Hyperferritinaemia in Dengue Virus Infected Patients Is Associated with Immune Activation and Coagulation Disturbances

During a dengue outbreak on the Caribbean island Aruba, highly elevated levels of ferritin were detected in dengue virus infected patients. Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis. The aim of this study was to investigate whether hyperferritinaemia in dengue patients was associated with clinical markers of extensive immune activation and coagulation disturbances.Levels of ferritin, standard laboratory markers, sIL-2R, IL-18 and coagulation and fibrinolytic markers were determined in samples from patients with uncomplicated dengue in Aruba. Levels of ferritin were significantly increased in dengue patients compared to patients with other febrile illnesses. Moreover, levels of ferritin associated significantly with the occurrence of viraemia. Hyperferritinaemia was also significantly associated with thrombocytopenia, elevated liver enzymes and coagulation disturbances. The results were validated in a cohort of dengue virus infected patients in Brazil. In this cohort levels of ferritin and cytokine profiles were determined. Increased levels of ferritin in dengue virus infected patients in Brazil were associated with disease severity and a pro-inflammatory cytokine profile.Altogether, we provide evidence that ferritin can be used as a clinical marker to discriminate between dengue and other febrile illnesses. The occurrence of hyperferritinaemia in dengue virus infected patients is indicative for highly active disease resulting in immune activation and coagulation disturbances. Therefore, we recommend that patients with hyperferritinaemia are monitored carefully

Spt4 modulates Rad26 requirement in transcription-coupled nucleotide excision repair

The nucleotide excision repair machinery can be targeted preferentially to lesions in transcribed sequences. This mode of DNA repair is referred to as transcription-coupled repair (TCR). In yeast, the Rad26 protein, which is the counterpart of the human Cockayne syndrome B protein, is implicated specifically in TCR. In a yeast strain genetically deprived of global genome repair, a deletion of RAD26 renders cells UV sensitive and displays a defect in TCR. Using a genome-wide mutagenesis approach, we found that deletion of the SPT4 gene suppresses the rad26 defect. We show that suppression by the absence of Spt4 is specific for a rad26 defect and is caused by reactivation of TCR in a Rad26-independent manner. Spt4 is involved in the regulation of transcription elongation. The absence of this regulation leads to transcription that is intrinsically competent for TCR. Our findings suggest that Rad26 acts as an elongation factor rendering transcription TCR competent and that its requirement can be modulated by Spt4

Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances

During a dengue outbreak on the Caribbean island Aruba, highly elevated levels of ferritin were detected in dengue virus infected patients. Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis. The aim of this study was to investigate whether hyperferritinaemia in dengue patients was associated with clinical markers of extensive immune activation and coagulation disturbances. Levels of ferritin, standard laboratory markers, sIL-2R, IL-18 and coagulation and fibrinolytic markers were determined in samples from patients with uncomplicated dengue in Aruba. Levels of ferritin were significantly increased in dengue patients compared to patients with other febrile illnesses. Moreover, levels of ferritin associated significantly with the occurrence of viraemia. Hyperferritinaemia was also significantly associated with thrombocytopenia, elevated liver enzymes and coagulation disturbances. The results were validated in a cohort of dengue virus infected patients in Brazil. In this cohort levels of ferritin and cytokine profiles were determined. Increased levels of ferritin in dengue virus infected patients in Brazil were associated with disease severity and a pro-inflammatory cytokine profile. Altogether, we provide evidence that ferritin can be used as a clinical marker to discriminate between dengue and other febrile illnesses. The occurrence of hyperferritinaemia in dengue virus infected patients is indicative for highly active disease resulting in immune activation and coagulation disturbances. Therefore, we recommend that patients with hyperferritinaemia are monitored carefull

General characteristics cohort Aruba.

<p>In one patient ferritin levels were not determined. Abbreviations: WS− = non-severe dengue without warning signs. WS+ = non-severe dengue with warning signs, OFI = other febrile illness, F = Fisher's exact test, Chi = Chi-squared test, DENV = dengue virus.</p><p>* = Values are in median (interquartile range).</p><p>General characteristics cohort Aruba.</p

Hyperferritinaemia is associated with certain markers of HLH and MAS.

<p>The platelet count (A) was significantly decreased and the liver enzyme ASAT (C) significantly increased in patients with hyperferritinaemia compared to patients with no hyperferritinaemia and OFI at each time point in the cohort from Aruba. Levels of fibrinogen were significantly decreased in patients with hyperferritinaemia compared to patients without hyperferritinaemia at day 6–8 (B). Levels of ALAT were significantly increased in patients with hyperferritinaemia at day 4–5 and 6–8 (D). Levels of sIL-2R were significantly increased in patients with hyperferritinaemia compared to OFI at day 2–3 (E). Levels of IL-18 were significantly increased in patients with no hyperferritinaemia compared to OFI at day 2–3 and in patients with hyperferritinaemia compared to OFI at day 4–5 (F). Missing values: Platelet count, ASAT, ALAT: no missing values. sIL-2R and IL-18: Day 2–3: No HF (N = 3), HF (N = 2). Day 4–5: No HF (N = 5), HF (N = 3). Area between two dotted horizontal lines: interquartile range from the autologous control group. Boxplots indicate the interquartile range, the horizontal line inside the box indicates the median. The whiskers reach from the 10^th till the 90^th percentile. P-value≤0.006 is considered significant.</p

Ferritin levels and fold change are associated with viraemia.

<p>The absolute ferritin levels were significantly increased in viraemic patients compared to non-viraemic patients at day 6–8 (A) and the ferritin fold change was significantly elevated in viraemic patient at each time point (B) in the cohort from Aruba. Area between two dotted horizontal lines: interquartile range from the autologous control group. Boxplots indicate the interquartile range. The horizontal line inside the box indicates the median. The whiskers reach from the 10^th till the 90^th percentile. P-value≤0.02 is considered significant.</p