Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation,... Show moreBiallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV1 at diagnosis, but only similar to 30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD81 T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma. Show less
Zoest, R.A. van; Law, M.; Sabin, C.A.; Vaartjes, I.; Valk, M. van der; Arends, J.E.; ... ; Elst-Laurijssen, D.H. 2019
BACKGROUND: Excessive prescription of antibiotics in patients with lower respiratory tract infection (LRTI) is common in primary care and might be reduced by rapid point-of-care (POC) C-reactive... Show moreBACKGROUND: Excessive prescription of antibiotics in patients with lower respiratory tract infection (LRTI) is common in primary care and might be reduced by rapid point-of-care (POC) C-reactive protein (CRP) testing. However, the exact benefits of this test are unclear. OBJECTIVE: To review the available evidence for the role of POC CRP measurement in (i) guiding antibiotic prescription, (ii) predicting aetiology, (iii) prognosis and (iv) diagnosis (pneumonia) in LRTI patients. METHODS: For each research question, studies were retrieved through an electronic literature search in Medline, Embase and the Cochrane Library using synonyms for CRP and LRTI combined with different relevant subheadings. Study quality was assessed using validated instruments and predefined outcome measures were extracted from each study. RESULTS: The search yielded 13 articles, each answering one or more questions; one was excluded by insufficient internal validity. (i) One of four studies showed a significant reduction in the antibiotic prescriptions when applying POC CRP measurement [relative risk (RR) 0.6, 95% confidence interval (CI) 0.5-0.7]. (ii) Three studies on aetiology demonstrated that an elevated CRP was associated with bacterial [odds ratio (OR) 2.46-4.8] and one with viral (OR 2.7) aetiology. (iii) Results on the prognostic value were contradictory, providing evidence for faster symptom resolution (RR 1.16, 95% CI 1.1-1.3), higher mortality rate (RR 2.5, 95% CI 1.2-5.1) and no difference in outcome in patients with high CRP levels. (iv) Four studies showed that CRP had limited value as a single predictor of pneumonia. When combined with clinical assessment, its value increased according to two of these studies (receiver operating characteristic area from 0.7 to 0.9). However, methodological flaws and/or wide CIs limit the generalizability of findings in all studies. CONCLUSION: The evidence for the benefits of POC CRP measurement in LRTI patients in primary care is limited, contradictory and does not support its use to guide treatment decisions yet. Show less
Objective-To compare the effects of rosiglitazone (8 mg/d, n = 19) and metformin (2 g/d, n = 18) on postprandial lipemia in patients with HIV-lipodystrophy. Methods and Results-Lipodystrophy in HIV... Show moreObjective-To compare the effects of rosiglitazone (8 mg/d, n = 19) and metformin (2 g/d, n = 18) on postprandial lipemia in patients with HIV-lipodystrophy. Methods and Results-Lipodystrophy in HIV is associated with insulin resistance and disturbed postprandial triglyceride and free fatty acid (FFA) metabolism. We conducted an open randomized 6-month study with standardized 10-h oral fat-loading tests at baseline and after treatment. Rosiglitazone (-34%) and metformin (-37%) reduced homeostasis model assessment similarly (P < 0.05). Rosiglitazone did not change the area under the curve for FFA and triglyceride; however, it did reduce the area under the curve for hydroxybutyric acid (a marker of hepatic FFA oxidation) by 25% (P < 0.05). Rosiglitazone increased the area under the curve for remnantlike particle cholesterol by 40% (P < 0.01) compared with baseline. Metformin did not change any of the postprandial measurements. Conclusion-Rosiglitazone improved insulin sensitivity and decreased postprandial hydroxybutyric acid levels in patients with HIV-lipodystrophy, suggesting improved FFA handling. Despite metabolic improvements, rosiglitazone caused a marked increase in postprandial remnantlike particle cholesterol, which may adversely affect cardiovascular risk. Metformin did not affect postprandial lipemia and could be used to treat insulin resistance in this population. (Arterioscler Thromb Vasc Biol. 2011;31:228-233.) Show less
Treatment of community-acquired pneumonia (CAP) with newer fluoroquinolones may contribute to selection for Clostridium difficile. We studied the prevalence of C. difficile carriage and C.... Show moreTreatment of community-acquired pneumonia (CAP) with newer fluoroquinolones may contribute to selection for Clostridium difficile. We studied the prevalence of C. difficile carriage and C. difficile infection (CDI) on admission, and nosocomial acquisition rates in patients hospitalized for CAP and compared different empirical treatment strategies. In a prospective study among patients admitted for antibiotic treatment of CAP, consecutive stool and skin samples were collected and cultured for C. difficile. Cultured isolates were typed by PCR ribotyping and characterized for toxinogenicity. In total, 20 of 107 (18.7%) patients included carried C. difficile. Various ribotypes were found and 14 (70%) isolates were toxinogenic. On admission, prevalence of C. difficile carriage was 9.4% (n = 9), of which 22% also carried C. difficile on the skin and one patient had mild CDI with persistent positive cultures. The overall nosocomial acquisition rate of C. difficile carriage was 11.2%. No nosocomially acquired CDI occurred. Acquisition rates of C. difficile were 11.9% (5/45) in moxifloxacin-, 11.1% (5/47) in beta-lactam- and 9.0% (1/14) in beta-lactam plus macrolide- or fluoroquinolone-treated patients (P = 0.84). Risk factors for C. difficile carriage were intravenous antibiotic treatment > 7 days [odds ratio (OR) 3.89; 95% confidence interval (CI) 1.30 to 11.79] and hospitalization during the past 3 months (OR 4.08; 95% CI 1.40 to 11.90). In a non-outbreak setting with a low endemic rate, the prevalence of C. difficile carriage in patients admitted because of CAP is high and nosocomial acquisition rates for C. difficile colonization are 11%. Fluoroquinolones were not associated with increased acquisition rates for C. difficile as compared with other empirical regimens for CAP. Show less
