Research

A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4.

January 22, 2015 By Manish Butte

A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4.

Nat Immunol. 2014 Dec;15(12):1134-42

Authors: Alsina L, Israelsson E, Altman MC, Dang KK, Ghandil P, Israel L, von Bernuth H, Baldwin N, Qin H, Jin Z, Banchereau R, Anguiano E, Ionan A, Abel L, Puel A, Picard C, Pascual V, Casanova JL, Chaussabel D

Abstract
Loss of function of the kinase IRAK4 or the adaptor MyD88 in humans interrupts a pathway critical for pathogen sensing and ignition of inflammation. However, patients with loss-of-function mutations in the genes encoding these factors are, unexpectedly, susceptible to only a limited range of pathogens. We employed a systems approach to investigate transcriptome responses following in vitro exposure of patients’ blood to agonists of Toll-like receptors (TLRs) and receptors for interleukin 1 (IL-1Rs) and to whole pathogens. Responses to purified agonists were globally abolished, but variable residual responses were present following exposure to whole pathogens. Further delineation of the latter responses identified a narrow repertoire of transcriptional programs affected by loss of MyD88 function or IRAK4 function. Our work introduces the use of a systems approach for the global assessment of innate immune responses and the characterization of human primary immunodeficiencies.

PMID: 25344726 [PubMed – indexed for MEDLINE]

C1 inhibitor deficiency: 2014 United Kingdom Consensus Document.

January 22, 2015 By Manish Butte

C1 inhibitor deficiency: 2014 United Kingdom Consensus Document.

Clin Exp Immunol. 2015 Jan 20;

Authors: Longhurst HJ, Tarzi MD, Ashworth F, Bethune C, Cale C, Dempster J, Gompels M, Jolles S, Seneviratne S, Symons C, Price A, Edgar D

Abstract
C1 inhibitor deficiency is a rare disorder manifesting with recurrent attacks of disabling and potentially life-threatening angioedema. Here we present an updated 2014 United Kingdom consensus document for the management of C1 inhibitor-deficient patients, representing a joint venture between the United Kingdom Primary Immunodeficiency Network and Hereditary Angioedema UK. To develop the consensus, we assembled a multi-disciplinary steering group of clinicians, nurses and a patient representative. This steering group first met in 2012, developing a total of 48 recommendations across 11 themes. The statements were distributed to relevant clinicians and a representative group of patients to be scored for agreement on a Likert scale. All 48 statements achieved a high degree of consensus, indicating strong alignment of opinion. The recommendations have evolved significantly since the 2005 document, with particularly notable developments including an improved evidence base to guide dosing and indications for acute treatment, greater emphasis on home therapy for acute attacks and a strong focus on service organisation. This article is protected by copyright. All rights reserved.

PMID: 25605519 [PubMed – as supplied by publisher]

Decreased immunoglobulin G levels after living-donor liver transplantation is a risk factor for bacterial infection and sepsis.

January 22, 2015 By Manish Butte

Decreased immunoglobulin G levels after living-donor liver transplantation is a risk factor for bacterial infection and sepsis.

Transpl Infect Dis. 2014 Apr;16(2):225-31

Authors: Yoshizumi T, Shirabe K, Ikegami T, Yamashita N, Mano Y, Yoshiya S, Matono R, Harimoto N, Uchiyama H, Toshima T, Maehara Y

Abstract
BACKGROUND: Several studies have suggested an association between post-transplant immunoglobulin (Ig) levels and the development of infection in solid organ transplantation. We therefore conducted exploratory analyses of potential factors associated with bacterial infection/sepsis after living-donor liver transplantation (LDLT).
METHODS: Blood samples from 177 recipients who received primary LDLT between September 1999 and November 2011 were available for study. Hypogammaglobulinemia was defined as having at least 1 IgG level <650 mg/dL within 7 days after LDLT. Risk factors for developing post-transplant bacterial infection and sepsis within 3 months after LDLT were analyzed.
RESULTS: Fifty (28.2%) recipients experienced bacterial infection within 3 months of LDLT. Eighty-four (47.5%) recipients had hypogammaglobulinemia, although no recipients had hypogammaglobulinemia before LDLT. Hypogammaglobulinemia, undergoing hepaticojejunostomy, and portal pressure at closure >15 mmHg were independent risk factors for developing bacterial infection within 3 months of LDLT (P < 0.0001 P = 0.0008, and P = 0.011, respectively). The odds ratio (OR) and confidence interval (CI) for hypogammaglobulinemia were 4.79 and 2.27-10.7, respectively. Twenty-four (13.6%) recipients developed bacterial sepsis within 3 months. Hypogammaglobulinemia, operative time >14 h, model for end-stage liver disease score >15, and no mycophenolate mofetil use were independent risk factors for developing bacterial sepsis (P = 0.009, P = 0.001, P = 0.003, and P = 0.005, respectively). The OR and CI for hypogammaglobulinemia were 3.83 and 1.38-12.0, respectively.
CONCLUSIONS: Hypogammaglobulinemia within 7 days of LDLT was a significant risk factor for post-transplant bacterial infection and sepsis.

PMID: 24593220 [PubMed – indexed for MEDLINE]

Chronic infections of the small intestine.

January 21, 2015 By Manish Butte

Chronic infections of the small intestine.

Curr Opin Gastroenterol. 2015 Jan 16;

Authors: Bourke B, Hussey S

Abstract
PURPOSE OF REVIEW: Chronic infections of the small intestine cause significant morbidity and mortality globally. This review focuses on the recent advances in the field of our understanding of selected intestinal infections.
RECENT FINDINGS: Primary and secondary immunodeficiency increase the susceptibility to many chronic intestinal infections. Endoscopy and intestinal biopsies are central to establishing a diagnosis of these conditions. Tuberculosis (TB) remains a major global health challenge. Emerging therapeutic agents to counteract multidrug-resistant strains have shown clinical efficacy, but concerns regarding mortality remain. PCR-based diagnostic TB tests have the potential to reduce diagnostic delays, but remain to be validated for intestinal infections. Adjunctive diagnostic imaging modalities can differentiate infections from Crohn’s disease with increasing accuracy. Whipple’s disease remains rare, but there have been substantial advances in our understanding of the causative organism Tropheryma whipplei. Extended treatment with broad-spectrum antibiotics is effective in most cases. The narrow therapeutic window and limited armamentarium for treating invasive filamentous fungal infections contribute to their significant morbidity and high rates of mortality.
SUMMARY: The speed and accuracy of diagnosing chronic intestinal infections have improved with recent imaging and laboratory methodologies. Significant research opportunities remain for clinicians and scientists to improve the diagnostic accuracy and clinical outcomes of chronic intestinal infections.

PMID: 25603404 [PubMed – as supplied by publisher]

Analysis of specific IgG titers against tick-borne encephalitis in patients with primary antibody deficiency under immunoglobulin substitution therapy: impact of plasma donor origin.

January 21, 2015 By Manish Butte

Analysis of specific IgG titers against tick-borne encephalitis in patients with primary antibody deficiency under immunoglobulin substitution therapy: impact of plasma donor origin.

Front Immunol. 2014;5:675

Authors: Goldacker S, Witte T, Huzly D, Schlesier M, Peter HH, Warnatz K

Abstract
Immunoglobulin (Ig) replacement therapy is effective in reducing infections in patients with primary antibody deficiency (PAD). Diversity of specific antibodies is achieved by pooling plasma from over 1000 donors usually of a given geographic region. However, there is no agreement with regard to an optimal vaccination schedule for plasma donors. Especially for tick-borne encephalitis (TBE), regional vaccination rates differ widely among populations due to the epidemiology of the disease. We analyzed specific antibody titers against TBE in comparison to total IgG levels in 162 serum samples collected from 110 PAD patients substituted with polyvalent intravenous IgG or subcutaneous IgG. Some patients received different IgG products over time leading to a total number of 122 different patient-IgG product combinations. Positive TBE-specific IgG levels were detected in 35 cases when measured by standard ELISA and could be confirmed by demonstration of neutralizing antibodies in 31 cases. The detection of specific antibody levels correlated with the geographic origin of the IgG preparations. No titers were detectable in patients substituted with IgG products from North-American donors, whereas variable degrees of anti-TBE titers were observed in patients receiving products from different European countries. We suggest considering the patients’ personal risk for TBE when selecting an appropriate Ig preparation. These data support regional plasma donation in order to address the diverse local infection profile.

PMID: 25601868 [PubMed]

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]

Subcutaneous abscess due to the basidiomycete Phellinus mori in a patient with chronic granulomatous disease.

January 21, 2015 By Manish Butte

Subcutaneous abscess due to the basidiomycete Phellinus mori in a patient with chronic granulomatous disease.

Infection. 2015 Jan 20;

Authors: Shigemura T, Nakazawa Y, Amano Y, Sudo A, Watanabe M, Kobayashi M, Kobayashi N, Koike K, Agematsu K, Nishimura K

Abstract
Chronic granulomatous disease (CGD), a primary immunodeficiency caused by impaired phagocyte killing of intracellular pathogens, is characterized by recurrent, life-threatening, bacterial and fungal infections. As a result of improvements in microbiologic culture and identification techniques, a number of unique filamentous fungi have been reported as significant pathogens in patients with CGD. We report a case of subcutaneous basidiomycete Phellinus mori infection in a patient with CGD. To the best of our knowledge, this is the first reported case of human infection by this fungus. The causative fungus was identified on the basis of its morphological characteristics and nucleotide sequence on the internal transcribed spacer region of the ribosomal RNA gene. This is the fifth case report of filamentous basidiomycetes infecting a patient with CGD; all of these cases have been caused by Phellinus species. We highlight the importance of recognizing filamentous basidiomycetes Phellinus species as possible agents of non-Aspergillus fungal infections in patients with CGD.

PMID: 25600930 [PubMed – as supplied by publisher]

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]