The worldwide outbreak of coronavirus disease 2019 (COVID-19) has demonstrated that
we are all part of a small world where diffusion of contagious diseases is inevitable
[1]. Although the new coronavirus originated in Wuhan seems to present lower lethality
compared to previous epidemic outbreaks from other coronaviruses, its capacity of
diffusion has been phenomenal [2, 3]. One infected individual may transmit the virus
to 2 or 3 others [4]. Of note, screening based on symptoms and signs is ineffective
and asymptomatic persons can spread the disease [5]. In the very early phases, before
this wide diffusion of the virus, a call to action was published in Lancet Respiratory
Medicine [6] underlining the need of alertness for zoonotic virus infections crossing
species and infecting human populations [7]. In particular, recommendation was made
to prepare intensive care teams to deliver extracorporeal organ support (ECOS) therapies
in infected patients whose pulmonary syndromes are particularly severe [8]. Once again,
despite previous experiences presented higher incidence of severe complications and
lethality, the current outbreak still requires intensive care for 5% of the infected
population. Among those critically ill patients, the mortality rate is 49%. Even with
the specific tropism for airway epithelial cells, the infection seems to be weak in
humans and transmission is likely to occur only when lower respiratory tract disease
develops. COVID-19 causes mild flu-like symptoms or even no symptoms in the majority
of the patients [3]. Coronaviruses bind to receptors such as angiotensin-converting
enzyme 2. Angiotensin-converting enzyme 2 is present in the epithelia of the lung,
small intestine, colon, and biliary tract. In fact, viral nucleic acids were found
in stools and anal swabs of patients diagnosed with COVID-19 infection [9]. In a cohort
of COVID-19-infected patients from Singapore, half (4 out of 8) of patients tested
had the virus detected in stools [10]. This might explain liver dysfunction, diarrhea,
nausea, and vomiting that occurred in patients with pneumonia, namely, the gut-lung
crosstalk [8, 11].
In a Chinese group of patients with pneumonia caused by COVID-19, 23% were admitted
to intensive care unit (ICU), 17% had acute respiratory distress syndrome, and 11%
died [11]. Major preventive measures have been undertaken in specific areas where
the incidence was significantly higher, to limit the diffusion of the virus [7]. Despite
those measures, the requirement of ICU services and stations still has dramatically
increased. Personal communications and early reports mostly coming from China suggest
that 67% of severely ill COVID-19 patients may present with additional organ dysfunction
syndromes [8, 11, 12]. This has been, at least in part, related to a sepsis-like syndrome
induced by high level of circulating cytokines [2, 12]. In such circumstances, while
pulmonary exchanges are compromised and dominate the clinical scenario, acute kidney
injury and heart and liver dysfunction may also become evident [8, 12, 13, 14]. Cytokine
storm may be induced by a superimposed septic syndrome or by the direct effect of
the virus on the infected host. In the past, the experience matured with H1N1 influenza,
SARS, and MERS has suggested that the severity of illness depended on comorbidities
and the immune-competence of the individual. In severe situations, however, an uncontrolled
inflammatory state or a subsequent/simultaneous immune-paralysis is the direct consequence
of endocrine effects of pro- and anti-inflammatory cytokines spilled over into the
systemic circulation. Of special interest, in a retrospective analysis of a German
cohort [15] of 25 critically ill H1N1-infected patients, the prevalence of virus-associated
hemophagocytic syndrome (VAHS) was 36%. All patients with the syndrome had received
extracorporeal membrane oxygenation (ECMO). ECMO could have been a trigger or an amplifier
of cytokine activation. The pathogenesis of VAHS involves excessive production of
interferon gamma and interleukin-2 [16]. VAHS itself is a prototype of a cytokine
storm syndrome. In our present experience in San Bortolo Hospital, all our 4 COVID-19
critically ill patients have hyperferritinemia, raising awareness of VAHS as a differential
diagnosis.
In organ dysfunction syndromes when pharmacological treatment is simply not available
or efficacious, mechanical ventilation and hemodynamic support seem to be the only
possible therapeutic strategy [17]. However, extracorporeal therapies such as hemofiltration
or hemoperfusion (HP) offer a new possibility to support different organs in a multiple
organ dysfunction condition. Using specific extracorporeal circuits and devices, heart,
lungs, kidneys, and liver can be partially replaced or at least sustained during the
severe phase of the syndrome. The concept is known as ECOS [18, 19, 20]. The most
important technique in these cases is the ECMO mostly applied in veno-venous mode
[21, 22, 23]. Furthermore, extracorporeal CO2 removal is another option that can be
performed in less severe cases to facilitate a less invasive and traumatic mechanical
ventilation [24]. Although acute kidney injury in these patients is not common, continuous
renal replacement therapies may offer in conditions of mild to severe kidney dysfunction
a significant support for solute and fluid control. The same is true for left ventricular
assist devices in case of refractory heart failure or albumin dialysis and HP in case
of liver dysfunction and hyperbilirubinemia [25]. However, according to information
collected from Chinese colleagues who faced a large proportion of patients with complicated
COVID-19 syndromes in their ICUs, a significant benefit seems to have been obtained
with the use of direct HP with cartridges containing highly biocompatible sorbents
and microporous resins [26]. Such therapies, designed to remove the excess of circulating
cytokines, seem to have displayed a remarkable benefit in terms of hemodynamic support
and organ function recovery [2]. The suggested scheme of application of HA380 cartridges
(Jafron Biomedical Co., China) was 2-1-1, that is, 2 units utilized for 12 h in the
first 24 h and 1 unit per day utilized for 24 h in the following 2 days. In Europe,
we had matured some experience with the use of Cytosorb© cartridges (CytoSorbents
Corporation, NJ, USA), exactly for the same purpose of controlling deadly inflammation
in critically ill and cardiac surgery patients [27, 28]. This approach may be just
one of many others [29] utilizing extracorporeal therapies in these severe syndromes
and will require scientific validation once the emergency of the current epidemic
will be over. The suggested mechanism is the nonspecific removal of the peaks of the
circulating cytokines both in the pro- and in the anti-inflammatory side. This is
consistent with the “peak concentration hypothesis” suggested some time ago [30].
In presence of our inability to obtain instantaneous monitoring of biological levels
of cytokines, the reasonable approach is to promote a nonspecific removal assuming
that those cytokines with the highest concentration will be removed in higher amount
(Fig. 1) [31]. This would facilitate a return to a less severe derangement of the
immune system and to an improved level of the immunological response of the host.
The same concept has been expressed by the “cytokinetic model.” In this theory, the
reduction of circulating levels of cytokines may allow the immune system of the patient
to redirect the immunocompetent cells to the source or site of inflammation [32].
We warn users of these techniques that together with the removal of cytokines, some
drugs and antibiotics like vancomycin are also removed. In vitro models proved that
[33]. In this case, a specific adjustment of antibiotic dosage in patients with bacterial
infections should be carefully planned. Another adjunctive potential extracorporeal
therapy is lectin affinity plasmapheresis for coronavirus trapping. Blood runs into
a plasma filter, and the filtered plasma containing viral copies passes through a
matrix of lectins. There is a high affinity between the viral envelope and lectins.
Likewise, some viral copies are captured and the viremia is reduced [34]. This therapy
should be further explored and validated.
The main message the present editorial tries to convey is that the ICU staff and treating
physicians should be familiar with the concept that extracorporeal therapies represent
today an important strategy in critically ill patients with multiple organ dysfunction.
Training and research should be planned to further develop skills and knowledge in
this area where new membrane separation processes and adsorption techniques appear
to be a new frontier in fighting the so-called “cytokine storm syndrome.” We will
need to increase awareness of the basic principles, to study mechanisms, to optimize
prescription and delivery of different techniques. We need to stimulate research and
data collection to create sufficient scientific evidence. We need to prepare for the
uncertain future where the frequency of these crises will be probably increasing [4].
We must retool ourselves with new strategies and new therapies, and among those, new
ECOS therapies. As the ancients used to say: “Si vis pacem, para bellum,” if you want
peace, get prepared to war.
Disclosure Statement
The authors have no conflicts of interest to declare.
Funding Sources
There are no funding sources to declare.
Author Contributions
All authors contributed equally to the manuscript and approved submission.