Coronavirus disease 2019 (COVID 19) is the largest outbreak to date caused by the Coronaviridae (CoV). Cases have grown in an exponential manner, with a significant percentage of cases requiring ICU admission (10%), placing significant stress, and testing the capabilities of some of the most robust healthcare systems in the world [1,2].
To date, there is no single body system that has been spared by the disease. Despite being primarily a respiratory virus, other organs involved include the central nervous system (CNS), the peripheral nervous system (PNS), myocardium, and the liver [3–6]. Yet, it has been found that organ involvement does not always correspond with the peak of viremia, as well, there is often failure to isolate the virus from these respective organs [7,8]. Moreover, the peak of organ involvement seems to coincide with the culmination of hypercytokinemia, with specific elevation of interleukin 6 (IL-6). IL-6 is a key contributor in the development of cytokine storm; a syndrome associated with a high profile of organ failure and mortality. The association of COVID-19 with IL-6 has led to the launching of many clinical trials repurposing the use of anti-IL-6 agents such as toclizumab and sarlizumab, as well as other anti-cytokine therapies in the treatment of critically ill patients [9–14].
IL-6 mediates a vast array of inflammatory changes that cause alterations in vascular function. In organ systems affected by COVID-19, constant findings that point towards strong evidence of vascular involvement include; remarkable injury of the lung interstitium, marked elevation of cardiac ischemic isozymes, and CNS vascular involvement [8,15–18]. These findings suggest that COVID-19 induced hypercytokinemia might be targeting organs mainly by inducing vascular dysfunction.
We thereby hypothesize that multi-organ system affected by COVID-19 is mainly immune-induced rather than direct damage caused by the virus, and we further postulate that this immune-induced effect operates through microvascular injury. Proving such hypotheses, might explain the severity of manifestations in obese and geriatric subgroups, as such groups have an upregulated cytokine profile. Knowledge of that may help to tailor a new strategy in the management of COVID-19 cases, by screening all positive cases for serum cytokine levels, to determine the need of anti-IL 6 therapy early in the course of the disease before the development of complications.
Coronavirus disease 2019 signaling of inflammation and evidence of vascular endothelial inflammation
Pathways of coronavirus disease 2019 inflammation
Angiotensin-converting enzyme-dependent pathway
Angiotensin-converting enzyme-2 (ACE2) is a zinc-containing metalloenzyme and transmembrane protein attached to the outer surface of many cells including enterocytes of the small intestine, arterial and venous endothelial cells, arterial smooth muscle cells, and lung type II alveolar cells. ACE2 messenger RNA (mRNA) expression is also found in the cerebral cortex, striatum, hypothalamus, and brainstem. In the pathogenesis of COVID-19, ACE2 is recognized as the site of entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into human cells. The expression of ACE2 in the aforementioned sites means that these cells and organ systems are susceptible to infection by the virus .
A special interest has been given to the link between ACE2 and upregulation of inflammation as a potential cause of microvascular dysfunction and atherogenesis. ACE2, and its end product angiotensin 1-7, are key counter-regulatory proteins that offset the deleterious cardiovascular effects of angiotensin II. Dysregulation of ACE2 and angiotensin 1-7 is linked to the release of proinflammatory cytokines, especially IL-6, accelerating endothelial dysfunction and atherogenesis, as seen in the overexpression of ACE2 in metabolically active atheroma .
Furthermore, soon after infection of cells by SARS-CoV-2, a reduction in the transcription of ACE2 mRNA occurs, thereby reducing its anti-inflammatory effects. The latter leads to upregulation of cytokine profile, with major infection-mediated damage of the endothelium and resultant loss of endothelial-dependent vasodilatation, and increased permeability [21,22].
The Janus kinase-signal transducer and activator of transcription pathway.
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is a critical component of many cytokine receptor systems; regulating growth, survival, differentiation, and pathogen resistance. An example of these pathways involves the IL-6 family of receptors, which co-regulate B cell differentiation, plasma-cytogenesis, and the acute phase reaction, where activation of the JAK-STAT signaling pathway resulted in the production of IL-6 . Most critically; however, is the involvement of the JAK-STAT pathway (mediated via JAK1 and JAK2) in the transcription of interferons which play a major role in preventing viral replication. The importance of JAK-STAT is confirmed by the fact that some microorganisms have adapted methods to prevent its signaling and therefore the production of interferon. Favalli et al. , points out the use of JAK inhibitor baricitinib in SARS-CoV-2 infection due to its role in affecting viral endocytosis mediated by two members of the numb-associated kinase family of this drug class and does so at dosages already approved for the treatment of rheumatoid arthritis. However, it may initially appear counterproductive to use JAK inhibitors, which ultimately would impair the very necessary interferon-mediated antiviral response, in the treatment of viral infection such as SARS-CoV-2. Indeed, JAK-STAT inhibitors have been found to increase the risk of viral infections such as herpes simplex, and zoster infections. However, in a 2006 study by de Lang et al., interferon-gamma (IFN-γ), as well as IL-4, seemed to not only downregulate ACE2 cell surface expression but also decreased ACE2 mRNA transcription levels. These effects are highly polarizing; on one hand, interferon may decrease susceptibility to coronavirus by modulating ACE2 surface expression, yet without the immunoregulatory function of ACE2, an aggravated immune response may be detrimental to an already infected person, especially because ACE2 also has a recognized protective effect on the lungs . It would seem that the rationale to use JAK inhibitors is not only in lieu of its ability to block SARS-CoV-2 but that it also functions to mitigate the interferon proinflammatory action. Interestingly, Napolitano et al., note the reduced levels of IL-6 in patients on selective JAK-1 inhibitor, upadacitinib. These findings suggest the multifaceted methods by which JAK inhibitors can aid the treatment of patients infected with COVID-19; preventing endocytosis, dampening an aggravated immune response, as well as potentially mitigating the occurrence of cytokine storm by decreasing its main perpetrator, IL-6. While promising, JAK inhibitors should be approached with caution and tailored uniquely depending on each patient’s case. Some studies have shown reactivation of latent viral infections such as Ebstein-Barr virus, herpes simplex, and zoster infection with the use of JAK inhibitors. However, in a study by Haberman et al., in confirmed COVID-19 patients with inflammatory immune-mediated disease, baseline use of JAK-kinase inhibitors was not associated with worse COVID-19 outcomes .
The Notch signaling cascade is a system that allows for cells to interact and integrate within their microenvironment, as well, it plays a major role in development through its involvement with gene regulatory mechanisms that control proliferative signals during embryonic life. The Notch signaling pathway is further implicated in cardiovascular development and angiogenesis, endocrine organ development as well as the occurrence of some cancers where aberrant or mutated Notch signaling has been implicated in T-cell acute lymphoblastic leukemia . Notch pathways have recently been suggested by Rizzo et al. to be involved in SARS-CoV-2 viral entry, and in IL-6-mediated inflammation. Notch pathway works hand in hand with ACE2 to promote viral endocytosis by integrating with furin , a protease responsible for mediating viral entry. Furthermore, SARS-CoV-2 has been found to possess a furin-like cleavage site on its spike glycoprotein, hammering in the suggestion that not only inhibition of furin activity, but also that of the Notch system through its association with furin, may serve as a potential therapeutic option in the management of SARS-CoV-2. Additionally, the Notch system plays a major role in the differentiation and development of immune cells, as well as binding directly to IL-6 on macrophages. This binding causes the upregulation of IL-6 production, while at the same time IL-6 causes upregulation of Notch ligands, to the result of a positive feedback loop that continuously promotes IL-6 production. These recent updates involving the NOTCH pathway might help in creating alternative strategies for reducing the levels of IL-6 by means other than IL-6 inhibitors. However, its feasibility is currently questionable, as the inhibition of NOTCH pathway may result in undesirable effects, such as oncogenicity .
Level of circulating cytokines
There are two types of upregulated cytokines which have been observed in COVID-19: the cytokines of the innate immune system cells and those secreted by sensitized T helper cells. IL-6, secreted by the macrophages, is the main cytokine that has been linked to a poorer prognosis in COVID-19. Other upregulated cytokines include IL-1, IL-1 beta, tumor necrosis factor (TNF), and IL-18, of the innate immune system, and IFN-γ secreted by T helper cells . Such cytokines are mainly proinflammatory, especially in the setting of downregulation of key regulatory cytokines, and have been linked to augmented vascular dysfunction, endothelial degeneration, and arrest of endothelial cell migration [29,30].
Two key vascular protective cytokines are decreased in COVID-19, namely type-I IFN and IL-7. Type-I IFN prevents endothelial cell apoptosis and therefore prevents endothelial degeneration while, IL-7 prevents T cell exhaustion , and regulates the secretion of proinflammatory cytokines, thereby preventing their unopposed action. The reduction of secretion of both cytokines, not only prevents the immune system from targeting SARS-CoV-2 in an efficient way, but also facilitates the development of hyperinflammation [32,33].
Figure 1 summarizes the aforementioned findings of COVID-19 inflammatory cascade.
As mentioned above, the knowledge of the dysregulated inflammation in COVID-19 has led to several clinical trials to either decrease the injurious immune activity or to improve the protective immune response. The main bulk of clinical trials that have been conducted involve the use of IL-6 inhibitors [10,12,34], summarized in Tables 1 and 2. Other potential therapies have been targeting other dysregulated cytokines (summarized in Table 3), either by antagonizing upregulated pathways or by supplying reduced key regulatory cytokines [9,11,14,35,36].
Evidence of endothelial inflammation
In a postmortem study of COVID-19 by Varga et al., patients, who had rapidly deteriorated with multi-organ failure, showed evidence of endotheliitis with lymphocytic infiltration present within the endothelial cells. This widespread endothelial damage and dysfunction have led to apoptosis with loss of microcirculatory control; a function of paramount importance by the endothelium. This goes in agreement with our suspected hypothesis that vascular inflammation is at the core of the pathogenesis of COVID-19 manifestations .
Lung involvement, evidence of predominant inflammation over infection
In those patients infected by SARS-CoV-2, acute respiratory distress syndrome (ARDS) is the leading cause of mortality . Controversy underlies the actual reason behind respiratory involvement; whether it is due to direct viral damage or the result of an infection-mediated local immune response. Zhao et al. benchmarked viral detection by PCR against antibody responses to SARS-CoV-2. Within the first week, RNA test showed the highest sensitivity of 66.7%, whereas the total antibody assay had a value of 38.3%. However, from day 15 onwards, the presence of antibodies rapidly increased to 100.0% (94.3 and 79.8% for antibody, IgM and IgG), while the positive rate of RNA decreased to 45.5%. Moreover, a higher titre of antibody was independently associated with a poor clinical outcome. Furthermore, it was found that patients who were symptomatic throughout the three phases of the disease, had no observable RNA in their respiratory samples, yet had detectable antibody in total antibody assay; evidence that is highly suggestive of an overt inflammatory process .
In 2006, Tang et al. studied the levels of elevated cytokines during the course of SARS-1, and the prediction of disease outcome accordingly .
In his study, Nelson measured chemokine levels, including interferon-inducible protein-10 (IP-10), monokine induced by interferon (MIG), IL-8, and monocyte chemoattractant protein-1, in 225 plasma samples collected during the first or second week of disease onset. An association was made via univariate analysis, in that, elevated levels of IP-10, MIG, and IL-8 during the first week, were associated with adverse outcomes including ICU admission or death, while only elevated MIG during the second week was prognostic. Ultimately, elevated IL-10 plasma levels during the first week were recognized as an independent predictor of outcome in those affected by SARS [odds ratio for the adverse outcome of 1.52 (95% confidence interval, 1.05–2.55)] . Similar findings were noted by Huang et al., where the same chemokines were elevated and linked with poor prognosis. Other studies also point out the presence of increased IL-8 in bronchoalveolar lavage fluid and in the systemic circulation, both before and after the onset of ARDS. The aforementioned chemokines are implicated in the pathogenesis of ARDS in SARS infection, as well as being obviously detectable during the early period of acute febrile illness, they play a major role in the recruitment of inflammatory cells; known culprits of pulmonary damage in the setting of ARDS .
Gross evidence of inflammation and endothelial dysfunction was noticed by Zhang et al., where postmortem lung biopsies from four patients, with COVID-19-related refractory respiratory failure, revealed the following: diffuse alveolar damage, denuded alveolar lining cells with reactive type II pneumocyte hyperplasia, intra-alveolar fibrinous exudates with loose interstitial fibrosis, chronic inflammatory infiltrates, heterogeneously distributed pulmonary microthrombi, and significant pulmonary vasodilatory regions. Likewise, these findings were also noticed in autopsy studies of patients from the 2002 SARS outbreak .
McGonagle et al., also points out the findings of vessel wall edema, inflammatory cell infiltration into the walls of the pulmonary microvasculature, marked hemorrhagic necrosis, and vessel microthrombi confined to the lung, pulmonary tissue infarction, and extensive pulmonary macrophage activation (MAS-like). Noted as well are elevated fibrin degradation products and D-dimer levels which also remained progressively elevated in nonsurvivors, while D-dimer levels (above 1 μg/mL) constituted a significant independent biomarker of poor prognosis (18 times increased odds ratio for fatal outcome). Overt disseminated intravascular coagulapathy (DIC) seemed to be restricted to late-stage disease .
These findings were also supported by Poor et al., who reported on four cases, all of whom had elevated D-dimer levels in which there was no evidence of DIC contributing to such condition, proven by the absence of other laboratory DIC findings. It was found that the cause of respiratory failure associated mortality, to be due to pulmonary microthrombi, pulmonary vascular dilatation, and pulmonary infarctions; all of which occurred secondary to inflammation resulting in gas exchange abnormalities, and multi-organ system dysfunction. However, those four cases had hypertension, diabetes mellitus, and obesity which could be contributing factors to endothelial injury .
Interestingly, McGonagle et al. also detailed the involvement of ACE2 and COVID-19 on pulmonary vascular biology. His findings mirrored the previously mentioned ACE2-dependent mechanisms in signaling inflammation. ACE2 had been shown to regulate innate immunity, where in a study of mice with a genetic deletion of ACE2, they developed more severe pulmonary inflammation, significant pneumonitis, and higher mortality rates, after acid inhalation than did wild-type mice. These findings suggest that downregulation of ACE2 may aggravate inflammation within the alveolar-capillary network via the prevention of ACE2 generation of immunoregulatory angiotensin 1-7. Indeed, upon cellular infection with coronavirus, the ACE2 receptor becomes internalized with subsequent inhibition of its immunoregulatory role.
Elevated chemokines, both in circulation and bronchial alveolar lavage, absence of viral particles in interstitium, proof of gross inflammatory events within the respiratory system, elevated D-dimers and increased dead space, go in agreement with the hypothesis that a predominant inflammatory pulmonary vascular endothelial dysfunction is an integral part of coronavirus-related lung injury .
Myocardial sequelae have been described in COVID-19, where series of reports describe left or biventricular hypokinesis with elevation of cardiac isozymes of ischemia [43–45]. An interesting case described, by Sala et al. , was the first report where endomyocardial biopsy has been performed in the context of COVID-19. Sala et al. showed the absence of SARS-CoV-2 with lymphocytic infiltration. Despite viral isolation, in Tavazzi et al. case report, likely the result of migration of infected macrophages into the myocardium, the virus failed to be isolated from cardiomyocytes .
AbdelMassih et al.  linked the abovementioned proinflammatory mechanisms to suggest the possible causes of the observed myocardial injury. It seems that the viral induction of the immune system induces cardiomyocyte and endothelial injury. It is also highly probable, that the endothelial injury pathway with subsequent coronary involvement is the most prominent pathway. Evidences are the elevation of highly sensitive cardiac troponins, and the specific involvement of IL-6 as suggested by AbdelMassih et al. , in the acceleration of endothelial dysfunction; IL-6 being the most upregulated cytokine in COVID-19. Further evidence by AbdelMassih et al., points to a case report by Jones et al., which highlights the features of Kawasaki disease with coronary involvement, in the context of COVID-19; IL-6 is implicated in the manifestations of Kawasaki disease .
Hematological: a significant hypercoagulable state, another evidence of vascular inflammatory process
COVID-19 is associated with a severe hypercoagulable state, as suggested by Panigada et al., Spiezia et al., and Escher et al. . This hypercoagulable state explains the marked elevation of D-dimers in patients with COVID-19, due to the occurrence of severe consumption coagulopathy. These reports also might justify the significant need for anticoagulation in the terminal stages of the illness [11,50]. The linkage between hypercoagulable state and COVID-19 vascular inflammatory state seems obvious. Inflammatory cytokines not only affect the intactness of the endothelium, but IL-6 has been shown to affect red cell dynamics and plasticity, thereby hindering red cell ability to cross narrow microvasculature leading to the observed augmented risk of thrombosis .
Central nervous system involvement, is it encephalitis or rather an acute vascular encephalopathy?
Several series have pointed to CNS involvement in COVID-19. A published report by Poyiadji et al.  describes an acute hemorrhagic necrotizing encephalopathy pattern in the context of COVID-19. The observed pattern mimics several similar types of autoimmune encephalitis. Acute hemorrhagic leukoencephalitis is a fulminant demyelinating disease and commonly considered as a rare and severe variant of acute disseminated encephalomyelitis (ADEM). ADEM, being considered as the commonest of autoimmune encephalitis , is thought to be a disorder of the CNS in which myelin is targeted. Pathological studies on closely related human diseases, and on animal models for these demyelinating disorders, have suggested the involvement of cytokines. Studies on peripheral immunocytes, and on cerebrospinal fluid, revealed the presence of cytokine-mediated responses in ADEM. The findings suggest that these cytokines are toxic to myelin. The inflammation and increased vascular permeability associated with ADEM has also been proposed as a mechanism by which breakdown of the blood–brain barrier occurs, allowing infiltration of the CNS by both antigens and inflammatory cells involved in the concomitant cell-mediated immune response .
To the evidence of cerebral vascular involvement, Moshayedi et al. reported a patient with COVID-19 presenting with middle cerebral artery occlusion. The displayed patterns, with mainly vascular involvement are a strong additive proof to our suggested hypothesis .
Moreover, the exact route by which SARS-CoV or Middle East respiratory syndrome coronavirus (MERS-CoV) enters the CNS is still uncertain and poorly understood. However, hematogenous or lymphatic route seems impossible, especially in the early stage of infection, since almost no virus particle was detected in the nonneuronal cells in the infected brain areas .
The peripheral nervous system, coronavirus disease 2019-induced Guillain–Barré syndrome, another evidence of immune sequelae
With regards to the PNS, a case was recently reported, on the 31 December 2019, of a 65-year old man who suffered from symptoms of acute progressive symmetric ascending quadriparesis. The symptoms ranged from acute progressive weakness of distal lower extremities to quadriplegia, and bilateral facial paresis. He also suffered from cough, fever, and dyspnea. After further diagnostic tests, he was confirmed as a case of Guillain–Barré syndrome (GBS) after a COVID-19 infection .
There is no clear evidence about the relationship between COVID-19 infection and the development of an autoimmune syndrome such as GBS. However, according to a previous study by Lu et al., IL-6 might be implicated in the immunopathogenesis of GBS. In their study, serum IL-6 levels were increased in 6 (26%) of 23 patients with GBS, and detectable levels of IL-6 were also found in the cerebrospinal fluid of 13 (57%) patients. Knowing that IL-6 is one of the major cytokines involved in the pathogenesis of COVID-19, this might explain the observed manifestations . Doyle et al. confirmed in a relatively recent report, the role of ischemic injury in induction of demyelination. Ischemic conditions trigger activation of myelinic N-methyl-d-aspartate (NMDA) receptors incorporating GluN2C/D subunits following the release of axonal vesicular glutamate into the periaxonal space, under the myelin sheath. Glial sources of glutamate such as reverse transport did not contribute significantly to this phenomenon. We demonstrate selective myelin uptake and retention of a GluN2C/D NMDA receptor negative allosteric modulator that shields myelin from ischemic injury . It would seem that an inflammatory process, due to IL-6-induced effects on vascular endothelium resulting in ischemic injury to the myelin sheath, is the means by which COVID-19 affects the PNS.
Hepatopathy, microvesicular steatosis, and implication of vascular inflammation
Gastrointestinal involvement of SARS-CoV-2 was first noticed by Bangash et al., who called attention to the laboratory liver dysfunction in patients with COVID-19, mainly in alanine aminotransferase (ALT) derangement. This finding was further supported by several other studies, which reported that liver dysfunction was often indicative of severe COVID-19 symptoms. Compromise in patients with COVID-19 liver functions was highlighted by Cai et al. where 318 of 418 (76.3%) patients had abnormal ALT, aspartate aminotransferase, total bilirubin, and gamma-glutamyl transferase results, with only a few with underlying liver disease. This became more pronounced during hospitalization and carried a greater risk of progressing into severe pneumonia when detected at admission. Bangash et al. further explains the possibility of an immune cause for this by stating that COVID-19 patients with chronic liver disease (thus lacking many intrahepatic cytotoxic T cells and Kupffer cells responsible for immune-mediated damage) did not have worse mortality [3,59].
Histopathologically, Xu et al. failed to find viral inclusions in the postmortem liver biopsy of a 50-year-old patient with COVID-19, in the presence of moderate microvesicular steatosis, and mild lobular and portal activity detected by light microscopy. The same study also showed evidence of hyperactivated, but considerably diminished cluster of differentiation (CD4) and CD8 T cells in the peripheral blood, bolstering the theory for immune-mediated damage. These findings were also confirmed in another study discussing a MERS-CoV postmortem liver biopsy which found no viral particles by electron microscopy despite findings of mild chronic lymphocytic portal inflammation as well as both CD4+ and CD8+ T lymphocytes in the portal inflammatory infiltrate as seen by immunohistochemistry studies. This goes as well in agreement with a 2003 study on SARS-CoV-1 in which the percutaneous liver biopsies of two out of three patients showed no viral particles on electron microscopy in spite of similar changes spotted by light microscopy stated above .
The elicited pattern of liver injury, in the form of microvesicular steatosis, is known to be linked to accelerated vascular degeneration in the liver and is usually described in the context of nonalcoholic steatohepatitis, the latter induces a state of local hypercytokinemia leading to the microvascular hepatic injury and subsequent microvesicular steatosis .
The reproductive system
It has been reported by Fan et al. that SARS-CoV-2 targets primarily the Leydig cells in the reproductive system of affected males. Winters et al. outlined in his study in 2018, that the primary mechanism of Leydig cell insufficiency is chronic inflammation triggering microvascular dysfunction. Linking the two reports, goes in agreement with the abovementioned evidences, that SARS-CoV-2 acts by inducing an augmented state of inflammation, which impairs microvascular function and causes the observed organ dysfunction [62,63].
Geriatric and obesity models, additional evidence of the role of hypercytokinemia
Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at an older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a proinflammatory phenotype has been called ‘inflamm-aging’.
Specifically, there is strong evidence that IL-6 serum concentration increases with age. Age-related increments in IL-6 are not explained by the differential prevalence of IL-6 gene polymorphisms (51), while there is evidence that the excessive production or reduced clearance of oxygen-free radicals, which stimulate IL-6 production, may be important. This might explain the severity of manifestations observed in elderly people suffering from COVID-19 .
It appears that, in obesity, there is an association with low-grade inflammation of white adipose tissue (WAT), resulting from chronic activation of the innate immune system. This low-grade inflammation of WAT is found to induce a state of hypercytokinemia, with upregulated secretion of multiple inflammatory mediators including various types of TNF and IL-6 [65–68].
Evidence-based recommendations, is it cost-effective?
The positive correlation between high levels of IL-6 and the increase of COVID-19 severity should shed the light on prophylactic measurement of IL-6 levels in recently admitted patients, in order to anticipate any chances of clinical deterioration early measurement of IL-6 in patients with COVID-19, is aiding in predicting the likelihood of respiratory distress as stated in an article written by Herold et al., where IL-6 levels above 80 pg/mL were adequate at identifying COVID-19 patients with high risk of respiratory failure . Owing to the fact that the world is witnessing an overpowering need for ICU with mechanical ventilators, which is creating an economic burden in many countries, comparing the cost-effectiveness of human IL-6 ELISA kit high sensitivity versus the cost of ICU with mechanical ventilators, may create a novel approach to recent COVID-19 positive patients. In France, there have been at least 5433 patients admitted in ICU, with an average length of stay of 15 days . According to a systematic review and meta-regression on the impact of mechanical ventilation on the daily cost of ICU care, a micro-costing study by Lefrant et al.  showed that in 23 French ICU showed costs of to €1425 per day. In addition to the increase in ventilation-related cost by 25.8%, the resulting daily expense of a single ventilated ICU day is €1654  according to 2009 unitary cost data. Therefore, considering the average length of stay of 15 days, it will cost approximately €24810 for each critically ill patient requiring ventilation. In comparison, the cost of human IL-6 ELISA kit costs €5.18  per one test for each patient. This supports the cost-effectiveness of early measurements of IL-6 to predict critical cases, in order to avoid the need for high budget ICU with mechanical ventilators (Fig. 2).
Evidence suggests that microvascular dysfunction driven by inflammation, mainly orchestrated by IL-6, is the means by which COVID-19 causes transfection of almost all body cells. This finding may be a game-changer in the management of COVID-19. Knowledge of baseline levels of IL-6 in affected patients might help in initiating anti-IL-6 therapy early in the course of the disease, before the development of life-threatening complications. Such a strategy seems to be cost-effective and will eliminate the risk of collapse of healthcare systems worldwide due to increased demand for ICU beds and ventilation.
In view of the above, we strongly urge working groups in all affected countries, to conduct prospective studies to measure the baseline levels of IL-6 and other upregulated cytokines. Setting cutoff levels of IL-6 that can predict subsequent complications, and the need for mechanical ventilation, will help healthcare systems in decreasing the need for ICU beds.
As a first author, I wanted to thank all my co-authors and their families who raised them in such a wonderful way. I also wanted to thank my family, my mother, my brother Philippe, my sister Viviane and my Wife Sally and her wonderful family. A special thank you note goes to my three children Maria, George, and Marc, the jewels of my life. Finally, yet importantly, I hold the deepest gratitude to all staff members of Kasr Al Ainy headed by Prof. Hala Salah and our Pediatrics department headed by Prof. Mona El Falaki.
Conflicts of interest
There are no conflicts of interest.
1. Callaway E. Time to use the p-word? Coronavirus enters dangerous new phase. Nature. 2020
2. Truog RD, Mitchell C, Daley GQ. The toughest triage – allocating ventilators in a pandemic. N Engl J Med. 2020; 382:1973–1975
3. Bangash MN, Patel J, Parekh D. COVID-19 and the liver: little cause for concern. Lancet Gastroenterol Hepatol. 2020; 1253:20–21
4. Moshayedi P, Ryan TE, Luciano L, Mejia P, Nour M, Liebeskind DS. Triage of acute ischemic stroke in confirmed COVID-19 : large vessel occlusion associated with coronavirus infection. Front Neurol. 2020; 11:10–12
5. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395:4972013506
6. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA - J Am Med Assoc. 2020; 323:1061–1069
7. Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019
. SSRN Electron J. 20201–22
8. Ren YH, Wang SY, Liu M, Guo YM, Dai HP. When COVID-19 encounters interstitial lung disease: challenges and management. Zhonghua Jie He He Hu Xi Za Zhi. 2020; 43:E039
9. Vallurupalli M, Berliner N. Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis. Blood. 2019; 134:1783–1786
10. Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: a single center experience. J Med Virol. 2020
11. Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016; 44:275–281
12. Gritti G, Raimondi F, Ripamonti D, et al. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv. 2020
13. Sallard E, Lescure FX, Yazdanpanah Y, Mentre F, Peiffer-Smadja N. Type 1 interferons as a potential treatment against COVID-19. Antiviral Res. 2020; 178:104791
14. Favalli EG, Biggioggero M, Maioli G, Caporali R. Baricitinib for COVID-19: a suitable treatment? Lancet Infect Dis. 2020; 3099:30262
15. Spiezia L, Boscolo A, Poletto F, Cerruti L, Tiberio I, Campello E, et al. COVID-19-related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure. Thromb Haemost. 20204–6
16. Sala S, Peretto G, Gramegna M, Palmisano A, Villatore A, Vignale D, et al. Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection. Eur Heart J. 20201–2
17. Inciardi RM, Lupi L, Zaccone G, Italia L, Raffo M, Tomasoni D, et al. Cardiac involvement in a patient with coronavirus disease 2019
(COVID-19). JAMA Cardiol. 2020
18. Baumeister H. Indo Am J Pharm Sci. 2019; 23:6
19. Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203:631–637
20. Lakhani CM. Physiol Behav. 2019; 176:139–148
21. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000; 87:E1–E9
22. Lovren F, Pan Y, Quan A, Teoh H, Wang G, Shukla PC, et al. Angiotensin converting enzyme-2 confers endothelial protection and attenuates atherosclerosis. Am J Physiol Heart Circ Physiol. 2008; 295:H1377–H1384
23. Booz GW, Day JN, Baker KM. Interplay between the cardiac renin angiotensin system and JAK-STAT signaling: role in cardiac hypertrophy, ischemia/reperfusion dysfunction, and heart failure. J Mol Cell Cardiol. 2002; 34:1443–1453
24. de Lang A, Osterhaus AD, Haagmans BL. Interferon-gamma and interleukin-4 downregulate expression of the SARS coronavirus receptor ACE2 in Vero E6 cells. Virology. 2006; 353:474–481
25. City NY, Appendix S. Correspondence Covid-19 in Immune-Mediated Inflammatory Diseases – Case Series from New York. 20208–10
26. Göthert JR, Brake RL, Smeets M, Dührsen U, Begley CG, Izon DJ. NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis. Blood. 2007; 110:3753–3762
27. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020; 176:104742
28. Rizzo P, Vieceli Dalla Sega F, Fortini F, Marracino L, Rapezzi C, Ferrari R. COVID-19 in the heart and the lungs: could we “Notch” the inflammatory storm? Basic Res Cardiol. 2020; 115:31
29. Herbst S, Schaible UE, Schneider BE. Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis. PLoS One. 2011; 6:e19105
30. Kofler S, Nickel T, Weis M. Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation. Clin Sci (Lond). 2005; 108:205–213
31. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company ’ s public news and information. 2020;(January).
32. Juffroy O, Bugault F, Lambotte O, Landires I, Viard JP, Niel L, et al. Dual mechanism of impairment of interleukin-7 (IL-7) responses in human immunodeficiency virus infection: decreased IL-7 binding and abnormal activation of the JAK/STAT5 pathway. J Virol. 2010; 84:96–108
33. Pammer J, Reinisch C, Birner P, Pogoda K, Sturzl M, Tschachler E. Interferon-alpha prevents apoptosis of endothelial cells after short-term exposure but induces replicative senescence after continuous stimulation. Lab Invest. 2006; 86:997–1007
34. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv. 2020; 17:10970–10975
35. Feldmann M, Maini RN, Woody JN, López CM, Tabb A, Cole GS, Knapp SJ. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet. 2020; 9:giaa030
36. Monteagudo LA, Boothby A, Gertner E. Continuous intravenous anakinra infusion to calm the cytokine storm in macrophage activation syndrome. ACR Open Rheumatol. 2020; 2:276–282
37. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020; 395:1417–1418
38. Vincent JL, Taccone FS. Understanding pathways to death in patients with COVID-19. Lancet Respir Med. 2020; 8:430–432
39. Tang NL, Chan PK, Wong CK, To KF, Wu AK, Sung YM. Early enhanced expression of interferon-inducible protein-10 (CXCL-10) and other chemokines predicts adverse outcome in severe acute respiratory syndrome. Clin Chem. 2005; 51:2333–2340
40. Zhang H, Zhou P, Wei Y, Yue H, Wang Y, Hu M, et al. Histopathologic changes and SARS–CoV-2 immunostaining in the lung of a patient with COVID-19. Ann Intern Med. 2020; 172:629–632
41. McGonagle D, O’Donnell J, Sharif K, Emery P, Bridgewood C. Immune Mechanisms of Pulmonary Intravascular Coagulopathy (PIC) in COVID-19 pneumonia. Lancet Rheumatol. 2020; 2019:1–9
42. Poor HD, Ventetuolo CE, Tolbert T, et al. COVID-19 critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to thrombolysis. medRxiv. 2020
43. Li SS, Cheng CW, Fu CL, Chan YH, Lee MP, Chan JW, Yiu SF. Left ventricular performance in patients with severe acute respiratory syndrome: a 30-day echocardiographic follow-up study. Circulation. 2003; 108:1798–1803
44. Xiong TY, Redwood S, Prendergast B, Chen M. Coronaviruses and the cardiovascular system: acute and long-term implications. Eur Heart J. 2020; 41:1798–1800
45. Xu H, Hou K, Xu H, Liu Q, Chen H, Wang H, et al. Acute myocardial injury of patients with coronavirus disease 2019
. medRxiv. 2020heartjnl-2020-317007
46. Tavazzi G, Pellegrini C, Maurelli M, Belliato M, Sciutti F, Bottazzi A, et al. Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail. 20201–5
47. Fakhry A, Ramzy D, Nathan L, et al. Possible molecular and paracrine involvement underlying the pathogenesis of COVID-19 cardiovascular complications. 2020121–124
48. Jones VG, Mills M, Suarez D, Hogan CA, Yeh D, Bradley Segal J, et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020hpeds.2020-0123
49. Escher R, Breakey N, Lämmle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res. 2020; 190:62
50. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020
51. Kuhn V, Diederich L, Keller TCS, Kramer CM, Lückstädt W, Panknin C, et al. Red blood cell function and dysfunction: redox regulation, nitric oxide metabolism, anemia. Antioxid Redox Signal. 2017; 26:718–742
53. Tenembaum S, Chitnis T, Ness J, Hahn JS; International Pediatric MS Study Group. Acute disseminated encephalomyelitis. Neurology. 2007; 68:S23–S36
54. Kadhim H, De Prez C, Gazagnes MD, Sébire G. In situ cytokine immune responses in acute disseminated encephalomyelitis: insights into pathophysiologic mechanisms. Hum Pathol. 2003; 34:293–297
55. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients. J Med Virol. 2020
56. Zhao H, Shen D, Zhou H, Liu J, Chen S. Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence? Lancet Neurol. 2020; 19:383–384
57. Lu MO, Zhu J. The role of cytokines in Guillain-Barré syndrome. J Neurol. 2011; 258:533–548
58. Kukley M, Capetillo-Zarate E, Dietrich D. Vesicular glutamate release from axons in white matter. Nat Neurosci. 2007; 10:311–320
59. Cai B, Dongiovanni P, Corey KE, Wang X, Shmarakov IO, Zheng Z, et al. Macrophage MerTK promotes liver fibrosis in nonalcoholic steatohepatitis. Cell Metab. 2020; 31:406–421.e7
60. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int. 20201–7
61. Sánchez-Garrido MA, Chico Y, González R, Ranchal I, González-Rubio S, Hidalgo AB, et al. Interleukin-6 is associated with liver lipid homeostasis but not with cell death in experimental hepatic steatosis. Innate Immun. 2009; 15:337–349
62. Winters SJ, Moore JP Jr, Clark BJ. Leydig cell insufficiency in hypospermatogenesis: a paracrine effect of activin-inhibin signaling? Andrology. 2018; 6:262–271
63. Fan C, Li K, Ding Y, Lu WL, Wang J. ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-nCoV infection. medRxiv. 20202020.02.12.20022418
64. Koelman L, Pivovarova-Ramich O, Pfeiffer AFH, Grune T, Aleksandrova K. Cytokines for evaluation of chronic inflammatory status in ageing research: reliability and phenotypic characterisation. Immun Ageing. 2019; 16:11
65. Wisse BE. The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol. 2004; 15:2792–2800
66. Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, et al. A central role for JNK in obesity and insulin resistance. Nature. 2002; 420:333–336
67. King GL. The role of inflammatory cytokines in diabetes and its complications. J Periodontol. 2008; 79:1527–1534
68. Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. ISRN Inflamm. 2013; 2013:139239
69. Dasta JF, McLaughlin TP, Mody SH, Piech CT. Daily cost of an intensive care unit day: the contribution of mechanical ventilation. Crit Care Med. 2005; 33:1266–1271
70. Lefrant JY, Garrigues B, Pribil C, Bardoulat I, Courtial F, Maurel F, Bazin JÉ; CRREA Study Group; AzuRea Group. The daily cost of ICU patients: a micro-costing study in 23 French intensive care units. Anaesth Crit Care Pain Med. 2015; 34:151–157
71. Kaier K, Heister T, Motschall E, Hehn P, Bluhmki T, Wolkewitz M. Impact of mechanical ventilation on the daily costs of ICU care: a systematic review and meta regression. Epidemiol Infect. 2019; 147:e314
72. Thompson DK, Huffman KM, Kraus WE, Kraus VB. Critical appraisal of four IL-6 immunoassays. PLoS One. 2012; 7