Research

Bronchiectasis and deteriorating lung function in agammaglobulinaemia despite immunoglobulin replacement therapy.

January 29, 2019 By Manish Butte

Bronchiectasis and deteriorating lung function in agammaglobulinaemia despite immunoglobulin replacement therapy.

Clin Exp Immunol. 2018 02;191(2):212-219

Authors: Stubbs A, Bangs C, Shillitoe B, Edgar JD, Burns SO, Thomas M, Alachkar H, Buckland M, McDermott E, Arumugakani G, Jolles MS, Herriot R, Arkwright PD

Abstract
Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinaemia. We hypothesized that despite regular immunoglobulin therapy, some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. One hundred and thirty-nine (70%) of 199 patients aged 1-80 years from nine cities in the United Kingdom with agammaglobulinaemia currently listed on the UK Primary Immune Deficiency (UKPID) registry were recruited into this retrospective case study and their clinical and laboratory features analysed; 94% were male, 78% of whom had Bruton tyrosine kinase (BTK) gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were 2 years old. Sixty per cent were also taking prophylactic oral antibiotics; 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 and 45 years. Multivariate analysis showed that three factors were associated significantly with bronchiectasis: reaching 18 years old [relative risk (RR) = 14·2, 95% confidence interval (CI) = 2·7-74·6], history of pneumonia (RR = 3·9, 95% CI = 1·1-13·8) and intravenous immunoglobulin (IVIG) rather than subcutaneous immunoglobulin (SCIG) = (RR = 3·5, 95% CI = 1·2-10·1), while starting immunoglobulin replacement after reaching 2 years of age, gender and recent serum IgG concentration were not associated significantly. Independent of age, patients with bronchiectasis had significantly poorer lung function [predicted forced expiratory volume in 1 s 74% (50-91)] than those without this complication [92% (84-101)] (P < 0·001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinaemia can develop chronic lung disease and progressive impairment of lung function.

PMID: 28990652 [PubMed – indexed for MEDLINE]

Gastrointestinal manifestations of primary immune deficiencies in children.

January 29, 2019 By Manish Butte

Gastrointestinal manifestations of primary immune deficiencies in children.

Int Rev Immunol. 2018 03 04;37(2):111-118

Authors: Nazi N, Ladomenou F

Abstract
Primary immune deficiencies (PID) in children are a rare but serious group of genetic disorders of the immune system which apart from the host’s defenses, can also affect every system of the human body, including the gastrointestinal tract. In their severe form they can lead to increased susceptibility to serious infections during infancy and even death. In the less severe form, they can present later in childhood or adolescence with subtle signs and symptoms. As PID can often mimic gastrointestinal diseases, children presenting with atypical gastrointestinal disease and/or failure to respond to conventional therapy should be evaluated for an underlying primary immune disorder and initiated appropriate treatment. The current review of the literature will summarize the gastrointestinal manifestations of primary immune deficiencies in children.

PMID: 28876962 [PubMed – indexed for MEDLINE]

Low IgA and IgM Is Associated with a Higher Prevalence of Bronchiectasis in Primary Antibody Deficiency.

January 29, 2019 By Manish Butte

Low IgA and IgM Is Associated with a Higher Prevalence of Bronchiectasis in Primary Antibody Deficiency.

J Clin Immunol. 2017 05;37(4):329-331

Authors: Hodkinson JP, Bangs C, Wartenberg-Demand A, Bauhofer A, Langohr P, Buckland MS, Guzman D, Yong PFK, Kiani-Alikhan S

PMID: 28293897 [PubMed – indexed for MEDLINE]

Ataxia-telangiectasia: A review of clinical features and molecular pathology.

January 28, 2019 By Manish Butte

Ataxia-telangiectasia: A review of clinical features and molecular pathology.

Pediatr Allergy Immunol. 2019 Jan 27;:

Authors: Amirifar P, Ranjouri MR, Yazdani R, Abolhassani H, Aghamohammadi A

Abstract
Ataxia telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase. A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies and increased metabolic diseases. This congenital disorder has phenotypic heterogeneity, and the severity of symptoms varies in different patients based on severity of mutations and disease progression. The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and cell cycle checkpoint. The pathogenesis of A-T is not limited to the role of ATM in the DNA-damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms. However, ATM has other functions in the cells (especially cell viability) that need further investigations. In this review, we described functions of ATM in the nucleus and cytoplasm, and also its association with some disorder formation such as neurological, immunological, vascular, pulmonary, metabolic and dermatologic complications. This article is protected by copyright. All rights reserved.

PMID: 30685876 [PubMed – as supplied by publisher]

Specific antibody deficiencies in clinical practice.

January 27, 2019 By Manish Butte

Specific antibody deficiencies in clinical practice.

J Allergy Clin Immunol Pract. 2019 Jan 22;:

Authors: Sorensen RU, Edgar D

Abstract
Specific antibody deficiency (SAD) is defined as the inability to mount an antibody response to purified S. pneumoniae capsular polysaccharide antigens in presence of normal immunoglobulin concentrations and normal antibody responses to protein antigens. In this review we discuss the difficulties in using presently available testing methods to adequately define SAD. The fact that there are different forms of specific antibody deficiencies to pneumococcal surface polysaccharides is detailed. The diagnostic and therapeutic implications of recognizing that in addition to SAD, there are other forms of specific antibody deficiency in the response to S. pneumoniae polysaccharides is described in detail. The conclusion of this review is that assessment of immunity and therapeutic actions to deal with specific antibody deficiencies need to be based on clinical evidence rather than solely on arbitrarily defined antibody responses.

PMID: 30682575 [PubMed – as supplied by publisher]

Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency.

January 27, 2019 By Manish Butte

Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency.

Blood Adv. 2019 Feb 12;3(3):237-241

Authors: Magnani A, Jouannic JM, Rosain J, Gabrion A, Touzot F, Roudaut C, Kracker S, Mahlaoui N, Toubert A, Clave E, Macintyre EA, Radford-Weiss I, Alcantara M, Magrin E, Ternaux B, Nisoy J, Caccavelli L, Darras AM, Picard C, Blanche S, Cavazzana M

PMID: 30683657 [PubMed – in process]

Combined liver and hematopoietic stem cell transplantation in X-linked hyper IgM syndrome.

January 27, 2019 By Manish Butte

Combined liver and hematopoietic stem cell transplantation in X-linked hyper IgM syndrome.

J Allergy Clin Immunol. 2019 Jan 22;:

Authors: Bucciol G, Nicholas SK, Calvo PL, Cant A, Edgar JDM, Español T, Ferrua F, Galicchio M, Gennery AR, Hadzic N, Hanson IC, Kusminsky G, Lange A, Lanternier F, Mahlaoui N, Moshous D, Nademi Z, Neven B, Oleastro M, Porta F, Quarello P, Silva M, Slatter MA, Soncini E, Stefanowicz M, Tandoi F, Teisseyre M, Torgerson TR, Veys P, Weinacht KG, Wolska-Kuśnierz B, Pirenne J, de la Morena MT, Meyts I

Abstract
Liver disease in X-linked hyper IgM syndrome (XHIGM) is an important predictor of mortality. In case liver transplantation (LT) is required, a survival benefit is observed when LT is combined with HSCT.

PMID: 30682461 [PubMed – as supplied by publisher]

CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives.

January 27, 2019 By Manish Butte

CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives.

Expert Rev Clin Immunol. 2019 Jan 25;:

Authors: França TT, Barreiros LA, Al-Ramadi BK, Ochs HD, Cabral-Marques O, Condino-Neto A

Abstract
INTRODUCTION: CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite current available treatments, CD40L-deficient patients remain susceptible to life-threatening infections and have poor long term survival. Areas covered: Here, we discuss clinical and immunological characteristics of CD40L deficiency as well as current therapeutic strategies used for patient management. This review highlights that beyond B cell defects, patients’ susceptibility to opportunistic pathogens might be due to impaired T cell and innate immune responses. In this context, we discuss how better knowledge of CD40L function and regulation may result in the development of new treatments. Expert opinion: Despite introduction of hematopoietic stem-cell transplantation, immunoglobulin replacement, granulocyte colony-stimulating factor (G-CSF) administration, and prophylactic antibiotic therapies, life-threatening infections still cause high morbidity and mortality among CD40L-deficient patients. The reasons for this inadequate response to current therapies remains poorly understood, but recent reports suggest the involvement of CD40L-CD40 interaction in early stages of the innate immune system ontogeny. The development of novel gene therapeutic approaches and the use of redirected immunotherapies represent alternative treatment methods that could offer reduced morbidity and mortality rates for patients with CD40L deficiency.

PMID: 30681380 [PubMed – as supplied by publisher]

Outcomes for Nitazoxanide Treatment in a Case Series of Patients with Primary Immunodeficiencies and Rubella Virus-Associated Granuloma.

January 27, 2019 By Manish Butte

Outcomes for Nitazoxanide Treatment in a Case Series of Patients with Primary Immunodeficiencies and Rubella Virus-Associated Granuloma.

J Clin Immunol. 2019 Jan 24;:

Authors: Perelygina L, Buchbinder D, Dorsey MJ, Eloit M, Hauck F, Hautala T, Moshous D, Uriarte I, Deripapa E, Icenogle J, Sullivan KE

Abstract
PURPOSE: Nitazoxanide was recently reported as having in vitro effectiveness against the rubella virus. Immunodeficiency-related vaccine-derived rubella occurs in some patients who have an inherited immunodeficiency and who received the MMR vaccine. This study investigated the in vivo effectiveness of nitazoxanide therapy.
METHODS: This is a retrospective analysis of seven patients treated with nitazoxanide as salvage therapy for immunodeficiency-related vaccine-derived rubella infection. The patients were recruited from an ongoing rubella detection surveillance project.
RESULTS: Seven patients with persistent rubella were treated with nitazoxanide and one demonstrated significant clinical improvement. Two additional patients exhibited diminished viral capsid production with one patient having transient slowing of progression. The cohort overall generally had low T cell counts and had a high burden of comorbidities. There were three deaths. Two deaths were from PML and one was related to hematopoietic stem cell transplantation.
CONCLUSIONS: Nitazoxanide has limited in vivo anti-viral effects for immunodeficiency-related vaccine-derived rubella. Most patients did not exhibit clinical improvement.

PMID: 30680653 [PubMed – as supplied by publisher]

Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study.

January 27, 2019 By Manish Butte

Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study.

BMJ. 2019 Jan 24;364:l67

Authors: Gottenberg JE, Morel J, Perrodeau E, Bardin T, Combe B, Dougados M, Flipo RM, Saraux A, Schaeverbeke T, Sibilia J, Soubrier M, Vittecoq O, Baron G, Constantin A, Ravaud P, Mariette X, French Society of Rheumatology and the investigators participating in AIR, ORA, and REGATE registries

Abstract
OBJECTIVE: To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis.
DESIGN: Population based prospective study.
SETTING: 53 university and 54 non-university clinical centres in France.
PARTICIPANTS: 3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months.
INTERVENTION: Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis.
MAIN OUTCOME MEASURE: The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LEDwf), which measures the difference between average duration of survival without failure.
RESULTS: Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LEDwf 4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (-0.7, -1.9 to 0.5). No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events.
CONCLUSION: Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.

PMID: 30679233 [PubMed – in process]