by: Shalla Newton MSN, RN, NE-BC and David Maher
We have been absolutely overwhelmed by the outpouring of support and responses from patients, family members/care-givers and rheumatology experts! Our target audience has responded saying they feel heard and better equipped with the science behind the complexity of Still’s disease. We are excited to be collaborating with a great start-up partnered with a large advocacy organization. We will be participating in some biopharma discussions as well.
In this post we’re going to get meteorological with a discussion of all things cytokine storms and we wrap it up relating all this information to COVID-19, including the pediatric mystery post-viral syndrome.
Due to recent global events with the COVID-19 pandemic and related confusion from the virus causing a systemic immune response known as a cytokine storm, we felt it was the right time to talk about Still’s disease-related cytokine storms and the related complication of Macrophage Activation Syndrome (MAS).
We briefly introduced you to cytokine storms and MAS in our post on AOSD in regards to Still’s and cytokine storm complications.You can also read our backstories as patients affected by cytokine storms.
Our pediatric partners with Still’s disease, Systemic Juvenile Idiopathic Arthritis (SJIA), have well reported incidences of MAS. Thus, SJIA related MAS fosters a greater research presence with active clinical treatment trials. The AOSD population also suffers from MAS activity, but research has been focused primarily on the SJIA population. It is arguable that the lack of research on AOSD-MAS has created a self-fulfilling prophecy, obscuring the actual incidence in the comprehensive Still’s population.
If you are like us, you have had your Oprah Ah ha moment, recognizing SJIA-MAS symptoms as oddly similar to this new “pediatric mystery illness” related to COVID-19, called pediatric multisystem inflammatory syndrome (PMIS). However, PMIS or most recently named Multisystem Inflammatory Syndrome in Children, is currently being described as akin to another rare systemic inflammatory disease, Kawasaki disease (KD). Like SJIA-MAS, KD has a MAS-associated complication called KD-MAS. We discuss this below.
We recognize all this information around COVID-19 can be overwhelming, anxiety provoking and confusing. It can be a lot of information to process. As patients with cytokine storm activity ourselves, we live with these storms in our daily lives as do others in our Still’s community. We had to learn about MAS and cytokine storms as something that happens to us. So, we are here to be your guides through this new and confusing territory, because this is our home. To help with that, we are going to talk through some basics before we put it all together in relation to COVID-19.
A cytokine is a protein used by various body systems to communicate, such as interleukins, complement, interferons, and growth factors. Cytokines are often used in reference to the immune system, but they interact with cells in every system and organ in the body.
Individual cytokines can have different effects depending on what is going on in the body. This means not all cytokines are strictly pro- or anti-inflammatory. There are a lot of different cytokines, each with their own functions, lifecycles, and metabolisms. The important thing to know is that cytokines are messenger molecules that your cells use to talk to each other.
Still’s disease and viruses
As we have said before and will say many times again, Still’s disease is a rare, systemic autoinflammatory disorder. What we have not addressed yet is that Still’s is thought to be associated with a number of viral infections, with data stretching back to at least the 1980s. Cytomegalovirus, Respiratory Syncytial virus (RSV), Influenza A and Epstein-Barr virus have all been associated with Still’s disease flares in some patient populations. Still’s disease patients tend to have powerful overreactions to viral and bacterial infections, including the possibility of triggering MAS. Some of the links here refer to “the hemophagocytic syndrome” which is a now-defunct name for MAS.
Before it was realized that Still’s is autoinflammatory, the association of viruses with disease flares and MAS events led some experts to hypothesize that viral infections were the cause of the disease. In a way they were half right as it appears to be a complex interplay of autoinflammation-associated genes and environmental exposures that somehow lead to Still’s disease. But, the fact remains that Still’s disease cytokine storms still have a strong association with viruses.
A cytokine storm is a wild, uncontrolled, unforgiving release of cytokines. Just like meteorological storms, they can loosely be grouped into two categories: regular, everyday storms, and the really big storms like hurricanes or tropical storms.
So, where do regular, everyday cytokine storms occur? These routine storms can occur at the very least, during flares of Still’s disease. Though some Still’s patients can experience them any time their immune system is not properly suppressed. Other autoinflammatory diseases likely feature these downregulated cytokine storms as well, though the exact mixture of cytokines will differ depending on the precise pathophysiology of the disease in question.
The big storms are properly called Cytokine Storm Syndromes, and in some contexts hypercytokinemia. The prototypical Cytokine Storm Syndrome is Sepsis, an often fatal complication of severe or full body bacterial infection that results in a cacophony of both pro- and anti-inflammatory cytokines. Though all Cytokine Storm Syndromes have different triggers, including genetics, any kind of infection, and even some medications can up-regulate a storm to a hurricane.
Treating Cytokine Storm Syndromes generally involves targeting the cytokine that is driving the reaction, most commonly interleukin 1 (IL-1), IL-6, IL-18, and interferon gamma(IFN-γ) via treatment with their associated biologic drugs. General immunosuppressants like prednisone, methotrexate, cellcept or hydroxychloroquine may also be used to help calm the cytokine storm. If it is suspected that mast cells and/or eosinophils, most commonly associated with allergic reactions, have been recruited to play a secondary role in the storm, antihistamines may also be used. Cytokine storm activity with recruitment of histamines is even more common in patients with high risk respiratory comorbidities (asthma, etc.). In infection-associated cytokine storms these are also supplemented by antibiotics, antivirals, etc.
Macrophage Activation Syndrome (MAS)
MAS is a hyperinflammatory complication of autoinflammatory diseases, such as Still’s disease. Traditionally it has been seen as a consequence of SJIA. However reports in AOSD, lupus, KD, and a smattering of other autoinflammatory diseases have pushed beyond the idea that MAS is exclusive to SJIA.
The hallmark of MAS is the expansion of T lymphocytes and macrophages resulting in cytokine storm activity. This cytokine storm activity leads to a hyper activation of macrophages and T cells, resulting in “hemophagocytic lymphohistiocytosis.” When translated into English that means an expansion of white blood cells originating from the lymph organs that eat other blood cells. Often this inflammatory response can cause the expansion and destruction of red blood cells leading to vascular damage and clotting concerns. This describes one of the most problematic things that happens in MAS with the invasion of bone marrow and other organs by these crazed cells that start consuming other cells.
The scariest part of MAS is its unpredictability. It can develop in the absence of any trigger such as a disease flare in autoimmune or autoinflammatory disorders, exposure to infection, change in therapy or, rarely, as an adverse reaction to a treatment.
MAS clinical features
Clinically, MAS may be as variant as the patient’s disease and thus extremely hard to recognize upon onset. Furthermore, like Still’s disease diagnostic criteria in general, MAS can be based on an antiquated diagnostic criteria known as the 2004 hemophagocytic lymphohistiocytosis (HLH) guidelines.
MAS presents with the following most common symptoms:
- hepatomegaly (inflamed liver)
- splenomegaly (inflamed spleen)
- central nervous system dysfunction
- more commonly seen in pediatric SJIA cases
- systemic hemorrhages
Additionally, many with MAS present with:
- prolonged pancytopenia (low white, red blood cells and platelets)
- coagulation dysregulations (thrombosis or blood clots)
- hyperferritinemia (discussed below)
A massive study in 2016 evaluated key determinants of the following 11 laboratory tests in earliest detection of MAS. Of the 11, the results indicated ferritin, platelet count and AST exhibited the biggest change over time and recommended these 3 labs to be critical to early detection of MAS.
- platelet count
- liver transaminase
- AST and ALT
- lactate dehydrogenase (LDH)
- neutrophil count
- sedimentation rate (ESR)
- shifts in white cell count
Once a patient has had a MAS episode, generally laboratory values should be monitored frequently (every four to eight weeks) to monitor for changes over time from a baseline (or if the patient is exhibiting symptoms).
If much of this all sounds very familiar to you as the symptoms and testing in Still’s, you would be correct! These same labs are used for regular monitoring of Still’s patients and many of these symptoms occur in more routine cytokine storms, or chronic inflammation. MAS has laboratory threshold guidelines regarding discerning a true MAS episode but we are specifically not defining normal and abnormal ranges for the 11 labs. Like Still’s, MAS will present differently per patient. This is where monitoring for trends and abberciences from baseline trends should be monitored frequently.
MAS has a long historical association with Still’s disease, both SJIA and AOSD. Still’s disease and MAS are so intertwined that Still’s mortality rates are markedly driven by MAS and account for as many as 10-20% of patient deaths. Alarmingly, 30-40% of cases exhibit a subclinical MAS that is often missed upon clinical visits or laboratory findings. As fulminating MAS events can be avoided with proper treatment it is crucial that patients are monitored with the above labs to review change over time in their presentation and to learn to recognize sub-clinical MAS prior to a massive episode.
Treatments for Still’s associated MAS are often those same treatments used to keep Still’s inflammation under control on a routine basis. We will be digging into treatment strategies in a separate post. It is believed that Still’s driven MAS episodes are ignited primarily by IL-1, and thus agents directed at inhibiting IL-1 are typically used. The IL-1 treatment preference is generally for short-acting drugs if available in conjunction with longer-acting if the patient is not already taking both. Steroid dosing (prednisone) is increased to include pulse steroids or IV-steroid dosing at much higher dosage than oral routes. Further immunosuppression can be used as well with methotrexate and cellcept. Antihistamines and broad-spectrum antibiotics with known anti-inflammatory properties, such as azithromycin can be beneficial regarding targeting respiratory inflammation.
Kawasaki disease (KD)
KD is a rare systemic inflammatory disease of the pediatric population generally seen in children under the age of five. KD specifically targets the vascular system and was originally thought to be a systemic vasculitis in the early 1960’s. KD tends to attack the medium and small vessels in the vascular system.
What causes KD is still quite unclear, but like many inflammatory or immune-driven diseases, like Still’s disease, KD is believed to have both genetic predispositions to inflammatory marker mutations and viral or bacterial rooted infections as plausible causes. Interestingly enough, KD tends to follow a seasonal trend like influenza with greater incidence from fall to early spring.
KD can mimic Still’s disease and vice versa, especially as SJIA and KD are both pediatric diagnoses. If you compare symptoms of KD and Still’s, you will find sustained fevers for more than 5 days, lymphadenopathy (swollen lymph nodes), skin rashes, mouth ulcers and swollen throat. KD has some distinguishing features however: bilateral conjunctival hyperemia (red eyes), dried and often bleeding lips, strawberry tongue and rash presentation on the palms of the hand and soles of feet (looking almost like another pediatric infectious condition called hand, foot and mouth disease).
KD-MAS…looks a lot like Still’s-MAS…
There is a lot of overlap with KD-MAS and Still’s-MAS. So, how do we differentiate them? KD and Still’s associated MAS are both driven by cytokine storms, so we already know they are related. However, KD-MAS is primarily driven by IL-6 inflammatory cytokines versus mostly IL-1 driven in Still’s-MAS.
You might be wondering where the similarities of the two diseases come from. Well, IL-1 is capable of driving IL-6 production. Thus, while each storm starts in a different place, they are driving the same car.
KD can actually trigger the adaptive immune system, in a very autoimmune disease-like fashion, by activation of antigen T lymphocytes and plasma cell activation causing vascular damage often affecting the heart. The infected and inflamed coronary tissue then secretes multiple cytokines such as growth factors, tumor necrosis factor-alpha (TNFa), etc., causing damage to the coronary artery and development of a coronary artery aneurysm or heart failure.
Treatment for KD-MAS is generally intravenous immunoglobulin therapy (IVIG), as IVIG has been proven as an anti-inflammatory agent regarding coronary artery damage. IVIG allows the body to reset regarding immune dysregulation and overall inflammation. IVIG is generally the front line agent for KD. When KD-MAS is suspected, IVIG is still initiated, but many patients with MAS from KD are refractory (non-responsive) to IVIG alone and require adjunct therapy. Typically adjunctive therapy involves: IL-6 inhibitors, TNFa inhibitors, monoclonal antibody treatment (infliximab), antiplatelet or anticoagulant agents (preventing blood clots, strokes and cardiac events), and general immunosuppressants such as methotrexate and cyclosporin A. Aspirin is believed to modify the immune system in overdrive with KD-MAS and often given to lower the risk of thrombosis (blood clots). Interestingly, although steroids are a front line treatment for Still’s-MAS, steroids are not believed to be very effective in KD-MAS.
Wrap this up already! Where’s the COVID-19 association?
Grab your face mask, a beverage of your choice (we recommend wine if you are of age) and take a seat at your favorite socially-distant spot! We feel there is so much anticipation for an epic ending to a great movie, but spoiler alert, we have been giving you an ending in small pieces throughout the plot, or discussion.
COVID-19, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a viral infection that can evoke a cytokine storm in some patients leading to MAS. There is some suggestion that this is a hyperferritinemic syndrome, which is the umbrella term encompassing four clinical conditions: MAS, AOSD (Still’s), catastrophic antiphospholipid syndrome (CAPS) and septic shock. All four conditions are characterized by high serum ferritin levels and life-threatening hyper-inflammation caused by cytokine storms leading to multiple organ failure as well as the following conditions: strokes, pulmonary embolisms (PE), local clotting, acute respiratory distress syndrome (ARDS), coronary aneurysms, heart failure, myocarditis and sepsis. If you have heard these devastating outcomes associated with COVID-19 and the acute monitoring of ferritin, platelet and liver enzymes of hospitalized patients, our discussion should resonate with you as a Still’s patient or provider and have come full circle now!
It is believed that COVID-19 exerts its immunological damage via cytokine storms on both the innate and adaptive immune systems as discussed above identifying certain cytokine triggers per underlying disease state, IL-1 and IL-6. Thus, COVID-19 may be causing both Still’s (innate) and Kawasaki (adaptive) driven MAS. In the pediatric population, KD-MAS presentations are believed to be causing this post-viral Multisystem Inflammatory Syndrome in children which is still evolving with more cases identified globally. However, SJIA-MAS can be present in this syndrome as well.
Putting all of this information together, we believe it reasonable that this new mystery Multisystem Inflammatory Syndrome in children is not new, but rather the unique cytokine response some immune systems generate to this novel virus. Thus, a post-viral cytokine storm falling on the same continuum as both Still’s and KD associated MAS.
Leaving you with a couple thoughts…
There are a few ah ha moments we had as we were putting together all of this information. We have no doubt that our readers with backgrounds in autoinflammatory diseases are currently wrestling with some of those connections as well. Rather than tell you something no one knows, we are going to leave you with some questions this brought up for us.
If Still’s and other autoinflammatory disorders are potentially triggered by viral infections, say like the novel COVID-19, and patients are clearly having cytokine storm activity in response, does this mean some of these patients might have underlying immune-mediated inflammatory conditions?
The honest answer is we just do not know. Research articles on this subject matter do not seem to conclusively link autoinflammationary diseases to causation of these post-viral syndromes. The key cytokine players are there though!