Research

An evaluation of the budget impact of a new 20% subcutaneous immunoglobulin (Ig20Gly) for the management of primary immunodeficiency diseases in Switzerland.

Clinicoecon Outcomes Res. 2018;10:223-229

Authors: Pollock RF, Meckley LM

Abstract
Introduction: While most individual primary immunodeficiency diseases (PID) are rare, the collective prevalence of PID results in a substantial economic and clinical burden. The aim of this study was to evaluate the budgetary implications of Ig20Gly (Immune Globulin Subcutaneous [human] 20% solution; CUVITRU ® , Baxalta US Inc, now part of Shire Plc, Westlake Village, CA, USA) as a treatment for PID relative to intravenous immunoglobulin (IVIG) and other subcutaneous immunoglobulin (SCIG) formulations in the Swiss health care setting.
Materials and methods: A budget impact model was developed in Microsoft Excel to capture the estimated prevalence of PID in Switzerland, the proportion of patients treated in different health care settings, and the costs of administering SCIG and IVIG in each setting. Unit costs were based on a recent cost-minimization analysis of SCIG in Lausanne, and drug costs were taken from the Spezialitätenliste. All costs were reported in 2016 Swiss Francs (CHF), and future costs were not discounted.
Results: The total cost of treating PID in Switzerland was estimated to be CHF 11.16 m over 3 years, comprising CHF 9.28 m of drug costs and CHF 1.87 m of ancillary costs, including health care professional time and other administration costs, such as pumps and needle sets. The analysis showed that using Ig20Gly in place of other SCIG formulations would be cost neutral, while using Ig20Gly in place of IVIG would result in savings of 4.0%.
Conclusion: Ig20Gly would be cost neutral relative to existing SCIG products and would result in cost savings relative to IVIG in patients with PID in Switzerland, even with modest uptake.

PMID: 29692618 [PubMed]

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Diffuse large B-cell lymphoma chemotherapy reveals a combined immunodeficiency syndrome in cartilage hair hypoplasia.

Swiss Med Wkly. 2018 Apr 24;148:w14606

Authors: Ngyen A, Martin Silva N, de Boysson H, Damaj G, Aouba A

Abstract
Cartilage hair hypoplasia (CHH) is a rare autosomal recessive ribosomopathy characterised by skeletal and integumentary system manifestations. It may also present with varied forms and intensities of haematopoietic and/or immune disorders. We report a 27-year-old female who presented a picture of combined immunodeficiency after receiving an adriamycin-based chemotherapy regimen followed by autologous stem cell transplantation. Her medical history indicated neonatal dwarfism, recurrent ear, nose and throat and respiratory infections, and hypogammaglobulinaemia, which were suggestive of a primary minor B-cell immune deficiency. Taken together, the diagnosis of cartilage hair hypoplasia was suspected and confirmed by means of molecular biological analysis. Here, we discuss the causal relationship and molecular mechanisms existing between both primary immunodeficiency and lymphoma conditions and between chemotherapy cytotoxicity and aggravation of the immune system and associated hematopoietic dysfunction, considering the role of all these components in light of the initially undiagnosed cartilage hair hypoplasia. Finally, this case highlights the importance of screening for primary immunodeficiencies in the setting of a diagnosis of lymphoma and/or dwarfism; moreover, CHH must be distinguished from other causes of small size; its diagnosis and complete check-up must include the molecular characterisation, and its management must be global in collaboration with haematologists, immunologists and internists.

PMID: 29688570 [PubMed – in process]

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Takayasu arteritis in childhood: misdiagnoses at disease onset and associated diseases.

Rheumatol Int. 2018 Apr 23;:

Authors: Clemente G, Silva CA, Sacchetti SB, Ferriani VPL, Oliveira SK, Sztajnbok F, Bica BERG, Cavalcanti A, Robazzi T, Bandeira M, Terreri MT

Abstract
Juvenile-Takayasu arteritis (j-TA) is a difficult diagnosis and some patients develop uncommon manifestations and associated diseases that may contribute to the delayed diagnosis. Our aim was to identify the misdiagnoses, the associated diseases and the atypical manifestations observed in a j-TA Brazilian multicentre study. 71 children and adolescents who met the classification criteria for j-TA were included. The misdiagnoses, the associated diseases and the atypical manifestations were evaluated. 19 (26.8%) patients had misdiagnoses. The most common of them was aortic coarctation in six (8.4%) patients, followed by rheumatic fever in five (7.0%) and one patient presented with both former diagnoses. Limb pain (two patients), spondyloarthropathy, juvenile idiopathic arthritis (JIA), spinal arteriovenous malformation, polyarteritis nodosa (PAN) and fever of unknown origin (FUO) were other misdiagnoses. Patients who had misdiagnoses previously to j-TA diagnosis presented a trend to have a longer diagnosis delay. 11 (15.5%) patients had 14 TA-associated diseases, such as pulmonary tuberculosis (5 patients), rheumatic fever (2 patients), spondyloarthropathy, polyarticular JIA, Crohn’s disease, Prader-Willi disease, diabetes mellitus, Moyamoya and primary immunodeficiency. 7 (9.9%) patients presented 10 atypical manifestations, such as pyoderma gangrenosum, erythema nodosum, myositis, chorea, enthesitis, episcleritis, uveitis, hepatomegaly, splenomegaly and necrosis of extremities. Our study emphasizes the main misdiagnoses, associated diseases and atypical manifestations that occur in patients with j-TA and warns of the features that may alert paediatricians to this diagnosis, such as constitutional symptoms and elevated inflammatory markers.

PMID: 29687155 [PubMed – as supplied by publisher]

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Predictive markers for humoral influenza vaccine response in patients with common variable immunodeficiency (CVID).

J Allergy Clin Immunol. 2018 Apr 17;:

Authors: Gardulf A, Abolhassani H, Gustafson R, Eriksson LE, Hammarström L

Abstract
BACKGROUND: A subgroup of patients with common variable immunodeficiencies (CVID) responds to vaccination. The aim of the study was to try to identify predictive markers for those who developed a humoral immune response after influenza vaccination.
METHODS: 48 patients with CVID (29 females, 19 males, mean age 59.4 years) were vaccinated with the A(H1N1) influenza vaccine Pandemrix® and boosted after one month. Blood samples were collected prior to each vaccination and two months later. Patients with a 4-fold titer increase of the hemagglutinin inhibition test (≥ 1:40) were considered responders and compared to non-responders for clinical, immunological and genetic markers.
RESULTS: Eight (16.7%) patients responded to the vaccination. A significantly higher proportion of the responders, who showed a Euroclass SmB-Trnorm21norm profile (p=0.03) with a post-germinal center B cell pattern (p=0.04) in blood, suffered from enteropathies (p=0.04) as compared to non-responders. Bronchiectasis on the other hand, was exclusively found among non-responders (n=7), as was autoimmune cytopenia (n=5). Non-responders with a Euroclass SmB-21lowTrnorm profile (p=0.02), had a significantly higher prevalence of progressive antibody deficiency (p=0.048) and, at diagnosis, a higher mean serum IgM level (p=0.03), a lower mean serum IgG1 level (p=0.007), an expansion of absolute counts of cytotoxic CD8+ T-cells (p=0.033) and an increased proportion of memory CD8+ T-cells (p=0.044) in blood. CVID associated HLA markers were not detected in non-responders (p=0.03).
CONCLUSION: About one-fifth of the CVID patients achieved protective antibody levels after A(H1N1) vaccination and selected clinical and immunological markers were identified that may predict a positive outcome of influenza vaccination.

PMID: 29678747 [PubMed – as supplied by publisher]

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Lymphomatoid granulomatosis: A case series from South India.

Indian J Pathol Microbiol. 2018 Apr-Jun;61(2):228-232

Authors: Sigamani E, Chandramohan J, Nair S, Chacko G, Thomas M, Mathew LG, Pulimood S, Manipadam MT

Abstract
Context: Lymphomatoid granulomatosis (LYG) is a rare B-lymphoproliferative disorder characterised by an angiocentric and angiodestructive pattern along with Epstein – Barr virus (EBV) association. It is one of the diagnostic challenges in lymphoma pathology. Deregulation of EBV immune surveillance is one of the narrated hypotheses in the literature. Extrapulmonary manifestations are rare with LYG. Morphological grading is done based on the number of EBV-positive B cells, which is useful to strategize treatment protocol.
Aims: We report here a series of nine cases of LYG to discuss the clinical, histological, and immunohistochemistry findings.
Settings and Design: This is the first case series from India in published literature.
Subjects and Methods: We reviewed cases of LYG diagnosed at our center for the past 11 years (2006-2016). A total of nine cases were included in this study. Histomorphology was studied in conjunction with immunohistochemistry and clinical details. Cases without classical morphology and negative for EBV immunostain were excluded from the study.
Results: There were nine patients in our study (7 males and 2 female; M:F ratio 3.5:1). The age of these patients ranged from 4 years to 57 years (mean age: 30 years). The most common site involved was the lung (4, 44%), followed by the skin (2, 22%), central nervous system (2, 22%) and lymph node (1, 11%). One patient had primary immunodeficiency. Another patient had undergone renal transplant 11 years before the development of the lesion. Angiocentricity and angioinvasion were appreciated in all nine cases (9/9) with necrosis in four cases (44%) and ill-defined histiocytic aggregates in three cases (33%). The histological features were as follows: Grade 1(4 cases, 44%), Grade 2(2 cases, 22%), and Grade 3(3 cases, 33%).
Conclusion: LYG is a rare EBV driven angiodestructive disease with predominantly lung involvement as well as isolated extrapulmonary sites as seen in our study. It is often progressive and ultimately fatal in the absence of appropriate treatment. Grading of the lesion helps to initiate the appropriate treatment of choice.

PMID: 29676363 [PubMed – in process]

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Use of Genetic Testing for Primary Immunodeficiency Patients.

J Clin Immunol. 2018 Apr 19;:

Authors: Heimall JR, Hagin D, Hajjar J, Henrickson SE, Hernandez-Trujillo HS, Tan Y, Kobrynski L, Paris K, Torgerson TR, Verbsky JW, Wasserman RL, Hsieh EWY, Blessing JJ, Chou JS, Lawrence MG, Marsh RA, Rosenzweig SD, Orange JS, Abraham RS

Abstract
Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS’s recommendations for the use of genetic testing in light of these issues.

PMID: 29675737 [PubMed – as supplied by publisher]

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Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome.

Front Immunol. 2018;9:568

Authors: Asano T, Okada S, Tsumura M, Yeh TW, Mitsui-Sekinaka K, Tsujita Y, Ichinose Y, Shimada A, Hashimoto K, Wada T, Imai K, Ohara O, Morio T, Nonoyama S, Kobayashi M

Abstract
Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in PIK3CD, PIK3R1, or PTEN, which are related to the hyperactive phosphoinositide 3-kinase (PI3K) signaling, were recently presented to cause APDS1 or APDS2 (APDSs), or APDS-like (APDS-L) disorder. In this study, we examined the AKT phosphorylation of peripheral blood lymphocytes and monocytes in patients with APDSs and APDS-L by using flow cytometry. CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation. The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor. In contrast, CD3+ T cells and CD14+ monocytes did not show the enhanced pAKT in the absence of stimulation. These findings were similarly observed in patients with APDS1 and APDS-L. Among CD19+ B cells, enhanced pAKT was prominently detected in CD10+ immature B cells compared with CD10- mature B cells. Enhanced pAKT was not observed in B cells of healthy controls, patients with common variable immunodeficiency, and hyper IgM syndrome due to CD40L deficiency. These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.

PMID: 29675019 [PubMed]

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Droplet Digital PCR-Based Chimerism Analysis for Primary Immunodeficiency Diseases.

J Clin Immunol. 2018 Apr 18;:

Authors: Okano T, Tsujita Y, Kanegane H, Mitsui-Sekinaka K, Tanita K, Miyamoto S, Yeh TW, Yamashita M, Terada N, Ogura Y, Takagi M, Imai K, Nonoyama S, Morio T

Abstract
OBJECTIVE: In the current study, we aimed to accurately evaluate donor/recipient or male/female chimerism in samples from patients who underwent hematopoietic stem cell transplantation (HSCT).
METHODS: We designed the droplet digital polymerase chain reaction (ddPCR) for SRY and RPP30 to detect the male/female chimerism. We also developed mutation-specific ddPCR for four primary immunodeficiency diseases.
RESULTS: The accuracy of the male/female chimerism analysis using ddPCR was confirmed by comparing the results with those of conventional methods (fluorescence in situ hybridization and short tandem repeat-PCR) and evaluating dilution assays. In particular, we found that this method was useful for analyzing small samples. Thus, this method could be used with patient samples, especially to sorted leukocyte subpopulations, during the early post-transplant period. Four mutation-specific ddPCR accurately detected post-transplant chimerism.
CONCLUSION: ddPCR-based male/female chimerism analysis and mutation-specific ddPCR were useful for all HSCT, and these simple methods contribute to following the post-transplant chimerism, especially in disease-specific small leukocyte fractions.

PMID: 29671114 [PubMed – as supplied by publisher]

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