Microbiota in COVID-19 Patients for Future Therapeutic and Preventive Approaches

In December 2019, severe pneumonia cases were reported in relation to the Huanan Seafood Wholesale Market in Wuhan, China. Four months and more than thousand deaths later, the responsible pathogen of the largest and most critical global health emergency in the last 100 years is known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The Coronavirus Disease 2019 (COVID-19) is characterized as a transmittable disease with a long incubation period of between 7 and 14 days. In around 10% of cases a severe disease course is observed. While predisposing factors such as older age, chronic arterial hypertension, diabetes, as well as other comorbidities have been described, little is known about the pathophysiological mechanism, which induce acute lung failure, coupled to the often-appearing heart, kidney and vascular injury pathognomonic for the deadly course of this disease.

The alveolar exudative and interstitial inflammation impairing alveolo-capillary gas exchange described in relation to SARS-CoV-2 complies with the definition of acute respiratory distress syndrome (ARDS). The pathophysiological mechanics behind this injury to the lung have been best described in bacterial sepsis induced ARDS, and are mainly induced by the extravasation of neutrophil granulocytes from the capillary vasculature into the lung. One of the main mediators of neutrophil extravasation is the degeneration of the endothelial surface layer, namely the glycocalyx, induced by endotoxin-activated heparan sulfate. The thinning and destructuration of the glycocalyx reveal hidden endothelial surface adhesion molecules like VCAM-1 and ICAM-1. The thereby increased adhesion of Neutrophils coupled to the inflammatory cytokine mediated dis-placement of VE-cadherin to the insides of the endothelial cells, loosening the endothelial tight junctions, allows for an increased extravasation of neutrophils and diffusion of protein-rich fluid into the interstitium. The thereby created milieu induces neutrophil granulocytes activation and degranulation, and provokes the release of toxic mediators that destroy the alveolar epithelium and produce further immunocytokines, induce a cytokine storm and augment neutrophil recruitment. Finally the aggregation of the inactivated pulmonary surfactant by the protein rich edema con-joined with the degenerated type 1 alveolar epithelial cells and the hyaline membrane covered, de-nuded alveolar basement membrane disrupt the gas exchange capacity of the alveolo-capilar membrane, impairing blood oxygenation and decarboxylation.

In contrast to bacterial-induced ARDS, viral agents causing ARDS mainly reach the alveolar epithelium through viral transport from the nasopharynx, from the upper to the lower respiratory tract. In viral infections, the damage to the lung is primarily caused by a direct viral invasion of type 1 and 2 pneumocytes. This causes the accumulation of protein-rich edema in a two-fold fashion by disabling the ENaC channels, mainly responsible for the decongestion of the alveolar room through osmotic gradient creation, and by breaching the physio-chemical barrier established by the pneumocytes. Albeit the effect of alveolar barrier disruption by means of vascular endothelial dysfunction being reduced in contrast to bacterial sepsis, with the ARDS advancing, both the endothelium and epithelium secrete chemotactors to attract macrophages and neutrophils to the inflamed lung, which in analogy to bacterial ARDS induce a secondary damage to the lung as already described. However point to an exaggerated initial capillary leak as compared to other forms of ARDS, which strongly suggests endothelial dysfunction as a primary mechanism.

Endothelial cell damage may be assessed using both glycocalyx degradation products such as syndecan-1, heparan sulfate, and VE-cadherins and direct visualization of red blood cell flow properties within the capillaries via handheld vital microscopy (HVM) employing the dark field microscopy technique. Recent advances in the investiagtors group have enabled the accurate differentiation of modes of microcirculatory failure by quantification of the microcirculatory diffusion and convection capacity. From a global perspective, the alveolar leakage has previously been quantified using transpulmonary thermodilution. These tools provide the optimal prerequisites to specifically detect (glycocalyx degradation products in the alveolar lavage fluid) and quantify (transpulmonary thermodilution) endothelial cell damage in the lung during ARDS caused by SARS-CoV-2 infection. Further, approximately 20% of critically ill patients suffering from ARDS due to SARS-CoV-2 infection have been described in preliminary reports to develop severe systemic inflammatory response and circulatory shock. In these patients, the relation between alveolar endothelial cell damage and systemic endothelial cell damage is of central interest and may be assessed by concomitant sublingual HVM measurement.

Following the viral and inflammatory mediated lung damage as the initial trigger for ARDS, the further deterioration of the lung function may mainly depend upon superinfection. Bacterial and fungal superinfection has been described as mainly responsible for morbidity and mortality in mid- to late-phase viral ARDS during similar pandemics, such as the Spanish Flu in 1918. In the current outbreak in China, presence of bacterial and fungal superinfections was found in 10 to 30%. Superinfection seemed to represent a major risk factor for mortality in the COVID-19 patients. Albeit being unclear if detection of bacterial and fungal superinfection has a clinical and therapeutic relevance, several authors advocate empirical antibiotic treatment targeting mainly S. aureus and S. pneumonia.