Manish Butte

New onset colitis in an adult patient with chronic granulomatous disease treated with hematopoietic stem cell transplantation: a diagnostic dilemma.

Allergy Asthma Clin Immunol. 2018;14:17

Authors: Robertson K, Couban S, Leddin D, Ahmad I, Connors L

Abstract
Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency characterized by recurrent life-threatening bacterial and fungal infections, granuloma formation and intestinal disease. This disease is caused by defects in NADPH oxidase, which result in the inability of phagocytes (neutrophils, monocytes and macrophages) to destroy certain microbes. The only established curative therapy for CGD is hematopoietic stem cell transplantation.
Case presentation: A 23-year-old Caucasian male with X-linked chronic granulomatous disease underwent a reduced-intensity conditioning, matched unrelated donor peripheral blood stem cell transplant, after which he was started on tacrolimus and mycophenolate for graft-versus-host disease prophylaxis. Seven months later, he was admitted to hospital for nutritional support secondary to odynophagia and anorexia. Upper endoscopy revealed ulcers in his esophagus, and he was initially treated with acyclovir due to the risk of CMV infection until biopsies came back negative for viral colitis. Following a sigmoidoscopy that showed nonspecific colitis, he was started on mesalamine. Although pathology showed a pattern of widespread inflammatory changes initially suggestive of CGD colitis, a peripheral blood chimerism study showed 100% donor alleles suggesting CGD remission. Since this patient’s colitis was refractory to other immunomodulators, and due to its severity, the patient underwent a partial colectomy 1 year after his HSCT and will likely require the removal of the remaining large bowel.
Conclusions: This case demonstrates a unique presentation of colitis in a post-transplant CGD patient. Since CGD colitis could be excluded due to the patient’s recent successful hematopoietic stem cell transplantation, a broad differential diagnosis is required for determining the etiology of this new-onset colitis in this patient with pre-existing chronic granulomatous disease. This case delineates the need for interdisciplinary care and describes a severe case of colitis after hematopoietic stem cell transplantation.

PMID: 29755533 [PubMed]

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Gastrointestinal Disorders Associated with Primary Immunodeficiency Diseases.

Clin Rev Allergy Immunol. 2018 May 13;:

Authors: Hartono S, Ippoliti MR, Mastroianni M, Torres R, Rider NL

Abstract
There are now 354 inborn errors of immunity (primary immunodeficiency diseases (PIDDs)) with 344 distinct molecular etiologies reported according to the International Union of Immunological Sciences (IUIS) (Clin Gastroenterol Hepatol 11: p. 1050-63, 2013, Semin Gastrointest Dis 8: p. 22-32, 1997, J Clin Immunol 38: p. 96-128, 2018). Using the IUIS document as a reference and cross-checking PubMed ( www.ncbi.nlm.nih.pubmed.gov ), we found that approximately one third of the 354 diseases of impaired immunity have a gastrointestinal component [J Clin Immunol 38: p. 96-128, 2018]. Often, the gastrointestinal symptomatology and pathology is the heralding sign of a PIDD; therefore, it is important to recognize patterns of disease which may manifest along the gastrointestinal tract as a more global derangement of immune function. As such, holistic consideration of immunity is warranted in patients with clinically significant gastrointestinal disease. Here, we discuss the manifold presentations and GI-specific complications of PIDDs which could lead patients to seek advice from a variety of clinician specialists. Often, patients with these medical problems will engage general pediatricians, surgeons, gastroenterologists, rheumatologists, and clinical immunologists among others. Following delineation of the presenting concern, accurate and often molecular diagnosis is imperative and a multi-disciplinary approach warranted for optimal management. In this review, we will summarize the current state of understanding of PIDD gastrointestinal disease involvement. We will do so by focusing upon gastrointestinal disease categories (i.e., inflammatory, diarrhea, nodular lymphoid hyperplasia, liver/biliary tract, structural disease, and oncologic disease) with an intent to aid the healthcare provider who may encounter a patient with an as-yet undiagnosed PIDD who presents initially with a gastrointestinal symptom, sign, or problem.

PMID: 29754192 [PubMed – as supplied by publisher]

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Antiviral T-Cells for Adenovirus in the Pre-Transplant Period: a Bridge Therapy for Severe Combined Immunodeficiency.

Biol Blood Marrow Transplant. 2018 May 09;:

Authors: Miller HK, Hanley PJ, Lang H, Lazarski CA, Chorvinsky EA, McCormack S, Roesch L, Albihani S, Dean M, Hoq F, Adams RH, Bollard C, Keller MD

Abstract
Viral infections can be life-threatening in patients with severe combined immunodeficiency (SCID) and other forms of profound primary immunodeficiency disorders both before and after hematopoietic stem cell transplant (HSCT). Adoptive immunotherapy with virus-specific T-cells (VST) has been utilized in many patients in the setting of HSCT, but has very rarely been attempted for treatment of viral infections before HSCT. Here we describe the use of VSTs in an infant with RAG1 SCID who had developed disseminated adenovirus which failed to improve on cidofovir. Adenovirus cleared following two doses of VSTs and marrow infusion from a matched unrelated donor, without incidence of graft versus host disease. T cell receptor-b sequencing demonstrated expansion of adenovirus-specific T-cell fraction of the VSTs, suggesting that infusion facilitated viral clearance. This report suggests that VSTs are likely safe in the pre-HSCT period, and may be a useful bridge therapy for infants with SCID and persistent viral infections.

PMID: 29753156 [PubMed – as supplied by publisher]

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Erratum to: Delivery of Designer Epigenome Modifiers into Primary Human T Cells.

Methods Mol Biol. 2018;1767:E1

Authors: Mlambo T, Romito M, Cornu TI, Mussolino C

PMID: 29748848 [PubMed – in process]

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Prevention of Infectious Complications in Patients With Chronic Granulomatous Disease.

J Pediatric Infect Dis Soc. 2018 May 09;7(suppl_1):S25-S30

Authors: Slack MA, Thomsen IP

Abstract
Chronic granulomatous disease (CGD) is a primary immunodeficiency that confers a markedly increased risk of bacterial and fungal infections caused by certain opportunistic pathogens. Current evidence supports the use of prophylactic antibacterial, antifungal, and immunomodulatory therapies designed to prevent serious or life-threatening infections in patients with CGD. In this review, we discuss current strategies for the prevention of infections in children and adults with CGD and the evidence that supports those strategies. In addition, we address current challenges and opportunities for future research in this important area.

PMID: 29746681 [PubMed – in process]

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Noninfectious Manifestations and Complications of Chronic Granulomatous Disease.

J Pediatric Infect Dis Soc. 2018 May 09;7(suppl_1):S18-S24

Authors: Henrickson SE, Jongco AM, Thomsen KF, Garabedian EK, Thomsen IP

Abstract
Chronic granulomatous disease (CGD), a primary immunodeficiency characterized by a deficient neutrophil oxidative burst and the inadequate killing of microbes, is well known to cause a significantly increased risk of invasive infection. However, infectious complications are not the sole manifestations of CGD; substantial additional morbidity is driven by noninfectious complications also. These complications can include, for example, a wide range of inflammatory diseases that affect the gastrointestinal tract, lung, skin, and genitourinary tract and overt autoimmune disease. These diseases can occur at any age and are especially problematic in adolescents and adults with CGD. Many of these noninfectious complications present a highly challenging therapeutic conundrum, wherein immunosuppression must be balanced against an already markedly increased risk of invasive fungal and bacterial infections. In this review, the myriad noninfectious complications of CGD are discussed, as are important gaps in our understanding of these processes, which warrant further investigation.

PMID: 29746679 [PubMed – in process]

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Considerations in the Diagnosis of Chronic Granulomatous Disease.

J Pediatric Infect Dis Soc. 2018 May 09;7(suppl_1):S6-S11

Authors: Yu JE, Azar AE, Chong HJ, Jongco AM, Prince BT

Abstract
Chronic granulomatous disease (CGD) is a rare primary immunodeficiency that is caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease presents in most patients initially with infection, especially of the lymph nodes, lung, liver, bone, and skin. Patients with CGD are susceptible to a narrow spectrum of pathogens, and Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, and Aspergillus species are the most common organisms implicated in North America. Granuloma formation, most frequently in the gastrointestinal and genitourinary systems, is a common complication of CGD and can be seen even before diagnosis. An increased incidence of autoimmune disease has also been described in patients with CGD and X-linked female carriers. In patients who present with signs and symptoms consistent with CGD, a flow cytometric dihydrorhodamine neutrophil respiratory burst assay is a quick and cost-effective way to evaluate NADPH oxidase function. The purpose of this review is to highlight considerations for and challenges in the diagnosis of CGD.

PMID: 29746674 [PubMed – in process]

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Individualized Immunoglobulin Treatment in Pediatric Patients with Primary Humoral Immunodeficiency Disease.

Pediatr Allergy Immunol. 2018 May 09;:

Authors: Patel NC

Abstract
Primary immunodeficiency diseases (PIDD) are a group of genetic conditions that are generally considered to be underdiagnosed, and gaps may exist in the knowledge of treatment options. This review focuses on the diagnosis of pediatric patients with primary antibody deficiency and considerations for treatment with immunoglobulin (IgG) to optimize multiple dosing variables and minimize adverse events. The possibility of individualizing IgG therapy in clinical practice represents, in this field, the next pivotal step with the goal of improving the quality of life of pediatric patients with PIDD. This article is protected by copyright. All rights reserved.

PMID: 29744952 [PubMed – as supplied by publisher]

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ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome.

J Clin Immunol. 2018 May 09;:

Authors: Cagdas D, Gur Cetinkaya P, Karaatmaca B, Esenboga S, Tan C, Yılmaz T, Gümüş E, Barış S, Kuşkonmaz B, Ozgur TT, Bali P, Santisteban I, Orhan D, Yüce A, Cetinkaya D, Boztug K, Hershfield M, Sanal O, Tezcan İ

Abstract
INTRODUCTION: Adenosine deaminase (ADA) deficiency is an autosomal recessive primary immunodeficiency. It results in the intracellular accumulation of toxic metabolites which have effects particularly on lymphocytes and the brain. The aim of this study was to evaluate the outcome of 13 ADA-deficient patients. We planned to evaluate their clinical and laboratory findings before and after enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (aHSCT), and hematopoietic stem cell gene therapy (HSCGT).
METHODS: Measurement of ADA enzyme activity and metabolites and sequencing of the ADA gene were performed in most of the patients with ADA deficiency. One of the patients with late-onset ADA deficiency was diagnosed by the help of primary immunodeficiency panel screening.
RESULTS: Ten out of 13 patients were diagnosed as SCID, while 3 out of 13 were diagnosed as delayed-/late-onset ADA deficiency. Late-onset ADA deficiency patients had clinical and laboratory findings of combined immunodeficiency (CID). Eight patients with ADA-SCID were found to have higher levels of ADA metabolite (dAXP%) (62.1% (34.6-71.9)) than 3 patients with delayed-/late-onset ADA deficiency (6.9% (2.1-8.9). All but one patient with SCID had T-B-NK- phenotype, one had T-B-NK+ phenotype. Genetic defect was documented in 11 patients. Four out of 11 patients had compound heterozygous defects. Three out of 4 patients with compound heterozygous defects had delayed-onset/late-onset ADA deficiency. Seven out of 11 patients with SCID had homozygous defects. Five out of 7 had the same homozygous indel frameshift mutation (c.955-959delGAAGA) showing a founder effect. There were two novel splice site defects: one (IVS10+2T>C) was heterozygous in a patient with late-onset ADA deficiency, and the other was homozygous (IVS2delT+2) in a SCID patient. Other defects were missense defects. Nine out of 13 patients were put on pegylated ADA ERT. Four out of six patients were transplanted without using a conditioning regimen. HSCGT was performed to one of the patients.
CONCLUSION: The genetic diagnosis of SCID is utmost important. There is a chance to give ERT before the definitive therapy if the patient with SCID/CID has ADA deficiency. Although ERT was insufficient to restore a normal immune function in ADA-SCID patients, it was useful to improve and stabilize the clinical status before curative therapy (aHSCT/HSCGT). Enzyme replacement therapy was successful in patients with late-/delayed-onset ADA deficiency who presented with the features of combined immunodeficiency. Gastrointestinal polyposis in a patient with late-onset ADA deficiency may be an association or a coincidental finding. Intermittent neurodevelopmental evaluation especially for hearing impairment should be performed in most of the ADA-deficient patients. This may alleviate the speech delay and cognitive abnormalities which may be observed in the follow-up.

PMID: 29744787 [PubMed – as supplied by publisher]

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