Update on eosinophilic lung diseases.

The eosinophilic lung diseases are a group of pulmonary disorders characterized by an increase in blood and/or lung eosinophils. These disorders can be primary pulmonary disorders or the secondary manifestation of other systemic or pulmonary conditions, infection, drug reaction, or malignancy. The approach to a patient with eosinophilic lung disease involves a thorough history and physical examination, review of exposures and appropriate testing, often including bronchoscopy or lung biopsy, to establish a specific etiology and determine therapy. Eosinophilic lung disease can be suspected based on either the finding of pulmonary disease with blood eosinophilia, pulmonary disease with bronchoalveolar lavage eosinophilia, or pulmonary disease with lung tissue eosinophilia on lung biopsy.

The role of anti-endothelial cell antibody-mediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease.

We encountered 16 patients with connective tissue disease in whom pulmonary fibrosis developed. Routine light microscopic, ultrastructural, and direct immunofluorescent analyses were conducted, and circulating antibodies, including those of endothelial cell derivation, were assessed using indirect immuno-fluorescence and Western blot assays. Underlying diseases were dermatomyositis, scleroderma, mixed connective tissue disease, sclerodermatomyositis, Sjögren syndrome, rheumatoid arthritis, and anti-Ro-associated systemic lupus erythematosus. Antibodies to one or more Ro, RNP, Jo 1, OJ, and/or nucleolar antigens were seen in all cases and antiphospholipid antibodies in half. All biopsies revealed microvascular injury in concert with intraparenchymal fibrosis; in some cases, there were corroborative ultrastructural findings of microvascular injury. Patterns of fibroplasia represented nonspecific interstitial pneumonitis and usual interstitial pneumonitis. We noted IgG, IgA, and/or complement in the septal microvasculature. In 6 cases with available serum samples, indirect immunofluorescent endothelial cell antibody studies were positive and Western Blot studies showed reactivity of serum samples to numerous endothelial cell lysate-derived proteins. Pulmonary fibrosis, a recognized complication of systemic connective tissue disease, develops in connective tissue disease syndromes with pathogenetically established immune-based microvascular injury at other sites. A similar mechanism of antibody-mediated endothelial cell injury may be the basis of the tissue injury and fibrosing reparative response.

Idiopathic pulmonary fibrosis related to endothelial injury and antiendothelial cell antibodies.

Mechanisms underlying idiopathic pulmonary fibrosis are not well understood. This paper presents data supporting the hypothesis that microvascular endothelial cell injury and antiendothelial cell antibodies play roles in human idiopathic pulmonary fibrosis. Serologic and pathologic features of 40 patients diagnosed with idiopathic pulmonary fibrosis were evaluated. All patients had open lung biopsies indicating either usual or nonspecific interstitial pneumonitis. All biopsies had morphologic evidence of microvascular injury to the endothelium, and direct immunofluorescence testing revealed variable deposition of IgG, IgM, or IgA within septal microvasculature suggestive of humorally mediated microvascular injury. Ultrastructural studies revealed changes of endothelial cell injury and necrosis and evidence of repetitive episodes of microvascular injury characterized by basement membrane zone collagen deposition and lamellation. Serum samples demonstrated reactivity to multiple endothelial cell antigenic epitopes, and indirect immunofluorescent testing demonstrated a prominent pattern of fluorescence in pulmonary endothelial cell preparations. Serum samples were positive in 37/40 patients for antiphospholipid antibodies with one fourth having positive lupus anticoagulant tests accompanied by thrombotic episodes. In patients with idiopathic pulmonary fibrosis, Factor VIII levels and C-reactive protein levels were also elevated, supporting the presence of endothelial cell injury and inflammation. These data underscore a potential role for immune-based microvascular injury in the evolution of usual or nonspecific interstitial pneumonitis and indicate that those patients have evidence of microvascular injury and endothelial cell necrosis. The high prevalence of antiphospholipid antibodies in these patients may lead to an inherent thrombophilic tendency.

Cytomegalovirus-associated pulmonary septal capillary injury sine inclusion body change: a distinctive cause of occult or macroscopic pulmonary hemorrhage in the immunocompetent host.

The authors describe four patients with symptomatic lung disease morphologically representing a septal capillary injury syndrome temporally associated with serologic and culture evidence of active cytomegalovirus (CMV) infection but without classic cytopathic changes. The authors conducted a thorough review of clinical data, microscopic examination, and in situ hybridization to detect CMV mRNA encoding immediate early protein. The assay detects transcripts that encode early and immediate early proteins. In two cases additional tissue was available for direct immunofluorescent studies. The disease process in each of the patients was morphologically indistinguishable from the pattern of organ injury associated with autoimmune diseases including a small vessel microvascular injury syndrome involving skin and lung and immune complex- mediated glomerulonephritis. Cytopenias were seen in all cases, most commonly thrombocytopenia. All treated patients demonstrated improvement on combined ganciclovir and low-dose steroid therapy. CMV infection may be of pathogenetic importance in some cases of alveolar hemorrhage, especially when accompanied by peripheral blood cytopenia in otherwise healthy patients and if clinical worsening occurs in the setting of a traditional immunosuppressive regimen typically used to treat vasculitis.

Drug-induced eosinophilic lung disease.

For most patients who have suspected drug-induced eosinophilic lung disease, the history provides a presumptive diagnosis that can be confirmed by pulmonary findings and eosinophilia after cessation of the drug. As new drugs are developed and released for clinical use, many will result in eosinophilic lung disease in susceptible patients. Therefore, development of pulmonary abnormalities in conjunction with blood or lung eosinophilia after prescription ofa newly released medication should raise the possibility of drug-induced lung disease, even if that medication has not yet been reported to cause eosinophilic lung disease. In all patients, the diagnosis requires exclusion of other causes of eosinophilic lung disease by history, and, if necessary, laboratory testing or lung biopsy.

The eosinophilic pneumonias.

Acute and chronic eosinophilic pneumonia can be distinguished by their clinical, laboratory, and radiographic features. Patients with both acute and chronic eosinophilic pneumonia present with cough, dyspnea, and fever. Patients with chronic eosinophilic pneumonia present subacutely over weeks to months but patients with acute eosinophilic pneumonia present within 5 days of symptom onset. Chest radiographs in chronic eosinophilic pneumonia show peripheral alveolar infiltrates. In contrast, radiographs in acute eosinophilic pneumonia show mixed interstitial and alveolar infiltrates, Kerley B lines, and pleural effusions. Both disorders are characterized by high percentages of bronchoalveolar lavage eosinophils, but high numbers of blood eosinophils accompanies only chronic eosinophilic pneumonia. The diagnosis of both disorders can usually be made based on clinical and radiographic findings; however, lung biopsy is occasionally necessary to distinguish the eosinophilic pneumonias from other eosinophilic lung diseases. In both conditions, patients will respond rapidly and completely to corticosteroids but patients with chronic eosinophilic pneumonia usually relapse if less than 6 months of treatment is given, whereas patients with acute eosinophilic pneumonia do not relapse after a brief course of treatment.