By Cristina Piñel Neparidze
Have you ever heard about cytokine storms? Most of the time, when people say that someone has died from COVID-19, the cause of death is simply attributed to the virus and its ability to induce multiple organ failure. We imagine that the unfortunately deceased individual lost their battle against this sneaky pathogen, which eventually managed to effectively propagate through their body. What is not commonly mentioned is that, in people with old or compromised immune systems, an excessive production of inflammatory cytokines (especially Interleukin 6 (IL-6)) is observed as a response to the COVID-19 infection (Tang et. al., 2020).
The tendency of these individuals to induce such an elevated pro-inflammatory response to the infection often culminates in what we know as a “cytokine storm” or sepsis, which is the body’s overwhelming and life-threatening response to infection. Sepsis is, in other words, an excessive and toxic reaction to an infectious pathogen, which leads to tissue damage, multiple organ failure and a mortality of 30-50% in the state-of-the-art intensive care units (Kang et. al., 2014).
Sepsis is thus the primary cause of death for patients infected with COVID-19 and, amidst the circumstances, we are all very well aware that millions of individuals have passed away as a result of this excessive response to infection. Interestingly, sepsis can additionally be caused by pathogens other than viruses. Before, COVID-19 had been identified, it was estimated that sepsis accounted for approximately 1 in 5 global fatalities, making it a substantial health burden worldwide (Rudd et. al., 2020). Among the pathogens documented to be majorly responsible for these sepsis cases were bacteria. Remarkably, a bacterial species known as Escherichia coli (E. coli), was known to induce as many as 40% of sepsis episodes before the documentation of COVID-19 (Burki, 2018).
Hence, given that both viruses (such as COVID-19) and bacteria (such as E. coli) are causing such a life-threatening condition, one cannot help but wonder what are the current treatments available to avoid sepsis episodes. In the case of COVID-19, sepsis treatment often involves the administration of anti-viral agents (such as Remdesivir) or immunomodulators (such as Tocilizumab, which acts as an IL-6 inhibitor), which have been shown to be safe and helpful but still not entirely effective (as evidenced by the high mortality observed despite their use) (Beigel et. al., 2020). As for bacteria-induced sepsis, treatment usually involves the use of empiric, broad-spectrum antibiotic therapy because it takes days to identify the source of the infection. This can lead to serious side effects, which makes sepsis mortality rates increase as much as 9% for every hour before the correct antibiotic therapy is administered (especially difficult for treating multi-resistant strains) (Kang et. al., 2014).
Given the far-from-perfect treatment effectivity for both virus and bacteria-induced sepsis, it is undeniable that alternative therapies must be introduced or co-implemented to tackle this condition (Beigel et. al., 2020). An emerging and promising field which might help overcome the shortcomings of the mentioned therapeutic approaches for sepsis is that of magnetic haemofiltration. Magnetic blood filtration technologies employ the powers of magnetism to selectively remove desired pathogenic substances from a patient’s blood. There are many approaches to implementing this technology, but one that has particularly attracted a lot of attention is the removal of pathogenic substances from the blood using targeted magnetic nanobeads. Exciting sepsis-focused research is currently being carried out by scientists aiming to design antibody-functionalised nanobeads that selectively target and magnetically remove pathogens from the blood. Similar to dialysis, the application of these targeted, magnetic nanobeads includes infusing them into a loop with a magnet through which a patient’s blood is circulated. These antibody-conjugated nanobeads can therefore bind to their targeted pathogenic substance and get captured when passing through the magnet (thus only allowing pathogen-free blood to be reinfused back into the patient’s bloodstream) (Frodsham et. al., 2015).
As mentioned before, exploring co-delivery of drugs Remdesivir or Tocilizumab with alternative inflammation modulating treatments is necessary to reduce ICU mortality due to COVID-19 (Beigel et. al., 2020). Interestingly, previous studies have shown how functionalising magnetic nanobeads with antibodies targeting IL-6 and infusing them into an extra-corporeal magnetic separator device allowed a filtration of up to 38% of IL-6 in human plasma in a single pass through the device (Hack et. al., 1989). A similar study used iron oxide magnetic nanobeads conjugated to appropriate antibodies to target interleukin-1 and tumour necrosis factor α and achieved a removal percentage of 80-90% (Dinarello et. al. 1986). This suggests that dialysis-like magnetic blood filtration devices using infused cytokine-targeting magnetic nanobeads could represent an attractive co-treatment to reduce the excessive inflammatory response observed in ICU COVID-19 patients.
Similarly, in the case of bacteria-induced septic shocks, the implementation of such magnetic blood filtration devices could represent a promising alternative for early treatment of sepsis. This is because, infusion of targeted magnetic nanobeads into a haemofiltration device does not require any form of systemic antibiotic administration, which could therefore avoid the severe side effects associated with the current non-specific, broad-spectrum antibiotics given to patients prior to the identification of the infectious bacterial pathogen. This approach would also be particularly attractive to treat patients with multi-resistant bacterial infections (Kang et. al., 2014).
As an example of a successful strategy aiming to attenuate bacterial sepsis through magnetic blood filtration, a research group functionalised cobalt-iron magnetic nanobeads with polymyxin B in order to remove E. coli-derived lipopolysaccharide (LPS) from whole blood. Polymyxin B is a type of antibiotic that can bind to Gram-negative bacteria, and LPS (also known as endotoxin) is a bacterial toxin responsible for triggering an inflammatory cascade by the host’s organism. After mixing E. coli-spiked blood with Polymyxin B-functionalised nanobeads, this research group reported a significant reduction of LPS under static magnetic filtration conditions after a brief 15-minute incubation (Herrmann et. al., 2012).
As previously mentioned, sepsis is a life-threatening condition that affects millions of individuals around the globe, and its impact this past year has become even more devastating after the propagation of COVID-19. For this reason, the emergence of alternative strategies such as magnetic blood filtration to tackle this condition are particularly promising. Magnetic haemofiltration holds a number of potential advantages over current sepsis treatments (be it viral or bacterial-induced). It does not require pathogen diagnosis nor systemic administration of medicines (thus reducing time needed to begin treatment). Furthermore, in the case of bacterial septic shock, this promising new therapy could constitute an attractive novel therapeutic avenue for multi-resistant bacterial strain treatment, as it is immune to the resistance that can plague anti-bacterials. It is no understatement to say that a cocktail of different targeted magnetic nanobeads could be able to target 99% of sepsis-causing pathogens, which could in turn revolutionise healthcare (Frodsham et. al., 2015). While it is true that most magnetic blood filtration-focused research carried out to date is pre-clinical, industry and academia are currently in the process of accelerating the delivery of this new and exciting sepsis treatment to the clinic.
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