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Granulomatous-lymphocytic interstitial lung disease and recurrent sinopulmonary infections in a patient with Good’s syndrome.

BMJ Case Rep. 2015;2015

Authors: Jensen ML, Bendstrup E, Hilberg O

Abstract
Good’s syndrome is a rare primary immunodeficiency associated with adult thymoma. Complications are mainly autoimmune manifestations and recurrent infections with encapsulated bacteria. Only one possible case of combined granulomatous-lymphocytic interstitial lung disease (GL-ILD) and Good’s syndrome have been described earlier, but the patient died at the time of diagnosis. This is the first case of GL-ILD in Good’s syndrome with a successful outcome. We present a case of a 43-year-old man with GL-ILD, who suffered from recurrent infections of Haemophilus influenzae and Pneumocystis jirovecii, with 8-year follow-up. After a thymectomy, he was diagnosed with Good’s syndrome and GL-ILD. He was treated with prophylactic pivampicillin, quinolones and cephalosporins for his recurrent P. jirovecii and H. influenzae infections, an approach that proved unsuccessful due to resistance, with relapse after cessation. He was stabilised with oral diaminodiphenyl-sulfone for P. jirovecii and colistimethate-sodium inhalations for H. influenzae, which is a new approach to prophylactic treatment.

PMID: 26424818 [PubMed – in process]

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Primary Immunodeficiencies Associated with EBV Disease.

Curr Top Microbiol Immunol. 2015;390:241-65

Authors: Cohen JI

Abstract
Epstein-Barr virus (EBV) infects nearly all humans and usually is asymptomatic, or in the case of adolescents and young adults, it can result in infectious mononucleosis. EBV-infected B cells are controlled primarily by NK cells, iNKT cells, CD4 T cells, and CD8 T cells. While mutations in proteins important for B cell function can affect EBV infection of these cells, these mutations do not result in severe EBV infection. Some genetic disorders affecting T and NK cell function result in failure to control EBV infection, but do not result in increased susceptibility to other virus infections. These include mutations in SH2D1A, BIRC4, ITK, CD27, MAGT1, CORO1A, and LRBA. Since EBV is the only virus that induces proliferation of B cells, the study of these diseases has helped to identify proteins critical for interactions of T and/or NK cells with B cells. Mutations in three genes associated with hemophagocytic lymphohistocytosis, PRF1, STXBP2, and UNC13D, can also predispose to severe chronic active EBV disease. Severe EBV infection can be associated with immunodeficiencies that also predispose to other viral infections and in some cases other bacterial and fungal infections. These include diseases due to mutations in PIK3CD, PIK3R1, CTPS1, STK4, GATA2, MCM4, FCGR3A, CARD11, ATM, and WAS. In addition, patients with severe combined immunodeficiency, which can be due to mutations in a number of different genes, are at high risk for various infections as well as EBV B cell lymphomas. Identification of proteins important for control of EBV may help to identify new targets for immunosuppressive therapies.

PMID: 26424649 [PubMed – in process]

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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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Determinants of the t(14;18) translocation and their role in t(14;18)-positive follicular lymphoma.

Cancer Causes Control. 2015 Sep 30;

Authors: Kelly RS, Roulland S, Morgado E, Sungalee S, Jouve N, Tumino R, Krogh V, Panico S, Polidoro S, Masala G, Sánchez MJ, Chirlaque MD, Sala N, Gurrea AB, Dorronsoro M, Travis RC, Riboli E, Gunter M, Murphy N, Vermeulen R, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Trichopoulos D, Lagiou P, Nieters A, Canzian F, Kaaks R, Boeing H, Weiderpass E, Stocks T, Melin B, Overvad K, Tjønneland A, Olsen A, Brennan P, Johansson M, Nadel B, Vineis P

Abstract
PURPOSE: The strong association between t(14;18) translocation and follicular lymphoma (FL) is well known. However, the determinants of this chromosomal aberration and their role in t(14;18) associated FL remain to be established.
METHODS: t(14;18) frequency within the B cell lymphoma 2 major breakpoint region was determined for 135 incident FL cases and 251 healthy controls as part of a nested case-control study within the European Prospective Investigation into Cancer cohort. Quantitative real-time PCR was performed in DNA extracted from blood samples taken at recruitment. The relationship between prevalence and frequency of the translocation with baseline anthropometric, lifestyle, and dietary factors in cases and controls was determined. Unconditional logistic regression was used to explore whether the risk of FL associated with these factors differed in t(14;18)(+) as compared to t(14;18)(-) cases.
RESULTS: Among incident FL cases, educational level (χ (2) p = 0.021) and height (χ (2) p = 0.025) were positively associated with t(14;18) prevalence, and cases with high frequencies [t(14;18)(HF)] were significantly taller (t test p value = 0.006). These findings were not replicated in the control population, although there were a number of significant associations with dietary variables. Further analyses revealed that height was a significant risk factor for t(14;18)(+) FL [OR 6.31 (95 % CI 2.11, 18.9) in the tallest versus the shortest quartile], but not t(14;18)(-) cases.
CONCLUSIONS: These findings suggest a potential role for lifestyle factors in the prevalence and frequency of the t(14;18) translocation. The observation that the etiology of FL may differ by t(14;18) status, particularly with regard to height, supports the subdivision of FL by translocation status.

PMID: 26424368 [PubMed – as supplied by publisher]

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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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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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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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