Congenital Immunodeficiency Syndromes Research Articles

Genetic background of primary and familial HLH in Qatar: registry data and population study.

Familial hemophagocytic lymphohistiocytosis (FHLH) is an inherited life-threatening disease. Five types are identified, with the addition of congenital immunodeficiency syndromes in which HLH is a typical manifestation. The literature on this disease is very scarce in the Middle East, with only a few scattered reports. We report detailed demographic, clinical, and genomic data from 28 patients diagnosed with primary and familial HLH over the last decade in Qatar. An evaluation was performed of allele frequencies of deleterious variants from 12 primary and familial HLH causative genes on the Qatar Genome Programme (QGP) cohort of 14,669 Qatari individuals. The genetic diagnosis was obtained in 15 patients, and four novel mutations in Perforin 1 (PRF1), UNC13D, LYST, and RAB27A genes were found. We identified 22,945 low/high/moderate/modifier impact variants significantly enriched in the QGP in those 12 genes. The variants rs1271079313 in PRF1 and rs753966933 in RAB27A found in our patient cohort were significantly more prevalent in the QGP compared to the Genome Aggregation Database (gnomAD) database, with a high carrier frequency in the Qatari population. We established the first primary and familial HLH Registry in the Gulf Region and identified novel possibly pathogenic variants present at higher frequency in the Qatari population, which could be used for screening purposes. Raising awareness about primary and familial HLH and implementing screening activities in the Qatari highly inbred population could stem into more comprehensive premarital and prenatal evaluations and faster diagnosis.

Epidemiology, characteristics, and outcomes of adult haemophagocytic lymphohistiocytosis in the USA, 2006–19: a national, retrospective cohort study

Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome characterized by an excessive inflammatory response. Limited data exist on adult HLH. In this national, retrospective cohort study, we analysed data from the US National Inpatient Sample database collected between October 1, 2006 and December 31, 2019. Using the International Classification of Diseases (ICD) codes, we identified all adult patients who were admitted non-electively with the diagnosis of HLH. We described demographic characteristics, triggers, and associated conditions. Trends of diagnosis, treatment, and in-hospital mortality were analysed using joinpoint models. In-hospital mortality rates were compared using multivariable logistic regression models that adjusted for demographic characteristics and associated conditions. Finally, we described resource utilization outcomes including cost of hospitalization and length of stay. We identified 16,136 non-elective adult HLH admissions. The population pyramid showed a bimodal distribution, with peaks in young adults (16-30 years) and older adults (56-70 years). Joinpoint regression analysis revealed a significant increase in HLH incidence per 100,000 admissions over the study period (Average Annual Percent Change [APC]=25.3%, p<0.0001), and no significant change in rates of in-hospital mortality (slope=-0.01; p=0.95) or administration of in-hospital HLH treatment (slope=0.46, p=0.20). The most common associated conditions were malignancy (4953 admissions [30.7%]), infections (3913 admissions [24.3%]), autoimmune conditions (3362 admissions [20.8%]), organ transplant status (639 admissions [4%]), and congenital immunodeficiency syndromes (399 admissions [2.5%]). In-hospital mortality was higher in older adults and males. Furthermore, Congenital immunodeficiency syndromes had the worst in-hospital mortality rate (mortality rate 31.1%, adjusted OR 2.36 [1.56-3.59]), followed by malignancies (mortality rate 28.4%, adjusted OR 1.80 [1.46-2.22]), infections (mortality rate 21.4%, adjusted OR 1.33 [1.10-1.62]), other/no trigger (mortality rate 13.6%, adjusted OR 0.73 [0.58-0.92]), autoimmune (mortality rate 13%, adjusted OR 0.72 [0.57-0.92]), and post-organ transplant status (mortality rate 14.1%, adjusted OR 0.64 [0.43-0.97]). The overall mean length of stay was 14.3±13.9 days, and the mean cost of hospitalization was $54,900±59,800. We provide insight into the burden of adult HLH in the USA. The incidence has been increasing and the outcomes remain dismal. This signifies the growing need for the development of updated diagnosis and treatment protocols that are specific to adult HLH. None.

Utility of Neonatal Sequential Organ Failure Assessment (nSOFA) Score for Neonatal Mortality Prediction

Aims and Objectives: (a) Utility of neonatal sequential organ failure assessment (SOFA) score for predicting mortality in neonatal sepsis. (b) Determining a cut-off score of neonatal sequential organ failure assessment (nSOFA) score in relation to mortality. Materials and Methods: Prospective pilot study in neonatal intensive care unit (ICU) for 1 year (January-December 2021). Inclusion Criteria: All neonates (inborn and outborn) admitted to neonatal ICU with the diagnosis of presumed or proven sepsis. Exclusion Criteria: Neonates with critical congenital heart disease, congenital malformations, congenital immunodeficiency syndromes, inborn errors of metabolism, and neonates with birth asphyxia. All neonates admitted in neonatal ICU with the diagnosis of presumed or proven sepsis were included in the study. Variables required for nSOFA were assessed along with general demographic like age, gestational age, and so on. The nSOFA score was documented twice, once at the time of admission (initial evaluation) for sepsis and later at 24 h. The final outcome (survivor/nonsurvivor) was recorded. Data was analyzed to see the correlation of nSOFA to outcome and also to see the predictive value of cut-off nSOFA score to outcome. Results: A total of 60 neonates with presumed or proven sepsis (30 each in term and preterm) were admitted, of which 10 (16.7%) were nonsurvivors (6 preterms and 4 term), P value .731. Four deaths were observed in outborn (n = 38) and 6 in inborn (n = 22) babies, P value .149. The mean (±standard deviation [SD]) of age (days) and weight (kg) among survivors was 11.24 (9.47) and 2.23 (0.69) and for nonsurvivors was 11.2 (11.9) and 1.9 (1.1), respectively, P value &gt;.05. There was no statistical significance observed between survivors and nonsurvivors in relation to blood culture positivity, P value .17. Mean (±SD) nSOFA score among survivors at the time of admission (initial evaluation) was 1.96 (1.69) and at 24 h was 1.16 (1.48). Among nonsurvivors mean (±SD), admission (initial evaluation) nSOFA score was 7.6 (2.0) and at 24 h 10 (2) was observed, P value of &lt;.001. The mean (±SD) of nSOFA changes (at the time of admission and at 24 h) for survivors (–)0.8(1.14) and for nonsurvivors 2.4 (1.17) was observed, P value &lt;.001. Outcome in relation to nSOFA score, 90.0% mortality was observed with the score of ≥6 at the time of admission (initial evaluation) and score of ≥5 at 24 h. Based on these cut-off values, receiver operating characteristic curve for mortality prediction was calculated. Area under curve (AUC) for admission (initial) was 0.972 (sensitivity 90%, specificity 98%, positive predictive value 90%, negative predictive value 98, with accuracy of 96.7%). At 24 h, AUC was 0.999 (sensitivity 100%, specificity 98%, positive predictive value 90.9%, negative predictive value 100, with accuracy of 98.3%). Conclusion: nSOFA can predict neonatal mortality due to sepsis. Admission nSOFA score of ≥6 and ≥5 at 24 h correlate well with mortality.

Role of Next Generation Sequencing in the Diagnosis of Unexplained Thrombocytopenias- an Experience at a Tertiary Care Hospital

▪BACKGROUNDNext Generation Sequencing (NGS) has been enormously rewarding in the field of diagnostic hematology. In particular, the diagnosis of inherited disorders has progressed in leaps and bounds. These patients tend to remain undiagnosed for a long period of time not only because of unavailability of molecular diagnostics but also due to lack of cognizance and atypical presentations.Thrombocytopenia (TCP) is a common hematological presentation and can lead to chronic hospital visits to life-threatening bleeds. Most of these patients have acquired disorders such as immune TCP, malignancies, liver disease etc. However, some of them are likely to have unidentified inherited causes. We thus intended to study the utility of NGS in the definitive diagnosis of unexplained TCPs with or without other cytopenias to understand the clinicopathologic characteristics of these patients.METHODOLOGYThis was a retrospective descriptive study done at two centres over three years from May 2018 to May 2021. Patients with TCP with one of the following: (a) positive family history (b) clinical/ laboratory clues to an inherited cause (c) chronic TCP with no response to conventional therapies and sent for clinical exome sequencing done by NGS were included in the study. Patients who were negative for germline mutations were excluded.Sequencing of targeted genes was performed on the Illumina platform with a mean coverage of >80-100X. Mutations annotated as pathogenic, likely pathogenic and variant of uncertain significance (VUS) were considered clinically significant. VUS are mutations that are difficult to classify as pathogenic and require clinical validation and family testing.RESULTSOur cohort included 18 patients and were divided into two groups- cases of isolated TCP and cases of TCP with anemia and/or neutropenia.Patients presenting with isolated thrombocytopeniaWe had nine cases of isolated TCP out of which there were three cases of X-linked macrothrombocytopenia with MYH9 mutation, two cases of Wiskott Aldrich syndrome (WAS) and one case each of congenital thrombotic thrombocytopenic purpura (TTP), atypical Hemolytic Uremic Syndrome (HUS), Fanconi anemia (FA) and grey platelet syndrome. The demographic and mutational characteristics are described in Table 1. Clinical and laboratory clues were present in 7 cases, such as chronic kidney disease, micro/ macrothrombocytopenia, neutrophil inclusions etc. Bone marrow examination was carried out in 4 cases- the significant dyspoiesis in FA and myelofibrosis in grey platelet syndrome mislead to a diagnosis of MDS and myelofibrosis respectively. Seven patients had received treatment with steroids, immunosuppressants, splenectomy, danazol and TPO mimetics before the NGS diagnosis.Patients presenting with thrombocytopenia and other cytopeniasThis group consisted of nine cases with two cases each of Dyskeratosis Congenita (DKC) and WAS and one case each of TTP, Ghosal hematodiaphyseal dysplasia, Congenital Amegakaryocytic Thrombocytopenia (CAMT), B-cell immunodeficiency with hypogammaglobulinemia type-25 and double homozygous for FA and DKC. The majority of patients in this group were young and had lower platelet counts (Table 2). The most common associated cytopenia was anemia. Phenotypic clues to diagnosis were present in cases of DKC and WAS. The common differentials considered in this group were inherited bone marrow failure syndromes (IBMFS), congenital immunodeficiency syndromes etc. Bone marrow examination was done more frequently in these patients and showed hypocellular marrow in IBMFS and absent megakaryocytes in CAMT. These patients have also been treated with steroids, IVIg, danazol and TPO mimetics.CONCLUSIONPatients with inherited isolated TCPs have a chronic course and heterogenous causes therefore tend to be diagnosed later in life. However, patients with TCPs and other cytopenias tend to present at a younger age with infrequent family history. IBMFS was the most common disorder identified in this latter group of patients. Positive family history, clinical and laboratory clues and absence of response to conventional therapies should prompt workup of inherited causes by NGS to avoid long term ineffectual treatment. Further, NGS mutations, in particular VUS have to be interpreted with caution with the help of parental study, clinical presentation, in-silico analysis and inputs from molecular and genetic experts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

U.S-Based Community Oncologists/Hematologists' Perceptions Regarding Future Use of Gene Therapies for Patients with Hematological Disorders

IntroductionGene therapies, defined as the introduction, removal, or change in genetic material into a patient's cells to treat a specific disease, represent a significant advance in medicine, with the potential to cure or significantly improve outcomes of various benign and malignant hematologic disorders (American Society of Gene Therapy). Gene therapies have received approvals for subsets of patients with spinal muscular atrophy or retinal dystrophy, and almost a thousand studies are actively recruiting patients for various gene therapy trials. Aside from CAR-T therapies, several gene therapies are in advanced clinical development in the U.S. for disorders such as hemophilia, hemoglobinopathies, and congenital immunodeficiency syndromes. Results of many such trials were presented at the 2020 ASH annual meeting. While approvals for some gene therapy products are expected in the near future, the complexity of treatment, knowledge gaps among providers, or barriers with accessibility or cost may limit the integration of these treatments into routine clinical practice. Therefore, the present study surveyed U.S.-based community oncologists/hematologists (cO/H) to evaluate their perceptions of the utility of gene therapies and barriers to adoption or integration into clinical practice.MethodsBetween February and April 2021, cO/H from across the U.S. were invited to complete a web-based survey about gene therapies. Physician demographics and practice characteristics were also captured in the survey. Responses were aggregated and analyzed using descriptive statistics.ResultsA total of 369 cO/H completed the survey; 36% identified as a medical oncologist and 63% as a hematologist/oncologist. cO/H had an average of 19 years of clinical experience and spent an average of 86% of their working time in direct patient care and saw an average of 17 patients per day on clinic days. Half of cO/H stated that they were not aware of recent data of gene therapies for adult hematology/oncology indications (35% “not very aware”; 15% “not at all aware”). When asked to report the number of approved gene therapy products (excluding CAR-T products) in the U.S. in early 2021, 27% of participants reported 0, 24% reported 1, and 20% reported 2 products were currently available. Regarding gene therapy use for adult hematologic/oncologic indications in the next 2 years, 53% of cO/H reported that they expect gene therapies to mostly be administered and managed by academic centers to which they will refer their patients; 27% reported that indications will be limited and unlikely to affect their practice (Table 1). cO/H perceived cost as the greatest barrier to adopting gene therapies into their clinical practice; specifically, cO/H cited cost limitations by payers (49%), the prohibitive cost to patients (46%), and the prohibitive cost to practices/hospitals (37%). Other barriers to adoption were limited real-world efficacy data (18%) and long-term complications (13%). Most cO/H reported a moderate (39%) or high (43%) comfort level with prescribing a gene therapy for adult hematology/oncology indications if it were reimbursed.ConclusionsMany cO/H were not aware of recent data of gene therapy products, with over half expecting to refer their patients to large academic centers for gene therapies. While most cO/H would be comfortable prescribing gene therapies for their patients, cost was perceived as prohibitive. This information can inform various stakeholders, including patients, advocacy groups, pharmaceutical manufacturers, payers, and professional societies, in laying the foundations for gene therapy products in hematology. Future work should focus on enhancing education of gene therapy products to community providers as well as identifying support programs that lessen the burden of cost. [Display omitted] DisclosuresGajra: Cardinal Health: Current Employment, Current equity holder in publicly-traded company. Fortier: Cardinal Health: Current Employment. Jeune-Smith: Cardinal Health: Current Employment. Feinberg: Cardinal Health: Current Employment.

PO-0251 Tuberculosis In Children: A Study Of 32 Cases

Introduction Tuberculosis (TBC) continues to cause an unacceptably high toll of disease and death among children worldwide, particularly in the developing countries. Objective Study the epidemiological and clinical aspects of TBC in Tunisian children and clarify its treatment. Population and methods A descriptive study was carried out, included all cases of TBC diagnosed in Sahloul paediatric unit hospital between 2004 and 2013. Epidemiological, clinical and microbiological data were recorded. Therapeutic and evolutionary aspects were clarified. Results We reviewed 32 cases (16 boys and 16 girls), aged from 6 months to 15 years. All patients were vaccinated against tuberculosis. No case of malnutrition none immune deficiency had been recorded until the first hospitalisation. The diagnosis of TBC was based on clinical features, tuberculin skin test, chest radiography and the histological examination of lymph node, peritoneal and pleural biopsy. Diagnoses were identified: Lymph node tuberculosis (11 cases), pulmonary tuberculosis (4 cases), peritoneal tuberculosis (4 cases), bone tuberculosis (4 cases), tuberculous meningitis (2 cases), cutaneous tuberculosis (1 case), renal tuberculosis (1 case), tuberculosis in hematopoietic stem cell (1 case), pleuro-pericarditis tuberculosis (1 case), and the disease has affected several organs (disseminated) in 3 cases. Two cases of congenital immunodeficiency syndrome were identified. All our patients were treated with an association of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol for 2 months, and then they received Isoniazid and Rifampicin for a period ranging from 2 to 16 months. 27 children were cured (24 without sequelae and 3 with sequelae). Two children died. Conclusion Tuberculosis in children presents particularly difficult challenges, but advances in paediatric tuberculosis research could provide wider insights and opportunities for tuberculosis control especially in developing countries.

P-001 Crohn’s-like Disease in a Patient with Good Syndrome

There has been described a Crohn’s-like disease in patients with congenital immunodeficiency syndromes (chronic granulomatous disease, glycogen storage disease type Ib, common variable immunodeficiency…). We report a case of a Crohn’s-like colitis and perianal fistula in a patient with Good Syndrome, an acquired immunodeficiency. A 58 years old male, was diagnosed in January 2004 of thymoma and secondary hypogammaglobulinemia (Good Syndrome). He was treated by thymectomy and radiotherapy. Eleven months later the surgery, the patient developed bloody diarrhea, colicky abdominal pain, fever, weight loss and complex perianal fistula. In physical exam, abdomen exploration was not remarkable; there was a perianal fistula with fecal and purulent drainage. The laboratory findings were: hemoglobin 12.4 g/dL, platelets 70 × 10^9, CD4 293 cells/μL, CD3 and CD8 were normal, ratio CD4/CD8 0.34, IgA 14 mg/dL and IgM 5 mg/dL. The rest of results were normal. A colonoscopy was carried out finding multiple superficial ulcers in rectum, sigma, left colon and cecum. Transverse, right colon and ileum were unaffected. Biopsies showed nonspecific moderate inflammatory infiltrate of lymphocytes and plasma cells. No granulomas, crypt abscesses or CMV inclusions were found. Fecal cultures were all negative. Finally a probability diagnosis of Crohn’s disease was done and the patient was treated with mesalazine, steroids and metronidazole without any improvement. Monthly IV immunoglobulins were also administered. Thiopurines and anti-TNF were not used because of recent diagnosis of thymoma. During the following 5 years progressive pancytopenia was developed and recurrent fungal, bacterial and viral infections occurred including a septic shock. Finally the patient died in February 2009 because of E. coli septicemia. Thymomas represent 0.2%–1.5% of malignant neoplasias; 3%–6% of them develop hypogammaglobulinemia after the surgery, what it is called Good syndrome. This acquired immunodeficiency is both cellular and humoral; Immunoglobulins are absent or very low and CD4 are low with a CD4/CD8 ratio <1. The patient suffers different recurrent and opportunistic infections; being the general survival 4 years. There is no specific treatment despite IV immunoglobulins therapy. A Crohn’s-like disease has been reported in other immunodeficiency syndromes (as a chronic granulomatous disease, glycogen storage disease type Ib or common variable immunodeficiency). Our patient had a phenotypically Crohn’s disease pattern, but biopsy was not specific and he did not have a response after steroids treatment. We hypothesize that this patient had a Crohn’s-like syndrome similar to those have been reported in other immunodeficiencies. Congenital immunodeficiency syndromes sometimes developed a Crohn’s-like syndrome. - Good syndrome is an acquired immunodeficiency syndrome compromising both cellular and humoral immune response. - We describe a Crohn’s-like syndrome on a patient with Good syndrome, suggesting a similar pathogenic mechanism with congenital immunodeficiency and possibly Crohn’s disease.

Biosimilar Compared With Originator Filgrastim For Related-Donor Allogeneic Stem Cell Mobilisation: A Prospective-Historical Control Study

IntroductionBiosimilars of filgrastim have been available for over five years In Europe, where their use now exceeds that of the originator product. However, some professional bodies have raised concerns over their use in healthy donors for allogeneic mobilisation given the absence of clinical data in this setting. Here we report the use of biosimilar filgrastim compared with a matched historical control group in allogeneic transplant. MethodsA total of 26 healthy related-donors (parent or sibling) received biosimilar filgrastim (HX575) for allogeneic stem cell mobilisation at a single centre between 2011 and 2013. Donors and recipients were compared with a matched historical control group (n=48) who had been treated with original filgrastim (Neupogen) at the same centre between 2005 and 2011. Donors and patients in both groups were treated according to the same clinical protocol, with G-CSF 10 µg/kg/day administered to donors on days 1-5 with leukapheresis performed on day 5. ResultsDonor and recipient characteristics (age, gender, body weight) were similar in both groups. Both the biosimilar and originator groups had similar donor mean white blood cell counts at baseline (6.13 vs 6.24 x 109/l) and on day 5 (46.9 vs 45.3 x 109/l). Mean donor CD34+ cell count on day 5 was 92/µl in the biosimilar group and 88/µl in the originator group (p=0.713). Mean number of CD34+ cells per recipient body weight was 9.7 x 106 in the biosimilar group and 8.00 x 106 in the originator group (p=0.437). Occurrence and intensity of bone pain was similar in donors in both groups. The majority of recipients in both groups had acute leukemia, myeloma, lymphoma or congenital immunodeficiency syndrome and around half underwent a non-myeloablative transplant. Median time to neutrophil engraftment (>500/µl) was similar in both the biosimilar and originator groups (16.5 [range 11-44] vs 15.0 [range 9-23] days; p=0.078), as was platelet recovery (>20 g/l) (12.5 [range 8-28] vs 12.5 [range 3-38] days; p=0.990). Acute graft-versus-host disease (GVHD) occurred in 27% of patients in the biosimilar group and 38% patients in the original group, while chronic GVHD occurred in 15% and 19% of recipients, respectively. ConclusionsBiosimilar G-CSF is as effective and well tolerated as originator G-CSF for related-donor allogeneic stem cell mobilisation. Long-term follow-up of donors is required to confirm the safety of biosimilar and originator G-CSF. Disclosures:Lefrère:Sandoz Biopharmaceuticals: Consultancy, Honoraria. Turner:Sandoz Biopharmaceuticals: Employment.

Allogeneic Hematopoietic Stem Cell Transplantation Of Patients With Wiskott-Aldrich Syndrome With Total Body Irradiation (TBI), Thiotepa and Fludarabine Or Cyclophosphamide Followed By T-Cell Depleted Grafts From Alternative Donors

Wiskott-Aldrich syndrome (WAS) is a rare X-linked congenital immunodeficiency syndrome characterized by micro-thrombocytopenia, eczema, autoimmune syndromes and malignancies that are often fatal. Early hematopoietic stem cell transplant (HSCT) experience for patients with WAS from alternative donors was associated with poor outcome including a high rate of graft rejection. Since 1998 we have transplanted 13 patients with WAS with grafts from alternative donors. Specifically, 9 of these patients received T cell depleted transplants and are the focus of this abstract. Grafts were from matched unrelated donors (N=5) mismatched unrelated donors (N=2) mismatched related donors (N=2). Patient age at transplant ranged from 1.1-21.5 years (median 3.3). Cytoreduction included Hyperfractionated TBI with Thiotepa and Cyclophosphamide or Fludarabine (N=7) Busulfan with Melphalan and Fludarabine (N=1) Cyclophosphamide with Thiotepa and Fludarabine (N=1). Prior to 2002 no children under 24 months received TBI. Subsequently CNS shielding was used with TBI for patients under the age of 3. All patients received ATG for graft rejection prophylaxis. Six patients had previously undergone splenectomy. Stem cell grafts were Lectin/E rosette separated T cell depleted bone marrow (N=4) or Isolex/E rosette separated T-cell depleted PBSC (N=5). Eight patients engrafted with median neutrophil engraftment on day 12 (11 -16). One patient who received cytoreduction with Cyclophosphamide, Thiotepa and Fludarabine suffered primary graft failure, had autologous recovery and went on to receive a second transplant and is alive and well. All patients developed Grade I – II mucositis. One patient suffered an early toxic death after developing acute encephalopathy during cytoreduction with Busulfan (8mg/kg) Melphalan (140mg/m2) and Fludarabine (125mg/m2) and one other patient with a prior history of lymphoma had progression of lymphoma and early death post HSCT. One developed acute GvHD (Grade III GI). Three patients developed autoimmune disorders associated with mixed chimerism. All three patients had complete resolution of their autoimmune disease and two of these three patients reverted to full donor chimerism. With a post HSCT follow-up period of a median of 7.5 years (3-15 years) seven of these nine patients are alive and disease-free. In summary, T-cell depleted grafts appear to extend transplant as a treatment option for patients with WAS who are without matched related donors. Recent successful experience with T cell depletion following chemotherapy only regimens for other patient populations will provide a way to explore non-TBI based cytoreduction and T cell depletion as an approach for future patients. Disclosures: No relevant conflicts of interest to declare.

A Case Study on Family Therapy for Solving Martial Conflicts of Family with a Child Suffering Congenital Immuno-Deficiency Syndrome

본 연구는 선천성 면역결핍질환아 부모가 경험하고 있는 부부갈등의 특징과 부부갈등에 영향을 미친 요인 그리고 부부갈등을 해결하기 위한 가족치료 개입과정과 치료개입의 효과성을 살펴보았다. 본 연구는 생후 2개월부터 7년 간 아들의 불치병을 치료하는 과정에서 부부관계가 악화되면서 부부가 상담을 의뢰하여 2006년 11월부터 2007 년 4월까지 총 13회기 동안 개인상담과 부부상담을 진행한 가족치료 사례를 Miles와 Huberman(1994)의 질적 분석방법을 활용하여 분석하였다. 분석결과 선천성 면역결핍질환아 부모가 경험하고 있는 부부갈등의 특징은 재정악화와 역할기대로 인한 충돌, 아 들의 질병악화로 인한 충돌, 감정조절이 안되는 심리적 불안정 상태, 극단적인 부부위기 상황으로 분석되었다. 부 부갈등에 영향을 미친 요인으로는 부부의 원가족 경험과 이로 인한 역기능적으로 시도해온 ‘해결책’인 것으로 분 석되었다. 치료개입은 문제확인 및 상담의 구조화, 원가족과 핵가족의 정서과정 탐색, 딸이 지각하는 가족관계 패 턴 및 딸의 정서적 문제 탐색, 치료적 삼각관계 유지 및 변화계획 수립, 새로운 해결책의 효과성 확인 및 변화유지 권유의 과정으로 분석되었다. 보웬의 가족체계모델과 MRI 의사소통모델에 근거한 치료개입을 통하여 부부 는 의사소통이 원활해지고, 정서적 교류가 이루어졌으며, 부부갈등이 완화되었다. 이러한 연구결과는 선천성 면역결핍질환아 가정이 직면하는 복합적인 문제 중에서 부부문제 해결을 위한 전문적인 임상적 접근으로써 가족치료 개입의 효과성을 제시하였다.

Transforming growth factor‐β1 polymorphisms and the outcome of hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is a medical procedure used to treat malignant and nonmalignant haematological diseases, congenital immunodeficiency syndromes, solid tumours and metabolic diseases. Despite its usefulness, several major complications, such as graft-versus-host disease, can negatively affect patients treated with HSCT. Apart from clinical factors well known to affect the outcome of HSCT, patient and donor genetics have been shown to play an important role in the susceptibility to post-transplant complications. Histocompatibility as determined by the human leucocyte antigen (HLA) system has been a major genetic determinant of the success of HSCT. Non-HLA immunogenetics are increasingly recognized to play a part in the events related to transplantation. Cytokine genes, and their receptors, bear a considerable amount of polymorphism. One of the genes that may play an important role on the outcome of allogeneic HSCT is TGFB1, which encodes transforming growth factor, βeta 1 (TGF-β1). TGF-β1 is a pleiotropic cytokine, which plays a central role in the development, homeostasis and responses of the immune system. Several functional polymorphisms in TGFB1 have been identified, and these are known to cause alterations in cytokine secretion in several settings. The present review will focus on the current knowledge surrounding the effect of polymorphisms within TGFB1 on the outcome of HSCT.

Risk factors for severe respiratory syncytial virus lower respiratory tract infection.

RSV infection is a leading cause of lower respiratory tract infection, especially in High-risk infants with a history of prematurity, bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), neuromusculair impairment, immunodeficiency, and Down syndrome. Host related risk factors that have been identified to be associated with severe RSV related lower respiratory tract infection include young age below 6 months at the beginning of RSV season, multiple birth, male sex, low socioeconomic status and parental education, crowded living conditions, young siblings, maternal smoking and indoor smoke pollution, malnutrition/small for gestational age, family history of atopy or asthma, low cord serum RSV antibody titers, and living at altitude.Risk factors increasing the risk of acquisition of RSV have been identified to be birth before and/or during RSV season, day care attendance, presence of older siblings in school or day-care, and lack of breast feeding. Some of these risk factors are discussed controversially and some of them are found continuously throughout the literature.Given the high cost of RSV prophylaxis, especially for the large population of late preterm infants, algorithms and risk score systems have been published that could identify high-risk infants for treatment with palivizumab out of this gestational age group. Several models reported on an average sensitivity and specificity of 70 percent and, thus, are helpful to identify infants at high risk for severe RSV infection and need for prophylaxis with palivizumab.

Adenovirus

Adenoviruses (AdV) are DNA viruses that typically cause mild infections involving the upper or lower respiratory tract, gastrointestinal (GI) tract, or conjunctiva. Rare manifestations of AdV infections include hemorrhagic cystitis, hepatitis, hemorrhagic colitis, pancreatitis, nephritis, or encephalitis. Adenovirus infections are more common in young children, owing to lack of humoral immunity. Epidemics of AdV infections may occur in healthy children or adults in closed or crowded settings (particularly military recruits). The disease is more severe, and dissemination is more likely in patients with impaired immunity (eg, organ transplant recipients, human immunodeficiency virus infection, congenital immunodeficiency syndromes). Fatality rates for untreated severe AdV pneumonia or disseminated disease may exceed 50%. More than 50 serotypes of AdV have been identified. Different serotypes display different tissue trophisms and correlate with clinical manifestations of infection. The predominant serotypes differ among countries or regions and change over time. Transmission of novel strains between countries or across continents and replacement of dominant serotypes by new strains may occur. Treatment of AdV infections is controversial because prospective, randomized therapeutic trials have not been done. Cidofovir is considered the drug of choice for severe AdV infections, but not all patients require treatment. Vaccines have been shown to be highly efficacious in reducing the risk of respiratory AdV infection but are currently not available.

Long-Term Observation of Herpes Simplex Virus Type 1 (HSV-1) Infection in a Child with Wiskott-Aldrich Syndrome and a Possible Reactivation Mechanism for Thymidine Kinase-Negative HSV-1 in Humans

Herpes simplex virus type 1 (HSV-1) infections in a child with congenital immunodeficiency syndrome were observed over a 10-year period. The child suffered from recurrent and severe HSV-1 mucocutaneous infections. He frequently suffered from acyclovir (ACV)-resistant (ACV(r)) HSV-1 infection in the later phase of his life, especially after the episode of ACV(r) HSV-1 infection. Virological analyses on the HSV-1 isolates recovered from this patient revealed that all the ACV(r) HSV-1 isolates were thymidine kinase (TK)-negative (TK(-)) due to a single cytosine (C) deletion within the 4-C residues (positions 1061 to 1064) in the TK gene, indicating that the recurrent TK(-)/ACV(r) HSV-1 infections throughout the patient's life were due to the identical ACV(r) HSV-1 strain. Furthermore, it was found that the ACV-sensitive (ACV(s)) isolate recovered from the skin lesions that appeared between the episodes of ACV(r) infection at the ages of 8 and 9 contained ACV(r) HSV-1 with the same mutation in the TK gene. These results indicate that, although TK activity is required for reactivation of TK(+)/ACV(s) HSV-1 from latency and TK(-)/ACV(r) HSV-1 is unable to reactivate from latency, the TK(-)/ACV(r) HSV-1 strain isolated herein reactivated in this patient, possibly by using the TK activity induced by the latently co-infected TK(+)/ACV(s) HSV-1.

Concomitant Usage of Rasburicase and Allopurinol May Augment Toxic Epidermal Necrolysis Syndrome TEN

AbstractAbstract 4949Rasburicase is used succesfully in conjunction with Allopurinol in the tratment and prevention of tumor lysis syndrrome. Rasburicase is a recombinant form of urate oxidase, which is an enzyme present in primates but not humans and convert uric acid to allantoin, which is five to ten time soluble than uric acid. This abstract represent our experience in four males patients, mean age is thirty five years, two with Acute Lymphoblastic Leukemia ALL and two patients with Burkitt's Lymphoma. Three patients has successful outcome in the treatment with Rasburicase followed by allopurinol. Only one patient with Burkitt's Lymphoma arising from congenital combined immunodeficiency syndrome who developed fatal Toxic Epidermal Necrolysis syndrome TEN. TEN is a relatively rare incidence and can be deadly. The mechanism of action is different for both drugs. In this patient Rasburicase was used initially with excellent reduction of uric acid levels, then patient was put latter on allopurinol. The TEN syndrome appeared after three days of initiating the drug and progressed rapidly. High dose Methotrexate and sever neutropenia may contributed to the fast progression and not respoding to steriods after allopurinol was stopped. Since this patient has combined humoral and cellular immunodeficiency with no recent administartion of immunoglobulins therapy, it is difficult to explain the allopurinol reaction based on any type of immune response, particulary type IV hypersensitivity reaction.In conclusion: This particular case may draw the light on Rasburicase possible role in contribution or augumentation of TEN syndrome induced by allopurinol. Disclosures:No relevant conflicts of interest to declare.

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Transfusion-Associated Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease (TA-GvHD) is a rare complication of blood transfusion that has a fatal outcome in most patients. It is caused by the transfusion of viable T cells present in blood products that are not rejected by the transfusion recipient, either because of recipient immunodeficiency or because of a common HLA haplotype between the blood donor and recipient. Because effective treatment is not available, risk identification and prevention are of central importance. Among the potential risk factors that have been discussed to date, a definite hazard for developing TA-GvHD has been recognized for HLA-matched transfusions or transfusions from blood relatives, intrauterine and exchange transfusions, patients with congenital immunodeficiency syndromes, bone marrow transplantation, stem cell transplantation, or lymphomas. Patients at possible TA-GvHD risk who will require further evaluation include patients with hematologic malignancies, solid tumors, or solid organ transplantation. Although postulated, an increased risk for term or preterm newborns and patients with HIV/AIDS has not thus far been demonstrated.

Dermatofibrosarcoma Protuberans in 3 Patients with ADA-SCID

Dermatofibrosarcoma protuberans (DFSP) is a rare malignant skin tumor with characteristic cytogenetic findings (t(17;22)(q22;q13)) resulting in a fusion COL1A-PDGFB gene. Here we report an association between DFSP and Adenosine Deaminase Deficient Severe Combined Immunodeficiency (ADA-SCID), a rare congenital immunodeficiency syndrome. We observed DFSP in 3 ADA-SCID patients. The first patient is a 3.6-year-old boy who developed a 1.5 cm soft tissue mass on the right medial thigh. The second patient is a 2.4-year-old girl with 12 plaques (0.4– 0.8 cm) distributed on the trunk, thigh and lower extremities. The third patient is a 6-year-old boy with 5 depressed plaques ranging from 1–2 cm. The diagnosis in the first two patients was confirmed by immunohistochemistry (CD34 positive/Factor XIIIa negative) and demonstration of the COL1A1-PDGFB fusion by Fluorescent In Situ Hybridization (FISH). In the third patient, lesional tissue was positive for CD34 and negative for Factor XIIIa. FISH was inconclusive and further molecular analysis (RT-PCR) is ongoing. We came across two additional ADA-SCID patients in the literature who developed DFSP and we conclude therefore that this unique and unreported association between two rare disease entities merits further study. Importantly, our observations describe the first 2 cases presenting with multiple multicentric DFSPs. DFSP may be overlooked particularly in children who may present with an indolent plaque-like lesion mistaken as birthmark or benign vascular proliferation. DFSP in ADA-SCID may be caused by an unknown virus in the setting of defective immune surveillance. The search for a viral etiology is ongoing. Alternatively, the increased DNA breakage characteristic of ADA-SCID may play a role in the onset of this malignancy.

Rituximab for lymphoproliferative disease prior to haematopoietic stem cell transplantation for X‐linked severe combined immunodeficiency

Lymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate. We recently managed an infant found to have polymorphic LPD concurrent with X-linked severe combined immunodeficiency (SCID). Haematopoietic stem cell transplantation (HSCT) had to be deferred because of progressive LPD. Treatment with rituximab resulted in regression of the LPD following which the patient received a 5/6 HLA matched umbilical cord blood (UCB) transplant. The patient remains well 20 months following transplantation. Rituximab treatment may have a useful role in the control of LPD associated with congenital immunodeficiency prior to HSCT.

Establishment of the NMDP Cord Blood Banking Network.

Bone marrow transplantation can successfully treat patients with advanced malignancies, bone marrow failure syndromes, congenital immunodeficiency syndromes, hemoglobinopathies and inborn errors of metabolism. However the majority of patients in need of this therapy lack a matched related family member to serve as the donor. The National Marrow Donor Program was established 17 years ago to provide a registry of volunteer adult unrelated donors for patients in need of a hematopoietic stem cell transplant. The NMDP lists >5,000,000 donors and has facilitated >20,000 unrelated transplants to date. Despite this success, approximately 30% of Caucasian and 80% of African American patients are unable to find a suitably matched living volunteer adult donor.Over the past 11 years, studies have demonstrated that partially HLA mismatched, banked unrelated donor umbilical cord blood could substitute for bone marrow as an allogeneic hematopoietic cell source for transplantation. This resource may help increase access to transplantation therapy for the majority of patients lacking a fully HLA matched volunteer adult donor. This has created a need to increase the inventory of banked unrelated donor cord blood units nationwide. To date, existing banks have operated independently without a central registry to list and manage donors. In addition, overall banking practices had not been standardized leading to confusion about product quality and content. Finally, increased diversity and larger units are needed to best meet the needs of patients looking for an allogeneic donor.The NMDP has created a network of 13 cord blood banks, with a registered inventory of > 30,000 banked cord blood units, that are working together to establish and follow common quality standards. In addition, the network of banks lists their inventory in a single registry in order to facilitate and increase the efficiency of patient and transplant center access. Additional objectives of the network include the establishment of an ongoing inter-bank proficiency program; an educational program to train transplant center search coordinators on cord blood unit selection and to train transplant center laboratory staff on cord blood thawing and testing; a collections subcommittee to evaluate collection activities, donor selection criteria, donor testing; and an informatics program for intra and interbank cord blood unit information, HLA typing, searching and post transplant followup clinical data collection and analysis (CORDLink® and TRANSLink®).All member banks have agreed upon criteria for quality standards for future cord blood units collected through the members of the network. Specific details of donor education, recruitment, selection; cord blood collection, processing, cryopreservation and banking; information technology for cord blood data, inventory and search management; thawing and post transplant clinical data acquisition and analysis have been established.This NMDP Cord Blood Banking Network represents the first cooperative effort of multiple unrelated donor cord blood banks to agree to common practices and quality standards on a National basis. Of utmost importance is the additional fact that these units will be listed on a single, search registry ensuring access to all NMDP Transplant Centers.