Plea for multitargeted interventions for severe COVID-19.

Severe coronavirus disease 2019 (COVID-19) is not just a serious respiratory viral disease, as influenza is, but rather a systemic multiorgan viral invasion. It is frequently complicated by overwhelming immunological reactions, with overactivation of T cells, leading to acute respiratory distress syndrome and multiorgan failure, secondary to immunopathological processes. The viral load of severe acute respiratory syndrome coronavirus 2 is not correlated with worsening symptoms, but it is the host inflammatory response that is a major cause of lung damage and subsequent mortality.1, 2 Hyper-inflammatory responses in patients with COVID-19 are associated with a cytokine storm that is characterised by an increase in proinflammatory cytokines, including tumour necrosis factor, interleukin (IL)-1β, IL-6, and other chemokines in serum.3, 4 Overwhelming secretion of cytokines causes severe lung damage, which manifests as extensive damage to pulmonary vascular endothelial cells and alveolar epithelial cells, as well as increased pulmonary vascular permeability, leading to pulmonary oedema and hyaline membrane formation.2, 3, 4

Most clinical trials to date have evaluated various strategies of antivirals, immunomodulators, host-targeted drugs, immune-based therapies, or immunosuppressive drugs, including steroids, IL-6 or IL-1 antagonists, and selinexor; all have assessed single drugs with a clinical endpoint using the WHO seven-point ordinal scale. Although some of these drugs might have clinically meaningful effects on viral burden or some of the immune-related signs, it is highly improbable that a single drug will be enough to control and improve the most severe forms of COVID-19. It is likely that both antivirals and blockage of inflammatory pathways are needed to optimise responses. For example, it would be relevant to understand the role of steroids in combination with or sequential to antiviral treatments. Without studying combinations, and their potential synergies or additive effects, potentially useful agents could be disregarded. Furthermore, in the absence of synergistic combinations, single drugs might cause more harm—for example, mass killing of the virus might enhance inflammatory responses. Because of the urgency of the current situation and, so far, an absence of clear evidence of a clinically meaningful effect of any monotherapy strategy, investigators should join their efforts in proposing, rather than adaptive or sequential studies of a single strategy, combined approaches through multifactorial designs. This approach will enable determination of the risks and benefits of combinations versus monotherapies. Such trials with multifactorial designs (eg, with randomisation first to antivirals and then to adjunctive immune-based therapy) are urgently needed and could provide more rapidly clinically meaningful results.

Furthermore, with improving knowledge of the various clinical presentations of COVID-19, better definitions of patient populations at highest risk of poor outcomes, based not only on clinical status but also on biomarkers (eg, C-reactive protein, D-dimer, ferritin, and IL-6), should be incorporated into inclusion criteria and stratifications. Finally, the optimal timing or sequence of administration of the components of therapy during a worsening COVID-19 disease course need to be explored. We call for collaboration between pharmaceutical companies, institutions, and policy makers to either allow individuals to be enrolled simultaneously in trials of different investigational drugs with distinct targets or to collaborate on trials that include study arms that investigate combination therapy.