What makes cytokine

The new virus, nCoV, so called then, was isolated on 7 January and identified as the cause of the outbreak 1. The nCoV virus rapidly spread across China and many other countries and caused a rapidly growing global outbreak. As of 26 May , COVID has been confirmed in 5,, individuals globally with deaths reaching , with a morality of 6.

Coronaviruses are enveloped, positive single stranded large RNA viruses. Although the first data available about COVID indicates possible animal-to-human transmission via wild animals in Huanan seafood Market in Wuhan 5 , 6 , epidemiological data and studies, after that, have increasingly demonstrated that the virus transmits human-to-human, through droplets or direct contact, with the reporting that individuals who did not have direct contact with the Huanan seafood market were diagnosed with COVID and with secondary cases occurring at hospitals among health care workers who had extensive contact with COVID patients.

The virus was confirmed to spread through respiratory droplets from coughs or sneezes 7 — 9 with the ability of the host to shed the infection while asymptomatic Studies are now also proposing the possible feco-oral transmission of the virus COVID patients are mainly adults older than 18 years old with a male predominance, the preconceived notion that pediatrics are not subjected to infection later changed with confirmed cases occurring in pediatrics in China and worldwide 12 , 13 , however, mortality is still much more in the adult group above the age of 65 years.

Adults with pre-existing cardiovascular diseases, respiratory diseases, endocrine diseases, diabetics, or immunocompromised adults remain the most exposed to serious complication of COVID Patients usually present with fever, dry cough, shortness of breath, headache, malaise, muscle, and bony aches.

Less common symptoms include sore throat, confusion, productive cough, hemoptysis, diarrhea, nausea, and chest pain Progression to pneumonia is documented by radiological findings and usually occurs 1—2 weeks after the beginning of the symptoms.

Patients presenting late or deteriorating hospitalized patients usually suffer from acute respiratory distress syndrome ARDS , acute respiratory failure, acute renal injury, and multi-organ failure 15 — Complete blood picture of COVID patients usually shows lymphopenia with or without total leukopenia. NLR is calculated from a routine blood picture by dividing the absolute neutrophil count by the absolute lymphocyte count and indicates a patient's overall inflammatory status.

Increasing NLR is a risk factor of mortality not only in infectious diseases but also in malignancy, acute coronary syndrome, intracerebral hemorrhage, polymyositis, and dermatomyostis Platelet count is usually normal or mildly decreased.

C-reaction protein and erythrocyte sedimentation rate are usually increased while procalcitonin levels are normal and elevation of procalcitonin usually indicates secondary bacterial infection.

Lactate dehydrogenase, ferritin, D-dimer, and creatine kinase elevation is associated with severe disease. Elevation in creatinine or liver enzyme levels ALT and AST occurs in complicated cases progressing to multi-organ failure The newly emerging COVID is continuing to challenge medical health systems all over the world and the scenario is still getting worse. Several studies analyzing cytokine profiles from COVID patients suggested that the cytokine storm correlated directly with lung injury, multi-organ failure, and unfavorable prognosis of severe COVID 16 , 20 — The immune system has an exquisite mechanism capable of responding to various pathogens.

Normal anti-viral immune response requires the activation of the inflammatory pathways of the immune system; however, aberrant or exaggerated response of the host's immune system can cause severe disease if remains uncontrolled Cytokines are an essential part of the inflammatory process.

Cytokines are produced by several immune cells including the innate macrophages, dendritic cells, natural killer cells and the adaptive T and B lymphocytes.

During an innate immune response to a viral infection, pattern recognition receptors PRRs recognize different molecular structures that are characteristic to the invading virus. These molecular structures are referred to as pathogen associated molecular patterns PAMPs. Binding of PAMPs to PRRs triggers the start of the inflammatory response against the invading virus resulting in the activation of several signaling pathways and subsequently transcription factors which induce the expression of genes responsible for production of several products involved in the host's immune response to the virus, among which are the genes encoding several pro-inflammatory cytokines.

The major transcription factors that are activated by PRRs are nuclear factor kB, activation protein 1, interferon response factors three and seven. These transcription factors induce the expression of genes encoding inflammatory cytokines, chemokines and adhesion molecules.

This sequence of events results in recruitment of leukocytes and plasma proteins to site of infection where they perform various effector functions that serve to combat the triggering infection Tissue macrophages, mast cells, endothelial, and epithelial cells are the major source of these cytokines during innate immune response. This increase in cytokines results in influx of various immune cells such as macrophages, neutrophils, and T cells from the circulation into the site of infection with destructive effects on human tissue resulting from destabilization of endothelial cell to cell interactions, damage of vascular barrier, capillary damage, diffuse alveolar damage, multiorgan failure, and ultimately death.

Lung injury is one consequence of the cytokine storm that can progress into acute lung injury or its more severe form ARDS Although the exact mechanism of ARDS in COVID patients is not fully understood, the excessive production of pro-inflammatory cytokines is considered to be one of the major contributing factors 15 — A similar study by Gao et al. Similarly, Chen et al. Cytokine storm CS is a critical life-threating condition requiring intensive care admission and having a quite high mortality.

Highlighted Scientific Opportunities. Research Grants. Research Funding Opportunities. Cancer Grand Challenges. Research Program Contacts. Funding Strategy.

Grants Policies and Process. Introduction to Grants Process. NCI Grant Policies. Legal Requirements. Step 3: Peer Review and Funding Outcomes. Manage Your Award. Grants Management Contacts. Prior Approvals. Annual Reporting and Auditing. Transfer of a Grant. Grant Closeout. Cancer Training at NCI. Resources for Trainees. Funding for Cancer Training. Building a Diverse Workforce. National Cancer Act 50th Anniversary Commemoration. Resources for News Media. Media Contacts. Cancer Reporting Fellowships.

Advisory Board Meetings. Social Media Events. Cancer Currents Blog. Contributing to Cancer Research. Strategic Planning. Principal Deputy Director's Page. Previous NCI Directors. NCI Frederick. Advisory Boards and Review Groups. NCI Congressional Justification.

Current Congress. Committees of Interest. Legislative Resources. Recent Public Laws. Search Search. Cancer Information Summaries. Adult Treatment. The editorial concludes correctly that the linkage of cytokine storm to COVID maybe nothing more than a tempest in a teapot, but fails to offer an alternative explanation.

I would like to point out that there is an alternative hypothesis that explains much more of the 'unusual' features observed with CoVID19, that the primary pathogenic feature is a virally induced coagulopathy 1,2. This includes the microthrombi reported in the post mortems of CoVID deaths but also a number of other 'thrombolytic complications' 2 which include the characteristic CT scans and the low O2 saturation in the absence of breathing difficulty seen in some CoVID patients 2.

Moreover, given the variable IL6 levels noted in the editorial, elevated levels of d-dimer consistent with coagulopathy has been widely reported as an early marker of CoVID19 infection and very high levels correlated with mortality 2,3.

Most importantly, the early use of LMW heparin in CoVID19 patients has changed mortality outcomes in hospitalized patients 2 and may also be beneficial in reducing cytokine storms 3 and needs to be more widely appreciated than simply in clinical practice.

Lancet Rheumatology Published online May 7, Oudkerk M et. Radiology Published Online Apr 23 Chen S et. The potential of low molecular weight heparin to mitigate cytokine storm in severe COVID patients: a retrospective clinical study. Chaos theory helps in the understanding of a cytokine storm. The National Cancer Institute definition of a cytokine storm is "a severe immune reaction in which the body releases too many cytokines into the blood too quickly.

In the context of COVID, the term is seemingly being used in a sensational sense — "an inflammatory response flaring out of control", as discussed in [2] — to describe the severe inflammatory reaction in the lungs that is a widely recognised feature of the coronavirus infection.

As occurs with other inflammatory pathologies, there is a lesser or greater degree of spill-over of inflammatory cytokines into the blood. When the cytokine IL-6 escapes from a local site of inflammation into the blood and then reaches the liver, it triggers the secretion of C-reactive protein, a well-known and widely used marker of inflammation.

A raised IL-6 level is a feature of inflammatory pathologies, but it is only one of many pro- and anti-inflammatory cytokines that are released when inflammation occurs. The tune that this orchestra plays is determined by the principles espoused by "chaos theory" now also called complexity theory , which in practical terms means that you can't predict exactly what that tune will be — as discussed in [3]. In chaos theory parlance, the tune will be "critically dependant on initial conditions" — otherwise described as "the butterfly effect".

And the tune will settle to "a strange attractor" or "emergent phenomenon", that will be slightly different in each individual patient. This will be as predictable as, but no more predictable than, the weather.

The cytokine storm can still be raging. COVID a riddle wrapped in a mystery inside an enigma. In COVID front-line white blood cells release inflammatory molecules called cytokines, which in turn summon more immune cells that target and kill virus-infected cells, leaving a stew of fluid and dead cells behind.

This is the underlying pathology of pneumonia, with its corresponding symptoms: coughing; fever; and rapid, shallow respiration. But others deteriorate, often quite suddenly, developing a condition called acute respiratory distress syndrome ARDS. Oxygen levels in their blood plummet and they struggle ever harder to breathe. Their lungs are riddled with white opacities where black space—air—should be. Commonly, these patients end up on ventilators. Many die. Autopsies show their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells.

COVID is a viral sepsis. Sepsis is one of the oldest and most elusive syndromes in medicine. In , an international consensus panel defined sepsis as a systemic inflammatory response to infection, noting that sepsis could arise in response to multiple infectious causes. Thus, it was suggested that it was the host, not the germ, that drove the pathogenesis of sepsis 2. According to the third international consensus definitions for sepsis and septic shock sepsis-3 , sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

Acute organ dysfunction most commonly affects the respiratory and cardiovascular systems3. Respiratory compromise is classically manifested as the acute respiratory distress syndrome ARDS , which is defined as hypoxemia with bilateral infiltrates of noncardiac origin. COVID can attack almost anything in the body with devastating consequences. Understanding the rampage could help the doctors on the front lines treat the fraction of infected people who become desperately and sometimes mysteriously ill.

Taking a systems approach may be beneficial as we start thinking about therapies. A clear picture is elusive, as the virus acts like no microbe humanity has ever seen. We need to keep a very open mind as this phenomenon goes forward. Front Med. Chest ; Although this process may start locally at the point of initial entry of the virus, it evidently spreads systemically.

Hyperinflammation is like a tropical cyclone with its three evolutionary stages. If we evaluate the levels of cytokines and the inflammatory response that characterizes hemophagocytic lymphohistiocytosis, we would classify it from the meteorological point of view as a hurricane or a tropical storm, perhaps that is where the term cytokine storm comes from. It is true that the levels described in COVID are not the magnitude of a storm or hurricane, but neither are they slight elevations.

If we use the meteorological classification we could name it as a tropical depression. The use of Itolizumab reduced IL-6 in critically and severely ill patients and stabilizes its levels in moderately ill patients [2]. A study pending publication shows improvement in a group of clinical variables related to oxygenation and radiological imaging. In the author's opinion, the results achieved were related to: hygienic-epidemiological measures eg isolation of patients and contacts designed in close relationship between the health authority and the government [3], combined antiviral strategy including Interferon , antithrombotic prophylaxis and treatment of hyperinflammation Itolizumab, CIGB Cytokine increase storm or tropical depression as in meteorology must be modulated.

Research Square pre print. DOI: doi.