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NEWSLETTER 12: SINGULAIR-INDUCED CHURG-STRAUSS SYNDROME
Synonyms and related keywords: CSS, allergic granulomatosis angiitis, granulomatous small-vessel vasculitis, syndrome of small- to medium-sized arteries and veins, antibodies to neutrophil cytoplasmic antigens, ANCA, asthma, wheezing, expiratory rhonchi, eosinophilia, paranasal sinusitis, pulmonary infiltrates, vasculitis with extravascular eosinophils, mononeuritis multiplex or polyneuropathy, CSS-like syndrome, allergic rhinitis, eosinophilic pneumonia, gastroenteritis.  Churg Strauss Syndrome is a rare systemic autoimmune disease characterized by inflammation of small to medium sized arteries, arterioles and venules. This inflammatory process of blood vessels is more commonly known as vasculitis. Churg Strauss vasculitis is characterized by the invasion and abnormal increase of a white blood cell known as an eosinophil. The eosinophils cluster together and release harmful granules that collect in different parts of the body as inflammatory nodule lesions. This is called granulomatosis. This eosinophilic inflammation, along with asthma, are the hallmarks of Churg Strauss Syndrome. The inflammatory process can cause impaired blood flow to various organ systems. The resultant damage to different organs may be temporary or permanent. Churg Strauss is a baffling disorder that is difficult to diagnose and one whose effects vary widely from patient to patient. Some people have mild symptoms which barely affect day to day living while others suffer from a wide variety of problems including sinus problems, rashes, lung involvement, peripheral neuropathy, gastrointestinal problems and heart involvement. CSS is not contagious and is not inherited. Its cause is unknown. There is no cure, but many people achieve long term remissions. It affects men slightly more than women. It can affect people of all ages with the average age at diagnosis being 35 to 45. Estimates about the incidence of CSS vary widely and range from 1 in 100,000 to 2.4 in 1 million people, or roughly from 720 to 3,000 people in the United States. CSS was almost always a fatal disease until the discovery of effective drug therapy. Treatment consists of quieting the inflammation of the blood vessels and suppressing the immune system. Although one alarming study gives patients a 62% survival rate after five years, recent advances in diagnosis and treatment have greatly improved those odds. There are patients who have had the disease for over 30 years and are doing well.  Symptoms CSS is a progressive disease consisting of three distinct phases: the allergic stage, the hypereosinophilic stage and the vasculitic stage. With early diagnosis and effective treatment, not everyone diagnosed with Churg Strauss Syndrome experiences all three phases, or experiences them sequentially. The first stage is often called the prodromal phase. Prodromal simply means symptoms that occur at the onset of a disease. This first, allergic phase, is almost always characterized by asthma. Often the individual develops asthma late in life. This is called late onset asthma. Some people who have had asthma throughout their lives experience a worsening of symptoms that become more difficult to treat. Sinus disease, which is characterized by facial pain from sinusitis, nasal polyps, allergic rhinitis (inflammation of the mucous membranes of the nose causing sneezing, itching, runny nose) and recurrent pneumonia and/or bronchitis are also typical of this prodromal phase. This phase can last from 4 to 27 months, although some patients stay in this phase for many years. The next phase is called the hypereosinophilic phase. Hypereosinophilia means there is an overabundance of a certain white blood cell called an eosinophil. This overabundance of eosinophils can occur either in the blood or in the tissues. Often during this phase, patients suffer from chronic eosinophilic pneumonia and eosinophilic gastroenteritis (inflammation of the esophagus, stomach or intestines). The symptoms during this phase can include feeling generally unwell with weight loss, fever, and night sweats. In addition if the lungs are affected, the patient may experience shortness of breath, a feeling of heaviness in the chest and a constant cough. If the gastrointestinal tract is involved people may experience abdominal pain, bloating, vomiting, diarrhea, and nausea. Inflammation of the esophagus may cause dysphagia, or difficulty swallowing. Many people with eosinophilic gastroenteritis find it very difficult to eat. They often experience increasing and sometimes very severe pain after meals. After eating they may experience bouts of vomiting and/or diarrhea, sometimes resulting in weight loss and even anorexia. Some patients get ulcers. Patients may stay in the this second phase for months or years. During this time, their symptoms may become less severe and may even go away, only to recur. Some people experience the second and third phases simultaneously. With treatment and medication some folks never even get to the third phase which is: The systemic vasculitis phase. Systemic vasculitis means that there may be inflammation and damage to blood vessels throughout the body. This, in turn, may cause damage to many different organs. Because CSS can affect so many different organs at this stage, symptoms vary widely depending on the organ affected. General symptoms include fever, weight loss and adenopathy (enlargement of the glands, especially the lymph glands). Common organs affected by CSS include the skin, the heart, the lungs, the central nervous system, the peripheral nervous system, the gastrointestinal tract and less commonly, the kidneys, the eyes and the musculoskeletal system. CSS involving the skin can manifest itself in many way. Rashes, purpura (purplish discolorations caused by bleeding vessels near the surface of the skin) or nodules (solid raised bumps of more than 10 millimeters in diameter) are common. In addition, livedo reticularis (a blotchy mottling of the skin), urticaria (raised red welts) and vesicles (small fluid filled blisters) might occur. If the lungs are involved the following symptoms might be present: cough, shortness of breath, hemoptysis (coughing up blood stained sputum), rales (small clicking, bubbling or rattling sounds in the lung), rhonchi (chest sounds that sound like snoring) and a feeling of pressure in the chest. If the disease progresses to the heart the CSS patient might experience fatigue, dyspnea (shortness of breath), chest pain, irregular heartbeat, increased blood pressure, difficulty in breathing except when upright, swollen legs, appetite loss and fainting episodes. Some of these symptoms are related to pericarditis, which is inflammation of the sac-like covering of the heart, where others are related to congestive heart failure. Heart problems are a leading cause of death in Churg Strauss Syndrome. Involvement of the central nervous system, or the brain, might cause intellectual or motor disturbances, seizures, confusion, difficulty in speaking and headaches. Cerebral hemorrhage is a cause of death in Churg Strauss Syndrome and usually occurs in patients who also have hypertension. Patients more commonly have problems associated with the peripheral nervous system, such as peripheral neuropathy, including mononeuritis multiplex. Symptoms occur in the limbs and include feelings of numbness or hypoesthesia, and hyperesthesia, which is an increased sensitivity to any stimulation and can be experienced as tingling or a burning pain. Other symptoms include abnormal sensations, and difficulty in moving a part of the body. Some people experience foot drop. Patients with foot drop cannot lift up the ankle, straighten or extend the toes, or turn the foot outward. Gastrointestinal problems occur in approximately 40% to 60% of patients whose disease progresses to the vasculitic phase. The main symptoms are severe abdominal pain, bloody diarrhea, vomiting and nausea. The symptoms may be the same or similar to those of eosinophilic gastroenteritis. Some patients may develop obstructions or perforated intestines. Involvement of the musculoskeletal system may result in swelling of the joints, muscle pain and arthritis. Kidney involvement is not common in CSS. If the kidneys themselves are damaged there might not be any symptoms at all. Tests, however might show there to be blood or protein in the urine. Sometimes kidneys can be damaged by obstructive uropathy which occurs when urine cannot drain through a ureter because of a blockage, causing urine to back up into the kidney. Symptoms of kidney involvement include fever, urinary tract infection, nausea, edema (swelling), and difficulty or pain while urinating. Although not common, the optic nerve can be affected by vasculitis causing eye pain and vision problems. During the vasculitic phase patients may be anemic or have low platelet counts, resulting in weakness and fatigue. In addition to all the possible symptoms caused by Churg Strauss Syndrome in any of the three phases, patients might also experience the general effects of anyone who has a a chronic illness, such as depression, fatigue and general malaise. In addition, the medications used to treat the disease may also cause side effects. Treatment sometimes causes the immune system to be suppressed leading to a greater vulnerability to all sort of illnesses, including a greater susceptibility to pneumonia. CSS is a type of vasculitis and people with vasculitis have an increased risk of blood clots. Because it is often hard to sort out what is disease, what are the effects of medications, and what is something else all together, it is helpful to keep a medical journal to keep track of symptoms, problems and concerns for discussion with your doctors. It is easy to feel overwhelmed and discouraged after reading about all the possible problems associated with having Churg Strauss Syndrome, but it is essential to remember that: 1) with early diagnosis and treatment, many people never experience the vasculitic phase of the disease, 2) with effective treatment most of the symptoms in any of the three phases can be relieved, and 3) researchers are working to achieve a greater understanding of the disease which will lead to better treatment and possibly, a cure.  Diagnosis and Tests In 1990 The American College of Rheumatology (ACR) established criteria that distinguished Churg Strauss Syndrome from other vasculitic diseases. A criterion for the classification of Churg Strauss Syndrome was developed by comparing 20 patients who had this diagnosis with 787 control patients with other forms of vasculitis. Six disease features were selected as being those that best distinguished it from other vasculitic diseases. To make a diagnosis of CSS requires at least four out of six of the criteria listed below. The six criteria are:
A classification tree was also constructed with 3 selected criteria: asthma, eosinophilia greater than 10% on differential white blood cell count, and history of documented allergy other than asthma or drug sensitivity. If a subject has eosinophilia and a documented history of either asthma or allergy, then that subject is classified as having CSS. For the tree classification, the sensitivity was 95% and the specificity was 99.2%. When CSS is diagnosed early, patients may have asthma and tissue eosinophilia without detectable vasculitis. They may have eosinophilic pneumonia and/or lymph node involvement. The disease at this early stage can often be treated with steroids instead of more damaging chemotherapy. That is why early diagnosis is so important. Treatment of Churg Strauss Syndrome Once diagnosed with Churg-Strauss Syndrome (CSS), systemic steroids are usually the initial therapy. Prednisone and Medrol are the most commonly used steroids for treatment. Initially, high doses of oral steroids (e.g. 40-80mg) are given in an attempt to get the disease into remission as quickly as possible. Once improvement is seen, the steroids are very slowly tapered down to a lower dose for maintenance. Much of the literature on CSS states that most people are able to completely wean off steroids. However, in our experience that seems to be more the exception than the rule. Most people seem to require a maintence level of steroids indefinitely. For those who have more severe, life-threatening complications or who fail to respond to steroids alone, an additional immunosuppressant drug such as Cyclophosphamide (Cytoxan) may be added. High doses of IV steroids (e.g. Solumedrol) may also be used for more severe cases. Other immunosuppressant drugs, that are usually less toxic can be used and can help you be able to reduce your steroid dose to avoid some of the steroid side effects. These drugs include Methotrexate, Azathioprine, Cellcept, and Cyclosporin. Other treatments that have been known to work in some cases of CSS are IVIG and interferon alpha. IVIG is an infusion of immune globulins. It is a very costly treatment, with fewer side effects than the other traditional treatments. Reports show it to be effective for some especially initially, but some are not able to maintain a good response. Interferon alpha is a man made substance that is part of your immune system. It is given either by IV or injection. The literature on interferon alpha used in treating CSS is mostly encouraging, with most showing some improvement. Unfortunately, most of the treatments for CSS have significant side effects. The key is to try and be maintained on as low a dose of medication as possible to avoid side effects. Many find they can be maintained on fairly low doses of steroids alone after the initial therapy. With any flares of disease a high dose of steroids will again be given and then tapered when symptoms improve. If steroids alone can control the disease they are often the best option. If you continue to have symptoms or “flare” then many times that is when an additional immunosuppressive drug is added. The nature of CSS tends to be one where symptoms go up and down, and you will find that your dosage of medications will also go up and down. It is our hope that more and more research will be done for CSS, and that new medications with fewer side effects will become available. There are a few promising studies researching new medications for CSS. One such study is on the anti-IL-5 drug. In the promising studies so far, it has shown to greatly reduce eosinophil counts and symptoms, with very few side effects. More research is needed and our organization is committed to supporting all research into CSS and the treatments of this disease. PE (Pulmonary Eosinophilia) with only lung involvement. The Loffler syndrome is manifested by a dry cough, wheezing and sometimes fever/myalgia. The blood eosinophilia is modest and chest x-rays show fleeting, peripheral, non-segmental infiltrates. This syndrome is benign, self-limited after several weeks. Chronic Eosinophilic Pneumonia (CEP) occurs mainly in middle-aged individuals (females > males) with fever, night sweats, cough and progressive dyspnea. Blood eosinophilia is present in about 2/3 of patients. Serum IgE levels and the ESR are often increased and the chest x-ray shows typically symmetric peripheral infiltrates called "photographic- negative pulmonary edema." Progressive pulmonary impairment is common with occasional mortality in untreated cases. However, corticosteroid therapy often leads to dramatic improvement. Acute eosinophilic pneumonia looks fairly similar to the chronic version except for a more acute onset and self-limited course. Bronchiolitis Obliterans Organizing Pneumonitis (BOOP) is characterized by cough, dyspnea and eosinophil-rich patchy infiltrates on chest x-ray. The latter occur more in the lower lobes as contrasted to upper lobe predominance in chronic eosinophilic pneumonia. The x-ray infiltrates in BOOP also tend to be triangular and peripheral in distribution. Corticosteroid therapy is usually effective although cytotoxic agent therapy may be needed in some cases. Background: Churg-Strauss Syndrome (CSS), or Allergic Granulomatous Angiitis, is a rare syndrome that affects small- to medium-sized arteries and veins. Wegener's granulomatosis (WG), CSS, and the microscopic form of periarteritis (ie, microscopic polyangiitis) are 3 vasculitic syndromes involving medium- and small-sized vessels that are closely related and are associated with antibodies to neutrophil cytoplasmic antigens (ANCA). In 1951, Churg and Strauss first described the syndrome in 13 patients who had asthma, eosinophilia, granulomatous inflammation, necrotizing systemic vasculitis, and necrotizing glomerulonephritis. The American College of Rheumatology (ACR) has proposed 6 criteria for diagnosis of CSS. The presence of 4 or more criteria yields a sensitivity of 85% and a specificity of 99.7%. These criteria are:
 Pathophysiology: CSS is a granulomatous small-vessel vasculitis. The cause of this allergic angiitis and granulomatosis is not known. No data have been reported regarding the role of immune complexes or cell-mediated mechanisms in this disease, although autoimmunity is evident with the presence of hypergammaglobulinemia, increased immunoglobulin E (IgE) levels, rheumatoid factor, and ANCA. A CSS-like syndrome develops as a rare complication in people with asthma who are steroid dependent and who are treated with leukotriene receptor antagonists (eg, montelukast, zafirlukast) with reduction in their oral steroid dose. The CSS-like complication is reported in people whose withdrawal of oral steroids is facilitated by inhaled steroids as well. This complication might be related to steroid withdrawal, which unmasks underlying CSS, rather than to the drugs themselves. However, in rare cases, this syndrome has occurred when a leukotriene receptor antagonist has been substituted for inhaled steroids, without a history of oral steroid withdrawal. Frequency:
Age: The age at onset varies from 15-70 years, with a mean of approximately 38 years. History: CSS has 3 phases—allergic rhinitis and asthma; eosinophilic infiltrative disease, such as eosinophilic pneumonia or gastroenteritis; and systemic medium- and small-vessel vasculitis with granulomatous inflammation. The vasculitic phase usually develops within 3 years of the onset of asthma, although it may be delayed for several decades. The most prominent symptoms and signs are the ones related to pulmonary, cardiac, dermatologic, renal, and peripheral nerve involvement. Mononeuritis multiplex is a major clinical finding. The following list includes the symptoms and signs of the disease as reported by Guillevin et al (1999) in his case series:
An article by DuMouchel from AT&T Labs — Research, Florham Park, New Jersey and Eric T. Smith PharmD from The Risk Management and Pharmacovigilance Group, Global Clinical Safety and Pharmacovigilance, GlaxoSmithKline, Research Triangle Park, North Carolina appeared the July 2004 Clinical therapeutics Volume 26 Issue 7 Pages 1092-1104 entitled, "Association of asthma therapy and Churg-Strauss Syndrome: An analysis of postmarketing surveillance data." In it they discuss Churg-Strauss syndrome (CSS), also known as Allergic Granulomatous Angiitis (AGA), and that it is a rare vasculitis that occurs in patients with bronchial asthma. The nature of the association of CSS/AGA with various asthma therapies is unclear. This study investigated the associations of different multidrug asthma therapy regimens and the reporting of AGA by searching the FDA's Adverse Event Reporting System [AERS] for AGA (Allergic Granulomatous Angiitis) or CSS (Churg Strauss Syndrome) associated with asthma treatments, including: ICS (Inhaled Corticosteroids); LTRA (Leukotriene Receptor Antagonist); SABA (Short-Beta 2-Agonist); or LABA (Long-Acting Beta 2-Agonist). They found a strong association between LTRA use and AGA. AGA was also associated with the ICS, SABA and LABA classes. However, the latter associations were mostly dependent on the presence of concurrent LTRA and, to a lesser extent, oral corticosteroid therapy and became negligible for patients who were not receiving these concurrent treatments. Differences based on relative reporting were observed in the patterns of association of AGA with LTRA, ICS, and Beta 2-agonist therapies. A strong association between LTRA use and AGA was present regardless of the use of other asthma drugs. In a Lancet 2003 February 15;361 article by Noth et al he states that treatments that block cysteinyl leukotriene receptors (LTRA like Singulair) have been assessed. Although evidence points clearly to a fortuitous association, possibly related to withdrawal of corticosteroids during treatment and unmasking of forme frustes Churg-Strauss syndrome, the role of drugs in the cause of the disorder is not entirely resolved. CSS may develop after exposure to certain drugs (Singulair), corticosteroid withdrawal, and in association with pulmonary infections. These events could initiate an inflammatory cascade (22, 23,24). This inflammatory cascade can lead to CSS. In a letter to the editor in Lancet 2003 May 17;361(9370):1746 in reference to the Noth article, Wardle speculates on how the association of CSS with use of leukotriene antagonists (Singulair) has occurred. Dendritic cells produce and are responsive to leukotriene B4, (25) but that does not seem to offer an answer. He states that he could speculate that, since eosinophils produce 15-hydroxyeicosatetaraenoic acid (15-HETE), which is implicated in endothelial-cell proliferation in some circumstances, that leukotriene-receptor blockade might influence that. Differential Diagnosis Acute Mesenteric Ischemia Antiglomerular Basement Membrane Disease Asthma Cryoglobulinemia Eosinophilia Eosinophilic Gastroenteritis Eosinophilic Pneumonia Glomerulonephritis, Crescentic Goodpasture Syndrome Hypereosinophilic Syndrome Infective Endocarditis Leukocytoclastic Vasculitis Microscopic Polyangiitis Pneumonia, Bacterial Polyarteritis Nodosa Wegener's Granulomatosis  Other Problems to be Considered: Glomerulonephritis, segmental Nephritis, acute Allergic bronchopulmonary aspergillosis Asthma Other vasculitis syndromes (including Wegener's granulomatosis) Medication-induced eosinophilia Other causes of Pulmonary Infiltration with Eosinophilia (PIE) Lab Studies:
Glomerulonephritis is not as common or severe as in WG, but, when present, it usually is focal and segmental and indistinguishable from other forms of so-called pauci-immune (without significant tissue deposition of immune complexes) glomerulonephritis. Medications Glucocorticoids alone usually are adequate for treatment of CSS. Cytotoxic drugs like Cytoxan (Cyclophosphamide) are necessary in fewer than 20% of patients. Major life-threatening organ involvement may require treatment with pulse doses of IV corticosteroids as well as other cytotoxic agents. Other treatments include intravenous immune globulin, interferon-alpha, and plasma exchange. Plasma exchange has not improved the course of the disease. Further Inpatient Care:
 Some drugs, like Singulair, are associated with CSS. In the product insert for Singulair Merck describes the following: Eosinophilic Conditions; in rare cases, patients with asthma on therapy with SINGULAIR may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral (and systemic) corticosteroid therapy. (Physicians should be quick to discontinue Singulair and Advair, search for evidence of systemic vasculitis and be especially alert to the following especially in patients with Pneumonitis plus Eosinophilia):
It is my humble opinion that a causal association between Singulair and CSS already exists. I believe Merck says it doesn’t because a randomized, double-blind, placebo controlled trial is not done yet comparing Singulair with placebo in high risk patients with signs and symptoms as follows:
On the FDA's website in December 1998 a letter from Louis M. Sherwood, M.D., Senior Vice President, Medical and Scientific Affairs appeared where he says, "...we have become aware of case reports in which patients who were receiving SINGULAIR presented with eosinophilic conditions sometimes consistent with the Churg-Strauss syndrome (CSS). Patients presenting with these conditions had significant asthma histories and were receiving multiple asthma medications, often including systemic corticosteroids. On review some of these cases had features consistent with these conditions present prior to initiation of therapy with SINGULAIR. In most but not all of these cases clinical features associated with CSS occurred or worsened during corticosteroid reduction. A causal association between SINGULAIR and these underlying conditions has not been established."  An article by Robert S. Rust, Jr., MD appeared in emedicine 18 November 2003 entitled, "Churg Strauss Disease." In it he states that Leukotriene-receptor antagonists are used in some patients who are undergoing withdrawal of steroid treatment of asthma. This has prompted some clinicians to ascribe the onset of Churg-Strauss disease to steroid withdrawal rather than to direct effects of the leukotriene-receptor antagonist. However, several patients who were not in the midst of a steroid taper have developed Churg-Strauss disease after administration of leukotriene-receptor antagonists. Some authorities now recommend the use of inhaled steroids rather than leukotriene-receptor antagonists when attempting to taper systemically administered steroid treatment of asthma.  An article by Katsura et al appeared in the Annals of Internal Medicine 2003; 139:387 entitled: "The Churg-Strauss Syndrome after pranlukast treatment in a patient not receiving corticosteroids." This stresses the fact that LTRAs are directly associated with CSS independent of exposure to systemic steroids. This helps to diminish the form fruste theory of Singulair use allowing the steroid dose to taper down and reveal latent CSS that was there all the time but merely masked by the steroids. An article by Lipworth (26) appeared in The Lancet where he described There have been several case reports of patients with corticosteroid-dependent asthma who developed a Churg-Strauss-like syndrome (allergic angiitis and granulomatosis) in association with starting zafirlukast, usually associated with a reduction in concomitant systemic corticosteroid therapy. Subsequently, there were similar reports after the launch of montelukast in 1998. He references Wechsler’s article (27). He suggests that leukotriene antagonists should not be used as a substitute in patients dependent on systemic corticosteroids. Further pharmacovigilance data are required with both drugs (Singulair & Accolate) to investigate whether this finding is a class effect of leukotriene antagonists in terms of uncovering underlying Churg-Strauss-like syndrome. Other experts believe Singulair is a risk factor for CSS and label patients who have this "allergic" to Singulair. There are case reports describing CSS in patients not on systemic steroids. Physicians should use caution when they co-prescribe steroids and Singulair. Articles that support this can be found as follows: A case review by Oberndorfer et al from the Department of Neurology and Ludwig Boltzmann Institute for Neurooncology, Kaiser Franz Josef Hospital, Vienna, Austria. stefan.oberndorfer@kfj.magwien.gv.at appeared in Neurologia. 2004 Apr;19(3):134-8. He presents a 79-year-old male patient with bronchial asthma for twenty years was admitted due to progressing gait disorder developing within the last two weeks. Asthma had been treated with a leucotriene receptor antagonist (Montelukast) for four years, as well as low doses of inhaled steroids and beta-2-agonists. (No systemic steroids). Laboratory examination showed leucocytosis and marked eosinophilia. A diagnosis of CSS was made. This case demonstrates a severe neuropathy in an asthmatic patient, during long lasting treatment with a LTA (Singulair) and continuous low doses of inhaled steroid, as the initial clinical feature of CSS. A case review by Michael et al from Birmingham Heartlands Hospital, Bordsley Green, Birmingham B9 5SS, UK. abmichael@ukonline.co.uk appeared in Age Ageing. 2003 Sep;32(5):551-2 entitled, Montelukast-associated Churg-Strauss syndrome. In it he describes a 68-year-old asthmatic presented markedly unwell with arthralgia, mononeuritis multiplex, peripheral neuropathy, and eosinophilia. His past medical history included perennial rhinitis, and nasal polyps. Three months prior to admission his prednisolone was stopped and Montelukast was started. The diagnosis of Montelukast-associated Churg-Strauss syndrome was made. The drug was stopped and steroids started with general improvement and reduction of eosinophilia; however, the neurological deficit persisted. A case report by Mukhopadhyay et al from Department of Medicine, Lister Hospital, Coreys Mill Lane, Stevenage, Herts SG1 4AB, UK appeared in Postgrad Med J. 2001 Jun;77(908):390-1 entitled, “Churg-Strauss syndrome associated with montelukast.” In it he describes how Churg-Strauss syndrome (CSS) has recently been reported in patients with asthma receiving leukotriene receptor antagonists (LTRAs). In this paper a case of CSS after treatment with montelukast is described. As in other LTRA treated cases, prior withdrawal of maintenance oral steroid may have unmasked a previously occult CSS in the patient, but a dramatic improvement in his eosinophilia after withdrawing montelukast implied that the drug also had a direct effect in activating this condition. This helps to show cause and effect linking Singulair with CSS. In the J Thorac Imaging. 2005 May;20(2):74-80 Silva et al from the Department of Diagnostic Imaging, University Federal of Sao Paulo, Brazil published a radiology article entitled, “Churg-Strauss syndrome: high resolution CT and pathologic findings.” The main high-resolution CT findings of Churg-Strauss syndrome consist of airspace consolidation or ground-glass opacities, septal lines, and bronchial wall thickening. These reflect the presence of eosinophilic infiltration of the airspaces, interstitium, and airways, and interstitial edema. Villena et. al. sent a letter to the editor of the European Respiratory Journal Volume 15 Page 626 - March 2000 Volume 15 Issue 3 entitled, "Montelukast and Churg-Strauss Syndrome." They report a case of Churg-Strauss Syndrome (CSS) while the patient was on montelukast (Singulair) treatment. This patient had not been on steroid treatment, other than inhaled, for the past 10 months, and so, in this patient, CSS was not a consequence of decreasing the steroid doses, as has been previously suggested in some cases with zafirlukast or pranlukast. Although the causal role of these drugs in CSS is not completely clarified, we think that reporting such cases will help to determine the clinical impact of this complication and that these drugs should be withdrawn if the patient develops vasculitis. Deanna L McDanel Department of Pharmaceutical Care, University of Iowa Hospitals and Clinics published in the Dov Medical Press in Print ISSN: 1176-6336 Volume: 1 | Issue: 2 Cover date: April 2005 Page(s): 125-140 an article entitled, "The linkage between Churg-Strauss syndrome and leukotriene receptor antagonists: fact or fiction?" In it she describes Epidemiologic evidence has shown that the worldwide prevalence of asthma is increasing. The leukotriene receptor antagonists (LTRAs) represent a new class of therapy for asthma. They have been developed in the last decade and play a pivotal steroid-sparing role in treating the inflammatory component of asthma. Consequently, reports of Churg-Strauss syndrome (CSS), a rare form of systemic vasculitis, have been recognized as a potential side effect in individuals with moderate to severe asthma on LTRA therapy. The serious nature of this disorder is worthy of prompt recognition by clinicians and aggressive therapy to avoid the subsequent longstanding effects of vasculitis. To validate the postulated linkage between the LTRAs and CSS, this review comprehensively evaluates reported cases in the literature and supports a pathophysiological relationship between the LTRAs and the development of CSS. A case report by Tuggey et. al. appeared in Thorax 2000;55:805-806 (September) entitled, "Churg-Strauss syndrome associated with montelukast therapy." They report a case of Churg-Strauss syndrome in a patient with late onset asthma who developed clear-cut eosinophilic vasculitis in association with worsening asthma which developed a few days after commencing montelukast (Singulair). She had not been receiving continuous systemic corticosteroid previously. We believe that this is the first case of Churg-Strauss syndrome associated with montelukast in a patient not previously taking either continuous or multiple short courses of oral corticosteroids. Donohue from University of North Carolina/Chapel Hill Chapel Hill had a letter to the editor of Chest published 2001;119:668 entitled, "Montelukast and Churg-Strauss Syndrome." In it he reviews the March 2000 article by Wechsler et. al. where they stated that the relationship between montelukast and Churg-Strauss syndrome (CSS) is not a direct drug effect, but rather it arises from unmasking a previously existing condition via corticosteroid withdrawal. However, since the true background incidence of CSS in asthmatics remains unknown, the possibility that leukotriene modifiers have a causative role in CSS, perhaps due to an allergic response, remains equally plausible. First, there seems to be a high total number of cases of CSS associated with leukotriene-modifying agents. Wechsler and Drazen reported that, as of July 1999, there had been at least 52 suspected cases of CSS associated with zafirlukast, 42 of which were confirmed by Zeneca (Wilmington, DE); and at least 52 suspected cases of CSS associated with montelukast, 36 of which were confirmed by Merck (Whitehouse Station, NJ). A recent presentation indicated that > 100 cases of CSS have been reported to the US Food and Drug Administration, in association with the use of leukotriene modifiers. Historically, there was no similar increase in the number of CSS cases when cromolyn was introduced for the treatment of perennial asthma in 1973. There was a report of a few cases that appeared to match the description of CSS. Unfortunately, no data were reported on the incidence of CSS for the years following the introduction of beclomethasone dipropionate and triamcinolone in this country. These drugs also were widely used as oral steroid-sparing agents. Perhaps their manufacturers could provide additional data on the occurrence of CSS with these agents. Data from the United Kingdom, from the Medicines Control Agency Committee on Safety of Medicines, reported 63 cases of CSS through the Yellow Card Scheme since 1963. Of these, 59 cases were documented during the 2-year period from 1998 to 1999, and 90% of the cases were associated with drugs used to treat asthma, particularly leukotriene receptor antagonists. Indeed, in many cases there was documented evidence of reduction or withdrawal of oral corticosteroid therapy prior to the onset of the reaction. Although the reliability of reporting cases of CSS by general practitioners is questionable, it is important to note that other steroid-sparing agents introduced in the United Kingdom during that period, such as beclomethasone, budesonide, and salmeterol, were not accompanied by a similar rise in CSS, although occasional case reports were noted. In addition, cases of CSS have been observed in steroid-naïve individuals. This possibility is also mentioned by the manufacturer in the package insert. In light of the above, the concluding statement by Wechsler et al, that "montelukast does not appear to directly cause the syndrome (CSS) in these patients," would seem to be somewhat premature. Clearly, further study is imperative. A case report appeared in Chest. 2001;120:2116 by Sabio et. al. from Grenada Spain entitled, "More About Churg-Strauss Syndrome and Montelukast (Singulair) Treatment." In it they present the case of a 49-year-old woman with a 15-year history of allergic rhinitis and mild-to-moderate asthma, for which she received only the inhaled ß2-agonist Salmeterol twice daily, but with good control of her disease. She had never received inhaled or systemic corticosteroids. (Thus refuting the argument regarding how it has been suggested that the reduction or withdrawal of systemic or inhaled corticosteroid therapy because of the clinical improvement of asthma after leukotriene-modifying drug treatments may play a decisive role in the appearance of a fruste form of Churg-Strauss syndrome (CSS) that previously existed.) Five months after her physician changed her regimen from Salmeterol to montelukast, she presented with arthralgias in her hands and feet, vomiting, severe abdominal pain, anemia, leukocytosis with hypereosinophilia (40%), and an accelerated erythrocyte sedimentation rate. A laparotomy was performed, and inflammation in the first portion of the duodenum was observed. Histologic examination revealed a necrotizing vasculitis with extravascular granulomas, which is compatible with CSS. Montelukast therapy was discontinued, and high doses of corticosteroids and an IV bolus of cyclophosphamide (Cytoxan) were prescribed. Thus, they report an unusual and severe case of CSS with GI involvement that developed 5 months after montelukast therapy was started in a patient who had never used systemic or inhaled corticosteroids for asthma treatment. We do not know whether the appearance of CSS after montelukast use in our patient could be due to a casual association, but we cannot rule out a possible pathogenic link between leukotriene-modifier drug use and CSS development. An article by Franco J; Artés MJ appeared in Thorax - 01-JUN-1999; 54(6): 558-60 that describes Pulmonary Eosinophilia that developed while the patient was receiving treatment with montelukast (Singulair) who in the past was on intermittent pulse therapy with oral corticosteroids for allergic rhinitis and asthma; but not currently. After discontinuation of montelukast (Singulair) therapy and administration of systemic corticosteroids the patient's symptoms reversed rapidly and there was prompt resolution of the pulmonary infiltrates. Caution is needed for those patients with more severe disease who require systemic corticosteroids, especially if they show characteristics of the atypical allergic diathesis seen in the prodromal phase of Churg-Strauss syndrome. A case report in Norwegian by Hammer entitled, "Churg-Strauss syndrome after treatment with Singulair (montelukast)" appeared in the Tidsskr Nor Laegeforen. 2002 Feb 20;122(5):484-6 where they state: Montelukast (Singulair) is the only available antileukotriene drug in Norway. In the literature there are some reports on an association between the use of the leukotriene antagonists zafirlukast, pranlukast, montelukast (Singulair) and the appearance of Churg-Strauss syndrome. This rare syndrome is a systemic vasculitis characterized by allergic rhinitis, asthma and prominent peripheral blood eosinophilia. This is a case report of the appearance of Churg-Strauss syndrome in a 20-year-old asthmatic woman treated with montelukast and with no recent oral corticosteroid use. To our knowledge, this is the first report in a Nordic country of an association between montelukast and Churg-Strauss syndrome. Although this is a rare association, the clinicians need to be vigilant in all patients who develop systemic symptoms when starting treatment with leukotriene antagonists. An article by Conen D et al appeared in the Swiss Med Wkly. 2004 Jun 26;134(25-26):377-80 entitled, "Montelukast and Churg-Strauss syndrome." They describe a case that is noteworthy because the time course of events strongly suggests a direct aetiological role for montelukast (Singulair) in the development of CSS. An article by Boccagni C appeared from the Department of Neurology, A. Avogadro University, Corso Mazzini 18, I-28100 Novara, Italy, form Neurol Sci. 2004 Apr;25(1):21-2 entitled, “Churg-Strauss syndrome associated with the leukotriene antagonist montelukast.” In it they state that Recently, several cases of CSS have been reported in patients treated with leukotriene antagonists (Singulair) after weaning corticosteroids. We describe a case of CSS developed while the patient was receiving montelukast for asthma treatment, after corticosteroids withdrawal. A causal relationship between montelukast therapy and CSS is hypothesized. A French paper appeared in Rheumatology 2002; 41: 535-539 by P. Guilpain, et. al. entitled, "Churg–Strauss syndrome in two patients receiving montelukast." In it they describe Churg–Strauss syndrome (CSS) has been described in association with the treatment of asthmatic patients with leukotriene receptor antagonist. The main mechanism proposed to explain this condition is the unmasking of CSS after the leukotriene receptor antagonist has allowed corticosteroid tapering. Other hypotheses might be proposed. They described two patients who developed CSS after starting treatment with montelukast, a new antileukotriene drug. Both patients presented with CSS after 4–5 months of treatment with montelukast. Neither patient received long-term systemic steroids for asthma, but both were on inhaled steroids. One patient had a myocardial involvement and experienced a stroke. Our two patients were treated with systemic steroids and cyclophosphamide. Their conclusion was CSS does not appear to relate to steroid tapering in our patients. The other hypotheses are a coincidence or a direct adverse effect of the antileukotriene. Long-term data on these drugs are lacking and leukotriene's role in vasculitis remains to be elucidated. A case report was published in Thorax 2002;57:183-185 by R Solans, et al. entitled, "Montelukast and Churg-Strauss syndrome." In it they describe: Several cases of eosinophilic conditions including Churg-Strauss syndrome (CSS) have recently been reported in asthmatic patients being treated with antileukotriene receptor antagonists. One patient with CSS who experienced a clinical relapse after treatment with montelukast and two asthmatic patients who developed CSS while receiving montelukast treatment are described. In one case reduction in the dose of oral steroid preceded the onset of CSS. To our knowledge, no case of CSS relapse has previously been reported in association with leukotriene antagonists. An editorial in Chest. 2000;118:1515-1516 by Stoloff, et al entitled, "Is There an Association With Leukotriene Modifiers?" In it they refute the conclusion of an article by Wechsler and colleagues (March 2000)1 that addresses the question of the association of Churg-Strauss syndrome (CSS) and the use of montelukast in the treatment of patients with asthma. They call for the manufacturers of the leukotriene modifiers and the ICS to present to an expert panel their reports of CSS in patients on these therapies. An article by Pagnoux et. al. appeared in Clinical Pulmonary Medicine 11(6):349-354, November 2004 entitled, "Churg-Strauss Syndrome and Leukotriene-Modifying Agents." In it they describe that Churg-Strauss syndrome (CSS) is a primary systemic necrotizing vasculitis of unknown origin, which is typically characterized by the association of asthma and blood eosinophilia. Leukotriene-modifying agents include zileuton, a 5-lipoxygenase inhibitor, and 3 selective leukotriene type 1 receptor antagonists (LTRA: zafirlukast, montelukast (Singulair), and pranlukast) that have all been approved for the treatment of persistent asthma. Since 1996, when the first LTRA (Singulair) became available, more than 100 cases of CSS possibly related to LTRA use have been recorded by the US Food and Drug administration, and more than 50 cases have been described in the literature. These CSS developed 2 days to 15 months after LTRA introduction. Their clinical and biologic manifestations were similar to those of CSS occurring independently of LTRA use; however, the former (Singulair-induced CSS) may develop more often cardiomyopathy, but neuropathy and anticytoplasmic autoantibody positivity less frequently than in the latter form of CSS. Notably, outcome after LTRA discontinuation and under systemic steroid therapy was usually good. These cases of CSS may result from the unmasking of an underlying incipient "forme fruste" of the vasculitis, during the steroid withdrawal or tapering made possible by LTRA therapy, or from a direct causal role of LTRA. Pertinently, these hypotheses are not exclusive and, until further studies clarify this point, the wisest strategy seems to be to discontinue or avoid their use in CSS patients, to carefully monitor asthmatic patients taking these drugs and to remember that CSS onset may resemble a worsening of persistent mild or severe asthma.  References Sincerely: Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP Member, ACFEI (American College of Forensic Examiners Institute of Forensic Science) Expert Medical Witness, ExpertMD PI (Principal Investigator), DSI (Drug Study Institute) Board Certified Internist, JPMC (Jupiter Preventive Medicine Center) DABIM (Diplomat American Board of Internal Medicine) FACP (Fellow American College of Physicians) CPI (Certified Physician Investigator) by the APPI (American Academy of Pharmaceutical Physicians) CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals) CCI (Certified Clinical Investigator) by the DIA (Drug Information Association) CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals) CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates) Member, SIMPD (Society for Innovative Medical Practice Design) Member, ACPM (American College Preventive Medicine) Ethics Committee Member, Jupiter Medical Center IRB Member, Jupiter Medical Center Founder, CertifiedResearchers.com |