key: cord-1054534-2096ae9y authors: Criado, Paulo Ricardo; Miot, Hélio Amante; Pincelli, Thais Prota Hussein; Fabro, Alexandre Todorovic title: From dermatological conditions to COVID‐19: Reasoning for anticoagulation, suppression of inflammation, and hyperbaric oxygen therapy date: 2020-11-30 journal: Dermatol Ther DOI: 10.1111/dth.14565 sha: da0cdab91a5358373607fd44fe8cacd1914714e7 doc_id: 1054534 cord_uid: 2096ae9y COVID‐19 generates a complex systemic inflammatory response that can lead to death due to wide macrophage activation, endothelial damage, and coagulation in critically ill patients. SARS‐CoV‐2‐induced lung injury due to inflammatory mediated thrombosis could be similar to the livedoid vasculopathy in the skin, supporting a translational comparison of these clinical settings. In this article, we discuss anticoagulation, suppression of inflammatory response, and hyperbaric oxygen therapy in the context of severe COVID‐19 and livedoid vasculopathy. The pathogenesis of LV is yet to be understood, with the main mechanism being hypercoagulability and inflammation playing a secondary role 3 , as opposed to the sequence observed in COVID-19 during the early phases within the lungs. Both diseases may benefit from corticosteroids and could be treated by the combined therapy of hyperbaric oxygen therapy (HBOT) and anticoagulation. The histopathology of LV is characterized by intraluminal thrombosis, proliferation of the endothelium, and segmental hyalinization of dermal vessels, often only in the lower limbs. 3 Nevertheless, lymphocyte infiltrate can be present and perpetuate thrombotic phenomena, leading to skin necrosis ( Figure 1 ). Similarly, pulmonary endothelial damage with microthrombi ( Figure 1A ) and hemorrhagic lung infarction by septal necrosis ( Figure 2B ) were observed. In addition, the inflammatory process is accompanied by fibrinoid plugs ( Figure 2C ) and lymphocytic interstitial infiltration ( Figure 2D ). In this article, we present a rationale for the efficacy of anticoagulation and hyperbaric oxygen therapy in both disorders. In 2003, Yang et al 4 described two patients with an intractable LV whose ulcers were successfully treated with HBOT. After this, other authors published case reports with similarly satisfactory results in LV patients. [5] [6] [7] [8] [9] [10] [11] In February 2020, Zhong et al 12 pneumonia who had been treated under HBOT. These five patients were 24 to 69 (mean 47.6) years old and received three to eight (mean 4.6) sessions of HBOT in addition to routine therapies. 13 These patients' daily average oxygen saturation levels (SpO 2 ) were restored to above 95% after one to eight HBOT treatments. Following HBOT, patients' PaO 2 and SaO 2 levels had significantly increased (P < .05) and their lactate levels had declined. The patients' peripheral blood lymphocytes were obviously elevated after HBOT treatments (P < .05) and their fibrinogen and D-dimer serum levels had decreased. Chest computerized tomography (CT) scans obtained during or after HBOT showed significantly improved imaging status of lung lesions in each patient. 13 The HBOT methods applied by Chen et al 13 Regarding the safety of disease control and the prevention of airborne contagion, a hyperbaric chamber and oxygen inhalation system are perfect gas management systems for disease control due to their properties of closed, one-way gas flow, all-fresh-air, and relatively independent gas lines for medical staff and patients, which suggest that the risk of infection for medical staff in the chamber is not higher than in the ward. Rigorous measures of disease control and prevention were applied for HBOT. 13 For the treatment of COVID-19 patients, the measures for disease control outside the chamber were the same as in the infection wards, such as implementation of separate paths for medical staff and patients and the distinction of infectious areas. 13 Disinfection measures in the chamber were further strengthened to similar levels as in infectious ward areas. 13 In regards to the treatment procedure, patients respired with built-in breathing apparatus immediately upon entering the chamber. 13 The chamber maintained continuous ventilation with a high volume of fresh air. 13 Guo et al 14 reported the same success in two other male COVID-19 patients, each of whom met at least one of the following criteria: shortness of breath; a respiratory rate (RR) of ≥30 breaths per minute; finger pulse oxygen saturation (SpO 2 ) of ≤93% at rest; and an oxygen index with a P/F ratio of PaO 2 /FiO 2 ≤ 300 mm Hg. Patients were treated with HBOT of 1.5 atm with an oxygen concentration of more than 95% for 60 minutes per treatment once a day for 1 week. No patient became critically ill; they demonstrated a decreasing trend of SO 2 and their P/F ratios were immediately reversed and increased daily. In addition, their lymphocyte counts and ratios reflecting F I G U R E 1 Livedoid vasculopathy in the skin: dermal necrosis with hemorrhagic, lymphocyte infiltrate, and endothelial damage with fibrin microthrombi (HE 400×) immune function gradually recovered, their D-dimer corresponding to peripheral circulation disorders and serum cholinesterase (reflecting liver function) improved. Subsequent chest CTs showed that patients' pulmonary inflammation had clearly subsided. A single-center prospective study was also conducted on HBOT as an adjunct to standard therapy for a pilot cohort of 40 COVID- Winthrop Hospital (registered at clinicaltrial.gov under the identifier NCT04332081). 15 The initial result of this study was that following infection by SARS-CoV-2, morbidity and mortality from this condition are due to the incidence of ARDS, which is defined as a condition of extremely low arterial oxygen concentration or hypoxia with a ratio of partial pressure of arterial oxygen and a fraction of inspired oxygen (PaO2/ FiO2 ratio) of ≤300, as well as bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules identified by chest radiography or CT. 16 ARDS as seen in severe COVID-19 is characterized by difficulty in breathing and low blood oxygen levels. 17, 18 As a result, some patients may experience complications with secondary bacterial and fungal infections. ARDS may lead directly to respiratory failure, which is the cause of death in 70% of fatal COVID-19 cases. 17 The development of ARDS is likely the product of inflammation mounted by the patient's response to the virus and secondary bacterial infections. 18 Harch PG 19 analyzed the outcomes of the first two Chinese with COVID-19 for whom HBOT was applied 12, 13 and reinforced the application of HBOT in this clinical scenario based on sound physiology and Henry's law. Named after the English physician William Henry, this law defines the relationship between the partial pressure of gases overlying a solution and the gases' ability to dissolve in that solution. 20 Henry's law states that when a gaseous mixture (eg, the atmosphere) is in contact with a solution, the amount of any gas in that mixture that dissolves in the solution is directly proportionate to the partial pressure of that gas. 20 The partial pressure of a gas is the amount of pressure that the gas contributes to the total pressure of that gas mixture. 20 According to Henry's law, if the pressure of a gas over liquid increases, the amount of gas dissolved in the liquid will increase proportionally. As the gas pressure decreases, the amount of gas dissolved in the solution drops. 20 In COVID-19 lung injury, the alveolar-capillary barrier is damaged by an inflammatory exudate with edema and a lymphocytic infiltrate, leading to reduced gas exchange in the distal airway spaces. 19 Additionally, there is associated microvascular thrombosis in the perialveolar blood vessels ( Figure 2 ). Dr. Richard Levitan, an emergency physician at Bellevue Hospital in New York City, made some striking patient observations regarding blood O 2 levels that he shared in a New York Times opinion piece (April 20, 2020). 18 He noted that the initial stage of COVID-19 is only now being understood as "silent hypoxia," alluding to its "insidious, hard-to-detect nature." 18 In Levitan's observations, SpO 2 fell from the normal range of 94-100% to as low as 50%, but patients did not experience any dyspnea until the depleted levels reached critical values. This was most likely due to the fact that CO 2 continued to be released. By the time CO 2 started to accumulate, a feeling of breathlessness developed and many COVID-19 patients declined quickly into respiratory failure. 18 According to Henry's law, the HBOT acts by (a) dissolving oxygen in the inflamed alveolar-capillary barrier, (b) increasing the diffusion rate of oxygen, (c) the diffusion distance of oxygen, (d) increasing the dissolution of oxygen in blood plasma, (e) achieving more oxygen saturation of hemoglobin in the red blood cells, and (f) achieving the best delivery of oxygen to the microcirculation and tissue. 19 The next result is a reversal of the downward spiral of COVID-19 patients. 19 Elevated systemic levels of oxygen secondary to HBOT has been tra- The main side effects of HBOT are limited to the pulmonary and neurological (eg, visual impairment, tinnitus, nausea, facial spasms, dizziness, and disorientation) systems. 22 Pulmonary toxicity usually manifests with tracheobronchial irritation. Oxygen toxicity has also been previously reported. 22 However, the adverse effects of HBOT seem of relatively small concern in COVID-19 cases considering the rather limited number of patients in whom such therapy could be considered and applied. 22 Several of HBOT's effects in reducing patients' inflammatory state have been described, 22 Hyperbaric exposition and decompression induce activation of fibrinolysis, even in the absence of detectable gas bubbles. 23 Fibrinolytic activity increases mainly due to decreases in concentration and activity of plasminogen activator inhibitor-1 (PAI-1). 23 Other HBOT effects under coagulation/fibrinolytic pathways include (a) increasing red blood cell (RBC) deformation (erythrocyte rheology), allowing RBCs to perfuse areas that they otherwise could not due to capillary and small arteriolar damage from purpura fulminans or duet to impaired RBC deformability, contributing to sludging and oxygen offload inability. 24 Endothelial cells represent one-third of the total lung cells. 24 Baseline endothelial damage may be chronically caused by increased adiponectin in diabetic and obese patients; this effect is related to activation of inflammasome NLRP3 and autocrine production of IL-1β. 24 Additional damage to pulmonary endothelial dysfunctional cells is acutely provoked by infections and, in turn, causes excess thrombin generation and reduced fibrinolysis. 26 Additionally, hypoxia may lead to increased expression and hypercoagulability of HIF-1α. 26 Therefore, a high rate of thrombotic episodes is reported in patients with COVID-19, while increased vascular permeability seems to be strongly related to increased thrombosis (inflammatory mediated). 26 In lymphopenia with organ failure, increased vascular permeability has been strongly correlated with severe lymphopenia. 26 Figure 3 summarizes the possible mechanisms by which HBOT may act in both LV and COVID-19 patients to repair inflammation, coagulation, and tissue damage. Histopathology of the lungs revealed diffuse alveolar damage consistent with early ARDS in eight cases. Predominant findings were hyaline membranes, activated pneumocytes, microvascular thrombi, capillary congestion, and protein-enriched interstitial edema. 31 Microthrombi were found within small lung arteries and occasionally within the prostate but not in other organs. 32 COVID-19 may predispose patients to venous thromboembolism in several ways. 32 The coagulation system may be activated by many Heparin has two different mechanisms of inhibition on the NF-κB signaling pathway: one focuses on inhibiting translocation of the transcription factor into the nucleus 33 and the other one has been explained as the ability of heparin to interfere non-specifically with the binding of NF-κB to DNA in the nucleus. 33 Hence, leukocyte adhesion and activation, as well as pro-inflammatory cytokine production, are downregulated as a result of the inhibitory effect of heparin on the NF-κB signaling. 34 Administering heparin to patients will not only activate their antithrombins but may also affect the functional state of a variety of other proteins. 35 By competing with cell-surface heparan sulfate (HS) for protein binding, heparin will displace proteins from their HSmediated anchoring and thus disrupt associated function. 35 The effects of potential value in COVID-19 treatment include the prevention of viral adhesion as well as promotion of antiinflammatory activity based on inhibition of neutrophil chemotaxis and leukocyte migration. 35 The recurrent involvement of proteins bound to cell-surface HS is striking. 35 Binding of a viral protein to cell-surface HS is often the first step in a cascade of interactions that are required for viral entry and initiation of the infection. 35 Heparin interacts with the receptor-binding domain of the SARS-CoV-2 Spike S1 protein and heparin use may have the potential to prevent viral adhesion. 35 A retrospective clinical study found that use of LMWH in the treatment of COVID-19 patients resulted in significantly lower plasma levels of IL-6, a key player in the "cytokine storm" associated with the severe outcomes of this viral disease. 35, 36 This review aim to contribute with additional information that may be applied in the futures randomized-controlled trails (RCT) on HBOT and LMWH is necessary as a proof of concept in the efficacy and safety of this approach for moderate to severe COVID-19 until an effective antiviral drug becomes available. The authors declare no potential conflict of interest. Paulo Ricardo Criado: article conception, article writing, Figure 1 Thais Prota Hussein Pincelli: article writing, final article organization, English review. Alexandre Todorovic Fabro: article writing, Figure 1 and 2 conception, final article organization. Data Availability Statement: Data sharing is not applicable to this article as no new data were created or analyzed in this study. Paulo Ricardo Criado https://orcid.org/0000-0001-9785-6099 Coagulopathy and Antiphospholipid antibodies in patients with Covid-19 The unique characteristics of COVID-19 coagulopathy. 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From dermatological conditions to COVID-19: Reasoning for anticoagulation, suppression of inflammation, and hyperbaric oxygen therapy