Abstract
Background
Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2–infected patients. Vitamin K activates both hepatic coagulation factors and ...extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease.
Methods
A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K–dependent MGP (desphospho-uncarboxylated dp-uc MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography.
Results
dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores.
Conclusions
dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.
Indirectly quantified extrahepatic vitamin K status is severely reduced in COVID-19. Data suggest pneumonia-induced vitamin K depletion leading to elastic fiber damage and thrombosis due to impaired vitamin K–dependent activation of matrix Gla protein and endothelial protein S, respectively.
Background
COVID‐19–associated pulmonary aspergillosis (CAPA) has emerged as an invasive fungal disease, often affecting previously immunocompetent, mechanically ventilated, intensive care unit (ICU) ...patients. Incidence rates of 3.8%–33.3% have been reported depending on the geographic area, with high (47%) mortality.
Objectives
Here, we describe a single‐centre prospective case series with CAPA cases from both the first (March‐May, n = 5/33) and second (mid‐September through mid‐December, n = 8/33) COVID‐19 wave at a 500‐bed teaching hospital in the Netherlands.
Patients/Methods
In the first COVID‐19 wave, a total of 265 SARS‐CoV‐2 PCR‐positive patients were admitted to our hospital of whom 33 needed intubation and mechanical ventilation. In the second wave, 508 SARS‐CoV‐2 PCR‐positive patients were admitted of whom 33 needed mechanical ventilation. Data were prospectively collected.
Results
We found a significant decrease in COVID‐19 patients needing mechanical ventilation in the ICU in the second wave (p < .01). From these patients, however, a higher percentage were diagnosed with CAPA (24.2% vs 15.2%), although not significant (p = .36). All CAPA patients encountered in the second wave received dexamethasone. Mortality between both groups was similarly high (40%–50%). Moreover, we found environmental TR34/L98H azole‐resistant Aspergillus fumigatus isolates in two separate patients.
Conclusions
In this series, 19.7% (n = 13/66) of mechanically ventilated SARS‐CoV‐2 patients were diagnosed with CAPA. In addition, we found a significant reduction in COVID‐19 patients needing mechanical ventilation on the ICU in the second wave. Numbers are too small to determine whether there is a true difference in CAPA incidence in mechanically ventilated patients between the two waves, and whether it could be attributed to dexamethasone SARS‐CoV‐2 therapy.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic welfare. The majority of ...infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in the prevention and treatment of severe Covid-19.
Knowledge on bacterial co-infections in COVID-19 is crucial to use antibiotics appropriately. Therefore, we aimed to determine the incidence of bacterial co-infections, antibiotic use and application ...of antimicrobial stewardship principles in hospitalized patients with COVID-19.
We performed a retrospective observational study in four hospitals (1 university, 2 non-university teaching, 1 non-teaching hospital) in the Netherlands from March to May 2020 including consecutive patients with PCR-confirmed COVID-19. Data on first microbiological investigations obtained at the discretion of the physician and antibiotic use in the first week of hospital admission were collected.
Twelve (1.2%) of the 925 patients included had a documented bacterial co-infection (75.0% pneumonia) within the first week. Microbiological testing was performed in 749 (81%) patients: sputum cultures in 105 (11.4%), blood cultures in 711 (76.9%), pneumococcal urinary antigen testing in 202 (21.8%), and Legionella urinary antigen testing in 199 (21.5%) patients, with clear variation between hospitals. On presentation 556 (60.1%; range 33.3-73.4%) patients received antibiotics for a median duration of 2 days (IQR 1-4). Intravenous to oral switch was performed in 41 of 413 (9.9%) patients who received intravenous treatment >48 h. Mean adherence to the local guideline on empiric antibiotic therapy on day 1 was on average 60.3% (range 45.3%-74.7%).
On presentation to the hospital bacterial co-infections are rare, while empiric antibiotic use is abundant. This implies that in patients with COVID-19 empiric antibiotic should be withheld. This has the potential to dramatically reduce the current overuse of antibiotics in the COVID-19 pandemic.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
COVID-19-associated pulmonary aspergillosis (CAPA) is a recently described disease entity affecting patients with severe pulmonary abnormalities treated in intensive care units. Delays in diagnosis ...contribute to a delayed start of antifungal therapy. In addition, the emergence of resistance to triazole antifungal agents puts emphasis on early surveillance for azole-resistant
species. We present a patient with putative CAPA due to
with identification of a triazole-resistant isolate during therapy. We underline the challenges faced in the management of these cases, the importance of early diagnosis and need for surveillance given the emergence of triazole resistance.
The hypercoagulable state observed in COVID‐19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has ...a beneficial effect in hospitalized COVID‐19 patients. This study included 1154 COVID‐19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 95% confidence interval; 0.80–1.30) or length of hospital stay (7.0 4–12 vs. 7.0 4–12 days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 0.05–0.80). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID‐19 patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Timely switch from intravenous (iv) antibiotics to oral therapy is a key component of antimicrobial stewardship programs in order to improve patient safety, promote early discharge and reduce costs. ...We have introduced a time-efficient and easily implementable intervention that relies on a computerized trigger tool, which identifies patients who are candidates for an iv to oral antibiotic switch.
The intervention was introduced on all internal medicine wards in a teaching hospital. Patients were automatically identified by an electronic trigger tool when parenteral antibiotics were used for >48 h and clinical or pharmacological data did not preclude switch therapy. A weekly educational session was introduced to alert the physicians on the intervention wards. The intervention wards were compared with control wards, which included all other hospital wards. An interrupted time-series analysis was performed to compare the pre-intervention period with the post-intervention period using '% of i.v. prescriptions >72 h' and 'median duration of iv therapy per prescription' as outcomes. We performed a detailed prospective evaluation on a subset of 244 prescriptions to evaluate the efficacy and appropriateness of the intervention.
The number of intravenous prescriptions longer than 72 h was reduced by 19% in the intervention group (
= 1519) (
< 0.01) and the median duration of iv antibiotics was reduced with 0.8 days (
= <0.05). Compared to the control group (
= 4366) the intervention was responsible for an additional decrease of 13% (
< 0.05) in prolonged prescriptions. The detailed prospective evaluation of a subgroup of patients showed that adherence to the electronic reminder was 72%.
An electronic trigger tool combined with a weekly educational session was effective in reducing the duration of intravenous antimicrobial therapy.
Background: In observational studies, high levels of desphospho-uncarboxylated matrix gla protein (dp-ucMGP) that result from vitamin K deficiency were consistently associated with poor clinical ...outcomes during COVID-19. Vitamin K-activated matrix gla protein (MGP) is required to protect against elastic fibre degradation, and a deficiency may contribute to pathology. However, intervention trials assessing the effects of vitamin K supplementation in COVID-19 are lacking. Methods: This is a single-centre, phase 2, double-blind, randomised, placebo-controlled trial investigating the effects of vitamin K2 supplementation in 40 hospitalised COVID-19 patients requiring supplemental oxygen. Individuals were randomly assigned in a 1:1 ratio to receive 999 mcg of vitamin K2—menaquinone-7 (MK-7)—or a placebo daily until discharge or for a maximum of 14 days. Dp-ucMGP, the rate of elastic fibre degradation quantified by desmosine, and hepatic vitamin K status quantified by PIVKA-II were measured. Grade 3 and 4 adverse events were collected daily. As an exploratory objective, circulating vitamin K2 levels were measured. Results: Vitamin K2 was well tolerated and did not increase the number of adverse events. A linear mixed model analysis showed that dp-ucMGP and PIVKA-II decreased significantly in subjects that received supplementation compared to the controls (p = 0.008 and p = 0.0017, respectively), reflecting improved vitamin K status. The decrease in dp-ucMGP correlated with higher plasma MK-7 levels (p = 0.015). No significant effect on desmosine was found (p = 0.545). Conclusions: These results demonstrate that vitamin K2 supplementation during COVID-19 is safe and decreases dp-ucMGP. However, the current dose of vitamin K2 failed to show a protective effect against elastic fibre degradation.
Pathology during COVID-19 infection arises partly from an excessive inflammatory response with a key role for interleukin (IL)-6. Both vitamin D and K have been proposed as potential modulators of ...this process.
We assessed vitamin D and K status by measuring circulating 25-hydroxyvitamin D (25(OH)D) and desphospho-uncarboxylated Matrix Gla-Protein (dp-ucMGP), respectively in 135 hospitalized COVID-19 patients in relation to inflammatory response, elastic fiber degradation and clinical outcomes.
Comparing good and poor disease outcomes of COVID-19 patients, vitamin 25(OH)D levels were not significantly different. IL-6 levels, however, were significantly higher in patients with poor outcome, compared to patients with good outcome (30.3 vs. 153.0 pg/mL;
< 0.0001). Dp-ucMGP levels as biomarker of extrahepatic vitamin K status was associated with IL-6 levels (r = 0.35;
< 0.0001). In contrast, 25(OH)D levels were only borderline statistically significant correlated with IL-6 (r = -0.14;
<0.050). A significant association was also found between IL-6 and elastic fiber degradation. Contrary to vitamin K status, 25(OH)D did not correlate with elastic fiber degradation.
Dp-ucMGP associates with IL-6 as a central component of the destructive inflammatory processes in COVID-19. An intervention trial may provide insight whether vitamin K administration, either or not in combination with vitamin D, improves clinical outcome of COVID-19.
We conducted a prospective study to update our knowledge of fever of unknown origin (FUO) and to explore the utility of a structured diagnostic protocol. From December 2003 to July 2005, 73 patients ...with FUO were recruited from 1 university hospital (n = 40) and 5 community hospitals (n = 33) in the same region in The Netherlands. FUO was defined as a febrile illness of >3 weeks' duration, a temperature of >38.3 degrees C on several occasions, without a diagnosis after standardized history-taking, physical examination, and certain obligatory investigations. Immunocompromised patients were excluded. A structured diagnostic protocol was used. Patients from the university hospital were characterized by more secondary referrals and a higher percentage of periodic fever than those referred to community hospitals. Infection was the cause in 16%, a neoplasm in 7%, noninfectious inflammatory diseases in 22%, miscellaneous causes in 4%, and in 51%, the cause of fever was not found (no differences between university and community hospitals). There were no differences regarding the number and type of investigations between university and community hospitals. Significant predictors for reaching a diagnosis included continuous fever; fever present for <180 days; elevated erythrocyte sedimentation rate, C-reactive protein, or lactate dehydrogenase; leukopenia; thrombocytosis; abnormal chest computed tomography (CT); and abnormal F-fluorodeoxyglucose positron emission tomography (FDG-PET). For future FUO studies, inclusion of outpatients and the use of a set of obligated investigations instead of a time-related criterion are recommended. Except for tests from the obligatory part of our protocol and cryoglobulins in an early stage, followed by FDG-PET, and in a later stage by abdominal and chest CT, temporal artery biopsy in patients aged 55 years or older, and possibly bone marrow biopsy, other tests should not be used as screening investigations.
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