Think back to the last time you got the flu (virus). The fever, the runny nose, the aches, the sore throat – what causes these and related symptoms? Most flu symptoms are not driven by the virus alone. Instead, they result from a “battle” between the virus and the human immune system. Symptoms begin when the immune system recognizes the flu virus and creates inflammatory proteins called cytokines in an effort to target infected cells. If infected cells are successfully killed, more inflammation is generated as toxins and cellular debris enter the bloodstream. In addition, antibodies may be created in response to these cell and viral byproducts, again leading to a rise in inflammation.

We don’t have antivirals capable of killing the flu virus. So we “treat” the illness by letting this immune system “battle” run its course. In most cases, the human immune system “wins” over time, and the inflammation caused by cytokines, toxins and antibodies drops. We begin to feel better and life goes on.

In some cases, patients manage the flu with over-the-counter medicines. These include Motrin, NyQuil, and antihistamines. In other cases a doctor may prescribe steroids or immunosuppressive medicines. These medicines lower symptoms but do nothing to target the virus driving the illness. In fact, these medicines “work” by shutting down various parts of the human immune response towards the virus. They “tone down” the battle between the immune system and the virus so that less inflammation is generated.

The above medications make patients FEEL better. But they may actually impede recovery from the flu by allowing the virus to survive with greater ease. For example, Canadian researchers found that anti-fever medications suppressed fever in patients with the flu, but also allowed flu viral particles to spread more easily from person to person. Indeed, the team estimates that the use of anti-fever medicines by flu patients contributes to a 5% increase in general flu cases and deaths.

Despite these negative outcomes, our entire medical system centers on immunosuppressive treatments that “knock down” parts of the immune system to suppress symptoms. Patients with autoimmune disease are regularly prescribed immunosuppressive medicines like prednisone, rituximab or TNF-alpha inhibitors. Humira – a TNF-alpha inhibitor used to treat arthritis and other “autoimmune” conditions – is the “best selling prescription drug in the world,” with a $38,000/year price tag per patient.

Why this focus on immunosuppressive therapies? Most immunosuppressive treatments were developed before ~2004, during a time when the human body was believed to be largely sterile. Under these conditions the “theory of autoimmunity” gained hold. If inflammation was detected in patients with a range of conditions it was assumed to be a result of the immune system “going crazy” and attacking human tissue.

The discovery of the human microbiome greatly challenges this “autoimmune” model of disease. We now understand that vast microbiome populations persist in every human body site – from the gut, to the brain, to the placenta, to the liver and beyond. An increasing number of “autoimmune”/inflammatory conditions are now tied to dysbiosis or imbalance of these microbiome communities. This means that in “autoimmune disease,” the human immune system may be attempting to target pathogens in the microbiome in lieu of attacking human tissue. Indeed, an increasing number of studies demonstrate that the “autoantibodies” used to diagnose autoimmune disease are often created in response to a range of bacterial, viral and parasitic infections.

This growing association between infection, “autoimmunity”, and inflammation helps explain the poor long-term outcomes associated with immunosuppressive therapies. Patients administered prednisone or TNF-alpha inhibitors tend to feel better in the short-term, but relapse is common, and often expected. Each relapse can require higher doses of immunosuppressive medication to get symptoms “under control.” Meanwhile, patients are at greater risk for developing a second or third inflammatory disease, and are more likely to suffer from acute infectious conditions like tuberculosis. Long-term health outcomes associated with prednisone are so poor that the slogan “pred ’til dead” is commonly invoked (patients who start prednisone often require higher and higher doses of the medicine until they die from the underlying disease).

This begs the question: what if we treated autoimmune disease in the exact opposite fashion? If microbiome dysbiosis contributes to autoimmune disease then treatments that SUPPORT the immune system could target pathogens driving inflammation. By addressing this infectious root cause of inflammatory symptoms, such treatments might induce actual improvement or even recovery.

How might patients with “autoimmune disease” or related inflammatory conditions respond to “immunostimulative” or immune-supporting treatments? Case histories from the turn of the century offer clues. In the early 1900s, mercury was used to treat syphillis: a sexually transmitted infection caused by the bacteria Treponema pallium. Mercury “deliberately stimulated the immune response” in patients with the disease. This resulted in a phenomenon known as the Jarisch-Herxheimer reaction (named after the researchers who characterized it). As the activated immune system targeted Tremponema pallium a “battle” not that different from that associated with targeting the flu virus ensued. Patients suffered a temporary increase in symptoms including fever, chills, myalgia, and headache as cytokines were released and debris from dying bacterial cells entered the bloodstream. However, if patients endured these symptoms they generally “turned a corner,” where symptoms subsided as Tremponema pallium was gradually eradicated.

In the 100 years since the Jarisch-Herxheimer reaction was described in syphilis, it has been further documented in patients administered immunostimulative therapies for a broad range of infectious conditions. These include Lyme disease, leptospirosis, brucellosis and tuberculosis. More recently, the term “immunopathology” has been used in place of Jarisch-Herxhimer to refer to “a systemic inflammatory response consistent with elevated immune activation.”

Immune activation and immunopathology in the treatment of HIV/AIDS

Over the past decade, immunostimulative treatments have been developed to treat HIV/AIDS and cancer. These therapies are also characterized by temporary symptom increases as the activated immune system attempts to target root causes of inflammation. Current HIV/AIDS treatment centers on highly active antiretroviral therapy (HAART). Patients administered HAART receive a cocktail of anti-retroviral drugs, each of which impedes the ability of the HIV virus to replicate and spread. Prior to HAART, the HIV virus survives by dramatically slowing key parts of the human immune response, including the CD4 cells that normally target infectious agents. This means that when the virus is “contained” by HAART, the immune system “wakes up” and identifies pathogens acquired during previous periods of immunosuppression.

What happens next is a form of immunopathology. The activated immune system starts to target pathogens it could not recognize before HAART was initiated. The patient begins to experience temporary increases in symptoms ranging from fever, to malaise, to neurological dysfunction. Symptoms wax and wane with time, but generally decrease as the immune system better targets a range of previously unrecognized pathogens. The HIV/AIDS community has named this process “Immune Reconstitution Inflammatory Syndrome”, or IRIS.

A number of well-known pathogens are linked to IRIS symptoms: the herpes viruses, cytomegalovirus, hepatitis B and C, M. tuberculosis and Mycobacterium avium among others. Often however, symptoms increase despite the fact that no pathogen can be identified on routine blood tests. This suggests that newly identified microbes, like many of the thousands recently detected in tissue/blood by Stanford researcher Stephen Quake, are also being targeted by the activated immune system.

Several key patterns have been observed in patients experiencing IRIS. One is the “unmaking” of infections that can range back to childhood. Let’s say a patient suffered from bacterial meningitis at age eight. The meningitis microbe may re-appear on IRIS-related blood tests thanks to the renewed immune “attack” against its presence. This supports the fact that pathogens acquired throughout life can persist in our microbiome communities, where they may contribute to chronic symptoms.

Second, patients experiencing IRIS often ‘develop’ autoimmune conditions as the immune system reactivates. These include sarcoidosis, diabetes mellitus, rheumatoid arthritis, lupus and Graves disease. This strongly suggests that pathogens targeted by the IRIS immune response also drive symptoms associated with these related inflammatory disease states.

Cancer therapies target tumors by activating the immune system

The latest cancer therapies also seek to activate the immune system. According to the American Cancer Society, these novel immunotherapies “stimulate your own immune system to work harder or smarter to attack cancer cells.” Cancer immunotherapy treatments include CAR-T therapies: treatments that remove disease-fighting T cells from a patient, genetically modify them to better recognize and attack tumor cells, and then add the activated cells back into a patient’s blood.

Response to CAR-T immunotherapy results in serious immunopathology. Nearly all patients administered CAR-T therapy experience a rise in symptoms due to what has been named Cytokine Storm Syndrome or CSS. As implied by the name, CSS results when an immune system “battle” between activated T cells and cancer cells causes massive amounts of inflammatory cytokines to be released into the bloodstream. Resulting symptoms are characterized by fever and in more severe cases, renal insufficiency, pulmonary insufficiency and altered mental status. Sometimes CSS is so strong that patients die from the reaction. Again however, if patients endure/survive the treatment they often enter a state of remission or recovery.

Factors driving CSS are debated by the cancer community. Researchers more familiar with the concept of immunopathology regard CSS as an “on-target” effect of CAR T-cell therapy—that is, its presence demonstrates that active T cells are at work in the body.” In other cases however, CSS is described as a poorly understood “side effect” of immunotherapy. For example, the Washington Post recently published an article on CSS titled: “New cancer therapies have perplexing side effects.”

This “side effect” viewpoint fails to consider a growing body of research linking cancer to infection. For example, “dramatic, continual alterations in the microbiome” were directly responsible for tumor development in a model of colon cancer. Another study found significantly altered microbiome populations in human breast tumor tissue. This imbalance was correlated with decreased expression of key antibacterial response genes. Even signaling peptides created by bacteria have been shown to directly induce tumor formation.

It follows that CSS may result, at least in part, from an immune response towards infected tumor cells. Immunotherapy may also target pathogens that control tumor development by altering the activity of human metabolic pathways. If this is the case, CSS may be the cancer equivalent of IRIS in HIV/AIDS. This is supported by case histories showing that some cancer patients undergoing immunotherapy also develop “new” autoimmune/inflammatory conditions.

For example, the Washington post describes a patient named Diane Legg’s response to cancer immunotherapy, stating: ”Her therapy knocked back her cancer, and she’s glad she got it. But the drug also gave her “almost every ‘itis’ you can get: arthritis-like joint pain, lung inflammation called pneumonitis and liver inflammation that bordered on hepatitis, in addition to the uveitis.”

Did immunotherapy really “cause” Legg to develop these new illnesses? Or, as with IRIS, did the conditions arise due to the “unmasking” of pathogens acquired during earlier periods of illness? It’s also worth noting that patients undergoing immunotherapy often present with “new” bacterial, fungal and viral infections. One study identified 43 infections in 30 immunotherapy patients in the first month of treatment, with infections causing the deaths of two patients.

More research is needed to clarify how these infections correlate with CSS. To move forward, researchers developing immunotherapy treatments must be trained to understand the complexity and extent of the human microbiome capable of driving inflammation. This poses a challenge, since at the moment the immunotherapy and microbiome research communities are not well connected.

Managing CSS in cancer and IRIS in HIV/AIDS is also a great challenge for doctors administering the immunostimulative therapies. Most physicians are not trained to consider the microbiome beyond the gut. They are also not taught to understand the general concept of immunopathology. Indeed, palliative medicine has gained such traction that early trials of cancer immunotherapy did not even anticipate a CSS response. This New York Times article titled “When drug trials go horribly wrong” describes testing of an early immunotherapy treatment (TGN1412). After infusion of TGN1412, all six human trial volunteers faced CSS leading to “life-threatening conditions involving multi-organ failure.” According to the Times, “the outpouring of toxic molecules when T-cells are activated…could not have been predicted from prior animal studies using the drug.”

Physicians also suffer from a lack of solid immunopathology treatment guidelines. According to the Washington Post “Many doctors are not up to speed on how to spot and handle an immune system revved up by immunotherapy.” In severe cases of both CSS and IRIS, physicians are forced to prescribe antibiotics and antivirals to manage symptoms associated with infection. However these drugs kill only a fraction of bacteria and viruses capable of driving symptoms. This forces many physicians to “dampen down” symptoms with corticosteroids or other immunosuppressants, the use of which counters the point of treatment in the first place.

For immunostimulative therapies to truly succeed then, medicine would need to embrace an entirely new paradigm. Drug companies would turn their energy towards developing new antivirals, new antibiotics or antibiotic alternatives. They would attempt development of palliative medicines that help symptoms without destroying the immune response. Tests that better detect and characterize pathogens in the microbiome would be prioritized. Physicians and drug developers would incorporate knowledge of the microbiome into all treatment practices.

The success of immunostimulative therapies also hinges on the willingness of institutional review boards (IRBs) to accept immunopathology. IRBs decide whether patients are allowed to enroll in a particular drug trial. At the moment, many IRBs are unwilling to allow patients with “autoimmune disease” or non-fatal inflammatory conditions to test immunostimulative therapies. This is based on a “do no harm” mentality that does not support increasing symptoms in an effort to improve long-term health.

What these IRB boards may not realize is that most patients with “autoimmune disease” or non-fatal inflammatory conditions are more than willing to feel temporarily worse (even for years) if offered hope of actual long-term improvement. Serious “autoimmune/inflammatory disease” can feel like a living death. For example, a patient named Anne Ortegren recently committed suicide after decades of suffering from the neuroimmune disease ME/CFS. In a letter written before her death she stated, “A very important factor [in choosing to die] is the lack of realistic hope for relief in the future. It is possible for a person to bear a lot of suffering, as long as it’s time-limited. But the combination of massive suffering and a lack of rational hope for remission or recovery is devastating.”

This leads to a final consideration: the greatest hope for immunostimulation in ANY disease hinges on the ability of treatment to be initiated early, or in a preventative fashion. Medicine must learn to support the immune system BEFORE pathogens push the microbiome far out of balance. “Bringing back” the immune system after years of neglect inevitably leads to severe symptoms and complications. For example, the severity of CSS in cancer is directly related to the tumor burden of the patients (patients with fewer, smaller tumors experience less CSS). In contrast, immunopathology in early-stage disease can be easy to treat and tolerate.

That is why I have a vision: In this vision, medicine respects and supports the immune system from the earliest days of life (even in the womb). Microbiome health forms the cornerstone of new therapies, with treatment administered at the first sign of symptoms. New drugs that target pathogenic bacteria, viruses and fungi are central to therapy. The need for immunosuppressive medicines in chronic inflammatory disease drops…to the point where maybe, one day, they are largely regarded as a failed relic of Medicine’s past.