Bronchiolitis interstitial pneumonitis: a pathologic study of 31 lung biopsies with features intermediate between bronchiolitis obliterans organizing pneumonia and usual interstitial pneumonitis, with clinical correlation

Bronchiolitis combined with interstitial pneumonitis generally has been equated with bronchiolitis obliterans organizing pneumonia (BOOP). We describe our experience with lung biopsies that had both bronchiolar and interstitial diseases. We studied 31 patients who had respiratory difficulty leading to open lung biopsy, which showed a combination of both prominent bronchiolitis and prominent interstitial pneumonitis. We compared these cases clinically and pathologically with 6 other pulmonary diseases, namely, bronchiolitis obliterans, BOOP, nonspecific interstitial pneumonitis, usual interstitial pneumonitis, airway-centered interstitial fibrosis, and idiopathic bronchiolocentric interstitial pneumonia, and with 10 cases of cystic fibrosis, an unrelated disease with both bronchiolar and interstitial pathology. The commonality of our cases was a combination of bronchiolitis and interstitial inflammation and fibrosis but little or no intra-alveolar organizing pneumonia. Bronchiolitis obliterans with organizing pneumonia involved less area than the interstitial pneumonitis in each case. All 19 patients for whom we had follow-up received corticosteroids for their pulmonary diseases. Seven patients had improvement in symptoms and pulmonary function test results and radiographic findings, 5 patients experienced subjective improvement with unchanged results of pulmonary function tests or chest x-ray, 1 patient's condition was unchanged, 6 patients' disease worsened, and 4 of these 6 died. The natural history of these cases, which we have designated bronchiolitis interstitial pneumonitis, seems more sanguine than usual interstitial pneumonitis and worse than BOOP at least in the short term. On the one hand, response to corticosteroids was not as frequent as generally accepted for BOOP. On the other hand, disease did not progress in most patients on corticosteroids.     

Chronic transmural bronchiolitis: a non-specific lesion of small airways.

AIMS: To investigate nine patients with histological changes at open lung biopsy compatible with so-called "small airways disease"; to define these changes and distinguish them from other types of bronchiolitis; and to correlate them with clinical features, respiratory physiology, and other laboratory investigations. METHODS: The open biopsy sections and the clinical records were reviewed. RESULTS: There was chronic inflammation of the walls of centri-acinar respiratory bronchioles and peribronchiolar alveoli. Peripheral alveoli of affected acini were spared. Although lumens were narrowed and distorted, obstruction by granulation tissue plugs was not a feature. Clinical backgrounds included Hodgkin's disease, yellow nail syndrome, sicca syndrome, asthma and psoriasis. The main presenting symptoms were cough, dyspnoea and wheeze, often associated with basal crackles and basal shadowing. There was no consistent immunological or haematological abnormality. Sputum culture was negative in six patients, and a variety of organisms were cultured from three others. In most cases respiratory function tests revealed an irreversible obstructive defect (combined in some cases with a restrictive defect), gas trapping, and well preserved gas transfer. Lung volumes were normal. Bronchodilators, with steroids and azathioprine in more seriously affected patients, stabilised the disease process. CONCLUSIONS: The histological changes may be distinguished from bronchiolitis obliterans and bronchiolitis obliterans organising pneumonia by the absence of intraluminal granulation tissue plugs, and from the obliterative bronchiolitis of rheumatoid disease and diffuse peribronchiolitis on clinical grounds. Although often striking, this lesion does not represent a clinico-pathological entity, and may occur in the distal lung in association with a number of different diseases. "Small airways disease" is often used by clinicians in a functional context, and may lead to confusion. It is suggested that "chronic transmural bronchiolitis" is a more appropriate term.     

The two forms of bronchiolitis obliterans in heart-lung transplant recipients.

Bronchiolitis obliterans has emerged as the major long-term complication of heart-lung transplantation. We reviewed the histologic findings in lungs obtained from 11 patients who had received a combined heart-lung transplant at The Johns Hopkins Hospital. Ten lungs were obtained at autopsy, and one was obtained from a patient who was retransplanted because of severe bronchiolitis obliterans. Bronchiolitis obliterans was identified in seven of these 11 lungs. Three of the seven lungs with bronchiolitis obliterans were from patients who had received their transplants more than 6 months previously; the bronchiolitis obliterans in these patients was characterized by a relatively acellular concentric fibrosing process that was limited to the terminal bronchioles. The bronchiolitis obliterans in these three patients was felt to be secondary to chronic lung allograft rejection. Four of the seven patients with bronchiolitis obliterans had received their transplants less than 6 months previously; the bronchiolitis obliterans in these patients was focal and cellular. It extended into the distal alveolar spaces and, in several cases, was associated with aspirated material and foreign body-type giant cells. All four of these patients had concurrent infections, aspiration, or large airway obstruction, which were felt to be responsible for the development of bronchiolitis obliterans. Bronchiolitis obliterans in lung allograft recipients may have a variety of etiologies, and the etiology of this process in a particular case can often be deduced by the morphologic appearance of this lesion.     

Bronchiolitis obliterans in ataxia-telangiectasia

Pulmonary disease was studied in four patients with ataxia-telangiectasia. Immunodeficiency was characterized by lymphopaenia, hypo-gammaglobulinaemia and decreased T -cell response to phytohaemagglutinin stimulation in mixed lymphocyte cultures. All four patients died from respiratory failure. Autopsy revealed that all four patients suffered from bronchiolitis obliterans in all lobes. Immunohistochemical examination demonstrated expression of MHC class II antigens on bronchiolar epithelium. Pulmonary infections in ataxia-telangiectasia patients included a case of mycoplasma pneumonia, one of cytomegalovirus pneumonia and one ofPseudomonas aeruginosa infection. The aetiology and immunological background of bronchiolitis obliterans are discussed. Bronchiolitis obliterans is a characteristic finding in ataxia-telangiectasia and may be due to the underlying immune deficit.     

Graft eosinophilia in lung transplantation.

Graft eosinophilia was observed in lung biopsies from nine patients who received lung allografts. Five cases were associated with moderate to severe acute cellular rejection and responded well to steroid therapy. In this group the eosinophilia occurred early after transplantation and was associated with an elevated white blood cell count and occasional peripheral blood (one of five cases) and bronchoalveolar lavage (one of five cases) eosinophilia. A second group of four patients had graft eosinophilia due to infectious agents. In these cases patients frequently had underlying bronchiolitis obliterans (two of four cases) and developed tissue eosinophilia late after transplantation. Bronchoalveolar lavage cell profiles often demonstrated dramatic eosinophilia. Histologically, the biopsy specimens displayed an acute eosinophilic pneumonia, which was attributed to Aspergillus sp (two cases), coxsackie A2 virus (one case), and Pseudomonas maltophilia (one case). Two patients in this group died from infection. While eosinophils are a frequent cellular component of acute rejection reactions, they also may be the dominant cellular component in graft infection.     

Bronchiolitis obliterans organizing pneumonia

In 50 of 94 patients with bronchiolitis obliterans we found no apparent cause or associated disease, and the bronchiolitis obliterans occurred with patchy organizing pneumonia. Histologic characteristics included polypoid masses of granulation tissue in lumens of small airways, alveolar ducts, and some alveoli. The fibrosis was uniform in age, suggesting that all repair had begun at the same time. The distribution was patchy, with preservation of background architecture. Clinically, there was cough or flu-like illness for 4 to 10 weeks, and crackles were heard in the lungs of 68 per cent of the patients. Radiographs showed an unusual pattern of patchy densities with a "ground glass" appearance in 81 per cent. Physiologically, there was restriction in 72 per cent of the patients, and 86 per cent had impaired diffusing capacity. Obstruction was limited to smokers. The mean follow-up period was four years. With corticosteroids, there was complete clinical and physiologic recovery in 65 per cent of the subjects; two died from progressive disease. This disorder differs from bronchiolitis obliterans with irreversible obstruction. It was confused most often with idiopathic pulmonary fibrosis. In view of the benign course and therapeutic response, a histologic distinction is important.     

Iatrogenic pulmonary lesions

Treatment of patients often includes the administration of medications and sometimes radiation. While the intent is to treat an underlying condition, in some cases, adverse effects occur due to these agents. Most of these adverse effects are mild, however, some can be severe and life-threatening. Furthermore, while these effects are often reversible upon cessation of exposure, especially if the inciting agent is recognized and withdrawn early, others might be permanent or even progressing.Most common histopathologic findings in drug-induced interstitial lung disease include nonspecific interstitial pneumonia (cellular and/or fibrotic), organizing pneumonia with or without bronchiolitis, eosinophilic pneumonia, pulmonary edema, diffuse alveolar damage, hypersensitivity pneumonitis, granulomatous interstitial lung disease, chronic bronchiolitis, and pulmonary hemorrhage. Pulmonary vascular changes or constrictive bronchiolitis can also occur. Drugs that are more commonly associated with lung toxicity include nitrofurantoin, amiodarone, and chemotherapeutic agents such as bleomycin and methotrexate. More recently introduced immune modulating agents including rituximab and immune checkpoint inhibitors such as anti-CTLA4, anti-PD-1 and anti-PD-L1 agents have also been associated with adverse effects in the lung.Radiation therapy to the chest can trigger acute or chronic lung toxicity. While newer radiation techniques are aimed to decrease and minimize side effects other risk factors such as additional chemotherapy, oxygen, and older age may be rising.Foreign substances such as talc, hydrogel, and medical devices such as hydrophilic polymer coated catheter may rarely also lead to pulmonary complications.It is important that clinicians and pathologists are aware of these potential adverse effects of drugs, radiation and medical devices and raise the possibility of drug-induced lung toxicity after exclusion of other differential diagnoses. It is the role of the clinician to provide the pathologist with an appropriate drug history. Early intervention to a drug-induced lung toxicity might prevent progression of side effects and permanent changes.     

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.     

Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis

Aims and methods: Pulmonary parenchymal disease is common in patients with connective tissue disorders (CTDs). However, most reports precede recognition of non‐specific interstitial pneumonia (NSIP). We have therefore reviewed 54 lung biopsies from 37 patients with polymyositis/dermatomyositis (PM/DM) (n = 13), Sjögren's syndrome (n = 5), rheumatoid arthritis (n = 17) and systemic lupus erythematosus (SLE) (n = 2) to assess the overall and relative frequencies of patterns of interstitial pneumonia and their impact on prognosis. Results and conclusions: NSIP was the most common pattern with an overall biopsy prevalence of 39% and patient prevalence of 41%. There was variation in prevalence between individual CTDs, with PM/DM commonly showing organizing pneumonia (n = 5), rheumatoid arthritis showing follicular bronchiolitis (n = 6) and Sjögren's syndrome showing chronic bronchiolitis (n = 4). These patterns presented either separately or in association with NSIP, occasionally with different patterns in biopsies from separate lobes. Only four patients showed a pattern of usual interstitial pneumonia (UIP): two with rheumatoid arthritis and one each with PM/DM and SLE. Overall mortality was 24%, the most frequently associated pattern being fibrotic NSIP (n = 5). In nine cases, pulmonary presentation preceded the systemic manifestation of the CTDs. When patients with CTDs present with chronic interstitial lung disease, the most common pattern is NSIP, although there is variation in pattern prevalence between individual disorders and patterns of interstitial pneumonia frequently overlap. These data suggest a different biology for intestitial pneumonias in CTDs when compared with the idiopathic interstitial pneumonias where UIP is the most common pattern. Mortality is similar to that seen in idiopathic NSIP and, coupled with pulmonary presentation occurring prior to the systemic manifestation of disease, this may have a bearing on the origin of some cases of putative idiopathic NSIP.     

Distinct histopathology of acute onset or abrupt exacerbation of hypersensitivity pneumonitis

Hypersensitivity pneumonitis is an inflammatory lung disease that develops in response to exposure to antigen. Cases can be stratified by the duration of exposure and speed of symptom progression into acute, subacute, and chronic hypersensitivity pneumonitis. Although the pathologic features of subacute hypersensitivity pneumonitis are well established and those of chronic hypersensitivity pneumonitis have been reported, little is known about the histopathology of acute hypersensitivity pneumonitis. We evaluated the pathologic features of 5 patients with clinically confirmed hypersensitivity pneumonitis and rapid onset of symptoms and 3 patients with subacute or chronic hypersensitivity pneumonitis with symptom exacerbation. Histopathologic features assessed in each case included those characteristic of subacute hypersensitivity pneumonitis (bronchiolocentric chronic inflammation, histiocytic aggregates, and bronchiolitis obliterans), those associated with acute inflammation (fibrin deposition and neutrophilic infiltrate), and fibrosis. The classic features of hypersensitivity pneumonitis were identified in all 8 cases, with 1 also exhibiting fixed fibrosis confirming underlying chronic hypersensitivity pneumonitis. Fibrin deposition was present in 8 (100%) of 8 cases, and its extent was significant (28% surface area fibrin deposition/total disease area on average). Two had intra-alveolar fibrin so marked that it resembled acute fibrinous and organizing pneumonia. In addition, prominent interstitial neutrophilic infiltrate (≥5 cells/high-power field) was seen in all cases. These features have not been reported as characteristics of subacute or chronic hypersensitivity pneumonitis. Increased fibrin deposition and neutrophilic infiltrate may characterize acute hypersensitivity pneumonitis or abrupt exacerbation of hypersensitivity pneumonitis, and these along with characteristic features of subacute hypersensitivity pneumonitis (granulomatous inflammation and bronchiolocentricity) are sufficient to establish a morphologic diagnosis, particularly in conjunction with clinicoradiologic features.     

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.     

Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation.

Pulmonary dysfunction is a significant complication following allogeneic hematopoietic stem cell transplantation (HSCT), and is associated with significant morbidity and mortality. Effective antimicrobial prophylaxis and treatment strategies have increased the incidence of noninfectious lung injury, which can occur in the early posttransplant period or in the months and years that follow. Late-onset noninfectious pulmonary complications are frequently encountered, but diagnostic criteria and terminology for these disorders can be confusing and therapeutic approaches are suboptimal. As a consequence, inaccurate diagnosis of these conditions may hamper the appropriate data collection, enrollment into clinical trials, and appropriate patient care. The purpose of this review is to clarify the pathogenesis and diagnostic criteria of representative conditions, such as bronchiolitis obliterans syndrome and bronchiolitis obliterans organizing pneumonia, and to discuss the appropriate diagnostic strategies and treatment options.     

Non‐specific interstitial pneumonia as a manifestation of graft‐versus‐host disease following pediatric allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans (BO) is generally believed to be a marker of pulmonary manifestation of graft‐versus‐host disease (GVHD) in patients who have undergone bone marrow transplantation for hematological malignancy. Pulmonary manifestations reported as GVHD (other than BO) include lymphocytic bronchiolitis with cellular interstitial pneumonia, lymphoid interstitial pneumonia, veno‐occlusive disease, and diffuse alveolar damage. Morphological reactions in the lungs of bone marrow transplant recipients associated with interstitial pneumonia have not been described systematically. Reported herein is a fibrosing non‐specific interstitial pneumonia (NSIP) pattern together with BO in both lungs in an 8‐year‐old girl following a second allogeneic hematopoietic stem cell transplantation for relapsed neuroblastoma of adrenal origin. The course was complicated by bilateral pneumothoraces, and the patient underwent lung transplantation 3 years after the second stem cell transplantation. Because the patient had chronic GVHD of the skin and the liver preceeded by the development of pulmonary involvement, NSIP may represent one of the facets of pulmonary GVHD.     

Bronchiolitis obliterans, bronchiectasis, and other sequelae of adenovirus type 21 infection in young children

A remarkably high incidence of bronchiectasis and other pulmonary sequelae was observed in young children affected during an epidemic of severe lower respiratory tract infections apparently caused by adenovirus type 21. The histopathological findings are described in four cases in which one or both lungs were obtained for examination at intervals ranging from two months to three years after the acute infections. Widespread bronchiolar obliteration (bronchiolitis obliterans) was a striking finding in all four. The severity of bronchial inflammation and of bronchiectasis was proportional to the time elapsed since the acute infections. Bronchiolar obliteration is a likely sequel of the necrotizing bronchiolitis which may occur during acute adenovirus infections. The role of bronchiolar obliteration in the pathogenesis of bronchiectasis and other chronic lung disease is discussed. Adenoviruses may be a major cause of post-infectious bronchiectasis in childhood.     

The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis.

The synthesis of collagen and EIIIA-containing cellular fibronectin in certain forms of pulmonary fibrosis occurs in discrete locations: in the Masson bodies in bronchiolitis obliterans with organizing pneumonia and in focal clusters of fibroblasts (fibroblastic foci) within airspaces in usual interstitial pneumonia. These sites were examined by electron microscopy and immunohistochemistry using antibodies against cytoskeletal markers and extracellular matrix components in biopsies from three patients with bronchiolitis obliterans with organizing pneumonia and four patients with usual interstitial pneumonia. Fibroblasts of both Masson bodies and fibroblastic foci expressed vimentin and alpha smooth muscle actin but not desmin, distinguishing them from true smooth muscle. In both structures fibroblasts with well-formed actin filament bundles were aligned parallel to one another, enmeshed in a matrix of fibronectin-containing fibrils (microtendons) that linked cells and collagen bundles. Similar features characterize the phase of contraction during the healing of skin wounds. This suggests that active contractions of fibroblasts plays a role in the remodeling of the lung in pulmonary fibrosis.     

Bronchiolitis, an update

Besides the classical forms of acute and chronic bronchiolitis, different special forms, such as obliterative, respiratory, and follicular bronchiolitis are recognized. In addition, even new entities emerge, such as Sauropus-induced bronchiolitis. Despite this progress in pathology, pulmonologists still prefer the diagnostic term 'small airways disease', instead of the more specific and even etiology-directed diagnoses provided by the morphologic examination. In this overview, an updated classification will be presented, which includes all forms of bronchiolitis described so far. This classification is structured along morphologic features of bronchiolitis. Different forms of acute and chronic bronchiolitis are described, so that a given reaction pattern can be associated with specific causes, such as eosinophilic bronchiolitis in asthma, or necrotizing bronchiolitis in viral infection. However, there exist more than just one morphologic reaction for a given etiologic agent, resulting in an overlap of morphologic appearances for a given disease.     

Inflammatory myopathy, bronchiolitis obliterans/organizing pneumonia, and anti-Jo-1 antibodies--an interesting association.

We report an interesting association of inflammatory myopathy, characterized pathologically as dermatomyositis, with bronchiolitis obliterans/organizing pneumonia and anti-histidyl-tRNA synthetase (Jo-1) antibody. The relations of different types of pulmonary involvement to inflammatory myopathy and antisynthetase antibodies are discussed.     

Hypersensitivity pneumonia: the role of lung biopsy in diagnosis and management

Hypersensitivity pneumonia is a form of diffuse interstitial lung disease resulting from sensitization to an inhaled antigen. Clinical and radiological features are relatively nonspecific, overlapping significantly with other forms of diffuse interstitial lung disease. Establishing the diagnosis in the absence of lung biopsy is challenging and is heavily dependent on being able to identify a specific antigenic exposure. Lung biopsy is especially important in diagnosing hypersensitivity pneumonia in patients for whom no incriminating exposure has been elucidated. Surgical lung biopsies show a classical combination of findings in the majority of patients, which include an airway-centered, variably cellular chronic interstitial pneumonia, a lymphocyte-rich chronic bronchiolitis, and poorly formed non-necrotizing granulomas distributed mainly within the peribronchiolar interstitium. The bronchiolitis may include variable degrees of peribronchiolar fibrosis and hyperplasia of the bronchiolar epithelium ('peribronchiolar metaplasia'), a characteristic but a nonspecific finding. In some patients, granulomatous inflammation may be lacking, resulting in a histological appearance resembling nonspecific interstitial pneumonia. Late-stage fibrotic hypersensitivity pneumonia results in clinical, radiological, and histological findings that closely mimic usual interstitial pneumonia. The presence of established collagen fibrosis, especially when associated with architectural distortion in the form of honeycomb change, is associated with shorter survivals.     

Antineutrophil cytoplasmic autoantibody in the absence of Wegener's granulomatosis or microscopic polyangiitis: implications for the surgical pathologist.

Antineutrophil cytoplasmic antibodies (ANCA) are useful serologic markers for the diagnosis and management of patients with Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). However, problems in diagnosis and classification may occur when patients with other disorders develop ANCA. A 7-year review (1993-1999) disclosed 247 patients whose sera tested positively for ANCA by an indirect immunofluorescence method: 166 patients for cytoplasmic-ANCA (C-ANCA) and 81 patients for perinuclear-ANCA (P-ANCA) Twenty-seven patients had active pulmonary disease and underwent open-lung biopsy or transbronchial biopsy. Eight patients (30%) had a disease other than WG or MPA, and their clinical, pathological, and serological findings were reviewed. The patients, all women, ranged in age from 28 to 77 years (median, 37 y). Dyspnea (n = 6), cough (n = 6), chest pain (n = 2), and/or hemoptysis (n = 2) were present. The duration of symptoms lasted from 3 weeks to 6 years (median, 6 mo). ANCA titers were C-ANCA (n = 4; range, 1:40-1280) or P-ANCA (n = 4; range, 1:40-640). The lung biopsies disclosed nonspecific interstitial pneumonia (n = 4), bronchiolitis obliterans organizing pneumonia (n = 1), diffuse alveolar damage (n = 1), organizing diffuse alveolar hemorrhage without capillaritis (n = 1), and necrotic granuloma (n = 1). No cases showed characteristic histology for WG or MPA. The final diagnoses were various connective tissue disorders (n = 5), chronic hypersensitivity pneumonia (n = 1), postinfectious bronchitis/bronchiectasis (n = 1), and ulcerative colitis-related lung disease (n = 1). Surgical pathologists should be aware that significantly elevated ANCA titers may be associated with diverse forms of pulmonary disease. ANCA positivity alone, in the absence of appropriate clinical or pathologic findings, should not be used to substantiate a diagnosis of WG or MPA.     

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.