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Exome Sequencing Analysis Reveals Variants in Primary Immunodeficiency Genes in Patients With Very Early Onset Inflammatory Bowel Disease.

July 21, 2015 By Manish Butte

Exome Sequencing Analysis Reveals Variants in Primary Immunodeficiency Genes in Patients With Very Early Onset Inflammatory Bowel Disease.

Gastroenterology. 2015 Jul 16;

Authors: Kelsen JR, Dawany N, Moran CJ, Petersen BS, Sarmady M, Sasson A, Pauly-Hubbard H, Martinez A, Maurer K, Soong J, Rappaport E, Franke A, Keller A, Winter HS, Mamula P, Piccoli D, Artis D, Sonnenberg GF, Daly M, Sullivan KE, Baldassano RN, Devoto M

Abstract
BACKGROUND & AIMS: Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed ≤5 y of age, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development.
METHODS: Patients with VEO-IBD and parents (when available) were recruited from the Children’s Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (ages 3 weeks to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by post-processing and variant calling. Following functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency <0.1%, and scaled combined annotation dependent depletion scores ≤10. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n=45) or adult-onset Crohn’s disease (n=20) and healthy individuals (controls, n=145) were obtained from the University of Kiel, Germany and used as control groups.
RESULTS: Four-hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling > 1 Mbp of coding sequence, were selected from the whole exome data. Our analysis revealed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19.
CONCLUSIONS: In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants.

PMID: 26193622 [PubMed – as supplied by publisher]

Five years of self-administered hyaluronidase facilitated subcutaneous immunoglobulin (fSCIg) home therapy in a patient with primary immunodeficiency.

July 19, 2015 By Manish Butte

Five years of self-administered hyaluronidase facilitated subcutaneous immunoglobulin (fSCIg) home therapy in a patient with primary immunodeficiency.

J Clin Pathol. 2015 Jul 17;

Authors: Carne E, Ponsford M, El-Shanawany T, Williams P, Pickersgill T, Jolles S

PMID: 26188056 [PubMed – as supplied by publisher]

Single-center experience of unrelated and haploidentical stem cell transplantation with TCR-alpha/beta and CD19 depletion in children with primary immunodeficiency syndromes.

July 19, 2015 By Manish Butte

Single-center experience of unrelated and haploidentical stem cell transplantation with TCR-alpha/beta and CD19 depletion in children with primary immunodeficiency syndromes.

Biol Blood Marrow Transplant. 2015 Jul 14;

Authors: Balashov D, Shcherbina A, Maschan M, Trakhtman P, Skvortsova Y, Shelikhova L, Laberko A, Livshits A, Novichkova G, Maschan A

Abstract
The transplantation of stem cells from a matched unrelated donor (MUD) or a haploidentical mismatched related donor (MMRD) is a widely used variant of curative treatment for patients with primary immunodeficiency (PID). Currently, different strategies are used to reduce the risk of posttransplant complications and enhance immune reconstitution. We report the preliminary results of MUD and MMRD transplantation with TCRαβ/CD19 depletion in patients with PID (trial registered at www.clinicaltrials.gov as #NCT02327351). Thirty-seven PID patients, with a median age of 2.6 years (range, 0.2-17 years), were transplanted from MUD (n=27) or haploidentical MMRD (n=10) after TCRαβ+/CD19+ graft depletion. The median numbers of CD34+ and TCRαβ+ cells in the graft were 11.7 × 10(6)/kg and 10.6 x10(3)/kg, respectively. Acute graft-versus-host disease (GVHD) was observed in 8 patients (22%), without a statistically significant difference between MUD and MMRD; 7 of those patients had grade II acute GVHD and responded to first-line therapy, whereas 1 patient had grade IV acute GVHD with transformation to extensive chronic GVHD. Primary and secondary graft failure (non-engraftment or rejection) was observed in 10 patients (27%), 9 of whom were treated with one alkylating agent in the conditioning regimen. All these patients were successfully re-transplanted with different rescue protocols. The preliminary data on immune reconstitution were very encouraging. Most patients had significant numbers of T lymphocytes detected on the first assessment (day +30) and more than 500 T cells/ul, primarily bearing the CD45RA+ naïve phenotype, on day +120. Based on our preliminary data, there was no significant difference between MMRD and MUD hematopoietic stem cell transplantation (HSCT). With a median follow-up period of 15 months, the cumulative probabilities of overall patient survival and transplant-related mortality were 96.7% and 3.3%, respectively. Based on the results, the ability to control the main posttransplant complications and the immune reconstitution rates are the main factors leading to successful outcome in patients with PID after TCRαβ+-depleted HSCT.

PMID: 26187864 [PubMed – as supplied by publisher]

Immunosuppression and Multiple Primary Malignancies in Kidney-Transplanted Patients: A Single-Institute Study.

July 18, 2015 By Manish Butte

Immunosuppression and Multiple Primary Malignancies in Kidney-Transplanted Patients: A Single-Institute Study.

Biomed Res Int. 2015;2015:183523

Authors: Santangelo ML, Criscitiello C, Renda A, Federico S, Curigliano G, Dodaro C, Scotti A, Tammaro V, Calogero A, Riccio E, Pisani A, Carlomagno N

Abstract
Immunodeficiency is associated with higher cancer incidence. However, it is unknown whether there is a link between immunodeficiency and development of multiple primary malignancies. In the present study we analyse this link focusing on kidney-transplanted patients, as they are at higher risk of developing cancer due to the chronic assumption of immunosuppressants. We followed up 1200 patients who underwent kidney transplantation between 1980 and 2012. A total of 77/1200 kidney-transplanted patients developed cancer and 24 of them developed multiple cancers. Most multiple cancers were synchronous with a nonsignificant association between cancer and rejection episodes. In the general cancer population, one-ninth of patients are at higher risk of developing a second tumor over a lifetime; hence it would be reasonable to conclude that, from a merely theoretical and statistical viewpoint, long-term transplanted patients potentially have a higher risk of developing MPMs. However, data did not confirm this assumption, probably because these patients die before a second primary malignancy appears. Despite many observations on the increased incidence of different tumor types in immunodeficient patients and despite immunosuppression certainly being a predisposing factor for the multicancer syndrome, data so far are not robust enough to justify a correlation between immunodeficiency and multiple primary malignancies in transplanted patients.

PMID: 26185750 [PubMed – as supplied by publisher]

Clinical and genotypic spectrum of chronic granulomatous disease in 71 Latin American patients: First report from the LASID registry.

July 18, 2015 By Manish Butte

Clinical and genotypic spectrum of chronic granulomatous disease in 71 Latin American patients: First report from the LASID registry.

Pediatr Blood Cancer. 2015 Jul 15;

Authors: de Oliveira-Junior EB, Zurro NB, Prando C, Cabral-Marques O, Pereira PV, Schimke LF, Klaver S, Buzolin M, Blancas-Galicia L, Santos-Argumedo L, Pietropaolo-Cienfuegos DR, Espinosa-Rosales F, King A, Sorensen R, Porras O, Roxo-Junior P, Forte WC, Orellana JC, Lozano A, Galicchio M, Regairaz L, Grumach AS, Costa-Carvalho BT, Bustamante J, Bezrodnik L, Oleastro M, Danielian S, Condino-Neto A

Abstract
AIM: We analyzed data from 71 patients with chronic granulomatous disease (CGD) with a confirmed genetic diagnosis, registered in the online Latin American Society of Primary Immunodeficiencies (LASID) database.
RESULTS: Latin American CGD patients presented with recurrent and severe infections caused by several organisms. The mean age at disease onset was 23.9 months, and the mean age at CGD diagnosis was 52.7 months. Recurrent pneumonia was the most frequent clinical condition (76.8%), followed by lymphadenopathy (59.4%), granulomata (49.3%), skin infections (42%), chronic diarrhea (41.9%), otitis (29%), sepsis (23.2%), abscesses (21.7%), recurrent urinary tract infection (20.3%), and osteomyelitis (15.9%). Adverse reactions to bacillus Calmette-Guérin (BCG) vaccination were identified in 30% of the studied Latin American CGD cases. The genetic diagnoses of the 71 patients revealed 53 patients from 47 families with heterogeneous mutations in the CYBB gene (five novel mutations: p.W361G, p.C282X, p.W483R, p.R226X, and p.Q93X), 16 patients with the common deletion c.75_76 del.GT in exon 2 of NCF1 gene, and two patients with mutations in the CYBA gene.
CONCLUSION: The majority of Latin American CGD patients carry a hemizygous mutation in the CYBB gene. They also presented a wide range of clinical manifestations most frequently bacterial and fungal infections of the respiratory tract, skin, and lymph nodes. Thirty percent of the Latin American CGD patients presented adverse reactions to BCG, indicating that this vaccine should be avoided in these patients. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

PMID: 26185101 [PubMed – as supplied by publisher]

Higher Cardiovascular Risk in Common Variable Immunodeficiency and X-Linked Agammaglobulinaemia Patients.

July 18, 2015 By Manish Butte

Higher Cardiovascular Risk in Common Variable Immunodeficiency and X-Linked Agammaglobulinaemia Patients.

Ann Nutr Metab. 2015 Jul 14;66(4):237-241

Authors: Vieira DG, Costa-Carvalho BT, Hix S, da Silva R, Correia MS, Sarni RO

Abstract
INTRODUCTION: Common variable immunodeficiency and X-linked agammaglobulinaemia are primary immunodeficiencies classified as antibody deficiencies, and they both result in hypogammaglobulinaemia.
OBJECTIVE: Evaluate the lipid profile and other cardiovascular risk biomarkers in CVID and XLA patients.
METHODS: In total, 24 patients and 12 healthy controls matched by age and gender were included in the study. We evaluated anthropometric measurements, and seric total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), apo A-I, small dense LDL (sdLDL), C-reactive protein (CRP), and tumour necrosis factor alpha (TNF-alpha), myeloperoxidase (MPO), cholesteryl ester transfer protein (CETP), and lecithin cholesterol acyltransferase (LCAT) were assessed.
RESULTS: CRP (p = 0.008) and TNF-alpha (p < 0.001) concentrations were significantly higher, whereas HDL-c (p = 0.025) and apo A-I (p = 0.013) levels were significantly lower in patients than in the controls. In the patient group, a negative and significant correlation was observed between HDL-c and TNF-alpha (r = -0.406; p = 0.049) and between HDL-c and TG (r = -0.641; p = 0.001).
CONCLUSION: Common variable immunodeficiency and X-linked agammaglobulinaemia patients presented themselves with increased inflammatory markers associated with a decreased HDL-c and apo A-I levels, which can predispose to a high cardiovascular risk. © 2015 S. Karger AG, Basel.

PMID: 26183722 [PubMed – as supplied by publisher]

Accelerated atherosclerosis in patients with common variable immunodeficiency: Is it overlooked or absent?

July 18, 2015 By Manish Butte

Accelerated atherosclerosis in patients with common variable immunodeficiency: Is it overlooked or absent?

Med Hypotheses. 2015 Jul 10;

Authors: Ucar R, Arslan S, Turkmen K, Calıskaner AZ

Abstract
Common variable immunodeficiency (CVID) is a heterogeneous primary deficiency characterized by hypogammaglobulinemia, recurrent infections, and an increased risk of autoimmune disease and malignancy, and so chronic inflammation. Cardiovascular disease is the leading cause of mortality in the general population. Recent studies have suggested that chronic inflammation is an important player in the pathogenesis of CVID. Accelerated atherosclerosis due to ongoing inflammation from recurrent infections and autoimmunity is an expected clinical entity in patients with CVID. However, cardiovascular mortality as a cause of death in CVID series is either absent or minor. We hypothesized that accelerated atherosclerosis and cardiovascular disease are overlooked by clinicians, or atherosclerosis is really lower than that in the general population that may be prevented by some factors such as life-long immunoglobulin replacement treatment.

PMID: 26182977 [PubMed – as supplied by publisher]

Chronic Granulomatous Disease: A Large, Single-Center U.S. Experience.

July 17, 2015 By Manish Butte

Chronic Granulomatous Disease: A Large, Single-Center U.S. Experience.

Pediatr Infect Dis J. 2015 Jul 15;

Authors: Bortoletto P, Lyman K, Camacho A, Fricchione M, Khanolkar A, Katz BZ

Abstract
BACKGROUND: CGD is an uncommon primary immunodeficiency, that can be inherited in an X-linked (XL) or an autosomal recessive (AR) manner.We reviewed our large, single-center U. S. experience with CGD.
MATERIAL AND METHODS: We reviewed 27 patients seen from March 1985 to November 2013. Fisher’s exact test was used to compare differences in categorical variables, and Student’s t-test was used to compare means for continuous variables. Serious infections were defined as those requiring intravenous antibiotics or hospitalization.
RESULTS: There were 23 males and 4 females; 19 were XL and 8 were AR. The average age at diagnosis was 3.0 years; 2.1 years for XL and 5.3 years for AR inheritance (p = 0.02). There were 128 serious infections. The most frequent infectious agents were Staphylococcus aureus (13), Serratia (11), Klebsiella (7), Aspergillus (6) and Burkholderia (4). The most common serious infections were pneumonia (38), abscess (32) and lymphadenitis (29). Thirteen patients had granulomatous complications. Five patients were below the 5 percentile for height and 4 were below the 5 percentile for weight.Average length of follow-up after diagnosis was 10.1 years. Twenty-four patients were compliant and maintained on interferon gamma, trimethoprim-sulfa and an azole. The serious infection rate was 0.62 per patient-year. Twenty-three patients are alive (one was lost to follow-up).
CONCLUSIONS: We present a large U.S. single center experience with CGD. Twenty-three of 27 patients are alive after 3276 patient-months of follow-up, (1 has been lost to follow-up) and our serious infection rate was 0.62 per patient/year.

PMID: 26181896 [PubMed – as supplied by publisher]

Antibody replacement therapy in primary antibody deficiencies and iatrogenic hypogammaglobulinemia.

July 17, 2015 By Manish Butte

Antibody replacement therapy in primary antibody deficiencies and iatrogenic hypogammaglobulinemia.

Expert Rev Clin Immunol. 2015 Aug;11(8):921-933

Authors: Hoffman TW, van Kessel DA, van Velzen-Blad H, Grutters JC, Rijkers GT

Abstract
Antibody replacement therapy has been used in the treatment of primary antibody deficiencies (PADs) for several decades, and an evidence-based guideline for its treatment is currently available. By contrast, the use of antibody replacement therapy in iatrogenic hypogammaglobulinemia (IHG), a condition that is associated with immunosuppressive medication, has hardly any evidence base and no guidelines. As IHG can be equally as severe as PAD and is much more prevalent, evidence-based guidelines are urgently needed. This review will focus on the differences and similarities between PAD and IHG and the use of antibody replacement therapy in both conditions. Suggestions for the development of evidence-based guidelines and future research are given.

PMID: 26181342 [PubMed – as supplied by publisher]

Do immune complexes play a role in hemolytic sequelae of intravenous immune globulin?

July 16, 2015 By Manish Butte

Do immune complexes play a role in hemolytic sequelae of intravenous immune globulin?

Transfusion. 2015 Jul;55(S2):S86-S89

Authors: Zimring JC

Abstract
Intravenous immune globulin (IVIG) was developed initially as an immunoglobulin replacement therapy for primary humoral immunodeficiency, but is now widely used in the treatment of autoinflammatory and autoimmune pathologies. In a small number of patients, hemolytic sequelae have been observed after IVIG administration. The lack of a simple one-to-one correlation between measurable hemagglutinins and hemolysis has led to complicated hypotheses involving coincident necessary variables (e.g., a two-hit hypothesis) and also to the positing of causal factors other than hemagglutinins. One such hypothesis is that immune complexes (ICs) contained within IVIG lead to hemolysis. IVIG-mediated hemolysis was addressed at a recent meeting sponsored by the Food and Drug Administration; the Plasma Protein Therapeutics Association; and the National Heart, Lung, and Blood Institute. The primary literature was reviewed at this meeting followed by detailed discussion. Participants concluded that there is both a theoretical basis by which ICs could contribute to hemolysis after IVIG administration and some published data in support of such a possibility. However, the reported data contain substantial caveats, and the existing evidence does not rise to a level sufficient to either confirm or reject a role for ICs. More detailed and focused human studies will be required to further assess the potential role of ICs in IVIG induced hemolysis. This paper summarizes the relevant literature and expands upon the conclusions of this workshop.

PMID: 26174903 [PubMed – as supplied by publisher]