Update on Eosinophilic Lung Diseases

Nitin Y. Bhatt, M.D.; James N. Allen, M.D.

Disclosures

Semin Respir Crit Care Med. 2012;33(5):555-571. 

In This Article

Churg-Strauss Vasculitis

Clinical Presentation

Allergic angiitis and granulomatosis was originally described by Churg and Strauss in 1951 as a necrotizing vasculitis affecting the small and medium-sized vessels with associated eosinophilic infiltrates and granulomas.[47] CSS is classified, along with Wegener granulomatosis and microscopic polyangiitis, as an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

In the classic presentation, patients typically have an initial history of allergic disease for 8 to 10 years before presentation. All patients have asthma or a history of asthma, and most have allergic rhinitis.[48] Dramatic peripheral blood eosinophilia (occasionally as high as 10,000/μl) and infiltration of a variety of tissues with eosinophils follows. Months to years later, a systemic vasculitic phase develops.[49] The mean age of onset of vasculitis is between 38 and 48 years; males and females are affected equally.[50] Interestingly, asthma symptoms may diminish as vasculitis symptoms become more prominent.[48] This triad of asthma, eosinophilia, and granulomatous vasculitis is most characteristic of advanced disease, and patients often present in a prevasculitic phase with less specific clinical and pathological findings.[51] Several organs can be involved in CSS, with the peripheral nerves, lung, and skin being the most commonly affected. Symptoms relate to eosinophilic tissue infiltration or to the development of the vasculitic process.[49,52,53] Upper airway findings can include sinusitis, rhinitis, and nasal polyps. The sinusitis, in contrast to Wegener granulomatosis, is generally not destructive. Skin findings occur in 70% of patients and may include nodules, purpura, or urticaria. Mononeuritis multiplex occurs in 66%, and central nervous system involvement occurs in 27%. Peripheral neuropathy is more likely in patients over the age of 65 than in younger patients.[54] Gastrointestinal symptoms include abdominal pain in 59%, diarrhea in 33%, and gastrointestinal bleeding in 18%. Gallbladder or pancreatic involvement can also be seen. Common cardiac findings include electrocardiographic abnormalities in up to 50%, heart failure in 47%, pericarditis in 32%, and hypertension in 29%. Other studies have also reported significant valvular insufficiency and endomyocarditis as common findings.[55] Cardiac involvement represents the most common cause of mortality. Renal involvement with proteinuria, glomerulonephritis, or insufficiency occurs in up to 30%, but renal failure is not common. Arthralgias or myalgias occur in about half of patients. Most patients have fever and weight loss.[48,50,54] Mild, generalized lymphadenopathy is common.[56] Reversible exophthalmos and hearing loss have also been reported.[57]

CSS has been associated with use of leukotriene antagonists in patients with preexisting asthma.[58] It has been unclear whether these medications actually cause the syndrome. Several studies seem to indicate that, after use of these medications, the permitted reduction of corticosteroids has resulted in unmasking the syndrome in patients previously felt to have simple asthma.[59,60] This effect has also been reported with anti-immunoglobulin E (IgE) antibody therapy.[61,62]

Laboratory

The IgE level is elevated, often to very high levels, and appears to correlate with disease activity.[49,57] Low titers of rheumatoid factors can be found in some patients but complement levels are usually normal.[49] The antinuclear antibody (ANA) is elevated in 10% of patients.[50] ANCA is present in ~40% of patients, usually in the perinuclear (P-ANCA) form.[63] Enzyme-linked immunosorbent assay demonstrates that these are antimyeloperoxidase antibodies.[50] The clinical presentation may vary between those that are ANCA positive and negative. ANCA-positive patients more frequently develop alveolar hemorrhage, glomerulonephritis, and mononeuritis multiplex, whereas ANCA-negative patients more often develop cardiac involvement. The presence of ANCA antibodies has not been shown to affect relapse or survival rates.[53,64] Most patients have anemia and an increased erythrocyte sedimentation rate.[48] Pleural fluid is exudative and may contain high numbers of eosinophils.[53]

The BAL typically shows very high percentages of eosinophils, with an average of 33% in one study.[65]

Pulmonary Function Tests

Pulmonary function tests generally show obstructive defects.[49] After treatment, patients may show partial clinical improvement in asthma severity and pulmonary function testing, but many are left with residual airflow obstruction.[66,67] In a retrospective study, 70% of patients had airflow obstruction at the time of diagnosis with CSS, and 50% had airflow obstruction at the time of clinical remission. Persistent airflow obstruction was found in 38% of patients at 3 year follow-up.[66]

Radiographic Features

Chest x-rays and CT scans show pulmonary infiltrates in the majority of patients (Fig. 3). These are most often patchy and transient; however, diffuse large and small noncavitary nodules and diffuse interstitial infiltrates have been reported. Pleural effusions occur in a third of patients, and hilar lymph node enlargement has occasionally been noted.[53] In some patients, angiograms may show hepatic or renal aneurysms resembling those seen in polyarteritis nodosa.[49]

Figure 3.

Chest x-ray from a patient with Churg-Strauss syndrome showing a peripheral left-sided lung mass.

Pathology

Based on the systemic nature of the disease, biopsy of a variety of organs may be diagnostic. In all organs, CSS can exist in three pathological phases. The earliest or prevasculitic phase is characterized by eosinophilic tissue infiltration without vasculitis. The vasculitic phase comes later and can demonstrate either necrotizing or nonnecrotizing eosinophilic vasculitis, especially of the small arteries and veins (Fig. 4). A late or postvasculitic phase can be seen in patients treated with corticosteroids and reveals thrombosed small blood vessels with healed vasculitis.[25] Because CSS responds quickly to steroids, histological specimens may not show eosinophil infiltration if patients have been treated, even for brief periods of time.[51] Lung tissue in the prevasculitic phase can closely resemble CEP; it can be difficult to distinguish these two diseases on the basis of histology alone, and the diagnosis should always incorporate both clinical and pathological findings. In this setting, the presence of an antimyeloperoxidase antibody favors CSS. Interstitial and perivascular granulomas are common, and eosinophils accumulate in blood vessels, interstitial tissue, and alveolar structures.[48] Transbronchial biopsy is usually insufficient for diagnosis because of the minimal vascular tissue obtained by this procedure.

Figure 4.

Lung biopsy from a patient with Churg-Strauss syndrome. There is perivascular granulomatous infiltrates with eosinophils.

Treatment

Corticosteroids dramatically alter the natural history of CSS. Approximately 50% of untreated patients die within 3 months of onset of vasculitis. In contrast, a mean survival of 9 years was reported in patients treated with steroids.[48] Prednisone in doses of 40 to 60 mg/d is required for several weeks for resolution of the vasculitis, and mononeuritis multiplex may require even longer treatment. Daily or alternate-day low-dose prednisone is typically continued for up to a year; relapses thereafter are uncommon.[49] Treatment of concurrent asthma with inhaled steroids may allow reduction in the dose of oral steroids necessary to control the vasculitis.

In patients who fail to respond to prednisone alone or those with myocardial, renal, or gastrointestinal involvement, the addition of cyclophosphamide is often effective.[50,68,69] Use of cyclophosphamide as a component of the initial treatment of patients with CSS can reduce the incidence of relapse.[70] Prednisone as a sole agent is usually effective in the prevasculitic phase, whereas prednisone plus cyclophosphamide is frequently necessary in patients with vasculitis.

Because only partial improvement in lung function and long-term airflow obstruction is observed in many patients, long-term oral corticosteroids may be necessary to control asthma symptoms.[50,66] Most patients have persistent airflow obstruction despite disease control and long-term oral corticosteroids. Transient increased doses of oral corticosteroids have been reported to improve the response to inhaled bronchodilators and measures of pulmonary function, even in patients receiving chronic therapy with inhaled corticosteroids, bronchodilators, and oral corticosteroids.[66]

Several scoring systems have been developed to assess disease activity and prognosis in patients with vasculitis. The five-factor score (FFS) was developed to predict survival of patients with systemic necrotizing vasculitides according to clinical and biological parameters and was recently revised.[71,72] This includes patients with polyarteritis nodosa (PAN), CSS, Wegener granulomatosis, and microscopic polyangiitis (MPA). The factors significantly associated with higher 5 year mortality were (1) age > 65 years, (2) cardiac symptoms, (3) gastrointestinal involvement, (4) renal insufficiency (stabilized peak creatinine > 150 μmol/L), and (5) the absence of ear, nose, and throat (ENT) symptoms. The presence of each of these factors is worth +1 point. Based on this, the 5 year mortality rates for total scores of 0, 1, and ≥ 2 were 9%, 21%, and 40%, respectively.[72]

Several randomized, controlled trials have used the FFS to assess the response to therapy. In patients without poor-prognosis factors (FFS of 0), clinical remission could be obtained in 93% of patients treated with corticosteroids alone.[73] A significant number of patients (35%) relapsed during the first year of treatment and required treatment with additional immunosuppressive therapy. Patients with poor-prognosis factors (FFS ≥ 1), receiving therapy with 12 intravenous cyclophosphamide pulses in addition to corticosteroids achieved better control than a 6-pulse regimen.[74] There was no statistically significant difference between the two treatment groups in terms of clinical remission, failure of treatment, survival, and major relapses.

In a prospective, randomized trial of 78 patients with CSS and polyarteritis nodosa, plasmapheresis was shown to be ineffective.[75] Alpha interferon was effective in a series of five cases.[76] The anti-CD20 monoclonal antibody rituximab has been shown to be effective in other ANCA-associated vasculitides.[77,78] There have been several case reports of efficacy in CSS, but larger studies have not been reported.[79,80]

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