In immunology, cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction.

The term cytokine storm is often used interchangeably with CRS but, despite the fact that they have similar clinical phenotype, their characteristics are different. When occurring as a result of a therapy, CRS symptoms may be delayed until days or weeks after treatment. Immediate-onset CRS is a cytokine storm, although severe cases of CRS have also been called cytokine storms.

Signs and symptoms
Symptoms include fever that tends to fluctuate, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rashes, fast breathing, rapid heartbeat, low blood pressure, seizures, headache, confusion, delirium, hallucinations, tremor, and loss of coordination.

Lab tests and clinical monitoring show low blood oxygen, widened pulse pressure, increased cardiac output (early), potentially diminished cardiac output (late), high levels of nitrogen compounds in the blood, elevated D-dimer, elevated transaminases, factor I deficiency and excessive bleeding, higher-than-normal level of bilirubin.

Cause
CRS occurs when large numbers of white blood cells, including B cells, T cells, natural killer cells, macrophages, dendritic cells, and monocytes are activated and release inflammatory cytokines, which activate more white blood cells in a positive feedback loop of pathogenic inflammation. Immune cells are activated by stressed or infected cells through receptor-ligand interactions.

This can occur when the immune system is fighting pathogens, as cytokines produced by immune cells recruit more effector immune cells such as T-cells and inflammatory monocytes (which differentiate into macrophages) to the site of inflammation or infection.  In addition, pro-inflammatory cytokines binding their cognate receptor on immune cells results in activation and stimulation of further cytokine production. This process, when dysregulated, can be life-threatening due to systemic hyper-inflammation, hypotensive shock, and multi-organ failure. 

Adoptive cell transfer of autologous T-cells modified with chimeric antigen receptors (CAR-T cell therapy) also causes CRS. Serum samples of patients with CAR-T associated CRS have elevated levels of IL-6, IFN-γ, IL-8 (CXCL8), IL-10, GM-CSF, MIP-1α/β, MCP-1 (CCL2), CXCL9, and CXCL10 (IP-10). The most predictive biomarkers 36h after CAR-T infusion of CRS are a fever ≥38.9 °C (102 °F) and elevated levels of MCP-1 in serum. Many of the cytokines elevated in CRS are not produced by CAR-T cells, but by myeloid cells that are pathogenically licensed through T-cell-mediated activating mechanisms. For example, in vitro co-culture experiments have demonstrated IL-6, MCP-1, and MIP-1 are not produced by CAR-T cells, but rather by inflammatory myeloid lineage cells. In vivo models have demonstrated NSG (NOD/SCID/γ-chain deficient mice) with defects of both lymphocyte and myeloid lineage compartments do not develop CRS after CAR-T cell infusion.

In addition to adoptive T-cell therapies, severe CRS or cytokine reactions can occur in a number of infectious and non-infectious diseases including graft-versus-host disease (GVHD), coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), sepsis, Ebola, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS).

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sufficiently cleared by the early acute phase anti-viral response in most individuals, some progress to a hyperinflammatory condition, often with life-threatening pulmonary involvement. This systemic hyperinflammation results in inflammatory lymphocytic and monocytic infiltration of the lung and the heart, causing ARDS and cardiac failure. Patients with fulminant COVID-19 and ARDS have classical serum biomarkers of CRS including elevated CRP, LDH, IL-6, and ferritin.

Hemophagocytic lymphohistiocytosis and Epstein-Barr virus-related hemophagocytic lymphohistiocytosis are caused by extreme elevations in cytokines and can be regarded as one form of severe cytokine release syndrome.

Medications
Cytokine reaction syndrome may also be induced by certain medications, such as the CD20 antibody rituximab and the CD19 CAR T cell tisagenlecleucel. The experimental drug TGN1412—also known as Theralizumab—caused extremely serious symptoms  when given to six participants in a Phase I trial. A controlled and limited CRS is triggered by active fever therapy with mixed bacterial vaccines (MBV) according to Coley; it is used for oncological and certain chronic diseases. CRS has also arisen with biotherapeutics intended to suppress or activate the immune system through receptors on white blood cells.  Muromonab-CD3, an anti-CD3 monoclonal antibody intended to suppress the immune system to prevent rejection of organ transplants; alemtuzumab, which is anti-CD52 and used to treat blood cancers as well as multiple sclerosis and in organ transplants; and rituximab, which is anti-CD20 and used to treat blood cancers and auto-immune disorders, all cause CRS.

Diagnosis
CRS needs to be distinguished from symptoms of the disease itself and, in the case of drugs, from other adverse effects—for example tumor lysis syndrome requires different interventions. As of 2015, differential diagnoses depended on the judgement of doctor as there were no objective tests.

Classification
CRS is a form of systemic inflammatory response syndrome and is an adverse effect of some drugs.

The Common Terminology Criteria for Adverse Events classifications for CRS as of version 4.03 issued in 2010 were:

Prevention
Severe CRS caused by some drugs can be prevented by using lower doses, infusing slowly, and administering anti-histamines or corticosteroids before and during administration of the drug.

In vitro assays have been developed to understand the risk that pre-clinical drug candidates might cause CRS and guide dosing for Phase I trials, and regulatory agencies expect to see results of such tests in investigational new drug applications.

A modified Chandler loop model can be used as a preclinical tool to assess infusion reactions.

Management
Treatment for less severe CRS is supportive, addressing the symptoms like fever, muscle pain, or fatigue. Moderate CRS requires oxygen therapy and giving fluids and antihypotensive agents to raise blood pressure. For moderate to severe CRS, the use of immunosuppressive agents like corticosteroids may be necessary, but judgment must be used to avoid negating the effect of drugs intended to activate the immune system.

Tocilizumab, an anti-IL-6 monoclonal antibody, was FDA approved for steroid-refractory CRS based on retrospective case study data.

Lenzilumab, an anti-GM-CSF monoclonal antibody, is also clinically proven to be effective at managing cytokine release by reducing activation of myeloid cells and decreasing the production of IL-1, IL-6, MCP-1, MIP-1, and IP-10.  Additionally, as a soluble cytokine blockade, it will not increase serum levels of GM-CSF (a phenomenon seen with tocilizumab and IL-6).

Although frequently used to treat severe CRS in people with ARDS, corticosteroids and NSAIDs have been evaluated in clinical trials and have shown no effect on lung mechanics, gas exchange, or beneficial outcome in early established ARDS.

Epidemiology
Severe CRS is rare. Minor and moderate CRS are common side effects of immune-modulating antibody therapies and CAR-T therapies.

Research
Key therapeutic targets to abrogate hyper-inflammation in CRS are IL-1, IL-6, and GM-CSF. An in vivo model found that GM-CSF knockout CAR-T cells do not induce CRS in mice. However, IL-1 knockout and IL-6 knockout hosts (whose myeloid cells are deficient in IL-1 and IL-6, respectively) were susceptible to CRS after the administration of wild-type CAR-T cells. It is thought this may be because while blockade of IL-1 and IL-6 are myeloid-derived cytokines are thus too far downstream of the inflammatory cascade. Moreover, while tocilizumab (anti-IL-6R monoclonal antibody) may have an anti-inflammatory and antipyretic effect, it has been shown to increase serum levels of IL-6 by saturating the receptor, thus driving the cytokine across the blood brain barrier (BBB) and worsening neurotoxicity. Monoclonal antibody blockade of GM-CSF with lenzilumab has been demonstrated to protect mice from CAR-T associated CRS and neurotoxicity while maintaining anti-leukemic efficacy.

See also 
 Macrophage activation syndrome
 sHLH

References 

Immune system disorders
Syndromes affecting immunity
Immunology
사이토카인 방출 증후군( - 放出 症候群, ) 또는 심한 경우 사이토카인 폭풍( - 暴風, )은 감염이나 특정 약물 등 다양한 요인에 의해 유발될 수 있는 전신 염증 반응 증후군의 일종이다.  사이토카인 방출 증후군은 많은 수의 백혈구가 활성화되고 염증성 사이토카인을 방출할 때 발생하며, 이는 다시 더 많은 백혈구를 활성화시킨다. 또한 사이토카인 방출 증후군은 일부 단클론항체 약물 뿐만 아니라 면역항암요법의 부작용으로 나타날 수도 있다. 약물 투여의 결과로 발생하는 경우는 주입물 반응(infusion reaction)이라 한다.

징후 및 증상 
증상으로는 발열, 피로, 식욕부진, 근육통 및 관절통, 구역, 구토, 설사, 발진, 빠른 호흡, 빠른 심장 박동, 저혈압, 발작, 두통, 혼란, 섬망, 환각이 있다. 

실험적 검사 및 임상 모니터링으로 나타난 증상은 저혈압, 맥박 증가, 심박출량 증가(초기), 심박출량 감소(후기), 고질소혈증, 높은 아미노 전이 효소, 인자 I 결핍, 과다출혈, 정상보다 높은 빌리루빈 수치가 있다.

원인 
사이토카인 방출 증후군은 B세포, T세포, 자연 살해 세포, 대식세포, 수지상 세포, 단핵구 등 백혈구가 대거 활성화되어 염증성 사이토카인을 분비할 때 발생하는데, 이는 결국 백혈구를 활성화시키면서도 더 많은 백혈구를 활성화시킨다. 이 세포들은 세포자살이나 괴사로 죽는 감염된 세포들에 의해 활성화된다. 

이것은 면역 체계가 병원체와 싸울 때 발생할 수 있는데, 사이토카인은 T세포나 대식세포와 같은 면역세포를 감염 현장으로 이동시키기 위해 신호를 보내기 때문이다. 게다가 사이토카인은 그러한 세포들을 활성화시켜 더 많은 사이토카인을 생산하도록 자극한다. 

또한 사이토카인 방출 증후군은 백혈구 수용체를 통해 면역체계를 억제하거나 활성화하기 위한 생체의약품으로도 생겨났다. 장기 이식의 거부를 막기 위해 면역체계를 억제하기 위한 목적으로 고안된 항체인 뮤로모나브-CD3, 항 CD52인 알렘투주맙, 다발성 경화증 및 장기 이식에 사용되는 혈액암 및 자가 면역 장애 치료에 사용되는 리툭시맙이 대표적인 예이다. 키메르 항원 수용체(CAR-T)로 변형된 T세포를 채택한 수용체 T세포 치료법도 사이토카인 방출 증후군을 유발한다. 

인터루킨 6은 사이토카인 방출 증후군의 주요 매개자인 것으로 본다. 

심각한 사이토카인 방출 증후군은 이식편대숙주병 (GVHD), 급성호흡곤란증후군 (ARDS), 패혈증, 에볼라 출혈열, 조류 인플루엔자, 천연두, 코로나19 및 전신 염증 반응 증후군을 포함한 다수의 감염성 및 비 감염성 질환에서 발생할 수 있다. Hemophagocytic lymphohistiocytosis 및 Epstein-Barr 바이러스 관련 hemophagocytic lymphohistiocytosis는 사이토카인의 극심한 상승에 의해 발생하며 심각한 사이토카인 방출 증후군의 한 형태로 간주 될 수 있다. 또한 사이토카인 반응 증후군은 CD20 항체 키툭시맙 및 CD19 CAR-T 세포 Tisagenlecleucel과 같은 특정 약물에 의해 유도 될 수 있다. Theralizumab으로도 알려진 실험용 약물 TGN1412는 임상 시험에서 6명의 참가자에게 주어졌을 때 매우 심각한 증상을 일으켰다.

진단 
사이토카인 방출 증후군은 질병 자체의 증상과 구별되고 약물의 경우 다른 부작용과 구별되어야한다. 예를 들어 종양 용해 증후군은 다른 치료 방법이 필요하다.

분류 
사이토카인 방출 증후군은 전신 염증 반응 증후군의 한 형태이며 일부 약물의 부작용이다. 

2010년에 발행된 4.03 버전의 사이토카인 방출 증후군에 대한 유해 사건 분류에 대한 공통 용어 기준은 다음과 같다.

예방 
약물 투여 전후에 저용량을 사용하고 천천히 주입하며 항히스타민제나 코르티코스테로이드를 투여하면 일부 약물로 인한 심한 사이토카인 방출 증후군을 예방할 수 있다.

조치 
심각하지 않은 사이토카인 방출 증후군의 치료는 발열, 근육통, 피로 등의 증상을 줄일 수 있는 치료를 동원해야 한다. 심각한 사이토카인 방출 증후군은 산소 흡입이 필요하며 혈압을 높이기 위해 수액과 항고혈압제를 투여해야 한다. 또한 코르티코스테로이드와 같은 면역억제제를 사용해야 할 수도 있지만, 면역계를 활성화시키기 위한 약물의 효과를 부정하지 않도록 판단해야 한다. 

항 IL6 단클론항체인 토실리주맙은 일부 병원에서 심각한 사이토카인 방출 증후군을 치료하기 위해 사용되었다.

급성호흡곤란증후군 환자에서 심한 사이토카인 방출 증후군을 치료하는 데 자주 사용되지만, 코르티코스테로이드 및 비스테로이드 항염증제는 임상시험에서 평가되었으며 폐 역학, 가스 교환 또는 초기에 확립된 급성호흡곤란증후군에서 유리한 결과에 영향을 미치지 않는다.

역학 
심각한 사이토카인 방출 증후군은 드물다. 경미한 사이토카인 방출 증후군은 면역 조절 항체 요법 및 CAR-T 요법의 일반적인 부작용이다.

각주 

면역 장애