Infective endocarditis (IE) may be misdiagnosed as ANCA-associated vasculitis (AAV), especially when antineutrophil cytoplasmic antibodies (ANCA) are detected. Distinguishing IE from AAV is crucial... Show moreInfective endocarditis (IE) may be misdiagnosed as ANCA-associated vasculitis (AAV), especially when antineutrophil cytoplasmic antibodies (ANCA) are detected. Distinguishing IE from AAV is crucial to guide therapy. However, little is known about ANCA positivity in IE patients. We present a case report and systematic review of the literature on patients with ANCA-positive IE, aiming to provide a comprehensive overview of this entity and to aid clinicians in their decisions when encountering a similar case. A systematic review of papers on original cases of ANCA-positive IE without a previous diagnosis of AAV was conducted on PubMed in accordance with PRISMA-IPD guidelines. A predefined set of clinical, laboratory, and kidney biopsy findings was extracted for each patient and presented as a narrative and quantitative synthesis. A total of 74 reports describing 181 patients with ANCA-positive IE were included (a total of 182 cases including our own case). ANCA positivity was found in 18-43% of patients with IE. Patients usually presented with subacute IE (73%) and had positive cytoplasmic ANCA-staining or anti-proteinase-3 antibodies (79%). Kidney function was impaired in 72%; kidney biopsy findings were suggestive of immune complexes in 59%, while showing pauci-immune glomerulonephritis in 37%. All were treated with antibiotics; 39% of patients also received immunosuppressants. During follow-up, 69% of patients became ANCA-negative and no diagnosis of systemic vasculitis was reported. This study reviewed the largest series of patients with ANCA-positive IE thus far and shows the overlap in clinical manifestations between IE and AAV. We therefore emphasize that clinicians should be alert to the possibility of an underlying infection when treating a patient with suspected AAV, even when reassured by ANCA positivity. Show less
Polak, S.B.; Gool, I.C. van; Cohen, D.; Thusen, J.H. von der; Paassen, J. van 2020
Since the outbreak of the COVID-19 pandemic, much has been learned regarding its clinical course, prognostic inflammatory markers, disease complications, and mechanical ventilation strategy.... Show moreSince the outbreak of the COVID-19 pandemic, much has been learned regarding its clinical course, prognostic inflammatory markers, disease complications, and mechanical ventilation strategy. Clinically, three stages have been identified based on viral infection, pulmonary involvement with inflammation, and fibrosis. Moreover, low and high elastance phenotypes can be distinguished in mechanically ventilated patients, based on lung mechanics, ventilation-to-perfusion ratio, and CT scans; these two phenotypes have presumed differences in their underlying pathophysiology. Although essential for therapeutic guidance, the pathophysiology of COVID-19 is poorly understood. Here, we systematically reviewed published case reports and case series in order to increase our understanding of COVID-19 pathophysiology by constructing a timeline and correlating histopathological findings with clinical stages of COVID-19. Using PRISMA-IPD guidelines, 42 articles reporting 198 individual cases were included in our analysis. In lung samples (n = 131 cases), we identified three main histological patterns: epithelial (n = 110, 85%), with reactive epithelial changes and DAD; vascular (n = 76, 59%) with microvascular damage, (micro)thrombi, and acute fibrinous and organizing pneumonia; and fibrotic (n = 28, 22%) with interstitial fibrosis. The epithelial and vascular patterns can present in all stages of symptomatic COVID-19, whereas the fibrotic pattern presents starting at similar to 3 weeks. Moreover, patients can present with more than one pattern, either simultaneously or consecutively. These findings are consistent with knowledge regarding clinical patterns of viral infection, development of hyperinflammation and hypercoagulability, and fibrosis. Close collaboration among medical staff is necessary in order to translate this knowledge and classification of pathophysiological mechanisms into clinical stages of disease in individual patients. Moreover, further research, including histopathological studies, is warranted in order to develop reliable, clinically relevant biomarkers by correlating these pathological findings with laboratory results and radiological findings, thus, increasing our understanding of COVID-19 and facilitating the move to precision medicine for treating patients. Show less
Workel, H.H.; Lubbers, J.M.; Arnold, R.; Prins, T.M.; Vlies, P. van der; Lange, K. de; ... ; Bruyn, M. de 2019
Somatic mutations in the proofreading domain of DNA polymerase epsilon denote a distinct molecular subgroup of endometrial cancer, characterized by an exceptionally high mutational burden.... Show moreSomatic mutations in the proofreading domain of DNA polymerase epsilon denote a distinct molecular subgroup of endometrial cancer, characterized by an exceptionally high mutational burden. Despite this so-called ‘ultramutated’ phenotype, POLE-mutant endometrial cancers have an excellent prognosis with very few recurrences. This thesis provides insights into somatic POLE exonuclease domain mutations in endometrial cancer and especially into the underlying mechanisms by which these POLE mutations contribute to the favorable clinical outcome. Studies in this thesis focus on the immune response in POLE-mutant endometrial cancers and show that these tumors are characterized by an intratumoral T cell response. This response correlates with an enrichment of neo-epitopes, providing a plausible mechanisms for the excellent prognosis of these cancers. We demonstrate that increased sensitivity to adjuvant treatment cannot explain the good clinical outcome. Furthermore, we show that somatic POLE mutations are early, and probably initiating events in endometrial and colorectal carcinogenesis. These insights provide a deeper understanding of the molecular mechanisms underlying this group of endometrial cancers and may facilitate the implementation of POLE mutation screening in routine clinical practice. This would be an important step towards a more tailored treatment approach in endometrial cancer. Show less
