Research

A review of the etiology and clinical presentation of non-cystic fibrosis bronchiectasis: A tertiary care experience.

Respir Med. 2018 Apr;137:35-39

Authors: Satırer O, Mete Yesil A, Emiralioglu N, Tugcu GD, Yalcın E, Dogru D, Kiper N, Ozcelik U

Abstract
INTRODUCTION: Non-cystic fibrosis(CF) bronchiectasis has been recognized in children for the past 200 years. Early childhood pneumonia and underlying conditions such as immunodeficiency, primary ciliary dyskinesia(PCD), and congenital lung pathology should be considered in the etiology. The aim of our study was to describe the clinical characteristics, laboratory, and radiological findings of a large population of patients with non-CF bronchiectasis at a tertiary center.
METHODS: We analyzed the clinical findings of 187 patients diagnosed with non-CF bronchiectasis over a period of 10 years (January 2005-December 2015) at the Hacettepe University Faculty of Medicine Department of Pediatric Pulmonology.
RESULTS: The median age at the time of diagnosis of non-CF bronchiectasis was 8 years (1-18 years). Consanguinity was positive in 59.4% (n = 111) of patients and 19.8% (n = 37) of patients had a positive family history for non-CF bronchiectasis. Common causes were PCD in 51.3% (n = 96), immunodeficiency in 15% (n = 28), history of tuberculosis in 5.9% (n = 11), post-infectious complication in 3.2% (n = 6) and other anomalies in 2.1% (n = 4) of patients. The frequency of pulmonary lobe involvement was as follows: 71.1% left-lower lobe, 59.4% right lower lobe, 54% right-middle lobe, 26.8% left lingula, 13.9% right upper lobe, and 9.6% left upper lobe.
CONCLUSIONS: Diagnosis of non-CF bronchiectasis is often delayed because of a failure to recognize the significance of symptoms. Through clinical investigation, including a HRCT scan of the chest, sweat test, studies of immune function, and ciliary function in a child with a prolonged suppurative cough, remains important. In Turkey, the most common causes of non-CF bronchiectasis are PCD and immunodeficiency, related to a high frequency of consanguinity.

PMID: 29605210 [PubMed – in process]

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Age-specific pediatric reference ranges for immunoglobulins and complement proteins on the Optilite™ automated turbidimetric analyzer.

J Clin Lab Anal. 2018 Mar 30;:e22420

Authors: Garcia-Prat M, Vila-Pijoan G, Martos Gutierrez S, Gala Yerga G, García Guantes E, Martínez-Gallo M, Martín-Nalda A, Soler-Palacín P, Hernández-González M

Abstract
BACKGROUND: Measurement of immunoglobulins and complement proteins are frontline tests used in the assessment of immune system integrity, and reference values can vary with age. Their measurement provides an insight into the function of the innate and adaptive immune systems.
METHODS: We generated pediatric reference ranges for IgG, IgA, IgM, IgD, the IgG and IgA subclasses, and C3 and C4 using the Optilite™ turbidimetric analyzer.
RESULTS: The concentrations of IgG, IgA, and IgD showed an increase with age, as expected, while IgM remained stable between the age groups. For the IgG subclasses, no significant differences were observed in IgG1 or IgG3, while IgG2 and IgG4 concentrations increased steadily with age. The concentration of IgG2 plateaued at 15-18 years, while IgG4 plateaued at 10-14 years. The trend of concentrations across all groups was IgG1 > IgG2 > IgG3 > IgG4. For both IgA1 and IgA2, concentrations increased significantly with age, plateauing at 15-18 years. The median IgA1 concentration was greater than IgA2 across all groups. There was a good correlation between the total IgG or IgA concentration and summation of their subclasses (R2  = 0.89, P < .0001, slope y = 0.98x + 14.51 mg/dL and R2  = 0.91, P < .0001, slope y = 1.35x-3.28 mg/dL, respectively). The concentration of C3 and C4 remained stable across the groups, with no significant differences observed.
CONCLUSION: We have generated age-specific reference ranges in healthy children for C3, C4, IgG, IgA, IgM, IgD and the IgG and IgA subclasses using the Optilite™ turbidimetric analyzer. These ranges will help identify individuals with abnormal concentrations, thus will aid in the diagnosis of both primary and secondary immunological disorders.

PMID: 29603375 [PubMed – as supplied by publisher]

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Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry.

Front Immunol. 2018;9:543

Authors: Maccari ME, Abolhassani H, Aghamohammadi A, Aiuti A, Aleinikova O, Bangs C, Baris S, Barzaghi F, Baxendale H, Buckland M, Burns SO, Cancrini C, Cant A, Cathébras P, Cavazzana M, Chandra A, Conti F, Coulter T, Devlin LA, Edgar JDM, Faust S, Fischer A, Prat MG, Hammarström L, Heeg M, Jolles S, Karakoc-Aydiner E, Kindle G, Kiykim A, Kumararatne D, Grimbacher B, Longhurst H, Mahlaoui N, Milota T, Moreira F, Moshous D, Mukhina A, Neth O, Neven B, Nieters A, Olbrich P, Ozen A, Schmid JP, Picard C, Prader S, Rae W, Reichenbach J, Rusch S, Savic S, Scarselli A, Scheible R, Sediva A, Sharapova SO, Shcherbina A, Slatter M, Soler-Palacin P, Stanislas A, Suarez F, Tucci F, Uhlmann A, van Montfrans J, Warnatz K, Williams AP, Wood P, Kracker S, Condliffe AM, Ehl S

Abstract
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2-3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

PMID: 29599784 [PubMed]

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Phenotypic characterization of patients with rheumatologic manifestations of common variable immunodeficiency.

Semin Arthritis Rheum. 2018 Feb 23;:

Authors: Gutierrez MJ, Sullivan KE, Fuleihan R, USIDNET Consortium, Bingham CO

Abstract
Patients with common variable immunodeficiency (CVID) have a higher incidence of rheumatologic disorders. To delineate this clinical association, we investigated the phenotypic features of patients with CVID affected by these conditions.
METHODS: We conducted a retrospective analysis of 870 pediatric and adult patients with CVID included in the United States Immunodeficiency Network (USIDNET) registry. Outcomes included clinical characteristics (age, gender, ethnicity, rheumatologic diagnosis, and comorbidities), infectious history and basic immunophenotype (serum immunoglobulin levels, CD19+ B cells, and CD4/CD8 ratio) in patients with CVID and rheumatologic disorders compared to those with non-inflammatory CVID. Demographic and clinical data were compared using chi-square, Fisher’s exact or Wilcoxon-Mann-Whitney tests. Non-parametric tests, single and multiple logistic regression models were used to evaluate the relationship between CVID-associated rheumatologic disorders and basic immunophenotypic parameters (IgA, IgM, CD19+ B-cell counts, and CD4/CD8 ratios).
RESULTS: Physician-reported rheumatic diseases were present in 5.9% of patients with CVID (n = 51) included in the registry. Although CVID affects both sexes equally, and patients are of predominantly White-Caucasian ethnicity, there were more females (3.3:1 female to male ratio) and increased proportion of non-white patients in the rheumatologic disease group (p < 0.05). Specific disorders included: inflammatory arthritis (n = 18), Sjogren's syndrome (n = 11), SLE (n = 8), Raynaud's syndrome (n = 8), vasculitis (n = 9), MCTD (n = 3), and other (n = 5). In about one-third of patients, a rheumatologic condition was associated with an additional inflammatory complication or malignancy. In regards to the immunophenotype parameters compared (CD19+ B-cell counts, CD4/CD8 ratio, IgA, and IgM), no significant differences were demonstrated between the two groups.
CONCLUSION: Our findings highlight the coexistence of primary antibody immunodeficiencies and systemic rheumatologic disorders, describe the spectrum of rheumatologic manifestations, and contrast differences in relevant demographic, clinical and immunophenotype parameters in the largest registry of CVID patients in the U.S. In spite of its limitations, our study details the intersection of systemic autoimmunity and CVID and provides valuable insights into these two groups of disorders. Further delineating the link between systemic autoimmunity and humoral immunodeficiencies can provide novel insights into the immune abnormalities underlying these related conditions.

PMID: 29599028 [PubMed – as supplied by publisher]

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Morphology of Immunomodulation in Breast Cancer Tumor Draining Lymph Nodes Depends on Stage and Intrinsic Subtype.

Sci Rep. 2018 Mar 28;8(1):5321

Authors: Seidl M, Bader M, Vaihinger A, Wellner UF, Todorova R, Herde B, Schrenk K, Maurer J, Schilling O, Erbes T, Fisch P, Pfeiffer J, Hoffmann L, Franke K, Werner M, Bronsert P

Abstract
Cancer research of immune-modulating mechanisms mainly addresses the role of tumor-infiltrating immune cells. Mechanisms modulating the adaptive immune system at the primary activation site – the draining lymph node (LN) – are less investigated. Here we present tumor-caused histomorphological changes in tumor draining LNs of breast cancer patients, dependent on the localization (sentinel LN vs. non-sentinel LN), the tumor size, the intrinsic subtype and nodal metastatic status. The quantitative morphological study was conducted in breast cancer patients with at least one sentinel LN and no neoadjuvant therapy. All LNs were annotated considering to their topographical location, stained for IgD/H&E, digitized and quantitatively analyzed. In 206 patients, 394 sentinels and 940 non-sentinel LNs were categorized, comprising 40758 follicles and 7074 germinal centers. Subtype specific immunomorphological patterns were detectable: Follicular density was higher in LNs of Her2 enriched hormone receptor positive and triple-negative breast cancers whereas hormone receptor positive breast cancers showed more macrophage infiltrations in the LN cortex. Follicles are rounder in metastatic LNs and non-sentinel LNs. The identified immunomorphological changes reflect different underlying immunomodulations taking place in the tumor-draining LNs and should therefore be considered as possible prognostic and predictive markers for LN metastasis and therapy associated immunomodulation.

PMID: 29593307 [PubMed – in process]

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Effect of oral exposure to acrylamide on biochemical and hematologic parameters in Wistar rats.

Drug Chem Toxicol. 2018 Mar 28;:1-10

Authors: Belhadj Benziane A, Dilmi Bouras A, Mezaini A, Belhadri A, Benali M

Abstract
The toxic effects of ACR monomer include carcinogenesis, cellular genotoxic, and neurotoxicity. In this study, we examined the effect of acrylamide on biochemical and hematologic parameters in Wistar rats and explored the renal and hepatic function of these animals through a complementary anatomopathologic study. For it, thirty female Wistar rats aged 4 weeks and weighing 100 ± 10 g were housed six animals per cage and divided as follows: two groups were exposed for 2 months to drinking water containing 5 mg (Group 2) or 10 mg acrylamide (Group 3); one group of 12 rats received the median lethal dose of acrylamide by gavage (Group 4); and the control group (Group 1) received pure water. The results clearly showed that acrylamide affects various biochemical parameters, such as creatinine, urea, and serum globulin levels and the lipid balance, which are directly related to renal and hepatic dysfunction and disruption of the hematologic system. In addition, the data revealed changes in the complete blood count (CBC); significant increases in the number of leukocytes (9.95 ± 1.44 and 10.44 ± 1.21) and lymphocytes (6.11 ± 0.48 and 6.33 ± 0.76) in Groups 3 and 4, respectively; and decreases in total protein (88.95 ± 6.36), albumin (37.65 ± 1.65) and α-1 globulin levels (24.84 ± 2.10) in Group 3. The anatomopathologic study confirmed liver damage in the animals administered an acrylamide containing diet compared with those in the control group. The present study confirmed the effects of acrylamide on different hematologic, biochemical and immunologic parameters, with a specific focus on the liver and kidney, and on the induction of neurotoxic disorders. The results showed that oral exposure to acrylamide via drinking water or gavage induces kidney damage, hepatocellular insufficiency and chronic liver disease, resulting in primary immunodeficiency and activation of the immune system following the possible expression of certain immunoreaction genes.

PMID: 29589771 [PubMed – as supplied by publisher]

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Clinical considerations in the hematopoietic stem cell transplant management of primary immunodeficiencies.

Expert Rev Clin Immunol. 2018 Mar 28;:

Authors: Laberko A, Gennery AR

Abstract
INTRODUCTION: Primary immunodeficiencies (PID) are genetic immune disorders causing increased predisposition to infections and autoimmunity. The only curative procedure is hematopoietic stem cell transplantation (HSCT), results from which have improved dramatically since 2000. Complications remain a serious issue, especially in HLA non-identical transplantation. In PID patients, persistent infection and autoimmunity with end-organ damage cause particular problems with approach to transplantation. This article examines these, emphasising approach to management and consequences. Areas Covered: It is challenging to know which patients should be offered HSCT. As new diseases are discovered, data are required to determine natural history, and HSCT outcomes. Treatment of adults can be challenging, although HSCT outcomes are encouraging. New methods of T-lymphocyte depletion show results comparable to those of matched sibling donor transplants. New cellular therapies to treat viral infections show promising results, and immunomodulatory methods are successful in treating acute graft-versus-host disease. Expert Commentary: New T-lymphocyte depletion methods are a paradigm shift in approach to HSCT for PID. In combination with new cellular approaches to treating viral infection, immunomodulatory approaches to acute graft-versus-host disease and better understanding of endothelial activation syndromes, survival approaches 90%. Widespread introduction of newborn screening for severe combined immunodeficiencies will improve survival further.

PMID: 29589971 [PubMed – as supplied by publisher]

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Mendelian Susceptibility to Mycobacterial Disease Caused by a Novel Founder IL12B Mutation in Saudi Arabia.

J Clin Immunol. 2018 Mar 27;:

Authors: Alodayani AN, Al-Otaibi AM, Deswarte C, Frayha HH, Bouaziz M, AlHelale M, Le Voyer T, Nieto-Patlan A, Rattina V, AlZahrani M, Halwani R, Al Sohime F, Al-Mousa H, Al-Muhsen S, Alhajjar SH, Dhayhi NS, Abel L, Casanova JL, Bin-Hussain I, AlBarrak MS, Al-Jumaah SA, Bustamante J

Abstract
PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guérin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-γ immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30).
METHODS: Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain.
RESULTS: Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect.
CONCLUSIONS: This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.

PMID: 29589181 [PubMed – as supplied by publisher]

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Ikaros family zinc finger 1 regulates dendritic cell development and function in humans.

Nat Commun. 2018 Mar 27;9(1):1239

Authors: Cytlak U, Resteu A, Bogaert D, Kuehn HS, Altmann T, Gennery A, Jackson G, Kumanovics A, Voelkerding KV, Prader S, Dullaers M, Reichenbach J, Hill H, Haerynck F, Rosenzweig SD, Collin M, Bigley V

Abstract
Ikaros family zinc finger 1 (IKZF1) is a haematopoietic transcription factor required for mammalian B-cell development. IKZF1 deficiency also reduces plasmacytoid dendritic cell (pDC) numbers in mice, but its effects on human DC development are unknown. Here we show that heterozygous mutation of IKZF1 in human decreases pDC numbers and expands conventional DC1 (cDC1). Lenalidomide, a drug that induces proteosomal degradation of IKZF1, also decreases pDC numbers in vivo, and reduces the ratio of pDC/cDC1 differentiated from progenitor cells in vitro in a dose-dependent manner. In addition, non-classical monocytes are reduced by IKZF1 deficiency in vivo. DC and monocytes from patients with IKZF1 deficiency or lenalidomide-treated cultures secrete less IFN-α, TNF and IL-12. These results indicate that human DC development and function are regulated by IKZF1, providing further insights into the consequences of IKZF1 mutation on immune function and the mechanism of immunomodulation by lenalidomide.

PMID: 29588478 [PubMed – in process]

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Non-malignant late cutaneous changes after allogeneic hematopoietic stem cell transplant in children.

J Am Acad Dermatol. 2018 Mar 24;:

Authors: Huang JT, Song JS, Hawryluk EB, London WB, Guo D, Sridharan M, Fisher DE, Lehmann LE, Duncan CN

Abstract
BACKGROUND: There are limited pediatric data on non-malignant cutaneous changes, including autoimmune conditions and permanent alopecia, after hematopoietic stem cell transplantation (HSCT).
OBJECTIVE: We sought to characterize late cutaneous changes and associated risk factors after allogeneic HSCT in children.
METHODS: A cross-sectional cohort study of pediatric HSCT recipients was performed at a single institution. All participants underwent a full skin examination.
RESULTS: Median visit age was 13.8 years with median time post-HSCT of 3.6 years. Of 85 patients, 14% (n=12) had vitiligo, 16% (n=14) had psoriasis/sebopsoriasis, 25% (n=21) had alopecia, and 6% (n=5) had nail changes. Factors significantly associated with vitiligo included a history of chronic graft-versus-host disease (cGVHD), transplant indication of primary immunodeficiency, and younger age at transplant (<10 years of age). Fifty-two percent of patients with alopecia had androgenetic alopecia patterns. Factors significantly associated with alopecia included cGVHD, busulfan conditioning, and family history of early male pattern alopecia. All patients with nail changes had cGVHD.
LIMITATIONS: The cross-sectional design did not allow time of onset identification. Histopathologic correlation was not performed.
CONCLUSION: Pediatric HSCT recipients, particularly those with cGVHD, are at risk for developing non-malignant late cutaneous changes.

PMID: 29588248 [PubMed – as supplied by publisher]

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