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Background Respiratory failure and thromboembolism are frequent in SARS-CoV-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 135 hospitalized COVID-19 patients were compared with 184 historical controls. Poor outcome was defined as invasive ventilation and/or death. Inactive vitamin K-dependent MGP (dp-ucMGP) 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 by computed tomography Results Dp-ucMGP was elevated in COVID-19 patients compared to controls (p<0.001), with even higher dp-ucMGP in patients with poor outcomes (p<0.001). PIVKA-II was normal in 82.1% of patients. Dp-ucMGP was correlated with desmosine (p<0.001), and coronary artery (p=0.002) and thoracic aortic (p<0.001) calcification scores Conclusions Dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome while hepatic procoagulant factor II remained unaffected. These data suggest a mechanism of 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. A clinical trial could assess whether vitamin K administration improves COVID-19 outcomes
Proposed sequential pathologic steps linking SARS-CoV-2 pneumonia to vitamin K insufficiency and accelerated elastic fiber degradation. (1) SARS-CoV-2 enters AT2 cell. (2) The infected AT2 cell responds by upregulating synthesis of proinflammatory cytokines. (3) This leads to an increase in the number and activation of pulmonary macrophages. (4) These infiltrating macrophages produce MMPs (5), which leads to accelerated degradation of elastic fibers (5a) and thereby the release of desmosine from these fibers (5b), leading to elevated desmosine levels in lungs and blood. (6) The increased polarity of partially degraded elastic fibers (7) enhances their affinity for calcium and, consequently, leads to increased elastic fiber calcium content. (7a) MMP synthesis is upregulated in parallel with the calcium content, which further accelerates elastic fiber degradation in a self-propagating vicious circle. (8) MGP synthesis is upregulated in an attempt to protect elastic fibers from calcification and degradation, (8a) which means that need for vitamin K to activate additional MGP increases. (8b) This increased use of vitamin K may induce vitamin K insufficiency, (9) in which case increased production of MGP in a state of vitamin K insufficiency leads to increased dp-ucMGP in lungs and blood. Abbreviations: AT2, alveolar type II; dp-uc, desphospho-uncarboxylated; MGP, matrix Gla protein; MMP, matrix metalloproteinase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 Downloaded from by guest on 29 October 2020
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Severe Vitamin K Insufficiency in COVID-19 • CID 2020:XX (XX XXXX) • 1
Clinical Infectious Diseases
Received 26 June 2020; editorial decision 19 August 2020; accepted 25 August 2020; published
online August 27, 2020.
aA. S.M. D., I.P., L.J. S., and M.P. J.V.contributed equally to this work.
bJ. W.and R.J.contributed equally to this work.
Correspondence: J.Walk, Department of Internal Medicine, Canisius-Wilhelmina Hospital,
Weg door Jonkerbos 100, 6532 SZ Nijmegen, The Netherlands (
Clinical Infectious Diseases® 2020;XX(XX):1–8
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail:
DOI: 10.1093/cid/ciaa1258
Reduced Vitamin K Status as a Potentially Modiable Risk
Factor of Severe Coronavirus Disease2019
AntonS.M. Dofferhoff,1,a Ianthe Piscaer,2,a LeonJ. Schurgers,3,a MargotP.J. Visser,4,a JodyM.W. vandenOuweland,5 PimA. deJong,6 Reinoud Gosens,7
TilmanM. Hackeng,3 Henny vanDaal,5 Petra Lux,3 Cecile Maassen,3 EstherG.A. Karssemeijer,1 Cees Vermeer,3 EmielF.M. Wouters,2,8
LoesE.M. Kistemaker,9 Jona Walk,1,b, and Rob Janssen4,b
1Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands, 2Department of Respiratory Medicine, Maastricht University Medical Center, Maastricht, The
Netherlands, 3Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands, 4Department of Pulmonary Medicine, Canisius-
Wilhelmina Hospital, Nijmegen, The Netherlands, 5Department of Clinical Chemistry, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands, 6Department of Radiology, University Medical
Center Utrecht and Utrecht University, The Netherlands, 7Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands, 8Ludwig Boltzmann Institute for Lung
Health, Vienna, Austria, and 9Aquilo BV, Groningen, The Netherlands
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, re-
quired for thrombosis prevention. In times of vitamin K insuciency, hepatic procoagulant factors are preferentially activated over
extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic
ber 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–de-
pendent 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 ber degradation.
Arterial calcication 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) calcication scores.
Conclusions. dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insuciency,
which was related to poor outcome; hepatic procoagulant factor II remained unaected. ese data suggest pneumonia-induced
extrahepatic vitamin K depletion leading to accelerated elastic ber damage and thrombosis in severe COVID-19 due to impaired
activation of MGP and endothelial protein S, respectively.
Keywords. COVID-19; elastic bers; factor II; matrix Gla protein; vitamin K.
Coronavirus disease 2019 (COVID-19) is caused by severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1].
The majority of individuals who contract SARS-CoV-2 have
mild symptoms; however, a significant proportion develop res-
piratory failure due to pneumonia [1]. COVID-19 may also
have extrapulmonary manifestations, including coagulopathy
and venous thromboembolism, which are associated with de-
creased survival [2]. The mechanisms that activate coagulation
in COVID-19 remain incompletely understood.
Coagulation is an intricate balance between clot promoting
and dissolving processes in which vitamin K plays a well-
known role. Procoagulant factor II (FII; ie, prothrombin) re-
quires vitamin K–dependent carboxylation to fulll its primary
function. Vitamin K is also a cofactor of anticoagulant pro-
tein S.In contrast to FII, a signicant proportion of protein S
is extrahepatically synthesized in endothelial cells, which play
a local suppressive role against thrombosis [3]. Vitamin K de-
ciency results in more severely compromised carboxylation
of extrahepatic than of hepatic vitamin K–dependent pro-
teins (Figure 1) [4]. is can paradoxically lead to enhanced
thrombogenicity in a state of low vitamin K [5].
Matrix Gla protein (MGP) is also vitamin K–dependent
but not involved in coagulation [6]. MGP is well known as a
calcication inhibitor in arterial walls [7], and MGP’s role in
the pulmonary compartment seems to be comparable [8, 9].
Elastic bers are essential matrix components in lungs and
have high calcium anity [10]. Degradation and mineraliza-
tion of elastic bers are interrelated processes [11, 12]. Matrix
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2 • CID 2020:XX (XX XXXX) • Doerho etal
metalloproteinase (MMP) synthesis increases parallel with
elastic ber calcication [13], and partially degraded elastic
bers become prone to mineralization [10]. Recent data show
that a subset of MMP-producing macrophages is increased in
severe SARS-CoV-2 pneumonia [14]. COVID-19 may theoret-
ically be linked to both vitamin K deciency and elastic ber
metabolism through a series of sequential pathologic steps
Individuals with severe SARS-CoV-2 infections oen have
comorbidities that are associated with reduced vitamin K status,
such as hypertension, diabetes, and cardiovascular diseases [1,
7]. e body uses vitamin K very eciently, and storage ca-
pacity is low [15]. ere are reasons to suspect that there is in-
creased use of vitamin K for carboxylation of pulmonary MGP
and coagulant factors during COVID-19 [16]. Vitamin K de-
pletion may have devastating consequences in the lungs [17].
Our aim in this study was to determine whether a reduced
vitamin K status plays a role in the pathogenesis of COVID-19
by interacting with both elastic ber metabolism and the coag-
ulation cascade, thereby linking pulmonary and coagulopathic
disease manifestations.
A total of 135 patients hospitalized with COVID-19 at the
Canisius-Wilhelmina Hospital between 12 March 2020 and
15 April 2020 were included. SARS-CoV-2 infection was con-
firmed using real-time polymerase chain reaction testing.
Patient data were extracted from hospital records, and vitamin
K antagonist (VKA) usage was determined from pharmacy
and anticoagulant clinic records. The United Medical Research
Ethics Committees of Canisius-Wilhelmina Hospital approved
the study and waived the need for written informed consent.
Patients could opt out after they were informed about thestudy.
A total of 186 controls from a previously published chronic
obstructive pulmonary disease (COPD) study were also in-
cluded [18]. Two control patients for whom the use of VKA was
unknown were excluded from the analysis.
Patients were followed up until discharge from the hospital,
intubation and mechanical ventilation, or death. e outcome
of COVID-19 patients was categorized as “good” if they were
discharged from the hospital without the need for invasive
ventilation and “poor” if they required either intubation and
mechanical ventilation or died. During admission, blood was
sampled 3 times per week and EDTA plasma and serum were
frozen at −80°C for retrospective analysis.
Direct quantification of blood vitamin K is not appropriate
to assess vitamin K status due to differences in bioavailability
and half-life time between the 2 naturally occurring forms
(vitamin K1 and K2). Additionally, the intake of vitamin K2
Figure 1. Distribution of vitamin K1 in the body. (1) After absorption, vitamin K1 is preferentially transported to the liver via the portal circulation, where it is used for
carboxylation of hepatic coagulation factors. This implies that during periods of vitamin K insufficiency, (2) the grade of carboxylation is usually higher for hepatic factor II (3)
than for endothelial protein S in veins and pulmonary MGP. Abbreviation: MGP, matrix Gla protein.
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Severe Vitamin K Insufficiency in COVID-19 • CID 2020:XX (XX XXXX) • 3
is too low to measure accurately. Measuring inactive levels of
vitamin K–dependent protein in the circulation is a valuable
method to quantify the combined deficit of vitamin K1 and
K2. Desphospho-uncarboxylated (dp-uc) MGP (inactive MGP)
is an appropriate indirect marker of extrahepatic vitamin K
status [19, 20]. Individuals with high dp-ucMGP levels have low
extrahepatic vitamin K status and viceversa.
Circulating dp-ucMGP levels were determined in EDTA
plasma using the commercially available IVD chemiluminescent
InaKif MGP assay on the IDS-iSYS system (IDS, Boldon, United
Kingdom) as previously described [21]. e within-run and total
precision of this assay were .8%–6.2% and 3.0%–8.2%, respectively.
e assay measuring range is between 200 and 12000 pmol/L
and was found to be linear up to 11651 pmol/L. dp-ucMGP
values <300 pmol/L are in the normal healthy range and values
>500 pmol/L reect vitamin K deciency [22].
Protein Induced by Vitamin K Absence-II
Protein induced by vitamin K absence (PIVKA)-II was used to
assess hepatic vitamin K status. Individuals with high PIVKA-II
levels have low hepatic vitamin K status and vice versa.
Circulating PIVKA-II levels were measured in serum using a
conformation-specific monoclonal antibody in an enzyme-
linked immunosorbent assay as previously described [23]. The
detection limit as well as upper limit of normal was .15 AU/mL
Plasma (p) desmosine and isodesmosine (DES) levels were used
as a marker for the rate of elastic fiber degradation [24]. DES are
formed during the cross-linking of tropo-elastin polymers and are
released in the bloodstream after degradation of elastic fibers [24].
pDES directly reflects the rate of systemic elastic fiber degradation.
DES fractions were measured using liquid chromatography-
tandem mass spectrometry as previously described [18, 24].
Coecients of variation of intra- and interassay imprecision
were <8.2%, the lower limit of quantication was 140ng/L, and
assay linearity was up to 210000ng/L.
Computed Tomography Assessment
Thin-slice computed tomography (CT) scans were acquired
using a Philips Ingenuity multidetector row scanner (Philips
Figure 2. Proposed sequential pathologic steps linking SARS-CoV-2 pneumonia to vitamin K insufficiency and accelerated elastic fiber degradation. (1) SARS-CoV-2 enters
AT2 cell. (2) The infected AT2 cell responds by upregulating synthesis of proinflammatory cytokines. (3) This leads to an increase in the number and activation of pulmonary
macrophages. (4) These infiltrating macrophages produce MMPs (5), which leads to accelerated degradation of elastic fibers (5a) and thereby the release of desmosine from
these fibers (5b), leading to elevated desmosine levels in lungs and blood. (6) The increased polarity of partially degraded elastic fibers (7) enhances their affinity for calcium
and, consequently, leads to increased elastic fiber calcium content. (7a) MMP synthesis is upregulated in parallel with the calcium content, which further accelerates elastic
fiber degradation in a self-propagating vicious circle. (8) MGP synthesis is upregulated in an attempt to protect elastic fibers from calcification and degradation, (8a) which
means that need for vitamin K to activate additional MGP increases. (8b) This increased use of vitamin K may induce vitamin K insufficiency, (9) in which case increased pro-
duction of MGP in a state of vitamin K insufficiency leads to increased dp-ucMGP in lungs and blood. Abbreviations: AT2, alveolar type II; dp-uc, desphospho-uncarboxylated;
MGP, matrix Gla protein; MMP, matrix metalloproteinase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
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4 • CID 2020:XX (XX XXXX) • Doerho etal
Healthcare). CT images of 1-mm thickness were reconstructed
using iterative model-based reconstruction in the axialplane.
Quantitative measurements of the volume of ground glass
and consolidation were undertaken using the Intellispace Portal
(COPD package, Intellispace version 10, Philips Healthcare).
In the soware, rst the lungs were segmented from the chest
wall and major vessels and main bronchi. Manual adjustments
were made where required by a board-certied chest radiol-
ogist. Subsequently, the lung voxels were counted to derive a
total lung volume in milliliters. Diseased lung tissue was de-
ned as those voxels with an attenuation of Hounseld units
(HU) greater than −700 as previously dened. e abnormal
voxels were expressed as a percentage diseased lung of the total
volume. An HU value at the 85th percentile was used [25, 26].
Coronary aortic calcication (CAC) and thoracic aortic cal-
cication (TAC) were also quantied in the Intellispace Portal
(Heartbeat CS package). Calcications were dened as areas
with an HU of 130 and higher. e calcications were visually
localized up to the arterial wall by a board-certied chest radi-
ologist and semiautomatically segmented. e volume was used
as a measure of calcication burden.
Statistical Analyses
Statistical analyses were performed using SPSS (version 24,
IBM, Chicago, IL). Analysis of variance was used to compare
dp-ucMGP, pDES, and radiological scores between groups.
Analysis of covariance was used to perform the aforementioned
analyses: dp-ucMGP, CAC, and TAC adjusted for age, sex, and
use of VKA and pDES adjusted forage.
For each pDES measurement in a COVID-19 patient, vir-
tual age-matched pDES values were calculated using pub-
lished pDES equations for never and (ex-) smokers [24].
pDES is strongly dialyzed (R. Janssen, unpublished data),
and patients receiving dialysis at baseline were excluded
from pDES analyses.
e Spearman correlation coecient was used to test the as-
sociation of closest time-matched dp-ucMGP with pDES and
For PIVKA-II, patients were categorized as follows: normal
<.15 AU/mL, mildly elevated .15–.5 AU/mL, moderately ele-
vated .5–2.0 AU/mL, and severely elevated >2.0AU/mL.
dp-ucMGP, pDES, and radiological scores had a log-normal
distribution and were therefore natural log-transformed prior
to analyses. Since CAC and TAC scores included values equal
to zero, these values were transformed using Ln(CAC + 1)
and Ln(TAC + 1), respectively. e mean dierence and
95% condence interval (CI) of log-transformed values was
backtransformed to the mean fold change. Normally distrib-
uted continuous variables are presented as mean ± standard
deviation, whereas continuous variables with a natural-log
distribution are presented as backtransformed mean and 95%
CI. AP value of < .05 was used as the threshold for statistical
The mean age of COVID-19 patients was 68 ± 12 years, 93
(69%) were male, and 12 (8.9%) used VKA. Of the historical
controls, 85 (46%) were male, 3 (1.6%) were taking VKA, and
the mean age was 61 ± 6.5years. Patient and control character-
istics are shown in Table1.
dp-ucMGP was measured in all available samples. Maximum
dp-ucMGP levels were significantly higher in COVID-19 pa-
tients (1476 pmol/L; 95% CI, 1341 to 1625) compared with
healthy controls (471 pmol/L; 95% CI, 434 to 511; mean fold
change, 3.14; 95% CI, 2.76 to 3.56; P < .001; Figure3A), which
remained significant after adjustment for age, sex, and use of
VKAs (P < .001). dp-ucMGP levels were significantly higher in
Table 1. Baseline Characteristics of Coronavirus Disease 2019 Patient and Healthy Control Cohorts
Coronavirus Disease 2019 Controls
Good Outcome, n (%) Poor Outcome, n (%) All, N (%)
Patients 75 60 135 184
Age, y 64 ± 13 72 ± 10 68 ± 12 61 ± 6.5
Male (%) 46 (61) 47 (78) 93 (69) 85 (46)
Vitamin K antagonist use (%) 5 (6.7) 7 (12) 12 (8.9) 3 (1·6)
Hypertension (%) 28 (37) 21 (35) 49 (36) 41 (22)
Diabetes mellitus (%) 15 (20) 15 (25) 30 (22) 14 (7.6)
Cardiac or cardiovascular disease (%) 17 (23) 21 (35) 38 (28) 12 (6.5)
Asthma/Chronic obstructive pulmonary disease (%) 13 (17) 12 (20) 25 (19) 7 (3.8)
Other respiratory disease (%) 5 (6.7) 10 (17) 15 (11) 3 (1.6)
Immunocompromised (%) 4 (5.3) 2 (3.3) 6 (4.4) 0 (0)
Dialysis dependent (%)a1 (1.3) 2 (3.3) 3 (2.2) 0 (0)
Active malignancy (%) 6 (8.0) 6 (10) 12 (8.9) 0 (0)
aAt admission.
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Severe Vitamin K Insufficiency in COVID-19 • CID 2020:XX (XX XXXX) • 5
COVID-19 patients with poor outcome (1998 pmol/L; 95% CI,
1737 to 2296)compared with those with good outcome (1157
pmol/L; 95% CI, 1022 to 1312; mean fold change, 1.73; 95% CI,
1.43 to 2.08; P < .001; Figure 3A), and significance was main-
tained after adjustments (P < .001).
PIVKA-II was measured in the first available sample after ad-
mission. Levels were normal in 82.1%, mildly elevated in 13.0%,
moderately elevated in 4.1%, and severely elevated in .8% of
COVID-19 patients not using VKA (Figure3B). PIVKA-II dis-
tribution was comparable between patients with good (78.6%,
15.7%, 4.3%, and 1.4%, respectively) and poor outcomes
(86.8%, 9.4%, 3.8%, and 0%, respectively). PIVKA-II levels were
severely elevated in 100% of COVID-19 patients using VKA.
Sufficient plasma for pDES measurements was available for 127
patients and measured in the first available sample after admis-
sion. Three dialysis-dependent patients were excluded from the
analysis. pDES levels were significantly higher in COVID-19
patients (380ng/L; 95% CI, 355 to 405) compared with age-
dependent reference values of never-smokers (243ng/L; 95%
CI, 228 to 260; mean fold change, 1.56; 95% CI, 1.42 to 1.71;
P < .001) and former or current smokers (278ng/L; 95% CI, 260
to 296; mean fold change, 1.37; 95% CI, 1.25 to 1.50; P < .001;
Figure 4A) [24]. pDES levels, corrected for age, were signifi-
cantly higher in COVID-19 patients with poor (430ng/L; 95%
CI, 384 to 481)compared with good outcomes (342ng/L; 95%
CI, 310 to 379; mean fold change, 1.25; 95% CI, 1.07 to 1.47;
P = .004). dp-ucMGP levels significantly correlated with pDES
(n = 124; r = .47; P < .001; Figure4B).
CT Assessment
CT scans were available for 109 patients, and CAC and TAC
scores were successfully determined for 107 of these patients.
TAC and CAC scores were significantly higher in COVID-19
patients with poor outcome compared with those with good
outcome; however, both lost significance after adjustments
(Supplementary Materials). The association between pulmo-
nary involvement on CT and time-matched dp-ucMGP levels
was not significant (n = 109; r = .18; P = .06). dp-ucMGP was
significantly associated with TAC scores (n = 107; r = .36;
P < .001) and CAC scores (n = 107; r = .30; P = .002).
dp-ucMGP, which indirectly indicates extrahepatic vitamin K
insufficiency, was severely elevated in hospitalized COVID-19
patients. Impaired MGP activation was associated with poor
outcome and accelerated elastic fiber degradation. In contrast,
procoagulant FII activity remained preserved.
dp-ucMGP, as a measure of extrahepatic vitamin K status,
is a relevant parameter given its close association with mor-
tality [22]. Low dietary vitamin K intake and VKA use are
evident causes of elevated dp-ucMGP [15, 22]. Pathological
processes leading to upregulation of vitamin K–dependent pro-
tein production and resulting in accelerated use of vitamin K
Figure 3. Circulating dp-ucMGP and PIVKA-II in COVID-19 patients. A, dp-ucMGP was measured in plasma of COVID-19 patients with a good outcome (discharge without
invasive ventilation, n = 75; orange) or poor outcome (invasive ventilation and/or death, n = 60; red) compared with a cohort of controls. Patients with high dp-ucMGP have
low extrahepatic vitamin K status and vice versa. The maximum dp-ucMGP measured during the study is shown, with open circles representing those patients using vitamin
K antagonist (VKA) at admission. B, PIVKA-II was measured in plasma at baseline in those patients not using VKA (n = 122). The detection threshold and normal range for
healthy controls is shown in gray. Asingle patient not using VKAs had a severely elevated PIVKA-II outside the detection range and is not shown in the figure. Abbreviations:
COVID-19, coronavirus disease 2019; dp-ucMGP, desphospho-uncarboxylated matrix Gla protein; PIVKA-II, protein induced by vitamin K absence. ***P < .001.
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6 • CID 2020:XX (XX XXXX) • Doerho etal
for carboxylation may be another important reason for severe
extrahepatic vitamin K insuciency in COVID-19. Vitamin
K supplementation reduced dp-ucMGP in various cohorts
[22, 27], with favorable eects on clinically relevant outcome
measurements [27]. It is reasonable to assume that vitamin K
administration reduces dp-ucMGP in COVID-19. Whether
improving dp-ucMGP results in a better outcome of COVID-
19 remains to be evaluated.
Intriguingly, many comorbid conditions related to poor
COVID-19 clinical outcomes are associated with compromised
vitamin K status [1, 7, 18]. e same holds true for ageing [1].
Elastic ber calcication and degradation are closely related
processes [11, 12]. ere seems to be an association between
vascular mineralization and lung pathologies [28–30]. We
demonstrated accelerated elastic ber degradation and arterial
calcication correlating with dp-ucMGP, suggesting interrela-
tionships between vitamin K shortage, insucient MGP car-
boxylation, and elastic ber pathologies in COVID-19.
Although signicance was lost aer adjustment for age, sex,
and VKA use, we found enhanced TAC and CAC in patients
with poor prognosis. Hypertension, diabetes, cardiovascular di-
sease, and older age are associated with remodeling of elastic
tissues [7]. ese damaged and calcied elastic bers are more
prone to further degradation than intact bers [11]. We specu-
late that this preexisting elastic ber dysfunction renders them
more susceptible to degradation following enhanced proteolytic
activity during COVID-19 [14].
We did not nd a signicant correlation between dp-ucMGP
and pneumonia severity. It is possible that the correlation is
confounded by the fact that those with preexisting conditions
are predisposed to both higher dp-ucMGP and the develop-
ment of respiratory failure with less pulmonary involvement.
Furthermore, CT severity is a dynamic process that may change
rapidly [31]. Aclinical trial in which change of both vitamin
K status and CT severity are simultaneously assessed before
and aer vitamin K supplementation would be a more suitable
Vitamin K1, the main source of vitamin K in the
Netherlands, is preferentially transported to the liver,
implying that the grade of carboxylation is usually higher
for hepatic than extrahepatic vitamin K–dependent proteins
(Figure1) [3, 4, 32]. is likely explains why dp-ucMGP was
severely elevated while PIVKA-II was normal in the majority
of patients. Similar to MGP, the activation of endothelial pro-
tein S is disproportionally impacted in times of vitamin K
deciency. eoretically, these observations could be com-
patible with enhanced thrombogenicity in COVID-19 [2],
where autopsies revealed bilateral deep venous leg throm-
bosis in all thromboembolic cases and thrombosis of the
prostatic venous plexus in the majority of men who died [33].
Future research should investigate this; however, there is
currently no readily available assay to measure carboxylated
(active) vs uncarboxylated (inactive) protein S. Enhanced
thrombosis in a state of vitamin K deciency has previously
been described in calciphylaxis [5]. Calciphylaxis is charac-
terized by cutaneous blood vessel occlusion due to calcica-
tion, leading to ischemic skin infarction [5]. Increased levels
of inactive MGP are found in skin tissues and the circulation
of calciphylaxis patients [5]. It may be speculated that, anal-
ogous to calciphylaxis, impaired local anticoagulant activity
due to vitamin K insuciency is responsible for microvessel
thrombosis in COVID-19 [34].
e major strength of our study is the use of robust bio-
markers and quantitative CT assessment. Our ndings are
Figure 4. Correlation between dp-ucMGP and desmosine. A, Scatterplot
showing circulating desmosine levels in those patients aged >40years (n = 121)
by age. The black line represents the deduced equation for coronavirus disease
2019 (COVID-19) patients. The green and blue lines represent Huang etal’s [24]
calculated equations for nonsmoking and smoking controls, respectively. B, For
all COVID-19 patients who were not dialysis-dependent at admission with a good
outcome (discharge without invasive ventilation, n = 69; orange) or poor outcome
(invasive ventilation and/or death, n = 58; red) log-transformed baseline dp-ucMGP
and desmosine values are shown, with open circles representing vitamin K antag-
onist users. The black line represents a linear regression analysis. Abbreviation:
dp-ucMGP, desphospho-uncarboxylated matrix Gla protein.
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Severe Vitamin K Insufficiency in COVID-19 • CID 2020:XX (XX XXXX) • 7
limited by the fact that it is impossible to determine which
proportion of circulating dp-ucMGP and DES levels origin-
ated from the lungs, as both biomarkers are not tissue-specic.
erefore, there is an urgent need for experimental data to
better link vitamin K insuciency specically with COVID-
19–related lung pathologies.
As low vitamin K levels are found in comorbidities that
are related to poor outcome of COVID-19 [1, 7], we were
unable to formally determine whether vitamin K insu-
ciency truly predisposes patients to the development of se-
vere COVID-19 or whether it is merely an epiphenomenon.
However, the latter seems highly unlikely given the extreme
elevation of dp-ucMGP levels in COVID-19 patients, which
was much more pronounced than in hypertensive, dia-
betic, cardiovascular, and COPD patients without COVID-
19 (Supplementary Table 1). e strong correlation that we
found between vitamin K status and the rate of elastic ber
degradation also suggests causality.
We had to make use of a historical control group due to the
implementation of quarantines and social distancing practices
to contain SARS-CoV-2. We do not consider this to be a signif-
icant problem, however, as dp-ucMGP levels of our historical
controls were higher than previously reported in large groups
of controls (Supplementary Table 2). Furthermore, dierences
in dp-ucMGP levels between COVID-19 patients and controls
were of such a magnitude that loss of signicance when com-
paring to a matched control group would be highly unlikely.
In conclusion, dp-ucMGP was strongly elevated in hos-
pitalized COVID-19 patients, which indirectly indicates
extrahepatic vitamin K insuciency. Impaired MGP activation
was associated with poor outcomes. COVID-19 patients with
premorbid elastic ber pathologies appeared, in particular, to
be at increased risk of a complicated disease course. Despite
extrahepatic vitamin K deciency, hepatic prothrombin acti-
vation remained preserved. Taken together, these data suggest
a mechanism of pneumonia-induced extrahepatic vitamin K
depletion leading to accelerated elastic ber degradation and
thrombosis formation. An intervention trial is now needed to
assess whether vitamin K administration improves outcomes
in patients with COVID-19 by increasing pulmonary MGP and
endothelial protein S activation.
Supplementary materials are available at Clinical Infectious Diseases online.
Consisting of data provided by the authors to benet the reader, the posted
materials are not copyedited and are the sole responsibility of the authors, so
questions or comments should be addressed to the correspondingauthor.
Author contributions. R.J.developed the theory. A.S. M. D., R.J., and
L.J. S.designed the study. L.J. S., P.L., and C.M.were responsible for the
desphospho-uncarboxylated matrix Gla protein and protein induced by vi-
tamin K absence-II measurements. J.M. W.O.and H.D.were responsible
for the (iso)desmosine measurements. P. A. J. performed the computed
tomography analyses. H.D., E.G. A.K., C.V., M.P. J.V., and J.W.analyzed
the data. I.P.performed the statistical analyses. I.P., J.W., and R.J.wrote the
rst dra of the manuscript. A.S. M.D., L.J. S., J.M. W.O., P.A. J., T.M. H.,
R.G., L.E. M.K., and E.F. M.W.critically revised the manuscript.
Acknowledgments. e authors thank Twan Beijers, Manon Bindels,
Monique Bruns, Edwin van Harn, Karin Hoppenbrouwers, Britt Hulsen,
Wim Kools, Maarten Paul, Anne Rikken-Krijnen, Franz Roos, Rotraut
Schoop, Leon Tax, Dirk Traufelder, and Yannick van Til, and the Departments
of Internal Medicine, Pulmonary Medicine, Microbiology, and Radiology of
the Canisius-Wilhelmina Hospital for their support. Upon publication, the
full deidentied patient dataset will be provided as a supplementary le.
Potential conicts of interest. L. J. S. reports a consultancy fee from
Immunodiagnostic Systems and grants from NattoPharma. J.M. W.O.and
R.J.are owners of R.J.is owner of Emphysema Solutions
BV and discloses application of a patent on vitamin K in coronavirus 2019
for prognostic and therapeutic purposes. All other authors report no poten-
tial conicts. All authors have submitted the ICMJE Form for Disclosure of
Potential Conicts of Interest. Conicts that the editors consider relevant to
the content of the manuscript have been disclosed.
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... These studies displayed discordant results, some suggesting an impact on the incidence of infection and/or the duration of symptoms while others showed no effect [6][7][8][9][10][11][12][13]. Studies in the context of COVID-19 have mostly been ecological [14], or conducted on patients in already infected patients, focusing on the prognosis of the COVID-19 disease, in a context of tertiary prevention [15][16][17][18][19]. These studies provide crucial insights for disease management but they are not appropriate to investigate the potential influence of dietary habits on the risk of being infected by SARS-CoV-2, in a context of primary prevention. ...
... See legend on next page.)[17,39]. Our data suggest that it could also help prevent the infection by SARS-CoV-2.The potential effect of dietary fibers on the risk of SARS-CoV-2 infection is likely resulting from their interaction with the gut microbiota, producing shortchain fatty acids (SCFA) and promoting a diverse and balanced community. ...
Full-text available
Background Nutritional factors are essential for the functioning of the immune system and could therefore play a role in COVID-19 but evidence is needed. Our objective was to study the associations between diet and the risk of SARS-CoV-2 infection in a large population-based sample. Methods Our analyses were conducted in the French prospective NutriNet-Santé cohort study (2009–2020). Seroprevalence of anti-SARS-CoV-2 antibodies was assessed by ELISA on dried blood spots. Dietary intakes were derived from repeated 24 h dietary records (at least 6) in the two years preceding the start of the COVID-19 pandemic in France (February 2020). Multi-adjusted logistic regression models were computed. Results A total of 7766 adults (70.3% women, mean age: 60.3 years) were included, among which 311 were positive for anti-SARS-CoV-2 antibodies. Dietary intakes of vitamin C (OR for 1 SD=0.86 (0.75–0.98), P =0.02), vitamin B9 (OR=0.84 (0.72–0.98), P =0.02), vitamin K (OR=0.86 (0.74–0.99), P =0.04), fibers (OR=0.84 (0.72–0.98), P =0.02), and fruit and vegetables (OR=0.85 (0.74–0.97), P =0.02) were associated to a decreased probability of SARS-CoV-2 infection while dietary intakes of calcium (OR=1.16 (1.01–1.35), P =0.04) and dairy products (OR=1.19 (1.06–1.33), P =0.002) associated to increased odds. No association was detected with other food groups or nutrients or with the overall diet quality. Conclusions Higher dietary intakes of fruit and vegetables and, consistently, of vitamin C, folate, vitamin K and fibers were associated with a lower susceptibility to SARS-CoV-2 infection. Beyond its established role in the prevention of non-communicable diseases, diet could therefore also contribute to prevent some infectious diseases such as COVID-19.
... There have been recent studies demonstrating the importance of combination therapy in individuals who have been diagnosed with comorbidity along with COVID, such as hypertension, kidney disease, or obesity. This is because individuals, who may have comorbidities, may also be vitamin K deficient [12]. Vitamin D and vitamin K combination therapy may also be beneficial because an increase of vitamin D through supplemental intake may increase calcium permeability of elastic fibers and stimulate degradation of these fibers. ...
... Vitamin K activates the Matrix Gla Protein (MGP) which serves as an inhibitor against the calcification of soft tissue and fiber degradation [13]. It is also important to note that soft tissues and fibrous tissues, especially those located in the upper respiratory tract, may serve as targets for SARS-CoV-2 due to the potential abundance of ACE-2 receptors although limited studies support this claim [12]. Vitamin C is best known for its amazing benefits for supporting immune health. ...
... In a study, it was reported that vitamin K decreased in COVID-19 patients and this decrease was related to poor prognosis. This study states that new studies are required to determine the effect of vitamin K administration on patients with COVID-19 [40]. In another study, it is reported that small intestine involvement and/or decreased dietary intake due to COVID-19 may be among the causes of decreased vitamin K status in COVID-19 patients. ...
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Coronavirus 2019 (COVID-19) is an infectious disease that has brought life to a standstill around the world. Until a vaccine was found to combat COVID-19, the world conducted research and made recommendations for nutritional natural foods. Considering the risks incurred by contracting the disease, even though the production of various vaccines and vaccination of healthy people has started in some countries, individuals need useful foods to be ready for the COVID-19 pandemic. Recently, nutrient contents such as antioxidant compounds, vitamins, minerals, and probiotics that contribute to the immune system have been investigated. This paper attempts to determine the role of these dietary supplements in reducing the risk of COVID-19 and/or changing the course of the disease in COVID-19 patients and their effects on mortality. Supplements used and recommended for the COVID-19 pandemic life were investigated. In conclusion, more research is needed to determine the effectiveness of nutrients, vitamins, minerals, probiotics, prebiotics, and antioxidants used during the COVID-19 pandemic to inhibit the effect of SARS-CoV-2. In order to overcome the new global crisis, nutritional cures and treatments should be upgraded. However, additional research on the subject is needed.
... [463][464][465] Third, studies have found that vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19 patients. 106,107 In addition, some other factors can also play a role by influencing the above three systems, such as RAS, 466 complement and coagulation cascade signaling, 125,467,468 mineralocorticoid receptor (MR) and its downstream target galectin-3 (Gal-3), 469 IL-6, 124 extrahepatic vitamin K insufficiency, 470 etc. These molecules and pathways form a complex network leading to the complexity of the disease and the difficulty of the treatment. ...
Full-text available
The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.
... Acute lung injury is related to cytokine storm and the VKDP protein S is involved in suppressing the cytokine storm by inhibiting the synthesis of inflammatory cytokines. Due to vitamin K deficiency, decreased levels of the activated protein S and MGP may increase the progression of thrombosis and lung damage [63,82]. ...
... MGP, a vitamin K-dependent protein, inhibits soft tissue mineralization and elastic fiber breakdown. To preserve the pulmonary extracellular matrix from breakdown caused by inflammation, the lungs of SARS-CoV-2 patients produce more Matrix Gla protein (MGP), which increases the use of vitamin K from extrahepatic vitamin K reserves [118,119]. ...
Full-text available
Optimized therapeutic bio-compounds supported by bio-acceptable nanosystems (i.e., precise nanomedicine) have ability to promote health via maintaining body structure, organ function, and controlling chronic and acute effects. Therefore, nano-nutraceuticals (designed to neutralize virus, inhibit virus bindings with receptors, and support immunity) utilization can manage COVID-19 pre/post-infection effects. To explore these approaches well, our mini-review explores optimized bio-active compounds, their ability to influence SARS-CoV-2 infection, improvement in performance supported by precise nanomedicine approach, and challenges along with prospects. Such optimized pharmacologically relevant therapeutic cargo not only affect SARS-CoV-2 but will support other organs which show functional alternation due to SARS-CoV-2 for example, neurological functions. Hence, coupling the nutraceuticals with the nano-pharmacology perspective of higher efficacy via targeted delivery action can pave a novel way for health experts to plan future research needed to manage post COVID-19 infection effect where a longer efficacy with no side-effects is a key requirement.
... Considering the high incidence of VKORC1-1639A in East Asia, this feature may be an explanation for the lower rates of COVID-19 related morbidity and mortality [96]. The increase of dp-ucMGP mediated by vitamin K insufficiency and derangement of TAM signaling can predispose to thrombosis and disseminate intravascular coagulation, which characterizes the microvascular damage observed in COVID patients [97,98]. ...
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Purpose of Review We describe the mechanism of action of vitamin K, and its implication in cardiovascular disease, bone fractures, and inflammation to underline its protective role, especially in chronic kidney disease (CKD). Recent Findings Vitamin K acts as a coenzyme of y-glutamyl carboxylase, transforming undercarboxylated in carboxylated vitamin K-dependent proteins. Furthermore, through the binding of the nuclear steroid and xenobiotic receptor, it activates the expression of genes that encode proteins involved in the maintenance of bone quality and bone remodeling. There are three main types of K vitamers: phylloquinone, menaquinones, and menadione. Summary CKD patients, for several conditions typical of the disease, are characterized by lower levels of vitamin K than the general populations, with a resulting higher prevalence of bone fractures, vascular calcifications, and mortality. Therefore, the definition of vitamin K dosage is an important issue, potentially leading to reduced bone fractures and improved vascular calcifications in the general population and CKD patients.
Although some studies have reported prognostic factors for coronavirus disease 2019 (COVID-19), they were conducted before standard treatment with remdesivir and dexamethasone was implemented. This retrospective, observational study was conducted to evaluate various prognostic factors in patients with COVID-19 pneumonia receiving standard treatment with remdesivir and dexamethasone. Of 99 patients with COVID-19 pneumonia, 68 (68.7%) died within 30 days of hospitalization. The mean age was 71.3 years. Remdesivir and dexamethasone were administered to 80 (80.8%) and 84 (84.8%) patients, respectively. Early antibiotic treatment was administered to 70 patients (70.7%) within 5 days of hospitalization. Dexamethasone (79.4% vs 96.8%, P = .033) was more frequently administered in the survived group, whereas early antibiotics (60.3% vs 93.5%, P = .001) were less frequently administered. In the multivariate analysis, a high National Early Warning Score (NEWS; odds ratio [OR] 1.272), high Charlson Comorbidity Index (CCI; OR 1.441), and dyspnea (OR 4.033) were independent risk factors for 30-day mortality. There was no significant difference in age, sex, and vaccination doses between the survived and fatal groups. Lymphopenia, monocytopenia and high levels of C-reactive protein (CRP)/lactate dehydrogenase (LDH) reflected poor prognosis. NEWS, CCI, and dyspnea were predictors of 30-day mortality in patients with COVID-19 pneumonia. Early antibiotic use did not lower the 30-day mortality risk.
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Objective To evaluate antithrombotic (AT) use in individuals with atrial fibrillation (AF) and at high risk of stroke (CHA 2 DS 2 -VASc score ≥2) and investigate whether pre-existing AT use may improve COVID-19 outcomes. Methods Individuals with AF and CHA 2 DS 2 -VASc score ≥2 on 1 January 2020 were identified using electronic health records for 56 million people in England and were followed up until 1 May 2021. Factors associated with pre-existing AT use were analysed using logistic regression. Differences in COVID-19-related hospitalisation and death were analysed using logistic and Cox regression in individuals with pre-existing AT use versus no AT use, anticoagulants (AC) versus antiplatelets (AP), and direct oral anticoagulants (DOACs) versus warfarin. Results From 972 971 individuals with AF (age 79 (±9.3), female 46.2%) and CHA 2 DS 2 -VASc score ≥2, 88.0% (n=856 336) had pre-existing AT use, 3.8% (n=37 418) had a COVID-19 hospitalisation and 2.2% (n=21 116) died, followed up to 1 May 2021. Factors associated with no AT use included comorbidities that may contraindicate AT use (liver disease and history of falls) and demographics (socioeconomic status and ethnicity). Pre-existing AT use was associated with lower odds of death (OR=0.92, 95% CI 0.87 to 0.96), but higher odds of hospitalisation (OR=1.20, 95% CI 1.15 to 1.26). AC versus AP was associated with lower odds of death (OR=0.93, 95% CI 0.87 to 0.98) and higher hospitalisation (OR=1.17, 95% CI 1.11 to 1.24). For DOACs versus warfarin, lower odds were observed for hospitalisation (OR=0.86, 95% CI 0.82 to 0.89) but not for death (OR=1.00, 95% CI 0.95 to 1.05). Conclusions Pre-existing AT use may be associated with lower odds of COVID-19 death and, while not evidence of causality, provides further incentive to improve AT coverage for eligible individuals with AF.
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Introduction COVID-19 has caused morbidity, hospitalisations and deaths worldwide. Despite four approved vaccines for COVID-19 in Canada, there is still a need for effective treatments, especially for people in the community. Vaccine efficacy is not 100% and long-term efficacy is still unknown. Furthermore, there are challenges to herd immunity including vaccine hesitancy and underlying conditions preventing vaccination. We aim to explore if the nutrients vitamin C, vitamin D, vitamin K 2 and zinc are an effective treatment option for outpatients diagnosed with COVID-19. The primary outcome is the difference in participant-reported overall health; secondary outcomes include the effect on health status, symptom severity and duration, frequency and length of hospitalisations and mortality. Methods and analysis This study is a two-arm, parallel-group, double-blind, placebo-controlled, phase III randomised controlled trial. 200 patients will be recruited remotely from COVID-19 test centres in Ottawa, Canada associated with The Ottawa Hospital. Overall health will be measured using the EuroQol Visual Assessment Scale; health status will be measured using the EuroQol 5-dimension 5-level questionnaire; symptom severity and duration will be measured using an independently developed questionnaire; analyses will use an area under the curve approach and compare mean scores using unadjusted t tests. Study data will be recorded on electronic case report forms using the Research Electronic Data Capture platform. An independent data safety and monitoring board will perform ongoing review of the study for feasibility and safety. Ethics and dissemination This study has received ethical approval from the research ethics boards of the Canadian College of Naturopathic Medicine and the Ottawa Health Sciences Network, as well as regulatory approval from the Therapeutic Products Directorate and Natural and Non-Prescription Health Products Directorate of Health Canada. Results will be published in a peer-reviewed scientific journal with open access. Trial registration number NCT04780061 .
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Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.
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COVID-19 infection has tremendously impacted our daily clinical practice as well as our social living organization. Virtually all organs and biological systems suffer from this new coronavirus infection, either because the virus targets directly specific tissues or because of indirect effects. Endocrine diseases are not an exception and some of endocrine organs are at risk of direct or indirect lesion by COVID-19. Although there is still no evidence of higher predisposition to contract the infection in patients with diabetes and/or obesity, the coexistence of these conditions contributes to a worse prognosis because both conditions confer an impaired immunologic system. Cytokines storm can be amplified by these two latter conditions thereby leading to multisystemic failure and death. Glycaemic control has been demonstrated to be crucial to avoiding long hospital stays, ICU requirement and also prevention of excessive mortality. Endocrine treatment modifications as a consequence of COVID-19 infection are required in a proactive manner, in order to avoid decompensation and eventual hospital admission. This is the case of diabetes and adrenal insufficiency in which prompt increase of insulin dosage and substitutive adrenal steroids through adoption of the sick day’s rules should be warranted, as well as easy contact with the health care provider through telematic different modalities. New possible endocrinological targets of COVID-19 have been recently described and warrant a full study in the next future.
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Respiratory immune characteristics associated with Coronavirus Disease 2019 (COVID-19) severity are currently unclear. We characterized bronchoalveolar lavage fluid immune cells from patients with varying severity of COVID-19 and from healthy people by using single-cell RNA sequencing. Proinflammatory monocyte-derived macrophages were abundant in the bronchoalveolar lavage fluid from patients with severe COVID-9. Moderate cases were characterized by the presence of highly clonally expanded CD8⁺ T cells. This atlas of the bronchoalveolar immune microenvironment suggests potential mechanisms underlying pathogenesis and recovery in COVID-19.
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), with a clinical outcome ranging from mild to severe, including death. To date, it is unclear why some patients develop severe symptoms. Many authors have suggested the involvement of vitamin D in reducing the risk of infections; thus, we retrospectively investigated the 25-hydroxyvitamin D (25(OH)D) concentrations in plasma obtained from a cohort of patients from Switzerland. In this cohort, significantly lower 25(OH)D levels (p = 0.004) were found in PCR-positive for SARS-CoV-2 (median value 11.1 ng/mL) patients compared with negative patients (24.6 ng/mL); this was also confirmed by stratifying patients according to age >70 years. On the basis of this preliminary observation, vitamin D supplementation might be a useful measure to reduce the risk of infection. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations and to confirm our preliminary observation.
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Background and aims COVID-19 and low levels of vitamin D appear to disproportionately affect black and minority ethnic individuals. We aimed to establish whether blood 25-hydroxyvitamin D (25(OH)D) concentration was associated with COVID-19 risk, and whether it explained the higher incidence of COVID-19 in black and South Asian people. Methods UK Biobank recruited 502,624 participants aged 37–73 years between 2006 and 2010. Baseline exposure data, including 25(OH)D concentration and ethnicity, were linked to COVID-19 test results. Univariable and multivariable logistic regression analyses were performed for the association between 25(OH)D and confirmed COVID-19, and the association between ethnicity and both 25(OH)D and COVID-19. Results Complete data were available for 348,598 UK Biobank participants. Of these, 449 had confirmed COVID-19 infection. Vitamin D was associated with COVID-19 infection univariably (OR = 0.99; 95% CI 0.99–0.999; p = 0.013), but not after adjustment for confounders (OR = 1.00; 95% CI = 0.998–1.01; p = 0.208). Ethnicity was associated with COVID-19 infection univariably (blacks versus whites OR = 5.32, 95% CI = 3.68–7.70, p-value<0.001; South Asians versus whites OR = 2.65, 95% CI = 1.65–4.25, p-value<0.001). Adjustment for 25(OH)D concentration made little difference to the magnitude of the association. Conclusions Our findings do not support a potential link between vitamin D concentrations and risk of COVID-19 infection, nor that vitamin D concentration may explain ethnic differences in COVID-19 infection.
Background Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19. Methods We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression. Results In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001). Conclusions In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)
Patients with diabetes who get coronavirus disease 2019 (COVID-19) are at risk of a severe disease course and mortality. Several factors especially the impaired immune response, heightened inflammatory response and hypercoagulable state contribute to the increased disease severity. However, there are many contentious issues about which the evidence is rather limited. There are some theoretical concerns about the effects of different anti-hyperglycaemic drugs. Similarly, despite the recognition of angiotensin converting enzyme 2 (ACE2) as the receptor for severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), and the role of ACE2 in lung injury; there are conflicting results with the use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in these patients. Management of patients with diabetes in times of restrictions on mobility poses some challenges and novel approaches like telemedicine can be useful. There is a need to further study the natural course of COVID-19 in patients with diabetes and to understand the individual, regional and ethnic variations in disease prevalence and course.
Background: The new coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS–CoV-2), has caused more than 210 000 deaths worldwide. However, little is known about the causes of death and the virus's pathologic features. Objective: To validate and compare clinical findings with data from medical autopsy, virtual autopsy, and virologic tests. Design: Prospective cohort study. Setting: Autopsies performed at a single academic medical center, as mandated by the German federal state of Hamburg for patients dying with a polymerase chain reaction–confirmed diagnosis of COVID-19. Patients: The first 12 consecutive COVID-19–positive deaths. Measurements: Complete autopsy, including postmortem computed tomography and histopathologic and virologic analysis, was performed. Clinical data and medical course were evaluated. Results: Median patient age was 73 years (range, 52 to 87 years), 75% of patients were male, and death occurred in the hospital (n = 10) or outpatient sector (n = 2). Coronary heart disease and asthma or chronic obstructive pulmonary disease were the most common comorbid conditions (50% and 25%, respectively). Autopsy revealed deep venous thrombosis in 7 of 12 patients (58%) in whom venous thromboembolism was not suspected before death; pulmonary embolism was the direct cause of death in 4 patients. Postmortem computed tomography revealed reticular infiltration of the lungs with severe bilateral, dense consolidation, whereas histomorphologically diffuse alveolar damage was seen in 8 patients. In all patients, SARS–CoV-2 RNA was detected in the lung at high concentrations; viremia in 6 of 10 and 5 of 12 patients demonstrated high viral RNA titers in the liver, kidney, or heart. Limitation: Limited sample size. Conclusion: The high incidence of thromboembolic events suggests an important role of COVID-19–induced coagulopathy. Further studies are needed to investigate the molecular mechanism and overall clinical incidence of COVID-19–related death, as well as possible therapeutic interventions to reduce it. Primary Funding Source: University Medical Center Hamburg-Eppendorf.