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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]

Diagnostic and therapeutic challenges in a child with complete interferon-γ receptor 1 deficiency.

July 16, 2015 By Manish Butte

Diagnostic and therapeutic challenges in a child with complete interferon-γ receptor 1 deficiency.

Pediatr Blood Cancer. 2015 Jul 14;

Authors: Olbrich P, Martínez-Saavedra MT, Perez-Hurtado JM, Sanchez C, Sanchez B, Deswarte C, Obando I, Casanova JL, Speckmann C, Bustamante J, Rodriguez-Gallego C, Neth O

Abstract
Autosomal recessive (AR) complete Interferon-γ Receptor1 (IFN-γR1) deficiency is a rare variant of Mendelian susceptibility to mycobacterial disease (MSMD). Although hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, outcomes are heterogeneous; delayed engraftment and/or graft rejection being commonly observed. This case report and literature review expands the knowledge about this rare but potentially fatal pathology, providing details regarding diagnosis, antimicrobial treatment, transplant performance, and outcome that may help to guide physicians caring for patients with AR complete IFN-γR1 or IFN-γR2 deficiency. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.

PMID: 26173802 [PubMed – as supplied by publisher]

Primary CNS Immunomodulatory Therapy-Induced Lymphoproliferative Disorder in a Patient with Ulcerative Colitis: a Case Report and Review of the Literature.

July 15, 2015 By Manish Butte

Primary CNS Immunomodulatory Therapy-Induced Lymphoproliferative Disorder in a Patient with Ulcerative Colitis: a Case Report and Review of the Literature.

World Neurosurg. 2015 Jul 11;

Authors: Alobaid A, Torlakovic E, Kongkham P

Abstract
BACKGROUND: Immunosuppression and immunomodulatory therapy-induced lymphoproliferative disorders (ILPD) represent a heterogeneous group of lymphoid cell disorders that occur secondary to iatrogenic immune dysfunction, best described in the post-transplant setting.
CASE DESCRIPTION: We describe, to the best of our knowledge, the first reported case of a primary central nervous system (CNS) ILPD in a patient with ulcerative colitis (UC) treated chronically with the immunomodulatory agents infliximab and azathioprine. This 52-year old female presented with a one-month history of left sided weakness and paresthesias. Neuroimaging identified multiple heterogeneously-enhancing lesions in her cerebrum. Extensive systemic infectious and malignancy-related investigations were negative, prompting neurosurgical referral to obtain a tissue diagnosis. Pathologic assessment of her open excisional biopsy specimen confirmed the diagnosis of a polymorphic lymphoproliferative disorder. She was treated by withdrawal of infliximab and azathioprine, along with a prolonged course of prednisone. At early 6-month follow up she demonstrated both clinical and radiologic improvement.
CONCLUSION: ILPD should be considered in the differential diagnosis in patients with iatrogenic immunodeficiency presenting with neurological symptoms and intra-axial mass lesions on neuroimaging investigations. A standard treatment regimen for ILPD remains to be determined, however withholding the immunomodulatory agents and trial of corticosteroids may be tried as one first-line option prior to the use of more aggressive chemotherapy and/or radiotherapy.

PMID: 26171889 [PubMed – as supplied by publisher]

Diagnostic Criteria and Evaluation of Severe Combined Immunodeficiency in the Neonate.

July 15, 2015 By Manish Butte

Diagnostic Criteria and Evaluation of Severe Combined Immunodeficiency in the Neonate.

Pediatr Ann. 2015 Jul 1;44(7):e181-e187

Authors: Diamond CE, Sanchez MJ, LaBelle JL

Abstract
Severe combined immunodeficiency disorders (SCID) are a group of primary immunodeficiencies resulting from any one of a diverse group of mutations impacting T-cell development. SCID is diagnosed and classified through assessment of the lymphocyte subset(s) affected and by the mechanisms responsible for the primary immune defect. Regardless of the genetics involved, patients invariably succumb to an early death without medical intervention. In the past, patients were primarily identified either by previous family history, physical manifestations, or after the onset of symptoms. However, the introduction of newborn screening for SCID has allowed the pediatrician to identify these patients at a much earlier age, greatly improving their survival. Currently, 23 states include SCID testing for T-cell deficiencies in their newborn screening platform. Protocols for confirmatory testing and medical intervention after a positive screen vary slightly from state-to-state. However, the standard curative treatment remains stem cell transplantation, although depending on the genetic cause of the disease, enzyme replacement and gene therapy may also be considered. [Pediatr Ann. 2015;44(7):e181-e187.].

PMID: 26171708 [PubMed – as supplied by publisher]

5-Methoxytryptophan-dependent inhibition of oral squamous cell carcinoma metastasis.

July 15, 2015 By Manish Butte

5-Methoxytryptophan-dependent inhibition of oral squamous cell carcinoma metastasis.

Electrophoresis. 2015 Jul 14;

Authors: Wang SH, Chang CW, Chou HC

Abstract
The metastatic status of oral cancer is highly associated with the overall survival rate of patients. Previous studies have revealed that the endogenous tryptophan metabolite 5-methoxytryptophan (5-MTP) can downregulate cyclooxygenase-2 expression; suppress tumor proliferation, migration, and invasion; and reduce the tumor size. To improve the understanding of the molecular mechanisms involved in the regulation of 5-MTP in the tumorigenesis of oral cancer, we conducted a comparative wound healing and transwell invasion assays. Our results revealed that 5-MTP reduce oral cancer cell migration and invasion ability. In addition, the results of an in vivo assay demonstrated that the growth of primary tumors was significantly inhibited by 5-MTP in OC3 oral cancer cells and in invasive OC3-I5 oral cancer cells. Moreover, enlarged spleens were observed in OC3-I5-implanted severe combined immunodeficiency mice although 5-MTP can inhibit spleen enlargement. Through comparative proteomics, we identified 32 differentially regulated protein spots by using 2D-DIGE/MALDI-TOF MS analyses. Some of the differentially regulated proteins such as amadillo-repeat-containing X-linked protein 1, phosphoglycerate kinase 1, tropomyosin alpha-1, and tropomyosin alpha-4 may be associated with the 5-MTP-dependent inhibition of oral cancer growth and metastasis. We conclude that 5-MTP plays a crucial role in inhibiting in vitro and in vivo cancer invasion and metastasis.

PMID: 26171676 [PubMed – as supplied by publisher]

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection.

July 15, 2015 By Manish Butte

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection.

Proc Natl Acad Sci U S A. 2015 Jul 13;

Authors: Allman WR, Dey R, Liu L, Siddiqui S, Coleman AS, Bhattacharya P, Yano M, Uslu K, Takeda K, Nakhasi HL, Akkoyunlu M

Abstract
The TNF family member, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), is a key molecule for plasma cell maintenance and is required in infections where protection depends on antibody response. Here, we report that compared with WT mouse, TACI KO Μϕs expressed lower levels of Toll-like receptors (TLRs), CD14, myeloid differentiation primary response protein 88, and adaptor protein Toll/IL-1 receptor domain-containing adapter-inducing IFN-β and responded poorly to TLR agonists. Analysis of Μϕ phenotype revealed that, in the absence of TACI, Μϕs adapt the alternatively activated (M2) phenotype. Steady-state expression levels for M2 markers IL-4Rα, CD206, CCL22, IL-10, Arg1, IL1RN, and FIZZ1 were significantly higher in TACI KO Μϕ than in WT cells. Confirming their M2 phenotype, TACI-KO Mϕs were unable to control Leishmania major infection in vitro, and intradermal inoculation of Leishmania resulted in a more severe manifestation of disease than in the resistant C57BL/6 strain. Transfer of WT Μϕs to TACI KO mice was sufficient to significantly reduce disease severity. TACI is likely to influence Mϕ phenotype by mediating B cell-activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL) signals because both these ligands down-regulated M2 markers in WT but not in TACI-deficient Μϕs. Moreover, treatment of Μϕs with BAFF or APRIL enhanced the clearance of Leishmania from cells only when TACI is expressed. These findings may have implications for understanding the shortcomings of host response in newborns where TACI expression is reduced and in combined variable immunodeficiency patients where TACI signaling is ablated.

PMID: 26170307 [PubMed – as supplied by publisher]