Endotoxemia and circulating bacteriome in severe COVID-19 patients

Abstract

Background When severe, COVID-19 shares many clinical features with bacterial sepsis. Yet, secondary bacterial infection is uncommon. However, as epithelium is injured and barrier function is lost, bacterial products entering the circulation might contribute to the pathophysiology of COVID-19. Methods We studied 19 adults, severely ill patients with COVID-19 infection, who were admitted to King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between 13th March and 17th April 2020. Blood samples on days 1, 3, and 7 of enrollment were analyzed for endotoxin activity assay (EAA), (1 → 3)-β-d-glucan (BG), and 16S rRNA gene sequencing to determine the circulating bacteriome. Results Of the 19 patients, 13 were in intensive care and 10 patients received mechanical ventilation. We found 8 patients with high EAA (≥ 0.6) and about half of the patients had high serum BG levels which tended to be higher in later in the illness. Although only 1 patient had a positive blood culture, 18 of 19 patients were positive for 16S rRNA gene amplification. Proteobacteria was the most abundant phylum. The diversity of bacterial genera was decreased overtime. Conclusions Bacterial DNA and toxins were discovered in virtually all severely ill COVID-19 pneumonia patients. This raises a previously unrecognized concern for significant contribution of bacterial products in the pathogenesis of this disease.

Preexisting and inducible endotoxemia as crucial contributors to the severity of COVID-19 outcomes

“…Several clinical reports demonstrate significantly increased levels of endotoxins in the plasma of severely affected COVID-19 patients. LPS levels were investigated in a prospective study on 19 patients with severe pulmonary forms of COVID-19; almost 90% of them had increased LPS levels—40% demonstrated high and 30% demonstrated very high endotoxin levels [ 9 ]. Application of mendelian randomization using 6,492 hospitalized cases and over 1 million controls demonstrated that serum LBP levels strongly correlate with the hospitalization rate of COVID-19 patients [ 10 ].…”

Is an EAA > 0.6 in severe COVID-19 patients synonymous with a toxic and pro-inflammatory endotoxin profile, and should we treat it?

“…The study by Sirivongrangson et al has demonstrated the presence of endotoxin with an EAA > 0.6 in blood of patients with COVID-19 acute respiratory distress syndrome (CARDS) [ 1 ]. The EAA and BG levels detected in this cohort of patients with CARDS were comparable to those reported in the authors’ previous study in 136 patients with severe sepsis or septic shock [ 1 ]. Recent insights suggest that obese patients are more at risk for COVID-19, as well as associated hospitalization, intensive care unit (ICU) admission, and mortality [ 2 ].…”

“…Recent insights suggest that obese patients are more at risk for COVID-19, as well as associated hospitalization, intensive care unit (ICU) admission, and mortality [ 2 ]. Unfortunately, the study by Sirivongrangson et al does not provide information on the BMI of included patients [ 1 ]. It is possible that endotoxin originated from secondary bacterial infections (all caused by Gram-negative bacteria) which occurred in several patients within the timeframe of the EAA measurements [ 1 ].…”

“…Unfortunately, the study by Sirivongrangson et al does not provide information on the BMI of included patients [ 1 ]. It is possible that endotoxin originated from secondary bacterial infections (all caused by Gram-negative bacteria) which occurred in several patients within the timeframe of the EAA measurements [ 1 ]. An alternative hypothesis is that the endotoxin originated from the gut microbiota.…”

“…In a recent issue of Intensive Care Medicine Experimental, Sirivongrangson et al reported the findings of their study examining endotoxemia in patients with severe COVID-19 [ 1 ]. Of the 19 patients studied, approximately half displayed elevated blood endotoxin levels, measured by the endotoxin activity assay (EAA), or increased intestinal permeability, reflected by increased serum levels of (1–3)-β-D-Glucan (BG), with a third of patients having both.…”