Research

Infectious Mononucleosis.

Curr Top Microbiol Immunol. 2015;390:211-40

Authors: Dunmire SK, Hogquist KA, Balfour HH

Abstract
Infectious mononucleosis is a clinical entity characterized by sore throat, cervical lymph node enlargement, fatigue, and fever most often seen in adolescents and young adults and lasting several weeks. It can be caused by a number of pathogens, but this chapter only discusses infectious mononucleosis due to primary Epstein-Barr virus (EBV) infection. EBV is a γ-herpesvirus that infects at least 90 % of the population worldwide. The virus is spread by intimate oral contact among teenagers and young adults. How preadolescents acquire the virus is not known. A typical clinical picture with a positive heterophile test is usually sufficient to make the diagnosis, but heterophile antibodies are not specific and do not develop in some patients. EBV-specific antibody profiles are the best choice for staging EBV infection. In addition to causing acute illness, there can also be long-term consequences as the result of acquisition of the virus. Several EBV-related illnesses occur including certain cancers and autoimmune diseases, as well as complications of primary immunodeficiency in persons with the certain genetic mutations. A major obstacle to understanding these sequelae has been the lack of an efficient animal model for EBV infection, although progress in primate and mouse models has recently been made. Key future challenges are to develop protective vaccines and effective treatment regimens.

PMID: 26424648 [PubMed – in process]

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A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma.

Haematologica. 2015 Mar;100(3):357-62

Authors: Chen R, Frankel P, Popplewell L, Siddiqi T, Ruel N, Rotter A, Thomas SH, Mott M, Nathwani N, Htut M, Nademanee A, Forman SJ, Kirschbaum M

Abstract
This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1-14 along with 375 mg/m(2) of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876.

PMID: 25596263 [PubMed – indexed for MEDLINE]

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Health-related quality of life in patients with primary immunodeficiency disease.

Allergy Asthma Clin Immunol. 2015;11:27

Authors: Jiang F, Torgerson TR, Ayars AG

Abstract
Primary immunodeficiency disease (PIDD) with hypogammaglobulinemia is characterized by recurrent and severe bacterial infections and IgG replacement is the standard of care in many of these patients. Health-related quality of life (HRQOL) is becoming increasingly recognized as a factor that affects patient well-being and treatment preferences. In an effort to better understand what factors affect HRQOL in patients with PIDD, we reviewed the published literature that used standardized instruments for the measurement of HRQOL. We investigated HRQOL in PIDD patients compared with normal controls and patients with other chronic diseases; we also investigated the impact of treatment administration on patient satisfaction. The most commonly encountered health-related quality of life instruments were the child heath questionnaire parental form 50, short form 36, PedsQL 4.0, Lansky’s play performance scale, and Life Quality Index. Patients with PIDD scored significantly lower on many of the instruments compared with normal controls. Also, while it appears that many patients appreciate home-based and subcutaneous IgG replacement therapy, patient satisfaction ultimately involves various clinical factors and individual patient preferences. By further analyzing what factors impact HRQOL, therapy adjustments can be made to maximize patient well-being and minimize disease impact on daily functioning.

PMID: 26421019 [PubMed]

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Does the frequency of respiratory tract infections help to identify humoral immunodeficiencies in a primary health-care cohort?

Infect Dis (Lond). 2015 Jan;47(1):13-9

Authors: Wågström P, Bengnér M, Dahle C, Nilsdotter-Augustinsson Å, Neumark T, Brudin L, Björkander J

Abstract
BACKGROUND: Primary immune deficiency (PID) due to humoral defects is associated with recurrent respiratory tract infections (RTIs). Reliable clinical warning signs of PID would facilitate early diagnosis and thereby reduce long-term complications. The aim of the present study was to evaluate the accuracy of the warning sign, ‘four or more antibiotic-treated RTIs annually for 3 or more consecutive years,’ for detecting PID among adults in a primary health-care setting.
METHODS: Fifty-three cases with ‘four or more antibiotic-treated RTIs annually for 3 or more consecutive years’ were selected from a Swedish primary health-care registry of RTIs. In addition, 66 age- and sex-matched controls were selected having a maximum of one antibiotic-treated RTI during the period covered by the study. Levels of immunoglobulin (Ig) IgG, IgA, IgM, IgG subclasses, and IgG antibodies against Haemophilus influenzae and Streptococcus pneumoniae as well as the inflammatory markers, C-reactive protein, interleukin (IL)-6 and IL-8 were determined.
RESULTS: IgG subclass deficiencies (IgGsd) were found in 5/53 (9.4%) of the cases and in 7/66 (10.6%) controls. The most frequent deficiency was IgG3sd and this was found in three participants in the case group and seven in the control group. The mean level of IgG3 was lower in the control group (p = 0.02). The mean level of IL-8 was lower in the case group (p = 0.02).
CONCLUSION: The results show that physicians working in primary health care cannot solely rely on the frequency of antibiotic-treated RTIs as a warning sign for the detection of common humoral immune deficiencies.

PMID: 25378084 [PubMed – indexed for MEDLINE]

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CD133-targeted gene transfer into long-term repopulating hematopoietic stem cells.

Mol Ther. 2015 Jan;23(1):63-70

Authors: Brendel C, Goebel B, Daniela A, Brugman M, Kneissl S, Schwäble J, Kaufmann KB, Müller-Kuller U, Kunkel H, Chen-Wichmann L, Abel T, Serve H, Bystrykh L, Buchholz CJ, Grez M

Abstract
Gene therapy for hematological disorders relies on the genetic modification of CD34(+) cells, a heterogeneous cell population containing about 0.01% long-term repopulating cells. Here, we show that the lentiviral vector CD133-LV, which uses a surface marker on human primitive hematopoietic stem cells (HSCs) as entry receptor, transfers genes preferentially into cells with high engraftment capability. Transduction of unstimulated CD34(+) cells with CD133-LV resulted in gene marking of cells with competitive proliferative advantage in vitro and in immunodeficient mice. The CD133-LV-transduced population contained significantly more cells with repopulating capacity than cells transduced with vesicular stomatitis virus (VSV)-LV, a lentiviral vector pseudotyped with the vesicular stomatitis virus G protein. Upon transfer of a barcode library, CD133-LV-transduced cells sustained gene marking in vivo for a prolonged period of time with a 6.7-fold higher recovery of barcodes compared to transduced control cells. Moreover, CD133-LV-transduced cells were capable of repopulating secondary recipients. Lastly, we show that this targeting strategy can be used for transfer of a therapeutic gene into CD34(+) cells obtained from patients suffering of X-linked chronic granulomatous disease. In conclusion, direct gene transfer into CD133(+) cells allows for sustained long-term engraftment of gene corrected cells.

PMID: 25189742 [PubMed – indexed for MEDLINE]

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Combined primary immune deficiency: diagnosis by clinical flow cytometry.

MLO Med Lab Obs. 2015 Feb;47(2):18, 20

Authors: Dasu T

PMID: 26268038 [PubMed – indexed for MEDLINE]

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A Case of Probable MHC Class II Deficiency with Disseminated BCGitis.

Iran J Immunol. 2015 Sep;12(3):219-25

Authors: Alyasin S, Abolnezhadian F, Khoshkhui M

Abstract
Major histocompatibility complex (MHC) class II deficiency is a primary immunodeficiency disease characterized by abnormality of MHC class II molecules surface expression on peripheral blood lymphocytes and monocytes. Clinical manifestations include extreme susceptibility to viral, bacterial, and fungal infections but the immunodeficiency is not as severe as SCID (severe combined immunodeficiency), as evidenced by failure to develop disseminated infection after BCG vaccination. Therefore, MHC II deficiency with BCGosis, that is disseminated BCGitis, is not reported commonly. We report an interesting case of BCGosis after vaccination that was diagnosed to have probable MHC II deficiency.

PMID: 26412640 [PubMed – in process]

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Report on the First Survey of Iranian Patients with Hereditary Angioedema.

Iran J Immunol. 2015 Sep;12(3):209-18

Authors: Shahinpour S, Tavakol M, Abolhassani H, Mohammadinejad P, Movahedi M, Arshi S, Aghamohammadi A

Abstract
BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant primary immunodeficiency with complement system defect characterized by recurrent episodes of angioedema involving the skin or mucosa of the upper respiratory and gastrointestinal tracts.
OBJECTIVE: To characterize the clinical and laboratory data of hereditary angioedema in Iran.
METHODS: Patients with probable diagnosis of angioedema were enrolled in this study. Demographic and clinical data were documented in the designed questionnaire including history of attacks, triggering factors and laboratory data such as C4, C1 esterase inhibitor level and function.
RESULTS: Among 63 patients who were clinically suspicious for angioedema (23 males and 40 females), 8 cases (12.7%) were diagnosed with HAE. Among these 8 HAE patients, 3 were diagnosed with HAE type 1 and five patients were diagnosed with HAE type 2. The mean ages of HAE type 1 and type 2 patients were 25.6 ± 13.5 and 22.4 ± 12.32 years. The mean age of onset in HAE type 1 group was 8 ± 5 years and in HAE type 2 group was 18.8 ± 11.84 years. The mean diagnosis delay was 17.6 years in HAE type 1 patients and 2.6 years in HAE type 2. The most common clinical manifestation was facial swelling presented in all HAE patients followed by swelling of extremities which was present in 7 patients with HAE.
CONCLUSION: The clinical criteria of the Iranian patients with HAE were consistent with the known clinical patterns of the disease.

PMID: 26412639 [PubMed – in process]

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A novel common gamma chain mutation in a Chinese family with X-linked severe combined immunodeficiency (X-SCID; T(-)NK(-)B(+)).

Immunogenetics. 2015 Sep 26;

Authors: Tan W, Yu S, Lei J, Wu B, Wu C

Abstract
X-linked severe combined immunodeficiency (X-SCID) is one of the most common causes of primary immunodeficiencies in humans. A 4-month-old boy with recurrent pulmonary infection had decreased numbers of CD3(+), CD4(+), CD8(+) T lymphocytes, and NK cells and increased levels of CD19(+) B cells but no memory B cells or plasma cells. The production of cytokines by T cells and the activation of T and B cells were either absent or inefficient. While B cell levels were high, they were all IgM-positive, and the secretion of all Ig isotypes by activated B cells in vitro was defective. Genomic DNA sequencing revealed that the patient had missense mutations in the IL2RG (exon 5, 718 T > C) and IL7R genes (exon 2, 197 T > C; exon 4, 412G > A). Although the patient’s father and one of his sisters have the same missense homozygous mutations of the IL7R gene, neither of them exhibited the immunological phenotype of SCID. The results indicate that the IL2RG gene mutation or a combination of the IL7R and IL2RG mutations in the sick boy had resulted in T(-)NK(-)B(+) SCID.

PMID: 26409833 [PubMed – as supplied by publisher]

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Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism.

J Clin Immunol. 2015 Sep 26;

Authors: Okuno Y, Hoshino A, Muramatsu H, Kawashima N, Wang X, Yoshida K, Wada T, Gunji M, Toma T, Kato T, Shiraishi Y, Iwata A, Hori T, Kitoh T, Chiba K, Tanaka H, Sanada M, Takahashi Y, Nonoyama S, Ito M, Miyano S, Ogawa S, Kojima S, Kanegane H

Abstract
Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8(+) and CD56(+) cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.

PMID: 26407811 [PubMed – as supplied by publisher]

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