Is there a rationale for endotoxin removal in severely ill COVID-19 patients? As a matter of fact, 90% of patients with severe pulmonary forms of COVID-19 have increased endotoxin levels and the level of endotoxin is directly related to the severity of COVID-19. 1,2 Also, these patients are at high risk of sepsis. 3

Endotoxin triggers cytokine storms

The spike protein in SARS-CoV-2 has been shown to bind to endotoxin, starting the inflammatory signalling and dysregulated immune response. 4 Endotoxin is one of the most potent bacterial inducers of cytokines and can induce a cytokine storm through binding to Toll-like receptor 4 (TLR4). 5,6,7,8

High risk and prevalence of bacterial infections

Dysregulation of the immune system may be associated with a high risk of developing a secondary bacterial infection. Studies show that up to 60% of COVID-19 patients in the ICU have secondary bacterial infections – most commonly respiratory infections from gram-negative bacteria. 9

COVID-19 patients with pulmonary superinfections require longer ICU-treatments 10 and are at higher risk of ventilator-associated pneumonia (VAP) 11 – in fact, it is the most frequent hospital acquired infection in these patients, and it is often caused by gram-negative bacteria. Furthermore, VAP has been demonstrated to be the most frequent hospital infection associated with septic shock. 12

In the absence of a bacterial infection, antibiotic treatment can cause release of endotoxin, triggering endotoxemia and over-production of pro-inflammatory cytokines – an antibiotic-induced inflammatory storm. 13

Translocation of bacteria from the gut

Endotoxin in COVID-19 does not originate from the virus itself but is thought to be released from gram-negative bacteria in the gut, due to inadequate blood flow. 14,15,16,17 The gut barrier dysfunction that allows endotoxin to leak out from the gut into the blood, can potentially cause sepsis and multiple organ failure.18 Also, it can travel to the lungs and affect the immune response as well as the lung microbial composition. 19

It is argued that comorbidities of COVID-19 such as obesity, type 2 diabetes, cardiovascular diseases, and old age of patients – comorbidities in which increased levels of endotoxin are found – are connected via viral–bacterial interactions, initiated by translocation of bacterial products such as endotoxin from the gut into circulation. 20 In fact, translocation of endotoxin could play a larger role than previously thought in severely ill COVID-19 patients. 21

Complement activation increases endotoxin levels

The use of mechanical and hemodynamic support heightens the immune response of the patient. Being on ECMO- and/or a CRRT machine, the patient may have an inflammatory response to extracorporeal circulation (complement activation) resulting in increased endotoxin levels. 22,23,24,25

Endotoxin removal in COVID-19 – conclusion

Extracorporeal techniques have a possible role in “restoring a balanced immune response by eliminating/deactivating inflammatory mediators”. 26 Binding and clearing endotoxins from circulation could be an appropriate intervention in the fight against COVID-19.

Studies have shown that endotoxin adsorbtion results in clinical improvement in severe COVID-19 patients with elevated endotoxin levels (measured by EAA, Endotoxin Activity Assay). 27 The Alteco LPS Adsorber removes endotoxin (lipopolysaccharide, LPS) from the patient’s blood as it passes through the device. Based on the significance of endotoxin in COVID-19, the Alteco LPS Adsorber may be of use in COVID-19 patients suspected to have gram-negative bacterial infection, signs of inflammatory response, endotoxemia or sepsis. 28 The removal of endotoxin turns down the exacerbated immune response, helping to stabilize the patient’s hemodynamic parameters. 29

References

1 Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans

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

3 WHO calls for global action on sepsis – cause of 1 in 5 deaths worldwide

4 A promiscuous interaction of SARS-CoV-2 with bacterial products

5 Exotoxins and endotoxins: Inducers of inflammatory cytokines

6 Cytokine storm”, not only in COVID-19 patients. Mini-review

7 COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation

8 SARS-CoV-2 and immune-microbiome interactions: Lessons from respiratory viral infections

9 Risks and features of secondary infections in severe and critical ill COVID-19 patients

10 Bacterial pulmonary superinfections are associated with longer duration of ventilation in critically ill COVID-19 patients

11 Bacterial coinfections in coronavirus disease 2019

12 Hospital-Acquired Infections in Critically Ill Patients With COVID-19

13 Possible Cause of Inflammatory Storm and Septic Shock in Patients Diagnosed with (COVID-19)

14 COVID-19: it’s all about sepsis

15 “Cytokine storm”, not only in COVID-19 patients. Mini-review

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

17 Endotoxin Adsorbent Therapy in Severe COVID-19 Pneumonia

18 Chapter 14 – Contribution of gut microbiota and multiple organ failure in the pathogenesis of COVID-19 infection

19 COVID-19 and the Microbiome: The Gut-Lung Connection

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

21 Endotoxemia and circulating bacteriome in severe COVID-19 patients

22 Update: Can COVID-19 Cause Sepsis? Explaining the Relationship Between the Coronavirus Disease and Sepsis

23 Risks and features of secondary infections in severe and critical ill COVID-19 patients

24 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

25 Elevated levels of endotoxin, oxygen-derived free radicals, and cytokines during extracorporeal membrane oxygenation

26 Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and Recommendation

27 Endotoxin Adsorbent Therapy in Severe COVID-19 Pneumonia

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

29 Prolonged Cardiopulmonary Bypass is a Risk Factor for Intestinal Ischaemic Damage and Endotoxaemia