Interrelationship of chronic eosinophilic pneumonia, bronchiolitis obliterans, and rheumatoid disease: a hypothesis.

Three patients with histologically proven bronchiolitis obliterans are presented, two of whom had rheumatoid disease. All three patients had, in addition, clinical and radiological evidence of chronic eosinophilic pneumonia; open lung biopsy in two showed coexistent features of chronic eosinophilic pneumonia and bronchiolitis obliterans. The association of both rheumatoid disease are chronic eosinophilic pneumonia with bronchiolitis obliterans in these patients may simply be coincidental, but the striking similarities between the cases suggest that a real interrelationship of these disease entities may exist.     

Total serum IgE levels in eosinophilic lung diseases]

BACKGROUND: We previously reported elevated levels of total serum IgE in patients with asthma, regardless of their atopic status. We hypothesized that certain factors inherent to asthma may contribute to this non-specific elevation of total serum IgE. In the current study, to evaluate the role of eosinophils in the regulation of total serum IgE, we examined whether peripheral blood eosinophil count is associated with total serum IgE level in patients with eosinophilic lung diseases. METHODS: Ninety-nine healthy controls, 277 patients with asthma, 15 patients with acute eosinophilic pneumonia, 21 patients with chronic eosinophilic pneumonia were studied for total serum IgE levels and peripheral blood eosinophil counts. RESULTS: Patients with acute or chronic eosinophilic pneumonia had significantly increased total serum IgE levels compared with healthy controls regardless as atopic status (p<0.001). In non-atopic subjects with eosinophilic lung diseases, total serum IgE level was significantly correlated with peripheral blood eosinophil count (r=0.42, p<0.001, n=57). CONCLUSION: Our findings suggest that, in addition to antigen-specific IgE production, non-specific IgE production may contribute to elevated levels of total serum IgE in patients with asthma or eosinophilic pneumonia. An increased number of activated eosinophils may underlie an increased total serum IgE level in these conditions.     

Pulmonary Eosinophilia

Eosinophils may infiltrate the lung tissue, thus impairing gas exchange and causing several symptoms as dyspnea, fever, and cough. This process may be secondary to several factors, including drugs or parasite migration, or primary (idiopathic). Acute eosinophilic pneumonia is life-threatening and presents frequently in young smokers as an acute hypoxemic respiratory failure of generally less than a week with bilateral lung infiltrates, frequently misdiagnosed as severe community-acquired pneumonia. This patients present without peripheral eosinophilia but usually have more than 25% eosinophils on bronchoalveolar fluid. Chronic eosinophilic pneumonia is a protracted disease of usually more than a month before presentation, with a predilection for middle aged asthmatic patients. Hypoxemia is mild-moderate, and there are usually more than 1,000 eosinophils/mm3 of peripheral blood. Bronchoalveolar fluid has high eosinophil levels (usually more than 25%). Migratory peripheral infiltrates are seen in the chest x-ray film. Both acute and chronic eosinophilic pneumonia are treated by glucocorticoids and respiratory support as well as avoidance of any recognized trigger.     

Cigarette smoking-induced acute eosinophilic pneumonia: a case report including a provocation test

The mechanism and cause of acute eosinophilic pneumonia are largely unknown. Many factors including the smoking of cigarettes have been suggested, but none have been proven to directly cause acute eosinophilic pneumonia. The authors report a case of acute eosinophilic pneumonia in a young Asian male who recently started smoking. The diagnosis was made based on his clinical course and results of chest radiography, lung spirometry, bronchoalveolar lavage, and transbronchial lung biopsies. After administration of methylprednisolone, his clinical course rapidly improved. A provocation test was designed to establish a connection between cigarette smoking and the development of acute eosinophilic pneumonia. After the provocation test, the patient showed identical symptoms, increase in sputum eosinophils, and worsening of pulmonary function. The results of the provocation test suggest that smoking may directly cause acute eosinophilic pneumonia, and support previous reports of cigarette smoking-induced acute eosinophilic pneumonia.     

Parainfluenza virus‐3‐induced cytopathic effects on lung tissue and bronchoalveolar lavage fluid in a bone marrow transplant recipient

Parainfluenza virus type 3(PIV‐3) commonly causes respiratory tract infections in hematopoietic stem cell transplant (HSCT) patients. The majority of PIV‐3 infections develop in patients who have undergone stem cell transplantation from unrelated donors. From these patients, bronchoalveolar lavage (BAL) fluid and/or lung biopsies are often collected and sent for evaluation of infectious processes. However, cytologic findings associated with a PIV‐3 infection in BAL fluid have not been reported in the literature. We describe BAL cytology and lung biopsy findings in a patient who received an HSCT from a related donor and subsequently developed a PIV‐3 infection. This patient was noted to have scattered reticular‐nodular opacities in both lungs on computed tomogram scan and underwent transbronchial biopsy and BAL of the left lower lobe. Examination of the BAL fluid revealed scattered multinucleated giant cells intermixed with inflammatory cells. The lung biopsy showed organizing pneumonia associated with several multinucleated respiratory epithelial cells containing rare intracytoplasmic inclusions. Gram, periodic acid Schiff, Gomori methenamine silver, and acid fast stains on the biopsy specimen failed to reveal microorganisms. A sample of the BAL fluid sent for respiratory viral culture grew PIV‐3. These findings suggest that the presence of giant cells in transplant patients with organizing pneumonia should raise suspicion of a PIV‐3 infection. Diagn. Cytopathol. 2014;42:521–524. © 2013 Wiley Periodicals, Inc.     

Pulmonary eosinophilic syndromes

Acute eosinophilic pneumonia, chronic eosinophilia, Churg-Strauss syndrome, and the hypereosinophilic syndrome are pulmonary eosinophilic syndromes characterized by an increased number of eosinophils in peripheral blood, in lung tissue, in sputum, in bronchoalveolar lavage fluid, or in all of these. These pulmonary eosinophilic syndromes generally are characterized by increased respiratory symptoms, abnormal radiographic appearance, and the potential for systemic manifestations. It is critical to exclude other causes of eosinophilia in patients who have lung disease, to make a quick diagnosis, and to treat aggressively with corticosteroids and other therapies to prevent long-term sequelae.     

Elevated soluble ADAM8 in bronchoalveolar lavage fluid in patients with eosinophilic pneumonia

BACKGROUND: ADAM (a disintegrin and metalloprotease) family members, characterized by a metalloprotease and a disintegrin domain, are membrane-anchored glycoproteins involved in proteolysis and cell adhesion. ADAM8 might have an important role in allergic inflammation. It can cleave a variety of substrates and is a sheddase for VCAM-1 and CD23, the low-affinity IgE receptors. METHODS: To evaluate the contribution of ADAM8 to the pathogenesis of eosinophilic pneumonia (EP), we measured the concentrations of soluble ADAM8 (sADAM8) and its substrates, soluble VCAM-1 (sVCAM-1) and soluble CD23 (sCD23), in bronchoalveolar lavage fluid from patients with smoking-induced acute eosinophilic pneumonia (AEP), chronic idiopathic eosinophilic pneumonia (CEP), and drug-induced eosinophilic pneumonia (drug-EP). RESULTS: The sADAM8 and sVCAM-1 concentrations were increased in AEP and CEP. The sCD23 concentration was elevated in AEP. In AEP, but not CEP, the sADAM8 concentration significantly correlated with those of both sVCAM and sCD23. CONCLUSION: The pathogenesis of AEP, CEP, and drug-EP was distinct with regard to ADAM8. Our results are the first to associate ADAM8 with eosinophilic responses and lung inflammation in humans.     

Acute eosinophilic pneumonia associated with amitriptyline in a hemodialysis patient.

Drugs are well known causes of eosinophilic lung disease. In many patients, drug-induced eosinophilic lung disease presents with transient eosinophilic infiltrates that disappear after discontinuation of the drug. Some patients, however, experience a fulminant, acute eosinophilia-like disease. Recently, we experienced a case of amitriptyline-associated acute eosinophilic pneumonia with respiratory failure in a diabetic hemodialysis patient. Eight days after treatment with amitriptyline, sudden fever, chill, dry cough and dyspnea developed. Subsequently, multiple patch consolidations appeared on the chest radiographs. Bronchoalveolar lavage (BAL), established a diagnosis of acute eosinophilic pneumonia. After immediate discontinuation of amitriptyline, a rapid clinical and radiological improvement was observed. The present case indicates that the possibility of acute eosinophilic pneumonia should be fully considered in dialysis patients developing unexplained respiratory symptoms while on amitriptyline therapy.     

Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure

Although chronic eosinophilic pneumonia is a well-known disorder, acute eosinophilic pneumonia has not been as well characterized. We describe the clinical features, results of bronchoalveolar lavage, and follow-up studies of four patients with acute eosinophilic pneumonia. The patients presented with an acute febrile illness, severe hypoxemia (partial pressure of arterial oxygen less than 60 mm Hg), diffuse pulmonary infiltrates, an increased number of eosinophils (mean +/- SEM, 42 +/- 4.8 percent) in bronchoalveolar-lavage fluid, and an absence of infection and previous atopic illness. The illness resolved rapidly after treatment with erythromycin and corticosteroids. The patients received doses of oral prednisone that were tapered over 10 days to 12 weeks, and none have relapsed since the steroids were discontinued. After a minimum follow-up period of five months, clinical evaluation, chest radiography, and pulmonary-function tests have shown no residual abnormalities attributable to the acute eosinophilic pneumonia. Follow-up bronchoalveolar lavage has demonstrated less than or equal to 1 percent eosinophils in all patients. We believe that we are describing an acute form of eosinophilic lung disease distinct from previously described syndromes. It can be diagnosed by bronchoalveolar lavage and seems to respond to treatment with corticosteroids.     

Eosinophilic lung disease: immunological studies of blood and alveolar eosinophils.

Five patients with eosinophilic lung diseases and blood hypereosinophilia (PIE syndrome) were investigated clinically and by bronchoalveolar lavage (BAL). Comparative studies on blood and alveolar eosinophils were carried out after purification and selection of eosinophil subpopulations according to their density. A predominant 'hypodense' alveolar eosinophil population was found in BAL fluids of active chronic eosinophilic pneumonia (CEP). In addition, supernatants of alveolar macrophages obtained from CEP are able to enhance spontaneously the generation of eosinophil oxygen metabolites. Such eosinophil stimulation emphasizes a probable tissue cell cooperation. In addition, BAL permitted the study of membrane immunological markers on eosinophilic inflammatory cells endowed with migratory properties. An increase in eosinophils carrying surface IgE was demonstrated in alveolar cells from PIE Syndrome particularly with hypodense eosinophils from CEP patients. Although no specific stimulus is known at the present time, this work underlines the potential implication of IgE-mediated hypersensitivity processes in the pathogenesis of eosinophilic lung diseases.     

Smoking-Induced Acute Eosinophilic Pneumonia in a 15-year-old Girl: A Case Report

Acute eosinophilic pneumonia is a very rare disease that is characterized by acute febrile respiratory failure, diffuse bilateral infiltrates on chest X-ray, and eosinophilia in bronchoalveolar lavage fluid in the absence of infection. We present the case of a 15-year-old girl diagnosed with smoking-induced acute eosinophilic pneumonia. A previously healthy young girl with a 1-day history of fever presented with cough, dyspnea, and diffuse bilateral infiltrates on chest X-ray. She had started smoking only 3 weeks before presentation. She was diagnosed by bronchoalveolar lavage fluid tests and lung biopsy and dramatically improved after steroid treatment. We emphasize that acute eosinophilic pneumonia must be considered when acute pneumonia does not respond to broad-spectrum antibiotics. Effective treatment and prompt institution of therapy can obviate unnecessary morbidity and mortality.     

Successful Treatment of Chronic Eosinophilic Pneumonia with Anti-IgE Therapy

Anti-IgE therapy, using recombinant humanized anti-IgE antibodies, is clinically effective in patients with eosinophil-related disorders such as allergic asthma, allergic rhinitis, and chronic urticaria. Chronic eosinophilic pneumonia tends to respond promptly to systemic corticosteroid therapy, however; relapses are common following corticosteroid tapering. We treated two patients (17- and 19-yr-old males) of chronic eosinophilic pneumonia whose symptoms were cough and dyspnea on exertion. The symptoms were recurrent while tapering off corticosteroid. They were treated with anti-IgE antibody without recurrence for 2 yr and 15 months. Here, we first describe clinical experience of the 2 cases of chronic eosinophilic pneumonia.     

Eosinophilic pneumonia-like areas in idiopathic usual interstitial pneumonia.

Usual interstitial pneumonia is the most common idiopathic chronic interstitial pneumonia, characterized by a temporally heterogenous pattern of interstitial injury with interstitial mononuclear infiltrates, septal fibromyxoid nodules, and parenchymal scarring. This report details the presence of focal eosinophilic pneumonia in six cases of usual interstitial pneumonia in the absence of known causes of this reaction. The relationship of eosinophilic infiltrates in usual interstitial pneumonia with regard to pathogenesis, differential diagnosis, and prognosis is discussed.     

Respiratory bronchiolitis-associated interstitial lung disease with fibrosis is a lesion distinct from fibrotic nonspecific interstitial pneumonia: a proposal.

Nine cases of clinical and radiographic chronic interstitial lung disease are presented that have features of respiratory bronchiolitis-associated interstitial lung disease, but were associated with a respiratory bronchiolitis having extensive paucicellular lamellar eosinophilic collagenous thickening of alveolar septa in a patchy, particularly subpleural distribution. Patients were middle-aged with shortness of breath, mixed obstructive and restrictive lung disease with markedly reduced diffusing capacity and radiographs demonstrating centrilobular micronodules, occasional ground glass opacities and emphysema. All were alive at follow-up. The morphology of this process raises the differential diagnosis with the fibrotic form of nonspecific interstitial pneumonia and highlights the role of cigarette smoking as a potential cause of fibrotic lung disease.     

Intraluminal fibrosis in interstitial lung disorders.

The histopathologic and ultrastructural features of intraluminal organizing and fibrotic changes were studied in open lung biopsies and autopsy specimens from 373 patients with interstitial lung disorders, including hypersensitivity pneumonitis (n = 44), idiopathic pulmonary fibrosis (n = 92), collagen-vascular diseases (n = 20), chronic eosinophilic pneumonia (n = 10), pulmonary histiocytosis X (n-90), pulmonary sarcoidosis (n = 62), pneumoconioses (n = 25), Legionnaire's disease (n = 5), drug- and toxin-induced pneumonitis (n = 4), radiation-induced pneumonitis (n = 2), lymphangioleiomyomatosis (n = 11), and chronic organizing pneumonia of unknown cause (n = 8). Three patterns of intraluminal organization and fibrosis were recognized: 1) intraluminal buds, which partially filled the alveoli, alveolar ducts and/or distal bronchioles; 2) obliterative changes, in which loose connective tissue masses obliterated the lumens of alveoli, alveolar ducts or distal bronchioles, and 3) mural incorporation of previously intraluminal connective tissue masses, which fused with alveolar, alveolar ductal, or bronchiolar structures and frequently became reepithelialized. All three patterns had common morphologic features, suggesting that, regardless of their severity, they resulted from a common pathogenetic mechanism, ie, the migration of activated connective tissue cells, through defects in the epithelial lining and its basement membrane, from the interstitial into the intraluminal compartment. Intraluminal buds were observed most frequently in hypersensitivity pneumonitis, chronic eosinophilic pneumonia, and organizing pneumonia of unknown cause. Mural incorporation and, to a lesser extent, obliterative changes were observed in most interstitial disorders and were very prominent in idiopathic pulmonary fibrosis. Mural incorporation and obliterative changes play an important role in pulmonary remodeling, especially when several adjacent alveoli and/or other air spaces are involved. Under these circumstances, intraluminal organization can mediate the fusion of adjacent alveolar structures by intraluminal connective tissue.     

Eosinophilic pneumonia caused by Alternaria alternata

We describe a patient who presented with hypoxemia and diffuse bilateral pulmonary infiltrates. The diagnosis of eosinophilic pneumonia was confirmed by bronchoalveolar lavage and transbronchial lung biopsy. The remarkable characteristic was reappearance of the symptoms on the patient's return home, suggesting the existence of etiologic agents in his house. An environmental survey of the patient's house yielded Alternaria alternata. A high liter of anti- A alternata antibody (IgG) was detected in his serum, and the inhalation bronchoprovocation test with A. alternata antigen was positive. This case indicates that A. alternata is a probable cause of eosinophilic pneumonia.     

Organic antigen-induced interstitial lung disease: diagnosis and management.

BACKGROUND: Traditionally, chronic idiopathic interstitial pneumonia/fibrosis (IIP/F) had included usual interstitial pneumonia, desquamative interstitial pneumonia, and nonspecific interstitial pneumonia (NSIP). More recent classifications have included bronchiolitis obliterans-organizing pneumonia (BOOP), respiratory bronchiolitis-associated interstitial lung disease, and acute interstitial pneumonia. Some chronic eosinophilic pneumonias (CEP)/pulmonary infiltrate with eosinophilia (PIE) have obvious causes, but many lack an identifiable etiology. We felt that hypersensitivity pneumonitis (HP) was being underdiagnosed and was hidden within this large heterogeneous group of interstitial lung disorders of unrecognized cause. OBJECTIVE: We sought to prove that detailed environmental histories and investigations would reveal causative contaminations in the home or workplace of some patients with idiopathic interstitial lung disease and remediation of the contamination would stabilize the disorder. METHODS: Consecutive cases of IIP/F were investigated. Patients were identified by compatible signs and symptoms, roentgenographic studies, pulmonary function tests, and lung biopsies. They were further evaluated with detailed environmental histories, serologic tests, and investigation into the suspected causative environment. Environmental and specific antigen challenges were done in some cases. Remediation of contaminations or moving into another environment were the methods used as therapy. RESULTS: Eighty-six consecutive patients with IIP/F were evaluated. Twelve patients were subsequently diagnosed with specific causes for interstitial lung disease. Fifty-seven of 74 patients were identified by clinical evaluation and lung biopsy with HP, CEP/PIE, NSIP, BOOP, UIP, and nonclassifiable morphologic patterns. Seventeen patients were not biopsied or had an inadequate transbronchial biopsy but had consistent findings radiographically and clinically of idiopathic interstitial lung disease. Contamination of the home was causative in 69 of 74 and the workplace in 3 of 74 cases. There were 9 positive and 33 negative environmental challenges with 4 positive and 1 negative specific challenges. Fifty of 74 (67%) patients are receiving no treatment and are free of active disease after remediation of the environmental contamination, with a mean survival of 8.2 years. CONCLUSIONS: Our data show that UIP, BOOP, NSIP, CEP/PIE, and nonclassifiable morphologic patterns represent a spectrum of interstitial lung disease that may be caused by inhalation of organic dusts in the home or workplace as described with HP. Remediation of, or moving from the contamination, can lead to arrest of the active inflammatory process and stability of the lung disorder.     

Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage

CONTEXT: The histologic patterns of diffuse alveolar damage (DAD), bronchiolitis obliterans with organizing pneumonia (BOOP), and eosinophilic pneumonia (EP) are well-recognized histologic patterns of lung injury associated with an acute or subacute clinical presentation. We have recognized acute fibrinous and organizing pneumonia (AFOP) as a histologic pattern, which also occurs in this clinical setting but does not meet the classic histologic criteria for DAD, BOOP, or EP and may represent an underreported variant. OBJECTIVE: To investigate the clinical significance of the AFOP histologic pattern and to explore its possible relationship to other disorders, including DAD and BOOP. DESIGN: Open lung biopsy specimens and autopsy specimens were selected from the consultation files of the Armed Forces Institute of Pathology, which showed a dominant histologic pattern of intra-alveolar fibrin and organizing pneumonia. Varying amounts of organizing pneumonia, type 2 pneumocyte hyperplasia, edema, acute and chronic inflammation, and interstitial widening were seen. Cases with histologic patterns of classic DAD, BOOP, abscess formation, or eosinophilic pneumonia were excluded. To determine the clinical behavior of patients with this histologic finding, clinical and radiographic information and follow-up information were obtained. Statistical analysis was performed using Kaplan-Meier and chi(2) analysis. RESULTS: Seventeen patients (10 men, 7 women) with a mean age of 62 years (range, 33-78 years) had acute-onset symptoms of dyspnea (11), fever (6), cough (3), and hemoptysis (2). Associations believed to be clinically related to the lung disease included definitive or probable collagen vascular disease (3), amiodarone (1), sputum culture positive for Haemophilus influenza (1), lung culture positive for Acinetobacter sp. (1), lymphoma (1), hairspray (1), construction work (1), coal mining (1), and zoological work (1). Six patients had no identifiable origin or association. Follow-up revealed 2 clinical patterns of disease progression: a fulminate illness with rapid progression to death (n = 9; mean survival, 0.1 year) and a more subacute illness, with recovery (n = 8). Histologic analysis and initial symptoms did not correlate with eventual outcome, but 5 of the 5 patients who required mechanical ventilation died (P =.007). CONCLUSIONS: Acute fibrinous and organizing pneumonia is a histologic pattern associated with a clinical picture of acute lung injury that differs from the classic histologic patterns of DAD, BOOP, or EP. Similar to these patterns of acute lung injury, the AFOP pattern can occur in an idiopathic setting or with a spectrum of clinical associations. The overall mortality rate is similar to DAD and therefore may represent a histologic variant; however, AFOP appears to have 2 distinct patterns of disease progression and outcome. The need for mechanical ventilation was the only parameter that correlated with prognosis. None of the patients with a subacute clinical course required mechanical ventilation.     

Chronic inflammation,lymphangiogenesis, and effect of an anti‐VEGFR therapy in a mouse model and in human patients with aspiration pneumonia

Chronic inflammation induces lymphangiogenesis and blood vessel remodelling. Since aged pneumonia patients often have repeated episodes of aspiration pneumonia, the pathogenesis may involve chronic inflammation. For lymphangiogenesis, VEGFR‐3 and its ligand VEGF‐C are key factors. No previous studies have examined chronic inflammation or vascular changes in aspiration pneumonia or its mouse models. In lung inflammation, little is known about the effect of blocking VEGFR‐3 on lung lymphangiogenesis and, moreover, its effect on the disease condition. This study aimed to establish a mouse model of aspiration pneumonia, examine the presence of chronic inflammation and vascular changes in the model and in patients, and evaluate the effect of inhibiting VEGFR‐3 on the lymphangiogenesis and disease condition in this model. To induce aspiration pneumonia, we repeated inoculation of pepsin at low pH and LPS into mice for 21–28 days, durations in which bronchioalveolar lavage and plasma leakage in the lung suggested the presence of exaggerated inflammation. Conventional and immunohistochemical analysis of tracheal whole mounts suggested the presence of chronic inflammation, lymphangiogenesis, and blood vessel remodelling in the model. Quantitative RT‐PCR of the trachea and lung suggested the involvement of lymphangiogenic factor VEGF‐C, VEGFR‐3, and pro‐inflammatory cytokines. In the lung, the aspiration model showed the presence of chronic inflammation and exaggerated lymphangiogenesis. Treatment with the VEGFR inhibitor axitinib or the VEGFR‐3 specific inhibitor SAR131675 impaired lymphangiogenesis in the lung and improved oxygen saturation in the aspiration model. Since the lung is the main site of aspiration pneumonia, the changes were intensive in the lung and mild in the trachea. Human lung samples also showed the presence of chronic inflammation and exaggerated lymphangiogenesis, suggesting the relevance of the model to the disease. These results suggest lymphatics in the lung as a new target of analysis and therapy in aspiration pneumonia. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Chronic eosinophilic pneumonia with subpleural curvilinear shadow

We report a rare case of chronic eosinophilic pneumonia with subpleural curvilinear shadow. CT scan showed a patchy consolidation in the bilateral upper lungs. In addition, subpleural curvilinear shadow was found in the bilateral upper lungs. A bronchoalveolar lavage obtained from the right middle lobe showed 25 % eosinophils. Although very rare, we should therefore keep in mind that patients, who have patchy consolidation with areas of subpleural curvilinear shadow in the bilateral upper lungs, may have chronic eosinophilic pneumonia.