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A 17-year old patient with DOCK8 deficiency, severe oral HSV-1 and aggressive periodontitis – A case of virally induced periodontitis?

January 21, 2015 By Manish Butte

A 17-year old patient with DOCK8 deficiency, severe oral HSV-1 and aggressive periodontitis – A case of virally induced periodontitis?

J Clin Virol. 2015 Feb;63:46-50

Authors: Betts K, Abusleme L, Freeman AF, Sarmadi M, Fahle G, Pittaluga S, Cuellar-Rodriguez J, Hickstein D, Holland SM, Su H, Moutsopoulos NM

Abstract
We present a 17-year old girl with DOCK-8 deficiency, severe untreated oral HSV-1 infection and associated aggressive periodontitis. DOCK-8 deficiency is a primary immunodeficiency, caused by biallelicloss-of-function mutations in the DOCK8 gene, often leading to severe viral and fungal mucocutaneous infections. Nevertheless, to date DOCK8 has not been associated with severe periodontitis and inflammatory bone loss around teeth. Understanding whether DOCK8 deficiency or severe HSV-1 infection underlies susceptibility to periodontitis is central to this case and may provide insights into susceptibility factors for periodontitis in the general population. Our clinical and microbiological data suggest that severe HSV-1 infection is the driver of periodontal inflammation in this case.

PMID: 25600604 [PubMed – in process]

Immunodeficiency-related vaccine-derived poliovirus (iVDPV) cases: A systematic review and implications for polio eradication.

January 21, 2015 By Manish Butte

Immunodeficiency-related vaccine-derived poliovirus (iVDPV) cases: A systematic review and implications for polio eradication.

Vaccine. 2015 Jan 16;

Authors: Guo J, Wagers SB, Srinivas N, Holubar M, Maldonado Y

Abstract
BACKGROUND: Vaccine-derived polioviruses (VDPVs), strains of poliovirus mutated from the oral polio vaccine, pose a challenge to global polio eradication. Immunodeficiency-related vaccine-derived polioviruses (iVDPVs) are a type of VDPV which may serve as sources of poliovirus reintroduction after the eradication of wild-type poliovirus. This review is a comprehensive update of confirmed iVDPV cases published in the scientific literature from 1962 to 2012, and describes clinically relevant trends in reported iVDPV cases worldwide.
METHODS: We conducted a systematic review of published iVDPV case reports from January 1960 to November 2012 from four databases. We included cases in which the patient had a primary immunodeficiency, and the vaccine virus isolated from the patient either met the sequencing definition of VDPV (>1% divergence for serotypes 1 and 3 and >0.6% for serotype 2) and/or was previously reported as an iVDPV by the World Health Organization.
RESULTS: We identified 68 iVDPV cases in 49 manuscripts reported from 25 countries and the Palestinian territories. 62% of case patients were male, 78% presented clinically with acute flaccid paralysis, and 65% were iVDPV2. 57% of cases occurred in patients with predominantly antibody immunodeficiencies, and the overall all-cause mortality rate was greater than 60%. The median age at case detection was 1.4 years [IQR: 0.8, 4.5] and the median duration of shedding was 1.3 years [IQR: 0.7, 2.2]. We identified a poliovirus genome VP1 region mutation rate of 0.72% per year and a higher median percent divergence for iVDPV1 cases. More cases were reported from high income countries, which also had a larger age variation and different distribution of immunodeficiencies compared to upper and lower middle-income countries.
CONCLUSION: Our study describes the incidence and characteristics of global iVDPV cases reported in the literature in the past five decades. It also highlights the regional and economic disparities of reported iVDPV cases.

PMID: 25600519 [PubMed – as supplied by publisher]

Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency.

January 18, 2015 By Manish Butte

Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency.

J Allergy Clin Immunol. 2015 Jan 14;

Authors: Wehr C, Gennery AR, Lindemans C, Schulz A, Hoenig M, Marks R, Recher M, Gruhn B, Holbro A, Heijnen I, Meyer D, Grigoleit G, Einsele H, Baumann U, Witte T, Sykora KW, Goldacker S, Regairaz L, Aksoylar S, Ardeniz Ö, Zecca M, Zdziarski P, Meyts I, Matthes-Martin S, Imai K, Kamae C, Fielding A, Seneviratne S, Mahlaoui N, Slatter MA, Güngör T, Arkwright PD, van Montfrans J, Sullivan KE, Grimbacher B, Cant A, Peter HH, Finke J, Gaspar HB, Warnatz K, Rizzi M, the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation and the European Society for Immunodeficiency

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted.
OBJECTIVE: We sought to define the outcomes of HSCT for patients with CVID.
METHODS: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012.
RESULTS: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved.
CONCLUSION: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.

PMID: 25595268 [PubMed – as supplied by publisher]

Primary immunodeficiency diseases: A primer for PCPs.

January 17, 2015 By Manish Butte

Primary immunodeficiency diseases: A primer for PCPs.

Nurse Pract. 2015 Feb 15;40(2):1-7

Authors: Younger EM, Epland K, Zampelli A, Hintermeyer MK

Abstract
: Primary care providers (PCPs) play a key role in identifying patients with primary immunodeficiency diseases (PIDDs). This diagnosis has implications for PCPs, as patients continue to require primary care and management after a PIDD diagnosis has been made. This review presents essential information for PCPs regarding PIDDs.

PMID: 25594294 [PubMed – as supplied by publisher]

Mutations in Bruton's tyrosine kinase impair IgA responses.

January 16, 2015 By Manish Butte

Mutations in Bruton’s tyrosine kinase impair IgA responses.

Int J Hematol. 2015 Jan 15;

Authors: Mitsuiki N, Yang X, Bartol SJ, Grosserichter-Wagener C, Kosaka Y, Takada H, Imai K, Kanegane H, Mizutani S, van der Burg M, van Zelm MC, Ohara O, Morio T

Abstract
X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by mutations in Bruton’s tyrosine kinase (BTK), and is characterized by markedly decreased numbers of blood B cells and an absence of all immunoglobulin isotypes. We performed whole exome sequencing in a male pediatric patient with dysgammaglobulinemia with IgA deficiency. Genetic analysis revealed a BTK missense mutation (Thr316Ala). To investigate whether a BTK mutation underlay this antibody deficiency with marked decrease of IgA in this patient, we performed functional analyses of B cells and phagocytes, and molecular analyses of somatic hypermutation and class switch recombination. The BTK missense mutation resulted in B cells with reduced BTK and high IgM expression. Equal proportions of CD19(low) and CD19(normal) fractions were observed, and both included naïve and memory B cells. Calcium influx and phospholipase Cγ2 phosphorylation upon IgM stimulation were marginally impaired in CD19(low), but not in CD19(+) B cells. Similar to XLA patients, IgA transcripts showed low SHM levels, whereas IgG transcripts were hardly affected. Our analyses suggest that the BTK mutation likely underlies the disease in this case, and that hypomorphic BTK mutations can result in normal circulating B cell numbers, but specifically impair IgA responses.

PMID: 25589397 [PubMed – as supplied by publisher]

Early cellular immune response to a new candidate mycobacterial vaccine antigen in childhood tuberculosis.

January 15, 2015 By Manish Butte

Early cellular immune response to a new candidate mycobacterial vaccine antigen in childhood tuberculosis.

Vaccine. 2015 Jan 9;

Authors: Schepers K, Dirix V, Mouchet F, Verscheure V, Lecher S, Locht C, Mascart F

Abstract
The search for novel vaccines against tuberculosis (TB) would benefit from in-depths knowledge of the human immune responses to Mycobacterium tuberculosis (Mtb) infection. Here, we characterised in a low TB incidence country, the immune responses to a new candidate vaccine antigen against TB, the heparin-binding haemagglutinin (HBHA), in young children in contact with an active TB case (aTB). Children with no history of BCG vaccination were compared to those vaccinated at birth to compare the initial immune responses to HBHA with secondary immune responses. Fifty-eight children with aTB and 76 with latent TB infection (LTBI) were included and they were compared to 90 non-infected children. Whereas Mtb-infected children globally secreted more interferon-gamma (IFN-γ) in response to HBHA compared to the non-infected children, these IFN-γ concentrations were higher in previously BCG-vaccinated compared to non-vaccinated children. The IFN-γ concentrations were similar in LTBI and aTB children, but appeared to differ qualitatively. Whereas the IFN-γ secretion induced by native methylated and recombinant non-methylated HBHA were well correlated for aTB, this was not the case for LTBI children. Thus, Mtb-infected young children develop IFN-γ responses to HBHA that are enhanced by prior BCG vaccination, indicating BCG-induced priming, thereby supporting a prime-boost strategy for HBHA-based vaccines. The qualitative differences between aTB and LTBI in their HBHA-induced IFN-γ responses may perhaps be exploited for diagnostic purposes.

PMID: 25583385 [PubMed – as supplied by publisher]

[Autoimmune diseases and auto antibodies in pediatric patients and their first-degree relatives with immunoglobulin A deficiency.]

January 15, 2015 By Manish Butte

[Autoimmune diseases and auto antibodies in pediatric patients and their first-degree relatives with immunoglobulin A deficiency.]

Rev Bras Reumatol. 2014 Nov 7;

Authors: Fahl K, Silva CA, Pastorino AC, Carneiro-Sampaio M, Jacob CM

Abstract
INTRODUCTION: Clinical manifestations of Immunoglobulin A Deficiency (IgAD) include recurrent infections, atopy and autoimmune diseases. However, to our knowledge, the concomitant evaluations of autoimmune diseases and auto antibodies in a cohort of IgAD patients with current age > 10 years-old and their relatives have not been assessed.
OBJECTIVES: To evaluate autoimmune diseases and the presence of auto antibodies in IgAD patients and their first-degree relatives.
METHODS: A cross-sectional study was performed in 34 IgAD patients (current age > 10 years-old) and their first-degree relatives. All of them were followed at a tertiary Brazilian primary immunodeficiency center: 27 children/adolescents and 7 of their first-degree relatives with a late diagnosis of IgAD. Autoimmune diseases and auto antibodies (antinuclear antibodies, rheumatoid factor, and anti-thyroglobulin, anti-thyroperoxidase and IgA class anti-endomysial antibodies) were also assessed.
RESULTS: Autoimmune diseases (n=14) and/or auto antibodies (n=10, four of them with isolated auto antibodies) were observed in 18/34 (53%) of the patients and their relatives. The most common autoimmune diseases found were thyroiditis (18%), chronic arthritis (12%) and celiac disease (6%). The most frequent auto antibodies were antinuclear antibodies (2%), anti-thyroglobulin and/or anti-thyroperoxidase (24%). No significant differences were observed in the female gender, age at diagnosis and current age in IgAD patients with and without autoimmune diseases and/or presence of auto antibodies (p>0.05). The frequencies of primary immunodeficiency’s in family, autoimmunity in family, atopy and recurrent infections were similar in both groups (p>0.05).
CONCLUSION: Autoimmune diseases and auto antibodies were observed in IgAD patients during follow-up, reinforcing the necessity of a rigorous and continuous follow-up during adolescence and adulthood.

PMID: 25582995 [PubMed – as supplied by publisher]

Posterior fossa mass in immunosuppressed patient.

January 13, 2015 By Manish Butte

Posterior fossa mass in immunosuppressed patient.

Bull Soc Sci Med Grand Duche Luxemb. 2014;(3):25-30

Authors: Gunness VR, Hana A, Berthold C, Dooms G, Hertel F

Abstract
BACKGROUND: Toxoplasmosis is the most frequent opportunistic infection of the central nervous system among individuals with the acquired immunodeficiency syndrome. Radiographic modalities include brain CT, MRI and PET scan. The differential diagnosis are usually: primary CNS lymphoma, cerebral metastasis, Progressive multifocal leukoencephalopathy, cytomegalovirus. It indicates severe immunodeficiency and, if it remains untreated, it may lead to death.
CASE DESCRIPTION: A 65 year old immunodeficiency woman with a Non Hodgkin Lymphoma treated with Chemotherapy. She had been suffering from vomiting, headache and vertigo. Treatment she received Dafalgan, Betaserc, neupogen and nexiam.
CONCLUSION: This case illustrates that a brain biopsy is compulsory before starting any treatment.

PMID: 25571670 [PubMed – in process]

Management of a Transcranial Abscess Secondary to Interleukin-1 Receptor Associated Kinase 4 Deficiency.

January 9, 2015 By Manish Butte

Management of a Transcranial Abscess Secondary to Interleukin-1 Receptor Associated Kinase 4 Deficiency.

J Craniofac Surg. 2015 Jan;26(1):e2-e3

Authors: Pidgeon TE, Ahmad F, Hackett S, Rodrigues D, Nishikawa H

Abstract
Interleukin-1 receptor associated kinase 4 (IRAK-4) deficiency is a primary immunodeficiency that predisposes to opportunistic pyogenic infections in affected patients. The presentation can be variable, and the microbiological and immunologic management of this condition has been documented; however, the atypical nature of its presentation calls for a different approach in its surgical management. This is the first reported case of transcranial progression of a soft tissue abscess in a patient with IRAK-4 deficiency, with an emphasis on a multidisciplinary approach to treat infection at an extremely vulnerable anatomic site.

PMID: 25569407 [PubMed – as supplied by publisher]

A genome-wide association study of marginal zone lymphoma shows association to the HLA region.

January 9, 2015 By Manish Butte

A genome-wide association study of marginal zone lymphoma shows association to the HLA region.

Nat Commun. 2015;6:5751

Authors: Vijai J, Wang Z, Berndt SI, Skibola CF, Slager SL, de Sanjose S, Melbye M, Glimelius B, Bracci PM, Conde L, Birmann BM, Wang SS, Brooks-Wilson AR, Lan Q, de Bakker PI, Vermeulen RC, Portlock C, Ansell SM, Link BK, Riby J, North KE, Gu J, Hjalgrim H, Cozen W, Becker N, Teras LR, Spinelli JJ, Turner J, Zhang Y, Purdue MP, Giles GG, Kelly RS, Zeleniuch-Jacquotte A, Ennas MG, Monnereau A, Bertrand KA, Albanes D, Lightfoot T, Yeager M, Chung CC, Burdett L, Hutchinson A, Lawrence C, Montalvan R, Liang L, Huang J, Ma B, Villano DJ, Maria A, Corines M, Thomas T, Novak AJ, Dogan A, Liebow M, Thompson CA, Witzig TE, Habermann TM, Weiner GJ, Smith MT, Holly EA, Jackson RD, Tinker LF, Ye Y, Adami H, Smedby KE, De Roos AJ, Hartge P, Morton LM, Severson RK, Benavente Y, Boffetta P, Brennan P, Foretova L, Maynadie M, McKay J, Staines A, Diver WR, Vajdic CM, Armstrong BK, Kricker A, Zheng T, Holford TR, Severi G, Vineis P, Ferri GM, Ricco R, Miligi L, Clavel J, Giovannucci E, Kraft P, Virtamo J, Smith A, Kane E, Roman E, Chiu BC, Fraumeni JF, Wu X, Cerhan JR, Offit K, Chanock SJ, Rothman N, Nieters A

Abstract
Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

PMID: 25569183 [PubMed – as supplied by publisher]