Research

An Update on the Use of Immunomodulators in Primary Immunodeficiencies.

Clin Rev Allergy Immunol. 2016 Nov 21;

Authors: Vignesh P, Rawat A, Singh S

Abstract
The genomic revolution in the past decade fuelled by breathtaking advances in sequencing technologies has defined several new genetic diseases of the immune system. Many of these newly characterized diseases are a result of defects in genes involved in immune regulation. The discovery of these diseases has opened a vista of new therapeutic possibilities. Immunomodulatory agents, a hitherto unexplored therapeutic option in primary immunodeficiency diseases have been tried in a host of these newly described maladies. These agents have been shown conclusively to favorably modulate immune responses, resulting in abatement of clinical manifestations both in experimental models and patients. While some of the treatment options have been approved for therapeutic use or have been shown to be of merit in open-label trials, others have been shown to be efficacious in a handful of clinical cases, animal models, and cell lines. Interferon γ is approved for use in chronic granulomatous disease (CGD) to reduce the burden of infection and and has a good long-term efficacy. Recombinant human IL7 therapy has been shown increase the peripheral CD4 and CD8 T cell counts in patients with idiopathic CD4. Anti-IL1 agents are approved for the management of cryopyrin-related autoinflammatory syndrome, and their therapeutic efficacy is being increasingly recognized in other autoinflammatory syndromes and CGD. Mammalian target of rapamycin (mTOR) inhibitors have been proven useful in autoimmune lymphoproliferative syndrome (ALPS) and in IPEX syndrome. Therapies reported to be potential use in case reports include abatacept in CTLA4 haploinsufficiency and LRBA deficiency, ruxolitinib in gain-of-function STAT1, tocilizumab in gain-of-function STAT3 defect, mTOR inhibitors in PIK3CD activation, magnesium in XMEN syndrome, and pioglitazone in CGD. Treatment options of merit in human cell lines include interferon α and interferon β in TLR3 and UNC-93B deficiencies, anti-interferon therapy in SAVI, and Rho-kinase inhibitors in TTC7A deficiency. Anti-IL17 agents have show efficacy in animal models of leukocyte adhesion defect (LAD) and ALPS. This topical review explores the use of various immunomodulators and other biological agents in the context of primary immunodeficiency and autoinflammatory diseases.

PMID: 27873163 [PubMed – as supplied by publisher]

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Newborn Screening for Severe Primary Immunodeficiency Diseases in Sweden-a 2-Year Pilot TREC and KREC Screening Study.

J Clin Immunol. 2016 Nov 21;

Authors: Barbaro M, Ohlsson A, Borte S, Jonsson S, Zetterström RH, King J, Winiarski J, von Döbeln U, Hammarström L

Abstract
Newborn screening for severe primary immunodeficiencies (PID), characterized by T and/or B cell lymphopenia, was carried out in a pilot program in the Stockholm County, Sweden, over a 2-year period, encompassing 58,834 children. T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) were measured simultaneously using a quantitative PCR-based method on DNA extracted from dried blood spots (DBS), with beta-actin serving as a quality control for DNA quantity. Diagnostic cutoff levels enabling identification of newborns with milder and reversible T and/or B cell lymphopenia were also evaluated. Sixty-four children were recalled for follow-up due to low TREC and/or KREC levels, and three patients with immunodeficiency (Artemis-SCID, ATM, and an as yet unclassified T cell lymphopenia/hypogammaglobulinemia) were identified. Of the positive samples, 24 were associated with prematurity. Thirteen children born to mothers treated with immunosuppressive agents during pregnancy (azathioprine (n = 9), mercaptopurine (n = 1), azathioprine and tacrolimus (n = 3)) showed low KREC levels at birth, which spontaneously normalized. Twenty-nine newborns had no apparent cause identified for their abnormal results, but normalized with time. Children with trisomy 21 (n = 43) showed a lower median number of both TREC (104 vs. 174 copies/μL blood) and KREC (45 vs. 100 copies/3.2 mm blood spot), but only one, born prematurely, fell below the cutoff level. Two children diagnosed with DiGeorge syndrome were found to have low TREC levels, but these were still above the cutoff level. This is the first large-scale screening study with a simultaneous detection of both TREC and KREC, allowing identification of newborns with both T and B cell defects.

PMID: 27873105 [PubMed – as supplied by publisher]

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Suspected myelodysplastic/myeloproliferative neoplasm in a feline leukemia virus-negative cat.

Vet Clin Pathol. 2016 Nov 21;:

Authors: Weeden AL, Taylor KR, Terrell SP, Gallagher AE, Wamsley HL

Abstract
A 10-year-old castrated Domestic Short-Haired cat was presented to a primary care veterinarian for a wellness examination and laboratory examination for monitoring of diabetes mellitus. The CBC revealed marked thrombocytosis, leukopenia and macrocytic, normochromic anemia. The cat tested negative for FeLV and feline immunodeficiency virus, but was positive for Mycoplasma haemominutum by PCR. Hematologic abnormalities were not responsive to therapy, so a repeat CBC and a bone marrow aspiration for cytology were performed. Additional blood smear findings included anisocytosis with megaloblastic erythroid precursors, large platelets, eosinophilic myelocytes and metamyelocytes, and rare unidentified blasts. The bone marrow smear was highly cellular, and the cytologic pattern was consistent with myelodysplastic syndrome with an erythroid predominance. At that time, 15% blasts were present. The cat was treated with a vitamin K2 analog, doxycycline, and prednisolone, but without a clinical response. Within 3 months, euthanasia was elected due to declining quality of life, and a necropsy was performed. Postmortem bone marrow smears were highly cellular and dominated by monomorphic blasts of unknown line of origin (52%), persistent marked erythroid and megakaryocytic dysplasia, and ineffective erythropoiesis and granulopoiesis. Immunohistochemical, immunocytochemical, and cytochemical stains resulted in a diagnosis of acute myeloid leukemia of unclassified type. Additional histologic findings included mixed hepatitis with trematode infestation and lymphoplasmacytic interstitial nephritis with fibrosis. The marked thrombocytosis with myelodysplastic syndrome and the FeLV-negative status of this cat were unusual. The difficulty in classifying the myelodysplasia and subsequent leukemia highlights a need for further reporting and characterization of these types of disease.

PMID: 27870069 [PubMed – as supplied by publisher]

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Prediagnostic circulating concentrations of plasma insulin-like growth factor-I and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition.

Int J Cancer. 2016 Nov 21;:

Authors: Perez-Cornago A, Appleby PN, Tipper S, Key TJ, Allen NE, Nieters A, Vermeulen R, Roulland S, Casabonne D, Kaaks R, Fortner RT, Boeing H, Trichopoulou A, La Vecchia C, Klinaki E, Hansen L, Tjønneland A, Bonnet F, Fagherazzi G, Boutron-Ruault MC, Pala V, Masala G, Sacerdote C, Peeters PH, Bueno-de-Mesquita HB, Weiderpass E, Dorronsoro M, Quirós JR, Barricarte A, Gavrila D, Agudo A, Borgquist S, Rosendahl AH, Melin B, Wareham N, Khaw KT, Gunter M, Riboli E, Vineis P, Travis RC

Abstract
Insulin-like growth factor-I (IGF-I) has cancer promoting activities. However, the hypothesis that circulating IGF-I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF-I concentration was measured in pre-diagnostic plasma samples from a nested case-control study of 1072 cases of lymphoid malignancies and 1072 individually matched controls from the European Prospective Investigation into Cancer and Nutrition. Odds ratios (ORs) and confidence intervals (CIs) for lymphoma were calculated using conditional logistic regression. IGF-I concentration was not associated with overall lymphoma risk (multivariable-adjusted OR for highest versus lowest third = 0.77 [95% CI=0.57-1.03], Ptrend = 0.06). There was no statistical evidence of heterogeneity in this association with IGF-I by sex, age at blood collection, time between blood collection and diagnosis, age at diagnosis, or body mass index (Pheterogeneity for all  ≥ 0.05). There were no associations between IGF-I concentration and risk for specific BCL subtypes, T-cell lymphoma or Hodgkin lymphoma, although number of cases were small. In this European population, IGF-I concentration was not associated with risk of overall lymphoma. This study provides the first prospective evidence on circulating IGF-I concentrations and risk of lymphoma. Further prospective data are required to examine associations of IGF-I concentrations with lymphoma subtypes. This article is protected by copyright. All rights reserved.

PMID: 27870006 [PubMed – as supplied by publisher]

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[Sepsis due to Pseudomona as a debut of a primary immunodeficiency in a child].

Arch Argent Pediatr. 2016 Dec 1;114(6):e444-e447

Authors: Vera Sáez-Benito MC, López Úbeda M, Madurga Revilla P, de Arriba Muñoz A, Bustillo Alonso M, Rodríguez-Vigil Iturrate C

Abstract
X-linked agammaglobulinemia is a primary humoral immunodeficiency. It is a recessive X-linked disorder characterized by low or absent circulating mature B cells, hypo/agammaglobulinemia and no humoral response to immunizations due to mutations along chromosome X. It is characterized by severe, recurrent and difficult treatment infections. It is diagnosed in the first 6 months of life in children; the only sign of alarm is the absent or decreased size of tonsils and lymph nodes, but it is not always present. The main cornerstones of treatment are immunoglobulin replacement therapy to maintain serum levels above 500-700 mg/dl and infection control; this allows these patients to do their day-to-day activities. We report a 2 year old boy with X-linked agammaglobulinemia, with no history of interest, who presented with P. aeruginosa sepsis. He had an excellent clinical improvement without further important infections after intravenous immunoglobulin replacement therapy.

PMID: 27869430 [PubMed – in process]

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Novel Mutation of Interferon-γ Receptor 1 Gene Presenting as Early Life Mycobacterial Bronchial Disease.

J Investig Med High Impact Case Rep. 2016 Oct-Dec;4(4):2324709616675463

Authors: Gutierrez MJ, Kalra N, Horwitz A, Nino G

Abstract
Mendelian susceptibility to mycobacterial diseases (MSMD) are a spectrum of inherited disorders characterized by localized or disseminated infections caused by atypical mycobacteria. Interferon-γ receptor 1 (IFNGR1) deficiency was the first identified genetic disorder recognized as MSMD. Mutations in the genes encoding IFNGR1 can be recessive or dominant and cause complete or partial receptor deficiency. We present the case of a 2½-year-old boy with a history of recurrent wheezing, diagnosed with endobronchial mycobacterial infection. Immunological workup revealed a homozygous nonsense mutation in the IFNGR1 gene, a novel mutation predicted in silico to cause complete IFNGR1 deficiency. This case demonstrates that (a) Interferon-γ receptor deficiency can present resembling common disorders of the lung; (b) mycobacterial infections should be suspected when parenchymal lung disease, hilar lymphadenopathy, and endobronchial disease are present; and (c) high index of suspicion for immunodeficiency should be maintained in patients with disseminated nontubercular mycobacterial infection.

PMID: 27868075 [PubMed – in process]

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Adolescent with recurrent tuberculosis: Can it be chronic granulomatous disease?

Indian J Tuberc. 2016 Jul;63(3):207-209

Authors: Gupta Y, Shah I

Abstract
Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder with recurrent bacterial and fungal infections like Staphylococcus aureus, Nocardia spp, Serratia marcescens, Burkholderia cepacia, Salmonella spp. and Aspergillus species. We present a 13-year-old male child who had 3 episodes of tuberculosis (TB) at 5 years, 8 years and 13 years of age, respectively, with no other intercurrent infections and who was diagnosed as CGD at the age of 13 years. This case highlights the possibility of phenotypic variations of CGD. The diagnosis of CGD should also be sought in all children with recurrent TB.

PMID: 27865245 [PubMed – in process]

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Approach to the management of autoimmunity in primary immunodeficiency.

Scand J Immunol. 2016 Nov 8;:

Authors: Azizi G, Ziaee V, Tavakol M, Alinia T, Yazdai R, Mohammadi H, Abolhassani H, Aghamohammadi A

Abstract
Primary immunodeficiency diseases (PIDs) consist of a genetically heterogeneous group of immune disorders that affect distinct elements of the immune system. PID patients are more prone to infections and non-infectious complications, particularly autoimmunity. The concomitance of immunodeficiency and autoimmunity appears to be paradoxical and leads to difficulty in the management of autoimmune complications in PID patients. Therefore, management of autoimmunity in patients with PID requires special considerations because dysregulations and dysfunctions of the immune system along with persistent inflammation, impair the process of diagnosis and treatment. This article is protected by copyright. All rights reserved.

PMID: 27862144 [PubMed – as supplied by publisher]

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Evaluating dose ratio of subcutaneous to intravenous immunoglobulin therapy among patients with primary immunodeficiency disease switching to 20% subcutaneous immunoglobulin therapy.

Am J Manag Care. 2016 Oct;22(15 Suppl):s475-s481

Authors: Krishnarajah G, Lehmann JK, Ellman B, Bhak RH, DerSarkissian M, Leader D, Bullinger AL, Sheng Duh M

Abstract
BACKGROUND: Current prescribing information recommends that physicians apply a dose ratio of 1.37:1 (1.53:1 prior to January 2015) in the United States (US) when switching patients with primary immunodeficiency disease (PI) from intravenous (IVIG) therapy to most subcutaneous therapy ([SCIG], except the 10% SCIG human hyaluronidase and immune globulin). However, a dose ratio of 1:1 was studied and approved for the European Union (EU). The dose-adjustment ratio used by prescribers in real-world US clinical practice is unknown.
OBJECTIVES: To examine real-world Hizentra 20% SCIG-to-IVIG dose ratios in the US after PI patients are switched from IVIG to 20% SCIG (Hizentra).
METHODS: A retrospective longitudinal study was conducted using prescription shipment data of patients with PI from specialty pharmaceutical and service providers from 2011 to 2016. Patients who had at least 1 shipment of IVIG prior to switching to 20% SCIG (Hizentra) and subsequently received at least 1 more 20% SCIG (Hizentra) shipment in the following 6 months were included. Monthly 20% SCIG (Hizentra) doses following a switch from IVIG were calculated for each 2-month interval by summing daily doses that were estimated by dividing shipped volume by days between shipments. Mean monthly IVIG dose was calculated from the total volume shipped prior to switch. Per-patient dose ratios of Hizentra 20% SCIG-to-IVIG were calculated by dividing monthly 20% SCIG (Hizentra) dose by monthly IVIG dose during each 2-month interval. To minimize the influence of outliers, median dose ratios were reported. Dose ratios at months 2 to 4, 4 to 6, and 6 to 8 were compared with the dose ratio at months 0 to 2 using the Wilcoxon signed rank test. A sensitivity analysis excluding pediatric patients was conducted to assess the impact of changes in weight.
RESULTS: Data from 278 patients who met the inclusion criteria showed that median Hizentra 20% SCIG-to-IVIG dose ratios were 1.14:1 at 0 to 2 months post switch, 1.09:1 at 2 to 4 months, and stabilized at 1.05:1 at 4 to 6 and 6 to 8 months post switch. Median dose ratios at months 2 to 4, 4 to 6, and 6 to 8 were statistically significantly lower than the median dose ratio at 0 to 2 months post switch (all P < .001). Similar results were seen in the sensitivity analysis excluding pediatric patients.
CONCLUSIONS: Real-world data indicate that patients were switched to 20% SCIG (Hizentra) from IVIG at dose ratios lower than recommended by US prescribing information but similar to prescribing information in the EU. The initial dose ratio of 1.14:1 at 0 to 2 months stabilized to 1.05:1 at 4 to 6 and 6 to 8 months, which was consistent with reports of dose-equivalent switching patterns used in management of PI in clinical practice in the US.

PMID: 27849353 [PubMed – in process]

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Hematopoietic Stem Cell Transplant in Patients with Activated PI3K Delta Syndrome.

J Allergy Clin Immunol. 2016 Nov 12;:

Authors: Nademi Z, Slatter MA, Dvorak CC, Neven B, Fischer A, Suarez F, Booth C, Rao K, Laberko A, Rodina J, Bertrand Y, Kołtan S, Dębski R, Flood T, Abinun M, Gennery AR, Hambleton S, Ehl S, Cant AJ, Inborn Errors Working Party of EBMT and ESID

PMID: 27847301 [PubMed – as supplied by publisher]

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