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The epidemiology and clinical features of selective immunoglobulin M deficiency: A single-center study in China.

J Clin Lab Anal. 2020 Mar 10;:e23289

Authors: Ni J, Zhang J, Chen Q, Chen Y, Liu J

Abstract
BACKGROUND: Selective immunoglobulin M deficiency (SIgMD) is a rare primary immunodeficiency that is frequently reported in Western countries. However, large epidemiological and clinical studies of SIgMD in China are still lacking. Herein, we describe a cohort of SIgMD subjects in a large tertiary university hospital in China.
METHODS: A cross-sectional study included 139 668 participants at First Affiliated Hospital of Wenzhou Medical University from January 2014 to October 2018 was conducted. Individuals with a serum IgM level less than 0.3 g/L with normal levels of serum IgA and IgG were defined as having SIgMD.
RESULT: A total of 63 subjects met the criteria for SIgMD(63/139668, 0.045%), with a male-to-female ratio of 0.85, aged from 19 to 99 years. The most common clinical manifestation was autoimmune disorders (38/63, 60.32%), while the second most common manifestation was infections (21/63, 33.33%). Neither allergies nor tumors were found among these 63 SIgMD subjects. Most importantly, there were 30 patients with systemic lupus erythematosus among these 63 SIgMD subjects, accounting for 47.62% of all SIgMD subjects.
CONCLUSION: To our knowledge, we describe here the first large single-center cohort of adult patients affected by SIgMD in China. The most common clinical manifestation was autoimmune disorders, specifically systemic lupus erythematosus.

PMID: 32157736 [PubMed – as supplied by publisher]

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Successful umbilical cord blood transplantation in children with leukocyte adhesion deficiency type I.

Transl Pediatr. 2020 Feb;9(1):34-42

Authors: Qian X, Wang P, Wang H, Jiang W, Sun J, Wang X, Zhai X

Abstract
Background: This study aims to investigate the efficacy and safety of umbilical cord blood transplantation (UCBT) without serotherapy for treating children with leukocyte adhesion deficiency type I (LAD-I).
Methods: Clinical characteristics and data of five children with LAD-I who underwent UCBT at our hospital between September 2016 and September 2018 were retrospectively analyzed.
Results: Five (two boys and three girls) patients with LAD-I were included. The median age at UCBT was 9 months (range, 8 to 32 months). The same myeloablative conditioning regimen was administered for each patient and included busulfan, fludarabine, and cyclophosphamide. HLA matching of patients and umbilical cord blood was 8/10 to 10/10. The median dose of total nucleated cells (TNC) infused was 10.2×107/kg (range, 4.5×107 to 20.6×107/kg) and the median dose of CD34+ cells was 3.2×105/kg (range, 1.9×105 to 5.7×105/kg). The median time of neutrophil engraftment was 20 days (range, 13 to 28 days). The median time of platelet engraftment was 36 days (range, 32 to 56 days). All patients received complete donor chimerism (CDC). Four of the five patients developed grade II-IV acute graft-versus-host disease (GvHD). The median follow-up time after transplantation was 19 months (range, 8 to 38 months). Four of the patients survived and achieved complete clinical remission. The other patient died of bronchiolitis obliterans 8 months after UCBT.
Conclusions: UCBT is an effective treatment method for LAD-I patients. Also, severe LAD-I patients should undergo stem cell transplantation as early as possible.

PMID: 32154133 [PubMed]

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Hematopoietic Cell Transplantation in Patients With Primary Immune Regulatory Disorders (PIRD): A Primary Immune Deficiency Treatment Consortium (PIDTC) Survey.

Front Immunol. 2020;11:239

Authors: Chan AY, Leiding JW, Liu X, Logan BR, Burroughs LM, Allenspach EJ, Skoda-Smith S, Uzel G, Notarangelo LD, Slatter M, Gennery AR, Smith AR, Pai SY, Jordan MB, Marsh RA, Cowan MJ, Dvorak CC, Craddock JA, Prockop SE, Chandrakasan S, Kapoor N, Buckley RH, Parikh S, Chellapandian D, Oshrine BR, Bednarski JJ, Cooper MA, Shenoy S, Davila Saldana BJ, Forbes LR, Martinez C, Haddad E, Shyr DC, Chen K, Sullivan KE, Heimall J, Wright N, Bhatia M, Cuvelier GDE, Goldman FD, Meyts I, Miller HK, Seidel MG, Vander Lugt MT, Bacchetta R, Weinacht KG, Andolina JR, Caywood E, Chong H, de la Morena MT, Aquino VM, Shereck E, Walter JE, Dorsey MJ, Seroogy CM, Griffith LM, Kohn DB, Puck JM, Pulsipher MA, Torgerson TR

Abstract
Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management.

PMID: 32153572 [PubMed – in process]

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Complement Activation in 22q11.2 Deletion Syndrome.

J Clin Immunol. 2020 Mar 09;:

Authors: Grinde D, Øverland T, Lima K, Schjalm C, Mollnes TE, Abrahamsen TG

Abstract
The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.

PMID: 32152940 [PubMed – as supplied by publisher]

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Autoinflammation in addition to combined immunodeficiency: SLC29A3 gene defect.

Mol Immunol. 2020 Mar 06;121:28-37

Authors: Çağdaş D, Sürücü N, Tan Ç, Kayaoğlu B, Özgül RK, Akkaya-Ulum YZ, Aydınoğlu AT, Aytaç S, Gümrük F, Balci-Hayta B, Balci-Peynircioğlu B, Özen S, Gürsel M, Tezcan İ

Abstract
INTRODUCTION: H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS).
AIM: The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect.
PATIENT AND METHODS: Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide.
RESULTS: Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient’s peripheral blood mononuclear cells secreted more IL-1β and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient.
CONCLUSION: Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.

PMID: 32151906 [PubMed – as supplied by publisher]

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Hereditary angioedema: examining the landscape of therapies and preclinical therapeutic targets.

Expert Opin Ther Targets. 2019 06;23(6):457-459

Authors: Farkas H

PMID: 31018718 [PubMed – indexed for MEDLINE]

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Infectious complications after hematopoietic stem cell transplantation for primary immunodeficiency in children: a multicenter nationwide study.

Pediatr Allergy Immunol. 2020 Mar 09;:

Authors: Zając-Spychała O, Zaucha-Prażmo A, Zawitkowska J, Wachowiak J, Kowalczyk JR, Frączkiewicz J, Salamonowicz M, Kałwak K, Gorczyńska E, Chybicka A, Czyżewski K, Dziedzic M, Wysocki M, Zalas-Więcek P, Goździk J, Styczyński J

Abstract
PURPOSE: The aim of this nation-wide study was to evaluate the characteristics of bacterial (BI), invasive fungal disease (IFD) and viral infections (VI) in pediatric patients with PID after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
PATIENTS AND METHODS: All-in 114 HSCT recipients were enrolled into the study. At least one infectious complication (IC) was diagnosed in 60 (52.6%) patients aged 0.1-17.7 years, i.e. 59.5% with SCID and 49.4% with non-SCID.
RESULTS: Among 60 HSCT recipients diagnosed with at least one IC, 188 episodes of infectious complications (EIC) were recorded, i.e. 46.8% of BI, 41.5% of VI and 11.7% of proven/probable IFD. According to PID and HSCT donor type the incidence of EIC was comparable (p=0.679). The localization of infections differed significantly due to PID type (p=0.002). After each HSCT donor type the most common site of infection was GI. Overall, BI caused by Gram-positive strains (59.1%) were prevalent, especially Staphylococcaceae. The multidrug-resistant (MDR) pathogens was diagnosed in 52.3%, especially ESBL+ Enterobacteriaceae. The profile of VI was comparable for SCID and non-SCID patients (p=0.839). The incidence of IFD was comparable for each PID and HSCT donor type. Survival after infection was 91.5% and was comparable for PID and HSCT donor type.
CONCLUSIONS: The rate of patients diagnosed with IC among pediatric PID HSCT recipients did not depend on PID type, but rather on HSCT donor type. The localization of IC depended on PID and HSCT donor type. Within bacterial infections predominated Gram-positive strains and the MDR pathogens were responsible for more than half of EIC.

PMID: 32150770 [PubMed – as supplied by publisher]

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Pulmonary complications of predominantly antibody immunodeficiencies in a tertiary lung center.

Interv Med Appl Sci. 2019 Mar;11(1):1-7

Authors: Mahdaviani SA, Darougar S, Mansouri D, Tashayoie-Nejad S, Movahedi M, Aghdam KR, Ghaffaripour H, Baghaie N, Hassanzad M, Eslaminejad A, Fakharian A, Pourdowlat G, Heshmatnia J, Bakhshayeshkaram M, Boloursaz M, Tabarsi P, Hashemitari SK, Velayati AA

Abstract
Background and aims: Respiratory infections are expressed very soon in the life in humoral immunodeficiencies and often lead to chronic irreversible complications such as bronchiectasis and chronic airflow limitation. This study was conducted to evaluate the pulmonary complications of predominantly antibody immunodeficiencies to show the benefits of timely diagnosis and appropriate therapy.
Patients and methods: The information of 48 patients involved with a type of predominantly antibody immunodeficiencies, including sex, type of primary immunodeficiency, age at the onset of symptoms, age at diagnosis, recurrent infections, respiratory symptoms, and pulmonary radiological and functional abnormalities were recorded and analyzed.
Results: In 48 patients evaluated, the mean age at diagnosis was 25.63 years. The mean diagnostic delay was estimated to be 13.62 years. The most recurring clinical manifestations, sinusitis (69.6%), otitis (43.5%), and recurrent pneumonia were the cause of frequent admissions in 68.8% of these patients. Bronchiectasis was frequently found (58.3%) in these patients mostly involving the middle and lower lobes (48.8% and 41.5%, respectively).
Conclusions: Respiratory complications, infectious or non-infectious, determine the prognosis of the disease in patients with predominantly antibody immunodeficiencies. Timely diagnosis and appropriate management may improve life expectancy and the quality of life in these patients.

PMID: 32148897 [PubMed]

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Vegan diet reduces neutrophils, monocytes and platelets related to branched-chain amino acids – A randomized, controlled trial.

Clin Nutr. 2020 Feb 24;:

Authors: Lederer AK, Maul-Pavicic A, Hannibal L, Hettich M, Steinborn C, Gründemann C, Zimmermann-Klemd AM, Müller A, Sehnert B, Salzer U, Klein R, Voll RE, Samstag Y, Huber R

Abstract
BACKGROUND: Vegan diet (VD) has improved inflammatory activity in patients with rheumatoid arthritis (RA) in several small controlled trials. The underlying mechanism remains widely unclear. We investigated the effect of a VD in comparison to a meat-rich diet (MD) on markers of inflammation (which have been shown to be relevant in patients with RA) in healthy volunteers.
METHODS: 53 healthy, omnivore subjects were randomized to a controlled VD (n = 26) or MD (n = 27) for 4 weeks following a pre-treatment phase of a one week controlled mixed diet. Primary parameters of interest were sialylation of immunoglobulins, percentage of regulatory T-cells and level of interleukin 10 (IL10). Usual care immune parameters used in patients with RA and amino acid serum levels as well as granulocytes and monocytes colony stimulating factor (GM-CSF) serum levels were secondary parameters.
RESULTS: In the VD group, total leukocyte, neutrophil, monocyte and platelet counts decreased and after four weeks they were significantly lower compared to the MD group (ANCOVA: leukocytes p = 0.003, neutrophils p = 0.001, monocytes p = 0.032, platelets p = 0.004). Leukocytes, neutrophils, monocytes, and platelets correlated with each other and likewise conform with serum levels of branched-chain amino acids, which were significantly lower in the VD compared to the MD group. The primary parameters did not differ between the groups and BMI remained stable in the two groups.
CONCLUSION: Four weeks of a controlled VD affected the number of neutrophils, monocytes and platelets but not the number or function of lymphocytes. The relation with branched-chain amino acids and GM-CSF suggests a mode of action via the mTOR signaling pathway. REGISTERED AT: http://www.drks.de (German Clinical Trial register) at DRKS00011963.

PMID: 32147197 [PubMed – as supplied by publisher]

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Noncystic Fibrosis Bronchiectasis: Evaluation of an Extensive Diagnostic Protocol in Determining Pediatric Lung Disease Etiology.

Pediatr Allergy Immunol Pulmonol. 2019 Dec 01;32(4):155-162

Authors: Beckeringh NI, Rutjes NW, van Schuppen J, Kuijpers TW

Abstract
Introduction: Pediatric noncystic fibrosis (CF) bronchiectasis has a variety of causes. An early and accurate diagnosis may prevent disease progression and complications. Current diagnostics and yield regarding etiology are evaluated in a pediatric cohort at a tertiary referral center. Methods: Available data, including high-resolution computed tomography (HRCT) characteristics, microbiological testing, and immunological screening of all children diagnosed with non-CF bronchiectasis between 2003 and 2017, were evaluated. Results: In 91% of patients [n = 69; median age 9 (3-18 years)] etiology was established in the diagnostic process. Postinfection (29%) and immunodeficiency (29%) were most common, followed by congenital anomalies (10%), aspiration (7%), asthma (6%), and primary ciliary dyskinesia (1%). HRCT predominantly showed bilateral involvement in immunodeficient patients (85%) and those with idiopathic bronchiectasis (83%). Congenital malformations (71%) were associated with unilateral disease. Completion of the diagnostic process often led to a change of treatment as started after initial diagnosis. Conclusion: Using a comprehensive diagnostic protocol, the etiology of pediatric non-CF bronchiectasis was established in more than 90% of patients. HRCT provides additional diagnostic information as it points to either a more systemic or a more localized etiology. Adequate diagnostics and data analysis allow treatment to be specifically adapted to prevent disease progression.

PMID: 32140286 [PubMed]

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