Understanding Cytokine Storms: When Your Immune System Becomes the Enemy

Table of Contents

• Introduction: What is a Cytokine Storm?
• Historical Background
• Defining Cytokine Storm
• Clinical Features and Symptoms
• Diagnosis and Laboratory Findings
• How Cytokine Storms Develop
• Causes and Triggers
• Treatment Approaches
• Clinical Implications for Patients
• Limitations and Challenges
• Patient Recommendations
• Source Information

Introduction: What is a Cytokine Storm?

The COVID-19 pandemic has highlighted the critical importance of a balanced immune response and the devastating effects when this system goes out of control. A cytokine storm represents one of the most dangerous immune system malfunctions—a life-threatening condition where the body produces excessive amounts of inflammatory proteins called cytokines, leading to widespread inflammation and organ damage.

This comprehensive review marks important anniversaries in our understanding of these dangerous immune reactions. It has been 10 years since the first description of a cytokine storm developing after chimeric antigen receptor (CAR) T-cell therapy (a cancer treatment that genetically modifies immune cells to attack cancer), and 27 years since the term was first used to describe a similar syndrome after bone marrow transplantation.

The term "cytokine release syndrome" was later coined to describe a comparable condition that occurred after treatment with the medication muromonab-CD3 (OKT3). Both cytokine storm and cytokine release syndrome represent dangerous systemic inflammatory conditions involving elevated levels of circulating cytokines and overactivation of immune cells that can be triggered by various treatments, infections, cancers, autoimmune conditions, and genetic disorders.

Historical Background

From a historical perspective, what we now call cytokine storm was previously referred to as an influenza-like syndrome that occurred after serious infections like sepsis and after early immunotherapies such as Coley's toxins (an early cancer treatment using bacterial extracts).

Even historical pandemics like the Black Death (caused by Yersinia pestis infection) triggered alveolar macrophages in the lungs to produce excessive cytokines, resulting in cytokine storm-like syndromes. Medical historians suspect that an exaggerated immune response contributed significantly to the lethality of the 1918-1919 influenza pandemic.

Researchers have found that a reconstructed H1N1 virus from the 1918 pandemic caused significantly more lung inflammation in mice compared to common reference strains of influenza A virus. This recognition that the immune response to a pathogen—not just the pathogen itself—can cause multiorgan damage led to investigating medications that modulate the immune system and target specific cytokines.

One of the earliest targeted therapies for calming a cytokine storm was tocilizumab, an anti-interleukin-6 receptor monoclonal antibody developed in the 1990s for treating idiopathic multicentric Castleman's disease (a rare disorder involving overgrowth of lymph nodes). Many other conditions have since been identified as causes of cytokine storm and treated with immune-directed therapies, including sepsis, primary and secondary hemophagocytic lymphohistiocytosis (HLH), autoinflammatory disorders, and COVID-19.

Defining Cytokine Storm

No single definition of cytokine storm or cytokine release syndrome is universally accepted, and there's disagreement about how these conditions differ from appropriate inflammatory responses. The National Cancer Institute's definition, based on the Common Terminology Criteria for Adverse Events, is considered too broad because its criteria for inflammatory syndrome can also apply to other physiological states.

The American Society for Transplantation and Cellular Therapy's definition focuses too specifically on doctor-induced (iatrogenic) causes of cytokine storm alone. While cytokine storm is easier to identify in conditions with elevated cytokine levels but no pathogens, the line between a normal and dysregulated response to a severe infection often remains blurry.

This is especially complicated because certain cytokines can be both helpful in fighting infections and harmful to the patient. The complex interplay between these inflammatory mediators further complicates distinguishing between normal and dysregulated immune responses.

The authors propose three essential criteria for identifying cytokine storm: (1) elevated circulating cytokine levels, (2) acute systemic inflammatory symptoms, and (3) either secondary organ dysfunction due to inflammation beyond what would be expected in a normal response to a pathogen (if a pathogen is present), or any cytokine-driven organ dysfunction (if no pathogen is present).

Clinical Features and Symptoms

Cytokine storm is an umbrella term covering several immune dysregulation disorders characterized by general symptoms, systemic inflammation, and multiorgan dysfunction that can progress to multiorgan failure if not properly treated. The onset and duration of cytokine storm vary depending on the cause and treatments administered.

Although the initial triggers may differ, the late-stage clinical manifestations of cytokine storm tend to converge and often overlap. Nearly all patients with cytokine storm develop fever, which may be very high in severe cases. Patients may also experience:

• Fatigue and extreme tiredness
• Loss of appetite
• Headaches
• Skin rashes
• Diarrhea
• Joint pain (arthralgia)
• Muscle pain (myalgia)
• Neuropsychiatric symptoms

These symptoms may result directly from cytokine-induced tissue damage, acute-phase physiological changes, or immune-cell-mediated responses. Cases can progress rapidly to serious complications including:

Disseminated intravascular coagulation with either blood vessel blockage or catastrophic bleeding, breathing difficulties, low oxygen levels, low blood pressure, imbalance in blood clotting systems, vasodilatory shock, and death. Many patients have respiratory symptoms including cough and rapid breathing that can progress to acute respiratory distress syndrome (ARDS), with low oxygen levels that may require mechanical ventilation with a breathing machine.

The combination of extreme inflammation, blood clotting problems, and low platelet counts places patients with cytokine storm at high risk for spontaneous bleeding. In severe cases, kidney failure, acute liver injury or cholestasis (reduced bile flow), and stress-related or takotsubo-like cardiomyopathy (a type of heart muscle weakness) can also develop.

The combination of kidney dysfunction, endothelial cell death, and acute-phase low albumin levels can lead to capillary leak syndrome and widespread swelling (anasarca)—changes similar to those seen in cancer patients treated with high-dose interleukin-2. Neurologic toxicity associated with T-cell immunotherapy is referred to as immune effector cell-associated neurotoxicity syndrome or cytokine release syndrome-associated encephalopathy. These neurologic effects are often delayed, developing several days after the cytokine storm begins.

Diagnosis and Laboratory Findings

The laboratory findings in cytokine storm are variable and influenced by the underlying cause. Nonspecific markers of inflammation such as C-reactive protein (CRP) are universally elevated and correlate with severity. Many patients have high triglyceride levels and various blood count abnormalities, such as:

• Increased white blood cells (leukocytosis) or decreased white blood cells (leukopenia)
• Anemia (low red blood cells)
• Thrombocytopenia (low platelets)
• Elevated ferritin and d-dimer levels

Changes in circulating cell counts likely result from a complex interaction between cytokine-induced changes in production and mobilization of cells from bone marrow, immune-mediated destruction, and chemokine-induced migration. Significant elevations in serum inflammatory cytokine levels are usually present, including:

Interferon-γ (or CXCL9 and CXCL10, chemokines induced by interferon-γ), interleukin-6, interleukin-10, and soluble interleukin-2 receptor alpha (a marker of T-cell activation). Highly elevated serum interleukin-6 levels are found in CAR T-cell therapy-induced cytokine storm and several other cytokine storm disorders.

The approach to evaluating a patient with suspected cytokine storm should accomplish three main goals: identifying the underlying disorder (while ruling out conditions that may mimic cytokine storm), establishing severity, and determining the clinical trajectory. A complete workup for infection should be performed in all suspected cases, along with laboratory assessment of kidney and liver function.

Measurements of inflammatory acute-phase biomarkers such as CRP and ferritin, and blood counts should be obtained since they correlate with disease activity. Arterial blood gas measurement should be performed if respiratory evaluation warrants it. Cytokine profiles may be helpful in determining trends from baseline values, though these results are typically not available quickly enough to guide immediate treatment decisions.

Establishing the specific disorder underlying the cytokine storm can be challenging. Cytokine storm is not a diagnosis of exclusion, and it can encompass many disorders. For example, patients may have both sepsis and cytokine storm simultaneously. It's particularly important to distinguish between cytokine storm due to an iatrogenic cause like CAR T-cell therapy and cytokine storm due to systemic infection, since immunosuppressive treatments could be harmful if used in patients with bloodstream infections.

Unfortunately, it's difficult to distinguish cytokine storm due to sepsis from cytokine storm due to CAR T-cell therapy based on clinical features alone. Levels of serum cytokines—most prominently, interferon-γ—are often more elevated in patients with cytokine storm due to CAR T-cell therapy than in patients with sepsis-induced cytokine storm, who often have higher levels of circulating interleukin-1β, procalcitonin, and markers of endothelial damage.

Thus, combinations of tests to rule out infection and measure serum cytokines can help identify the cause of the cytokine storm. However, CAR T-cell therapy and other noninfectious causes can also occur with infections, and infections can develop during therapy, so continued monitoring for infections is essential. Conditions that should be ruled out when considering cytokine storm include anaphylaxis and physiological responses to microbial infections.

The grading systems used to predict and assess the severity of cytokine storm differ according to the cause. Serum biomarkers, including glycoprotein 130 (gp130), interferon-γ, and interleukin-1-receptor antagonist (IL1RA), can be used to predict the severity of cytokine storm induced by CAR T-cell therapy, with a separate grading scale used to assess current severity.

HScore and MS score are used for classifying HLH-associated cytokine storm, and HLH-2004 guides treatment. For grading cytokine storm due to other causes, the immune systems disorders section of CTCAE is used.

How Cytokine Storms Develop

Inflammation involves biological mechanisms that evolved in multicellular organisms to contain invasive pathogens and resolve injuries by activating innate and adaptive immune responses. The immune system is designed to recognize foreign invaders, respond proportionally to the pathogen burden, and then return to balance (homeostasis).

This response requires a careful balance between producing enough cytokines to eliminate the pathogen while avoiding a hyperinflammatory response where excessive cytokines cause significant collateral damage. Cytokines play a key role in coordinating antimicrobial effector cells and providing regulatory signals that direct, amplify, and resolve the immune response.

Cytokines normally have short half-lives, which prevents them from having effects outside lymphoid tissue and inflammation sites. While typically considered pathological, sustained cytokine production leading to elevated circulating levels may sometimes be necessary to appropriately control certain widespread infections. At increased levels, cytokines can have systemic effects and cause collateral damage to vital organ systems.

Immune hyperactivation in cytokine storm can occur due to inappropriate triggering or danger sensing, with a response initiated without a pathogen present (as in genetic disorders involving inappropriate inflammasome activation or idiopathic multicentric Castleman's disease). It can also result from an inappropriate or ineffective amplitude of response, involving excessive effector immune-cell activation (as in cytokine storm due to CAR T-cell therapy), overwhelming pathogen burden (as in sepsis), or uncontrolled infections and prolonged immune activation (as in HLH associated with Epstein-Barr virus).

Another mechanism is failure to resolve the immune response and return to homeostasis (as in primary HLH). In each of these states, there is a failure of negative feedback mechanisms that normally prevent hyperinflammation and overproduction of inflammatory cytokines and soluble mediators. The excessive cytokine production leads to hyperinflammation and multiorgan failure.

Regulatory cell types, decoy receptors for proinflammatory cytokines such as IL1RA, and antiinflammatory cytokines such as interleukin-10 are important for counteracting inflammatory-cell populations and preventing immune hyperactivity.

The authors emphasize that cytokine storm involves an immune response that causes collateral damage that may be greater than the immediate benefit of the immune response. Thus, an exuberant inflammatory response to a large pathogen burden may be appropriate for controlling the infection if excessive secondary organ dysfunction does not occur.

Similarly high levels of cytokines in cancer-associated HLH or idiopathic multicentric Castleman's disease would be considered a pathologic state of cytokine storm because no pathogen requiring an immune response is involved, and patients benefit from treatment with cytokine neutralization and other antiinflammatory agents.

Causes and Triggers

Cytokine storms can be triggered by multiple factors falling into several categories:

• Iatrogenic causes: Doctor-induced causes including CAR T-cell therapy, blinatumomab (a bispecific T-cell engager immunotherapy), other T-cell engaging immunotherapies, and gene therapies
• Pathogen-induced triggers: Infections including bacterial sepsis, Epstein-Barr virus-associated HLH, and COVID-19
• Monogenic and autoimmune disorders: Genetic and autoimmune conditions such as autoinflammatory disorders and primary or secondary HLH
• Cancer: Certain malignancies can trigger cytokine storm syndromes

The cells involved in driving cytokine storms include adaptive T cells (CD4+, CD8+) and innate antigen-presenting cells (macrophages, dendritic cells). These cells can become overactivated through various pathways and signaling mechanisms that normally help regulate immune responses but become dysregulated during cytokine storms.

Treatment Approaches

Treatment approaches for cytokine storm target different aspects of the hyperinflammatory response. Several targeted therapies have been developed including:

• Tocilizumab: An anti-interleukin-6 receptor antibody
• Emapalumab: An anti-interferon-γ antibody
• Anakinra: An interleukin-1 receptor antagonist
• Infliximab: A tumor necrosis factor inhibitor
• Siltuximab: An anti-interleukin-6 antibody
• JAK inhibitors: Medications that block Janus kinase pathways
• Glucocorticoids: Broad anti-inflammatory steroids
• Sirolimus: An mTOR inhibitor that modulates immune responses

These treatments work by interrupting specific signaling pathways involved in the excessive immune activation, including MAPK, NF-κB, JAK-STAT3, and mTOR pathways. The choice of treatment depends on the underlying cause of the cytokine storm, the specific cytokines involved, and the patient's overall condition.

Clinical Implications for Patients

For patients, recognizing the potential for cytokine storm is important because it has significant implications for prognosis and treatment. Conditions that might predispose to cytokine storm include certain cancers, autoimmune disorders, genetic immune conditions, and patients undergoing specific immunotherapies.

The COVID-19 pandemic has particularly highlighted the importance of cytokine storm, as many severe COVID-19 cases involve this hyperinflammatory response. Patients and healthcare providers should be aware of the signs and symptoms of cytokine storm, especially in contexts where triggering factors are present.

Early recognition and appropriate treatment are crucial since cytokine storm can progress rapidly to multiorgan failure and death if not managed promptly. The improved outcomes with cytokine-targeted therapies support the pathological role of excessive cytokines and help confirm the diagnosis of cytokine storm.

Limitations and Challenges

Several challenges remain in the diagnosis and management of cytokine storms. Circulating cytokine levels can be difficult to measure because cytokines have short half-lives, circulating levels may not accurately reflect local tissue levels, and these measurements may not be readily available worldwide.

The authors do not propose specific thresholds for elevations in cytokine levels above the normal range, and they don't recommend specific cytokine panels or list particular cytokines whose levels must be elevated, given the lack of available evidence. This represents an important area for future research that could benefit from systematic assessment by a multidisciplinary consortium.

Another limitation is that lack of response to cytokine-targeted treatment doesn't necessarily rule out cytokine storm, because underlying conditions likely play a role, a different cytokine may be driving the disease, or the timing of treatment may have been suboptimal.

Distinguishing between a appropriate inflammatory response to a severe infection and a pathological cytokine storm remains challenging, particularly since some overlap exists between these states. This difficulty highlights the need for better diagnostic tools and clearer classification criteria.

Patient Recommendations

For patients who may be at risk for cytokine storm or who are experiencing concerning symptoms, several recommendations emerge from this research:

1. Seek immediate medical attention if you develop high fever along with symptoms like difficulty breathing, confusion, severe fatigue, or multiple symptoms affecting different organ systems, especially if you have underlying conditions or are undergoing treatments that might predispose to cytokine storm.
2. Inform healthcare providers about any recent treatments, particularly immunotherapies or new medications, as this history is crucial for accurate diagnosis.
3. Be aware that cytokine storms can develop rapidly, so timely medical evaluation is essential when concerning symptoms appear.
4. Understand that diagnostic testing will likely include blood tests for inflammatory markers, organ function tests, and possibly infection screening.
5. Know that treatment approaches have advanced significantly, with targeted therapies available that can specifically address the hyperinflammatory response in many cases.

For patients undergoing treatments known to potentially trigger cytokine storms (such as CAR T-cell therapy), close monitoring and prompt reporting of symptoms to healthcare providers is essential for early detection and management.

Source Information

Original Article Title: Cytokine Storm
Authors: David C. Fajgenbaum, MD and Carl H. June, MD
Publication: The New England Journal of Medicine, December 3, 2020
DOI: 10.1056/NEJMra2026131

This patient-friendly article is based on peer-reviewed research originally published in The New England Journal of Medicine. It has been adapted to make complex medical information more accessible while preserving all essential facts, data, and clinical implications from the original scientific publication.