Lymphohistiocytosis

What is Lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis (HLH) is a severe medical condition, leading to intense inflammation in the body, failure of multiple organs and could potentially result in death. The overall swelling and inflammation related to HLH are caused by overactive immune cells such as natural killer cells, CD8+ cytotoxic T-cells, and macrophages. These cells are supposed to protect the body against infections and diseases, but in the case of HLH, they react excessively and uncontrollably.

Hemophagocytic lymphohistiocytosis comes in two forms: primary, which is inherited through genetic mutations, or secondary, which is a sudden and intense response to an infection, cancer, or an autoimmune disease – a condition in which your body’s immune system mistakenly attacks your own healthy cells. Primary HLH affects children early on, while the secondary type tends to affect adults along with another acute illness, like a blood infection (sepsis) or blood cancer (a hematologic malignancy).

The primary approach to treating HLH is suppressing the immune system and complementing it with chemotherapy. Chemotherapy uses strong drugs to kill or slow down the growth of cancer cells. Without these treatments, a large number of patients would unfortunately not survive.

What Causes Lymphohistiocytosis?

HLH, or Hemophagocytic Lymphohistiocytosis, is a medical condition that can appear in two different forms: primary or secondary.

Primary HLH typically occurs in early childhood and is the result of genetic changes that affect the way certain cells in our immune system (NK cells, CD8+ cytotoxic T cells, and antigen-presenting cells) interact with each other. Because of these changes, the cells don’t function properly, leading to an increase in substances that promote inflammation throughout the body. This kicks off a chain reaction where other immune cells, known as macrophages, become overly active, leading to the damage of other cells in the body. Primary HLH is further categorized based on the way the genetic changes are inherited (X-linked, recessive, or dominant) or by the specific conditions it’s associated with, such as Chediak Higashi syndrome, Griscelli syndrome, X-linked lymphoproliferative disorder, and others. Primary HLH not associated with another genetic condition is often referred to as familial HLH.

Secondary HLH typically affects adults, (with an average age of around 50), and it’s usually triggered by an existing acute illness, not by a genetic mutation, like primary HLH. Some common conditions that can trigger secondary HLH include infection, cancer, and autoimmune disorders. When HLH occurs in the context of an autoimmune disorder, it’s sometimes referred to as macrophage activation syndrome (MAS), although this term is more of a historical designation than an indication of a separate disease. Interestingly, about 14% of adult patients with secondary HLH have slight genetic changes in the same genes associated with primary HLH. It’s unclear what these minor genetic variations might mean, but some researchers theorize that they could make someone more susceptible to developing secondary HLH when exposed to certain triggers or illnesses.

Risk Factors and Frequency for Lymphohistiocytosis

HLH is a condition that’s hard to measure within the population because it’s often confused with other illnesses and diagnosis can be unclear. One of the clearest sources of information we have comes from a Swedish study which collected data from 1987 to 2006, and they estimated around 1.5 cases per million people each year.

When it comes to children in the intensive care, a study at a Texas children’s Hospital found an even higher incidence: as much as 1 case in every 3,000 pediatric admissions.

For adults with secondary HLH, it’s even harder to get an accurate estimate. This is because the condition is hard to tell apart from other serious problems like sepsis or uncontrolled cancer. Further complicating matters is that tests to confirm HLH aren’t often done. However, some estimates suggest it could be as high as 1 in 2000 for adult critical care admissions. The likelihood of diagnosis often depends on doctors suspecting the condition and testing for it.

The data doesn’t show any clear preference for HLH in terms of racial or ethnic background. Often this reflects the make-up of the local population where the research was done. Among children, the gender distribution is about equal but in adults, there might be a slightly higher occurrence in males, with a ratio just under 2 males for every 1 female.

Signs and Symptoms of Lymphohistiocytosis

HLH, or Hemophagocytic lymphohistiocytosis, and other systemic inflammatory conditions such as severe infection, cancer, and autoimmune diseases can be difficult to distinguish because they share common symptoms. These symptoms are usually general signs of inflammation like fever, tiredness, and feeling run down. Interestingly, these other inflammatory conditions often precipitate the development of HLH.

Children may spontaneously develop HLH due to genetic mutations, or the condition can be triggered by an external factor such as an infectious agent. Among children with primary HLH, infections, especially from the herpesvirus family (like Epstein Barr virus), are the most frequent triggers. In adults, cancer triggers HLH in about 45% of cases. If the HLH is associated with autoimmune diseases, it’s historically and commonly known as macrophage activation syndrome (MAS), due to past naming conventions, not because of any unique physiological characteristics.

The physical symptoms of HLH can be diverse because it is a condition of overactive immune cells, with a significant impact on a network of structures and tissues in the body known as the reticuloendothelial system. Symptoms range from blood cell deficits that lead to bleeding, infection, or severe anemia-related stressors (like heart attack, stroke, fainting), to an enlarged liver or spleen, and swollen lymph nodes. Other severe symptoms include changes in mental status (which, in critical cases, might involve life-threatening inflammation of the brain and spinal cord), adult respiratory distress syndrome, acute liver failure, and acute kidney failure.

Given the wide range of potential symptoms, here are some key ones to be aware of:

• Fever
• Tiredness
• Feeling run down
• Bleeding disorders
• Infection risks
• Extreme anemia-related complications (e.g., heart attack, stroke, fainting)
• Enlarged liver or spleen
• Swollen lymph nodes
• Change in mental status
• Adult respiratory distress syndrome
• Acute liver failure
• Acute kidney failure

Testing for Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH), a rare but serious medical condition, has been classified in two major ways in recent times. Each of these classification systems came from large studies known as HLH-94 and HLH-2004. The numbers 94 and 2004 represent the years the studies began. More recent attempts to update this classification have been made, but neither are as accepted as the earlier two.

In the first system from the HLH-94 study, doctors needed to see five specific signs in a patient to diagnose them with HLH:

1. Fever
2. Cytopenias – this means a decrease in the number of cells that circulate in the blood.
3. Splenomegaly – or an enlargement of the spleen.
4. Hypertriglyceridemia or hypofibrinogenemia – these terms refer to having high levels of triglycerides (a type of fat) in the blood, or low levels of fibrinogen (a protein that helps blood clot).
5. Hemophagocytosis proven by a biopsy – this condition occurs when certain immune cells start to “eat” other cells in the blood.

In the more recent HLH-2004 study, three new criteria were added:

1. Ferritin greater than 500 ng/ml – Ferritin is a protein that stores iron in your body, and high levels can indicate inflammation.
2. Low or absent NK-cell activity – NK cells are a type of white blood cell important to the immune system.
3. Elevated sIL2Ra levels greater or equal to 2400 U/ml – sIL2Ra is a receptor on the surface of some immune cells, and high levels can indicate inflammation as well.

These three additions made it so that a total of five out of eight symptoms, rather than all five original symptoms, were required for a diagnosis. Significantly, it’s no longer necessary to prove the presence of hemophagocytosis through a biopsy to diagnose someone with HLH.

Treatment Options for Lymphohistiocytosis

The main treatment for HLH, a severe immune system disorder, focuses on using medicines that suppress the immune system and destroy harmful cells. However, these treatments can’t be used if the patient has a serious infection, which is why it’s so important to make a clear diagnosis before starting treatment. There have been a couple of important treatment plans developed for HLH, known as the HLH-94 and the HLH-2004 protocols.

The HLH-94 protocol was developed and tested in a big international study involving 113 children. This treatment plan included a combination of different medications, such as dexamethasone, etoposide, cyclosporine A, and methotrexate given directly into the spinal fluid (in select patients), followed by a pre-planned bone marrow transplant. The results were encouraging: 55% of children were still alive 3 years after treatment, and 22% were still alive after 5 years. These survival rates are much better than what was previously expected for children with this condition.

The HLH-2004 protocol, which included patients with both primary and secondary HLH, made slight changes to the previous treatment plan. This new plan added cyclosporine to the initial mix of medications and included steroid therapy given directly into the spinal fluid for patients with underlying neurological problems. However, adding these additional treatments didn’t seem to improve patient outcomes.

In both of these treatment plans, a process called reduced-intensity conditioning is used to prepare the patient for a bone marrow transplant. This process, which can include a treatment with medications like fludarabine and busulfan, reduces the patient’s immune cells to make room for the new cells that will be transplanted.

What else can Lymphohistiocytosis be?

Often, the symptoms of certain medical conditions can be vague or seemingly explained by other known diseases like sepsis (a severe reaction to an infection) or cancer. It’s important for doctors to always be alert to the possibility of conditions like Kawasaki disease or toxic shock syndrome, which can present similar symptoms, especially in children.

In adults, diagnosing these conditions can be even more challenging. This is because the symptoms are often overlooked due to the presence of another serious condition that affects multiple organs, such as cancer, sepsis, or an autoimmune disease. In such cases, doctors should consider the possibility of these diseases in any patient showing signs of failure in multiple organs, low platelet or white blood cell count (cytopenias), abnormal blood clotting (coagulopathy), and not responding to regular treatment.

What to expect with Lymphohistiocytosis

In general, Hemophagocytic lymphohistiocytosis (HLH) is a very serious condition in children. Unfortunately, it is fatal if not treated. On the other hand, adults can sometimes recover from HLH on their own without treatment. However, it’s challenging to pinpoint the exact mortality rates for adults, as it’s often unclear whether deaths are directly due to HLH or other underlying conditions such as infection or cancer.

Historical data has shown that about 55% of children who received treatment for HLH were still alive after 3 years. For children who survived long enough to receive bone marrow transplantation (BMT), the three-year survival rate increased slightly to 62%. Despite the possibility of spontaneous remission in adults, the overall mortality rate for HLH is quite high, around 41%.

A recent study carried out across multiple centers in the U.S. found that patients with cancer-related HLH had the lowest survival rates. On average, these patients survived only around 2.8 months after diagnosis, compared to nearly 11 months for patients with HLH not associated with cancer.

Possible Complications When Diagnosed with Lymphohistiocytosis

Talking about complications when it comes to HLH might seem strange because the nature of the condition is itself complex. Simply put, HLH is an illness that impacts multiple parts of the body due to the disordered activity of the immune system. It’s not selective – it can hit any area anywhere. The lungs may develop a severe difficulty in breathing, the heart might be affected with inflammation and its various consequences, kidneys could experience tiny blood vessel diseases, the brain might fall prey to a deadly inflammation of the brain and spinal cord, and the liver could fail all of a sudden. Unfortunately, this disease doesn’t spare any major organ in the body, having a destructive effect. Many patients who lose their lives to this disease do so because of the sudden drop in blood pressure.

Common Effects of HLH:

• Severe difficulty in breathing in the lungs (acute respiratory distress syndrome)
• Inflammation and its various consequences in the heart (myocarditis)
• Tiny blood vessel diseases (microangiopathies) in the kidneys
• Deadly inflammation of the brain and spinal cord (fatal meningoencephalitis)
• Sudden liver failure
• No major organ is immune to the destructive effect of HLH
• Many deaths are caused by a sudden drop in blood pressure (hemodynamic collapse)