key: cord-261470-sqxdwu6j
authors: Weichmann, Franziska; Rohdewald, Peter
title: Projected supportive effects of Pycnogenol® in patients suffering from multi-dimensional health impairments after a SARS-CoV2 infection
date: 2020-10-09
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106191
sha: 
doc_id: 261470
cord_uid: sqxdwu6j

Corona Virus Disease 2019 (COVID-19) is triggered by the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV2) and has rapidly developed into a worldwide pandemic. Unlike other SARS viruses, SARS-CoV2 does not solely impact the respiratory system, but additionally leads to inflammation of endothelial cells, microvascular injuries and coagulopathies, thereby affecting multiple organs. Recent reports of patients that were infected with SARS-CoV2 suggest persistent health problems even months after the initial infection. In over 90 human clinical studies, the French maritime pine bark extract Pycnogenol® demonstrated anti-inflammatory, vascular and endothelium-protective effects. We propose that Pycnogenol® may be beneficial in supporting recovery and mitigating symptoms and long-term consequences resulting from a SARS-CoV2 infection in COVID-19 patients.

Affected organs during COVID-19 and exemplary symptoms that are related to a SARS-CoV2 infection. In addition to pulmonary manifestations, several other organs can be impacted. The most frequent and dominant symptoms in the respective organs are summarized here.

The disease apparently triggers a generalized vascular or endothelial pathology [32] , [33] . The virus enters cells, expressing the ACE2 (angiotensin converting enzyme 2) receptor and other receptors/facilitators on their surface that mediate the entry of SARS-CoV2, including transmembrane serine protease 2 (TMPRSS2), starting in the nasal epithelial cells, which abundantly express these proteins [34] - [37] (Figure 2 ). ACE-2 receptors are densely present on the epithelial cells of the respiratory tract, but also on cell membranes of other organ tissues, like heart, kidney, stomach or colon tissue, as well as on glia cells, neurons and endothelial cells [38] , [39] . Being an essential part of the renin-angiotensin-system [40] , ACE-2 receptors are involved in the regulation of blood pressure and water balance [41] . The enzyme ACE-2 metabolizes angiotensin-II (AngII) to the vasodilatory and anti-inflammatory heptapeptide angiotensin (1-7) [40] , [41] . Upon virus admission in the early phases of infection, ACE-2 is down-regulated, with loss of catalytic effect of these receptors [35] . Local AngII concentrations are consequently elevated, which results in vasoconstriction, endothelial activation and pro-inflammatory cytokine release [35] . In addition, the cytokine paracrine signaling is dysregulated with the release of pro-and anti-inflammatory molecules as well as pro-apoptotic mediators [35] , [42] . Subsequently, lymphocytes are recruited through chemokines, resulting in depletion of natural killer, B-and T-cell decrease and possibly to lymphocytopenia, which is associated with severity of the disease [43] . This entails microvascular inflammation, triggering endothelial activation and eventually pro-thrombotic conditions [35] . Indeed, several cases of microvascular thrombosis or other thrombotic complications were described in patients suffering from COVID-19 [44] - [47] . In most cases, the lung gets infected by the SARS-CoV2, in which the pneumocytes (the alveolar epithelial cells) express less ACE2 receptor proteins and TMPRSS2 protease but enough to potentially bring this organ to its limits and to trigger a severe pneumonia [48] . The primary entrance of the virus via the respiratory epithelium can directly affect olfactory and taste abilities mediated by the olfactory epithelium [13] , [14] . The central nervous system can be infected when the virus uses the hematogenous or retrograde neuronal route [16] , [17] . To estimate the severity of neurological manifestations in COVID-19 patients, the "NeuroCovid stages I -III" classification scheme was proposed [49] . In stage I, the virus remains in the epithelial cells of the nose and mouth, stage II includes blood clotting and in stage III, patients suffer from a cytokine storm that can damage the blood-brain barrier [49] . The virus spreads into the gastrointestinal tract via swallowed secretion from the nasopharynx space, where it might invade gut enterocytes, harboring ACE2 receptors [50] - [52] . Additionally, cardiovascular cells expressing ACE2 receptors can be infected by SARS-CoV2, posing the risk for a severe cardiac injury [53] , [54] . Likewise, the liver can be affected potentially by infection of cholangiocytes [55] , [56] . Furthermore, the kidney presents ACE2 receptors mainly in the brush border of proximal tubular cells and in the podocytes, through which the coronavirus can infect this organ as well [20] , [57] . The fact of new-onset diabetes cases in COVID-19 patients could be explained by the expression of ACE2 receptor in endocrine pancreatic beta cells (islets of Langerhans) [25] , [39] . It has further been described that also eyes can be infected by the virus, triggering conjunctivitis [58] . The various skin problems that occur after a SARS-CoV2 infection are possibly due to a high expression of the ACE2 receptor on keratinocytes [59] . Endothelial cells are affected quite strongly by SARS-CoV2 infection through the ACE2 receptors, in some cases leading to a severe endotheliitis, which often leads to disorders in microcirculation and problems in blood clotting and coagulopathies [32] , [33] . Since endothelial cells line the inner membrane of blood vessels in the heart and other organs; thus, an infection of those cells affects the whole body. Figure 2| Infection mechanism of a SARS-coronavirus 2. The virus can enter a cell, using the attachment proteins (spikes), which are activated by serin protease TMPRSS2 and can then attach to the transmembrane receptor ACE2. Via endocytosis, the virus infects the cell, releases the viral RNA genome, which is translated and replicated within the host. Subsequently, several copies of the virus leave the cell via exocytosis. Kawasaki syndrome-like disease

epidemic are possibly connected [63] , [64] . The symptoms of this disease strongly resemble the Kawasaki syndrome, a mucocutaneous lymph node syndrome [63] - [65] . The Kawasaki syndrome is a pediatric acute febrile systemic vasculitis, which potentially can be fatal [66] . Children with this disease develop high fever for at least 5 days, enlarged lymph nodes, rash in genital area, red eyes, lips, palms and soles, a "strawberry tongue", sore throat, diarrhea, peeling skin and coronary artery aneurysms in ~25% of untreated cases, which makes it the leading cause of acquired heart disease in children [66] . The disease affects predominantly children under the age of 5 years and occurs relatively rarely with ~25 per 100,000 children in the USA and ~30 per 100,000 children in Asia [66] . The cause is still unknown, but it is probably triggered by a classic antigen, possibly transferred via a viral infection that triggers the immune system [67] . Clinical studies in Italy and England have shown an elevated rate of Kawasaki-like diseases [63] , [64] . In Bergamo, the incidence of this disease has increased by a factor of 30 since the beginning of the pandemic in February 2020. The affected children were older (7.5 vs 3 years) and showed a higher rate of cardiac involvement compared to cases seen before the SARS-CoV2 epidemic [64] . Two London based hospitals also found increasing numbers of patients with Kawasaki-like symptoms in communities with high rates of COVID 19, which was provisionally called pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) [68] - [70] .

Pycnogenol ®

Pycnogenol ® is extracted from the bark of Maritime pine trees (Pinus pinaster) originated from France. The result is a very fine, red/brown-colored, water-soluble powder. Pycnogenol ® contains mainly procyanidins and their monomers (catechin and epicatechin) as well as phenolic acids. The total amount of procyanidins is standardized to 70 ± 5%. Pycnogenol ® meets the specifications for Maritime Pine Extract, detailed in the United States Pharmacopeia (USP). The procyanidins are biopolymers consisting of units of catechin and epicatechin, with most chain lengths of 2-12 monomeric units [71] .

Pycnogenol ® is self-affirmed GRAS (Generally Recognized As Safe) for use in conventional foods, based on the evaluation of clinical safety and preclinical toxicology data by an independent panel of toxicology experts. Non-mutagenicity, lethal dose (LD50) above 5.0g/kg body weight, NOAEL above 1000mg/kg/day were determined [71] . Based on current European Food Safety Agency (EFSA) recommendations, this translates in a safe dosage of >700 mg per day. Typically, oral dosages tested in the literature are in the 30 to 200 mg/day, with some studies exploring higher dosages of 200 to 450 mg/day. There have been no reports of serious adverse effects in any clinical study or from commercial use of Pycnogenol ® since it was introduced into the market in Europe around 1970. Mild side effect of gastric discomfort has rarely been reported and was linked to stomach-sensitive patients. No interactions of Pycnogenol ® with other drugs, alcohol or food intake have been reported [71] . Pycnogenol ® does not affect INR (a measure of bleeding tendency) or platelet function in patients taking aspirin [72] . One University study evaluated patients (n = 28; 49-73 years of age) with stable coronary artery disease treated with both optimal standard therapy and 200 mg/day Pycnogenol ® for 8 weeks. Standard therapy included aspirin (100% of patients), statins (87%), ACE inhibitors/angiotensin receptor blockers (78%), β-blockers (74%), diuretics (35%), calcium antagonists (17%), clopidogrel (17%), ezetimibe (17%), oral antidiabetics (17%), phenprocoumon (4%), and αantagonists (4%). There were no adverse drug-herb interactions [72] .

The symptoms of COVID-19 comprise endothelial dysfunction, coagulopathy, cytokine storm, problems in microcirculation and capillary leak syndrome. For many of those conditions data from clinical studies with Pycnogenol ® exist, showing beneficial effects in terms of normalizing and stabilizing signs and symptoms related to COVID-19 ( Figure 3 ). 

Several clinical studies with patients having no or particular comorbidities, showed that Pycnogenol ® can improve endothelial function [72] - [76] . The suggested mechanism is an activation of the endothelial nitric oxide synthase (eNOS), thus amplifying the NO generation from L-arginine, eventually leading to an increase in vessel lumen and adequate tissue perfusion. In patients with coronary artery disease, endothelial function was assessed by measuring the flow-mediated dilatation (FMD) of the brachial artery. 200 mg Pycnogenol ® per day was supplemented in a randomized, double-blind, placebo-controlled crossover study for 8 weeks [72] . The FMD during supplementation was improved by 33 %, whereas during placebo, the FMD slightly decreased [72] . In a double-blind placebo-controlled randomized study with hypertensive patients, endothelin-1 -which acts as a vasoconstrictor -was significantly lowered by 20 % in the supplement group, whereas vasodilatory 6-keto prostaglandin F1a, the physiologically active and stable metabolite of prostacyclin, increased compared to the placebo group [76] . This indicates an improved endothelial function. The patients had been taking 100 mg Pycnogenol ® per day for 12 weeks [76] . Another double-blind, placebo-controlled study reported similar effects when supplementing type II diabetes and hypertensive patients, taking ACE inhibitor medication together with 125 mg Pycnogenol ® daily for 3 months. Here, the serum endothelin-1 levels were lowered by 17.8 %, compared to scarcely any change in placebo patients [74] . Nishioka et al. investigated the pharmacological effects of Pycnogenol ® on the endothelium dependent vasodilation via nitric oxide production by measuring the forearm blood flow in response to acetylcholine (an endothelium-dependent vasodilator) [75] . Following 200 mg Pycnogenol ® intake per day for 14 days, forearm blood flow in response to acetylcholine of healthy volunteers increased significantly up to 41 % [75] . As a negative control, the forearm blood flow was also measured in response to an endothelium independent vasodilator (sodium nitroprusside), which showed no change after Pycnogenol ® intake, compared to the placebo group. In this study, healthy individuals were supplemented with placebo or 180 mg Pycnogenol ® per day for 2 weeks in a double-blinded fashion [75] . This is a confirmation of Pycnogenol ® 's beneficial effects on endothelial function. Several studies reported that Pycnogenol ® efficacy on blood vessel depends on the endothelium as it could be abolished by administration of an endothelium-specific NO synthase inhibitor or by removing the endothelial lining [75] , [77] . These findings suggest that Pycnogenol ® acts by increasing NO production in the endothelium, which in turn leads to better perfusion and blood circulation within vessels [75] . As mentioned before (chapter 0), SARS-CoV2 strongly affects the endothelial cell lining, triggering an inflammation and/or coagulopathies and leading to endothelial activation and pro-thrombotic conditions. Regarding endotheliitis, Pycnogenol ® studies offer good evidence for potential beneficial effects for patients suffering from COVID-19 by improving endothelial function.

Insufficient microcirculation is observed in diabetes, hypertension or cardiovascular and lung diseases. Pycnogenol ® has been shown to improve this condition by strengthening the microcirculation perfusion system [78] , [79] . The microcirculation in fingernails for instance, was determined by measuring the diameter of micro vessels, which improved in patients, treated with Pycnogenol ® compared to placebo treatment [78] . In two clinical studies, the transcutaneous PO 2 and PCO 2 levels as well as the flux at rest and the level of venoarteriolar response were measured to investigate the effects of Pycnogenol ® on microcirculation in patients with microangiopathy resulting from diabetes or chronic venous insufficiency [79] , [80] . The PO 2 levels increased, whereas the PCO 2 levels decreased compared to control patients upon intake of Pycnogenol ® for 6 weeks [79] . The flux at rest was lower than at inclusion and the level of venoarteriolar response increased significantly upon supplementation [79] . Another measure for capillary leaking is the strain-gauge-derived rate of ankle swelling, which was significantly reduced after supplementation with Pycnogenol ® in diabetic patients with microangiopathy [81] . Tissue health is tightly connected to the strength of capillary walls. Increased capillary wall strength was demonstrated after intake of Pycnogenol ® for 3 months in a clinical study with diabetic patients suffering from retinopathy [82] . Here, retinal edema, assessed by measuring the retinal thickness was significantly reduced in patients taking 150 mg Pycnogenol ® per day. This resulted in improved visual acuity in the supplemented subjects, whereas it was unchanged in control patients. In severe cases of retinopathy, dysfunctional retinal capillaries can be leaking, which eventually leads to irreversible vision loss. This study suggests that Pycnogenol ® can counteract capillary leaking by strengthening the capillary walls [82] . The capillary leak syndrome is characterized by hyperpermeable capillaries through a disruption of endothelial cell-to-cell binding, which results in diffusion of blood plasma into surrounding tissues or the interstitial space [83] - [85] . In most cases, acute kidney injury or nephritis and a severe capillary leak syndrome are found together [84] . Pycnogenol ® supplementation has also been shown to improve kidney function in metabolic-syndrome patients with micro-albuminurea and in hypertensive patients with early signs of renal function impairment [86] , [87] . Urinary albumin levels significantly decreased and kidney cortical blood flow increased in patients taking Pycnogenol ® in addition to an ACE inhibitor, compared to subjects medicated only with the ACE inhibitor for six months [86] , [87] . A microcirculatory dysfunction accompanying endothelial problems has been reported for COVID-19 patients as well [32] , [33] . Again, Pycnogenol ® has the potential to act favorably and bring microcirculation to normal levels.

The activation and subsequent aggregation of blood platelets can result in severe, life-threatening conditions like thrombosis, strokes or heart attacks. By increasing the production of endothelial nitric oxide, Pycnogenol ® has the ability to lower blood platelet aggregation, as effectively as aspirin without increasing the bleeding time [88] , [89] . In individuals with increased blood platelet activity -smokers -Pycnogenol ® was shown to act dose-dependently on the aggregation of platelets [88] , [89] . This smoke-induced platelet aggregation was reduced to the level of non-smokers after supplementation with 200 mg Pycnogenol ® per day for 2 months [89] . This effect was not observed in healthy non-smokers, hence, Pycnogenol ® normalizes a pathologically increased platelet activity, but does not further decrease a normal platelet function [89] . Pycnogenol ® prevents platelet hyperactivity but is safe as it does not influence the bleeding time in contrast to aspirin, which significantly increased the time of bleeding from 167 to 236 seconds [88] . These results suggest that Pycnogenol ® acts on platelet aggregation as effectively as aspirin, but without increasing the risk of bleeding complications [88] . It has been confirmed in a university study, that Pycnogenol ® does not further decrease platelet activity in cardiovascular patients taking aspirin [72] . This property of Pycnogenol ® should be helpful in COVID-19 patients as well. Here, the percentage of patients with blood coagulation problems or thrombosis is relatively high (40%) [35] . One reason for this could be induced morphological changes of peripheral blood cells, such as giant platelets that have been found in COVID-19 patients [90] . Along with this, several cases of acute pulmonary embolism have been described in COVID-19 patients [91] , [92] . Normalizing the blood platelet activity by regular intake of Pycnogenol ® might be beneficial in these cases to prevent thrombosis and pulmonary embolism in COVID-19 patients [93] , [94] .

Intrusion of viruses, bacteria or other pathogens activates inflammatory cascades and pathways, like the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway, resulting in the release of inflammatory mediators, such as TNF-α and the interleukins IL-1 and IL-6 [95] . In severe cases of an inflammation, as observed in COVID-19 patients, this might provoke a cytokine storm or a hyperinflammation syndrome [35] . During an inflammation, a number of reactive oxygen species are produced, which in turn fuel the inflammasome, leading to the secretion of interleukins [96] . The antioxidant activity of Pycnogenol ® was investigated in a number of clinical studies [72] , [97] - [101] . Orally administered Pycnogenol® was shown to both increase the plasma anti-oxidant capacity, expressed as ORAC (oxygen radical absorbance capacity) [99] and to decrease the plasma oxidative stress measured as plasma free radicals [102] . Pycnogenol ® was further shown to protect lipids from peroxidation by free radicals in elderly people and patients with coronary artery disease [72] , [97] . Also the protective effect of Pycnogenol ® on DNA oxidation was shown in a randomized, double-blind, placebo-controlled study with children, suffering from ADHD by measuring the level of oxidized purines [100] . In multiple studies, an antiinflammatory activity of Pycnogenol ® has been observed [103]- [106] . To investigate the underlying mechanism in a context close to physiology "ex-vivo" approaches have been developed, in which healthy volunteers are supplemented with Pycnogenol ® and blood samples are taken after a specific time [104] - [106] . The respective serum/plasma samples contain bioactive molecules and can be used in cell culture studies as active ingredients and compared to plasma before supplementation [104] - [106] . Thus, by taking into account the process of absorption, distribution and gut metabolism, molecular pharmacological mechanisms of complex plant extracts can be investigated in a more rational way compared to in vitro studies [105] . To induce an inflammation ex vivo, leucocytes are primed with endotoxins such as lipopolysaccharides, which are present on the outer membrane of gram-negative bacteria, triggering a strong immune response [107] . In addition, the leucocytes can be stimulated with formyl-methionyl-leucylphenylalanine (fMLP) to activate the arachidonic acid cascade, a pathway involved in inflammation, whereby cyclooxygenase (COX) enzymes 1 and 2, as well as 5-lipooxygenase (5-LOX) metabolize arachidonic acid to prostaglandins, prostacyclin, thromboxanes and leukotrienes [108] . After the intake of 150 mg Pycnogenol ® per day for 5 days, the serum of volunteers decreased 5-LOX and COX-2 gene up-regulation and fMLP-enhanced leukotriene biosynthesis in an ex vivo study using polymorphonuclear leukocytes [104] . Another ex vivo study employed plasma from healthy individuals, consuming 200 mg Pycnogenol ® per day for 5 days, which was incubated with monocytes and subsequently with LPS to induce inflammation [105] . Plasma samples obtained after intake of Pycnogenol ® statistically significantly inhibited matrix metalloproteinase 9 (MMP-9) release from human monocytes and NF-κB activation as compared to control plasma samples before supplementation [105] . The Pycnogenol ® metabolite M1 (δ-(3,4-dihydroxy-phenyl)γ-valerolactone), which undergoes facilitated uptake by monocytes, macrophages, erythrocytes and endothelial cells, was shown to exert a direct anti-inflammatory activity by reducing iNOS (inducible nitric oxide synthase) expression and excessive nitrite production [73] , [105] , [109] . In a similar setup, a statistically significant inhibition of COX-1 and COX-2 was observed with serum samples of the volunteers obtained 30 minutes after a single dose of 300 mg Pycnogenol ® [106] . In an animal-based study, the effects of Pycnogenol ® on ventilator-induced lung injury of rats -which generally involves excessive inflammationwas investigated [103] . The production of pro-inflammatory cytokines, such as TNF-α, IL-1β, macrophage IL-6 and MIP-2 was reduced towards normal levels through the inhibition of NF-κB activation after administration of Pycnogenol ® . The authors suggested Pycnogenol ® to be a potential therapeutic option for ventilator-induced injury [103] . Hence, having anti-inflammatory and anti-oxidative effects in addition to the beneficial effects on ventilator-induced injuries, Pycnogenol ® presents two very important advantages regarding a COVID-19 infection. Additionally, there are hints, that Pycnogenol ® metabolites M1 (δ-(3,4dihydroxy-phenyl)-γ-valerolactone) as well as M2 (δ-(3-methoxy-4-hydroxyphenyl)-γ-valerolactone) bind to zinc (2+) ion [110] . Zinc ion is a known modulator of antiviral and antibacterial immunity and has inflammatory regulation ability, which could also be beneficial in COVID-19 [111] .

The effects of Pycnogenol ® on endothelial health, microcirculation, platelet reactivity and inflammation have been discussed above. In addition to clinical effects, the molecular mechanisms of action have been also investigated [73] , [75] , [109] , [112] , [113] . Pycnogenol ® mainly consists of highly condensed procyanidins [114] , and the uptake of these high molecular weight biopolymers in the gastrointestinal tract is not possible. However, the polymers are metabolized by gut bacteria yielding small molecules, which are actually taken up in the big intestine. After oral intake of single and multiple doses of Pycnogenol ® , catechin, ferulic acid, caffeic acid, and taxifolin, a metabolite M1 (δ-(3,4-dihydroxy-phenyl)-γ-valerolactone) and further, yet unknown compounds were detected in plasma samples of volunteers [112] . The metabolite M1 is no component of the pine bark extract, but a gut microbial metabolite, which is generated from catechin. The activity of M1 was then further investigated and it was found to dose-dependently inhibit both iNOS (inducible nitric oxide synthase) expression and excessive nitrite production as it is observed in inflammatory states [73] . The metabolite M1 was found to be enriched in macrophages, monocytes and endothelial cells by facilitated uptake, thus explaining the rather low plasma/serum concentrations [73] . Further analysis found M1 to be transported into erythrocytes and intracellularly conjugating to a new glutathione adduct, the function of which has yet to be elucidated [109] .

Possible treatment and support of recovery of symptoms of a SARS-CoV2 infection Several laboratories around the world are trying to find a vaccine against the new coronavirus SARS-CoV2, some already in clinical evaluation [115] . As long as no effective vaccine against the rapidly spreading virus is available, other measures and treatments have to be used. Non-pharmaceutical interventions, like the worldwide confinement procedures have been dominating the months after the pandemic break-out [116] . Severely diseased patients need invasive ventilation and treated with drugs to decrease viral replication or partially block the dysregulated immune response [117] - [120] . One exemplary medication to potentially treat COVID-19 symptoms is remdesivir [121] . Remdesivir is a monophosphoramidate (a nucleoside analogue) and inhibits the viral RNA-dependent RNA-polymerase, which decelerates viral replication [121] , [122] . This effect was already shown in the previous epidemical outbreaks of SARS-CoV1 and MERS coronavirus infections and was confirmed for SARS-CoV2 [121] , [122] . There are, however, also reports of clinical trials, in which remdesivir did not show statistically significant benefits in COVID-19 patients [123] . Though, by the end of June 2020, remdesivir was the first treatment against COVID-19 in the EU approved by the European medicine agency [124] . Very recently, in a large-scale study, dexamethasone emerged as a promising drug candidate to treat COVID-19, being the first drug to lower mortality [125] . The RECOVERY (Randomized evaluation of COVID-19 therapy) trial has found improved survival in severely ill COVID-19 patients [125] . The mortality was reduced by 35 % in patients on invasive ventilation and by 20 % in patients treated with oxygen only [125] . Dexamethasone is a corticosteroid with strong anti-inflammatory and immunosuppressive effects that has been used to treat various health issues for decades [126] . However, dexamethasone is also associated with considerable side effects and its immunosuppressive activities might impair the production of antibodies during recovery [127] , [128] . In COVID-19 patients, a significant decrease of T-lymphocytes has been connected with the severity of illness [129] . In contrast, Pycnogenol ® supplementation seems to be able to restore immune dysfunction by improving T-cell function, thus acting as a immune modulating agent [130] , [131] . As Pycnogenol ® offers antioxidant and anti-inflammatory activities and positively influences endothelial cell function as well as microcirculation and platelet reactivity, a supplementation might support the management of COVID-19 patients. Since COVID-19 seems to have severe long-term consequences for the health [29] , [30] , especially a sustained supplementation with Pycnogenol ® might be helpful and should be further investigated in a clinical setting.

COVID-19 can have severe, possibly persisting consequences, like endothelial dysfunction, microcirculatory problems, coagulopathy, cytokine storm and capillary leak syndrome. In various clinical studies, Pycnogenol ® revealed positive effects relating to conditions that are also present in SARS-CoV2 infections. Pycnogenol ® improves endothelial health and microcirculation, normalizes platelet reactivity and shows anti-inflammatory effects. We hypothesize possible additional beneficial effects of Pycnogenol ® in patients infected with the new coronavirus SARS-CoV2 and those who suffer from abiding health problems, when complemented to the standard treatment also upon the first day of symptoms or infection.

Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Franziska Weichmann is an employee of Horphag Research LTD.

The species and its viruses -a statement of the Coronavirus Study Group

A novel coronavirus from patients with pneumonia in China

Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19)

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-A n update on the status

Temporal dynamics in viral shedding and transmissibility of COVID-19

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China

The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings

Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a crosssectional study

Olfactory and gustatory dysfunctions as a clinical presentation of mild-tomoderate forms of the coronavirus disease (COVID-19): a multicenter European study

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Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: A Retrospective Case Series Study

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Evidence for Gastrointestinal Infection of SARS-CoV-2

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Real-time tracking of self-reported symptoms to predict potential COVID-19

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Endothelial cell infection and endotheliitis in COVID-19

Is COVID-19 an Endothelial Disease? Clinical and Basic Evidence

Cell entry mechanisms of SARS-CoV-2

Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

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Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease

A Novel Angiotensin-Converting Enzyme -Related to Angiotensin 1-9

Coronaviruses: An Overview of Their Replication and Pathogenesis

Dysregulation of immune response in patients with COVID-19 in Wuhan

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up

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Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

Neurobiology of COVID-19

SARS-CoV-2 productively infects human gut enterocytes

SARS-CoV-2 Gastrointestinal Infection Causing Hemorrhagic Colitis: Implications for Detection and Transmission of COVID-19 Disease

The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan, China

COVID-19 and the cardiovascular system

Specific ACE2 Expression in Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection

Liver injury in COVID-19: management and challenges

Should COVID-19 Concern Nephrologists? Why and to What Extent? the Emerging Impasse of Angiotensin Blockade

Characteristics of Ocular Findings of Patients With Coronavirus Disease

High Expression of ACE2 on Keratinocytes Reveals Skin as a Potential Target for SARS-CoV-2

Ophthalmologic evidence against the interpersonal transmission of 2019 novel coronavirus through conjunctiva

Clinical Characteristics of 138 Hospitalized Patients with 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Kawasaki-like disease: emerging complication during the COVID-19 pandemic

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study

Kawasaki Disease: Etiopathogenesis and Novel Treatment Strategies

Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the

Memory T-cells and characterization of peripheral T-cell clones in acute Kawasaki disease

Hyperinflammatory shock in children during COVID-19 pandemic

Rapid Risk Assessment: Paediatric inflammatory multisystem syndrome and SARS-CoV-2 infection in children

Clinical Characteristics of 58 Children with a Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2

ABC scientific and clinical Monograph for Pycnogenol 2019 UPDATE

Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: A double-blind, randomized, placebo-controlled, cross-over study

Facilitated cellular uptake and suppression of inducible nitric oxide synthase by a metabolite of maritime pine bark extract (Pycnogenol)

Reduction of cardiovascular risk factors in subjects with type 2 diabetes by Pycnogenol supplementation

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Endothelium-Dependent Vascular Effects of Pycnogenol

The Effect of Pycnogenol® on the Microcirculation, Platelet Function and Ischemic Myocardium in Patients With Coronary Artery Diseases

Diabetic ulcers: Microcirculatory improvement and faster healing with Pycnogenol

Venous Ulcers: Microangiopathy improvement and faster healing with local use of Pycnogenol

Improvement of diabetic microangiopathy with Pycnogenol®: A prospective, controlled study

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Systemic capillary leak syndrome

Capillary leak syndrome: etiologies, pathophysiology, and management

Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome

Kidney function in metabolic syndrome may be improved with Pycnogenol®

Kidney flow and function in hypertension: Protective effects of pycnogenol in hypertensive participants-a controlled study

Inhibition of smoking-induced platelet aggregation by aspirin and pycnogenol

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Coronavirus disease 2019 induces multi-lineage , morphologic changes in peripheral blood cells

Acute pulmonary embolism and COVID-19 pneumonia: a random association?

COVID-19 Complicated by Acute Pulmonary Embolism

Prevention of recurrent venous thrombosis and post-Thrombotic syndrome

Pycnogenol® in chronic venous insufficiency and related venous disorders

Origin and physiological roles of inflammation

Reactive oxygen species in inflammation and tissue injury

An examination of the effects of the antioxidant Pycnogenol® on cognitive performance, serum lipid profile, endocrinological and oxidative stress biomarkers in an elderly population

A mosaic intragenic microduplication of LAMA1 and a constitutional 18p11.32 microduplication in a patient with keratosis pilaris and intellectual disability

Supplementation with a pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile

Effect of polyphenolic extract, Pycnogenol®, on the level of 8-oxoguanine in children suffering from attention deficit/hyperactivity disorder

Lipid metabolism and erectile function improvement by Pycnogenol®, extract from the bark of Pinus pinaster in patients suffering from erectile dysfunction -A pilot study

A controlled study shows daily intake of 50 mg of French Pine Bark Extract (Pycnogenol®) lowers plasma reactive oxygen metabolites in healthy smokers

Pycnogenol, a compound isolated from the bark of pinus maritime mill, attenuates ventilator-induced lung injury through inhibiting NF-κB-mediated inflammatory response

The anti-inflammatory pharmacology of Pycnogenol® in humans involves COX-2 and 5-LOX mRNA expression in leukocytes

Inhibition of NF-κB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol)

Inhibition of COX-1 and COX-2 activity by plasma of human volunteers after ingestion of French maritime pine bark extract (Pycnogenol)

Lipopolysaccharide Endotoxins Endotoxins as Activators of Innate Immunity

Synopsis of arachidonic acid metabolism: A review

Facilitated Uptake of a Bioactive Metabolite of Maritime Pine Bark Extract (Pycnogenol) into Human Erythrocytes

Antioxidant activity and inhibition of matrix metalloproteinases by metabolites of maritime pine bark extract (Pycnogenol)

Zinc and respiratory tract infections: Perspectives for COVID-19 (Review)

Single and multiple dose pharmacokinetics of maritime pine bark extract (Pycnogenol) after oral administration to healthy volunteers

The anti-melanogenic effect of pycnogenol by its antioxidative actions

A review of the French maritime pine bark extract (Pycnogenol®), a herbal medication with a diverse clinical pharmacology

Draft landscape of COVID-19 candidate vaccines -29

Effect of non-pharmaceutical interventions to contain COVID-19 in China

Invasive mechanical ventilation in COVID-19 patient management: the experience with 469 patients in Wuhan

COVID-19: consider cytokine storm syndromes and immunosuppression

Plea for multitargeted interventions for severe COVID-19

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

Remdesivir for the Treatment of Covid-19 -Preliminary Report

Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebocontrolled, multicentre trial

First COVID-19 treatment recommended for EU authorisation

Effect of Dexamethasone in Hospitalized Patients with COVID-19 -Preliminary Report

Dexamethasone Monograph

Dexamethasone-induced immunosuppression: Mechanisms and implications for immunotherapy

Dexamethasone for COVID-19? Not So Fast

Suppressed T cell-mediated immunity in patients with COVID-19: A clinical retrospective study in Wuhan, China

Pycnogenol attenuates the symptoms of immune dysfunction through restoring a cellular antioxidant status in low micronutrient-induced immune deficient mice

Pycnogenol enhances immune and haemopoietic functions in senescence-accelerated mice