Research

Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells.

Blood Adv. 2018 Sep 25;2(18):2378-2388

Authors: Wang X, Hu CS, Petersen B, Qiu J, Ye F, Houldsworth J, Eng K, Huang F, Hoffman R

Abstract
Clinical trials of imetelstat therapy have indicated that this telomerase inhibitor might have disease-modifying effects in a subset of patients with myelofibrosis (MF). The mechanism by which imetelstat induces such clinical responses has not been clearly elucidated. Using in vitro hematopoietic progenitor cell (HPC) assays and in vivo hematopoietic stem cell (HSC) assays, we examined the effects of imetelstat on primary normal and MF HSCs/HPCs. Treatment of CD34+ cells with imetelstat reduced the numbers of MF but not cord blood HPCs (colony-forming unit-granulocyte/macrophage, burst-forming unit-erythroid, and colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte) as well as MF but not normal CD34+ALDH+ cells irrespective of the patient’s mutational status. Moreover, imetelstat treatment resulted in depletion of mutated HPCs from JAK2V617F+ MF patients. Furthermore, treatment of immunodeficient mice that had been previously transplanted with MF splenic CD34+ cells with imetelstat at a dose of 15 mg/kg, 3 times per week for 4 weeks had a limited effect on the degree of chimerism achieved by normal severe combined immunodeficiency repopulating cells but resulted in a significant reduction in the degree of human MF cell chimerism as well as the proportion of mutated donor cells. These effects were sustained for at least 3 months after drug treatment was discontinued. These actions of imetelstat on MF HSCs/HPCs were associated with inhibition of telomerase activity and the induction of apoptosis. Our findings indicate that the effects of imetelstat therapy observed in MF patients are likely attributable to the greater sensitivity of imetelstat against MF as compared with normal HSCs/HPCs as well as the intensity of the imetelstat dose schedule.

PMID: 30242099 [PubMed – in process]

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Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort.

J Allergy Clin Immunol Pract. 2018 Sep 18;:

Authors: Yazdani R, Abolhassani H, Kiaee F, Habibi S, Azizi G, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, Gharagozlou M, Movahedi M, Hamidieh AA, Behniafard N, Nabavi M, Bemanian MH, Arshi S, Molatefi R, Sherkat R, Shirkani A, Amin R, Aleyasin S, Faridhosseini R, Jabbari-Azad F, Mohammadzadeh I, Ghaffari J, Shafiei A, Kalantari A, Mansouri M, Mesdaghi M, Babaie D, Ahanchian H, Khoshkhui M, Soheili H, Eslamian MH, Cheraghi T, Dabbaghzadeh S, Tavassoli M, Kalmarzi RN, Mortazavi SH, Kashef S, Esmaeilzadeh H, Tafaroji J, Khalili A, Zandieh F, Sadeghi-Shabestari M, Darougar S, Behmanesh F, Akbari H, Zandkarimi M, Abolnezhadian F, Fayezi A, Moghtaderi M, Ahmadiafshar A, Shakerian B, Sajedi V, Taghvaei B, Safari M, Heidarzadeh M, Ghalebaghi B, Fathi SM, Darabi B, Bazregari S, Bazargan N, Fallahpour M, Khayatzadeh A, Javahertrash N, Bashardoust B, Zamani M, Mohsenzadeh A, Ebrahimi S, Sharafian S, Vosughimotlagh A, Tafakoridelbari M, Rahim M, Ashournia P, Razaghian A, Rezaei A, Samavat A, Mamishi S, Khazaei HA, Mohammadi J, Negahdari B, Parvaneh N, Rezaei N, Lougaris V, Giliani S, Plebani A, Ochs HD, Hammarström L, Aghamohammadi A

Abstract
BACKGROUND: Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses.
OBJECTIVE: We intended to report most common monogenic PADs and to investigate how PAD patients who were primarily diagnosed as agammaglobulinemia, hyper IgM syndrome (HIgM) and common variable immunodeficiency (CVID) have different clinical and immunological findings.
METHODS: Stepwise next generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as agammaglobulinemia, HIgM and CVID.
RESULTS: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 BTK and 6 μ heavy chain deficiencies), HIgM (21 CD40L and 7 AID deficiencies) and CVID (17 LRBA deficiency and 12 atypical ICF syndromes) were identified. Clinical disease severity was significantly higher in patients with μ heavy chain and CD40L compared to patients with BTK (P = 0.003) and AICDA (P = 0.009) mutations. Paralysis following live polio vaccination was considerably higher in patients with μ heavy chain deficiency compared with BTK deficiency (P <0.001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in the majority of ICF patients were respiratory complications (P = 0.008), while first presentations in LRBA patients were non-respiratory complications (P = 0.008).
CONCLUSION: This study highlights similarities and differences in clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.

PMID: 30240888 [PubMed – as supplied by publisher]

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CVID enteropathy is characterized by exceeding low mucosal iga levels and interferon-driven inflammation possibly related to the presence of a pathobiont.

Clin Immunol. 2018 Sep 18;:

Authors: Shulzhenko N, Dong X, Vyshenska D, Greer RL, Gurung M, Vasquez-Perez S, Peremyslova E, Sosnovtsev S, Quezado M, Yao M, Montgomery-Recht K, Strober W, Fuss IJ, Morgun A

Abstract
Common variable immunodeficiency (CVID), the most common symptomatic primary antibody deficiency, is accompanied in some patients by a duodenal inflammation and malabsorption syndrome known as CVID enteropathy (E-CVID). The goal of this study was to investigate the immunological abnormalities in CVID patients that lead to enteropathy as well as the contribution of intestinal microbiota to this process. We found that, in contrast to noE-CVID patients (without enteropathy), E-CVID patients have exceedingly low levels of IgA in duodenal tissues. In addition, using transkingdom network analysis of the duodenal microbiome, we identified Acinetobacter baumannii as a candidate pathobiont in E-CVID. Finally, we found that E-CVID patients exhibit a pronounced activation of immune genes and down-regulation of epithelial lipid metabolism genes. We conclude that in the virtual absence of mucosal IgA, pathobionts such as A. baumannii, may induce inflammation that re-directs intestinal molecular pathways from lipid metabolism to immune processes responsible for enteropathy.

PMID: 30240602 [PubMed – as supplied by publisher]

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Clinical effectiveness of influenza vaccination after allogeneic hematopoietic stem cell transplantation: A cross-sectional prospective observational study.

Clin Infect Dis. 2018 Sep 15;:

Authors: Piñana JL, Pérez A, Montoro J, Giménez E, Dolores Gómez M, Lorenzo I, Madrid S, González EM, Vinuesa V, Hernández-Boluda JC, Salavert M, Sanz G, Solano C, Sanz J, Navarro D

Abstract
Background: Allogeneic hematopoietic stem cell recipients (allo-HSCT) are at high risk for morbidity and mortality from influenza respiratory virus infection (RVI). Vaccination is the primary method for preventing influenza RVI. Although the influenza vaccine is able to achieve serological response in some allo-HSCT recipients, its clinical benefit is still uncertain.
Methods: In this prospective cross-sectional study, we retrospectively analyzed the effect of inactivated trivalent influenza vaccination status on the prevalence of influenza RVI in a consecutive cohort of 136 allo-HSCT adult recipients who developed 161 RVI over 5 flu seasons (from 2013 to 2018). Respiratory virus in upper and/or lower respiratory tract specimens were tested using multiplex PCR panel assays.
Results: Overall, we diagnosed 74 episodes (46%) of Influenza RVI in 70 allo-HSCT recipients. Influenza RVI occurred in 51% of the non-vaccinated compared to 36% of the vaccinated recipients (p= 0.036). Multivariate analysis showed that influenza vaccination was associated with lower prevalence of influenza RVI (OR 0.39, p= 0.01). Multivariate risk factor analysis of lower respiratory tract disease (LRTD) identified two conditions associated with the probability of influenza RVI progression; influenza vaccination (OR 0.12, 95% C.I. 0.014-1, p= 0.05) and high-risk immunodeficiency score index (OR 36, 95% C.I. 2.26-575, p= 0.011). Influenza vaccination was also associated with lower likelihood of influenza-related hospital admission (14% vs 2%, p= 0.04).
Conclusion: This study shows that influenza vaccination may have a clinical benefit in allo-HSCT recipients with virologicallly confirmed RVI, in terms of lower influenza RVI prevalence, LRTD progression and hospital admission.

PMID: 30239624 [PubMed – as supplied by publisher]

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Preliminary study on chronic granulomatous disease in Sri Lanka.

Allergy Asthma Clin Immunol. 2018;14:37

Authors: Fernando SJA, Faiz NM, Handunnetti SM, De Silva AD, Dasanayake WMDK, Wickramasinghe GD, Karunatilake RMCH, de Silva NR

Abstract
Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency of the phagocytic cells, which results in absent or diminished levels of microbicidal reactive oxygen species. The disease occurs due to germline mutations in the genes encoding the five subunits of NADPH oxidase complex. The present study is a pilot study to understand the clinical and genetic aspects of CGD in Sri Lanka.
Methods: Clinical records of thirteen CGD patients were analysed and compared with similar studies performed in different countries and regions to identify patterns in demographics, clinical manifestations and infectious agents. Genomic DNA and cDNA were analysed in eight patients to identify mutations in CYBB and NCF1 genes, thereby to ascertain the potential X-linked and autosomal recessive (AR) CGD patients.
Results: The onset of symptoms in the patient cohort was very early (mean 4.6 months) compared to 20 months in India and 23.9 months in Latin America. Similarly, the age at diagnosis was lower (mean 1.6 years after birth) compared to other studies; 4.5 years in India and 6.1 years in Europe. Pulmonary manifestations were the most common (85%), followed by skin/subcutaneous infections (77%) and lymphadenopathy (62%). The death rate of local patients (38%) was higher than other countries (India 35%, Europe 20%). Majority (77%) were treated for tuberculosis at some point in life. Genetic analysis confirmed six out of eight patients as X-linked CGD cases with mutations in CYBB gene. A novel splice site mutation was identified in P-07 at position c.141+6 which resulted in the deletion of entire exon 2. Two siblings (P-05 and P-06) from consanguineous parents, were identified with AR-CGD based on the homozygous GT deletion mutation in NCF1 gene.
Conclusions: The clinical presentation, manifestations and genetic subtypes in the local cohort, appear to be comparable with global trends. Mycobacterial infections should be investigated and treated with more prominence. Effective treatment options are required to control the high mortality rate.

PMID: 30237823 [PubMed]

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The role of genomic approaches in diagnosis and management of primary immunodeficiency.

Curr Opin Pediatr. 2018 Sep 17;:

Authors: Chinn IK, Bostwick BL

Abstract
PURPOSE OF REVIEW: Genetic testing serves an increasingly important role in the diagnosis and management of primary immunodeficiency. In this review, the strengths and limitations of various genetic testing methods are summarized, providing a foundation for the clinical approach to achieving a molecular diagnosis.
RECENT FINDINGS: Rapid advances in sequencing technology have enabled the incorporation of comprehensive genetic testing into first-line clinical diagnostics. Recent articles enable comparisons of the diagnostic utility of new testing strategies while simultaneously reminding clinicians of the strengths of traditional methods.
SUMMARY: Genetic testing in primary immunodeficiency cannot be standardized, but instead needs to be personalized based on the presenting phenotype and a basic understanding of the utility of different molecular methods. These tools, when correctly employed, can achieve a molecular diagnosis and inform the natural history, prognosis, recurrence risk, and therapeutic options.

PMID: 30234646 [PubMed – as supplied by publisher]

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Psychosocial services for primary immunodeficiency disorder families during hematopoietic cell transplantation: A descriptive study.

Palliat Support Care. 2018 Sep 18;:1-6

Authors: Mangurian C, Scalchunes C, Yoo J, Logan B, Henderson T, Iyengar S, Smith H, Cowan MJ

Abstract
OBJECTIVE: Caregivers for patients undergoing hematopoietic cell transplantation (HCT) are susceptible to significant psychosocial distress. This cross-sectional study aimed to describe psychosocial support services offered and used by caregivers of pediatric primary immune deficiency (PID) during HCT at 35 hospitals across North America.
METHOD: Caregivers of pediatric patients with PID were recruited by e-mail to participate in an anonymous 140-question survey instrument between April and May 2016 (N = 171).ResultOf those meeting inclusion criteria (53%), family counseling services were only offered to fewer than half of caregivers (42%). Of the survey participants not offered counseling services, the majority desired family counseling (70%) and sibling counseling (73%). That said, when offered counseling, utilization rates were low, with 22% of caregivers using family counseling and none using sibling counseling.Significance of resultsThese results indicate the need to offer and tailor counseling services for families throughout the HCT process. Further research should focus on reducing barriers to utilization of counseling services such as offering bedside counseling services, online modalities, and/or financial assistance.

PMID: 30223912 [PubMed – as supplied by publisher]

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Hematopoietic Stem Cell Transplantation for Primary Immunodeficiency Disorders: Experience from a Referral Center in India.

Indian Pediatr. 2018 Aug 15;55(8):661-664

Authors: Uppuluri R, Jayaraman D, Sivasankaran M, Patel S, Swaminathan VV, Vaidhyanathan L, Kandath S, Raj R

Abstract
OBJECTIVE: To share experience of over 15 years in hematopoietic stem cell transplantation in children with primary immunodeficiency disorders.
DESIGN: Medical record review.
SETTING: A referral center for pediatric hemato-oncological disorders.
PARTICIPANTS: Children (<18 y) diagnosed to have primary immune deficiencies who underwent hematopoietic stem cell transplantation between 2002 and August 2017.
MAIN OUTCOME MEASURES: Disease-free survival, morbidity and mortality.
RESULTS: 85 primary immunodeficiency disorder transplants were performed with engraftment noted in 80 (94%) transplants and an overall survival of 67%. The conditioning regimen was individualized based on the underlying immune defect. Mixed chimerism was noted in 20% children with 56% (9/16) remaining disease-free. Graft versus host disease was noted in 33 (39.2%) children with most seen in children with chronic granulomatous disease. Severe combined immune deficiency transplants were mainly complicated by infections. Immune cytopenias complicated Wiskott Aldrich syndrome and Hemophagocytic lymphohistiocytosis transplants. 29.4% (25/85) children underwent haploidentical transplant in our cohort with a survival of 70% in this group. Infectious complications were the most common cause of death.
CONCLUSIONS: Primary immunodeficiency disorders are curable in India when transplanted in centers with experienced and trained pediatric transplant physicians and intensivists.

PMID: 30218511 [PubMed – in process]

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Clinical & laboratory features of seventy-eight UK patients with Good’s syndrome (thymoma & hypogammaglobulinemia).

Clin Exp Immunol. 2018 Sep 14;:

Authors: Zaman M, Huissoon A, Buckland M, Patel S, Alachkar H, Edgar JD, Thomas M, Arumugakani G, Baxendale H, Burns S, Williams AP, Jolles S, Herriot R, Sargur RB, Arkwright PD

Abstract
Good’s syndrome (thymoma and hypogammaglobulinemia) is a rare secondary immunodeficiency disease, previously reported in the published literature as mainly individual cases or small case series. We use the national UK-Primary Immune Deficiency (UKPID) registry to identify a large cohort of patients in the UK with this PID to review its clinical course, natural history and prognosis. Clinical information, laboratory data, treatment and outcome were collated and analysed. Seventy-eight patients with a median age of 64 years, 59% of whom were females were reviewed. Median age of presentation was 54 years. Absolute B cell numbers and serum immunoglobulins were very low in all patients and all received immunoglobulin replacement therapy. All patients had undergone thymectomy and 9 (12%) had thymic carcinoma (four locally invasive and five had disseminated disease) requiring adjuvant radiotherapy and/or chemotherapy. CD4 T-cells were significantly lower in these patients with malignant thymoma. Seventy-four (95%) presented with infections, 35 (45%) had bronchiectasis, seven (9%) chronic sinusitis, but only eight (10%) had serious invasive fungal or viral infections. Patients with AB-type thymomas were more likely to have bronchiectasis. Twenty (26%) suffered from autoimmune diseases (pure red cell aplasia, hypothyroidism, arthritis, myasthenia gravis, SLE, Sjogren’s syndrome). There was no association between thymoma type and autoimmunity. Seven (9%) patients had died. Good’s syndrome is associated with significant morbidity relating to infectious and autoimmune complications. Prospective studies are required to understand why some patients with thymoma develop persistent hypogammaglobulinemia. This article is protected by copyright. All rights reserved.

PMID: 30216434 [PubMed – as supplied by publisher]

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Nijmegen Breakage Syndrome Complicated With Primary Pulmonary Granulomas.

Pediatrics. 2018 Sep 12;:

Authors: Marczak H, Heropolitańska-Pliszka E, Langfort R, Roik D, Grzela K

Abstract
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disease characterized by microcephaly, growth retardation, severe immunodeficiency, and predisposition to lymphoid malignancy. In this report, we describe a case of a 9-year-old boy, previously diagnosed with NBS and symptoms of dyspnea, dry cough, and fever. Despite initial recognition of pneumonia, there was no response to broad spectrum antimicrobial treatment, negative results from microbiological tests, and unclear changes in lung imaging were observed. Therefore, further diagnostics were focused on suspected lymphoid malignancy and involved lung biopsy. Unexpectedly, histopathological examination revealed noncaseating granulomas. The introduction of systemic steroids resulted in significant improvement of the patient’s clinical condition. This is the first description of primary pulmonary noncaseating granulomas without nodular involvement in a child with NBS.

PMID: 30209074 [PubMed – as supplied by publisher]

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