What is Churg Strauss Syndrome?

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Churg Strauss Syndrome

NORD gratefully acknowledges John H. Stone, MD, MPH, Director, Clinical Rheumatology, Massachusetts General Hospital, for assistance in the preparation of this report.

Synonyms of Churg Strauss Syndrome

• allergic angiitis and granulomatosis
• allergic granulomatosis
• allergic granulomatosis and angiitis
• Churg-Strauss vasculitis
• CSS
• eosinophilic granulomatosis with polyangiitis
• EGPA

General Discussion

Churg-Strauss syndrome is a rare disorder that may affect multiple organ systems, especially the lungs. The disorder is characterized by the abnormal clustering of certain white blood cells (hypereosinophilia) in the blood and tissues, inflammation of blood vessels (vasculitis), and the development of inflammatory nodular lesions called granulomas (granulomatosis). Most affected individuals have a history of allergy. In addition, asthma and other associated lung (pulmonary) abnormalities (i.e., pulmonary infiltrates) often precede the development of the generalized (systemic) symptoms and findings seen in Churg-Strauss syndrome by as little as six months or as much as two decades. Asthma, a chronic respiratory disorder, is characterized by inflammation and narrowing of the lungs’ airways, causing difficulties breathing (dyspnea), coughing, the production of a high-pitched whistling sound while breathing (wheezing), and/or other symptoms and findings.

Nonspecific findings associated with Churg-Strauss syndrome typically include flu-like symptoms, such as fever, a general feeling of weakness and fatigue (malaise), loss of appetite (anorexia), weight loss, and muscle pain (myalgia). Additional symptoms and findings may vary depending upon the specific organ systems affected. The nerves outside the central nervous system (peripheral nerves), kidneys, or gastrointestinal tract are often involved. Without appropriate treatment, serious organ damage and potentially life-threatening complications may result. Although the exact cause of Churg-Strauss syndrome is unknown, many researchers indicate that abnormal functioning of the immune system plays an important role.

Signs & Symptoms

Because multiple organ systems can potentially be affected, the specific symptoms of Churg-Strauss syndrome vary widely from case to case. The disorder is separated into three distinct phases – prodromal, eosinophilic and vasculitic. These phases may or may not occur sequentially. Some affected individuals will not develop all three phases. With proper treatment Churg-Strauss syndrome can be successfully managed. Without treatment the disorder may progress to cause life-threatening complications.

The prodromal (or allergic) phase is marked by various allergic reactions and is usually precedes the other first phases in individuals with Churg-Strauss syndrome. Affected individuals may develop late-onset asthma including a cough, wheezing, and shortness of breath (dyspnea). In individuals who have asthma, the condition may become worse. Some affected individuals develop hay fever (allergic rhinitis), a common condition in which allergic inflammation of the mucous membrane of the nose causes a runny nose, sneezing, itching and nasal obstruction. Hay fever may be a chronic, recurring condition. In some cases, repeated episodes of sinus inflammation may occur (sinusitis). Sinusitis may result in facial pain. Chronic inflammation of the nose may cause small benign growths (polyps) to form (polyposis) within the nose. The prodromal phase may last from months to many years. Respiratory symptoms are usually the first signs of Churg-Strauss syndrome and can precede the development of vasculitis by as little as six months or as much as two decades.

The eosinophilic phase of Churg-Strauss syndrome is marked by the accumulation of eosinophils in various tissues of the body. Eosinophils are a specific type of white blood cell. The exact role of eosinophils in the body is unknown, but they are often produced in response to allergies. In individuals with Churg-Strauss syndrome, abnormally high numbers of eosinophils (hypereosinophilia) are produced and may accumulate in various tissues of the body especially the lungs, gastrointestinal tract and skin.

The third phase of Churg-Strauss syndrome is known as the vasculitic phase and is marked by widespread inflammation of various blood vessels of the body (vasculitis). Chronic vasculitis may cause narrowing of affected blood vessels, blocking or slowing the flow of blood to various organs of the body. In addition, inflamed blood vessels may become thin and fragile, potentially rupturing and bleeding into surrounding tissue or the blood vessels may become stretched out or develop a bulge (aneurysm).

As mentioned above the symptoms of Churg-Strauss syndrome vary widely in presentation, severity, duration and onset. Since different organ systems will be affected in different people, all of the symptoms discussed below will not occur in every case.

The symptoms of Churg-Strauss syndrome vary depending upon the organ systems involved. Most individuals develop asthma-like symptoms (discussed above) usually before the onset of other symptoms. However, in some cases, individuals develop symptoms of vasculitis before respiratory symptoms.

Individuals with Churg-Strauss syndrome often develop nonspecific symptoms that may be associated with various illnesses including fatigue, fever, weight loss, night sweats, abdominal pain, cough, joint pain (arthralgia), muscle pain (myalgia), and a general feeling of ill health (malaise). Swollen lymph nodes and generalized weakness have also been reported. Inner ear infections with fluid build up (serous otitis media) may also occur and can result in hearing loss. The moist membrane lining the surface of the eyelids (conjunctiva) may be inflamed as well.

Neurological symptoms are common, affecting approximately 78 percent of individuals with Churg-Strauss syndrome. A condition called mononeuritis multiplex, in which two or more nerves in separate areas of the peripheral nervous system are affected, may occur. The peripheral nervous system refers to the nerves found outside the central nervous system (i.e., brain and spinal cord). Associated symptoms depend upon the specific nerves involved. A common symptom is pain, tingling or numbness and eventually weakness and muscle wasting in the hands and feet (extremities). Disease affecting multiple nerves in the same area of the body (polyneuropathy) may also occur. If untreated, serious neurological complications may develop including bleeding on the brain or lack of blood flow to the brain (stroke).

Approximately half of individuals with Churg-Strauss syndrome develop skin abnormalities caused by the accumulation of eosinophils in skin tissue. Symptoms may include the development of purplish skin lesions due to bleeding (hemorrhaging) into tissues under the skin (purpura), a rash with hives (urticaria), and small bumps (nodules), especially on the elbows. Gastrointestinal involvement results in abdominal pain, nausea, vomiting, diarrhea, blood in the stools and inflammation of the membrane lining the colon (colitis).

Individuals with Churg-Strauss syndrome may develop heart abnormalities including inflammation of the fibrous sac (pericardium) that surrounds the heart (percarditis), inflammation of the muscular wall (myocardium) of the heart (myocarditis), heart failure and potentially a heart attack. Symptoms associated with heart disease include fatigue, shortness of breath, irregular heartbeats, chest pain and fainting episodes. Heart abnormalities may be cause by inflammation of the blood vessels (vasculitis) and the development of inflammatory nodular lesions (granulomas) within heart tissue.

The kidneys can become involved in some cases eventually resulting in glomerulonephritis, a condition characterized by inflammation and degeneration of the tiny clusters of blood vessels (capillaries) called renal glomeruli that filter the blood as it passes through the kidneys. Glomerulonephritis results in an impaired ability to remove waster and fluid products from the body, which then build up in the bloodstream. Although it is an extremely rare occurrence in individuals with Churg-Strauss syndrome, life-threatening kidney failure can occur.

Causes

The exact cause of Churg-Strauss syndrome is unknown. Most researchers believe that several different factors (e.g., environmental, immunological, and genetic) all play a role in the development of the disorder. Churg-Strauss syndrome is classified as an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. Researchers do not know what sets off or “triggers” the abnormal immune system response in individuals with Churg-Strauss syndrome.

Approximately 39 to 59 percent of individuals with Churg-Strauss syndrome have detectable levels of antineutrophil cytoplasmic antibodies (ANCA). ANCAs have also been identified in related blood vessel disorders (vasculitides) including Wegener’s granulomatosis. The exact role of these antibodies in the development of Churg-Strauss syndrome is unknown.

The symptoms of Churg-Strauss syndrome are caused by an abnormal accumulation of large number of antibodies; increased numbers of certain white blood cells (eosinophilia), indicating an inflammatory or allergic response; inflammation of veins, capillaries, and small- and medium-sized arteries; and the development of inflammatory nodular lesions (granulomatosis) within certain tissues and the walls of blood vessels. Although the lungs are often predominantly affected, multiple organ systems may potentially be involved, including the skin, heart, and nerves outside the brain and spinal cord (peripheral nervous system).

In some cases, Churg-Strauss syndrome has been associated with use of zafirlukast (Accolate), a nonsteroidal medication that was approved in 1996 as a therapy for the prevention and treatment of asthma in individuals 12 years of age and older. In July 1997, the Food and Drug Administration (FDA) issued a health advisory reporting that six individuals with asthma developed Churg-Strauss syndrome while receiving zafirlukast therapy. In all reported cases, therapy with steroidal asthma medications was discontinued or was being slowly lowered (tapered) during zafirlukast therapy. According to the FDA, the data do not definitively show that use of zafirlukast caused the condition. In addition, the FDA cautions that individuals who are receiving asthma medication should not discontinue their therapy without consulting with their physicians. New labeling for the medication zafirlukast indicates that physicians should carefully monitor affected individuals as corticosteroid dosages are lowered or such therapy is discontinued.

Zafirlukast belongs to a class of medications known as leukotriene antagonists. Leukotrienes, which occur naturally in certain white blood cells (leukocytes), produce inflammatory or allergic responses and are thought to play some role in causing particular allergies and asthma. Leukotriene antagonists, also known as antileukotrienes, are medications that serve to block the action of leukotrienes. There have been some reports in the medical literature in which therapy with montelukast, another leukotriene antagonist, has been associated with the development of Churg-Strauss syndrome. In many of these cases, researchers now believe that the slow removal of steroid treatment revealed existing, but undiagnosed, cases of Churg-Strauss syndrome and that the disorder did not develop because of the drugs. However, the exact relationship, if any, between Churg-Strauss syndrome and leukotriene antagonists is unknown.

Affected Populations

Churg-Strauss syndrome affects males and females in equal numbers, although some reports suggest that males may be affected slightly more often. The disorder can affect individuals of almost any age and has ranged from 15 to 70 years of age. Most cases occur in individuals between 30 and 50 years of age. The estimated mean annual incidence is 2.4 individuals per million. Some researchers believe that Churg-Strauss syndrome is underdiagnosed, making it difficult to determine its true frequency in the general population.

Related Disorders

Symptoms of the following disorders can be similar to those of Churg-Strauss syndrome. Comparisons may be useful for a differential diagnosis.

Wegener’s granulomatosis is an uncommon disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some cases, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of Wegener’s granulomatosis is not known. (For more information on this disorder, choose “Wegener’s granulomatosis” as your search term in the Rare Disease Database.)

Polyarteritis nodosa, a rare multisystem disorder that usually becomes apparent between the ages of 40 to 50 years, is characterized by widespread inflammation, weakening, and degeneration of small and medium-sized arteries. Blood vessels in any organ or organ system may be affected, including arteries supplying the kidneys, heart, intestine, nervous system, and/or skeletal muscles. Damage to affected arteries may result in abnormally increased blood pressure (hypertension), “ballooning” (aneurysm) of an arterial wall, the formation of blood clots (thrombosis), obstructed blood supply to certain tissues, and/or tissue damage and loss (necrosis) in certain affected areas. In many cases, affected individuals experience weight loss, fever, a general feeling of ill health (malaise), fatigue, weakness, headache, muscle aches (myalgias), and/or abdominal pain. Additional symptoms and findings are often present and depend upon which areas of the body are affected. Although the exact cause of polyarteritis nodosa is not known, many researchers suspect that the disorder is due to disturbances of the body’s immune system. (For more information on this disorder, choose “polyarteritis nodosa” as your search term in the Rare Disease Database.)

Guillain-Barre syndrome (GBS) is a rare, rapidly progressive disorder that consists of inflammation of the nerves (polyneuritis) and, usually, muscle weakness, often progressing to frank paralysis. Although the precise cause of GBS is unknown, a viral or respiratory infection precedes the onset of the syndrome in about half of the cases. This has led to the theory that GBS may be an autoimmune disease (caused by the body’s own immune system). Damage to the covering of nerve cells (myelin) and nerve axons (the extension of the nerve cell that conducts impulses away from the nerve cell body) results in delayed nerve signal transmission. There is a corresponding weakness in the muscles that are supplied or innervated by the damaged nerves. The following variants of GBS (acute inflammatory neuropathy or acute inflammatory demyelinating polyradiculoneuropathy) are recognized: Miller Fisher syndrome, acute motor-sensory axonal polyneuropathy, acute motor axonal polyneuropathy, chronic inflammatory polyneuropathy, (chronic inflammatory demyelinating polyradiculoneuropathy; also called chronic relapsing or recurring inflammatory polyneuropathy), and chronic polyneuropathy with conduction block. (For more information on this disorder, choose “Guillain-Barre” as your search term in the Rare Disease Database.)

A variety of additional disorders may have similar findings (e.g., eosinophilia, pulmonary infiltrates, vasculitis) as those of Churg-Strauss syndrome. These disorders include allergic bronchopulmonary aspergillosis, acute eosinophilic pneumonia, hypereosinophilic syndrome, microscopic angiitis, certain malignancies, and certain fungal or bacterial infections. Certain drug reactions may cause a similar clinical picture as that found in Churg-Strauss syndrome.

Diagnosis

The diagnosis of Churg-Strauss syndrome may be suspected based upon a thorough clinical evaluation, characteristic physical findings, and specialized tests. In 1990, the American College of Rheumatology established diagnostic criteria for Churg-Strauss syndrome. An individual is classified as having Churg-Strauss syndrome and not another form of vasculitis if four of the following six findings are identified: 1. asthma; 2. eosinophilia (defined as greater than 10 percent in the circulating blood); 3. mono- or polyneuropathy; 4. nonfixed pulmonary infiltrates; 5. abnormality of the paranasal sinuses; and 6. extravascular eosinophilia.

Diagnostic procedures that may be used to aid in a diagnosis include surgical removal (biopsy) and microscopic examination of small samples of lung tissue, demonstrating inflammation of blood vessels and other associated changes. Chest x-rays and other specialized imaging techniques, such as computerized tomography (CT) scanning, typically reveal abnormalities in the lungs (i.e., pulmonary infiltrates). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of an organ's tissue structure. In addition, laboratory tests may be conducted, including tests that demonstrate elevated levels of certain white blood cells (eosinophils) and further suggest the presence of an inflammatory process.

Standard Therapies

Treatment

Most individuals with Churg-Strauss syndrome are first treated with corticosteroid medications such as prednisone or methylprednisonone, which suppress the activity of the immune system (immunosuppressive) and reduce inflammation. Individuals usually receive high-doses of corticosteroid initially and then after improvement is seen the dosage is slowly reduced (tapered off). Many affected individuals only need corticosteroids to achieve remission of their symptoms (monotherapy).

If individuals do not respond to steroid therapy alone or if they have advanced disease (e.g., the presence of kidney or neurological disease), they may require treatment with drugs that inhibit the growth and spread (proliferation) of certain cells (cytotoxic medications) such as cyclophosphamide or azathioprine. In some cases, other therapies may be recommended. (For more information, please see the “Investigational Therapies” section below.) Other treatment for individuals with Churg-Strauss Syndrome is symptomatic and supportive.

In 2017, Nucala (mepolizumab) was approved by the U.S. Food and Drug Administration (FDA) to treat adult patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Nucala is manufactured by GlaxoSmithKline.

Investigational Therapies

Studies are also being conducted to evaluate the use of intravenous infusions with antibodies (immunoglobulins) obtained from plasma (immune globulin [IVIG]) as a treatment for affected individuals who have an incomplete response to corticosteroid or cytotoxic therapy. According to some reports, in some individuals with Churg-Strauss syndrome, monthly IVIG therapy may result in decreased levels of certain white blood cells (eosinophils), improved lung (pulmonary) function, and additional improvement of other associated symptoms and findings. Further studies are needed to determine the long-term safety and effectiveness of IVIG therapy in individuals with Churg-Strauss syndrome.

Researchers are studying the uses of intravenous doses of methylprednisolone and cyclophosphamide in the treatment of individuals with Churg-Strauss syndrome. Initial results were positive. Additional drugs including interferon alpha, rituximab, and anti-interleukin-5 (IL-5) are being studied as potential treatment for individuals with Churg-Strauss syndrome. Interferon alpha has demonstrated promising results in study. More research is necessary to determine the long-term safety and effectiveness of these potential treatments for individuals with Churg-Strauss syndrome.

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EGPA can occur at any age, however the average age of diagnosis is between 35 and 50 years old. Women and men appear to be affected equally. EGPA is considered extremely rare, with an incidence in the United States of 1 to 3 cases per 100,000 adults per year. The international incidence of EGPA is estimated at 2.5 cases per 100,000 adults per year.