Research

Long-term Clinical Outcome of Antibody Replacement Therapy in Humoral Immunodeficient Adults With Respiratory Tract Infections.

EBioMedicine. 2017 Mar 21;:

Authors: van Kessel DA, Hoffman TW, van Velzen-Blad H, Zanen P, Grutters JC, Rijkers GT

Abstract
In severe humoral immunodeficiency the indication for antibody replacement therapy (ART) is clear, and supported by several large studies. However, for milder forms of humoral immunodeficiency, the indication for ART is less clear. This is a retrospective cohort study of 87 adults with recurrent respiratory tract infections who received ART. The patients had severe or mild humoral immunodeficiency, and were followed up for a median of 62months. Infection frequency, pharmacy-registered antibiotics use and hospital admissions significantly decreased under ART compared to the year prior to starting ART (median 5.50 (anamnestically)-0.82 (physician-confirmed) infections/year, p<0.001; median 4.00-2.05antibioticscourses/year, p<0.001; mean 0.75-0.44hospitaladmissions/year, p=0.009). These beneficial effects of ART were seen in both severe and mild immunodeficiency. Bronchiectasis was present in 27 patients when ART was started, but was not associated with clinical outcomes. An increase in hospital admissions under ART, observed in some patients, was significantly associated with pulmonary emphysema and current smoking. In conclusion, this study shows that ART is a long-term effective therapy in adults with recurrent respiratory tract infections with severe as well as with milder forms of humoral immunodeficiency.

PMID: 28347655 [PubMed – as supplied by publisher]

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Clinical Profile, Dosing, and Quality-of-Life Outcomes in Primary Immune Deficiency Patients Treated at Home with Immunoglobulin G: Data from the IDEaL Patient Registry.

J Manag Care Spec Pharm. 2017 Apr;23(4):400-406

Authors: Kearns S, Kristofek L, Bolgar W, Seidu L, Kile S

Abstract
BACKGROUND: Patients with primary immune deficiency (PID) often require immunoglobulin G (IgG, commonly referred to as Ig) replacement therapy to prevent infections and associated comorbidities. Ig therapy can be given either through intravenous or subcutaneous routes, and both can be done in the home setting. There is limited information available on the real-world diagnosis, management, and outcomes of this patient population, given the variable disease presentation and treatment options. The Immunoglobulin Diagnosis, Evaluation, and key Learnings (IDEaL) Patient Registry is designed to capture nursing, pharmacy, and patient-reported data for patients receiving Ig at home.
OBJECTIVES: To (a) present a real-world population of patients with PID who have received Ig at home and (b) examine how differences in administration, dosing, and insurance affect health and quality-of-life outcomes in these patients.
METHODS: As of July 2015, 383 patients receiving Ig therapy from Coram/CVS specialty infusion services, across multiple disease states, signed consent forms and enrolled in the IDEaL Patient Registry. Patients’ referral paperwork, including lab values, and standard of care nursing and pharmacy follow-up forms were collected. Patients were mailed quality-of-life surveys at the time of enrollment and every 6 months after their enrollment.
RESULTS: The most common diagnosis (78%) in these PID patients was common variable immunodeficiency (CVID). For Ig-naive adult patients, the average age at the start of treatment was 59 years. For pediatric patients, average age at start of treatment was 9 years. A majority of these PID patients (80%) received subcutaneous Ig (SCIg) at home, and 20% received intravenous Ig (IVIg). The average SCIg dose was 10 grams per week, or 130 mg per kg, and the average IVIg dose was 36 grams every 4 weeks, or 472 mg per kg. In the IVIg patient population, 34% had a dose or frequency change while on treatment, while 30% of the SCIg patients had a dose or frequency change. Patient-reported health and quality-of-life scores were generally positive. Route of administration did not affect patient perception of cost (P = 0.171), but whether the patient had private or government-backed health care did affect perception of cost (P = 0.036).
CONCLUSIONS: For a disease state with an extremely variable presentation, data from the IDEaL Patient Registry provides further insights into the real-world clinical and diagnostic characteristics of this population, as well as dosing and treatment outcomes of home administration of Ig therapy. The majority of patients received SCIg infusions. SCIg dosing was on the lower end of the recommended mg per kg dose range, while IVIg patients were more in the middle of the recommended dose range. Patient outcomes on treatment were correlated with baseline status, suggesting that earlier detection and treatment of primary immune deficiencies may be critical in achieving beneficial outcomes on Ig therapy.
DISCLOSURES: No outside funding supported this study. Seidu was compensated by Coram Clinical Trials for acting as primary investigator and reviewing data. Study concept and design were contributed by all the authors. Kearns, Kristofek, and Kiles collected the data, and data interpretation was performed by Kearns, Seidu, and Kristofek, along with Bolgar. The manuscript was written and revised primarily by Kearns, along with Kristofek, Bolgar, and Seidu.

PMID: 28345437 [PubMed – in process]

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2B4-SAP signaling is required for the priming of naive CD8(+) T cells by antigen-expressing B cells and B lymphoma cells.

Oncoimmunology. 2017;6(2):e1267094

Authors: Huang YH, Tsai K, Tan SY, Kang S, Ford ML, Harder KW, Priatel JJ

Abstract
Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8(+) T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a(-)(/)(-) CD8(+) T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a(-)(/)(-) CD8(+) T cells responded equivalently to wild-type CD8(+) T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8(+) T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8(+) T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8(+) T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.

PMID: 28344876 [PubMed – in process]

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RNA-Seq transcriptomics and pathway analyses reveal potential regulatory genes and molecular mechanisms in high- and low-residual feed intake in Nordic dairy cattle.

BMC Genomics. 2017 Mar 24;18(1):258

Authors: Salleh MS, Mazzoni G, Höglund JK, Olijhoek DW, Lund P, Løvendahl P, Kadarmideen HN

Abstract
BACKGROUND: The selective breeding of cattle with high-feed efficiencies (FE) is an important goal of beef and dairy cattle producers. Global gene expression patterns in relevant tissues can be used to study the functions of genes that are potentially involved in regulating FE. In the present study, high-throughput RNA sequencing data of liver biopsies from 19 dairy cows were used to identify differentially expressed genes (DEGs) between high- and low-FE groups of cows (based on Residual Feed Intake or RFI). Subsequently, a profile of the pathways connecting the DEGs to FE was generated, and a list of candidate genes and biomarkers was derived for their potential inclusion in breeding programmes to improve FE.
RESULTS: The bovine RNA-Seq gene expression data from the liver was analysed to identify DEGs and, subsequently, identify the molecular mechanisms, pathways and possible candidate biomarkers of feed efficiency. On average, 57 million reads (short reads or short mRNA sequences < ~200 bases) were sequenced, 52 million reads were mapped, and 24,616 known transcripts were quantified according to the bovine reference genome. A comparison of the high- and low-RFI groups revealed 70 and 19 significantly DEGs in Holstein and Jersey cows, respectively. The interaction analysis (high vs. low RFI x control vs. high concentrate diet) showed no interaction effects in the Holstein cows, while two genes showed interaction effects in the Jersey cows. The analyses showed that DEGs act through certain pathways to affect or regulate FE, including steroid hormone biosynthesis, retinol metabolism, starch and sucrose metabolism, ether lipid metabolism, arachidonic acid metabolism and drug metabolism cytochrome P450.
CONCLUSION: We used RNA-Seq-based liver transcriptomic profiling of high- and low-RFI dairy cows in two breeds and identified significantly DEGs, their molecular mechanisms, their interactions with other genes and functional enrichments of different molecular pathways. The DEGs that were identified were the CYP’s and GIMAP genes for the Holstein and Jersey cows, respectively, which are related to the primary immunodeficiency pathway and play a major role in feed utilization and the metabolism of lipids, sugars and proteins.

PMID: 28340555 [PubMed – in process]

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Granulocyte transfusions in patients with chronic granulomatous disease and refractory infections: the NIH experience.

J Allergy Clin Immunol. 2017 Mar 22;:

Authors: Marciano BE, Allen ES, Cantilena CC, Kristosturyan E, Klein HG, Fleisher TA, Holland SM, Malech HL, Rosenzweig SD

Abstract
Granulocyte transfusions are a relatively safe adjunctive therapeutic option for patients with chronic granulomatous disease and severe/refractory bacterial or fungal infections. Early initiation, high frequency and sustained therapy is associated with significantly better outcomes.

PMID: 28342916 [PubMed – as supplied by publisher]

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Infection Profile in Chronic Granulomatous Disease: a 23-Year Experience from a Tertiary Care Center in North India.

J Clin Immunol. 2017 Mar 22;:

Authors: Rawat A, Vignesh P, Sharma A, Shandilya JK, Sharma M, Suri D, Gupta A, Gautam V, Ray P, Rudramurthy SM, Chakrabarti A, Imai K, Nonoyama S, Ohara O, Lau YL, Singh S

Abstract
PURPOSE: Chronic granulomatous disease (CGD) is an inherited phagocytic disorder characterized by recurrent infections with usually catalase-positive organisms. Infections in CGD from developing countries are expected to be different from those in the Western countries. We report the profile of infections in children diagnosed with CGD from a tertiary care center in North India.
METHODOLOGY: Case records of children diagnosed with CGD at Pediatric Immunodeficiency Clinic, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India, from August 1993 to April 2016 (23 years) were analyzed.
RESULTS: Thirty-eight children were diagnosed to have CGD. Median follow-up of patients was 2 years (interquartile range 0.75, 6.0). Staphylococcus aureus and Pseudomonas spp. were the two most common causative bacteria isolated. Aspergillus was the most common fungus isolated. The most common organ involved was the lung (94.7%). Liver abscesses were identified in 5 patients (13.2%), and 20 (52.6%) patients had lymphadenitis. Infections with Pseudomonas spp. were high in our cohort (15.7%) compared to the other studies. Infections with some unusual organisms (e.g., Fusarium dimerium and Chryseobacterium gleum) were also seen in our cohort. Children with X-linked CGD presented earlier and also had a greater number of infections as compared to autosomal recessive CGD.
CONCLUSIONS: Various socioeconomic factors coupled with the lack of awareness and paucity of readily available diagnostic facilities for primary immunodeficiencies accounted for a late clinical presentation with severe infections and increased mortality (28.9%) in our cohort. However, mortality was similar in X-linked and autosomal recessive CGD as was the number of fungal infections. The incidence of infections and mortality was significantly lower after initiation of antibacterial and antifungal prophylaxis.

PMID: 28332028 [PubMed – as supplied by publisher]

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Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency.

Mol Ther Nucleic Acids. 2017 Mar 17;6:1-14

Authors: Ginn SL, Hallwirth CV, Liao SH, Teber ET, Arthur JW, Wu J, Lee HC, Tay SS, Hu M, Reddel RR, McCormack MP, Thrasher AJ, Cavazzana M, Alexander SI, Alexander IE

Abstract
In early gene therapy trials for SCID-X1, using γ-retroviral vectors, T cell leukemias developed in a subset of patients secondary to insertional proto-oncogene activation. In contrast, we have reported development of T cell leukemias in SCID-X1 mice following lentivirus-mediated gene therapy independent of insertional mutagenesis. A distinguishing feature in our study was that only a proportion of transplanted γc-deficient progenitors were transduced and therefore competent for reconstitution. We hypothesized that reconstitution of SCID-X1 mice with limiting numbers of hematopoietic progenitors might be a risk factor for lymphoid malignancy. To test this hypothesis, in the absence of transduction, SCID-X1 mice were reconstituted with serially fewer wild-type hematopoietic progenitors. A robust inverse correlation between hematopoietic progenitor cell dose and T-lymphoid malignancy was observed, with earlier disease onset at lower cell doses. Malignancies were of donor origin and carried activating Notch1 mutations. These findings align with emerging evidence that thymocyte self-renewal induced by progenitor deprivation carries an oncogenic risk that is modulated by intra-thymic competition from differentiation-committed cells. Although insertional proto-oncogene activation is required for the development of malignancy in humans, failure of γc-deficient thymocytes to effectively compete with this at-risk cell population may have also contributed to oncogenesis observed in early SCID-X1 trials.

PMID: 28325276 [PubMed – in process]

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Neonatal Group B Streptococcal Disease in Otherwise Healthy Infants: Failure of Specific Neonatal Immune Responses.

Front Immunol. 2017;8:215

Authors: Borghesi A, Stronati M, Fellay J

Abstract
Only a small proportion of newborn infants exposed to a pathogenic microorganism develop overt infection. Susceptibility to infection in preterm infants and infants with known comorbidities has a likely multifactorial origin and can be often attributed to the concurrence of iatrogenic factors, environmental determinants, underlying pathogenic processes, and probably genetic predisposition. Conversely, infection occurring in otherwise healthy full-term newborn infants is unexplained in most cases. Microbial virulence factors and the unique characteristics of the neonatal immune system only partially account for the interindividual variability in the neonatal immune responses to pathogens. We here suggest that neonatal infection occurring in otherwise healthy infants is caused by a failure of the specific protective immunity to the microorganism. To explain infection in term and preterm infants, we propose an extension of the previously proposed model of the genetic architecture of infectious diseases in humans. We then focus on group B streptococcus (GBS) disease, the best characterized neonatal infection, and outline the potential molecular mechanisms underlying the selective failure of the immune responses against GBS. In light of the recent discoveries of pathogen-specific primary immunodeficiencies and of the role of anticytokine autoantibodies in increasing susceptibility to specific infections, we hypothesize that GBS disease occurring in otherwise healthy infants could reflect an immunodeficiency caused either by rare genetic defects in the infant or by transmitted maternal neutralizing antibodies. These hypotheses are consistent with available epidemiological data, with clinical and epidemiological observations, and with the state of the art of neonatal physiology and disease. Studies should now be designed to comprehensively search for genetic or immunological factors involved in susceptibility to severe neonatal infections.

PMID: 28326082 [PubMed – in process]

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Staphylococcus aureus bacteremia in patients with rheumatoid arthritis – data from the prospective INSTINCT cohort.

J Infect. 2017 Mar 17;:

Authors: Joost I, Kaasch A, Pausch C, Peyerl-Hoffmann G, Schneider C, Voll RE, Seifert H, Kern WV, Rieg S

Abstract
OBJECTIVES: Patients with rheumatoid arthritis (RA) are considered to be at increased risk of severe infections. We here describe the clinical characteristics, course and outcome of RA patients with Staphylococcus aureus bacteremia (SAB).
METHODS: We conducted a post hoc analysis of data from a German bi-centre prospective SAB cohort study (period 2006-2014). Patients were followed-up for one year. Primary and secondary outcomes were survival time and osteoarticular infection (OAI).
RESULTS: A total of 1069 patients with SAB were analysed, with 31 patients suffering from RA. RA patients showed significantly more often OAI (15/31 patients, 48% vs. 152/1038, 15%), disseminated infection (12/31, 39% vs. 164/1038, 16%) and severe sepsis/septic shock (12/31, 39% vs. 235/1038, 23%). Day-30 mortality in RA patients was 36% (vs. 19% in non-RA patients, p=0.034), and day 90 mortality was 58% (vs. 32%, p=0.003). Multivariate analyses confirmed RA to be an independent risk factor for death (HR 2.3, 95% CI 1.4-3.7) and OAI (OR 4.2, 95% CI 1.8-9.8).
CONCLUSIONS: Patients with RA exhibit a complicated SAB course and a high mortality, their management is challenging. Adequate antibiotic treatment, prompt invasive diagnostic and therapeutic procedures like joint lavage or surgery are of pivotal importance. Joint damage due to RA may confer a higher risk of acquiring OAI than immunosuppression.

PMID: 28322887 [PubMed – as supplied by publisher]

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Early intracellular trafficking of Granulibacter bethesdensis in human macrophages.

Infect Immun. 2017 Mar 20;:

Authors: Chu J, Smelkinson MG, Dorward DW, Zarember KA, Gallin JI

Abstract
Granulibacter bethesdensis is a Gram-negative bacterium that infects patients with Chronic Granulomatous Disease (CGD), a primary immunodeficiency marked by a defect in NOX2, the phagocyte nicotinamide adenine dinucleotide phosphate oxidase. Previous studies have shown that NOX2 is essential for killing of G. bethesdensis by neutrophils and monocytes and that bacteriostatic activity of monocyte derived macrophages (MDM) requires NOX2 and IFNγ-pretreatment. To determine if G. bethesdensis evades phagolysosomal killing, a host defense pathway intact in both normal and CGD MDM, or occupies a distinct intracellular niche in CGD MDM, we assessed the trafficking patterns of this organism. We observed co-localization of G. bethesdensis with an early endosome antigen 1 (EEA1)-positive compartment followed by co-localization with lysosomal-associated membrane protein 1 (LAMP1)-positive and lysotracker-positive late phagosomes that was similar in both normal and CGD MDM. Despite localization to acidified late phagosomes, viable G. bethesdensis were recovered from viable MDM in numbers greater than initial input up to 6 days after infection. G. bethesdensis remains, and in some cases appears to divide, within a membrane-bound compartment for the entire 6-day time course. These findings indicate that this organism resists both oxygen-dependent and oxygen-independent phagolysosomal antimicrobial systems of human macrophages.

PMID: 28320834 [PubMed – as supplied by publisher]

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