What is hemophagocytic lymphohistiocytosis?

In November, the mixed martial arts (MMA) fighter Anthony Johnson died reportedly from organ failure due to a combination of non-Hodgkin lymphoma (NHL) and hemophagocytic lymphohistiocytosis. He was 38. About a year ago, he announced on social media that he had been diagnosed with non-Hodgkin lymphoma. The organ failure was most likely caused by the hemophagocytic lymphohistiocytosis which may have been triggered by the NHL.

What is hemophagocytic lymphohistiocytosis?

According to Wikipedia, hemophagocytic lymphohistiocytosis (HLH) “is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages … that secrete high amounts of inflammatory cytokines. It is classified as one of the cytokine storm syndromes. There are inherited and non-inherited (acquired) causes of hemophagocytic lymphohistiocytosis (HLH).” 

The inherited (familial, primary) form of HLH is more rare (~25% of cases) and usually affects children. The acquired (secondary) HLH typically affects adults and can be triggered by infections (e.g. Epstein-Barr virus), autoimmune disorders, and cancer. 

The primary culprits are hyperactive macrophages (also known as histiocytes), cytotoxic T-cells, and Natural Killer (NK) cells. The latter two are lymphocytes (see Figure 1), and are the lympho- part of lymphohistiocytosis. All three mediate a direct cellular attack on an invading pathogen (e.g. virus) employing phagocytosis or chemical warfare, releasing granules laden with toxic enzymes and chemicals (e.g. oxygen free radicals) on the pathogen itself or cells infected by the pathogen. They also secrete cytokines to recruit and activate neighboring immune cells leading to inflammation. The problem is when the system goes haywire causing hyperinflammation or even a cytokine storm.

One explanation for this hyperactivation is that the immune response trigger persists. Consistent with the hypothesis, many of the mutations that underlie familial HLH affect genes involved in granule-dependent cytotoxicity. As a result, infected cells that are the target of the activated macrophages and lymphocytes may survive and continue to act as triggers. Similarly, secondary HLH is associated with various cancers (e.g. blood cancers such as leukemia and lymphoma) as well as infections, which can act as persistent triggers if the cancer or infection are not ameliorated.

There are at least four types of treatments for HLH. The first approach is to remove the trigger. If it is an infection, then the patient is treated for the pathogen causing the infection. But sometimes the trigger cannot be cured (e.g. an intractable cancer), or even with the trigger eliminated, the hyperinflammation continues. Then the second option is to treat with drugs that fight inflammation such as corticosteroids or immunosuppressants. An example of the former is the steroid dexamethasone and of the latter is cyclosporine (which is used during transplant operations to prevent donor organ rejection). A third approach is to use chemotherapeutic drugs against blood cancers like lymphomas to try to kill off the hyperactivated proliferating lymphocytes. Finally, if none of the above work then allogeneic hematopoietic stem cell treatment (HSCT) in which the patient's hematopoietic stem cells (HSCs, see Figure 1) are killed off by radiation treatment, and then replaced with donor HSCs that hopefully will not give rise to the hyperactivated macrophages and lymphocytes. The term allogeneic refers to fact that the donor is some other person than the patient (recipient), whereas autologous HSCT would be HSCs supplied by the patient.

In the case of Mr. Johnson, the trigger appeared to have been non-Hodgkin lymphoma (NHL). The cancer most likely gave rise to the HLH, which in turn caused the hyperinflammatory response and infiltration of organs with activated immune cells which led to organ failure.

In previous posts I have mentioned the problem of hyperinflammation and cytokine storms with respect to other conditions. Immunotherapy uses the body's own immune system, and T-cells in particular, to attack cancer cells. A prominent side-effect is the cytokine storms from an excessive immune response induced by high levels of cytokines that also damages non-cancerous tissue. A second example comes from the severe cases of Covid-19 in which damage to the lungs results more from hyperinflammation than direct viral attack and infection of the tissue (QH). This commonality is underscored by the use of the anti-inflammatory corticosteroid dexamethasone in the treatment of both Covid-19 and HLH. 

The immune system is finely balanced to fight off a foreign invader while not mistakenly attacking self tissue. There is still much to learn about how the immune response can go haywire causing massive collateral damage even when the threat from the pathogen or cancer is minimal or non-existent. Investigations of a wide range of disorders that have hyperinflammation as a common element may provide new insights into the genetic and environmental factors that contribute to this complex condition, as well as helping to develop new treatments that bring the immune system back under proper control.

Figure 1. Macrophages and lymphocytes (e.g. Natural Killer cells and cytotoxic T-cells) are derived from hematopoietic stem cells (HSCs) via two distinct lineages. Macrophages are derived from myeloid progenitor cells whereas the lymphocytes are derived from lymphoid progenitors. Macrophages, also known as histiocytes, become hyperactivated during HLH and in their out-of-control frenzy phagocytose red blood cells (erythrocytes), and hence the name hemophagocytic lymphohistiocytosis.