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Bronchioles are noncartilaginous small airways with internal diameter of 2 mm or less, located from approximately the eighth generation of purely air conducting airways (membranous bronchioles) down to the terminal bronchioles (the smallest airways without alveoli) and respiratory bronchioles (which communicate directly with alveolar ducts and are in the range of 0.5 mm or less in diameter). Bronchiolar injury, inflammation, and fibrosis may occur in myriad disorders including connective tissue diseases, inflammatory bowel diseases, lung transplant allograft rejection, graft versus host disease in allogeneic stem cell recipients, neuroendocrine cell hyperplasia, infections, drug toxicity (e.g., penicillamine, busulfan), inhalation injury (e.g., cigarette smoke, nylon flock, mineral dusts, hard metals, Sauropus androgynous); idiopathic, common variable immunodeficiency disorder, and a host of other disorders or insults. The spectrum of bronchiolar disorders is wide, ranging from asymptomatic to fatal obliterative bronchiolitis. In this review, we discuss the salient clinical, radiographic, and histological features of these diverse bronchiolar disorders, and discuss a management approach.

Three major histologic patterns of bronchiolitis: obliterative bronchiolitis, follicular bronchiolitis, and diffuse panbronchiolitis, are reviewed in detail. These distinct patterns of primary bronchiolar injury provide a useful starting point for formulating a differential diagnosis and considering possible causes. In support of the aim toward a cause-based classification system of small airway disease, a simple diagnostic algorithm is provided for further subclassification of the above 3 bronchiolitis patterns according to the major associated etiologic subgroups.

Follicular bronchiolitis (FB) and lymphoid interstitial pneumonia (LIP) are a continuum of benign infiltration of the lungs by polyclonal mature lymphocytes. Rarely idiopathic, LIP and FB may represent an expression of systemic immunologic disorders in the lung and are commonly associated with immunodeficiencies, connective tissue diseases, and other autoimmune conditions. This chapter reviews the clinical, radiologic, and pathologic presentation of both entities in this continuum.

Respiratory bronchiolitis and follicular bronchiolitis are characterzed by ill-defined centrilobular nodules, while mosaicism and air-trapping are the imaging hallmark of obliterative bronchiolitis.

Objectives: Pediatric lymphocytic interstitial pneumonia (LIP) and follicular bronchiolitis (FB) are poorly characterized lymphoproliferative disorders. We present and quantify demographics, radiological and histopathologic patterns, treatments and their responses, and outcomes in non-HIV-infected children with LIP and FB. Methods: This structured registry-based study included a retrospective chart review, blinded analysis of imaging studies and lung biopsies, genetic testing, and evaluation of treatments and outcomes. Results: Of the 13 patients (eight females) studied, eight had FB, four had combined LIP/FB, and one had isolated LIP; diagnoses were highly concordant between the pathologists. Most patients became symptomatic during the first 2 years of life, with a mean lag time to diagnosis of 4 years. The most common symptoms were coughing and respiratory infections (11 out of 13 each), dyspnea (10 out of 13), and wheezing (eight out of 13). Autoantibodies were found in eight out of 13 patients. In three patients, disease-causing mutations in the COPA gene were identified. CT revealed hilar lymphadenopathy (five out of 12), ground-glass opacity (eight out of 12), consolidation (five out of 12), and cysts (four out of 13). Systemic steroids as intravenous pulses (11 out of 13) or oral intake (10 out of 13) were the main treatments and showed high response rates of 100% and 90%, respectively. Within the mean observation period of 68 months, all children had chronic courses, eight out of 13 had severe diseases, two died, and one worsened. Conclusions: Children with LIP/FB have chronic diseases that occurred in early childhood and were commonly associated with immune dysregulation as well as high morbidity and mortality. Early diagnosis and treatment may be crucial to improve the outcome.

BackgroundCopa syndrome is a rare autosomal dominant disorder with abnormal intracellular vesicle trafficking. The objective of this work is to expand the knowledge about this disorder by delineating phenotypic features of an unreported COPA family.Methods and resultsA heterozygous missense variant (c.698 G>A, p.Arg233His) in COPA was identified in four members of a three-generation kindred with lung, autoimmune and malignant disease of unknown aetiology. Ages of onset were 56, 26, 16 and 1 year, with earlier age of onset in successive generations. Presenting symptoms were cough and dyspnoea. Findings included small lung cysts, follicular bronchiolitis, interstitial lung disease, neuroendocrine cell hyperplasia, rheumatoid arthritis, avascular necrosis and select abnormal autoimmune serologies. Neither alveolar haemorrhage nor glomerular disease were present. Features not previously associated with Copa syndrome included neuromyelitis optica, pulmonary carcinoid tumour, clear cell renal carcinoma, renal cysts, hepatic cysts, nephrolithiasis, pyelonephritis and meningitis. Longitudinal evaluations demonstrated slow progression of lung disease and extrapulmonary cysts.ConclusionsWorsening severity with successive generations may be observed in Copa syndrome. Extrapulmonary cysts, malignancies, autoimmune neurological disorders and infections are clinical features that may be associated with Copa syndrome. Further studies are indicated to fully define the phenotypic spectrum of this disorder.

Migrating pulmonary lesions in children are uncommon, and most are caused by eosinophilic lung disease and parasite, fungus, and tuberculosis infections. A 12-year-old boy was referred to our hospital because of an abnormal chest x-ray. Serial computed tomography scans performed over several months showed a migrating pulmonary consolidation in the left lung, although the patient remained asymptomatic. Finally, surgical biopsy was performed and follicular bronchiolitis was diagnosed. The consolidation disappeared 17 months later without treatment, and the patient has remained asymptomatic. Primary follicular bronchiolitis could be considered as one of the differential diagnosis in patients with pulmonary reticulo-nodular consolidation. It should also be noted that follicular bronchiolitis can migrate. Pediatr Pulmonol. 2017;52:E22-E25. © 2016 Wiley Periodicals, Inc.

Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies, which is characterized by reduced serum immunoglobulin levels and B-lymphocyte dysfunction. There are many clinical manifestations of this disease, the most common of which are recurrent respiratory tract infections. Among the most recently recognized autoimmune manifestation of CVID is a disease described as granulomatous-lymphocytic interstitial lung disease (GLILD), where CVID coexists with a small airway lymphoproliferative disorder, mimicking follicular bronchiolitis, or lymphocytic interstitial pneumonitis (LIP) on histology specimens. We herein describe the clinical and radiological features of GLILD in a 55-year-old woman where the diagnosis of CVID was actively pursued and eventually confirmed after her lung biopsy showed characteristic features of GLILD. The patient had dramatic response to treatment with IVIG and corticosteroids for 3 months followed by Mycophenolate mofetil for maintenance therapy.

A 45 yo woman with a medical history of common variable immunodifficiency (CVID) was referred for a bleeding disorder. The bleeding was manifested daily with ecchymosis and epistaxis, but prior to the visit, she developed a lower pelvic mass that was a massive hematoma requiring transfusion. In 2011 she had a splenectomy for thrombocytopenia. After splenectomy, her liver enlarged and one year prior to being seen, she was started on everolimus as part of a protocol to reduce her liver size. Bleeding started 3-6 months after starting everolimus treatment, first manifesting with recurrent lower gastrointestinal hemorrhage. In 2011 she had normal PT and aPTT. At the present time her PT remains normal at 11.43+0.67 (Mean+SD) (normal 9.7-12.7 sec); but her aPTT is abnormal at 43+6.1 (normal 28-38 sec); clottable fibrinogen (Fb) 305+72 (normal 200-400 mg/dl); Fb antigen, 428+115 mg/dl (normal 196-441); ratio of clottable Fb/Fb antigen = 0.71+ 0.06; reptilase time 20+2.2 (normal 14-23 sec); and her thrombin time of 19+1.6 is prolonged (normal 10-16 sec). Blood coagulation factors XI, IX, VIII, VII, X, V, II, and XIII were normal. Further, she did not have excess alpha-1-antitrypin, antithrombin, or protein C to suppress thrombin generation. On a 1:1 mixing study of normal plasma:patient plasma, her thrombin time corrected to normal. Since the patient had an abnormal thrombin time with serious, spontaneous, clinical bleeding with a normal reptilase time, we postulated a fibrin polymerization defect. On a fibrin polymerization assay, the patient required 4-fold greater amounts (32 nM vs 8 nM) of human alpha thrombin to achieve complete fibrin polymerization (See Figure 1 below). On complete fibrinogen sequencing, the patient was found to have a pathologic mutation [Fb gamma chain exon 3, 124G>A, Gly42Ser (Gly16Ser in the mature gamma chain without the signal peptide)]. This defect had been previously described as Fibrinogen Krakow III (Pietrys D et al. Thromb Haemost. 2011;106:558-60). However, neither parent of the patient has a bleeding disorder. Sequencings of her parents' Fb gamma chains show no mutation. Since first being seen, the patient had a serious bleed into her right sacral plexus leaving her with a permanent foot drop. We managed her bleeding with cryoprecipitate replacement acutely and oral tranexamic acid as an outpatient. Everolimus is an mTor inhibitor which is a regulator of protein synthesis. We postulated that everolimus therapy produced the acquired abnormal Fb gamma synthesis, producing the fibrin polymerization defect associated with bleeding. Upon urging, the patient stopped everolimus therapy and has not had a major bleeding incident in 8 months although the abnormal thrombin time persists. Figure 1 Disclosures Wolberg: Novo Nordisk: Research Funding.

Small airways diseases are not uncommon in childhood. They account for about 28.4% of hospital admissions for lower respiratory tract infections in South West Nigeria, most of which are due to respiratory syncytial virus (RSV) infection. Noninfectious causes of small airways diseases, on the other hand, are poorly recognized and rarely feature in the differential diagnoses of chronic/recurrent lower respiratory tract disease in our environment. We present a case of follicular bronchiolitis in a 2.5-year-old Nigerian female who had left upper lobectomy on account of recurrent cough and progressive shortness of breath.

Here we report the case of a 72-year-old woman with nodular bronchiectaticMycobacterium aviumcomplex (MAC) disease. Chest computed tomography on admission revealed multiple micronodular and branching opacities in both lobes with segmental distribution; bronchiectasis and bronchial wall thickening were observed in the middle lobe and lingula. The patient consented to and underwent thoracoscopic lung biopsy; epithelioid granulomas were occasionally observed, but follicular bronchiolitis was widespread. While bronchial lesions from nontuberculous mycobacterial infection generally present as epitheliod granulomas, the present case suggests that follicular bronchiolitis can also be a histological counterpart to nodular opacities in nodular bronchiectatic MAC disease.

A 49-year-old woman, who had been diagnosed with asthma, showed a bilateral diffuse pattern of small centrilobular nodules on CT. Laboratory data revealed peripheral eosinophilia and a marked increase in total serum IgE levels. The nodules detected on CT were initially considered to be associated with bronchiolar infiltration of eosinophils. Pathological findings from thoracoscopy revealed infiltration of eosinophils into the airway lumen and walls, goblet cell hyperplasia, and thickening of the basement membrane in large bronchi, consistent with asthma. However, hyperplastic lymphoid follicles with reactive germinal centers were observed along the bronchioles. The follicles had no evidence of monoclonality suggested by immunohistological analysis, and no remarkable infiltrates of eosinophils, suggesting follicular bronchiolitis. After treatment with prednisolone, the small diffuse nodules improved markedly, and peripheral eosinophilia and total serum IgE levels also decreased. To the best of our knowledge, this is the first documented case report of follicular bronchiolitis associated with asthma, eosinophilia, and elevated IgE with a definite pathophysiological diagnosis.

This article comprehensively reviews and illustrates the imaging features of small airway diseases. The authors discuss the imaging findings of small airway diseases in general and how to differentiate them from other findings that can be confused with small airway diseases. The authors also discuss the features that aid in diagnosing specific diseases that affect the small airways.

The introduction of thin-section computed tomography (CT) has improved the diagnosis of bronchiolitis and contributed to establish bronchiolitis as an important part of pulmonary medicine. The histopathologic groups of bronchiolitis include cellular bronchiolitis, diffuse panbronchiolitis, follicular bronchiolitis, respiratory bronchiolitis, proliferative bronchiolitis, constrictive bronchiolitis, and mineral dust airway disease. Bronchiolitis can be readily identified and may lead to characteristic findings on thin-section CT. Various bronchiolitis manifests as one or a combination of 3 main patterns in thin-section CT: centrilobular nodules and branching densities, ground-glass attenuation and consolidation, and low attenuation and mosaic perfusion pattern.

Objective Anti-cyclic citrullinated peptide (anti-CCP) antibodies are highly specific markers for rheumatoid arthritis (RA) and useful for predicting RA development and progression. However, it has not been fully determined whether anti-CCP antibodies are associated with pulmonary diseases in RA patients. In the present study, we aimed to elucidate the relationships between anti-CCP antibodies and pulmonary diseases, particularly interstitial lung disease (ILD) and bronchiolitis. Design and methods Using an enzyme-linked immunosorbent assay, the presence of serum anti-CCP antibodies was examined in 18 RA patients with ILD and bronchiolitis who were diagnosed based on pathologic findings. A further 36 RA subjects without any pulmonary diseases served as a reference population. Results No significant differences were found for the prevalences and levels of anti-CCP antibodies between patients with and without ILD and follicular bronchiolitis. Conclusion Detection of serum anti-CCP antibodies has no association with pulmonary diseases in RA patients.

PubMed ID: 25587165, Follicular bronchiolitis (FB) is a rare small-airway pathology that is associated mainly with connective tissue diseases. This case report presents a new, diagnosed, different airway disease in a non-smoker with rheumatoid arthritis in remission who was treated for presumed asthma, but was not controlled. She was ultimately diagnosed with FB after video-assisted thoracoscopic surgery. The clinical findings of FB were controlled successfully by colchicine after she did not respond to systemic steroid therapy. This is the first case report of FB associated with rheumatoid arthritis that responded to colchicine. © 2015 Daedalus Enterprises.

Although atelectasis is common in children, its persistence or refractoriness to treatment should lead prompt evaluation to identify causal mechanism. We describe the case of a child presenting in first year of life with persistent left upper lobe atelectasis, recurrent wheezing and respiratory infections refractory to medical therapy, submitted to partial lobectomy when he was 3 years old age. Histopathological examination revealed follicular bronchiolitis. Systemic underlying diseases were excluded. Clinical improvement was initially achieved using inhaled corticosteroids, but oral therapy was needed due to clinical relapse, with favorable response.Follicular bronchiolitis, a rare pulmonary primary lymphoid lesion, consists of numerous reactive lymphoid follicles in a peribonchiolar distribution. Its precise cause is unknown, particularly in children, in which few cases have been reported. Treatment usually includes steroids and prognosis is generally good.

Ciliary dysfunction in primary ciliary dyskinesia (PCD) may be associated with bronchiolitis. Diffuse bronchiolitis has been reported in a subset of PCD patients who have Kartagener's syndrome in Japan. We report a case of follicular bronchiolitis (FB) in a case of PCD presenting with recurrent episodes of cough, dyspnea, and bronchiectasis. This may motivate researchers to study rarer variants and presentations in PCD.

The role of the surgical pathologist in dealing with breast biopsies has changed enormously during the last few years. The introduction of mammographic screening, conservative breast surgery, core biopsies and, more recently, sentinel lymph node techniques, have changed the type of material received by the pathologist for diagnosis, and the type of information required from him/her. Requests for frozen sections have markedly diminished, but new challenges have arisen, particularly in respect of diagnosing borderline lesions which are being increasingly detected by mammography. This article presents a detailed account of the handling and reporting of breast biopsies, based partly on National Guidelines and the practice at Charing Cross Hospital, London.

This review is the summary of a workshop on small airways disease, which took place in Porquerolles, France in November 2011. The purpose of this workshop was to review the evidence on small airways (bronchiolar) involvement under various pathophysiological circumstances, excluding asthma and chronic obstructive pulmonary disease. Histopathological patterns associated with small airways disease were reviewed, including cellular and obliterative bronchiolitis. Many pathophysiological conditions have been associated with small airways disease including airway infections, connective tissue diseases and inflammatory bowel diseases, bone marrow and lung transplantation, common variable immunodeficiency disorders, diffuse panbronchiolitis, and diseases related to environmental exposures to pollutants, allergens and drugs. Pathogenesis, clinical presentation, a computed tomography scan and pulmonary function test findings are reviewed, and therapeutic options are described with the objective of providing an integrative approach to these disorders., Congresses, SCOPUS: re.j, info:eu-repo/semantics/published

Multicentric Castleman's disease (CD) is a rare atypical lymphoproliferative disorder, which is characterized by various systemic manifestations. Some patients with multicentric CD may have concomitant lung parenchymal lesions, for which lymphoid interstitial pneumonia (LIP) is known to be the most common pathologic finding. Follicular bronchiolitis and LIP are considered to be on the same spectrum of the disease. We describe a case of multicentric CD with pulmonary involvement, which was pathologically proven as follicular bronchiolitis.

Follicular bronchiolitis (FB) is an uncommon but important pulmonary manifestation in children.In this report, we present the clinical presentations and histopathological data of an 8-year-old boy with FB.The patient had a history of recurrent cough and dyspnea for 5 years with progressive worsening of symptoms. An initial pulmonary function test showed an obstructive ventilatory defect. Chest X-ray demonstrated miliary nodules. High-resolution computed tomography showed reticulonodular opacification and central consolidation. Histopathological examination revealed that lymphoid follicles with reactive germinal centers distributed along the bronchioles. The boy responded favorably to corticosteroid therapy and recovered well.Diagnosis of FB should be considered when a child presents with chronic bronchial obstruction. Open lung biopsy is necessary for confirmation of the diagnosis.

This case report is the first confirmed case of follicular bronchiolitis (FB), a rare bronchiolar disorder characterized by peribronchiolar lymphoid follicles, in a series of over 400 lung transplantations performed in our center. It is to our knowledge, the first publication describing FB after lung transplantation (LTx), presenting as chronic allograft dysfunction or bronchiolitis obliterans syndrome (BOS).

A HIV-positive child was noted to have multiple small nodules with areas of consolidation on the chest radiograph (Fig. 1). Miliary tuberculosis (TB) was diagnosed, but there was no response to treatment. CT images demonstrated diffuse reticulonodular opacification and central consolidation (Fig. 2). Follicular bronchiolitis (FB) was diagnosed following open lung biopsy. Few examples of interstitial disease in HIV-positive children other than lymphocytic interstitial pneumonitis have been reported because children are not subjected to open lung biopsy [1]. FB is one of these, and is characterized

Hypertrophic osteoarthropathy (HOA) is a syndrome affecting the bones, soft tissue, and joints, often occurring in association with chronic pulmonary disorders. Radiography has traditionally been the imaging modality employed to confirm this diagnosis. However, radionuclide bone imaging provides a sensitive method for the detection of HOA and correlates well with the clinical manifestations. The authors's describe the case of a child with HOA in association with follicular bronchiolitis, a rare chronic pulmonary disorder, whose HOA was diagnosed by radionuclide imaging.