Overview

• Characterized by inflammation and/or fibrosis in the lung tissue.
• Pulmonary restriction with reduced total lung capacity, forced vital capacity, and forced expiratory volume at one second.
• Signs and symptoms:
  – Progressive dyspnea; most patients initially experience dyspnea only upon exertion but, over time, develop difficulty breathing even during rest.
• Dry, non-productive cough is common, and, some patients will present with digit clubbing.
• Chest x-rays often show opacities or other abnormalities.
• Complication of interstitial lung disease is pulmonary arterial hypertension.
• Diagnosis: Due to the non-specific and overlapping signs and symptoms diagnosis is often difficult, and often involves specialists from multiple fields who can integrate findings from chest imaging, pulmonary function tests, clinical exams, and histological sampling.
• Treatment varies, and is often targeted at the underlying disease; in some cases, anti-fibrotic drugs, such as pirfenidone, are helpful.

Histopathology

• We draw a healthy alveolar duct opening to alveolar spaces, which are separated by alveolar septi.
  – In healthy lungs, the alveolar walls are compliant and expand upon inhalation to facilitate gas exchange with the pulmonary capillaries.
• Interstitial lung disease develops when, in response to various stimuli, fibroblasts and myofibroblasts proliferate in the ducts and sacs.
• These proliferating cells promote extracellular matrix deposition and collagen accumulation.
• This leads to alveolar septal thickening; if left unchecked, fibrosis can develop.
• The thickened alveolar membranes are stiffer and cannot expand upon inhalation, which inhibits gas exchange.

TYPES OF INTERSTITIAL LUNG DISEASE

EXPOSURE

Let’s begin with interstitial lung diseases that develop in response to exposure to external agents.
Occupational

• Asbestosis and silicosis develop when pulmonary macrophages ingest asbestos fibers or silica dust, which triggers the histological changes we just drew.
  – Scarring is diffuse, and ground glass reticular opacities and pleural plaques are seen on chest x-ray.
• Coal worker’s pneumoconiosis, aka, “black lung” occurs when pulmonary macrophages ingest coal dust.
  – Numerous small nodular opacities are visible in chest x-rays.
• Hypersensitivity pneumonitis is a type III or mixed type III/type IV hypersensitivity that results from exposure to specific environmental triggers.
  – Farmer’s lung is caused by exposure to molds that grow in hay or other feed grains; additional examples include “bird fancier’s lung” and “humidifier lung.”

Drugs

Over 400 drugs can cause interstitial lung disease.

• Antibiotics (such as amphotericin B)
• Anti-inflammatories (Aspirin and NSAIDS)
• Cardiovascular medications (including ACE-inhibitors and beta-blockers)
• Chemotherapy drugs

Infections

• Examples include aspergillosis, histoplasmosis, and mycobacterial infections.

SYSTEMIC DISORDERS

Connective Tissue Disorders

Many connective tissue disorders are immune or autoimmune pathologies with excessive collagen deposition or mucus reduction; thus, when the lungs are involved, restriction occurs.

• Some key examples include: Systemic sclerosis, rheumatoid arthritis, systemic lupus, and sjogren’s syndrome.

ANCA vasculitides (ANCA = Anti-Neutrophilic Cytoplasmic Autoantibodies)
Remind ourselves that these disorders include: Granulomatosis with polyangiitis (aka, Wegener’s disease), eosinophilic granulomatosis with polyangiitis (aka, Churg-Strauss syndrome), and, microscopic polyangiitis.

Granulomatous lung diseases

• Granulomatous-lymphocytic interstitial lung disease & sarcoidosis.

IDIOPATHIC INTERSTITIAL PNEUMONIAS

The causes of these diseases are unclear, but each is associated with characteristic histological and clinical features; diagnosis is often based on exclusion.

Additional images

• Idiopathic pulmonary fibrosis is the most common idiopathic interstitial pneumonia.
  – It is characterized by a histological pattern called “usual interstitial pneumonia;” this comprises patches of honeycomb patterns and areas of fibroblasts and dense collagen.

• Nonspecific interstitial pneumonia is associated with younger women with no history of smoking; this type is sometimes associated with immune or connective tissue disorders.
  – The histological pattern comprises homogenous areas of fibrosis or cellular inflammation (not honeycomb).

• Desquamative interstitial pneumonia develops in cigarette smokers older than 30.
  – Characterized by diffuse inflammation with pigmented macrophages in the alveoli. The brownish pigments in the macrophages are iron-rich granules commonly found in cigarette smokers’ lungs.

• Respiratory bronchiolitis-associated interstitial lung diseasealso affects smokers older than 30 and is characterized by pigmented macrophages; however, in these patients, inflammation is patchy.

• Cryptogenic organizing pneumonia is a flu-like illness characterized by collections of collagen, fibroblasts, and myofibroblasts that plug the small airways and alveolar ducts, and alveoli are inflamed.
  – Be aware that cryptogenic organizing pneumonia was formerly known as bronchiolitis obliterans with organizing pneumonia.

• Lymphocytic interstitial pneumonia* is characterized by lymphocytes and plasma cell infiltration into the alveoli and septi.

• Acute interstitial pneumonia is characterized by diffuse alveolar damage and thickening, edema, and inflammatory cell infiltration, with possible hyaline membranes forming in the septa.
  – Acute interstitial pneumonia can quickly lead to respiratory distress.
  – Be aware that acute interstitial pneumonia is sometimes called Hamman-Rich syndrome.

Others:

• Lymphangioleiomyomatosis: Genetic defect; Characterized by smooth muscle cell growth throughout the lungs, kidney, and lymphatic system.
  – Almost always in women 30+ years old.
  – Often associated with tuberous sclerosis complex (an inherited syndrome).
  – Often associated with recurrent pneumothorax.
  –

• Pulmonary alveolar proteinosis
  – Lipoprotein surfactant accumulates in the alveoli (stains periodic acid-Schiff positive).
  – Can be hereditary or autoimmune.

• Langerhan’s cell histocytosis
  – Langerhans cells accumulate in the lungs.
  – Associated with cigarette smoking.

• Pleural parenchymal fibroelastosis
  – Fibrosis that is originally predominant in upper lobes, may progress throughout lung.

Overview

Bronchiectasis is a chronic, heterogeneous disorder caused by repeated bouts of infection and inflammation that cause permanent dilation of the medium and medium-large airways.
– Damage can be focal or diffuse, depending on the cause and extent of the damage.
– Etiologies:
Obstruction, which causes focal bronchiectasis, and can be due to tumor masses or foreign bodies in the bronchi.
Infections, often bacterial; common pathogens include Pseudomonas aeruginosa, Haemophilus influenzae, and Non-tuberculosis mycobacteria.
Immune deficiencies
Autoimmune disorders; for example, bronchiectasis is associated with inflammatory bowel disease and rheumatoid arthritis.
Allergic bronchopulmonary aspergillosis; as its name suggests, this form of bronchiectasis is caused by an allergic reaction to the common mold aspergillus;
Genetic conditions, including cystic fibrosis, alpha-1-anti-trypsin deficiency, and primary ciliary dyskinesia (aka, Kartagener syndrome) – these disorders are associated with increased mucus production, neutrophilic damage, and impaired muco-ciliary functions, respectively.
**Asthma and/or COPD
– Many cases of bronchiectasis are idiopathic.

Bronchiolitis is a common affliction of children younger than two years of age; it occurs as result of respiratory infections.

BRONCHIECTASIS:

• Most patients have cough with prominent sputum production.
  – The sputum itself is often described as thick and “tenacious.”
• Hemoptysis may also occur, and is the result of airway neovascularization and rupture.
• Lung crackles and rhonchi
• Some patients wheeze
• Historically, bronchiectasis was associated with digit clubbing, in which the ends of the digits are enlarged and rounded; however, this is less commonly reported, today. The mechanistic link between bronchiectasis and digit clubbing is uncertain.
• Some patients have so-called “dry” bronchiectasis – this is often associated with nontuberculous mycobacterial infection, and is characterized by less sputum production.
• Exacerbations are defined as worsening symptoms that last two days or longer, and require changes in treatment approach.
  – Exacerbations are especially problematic because they cause additional bronchial damage.
• Complications can lead to hypoxemia, due to airway obstruction, and even pulmonary hypertension and right heart failure.
• Treatments:
  – Airway clearance techniques
  – Exercise
  – Macrolides and other antibiotics
  – Hyperosmolar and mucolytic agents that transform mucus to facilitate clearance
  – Anti-inflammatory drugs

Pathogenesis: A Vicious Cycle

• Impaired mucociliary clearance and retention of airway secretions, which creates an environment vulnerable to chronic infections.
• Chronic infections results in chronic inflammation with neutrophilic and T-cell infiltration.
• These inflammatory cells release cytokines that cause tissue destruction and airway remodeling
• Over time, this degradation of the bronchial wall produces dilation.
• And, chronic infection and inflammation further impair mucociliary clearance.

Pause for a moment and consider where and how some of the causes of bronchiectasis promote this cycle: cystic fibrosis increases mucus production; infection, especially by antibiotic-resistant bacteria, cause chronic and harmful inflammation, and immune deficiencies fail to clear infections effectively.

• Despite the fact that medium-sized airways are dilated in bronchiectasis, they can also become obstructed by recurrent inflammation and infection and mucus accumulation.
• Furthermore, smaller, downstream airways, which significantly impact airflow, can become obstructed by the inflammation and infections.
  – Thus, the complications we discussed earlier, including hypoxemia and right heart failure, can occur.

###Bronchiolitis

• Common in children under two years of age.
• It is most often caused by RSV, though rhinovirus and parainfluenza virus can also cause bronchiolitis.
• Pathogenesis: bronchiolitis occurs when the small bronchial tubes become inflamed, necrotic, and, subsequently, narrowed by mucus and debris.
  – As a result, that some alveoli collapse because air cannot be delivered to them, whereas low-oxygen air is trapped in other alveoli.
• Signs and symptoms:
  – Infants can experience fever, congestion or runny nose, coughing, and wheezing. Indicate that cyanosis, particularly of the lips and nail beds, can occur as the result of reduced oxygen levels.
  – Other signs of bronchiolitis include: rapid, shallow breathing and/or apnea, with wheezing and crackling.
  – Infants struggling to breath may grunt and, as a result of accessory muscle involvement and straining, retractions may be observed – look for “sucking in” of the skin around the base of the neck as the infant struggles to bring in air.
  – Due to congestion and obstructed breathing, infants may also have difficulty bringing in foods and liquids, which can lead to dehydration.

Overview

• A heterogeneous chronic disease of the conducting airways.
• Characterized by intermittent and mostly reversible periods of bronchial obstruction, with bronchial hyper-reactivity, excessive mucus, and airway remodeling; in contrast, recall that COPD is characterized by constant, irreversible airway obstruction.
• Asthmatic patients experience episodes of cough, wheezing, dyspnea, and feelings of chest tightness.
• Characterized by increased total lung capacity because air is trapped in the lungs.
• The ratio of forced expiratory volume in one second to forced vital capacity is normal or low.
• The diffusing capacity of the lungs for carbon monoxide is normal or elevated.
• Ventilation to perfusion mismatches occur, which can lead to hypoxemia.
• Asthma is a heterogeneous disease with different etiologies and characteristics, and there are different ways to classify asthma types
  – Historically, asthma has been classified based on phenotypes, which are the observable characteristics – such as by the presence or absence of eosinophils.
  – Many researchers are now shifting towards classification based on endotypes, which are based on the pathophysiologic mechanisms that drive types of asthma – such as whether high levels of type 2 inflammation is involved.
• Diagnosis of asthma can include: pulmonary function tests (spirometry), methacholine bronchial challenge tests, and allergy tests.
• Treatments for asthma can be broad-based or more targeted, depending on the asthma type.

Types of Asthma

We organize these based on presence of granulocytes and the type of inflammation.

Eosinophilic asthma with high levels of type-2 inflammation

This group includes the most thoroughly studied subtypes of asthma.

• Type-2 inflammation is due to an imbalance towards T-helper 2 cells and Type-2 innate lymphoid cells and their cytokines (specifically, IL-4, IL-5, and IL-13) which promote IgE production from B cells.

• Early Onset with Allergy: because allergens are the triggers for asthma attacks, this subtype is sometimes called “Extrinsic asthma.”
  – Asthma attacks are IgE-mediated, and patients often have other allergies and history of rhinitis and atopic dermatitis. Click to review Hypersensitivity Type 1
  – Tends to be familial, is associated with early childhood respiratory viral infections (especially RSV and rhinovirus), and, is most common in boys.
  – Biomarkers include elevated eosinophils and serum IgE.
  – Common triggers include house dust mites, mold, pets, and pollen.

• Late-onset without atopy
  – Patients have fewer allergies, but often present with more severe asthma.
  – Often co-exists with chronic rhinosinusitis and nasal polyps.
  – Not familial, and tends to occur most often in adult females.
  – Biomarkers include elevated eosinophils, and, in a sub-set of patients, elevated levels of Staphylococcus aureusendotoxin-specific IgE.
  Be aware that, although most patients do not have elevated levels of IgE, it is thought that localized IgE in the airways occurs.
• Key triggers in this group include air pollution, especially diesel gas fumes and other irritants, as well as respiratory infections.

• Aspirin-exacerbated asthma (aka, aspirin-exacerbated respiratory disease – AERD)
• Form of asthma triggered by aspirin – it is often severe, and typically occurs in adults
  – Thus, some consider this to be a sub-sub-type of late-onset asthma.
  – Aspirin-exacerbated asthma is due genetic abnormalities that lead to dysregulation of arachidonic acid metabolism.

Next, let’s consider some other types of asthma.

Neutrophilic, type-2-low asthma

• Characterized by elevated levels of the cytokine IL-17 and oxidative stress.
• Neutrophilic asthma is usually adult-onset and is often severe.
  – Resistant to corticosteroids.
• Key at-risk populations include: smokers, obese people, and elderly people.

Mixed granulocytic asthma

• Characterized by elevated levels of T helper 2 and T helper 17 cytokines.

Paucigranulocytic asthma

• Characterized by non-inflammatory (or low inflammatory) changes in the bronchi: remodeling and hyper-reactivity.

Two additional asthma phenotypes that can overlap with those already listed:
Occupational, aka, work-related asthma

• Develops in response to exposure to workplace allergens or irritants (and, because it is occupation-related, tends to develop in adulthood).
  Exercise-induced/exacerbated asthma
• Triggered by exercise.
• Although the exact mechanisms are unclear, it is thought that exercise-related evaporation and water loss from the airway epithelia causes injury that leads to upregulation of pro-inflammatory mediators.

Comparison with healthy bronchi.

• Smooth muscle overgrowth, which contributes to hyper-reactivity and constriction of the airways.
• Possible inflammation and fibrosis with migration of eosinophils and/or neutrophils in the wall of the airway (depending on the type of asthma).
• The basement membrane is thickened.
• Respiratory epithelium displays goblet cell metaplasia.
• Excess mucus further narrowing the airway so that the lumen is much smaller than normal.
• Other hallmarks of asthma may be seen in the sputum:
  – Curschmann spirals are mucus plugs that comprise desquamated airway epithelial cells.
  – Charcot-Leyden Crystals are crystals formed from eosinophil proteins.

Treatments

Step-wise approach to treatment

• Short-acting beta-antagonists, such as Albuterol, are provide for quick relief during asthma attacks; they relax the smooth muscle lining the bronchi.
• Long-acting beta-antagonists, such as Salmeterol, may be used longer-term in conjunction with other drugs.
• Inhaled corticosteroids, such as beclomethasone, suppress airway inflammation and are first-line therapy for long-term asthma management.
• Leukotriene antagonists, such as montelukast, also reduce bronchoconstriction and inflammation, and are especially useful in exercise- and aspirin-exacerbated asthma.
• Anticholinergics, such as Ipratropium and Tiotropium, produce smooth muscle relaxation in the bronchi.
• Anti-IgE antibodies, such as Omalizumab, are effective in allergic asthma.
• Anti-IL-5 antibodies, such as Mepolizumab, are useful in severe eosinophilic asthma.
• Mast cell inhibitors, such as Cromolyn, prevent mast cells from releasing inflammatory mediators that lead to bronchospasm.
• Oral corticosteroids, such as prednisone, are used in severe asthma to reduce inflammation; because oral corticosteroids can have serious side effects, they are typically used for acute attacks.