identify virus in fixed bowel biopsies. Results: Having excluded known causes of enteropathy, 4 patients (2 with small bowel and 2 with large bowel disease) were found to have patchy inflammatory foci containing CMV antigen positive cells in bowel biopsies, although standard immunohistology failed to show positive staining. CMV copies in blood were undetectable and there was a high level of CD8+ T cell reactivity in the Quantiferon assay. A trial of short-term valganciclovir in

3 patients reduced the frequency of diarrhoea; 2 patients were later given long term infliximab (>5 years) with sustained symptomatic improvement. Conclusion: These cases suggest that some CVID patients with chronic enteropathy fail to completely control CMV replication in the bowel despite an apparent vigorous CD8+ T cell response that may itself contribute to the inflammation. Therapeutic strategies to either inhibit viral replication and/or reduce TNF-á levels are preferable to long-term steroids. P.24 LRBA deficiency, CMV disease, Lymphocytic Interstitial Pneumonitis (LIP) and early onset autoimmunity Seneviratne, Suranjith1; Verma, Nisha2; Hurst, John3; Dziadzio, Magdalena2; Rodriguez-Justo, Manuel4; Paterson, Jennifer4; Ambrose, Lyn5; Workman, Sary5; Haddock, Jamanda6; Chee, Ronnie2; Clarke, Ian7; Griffiths, Paul8; Gamez, Laura9; Cooper, Nichola10; Webster, David5; Burns, Siobhan2; Grimbacher, Bodo5 1

Clinical Immunology, Royal Free Hospital, Pond Street, London, UK; Clinical Immunology, Royal Free Hospital, UK; 3Respiratory Medicine, Royal Free Hospital, UK; 4UCL Advanced Diagnostics, UK; 5Royal Free Hospital, UK; 6Radiology, Royal Free Hospital, UK; 7Pathology, Royal Free Hospital, UK; 8Virology, Royal Free Hospital, UK; 9Centre for Chronic Immunodeficiency, Germany; 10Hammersmith Hospital, UK 2

Background and Methods: We describe two patients with LRBA deficiency, CMV disease, early onset autoimmunity, lymphoid proliferation and progressive LIP. The CD8+ T cells from both patients showed markedly reduced IFN-ã expression after CMV peptide stimulation although this was normal with PHA. Results: Case 1: A 25 year old Georgian male developed AIHA, ITP, hypogammaglobulinaemia, and generalised lymphadenopathy as a teenager. Multiple ill-defined pulmonary nodules and ground glass changes were seen on a chest CT. Despite no viraemia, high CMV copy numbers were found in a bronchoalveolar lavage, urine and saliva. Lung biopsy showed nodular interstitial lymphocytic infiltration. A combination of a reducing dose of steroids (starting at 60 mg daily) and valganciclovir markedly improved his chest CT appearance and cleared CMV from saliva and urine. Case 2: A 20 year old Indian female had AIHA at the age of 10. She later developed splenomegaly, a raised creatinine, lymphoid renal infiltration, granulomatous lymphadenopathy, LIP and hypogammaglobulinaemia. A lung biopsy showed a lymphoid infiltrate (CD4+ T cells and B cells). Although not viraemic, the urine and saliva contained high CMV copy numbers and immunohistochemistry on lung showed replicating CMV. Valganciclovir cleared

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



virus from saliva and urine, which together with prednisolone (starting at 50 mg daily) improved the radiographic changes of LIP. Discussion: These cases suggest that CMV may be a driver for LIP in patients with LRBA deficiency, with the control of local viral replication being compromised by a subtle CD8+ T cell defect.

P.25 Jejunal Gastrointestinal Stromal Tumour (GIST) in a patient with Common Variable Immunodeficiency (CVID) Seneviratne, Suranjith L1; Waters, Justin2; Bailey, Simon TR3; Bryant, Anna4; Burns, Siobhan O1; Chee, Ronnie1; Verma, Nisha1 1

Immunology, Royal Free Hospital, UK; 2Oncology, Maidstone Hospital,

UK; 3Surgery, Maidstone Hospital, UK; 4Histopathology, Maidstone Hospital, UK

Background: Description of a CVID patient with jejunal GIST and evaluation of Imatinib use in primary immunodeficiency (PID). Method: Clinical notes on our patient were analysed. A systematic literature search on the use and effects of Imatinib in PID was carried out. Results: The 59-year-old female with CVID was admitted to hospital in October 2011 with an acute abdomen. Surgical exploration found a bowel perforation and a 7 cm mid-jejunal mass (later confirmed as a nonsecretory jejunal GIST of moderate malignant potential). Imatinib, a competitive tyrosine kinase inhibitor of c-kit and PDGF-R (platelet-derived growth factor receptor), was commenced. In June 2012, she developed skin ulceration on her thighs (a known adverse effect of Imatinib) and following omission for a few weeks, the Imatinib was recommenced at a lower dose. The plan was to continue Imatinib for 3 years in total and though she was doing very well, with no increase in her infection burden, a recent nodule found on a CT chest scan has raised clinical suspicion of possible metatstasis. This is being further evaluated. Discussion: CVID is known to be associated with an increased risk of malignancy, particularly lymphoproliferative disorders. Previous publications have described some CVID patients with gastrointestinal lymphoma or gastric carcinoma. Our patient had a GIST, a rare sarcoma and is receiving Imatinib for this. Prospective longitudinal follow-up of our patient would help us to evaluate its use in primary immunodeficiency.

P.26 XIAP deficiency: It’s not just HLH Shahid, Nadia1; Cale, Catherine1; Bibi, Shahnaz2; Gilmour, Kimberly1 1

Immunology Laboratory, Great Ormond Street Hospital, UK; 2Genetics

Laboratory, Great Ormond Street Hospital, UK

Background: X-linked inhibitor of apoptosis (XIAP), encoded by the BIRC4 gene inhibits caspases thus regulating cell apoptosis. In 2006, deficiency in XIAP was found to be associated with an X-linked lymphoproliferative syndrome type 2 (XLP2). Patients with XLP2 typically present with haemophagocytic lymphohistiocytosis (HLH), with or without EBV association. Patients with suspected XLP or HLH are screened for XIAP expression before confirmation by genetic analysis. Due to the number of patients found to have XIAP deficiency since 2008 we suggest that the diagnosis is not as rare as initially suggested and that the disease presentation is not limited to HLH. Methods: Protein expression of XIAP was detected using intracellular flow cytometry. Direct sequencing of BIRC4 was undertaken on patients with abnormal XIAP expression (1.3 ug/ml by serotype and as % of serotypes was determined. Results: Pre-immunisation, serotype specific antibody >0.35 ug/ml and >1.3 ug/ml was detected in 52 (20– 76)% and 23 (2–35)% of individuals respectively. D28 post immunisation, this rose to 94(88–98)% and 73(52– 84)% for >0.35 and >1.3 ug/ml respectively. At 1Y post immunisation, 90(67–100)% and 66(42–83)% of individuals had retained Ab >0.35 and >1.3 ug/ml respectively. Based on UK recommendation of >70% serotypes < 0.35 ug/ml, 73% of healthy adults met criteria for vaccination and 4% met criteria for diagnosis of suboptimal antibody response/specific antibody deficiency; using the US recommendation of >70% serotypes < 1.3 ug/ml, 100% of healthy adults met criteria for vaccination and 27% for suboptimal antibody response/specific antibody deficiency at D28 with 40% at 1Y. Conclusion: In our assay, the UK criteria is likely to be more accurate than the US criteria in discriminating normal from suboptimal pneumococcal vaccine responses.

P.42 Antigen-specific memory B cell responses are significantly reduced in common variable immunodeficiency Evans, Caroline1; Bateman, Elizabeth1; Simpson, Dawn1; Sadler, Ross1; Ayers, Lisa1; Patel, Smita2; Misbah, Siraj2; Ferry, Berne1 1

Department of Clinical Laboratory Immunology, Churchill Hospital, Oxford University Hospitals NHS Trust, UK; 2Clinical Immunology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, UK

Background: Common variable immune deficiencies are a heterogeneous group of primary antibody deficiencies characterised by low serum immunoglobulins and poor vaccine responses. Although a number of associated genetic defects have been identified, the aetiology remains largely unknown. Methods: This study uses a B cell ELISpot to examine the capacity of memory B cells from CVID patients to differentiate into antigen-specific antibody-secreting

cells in vitro. B-cell ELISpot responses were compared in healthy controls and CVID patients with >2% switched memory B cells (EUROclass SmB+). The relationship between ELISpot responses and circulating B cell subpopulations was also assessed. Results: All 15 CVID patients produced IgG-secreting cells in vitro following 6 day culture. However, levels of antigen-specific IgG-secreting cells were significantly lower against both protein and polysaccharide antigens, with a number of patients demonstrating no antigenspecific response at all. This reduced antigen specific response could not be attributed solely to a reduction in switched memory B cell numbers. Discussion: All CVID patients in this study produced IgG-secreting cells in vitro, however the majority were not directed against common antigens. This suggests these patients may have a defect at the germinal centre level, with impaired response to antigen or subsequent proliferation and somatic hypermutation defects. A minority of patients did produce antigen-specific IgGsecreting cells, suggesting a post-germinal centre defect in plasma cell maturation or survival in these patients. This functional technique potentially highlights two distinct mechanistic defects in our CVID cohort, which could help direct further studies into the aetiology of this complex disease.

P.43 Investigation of common variable immunodeficiency patients and healthy individuals using autoimmune lymphoproliferative syndrome biomarkers Ferry, Berne1; Roberts, Ceri2; Ayers, Lisa2; Bateman, Elizabeth2; Sadler, Ross2; Misbah, Siraj3 1

Clinical Laboratory Immunology, Oxford University Hospitals Trust, Old Rd, Oxford, UK; 2Clinical Laboratory Immunology, Oxford University Hospitals Trust, UK; 3Clinical Immunology, Oxford University Hospitals Trust, UK

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of dysregulated lymphocyte homeostasis. Biomarkers including elevated CD3+TCRαβ+CD4– CD8– double negative T cells (TCRαβ+ DNT), IL-10, sCD95L and vitamin B12 can be used to differentiate between ALPS and common variable immunodeficiency (CVID) patients with an overlapping clinical phenotype. We investigated the utility of ALPS biomarkers in 13 CVID patients with lymphoproliferation and/or autoimmune cytopaenia with comparison to 33 healthy controls. Vitamin B12 (P < 0.01) and IL-10 (P < 0.0001), but not sCD95L or TCRαβ+ DNT, were increased in CVID compared to controls. The 95th percentile for TCRαβ+ DNT in healthy controls was used to define a normal range up to 2.3% of total lymphocytes or 3.4% of T cells.

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



These frequencies lie markedly beyond the cut offs used in current ALPS diagnostic criteria (≥ 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes), suggesting these limits may have poor specificity for ALPS. P.44 Coeliac disease and iga deficiency- an audit to identify patients in whom serology is not informative Furrie, Elizabeth1; Marshall, Sara E.2 1

Immunology service, Blood Sciences Dept, NHS Tayside, Ninewells

Hospital, Dundee, UK; 2Immunology service, Blood Sciences Dept, NHS Tayside, UK

Background: The use of serological tests has revolutionised the diagnosis of coeliac disease. The most reliable tests are based on the detection of IgA antibodies against tissue transglutaminase (tTG). However an important confounder in diagnosis is IgA deficiency, and it is essential to identify IgA deficient samples to avoid false negative IgA anti-tTG results. Aim: of this analysis was to calculate a cut-off value for IgA anti-tTG levels that would identify IgA deficient samples (IgA < 0.1 g/l) with 100% sensitivity using the Orgentec ELISA. Methods: Original protocol: Immunoglobulins were measured in samples with the 6 lowest IgA anti-tTG results (iu/ml) for each assay run. Audit 2010: 82 assay runs analysed =3741 samples IgA measured in 490 samples 31 IgA deficient samples identified (1:121) ROC curve constructed to identify cut-off Re-Audit 2012: 100 assay runs analysed =7290 samples IgA measured in 613 samples 41 IgA deficient samples identified (1:178) ROC curve constructed to identify cut-off Results: * Original analysis gave a cut-off value of 0.2 u/ml IgA anti-tTG Abs at 100% sensitivity, specificity 64.2% with an area under the curve (AUC) of 0.96. * Re-audit confirmed cut-off value of 0.2 u/ml IgA antitTG Abs at 100% sensitivity, specificity improved at 80% and an AUC of 0.97. Discussion It is possible to calculate a cut-off value that reliably identifies IgA deficient samples in patients being screened for coeliac disease. This minimises the likelihood of false negative IgA antitTG results in IgA deficient patients. P.45 Using the Elia Celikey assay – when to test for IgA deficiency and IgG class coeliac antibodies. Garcez, Tomaz1; Devlin, Lisa2; Coles, Philippa3; Foster, Gillian2 1

Immunology, Central Manchester NHS FT, Oxford Road, Manchester, UK; 2Regional Immunology Laboratory, Belfast Royal Hospitals, UK; 3 Immunology, Central Manchester NHS FT, UK


Background: Selective IgA deficiency (sIgAD) may result in false negative IgA coeliac disease (CD) serology. IgG coeliac disease serology can be measured as an alternative in patients with sIgAD. Aim: We aimed to evaluate the hypothesis that initial screening of samples for selective IgA deficiency (defined as IgA < 0.05 g/L) is not necessary if the fully automated EliATM Celikey® on the ImmunoCAP 250 (Thermo Fisher Scientific) is used to measure serum IgA anti Tissue Transglutaminase (anti-tTG). Previous assessment has concluded that only samples with the error message low fluorescence response unit (LOW RU) should be further investigated by measuring serum IgA to verify sIgAD. Methods: We analysed 107 sequential samples from two UK centres with a fluorescence response unit (RU) of ≤30. Results: 4 cases of sIgAD did not have LOW RU, but all cases of sIgAD had a RU of 70% 1.3 μg/ml, with adults responding to at least 70 % of the serotypes used. Aim The sensitivity and specificity of these criteria for the diagnosis of antibody deficiency was determined, in comparison with the ability of patients to achieve 0.35 mg/ml (the WHO, threshold concentration of anticapsular antibody required to protect against invasive pneumococcal-disease). Methods: We retrospectively selected 126 consecutive adult patients who had been referred to our immunodeficiency clinic, with a history of severe, recurrent, unusual or persistent infections. The investigations included, measurement of serum immunoglobulins, and specific-antibodies to 13 pneumococcal polysaccharides, 4 weeks after immunisation with “Pneumovax”, using a “Luminex” method using the FDA standard serum (89SF) as calibrant. Results: ROC curves were plotted for patients with antibody deficiency (IgG and at least one other isotype below 95th centile), and those with no antibody deficiency, using the number of serotypes >0.34 ug/ml or >1.29 ug/ml. Although the area under these curves were similar for both criteria (P < 0.45), US criteria for normality, poorly discriminated antibody deficient from non-antibody deficient patients (98% sensitivity and 10% specificity). In contrast, responses above 0.34 μg/ml

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



for G;p.C105W variant in FADD. Discussion: This case confirms previous association between FADD deficiency and a specific clinical phenotype. Whole exome sequencing again proves to be a powerful technique for investigating selected cases of primary immunodeficiency.

P.57 Development of C1-inhibitor antibodies in a patient with hereditary angioedema Seneviratne, Suranjith1; Manson, Ania2; Gurugama, Padmalal3; Eren, Efrem4; Goswami, Rajee4; Dziadzio, Magdalena5; Verma, Nisha5; Jolles, Stephen6; Roberts, Andrew6; Abdalla, Saad7 1

Royal Free Hospital, UCL Centre for Immunodeficiency, London, UK; Barts and the London NHS Trust, UK; 3Kings College Hospital, UK; 4 University Hospital Southampton NHS Foundation Tru, UK; 5Royal Free Hospital, UK; 6University Hospital of Wales,, UK; 7Imperial College Healthcare NHS Trust, UK 2

Background: Angioedema due to C1-inhibitor (C1INH) deficiency may be either hereditary or acquired. We present a patient with genetically confirmed hereditary C1-INH deficiency whose clinical profile worsened following the development of lymphoproliferative disease and C1-INH autoantibodies. Methods: Historical and current clinical and laboratory information on our patient was collected and analysed.


Results: A 75 year-old female, who had recurrent episodes of angioedema since the age of 2 years and a family history of sudden death was diagnosed with hereditary angiodema (HAE) on clinical grounds at 35 years of age. She had not found tranexamic acid to be helpful, but her clinical course was stable on intermittent danazol. Six years ago, she was diagnosed with autoimmune hypothyroidism and sero-positive rheumatoid arthritis and then, four years ago, serum paraproteinemia was found on routine blood tests. 12 months later she started getting frequent episodes of angioedema affecting her tongue, throat, pharynx and larynx associated with breathing difficulty. She needed several hospital visits for administration of C1-INH concentrate. A re-evaluation at this time showed her to have low C1q levels and to have antibodies against C1-INH. She was prescribed Icatibant and Tranexamic acid and at present her symptoms are stable. One year ago, NHL was diagnosed and a course of chemotherapy completed. Sequencing of the SERPING1 gene confirmed hereditary C1INH deficiency with a muatation in exon 8 resulting in a frame shift that causes premature termination 15 codons downstream. Discussion: Our patient with HAE, who had been stable for many years, developed a sudden worsening of her symptoms. This was associated with the appearance of a paraprotein, antibodies against her residual CI-inhibitor and low C1q. We concluded that she had developed acquired C1 inhibitor deficiency, in addition to her HAE, leading to her clinical deterioration. Acquired C1 inhibitor deficiency superimposed on HAE is a rare cause for increased attack severity, but it should be considered in patients in whom no other cause can be found.

P.58 Preliminary study for levels of IgA and IgM antibodies specific to pneumococcal capsular polysaccharide in healthy children. Walsh, Emer1; Lock, Lynne1; Schauer, Uwe2; Wurfel, Martina3; Harding, Stephen1; Parker, Antony, Holden, Neil1 1

The Binding Site Group Ltd., UK; 2Ruhr Universitat Bochum, Germany; The Binding Site Deutschland GmBH, Germany


Background: Pneumococcal Capsular Polysaccharide (PCP) IgA and IgM ELISAs have been developed to assess the risk of infection in immunodeficient patients. Aim: The aim of the study was to measure the normal serum levels of pneumococcal IgA and IgM antibodies in unvaccinated patients. Methods: 61 patients admitted for minor surgery were recruited with a median age of 5 years (range 0.5–15 years); 0.5–2 years (n = 9; median = 1 year), 2–4 years (n = 16; median = 3 years), 4–6 years (n = 12; median =5

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36


years), and >6 years (n = 24 median = 10 years). Exclusion criteria included patients with no parental consent, known infection and/or elevated serum CRP concentrations (>10mg/L). Serum was collected and analysed retrospectively utilising Anti-Pneumococcal IgA and IgM EIA kits (The Binding Site, Birmingham, UK). Results: There was a significantly lower median serum PCP IgA titre in the 0.5–2 years (2 U/mL) compared to aged 2–4 years (median 6.95 U/mL; p = 0.0071) and there was a significant difference in the median titre of patients aged 2–4 years compared with patients >4 years (median 19.55 U/mL; p = 0.0097). There was a significantly higher median serum PCP IgM titre in patients aged 0.5–2 years (28 U/mL) compared to those aged 2–4 years (median 7 U/mL; p = 0.006). There was a significantly lower median serum PCP IgM titre in the 2–4 years compared to aged 4–6 years (median 61 U/mL; p < 0.0001). In contrast, there was no significant difference in the median IgM titre of the group aged 4–6 years with any of the other groups >6 years. Conclusion: The data suggests that natural immunity for PCP IgA and IgM is reached by 6 years.

Molecular Diagnostics P.59 A novel homozygous mutation in G6PC3 presenting as cyclic neutropenia and severe congenital neutropenia in the same family Alangari, Abdullah1; Alsultan, Abdulrahman2; Elfaki, Mohamed2; Anazi, Shamsa3; Alkuraya, Fowzan3 1

Paediatrics, King Saud University, P.O. Box 2925, Riyadh, Saudi Arabia; Paediatrics, King Saud University, Saudi Arabia; 3Genetics, King Faisal Specialist Hospital/Research Center, Saudi Arabia 2

Background: Patients with autosomal recessive cyclic neutropenia have no known causative genetic defect yet. Methods: Autozygosity mapping on two branches of an extended multiplex consanguineous family presenting with cyclic neutropenia or severe congenital neutropenia to look for candidate gene, followed by candidate gene selection and sequencing. Results: A single autozygous interval on Chr17: 33,901,938–45,675,414 that is exclusively shared by the affected members was identified. This interval spans 11.8Mb and contains 30 genes. Review of these genes highlighted G6PC3 as the most likely candidate given its known role in neutrophil biology. Direct sequencing revealed a novel homozygous mutation (NM_138387.3, c.974T > G, p.Leu325Arg). Two of our patients had associated congenital defects that are known to occur in patients with G6PC3 mutations, including congenital heart disease and intermittent thrombocytopenia

Conclusion: Biallelic G6PC3 defects should be considered in patients with autosomal recessive cyclic neutropenia, especially those with typical associated congenital defects.

P.60 A genetic mutation in TTC7A leading to intestinal atresia and severe immunodeficiency Chandra, Anita1; Ugrinovic, Sanja2; Penagini, Francesca3; Noble-Jamieson, Gabrielle3; Desjardins, Sylvie4; Raymond, Vincent4; Maranda, Bruce5; Samuels, Mark6; Heuschkel, Robert3; Kumararatne, Dinakantha2 1

Department of Clinical Immunology, Cambridge University Hospitals

NHS Foundation Trus, Hill’d Rd, Cambridge, UK; 2Department of Clinical Immunology, Cambridge University Hospitals NHS Foundation Trus, UK; 3Department of Paediatric Gastroenterology, Cambridge University Hospitals NHS Foundation Trus, UK; 4Genotyping and Sequencing Platform, Laval University Hospital Research Centre, Canada; 5Medical Genetics, Universite de Sherbrooke, Canada; 6 Department of Medicine,Centre de Rechereche du CHU Ste-Justine, University of Montreal, Canada

Background: Primary immunodeficiency syndromes (PID’s) are rare inherited disorders of immunity. Their number is rapidly increasing and it is difficult for immunologists and physicians to keep abreast of them. We present an unusual case of a neonate, born to nonconsanguineous white British parents, who presented with intestinal atresia, exomphalos, and severe combined immunodeficiency (T-B+NK-) with hypogammaglobulinaemia without significant infective history. Lymphocyte proliferation in response to PHA was impaired. TRECS, TCR Vβ repertoire, enumeration of naïve T cells and thymic ultrasound were all normal. A genetic defect was pursued to explain the underlying clinical phenotype. Methods: A literature search was undertaken. Based on the clinical phenotype a mutation in the gene tetratricopeptide repeat domain 7A (TTC7A) was suspected. Targeted Sanger sequencing for the candidate gene was performed. Results: The patient was found to be compound heterozygote for 2 mutations in exon 2 of the TTC7A gene. The first mutation is Exon2:c.211G > A which leads to a lysine residue replacing the wild type glutamic acid at amino acid 77 and the second one is Exon2:c.286G > T which results in a stop codon at amino acid 96. Discussion: The discovery of a genetic mutation obviously has implications with respect to further management, genetic counseling and family planning. Further treatment options such as combined HSCT and bowel transplant are under discussion. This case highlights

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



the need for awareness of emerging genetic defects in primary immunodeficiencies and online resources that will link clinical phenotype with genetic defects enabling targeted search and avoiding diagnostic delays. P.61 Whole exome sequencing in the evaluation of a novel primary immunodeficiency characterized by megaloblastic anaemia, recurrent infection and low TRECS Ramakrishnan, Ananth1; Pengelly, Reuben2; Gao, Yifang3; Davies, Graham4; Ennis, Sarah2; Faust, Saul5; Williams, Anthony3 1

Cancer Sciences Division, University of Southampton, MP824,

University Hospital Southampton, Southampton, UK; 2Human Genetics and Genomic Medicine, University of Southampton, UK; 3Cancer Sciences Division, University of Southampton, UK; 4Department of Immunology, Great Ormond Street Hospital, London, UK; 5Clinical and Experimental Sciences Division, University Hospital Southampton, UK

Background: Two brothers presented in early childhood with megaloblastic anaemia, T cell lymphopaenia and recurrent infection. The older brother presented with PCP as an infant and megaloblastic anaemia aged 4 years. The younger sibling presented with recurrent invasive pneumococcal disease and megaloblastic anaemia. Absolute T cell numbers were moderately low and TRECS were noted to be consistently abnormal in both. Both siblings responded to daily folinic acid therapy. Methods: WES was performed on the brothers and father using 50 Mb Sure Select exon capture kit and HiSeq Ilimina platform with adequate depth (20x) and coverage (82%) obtained. Initial informatic analysis was directed to approximately 150 known PID genes (RAPID database), followed by a targeted analysis of genes involved in folate metabolism. Results: We identified significant variants in the methyl tetrahydrofolate dehydrogenase 1 (MTHFD1) gene in both siblings. This gene has recently been reported as causative in a single family with SCID and megaloblastic anaemia. A deletion in exon 13 was present in the siblings and shared with their father. In addition, a novel SNP in exon 3 predicted to be damaging was present in the siblings but absent in the father. We are currently confirming the presence of these heterozygous alterations and their partition within the family. Further functional testing of this pathway has been initiated to substantiate the detrimental impact of these changes. Conclusion: WES and clinically informed bioinformatics offers a new integrated approach for understanding the underlying cause of novel immunodeficiency disorders, offering an alternative to sequential candidate gene sequencing.


P.62 Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by loss-of-function mutation in IL21 Salzer, Elisabeth1; Kansu, Aydan2; Sic, Heiko3; Majek, Peter4; Ikinciogullari, Aydan5; Dogu, Figen E.5; Pickl, Winfried6; Ban, Sol A4; Prengemann, Nina Kathrin4; Kulog˘lu, Zarife2; Demir, Arzu Meltem2; Ensari, Arzu2; Colinge, Jacques4; Rizzi, Martha3; Rizzi, Martha3; Eibel, Hermann3; Boztug, Kaan4 1

CeMM Research Center for Molecular Medicine, Lazarettgasse 14

BT25.3, Vienna, Austria; 2Department of Pediatric Gastroenterology, Ankara University, Turkey; 3Centre of Chronic Immunodeficiency, Freiburg, Germany; 4CeMM Research Center for Molecular Medicine, Austria; 5Department of Pediatric Immunology, Ankara University, Turkey; 6Christian Doppler Laboratory for Immunomodulation and Institute of Immunology, Medical University Vienna, Austria

Background: An imbalanced immune system may change immune homeostasis and result in the development of inflammatory bowel disease (IBD). Recently, mendelian forms of IBD have been discovered as exemplified by deficiency of interleukin 10 or its receptors. In addition, other types of primary immunodeficiency disorders (PIDs) may be associated with intestinal inflammation as one of their leading clinical presentations. Aim: We here investigated a large consanguineous family with three children who presented with earlyonset inflammatory bowel disease within the first year of life, leading to infant death in two of them. Methods: Homozygosity mapping in combination with exome sequencing identified a homozygous missense mutation in the IL21 gene, which showed perfect segregation with the disease. Results: IL21 deficiency resulted in reduced numbers of circulating CD19+ B cells including IgM+ naïve and class-switched IgG memory B cells with a concomitant increase in transitional B cells. In vitro assays demonstrated that mutant IL21Leu49Pro failed to induce STAT3 phosphorylation and immunoglobulin class switch recombination. Conclusions: Our study uncovers IL21 deficiency as a novel cause of early-onset inflammatory bowel disease in humans accompanied by defects in B cell development similar to those found common variable immunodeficiency. Thus, inflammatory bowel disease may mask an underlying primary immunodeficiency as illustrated here for IL21 deficiency.

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36


P.63 Complement C2 deficiency: Clinical manifestations and gene mutations Seneviratne, Suranjith L1; Chee, Ronnie1; Burns, Siobhan O1; Roberts, Andrew2; Jolles, Stephen2; Verma, Nisha1 1

Immunology, Royal Free Hospital, UK; 2Immunology, University

Hospital Wales, UK

Background: We describe a family with complete C2 deficiency and analyse the published literature to assess clinical presentations and gene mutation findings in patients with C2 deficiency. Method: Clinical and investigative findings in a family with C2 deficiency were collected and analysed. The published English literature on C2 deficiency was searched from 1960 to the present time and systematically analysed. Results: The index patient (35 years) was diagnosed with complete C2 deficiency following an episode of pneumococcal meningitis at the age of 2 years. A second episode of meningitis occurred at the age of 5 years. She made a good recovery following both events and remains well on long-term prophylactic penicillin. She has not had any autoimmune manifestations. Her parents and sister also have complete C2 deficiency but so far have not shown an increased infection burden or any autoimmune manifestations. Her maternal grandmother had systemic lupus erythematosus (SLE) but her complement levels are not known. The index patient has been found to have a large homozygous deletion of 28bp from junction of exon 6 and intron 6. This mutation has been described in the majority of cases of type I C2 deficiency. C2 mutation testing in the family is pending. Discussion: Complement C2 deficiency predisposes some individuals (30–50%) to infections with encapsulated organisms and in a lower proportion it may be associated with an autoimmune disease such as SLE.

Mean Median N = (%) below range N = (%) above range Normal range

Over 90% of C2 deficient patients in whom a gene mutation has been reported have a homozygous 28 bp deletion.

Secondary Immunodeficiency P.64 Secondary immunodeficiency in chronic lymphocytic leukaemia Birtwistle, Jane1; Richter, Alex1; Parry, Helen2; Whitelegg, Alison1; Fellows, Mark1; Laurie, Fiona1; Ramnasting, Ramesh1; Taylor, Mat1; Murray, Jim2; Drayson, Mark1 1

Clinical Immunology Service, University of Birmingham, UK;


Haematology, University Hospitals Birmingham, UK

Background: Immunoparesis is well recognised in chronic lymphocytic leukaemia but there are no guidelines for monitoring of immune function or criteria for intervention. A consequence of impaired immunity is that 50% of patients develop infectious complications during the course of their disease and 30–50% of all deaths are directly attributable to infection. The purpose of this study was to systematically examine a CLL cohort with respect to serum humoral immunity and infection frequency/severity. Methods: Serum was collected from 59 CLL patients at the Queen Elizabeth and Heartlands Hospitals, Birmingham. These samples were measured for a variety of immunological markers including: IgG, IgA and IgM; functional antibody levels to 12 pneumococcal serotypes, 4 meningococcal serotypes, tetanus, diphtheria and haemophilus influenza type B (19plex) and complement. We then compared these results for a subset of patients (n = 24) with results from a questionnaire assessing infection frequency and severity. Results:






K/L ratio


1.09 0.87 26 (44) 2 (2) 0.80–4.0

7.29 7.44 22 (37) 1 (2) 6.0–16.0

0.58 0.23 44 (75) 2 (3) 0.50–2.0

46.60 16.16 0 (0) 25 (42) 3.30–19.40

16.05 11.36 4 (7) 5 (8) 5.71–26.30

10.21 1.31 2 (3) 19 (32) 0.26–1.65

0.27 0.26 5 (8) 1 (2) 0.14–0.54

Patients with polyclonal IgG 6 g/l

5% protected 8/12 WHO 45% protected Tetanus 9% protected Diptheria 14% protected Hib

19% protected 8/12 WHO 67% protected Tetanus 25% protected Diptheria 58% protected Hib

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



Conclusion: The incidence of prevalence of hypogammaglobulinaemia is this cohort was 37%. The total IgG may not reflect specificity of the antibody so functional IgG testing was undertaken against common bacterial vaccine antigens. This revealed a significant proportion who were unprotected against Pneumococcus > Diphtheria > Hib > Tetanus. Having an IgG 1.3 mg/l to 70% or more of the serotypes, 4–6 weeks following the immunization). Controlling for age as a confounder in the analysis,


children with impaired antibody responses to pneumococcal polysaccharide immunization had significantly lower Shwachman-Kulczyki scores (p = 0.01), with a trend towards higher Northern radiology scores and lower age-adjusted FEV1% predicted, than children with normal pneumococcal antibody responses. All isolates of Pseudomonas aeruginosa occurred in patients with impaired anti-pneumococcal antibody responses. Conclusions: Our data suggest that impaired antibody responses to bacterial polysaccharide antigens in children with CF are common, and may be associated with increased disease severity. Longitudinal studies are required to assess the long-term significance of impaired anti-pneumococcal antibody responses in children with CF.

Background: Myotonic dystrophy type 1 (DM1) is an autosomal dominant multi-system disorder caused by a mutational expression of a polymorphic CTG repeat located in DMPK . Individuals commonly have a mildly reduced serum IgG concentration. This is attributed to reduced expression of the FcRn receptor that acts as a chaperone protein to IgG preventing its endosomal degradation and re-circulation. It has been hypothesised that the number of CTG repeats is inversely correlated to the serum IgG level although this is debated. Recurrent infections are not reported in this group. Aims: To evaluate severity of hypogammaglobulinaemia and frequency of infections in patients with DM1 referred to our immunology clinic. Methods: Case notes of three patients with genetically confirmed DM1 were reviewed with particular reference to a history of recurrent infection. Serum immunoglobulin levels and response to pneumococcal polysaccharide vaccination were evaluated and lymphocyte subset analysis performed. Results: Patient A had an incidental finding of hypogammaglobulinaemia with no history of recurrent infections. IgG was 4.0 g/l . She made a good response to Pneumovax II. Patient B had an IgG 2.1 g/l and made a poor response to Pneumovax II (9/13 serotypes 25% reduction in antibiotic prescriptions in only 15% of patients with SPAD. Discussion: This audit suggests that IRT reduces the frequency of acute primary care antibiotic prescriptions in patients with CVID but not those with SPAD. This data questions the clinical and cost effectiveness of IRT in Specific Polysaccharide Antibody Deficiency. The use of immunoglobulin replacement therapy in SPAD requires formal evaluation.

P.70 Home penicillin treatment for actinomycosis in CGD Drinkwater, Sara1; Qamruddin, Ahmed2; Blackburn, Tim3; Farragher, Alex4; Helbert, Matthew4 1

Immunology, Central Manchester University Hospitals NHS FT, Manchester Royal Infirmary, Oxford Road,, Manchester, UK; 2 Microbiology, Central Manchester University Hospitals NHS FT, UK; 3 Oral and Maxillofacial Surgery, Central Manchester University Hospitals NHS FT, UK; 4Immunology, Central Manchester University Hospitals NHS FT, UK

Background: A 24 year old man with X-CGD was referred in 2010. He originally presented in the neonatal period with cutaneous abscesses requiring drainage. He underwent drainage of a liver abscess aged 14 followed by ongoing suppurative adenitis. On presentation to us


he was on background co-trimoxazole and itraconazole prophylaxis. He lived over 100 km for our hospital. He continued to have intermittent cervical abscesses which resolved transiently with oral flucloxacillin. Methods: In 2012 he underwent excision and drainage of a large cervical abscess and pus was assiduously collected. He had previously had similar surgical procedures pre 2010 and in 2011, with no pathogens identified in microbiology samples. Results: Surgical samples grew Actinomyces species shown to be A. naeslundii complex (A. naeslundii, A. viscosus or A. oris) on gene sequencing. He responded to IV benzylpenicillin for 4 weeks, followed by 1 g amoxicillin tds for a total of 8 months (to date), initially with probenecid 500 mg qds for 3 months. There were no side effects. Discussion: Actinomyces in CGD has been reported before and delayed diagnosis is common. Invasive sampling may be required. We have shown here that probenecid can safely be given to enable patients who need prolonged high dose penicillin to switch to oral therapy. Conclusion: Although rare in CGD, catalase negative infections should not be overlooked and provides evidence for the idea that deficient hypochlorite secretion is not sufficient to cause infection in CGD. Probencid may provide an adjunct to penicillin treatment. P.71 Stem cell transplant for life threatening infection in an adult with DCML Drinkwater, Sara1; Tholouli, Eleni2; Woodhead, Mark3; Blanchard, Tom4; Helbert, Matthew1 1

Immunology, Central Manchester University Hospitals NHS FT, UK; Haematology, Central Manchester University Hospitals NHS FT, UK; 3 Respiratory Medicine, Central Manchester University Hospitals NHS FT, UK; 4Infectious Diseases, Pennine Acute Hospitals NHS Trust, UK 2

Background: A 39 year old man was referred with pulmonary M. malmoense infection, extensive warts and a history of COPD. A four drug anti mycobacterial regime was complicated by hepatotoxicity. There was no evidence of pulmonary alveolar proteinosis. Two maternal uncles had been diagnosed with myelodysplasia in their 20 s/30 s. One received a BMT and is currently healthy. Our patient had absent monocytes, dendritic cells and B cells in peripheral blood and a reduced CD4 T cell count. Macrophages were present on skin biopsy. A GATA 2 mutation was found, confirming DCML. Methods: He underwent reduced intensity conditioning with Campath, treosulphan and fludarabine followed by matched unrelated donor peripheral blood stem cell transplantation.

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36


Results: Donor monocyte reconstitution occurred quickly and he was discharged 17 days post transplant. Lymphocyte recovery over the following months coincided with clearance of the warts and no recurrence of the mycobacterial infection. Transplant was complicated by early grade 1 cutaneous GVHD. He developed AIHA 8 months post transplant and ITP 14 months post transplant. At 15 months post transplant, aside from these autoimmune phenomena, he remains well. Exercise tolerance had increased and there have been improvements in pulmonary function and gas transfer. Conclusion: In DCML development of myelodysplasia with transformation into acute leukaemia appears almost universal and provides a compelling argument for SCT. In the case described here, the short term argument for SCT was overwhelming infection, which appears to have responded to immune reconstitution.

P.72 Active transfer of polymeric immunoglobulins into the CVID lung following intravenous infusion of an IgA and IgM enriched IVIg Kiani-Alikhan, Sorena1; Smith, David2; Howard, Amiee2; Hodkinson, John3; Ibrahim, Mohammad AA4 1 Clinical Immunology & Allergy, Royal Surrey County Hospital NHS Foundation Trust, UK; 2Sheffield Hallam University, UK; 3Biotest UK, UK; 4King’s College Hospital NHS Foundation Trust, UK

Background: A CVID patient with bronchiectasis developed recurrent lower respiratory infections requiring intravenous antibiotics despite adequate IgG trough levels and trials of different prophylactic antibiotics. The IVIg was switched to an IgA and IgM enriched IVIg (IVIg G/A/M) product. Maintenance on IVIg G/A/M reduced infective exacerbations and in-patient admissions for IV antibiotics from 10 admissions in 18 months, to 3 in 28 [Ref 1]. For the IVIg G/A/M to have a role in reduction of infective exacerbations, we hypothesised that at least some isotypes had to become available on the respiratory mucosal surfaces. Methods: Sputum samples were collected before and 1,2,3,4 & 7 days after IVIg G/A/M administration. Western blots against immunoglobulin isotypes and the secretory piece (SP) were employed to detect Ig isotypes and to determine the macromolecular form of IgA and IgM in sputum samples. Albumin was used as the internal standard. Results: Following intravenous Ig G/A/M, the concentration of IgA and IgM but not IgG increased in sputum samples, peaking at 2 days and returning to baseline by 7 days. SP concentration also increased in parallel. Co-blotting of SP and IgA in conjunction with molecu-

lar weight determination confirmed that the detected IgA is a secretory macromolecule. Discussion: Administration of IVIg G/A/M resulted in increased active transport of secretory IgA, and IgM across the mucosal epithelium. Passive leakage was not responsible for the transfer as evidenced by the changes in SP and IgG concentrations. These results need to be repeated in other patients on IVig G/A/M. Reference: [1] J Allergy Clin Immunol. 2012 Aug;130(2):553–4; Immunoglobulin replacement therapy: is there a role for IgA and IgM? Kiani-Alikhan S, Yong PF, Grosse-Kreul D, Elston C, Ibrahim MA.

P.73 Are primary immunodeficient patients on immunoglobulin replacement receiving adequate monitoring? Ramasamy, Moganadeven; Bourne, Helen; Spickett, Gavin; Catherine, Stroud Regional Department Of Immunology and Allergy, Newcastle Upon Tyne NHS Foundation Trust, UK

Background: The immunology department at the Newcastle Upon Tyne NHS Foundation Trust has 90 patients currently receiving replacement immunoglobulin for both primary and secondary immunodeficiencies. The aims of the study were to ensure compliance with departmental and national monitoring guidelines in the following areas 1. Documentation of current patient weight and immunoglobulin as a dose/kg/month. 2. Measurement of trough IgG at 6 monthly intervals 3. Measurement of liver function tests (LFT) at 6 monthly intervals 4. Annual pulmonary function test (PFT) measurement 5. Ensuring an adequate trough IgG. Methods: An initial retrospective study of 27 patients randomly selected from a total of 90 patients on the primary immunodeficiency database within the Immunology Department was carried out. Data was collected by reviewing the database and patient notes. Results: Trough IgG, LFTs and PFTs were regularly reviewed in 89%, 93% and 44% of cases respectively. Trough IgG was considered adequate in 85% of patients while 7 patients were identified to have abnormal LFTs. Finally, 15% of patients did not have a documented weight. Discussion: Actions points included the possible introduction of in-house spirometry to enhance lung function monitoring by improving patient access. A management plan will be discussed with the hepatologists regarding referral and investigation for

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36



abnormal LFTs. A further survey is planned to identify all patients with a sub therapeutic IgG trough and document potential causes. A reaudit is planned for 2015. P.74 Experience with rapid push subcutaneous immunoglobulin therapy from a UK clinic Richter, Alex Clinical Immunology Service, University of Birmingham, Edgbaston, Birmingham, UK

Background: Rapid push is a subcutaneous (SC) technique where immunoglobulin (Ig) is given manually by slow injection, using a butterfly needle and syringe in divided doses over the week. Two cases are described where rapid push was the patient preferred technique for clinical and practical reasons. Case 1: A 73 year old patient with CLL, recurrent life threatening chest infections, bronchiectasis and hypogammaglobulinaemia

Patient rationale Time to train Time per injection (mins) Drawing up + injection Side effects Hizentra dose

Case 1

Case 2

Reducing fluctuations of Ig, didnt want to use a pump 2x 1hour clinic visit, 1x 1 hour home visit 10 + 5

Flexibility, speed of single administration 2x 1hour clinic visit, 1x 1 hour home visit 7+7

1x bruise 2 g (10 mls) 3x week

2x mild local reaction 2 g (10 mls) 4x week

Conclusion: The SC rapid push technique is a safe, efficient alternative to an infusion pump that achieves rapid normalisation of immunoglobulin trough levels. Patients have commented on the simplicity, speed and flexibility


(IgG 4.28 g/l) with failure to mount a vaccine response was commenced on IVIG. After 4 infusions she suffered a stroke. She and her husband choose to continue with Ig due to the significant improvement in clinical symptoms but by SC rapid push to minimise fluctuations Ig concentrations and because they didn’t want to use a pump. The husband was trained to give the injections. The IgG concentration as 8.33 g/l after 12 injections. Case 2: A 38 year old teaching assistant was newly diagnosed with CVID (IgG 3.2 g/l,). All options for Ig administration were discussed and the patient opted for rapid push because of the flexibility (dogs and children) and short time of individual injections. After 12 injections she achieved an IgG of 6.78 g/l and 20 injections 7.18 g/l. She has been infection free since commencing Ig and has returned to work after a prolonged leave of absence. The patient has had to 2 mild local erthythematous reactions that settled within 8 hours.

of administration. Training time was mostly directed at drawing up the infusion; pre-filled syringes would even further reduce infusion time and daily time spent on dose administration.

© 2013 The Authors Clinical and Experimental Immunology © 2013 British Society for Immunology, Clinical and Experimental Immunology, 174 (Suppl. 1), 1–36

Abstracts of the UK PIN (Primary Immunodeficiency Network) Meeting. December 6-7, 2013. Liverpool, United Kingdom.

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