key: cord-1044462-g0xfflzh
authors: Bassetti, Matteo; Ansaldi, Filippo; Icardi, Giancarlo; Pelosi, Paolo; Robba, Chiara; Taramasso, Lucia; Trucchi, Cecilia; Vena, Antonio; Giacobbe, Daniele Roberto
title: COVID‐19: some clinical questions after the first four months
date: 2020-06-20
journal: Eur J Clin Invest
DOI: 10.1111/eci.13326
sha: c6d5817af00ce3f922dffeae2466c8047397e3e6
doc_id: 1044462
cord_uid: g0xfflzh

Coronavirus disease 2019 (COVID‐19) is a multiorgan disease with multiple faces and clinical features. Most patients present with none or only mild symptoms, but severe presentations with need for mechanical ventilation and high case fatality may be observed.

the virus; (ii) a dysregulated host response to the virus. In the last few months, particular attention has been devoted to the latter, in particular to the so-called cytokine release syndrome (CRS, characterized by an aberrant production of pro-inflammatory cytokines) that may be observed in critically ill patients with . Notably, the concomitant, intertwined presence of CRS, organ damage, and cytopenia is consistent with secondary hemophagocytic lymphohistiocytosis, also known as macrophage activation syndrome 5 .

It is thus little wonder that various anti-inflammatory drugs (e.g., tocilizumab, a recombinant humanized monoclonal antibody that inhibits membrane-bound and soluble IL-6 receptors and is approved for the treatment of patients with chimeric antigen receptor T-cell-induced severe CRS) have been proposed and are either being tested in randomized clinical trials (RCT) or used as off-label treatments in patients with severe COVID-19 6,7 . For example, this rationale guided the choice of administering tocilizumab and/or other anti-inflammatory agents in some critically ill patients with COVID-19 in some early clinical experiences, based on high-level of serum IL-6, c-reactive protein,

This article is protected by copyright. All rights reserved ferritin levels, and/or other non-specific markers 8, 9 . Although with the important limitations of residual and unmeasured confounding inherent to the observational nature of the analyses (with RCT remaining necessary to ultimately support efficacy), some groups observed a possible beneficial effect in critically ill COVID-19 patients receiving anti-inflammatory agents 8,10-12 .

Although we are in line with this vision (i.e., we also administered antiinflammatory agents in selected cases 13 ), we would also like to highlight two important, still unresolved questions that we encountered in our clinical practice at the bedside of critically ill patients with COVID-19 treated with anti-inflammatory agents. The first regards the role of the virus. Indeed, the fact of administering anti-inflammatory agents based on laboratory markers of exaggerated host response does not take into account possible inter-personal differences in the direct viral component of the damage. That is, we cannot exclude that an excessive anti-inflammatory effect could ultimately be detrimental in some patients, because of slowed/reduced viral clearance and delayed/impaired development of protective immunity 4, 14 . From this standpoint, we feel an important additional question that will need to be answered in the near future is as to whether combinations of efficacious anti-viral agents (e.g., preliminary RCT results have been recently released for remdesivir 15 ) and efficacious anti-inflammatory agents (if positive observational results are confirmed in RCT) could be synergistic in further improving the outcome of critically ill COVID-19 patients. Since this will mean to find a new pro-inflammatory/anti-inflammatory balance, the answer is not automatically affirmative. The second important question we would like to bring to the attention of readers is the possible effect of anti-inflammatory treatments in favoring bacterial/fungal superinfections. In general, this possibility is long-known 16, 17 , and we recently provided preliminary, observational evidence that the use of anti-inflammatory agents was associated with an increased risk of developing bloodstream infections (BSI) in critically ill patients with COVID-19 in two intensive care units 13 . Notably, other commentaries have highlighted a possibly overlooked risk of superinfection in critically ill COVID-19 patients 18, 19 . Again, the key term remains balance, with the accumulating observational literature (on the one hand, about possible beneficial effects of anti-inflammatory treatments, and on the other hand, about the risk of superinfection) becoming increasingly important as hypothesis-generating data to optimize the design of future RTC further investigating

This article is protected by copyright. All rights reserved treatments for COVID-19 in critically ill patients. Of note, potential favorable effect of antiinflammatory treatment (e.g., of low-dose steroids) to be weighed in the balance should also include a possibly reduced lung fibrotic response. In addition, the precise role of convalescent plasma therapy will also need to be further clarified, especially after nonadequately powered but still possibly positive RCT results deserving further investigation 20 .

Regarding the host, some patient-specific characteristics may strongly participate in influencing the disease progression and outcome. In particular, elderly patients are more likely than young patients to require intensive care and to experience poor outcomes [21] [22] [23] . Of note, this is in line with what observed in previous studies conducted in patients with SARS-CoV-1 and MERS-CoV infections 24, 25 . In a recent study, that confirmed the trend toward poorer outcomes in elderly than young COVID-19 patients, the blood lymphocyte proportion in the elderly group was significantly lower than in the young group (19% vs. 29%, p < 0.001), whereas an inverse association was observed for C-reactive protein (CRP) serum levels (22.7 mg/L vs. 6.49 mg/L, p < 0.001) 26 . Although the reasons for the observed increased severity and poorer outcome in the elderly are still not completely clear (e.g., a heavier burden of baseline comorbidities may also play a key role), these laboratory alterations may suggest a role of the host inflammatory response in influencing illness severity in the elderly 27, 28 . In turn, this supports the hypothesis that discrepancies in the innate and/or adaptive immune response could predispose to high morbidity and mortality also is some young patients affected by COVID-19 or unfavorable prognosis is also gender, with male patients having been deemed to be more at risk than women in the first clinical experiences 30, 31 . Whether this difference in risk could be a proxy for differences in immune, hormonal, and/or behavioral

This article is protected by copyright. All rights reserved factors is under investigation. An attempt to represent the complex interplay of heterogenous factors in predicting answers to some arising clinical questions in patients with COVID-19 is available in Figure 1 .

Of course, an alternative and much more awaited strategy for preventing disease development/progression in both young and elderly individuals is vaccine development.

In this regard, the dramatic spread of COVID-19 and its disrupting social and economic impact have urgently impelled over 100 pharmaceutical companies and scientific institutions to concentrate their efforts for the rapid development of safe and efficacious vaccines 32 . Notably, the current emergency situation has made it impossible to wait for the results of basic and translational studies that usually guide vaccine development and evaluation in a non-pandemic context 33 . However, the combination of already available data for related viral family members and innovative approaches have allowed for rapid identification and sequencing of SARS-CoV-2, as well as for exploiting new technologies for more rapid vaccine development 33 .

According to World Health Organization, there are at least 120 and 10 candidate vaccines in preclinical and clinical evaluation, respectively 34 . In addition to traditional inactivated and live-attenuated virus vaccines, several among SARS-CoV-2 vaccine candidates are based on new approaches, such as mRNA in lipid nanoparticles, protein subunits, virus-like particles, recombinant vectors, and DNA vaccines 35, 36 . As observed for other emerging pathogens, vaccine candidates are rapidly progressing through safety and immunogenicity trials, and a subgroup of vaccine candidates will be further evaluated in phase III trials 36 . Overall, there is increasing expectation that almost one of these strategies will be successful in the short term 37 . Nonetheless, many challenges remain that may delay/hamper current vaccine development: (i) the necessity to fill some knowledge gaps about effective immunity to coronaviruses; (ii) the need for a careful and solid assessment of vaccines efficacy; (iii) the necessity to limit/avoid any possible safety issue; (iv) the need to precisely define an effective early plan for scale-up and manufacture, owing to an expected extraordinary demand 36 .

Regarding the first point, some important questions remain about how to obtain a protective (and preferentially long-lasting) immune response. In particular, all of the following should be further investigated and better characterized: (i) the correlation between neutralizing antibodies and protection; (ii) which specific epitopes to target in

This article is protected by copyright. All rights reserved order to obtain protective responses; (iii) the definition of a threshold for a protective, neutralizing antibody response; (iv) the performance of assays commonly used in vitro for predicting protective activity in vivo; (v) the possible contribution of the respiratory tract mucosal immunity in the protection against infection or dissemination; (vi) the relevance of the contribution of T cell responses to vaccine-mediated protection 33 .

In addition, vaccine safety needs to be guaranteed 36 . For example, a possible concern is the "disease enhancement" syndrome, which is characterized by increased infection severity or death after encountering the virus. Since this syndrome has been In conclusion, COVID-19 is a complex systemic disease, to be considered as a multiple organ dysfunction syndrome (MODS), now proposed as MODS-COVID-19. It is a serial killer with three bullets: first, lung attack, as pneumonia; second, vascular attack, as

This article is protected by copyright. All rights reserved coagulation disorders with increased thrombophilia and/or hemorrhagic risk; and third, pulmonary structure remodeling leading to fibrosis 42 . We have certainly learned a lot in these first four months of the COVID-19 pandemic, and the unprecedented efforts of researchers around the world have certainly allowed to improve our clinical approach to COVID-19 patients. Nonetheless, four months are also a very short window of time, and many important challenges still remain. We should not let our guard down if we were to further understand and effectively counteract both the spread and the worrisome clinical, societal, and economic impacts of SARS-CoV-2.

None.

Outside the submitted work, M. Bassetti has received funding for scientific advisory boards, travel and speaker honoraria from Angelini, Astellas, AstraZeneca, Basilea, Bayer, BioMèrieux, Cidara, Correvio, Cubist, Menarini, Molteni, MSD, Nabriva, Paratek, Pfizer, Roche, Shionogi, Tetraphase, Thermo Fisher, and The Medicine Company.

Outside the submitted work, D.R. Giacobbe reports honoraria from Stepstone Pharma GmbH and unconditional grants from MSD Italia and Correvio Italia.

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