COPD: Pathophysiology and Chronic Bronchitis

• COPD stands for Chronic Obstructive Pulmonary Disease and is defined by the Global Initiative for Chronic Obstructive Lung Disease.

Pathophysiology of COPD

• Pathologic changes occur in large central airways, small peripheral airways, and the lung parenchyma.
• Chronic irritant exposure recruits neutrophils, macrophages, and lymphocytes, which leads to progressive damage from inflammation, oxidative stress, extracellular matrix proteolysis, and apoptotic and autophagic cell death.
• Frequent infectious exacerbations and lung senescence with aging contribute to disease progression.

Chronic Bronchitis

• Inspired irritants result in airway inflammation with infiltration of neutrophils, macrophages, and lymphocytes into the bronchial wall.
• Continual inflammation causes bronchial edema, an increase in mucous glands and goblet cells, smooth muscle hypertrophy with fibrosis, and narrowing of airways.
• Thick, tenacious mucus is produced but cannot be cleared due to impaired ciliary function.
• Pathophysiological changes increase susceptibility to pulmonary infection, contributing to injury and ineffective repair.
• Frequent infectious exacerbations from bacterial colonization of damaged airways are complicated by bronchospasm with dyspnea and productive cough.
• Exacerbations contribute to the overall severity and progression of disease.
• The process initially affects larger bronchi, but eventually, all airways are involved.
• Thick mucus and hypertrophied bronchial smooth muscle constrict the airways, leading to obstruction, especially during expiration when airways are narrowed.
• Expiratory obstruction traps air in the distal portions of the lung (hyperinflation), which expands the thorax and positions respiratory muscles at a mechanical disadvantage, leads to decreased tidal volume, hypoventilation, and hypercapnia.
• Airway obstruction also leads to ventilation-perfusion mismatch with hypoxemia.

Emphysema

• Emphysema involves destruction of alveolar walls resulting in abnormal permanent enlargement of gas-exchange airways.
• Obstruction results from inflammatory and destructive changes in lung tissues rather than mucus production in chronic bronchitis
• Most often, it results from the inhalation of toxic gases like cigarette smoke.
• Emphysema is characterized by inflammation and an imbalance between proteases and antiproteases, oxidative stress, and apoptosis of lung structural cells.
• Autoimmune response is triggered by infiltration of lymphocytes and the release of toxic immune cytokines, which leads to the destruction of alveoli through elastin breakdown within the septa.
• Alveolar destruction produces large air spaces within the lung parenchyma (bullae) and air spaces adjacent to pleurae (blebs).
• Bullae and blebs are not effective in gas exchange, contributing to ventilation-perfusion mismatching and hypoxemia.
• Airflow limitation's main mechanism is loss of elastic recoil with collapse of the airways during expiration.
• Air trapping causes hyperexpansion of the chest, placing the muscles of respiration at a mechanical disadvantage and increasing workload of breathing.
• This gradually progresses, leading to reduced tidal volumes, hypoventilation, and hypercapnia.
• Persistent inflammation results in hyperreactivity of the bronchi causing bronchoconstriction; acute bronchoconstriction may be partially reversible with bronchodilators.
• Continued destruction of alveolar walls and pulmonary capillaries causes pulmonary hypertension (PH) and cor pulmonale.
• Approximately one-third of individuals with emphysema have significant eosinophilic inflammation, which contributes to airway injury and may predict lack of treatment responsiveness.
• Chronic inflammation can also have significant systemic effects, including weight loss, muscle weakness, and increased susceptibility to comorbidities.

a1-Antitrypsin Deficiency

• Inherited a1-antitrypsin deficiency (primary emphysema) accounts for 1% to 3% of all emphysema cases.
• Normally, a1-antitrypsin inhibits the action of proteolytic enzymes that break down lung tissue.
• Without this inhibitory activity, neutrophils are recruited into the lung, protease activity is unopposed, and structural damage develops.
• Deficiency is suggested in individuals who develop emphysema before 40 years of age and never smoked.
• Nonsmoking individuals with a1-antitrypsin deficiency develop COPD at an older age than those with the deficiency who also smoke, and hepatic fibrosis may also occur.
• All individuals with diagnosed COPD should be screened for alpha-1 antitrypsin deficiency, and family screening is indicated for those who test positive.
• Supportive treatment for the lung disease associated with a1-antitrypsin deficiency is the same as COPD treatment with specific IV augmentation therapy using plasma-purified a1-antitrypsin slows disease progression; new treatments like gene therapy and stem cell technologies are being explored.

Clinical Manifestations of COPD

• Dyspnea on exertion that progresses to marked dyspnea, even at rest, is the most common symptom.
• In chronic bronchitis, individuals have a persistent productive cough, whereas in emphysema, cough is usually productive only during acute exacerbations.
• Individuals with COPD are often thin, have tachypnea with prolonged expiration, and must use accessory muscles for ventilation.
• Chest has an increased anteroposterior diameter (barrel chest), and has a hyperresonant sound with percussion.
• Individuals often lean forward with arms extended and braced on knees when sitting and exhaling through pursed lips, which helps prevent expiratory airway collapse.
• As the disease progresses, marked hypoxemia leads to polycythemia and cyanosis.
• If not reversed, respiratory failure leads to PH and eventually results in cor pulmonale with right heart failure and peripheral edema.

Evaluation and Treatment of COPD

• Diagnosis is based on history of exposures, family history, respiratory symptoms, physical examination, chest imaging, and pulmonary function tests.
• Pulmonary function testing reveals airway obstruction (decreased FEV1) that is progressive and unresponsive to bronchodilators.
• Chest x-ray may reveal changes in thoracic diameter, distended lung fields, and flattening of the diaphragm.
• High-resolution CT scanning provides detailed information about the underlying COPD phenotype to guide management.
• Oximetry should be obtained, and arterial blood gas analysis should be performed in those with significant hypoxemia.
• Hypoxemia may first occur with exercise but gradually progresses to hypoxemia at rest. Hypercapnia develops as air trapping worsens and the work of breathing increases, and serum eosinophil counts should also be obtained.
• Prevention is the best treatment because pathologic changes aren't reversible.
• Stopping smoking and optimal pharmacotherapy can slow disease progression.
• Influenza, COVID-19, and pneumococcal vaccination should be kept up to date.
• Pharmacologic management is based on clinical severity as described by the GOLD classification for COPD (mild, moderate, severe, or very severe).
• Initial treatment most often begins with a LAMA (e.g., tiotropium or revefenacin).
• Additional medications include LABA and inhaled glucocorticoids, and combinations of these are useful for severe COPD (triple combination).
• Inhaled corticosteroids are associated with an increased risk of pneumonia and shouldn't be used alone.
• A phosphodiesterase E4 (PDE4) inhibitor (e.g., roflumilast) and a macrolide antibiotic (azithromycin) can be considered for those with moderate to severe COPD.
• Acute exacerbations of COPD are characterized by increased dyspnea, cough, or sputum purulence, often caused by bacterial or viral infection but may also occur due to changes in air quality or medication use.
• These exacerbations may be life-threatening and contribute to overall disease progression.
• Therapy includes bronchodilators (often given via nebulizer), systemic corticosteroids, and antibiotics.
• If respiratory failure develops, high-flow nasal cannula or noninvasive ventilation are indicated.
• Pulmonary rehabilitation improves symptoms and quality of life in individuals with moderate to severe COPD, and efforts at creating effective programs using telehealth modalities are being developed.
• Progressive pulmonary dysfunction with hypoxemia and hypercapnia may require long-term oxygen therapy and ventilation; oxygen is titrated with care to individuals with severe hypoxemia and CO2 retention.
• Lung volume reduction surgery improves symptoms in selected individuals with severe COPD but is associated with significant postoperative complications, and new safer bronchoscopic techniques are emerging.
• Lung transplantation can be considered, especially in younger individuals with inherited alpha-1 antitrypsin deficiency. In addition, many comorbidities accompany COPD and require monitoring and therapy.

Respiratory Tract Infections

• Respiratory tract infections are the most common cause of short-term disability in the United States.
• Most of these infections involve only the upper airways and aren't discussed in this chapter.
• Infections of the lower respiratory tract occur most often in the very young and old, smokers, or those with impaired immunity; however, viral pneumonias can occur in healthy individuals of any age.

Acute Bronchitis

• Acute bronchitis is an acute infection or inflammation of the airways or bronchi that's usually self-limiting, and most cases are caused by viruses.
• Manifestations are similar to those of pneumonia, but the physical examination doesn't reveal signs of pulmonary consolidation, and chest radiographs don't show infiltrates.
• Individuals with viral bronchitis usually have a nonproductive cough in paroxysms and is aggravated by cold, dry, or dusty air.
• Purulent sputum may be produced in bacterial bronchitis, and chest pain often develops from coughing; treatment consists of rest, hydration, humidity, analgesics, and a cough suppressant, such as codeine; antibiotics are indicated for bacterial bronchitis.

Pneumonia

• Pneumonia is an infection of the lower respiratory tract caused by bacteria, viruses, fungi, protozoa, or parasites: estimated that lower respiratory tract infections affected nearly 500 million people and resulted in 1.23 million deaths globally in 2019
• Pneumonia accounts for over 45,000 deaths per year in the United States.
• Pneumonia can be categorized as community-acquired (CAP) or hospital-acquired (HAP).
• CAP is defined as pneumonia acquired outside of the hospital setting and is one of the most common reasons for hospitalization in the United States.
• Risk factors for pneumonia include age below 5 or above 70 years, compromised immunity, an underlying cardiac, and liver disease.
• HAP is defined as pneumonia that develops during hospitalization and is the second most common nosocomial infection and has the greatest mortality.
• Ventilator-associated pneumonia (VAP) is a subset of HAP and is a nosocomial infection that occurs in many individuals who require intubation and mechanical ventilation; VAP affects nearly a third of all individuals in ICUs and has a higher mortality than HAP in nonventilated individuals.

Pneumonia - Pathophysiology

• Viruses can target the airway and alveolar epithelial cells, especially pneumocytes, through direct inoculation/inhalation, spread from viral infections near the upper respiratory tract, or hematogenously.
• In bacterial pneumonia, colonization of the upper respiratory tract followed by aspiration of oropharyngeal secretions is the most common route of lower respiratory tract infection.
• In VAP, bacteria form biofilms on the endotracheal tube, allowing bacteria to bypass protective mechanisms and directly invade the lung; bacterial pneumonia can also occur when pathogens are spread to the lung hematogenously from infection from IV drug use.
• The alveolar macrophage is the most important guardian cell of the lower respiratory tract; Some bacteria have capsules that make phagocytosis by alveolar macrophages more difficult, and opsonization with complement and antibodies is required.
• Neutrophils release neutrophil extracellular traps (NETs);Adaptive immune activation leads to the production of antibodies and immune cytokines that activate lymphocytes.

Pneumonia - Clinical Manifestations

• Most pneumonia cases are preceded by a viral upper respiratory tract infection.
• Then individuals develop fever, chills, a cough (productive or dry), malaise, pleural pain, and sometimes dyspnea and hemoptysis.
• Physical examination may show signs of pulmonary consolidation such as dullness to percussion, inspiratory crackles, increased tactile fremitus, and egophony; a pleural effusion may develop.
• Pneumonia may contribute to decreased left ventricular function, arrhythmias, ischemia, and infarction; individuals hospitalized for pneumonia have an increased risk for cardiovascular disease whose symptoms may be erroneously attributed to persistent or recurrent pneumonia.

Pneumonia - Evaluation and Treatment

• Diagnosis of pneumonia is made based on the history of exposures and symptoms, followed by physical examination.
• The white blood cell count is usually elevated, although it may be low if the individual is immunocompromised or has significant comorbidities.
• Chest radiographs show infiltrates that may involve a single lobe of the lung or may be more diffuse; no further evaluation is indicated for outpatients with mild to moderate CAP, but with severe CAP requiring hospitalization, the pathogen is identified using sputum characteristics.
• Prevention of pneumonia includes avoidance of aspiration, respiratory isolation of infected individuals, and vaccination; measures to prevent VAP include head of bed elevation, oral hygiene, hand hygiene, and the use of specialized endotracheal tubes.
• The first step in pneumonia management is establishing adequate ventilation and oxygenation and hydration and good pulmonary hygiene.
• Viral pneumonia is treated with supportive therapy; antibiotics should be given promptly for bacterial pneumonia.

Tuberculosis

• Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, which affects lungs but may invade other body systems.
• TB affects an estimated 10 million people worldwide, resulting in 1.6 million deaths and is the leading cause of death in the world from a curable infectious disease; emigration of infected individuals from high-prevalence countries.
• TB is highly contagious and is transmitted from person to person in airborne droplets.

Tuberculosis - Pathophysiology

• TB is contained by the person's inflammatory and immune response systems, resulting in latent TB infection (LTBI) and is associated with no clinical evidence of disease.
• Once the bacilli are inspired, they lodge in the lung, usually in the upper lobe, and cause localized nonspecific inflammation to the lung tissue.
• Alveolar macrophages and neutrophils engulf and isolate the bacilli, preventing them from spreading; a granulomatous lesion called a tubercle is formed if the bacterium can evade the person's defense mechanism.
• The immune response is complete after about 10 days, preventing further multiplication of bacilli; if the immune system is impaired, reactivation with progressive disease can occur and may spread to other organs.

Tuberculosis - Clinical Manifestations

• LTBI is asymptomatic.
• Symptoms of active disease develop gradually and aren't diagnosed until the disease has advanced.
• Extrapulmonary TB is common in HIV-infected individuals and may cause neurologic deficits, meningitis symptoms, bone pain, and urinary symptoms.

Tuberculosis - Evaluation and Treatment

• Screening is usually conducted using the tuberculin skin test; high-risk individuals should be screened with the interferon-gamma release assay.
• Prevention of reactivation of LTBI through the use of antituberculous medications is recommended for at-risk individuals; those with active TB must be kept in respiratory isolation until their sputum is negative for bacilli.

Abscess Formation and Cavitation

• An abscess is a circumscribed area of suppuration and destruction of lung parenchyma, and is often caused by aspiration associated with alcohol abuse, seizure disorders, general anesthesia, and swallowing disorders.
• Abscess communication with a bronchus causes production of copious amounts of malodorous sputum and hemoptysis; other clinical manifestations include fever, cough, chills, and pleural pain Diagnosis is made by chest radiography and sputum analysis.
• Treatment includes appropriate antibiotics and chest physical therapy; bronchoscopy may be needed to drain the abscess.

Pulmonary Embolism - Overview

• Pulmonary embolism (PE) is the occlusion of a portion of the pulmonary vasculature by an embolus; an estimated 900,000 people in the United States develop deep venous thrombosis.
• PE most commonly results from embolization of a clot from DVT involving the lower leg; other less common types of emboli include tissue fragments, lipids, a foreign body, an air bubble, or amniotic fluid.

Pulmonary Embolism - Pathophysiology

• The effect of the embolus depends on the extent of pulmonary blood flow obstruction, the size of the affected vessels, and the nature of the embolus.
• Small pulmonary emboli typically cause ventilation-perfusion mismatch and associated hypoxemia without damaging the lung itself.
• More significant obstruction of the pulmonary vasculature leads to pulmonary artery vasoconstriction, PH, and an increased workload for the right ventricle.

Pulmonary Embolism - Clinical Manifestations

• Clinical manifestations of PE are nonspecific and may be confused with many other conditions, so evaluation of risk factors and predisposing factors is an important diagnosis aspect.
• The classic clinical presentation of PE is the sudden onset of pleuritic chest pain, dyspnea, tachypnea, tachycardia, and unexplained anxiety; recurrent small emboli may not be detected until progressive incapacitation is exhibited.

Pulmonary Embolism - Evaluation and Treatment

• The diagnosis of PE is made by assessing the clinical probability followed by measuring D-dimer levels in the blood.
• Anticoagulant therapy is the primary treatment for PE; prevention of PE includes elimination of predisposing factors for individuals at risk.

Pulmonary Hypertension

• Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure greater than 25 mm Hg at rest One major category of PH is termed pulmonary artery hypertension and includes subcategories of idiopathic, heritable, drug and toxin-induced.
• Left heart disease is the most common cause of PH, and COPD and interstitial fibrosis are the most common lung diseases associated with PH.
• PAH is characterized by endothelial dysfunction combined with hypoxic pulmonary vasoconstriction leads to increased pressures in the right heart and cor pulmonale. Symptoms of PH may not develop until late in the disease process.

Pulmonary Hypertension -Manifestations and Treatment

• Manifestations include fatigue, chest discomfort, tachypnea, and dyspnea.
• General therapies for PAH include administration of oxygen, diuretics, and anticoagulants; avoidance of contributing factors.
• Pharmacologic interventions for PAH may include vasodilators, but none are curative.

Cor Pulmonale

• Cor pulmonale is right ventricular enlargement (hypertrophy, dilation, or both) due to pulmonary disorders that cause PH.
• Chronic pulmonary disease associated with hypoxemia and hypercapnia cause pulmonary vasoconstriction and increased pressures in the pulmonary system; chronic pressure overload leads to hypertrophy of the heart muscle.
• The diagnosis is based on the physical examination, thoracic imaging, and electrocardiography or echocardiography; treatment is the same as that for PH, and its success depends on reversal of the underlying lung disease.

Laryngeal Cancer - Overview

• Laryngeal cancer represents less than 1% of Cancers.
• Laryngeal cancer is much more common among men and the primary risk factor is smoking.

Laryngeal Cancer - Symptoms

• Dysphagia, hoarseness (dysphonia), and dyspnea, are symptoms of laryngeal cancer.
• Early diagnosis and treatment of laryngeal cancer saves the lives of patients.
• The process to diagnose it includes palpitation of the larynx, direct laryngoscopy with a biopsy for definitive diagnosis.

Lung Cancer - Overview

• Lung cancer is the second most common cancer in the United States and is the cause for major cancer deaths.
• The 5 year survival rate is very low (22%)
• Smoking accounts for 80% of all primary lung cancers

Lung Cancer - Pathophysiology

• Tobacco contains close to 7000 chemicals and air toxins are major causes of tumors to develop.
• When there is an initiation in carcinogen induction, the development of tumors are promoted by growth factors that increases the the production and response to cell growth which later leads to cancer

Lung Cancer - Clinical Manifestations and Treatment

• Coughing is a common symptoms.
• Dysphagia, weight loss, fatigue etc , are symptoms for underground lung cancer
• Diagnosis can be done by CT scans and annual checkups.
• It can be evaluated through tests like: sputum cytotoxic studies, chest CT
• It's classified through TNM classification.

Lung Cancer - Neuroendocrine Tumors

• Small cell lung carcinoma (SCLC) is the most common type of neuroendocrine lung tumor and causes 25% of lung cancer deaths.
• Tumors are typically located in the hilar and mediastinal,
• Malignant mesotheliomas arise from the mesothelial cells that line the pleura, and are linked to the exposure of asbestos.