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Neutrophil functional disorder in childhood.

June 17, 2015 By Manish Butte

Neutrophil functional disorder in childhood.

Prilozi. 2015;36(1):183-90

Authors: Mironska K

Abstract
(Full text is available at http://www.manu.edu.mk/prilozi). Neutrophil functional disorders thought to be uncommon, yet important as a cause of morbidity and mortality in infants and children. During the first years of life, when the immune system is still not completely mature, when the viral infections are frequent and antibiotic overuse can damage and alter the immune response, the inadequate nutrition followed with iron deficient anemia and malnutrition can lead the child`s organism in state of immunodeficiency. Sometimes is difficult to distinguish at the beginning weather the cause of patient suffering from frequent infections is existing of primary immunodeficiency disorder or the cause of the immunodeficiency state is just from exogenous factors. Fortunately, primary immune deficiencies are rare diseases and only 6-7% of all of them, due to the neutrophilic functional disorders. Unfortunately, many exogenous and environmental factors have influence to the immune system, and the percentage of secondary caused neutrophilic functional disorders is much higher and should be considered when children are investigated for immunodeficiency. So, when to suspect neutrophil functional disorder? The hallmarks for diseases related to the neutrophilic functional disorders are discussed in this article. Key words: neutrophil, phagocytosis, NBT test, Neutrophil function, Neutrophil functional disorder, malnutration.

PMID: 26076788 [PubMed – in process]

Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: A single-center experience.

June 16, 2015 By Manish Butte

Hematopoietic stem cell transplant for hyper-IgM syndrome due to CD40L defects: A single-center experience.

Pediatr Transplant. 2015 Jun 13;

Authors: Al-Saud B, Al-Mousa H, Al-Ahmari A, Al-Ghonaium A, Ayas M, Alhissi S, Al-Muhsen S, Al-Seraihy A, Arnaout R, Al-Dhekri H, Hawwari A

Abstract
HIGMI is a disease with a high risk for morbidity and mortality. HSCT has been shown to be a curative option. This study retrospectively reviewed and analyzed data from five patients who received HSCT at King Faisal Specialist Hospital & Research Centre (KFSH&RC) in Riyadh, Saudi Arabia, between 2005 and 2013. Five patients with HIGMI syndrome underwent HSCT at a median age of 41 months (range, 9-72 months). The median time from diagnosis to transplantation was 30 months (range, 5-58 months). For all five patients, the donors were HLA-identical siblings. In three patients, the conditioning regimen was composed of BU and CY. Fludarabine and melphalan with either ATG or alemtuzumab was used in two patients. For GVHD prophylaxis, cyclosporine was used in two patients, and the combination of cyclosporine and MTX was used in three patients. The survival rate was 100%, with a median follow-up of 69 months (range, 13-100 months). All patients engrafted. Two patients developed acute GVHD. Four patients showed complete immune recovery with positive CD40L expression in activated T cells and discontinued IVIG replacement. HSCT in early stage from an HLA-matched sibling donor is potentially effective at curing the disease.

PMID: 26073206 [PubMed – as supplied by publisher]

A novel treatment in X-linked agammaglobulinaemia – hyperbaric oxygen therapy in refractory chronic wounds.

June 16, 2015 By Manish Butte

A novel treatment in X-linked agammaglobulinaemia – hyperbaric oxygen therapy in refractory chronic wounds.

J Clin Immunol. 2014 Oct;34(7):784-7

Authors: Steele CL, Cridge C, Edgar JD

Abstract
Chronic wounds are a rare complication of X-linked agammaglobulinaemia (XLA). Fastidious organisms such as helicobacter bills have been reported in XLA with chronic wounds but sterile chronic wounds also occur. Hyperbaric Oxygen Therapy has been used in chronic wounds but has not previously been reported in primary antibody deficiencies. We present a case of a chronic wound in a patient with XLA refractory to antimicrobial therapy that made a remarkable recovery following Hyperbaric Oxygen Therapy.

PMID: 25091287 [PubMed – indexed for MEDLINE]

Inborn errors of metabolism underlying primary immunodeficiencies.

June 16, 2015 By Manish Butte

Inborn errors of metabolism underlying primary immunodeficiencies.

J Clin Immunol. 2014 Oct;34(7):753-71

Authors: Parvaneh N, Quartier P, Rostami P, Casanova JL, de Lonlay P

Abstract
A number of inborn errors of metabolism (IEM) have been shown to result in predominantly immunologic phenotypes, manifesting in part as inborn errors of immunity. These phenotypes are mostly caused by defects that affect the (i) quality or quantity of essential structural building blocks (e.g., nucleic acids, and amino acids), (ii) cellular energy economy (e.g., glucose metabolism), (iii) post-translational protein modification (e.g., glycosylation) or (iv) mitochondrial function. Presenting as multisystemic defects, they also affect innate or adaptive immunity, or both, and display various types of immune dysregulation. Specific and potentially curative therapies are available for some of these diseases, whereas targeted treatments capable of inducing clinical remission are available for others. We will herein review the pathogenesis, diagnosis, and treatment of primary immunodeficiencies (PIDs) due to underlying metabolic disorders.

PMID: 25081841 [PubMed – indexed for MEDLINE]

Adequate patient's outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies.

June 16, 2015 By Manish Butte

Adequate patient’s outcome achieved with short immunoglobulin replacement intervals in severe antibody deficiencies.

J Clin Immunol. 2014 Oct;34(7):813-9

Authors: Milito C, Pulvirenti F, Pesce AM, Digiulio MA, Pandolfi F, Visentini M, Quinti I

Abstract
PURPOSE: The optimal immune globulin replacement dosages required over time to minimize infection risks in patients with Primary Antibody Deficiencies are not definitely established. As with many interventions, there may be specific subgroups of patients who are more likely to benefit from treatment with higher or lower dosages. The aim of the study was to verify the efficacy of a rationale for individualized immune globulin utilization and to elucidate the effects of care on patient outcome.
METHODS: Single centre interventional study on 108 patients with Primary Antibody Deficiencies. The objective was to determine for each patient the best interval between immune globulins administration in order to: • Keep IgG trough levels >500 mg/dL, • Minimize of major infections (pneumonias and infections requiring hospitalization), • Minimize of adverse events (AE).
RESULTS: Ninthly eight per cent of patients achieved the objective of the study. Patients who had low switched memory B cells and low IgA serum levels and/or are affected by bronchiectasis and/or enteropathy and/or continued to experience adverse events despite pre-medications, achieved the study objective by shortening the administration intervals to 2-weeks or to 1-week without the need to increase the monthly cumulative immunoglobulin dosage and its relative cost. The adverse events were reduced by administrating low Ig dosages in a single setting. Patients without risk factors achieved the study objective with immune globulin replacement administered with the widely used interval of 3 or 4 weeks.
CONCLUSIONS: The exact timing and optimal immunoglobulin prophylaxis regimen might be tailored according to clinical and immunological markers.

PMID: 25047154 [PubMed – indexed for MEDLINE]

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]