Chapter 14: The Respiratory System

Learn the role of blood gases in the evaluation of the patient with pulmonary disease.
Understand how pleural fluid analysis is used in the diagnosis of pulmonary disorders.
Understand how bronchoalveolar lavage can aid in the diagnosis of respiratory disease.
Recognize the different laboratory tests used for assessing fetal lung maturity.

Approach to the Patient With Pulmonary Disease

Impaired exchange of gases is the unifying theme of respiratory disorders (Figure 14–1). Although they do not play a significant role in the diagnosis of specific pulmonary diseases, blood gas and electrolyte measurements (see Chapter 2 for blood gas determinations) are commonly used to assess the severity of different pulmonary abnormalities. The analysis of fluid located in the pleural space, which collects with certain abnormalities, constitutes another battery of tests often useful in the evaluation of pulmonary diseases. Careful analysis of respiratory secretions along with accompanying white blood cells, immune mediators, and foreign pathogens through bronchoalveolar lavage (BAL) aids in the diagnosis and management of lung disease. Infections in the respiratory tract are a major cause of pulmonary disorders. These are nearly always diagnosed using clinical laboratory tests (respiratory infections are discussed in Chapter 5). This chapter begins with a discussion of laboratory tests utilized in the diagnosis and monitoring of respiratory diseases and is followed by a section describing the most common lung diseases—asthma, respiratory distress syndrome (RDS) in adults and neonates, chronic obstructive pulmonary disease (COPD), and lung cancer.

Figure 14–1

An overview of the major causes of respiratory disease.

Pulmonary disorders other than infections and tumors can be classified into 3 major groups. One group of disorders includes emphysema, bronchitis, asthma, and RDS. These are airway-based (bronchial) diseases. Inflammation or damage to the bronchi results in impaired ventilation of alveoli (Figure 14–2). Another group of disorders affects the blood vessels, and, thereby, blood flow in the lung. Pulmonary vascular diseases are associated with reduced blood flow, resulting in nonuniform perfusion of the lungs (Figure 14–3). The third major group of pulmonary diseases is the interstitial lung disorders, which affect the tissue and space around the alveoli. These are a heterogeneous group of disorders associated with lung tissue damage due to scarring or inflammation. Damaged lung tissue is unable to fully expand, leading to thickening of the interface between alveoli and adjacent capillaries resulting in impaired diffusion of gases (Figure 14–4).

Figure 14–2

Diagram of diseases of the airway resulting in impaired ventilation.

Figure 14–3

Diagram of diseases with reduced blood flow, resulting in impaired perfusion of the lung.

Figure 14–4

Diagram of diseases with a thickened interface between alveoli and adjacent capillaries, resulting in impaired diffusion of gases.

Clinical progression of pulmonary disease can lead to life-threatening respiratory failure. Acute RDS is a rapid-onset disease associated with severe breathing problems resulting from multiple insults to the lung (see more information below). It is distinct from “end-stage lung,” which is the result of a chronic pulmonary disorder.

Blood Gases and Blood pH

Many disorders are associated with abnormalities in arterial blood pO₂, pCO₂, and pH. While these tests are not themselves diagnostic, they are valuable in assessment of the severity of respiratory diseases. The blood gas test panel includes:

pO₂ or partial pressure of oxygen
pCO₂ or partial pressure of carbon dioxide
pH

The functional abnormalities most commonly detected with this battery of tests are:

Low pO₂ (hypoxemia or low O₂ in blood, as opposed to hypoxia, which is reduced O₂ in tissues)
High pCO₂ (hypercapnia)
Low arterial blood pH with a primary respiratory cause (respiratory acidosis from an increased arterial pCO₂)
Low arterial blood pH with a primary metabolic cause (metabolic acidosis, usually from increased acid production and/or impaired renal H⁺ elimination, resulting in a decreased arterial HCO₃⁻)
High arterial blood pH with a primary respiratory cause (respiratory alkalosis from a decreased arterial pCO₂)
High arterial blood pH with a primary metabolic cause (metabolic alkalosis from an increased arterial HCO₃⁻)

The lungs respond within minutes to acid–base disturbances by 1) eliminating CO₂ (hyperventilation) to increase blood pH or 2) retaining CO₂ (hypoventilation) to decrease the pH.

The lungs respond within minutes to acid–base disturbances by 1) eliminating CO₂ (hyperventilation) to increase blood pH or 2) retaining CO₂ (hypoventilation) to decrease the pH. The kidney has the ability to 1) excrete H⁺ and retain HCO₃⁻ to increase pH or 2) retain H⁺ and excrete HCO₃⁻ to lower blood pH. However, renal compensation is slow and occurs over hours to days. Table 14–1 lists selected respiratory and nonrespiratory disorders associated with hypoxemia, and Table 14–2 presents selected respiratory and nonrespiratory disorders that can result in acid–base abnormalities.

Table 14–1Selected Disorders Associated With Hypoxemia

Table 14–1 Selected Disorders Associated With Hypoxemia

Disorder

Basis of Abnormality

Chronic bronchitis

Impaired ventilation of lung

Emphysema

Impaired ventilation of lung

Asthma

Impaired ventilation of lung

Pneumoconioses

Impaired ventilation of lung

Central or peripheral neuromuscular disorders

Impaired ventilation of lung

Right-to-left shunts of great vessels

Impaired perfusion of blood into lungs

Pulmonary embolism and pulmonary infarction

Impaired perfusion of blood into lungs

Sarcoidosis

Impaired diffusion of gases into blood

Selected lung cancers

Impaired diffusion of gases into blood

Table 14–2Selected Disorders Associated With Acid–Base Abnormalities^a

Table 14–2 Selected Disorders Associated With Acid–Base Abnormalities^a

Disorder

Metabolic Alterations

Selected causes of metabolic acidosis:
Arterial pH decreased with arterial HCO₃⁻ decreased (often from increased acid production associated with an elevated anion gap or impaired renal elimination) as a primary change and arterial pCO₂ decreased as a compensatory change

Uncontrolled diabetes
Methanol intoxication
Tissue hypoxia
Renal failure from a variety of causes
Gastrointestinal HCO₃⁻ loss from diarrhea

Increased ketoacids, increased anion gap
Increased formic acid, increased anion gap
Increased lactic acid, increased anion gap
Impaired H⁺ excretion and/or HCO₃⁻ absorption
Decrease in HCO₃⁻ results in a relative increase in acidity, normal anion gap, increased Cl⁻, decreased Na⁺ and K⁺

Selected causes of respiratory acidosis:
Arterial pH decreased with arterial pCO₂ increased as a primary change and arterial HCO₃⁻ increased as a compensatory change

Neuromuscular disorders that decrease breathing such as brain stem injury, myasthenia gravis, and poliomyelitis
Severe pulmonary emboli, infections, lung cancers, asthma, COPD, and respiratory distress syndrome with impaired ventilation, perfusion, and/or diffusion

Decreased pCO₂ excretion results in increased carbonic acid (H₂CO₃)
Decreased pCO₂ excretion results in increased carbonic acid (H₂CO₃)

Selected causes of metabolic alkalosis:
Arterial pH increased with arterial HCO₃⁻ increased as a primary change and arterial pCO₂ increased as a compensatory change

Vomiting or nasogastric suction
Diuretic (ab)use
Cushing syndrome and hyperaldosteronism

Loss of stomach acids (HCl); decreased Cl⁻; increased HCO₃⁻ reabsorption by the kidneys
Decreased H⁺ and K⁺ from increased renal excretion; increased HCO₃⁻ reabsorption by the kidneys
Decreased K⁺ from increased renal excretion; leads to increased H⁺ excretion and HCO₃⁻ reabsorption by the kidneys

Selected causes of respiratory alkalosis:
Arterial pH increased with arterial pCO₂ decreased as a primary change and arterial HCO₃⁻ decreased as a compensatory change

Hyperventilation in response to hypoxemia from a variety of causes
Hyperventilation without hypoxemia as a stimulus, as in anxiety and central nervous system disorders that increase the respiratory rate

Increased pCO₂ excretion results in decreased carbonic acid (H₂CO₃)
Increased pCO₂ excretion results in decreased carbonic acid (H₂CO₃)

^aBlood pH = 6.1 + (log[arterial HCO₃⁻ concentration]/[0.03 × pCO₂]) is the equation that associates the measured parameters in this table.

Electrolytes and Anion gap

Electrolytes are defined as either positively (cations) or negatively (anions) charged ions in the blood. Four freely circulating electrolytes are typically considered when evaluating acid–base disturbances (Na⁺, K⁺, Cl⁻, and HCO₃⁻). Blood gas and pH results are most important when investigating acid–base disruptions, and electrolytes play an important role in identifying the nature of the problem. Modern blood gas analyzers have expanded test menus to include electrolytes, facilitating their use in the evaluation of patients with suspected respiratory and/or metabolic disorders.

The anion gap refers to the difference between the major free cations (Na⁺ and K⁺) and free anions (Cl⁻ and HCO₃⁻). The calculation of the anion gap from measured electrolyte concentrations is critical for evaluation of acidosis. An elevated anion gap occurs when acid anions (such as lactate or ketones) are present. The amount of the increase in anion gap is equal to the amount of acid present because an increase in acid results in a proportional decrease in bicarbonate. Table 14–2 presents selected metabolic acidoses associated with an elevated anion gap.

Pleural Fluid Analysis

There are a number of disorders associated with the accumulation of fluid in the pleural space (Table 14–3). Pleural fluid can be collected by a pleural tap, also known as thoracentesis. An initial evaluation of color, physical characteristics, and odor of the fluid may help identify the source. Next, the fluid is classified as an exudate or a transudate to limit the differential diagnosis and help identify the cause of its accumulation. Exudates and transudates are defined by the following criteria:

Exudate—A filtrate of plasma out of the blood vessel, resulting from capillary damage or lymphatic obstruction (ie, significant loss of the blood/tissue barrier), with a relatively high concentration of protein (>3.0 g/dL) and:
- (a) Display Formula $\frac{Pleural fluid total protein}{Serum total protein} > 0.5$
- (b) Pleural fluid lactate dehydrogenase (LDH) > 20 IU/dL
- (c) Display Formula $\frac{Pleural fluid LDH}{Serum LDH} > 0.6$
Transudate—An ultrafiltrate of plasma with a relatively low protein concentration (<3.0 g/dL) and values for ([pleural fluid total protein]/[serum total protein]), pleural fluid LDH, and ([pleural fluid LDH]/[serum LDH]) below what is required to define the fluid as an exudate.
- (a) Display Formula $\frac{Pleural fluid total protein}{Serum total protein} > 0.5$
- (b) Display Formula $\frac{Pleural fluid LDH}{Serum LDH} > 0.6$

Table 14–3Selected Disorders With Transudate or Exudate Formation

Table 14–3 Selected Disorders With Transudate or Exudate Formation

Basis of Abnormality

Disorders associated with transudate formation

Congestive heart failure

An increased systemic venous pressure and pulmonary capillary pressure, due to the decreased effectiveness of the heart as a pump, results in leakage of fluid into the pleural space

Hypoalbuminemia

Decreased albumin results in a low vascular osmotic pressure and fluid accumulation in body tissues and cavities, including the pleural space

Disorders associated with exudate formation

Pulmonary embolism and pulmonary infarction

Blockage of blood vessels results in tissue damage and leakage of fluid, or in some cases whole blood, into the pleural space

Pulmonary infections

Tissue damage results in leakage of fluid into the pleural space

Lung tumors

Tissue damage results in leakage of fluid into the pleural space

Autoimmune diseases with pulmonary involvement

Tissue damage results in leakage of fluid into the pleural space

Trauma to the lung or chest wall

Tissue damage results in leakage of fluid into the pleural space

Other laboratory testing on pleural fluid, while not diagnostic, may provide useful information in identifying the source of the fluid accumulation. These include total cell counts and differential, Gram stain, pH, glucose, lactate, amylase, triglycerides, and tumor markers. The section “Infections of the Lung and Pleurae” in Chapter 5 contains information on pleural fluid testing that is specific for infections.

Bronchoalveolar Lavage Fluid Analysis

Analysis of the components of BAL fluid is an important diagnostic tool in assessment of numerous respiratory disorders. BAL analysis is most helpful when used in conjunction with clinical data and imaging results to aid in the diagnosis of pulmonary infections, particularly ventilator-acquired pneumonia, interstitial lung diseases, and lung cancers, and for monitoring of the allograft postlung transplant. Several aliquots of warmed saline are instilled in different areas of the lungs. At least 30% of the instilled fluid is carefully aspirated. BAL fluid is collected with the aid of a bronchoscope.

Bacterial cultures of the pooled fluid sample help identify an infectious cause of respiratory disease. Analysis of physical characteristics of the BAL collections also aids in the differentiation of disease. Bloody BAL fluid may indicate a diffuse alveolar hemorrhage, while cloudy BAL fluid suggests a diagnosis of pulmonary alveolar proteinosis. BAL fluid can also be processed to allow analysis of soluble biomarkers and cells. Studies of the BAL cell pellet include bacterial cultures, WBC count and differential, and Gram stain.

Laboratory Tests Useful in the Diagnosis or Management of Pulmonary Diseases

There are a number of pulmonary diseases for which laboratory tests (other than blood gases, BAL, and exudate/transudate determination discussed above) are useful in establishing a diagnosis. The most common of these are described below, while the rarer disorders are listed in Table 14–4 with their accompanying clinical laboratory test results. The infectious diseases of the respiratory tract and pleurae are presented in Chapter 5. Pulmonary function tests provide information on airflow and lung volumes. Spirometry assesses pulmonary mechanics by quantitating the volume of air moved in different inspiratory and expiratory maneuvers, and the rate at which the air is moved. In addition, the uptake of a gas can be measured as an indicator of an impaired alveolar–capillary interface. These tests on airflow and gas exchange often do not identify a specific respiratory disorder, but they can suggest a category of diseases that may account for the airflow abnormalities. Because pulmonary function tests are performed outside the clinical laboratory, they are not discussed further in this text.

Table 14–4Selected Respiratory Diseases and Laboratory Tests Useful in Their Diagnosis or Management

Table 14–4 Selected Respiratory Diseases and Laboratory Tests Useful in Their Diagnosis or Management

Disorder

Results/Comment

Sarcoidosis

Elevated serum angiotensin-converting enzyme is found in 30%-80% of sarcoidosis cases and may be a surrogate marker of disease burden; a CD4/CD8 ratio from BAL fluid >3.5 suggests sarcoidosis

Pulmonary embolism

A diagnostic algorithm based on a clinical significance score combined with radiography and laboratory testing is most accurate in predicting an embolism. A negative test result for D-dimer (a fibrin degradation product) in a patient with low-to-moderate clinical probability effectively rules out PE. A pulmonary embolism is confirmed with a multidetector CT pulmonary angiogram in patients with a high clinical probability or a positive D-dimer test; elevated BNP and troponin measurements are associated with a poor prognosis in patients with PE (see Chapter 8 for a related discussion in the section “Deep Vein Thrombosis and Pulmonary Embolism”; thrombosis is also reviewed in Chapter 11)

Alpha-1 antitrypsin deficiency

Decreased serum alpha-1 antitrypsin; AAT phenotype assay to identify protein variants; molecular testing of the SERPINA1 gene to identify allelic variants associated with reduced activity in adults with early onset COPD or emphysema. (see Chapter 16 for a discussion of alpha-1 antitrypsin deficiency)

Goodpasture syndrome

Increased concentrations of serum glomerular basement membrane (GBM) antibodies are found in Goodpasture syndrome; ANCA antibody testing helps classify disease and rule out other syndromes; blood cell counts are important to monitor anemia; and renal function tests are useful for detection of renal failure

Pulmonary vasculidites

Discussed in the section “Vasculitis” of Chapter 8 (such as Wegener granulomatosis and Churg–Strauss syndrome)

Cystic fibrosis

Discussed in Chapter 7

Autoimmune-related

Discussed in Chapter 3

Radiologic studies, particularly plain chest radiographs, computed tomographic (CT) scans, magnetic resonance imaging (MRI), positron emission tomography (PET) scans, and nuclear medicine studies such as ventilation/perfusion scanning, play a prominent role in the diagnosis of pulmonary disorders.

Common Lung Disorders

Asthma

Asthma is a chronic disease associated with reversible inflammation of the bronchial walls leading to narrowing of the airways. It is among the most common chronic diseases, and its prevalence is rising particularly in children. Acute onset of bronchial inflammation can lead to an asthma attack, with severe forms being life-threatening. While the exact cause of bronchial inflammation is unknown, there are numerous triggers including: environmental allergens (pollen, dust, and others), chemical allergens (cleaning agents, smoke, and others), exercise, stress, cold air, and medications.

Diagnosis and Management

The diagnosis of asthma is challenging because the clinical signs and symptoms overlap with many other respiratory diseases. Laboratory testing to rule out diseases such as cystic fibrosis (see Chapter 7) and infections (see Chapter 5) is important for the evaluation. Diagnosis begins with assessment of airway obstruction with spirometry and chest x-ray. The diagnostic evaluation for asthma must involve identification of inflammatory triggers. Identification of elevated concentrations of IgE in the plasma indicates a generalized allergic response. Antigen-specific IgE testing identifies immune responses to specific allergens and is useful in young children and patients with a contraindication to skin testing.

Initial diagnosis and monitoring of patients with an acute asthmatic reaction involves assessment of oxygenation for disease severity and pulmonary function. Evaluation of arterial blood gases also assesses oxygenation status. Evaluation of electrolytes, pH, and anion gap is helpful in evaluating acid–base status, pulmonary function, and tissue hypoxia (Table 14–2).

Chronic Obstructive Pulmonary Disease

Like asthma, COPD is a chronic inflammatory lung disease associated with airway obstruction. Inflammation leads to thickening of the airway wall and decreased air flow, as well as destruction of the alveoli and increased airspace. Patients with COPD have 2 main conditions, emphysema or chronic bronchitis. The biggest risk factor for both is cigarette smoking, followed by exposure to pollution. Currently, COPD is a major cause of morbidity and mortality worldwide, because it can lead to respiratory failure.

Diagnosis and Monitoring

A diagnosis of COPD is confirmed by the presence of clinical symptoms such as chronic cough, wheezing, and/or respiratory failure, combined with airflow obstruction determined by spirometry. Patients with COPD are followed by measuring arterial blood gases to assess oxygen status and monitor the benefit of long-term oxygen therapy. Exacerbations and increased disease severity are commonly monitored by measuring a complete blood count (CBC) to assess the level of inflammation, testing for respiratory infections (Chapter 5), and measurement of electrolytes, pH, and anion gap to assess acid–base status, pulmonary function, and tissue hypoxia (Table 14–2).

Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS)

ARDS is the rapid onset of respiratory failure due to systemic inflammation, trauma, or severe pulmonary infection in anyone over 1 year of age. It is associated with significant morbidity and mortality primarily due to oxygen deprivation and multisystem organ failure that results from pulmonary failure. A consensus group published the Berlin definition of ARDS as hypoxemia with bilateral lung infiltrates and/or respiratory failure within 1 week of a clinical insult, with new or worsening respiratory symptoms in the absence of cardiovascular insult or left pulmonary hypertension.

Diagnosis

The diagnosis of ARDS requires a careful clinical history to identify a recent clinical insult and/or the timing of new-onset respiratory symptoms. Chest x-ray or CT scan should be performed to visualize bilateral opacities. Cardiovascular ischemia and fluid overload should be ruled out by echocardiogram and/or cardiac biomarker analysis. Hypoxemia is classified by measuring arterial blood gasses and calculating the ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen (PaO₂/). The Berlin definition divides hypoxemia into mild (PaO₂/ between 200 and 300 mm Hg), moderate (PaO₂/ between 100 and 200 mm Hg), and severe (PaO₂/ <100 mm Hg).

Neonatal Respiratory Distress Syndrome

RDS of the newborn is most commonly associated with incomplete development of the fetal lungs. The pulmonary system is one of the last to completely develop, and as a result, RDS is a common cause of morbidity and mortality in preterm infants. Symptoms of RDS begin within a few hours of birth due to a deficiency of pulmonary surfactant. Surfactant, a mixture of phospholipids and proteins, coats the alveolar surfaces and separates alveolar airspace from liquid-coated lung epithelial cells, preventing lung collapse during exhalation. RDS patients suffer both lung collapse and hyperextension of alveoli leading to fibrosis, or hyaline membrane disease. The alveoli in an RDS lung are perfused, but not ventilated, resulting in hypoxia, hypercapnia, and respiratory acidosis.

Respiratory distress syndrome of the newborn is most commonly associated with incomplete development of the fetal lungs. The pulmonary system is one of the last to completely develop, and as a result, RDS is a common cause of morbidity and mortality in preterm infants.

RDS can be addressed by preventing preterm births or by administration of corticosteroids at least 48 hours prior to a premature birth. Corticosteroids induce surfactant production, significantly reducing neonatal morbidity and mortality due to RDS. Assessment of FLM status is essential for clinical decisions for women with symptoms of preterm labor and for those whose labor is induced prior to 39 weeks gestation.

Selected Laboratory Tests for Assessment of Fetal Lung Maturity

FLM is most commonly assessed by testing the amount of surfactant in the amniotic fluid in women after 30 weeks gestation. The diagnostic test most commonly used to assess FLM is the lamellar body count (LBC) assay. Surfactant is packaged into storage granules called lamellar bodies that pass into amniotic fluid in the third trimester of pregnancy. LBCs >50,000/μL suggest maturity. Lamellar bodies are similar in size to platelets and can be counted on a standard whole blood counter.

Fetal lung maturity can also be predicted by measuring the lecithin–sphingomyelin ratio. An L/S ratio >2.0 indicates lung maturity.

Another method to assess fetal lung maturity is through calculation of the surfactant–albumin (S/A) ratio. The S/A ratio increases throughout gestation proportionally with lung maturity. Surfactant-based phospholipids, particularly lecithin (phosphatidylcholine) and phosphatidyl–glycerol (PG), also increase in the amniotic fluid during fetal lung maturation, while lipids not originating from the lung, such as sphingomyelin, remain fairly constant throughout gestation. Because of this, FLM can also be predicted by measuring the lecithin–sphingomyelin ratio. An L/S ratio >2.0 indicates lung maturity. Qualitative detection of PG in amniotic fluid is a rapid and sensitive alternative for predicting FLM in late pregnancy. PG measurements are particularly useful in blood and meconium-contaminated amniotic fluid specimens as all other tests described above are affected by these contaminants.

Lung Cancer

Lung cancer, defined as any tumor of the respiratory epithelium or pneumocytes, is the leading cause of cancer-related mortality worldwide. The leading risk factor for lung cancer is cigarette smoking, accounting for up to 90% of cases. Exposure to environmental carcinogens, irradiation, and genetic disorders are also risk factors for developing lung cancer. There are 2 main types of lung cancers: small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). Among NSCLCs the most common lung tumor type is adenocarcinoma. Most lung cancers are caused by acquired mutations, amplifications, or rearrangements in oncogenes including epidermal growth factor receptor (EGFR), fibroblast growth factor receptor type 1 (FGFR1), anaplastic lymphoma kinase (ALK), KRAS, NRAS, BRAF, HER2, PTEN, and MET, among others. Although some lung cancers are discovered in asymptomatic patients, the most common clinical signs include coughing up blood, wheezing, and shortness of breath.

Diagnosis and Monitoring

The diagnostic workup for lung cancer begins with discovery of a new pulmonary mass by chest x-ray, CT scan, or MRI. A definitive diagnosis of lung cancer and type is determined through histological and immunohistochemical analysis of tumor tissue. Molecular testing of advanced-stage adenocarcinoma type (NSCLC) is required to direct therapy. In particular, patients with EGFR mutations are more likely to respond to tyrosine kinase inhibitor (TKI) therapy and have longer progression-free survival. Patients with a KRAS gene mutation with or without an EGFR mutation do not respond to TKI therapy and should be treated alternatively. Advanced-stage non-small cell lung adenocarcinomas should also be tested for rearrangements in the ALK gene. About 5% to 10% of all NSCLC patients carry this rearrangement, which can be treated with an ALK inhibitor.

Prior to initiating therapy, baseline CBC and liver function panel should be measured to screen for metastases. Response to therapy and tumor recurrence can be monitored by performing regular chest x-rays and/or CT scans, as well as a CBC and liver function tests. Measurement of cytokeratin 19 fragments (CYFRA 21-1) in serum is useful for assessing prognosis in early and late stages, and in monitoring therapy in advanced stages of NSCLC. Serum neuron-specific enolase (NSE) may be useful in monitoring therapy and tumor recurrence in both NSCLC and SCLC.

References