Lung

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 21, and is acute asthma exacerbation in the lung.

The information provided in this case was accurate and correct at the time of publication in 2021.

Any changes in terminology since the time of publication may not be reflected in this case.

Sections show a dilated, ectatic bronchus filled with mucus, sloughed epithelial cells, inflammatory cells (predominantly eosinophils), and rare Charcot-Leyden crystals, consistent with allergic mucin. The lining mucosa is partially denuded but shows a thickened basement membrane. The underlying smooth muscle appears hypertrophic with prominent eosinophilic and lymphocytic inflammation in the bronchial walls. The alveolated lung parenchyma shows focal evidence of air trapping but is devoid of intraalveolar collections of inflammatory cells, fluid, fibrin, and blood. Capillary congestion is present. No viral cytopathic effect is present. No fungal elements are found in the mucus. The pleura and vascular anatomy are unremarkable. The findings are supportive of a diagnosis of acute asthma exacerbation.

Asthma is a global health problem. Approximately 300 million people are affected by asthma, leading to an estimated 250,000 deaths per year. The steady increase in urbanization over the past century has led to a parallel increase in allergic diseases, including asthma. Children are the most affected age group. In the US, asthma affects 5% of the population. It accounts for 2 million emergency department visits, 470,000 hospitalizations, and 4,500 deaths annually.

Asthma is characterized by intermittent but reversible airway obstruction, triggered by trivial stimuli. Several factors contribute to the development of asthma, including genetic predisposition to produce type I hypersensitivity responses (i.e. atopy), inflammation, and bronchial hyperreactivity. Both atopic and non-atopic variants of asthma are characterized by episodes of bronchospasm triggered by ​various ​stimuli, including allergens, smoke, fumes, stress, exercise, and/or respiratory infections (largely viral). Atopic responses result in type 2 helper T-cell activation with release of cytokines, including IL-4, IL-5, IL-9, and IL-13. In turn, IL-5 recruits and activates tissue eosinophils, while IL-13 stimulates mucus production. IL-4 and IL-13 result in further activation of B cells and IgE production, culminating in mast cell/basophil and eosinophil activation and degranulation. The inflammatory milieu results in mucus plugging and hyperreactivity of the smooth muscle, resulting in bronchospasm. Repeated bouts of inflammation lead to structural changes in the bronchial wall, including hypertrophy of bronchial smooth muscle and mucus glands, increased vascularity, and deposition of subepithelial collagen. These changes are collectively referred to as airway remodeling. Several drugs, including aspirin, ​can also ​provoke drug-induced asthma​ attacks​. Patients on aspirin present with recurrent rhinitis, nasal polyps, urticaria, and bronchospasm.

​​Gross descriptions of ​lungs with asthma ​have largely been​ from autopsy studies of individuals who have died in status asthmaticus, which is defined as severe acute asthma exacerbation resistant to initial therapy. Findings include overinflation of the lungs and mucus plugs occluding medium-sized bronchi and bronchioles. In contrast to emphysema, destruction of the alveolated parenchyma is rarely seen. Secondary changes of bronchiectasis and pneumomediastinum may be seen in a subset of cases.

Microscopically, airways may be normal or only show mild histologic changes between exacerbations. Segmental and subsegmental bronchi are typically affected. The bronchial epithelium is usually denuded but, when intact, may show features of goblet cell hyperplasia. Epithelial desquamation results in formation of Creola bodies (sloughed ciliated bronchial cells) and Curschmann spirals (spiral-shaped mucus plugs). Squamous metaplasia may also be seen. Mucus plugs fill both bronchi and bronchioles, attributable to submucosal gland hypertrophy and goblet cell hyperplasia, resulting in mucoid impaction bronchiectasis. Features of airway remodeling may be seen in chronic cases. These include thickened airway walls, goblet cell metaplasia of the lining epithelium, sub-basement membrane fibrosis, increase in size of submucosal glands, increased vascularity in the submucosa, and hypertrophy and hyperplasia of the smooth muscle. Surgical pathologists may occasionally encounter an endobronchial biopsy from asthmatic patients, especially if they are undergoing bronchial thermoplasty for therapeutic management of refractory disease.

Allergic bronchopulmonary aspergillosis (ABPA) or allergic bronchopulmonary fungal disease is a term used for exacerbation of a chronic airway injury (asthma and/or bronchiectasis) by hypersensitivity to fungal antigens. Aspergillus-related antigens are most often implicated. Although hypersensitivity to Aspergillus antigens is a common phenomenon in patients with asthma, ABPA occurs​ only​ in 1% to 13%​ of asthma patients​. Patients with steroid-dependent asthma are at a higher risk to develop ABPA in comparison to those with non-steroid-dependent asthma. Patients with ABPA present with exacerbation of symptoms with fever and/or hemoptysis. These patients also demonstrate cutaneous reactivity to Aspergillus antigens, elevated IgE levels with increased serum anti-Aspergillus levels, and peripheral eosinophilia (more than 500/mm2). Biopsies or surgical specimens in patients with ABPA show allergic-type mucin, a layered mucus plug containing acellular mucin alternating with cellular mucin. The cellular mucin comprises eosinophils and degranulated cellular debris. Rare, degenerated forms of fungal elements may be identified in the mucin, further ​demonstrated​​ with​ histochemical stains such as GMS. Bronchial wall invasion by fungal organisms is usually absent.

Aspiration pneumonia is caused by microaspiration or macroaspiration of oral and gastric contents. In the pediatric population, this can be due to inhalation and impaction of foreign objects. Impaction of large objects within the tracheobronchial lumen can result in parenchymal collapse and post-obstructive bronchopneumonia. Chronic microaspiration is characterized by poorly formed granulomas, lipid-laden macrophages, and foreign body-type giant cell reaction. Occasionally, aspirated fragments (pill fragments and/or organic matter) may be found within foci of active suppurative inflammation.

Chronic obstructive pulmonary disease is a clinical spectrum of conditions that include chronic bronchitis, emphysema, and small airway disease. Chronic bronchitis is histologically characterized by chronic inflammation of the large airways with mucostasis, submucosal gland hyperplasia (resulting in increased Reid index), and goblet cell metaplasia. Emphysema, on the other hand, shows permanent enlargement of airspaces distal to terminal bronchioles (usually without significant fibrosis).

Cystic fibrosis (CF) is a multisystem, inherited, autosomal recessive disorder resulting from mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Bronchiectasis is the hallmark finding in the lungs of CF patients. Bronchiectasis is characterized by permanent dilatation of the cartilaginous airways, resulting in inflammation-induced destruction and weakening of the wall. Non-CF bronchiectasis is seen in patients prone to develop recurrent respiratory infections (eg, common variable immunodeficiency, primary ciliary dyskinesia) or secondary to asthma, tuberculosis, or aspiration. Rheumatological diseases may be associated with bronchiectasis. Grossly, these ectatic airways extend almost to the pleural surface and are filled with mucopurulent material. Microscopically, there is destruction of the cartilage and smooth muscle by inflammation, and bronchial lumina are filled with acute inflammatory debris and mucus. The inflammation extends beyond the bronchi into adjacent dilated bronchioles and airspaces.

Eosinophilic pneumonia is characterized by prominent intra-alveolar and interstitial eosinophil infiltrates with preservation of lung architecture. Features of organizing pneumonia may be present. In the acute form, hyaline membranes and other features of diffuse alveolar damage are usually present. In the chronic form, non-necrotizing sarcoid granulomas may be identified. Tissue biopsy is not commonly received, as bronchoalveolar lavage is often ​diagnostic at​ a threshold of more than 25% eosinophils.

1. Interleukins (IL) are key inflammatory mediators in asthma. Which of the following IL is a major factor in eosinophil chemotaxis?
   
   
   1. IL-2
   2. IL-4
   3. IL-5
   4. IL-9
   5. IL-13
2. Basement membrane thickening, goblet cell metaplasia, eosinophils in the submucosa, and smooth muscle hyperplasia are part of the histologic manifestations of which of the following conditions?
   
   
   1. Aspiration
   2. Asthma
   3. Bronchopneumonia
   4. Cystic fibrosis
   5. Eosinophilic pneumonia
3. Which histological feature is prototypical of allergic bronchopulmonary aspergillosis (ABPA)?
   
   
   1. Allergic-type mucin with rare degenerated fungal filaments
   2. Large aggregates of fungal filaments filling bronchial lumina
   3. Mucoid impaction and abundant neutrophil debris
   4. Necrosis and tissue invasion by fungal filaments
   5. Suppurative granulomatous inflammation with yeast forms

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1. IL-5 (c)
2. Asthma (b)
3. Allergic-type mucin with rare degenerated fungal filaments (a)