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Quality of life in children with primary antibody deficiency.

June 16, 2015 By Manish Butte

Quality of life in children with primary antibody deficiency.

J Clin Immunol. 2014 Oct;34(7):844-52

Authors: Titman P, Allwood Z, Gilmour C, Malcolmson C, Duran-Persson C, Cale C, Davies G, Gaspar H, Jones A

Abstract
Primary antibody deficiency disorders (PADs) can have an excellent outlook if diagnosed early and treated appropriately, but require lifelong treatment with immunoglobulin replacement. Some carry risks of inflammatory complications even with optimal treatment. Quality of life (QoL) and the psychological impact of PADs has been relatively little studied, particularly in children. The purpose of this study was to evaluate QoL and psychological impact in a large group of children affected by a range of PADs, as well as a group with transient hypogammaglobulinemia of infancy (THI). Both parental and, where appropriate, child ratings, were collected using standardised questionnaires (PedsQL and SDQ). Higher rates of psychological difficulties, particularly emotional and peer-relationship difficulties were found in children with PAD when compared with healthy controls. Quality of life was poorer than in healthy controls, and also worse than in children affected by diabetes mellitus. Variations in QoL and the degree of psychological difficulties were found between specific diagnostic groups, with children affected by THI being amongst those with the lowest scores for QoL. Further studies are needed to corroborate and extend these findings, but this study confirms previous findings that primary antibody deficiency has a significant impact on quality of life and psychological well-being, and additionally suggests that the impact varies according to severity of the underlying condition. For those with significant difficulties psychological intervention at an early stage may be beneficial.

PMID: 25005831 [PubMed – indexed for MEDLINE]

Positive Impact of Fungal Histopathology on Immunocompromised Pediatric Patients With Histology-Proven Invasive Fungal Infection.

June 14, 2015 By Manish Butte

Positive Impact of Fungal Histopathology on Immunocompromised Pediatric Patients With Histology-Proven Invasive Fungal Infection.

Am J Clin Pathol. 2015 Jul;144(1):61-7

Authors: Dekio F, Bhatti TR, Zhang SX, Sullivan KV

Abstract
OBJECTIVES: We investigated the performance and the clinical impact of histologic examination of infected tissue in patients with suspected invasive fungal infection (IFI) at a tertiary pediatric center.
METHODS: Unique episodes of IFI were identified from January 1, 2001, through December 31, 2012. Surgical pathology reports, fungal culture results, and clinical data were abstracted from medical records.
RESULTS: Forty-seven patients with IFI were identified. Each patient had one episode of IFI. Risk factors included chemotherapy for an oncologic condition (n = 35), hematopoietic stem cell transplantation (n = 6), solid organ transplantation (n = 4), and primary immunodeficiency (n = 2). Tissue was obtained from deep subcutaneous tissue (n = 21), visceral organs (14 lungs, five livers, and one spleen), or the sinonasal cavity (n = 6). Fungal culture was ordered in 40 of the 47 episodes of IFI. Fungus grew in 27 (68%) of the 40 cultures submitted, and all isolates were concordant with histology. Medical records were available for 36 (77%) of 47 patients. Communication of histology results prompted changes in antifungal therapy 64% of the time. This included initiation of antifungal therapy in 13 patients who were not previously receiving therapy. Fifteen (42%) patients underwent surgical excision within 48 hours of histologic diagnosis.
CONCLUSIONS: Histology can provide rapid, accurate, and clinically actionable information to clinicians caring for children with IFI.

PMID: 26071462 [PubMed – in process]

Lung Magnetic Resonance Imaging with Diffusion Weighted Imaging Provides Regional Structural as well as Functional Information Without Radiation Exposure in Primary Antibody Deficiencies.

June 13, 2015 By Manish Butte

Lung Magnetic Resonance Imaging with Diffusion Weighted Imaging Provides Regional Structural as well as Functional Information Without Radiation Exposure in Primary Antibody Deficiencies.

J Clin Immunol. 2015 Jun 12;

Authors: Milito C, Pulvirenti F, Serra G, Valente M, Pesce AM, Granata G, Catalano C, Fraioli F, Quinti I

Abstract
PURPOSE: Primary antibody deficiency patients suffer from infectious and non-infectious pulmonary complications leading over time to chronic lung disease. The complexity of this pulmonary involvement poses significant challenge in differential diagnosis in patients with long life disease and increased radio sensitivity. We planned to verify the utility of chest Magnetic Resolution Imaging with Diffusion-Weighted Imaging as a radiation free technique.
METHODS: Prospective evaluation of 18 patients with Common Variable Immunodeficiency and X-linked Agammaglobulinemia. On the same day, patients underwent Magnetic Resonance Imaging with Diffusion Weighted Imaging sequences, High Resolution Computerized Tomography and Pulmonary Function Tests, including diffusing capacity factor for carbon monoxide. Images were scored using a modified version of the Bhalla scoring system.
RESULTS: Magnetic Resonance Imaging was non-inferior to High Resolution Computerized Tomography in the capacity to identify bronchial and parenchymal abnormalities. HRCT had a higher capacity to identify peripheral airways abnormalities, defined as an involvement of bronchial generation up to the fifth and distal (scores 2-3). Bronchial scores negatively related to pulmonary function tests. One third of consolidations and nodules had Diffusion Weighted Imaging restrictions associated with systemic granulomatous disease and systemic lymphadenopathy. Lung Magnetic Resolution Imaging detected an improvement of bronchial and parenchymal abnormalities, in recently diagnosed patients soon after starting Ig replacement.
CONCLUSIONS: Magnetic Resonance Imaging with Diffusion Weighted Imaging was a reliable technique to detect lung alterations in patients with Primary Antibody Deficiencies.

PMID: 26067227 [PubMed – as supplied by publisher]

Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.

June 11, 2015 By Manish Butte

Deficiency of the B cell-activating factor receptor results in limited CD169+ macrophage function during viral infection.

J Virol. 2015 May;89(9):4748-59

Authors: Xu HC, Huang J, Khairnar V, Duhan V, Pandyra AA, Grusdat M, Shinde P, McIlwain DR, Maney SK, Gommerman J, Löhning M, Ohashi PS, Mak TW, Pieper K, Sic H, Speletas M, Eibel H, Ware CF, Tumanov AV, Kruglov AA, Nedospasov SA, Häussinger D, Recher M, Lang KS, Lang PA

Abstract
UNLABELLED: The B cell-activating factor (BAFF) is critical for B cell development and humoral immunity in mice and humans. While the role of BAFF in B cells has been widely described, its role in innate immunity remains unknown. Using BAFF receptor (BAFFR)-deficient mice, we characterized BAFFR-related innate and adaptive immune functions following infection with vesicular stomatitis virus (VSV) and lymphocytic choriomeningitis virus (LCMV). We identified a critical role for BAFFR signaling in the generation and maintenance of the CD169(+) macrophage compartment. Consequently, Baffr(-) (/) (-) mice exhibited limited induction of innate type I interferon production after viral infection. Lack of BAFFR signaling reduced virus amplification and presentation following viral infection, resulting in highly reduced antiviral adaptive immune responses. As a consequence, BAFFR-deficient mice showed exacerbated and fatal disease after viral infection. Mechanistically, transient lack of B cells in Baffr(-) (/) (-) animals resulted in limited lymphotoxin expression, which is critical for maintenance of CD169(+) cells. In conclusion, BAFFR signaling affects both innate and adaptive immune activation during viral infections.
IMPORTANCE: Viruses cause acute and chronic infections in humans resulting in millions of deaths every year. Innate immunity is critical for the outcome of a viral infection. Innate type I interferon production can limit viral replication, while adaptive immune priming by innate immune cells induces pathogen-specific immunity with long-term protection. Here, we show that BAFFR deficiency not only perturbed B cells, but also resulted in limited CD169(+) macrophages. These macrophages are critical in amplifying viral particles to trigger type I interferon production and initiate adaptive immune priming. Consequently, BAFFR deficiency resulted in reduced enforced viral replication, limited type I interferon production, and reduced adaptive immunity compared to BAFFR-competent controls. As a result, BAFFR-deficient mice were predisposed to fatal viral infections. Thus, BAFFR expression is critical for innate immune activation and antiviral immunity.

PMID: 25673724 [PubMed – indexed for MEDLINE]

Persistent lymphopenia after diagnosis of sepsis predicts mortality.

June 10, 2015 By Manish Butte

Persistent lymphopenia after diagnosis of sepsis predicts mortality.

Shock. 2014 Nov;42(5):383-91

Authors: Drewry AM, Samra N, Skrupky LP, Fuller BM, Compton SM, Hotchkiss RS

Abstract
OBJECTIVE: The objective of this study was to determine whether persistent lymphopenia on the fourth day following the diagnosis of sepsis predicts mortality.
METHODS: This was a single-center, retrospective cohort study of 335 adult patients with bacteremia and sepsis admitted to a large university-affiliated tertiary care hospital between January 1, 2010, and July 31, 2012. All complete blood cell count profiles during the first 4 days following the diagnosis of sepsis were recorded. The primary outcome was 28-day mortality. Secondary outcomes included development of secondary infections, 1-year mortality, and hospital and intensive care unit lengths of stay.
RESULTS: Seventy-six patients (22.7%) died within 28 days. Lymphopenia was present in 28-day survivors (median, 0.7 × 10 cells/μL; interquartile range [IQR], 0.4-1.1 × 10 cells/μL) and nonsurvivors (median, 0.6 × 10 cells/μL; IQR, 0.4-1.1 × 10 cells/μL) at the onset of sepsis and was not significantly different between the groups (P = 0.35). By day 4, the median absolute lymphocyte count was significantly higher in survivors compared with nonsurvivors (1.1 × 10 cells/μL [IQR, 0.7-1.5 × 10 cells/μL] vs. 0.7 × 10 cells/μL [IQR, 0.5-1.0 × 10 cells/μL]; P < 0.0001). Using logistic regression to account for potentially confounding factors (including age, Acute Physiology and Chronic Health Evaluation II score, comorbidities, surgical procedure during the study period, and time until appropriate antibiotic administration), day 4 absolute lymphocyte count was found to be independently associated with 28-day survival (adjusted odds ratio, 0.68 [95% confidence interval, 0.51-0.91]) and 1-year survival (adjusted odds ratio, 0.74 [95% confidence interval, 0.59-0.93]). Severe persistent lymphopenia (defined as an absolute lymphocyte count of 0.6 × 10 cells/μL or less on the fourth day after sepsis diagnosis) was associated with increased development of secondary infections (P = 0.04).
CONCLUSIONS: Persistent lymphopenia on the fourth day following the diagnosis of sepsis predicts early and late mortality and may serve as a biomarker for sepsis-induced immunosuppression.

PMID: 25051284 [PubMed – indexed for MEDLINE]

Global overview of primary immunodeficiencies: a report from Jeffrey Modell Centers worldwide focused on diagnosis, treatment, and discovery.

June 10, 2015 By Manish Butte

Global overview of primary immunodeficiencies: a report from Jeffrey Modell Centers worldwide focused on diagnosis, treatment, and discovery.

Immunol Res. 2014 Oct;60(1):132-44

Authors: Modell V, Knaus M, Modell F, Roifman C, Orange J, Notarangelo LD

Abstract
Primary immunodeficiencies (PI) are defects of the immune system that cause severe infections if not diagnosed and treated appropriately. Many patients with PI are undiagnosed, under-diagnosed, or misdiagnosed. Over the last decade, the Jeffrey Modell Foundation has implemented a Physician Education and Public Awareness Campaign (PEPAC) to raise awareness, assure early diagnosis, appropriate treatment, and management, with the overall goal to reduce morbidities and mortalities related to PI. In order to evaluate the PEPAC program, data are requested annually from physician experts within the Jeffrey Modell Centers Network (JMCN). The JMCN, consisting of 556 expert physicians, at 234 academic institutions, in 196 cities, and 78 countries spanning six continents, provides the infrastructure for referral, diagnosis, and appropriate treatment for patients with PI. In addition, the JMCN has made a significant contribution to the field of immunology with the discovery of new genes at the centers. These advancements have led to an overall better understanding of the immune system and will continue to improve quality of life of those with PI.

PMID: 24668296 [PubMed – indexed for MEDLINE]

Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies.

June 9, 2015 By Manish Butte

Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies.

Front Immunol. 2015;6:250

Authors: Ott de Bruin LM, Volpi S, Musunuru K

Abstract
Severe combined immunodeficiency (SCID) and other severe non-SCID primary immunodeficiencies (non-SCID PID) can be treated by allogeneic hematopoietic stem cell (HSC) transplantation, but when histocompatibility leukocyte antigen-matched donors are lacking, this can be a high-risk procedure. Correcting the patient’s own HSCs with gene therapy offers an attractive alternative. Gene therapies currently being used in clinical settings insert a functional copy of the entire gene by means of a viral vector. With this treatment, severe complications may result due to integration within oncogenes. A promising alternative is the use of endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 to introduce a double-stranded break in the DNA and thus induce homology-directed repair. With these genome-editing tools a correct copy can be inserted in a precisely targeted “safe harbor.” They can also be used to correct pathogenic mutations in situ and to develop cellular or animal models needed to study the pathogenic effects of specific genetic defects found in immunodeficient patients. This review discusses the advantages and disadvantages of these endonucleases in gene correction and modeling with an emphasis on CRISPR/Cas9, which offers the most promise due to its efficacy and versatility.

PMID: 26052330 [PubMed]

A novel thymoma-associated immunodeficiency with increased naive T cells and reduced CD247 expression.

June 9, 2015 By Manish Butte

A novel thymoma-associated immunodeficiency with increased naive T cells and reduced CD247 expression.

J Immunol. 2015 Apr 1;194(7):3045-53

Authors: Christopoulos P, Dopfer EP, Malkovsky M, Esser PR, Schaefer HE, Marx A, Kock S, Rupp N, Lorenz MR, Schwarz K, Harder J, Martin SF, Werner M, Bogdan C, Schamel WW, Fisch P

Abstract
The mechanisms underlying thymoma-associated immunodeficiency are largely unknown, and the significance of increased blood γδ Τ cells often remains elusive. In this study we address these questions based on an index patient with thymoma, chronic visceral leishmaniasis, myasthenia gravis, and a marked increase of rare γδ T cell subsets in the peripheral blood. This patient showed cutaneous anergy, even though he had normal numbers of peripheral blood total lymphocytes as well as CD4(+) and CD8(+) T cells. Despite his chronic infection, analyses of immunophenotypes and spectratyping of his lymphocytes revealed an unusual accumulation of naive γδ and αβ T cells, suggesting a generalized T cell activation defect. Functional studies in vitro demonstrated substantially diminished IL-2 and IFN-γ production following TCR stimulation of his “untouched” naive CD4(+) T cells. Biochemical analysis revealed that his γδ and αβ T cells carried an altered TCR complex with reduced amounts of the ζ-chain (CD247). No mutations were found in the CD247 gene that encodes the homodimeric ζ protein. The diminished presence of CD247 and increased numbers of γδ T cells were also observed in thymocyte populations obtained from three other thymoma patients. Thus, our findings describe a novel type of a clinically relevant acquired T cell immunodeficiency in thymoma patients that is distinct from Good’s syndrome. Its characteristics are an accumulation of CD247-deficient, hyporresponsive naive γδ and αβ T cells and an increased susceptibility to infections.

PMID: 25732729 [PubMed – indexed for MEDLINE]

Early diagnosis of celiac disease in IgA deficient children: contribution of a point-of-care test.

June 9, 2015 By Manish Butte

Early diagnosis of celiac disease in IgA deficient children: contribution of a point-of-care test.

BMC Gastroenterol. 2014;14:186

Authors: Bienvenu F, Anghel SI, Besson Duvanel C, Guillemaud J, Garnier L, Renosi F, Lachaux A, Bienvenu J

Abstract
BACKGROUND: The serological diagnosis of celiac disease (CD) often relies on the presence of anti-tissue transglutaminase (tTG) IgA autoantibodies. Patients suffering from selective IgA deficiency (IgAD) are often not aware of their IgA deficiency and are tested as CD negative, delaying considerably the diagnosis. The detection of IgG against deamidated gliadin peptides (DGP) has high specificity and better sensitivity than IgG anti-tTG. A multi-analytic lateral-flow immunochromatographic assay (CD-LFIA) based on the detection of IgA and IgG anti-DGP and total IgA was shown to have a good diagnostic accuracy for CD. The aim of this study was to evaluate the clinical accuracy of its use in children suffering from IgAD.
METHODS: 45 IgAD children ranging from 1.1 to 17.4 years and suspected of CD or having high CD risk factors were referred from outpatient clinics located in the area of Rhone-Alpes (France) to the Hospices Civils de Lyon, Paediatric Hospital-Gastroenterology-Hepatology- Nutrition Department for further CD investigations. The CD investigations, including the sample collection, were performed within the Paediatric Hospital-Gastroenterology-Hepatology- Nutrition Department, and the serological testing was performed at the Lyon-Sud Hospital-Immunology Laboratory. The diagnosis of CD was based on IgG anti-tTG serology, biopsy results and patient follow-up. The serum samples were retrospectively tested on the CD-LFIA test.
RESULTS: A total of eight (8) patients were diagnosed as new CD. All were correctly identified by the CD-LFIA. The test yielded four (4) false positive results. Two patients with positive IgG anti-tTG were negative on CD-LFIA, but were classified as CD negative based on biopsy results and patient follow-up. The remaining 33 patients were found negative by both methods. The specificity and sensitivity of CD-LFIA was of 89.2% [74.6-97.0] and of 100% [63.1-100] respectively. The negative predictive value (NPV) was of 100% [89.4-100], and the Likelihood Ratio for Negative Test (LR-) was of 0 [0.0-0.91].
CONCLUSIONS: CD-LFIA is a useful, non-invasive and rapid tool to rule out CD in primary care paediatric patients having CD-related symptoms and IgAD. Patients having a positive CD-LFIA result could be then readily directed to secondary care setting for further evaluation by standard serology and biopsy.

PMID: 25376178 [PubMed – indexed for MEDLINE]

Gene therapy for monogenic disorders of the bone marrow.

June 6, 2015 By Manish Butte

Gene therapy for monogenic disorders of the bone marrow.

Br J Haematol. 2015 Jun 5;

Authors: Ghosh S, Thrasher AJ, Gaspar HB

Abstract
Ex-vivo gene transfer of autologous haematopoietic stem cells in patients with monogenic diseases of the bone marrow has emerged as a new therapeutic approach, mainly in patients lacking a suitable donor for transplant. The encouraging results of initial clinical trials of gene therapy for primary immunodeficiencies were tempered by the occurrence of genotoxicity in a number of patients. Over the last decade, safer viral vectors have been developed to overcome the risk of insertional mutagenesis and have led to impressive clinical outcomes with considerably improved safety. We review the efforts in specific immunodeficiencies including adenosine deaminase deficiency, X-linked severe combined immunodeficiency, chronic granulomatous disease and Wiskott Aldrich syndrome. Major recent progress has also been made in haemoglobinopathies, such as beta-thalassaemia, sickle cell disease and Fanconi anaemia, and also specific lysosomal storage diseases, which, although not strictly bone marrow specific conditions, have been effectively treated by bone marrow-based treatment. The success of these recent studies and the advent of new technologies, such as gene editing, suggest that gene therapy could become a more generally applied treatment modality for a number of haematopoietic disorders.

PMID: 26044877 [PubMed – as supplied by publisher]