Obesity and risk of severe COVID-19.

Obesity represents a higher risk of severe COVID-19 infection, which may lead to the requirement of a mechanical ventilation in intensive care units and premature death. The underlying mechanisms are multiple: alteration of the respiratory performance, presence of comorbidities such as diabetes, hypertension or obstructive sleep apnea, finally inadequate and excessive immunological responses, possibly aggravated by ectopic intrathoracic fat depots. Thus, COVID-19 may challenge the so-called <<obesity paradox>> commonly reported by intensivists in patients with acute respiratory distress syndrome. These findings require reinforced preventive and curative measures among obese patients to limit the risk of progression towards an unfavorable outcome in case of COVID-19.Copyright © 2020 Editions Medecine et Hygiene. All rights reserved.

[Anti-inflammatory drugs : from old classical ones to biotherapies and JAK inhibitors]

Anti-inflammatory medications are known since a long time and still remain among the most used drugs in clinical practice. They belong to a variety of pharmacological classes and act via very different biochemical mechanisms. Nonsteroid anti-inflammatory drugs, which are derived from acetylsalicylic acid, and cortisone with its multiple derivative molecules (glucocorticoids) remain the background therapy of diseases associated with inflammation, either acute or chronic. Some old molecules, known to exert an anti-inflammatory activity, still have specific indications, colchicine and methotrexate as examples. However, the greatest innovation of the last two decades results from the launch of biological therapies, starting with the use of anti-TNF? agents to move towards monoclonal antibodies targeting various pro-inflammatory interleukins (IL-1, IL-6, IL-5, IL-17, IL-23, ...). Finally, small molecules acting as JANUS kinase inhibitors or tyrosine kinase 2 inhibitors open new alternatives in severe diseases that are resistant to other anti-inflammatory drugs. The interest for anti-inflammatory medications has been reinforced since the COVID-19 outbreak.

Obesity and risk of severe COVID-19

Obesity represents a higher risk of severe COVID-19 infection, which may lead to the requirement of a mechanical ventilation in intensive care units and premature death. The underlying mechanisms are multiple: alteration of the respiratory performance, presence of comorbidities such as diabetes, hypertension or obstructive sleep apnea, finally inadequate and excessive immunological responses, possibly aggravated by ectopic intrathoracic fat depots. Thus, COVID-19 may challenge the so-called «obesity paradox» commonly reported by intensivists in patients with acute respiratory distress syndrome. These findings require reinforced preventive and curative measures among obese patients to limit the risk of progression towards an unfavorable outcome in case of COVID-19.

Severe COVID-19, a new complication to be added to numerous comorbidities associated to obesity

Obesity is associated with a huge number of well-known comorbidities. Nowadays, it represents a higher risk of severe COVID-19 infection, which may lead to the requirement of a mechanical ventilation in intensive care units and premature death. The increase in relative risk of poor prognosis in presence of obesity is particularly high in patients at a younger age. The underlying mechanisms are multiple: alteration of the respiratory performance, presence of frequent comorbidities (diabetes, hypertension or obstructive sleep apnea), finally inadequate and excessive immunological responses, with massive liberation of cytokines (especially interkeukin-1 and interleukin-6). Thus, COVID-19 may challenge the so-called «obesity paradox» in intensive care units among patients with acute respiratory distress syndrome where obesity is commonly reported as associated with a better prognosis. In the special case of COVID-19, a condition where obviously obesity aggravates the prognosis, hypothetical mechanisms remain to be welldefined and deserve further validation.

Continuing or stopping metformin in patients with type 2 diabetes exposed to SARS-CoV-2 ?

Both obesity and type 2 diabetes (T2D) are recognized risk factors for developing a more severe form of COVID-19, with a higher death rate. Metformin is considered as the first-line medication for the treatment of T2D, especially in obese patients. Beyond its glucose-lowering activity, metformin exerts pleiotropic effects, among which an anti-inflammatory effect that could be beneficial. However, metformin is contraindicated in case of severe renal insufficiency, liver failure and/or unstable heart failure, because of a risk of lactic acidosis. Yet, COVID-19, besides the well-known pneumonia that can be responsible for severe hypoxemia, may be associated with multisystemic organ failure, among which kidneys, liver and heart. Thus, the question arises whether metformin, which represents the background therapy in above 80 % of patients with T2D, should be continued in patients exposed to SARS-CoV-2 or instead be stopped. This article summarizes the most important results of observational studies, which all argue for a beneficial effect of metformin therapy that is associated with a significant reduction in mortality among hospitalized patients with T2D due to COVID-19. Finally, some practical advices will be given. L’obésité et le diabète de type 2 (DT2) représentent deux facteurs de risque reconnus pour développer une infection COVID-19 plus sévère, grevée d’un taux de mortalité accru. La metformine est considérée comme le premier médicament de choix pour traiter les patients DT2, a fortiori s’il existe une obésité. Outre son effet anti-hyperglycémiant, la metformine exerce des effets pléiotropes favorables, dont une action anti-inflammatoire potentiellement bénéfique. Cependant, cet antidiabétique oral est contre-indiqué en cas d’insuffisance rénale sévère, d’atteinte hépatique majeure et/ou d’insuffisance cardiaque non stabilisée, en raison d’un risque d’acidose lactique. Or, l’infection COVID-19, outre la pneumonie bien connue responsable d’une hypoxémie plus ou moins sévère, peut entraîner des situations critiques avec des défaillances d’organes, dont le rein, le foie, le cœur. Dès lors se pose la question de savoir si la metformine, qui est le traitement de base de plus de 80 % des patients DT2, peut ou doit être maintenue chez un patient infecté par le SARS-CoV-2 et quand elle doit être éventuellement interrompue. Cet article résume les principaux résultats des études observationnelles qui, toutes, plaident pour un effet plutôt favorable de la metformine entraînant une réduction de la mortalité chez les patients DT2 hospitalisés pour COVID-19. Il se termine par quelques conseils pour la pratique clinique.

[Renin-angiotensin-aldosterone system : brief history and questions related to the COVID-19 pandemic]

The breakthrough of the secrets of hypertension and the renin-angiotensin-aldosterone system (RAAS) is one of the legends of medicine. The first chapter is the one of Tigerstedt's experiments about renin, and Loesch and Gollblatt's model of renal hypertension. The race to elucidate the mechanisms of angiotensin, angiotensinogen and the angiotensin conversion enzyme cascade, by Braun Menendez and Page teams, is a second chapter. The puzzle of this elegant cascade is completed by aldosterone isolation by the collaboration of Tait spouses and Tadeus Rechstein. As a corollary of these findings, Conn made the first description of primary hyperaldosteronism. The elucidation of RAAS pathophysiology naturally led to the synthesis of the antihypertensive captopril by Ondetti and Cushman, thereby opening the modern era of ACE inhibitors and ARII blockers. In March 2020, a viral pandemic caused by SARS-Cov-2 ignites the entire planet. This new coronavirus uses the RAAS angiotensin conversion enzyme type 2 (ACE-2) as a gateway. The SARS-CoV-2/ACE-2 signalling pathway and its pathological effects on the cardio-respiratory and renal system of these patients initiate a new chapter. The interaction of SARS-Cov-2/ACE-2 axis with anti-hypertensive agents, as well as with ACE-2 activators and ACE-2 homologs, takes a part of an active international study searching for therapeutic targets. This modern research, summarized in this article, will further develop our knowledge of RAAS and, hopefully, will improve the management of COVID-19 patients.

[Pharmacological therapies against COVID-19 : state of the art, between hopes and disappointments]

The COVID-19 outbreak has raised numerous attempts of diverse pharmacological interventions to improve the prognosis of the infection, especially among hospitalized patients due to an acute respiratory distress syndrome (ARDS). Initially, these interventions used known medications capable to directly target SARS-CoV-2 by investigating several antiviral therapies already applied with some success in other viral infections. Among them remdesivir appears to be the most promising drug against SARS-CoV-2. Then, owing to the deleterious impact of the cytokine storm, medications that more specifically inhibit proinflammatory cytokines (especially interleukin-1 and interleukin-6) were tested. Hydroxychloroquine, sometines combined with azithromycin, has benefited for a while from a media buzz. However, hopes initially founded in all such drugs turned into disappointments because the specificities of SARS-CoV-2 make this virus resistant to most pharmacological interventions. Only glucocorticoids, dexamethasone and hydrocortisone, were associated with a significant reduction in mortality of patients with ARDS due to COVID-19, most probably via non-specific anti-inflammatory effects. These corticosteroids are currently recommended by the World Health Organisation. An intensive research is ongoing worldwide to find effective combined therapies or innovative drugs which could unequivocally improve the prognosis of COVID-19 at the different stages of the infection.

Metformin and COVID-19: From cellular mechanisms to reduced mortality.

Type 2 diabetes mellitus (T2DM) is associated with both poorer clinical outcomes during the COVID-19 pandemic and an increased risk of death in such hospitalized patients. While the role of glucose control has been emphasized to improve the prognosis, the impact of different glucose-lowering agents remains largely unknown. Metformin remains the first-line pharmacological choice for the management of hyperglycaemia in T2DM. Because metformin exerts various effects beyond its glucose-lowering action, among which are anti-inflammatory effects, it may be speculated that this biguanide might positively influence the prognosis of patients with T2DM hospitalized for COVID-19. The present concise review summarizes the available data from observational retrospective studies that have shown a reduction in mortality in metformin users compared with non-users, and briefly discusses the potential underlying mechanisms that might perhaps explain this favourable impact. However, given the potential confounders inherently found in observational studies, caution is required before drawing any firm conclusions in the absence of randomized controlled trials.

Obesity and COVID-19: The fatal shock between two pandemics

The current pandemic caused by the coronavirus 2019 (COVID-19) is superimposed on another well-known pandemic in our society, that of overweight and obesity. Obesity represents a higher risk of severe COVID-19 infection, which may lead to the requirement of a mechanical ventilation in intensive care units (ICU) and premature death. The underlying mechanisms are multiple: alteration of the respiratory performance, presence of comorbidities such as diabetes, hypertension or obstructive sleep apnea, finally inadequate and excessive immunological and inflammatory responses, possibly aggravated by ectopic intrathoracic fat deposits. Thus, COVID-19 may challenge the so-called “obesity paradox” commonly reported in ICU among patients with acute respiratory distress syndrome. Furthermore, the presence of obesity increases the risk of worse outcome at a younger age. These findings require reinforced preventive and curative measures among obese patients to limit the risk of progression towards an unfavorable outcome in case of COVID-19.

Prognostic factors in patients with diabetes hospitalized for COVID-19: Findings from the CORONADO study and other recent reports.

Diabetes mellitus is challenging in the context of the COVID-19 pandemic. The prevalence of diabetes patients hospitalized in intensive care units for COVID-19 is two- to threefold higher, and the mortality rate at least double, than that of non-diabetes patients. As the population with diabetes is highly heterogeneous, it is of major interest to determine the risk factors of progression to a more serious life-threatening COVID-19 infection. This brief review discusses the main findings of CORONADO, a prospective observational study in France that specifically addressed this issue as well as related observations from other countries, mainly China and the US. Some prognostic factors beyond old age have been identified: for example, an increased body mass index is a major risk factor for requiring respiratory assistance. Indeed, obesity combines several risk factors, including impaired respiratory mechanics, the presence of other comorbidities and inappropriate inflammatory responses, partly due to ectopic fat deposits. While previous diabetic microvascular (renal) and macrovascular complications also increase risk of death, the quality of past glucose control had no independent influence on hospitalized diabetes patient outcomes, but whether the quality of glucose control might modulate risk of COVID-19 in non-hospitalized diabetes patients is still unknown. In addition, no negative signs regarding the use of RAAS blockers and DPP-4 inhibitors and outcomes of COVID-19 could be identified. Hyperglycaemia at the time of hospital admission is associated with poor outcomes, but it may simply be considered a marker of severity of the infection. Thus, the impact of glucose control during hospitalization on outcomes related to COVID-19, which was not investigated in the CORONADO study, is certainly deserving of specific investigation.