Cytokine storm is a special severe form of systemic inflammatory reaction characterized by excessive activation of immunocompetent cells, the production of a large number of inflammatory cytokines. It can develop with sepsis, viral infections (influenza, coronavirus infection, Ebola fever), rejection of a transplanted organ, etc. The main clinical manifestations include fever, pain in the head, lumbar region, difficulty breathing. The diagnosis is established when a high concentration of cytokines in the serum is detected – TNF-α, IL-6, IFN-γ. Monoclonal antibodies, interleukin blockers, and immunoglobulin are used as treatment.
General information
The term “cytokine storm” (syn. cytokine storm, hypercytokinemia) was first used by the American hematologist-oncologist James Ferrara in 1993 when studying the transplant rejection reaction. In most cases, hypercytokinemia carries a much more serious danger to human life than the disease against which it developed. Hypercytokinemia is associated with severe forms of diseases and is itself considered a predictor of an unfavorable prognosis. Cytokine storm is a rare phenomenon, there are no accurate epidemiological data on its prevalence.
Causes
To date, despite numerous studies, the exact etiological factor triggering the cascade of pathological reactions of the cytokine storm has not been established. It is assumed that the immediate cause of cytokine release is the activation of Toll-like receptors (TLR) of mononuclear cells.
The role of genetic predisposition (for example, overexpression of receptors on the surface of immune cells) is not excluded. The following are diseases and conditions in which potentially fatal hypercytokinemia may occur:
- Viral infections. Quite often, cytokine storm occurs with prolonged complicated forms of avian influenza (H5N1), swine flu (H1N1). The most urgent problem at present is hypercytokinemia in severe form of coronavirus infection COVID-19, occurring with pneumonia and respiratory failure. It is with the development of a cytokine storm that fatal cases of this disease are associated.
- Sepsis and septic shock. An increase in the level of cytokines is considered one of the main links of pathogenesis in the generalization of bacterial, fungal infections – staphylococcal, streptococcal, candidiasis.
- Oncological diseases. Cytokine storm can be observed at the terminal stages of oncohematological diseases – leukemias, lymphomas.
- Organ transplantation. Hypercytokinemia underlies the rejection of the transplanted organ, the “graft versus host” reaction during transplantation of hematopoietic stem cells of the bone marrow.
- In vitro fertilization. Activation of T-lymphocytes, NK cells with excessive cytokine production can be observed after artificial insemination (implantation of embryos into the uterine wall) and cause miscarriages or premature birth.
- Other causes: acute pancreatitis with pancreonecrosis, hepatic encephalopathy, severe forms of bronchial asthma resistant to therapy with glucocorticoids and bronchodilators. In these diseases, cytokine storm is extremely rare.
Pathogenesis
Cytokines are proteins that are synthesized by immune cells (lymphocytes, macrophages, NK cells). They perform a regulatory function, control the processes of inflammation, immune response to foreign antigens, also take part in hemostasis, in maintaining microcirculation. However, their excessive amount has an extremely toxic effect on almost all organs and tissues.
A large number of cytokines and pro-inflammatory mediators take part in the development of the cytokine storm, but the leading role in the pathogenesis is played by tumor necrosis factor alpha TNF-α, gamma interferon IFN-γ, interleukin-6 (IL-6). There is no consensus on the cascade of pathological reactions in cytokine storm, active discussions are still underway among specialists and researchers.
Upon contact with a foreign antigen, macrophages and endothelial cells begin to produce interleukin-6, which causes activation of T-lymphocytes and other immune cells, their migration to the focus of inflammation. Activated lymphocytes, in turn, synthesize TNF and interferon. Also, under the influence of interleukin, the formation of collagenases, metalloproteinases, and neutral proteases is triggered.
As a result of the increase in cytokine levels, vascular permeability increases, damage to the vascular wall, cell membranes, systemic microcirculation disorders and intravascular thrombosis occur. The production of adenosine triphosphate is suppressed in the cells, which causes a hypoenergetic state.
The “vicious circle” lies in the mechanism of positive feedback, i.e. the formation of cytokines and the activation of immunocompetent cells leads to the activation of other cells of the immune system, the synthesis of other cytokines. The process takes on a generalized character, which often causes multiple organ failure. Other researchers associate the development of a cytokine storm with a reduced serum content of anti-inflammatory cytokines (IL-1Ra, IL-10) and activation of lymphocyte receptors by peroxisomes (PPAR).
Symptoms
The clinical picture is quite bright and diverse. Symptoms occur fairly quickly. First, non–specific signs appear – high fever, headache, myalgia. Then nausea, vomiting, diarrhea are added. Patients become restless. Heart rate increases, blood pressure decreases. In patients with a viral infection of the respiratory tract, dry cough worsens and becomes debilitating. Breathing becomes much more difficult.
A characteristic symptom is an increase in the size of the neck due to swelling of subcutaneous fat, which is associated with a sharp increase in vascular permeability. Some patients complain of aching or dull pain in the lower back, a decrease in the volume of urination. Skin rashes are possible. Some patients develop confusion, hallucinations, epileptiform seizures.
Complications
Cytokine storm has a wide range of adverse effects. The respiratory system suffers most often – the vast majority of patients with severe forms of COVID-19 and influenza have acute respiratory distress syndrome with respiratory insufficiency, requiring immediate connection to a ventilator. Due to severe damage to the kidneys, the liver develops renal failure, liver failure with encephalopathy.
Possible myocardial infarction and acute heart failure and cardiogenic shock. In some patients, there is a simultaneous lesion of several organs – multiple organ failure. A frequent complication is disseminated intravascular coagulation syndrome, which is characterized by a combination of thrombosis and massive bleeding.
Diagnostics
Due to the severe somatic status, patients with cytokine storm are supervised by resuscitators. Also, according to the main disease, these patients are observed by infectious diseases specialists, therapists. A combination of the clinical picture and anamnestic information helps to suspect this condition. Laboratory predictors of the onset of a cytokine storm are extremely high serum markers of inflammation – erythrocyte sedimentation rate, C-reactive protein, ferritin.
Patients with respiratory disorders, especially with symptoms of COVID-19, must undergo auscultation and percussion of the lungs, the level of oxygen saturation of the blood (saturation) is measured using a pulse oximeter. An additional examination is also prescribed, including:
- Blood test. In the blood test, there is a decrease in the total level of leukocytes, absolute lymphopenia, anemia, thrombocytopenia are possible. Biochemical analysis often reveals an increase in the content of hepatic transaminases (ALT, AST), total bilirubin, urea, creatinine. In sepsis, indicators of procalcitonin and presepsin are measured.
- Determination of cytokines. High concentrations of IL-6, TNF-α, and IFN-γ are detected by electrochemiluminescence analysis.
- Identification of the pathogen. If a viral infectious disease is suspected, a smear is taken from the pharynx and nasal cavity for further PCR analysis and determination of SARS-CoV-2 RNA, influenza virus RNA. To confirm sepsis, a 3-fold bacteriological blood culture is performed.
- Coagulogram. Changes in both hypercoagulation and hypocoagulation can be detected (depending on the stage of DIC syndrome). Such indicators as D-dimer, prothrombin time, activated partial thromboplastin time are investigated.
- Gas blood test. In many patients, there is a decrease in the partial pressure of oxygen (PaO2) in arterial blood (hypoxemia), a shift in the pH of the blood to the acidic side (acidosis).
- Radiation diagnostics. During x-ray or computed tomography of the chest organs, infiltrates in the lungs, areas of darkening, a picture of “frosted glass” are detected.
Cytokine storm has a similar pathogenesis and clinical course with some conditions from which it needs to be distinguished. These include hemophagocytic lymphohistiocytosis (macrophage activation syndrome), which develops in rheumatological patients, especially in juvenile rheumatoid arthritis, and cytokine release syndrome, an iatrogenic condition that occurs as a response to the introduction of genetically engineered biological drugs.
Treatment
All patients should be hospitalized in the intensive care unit or intensive care unit. When the saturation level is low, the patient is connected to artificial lung ventilation. To reduce the frequency of deaths, regardless of the cause, the following drugs are used to reduce the severity of the cytokine storm:
Targeted therapy. Monoclonal antibodies to IL-6 – tocilizumab, sarilumab are considered the most effective in suppressing multi-organ damage caused by hypercytokinemia. Also effective were janus kinase inhibitors (JAK kinases) – baricitinib, tofacitinib. If they are ineffective, antagonists IL-6 and IL-1 – olokizumab, RPH-104 are used.
- Glucocorticosteroids. In order to reduce excessive activation of the immune system, glucocorticoids (dexamethasone, methylprednisolone) are added to the treatment regimen
- Intravenous immunoglobulin. Having an immunosuppressive effect, human immunoglobulin for intravenous administration is able to suppress the biological effects of cytokines.
It should be remembered that these drugs have an inhibitory effect on several parts of the immune system, so their use is associated with an increased risk of secondary infection, most often bacterial. In addition to the “anti-cytokine treatment”, the following therapy is carried out:
- Antiviral. For influenza, neuraminidase inhibitors, oseltamivir, are prescribed. For the treatment of COVID-19, drugs for the treatment of HIV infection and viral hepatitis are used – recombinant interferon, lopinavir, ritonavir.
- Antibacterial. For sepsis, a combination of 2 or 3 antibiotics from different groups is recommended – amoxicillin, gentamicin, levofloxacin.
- Correction of DIC syndrome. In the case of hypercoagulation, anticoagulants are needed to prevent thrombosis – heparin, rivaroxaban. With hypocoagulation, hemostatics (aminocaproic acid, ethamzylate) and transfusion of freshly frozen plasma are prescribed.
- Fighting hypotension and shock. With a marked decrease in blood pressure, vasopressors (norepinephrine, dopamine) and cardiotonics (dobutamine) are administered to the patient.
Prognosis and prevention
Cytokine storm is an extremely serious condition characterized by high mortality. With COVID-19, more than 70% of deaths occur as a result of this disorder. The main causes of death are acute respiratory or multiple organ failure, thrombotic complications within the framework of DIC syndrome.
Due to the fact that the etiological factor provoking the occurrence of a cytokine storm has not been established, there are no effective methods of prevention. The main measures to prevent hypercytokinemia are reduced to timely diagnosis and competent treatment of those diseases in which this condition develops. To reduce fatality, it is necessary to apply targeted therapy as early as possible.
