Research

Melioidosis in children: a retrospective study.

Int J Dermatol. 2015 Mar 13;

Authors: Foong YW, Tan NW, Chong CY, Thoon KC, Tee NW, Koh MJ

Abstract
BACKGROUND: Melioidosis, caused by Burkholderia pseudomallei, is endemic in Singapore and can present as localized or disseminated disease.
METHODS: Demographic data, clinical features, investigation results, treatments, and outcomes in patients aged <16 years diagnosed with melioidosis at KK Women’s and Children’s Hospital between January 2002 and January 2014 were retrospectively reviewed. Data for patients with primary skin disease and those with other organ involvement were compared.
RESULTS: Seventeen children were diagnosed with melioidosis. Their median age was 12.5 years (range: 2-15 years). Nine (53%) patients presented with localized cutaneous melioidosis and five (29%) with localized lymphadenitis, pneumonia, or septic arthritis. The remaining three (18%) patients had melioidosis sepsis; two of these patients died from septic shock. Treatment included an initial 1-2 weeks of IV antibiotics followed by 3-6 months of oral combination antibiotics. All cases of localized cutaneous disease resolved completely with no recurrences. Three (60%) of the five patients with localized involvement of other organ systems achieved complete resolution of disease, and the remaining two were lost from follow-up.
CONCLUSIONS: Although uncommon, melioidosis can occur in children living in endemic regions. Patients with localized skin disease have good outcomes with no recurrences. Systemic disease can be fatal, especially in the presence of underlying immunodeficiency. Diagnosis requires a high index of suspicion, and treatment requires prolonged combination antibiotic therapy.

PMID: 25771733 [PubMed – as supplied by publisher]

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[Primary immunodeficiencies are a topical problem of modern medicine].

Ter Arkh. 2014;86(11):12-5

Authors: Troitskaya EV, Sofronova LV, Tsvetkova TY

Abstract
AIM: To analyze the incidence of primary immunodeficiencies (PIDs), to reveal the specific features of the course of this condition at the present stage, and to estimate the quality of health care to patients with PIDs.
SUBJECTS AND METHODS: An open-label prospective trial was performed in 94 patients with different forms of PIDs (63 with selective immunoglobulin A (IgA) deficiency and 31 with other more severe primary immunodeficiencies) who had been permanent residents in the Perm Territory in the period 1990 to 2012.
RESULTS: The registered PID cases were noted to be lower than the estimated ones. Over 22 years of follow-ups, the death rates for this group of patients with these diseases were 11%, and the disability rates were 27%. In severe PIDs (exclusive of selective IgA deficiency), these rates were as high as 35.5 and 96%, respectively. The rate of untimely diagnosis of severe PIDs was high (43%). Molecular genetic studies were conducted in only one tenth of the patents with this disease. PID treatment generally complied with the accepted medical standards. However, all patients with X-linked agammaglobulinemia were observed to have periodic irregularities of replacement therapy with intravenous immunoglobulins, which was a cause of death in 2 patients. Adult patients with common variable immune deficiency received no adequate replacement therapy. Timely diagnosis and adequate therapy could not only preserve the life of many patients with severe PIDs (64.5% survived), but could achieve its relatively satisfactory quality.
CONCLUSION: As of now, PIDs ceased to be fatal diseases. To improve the quality of health care to patients with this pathology, there is a need to increase the awareness of the diagnosis and treatment of immunodeficiencies among physicians of different specialties, to extend the application of molecular genetic techniques, including those for prenatal diagnosis, and to continuously provide patients with essential drugs.

PMID: 25715480 [PubMed – indexed for MEDLINE]

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Rare mendelian primary immunodeficiency diseases associated with impaired NF-κB signaling.

Genes Immun. 2015 Mar 12;

Authors: Paciolla M, Pescatore A, Conte MI, Esposito E, Incoronato M, Lioi MB, Fusco F, Ursini MV

Abstract
Mendelian primary immunodeficiency diseases (MPIDs) are rare disorders affecting distinct constituents of the innate and adaptive immune system. Although they are genetically heterogeneous, a substantial group of MPIDs is due to mutations in genes affecting the nuclear factor-κB (NF-κB) transcription pathway, essential for cell proliferation and cell survival and involved in innate immunity and inflammation. Many of these genes encode for crucial regulatory components of the NF-κB pathway and their mutations are associated with immunological and developmental signs somehow overlapping in patients with MPIDs. At present, nine different MPIDs listed in the online mendelian inheritance in man (OMIM) are caused by mutations in at least nine different genes strictly involved in the NF-κB pathway that result in defects in immune responses. Here we report on the distinct function of each causative gene, on the impaired NF-κB step and more in general on the molecular mechanisms underlining the pathogenesis of the disease. Overall, the MPIDs affecting the NF-κB signalosome require a careful integrated diagnosis and appropriate genetic tests to be molecularly identified. Their discovery at an ever-increasing rate will help establish a common therapeutic strategy for a subclass of immunodeficient patients.Genes and Immunity advance online publication, 12 March 2015; doi:10.1038/gene.2015.3.

PMID: 25764117 [PubMed – as supplied by publisher]

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Successful Newborn Screening for SCID in the Navajo Nation.

Clin Immunol. 2015 Mar 8;

Authors: Kwan A, Hu D, Song M, Gomes H, Brown DR, Bourque T, Gonzalez-Espinosa D, Lin Z, Cowan MJ, Puck JM

Abstract
Newborn screening (NBS) for severe combined immunodeficiency (SCID) identifies affected infants before the onset of life-threatening infections, permitting optimal treatment. Navajo Native Americans have a founder mutation in the DNA repair enzyme Artemis, resulting in frequent Artemis SCID (SCID-A). A pilot study at 2 Navajo hospitals assessed the feasibility of SCID NBS in this population. Dried blood spots from 1,800 infants were assayed by PCR for T-cell receptor excision circles (TRECs), a biomarker for naïve T cells. Starting in February 2012, TREC testing transitioned to standard care throughout the Navajo Area Indian Health Service, and a total of 7,900 infants were screened through July 2014. One infant had low TRECs and was diagnosed with non-SCID T lymphopenia, while 4 had undetectable TRECs due to SCID-A, all of whom were referred for hematopoietic cell transplantation. This report establishes the incidence of SCID-A and demonstrates effectiveness of TREC NBS in the Navajo.

PMID: 25762520 [PubMed – as supplied by publisher]

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HkRP3 Is a Microtubule-Binding Protein Regulating Lytic Granule Clustering and NK Cell Killing.

J Immunol. 2015 Mar 11;

Authors: Ham H, Huynh W, Schoon RA, Vale RD, Billadeau DD

Abstract
NK cells provide host defense by killing viral-infected and cancerous cells through the secretion of preformed lytic granules. Polarization of the lytic granules toward the target cell is dependent on an intact microtubule (MT) network as well as MT motors. We have recently shown that DOCK8, a gene mutated in a primary immunodeficiency syndrome, is involved in NK cell killing in part through its effects on MT organizing center (MTOC) polarization. In this study, we identified Hook-related protein 3 (HkRP3) as a novel DOCK8- and MT-binding protein. We further show that HkRP3 is present in lytic granule fractions and interacts with the dynein motor complex and MTs. Significantly, depletion of HkPR3 impaired NK cell cytotoxicity, which could be attributed to a defect in not only MTOC polarity, but also impaired clustering of lytic granules around the MTOC. Our results demonstrate an important role for HkRP3 in regulating the clustering of lytic granules and MTOC repositioning during the development of NK cell-mediated killing.

PMID: 25762780 [PubMed – as supplied by publisher]

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Efficacy and tolerability of 16% subcutaneous immunoglobulin compared with 20% subcutaneous immunoglobulin in primary antibody deficiency.

Clin Exp Immunol. 2015 Mar 11;

Authors: Niebur HB, Duff CM, Shear GF, Nguyen D, Alberdi TK, Dorsey MJ, Sleasman JW

Abstract
PURPOSE: Multiple subcutaneous immunoglobulin (SCIG) products are available to treat primary antibody deficiency (PAD). Efficacy and tolerability of 16% SCIG (Vivaglobin®) was compared with 20% SCIG (Hizentra(®) ) in PAD subjects.
METHODS: The study was a prospective, single-center, open-label study of PAD subjects transitioning Vivaglobin to equivalent Hizentra doses, rounded to the nearest vial size. Comparisons included IgG levels; tetanus, varicella, and S pneumoniae titers; adverse events (AEs), annual infection rate, and quality of life over 8 weeks of Vivaglobin and 24 weeks of Hizentra.
RESULTS: 32 subjects (2-75 years) participated. Rounding to the nearest Hizentra vial size resulted in 12.8% (±2.9%) increase in SCIG dose. Median IgG level following 8 weeks of Vivaglobin was similar to 24 weeks of Hizentra (1050 vs 1035mg/dL, respectively; P=0.77). Both products had similar protective titers to tetanus, varicella, and serotypes of S. pneumoniae which were variable but well above protective levels. After 12 weeks of Hizentra, subjects reported fewer local site reactions compared with Vivaglobin. Switching products resulted in increased systemic AEs in some subjects but overall, not significantly higher than during Vivaglobin treatment. Average infusion time decreased from 104.7 minutes (3.3 sites) with Vivaglobin to 70.7 minutes (2.2 sites) with Hizentra (P=0.0005). Acute serious bacterial infections were similar. Treatment satisfaction was superior with Hizentra.
CONCLUSIONS: Hizentra and Vivaglobin have similar pharmacokinetics and efficacy. Although transition to a different SCIG product initially increased AEs, Hizentra is well-tolerated and can be infused more rapidly and with fewer sites compared to Vivaglobin. This article is protected by copyright. All rights reserved.

PMID: 25761372 [PubMed – as supplied by publisher]

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Related Articles

High levels of SOX5 decrease proliferative capacity of human B cells, but permit plasmablast differentiation.

PLoS One. 2014;9(6):e100328

Authors: Rakhmanov M, Sic H, Kienzler AK, Fischer B, Rizzi M, Seidl M, Melkaoui K, Unger S, Moehle L, Schmit NE, Deshmukh SD, Ayata CK, Schuh W, Zhang Z, Cosset FL, Verhoeyen E, Peter HH, Voll RE, Salzer U, Eibel H, Warnatz K

Abstract
Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.

PMID: 24945754 [PubMed – indexed for MEDLINE]

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[Prevalence of gastrointestinal disorders in adults with common variable immunodeficiency at Specialty Hospital Dr. Bernardo Sepulveda].

Rev Alerg Mex. 2015 Jan-Mar;62(1):1-7

Authors: Rodríguez-Negrete EV, Mayoral-Zavala A, Rodríguez-Mireles KA, Díaz de León-Salazar OE, Hernández-Mondragón O, Gómez-Jiménez LM, Moreno-Alcántar R, González-Virla B

Abstract
BACKGROUND: The common variable immunodeficiency (CVID) shows a variable incidence, from 1:15,000 to 1:117,000, without gender predominance. The incidence of gastrointestinal manifestations in these patients ranges from 20-60%, and these may be the first and only clinical manifestation of CVID, while other patients develop gastrointestinal complications during the course of it. In Mexico there is little information regarding the type and frequency of gastrointestinal disorders presented by adult patients with CVID.
OBJECTIVE: To determine the prevalence of gastrointestinal manifestations in adult patients with CVID.
MATERIAL AND METHOD: A descriptive, cross-sectional and observational study was made including patients with CVID attending Primary Immunodeficiency Clinic of Allergy and Clinical Immunology Department, Specialties Hospital, National Medical Center SXXI, Mexico City. All patients underwent gastrointestinal symptoms questionnaire, laboratory, cabinet, endoscopy and breath test for bacterial overgrowth.
RESULTS: We evaluated 17 patients, 8 men and 9 women with an average age of 36 years with a definitive diagnosis of CVID according to international criteria; 59% had abdominal pain, 53% abdominal distension; only 3 patients (17.6%) reported constipation; 47% had chronic diarrhea, of which only 2 (11.8%) had rectal pushing. The diagnoses of gastrointestinal manifestations of this population were: 18% chronic diarrhea, celiac disease and bacterial overgrowth, 24% gastrointestinal functional disorder, 12% constipation and 6% dyspepsia. One patient (6%) had no gastrointestinal symptoms.
CONCLUSIONS: Prevalence of gastrointestinal diseases in adult patients with common variable immunodeficiency was 94%. There was no gender predominance. It is therefore important that patients with CVID will conduct a study protocol that includes a complete medical history considering gastrointestinal symptoms and signs, in order to determine timely diagnosis and therapeutic approach.

PMID: 25758107 [PubMed – as supplied by publisher]

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[Malignancies in adult patients with common variable immunodeficiency].

Rev Alerg Mex. 2015 Jan-Mar;62(1):22-27

Authors: López-Rocha E, Rodríguez-Mireles K, Segura-Méndez NH, Yamazaki-Nakashimada MA

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) implies an increased risk of cancer, with an estimated incidence of 11-13%, particularly during the 5th and 6th decade of life. B cell-Hodgkin lymphomas are the more frequent cancer, followed by non-Hodgkin lymphoma and epithelial tumors (gastric, breast, bladder and cervix).
OBJECTIVE: To describe the types of cancers in a cohort of adult patients with CVID.
MATERIAL AND METHOD: An observational, cross-sectional and descriptive study was made in which we reviewed the charts of patients with CVID attending the Primary Immunodeficiencies Clinic at Specialties Hospital Dr. Bernardo Sepulveda, Centro Medico Nacional Siglo XXI, Mexico City.
RESULTS: There were included 23 patients with CVID diagnosis, 13 women (56%) and 10 men (44%), with an average age of 36.7 years. Four patients developed malignancies (2 men and 2 women), with a prevalence of 17.3%. The types of cancers in this group of patients were: B cell-Hodgkin lymphoma (1/23), neuroendocrine carcinoma of the pancreas (1/23), myeloid chronic leukemia (1/23) and thyroid papillary carcinoma (1/23). In two of the subjects the diagnosis of cancer was established previous to CVID diagnosis. The average age of diagnosis of cancer was 27 years (19-34 years).
CONCLUSIONS: In our patients we found different types of malignancies compared to previously described. We consider necessary a screening protocol for an early diagnosis of cancer in these patients. The frequency of cancer in our population was the same as reported in the literature.

PMID: 25758110 [PubMed – as supplied by publisher]

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Idiopathic Non-Cirrhotic Intrahepatic Portal Hypertension (NCIPH)-Newer Insights into Pathogenesis and Emerging Newer Treatment Options.

J Clin Exp Hepatol. 2014 Sep;4(3):247-56

Authors: Goel A, Elias JE, Eapen CE, Ramakrishna B, Elias E

Abstract
Chronic microangiopathy of portal venules results in idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH). Recent data suggest a role for vasoactive factors of portal venous origin in the pathogenesis of this ‘pure’ vasculopathy of the liver. Enteropathies (often silent), are an important ‘driver’ of this disease. NCIPH is under-recognized and often mis-labeled as cryptogenic cirrhosis. Liver biopsy is needed to prove the diagnosis of NCIPH. In these patients, with advancing disease and increased porto-systemic shunting, the portal venous vasoactive factors bypass the liver filter and contribute to the development of pulmonary vascular endothelial disorders-porto-pulmonary hypertension and hepato-pulmonary syndrome as well as mesangiocapillary glomerulonephritis. Prognosis in NCIPH patients is determined by presence, recognition and management of associated disorders. With better understanding of the pathogenesis of NCIPH, newer treatment options are being explored. Imbalance in ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13): vWF (von-Willebrand factor) ratio is documented in NCIPH patients and may have a pathogenic role. Therapeutic interventions to correct this imbalance may prove to be important in the management of NCIPH.

PMID: 25755567 [PubMed]

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