Manish Butte

Update: Vaccines in Primary Immunodeficiency.

December 31, 2017 By Manish Butte

Update: Vaccines in Primary Immunodeficiency.

J Allergy Clin Immunol. 2017 Dec 26;:

Authors: Bonilla FA

Abstract
Vaccines were originally developed in order to prevent or ameliorate infectious disease. As knowledge of immune function and the appreciation of immunodeficiency has developed, researchers have used vaccine responses as a tool to characterize the phenotypes of patients exhibiting various syndromes. Thus, it has become possible for a clinician to evaluate individual responses to vaccines in order to interrogate the immunocompetence of their patients. Although there have been many advances in these areas, we still have much to learn about the quantity and quality of humoral and cellular vaccine responses in normal and immunodeficient individuals and how that knowledge may then be extrapolated to diagnostic purposes. Adverse effects of vaccines have been recognized for many years, especially the occurrence of infections caused by viable vaccine organisms in immunodeficient hosts. Nevertheless, vaccines are essential for disease prevention in immunodeficient patients just as they are for healthy individuals. Clinicians must understand the appropriate and safe use of vaccines in patients with immunodeficiency. This review highlights some recent advances and ongoing challenges in application of vaccines for the diagnosis and treatment of immunodeficiencies.

PMID: 29288077 [PubMed – as supplied by publisher]

Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.

December 31, 2017 By Manish Butte

Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1.

Immunity. 2017 Dec 21;:

Authors: Bloch Y, Bouchareychas L, Merceron R, Składanowska K, Van den Bossche L, Detry S, Govindarajan S, Elewaut D, Haerynck F, Dullaers M, Adamopoulos IE, Savvides SN

Abstract
Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.

PMID: 29287995 [PubMed – as supplied by publisher]

Proinflammatory T Cell Status Associated with Early Life Adversity.

December 30, 2017 By Manish Butte

Proinflammatory T Cell Status Associated with Early Life Adversity.

J Immunol. 2017 Dec 15;199(12):4046-4055

Authors: Elwenspoek MMC, Hengesch X, Leenen FAD, Schritz A, Sias K, Schaan VK, Mériaux SB, Schmitz S, Bonnemberger F, Schächinger H, Vögele C, Turner JD, Muller CP

Abstract
Early life adversity (ELA) has been associated with an increased risk for diseases in which the immune system plays a critical role. The ELA immune phenotype is characterized by inflammation, impaired cellular immunity, and immunosenescence. However, data on cell-specific immune effects are largely absent. Additionally, stress systems and health behaviors are altered in ELA, which may contribute to the generation of the ELA immune phenotype. The present investigation tested cell-specific immune differences in relationship to the ELA immune phenotype, altered stress parameters, and health behaviors in individuals with ELA (n = 42) and those without a history of ELA (control, n = 73). Relative number and activation status (CD25, CD69, HLA-DR, CD11a, CD11b) of monocytes, NK cells, B cells, T cells, and their main subsets were assessed by flow cytometry. ELA was associated with significantly reduced numbers of CD69+CD8+ T cells (p = 0.022), increased numbers of HLA-DR+ CD4 and HLA-DR+ CD8 T cells (p < 0.001), as well as increased numbers of CD25+CD8+ T cells (p = 0.036). ELA also showed a trend toward higher numbers of CCR4+CXCR3-CCR6+ CD4 T cells. Taken together, our data suggest an elevated state of immune activation in ELA, in which particularly T cells are affected. Although several aspects of the ELA immune phenotype were related to increased activation markers, neither stress nor health-risk behaviors explained the observed group differences. Thus, the state of immune activation in ELA does not seem to be secondary to alterations in the stress system or health-risk behaviors, but rather a primary effect of early life programming on immune cells.

PMID: 29133294 [PubMed – indexed for MEDLINE]

Chronic lung disease in common variable immune deficiency (CVID): A pathophysiological role for microbial and non-B cell immune factors.

December 30, 2017 By Manish Butte

Chronic lung disease in common variable immune deficiency (CVID): A pathophysiological role for microbial and non-B cell immune factors.

Crit Rev Microbiol. 2017 Aug;43(4):508-519

Authors: Mooney D, Edgar D, Einarsson G, Downey D, Elborn S, Tunney M

Abstract
One of the most common and most severe forms of primary antibody deficiency encountered in the clinical setting is a heterogeneous group of syndromes termed common variable immune deficiency (CVID). This disorder is characterized by reduced immunoglobulin production and increased susceptibility to infection, particularly of the respiratory tract. Infection and subsequent immunological/inflammatory processes may contribute to the development of pulmonary complications such as bronchiectasis and interstitial lung disease. Immunoglobulin replacement and/or antibiotic therapy, to prevent infection, are routinely prescribed treatments. However, chronic lung disease, the major cause of morbidity and mortality in this patient cohort, may still progress. This clinical progression suggests that pathogens recalcitrant to currently prescribed treatments and other immunological defects may be contributing to the development of pulmonary disease. This review describes the potential role of microbiological and non-B cell immunological factors, including T-cells, neutrophils, complement, toll like receptors, and antimicrobial peptides, in the pathogenicity of chronic lung disease in patients with CVID.

PMID: 28068853 [PubMed – indexed for MEDLINE]

Occupational CNS aspergillosis in an immunocompetent individual a diagnostic challange.

December 29, 2017 By Manish Butte

Occupational CNS aspergillosis in an immunocompetent individual a diagnostic challange.

Arch Environ Occup Health. 2017 Dec 28;:1-4

Authors: Punia P, Goel N, Singh I, Chaudhary U

Abstract
INTRODUCTION: Immunocompetent individuals are rarely affected by Aspergillus species and its prime importance lies in immunocompromised patients where it can cause disease, ranging from primarily pulmonary infections to dissemination anywhere in the body. Invasive aspergillosis (IA) occurs in patients with risk factors including prolonged neutropenia, neutrophil dysfunction, patient on cytotoxic drugs, steroid therapy, hematological malignancy, AIDS or in patients with bone marrow transplantation. A recently documented risk factor for IA is the exposure to environmental aspergillus spores at construction sites which makes it an important public health issue. We report here a case of primary CNS aspergillosis in an immunocompetent person who was initially diagnosed as a case of meningioma, and had a history of working in an area with excessive ongoing construction. He had no other primary focus of infection anywhere in the body. He was timely diagnosed and broad spectrum antifungals were started immediately.
MATERIAL AND METHODS: The brain biopsy and pus sampleas were subjected to direct microscopy using KOH mount and lactophenol cotton blue (LPCB) stain and culture on Sabourad’s Dextrose Agar in Microbiology laboratory. Later patient was started on fluconazole and caspofungin.
RESULTS: Thin, hyaline, septate hyphae on direct microscopy and growth of Aspergillus flavus on SDA culture were observed. The patient improved only with antifungals, without surgery.
DISCUSSION: This case study highlights the importance of keeping the differential diagnosis of Aspergillus spp. in mind even in individuals with no immunodeficiency. The immunocompetent individuals have better prognosis and if timely diagnosed, can be treated even without surgery. The prevalence of aspergillus spores at construction and demolition sites makes it an important public health issue, hence precautions must be advocated at these sites.

PMID: 29283878 [PubMed – as supplied by publisher]

Type 1 Diabetes Mellitus Associated with Activated Phosphoinositide-3-kinase Delta Syndrome, Type 2.

December 28, 2017 By Manish Butte

Type 1 Diabetes Mellitus Associated with Activated Phosphoinositide-3-kinase Delta Syndrome, Type 2.

J Diabetes. 2017 Dec 27;:

Authors: Nakagawa R, Takasawa K, Yeh TW, Imai K, Kashimada K, Morio T

Abstract
Primary immunodeficiency (PID) is a disorder in which the immune system does not function normally1 . In addition to the increased risk of infection, autoimmune disorders are often observed in PID.1.

PMID: 29280567 [PubMed – as supplied by publisher]

Subcutaneous immunoglobulin for the treatment of deep morphoea in a child.

December 28, 2017 By Manish Butte

Subcutaneous immunoglobulin for the treatment of deep morphoea in a child.

Clin Exp Dermatol. 2017 Dec 27;:

Authors: Yamazaki-Nakashimada MA, Saez-de-Ocariz M, Maldonado-Colin G, García-Romero MT

Abstract
Morphoea, also known as localized scleroderma, is a disorder characterized by excessive collagen deposition leading to thickening of the dermis and/or subcutaneous tissues. Intravenous IgG therapy has induced improvement in some fibrotic conditions. The primary indication for subcutaneous IgG (SCIG) is in primary immunodeficiency disorders as replacement therapy; however, recently there has been considerable interest in SCIG as an immunomodulatory agent. We report an 11-year-old girl with deep morphoea who was successfully treated with SCIG.

PMID: 29280519 [PubMed – as supplied by publisher]

Intranasal tissue necrosis associated with opioid abuse: Case report and systematic review.

December 28, 2017 By Manish Butte

Intranasal tissue necrosis associated with opioid abuse: Case report and systematic review.

Laryngoscope. 2017 Dec 27;:

Authors: Morrison DA, Wise SK, DelGaudio JM, Chowdhury NI, Levy JM

Abstract
OBJECTIVE: Opioid abuse is a common disorder affecting over 2 million Americans. Intranasal tissue necrosis is a previously described sequela of nasal opioid inhalation, with a similar presentation to invasive fungal rhinosinusitis (IFRS). The goal of this case report and systematic review is to evaluate the evidence supporting this uncommon disease, with qualitative analysis of the presentation, management and treatment outcomes.
DATA SOURCES: MEDLINE, EMBASE, Google Scholar, Scopus, and Web of Science.
REVIEW METHODS: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were utilized to identify English-language studies reporting intranasal mucosal injury associated with prescription opioid abuse. Primary outcomes included clinical presentation, treatment strategies, and outcomes.
RESULTS: Systematic review identified 61 patients for qualitative analysis. Common clinical features include facial pain without a history of chronic sinusitis or known immunodeficiency. Diagnostic nasal endoscopy revealed superficial debris with underlying tissue necrosis, consistent with a preliminary diagnosis of IFRS. Characteristic pathologic findings include mucosal ulceration with an overlying acellular substrate, often with polarizable material. Fungal colonization is often reported, with several accounts of angiocentric invasion in immunocompetent patients. Complete symptom resolution is expected following surgical debridement with cessation of intranasal opioid inhalation, with 89% of identified patients experiencing a complete resolution of disease.
CONCLUSION: Intranasal opioid abuse is a prevalent condition associated with chronic pain and tissue necrosis that is clinically concerning for invasive fungal disease. Whereas IFRS must be excluded, even in patients without known immunodeficiency, complete resolution of symptoms can be expected following surgical debridement with cessation of opioid abuse. Laryngoscope, 2017.

PMID: 29280484 [PubMed – as supplied by publisher]

Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency.

December 28, 2017 By Manish Butte

Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency.

Blood. 2017 Dec 26;:

Authors: Fox TA, Chakraverty R, Burns S, Carpenter B, Thomson K, Lowe D, Fielding A, Peggs K, Kottaridis P, Uttenthal B, Bigley V, Buckland M, Grandage V, Denovan S, Grace S, Dahlstrom J, Workman S, Symes A, Mackinnon S, Hough R, Morris E

Abstract
INTRODUCTION: The primary immunodeficiencies (PID), rare inherited diseases characterised by severe dysfunction of immunity have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in childhood. Controversy exists regarding optimal timing and use of Allo-HSCT in adults, due to lack of experience and previous poor outcomes.
MATERIALS AND METHODS: 29 consecutive adult patients, with a mean age at transplant of 24 years (range 17-50) underwent Allo-HSCT. Reduced intensity conditioning included Flu/Mel/Alemtuzumab (n=20), Flu/Bu/Alemtuzumab (n=8) and Flu/Bu/ATG (n=1). Stem cell donors were matched or mismatched unrelated (MUD/MMUD) (n=18) and matched related donors (MRD) (n=11). Overall survival, event free survival, transplant related mortality, acute and chronic GVHD incidence and severity, time to engraftment, lineage specific chimerism, immune reconstitution and discontinuation of immunoglobulin replacement therapy were recorded.
RESULTS: Overall survival (OS) at 3 years for the whole cohort was 85.2%. The rarer, non-CGD PID patients achieved an OS at 3 years of 88.9% (n=18), compared to 81.8% for CGD patients (n=11). Transplant related mortality (TRM) was low with only four deaths observed at a median follow-up of 3.5 years. There were no cases of early or late rejection. In all surviving patients either stable mixed chimerism or full donor chimerism were observed. At last follow-up 87% of the surviving patients had no evidence of persistent or recurrent infections.
CONCLUSION: Allo-HSCT is safe and effective in young adult patients with severe PID and should be considered the treatment of choice where an appropriate donor is available.

PMID: 29279357 [PubMed – as supplied by publisher]

Inflammatory Bowel Disease in Primary Immunodeficiencies.

December 27, 2017 By Manish Butte

Inflammatory Bowel Disease in Primary Immunodeficiencies.

Curr Allergy Asthma Rep. 2017 Aug;17(8):57

Authors: Kelsen JR, Sullivan KE

Abstract
PURPOSE OF REVIEW: Inflammatory bowel disease is most often a polygenic disorder with contributions from the intestinal microbiome, defects in barrier function, and dysregulated host responses to microbial stimulation. There is, however, increasing recognition of single gene defects that underlie a subset of patients with inflammatory bowel disease, particularly those with early-onset disease, and this review focuses on the primary immunodeficiencies associated with early-onset inflammatory bowel disease.
RECENT FINDINGS: The advent of next-generation sequencing has led to an improved recognition of single gene defects underlying some cases of inflammatory bowel disease. Among single gene defects, immune response genes are the most frequent category identified. This is also true of common genetic variants associated with inflammatory bowel disease, supporting a pivotal role for host responses in the pathogenesis. This review focuses on practical aspects related to diagnosis and management of children with inflammatory bowel disease who have underlying primary immunodeficiencies.

PMID: 28755025 [PubMed – indexed for MEDLINE]