Chest Film Clinic: What caused progressive dyspneain this patient with chronic asthma?

A 51-year-old man with a 20-year history of asthma and seasonal allergies presented with low-grade fever, progressive dyspnea on exertion, and wheezing that had persisted for 2 weeks. Four days earlier, he had been seen by his primary care physician and had started levofloxacin therapy. However, his respiratory symptoms had worsened, warranting hospitalization. He also reported pain in the abdomen and left flank and pain and swelling in the right metacarpophalangeal and right shoulder joints.

The patient's daily medications included salmeterol and budesonide. He reported intermittent use of albuterol, particularly before exercise. Within the previous year, he had required multiple brief courses of prednisone for asthma exacerbations, which represented worsening of his asthma control compared with previous years.

Two months before presentation, he was treated with antibiotics for left lower lobe pneumonia. Within the 6 months before presentation, he had multiple, recurrent episodes of sinus congestion and purulent discharge, which were treated with 3 courses of antibiotics and nasal irrigation with a mucolytic agent.

He had a family history of asthma. He was a chiropractor, and he denied significant occupational exposures; contact with birds or other animals, except for a pet dog; recent travel; and exposure to tuberculosis. He also denied smoking.

The patient was in no acute distress, with normal pulse, respiration rate, and blood pressure. His temperature was 37.7ºC (99.8ºF). Oxygen saturation was 99% on room air. Auscultation of the lungs revealed bilateral diffuse expiratory wheezing. The remaining examination findings were remarkable for erythematous patches on the scalp and mild erythema and tenderness in the metacarpophalangeal joints of the right hand.

Peak expiratory flow rates in the setting of acute symptoms were 300 L/min, compared with his baseline of 500 L/min. Laboratory tests revealed a white blood cell (WBC) count of 17,400/µL, with 48% neutrophils, 3% bands, 11% lymphocytes, 4% monocytes, and 34% eosinophils. Other findings: a hematocrit value of 40.3%, with mean corpuscular volume of 97 fL; platelet count of 569 3 10³/µL; erythrocyte sedimentation rate (ESR) of 67 mm/h; and an IgE level of 935 IU/mL. Rheumatoid factor and antinuclear antibody test results were negative.

The patient's chest radiograph obtained on admission is shown below (Figure 1).

Making the diagnosis

The patient's chest radiograph revealed nonsegmental areas of consolidation with a predominantly peripheral and upper lobe distribution. An additional focus of consolidation was seen in the lingula.

Axial CT scanning of the chest with coronal reformations demonstrated peripheral, nonsegmental foci of airspace consolidation and ground-glass opacities (defined as hazy areas of increased opacity that do not obscure normal vascular structures) in both upper lobes (Figure 2). Less prominent ground-glass opacities were present in the right middle lobe, lingula, and the lower lobes.

These findings were new compared with those from a CT scan obtained 4 months earlier for follow-up of small noncalcified lung nodules. The number and size of mediastinal lymph nodes were increased. Prominent bilateral hilar lymph nodes appeared unchanged from the previous CT scan. A concurrent CT scan of the sinuses revealed sinonasal polyposis.

Based on the imaging findings of peripheral lung opacities, along with the history of asthma and eosinophilia, the patient was thought to have eosinophilic pneumonia. Levofloxacin was discontinued, and oral prednisone therapy was initiated. The patient remained afebrile, and his respiratory status improved. He was discharged. A chest radiograph at 1-week follow-up demonstrated marked improvement in pulmonary opacities. He was maintained with oral prednisone, 40 mg daily.

Three months later, the patient presented with a 10-day history of intermittent, periumbilical abdominal pain, which was sharp and burning, worse after eating, and worse when lying flat or with movement. The patient denied fever and shortness of breath. His WBC count was 21,500/µL, with 8% eosinophils.

Abdominal CT findings were compatible with gastroparesis. Results from an upper endoscopy demonstrated mild gastritis and duodenitis. Results of antral and duodenal biopsies, performed while the patient was taking prednisone, did not reveal any evidence of eosinophilic gastroenteritis. The patient's symptoms were relieved by metoclopramide.

On admission, the patient reported a 2-month history of transient, migratory distal muscle weakness and paresthesias. The symptoms began after a low-speed motor vehicle accident and were initially associated with neck stiffness. Findings from MRI of the head and cervical spine performed at another institution were reportedly normal.

A left exophthalmus and right-sided ophthalmoplegia localized to the inferior oblique muscle developed 2 to 4 months after admission. Polyneuropathy secondary to Churg-Strauss syndrome was suspected. Results of a left sural nerve biopsy, performed while the patient was taking prednisone, showed no significant inflammation. However, based on the constellation of imaging, clinical, and laboratory findings, a diagnosis of Churg-Strauss syndrome was made.

Discussion

Churg-Strauss syndrome is a rare, necrotizing vasculitis that occurs almost exclusively in patients with asthma. Affected patients typically also have allergic rhinitis and recurrent rhinosinusitis. This disorder is characterized by peripheral eosinophilia, tissue eosinophilia, and a necrotizing eosinophilic vasculitis that may affect most major organ systems. Pulmonary involvement is nearly universal. Neurologic, skin, GI, cardiac, and renal manifestations of vasculitis are also common.¹

Most patients with Churg-Strauss syndrome experience all 3 phases of the disease. The prodromal, or allergic, phase involves asthma and rhinosinusitis. The eosinophilic phase of this syndrome is characterized by peripheral and tissue eosinophilia, with eosinophilic pneumonia and gastroenteritis being especially common.

The vasculitic phase involves a necrotizing eosinophilic vasculitis of medium-sized and small vessels, which is often associated with vascular and extravascular granulomas and may affect most major organ systems. Constitutional symptoms, including fever and weight loss, commonly signal the beginning of the vasculitic phase.¹

The pathophysiology of Churg-Strauss syndrome is unknown. In 1998, an association between this syndrome and asthma treatment with a leukotriene receptor antagonist was proposed.² It was suggested that the syndrome might represent an idiosyncratic or hypersensitivity reaction to this class of medications.

An alternative theory is that the syndrome may be triggered by the reduction in oral corticosteroid therapy that occurs with the addition of a leukotriene receptor antagonist to an asthma regimen. Interestingly, the development of Churg-Strauss syndrome is frequently associated with a taper of oral corticosteroid treatment, which may indicate unmasking of previously suppressed disease. According to the 2001 FDA report to the NIH, no single antiasthma drug is causatively associated with Churg-Strauss syndrome.³

• Diagnosis: The diagnosis of Churg-Strauss syndrome is often missed initially. Asthma is commonly associated with allergic rhinitis or sinus disease, and the early manifestations of the syndrome usually precede the onset of vasculitis by several years.

In 1951, Churg and Strauss first described this syndrome (initially named allergic granulomatosis and angiitis) based on pathologic criteria established by autopsy findings. Their criteria included necrotizing vasculitis of medium-sized to small arteries and veins, eosinophilic perivascular infiltration, and extravascular granulomas. However, later studies showed that all 3 criteria were present in fewer than 20% of patients.¹

Subsequently, the syndrome was redefined on the basis of clinical findings, with or without pathologic data. In 1990, the American College of Rheumatology established the following 6 criteria:

• Asthma.

• Peripheral eosinophilia greater than 10%.

• The presence of mononeuropathy or polyneuropathy.

• Pulmonary opacities.

• Paranasal sinus abnormalities.

• Extravascular eosinophilic infiltration on biopsy findings.⁴

The presence of 4 of 6 criteria is 85% sensitive and 99.7% specific for Churg-Strauss syndrome. The syndrome remains a clinical diagnosis that should be considered in patients who have asthma and peripheral eosinophilia or pulmonary opacities. While pathologic confirmation of tissue eosinophilia or vasculitis is helpful, an invasive biopsy is not always feasible in acutely ill patients who require therapy.¹

No laboratory findings are specific for Churg-Strauss syndrome. Peripheral eosinophilia is frequent but nonspecific. About 50% to 75% of patients test positive for antineutrophil cytoplasmic antibodies (ANCA) directed against myeloperoxidase with a perinuclear staining pattern (p-ANCA). p-ANCA also may be found in other systemic vasculitides, including microscopic polyangiitis and Wegener granulomatosis, although a positive test for ANCA with a cytoplasmic staining pattern is more likely to occur in patients with Wegener granulomatosis. Patients with Wegener granulomatosis or microscopic polyangiitis usually do not have asthma or peripheral eosinophilia.

Other laboratory abnormalities in Churg-Strauss syndrome may include normocytic anemia, leukocytosis, an elevated ESR, an elevated IgE level, circulating immune complexes, hypergammaglobulinemia, and a positive rheumatoid factor at a low titer.¹

In 96% to 100% of patients, asthma develops early in the course of the disease. In rare cases, asthma coincides with or follows the onset of vasculitis. Although the severity of asthma tends to increase, it may demonstrate paradoxical improvement early in the vasculitic phase. In more than 80% of patients, asthma persists after successful treatment of vasculitis.¹

Pulmonary eosinophilic disease is present in most patients. A high percentage of eosinophils is usually present in bronchoalveolar lavage fluid. However, this finding may also be seen in persons with acute and chronic eosinophilic pneumonia, allergic bronchopulmonary aspergillosis (ABPA), hypereosinophilic syndromes, helminthic or other infections, and other lung diseases.

Chest imaging studies in patients who have Churg-Strauss syndrome usually reveal transient abnormalities. Although the radiographic features are diverse, the most common presentation consists of nonsegmental areas of consolidation without any zonal predominance. The areas of consolidation typically demonstrate a characteristic peripheral distribution. Less common radiographic findings include pulmonary nodules, diffuse reticulonodular opacities, and bronchial wall thickening. Diffuse alveolar opacities may represent alveolar hemorrhage.^1,5 Pleural effusions are present in 30% of patients.⁶

High-resolution CT (HRCT) findings are characterized by nonsegmental, ground-glass opacities and/or areas of consolidation with a predominantly peripheral distribution. Less commonly, a random distribution may be seen. Multiple 1- to 3-cm pulmonary nodules are a less common manifestation of Churg-Strauss syndrome. Unlike in Wegener granulomatosis, cavitation of the nodules rarely occurs.

Other HRCT findings may include small centrilobular nodules and interlobular septal thickening. The latter may represent eosinophilic infiltration or pulmonary edema secondary to cardiac involvement.^7,8 Bronchial dilatation and bronchial wall thickening are identified by HRCT in 35% of patients. Because these findings are also identified in about one third of patients with asthma, they are likely related to the asthma component of Churg-Strauss syndrome.⁸

^{A variety of pulmonary complications may be encountered in patients with asthma, including atelectasis, pneumonia, mucoid impaction, ABPA, and eosinophilic lung disease. Like Churg-Strauss syndrome, ABPA and eosinophilic lung disease are associated with eosinophilia. ABPA is characterized on HRCT by distinctive tubular and branching endobronchial opacities, often with central bronchiectasis--imaging findings that are not likely to be confused with Churg-Strauss syndrome.}

^{In contrast, the HRCT features of chronic eosinophilic pneumonia can be identical to those of Churg-Strauss syndrome. Thus, it may not be possible to distinguish Churg-Strauss syndrome from eosinophilic pneumonia by CT findings alone.}7,8

Churg-Strauss syndrome has a good prognosis, with a remission rate of 81% to 92%. Asthma symptoms tend to persist during treatment and remission. Approximately one fourth of patients experience relapses; 40% of relapses occur within the first year of treatment. In patients who have recurrent disease, the mortality rate is estimated to be about 3%. The most frequent cause of death is severe end-organ vasculitis, followed by cardiac involvement. Poor prognostic factors include coronary vasculitis; cardiomyopathy; congestive heart failure; and severe GI disease with bleeding, perforation, or necrosis.¹

• Treatment: First-line therapy for patients who have Churg-Strauss syndrome consists of systemic corticosteroids. High-dose oral prednisone is usually administered for a month or longer, until there are no remaining clinical signs of disease; it is then tapered slowly. The recommended total duration of corticosteroid therapy is, at a minimum, 1 year. Some patients require long-term therapy with low-dose prednisone or with inhaled corticosteroids for persistent asthma.

Adjuvant cyclophosphamide is used in patients who have severe end-organ vasculitis, who have not responded to corticosteroids, or who have relapsed. Cyclophosphamide increases the rate and rapidity of remission, but it has not been shown to improve 10-year survival.¹

Response to therapy may be assessed by monitoring the severity of vasculitis symptoms and the levels of inflammatory markers, such as ESR. Peripheral and sputum eosinophilia correlate with disease status, decreasing during treatment and increasing during a relapse. Pulmonary opacities resolve in patients who respond to therapy.¹

Data on the use of p-ANCA levels to monitor disease activity are limited. In most patients who test positive for p-ANCA, antibody titers become undetectable in remission. However, the titers do not reliably increase during relapses.^9,10

The outcome in this case

Once the diagnosis of Churg-Strauss syndrome was established, the patient's prednisone dosage was increased and cyclophosphamide was added to his regimen. His respiratory, abdominal, and neurologic symptoms abated; the ESR decreased; and peripheral eosinophilia resolved. Follow-up chest radiographs showed no recurrent abnormalities. Cyclophosphamide was discontinued after 1 year. However, the patient continued to have frequent asthma exacerbations and required long-term prednisone therapy.

References:

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