Churg-Strauss Disease Clinical Presentation

Updated: Jul 21, 2020
  • Author: Nir Shimony, MD; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP  more...
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Presentation

History

Clinical features of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), follow two-pronged themes of eosinophilic tissue infiltration or small- and medium-vessel vasculitis. Lanham divided the clinical evolution of EGPA into 3 phases. [4]  Yet, the clinical course of a specific patient does need to include all of them. They may even overlap in the natural history of an individual’s disease.

First phase

The initial prodromal phase commonly includes nonspecific symptoms of malaise, fever, migrating polyarthralgia, and weight loss along with a severe adult-onset form of asthma that is refractory to conventional treatment. The bronchial asthma is the initial disease manifestation in as many as 80%–90% of cases of EGPA. [27]  The asthma is severe in as many as one third of all patients. An additional 6% will develop asthma within a year of onset of manifestations in other organ systems. In most series, bronchial asthma is the first clinical feature and is the nearly constant finding of the first phase, preceding fever or eosinophilia. Some authors have estimated that less than 3% of all individuals who develop EGPA have no asthma as an element of their presentation.

  • Additional findings that often precede or accompany the first phase of EGPA include allergic rhinitis, nasal polyposis, sinusitis, and recurrent bronchitis, or pneumonia. Nasal rhinitis and polyposis, in particular, are likely to precede the onset of reactive airway disease. Upper respiratory symptoms are more common with chronic rhinosinusitis (47%–93%) and nasal polyps (62%–77%). However nasal granulomas, erosion, and crusting or epistaxis as seen in GPA are absent here.
  • An additional historical fact of importance is the recent addition of leukotriene receptor antagonists to the treatment regimen for asthma. This association is found in perhaps half of cases; in three quarters of these patients, the addition of those drugs was made within 3 months prior. [33]
  • The presence of an asthmatic condition (usually steroid-dependent) is the historical feature that most commonly prompts consideration of EGPA in individuals who manifest any of the many vasculitic abnormalities of various other organ systems that may be present in ensuing stages of the disease.
  • Recurrent fevers of unclear etiology and weight loss, either of which may occur in the first phase of illness in more than half of individuals developing EGPA, enable the careful clinician to suspect that EGPA underlies the allergic and asthmatic manifestations. Another clue is the fact that the reactive airway component of EGPA tends to develop at a later age (commonly, the fourth decade of life) than is typical for idiopathic asthma. However, fairly typical early childhood-onset asthma may presage the development of the vasculitic stages of EGPA in adolescence.
  • Diffuse myalgia and polyarthralgia have been reported in 37%–57% of EGPA patients, particularly at the onset of disease. [101]
  • Exceedingly rarely, EGPA pathogenesis may result in development of the systemic vasculitic stages of EGPA in individuals who do not have either asthma or eosinophilia.
  • However, also remember that it is possible for asthmatic individuals to develop vasculitic or inflammatory diseases other than EGPA as explanations for the disease of either pulmonary or nonpulmonary organ systems. The occurrence of tissue and blood eosinophilia provides an additional important clue in the individual who has asthma and abnormalities of sudden onset in several organ systems that EGPA is the likely cause of the various organ system disease manifestations noted below as comprising the systemic vasculitic stages of EGPA.
  • The duration of the first phase, prior to progression of illness, averages about 28 months (range, 4–72 mo). However, a few patients remain in the prodromal stage of illness for 30 years or more before the second or third phase of EGPA manifests.
  • The frequency of CSD–related reactive airway disease increases and the severity of the disease worsens, as the vasculitic stage of EGPA is reached. In some cases, an unexpected remission of asthma occurs with the onset of vasculitic manifestations of the second phase of EGPA.

Second phase

During the second phase of illness, eosinophilic infiltrates are seen in end organs along with peripheral eosinophilia. Patchy peripheral nodular pulmonary infiltrates, eosinophilic gastroenteritis, serosal effusion, are common. Hence, hypereosinophilia of blood develops in association with tissue eosinophilia and Loeffler syndrome. During this phase, the eosinophils comprise on average 40% of the WBC count on peripheral blood film (range, 18%–65%). Particularly characteristic complications of this phase of illness are chronic eosinophilic pneumonia and eosinophilic gastroenteritis. Hemoptysis may occur. Patients experience a relapsing and remitting course of eosinophilic infiltrative disease and blood eosinophilia.

In some instances, the second phase of illness consists of the combination of chest pain, shortness of breath, and development of cardiogenic shock. ECG may suggest myocardial infarction, although coronary arteries may appear normal on angiography. Valvular insufficiency and segmental or global hypokinesis of the myocardium may be found. These findings suggest EGPA myocarditis. [28]

Fever always is present during periods of exacerbation.

Third phase

This is a late phase that can present 3 to 9 years after the onset of the initial asthma. It is characterized by systemic vasculitis and neurologic sequela.

Before the presence of this phase, the patient has intermittent bouts of symptoms that were mentioned in the two previous phases. Patients with continued reactive airway manifestations may experience remission, often to a remarkable extent, at the onset of this third phase of the disease. As vasculitis develops and worsens, weight loss may be noted.

In some fulminant cases, systemic vasculitic manifestations may develop without a prior second phase of relapsing-remitting complications. In other cases, the second and third phases of EGPA develop simultaneously. The interval between first and third phases of EGPA is prognostically significant. As might be expected, the shorter the duration of that interval, the worse the prognosis.

Signs and symptoms may include any of the following:

  • Symptoms related to congestive heart failure ranging from congestive heart failure to cardiogenic shock. ECG may suggest myocardial infarction, although coronary arteries may appear normal on angiography. Valvular insufficiency and segmental or global hypokinesis of the myocardium may be found, all in keeping with EGPA myocarditis.
  • Neurologic findings are most commonly peripheral polyneuropathy, usually mononeuritis multiplex pattern with motor and sensory deficits unexplainable by a single central lesion. Deficits tend to be asymmetrically distributed, involving individual peripheral nerves without reference to specific fiber types. The distribution is not in the "glove-stocking" distribution suggestive of toxic neuropathies. Peripheral muscle stretch reflexes may be diminished or lost. Sensory disturbances may include hypoesthesia, hyperesthesia, allodynia, or other forms of pain. Pain and paresthesia tend to involve the legs. However, other manifestations may result in vasculitic disease of the brain with stroke or hemorrhage. These may result in abrupt onset of motor, intellectual, or sensory deficits, brainstem signs, stupor, or coma. Seizures may occur.
  • Eosinophilic gastroenteritis may result in abdominal pain, weight loss, or bloody diarrhea.
  • Skin changes may include the development of petechiae and palpable purpura.
  • Acute renal failure, developing rapidly over several weeks, is a characteristic feature of the rapidly progressive glomerulonephritis of EGPA. Gross hematuria or pyuria may be found. These findings, due to inflammatory glomerulonephritis, may be misinterpreted as urinary tract infection.
  • Testicular pain may occur in men with EGPA.

Organ system involvement

Different organs are affected by the disease, and many of the manifestations are related to vasculitis and hence hemorrhages or thrombosis-related symptoms (e.g., retinal artery or vein occlusion). [126]

Respiratory and pulmonary manifestations

Asthma in the prodromal phase is seen nearly in all the cases, and it is reported in 96% to 100% patients. The mean age of onset of asthma is 35 to 50 years. As mentioned above there is debate about whether some asthma medications from the leukotriene receptor antagonists family, montelukast as well as omalizumab, can trigger the eruption of EGPA. The asthma tends to be severe and progressive with up to 75% of patients becoming steroid-dependent even before the diagnosis of EGPA is achieved. 

EGPA patients tend to present with adult-onset asthma with an eosinophilic phenotype. The asthma is accompanied by upper airways manifestations like rhinitis, sinusitis, and nasal polyposis. Chronic rhinitis is the most common extra-thoracic manifestation occurring in about 75% of cases.

Asthma tends to be the last manifestation, if at all, to respond to treatment. Even when most of the symptoms are under control, asthma tends to stay active. The involvement of the respiratory system involves parenchymal eosinophilic infiltration as well as the vasculitic process, upper respiratory allergic response, and eosinophilic asthma. During the first two clinical phases described, transient pulmonary infiltrates and eosinophilia is common, whereas in the vasculitic phase, necrotizing vasculitis and granuloma are more common. Alveolar hemorrhage is reported more often in ANCA-positive cases and hence is less common among EGPA patients than in GPA patients.

Cardiac involvement

The cardiac manifestation of EGPA can be devastating. The cardiac injury can include coronary artery disease, primary arrhythmias, cardiomyopathy, acute constrictive pericarditis, myocarditis, and eosinophilic pericardial effusion. The cardiac involvement happens in about two-thirds of cases, yet most will not be symptomatic. It is caused by both mediators released from activated eosinophils as well as vasculitis lesions in the myocardium and coronary arteries. The myocarditis can lead to post inflammatory fibrosis and restrictive cardiomyopathy. Cardiac changes are associated with a poor prognosis and high mortality if left untreated. [127]

Gastrointestinal involvement

The involvement of the gastrointestinal system is related to infiltrates as well as the eosinophilic response. Gastroenteritis can evolve as a result of eosinophilic reaction, usually with prodrome of abdominal pain, nausea, vomiting, and diarrhea or more severe complications like bleeding or intestinal obstruction (mediated by submucosal nodular masses). In some cases the gastroenteritis is accompanied by mesenteric vasculitis. The vasculitis can lead to ischemic bowel, mucosal ulceration, and even perforation necessitating exploratory laparotomy. Serosal involvement can cause eosinophilic ascites and peritonitis. In rare cases the gastroenteric system will have manifestations of necrotizing acalculous cholecystitis, pancreatitis, and eosinophilic liver disease. [40]

Renal involvement

Renal involvement is seen in 25% of patients. The renal manifestations can include necrotizing crescentic glomerulonephritis, focal sclerosing disease, IgA nephropathy, or eosinophilic interstitial nephritis. Necrotizing crescentic glumeronephritis is the most common. Biopsy alone is not enough to establish diagnosis in many cases. Hypertension is seen in up to one third of cases and might reflect early renal involvement in EGPA. [27]

Neurologic involvement 

Neurologic injury can involve the peripheral (up to 80% of cases) as well as the central nervous systems (up to 40% of cases). The injury involves different kinds of neuropathies as well as possible brain vasculitis that can lead to brain infarcts and hemorrhages in some cases. [129] The peripheral injury usually includes mononeuritis multiplex or mixed sensorimotor peripheral neuropathy. Common peroneal and internal popliteal nerves are most commonly involved in lower limbs, while radial and ulnar nerves in upper limbs are usually affected in those cases that have upper limbs involvement. [117]  Cranial nerve palsies can be found in some cases and usually will include the optic nerves. The neurologic injury in EGPA, although quite common, is usually efficiently treated with the regular systemic treatment of EGPA.

Skin involvement

Up to two thirds of cases will have skin manifestations. Palpable purpura without thrombocytopenia is the most common finding as well as extravascular granulomas, scalp nodules, urticarial rashes, skin infarcts, livedo reticularis, and other changes that are consistent with leukocytoclastic vasculitis.

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Physical

In the first phase of Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), examination reveals nasal polyposis, intermittent fever, and findings consistent with sinusitis, allergic rhinitis, and bronchial asthma. The signs of reactive airway disease gradually worsen over time.

During the systemic vasculitic phase, examination of the skin, heart, abdomen, joints, peripheral nerves, and muscles may reveal evidence for the various characteristic changes of EGPA as noted in History. Two thirds of patients in this advanced state of illness are found to have cutaneous purpura or nodules.

Cardiopulmonary findings that are consistent with congestive heart failure, low-output state, or pericardial effusion may be discerned.

Abdominal tenderness and evidence for gastrointestinal bleeding may be found on examination. Occasionally, the examination reveals evidence of bowel obstruction. The findings of acute abdomen develop in patients with bowel perforation.

Arthritis may be noted; any joint may be involved.

Neurologic examination

In patients in the systemic vasculitic phase of illness, neurologic examination may reveal evidence of peripheral neuropathy limited to the extremities. At first, the pattern usually is that of mononeuritis multiplex, but with progression of illness, asymmetrical sensory and motor polyneuropathy is found (legs > arms).

Neurologic findings tend to develop late. Pulmonary manifestations with eosinophilia usually establish the diagnosis of EGPA prior to the development of neurologic disease.

The examination may disclose CNS manifestations due to intraparenchymal or subarachnoid brain hemorrhages.

Optic neuritis, cranial neuritis, and psychosis have been described in adults with EGPA.

Children seldom manifest CNS findings. One girl with EGPA, who was in the early years of the second decade of her life, developed chorea.

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Causes

Genetic factors

Several lines of evidence suggest a genetic predisposition to Churg-Strauss disease (CSD), now known as eosinophilic granulomatosis with polyangiitis (EGPA), which may entail an inherited tendency to dysregulation of the cellular immune system. The features of this dysregulation are discussed in Pathophysiology.

The variation in age at onset of illness is not understood, but this variation suggests the possibility that secondary factors, such as environmental influences, may hasten the onset of disease for some individuals.

Environmental factors

Environmental factors may contribute to the development of EGPA. For example, the inhalation of fungal spores, such as those produced by actinomycetes and Aspergillus species, has been implicated in the pathogenesis of some cases.

Exposure to pigeons and the molds associated with their roosts may provoke the development of EGPA.

Smoking free-base cocaine was documented carefully as a circumstance preceding individual bouts of an illness similar to or identical to EGPA in one individual. The illness in that case was not sustained endogenously, recurring only with additional episodes of cocaine smoking. [26]

In summary, some environmental factors appear to provoke transient effects that resemble EGPA, but do not represent a chronic and self-perpetuating disease.

Drugs

Carbamazepine, macrolide antibiotics, and cysteinyl leukotriene-receptor antagonists have been implicated as provocative causes of EGPA. Leukotriene-receptor antagonists may be especially important in terms of provoking chronic EGPA that does not resolve with discontinuation of the inciting drug.

Leukotriene-receptor antagonists are used in some patients who are undergoing withdrawal of steroid treatment for asthma. This has prompted some clinicians to ascribe the onset of EGPA to steroid withdrawal rather than to direct effects of the leukotriene-receptor antagonist. They propose that EGPA manifestations were masked or perhaps prevented by the higher steroid doses. However, several patients who were not in the midst of a steroid taper have developed EGPA 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.

EGPA has developed in the wake of Basedow disease with autoimmune thyroiditis; whether this is a chance association is not known.

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