1874-3064/20 Send Orders for Reprints to reprints@benthamscience.net 32 The Open Respiratory Medicine Journal Content list available at: https://openrespiratorymedicinejournal.com EDITORIAL COVID-19: A Therapeutic Approach Based on Pathophysiological Staging Christian Domingo Ribas1,2,* 1 Pulmonary Service, Corporació Sanitària Parc Taulí, Barcelona, Spain 2 Departament of Medicine, Universitat Autònoma de Barcelona (UAB) Barcelona, Spain Abstract: The COVID-19 pandemic is a recently emerging problem. This has caused that the knowledge of the disease has been progressive and, therefore, the therapeutic decisions have been conditioned by this lack of knowledge on the one hand and by the therapeutic limitations on the other. Many published studies are methodologically weak and their conclusions, of limited value, have contributed to creating confusion on the therapeutic approach of the disease. In the present paper, we propose a therapeutic approach based on a new disease staging. The therapeutic approach is divided into two big sections: the pharmacological treatment for the phase of viral replication, cytokine storm or late respiratory events (which includes the adult respiratory distress syndrome (ARDS)) and the treatment of the respiratory failure In every stage, we discuss the pathophysiology and comment (accept or rule out) the pharmacological options according to the present evidence. Moreover, we indicate how respiratory failure should be treated. Some characteristics are based on the evidence found in the literature. Others are the result of my experience in other situations. 1. INTRODUCTION Distress Syndrome (ARDS). It is difficult to understand how an During the last five months, a new disease has appeared on episode of ARDS might occur during a phase of hyperinfla- the medical horizon: the COVID-19 infection. Initially, in mmation, since ARDS is the consequence rather than the response to the first reports from China, COVID-19 was cause. considered a mild disease with high infectivity (being termed the “new influenza”). Sooner than expected, the infection 1.1. New Pathophysiological Classification Proposal and moved to Europe, hitting Italy particularly hard. At that Therapeutic Approach moment, it became evident that the disease had many different We propose a different pathophysiological classification faces and that its severity was due to respiratory failure. At my basically driven by respiratory involvement, which divides the hospital, we saw more than 2700 patients with COVID-19 disease into four stages (stages I, II, and III, and post-COVID infection, more than a thousand of whom needed hospital complications) (Fig. 1). Stage I corresponds to the viral admission. In this paper, I summarize my experience acquired replication phase, in which constitutional symptoms are mild or during the worst moments of the pandemic, present an absent. As the disease progresses, as a consequence of the interpretation of the literature, and outline my views on the activation of macrophages and other cells, there is an pathophysiology of the disease. overproduction of early response proinflammatory cytokines A first attempt to classify the different stages of the disease (tumour necrosis factor [TNF], IL-6, and IL-1β). In some was made by Siddiqi et al. [1]. For these authors, the pulmo- cases, this initially protective immunological response occurs nary phase occurs before the hyperinflammation phase, without in an exaggerated manner, resulting in what has been described any overlap between them. In stage I, the constitutional symp- as a “cytokine storm” (stage II). This can cause severe toms are mild rather than moderate or severe. In stage II, it is constitutional symptoms (not represented in the figure) and/or difficult to explain how patients without hypoxia (stage IIA) progress to cause lung damage (pneumonia). As the disease could be short of breath. The definition of stage IIB is worsens, the hypoxia may eventually evolve into a classic PaO2/FiO2 < 300, which corresponds to diffuse alveolar da- ARDS with early lung fibrosis related to the SARS-CoV-2 mage, and may precede the development of Acute Respiratory infection itself; platelet-fibrin thrombi may appear in small arterial vessels (<1mm in diameter) causing hypoxemia and * Address correspondence to this author at the Pulmonary Service, Corporació Sanitària Parc Tauli, Parc Taulí s/n, 08208 Sabadell Barcelona, Spain; reducing CO transfer capacity [2]. In what follows, the scaling Tel: +34 93 723 10 10; Ext; 29142; E-mail: cdomingo@tauli.cat of the pharmacological treatment options and the oxygenation DOI: 10.2174/1874306402014010032, 2020, 14, 32-37 A Therapeutic Approach Based on Pathophysiological Staging The Open Respiratory Medicine Journal, 2020, Volume 14 33 techniques available (and appropriate) will be discussed in CRP were highly predictive of the need for mechanical accordance with this staging. ventilation. This suggests the possibility of using IL-6 or CRP levels to guide the escalation of treatment in patients with 1.2. Pharmacological Treatment COVID-19-related hyperinflammatory syndrome [15]. During viral replication, Chloroquine (CQ) and the more Tocilizumab (TCZ), a blocker of the soluble and potent Hydroxychloroquine (HCQ) have shown some in vitro membrane receptors for IL-6, has been shown to be effective in activity against SARS-CoV-2 [3, 4]. In a retrospective study, patients with severe disease in two retrospective studies [12, these drugs were significantly associated with viral load 16]. TCZ is indicated for several diseases including rheumatoid reduction in COVID-19 patients, and their effect was arthritis. Normally patients receive one dose per month. In reinforced by azithromycin [5]. Higher CQ dosage is not COVID-19 patients, up to three doses in 24 hours have been recommended for critically ill patients with COVID-19, and in proposed. Although there is no clinical evidence to support general clinical trials have provided inconsistent messages. A this, from a pathophysiological point of view the proposal recent study concluding that these drugs were not effective makes sense: in cases of molecules acting through membrane against COVID-19 was withdrawn from publication due to receptors, the increase in the blood mediator causes an methodological issues. Given that the study was deemed externalization of cell receptors. Given that TCZ is a receptor unreliable, one could easily be deceived into thinking that its blocker, it may cause a transient increase in membrane conclusion was incorrect, and that these drugs should in fact be receptors due to the persistence of high IL-6 concentration in recommended for treatment or prevention [6]. This is a blood. Moreover, Luo P. et al. [16] observed that the serum misapprehension: the evidence favouring the recommendation IL-6 levels tended to spike at first and then decrease after TCZ of CQ and HCQ is still uncertain. Azithromycin alone has not therapy in 10 patients. This transient increase could also be been tested, and the association of lopinavir–ritonavir, which explained by the theory just mentioned. As a result, since IL-6 has a high number of side effects, has not shown any benefits release to the blood is very intense, the administration of more [7]. The initial information on remdesivir was confusing since than one isolated dose of TCZ would be acceptable in the a randomized, double-blind, placebo-controlled, multicentre absence of other clinical information. Incidentally, TCZ is very trial in China [8] was inconclusive, although the study did not well tolerated. reach the sample size calculated. A later study [9] showed that remdesivir offered a 31% faster time to recovery than placebo Other mediators released during COVID-19 disease such (P< 0.001) and a lower median time to recovery (11 days vs as interferon β-1 (17) or thymosin alpha 1 (18) seem to offer a 15), and reduced the mortality rate from 11.6% to 8.0% (P = beneficial effect and their low concentration can be harmful. In 0.059). Corticosteroids are unlikely to be used since they a multicentre, prospective, open-label, randomized phase 2 trial would favour viral replication. in adults with COVID-19, interferon β-1 reduced the median time from the start of treatment to a negative nasopharyngeal As a result, at the present time, remdesivir seems to be the swab (the primary endpoint) from 12 days to seven in the only treatment recommended for stage I patients, and therefore treatment group, and the median hospital stay from 14.5 days the only drug recommended for treating viral replication [10]. to 9 [17]. Lymphocytes play an essential role in fighting Stage II is the storm mediator phase, with increased plasma against viral infections; therefore, boosting the number and concentrations of proinflammatory cytokines [11]. Moreover, enhancing the antiviral function of T cells in COVID-19 histopathological examination of lung tissue from deceased patients is of a paramount value for successful recovery. patients with COVID-19 showed evidence of extensive Lymphocytopenia and T-cell exhaustion are common in acute alveolar oedema, proteinaceous exudate and patchy COVID19 patients. Thymosin-α1 (Tα1), a polypeptide inflammatory cellular infiltration [12]. These findings suggest hormone produced by thymic epithelial cells, can effectively that severe SARS-CoV-2 infection is associated with a increase T-cell numbers, support T-cell differentiation, cytokine storm and pulmonary inflammation secondary to a maturation, and reduce cell apoptosis. Tα1 has been dysregulated host immune response. IL-6 is one of the most successfully used in clinical practice to treat patients infected important mediators that have been found to increase. Autopsy with hepatitis B (HBV), hepatitis C (HCV) and Human reports from SARS patients showed high levels of Immunodeficiency Viruses (HIV). In a retrospective study, it inflammatory cytokines in cells expressing angiotensin- reduced mortality in severe COVID-19 patients (11% vs. 30%, converting enzyme 2 [13], the functional receptor for SARS- p=0.044), enhanced blood T-cell numbers in COVID-19 CoV and with an even higher affinity for SARS-CoV2 [14]. patients with severe lymphocytopenia and decreased the levels Immunologically, C-Reactive Protein (CRP) and IL-6 are of T-cell exhaustion markers in CD8+ T cells [18]. IL-1 has closely intertwined. IL-6 is known to induce gene expression also been involved in the cytokine storm in sepsis and and the release of CRP from the liver. In a paper including a COVID-19 disease [19]. Anakinra, an IL-1 receptor inhibitor pilot study that allowed the calculation of the sample size for a has also been postulated as an alternative although the evidence subsequent prospective study, peak levels of IL-6 followed by of its clinical effectiveness is yet limited [20]. 34 The Open Respiratory Medicine Journal, 2020, Volume 14 Christian Domingo Ribas Respiratory failure treatment O2 Venturi mask – Non rebreather mask O2 Permanent CPAP O2 Permanent CPAP O2 Intermitent CPAP O2 NIMV O2 intubation Lung Fibrosis Lung Vessel Post-COVID disease STAGE II impairment STAGE I IMMUNOLOGIC RESPONSE STAGE III VIRAL REPLICATION MEDIATOR STORMS ARDS Coagulation impairment Skin symptoms Remdesivir Interferon beta 1b TCZ Hydrocichloroquine Systemic Systemic Chloroquine Corticosteroids Corticosteroids Systemic Azitromicine Thymosin alpha 1 (Tα1) Corticosteroids Lopinavir–ritonavir LMWH LMWH Avoid Systemic LMWH Corticosteroids Pharmacological treatment LMWH: Low molecular weight heparine Fig. (1). LMWH: Low Molecular Weight Heparin.The red crosses show the drugs without evidence of success for COVID – 19 infection. The controversy surrounding the benefits of corticosteroids significantly raised d-dimer concentrations, due to concerns seems to be reaching its end. Barely discussed in ARDS, in the regarding thrombi in the pulmonary circulation. Vandam et al hyperinflammation stage II a limited burst of 0.5-1 mg/kg of [28] showed that in COVID-19, thrombotic lesions were more methylprednisolone in two intravenous doses for three days widely distributed in the peripheral arteries of the lung and that [21] reduced severity, mechanical ventilation requirement and total clot burden was lower. Their data suggest that the mortality. More recently, low doses of dexamethasone seemed phenotype of Pulmonary Embolism (PE) in patients with to offer similar benefits in ventilated patients [22]. Other COVID-19 may be different from the PE phenotype in patients blockers of mediators, such as acalabrutinib [23], a selective without COVID-19 pneumonia. We have all seen cases of Bruton tyrosin kinase inhibitor with an interesting theoretical arterial and venous thrombus appearing after discharge, or basis, or statins [24], widely used as anti-inflammatory drugs, patients returning after discharge for dyspnoea, without need to be clinically tested. Among these drugs, there is no interstitial lung disease and with alterations in CO transfer. clear evidence to decide which one to test first, although TCZ This is probably due to peripheral “in situ” thrombosis of small seems to be the most readily available and probably should be vessels. In any case, this indication has not been proven to be the first to be used. Combinations with other alternatives such effective. as corticosteroids or other monoclonal antibodies should be considered. 1.3. Treatment of Hypoxia In stage III, the therapeutic options are limited. To complete the treatment, we should focus now on the Corticosteroid use in classic ARDS has been under discussion therapeutic options for hypoxia. Many of these patients have for the last 40 years. Some ventilated patients may present normal lung function and should, therefore, be treated in a benefits [22]. Maintenance treatment (including nutrition) totally different way from chronic respiratory patients who are seems to be crucial. In stages II and III, low molecular weight hypoxic and hypercapnic. In stage I, oxygen supplement should heparin (LMWH) has been included. The recently published be enough. Since some patients may develop peripheral ACCP guidelines [25] are very conservative, considering that atelectasis, I would start short sessions of CPAP (two hours in information on coagulation (D-dimer and partial the morning and two in the afternoon at least) to try to prevent thromboplastin time) and inflammatory markers (ferritin, LDH, this atelectasis, and train the patient in case they deteriorate and C-reactive protein) is easy to obtain and D-dimer has been need prolonged sessions of CPAP. In stage II, permanent found to correlate with in-hospital death in a multivariate CPAP or Non-Invasive Mechanical Ventilation (NIMV) should analysis [26]. Certain authors [27] (and I myself) tend towards be considered. Since the respiratory drive of these patients is a more aggressive attitude. Prophylactic doses of LMWH are high, low values of pressure support may cause high tidal recommended for hospitalized patients with COVID-19 to volumes (>1.000 ml). I advise the use of face masks rather than prevent venous thromboembolism and medium or treatment oro-nasal masks, for two reasons: first, to reduce airway leaks, doses of LMWH should be considered for those with and second, because these patients need to be fed due to the A Therapeutic Approach Based on Pathophysiological Staging The Open Respiratory Medicine Journal, 2020, Volume 14 35 Fig. (2). O2: Oxygen. CPAP: Continuous Positive Airway Pressure. NIMV: Non-Invasive Mechanical Ventilation. HFP: High Flow Oxygenation. high catabolism of the disease. The presence of a gastric tube benign cutaneous lesions appearing after several weeks of PCR itself produces an airway leak and thus puts health staff at a negativization, deterioration of well-established lung fibrosis higher risk of exposure. With the normal face mask, this risk is (with the disease acting as a trigger) and unexpectedly fast lower. Fig. (2) shows the indications for each technique. development of new fibrosis; with regard to coagulation impairment, we have seen the appearance of stroke episodes When a patient with respiratory failure cannot be [32, 33] and patients seeking medical attention three or four adequately oxygenated and requires additional measures, we weeks after hospital discharge due to the appearance of should decide first whether he is suitable for Intubation (IT) dyspnoea, in whom the CT scan rules out lung parenchymal and Invasive Mechanical Ventilation (IMV). If the answer is disease but CO transfer is impaired. Possibly, anticoagulation affirmative, then no time should be wasted: these patients should be considered in some of these patients if inflammatory deteriorate abruptly and a delay in intubation may be fatal. parameters are elevated. Patients not considered suitable for IT may be put on CPAP or NIMV, depending on their tolerance. In some cases High CONCLUSION Oxygen Flow (HOF) can be applied, although its use is sometimes discouraged due to the increased risk of viral spread To summarize, the following concepts should be borne in [29]. The patient’s presence in a ventilated room or in a room mind. First of all, a correct staging of the disease can help to with negative pressure aspiration should not be a limitation. decide on the most effective and safest pharmacological option. Prescribing a treatment in the inappropriate phase will add no In invasively ventilated patients, there is a dissociation clinical benefits and may instead increase the toxicity of the between the relatively well-preserved lung mechanics and the treatment. At the present time remdesivir seems to be the only severity of the hypoxemia. Curiously, patients with normal treatment recommended for stage I patients, and therefore the lung compliance have a high right-to-left shunt fraction. This only drug recommended for treating viral replication. For the again illustrates the unusual situation we are facing. For these storm mediators phase, TCZ is the drug with the most patients, two additional options exist: increasing the Positive substantial scientific evidence to be recommended. Limited End Expiratory Pressure (PEEP) and/or moving them into the prescription of systemic corticosteroid at moderate/high doses prone position [30]. Some patients with classic ARDS will seem to offer a certain benefit during the storm cytokine phase; improve due to alveoli recruitment, while patients with burst is not recommended. It seems reasonable to be generous refractory hypoxemia due to COVID-19 will show some in the initial prescription and maintenance treatment of improvement with these techniques due to the redistribution of LMWH. Second, the disease affects mostly normal lungs perfusion in response to pressure and/or gravitational forces which present an unexpected behaviour, in any case this [31]. On the basis of the response to an increase in PEEP, behaviour is absolutely different than chronic respiratory patients can be classified in two phenotypes: phenotype “L” (a patients. The treatment of respiratory failure should always low proportion of recruitable patients with near-normal underpin the therapeutic approach. The early stablishing of compliance); or phenotype “H” (high potential for recruitment therapeutic limitations can be helpful. Third and last, pursuing and low compliance, no different from classical non- research into intravascular pathology will probably help to COVID-19 ARDS). In phenotype L patients, PEEP may lead to clarify some problematic situations. 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