What is Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)?
Churg Straus syndrome, now known as eosinophilic granulomatosis with polyangiitis (EGPA), is a specific type of disease. As with other related diseases, it is characterized by damage and inflammation of small and medium-sized blood vessels throughout the body. What makes EGPA unique is the accompanying conditions of asthma, rhinosinusitis (inflammation of the nasal and sinus passages), and a high number of eosinophils, which are a type of white blood cell.
Historically
The syndrome was first defined by Jacob Churg and Lotte Strauss in 1951 when they noticed a pattern in 13 patients. All of these patients had severe asthma, fever, a high number of eosinophils, and showed evidence of damaging inflammation in their blood vessels. At first, the syndrome was named allergic granulomatosis and angiitis. Originally, for a patient to be diagnosed, they needed to show three specific symptoms:
* High level of eosinophils
* Inflamed and damaged small to medium-sized blood vessels
* Accumulation of immune cells (granuloma) outside the blood vessels
However, as not all patients showed all of these symptoms, more suitable diagnostic criteria were needed.
A new definition proposed by Lanham et al. focused on the following:
* Asthma
* Eosinophil count of over 1500/microliter in the blood
* Inflammation of at least two organs apart from the lungs
The disadvantage of this definition was that the diagnosis could be delayed until two or more body systems showed symptoms, potentially missing earlier cases with a better outlook.
A proposed classification by the American College of Rheumatology in 1990 indicated that four out of six features should be identified for diagnosis:
* Asthma
* Moving infiltration in the lung
* Irregularities in the paranasal sinus
* Mono or polyneuropathy (nerve damage)
* High eosinophil count in the blood (over 10% of white blood cells)
* The presence of eosinophils in tissue biopsy
This proposal made diagnosing EGPA 99.7% specific and 85% sensitive.
Later on, the Chapel Hill consensus conference in 1994 defined EGPA in a simpler way. It was described as inflammation of the respiratory tract, with inflammation of small to medium-sized vessels, and the existence of asthma and high eosinophil levels. The importance of this definition was that it removed the need for a biopsy, therefore, recognizing early cases with only asthma and high levels of eosinophils in the tissue and blood.
What Causes Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)?
In recent times, experts have tried to further classify a disease called eosinophilic granulomatosis with polyangiitis based on if inflammation of the blood vessels, or vasculitis, is present or not, which may seem odd as “polyangiitis” refers to inflammation of many blood vessels.
Patients who have a positive ANCA test (approximately 40% of all patients with this disease) typically have a form of the disease that does involve vasculitis. These patients often experience symptoms like muscle pain, migrating joint pain, weight loss, several nerves being damaged at once, and kidney issues, either as crescentic or necrotizing glomerulonephritis (two types of kidney inflammation).
On the other hand, patients who have a negative ANCA test typically have a type of the disease where there’s an excessive amount of a type of white blood cell called eosinophils, with a higher chance of inflammation of the heart muscle.
However, having a positive ANCA test doesn’t always mean there’s vasculitis. In one study, around 47% patients had vasculitis but their ANCA test was negative, while around 29% were positive for a specific type of ANCA but didn’t have vasculitis.
Around 41% of patients in the study didn’t have vasculitis but instead had an increase in eosinophil cells and involvement. Therefore, these researchers suggest creating a subgroup of patients who show signs of vasculitis.
Signs of vasculitis can include:
– Biopsy-proven inflammation of blood vessels of any organ
– Biopsy-proven necrotizing glomerulonephritis or crescentic glomerulonephritis (two types of kidney inflammation)
– Reddish-purple spots on the skin
– Bleeding in the lungs
– Inflammation of the coronary arteries causing a heart attack
Doctors look for signs that suggest vasculitis:
– Hematuria (blood in urine) with red casts greater than 10%, misshapen red blood cells, and/or protein in your urine
– Inflammation of the smallest blood vessels in your skin called capillaries
Patients who don’t fall into the vasculitic group usually belong to the eosinophilic asthma group. It’s crucial to identify this group early, particularly if they have inflammation of the heart muscle as they might benefit from early targeted therapy.
At the cellular level, the main cause seems to be an overactive T-helper cell pathway.
Different theories exist on what triggers an abnormal immune response in the first place. Some suggest allergies, infections, medications could be the cause. Despite high cases of IgE levels, a type of antibody, the allergy theory has not been proven as only 30% of patients show an allergic reaction to tested allergens. Other theories include colonization of airways with Aspergillus or Actinomyces, and certain medications like sulfonamides, macrolide, and diphenylhydantoin.
However, the strongest link seems to be between the onset of the disease and the use of leukotriene inhibitors montelukast and zafirlukast. In a survey of 181 cases of suspected pharmacologically triggered EGPA, 90% involved leukotriene receptor antagonists.
The role of T cells, a type of white blood cell, in the abnormal immune response has been further proven by the presence of specific, expanded subpopulations of T cells.
Patients also tend to have an increased presence of IL-10, a protein that can inhibit a certain type of immune response, making their immune system tilt towards a type of T-helper cell. It’s mainly seen in patients with ANCA negative disease.
Risk Factors and Frequency for Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
The disease is estimated to affect around 10.7 to 14 out of every million adults across the globe. Most people start showing signs of the disease between the ages of 38 and 54. However, it can appear at any age, even as young as 4 or as old as 74. Both genders have an equal chance of getting the disease.
Unlike some diseases that affect small blood vessels mostly in children, such as Henoch-Schonlein purpura and Kawasaki disease, this disease is not common in children. But both adults and children with this disease show similar symptoms, which include highly elevated IgE and eosinophil levels. Roughly 40% of affected adults and 25% of affected children test positive for ANCA.
Even though the disease presents similarly in adults and children, children with the disease tend to have a higher chance of having heart disease and lung infiltrations, but a lower chance of having multiple nerve inflammation. The increased risk of heart disease in children with this condition, like in adults, raises their risk of death.
Signs and Symptoms of Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
Churg-Strauss syndrome, also known as Eosinophilic Granulomatosis with Polyangiitis (EGPA), causes inflammation in small to medium-sized blood vessels. It affects multiple organs and manifests in two ways – through tissue infiltration or vasculitis (inflammation of blood vessels). This disease progresses in three stages, though not every patient experiences them all or in order. The stages might overlap, tracing the evolution of an individual’s illness.
The first stage or the prodromal phase includes general symptoms like fatigue, fever, pain in multiple joints, and weight loss. Patients may also have severe adult-onset asthma and other respiratory symptoms, such as chronic rhinosinusitis and nasal polyps. Interestingly, these symptoms occur more frequently at the beginning in 37% to 57% of patients.
The second stage involves eosinophilic infiltrates, a type of white blood cell, in different organs and the bloodstream. Features of this phase include non-specific nodules in the peripheral lungs, eosinophilic gastroenteritis (a condition that affects digestive organs) and serosal effusion (fluid accumulation in body cavities).
The third phase is marked by vasculitis (inflammation of blood vessels). This stage can start between 3 to 9 years from the onset of asthma, a common feature in most EGPA patients. Neurological symptoms like weakness or loss of sensation generally hallmark this phase.
Specific symptoms vary as per the organ system involved:
- In the respiratory system, most patients present with asthma (96% to 100%). Many need strong medicines like corticosteroids to control their asthma symptoms. Despite successful control of other disease manifestations, asthma often remains uncontrolled.
- Heart disease can occur in 62% of patients but only shows symptoms in about 26% of cases. Untreated heart changes can lead to poor outcomes.
- Gastrointestinal issues, due to inflammation of the gut lining or the blood vessels supplying the gut, include abdominal pain, nausea, vomiting, and diarrhea. In more severe cases, it can lead to bleeding or intestinal obstruction.
- Renal (kidney) involvement occurs in 25% of patients and is often manifested as necrotizing glomerulonephritis (inflammation and death of kidney cells).
- Neurological involvement can appear as a weakness in the wrist or foot, with peripheral neuropathy affecting about 75% to 80% of patients. Symptoms often improve with standard treatment.
- Lastly, skin manifestations occur in about half to two-thirds of all patients.
Less commonly, the disease can affect the eyes, cause thrombosis (blood clots), affect the salivary glands, and in some instances, the breasts.
Testing for Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
The diagnosis of EGPA, a disease with many different symptoms and manifestations, is largely based on an overall review of these symptoms rather than on specific lab results or tissue samples taken for testing (histopathology). One of the key things for your doctor to recognize is a pattern of problems affecting more than one part of your body, given the nature of this disease.
One of the main lab markers of EGPA is high level of a specific type of white blood cell called an eosinophil (greater than 10% of your total white blood cells or greater than 1500 per dl of blood). They also often see high levels of Immunoglobulin E (IgE), a type of antibody, in about 75% of patients.
Other lab results might show general signs of inflammation and disease, such as a high ESR or C-Reactive Protein (CRP), anemia, or rheumatoid factor (a protein that, when elevated, can suggest autoimmune diseases).
Only around 40% of EGPA patients will test positive for ANCA, a type of antibody that can indicate the presence of certain types of diseases. Two retrospective studies suggested that patients with EGPA that test positive for ANCA were more likely to have kidney disease, certain types of vasculitis, and peripheral neuropathy.
For your doctor to see what’s happening inside the body, they may use a CT scan. CT chest can show unusual infiltrates and bronchial wall thickening. It can also show if you have an excess of fluid in the protective layers surrounding your lungs (pleural effusion), which occurs in about 20% to 30% of cases. CT scans of your sinuses can show swelling and thickening without damage to the bones, which is typical of this condition.
Testing of lung function often shows that about 70% of EGPA patients have some degree of obstruction in the airways. Despite improvement with some treatments, about 40% of patients will continue to have this problem.
Doctors may use a cardiac MRI to check the health of your heart, even if you don’t have any symptoms, because heart problems can make the disease more severe.
If your doctor thinks you may have peripheral neuropathy (nerve damage outside of your brain and spinal cord), a sural nerve biopsy could be carried out. this procedure involves a tissue sample taken from a nerve in your calf.
And finally, skin biopsy, which can often be the easiest and most convenient to carry out, can show signs of vasculitis, an inflammation of the blood vessels, which is commonly seen in EGPA. A kidney biopsy can show evidence of particular types of damage.
Treatment Options for Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
Recognizing and treating Eosinophilic Granulomatosis with Polyangiitis (EGPA), a rare autoimmune disease, early on with drugs like corticosteroids and immune system suppressants can significantly alter its natural progression. This had led to a better prognosis and enhanced overall survival rates for patients.
Corticosteroids are a type of medication that help decrease the level of certain white blood cells, known as eosinophils, in the blood and body tissues. These medications also prevent these specific white blood cells from surviving in tissues outside the blood vessels.
If the disease is not severe, corticosteroids like oral prednisone have been typically used. However, if the disease is serious, it is often more effectively controlled with a large, single dose of corticosteroids like methylprednisolone, potentially in combination with a drug called cyclophosphamide. The dosage of medications is tailored based on the severity of the disease.
Research trials have helped establish standardized treatment plans. In patients with less severe prognosis, corticosteroids alone have brought about remission, the reduction or disappearance of disease signs, in about 93% of patients. However, disease relapse or recurrence was more common in these patients during the reduction of steroid dose, leading to additional use of cyclophosphamide or another drug called azathioprine for maintenance.
In recent years, maintaining remission has proven to be difficult due to a high frequency of disease relapses. While the preferred medications have been established, there is no specific agreement on the ideal length of treatment and which drug should be discontinued first.
If the disease is resistant to treatment or if it frequently relapses and manifests as severe symptoms, the treatment strategy relies on the affected organs. Plasmapheresis, a procedure that filters the blood, is effective and preferred for rapidly progressive kidney disease or lung bleeding. IVIG or Intravenous Immunoglobulin, a therapy that provides the body with antibodies, is considered for treating nerve disease or heart muscle disease which have not responded to conventional therapy.
If the disease is resistant to cyclophosphamide, interferon-alfa, a protein that regulates the immune system, has also been effectively used to induce remission. Some additional options include drugs such as Rituximab, Tumor Necrosis Factor inhibitors, Mepolizumab, and Omalizumab. These drugs are generally in use for moderate to severe persistent asthma with allergic characteristics.
Despite many studies, it is still a challenge to maintain disease remission because of a high incidence of relapses. The best length of treatment and which medications to stop first are still not well established and require further research.
What else can Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome) be?
When a doctor is trying to diagnose a condition known as Eosinophilic Granulomatosis with Polyangiitis (EGPA), there are several possible conditions that might also cause similar symptoms. These can be divided into two main categories: Eosinophilic Lung Diseases, and conditions causing Small and Medium Vessel Vasculitis.
Conditions that are Eosinophilic Lung Diseases could include:
- Acute and chronic eosinophilic pneumonia
- Allergic bronchopulmonary aspergillosis
- Bronchocentric granulomatosis
- Loffler’s syndrome
- Idiopathic hypereosinophilic syndrome
While conditions causing Small and Medium Vessel Vasculitis could include:
- Granulomatosis with polyangiitis
- Polyarteritis nodosa
- Microscopic polyangiitis
Some clues that might point to a different diagnosis include prolonged large amounts of eosinophils in the blood (more than 1500 per cubic mm for over six months), the complete absence of certain proteins called ANCAs, and rare late-onset asthma. This could suggest a condition called idiopathic hypereosinophilic syndrome rather than EGPA. There are also some specific genetic markers that can identify this syndrome.
On the other hand, certain symptoms like kidney damage or specific types of lung or nose damage can suggest a different condition called granulomatosis with polyangiitis.
What to expect with Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
If detected and treated promptly, Churg-Strauss Syndrome (CSS) has a good chance of survival, with 90% of those diagnosed surviving at least five years. There is, however, an estimated relapse rate of 20% to 30%. Relapses are often minor and can include symptoms like fever, joint pain, and other general health symptoms.
Relapse can be influenced by several factors, such as:
* A sudden increase in the number of eosinophils (a type of white blood cell that helps fight off certain infections)
* Persistent ANCA positivity (presence of a type of antibodies linked to autoimmune diseases)
* Problems in the gastrointestinal tract (this includes your stomach and intestines)
* An increase in ANCA titers (the amount of those specific antibodies in the blood)
Just like a high number of eosinophils is a marker for diagnosing CSS, there is a link between the number of eosinophils and the severity of vasculitis (inflammation of blood vessels). An increase in these cells can precede a vasculitis relapse.
A study by Guillevin and others identified 5 factors that relate to higher mortality rates:
* Proteinuria (greater than 1 gm per day) – high levels of protein in the urine
* Renal insufficiency (Creatinine greater than 1.58 mg/dl) – poor kidney function
* Cardiomyopathy – disease of the heart muscle
* Problems in the gastrointestinal tract
* CNS involvement – problems with the central nervous system, which includes the brain and spinal cord
These factors were used to create the Five-Factor Score (FFS), a tool that helps predict the outcome of CSS. The absence of any of the five factors indicates a good prognosis, while having 2 or more increases the risk of death. Of the 5 factors, cardiomyopathy itself carries the highest risk.
The Birmingham Vasculitis Activity Score (BVAS) is a detailed questionnaire with 66 questions used to assess the severity of vasculitis. The Vasculitis Damage Index (VDI) evaluates organ damage from both the disease and its treatment and can provide insight into you prognosis.
Several factors are linked with a worse prognosis, such as:
* Severe problems in the gastrointestinal tract
* Cardiomyopathy
* CNS vasculitis (inflammation of blood vessels in the CNS)
* Renal failure (the kidneys stop working properly)
Cardiac issues are the most common cause of death in patients with poor response to treatment.
Possible Complications When Diagnosed with Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
Asthma, when detected and treated early, generally has a good outlook. However, it often remains stubbornly persistent and affects the quality of life. When asthma symptoms are severe, the patient may need a longer course of treatments, like systemic corticosteroids, than other conditions affecting small blood vessels. According to a study by Solans et al., extended corticosteroid use can lead to a number of side effects. These include:
- Diabetes mellitus
- Myopathy, a disease that affects the muscles
- Osteoporosis and vertebral fractures, conditions that weaken the bones
- Osteonecrosis of the femoral head, a disorder that involves the hip joints
Additionally, almost every patient with EGPA, a rare form of asthma, develops long-lasting issues such as neuralgia (nerve pain) and myopathy (muscle weakness) which are resistant to treatment with steroids.
Preventing Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
Eosinophilic granulomatosis with polyangiitis, previously called Churg-Strauss syndrome, is a type of disease that affects various parts of your body and is caused by an abnormal response from your immune system. If you have uncontrolled asthma symptoms over a long time, along with sinus and nose problems, especially linked with a high count of a specific type of white blood cell called eosinophils, this could be a warning sign of this disease.
Starting treatment quickly with steroids and other medicines meant to weaken your immune system’s response (immunosuppressants), usually leads to good results and a longer life expectancy. However, some symptoms associated with this problem, like bronchial asthma (a type of severe asthma) and certain muscle and nerve weakness, may stick around for life.
It’s crucial to regularly monitor for any unwanted side effects caused by the use of corticosteroids (a group of drugs that includes steroids), since treating this disease may involve using high doses of these medicines for a long time.
Following the doctor’s instructions for diagnosis and treatment is very important. Regular check-ups with your healthcare provider should not be missed once this condition is identified.
