Blog

Neuropsychiatric Manifestation of Addison’s Disease: A Rare Case Report.

June 14, 2019 By Manish Butte

Neuropsychiatric Manifestation of Addison’s Disease: A Rare Case Report.

Cureus. 2019 Apr 01;11(4):e4356

Authors: Munawar M, Iftikhar PM, Hasan CA, Sohail CS, Rizvi SW

Abstract
Addison’s disease (AD), also known as primary adrenal insufficiency, is a rare autoimmune disorder affecting males and females equally. The most common cause of AD is autoimmune adrenalitis and other causes include metastatic cancers, tuberculosis and acquired immunodeficiency syndrome. AD presents with a wide variety of signs and symptoms and thus, making a diagnosis challenging. The common symptoms of this disease include weakness and fatigability, orthostatic hypotension, nausea, vomiting, diarrhea, anorexia and weight loss. Addison’s disease often presented with other autoimmune disorders, such as autoimmune polyglandular syndrome. We herein report a case of a patient who presented in a hospital emergency department, with Addisonian crisis and predominant neuropsychiatric manifestation. On review of the patient’s history, combined with biochemical testing, a diagnosis of Addison’s disease was established. This type of presentation is relatively uncommon.

PMID: 31192061 [PubMed]

IRIS as a post-transplantation complication in primary immunodeficiency with disseminated M. avium.

June 14, 2019 By Manish Butte

IRIS as a post-transplantation complication in primary immunodeficiency with disseminated M. avium.

Clin Infect Dis. 2019 Jun 12;:

Authors: Manion M, Dimitrova D, Pei L, Gea-Banacloche J, Zelazny A, Lisco A, Zerbe C, Freeman AF, Holland SM, Kanakry CG, Kanakry JA, Sereti I

Abstract
Patients with primary immunodeficiencies undergoing allogeneic hematopoietic cell transplantation (HCT) for difficult-to-control infections can experience immune reconstitution inflammatory syndrome (IRIS) following engraftment. We describe three patients with post-HCT IRIS related to mycobacterial infection, with in vitro data demonstrating emergence of pathogen-specific immune responses and concomitant rise in plasma inflammatory markers.

PMID: 31190050 [PubMed – as supplied by publisher]

Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response.

June 14, 2019 By Manish Butte

Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response.

Nat Commun. 2019 05 07;10(1):2087

Authors: Baeuerle PA, Ding J, Patel E, Thorausch N, Horton H, Gierut J, Scarfo I, Choudhary R, Kiner O, Krishnamurthy J, Le B, Morath A, Baldeviano GC, Quinn J, Tavares P, Wei Q, Weiler S, Maus MV, Getts D, Schamel WW, Hofmeister R

Abstract
T cells expressing CD19-targeting chimeric antigen receptors (CARs) reveal high efficacy in the treatment of B cell malignancies. Here, we report that T cell receptor fusion constructs (TRuCs) comprising an antibody-based binding domain fused to T cell receptor (TCR) subunits can effectively reprogram an intact TCR complex to recognize tumor surface antigens. Unlike CARs, TRuCs become a functional component of the TCR complex. TRuC-T cells kill tumor cells as potently as second-generation CAR-T cells, but at significant lower cytokine release and despite the absence of an extra co-stimulatory domain. TRuC-T cells demonstrate potent anti-tumor activity in both liquid and solid tumor xenograft models. In several models, TRuC-T cells are more efficacious than respective CAR-T cells. TRuC-T cells are shown to engage the signaling capacity of the entire TCR complex in an HLA-independent manner.

PMID: 31064990 [PubMed – indexed for MEDLINE]

Concomitant leukocytosis and lymphopenia predict significant pathology at CT of acute abdomen: a case-control study.

June 14, 2019 By Manish Butte

Concomitant leukocytosis and lymphopenia predict significant pathology at CT of acute abdomen: a case-control study.

BMC Emerg Med. 2019 01 18;19(1):10

Authors: Platon A, Frund C, Meijers L, Perneger T, Andereggen E, Becker M, Halfon Poletti A, Rutschmann OT, Poletti PA

Abstract
BACKGROUND: Acute abdominal pain accounts for about 10% of emergency department visits and has progressively become the primary indication for CT scanning in most centers. The goal of our study is to identify biological or clinical variables able to predict or rule out significant pathology (conditions requiring urgent medical or surgical treatment) on abdominal CT in patients presenting to an emergency department with acute abdominal pain.
METHODS: This was a retrospective cohort study performed in the emergency department of an academic center with an annual census of 60’000 patients. One hundred and-nine consecutive patients presenting with an acute non-traumatic abdominal pain, not suspected of appendicitis or renal colic, during the first semester of 2013, who underwent an abdominal CT were included. Two medical students, completing their last year of medical school, extracted the data from patients’ electronic health record. Ambiguities in the formulations of clinical symptoms and signs in the patients’ records were solved by consulting a board certified emergency physician. Nine clinical and biological variables were extracted: shock index, peritonism, abnormal bowel sounds, fever (> 38 °C), intensity and duration of the pain, leukocytosis (white blood cell count >11G/L), relative lymphopenia (< 15% of total leukocytes), and C-reactive Protein (CRP). These variables were compared to the CT results (reference standard) to determine their ability to predict a significant pathology.
RESULTS: Significant pathology was detected on CT in 71 (65%) patients. Only leukocytosis (odds ratio 3.3, p = 0.008) and relative lymphopenia (odds ratio 3.8, p = 0.002) were associated with significant pathology on CT. The joint presence of these two anomalies was strongly associated with significant pathology on CT (odds ratio 8.2, p = 0.033). Leukocytosis with relative lymphopenia had a specificity of 89% (33/37) and sensitivity of 48% (33/69) for the detection of significant pathology on CT.
CONCLUSION: The high specificity of the association between leukocytosis and relative lymphopenia amongst the study population suggests that these parameters would be sufficient to justify an emergency CT. However, none of the parameters could be used to rule out a significant pathology.

PMID: 30658580 [PubMed – indexed for MEDLINE]

Post-Transplant CD34+ Selected Stem Cell “Boost” for Mixed Chimerism after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation in Children and Young Adults with Primary Immune Deficiencies.

June 14, 2019 By Manish Butte

Post-Transplant CD34+ Selected Stem Cell “Boost” for Mixed Chimerism after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation in Children and Young Adults with Primary Immune Deficiencies.

Biol Blood Marrow Transplant. 2018 07;24(7):1527-1529

Authors: Chandra S, Bleesing JJ, Jordan MB, Grimley MS, Khandelwal P, Davies SM, Edwards S, Leemhuis T, Marsh RA

Abstract
Mixed chimerism and eventual graft loss occurs in a proportion of children with primary immune deficiencies receiving alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimens before allogeneic hematopoietic stem cell transplantation (HSCT). We investigated the usefulness of a CD34+ selected stem cell “boost” without conditioning to treat mixed chimerism in children and young adults who received predominantly an alemtuzumab, fludarabine, and melphalan RIC regimen for primary immune deficiencies and reported the outcomes. Patients with a primary immune deficiency disorder who were either enrolled on a prospective CD34+ boost study for treatment of mixed chimerism from 2011 to 2014 (n = 9) or treated with a CD34+ boost on a clinical basis from 2014 to 2016 (n = 3) were included in this analysis. Response to a CD34+ boost was defined as a rise in donor chimerism by ≥15% with donor chimerism of at least 20%, stabilization was defined as a rise in chimerism by <15% with donor chimerism ≥ 20%, and no response was defined as any decline in donor chimerism or need for a second HSCT after a CD34+ boost. Twelve patients received alemtuzumab, fludarabine, and melphalan. Median age was 4.5 years (range, .9 to 20.6), and median whole blood donor chimerism before the boost was 25% (range, 3% to 61%). Three patients (25%) met criteria for response, 1 patient (8%) was considered to have stabilization, and 8 patients (67%) had no response 12 months after the boost. None of the patients developed any complications from a CD34+ boost, including no acute graft-versus-host disease (GVHD). All patients are alive with a median follow-up of 32 months (range, 8 to 79). We conclude that a CD34+ selected stem cell boost can be considered for treatment of mixed chimerism after alemtuzumab, fludarabine, and melphalan RIC HSCT in children and young adults with primary immune deficiencies. Approximately one-third of patients can be expected to benefit from a CD34+ selected stem cell boost and may avoid the need for a second HSCT. Lack of any GVHD or toxicity makes a stem cell boost an attractive option compared with donor lymphocyte infusions for treatment of mixed chimerism.

PMID: 29555312 [PubMed – indexed for MEDLINE]

Disturbed Transcription of TLRs’ Negative Regulators and Cytokines Secretion among TLR4- and 9-Activated PBMCs of Agammaglobulinemic Patients.

June 13, 2019 By Manish Butte

Disturbed Transcription of TLRs’ Negative Regulators and Cytokines Secretion among TLR4- and 9-Activated PBMCs of Agammaglobulinemic Patients.

Immunol Invest. 2019 Jun 11;:1-15

Authors: Sanaei R, Rezaei N, Aghamohammadi A, Delbandi AA, Tavasolian P, Tajik N

Abstract
Toll-like receptors (TLRs) are inevitable elements for immunity development and antibody production. TLRs are in close interaction with Bruton’s tyrosine kinase which has been found mutated and malfunctioned in the prototype antibody deficiency disease named X-linked agammaglobulinemia (XLA). TLRs’ ability was evaluated to induce transcription of TLR-negative regulators, including suppressor of cytokine signaling 1 (SOCS1), interleukin-1 receptor-associated kinase 3 (IRAK-M), tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20), and Ring finger protein 216 (RNF216), and Tumor necrosis factor-α (TNF-α) and Interferon-α (IFN-α) production via Lipopolysaccharides (LPS) and CpG-A oligodeoxynucleotides (CpG-A ODN). Measured by TaqMan real-time polymerase chain reaction (PCR), meaningfully increased transcripts of SOCS1 and RNF216 were found in XLA peripheral blood mononuclear cells (PBMCs). Also, TLR inductions of XLA have led to similar downregulations in the regulator’s transcription which was different from that in healthy donors. Cytokine measurement by enzyme-linked immunosorbent assay (ELISA) revealed a significant lower TNF-α production both before and after LPS. By selected molecules in this study, TLRs’ potential defectiveness range expands TLRs expression, downstream signaling, and cytokine production. The results show new potential elements that could play a part in TLRs defect and pathogenesis of agammaglobulinemia as well.

PMID: 31185757 [PubMed – as supplied by publisher]

Association between primary immunodeficiency and asthma exacerbation in adult asthmatics.

June 13, 2019 By Manish Butte

Association between primary immunodeficiency and asthma exacerbation in adult asthmatics.

Korean J Intern Med. 2019 Jun 14;:

Authors: Lee SH, Ban GY, Kim SC, Chung CG, Lee HY, Lee JH, Park HS

Abstract
Background/Aims: Primary immunodef iciency (PID) is a serious comorbid condition in adult asthmatics that have frequent exacerbations, which requires monthly replacement of intravenous immunoglobulin (IVIG). However, the prevalence and clinical significance of PID in adult asthmatics in Korea have not yet been reported. The aim of this study is to assess the prevalence of PID and its association with asthma exacerbation in Korean adult asthmatics.
Methods: A total of 2,866 adult asthmatics were enrolled in this study. The PID group was defined as subjects who had lower levels of immunoglobulin G (IgG)/ A/M and/or IgG subclass presenting with recurrent respiratory infections. Serum samples were assayed for total IgG/A/M by immunoturbidimetry, and IgG subclasses by nephelometry.
Results: Of the 2,866 asthmatic patients enrolled, 157 (5.49%) had PID (classified as the PID group), while those without PID was classified as the non-PID group. IgG subclass deficiency (58%) is most prevalent, among which IgG3 subclass deficiency was most common (58%). The relative risk of asthma exacerbation was 1.70 times higher in the PID group compared to the non-PID group (1.696; 95% confidence interval, 1.284 to 2.239; p < 0.001); the prevalence of severe asthma was significantly higher in the PID group than in the non-PID group (32.48% vs. 13.00%, p < 0.001). Thirty-five among 157 patients in the PID group d maintained IVIG to prevent asthma exacerbation.
Conclusions: It is suggested that PID, especially IgG3 subclass deficiency, is a significant risk factor for asthma exacerbation. Screening of IgG subclass levels and IVIG replacement should be considered in the management in adult asthmatics.

PMID: 31185709 [PubMed – as supplied by publisher]

Respiratory Complications in Patients with Hyper IgM Syndrome.

June 12, 2019 By Manish Butte

Respiratory Complications in Patients with Hyper IgM Syndrome.

J Clin Immunol. 2019 Jun 11;:

Authors: Moazzami B, Yazdani R, Azizi G, Kiaei F, Tafakori M, Modaresi M, Shirzadi R, Mahdaviani SA, Sohani M, Abolhassani H, Aghamohammadi A

Abstract
PURPOSE: Hyper Immunoglobulin M (HIgM) syndrome is a heterogeneous group of primary immunodeficiency disorders, characterized by recurrent infections and associated with decreased serum IgG and IgA, but normal or increased IgM. The aim of the present study was to evaluate respiratory manifestations in patients with HIgM syndrome.
METHODS: A total number of 62 patients, including 46 males and 16 females were included in the present study. To investigate the respiratory complications among HIgM patients, we evaluated the clinical hospital records, immunologic and molecular diagnostic assays, pulmonary function tests (PFT), and high-resolution computed tomography (HRCT) scans.
RESULTS: Pneumonia was the most common respiratory manifestation (n = 35, 56.4%), followed by otitis media (45.1%), sinusitis (33.8%), and bronchiectasis (14.5%). 52.1% of the patients had abnormal PFT results, with a predominant restrictive pattern of changes. HRCT scans demonstrated abnormal findings in 85.7% of patients with found mutations. Ten cases had hilar lymphadenopathy and para-hilar infiltrates in their HRCT findings. Genetic diagnosis was confirmed in 29 HIgM patients (72.4% CD40 ligand (CD40L) and 24.1% activation-induced cytidine deaminase (AICDA/AID) deficiencies). Majority of patients with CD40L (71.4%) and AID (57.1%) deficiencies had missense mutations. Pneumonia and abnormal high-resolution computed tomography (HRCT) findings were more frequent among patients with CD40L mutation. Respiratory failure constituted the major cause of mortality (37.5%) with majority of cases occurring in CD40L-deficient patients (50%).
CONCLUSIONS: Respiratory complications are common in patients with HIgM syndrome. A proper awareness of respiratory manifestations in patients with HIgM may result in improved management, reduced morbidity and mortality, and an improvement in the quality of life of the patients.

PMID: 31183658 [PubMed – as supplied by publisher]

Clinical, genetic, and immunological characteristics of 40 Chinese patients with CD40 ligand deficiency.

June 11, 2019 By Manish Butte

Clinical, genetic, and immunological characteristics of 40 Chinese patients with CD40 ligand deficiency.

Scand J Immunol. 2019 Jun 10;:e12798

Authors: Du X, Tang W, Chen X, Zeng T, Wang Y, Chen Z, Xu T, Zhou L, Tang X, An Y, Zhao X

Abstract
CD40 ligand (CD40L) deficiency is a rare but life-threatening primary immunodeficiency caused by mutations in the CD40L gene. Here, we investigated a cohort of 40 genetically-diagnosed CD40L-deficient patients from the Chinese mainland, analyzed their clinical and genetic data, and examined CD40L expression, the proportion of T cell subsets, B cell subsets, and T follicular helper (Tfh) cells. The aim was to provide a complete picture of CD40L deficiency. Initial presentations of the patient cohort mainly involved recurrent fever (47.5%) and sinopulmonary infection (42.5%). Life-threatening infections (42.5%), caused by various pathogens, were the most serious threats faced by CD40L-deficient patients, while neutropenia (57.5%) remained the most common complication. Opportunistic infections, including Pneumocystis carinii pneumonia and invasive fungal disease associated with Talaromyces marneffei were also common in the cohort. In addition, seven patients (17.5%) suffered BCGitis /BCGosis, which is a major problem facing a planned immunization program in China. It was intriguing that reduced IgM levels were observed in 12.5% of patients, while normal or elevated IgA levels were shown in 47.5% of patients. Thirty-seven unique mutations were identified in 40 patients; of these, 10 were novel. Furthermore, we observed a lower percentage of NK cells, Tfh cells, and central memory CD4+ T cells, and an extremely small class-switched memory B cell population, in CD40L-deficient patients. Patients that underwent hematopoietic stem cell transplantation experienced better disease remission. Taken together, our data establish the largest database about CD40L deficiency in China and provide genetic, immunologic, and clinical information about Chinese CD40L-deficient patients. This article is protected by copyright. All rights reserved.

PMID: 31179555 [PubMed – as supplied by publisher]

Supporting caregivers during hematopoietic cell transplantation for children with primary immunodeficiency disorders.

June 11, 2019 By Manish Butte

Supporting caregivers during hematopoietic cell transplantation for children with primary immunodeficiency disorders.

J Allergy Clin Immunol. 2019 Jun;143(6):2271-2278

Authors: Yoo J, Halley MC, Lown EA, Yank V, Ort K, Cowan MJ, Dorsey MJ, Smith H, Iyengar S, Scalchunes C, Mangurian C

Abstract
BACKGROUND: Caregivers of children with primary immunodeficiency disorders (PIDs) experience significant psychological distress during their child’s hematopoietic cell transplantation (HCT) process.
OBJECTIVES: This study aims to understand caregiver challenges and identify areas for health care system-level improvements to enhance caregiver well-being.
METHODS: In this mixed-methods study caregivers of children with PIDs were contacted in August to November 2017 through online and electronic mailing lists of rare disease consortiums and foundations. Caregivers were invited to participate in an online survey assessing sociodemographic variables, the child’s medical characteristics, psychosocial support use, and the World Health Organization-5 Well-Being Index. Open-ended questions about health care system improvements were included. Descriptive statistics and linear multivariate regression analyses were conducted. A modified content analysis method was used to code responses and identify emergent themes.
RESULTS: Among the 80 caregiver respondents, caregivers had a median age of 34 years (range, 23-62 years) and were predominantly female, white, and married with male children given a diagnosis of severe combined immune deficiency. In the adjusted regression model lower caregiver well-being was significantly associated with lower household income and medical complications. Challenges during HCT include maintaining relationships with partners and the child’s healthy sibling or siblings, managing self-care, and coping with feelings of uncertainty. Caregivers suggested several organizational-level solutions to enhance psychosocial support, including respite services, online connections to other PID caregivers, and bedside mental health services.
CONCLUSIONS: Certain high-risk subpopulations of caregivers might need more targeted psychosocial support to reduce the long-term effect of the HCT experience on their well-being. Caregivers suggested several organizational-level solutions for provision of this support.

PMID: 31178019 [PubMed – in process]