Manish Butte

Persistent mammalian orthoreovirus, coxsackievirus and adenovirus co-infection in a child with a primary immunodeficiency detected by metagenomic sequencing: a case report.

BMC Infect Dis. 2018 Jan 11;18(1):33

Authors: Lewandowska DW, Capaul R, Prader S, Zagordi O, Geissberger FD, Kügler M, Knorr M, Berger C, Güngör T, Reichenbach J, Shah C, Böni J, Zbinden A, Trkola A, Pachlopnik Schmid J, Huber M

Abstract
BACKGROUND: We report a rare case of Mammalian orthoreovirus (MRV) infection in a child with a primary immunodeficiency (PID). Infections with Mammalian orthoreovirus are very rare and probably of zoonotic origin. Only a few cases have been described so far, including one with similar pathogenesis as in our case.
CASE PRESENTATION: The patient, age 11, presented with flu-like symptoms and persistent severe diarrhea. Enterovirus has been detected over several months, however, exact typing of a positive cell culture remained inconclusive. Unbiased metagenomic sequencing then detected MRV in stool samples from several time points. The sequencing approach further revealed co-infection with a recombinant Coxsackievirus and Adenovirus. MRV-specific antibodies detected by immunofluorescence proved that the patient seroconverted.
CONCLUSION: This case highlights the potential of unbiased metagenomic sequencing in supplementing routine diagnostic methods, especially in situations of chronic infection with multiple viruses as seen here in an immunocompromised host. The origin, transmission routes and implications of MRV infection in humans merit further investigation.

PMID: 29325543 [PubMed – in process]

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Novel X-Linked Inhibitor of Apoptosis Mutation in Very Early-Onset Inflammatory Bowel Disease Child Successfully Treated with HLA-Haploidentical Hemapoietic Stem Cells Transplant after Removal of αβ+ T and B Cells.

Front Immunol. 2017;8:1893

Authors: Cifaldi C, Chiriaco M, Di Matteo G, Di Cesare S, Alessia S, De Angelis P, Rea F, Angelino G, Pastore M, Ferradini V, Pagliara D, Cancrini C, Rossi P, Bertaina A, Finocchi A

Abstract
Monogenic defects in genes related to primary immunodeficiencies can be responsible for inflammatory bowel disease (IBD). Mutations in the X-linked inhibitor of apoptosis (XIAP) gene have been described in several patients suffering from IBD and, in particular, with very early-onset inflammatory bowel disease (VEOIBD) features. We report a VEOIBD child with a novel XIAP gene mutation characterized by a complicated disease course, which is unresponsive to several medical treatment options. A next-generation sequencing was performed and revealed a de novo hemizygous mutation in XIAP gene: c.565T>C p.L189P. After mutation discovery, we investigated the XIAP protein expression and nucleotide-binding oligomerization domain protein 2 (NOD2) signaling by western blotting. Flow-cytometry was used to analyze intracellular protein expression in different cell subsets and T cell apoptosis. We observed reduced protein expression in lymphocytes, granulocytes, monocytes, an Epstein-Barr virus-immortalized B cell line as well as increased apoptosis, and impairment in NOD2 signaling. The child was successfully treated with HLA-haploidentical hemapoietic stem cells transplant, acquired from his mother, after ex vivo elimination of α/β T cells and CD19 B cells. One year after the transplant, we repeated the analysis to appreciate the changes in his impairments. The recovery of XIAP protein expression, function, and normalization of apoptosis were observed. Our report emphasizes the important role of genetic analysis in the diagnosis of VEOIBD, illustrates the complete immunological and gastrointestinal recovery after transplant, and shows one of the few successful transplant cases of XIAP patients.

PMID: 29312354 [PubMed]

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EBV lymphoproliferative-associated disease and primary cardiac T-cell lymphoma in a STK4 deficient patient: A case report.

Medicine (Baltimore). 2017 Dec;96(48):e8852

Authors: Sherkat R, Sabri MR, Dehghan B, Bigdelian H, Reisi N, Afsharmoghadam N, Rahimi H, Rahmanian N, Klein C

Abstract
RATIONALE: Primary cardiac lymphoma (PLC) is an extremely uncommon malignancy. PCL is more common in secondary immunodeficient patients. In this report, we describe a unique case of PLC who had been diagnosed as a STK4 deficient patient. This case is the first Primary immunodeficiency (PID) patient developing PCL in the world.
PATIENT CONCERNS: An eleven-year-old girl, a known case of PID, was referred to the pediatric cardiology department because of chest pain and dyspnea. Her CXR revealed cardiomegaly without mediastinal involvement and the echocardiography showed a mild pericardial effusion and cystic-shape echogenic masses.
DIAGNOSES: After a period of missed follow up, she presented with respiratory distress following with syncope at the clinic because of a pressure effect of a large mass on the right ventricular outflow tract (RVOT) .An emergency operation was done for debulking of the tumors and resolving of RVOT obstruction. Biopsy and immunohistochemical staining was revealing “T-cell lymphoma”, non-Hodgkin’s type.
INTERVENTIONS: Chemotherapy was done with cyclophosphamide, methotrexate, adriamycine, vincristine, hydrocortisone and allopurinol.
OUTCOMES: The tumors shrank after chemotherapy initiation and she stayed stable for almost one month. Finally, she developed sever thrombocytopenia during her chemotherapy and died because of lung hemorrhage two months after her operation.
LESSONS: Although PCL is very rare, it must be considered in the differential diagnosis of intracardiac mass or refractory pericardial effusions, especially in PIDs which are widely known for developing EBV-associated diseases such as lymphoma.

PMID: 29310365 [PubMed – in process]

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A young girl with severe cerebral fungal infection due to card 9 deficiency.

Clin Immunol. 2018 Jan 04;:

Authors: Cetinkaya PG, Ayvaz DC, Karaatmaca B, Gocmen R, Söylemezoğlu F, Bainter W, Chou J, Chatila TA, Tezcan I

Abstract
Pattern recognition receptors (PRRs), receptors of the innate immune system, are important in interaction with pathogens. Caspase Recruitment Domain-containing protein 9 (CARD9), a member of PRRs, is an intracellular adaptor protein important in fungal defense. CARD9 deficiency causes a rare primary immunodeficiency (PID) characterized by superficial and deep fungal infections. We report a 17year-old female with a homozygous nonsense mutation in CARD9, who presented with severe cerebral fungal infection of the central nervous system. She was also found to have an heterozygous NLRP12 mutation, which may have had add-on effect on the severity of the infection.

PMID: 29307770 [PubMed – as supplied by publisher]

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Exercise Perception and Behaviors in Individuals Living with Primary Immunodeficiency Disease.

J Clin Immunol. 2018 Jan 06;:

Authors: Sowers KL, Litwin BA, Lee ACW, Galantino MLA

Abstract
BACKGROUND: Routine exercise has been established as an effective way to improve overall health. The value of exercise has been established in many diseases, however, there are no studies investigating the impact of exercise for individuals with primary immunodeficiency disease (PID). The purpose of this study was to investigate exercise perceptions and behaviors in individuals diagnosed with PID.
METHODS: An online survey was distributed over a four-week period.
RESULTS: Of the 264 responses collected, most were females, 45-54 years old. Respondents reported a measurable loss of function impairing their daily activities due to loss of mobility/physical activity (41.32%), or loss of lung/pulmonary function (40.08%,). They felt exercise decreased stress level and improved their mental well-being (46.25%). Some indicated they participate in exercise (33.20%), while 36.84% had not participated in exercise for at least 1 year. Exercise was limited primarily due to fatigue (86.97%).
CONCLUSION: Exercise is important for those with chronic medical conditions. Most individuals living with PID can participate in low/moderate physical activity, but struggle with vigorous physical activity, since fatigue is the greatest barrier. Respondents view exercise as beneficial, and would like to increase participation in an exercise program.

PMID: 29307028 [PubMed – as supplied by publisher]

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The Bronchiectasis Severity Index and FACED score for assessment of the severity of bronchiectasis.

Rev Port Pneumol (2006). 2018 Jan 03;:

Authors: Costa JC, Machado JN, Ferreira C, Gama J, Rodrigues C

Abstract
INTRODUCTION: Bronchiectasis (BC) is a multidimensional and etiologically diverse disease and, therefore, no single parameter can be used to determine its overall severity and prognosis. In this regard, two different validated scores are currently used to assess the severity of non-cystic fibrosis bronchiectasis (NCFB): the FACED score and the Bronchiectasis Severity Index (BSI).
OBJECTIVE: To describe the etiology of NCFB and compare the results of the assessment of NCFB severity obtained via FACED and BSI scores.
METHODS: Retrospective study of demographic and clinical data of a convenience sample of NCFB patients attending the Functional Breathing Re-adaptation appointment at the Pneumology B Unit, University Hospital Center of Coimbra. All patients underwent evaluation of the variables incorporated in the FACED score (FEV1% predicted, age, chronic colonization by Pseudomonas aeruginosa, radiological extent of the disease, and dyspnea) and in the BSI (age, body mass index, FEV1% predicted, hospitalization and exacerbations before study, dyspnea, chronic colonization by P. aeruginosa and other microrganisms, and radiological extent of the disease). Statistical analysis of the data was performed using Microsoft Excel® and IBM SPSS® v23.
RESULTS: The sample included 40 patients, 22 females and 18 males, aged 39-87 years. Regarding the etiology of NCFB, we found: idiopathic (60%), post-infectious (20%), sequelae of pulmonary tuberculosis (12.5%) and primary immunodeficiency related (7.5%). According to the FACED score we found 20 patients (50%) with mild BC, 15 patients (37.5%) with moderate and 5 patients (12.5%) with severe BC. The frequency of patients with low, intermediate and high BSI was 13 (32.5%), 13 (32.5%) and 14 (35%), respectively in relation to derived BSI, Moreover, we observed a weak but statistically significant association between FACED and BSI scores: Fisher’s exact test (p=0.004), tau-b de Kendall (0.469; p=0.001). The Kappa test (0.330; p=0.002) also shows us that there is 55% agreement between the two scales.
CONCLUSION: There is a small but significant correlation between the two scales: a tendency is observed for patients to be classified with a higher BSI compared to the FACED score. This can be explained by the fact that BSI (and not FACED) evaluates parameters including BMI, hospitalization and exacerbations before study, chronic colonization by other microorganisms and development of cystic bronchiectasis. Further studies should address how these scores may impact clinical practice.

PMID: 29306672 [PubMed – as supplied by publisher]

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Study of an extended family with CTLA-4 deficiency suggests a CD28/CTLA-4 independent mechanism responsible for differences in disease manifestations and severity.

Clin Immunol. 2018 Jan 03;:

Authors: Hou TZ, Olbrich P, Soto JML, Sanchez B, Moreno PS, Borte S, Stauss HJ, Burns SO, Walker LSK, Pan-Hammarström Q, Hammarström L, Sansom DM, Neth O

Abstract
The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.

PMID: 29305966 [PubMed – as supplied by publisher]

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RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias.

J Allergy Clin Immunol. 2018 Jan 02;:

Authors: Comrie WA, Faruqi AJ, Price S, Zhang Y, Rao VK, Su HC, Lenardo MJ

PMID: 29305315 [PubMed – as supplied by publisher]

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Hematopoietic cell transplantation in primary immunodeficiency – conventional and emerging indications.

Expert Rev Clin Immunol. 2018 Jan 04;:

Authors: Slatter MA, Gennery AR

Abstract
INTRODUCTION: Haematopoietic stem cell transplantation (HSCT) is an established curative treatment for many primary immunodeficiencies. Advances in donor selection, graft manipulation, conditioning and treatment of complications, mean that survival for many conditions is now around 90%. Next generation sequencing is identifying new immunodeficiencies, many of which are treatable with HSCT. Challenges remain however with short and long-term sequalae. This article reviews latest developments in HSCT for conventional primary immunodeficiencies and presents data on outcome for emerging diseases, Areas covered: This article reviews recently published literature detailing advances, particularly in conditioning regimens and new methods of T-lymphocyte depletion, as well as new information regarding approach and out come of transplanting patients with conventional primary immunodeficiencies. The article reviews data regarding transplant outcomes for newly described primary immunodeficiencies, particularly those associated with gain-of-function mutations. Expert commentary: New methods of graft manipulation have had significant impact on HSCT outcomes, with the range of PIDs treated using T-lymphocyte depletion significantly expanded. Outcomes for newly described diseases with variable phenotypes and clinical features, transplanted when the diagnosis was unknown are beginning to be described, and will improve as patients are identified earlier, and targeted therapies such as JAK inhibitors are used as a bridge to transplantation.

PMID: 29300535 [PubMed – as supplied by publisher]

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