Managing Out of Control Inflammation: Weathering the Seas of an Advancing Cytokine Storm

Managing inflammation can be like weathering the seas of an advancing storm. Our immune system is intricately designed to help us safely weather response to an immune trigger. Like weather changes at sea, our immune response may take the form of gentle waves, high seas, or at times, it can reach a point of a raging storm. When our immune system rages out of control, it results in a turbulent immune system, termed a cytokine storm, leading to collateral tissue damage, and even risking organ function or survival. Akin to predicting and navigating a weather pattern, there can be ways to escape, mitigate, or survive the storm.

Cytokines are important proteins that act as messengers between cells and are critical to our immune function. Earlier, I described the role of Nf-Kappa B as the master of inflammation and trigger of production and release of cytokines. There are many different types of cytokines with many different functions. Examples of cytokines include interleukin, interferon, chemokines, lymphokines, and tumor necrosis factor (TNF). Normally, cytokines, when activated, will subside once the immune trigger subsides.

Cytokines are regulators of our response to infection, immune triggers, inflammation, and trauma. Some cytokines act to make disease worse (proinflammatory cytokines), whereas others serve to reduce inflammation and promote healing (anti-inflammatory cytokines). How cytokines behave is dependent on many different factors including the cytokine itself, the type of trigger, and our immune system capacity. Most often, cytokines act locally in a part of the body in response to a trigger, although in some cases, they may need to act systemically. When a cytokine response occurs in a regulated way, it is called adaptive.

A cytokine storm results from uncontrolled systemic inflammation, which happens when the immune system becomes unregulated, resulting in an overwhelming hyper-inflammatory, systemic immune response. When this happens, the pro-inflammatory cytokines exceed any counterbalance by anti-inflammatory ones. This can lead to massive destructive damage to organ tissues and overwhelming sepsis such as in the case of uncontrolled infection or disease.

Some cytokines play a role more significantly in acute versus chronic inflammation.¹²  Interestingly there are some overlapping inflammatory functions between acute infection, autoimmune disease, and cancer. One example is Interleukin 17 or IL-17 which plays an important role in managing infection as well as for contributing to inflammation in autoimmune diseases such as Rheumatoid Arthritis and Multiple Sclerosis.³ Cytokine targeting which is used in cancer therapy is thought to be potentially one possible answer to acute infection.⁴

So, where does inflammation and cytokine release go awry?

Inflammation is important to us in that it helps us fight an immune trigger. Regardless of whether a full-blown storm is in the wind, inflammation can lead to varying degrees of cytokine release in both acute and chronic inflammation. However, if inflammation is severe, it can become problematic.

In a previous article, I referenced several factors that can lead to the perfect storm for chronic inflammatory disease. While severe cytokine storms have most often been associated with acute inflammation due to certain types of infection, chronic inflammation in some cases can also activate a cytokine storm. While the definition of cytokine storm is not well-defined across different conditions, its effects can impact survival.⁵

Some conditions associated with chronic inflammation and cytokine release:

• Autoimmune Disease-As one example, in Celiac disease, exposure to gluten activates cytokines, which may become interesting markers to measure to diagnose disease or monitor response to treatment. ⁶
• Cancer-Elevated inflammatory responses are associated with increased cytokine levels, contributing to cancer progression.⁷
• Heart Disease: Several cytokines are involved in the development of various inflammatory cardiac pathologies, including ischemic heart disease, myocardial infarction, heart failure, and cardiomyopathies.⁸
• Diabetes: In diabetes, cytokine release leads to insulin resistance and is responsible for progression of the disease.⁹

Conditions associated with uncontrolled inflammation and cytokine storm:

• Certain Infections: Most infections do not lead to a cytokine storm. Some infections such as Influenza A, the 1918 Spanish Flu, and Covid-19 may lead to a cytokine storm.¹⁰
• Autoimmune Disease-Lupus or Juvenile Idiopathic Arthritis have been associated with a cytokine storm, which may also be called Mast Cell Activation.¹¹
• Cancer-Leukemia, Dysregulation of chronic inflammation and cytokines fosters both tumor growth and viral replication in Epstein-Barr Virus associated Nasopharyngeal cancer.¹²
• Genetic Disorders- Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%¹³   It can be a genetic or an acquired condition.
• Certain Therapies-Some immunotherapies. T-cell based therapies for leukemia have been associated with cytokine storm, can be life-threatening, although they may be predictive.^14,15

What are symptoms that may be associated with a cytokine storm?

• Fever
• Chills
• Malaise
• Headache
• Joint Pain
• Muscle Aches
• Cough
• Rash
• Shortness of breath
• Tremors
• Seizures
• Confusion/Hallucinations
• Poor responsiveness
• Low blood sugar

A variety of symptoms may occur. Significant symptoms, for example, seizures or confusion, or high fever should be addressed immediately. This is critical, as, with progressive symptoms of a cytokine storm, there can be decreasing blood pressure or the potential for abnormal clotting or respiratory failure.

Here are some tips to predict the weather and the advancing storm:

• Prevention– (aka how to stay off the high seas.) The first-line approach is to prevent disease. In the case of infection, it would be to limit exposure as well as to maintain a healthy immune system and immunity. Chronic disease prevention targets a healthy diet and lifestyle. Here are some tips to make sure your immune system is functioning well:
  • Vitamin D-Ask your provider to check your vitamin D levels. Many individuals are depleted in vitamin D. Vitamin D levels are simple to obtain.
  • Eat an anti-inflammatory diet
  • Check for Food Sensitivities if you have either gut or non-gut symptoms
  • If you have symptoms, know that this is not normal. A functional practitioner can help uncover hidden causes of metabolic stress that may be causing your symptoms and impacting your ability to have an intact immune system.
  • Manage your blood sugar-Blood sugar regulation is key to a healthy immune system. Obesity and insulin resistance can make your immune system less able to resist disease.
  • Manage stress-Stress is the number one cause of inflammation. Learning to manage stress is key. This is where a health coach can help you find ways of addressing stress whether it is emotional, physical or chemical.
• Mitigation-(aka how to recognize the advancing storm, stay afloat and weather the Storm). Once disease is present, whether infection or chronic disease, the goal is to manage inflammation.  
  • Work with a functional practitioner to address the root cause(s) of inflammation and promptly manage it.
  • A health coach or functional practitioner can help serve as a guide for developing healthy lifestyle and behavior changes to reduce inflammation.
  • Medication often may only provide temporary relief and does not address the underlying causes of inflammation.
• Survival-(How to avoid shipwreck). Recognizing symptoms of a cytokine storm can be challenging, as it begins with normal responses of inflammation to immune triggers. It is important, however, to use your intuition and good judgment on when to contact your provider or Emergency Medical Services, depending on the type and severity of the symptom(s). Early intervention and management is essential if a cytokine storm is brewing.

Summary

Inflammation leads to cytokine release and its release can be protective or mount into an uncontrollable storm. While inflammation initially serves a purpose to fight an immune trigger, depending on the trigger and the state of your immune system, it can subside, become chronic, or get totally out of control. At its worst, a cytokine storm can overwhelm our immune system leading to serious health conditions.

While a healthy lifestyle and behaviors can help set up an individual to have a healthy immune system, it is also important to understand how to mitigate symptoms to manage inflammation to prevent serious complications. Be a good captain of your ship and find the resources you need to help you keep your immune system functioning well.

Resources:

1.          Zuber Shaikh P. Cytokines & their physiologic and pharmacologic functions in inflammation: A review. Int J of Pharm & Life Sci (IJPLS). 2011;2(11).

2.          Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Frontiers in bioscience : a journal and virtual library. 1997;2. doi:10.2741/a171

3.          Kuwabara T, Ishikawa F, Kondo M, Kakiuchi T. The Role of IL-17 and Related Cytokines in Inflammatory Autoimmune Diseases. Mediators of Inflammation. 2017;2017. doi:10.1155/2017/3908061

4.          Amere Subbarao S. Cancer vs. SARS-CoV-2 induced inflammation, overlapping functions, and pharmacological targeting. Inflammopharmacology. 2021;29(2). doi:10.1007/s10787-021-00796-w

5.          Stolarski AE, Kim J, Zhang Q, Remick DG. Cytokine Drizzle-The Rationale for Abandoning “Cytokine Storm.” Shock (Augusta, Ga). 2021;56(5). doi:10.1097/SHK.0000000000001769

6.          Goel G, Daveson AJM, Hooi CE, et al. Serum cytokines elevated during gluten-mediated cytokine release in coeliac disease. Clinical and Experimental Immunology. 2020;199(1). doi:10.1111/cei.13369

7.          Chen DS, Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity. 2013;39(1):1-10. doi:10.1016/j.immuni.2013.07.012

8.          Bartekova M, Radosinska J, Jelemensky M, Dhalla NS. Role of cytokines and inflammation in heart function during health and disease. Heart Failure Reviews. 2018;23(5). doi:10.1007/s10741-018-9716-x

9.          Cieslak M, Cieslak M. Role of purinergic signalling and proinflammatory cytokines in diabetes. Clinical Diabetology. 2017;6(3). doi:10.5603/DK.2017.0015

10.        Hu B, Huang S, Yin L. The cytokine storm and COVID-19. Journal of Medical Virology. 2021;93(1). doi:10.1002/jmv.26232

11.        Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Frontiers in Immunology. 2019;10(FEB). doi:10.3389/fimmu.2019.00119

12.        Looi CK, Hii LW, Chung FFL, Mai CW, Lim WM, Leong CO. Roles of inflammasomes in epstein–barr virus-associated nasopharyngeal cancer. Cancers. 2021;13(8). doi:10.3390/cancers13081786

13.        Hansen S, Alduaij W, Biggs CM, et al. Ruxolitinib as adjunctive therapy for secondary hemophagocytic lymphohistiocytosis: A case series. European Journal of Haematology. 2021;106(5). doi:10.1111/ejh.13593

14.        Aldoss I, Khaled SK, Budde E, Stein AS. Cytokine Release Syndrome With the Novel Treatments of Acute Lymphoblastic Leukemia: Pathophysiology, Prevention, and Treatment. Current Oncology Reports. 2019;21(1). doi:10.1007/s11912-019-0753-y

15.        Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discovery. 2016;6(6). doi:10.1158/2159-8290.CD-16-0040