key: cord-0888569-g6gduktp
authors: Cárdenas, Graciela; Torres-García, Diana; Cervantes, Jaquelynne; Rosales-Mendoza, Sergio; Fleury, Agnes; Fragoso, Gladis; Laclette, Juan Pedro; Sciutto, Edda
title: Role of Systemic and Nasal Glucocorticoid Treatment in the Regulation of the Inflammatory Response in Patients with Sars-Cov-2 Infection
date: 2020-10-26
journal: Arch Med Res
DOI: 10.1016/j.arcmed.2020.10.014
sha: ac4abff0a8525f6e279eea0aea647e72e55cfe5a
doc_id: 888569
cord_uid: g6gduktp

The Chinese outbreak of SARS-CoV-2 during 2019 has become pandemic and the most important concerns are the acute respiratory distress syndrome (ARDS) and hyperinflammation developed by the population at risk (elderly and/or having obesity, diabetes, and hypertension) in whom clinical evolution quickly progresses to multi-organ dysfunction and fatal outcome. Immune dysregulation is linked to uncontrolled proinflammatory response characterized by the release of cytokines (cytokines storm). A proper control of this response is mandatory to improve clinical prognosis. In this context, glucocorticoids are able to change the expression of several genes involved in the inflammatory response leading to an improvement in acute respiratory distress. Although there are contradictory data in the literature, in this report we highlight the potential benefits of glucocorticoids as adjuvant therapy for hyperinflammation control; emphasizing that adequate dosage, timing, and delivery are crucial to reduce the dysregulated peripheral-and neuro-inflammatory response with minimal adverse effects. We propose the use of the intranasal route for glucocorticoid administration, which has been shown to effectively control the neuro-and peripheral-inflammatory response using low doses without generating unwanted side effects.

The nasal cavity is an important gate for SARS-CoV-2 entry; in fact, the virus is able to invade olfactory and respiratory epitheliums through the interaction of the spike (S) protein and the angiotensin-converting enzyme 2 (ACE2) receptor, which involves cleavage of the S protein most likely by the cell surface protease TMPRSS2 ( Figure 1A ). The ACE2 receptor has been found widely distributed on hepatic tissues and the human upper airway (including nasal respiratory epithelium, basal, and ciliated cells), intestinal, renal, cardiac, and nervous systems (glial cells and neurons) ( Figure 1B ) (6) (7) (8) (9) (10) (11) (12) (13) .Therefore, the virus can spread into lungs where it causes pneumonia and subsequently disseminate to several organs and systems causing different degrees of damage; further increasing the inflammatory response.

Another route of entry for the virus in the central nervous system (CNS) is through olfactory and trigeminal nerves (14, 15) ; as described for other human CNS viral infections such as the poliomyelitis virus. This situation has also been described for other animal models (16) . Findings of altered smell sense in the early stages of COVID-19 support this possibility, while affectation of the CNS will manifest by acute cerebrovascular disease, encephalitis, and epilepsy; frequently observed in patients with severe forms of COVID-19 (9, 14, 15) . In addition, in later stages of the infection (characterized by general damaged endothelium) the virus can also reach the CNS through this via (17) .

Higher systemic levels of IL-6, IL-2, IL-7, IL-10, G-CSF, IP-10, MCP1, MIP1α, and (TNF) have been observed in COVID-19 patients (18, 19) . In addition, increased IL-1β levels are believed to be a consequence of pyroptosis favored by the virus-mediated antagonism of the interferon (IFN) response; with an overall promotion of aberrant inflammatory responses (20) . Another mechanism likely involved in lung inflammation is the antibody-dependent enhancement mediated by preexisting antibodies to other coronaviruses or anti-S protein antibodies induced earlier in the infection.

The binding of antibody-virus immune complexes activating Fc receptors on alveolar macrophages could be involved in the induction of pro-inflammatory factors and complement activation (21) (22) (23) .

This uncontrolled and sustained hyperinflammation in the respiratory system results in severe pneumonia; the main condition that leads to severe acute respiratory distress (SARD) often requiring weeks of mechanical ventilation. This situation leads to high mortality, 71 to 96% of patients with severe pneumonia die according to data available in Mexico.

Exacerbated inflammation also affects functionality of the vascular endothelium with an altered permeability that favors cell migration and arterial vasoconstriction. Altered endothelium is also involved in the development of a disseminated intravascular coagulation in patients with severe COVID-19 (24) . Respiratory dysfunction is mediated by exacerbated lung inflammation coupled with dysfunction of respiratory control centers from the brain (9, 25, 26) . Indeed, SARS-CoV-2 may enter neurons and glial cells resulting in cellular stress and injury and the expression of Damage-associated molecular patterns (DAMPs), which promote the strong release of cytokines (cytokines storm), excessive production of reactive oxygen species (ROS), and the activation of microglia; favoring the migration of inflammatory peripheral cells through a damaged brain blood barrier. Sustained neuroinflammation may exacerbate neuron injury, therefore spreading damage and contributing J o u r n a l P r e -p r o o f towards central respiratory failure. The frequent finding of neurological manifestations in COVID-19 patients strongly supports this possibility (17) . Hence, it is essential not only to treat the peripheral inflammatory response, but the neuroinflammation to reduce central dysfunctions.

Comorbidities such as aging, hypertension, diabetes, obesity, and cardiovascular disease are the main COVID-19 factors predicting poor outcomes. The exacerbated inflammation status (27) is a common denominator of all these conditions underlying, at least in part, pathogenesis in SARS-CoV-2 infection. In older people immune homeostasis loosens and inflammatory responses become less regulated. Severe oxidative stress, DNA damage, cytokine response dysregulation, and reduced autophagy are all involved in the "inflammaging" of elderly people (28) . Hypertension is considered a pro-inflammatory disease often associated with endothelial dysfunction. Obesity and diabetes are also associated with metabolic dysregulation and a chronic low-grade of inflammation (29) triggered by antigen-presenting cells involved in recognizing damaged and death cells; mediated by increased oxidative stress (30) . Finally, cardiovascular diseases are associated with systemic metabolic and inflammatory signals (chronic inflammatory state affecting immune cell response), which seem to be relevant for a poor outcome (31) .

Currently several clinical stages have been described for COVID-19 (32) . These stages are distinguished by the factor that is mainly involved in pathogenicity. The following staging was J o u r n a l P r e -p r o o f proposed: the first stage (mild, early infection) occurs at the time of inoculation and early establishment of the disease. Symptoms are very mild and nonspecific, while virus replication is intense. Most of the patients will only present this stage and their recovery will be excellent. In the second stage (moderate, pulmonary involvement without (2A) or with hypoxia) (2B) patients present pneumonia that can be diagnosed by radiological tools. They frequently have an increase of systemic inflammatory markers; although this reaction is mild. Virus is still present, but its burden is decreasing. A small group of patients will then pass to stage 3 (severe); characterized by severe ARDS and systemic hyperinflammation and neuroinflammation with the risk of multi-organ failure.

Here, the virus is nearly undetectable and pathogeny is almost exclusively driven by the inflammatory response (cytokines storm) (33) .

An uncontrolled inflammatory response promotes detrimental events in the host Dysregulated inflammatory response also affects the coagulation and the fibrinolytic cascade promoting a prothrombotic state that contributes to cardiovascular disorders and hypertension, as well as hematological disorders observed in COVID-19 patients (34) . In this context, several drugs are currently used to control the exacerbated inflammation immune. Glucocorticoids (GC) are among these since it is one of the commonest and powerful anti-inflammatory drugs. Three critical point must be considered to use GC to control the dysregulated inflammatory response ( Figure 1C ). The timing, the dose, and the route of administration. First, GC will not be employed from the beginning of the infection, the time at which the inflammation favors the host. Second, it must be given in a low dose to minimize negative side effects. The intranasal delivery would allow direct access of GC to the J o u r n a l P r e -p r o o f central nervous system thereby controlling the sustained neuroinflammation provoked by damage to infected CNS cells that provoke fatal central respiratory and cardiac failure of COVID19 patients. In addition, intranasal GC efficiently reach the respiratory system and control peripheral inflammation (4) .

Considering that severe complications associated with COVID-19 mainly result from exacerbated and uncontrolled peripheral-and neuro-inflammation, one widely employed therapeutic approach is GC administration (35) . In fact, synthetic GC are one of the most potent anti-inflammatory therapeutic drugs commonly used in the treatment of an array of inflammatory disorders (36) .

The experience of employing corticosteroids to treat the exacerbated inflammation in patients with SARS during 2002-2004 may orientate the use of these steroids in the present COVID-19 pandemic disease. Similarities in the inflammatory response are found between SARS-CoV-1 and SARS-CoV-2. Several protocols to treat the inflammatory response in SARS and deal with the virus or secondary bacterial infections were assayed (Table 1) , however many of them were not randomized controlled trials. The treatments included an antiviral drug (Ribavirin) or two or more antibiotics (i.e. levofloxacin or levofloxacin plus azithromycin or clarithromycin plus amoxi-clav) combined with steroids. Most of these studies employed a 2 corticosteroid schedule with methylprednisone (MP) and prednisone and a pulse of MP, which was given if clinical condition, chest radiograph, or oxygen saturation worsened and lymphopenia persisted. The general conclusion of these studies was that the inclusion of the corticosteroid therapy for the treatment of SARS-affected patients resulted in better response when administered appropriately: several days after the onset of the symptoms (stage 2) in J o u r n a l P r e -p r o o f medium or low doses and for a moderate period. However, in some studies, low levels of T cells (CD4 and CD8) or high viral load were reported, but no association with disease severity was reported. In one study an increase in 30 d mortality was found, which was associated with the administration of high-dose steroids. Nonetheless, in this study no strictly matching of SARS cases was performed.

Upon most of viral infections, the initial inflammatory reaction is triggered as an attempt to control the infection and promote the development of an efficient immune response. Therefore, inhibition of inflammatory/immune responses in this phase may favor viral replication. This was shown in a study including patients affected by SARS-CoV-1 who received GC early after infection resulting in increased viral load (37) . In contrast, in a recent large multicenter and randomized study conducted in patients with moderate to severe ARDS, administration of dexamethasone (0.25 mg/kg) reduced mortality and the time needed for mechanical ventilation (38) .

There is little experience in using GC on SARS-CoV-2 to date as shown in Table 2 . For this reason the World Health Organization (WHO) has pointed the need of randomized clinical trials for the use of GC to determine safety and efficacy (https://www.who.int/blueprint/prioritydiseases/keyaction/Global_Research_Forum_FINAL_VERSION_for_web_14_feb_2020.pdf ? ua = 1). Therefore, there are numerous clinical studies currently underway (Table 2) .

Certainly, the decision of administrating GC in SARS-Cov2 infected patients will also depend on their clinical history accounting a compromised immunological condition, as potential risk can be developed in those in which a GC administration can increase a previous immunosuppressive immune response Taken together, these precedent studies provide crucial information on three fundamental aspects to be considered for modulation of inflammation during COVID-19: the time in which GC are J o u r n a l P r e -p r o o f recommended to start, the effective dose to control inflammation with minimal negative side effects, and the delivery route selected to reach the CNS ( Figure 1C ).

The SARS-CoV-2 infection dramatically illustrates the double edge of inflammation. While it is essential to contain infection and develop an adaptive immune response that increases the efficiency to deal with the virus; its dysregulation and exacerbation can produce negative results that include a fatal outcome for the patient. The analysis presented in this review emphasizes the relevance of controlling inflammation during stage 2 of infection, allowing the establishment of adaptive immunity that prevents the appearance of severe symptoms. Based on the available evidence, we propose that the optimal time to start a low-dose GC-based treatment is at least 5 d after the onset of symptoms. It would be very important to define inflammatory markers to standardize the timing of GC administration. Unfortunately, due to the high number of patients and the difficulties to perform laboratory tests in all the settings, clinical criteria are more feasible to be used now. It is also important to emphasize the relevance to control not only the dysregulated peripheral inflammatory response, but also the neuroinflammation to reduce cerebral dysfunctions. In order to increase the efficacy of reaching the central nervous and respiratory systems, we propose the use of the intranasal route for GC administration. This route avoids the requirement of high GC doses to reach the CNS.

The available experimental evidence derived from a mice model of sepsis supports that this route is more efficient than the intravenous route to control the exacerbated peripheral-and neuroinflammatory response (4, 5) . Moreover, since lower doses are administered when compared to the parenteral scheme the negative collateral effects are reduced. A clinical protocol is being reviewed to J o u r n a l P r e -p r o o f begin evaluation of intranasal GC at low doses in COVID-19 hospitalized patients. The treatment will begin when shortness of breath appears, usually in the second week of illness; seeking to prevent the progress to hypoxemia.

No potential conflict of interest was disclosed.

This research was funded by DGAPA (PAPIIT 207720). 

COVID-19 situation reports

Clinical progression of patients with COVID-19 in Shanghai

Intranasal delivery of dexamethasone efficiently controls LPS-induced murine neuroinflammation

Sepsis: Developing new alternatives to reduce neuroinflammation and attenuate brain injury

SARS -CoV-2 receptor ACE 2 and TMPRSS 2 are primarily expressed in bronchial transient secretory cells

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

Comment on "The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

SARS-CoV-2 Cell Entry Depends on ACE2

Blocked by a Clinically Proven Protease Inhibitor

The emergence of a novel coronavirus (SARS-CoV-2) disease and their neuroinvasive propensity may affect in COVID-19 patients

Central Nervous System Involvement by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

Spread of a neurotropic murine coronavirus into the CNS via the J o u r n a l P r e -p r o o f trigeminal and olfactory nerves

Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms

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

Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients

The trinity of COVID-19: immunity, inflammation and intervention

The potential danger of suboptimal antibody responses in COVID-19

Is COVID-19 receiving ADE from other coronaviruses?

Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

COVID-19 update: Covid-19-associated coagulopathy

Systemic inflammation impairs respiratory chemoreflexes and plasticity

Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2

Origin and physiological roles of inflammation

Age and age-related diseases: Role of inflammation triggers and cytokines

Diabetes mellitus and inflammation

Adipocyte Death and Chronic Inflammation in Obesity

Immune system and cardiovascular disease

COVID-19 illness in native and immunosuppressed states: A clinicaltherapeutic staging proposal

The pathogenesis and treatment of the 'Cytokine Storm'' in COVID-19

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

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China

Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis

Effects of early corticosteroid treatment on plasma SARSassociated Coronavirus RNA concentrations in adult patients

Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial

Treatment of severe acute respiratory syndrome with glucosteroids: The Guangzhou experience

Description and clinical treatment of an early outbreak of severe acute respiratory syndrome (SARS) in Guangzhou, PR China

Outcome of coronavirus-associated severe acute respiratory syndrome using a standard treatment protocol

Glucocorticoid in the Treatment of Severe Acute Respiratory Syndrome Patients: A Preliminary Report

Development of a standard treatment protocol for severe acute respiratory syndrome

High-Dose Pulse Versus Nonpulse Corticosteroid Regimens in Severe Acute Respiratory Syndrome

Severe acute respiratory syndrome: Report of treatment and outcome after a major outbreak

Coronavirus-positive Nasopharyngeal Aspirate as Predictor for Severe Acute Respiratory Syndrome Mortality

Rheumatologists' perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets

Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19)

Effectiveness of glucocorticoid therapy in patients with severe coronavirus disease 2019: protocol of a randomized controlled trial

Datos Abiertos de México -Información referente a casos COVID-19 en México

The authors thank to the Programa de Investigación para el Desarrollo y la Optimización de Vacunas, Inmunomoduladores y Métodos Diagnósticos of the Instituto de Investigaciones Biomédicas, UNAM