COVID-19: Looking Into the Overlooked

"Viral infections have plagued humanity since the beginning of time causing numerous deaths through specific pathogenic events directly related to the virus and indirectly, through secondary infections accompanying or following the viral episode. Highly pathogenic bacteria, such as Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae can overgrow during viral infections, and cause severe bacterial infections. During the 1918 Spanish influenza pandemic, for instance, the majority of influenza fatalities were likely caused by secondary pneumococcal pneumonia (Morens et al., 2008), but we were not aware of it until 2008, when tissue biopsy investigations revealed this important association. Secondary bacterial infections also accounted for 25–50% of deaths during the 2009 H1N1 influenza pandemic (Macintyre et al., 2018). In this instance, the association with secondary infections, particularly with S. pneumoniae, was acknowledged only almost 10 years after the pandemic. In the current COVID-19 pandemic, the role of co-infectiveness remains unclear. At the peak of the pandemic, broad-spectrum antibiotics have been administered to the majority of patients admitted with COVID-19 to hospital to prevent secondary infections but also, some antibiotics, like teicoplanin, have been used due to their alleged antiviral properties. In an early report, secondary infections were detected in 1 out of 7 patients. Among those that died, 50% had secondary infections (Zhou F. et al., 2020). Other reports indicate that bacterial infections were documented in <10% of COVID-19 patients (Zhou P. et al., 2020). In light of this uncertainty, antibiotic use has been reported to be as high as 74% among patients with COVID-19 who were admitted to ICUs (Cox et al., 2020). Some infections may have been caused by changes in colonization resistance, others due to increase use of corticosteroids, parenteral nutrition or just intravenous catheter infections. The administration of broad-spectrum antibiotics in the absence of high suspicion or documented infection challenges the current dogma of antimicrobial stewardship. This problem is further compounded by the fact that acute respiratory syndromes due to infection or non-infection are notoriously difficult to discriminate. However, the risk and potential severity of secondary infections associated with COVID-19, particularly in overcrowded clinical settings and in immune-compromised patients, has in many cases reduced the compliance with the local prescription practice guidelines. A quick look at host factors may now be more relevant than ever. As the first wave of the pandemic is tailing off in Europe, we have gathered substantial and actionable evidence that suggests that both severity and mortality associated with COVID-19 is due to host factors, ranging from endothelial and coagulation disturbances leading to the formation of micro thrombi to a major dysregulation of the host immunity and inflammatory response. Here, a recent study has shown significant survival benefits of corticosteroids administration to patients with severe COVID-19 infection. How is the host contributing to the severity of COVID-19? It was a matter of time that a genome wide analysis study (GWAS) showed some association with disease severity. Indeed, we have recently learnt that particular blood groups (group A) may be linked to respiratory failure in COVID-19 patients (Ellinghaus et al., 2020). However, with a moderate increase severity risk (odds ratio: 1.45 with respect to other blood groups), it is unlikely that this association explain all the variability of disease severity. Here we should not forget that one of the major contributors that regulate individual immune/inflammatory responses is the human microbiome. In particular, the gut microbiome may influence directly and indirectly the immune response generated. Accordingly, the lymphocyte populations may adopt a more pro-inflammatory phenotype when microbiome diversity is reduced, as typically observed in old age patients (Figure 1) and recently reviewed by Dhar and Mohanty (2020)."@eng

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