Hypereosinophilic Syndrome

Hypereosinophilic syndrome is a rare group of blood disorders caused by an excess of white blood cells called eosinophils, which can damage organs throughout the body. Without treatment, this condition can be life-threatening, but with prompt diagnosis and care, more than 80% of people are alive five years after diagnosis.

Table of contents

• What is Hypereosinophilic Syndrome?
• Symptoms
• Causes and Types
• Who is Affected?
• Diagnosis
• Treatment
• Complications
• Outlook and Prognosis

What is Hypereosinophilic Syndrome?

Hypereosinophilic syndrome, often called HES, is a group of rare blood disorders that occur when your body has too many eosinophils (a type of white blood cell) for an extended period^[1]. These cells are normally an important part of your immune system, protecting your body from parasitic infections and responding to allergens^[3].

In healthy people, the blood contains about 100 to 500 eosinophils per microliter. With HES, this number rises to 1,500 or more per microliter and stays elevated for at least six months^[3][5]. When these cells remain at such high levels over time, they can move into various tissues throughout the body, causing inflammation and eventually damaging organs^[7].

HES is defined by specific criteria that must be met for diagnosis. These include having more than 1,500 eosinophils per microliter on at least two separate blood tests taken more than one month apart, evidence that organs or tissues have been damaged by these high levels, and the absence of other known causes for the elevated eosinophil count, such as parasitic infections or allergic diseases^[1][7].

• Skin
• Lungs
• Heart
• Digestive tract
• Nervous system
• Liver
• Spleen
• Bone marrow

Symptoms

The symptoms of hypereosinophilic syndrome can vary widely from person to person, depending on which organs or body systems are affected by the excess eosinophils^[2]. Some people may experience only mild symptoms, while others develop serious complications.

Early symptoms commonly include fatigue, cough, shortness of breath, muscle pain, fever, and skin rash^[2][5]. Many people with HES develop an itchy rash that may resemble eczema or hives^[3]. In fact, skin rashes are the most common symptom reported^[3].

Additional symptoms can include dizziness, memory loss or confusion, mouth sores, and unexplained weight loss^[5][3]. If the digestive system is affected, people may experience belly pain, nausea, and diarrhea^[3]. When the heart is involved, symptoms may include chest pain and heart palpitations^[3].

Respiratory symptoms such as wheezing and difficulty breathing are also common^[2]. Some people experience numbness and tingling on one or both sides of the body, or develop brain fog^[3]. Because these symptoms overlap with many other medical conditions, HES can be difficult to diagnose initially^[5].

Causes and Types

The exact causes of hypereosinophilic syndrome are not fully understood, but researchers have identified several factors that can trigger the overproduction of eosinophils^[3]. There are three main types of HES, each with different underlying causes.

Primary or neoplastic HES (also called myeloproliferative HES) occurs when genetic changes or mutations cause the bone marrow to produce too many eosinophils^[1][3]. One well-known variant involves a chromosomal deletion that creates a fusion gene called FIP1L1-PDGFRA, which has tyrosine kinase activity (an enzyme that can transform blood-forming cells)^[4]. People with this variant are often males and may respond well to specific targeted treatments^[4].

Secondary or reactive HES (also called lymphocytic HES) happens when abnormal T cells (a type of white blood cell) release too much interleukin-5 (IL-5), a protein that activates eosinophils^[3][4]. This type is associated with a clonal population of T cells with an abnormal appearance^[4].

Idiopathic HES is diagnosed when doctors cannot identify a specific cause for the elevated eosinophil levels, even after thorough testing^[3][6]. This can occur in up to three out of four people with HES^[3].

Some people may inherit a gene variation from a biological parent that causes hypereosinophilia, known as familial HES^[3]. In other cases, untreated infections, allergies, or cancer can lead to elevated eosinophil levels^[3].

Who is Affected?

Hypereosinophilic syndrome is rare, with prevalence rates ranging from 0.36 to 6.3 cases per 100,000 people^[1][8]. The condition can affect anyone at any age, although it is most commonly diagnosed in adults between 20 and 50 years old^[3][7].

While both men and women can develop HES, certain variants show a clear pattern. The myeloproliferative variant, particularly the type associated with the FIP1L1-PDGFRA fusion gene, is much more common in males^[4][8]. Some older studies reported a male-to-female ratio as high as 4 to 9 males for every female, though this likely reflects the predominance of males with this specific genetic variant^[9].

Although HES is more commonly diagnosed in adulthood, it has also been identified in children^[7]. The condition has been reported across different ethnic groups and geographic regions worldwide.

Diagnosis

Diagnosing hypereosinophilic syndrome can be challenging because many other conditions cause similar symptoms^[5]. Healthcare providers use a process of elimination, first ruling out other causes of elevated eosinophils before confirming HES.

The diagnostic process begins with a thorough medical history and physical examination. Your healthcare provider will ask about your symptoms, family medical history, medications you take, and possible exposures to diseases or allergens^[10].

Blood tests are essential for diagnosis. A complete blood count with differential will measure your eosinophil levels^[7]. For HES, eosinophils must be greater than 1,500 per microliter on at least two different occasions^[3]. Additional blood tests may check liver and kidney function, vitamin B12 levels, tryptase (an enzyme that indicates certain cell activation), and screen for autoimmune conditions or blood-related cancers^[10][7].

To rule out parasitic infections, which are a common cause of elevated eosinophils worldwide, stool tests may be performed^[10][5]. Allergy tests can help determine if environmental or food allergies are responsible for the elevated counts^[10].

Genetic testing is important to check for mutations that cause HES, particularly the FIP1L1-PDGFRA fusion gene and other chromosomal abnormalities^[10][5]. This information helps determine the specific type of HES and guides treatment decisions.

A bone marrow biopsy is commonly recommended to examine the production of blood cells and look for abnormalities^[7][10]. In bone marrow affected by HES, eosinophils may make up more than 20% of all cells^[1].

Tests to assess organ damage are crucial, as damage to organs is a defining feature of HES. These may include chest X-rays and echocardiograms to evaluate the heart and lungs, imaging tests such as CT scans to study other organs, lung function tests, and tissue biopsies to check for the presence of eosinophils or evidence of damage^[10][5].

Treatment

The goals of treatment for hypereosinophilic syndrome are to reduce eosinophil levels, relieve symptoms, and prevent further organ damage^[10]. Treatment approaches vary depending on the type of HES, the severity of symptoms, and which organs are affected.

For most people without the FIP1L1-PDGFRA mutation, corticosteroids (medications that reduce inflammation) are the first-line treatment^[11][12]. These medications help lower eosinophil counts and control symptoms. About one-third of patients do not respond adequately to corticosteroids alone^[12].

For people with the FIP1L1-PDGFRA fusion gene, a medication called imatinib is the treatment of choice^[4][12]. This drug is a tyrosine kinase inhibitor (a medication that blocks specific enzymes involved in cell growth) and has response rates approaching 100% in patients with this genetic variant^[12]. These patients are treated aggressively because they carry a worse prognosis without treatment^[12].

When corticosteroids are not effective or cannot be used long-term due to side effects, second-line treatments include hydroxyurea (a medication that reduces blood cell production), interferon-alpha (a protein that helps regulate the immune system), or higher doses of imatinib^[12].

Mepolizumab, a medication that is a monoclonal antibody (a laboratory-made protein that targets specific substances in the body) directed against interleukin-5, has been approved for treating HES in adults and children 12 years and older who have had the condition for at least six months without an identifiable cause^[12][14]. This treatment helps reduce disease flares and allows patients to lower their corticosteroid doses^[12].

Other medications that may be used in resistant cases include various chemotherapeutic agents, though these are generally reserved for severe, treatment-resistant disease^[12]. In very rare, refractory cases, hematopoietic stem cell transplantation (a procedure that replaces damaged bone marrow with healthy cells) has been shown to reverse organ dysfunction, though it carries significant risks^[12].

Patients who are not experiencing symptoms but have elevated eosinophil counts are typically monitored closely rather than treated immediately^[12]. This monitoring includes blood tests every 3 to 6 months and heart and lung function tests every 6 to 12 months^[12].

If an underlying condition is found to be causing HES, treating that condition may also help lower eosinophil levels^[2][10].

Complications

Without treatment, hypereosinophilic syndrome can lead to serious, life-threatening complications. The excess eosinophils can build up in organs and eventually cause them to stop working properly^[3].

Heart damage is the most serious complication of HES. Cardiac involvement typically progresses through three stages. The early stage involves damage to the inner and middle layers of the heart muscle, though this rarely causes symptoms. Next, blood clots form along the damaged heart tissue and may break off, causing blockages elsewhere in the body. The final stage involves scarring and stiffening of the heart tissue, called endomyocardial fibrosis (permanent scarring of the heart’s inner lining), which can lead to heart failure^[8]. Most people who die from HES do so because of heart damage^[3].

HES can also increase the risk of serious blood clots, which may occur despite treatment with blood-thinning medications^[12]. These clots can travel to vital organs and cause strokes or other complications.

Depending on the underlying cause, some types of HES can progress to blood cancers such as leukemia or lymphoma, although this is uncommon^[3][4]. The myeloproliferative variant may rarely develop into acute myeloid leukemia or acute lymphoblastic leukemia^[4].

Other organs that can be damaged include the lungs, kidneys, skin, digestive system, and nervous system. The specific complications depend on which organs are affected by eosinophil infiltration^[9].

Outlook and Prognosis

The outlook for people with hypereosinophilic syndrome has improved significantly since the condition was first defined^[9]. With prompt diagnosis and appropriate treatment, more than 80% of people diagnosed with HES are alive five years after diagnosis^[3].

Prognosis depends on several factors, including the type of HES, how quickly it is diagnosed and treated, and whether irreversible organ damage, particularly to the heart, has already occurred^[9]. People with the FIP1L1-PDGFRA fusion gene generally have an excellent prognosis when treated with imatinib^[4].

Long-term outcomes also depend on whether there is malignant transformation of blood cells, meaning the development of blood cancers, though this is relatively uncommon^[9]. Regular monitoring and adherence to treatment are essential for managing this chronic condition and preventing complications.

Without treatment, HES is progressive and can be fatal^[3][8]. However, with the availability of newer targeted therapies and biologic medications, the future for patients with eosinophilic disorders continues to improve^[14].

HES, idiopathic hypereosinophilic syndrome, myeloproliferative HES, lymphocytic HES, primary hypereosinophilic syndrome, secondary hypereosinophilic syndrome