FA Organ Systems Respiration- Pathology

Klebsiella pneumoniae

Gram-negative rod. Associated with aspiration pneumonia in diabetics, alcoholics, and IV drug users. Red "currant-jelly" sputum. Large mucoid colonies with abundant polysaccharide capsules. Treat Aminoglycosides First-, second-, or third-generation cephalosporins

Pneumoconiosis Asbestosis is from the roof (roofers), but affects the base (lower lobes). Silica and coal are from the base (earth), but affect the roof (upper lobes). Adverse effects associated with supplemental O2 administration in patients with NRDS— RIB: Retinopathy of prematurity Intraventricular hemorrhage Bronchopulmonary dysplasia Remember your ABCs: Airway, Breathing, Circulation. Assess these three parameters and manage them (if needed) before any other physical examination maneuvers are carried out.

A group of interstitial lung diseases caused by the inhalation of inorganic and organic particulate matter. This produces varying degrees of pulmonary fibrosis, characterized by decreased compliance, reduced lung volumes, and destruction of the alveolar- capillary interface, leading to V ̇/Q ̇ mismatch and hypoxemia. Four common inorganic pneumoconioses are listed in Table 10-15. PRESENTATION Dyspnea, especially with exertion. DIAGNOSIS ■ Physical exam: Bibasilar crackles heard on auscultation. Clubbing may also be seen. ■ Chest film: Nodular opacities seen in silicosis, coal worker's pneumoconiosis, and berylliosis. A more linear pattern is seen in asbestosis. Calcified pleural plaques are also seen in asbestosis. ■ PFT: Decreased TLC, FRC, RV, FEV1, and FVC, with a normal or increased FEV1:FVC ratio. Dlco is also decreased. ■ Arterial blood gas testing: Hypoxemia, often with normo- or hypocapnia. ■ Pathology: Refer to Table 10-15. TREATMENT Avoid further exposure. No curative treatment. PROGNOSIS ■ Silicosis: Associated with increased susceptibility to tuberculosis (TB). ■ Coal worker's pneumoconiosis (CWP): Simple CWP is often inconsequential. If CWP is complicated by progressive massive fibrosis (PMF), it can lead to bronchiectasis, pulmonary hypertension, and death from respiratory failure or right-sided heart failure. ■ Asbestosis: Predisposes to bronchogenic carcinoma and, less commonly, malignant mesothelioma of the pleura or peritoneum. Concomitant cigarette smoking multiplies the risk of developing cancer. ■ Berylliosis: Can mimic sarcoidosis, with granulomas in multiple organ systems.

Laryngeal Carcinoma

Accounts for 2% of all cancers. Presents in patients aged > 40 years, more often in men than in women. Associated with smoking, alcohol consumption, and asbestos exposure. Manifests as persistent hoarseness. ■ Glottic tumors: On the true vocal cords, usually keratinizing. ■ Supraglottic tumors: Above the vocal cords; one-third metastasize. ■ Subglottic tumors: Below the vocal cords.

Acute Respiratory Distress Syndrome Pulmonary edema is an intra-alveolar accumulation of fluid. It can be caused by increased hydrostatic pressure (eg, left ventricular failure), increased capillary permeability (eg, ARDS), or several other mechanisms (eg, high altitude, neurologic injury, or opiate overdose).

Acute respiratory distress syndrome (ARDS) is characterized by acute-onset diffuse alveolar damage and leakage of fluid out of the pulmonary capillaries into the interstitium and alveolar spaces. ARDS is defined by four major criteria, all of which must be met: 1. Reduced arterial oxygen to inspired oxygen ratio Pao2/Fio2: ■ Mild ARDS: 200-300. ■ Moderate ARDS: 100-200. ■ Severe ARDS: < 100. ■ A low ratio reflects poor oxygenation despite ample inspired oxygen; normal ratio is 500 mm Hg. 2. Acute onset. 3. Bilateral lung infiltrates (Figure 10-41). 4. Must not be fully explained by left-sided heart failure or fluid overload. Etiologies include pneumonia, inhalation of irritants, O2 toxicity, heroin overdose, shock, sepsis, aspiration of gastric contents, trauma, uremia, acute pancreatitis, head trauma, multiple transfusions of blood products (transfusion-related acute lung injury [TRALI]), disseminated intravascular coagulation (DIC), and fat or amniotic fluid embolism. In all of these cases, the initial injury in ARDS affects the type I pneumocytes and/ or capillary endothelial cells, resulting in leakage of protein-rich fluid. Alveoli become flooded with fluid, inhibiting gas exchange and oxygenation. This leads to hypoxemia in the forms of shunting and V ̇ /Q ̇ mismatch, with the latter being exacerbated by altered distribution of pulmonary blood flow due to increased PVR. Additionally, surfactant function and production is altered, resulting in alveolar collapse. PRESENTATION Acute-onset dyspnea accompanied by tachypnea and hypoxemia, usually in a critically ill patient. DIAGNOSIS ■ Physical exam: Crackles are often heard on auscultation. ■ Chest film: Diffuse, symmetrical interstitial and alveolar edema (see Figure 10-41; note that this is criterion 3 from the previous diagnostic criteria). Air bronchograms— visualization of distal bronchioles due to the contrasting opacity of infiltrates around the airway—may be present. ■ PFT: Not usually performed, but would see a restrictive pattern with a reduced Dlco. ■ Arterial blood gas testing: Hypoxemia, with a large A-a gradient. Supplemental O2 may not increase Pao2 significantly due to shunt. PATHOLOGY Damage to type I alveolar epithelial cells, with regenerative hyperplasia of type II cells. Interstitial and alveolar fluid is present, with an inflammatory cell infiltrate and areas of alveolar collapse. Hyaline membranes (composed of eosinophilic, acellular material), fibrosis, and changes in the pulmonary vasculature can also be seen (Figure 10-42). TREATMENT Treat underlying cause; patients are typically intubated and mechanically ventilated using low tidal volume ventilation and high PEEP in an ICU. PROGNOSIS High mortality (30-50%), largely due to the underlying cause rather than the pulmonary effects of ARDS.

Adenocarcinoma

Adenocarcinoma is the most common primary lung cancer (50% of cases) in the overall population, as well as in nonsmokers. It is more common in women than men. There is no clear relationship between adenocarcinoma and smoking. Adenocarcinoma arises from mucin glands located peripherally in the lung or old scar sites (usually due to infection or injury and found in a subpleural location). The clinical picture of hypertrophic osteoarthropathy is associated with adenocarcinoma of the lung and is characterized by digital clubbing and sudden-onset symmetrical arthropathy, usually involving the wrists and hands. Adenocarcinoma is associated with activating mutations of k-ras, EGFR, and ALK. On histology, adenocarcinoma shows a glandular pattern that often stains positive for mucin (Figure 10-50B). Stains such as periodic acid-Schiff (PAS) or mucicarmine are required to demonstrate intracellular mucin. Bronchioloalveolar adenocarcinoma (BAC) originally described a subtype of invasive adenocarcinoma of the lung characterized by well-differentiated cytology, peripheral location, and growth along intact alveolar walls ("lepidic" growth pattern). BAC has since been reclassified into new subgroups based on histology. BAC is discussed below; however, a detailed description of each subgroup is beyond the scope of this text BAC arises from Clara cells (nonciliated columnar epithelium) and grows along alveolar septa, giving the appearance of thickened alveolar walls on histology. Many cases of BAC are asymptomatic and detected after incidental imaging. The classic radiologic presentation of BAC is a solitary pulmonary nodule in the lung periphery, appearing as ground glass on chest computed tomography or hazy infiltrates on chest radiograph. More extensive disease may present with lobar consolidation, mimicking bacterial pneumonia. BAC rarely invades the basement membrane and has a good prognosis. BAC has been traditionally described as having no relationship to smoking. However, newer studies show a definite and direct relationship between smoking and BAC.

Aspiration

Anaerobes (eg, Peptostreptococcus, Fusobacterium, Prevotella, Bacteroides)

Pseudomonas aeruginosa

Gram-negative rod. Non-lactose fermenting, oxidase (+). Produces pyocyanin (blue-green pigment) and has grape-like odor. Treat Extended-spectrum β-lactams Carbapenems Aztreonam Ciprofloxacin Aminoglycosides Colistin, polymyxin B (multidrug-resistant strains)

Staphylococcus aureus

Gram-positive cocci (clusters). Usually causes bronchopneumonia Treat MSSA: First or second-generation cephalosporins Penicillinase-resistant penicillins MRSA: Vancomycin, ceftaroline, linezolid, tigecycline

Asbestosis

Asbestos fibers (associated with shipbuilding, roofing, plumbing, insulation, construction work "Ivory white" calcified pleural plaques A B are pathognomonic for asbestos exposure but are not precancerous. Asbestos (ferruginous) bodies are golden-brown fusiform rods resembling dumbbells C . Interstitial fibrosis primarily affects the lower lobes. Associated with an increased incidence of bronchogenic carcinoma and mesothelioma (bronchogenic >> mesothelioma). Concomitant cigarette smoking multiplies the risk of developing lung cancer.

Lung Palpation Findings Chest wall expansion

Assessed by placing your hands on each side of the patient's back with thumbs pointed toward the spine and fingers wrapped around each hemithorax. Have the patient take a deep breath and feel for equal movement of your hands away from the midline as the chest expands. Asymmetrical expansion: hemidiaphragmatic paralysis, large pleural effusion, pneumothorax

Types of Emboli Fat

Associated with long-bone fractures and liposuction. Classic triad: Hypoxemia, neurologic abnormalities, and petechial rash on the chest and truck. Pathology: The emboli stain black with osmium tetroxide. A 24-year-old patient is hospitalized following a motor vehicle accident. The next day, he develops sudden-onset dyspnea and confusion. On physical examination, a petechial rash is seen across his ches

Goodpasture Syndrome Both Goodpasture syndrome and granulomatosis with polyangiitis are causes of rapidly progressive glomerulonephritis, which presents as a nephritic syndrome. Histology will reveal crescent-shaped proliferation of glomerular parietal cells and accumulation of fibrin in glomeruli.

Autoimmune disease targeting the lungs and kidneys. Caused by type II hypersensitivity against the α3-chain of type IV collagen, located in the basement membranes of alveoli and glomeruli. PRESENTATION Pulmonary hemorrhage with concomitant nephritic syndrome (hematuria, etc; see Chapter 8). DIAGNOSIS ■ Anti-type IV collagen autoantibodies. ■ Kidney biopsy: Immunofluorescence demonstrates linear, ribbon-like deposition of IgG along the glomerular basement membrane. Lung biopsy may be necessary if renal biopsy is not possible. TREATMENT Plasmapheresis with or without immunosuppressive therapy to reduce the burden of autoantibodies. PROGNOSIS Therapy can often control symptoms. However, immune-mediated damage to the lung parenchyma can result in scarring and eventual fibrosis.

Tumor cells

Be suspicious of malignancy when an adult presents with signs of new-onset hypercoagulability A 59-year-old man presents with sudden-onset right-sided weakness. He has a 40 pack-year smoking history. Chest x-ray shows a 4-cm lung nodule

Berylliosis

Beryllium (found in aerospace, electronics, nuclear materials, and manufacturing industries) Noncaseating granulomas. Interstitial fibrosis primarily affects the upper lobes. Associated with an increased risk of primary lung cancer. Can mimic sarcoidosis (granulomas in multiple organ systems).

Extrapulmonary Restrictive Disease (Poor Breathing Mechanics)

The restrictive defect is extrinsic to the lung parenchyma. This includes mainly disorders of the chest wall and neuromuscular disease leading to impaired ability to fully expand the lungs. Hypoxemia develops secondary to hypoventilation. There are two broad classes: poor muscular effort and poor structural apparatus.

Bronchial Neuroendocrine (Carcinoid) Tumors Both small cell carcinoma and large cell carcinoma are composed of undifferentiated cells and have a poor prognosis. Small cell carcinoma is unresectable because the cells are too small for the surgeon to see. Large cell carcinoma is surgically resectable because the cells are large. Hypercalcemia commonly presents with nephrolithiasis (stones), bone pain (bones), constipation (groans), and altered mental status (psychiatric overtones) New-onset hypercalcemia is due to primary hyperparathyroidism or hypercalcemia of malignancy in over 90% of cases. Very high Ca2+ (> 13 mg/dl) is more commonly due to malignancy. SPHERE of complications (of lung cancer): Superior vena cava syndrome Pancoast tumor Horner syndrome, Hoarseness Endocrine (paraneoplastic) Recurrent pneumonia Effusions (pleural or pericardial) The recurrent laryngeal nerve provides motor innervation to all of the laryngeal muscles except for the cricothyroid muscle. Bronchial hamartoma is the most common benign lung tumor. They contain islands of mature hyaline cartilage (hence the term, "hamartoma") and typically present as a well-defined coin lesion with "popcorn" calcification on chest x-ray. Of note, not all coin lesions are hamartomas.

Bronchial neuroendocrine (carcinoid) tumors (NETs) are a group of lung neoplasms that arise from peptide- and amine-producing neuroendocrine cells. There is no clear association with smoking or genetic predisposition, with rare exceptions (eg, multiple endocrine neoplasia, type 1). Bronchial NETs can arise centrally or peripherally in the lung, and growth as a bronchial polyp-like mass is a classic description. Bronchial NETs are generally low-grade (well-differentiated) benign tumors with an excellent prognosis. Metastasis is rare. While most symptoms are due to mass effect (eg, dyspnea, wheezing), bronchial NETs may be associated with carcinoid syndrome (flushing, diarrhea, wheezing) secondary to ectopic serotonin (5-HT) production. Histology shows nests of neuroendocrine cells that, similarly to small cell carcinoma, stain positive for synaptophysin, chromogranin A, and neuron-specific enolase. PRESENTATION Patients with lung cancer generally present with nonspecific complaints, such as coughing, hemoptysis, dyspnea, and wheezing. As with all malignancies, weight loss and anorexia are common. Additionally, lung neoplasms can obstruct airways, causing distal infections (eg, lobar pneumonia). Based on the location and other characteristics (discussed below), lung cancer is also associated with certain clinical syndromes: ■ Superior vena cava (SVC) syndrome: Tumor compression of the SVC obstructs venous drainage from the head/neck (sometimes causing facial plethora) and upper extremities. This leads to swelling, cyanosis, and venous distension in the aforementioned regions. Blanching can be appreciated in these regions (Figure 10-51A). Patients present with headaches and dizziness due to increased intracranial pressure. Commonly caused by Pancoast tumors (see below) and thrombosis from indwelling catheters (Figure 10-51B). This is a medical emergency, as patients are at increased risk of aneurysm formation/rupture within the intracranial arteries. ■ Pancoast tumor (superior sulcus tumor): Carcinoma that arises in apex of the lung (Figure 10-51C). Can involve surrounding structures, causing a variety of syndromes (discussed below). These syndromes can coexist in a variety of combinations, collectively referred to as Pancoast syndrome. ■ SVC syndrome: Discussed above. ■ Horner syndrome: Ipsilateral ptosis, miosis, and anhydrosis. Due to invasion of cervical sympathetic chain. ■ Sensorimotor deficits: Due to compression of brachial plexus. A commonly tested presentation is Klumpke palsy ("claw hand"), secondary to lower trunk involvement. ■ Thoracic outlet syndrome: Use-dependent ischemic arm pain. Due to compres- sion of subclavian vessels. ■ Hoarseness: From involvement of the recurrent laryngeal nerve (branch of the vagus nerve). ■ Paraneoplastic syndromes: Includes hypercalcemia (squamous cell carcinoma), Cushing syndrome, SIADH, and Lambert-Eaton syndrome (small cell carcinoma). ■ Recurrent lobar pneumonia: Due to persistent blockage (either internal obstruction of external compression) of a bronchus segment. ■ Effusions (pleural or pericardial): Malignancy should always be considered in these cases. In the event of metastasis, primary lung cancer most commonly spreads to the adrenals, brain, bone, and liver. In many cases, lung cancer is asymptomatic and incidentally detected as a solitary well-defined lung nodule ("coin lesion") on imaging. Of note, metastasis to the lung (secondary lung cancer) is more common than primary lung cancer, as the lung's extensive vasculature renders it vulnerable to hematogenous seeding from distant sites. Multiple tumors on imaging should raise suspicion for metastatic disease. Metastasis to the lung is most commonly from primary breast cancer. Colon cancer, prostate cancer, and renal cell carcinoma are also frequent primary neoplasm sites. DIAGNOSIS ■ Chest film: Nodule or mass within the lung. ■ Centrally located: Squamous and small cell. ■ Peripherally located: Adenocarcinoma and large cell. Involvement of the hilar lymph nodes or pleura can also be seen. ■ An exception to this is the bronchioloalveolar subtype of adenocarcinoma, which often has a more diffuse radiographic appearance, termed ground-glass opacity, similar to pneumonia. ■ CT or positron emission tomography (PET) scans: To determine location, lymph node involvement, or metastasis for staging. ■ Cytologic examination of sputum or washings from bronchoscopy, or tissue pathology from a lung biopsy. ■ PFT: To assess whether a patient has the residual capacity to survive surgical resec- tion of a tumor. ■ Pathology: Multiple tumors arising at once should raise suspicion for metastatic disease from a primary tumor outside the lungs, as the lung's extensive vasculature makes it a nidus for hematogenous seeding. TREATMENT ■ Small-cell carcinoma: Metastases occur very early in the disease course, so surgery is not an option, only chemotherapy and/or radiation. ■ NSCLC: Surgical resection if there is no distant spread. If metastases are present, then chemotherapy and/or radiation. PROGNOSIS Overall 5-year survival is about 14%. Squamous cell carcinoma has the best prognosis, and small-cell carcinoma has the worst. Early-stage disease, while rarely found, has a much better prognosis than late-stage disease.

Bronchiectasis Persistent obstruction of any portion of the respiratory tract (either internal blockage or external compression) can lead to bacterial colonization, inflammation, and eventual destruction of regions distal to the obstruction.

Bronchiectasis is irreversible dilation of the airways caused by repeated episodes of infection and/or inflammation with eventual destruction of the bronchi and bronchiole walls. Over time, as the airways lose their elastic recoil, they become unable to expel air. As a.result, air is functionally trapped in the lungs. Also, the damaged airways compromise the ability to fight infection. This allows bacterial colonization, pooling of secretions, and additional inflammation, thus perpetuating a vicious cycle. Bronchiectasis (Figure 10-39) has several causes, including the following: ■ Infection: May be viral, bacterial, or fungal. Examples include tuberculosis, pertussis, and allergic bronchopulmonary aspergillosis. ■ Obstruction by tumor, foreign body, or mucus plug. ■ Defective airway or ciliary clearance: ■ Smoking: Irritants from cigarette smoke paralyze cilia and inhibit their ability to clear secretions. ■ Primary ciliary dyskinesia (Kartagener syndrome): Genetic dynein arm defect, resulting in immotile cilia. Affected patients also present with infertility (due to immotile sperm in males and dysfunctional fallopian tubes in females) and situs inversus (dextrocardia on chest x-ray and right-sided point of maximal impulse [PMI]). ■ Patients with cystic fibrosis develop bronchiectasis due to the production of thick secretions that are difficult to clear as well as chronic infection with multiple pathogens (Figure 10-39). The lungs of these patients are often colonized with Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae; less common organisms include Burkholderia cepacia, which almost exclusively appears in patients with cystic fibrosus. PRESENTATION Cough; copious mucoid, mucopurulent, or purulent sputum production; dyspnea; rhinosinusitis; hemoptysis. DIAGNOSIS ■ Physical exam: ■ Localized crackles or rhonchi may be heard. Some patients also present with wheezing. ■ Clubbing of the fingernails may also be seen in some patients. ■ Chest film: Often nonspecific abnormal findings, including increased markings, crowded vessels, or "ring" shadows corresponding to the dilated airways. ■ CT: Has become the preferred method both to diagnose bronchiectasis and to evaluate location and extent of disease. ■ PFT: Often normal, but can also show obstructive pattern. ■ Arterial blood gas testing: Usually normal, except in patients with very diffuse disease, who can exhibit hypoxemia and hypercapnia. ■ Pathology: Marked dilation of the airways in one of three patterns: cylindrical, varicose, or saccular (Figure 10-39). Increased secretions are also seen. The arteries also enlarge and proliferate. New anastomoses may form, leading to hemoptysis. TREATMENT ■ Removal of any foreign body or tumor (if possible). ■ Inhaled bronchodilators are useful in patients with coexisting causes of airway obstruction. ■ Antibiotics for both acute and chronic infections. ■ Bronchopulmonary drainage with chest physiotherapy helps to clear secretions from the dilated airways. ■ DNase is used to break up thick secretions in CF patients. PROGNOSIS In severe cases, cor pulmonale can develop. Colonization with P aeruginosa is frequent.

Endothelin-1

Bronchoconstriction

Fungal and Viral Causes of Pneumonia Pneumocystis jirovecii (PCP)

Causes interstitial pneumonia in immunosuppressed patients (especially AIDS). Diagnosed by lung biopsy or lavage. Disc-shaped yeast seen with methenamine silver stain of lung tissue. Treat Treatment: TMP-SMX, pentamidine Prophylaxis: TMP-SMX, pentamidine, dapsone, atovaquon

Poor Structural Apparatus

Commonly due to scoliosis and morbid obesity. ■ Kyphoscoliosis: Lateral curvature of the spine prevents proper chest wall expansion. ■ Morbid obesity: The excess weight surrounding the chest wall presses down on the wall and inhibits proper expansion. Obesity is also associated with decreased respiratory rate, which also contributes to hypoventilation (see discussion on obesity hypoventilation syndrome below). PRESENTATION Dyspnea, especially with exertion. Other possible signs and symptoms are etiology dependent. DIAGNOSIS ■ A-a gradient: normal, because gas exchange in alveoli is not impaired. ■ Physical exam: ■ Neuromuscular disease: Etiology dependent, nonpulmonary manifestations of specific disease; assess for UMN and LMN lesions (see Chapter 6). ■ Diaphragmatic disease: Paradoxical movement of paralyzed regions of the dia- phragm upward during supine inspiration. ■ Assess for kyphoscoliosis. ■ Chest film: Assess for kyphoscoliosis, diaphragmatic paralysis. ■ PFT: Variable depending on the specific disease and disease severity. In general, FEV1, FVC, TLC, and RV are usually decreased, but these are neither sensitive nor specific. TREATMENT Supplemental O2 or mechanical ventilation may be needed for patients with severe disease. The underlying disorder must be treated, or irreversible pulmonary sequelae will develop. PROGNOSIS Extrapulmonary restrictive diseases resulting in hypoxemia can lead to pulmonary hyper- tension and cor pulmonale. Progressive disease can lead to chronic respiratory acidosis.

Crepitus

Crackles sensation or "rice krispies" felt under the skin. Indicative of subcutaneous air Pneumothorax, pneumomediastinum

Deep Venous Thrombosis Virchow triad (SHE): Stasis Hypercoagulability Endothelial damage For acute management of DVT, give heparin before transitioning to warfarin. Heparin has a faster onset than warfarin, and this sequence also decreases the risk of warfarin-induced skin necrosis. The differential diagnosis for hypercoagulable states includes primary thrombotic disorders and acquired risk factors. Primary genetic disorders include factor V Leiden, prothrombin G20210A, antithrombin deficiency, protein C or S deficiency, and dysfibrogenemias. Secondary risk factors include antiphospholipid syndrome (APLS), immobility, pregnancy, oral contraceptive use, and obesity.

DVT refers to the formation of an occlusive blood clot (thrombus) in the deep veins of the lower extremity. The physiologic risk factors that predispose a patient to thrombus formation are described by the Virchow triad: ■ Stasis: Occurs in patients who are immobile for prolonged periods (eg, postoperative state, long plane flights, truck drivers). ■ Hypercoagulability: Due to defects in coagulation cascade proteins. The most common genetic hypercoagulable condition is factor V Leiden. Other causes include malignancy, multiple bone fractures, and use of oral contraceptive pills (OCPs). ■ Endothelial damage: Exposure of subendothelial collagen activates the clotting cascade (intrinsic pathway). Most commonly, DVTs form in the femoral and popliteal veins, as well as the veins in the calf. PRESENTATION Sudden-onset unilateral lower extremity pain and swelling (Figure 10-47) in a patient with prolonged immobilization or another risk factor mentioned above. DIAGNOSIS ■ Physical exam: ■ Unilateral lower extremity swelling and tenderness to palpation (Figure 10-47). Pitting edema is also seen in the affected leg due to excessive hydrostatic pressure. ■ Calf pain with passive dorsiflexion of the foot (positive Homan sign). This find- ing is not always present. ■ Compression ultrasound of the lower extremity can be used for confirmation. TREATMENT ■ DVTs are initially managed with unfractionated heparin or a low-molecular-weight heparin (LMWH), such as enoxaparin. This is followed with oral anticoagulants (eg, warfarin, rivaroxaban) for long-term prophylaxis as outpatient therapy. ■ Many hospitalized patients are given heparin (unfractionated or LMWH) prophylactically due to increased risk for developing a DVT secondary to immobilization (stasis). PROGNOSIS In some cases, DVTs can break off and become lodged in the pulmonary circulation (PE). The majority of PEs arise from the proximal deep veins of the lower extremity.

Chronic Bronchitis COPD is a broad term encompassing both emphysema and chronic bronchitis, as these two conditions can coexist. The term "blue bloater" is sometimes used to describe the clinical picture of chronic bronchitis. These patients are classically overweight ("bloated") and exhibit varying degrees of cyanosis ("blue") due to hypoxemia. Emphysema has decreased DLCO, whereas chronic bronchitis has normal DLCO.

Defined clinically as a productive cough occurring for at least 3 months per year over at least 2 consecutive years. Characterized by excessive mucus production in the airways. The mucus itself is typically more viscous than normal. Smoking causes proliferation and hypertrophy of bronchial mucous glands. It also damages cilia lining the bronchial lumen, impeding mucus clearance. There is also an influx of inflammatory cells, leading to airway inflammation. The increased mucus production and airway wall thickness decreases the cross-sectional area of the lumen, increasing resistance and inhibiting air flow. The obstruction to airflow in chronic bronchitis is in the terminal bronchioles, which is proximal to the obstruction in emphysema. PRESENTATION ■ Chronic cough productive with copious mucus and sputum. Blood-tinged mucus can be seen with rupture of pulmonary microvasculature. ■ "Blue bloater": Often hypoxemic and cyanotic ("blue") due to decreased ventilation but relatively preserved perfusion; V ̇/Q ̇ mismatch. ■ Often obese ("bloater"); can have peripheral edema due to RV. ■ Dyspnea, chronic smoking history; large overlap with emphysema. DIAGNOSIS ■ Physical exam: ■ Often obese and sometimes cyanotic. The fingertips, lips, and tongue in par- ticular may appear purplish blue. ■ Clubbing of fingertips associated with hypoxemia. ■ Rhonchi and wheezing on auscultation. ■ Chest film: May show increased airway markings (appearing as a "dirty lung"), and there may be evidence of pulmonary hypertension and cor pulmonale. ■ Pulmonary function testing: ■ Spirometry: Airflow obstruction results in decreased FEV1 and FEV1:FVC ratio. FVC is often preserved. ■ Lung volumes: In patients with dynamic hyperinflation, TLC, FRC, and RV may be increased. ■ Diffusing capacity (DLCO): Typically normal. Despite the airway obstruction due to mucus plugging, the alveolar walls function normally. ■ Arterial blood gas testing: Pao2 is often decreased, and Paco2 is increased. Bicarbonate is elevated by the kidneys in an attempt to compensate for the decreased pH. ■ Pathology: Increased number of goblet cells. The Reid index, which is the ratio of bronchial mucous gland depth to the total thickness of the bronchial wall, is abnormally high in chronic bronchitis. TREATMENT Bronchodilators and corticosteroids are used as in emphysema. Supplemental O2 can treat hypoxemia, reduce hypoxic vasoconstriction and polycythemia, thereby reducing the incidence of pulmonary hypertension. Supplemental O2 and cessation of cigarette smoking are the only interventions that have been shown to reduce mortality. Chest physiotherapy (percussion, coughing, and postural changes) can loosen and clear airway secretions, and pulmonary rehabilitation is helpful. PROGNOSIS ■ Chronic hypoxemia increases the risk of developing pulmonary hypertension sec- ondary to pulmonary vasoconstriction. In turn, right-sided heart failure can ensue (cor pulmonale). ■ In a compensatory effort to increase oxygen delivery to tissues, erythropoietin production is upregulated in the kidneys, resulting in secondary polycythemia

Thrombus (DVT)

Develops after prolonged immobilization (usually ≥ 3 days). Five days after abdominal surgery, a 68-year-old woman develops dyspnea and pleuritic chest pain.

Air

Develops in divers when nitrogen bubbles precipitate in their blood as they ascend too rapidly. A 26-year-old patient develops rapid-onset dyspnea and pleuritic chest pain. On further questioning, patient reports symptoms developed while scuba diving.

Bacteria

Develops in infective endocarditis, when the bacterial vegetations dislodge from the heart valves. Can travel to brain or lungs, resulting in an abscess. A 36-year-old IV drug user presents with sudden-onset left-sided weakness. His temperature is 101.6°F. Physical examination shows a heart murmur, painless erythematous nodules on his palms, and nail-bed hemorrhages.

Amniotic fluid

Develops when amniotic fluid leaks into the maternal bloodstream, usually postpartum. Can lead to disseminated intravascular coagulation (DIC). A 27-year-old woman develops sudden-onset dyspnea shortly after giving birth.

Pathology

Discussion of respiratory pathology will begin with an overview of physical examination findings commonly associated with respiratory dysfunction. Pathologic conditions of the upper airways (eg, nasopharynx, oropharynx, larynx) are then covered, followed by those of the lower airways (eg, tracheobronchial tree, lung parenchyma).

Emphysema Lung compliance describes how much the lung volume increases for any given increase in pressure. Imagine how large you can inflate a balloon with a single breath. Now imagine how much larger you can inflate a plastic bag with a single breath. The plastic bag is more compliant than the balloon.

Emphysema is abnormal and permanent airway enlargement distal to the terminal bronchiole, accompanied by progressive destruction of alveolar walls and surrounding interstitium. The result is loss of elastic recoil, increased lung compliance, dilation of the terminal air spaces, and air trapping. The loss of elastic recoil in the lung parenchyma shifts the compliance curve of the lung upward and to the left (Figure 10-34). Normally, alveolar neutrophils and macrophages produce elastase in response to air pol- lutants. Elastase is a proteolytic enzyme that digests elastin (the component responsible for elastic recoil of alveolar walls). α1-Antitrypsin is an anti-proteolytic enzyme (protease inhibitor) that neutralizes elastase, thus maintaining the elastic properties of alveolar walls. Emphysema develops from either excess elastase or deficient α1-antitrypsin production.

Epistaxis

Epistaxis is a nose bleed; the nasopharynx receives its blood supply from four arteries listed below (origins in parentheses) and illustrated in Figure 10-33: ■ Anterior ethmoidal arteries (ophthalmic artery) ■ Septal branch of the superior labial artery (facial artery) ■ Greater palatine artery (maxillary artery) ■ Nasopalatine branch of the sphenopalatine artery (maxillary artery) The terminal branches of these arteries form an anastomotic network in the anterior segment of the nasopharynx called Kiesselbach plexus. Epistaxis most commonly arises from vascular damage within this plexus. Although less common, epistaxis arising from the posterior segment of the nasopharynx (sphenopalatine artery) can be life threatening. If a board question describes a patient who "picks their nose" and presents with persistent large-volume epistaxis, and no other localizing information is given, Kiesselbach plexus or sphenopalatine artery is the likely injured vessel.

Hyperresonance, tympany

Excess air in pleural cavity or lung parenchyma Emphysema, pneumothorax

Growth factors: ■ EGF ■ IGF-1 ■ PDGF

Fibrosis Smooth muscle hyperplasia

Lung Percussion Findings Dullness, flatness

Fluid in pleural cavity or lung parenchyma Pleural effusion, lobar pneumonia

Gram-Negative Bacteria Haemophilus influenzae

Gram-negative coccobacilli. Requires chocolate agar with hematin (factor X) and NAD+ (factor V) for culture. Treat Amoxicillin +/- clavulanate Second- or third-generation cephalosporins

Moraxella catarrhalis

Gram-negative diplococcus. Typically associated with otitis media (children) and COPD exacerbations (elderly), but can cause pneumonia in the latter population. Treat Second- or third-generation cephalosporins Macrolides Quinolones

Legionella pneumophila

Gram-negative rod that stains poorly; requires silver stain. Grows on charcoal yeast extract culture with iron and cysteine. Aerosol transmission from environmental water sources (eg, air conditioning systems, hot water tanks, cruise ships). Labs show hyponatremia. Treat Macrolides Quinolones

Granulomatosis with Polyangiitis (Formerly Wegener Granulomatosis)

Granulomatosis with polyangiitis is an autoimmune vasculitis affecting primarily the upper respiratory tract, lungs, and kidneys, but also affecting the joints, skin, eyes, or nervous system in certain cases. Characterized by vasculitis of small and medium blood vessels in affected organs, with granulomas surrounding these vessels. PRESENTATION Extremely varied. Cough, dyspnea, hemoptysis. Persistent rhinorrhea, bloody/purulent nasal discharge, nasal pain. Nonrespiratory symptoms include nephritic syndrome, eye and ear symptoms, arthritis, and cutaneous vasculitis. DIAGNOSIS ■ CT: One or several nodules ("coin lesions") and infiltrates, often with cavitation (Figure 10-46). ■ c-ANCA-positive (antiproteinase 3 autoantibodies). ■ Biopsy: Necrotizing granulomatous vasculitis. TREATMENT Prednisone used during initial therapy. Cytotoxic agents like cyclophosphamide are also used. PROGNOSIS Complete and long-term remission can often be achieved with proper treatment.

Most Common Causes of Pneumonia by Age NEONATES (< 4 WK

Group B streptococci Escherichia coli

Endemic mycoses

Histoplasmosis: Mississippi and Ohio River valleys. Found in bird/bat droppings. Macrophages filled with Histoplasma. Blastomycosis: States east of Mississippi River and Central America. Broad-based budding. Coccidiomycosis: Southwestern United States, California. Spherules filled with endospores. Paracoccidioidomycosis: Latin America. Budding yeast with "captain's wheel" formation. Treat Azoles Amphotericin B (for disseminated infections

Idiopathic Pulmonary Fibrosis Drugs that cause pulmonary fibrosis: Breathing Air Badly [from] Medications: Bleomycin, Amiodarone, Busulfan, Methotrexate

Idiopathic pulmonary fibrosis (IPF) pathogenesis is believed to be precipitated by an unknown agent that causes cytokine release, resulting in repeated cycles of inflammattory lung injury, followed by wound healing. Collagen deposits accumulate in the lungs with each cycle, eventually leading to fibrosis. IPF accounts for approximately 15% of cases of chronic interstitial lung disease. PRESENTATION Insidious onset, often between 40 and 70 years of age. Most commonly presents with progressive dyspnea. DIAGNOSIS ■ Physical exam: Dry crackles or rales on auscultation, clubbing of fingernails. ■ Chest film and CT: Diffuse, interstitial pattern bilaterally. Seen more at the bases and peripheral portions of the lung. CT classically shows "honeycombing"—a cav- ernous network of fibrosis within the lungs (Figure 10-45). ■ Biopsy/pathology: Provides definitive diagnosis; shows chronic inflammation and fibrosis of the alveolar walls as well as interstitial fibrosis; dilation of bronchioles proximal to fibrotic alveoli produces "honeycomb lung" appearance in UIP. TREATMENT Systemic corticosteroids and other immunosuppressive drugs are not effective. Lung transplantation may be an option for younger patients. Two new drugs can now be considered—pirfenidone and nintedanib. PROGNOSIS Rapid disease progression with a mean survival of 2-5 years.

Cytokines: ■ GM-CSF ■ IL-8 ■ RANTES ■ Eotaxin

Inflammation

Rhinosinusitis

Inflammation of the paranasal sinuses. The paranasal sinuses refer to the hollow, air- filled cavities surrounding the nose, which are lined with mucus and drain into the nasal cavity. They serve to humidify inspired air. The four groups of paranasal sinuses are the frontal, sphenoid, ethmoid, and maxillary sinuses, illustrated in Figure 10-31. When sinus drainage into the nasal cavity becomes obstructed (typically by mucus), the sinuses can become infected. The vast majority of infectious rhinosinusitis is caused by viral upper respiratory tract infections (URIs). In certain cases, viral URIs can be superimposed by bacterial infections, with the most common organisms being Streptococcus pneumoniae (40%), Haemophilus influenzae (35%), and Moraxella catarrhalis (5%). The widespread use of conjugated pneumococcal vaccination in children is changing the incidence rate of the major pathogens. The percentage of bacterial sinusitis due to S pneumoniae is decreasing, while the number of cases caused by nontypeable H influenzae is increasing. If indicated, empiric treatment with antibiotics is generally directed toward these agents. PRESENTATION ■ Sinus inflammation presents with tenderness to palpation, a sensation of "fullness" in the affected paranasal regions (may mimic toothache), and, rarely, earache. These symptoms are often associated with viral URI symptoms (eg, rhinorrhea, nonproductive cough). ■ When rhinosinusitis is superimposed by bacterial infections, patients present with fever and purulent nasal discharge, in addition to their pre-existing symptoms. Bacterial infections can also be suspected when viral URI symptoms persist or worsen after 1-2 weeks. Antibiotics are generally not indicated for sinusitis, unless symptoms have persisted longer than 10 days, although exceptions exist. DIAGNOSIS ■ Primarily clinical suspicion based on patient history and physical examination. ■ CT scan (coronal view) can show air-fluid levels (Figure 10-32). CT is the imaging method of choice but is rarely clinically indicated in uncomplicated sinusitis. ■ Nasal swabs for culture are not reliable and almost never indicated. TREATMENT ■ Rhinosinusitis due to viral URI is typically self-limiting. ■ If complicated by bacterial infections, antibiotics are indicated. ■ Amoxicillin-clavulanate is first-line pharmacologic treatment; use doxycycline, ciprofloxacin, or moxifloxacin if patient is allergic to penicillin.

Sarcoidosis Caplan syndrome is characterized by rheumatoid arthritis and pneumoconiosis with intrapulmonary nodules. Pneumoconiosis associations: Silicosis → lung nodules, "egg- shell" calcification in hilar nodes, tuberculosis Coal workers' pneumoconiosis → "dust cells" (alveolar macrophages with anthracotic pigment) Asbestosis → bronchogenic carcinoma >> malignant mesothelioma Berylliosis → granulomas mimicking sarcoidosis

Inflammatory disease characterized by noncaseating granulomas, often involving mul- tiple organ systems. The initial exposure that leads to granuloma formation is unknown. PRESENTATION Classic presentation of sarcoidosis is an African-American female in her thirties with progressive dyspnea, often accompanied by a dry or nonproductive cough. More common in women and African Americans. Presents in young adulthood. Often discovered in asymptomatic patients on chest film (Figure 10-44A). Less often, presents with extra- pulmonary symptoms. DIAGNOSIS ■ Chest film: Bilateral hilar lymphadenopathy, diffuse (coarse) reticular densities. ■ Reduced sensitivity/anergy to skin test antigens. ■ Laboratory findings: Hypercalcemia (due to increased 1-α-hydroxylase production by activated macrophages leading to increased 1,25-(OH)2-vitamin D), hypercalciuria, hypergammaglobulinemia, increased ACE activity. Hypercalcemia/hypercalciuria may present as nephrolithiasis. ■ Biopsy showing noncaseating granulomas in the lung with a negative microbiology work-up is highly suggestive. Granulomas are often seen in other organs as well. The granuloma consists of a core of macrophages surrounded by T lymphocytes, as illustrated in Figure 10-44B. ■ Differential diagnosis: TB, fungal infections (see Table 10-15), other infectious diseases, malignancy, rheumatologic disease. TREATMENT Many patients do not need treatment. Criteria for receiving treatment include impaired pulmonary function or worsening radiologic findings, systemic symptoms that interfere with activities of daily living, ocular disease, heart disease, neurologic involvement, and hypercalcemia. Treatment consists of systemic corticosteroids or other immunosuppressive drugs. PROGNOSIS Natural history varies widely. In some patients, clinical and radiographic manifestations resolve spontaneously. In others, symptoms persist without progression. In a small minority, the disease progresses to widespread pulmonary fibrosis.

Large Cell Carcinoma

Large cell carcinoma (LCC) is a highly anaplastic undifferentiated tumor with a poor prognosis. LCC is associated with smoking and arises from epithelial cells, commonly in the lung periphery, though central tumors sometimes occur. No glandular or squamous differentiation is present in LCC. Thus, LCC is a diagnosis of exclusion and includes all non-small-cell lung carcinomas (NSCLCs) that cannot be further classified. Unlike SCLC, it is less responsive to chemotherapy and is usually surgically resected. Histology shows sheets of pleomorphic giant cells, polygonal in shape with prominent nucleoli and pale-staining cytoplasm. In some cases, these cells can secrete β-hCG.

Rhonchi

Low-pitched "snoring" sound. Suggests secretions in large airways. Asthma, COPD, bronchitis

Percussion To become more familiar with percussion sounds, you can generate different tones by percussing over certain areas: ■ Flatness—thigh ■ Dullness—liver ■ Resonance—normal lung ■ Tympany—puffed out cheek

Lung percussion provides the examiner with information regarding the nature of the underlying tissue (ie, air-filled, fluid-filled, solid). In general, percussion over solid or fluid-filled cavities tends to generate duller tones, whereas percussion over air-filled cavities produces more resonant or "drum-like" tones. In order of increasing resonance, the five tones generated by percussion are flatness, dullness, resonance, hyperresonance, and tympany (Table 10-12)

Mesothelioma Asbestosis increases the risk for both mesothelioma and bronchogenic carcinoma. While this risk is amplified more in mesothelioma than in bronchogenic carcinoma, the latter is still more common in people with asbestos exposure. Sites for metastasis of primary lung cancers (ranked by frequency): 1. Hilar lymph nodes 2. Adrenal glands 3. Liver 4. Brain 5. Bone (osteolytic) Squamous and Small cell carcinomas are Sentral (central) and strongly associated with Smoking.

Mesothelioma is a malignancy of the pleura, strongly associated with asbestosis. Clas- sically presents with pleural thickening and recurrent pleural effusions (often hemorrhagic) on imaging. Electron microscopy is the gold standard for diagnosis and shows tumor cells with numerous long, slender microvilli and abundant tonofilaments. Psamomoma bodies are seen on histology.

ADULTS (18-40 YR)

Mycoplasma C pneumoniae Streptococcus pneumoniae

Neonatal (Infant) Respiratory Distress Syndrome

Neonatal respiratory distress syndrome (NRDS) is the most common cause of respiratory failure in newborns and the most common cause of death in premature infants. It results from a deficiency of surfactant in immature lungs, leading to atelectasis due to increased surface tension in the air-liquid interface, V ̇/Q ̇ mismatch, and shunting. Predisposing factors include: ■ Prematurity. ■ Maternal diabetes: Excess glucose in the mother's blood reaches the fetus through the placenta. Fetal insulin production increases, which suppresses corticosteroids normally involved in surfactant production. ■ C-section delivery: During a normal vaginal delivery, maternal uterine contractions compress the fetal head, inducing corticosteroid production. This process is bypassed in a C-section, causing the fetus to produce fewer corticosteroids. Incidence and mortality decrease dramatically with gestational age, with the most severe disease seen prior to the alveolar stage of lung development. PRESENTATION Dyspnea and tachypnea in a newborn, with risk factors described above, especially if premature. DIAGNOSIS ■ Physical exam: Tachypnea, often with grunting, cyanosis, and retractions; crackles on auscultation. ■ Fetal pulmonary maturity can be assessed by measuring the ratio of surfactant lecithin to sphingomyelin in the amniotic fluid. A ratio of 2:1 or greater indicates lung maturity. Chest film: Low lung volumes, diffuse ground-glass appearance with air broncho- grams (Figure 10-43). ■ Arterial blood gas testing: Hypoxemia, with a large A-a gradient. Hypoxemia may be refractory to supplemental O2 due to shunting. ■ Pathology: Lungs are heavier than normal, with alternating atelectatic areas and dilated alveoli. The pulmonary vessels are engorged, with leakage of fluid into the alveoli. Hyaline membranes are also seen (note that neonatal RDS was formerly called hyaline membrane disease). ■ Differential diagnosis: Transient tachypnea of the newborn (TTN—self-resolving, relatively benign respiratory distress associated with pulmonary edema), bacterial pneumonia, congenital heart disease. TREATMENT Exogenous surfactant administration. Mechanical ventilation with PEEP. Inhaled nitric oxide. Antenatal maternal corticosteroid therapy to promote surfactant production. PROGNOSIS Mortality rates have improved dramatically with the use of exogenous surfactant but remain over 10%. NRDS may also be associated with metabolic acidosis, patent ductus arteriosus (PDA), and necrotizing enterocolitis.

Mycoplasma pneumoniae

No cell wall. Not seen on Gram stain. Cultured on Eaton agar. Classic cause of atypical ("walking") pneumonia. Interstitial pattern on CXR looks worse than patient does. Outbreaks are frequently seen among military recruits and in prisons. Associated with cold-agglutinin (IgM) autoimmune hemolytic anemia. Treat Macrolides Doxycycline Fluoroquinolone

Resonance

Normal lung finding Normal lung

Chlamydia

Obligate intracellular organisms. Cell wall lacks muramic acid. Does not show up on Gram stain. Giemsa or fluorescent antibody-stained smear shows cytoplasmic inclusions. C pneumoniae and C psittaci cause atypical pneumonia. Treat Macrolides Doxycycline

Adventitious Lung Sounds Crackles (rales

Often equated to the sound of rubbing strands of hair between the fingers or the sound produced by velcro. Due to fluid/consolidation within the lung parenchyma (wet crackles) or pulmonary fibrosis (dry crackles). Wet crackles: pneumonia, pulmonary edema (eg, congestive heart failure) Dry crackles: pulmonary fibrosis

Auscultation

On a normal physical examination, breath sounds can be heard differently depend- ing on the auscultated region. Physiologic breath sounds can be described as tracheal (auscultated over the trachea), bronchial (over the manubrium), vesicular (over most of the lung), and bronchovesicular (between the scapulae and in the first and second intercostal spaces anteriorly). Although physiologic breath sounds are usually not directly tested on board exams, it is important to be familiar with the terminology, as it does show up in question stems. On the other hand, adventitious (pathologic) breath sounds are high yield for exams and are described in Table 10-11. Egophony describes modified voice transmission on lung auscultation. It is classically detected by having the patient produce and hold an "E" sound. In cases of egophony, transmission will be such that the examiner hears an "A" sound through the stethoscope. This finding is highly specific for lung consolidation (ie, lobar pneumonia).

Cryptococcus neoformans

Opportunistic infection (classically HIV patients). Found in soil and pigeon droppings. Acquired through inhalation. Cryptococcosis presents like pneumonia. Can disseminate hematogenously to meninges, causing cryptococcal meningitis. Heavily encapsulated yeast. Culture on Sabouraud agar; stains with India ink and mucicarmine. Definitively diagnosed with latex agglutinin test (detects polysaccharide capsular antigen). Treat Cryptococcal meningitis: Amphotericin B + flucytosine Non-CNS cryptococcosis: Fluconazole

Pulmonary Embolism Types of emboli: An embolus moves like a FAT BAT (Fat, Air, Thrombus, Bacteria, Amniotic fluid, Tumor). Lines of Zahn (Figure 10-48B) are interdigitating areas of pink (platelets, fibrin) and red (RBCs) found only in thrombi formed before death. As such, they are used to assess whether a thrombus formed pre- or postmortem

PE is often missed clinically and is seen in > 60% of autopsies. It occurs when a blood clot from a systemic vein lodges in one or more branches of the pulmonary artery. Most often, a PE arises from a deep vein thrombosis (DVT), but it can also result from embolization of fat, air, bacteria (infectious vegetations), amniotic fluid, and tumor cells (Table 10-16). As mentioned earlier, the majority of PEs arise from DVTs. As such, similar risk factors apply. Decreased perfusion with continued ventilation causes an increase in dead space following a PE. One may expect this to lead to hypercapnia, but patients often hyperventilate and become hypocapnic. The release of inflammatory mediators can lead to bronchoconstriction, V ̇ /Q ̇ mismatch, and hypoxemia. Reduced output of the right ventricle can lead to hypotension, syncope, and/or shock. PRESENTATION Tachypnea, tachycardia, hypoxia, and sudden-onset dyspnea with pleuritic chest pain (pain that worsens with breathing) are the classic signs and symptoms, but the presentation is often varied. Can be associated with hemoptysis (secondary to infarcted lung tissue) and syncope. Smaller PEs are often asymptomatic. Deep venous thrombosis in right lower extremity. DIAGNOSIS EXAMPLE PRESENTATION A 24-year-old patient is hospitalized following a motor vehicle accident. The next day, he develops sudden-onset dyspnea and confusion. On physical examination, a petechial rash is seen across his chest. A 26-year-old patient develops rapid-onset dyspnea and pleuritic chest pain. On further questioning, patient reports symptoms developed while scuba diving. Five days after abdominal surgery, a 68-year-old woman develops dyspnea and pleuritic chest pain. A 36-year-old IV drug user presents with sudden-onset left-sided weakness. His temperature is 101.6°F. Physical examination shows a heart murmur, painless erythematous nodules on his palms, and nail-bed hemorrhages. A 27-year-old woman develops sudden-onset dyspnea shortly after giving birth. A 59-year-old man presents with sudden-onset right-sided weakness. He has a 40 pack-year smoking history. Chest x-ray shows a 4-cm lung nodule. ■ Physical exam: ■ Tachycardia and tachypnea. ■ Localized crackles or wheezes; however, the lung exam is often normal. ■ A pleural rub may be present. The pleural rub is produced by a fibrinous exudate that is released from the pleural surface overlying the region of ischemic lung tissue. ■ In the case of a massive PE (Figure 10-48A), the sudden increase in vascular resistance can lead to right ventricular overload (acute cor pulmonale), in which case a right-sided S4 and loud P2 may be heard (see Heart Sounds, discussed in Chapter 1). Jugular venous distention (JVD) may also be observed. ■ Lower extremity tenderness, swelling, and a palpable cord suggestive of a DVT may be seen. ■ Laboratory results and imaging: ■ CT angiography can show the filling defect due to the thrombus (Figure 10-48C,D). This is the preferred method of definitive diagnosis. ■ V ̇ /Q ̇ scan: Shows an area of V ̇ /Q ̇ mismatch. ■ Chest film: Usually nonspecific. Dilation of the pulmonary arteries, Hampton hump (wedge-shaped consolidation in the lung periphery adjacent to the pleura), Westermark sign (abrupt cutoff of pulmonary vascularity distal to a PE), or a pleural effusion may also be seen. ■ d-dimer level: Fibrin degradation product. Elevated levels indicate thrombus formation. Has high sensitivity (hence, used for ruling out PEs). ■ Arterial blood gas testing: Decreased Pao2 due to increased dead space. Decreased Paco2 due to tachypnea. A-a gradient increased due to V ̇/Q ̇ mismatch. TREATMENT Supplemental oxygen if hypoxemic. Anticoagulation therapy, usually with IV heparin or low-molecular-weight heparin followed by oral anticoagulation for 3-6 months. Thrombolytic therapy may be useful in a subset of patients with massive PE and hypotension. Placement of a filtering device in the IVC can be used in patients who cannot tolerate anticoagulation due to an elevated bleeding risk. PROGNOSIS Variable, ranging from sudden death to asymptomatic resolution.

Chronic Eosinophilic Pneumonia

PRESENTATION Presents over weeks to months, with fever, weight loss, dyspnea, and nonproductive cough. DIAGNOSIS ■ Chest film: Peripheral pulmonary infiltrates and a pattern suggestive of alveolar filling. ■ Eosinophilia. ■ Pathology: Pulmonary interstitium and alveolar spaces infiltrated by eosinophils and macrophages. TREATMENT Administration of corticosteroids. PROGNOSIS Clinical improvement can be seen within days to weeks after therapy with steroids is initiated.

Tracheal positioning

Palpated along the patient's neck. Tracheal deviation can be ipsilateral or contralateral to the affected lung; can also be confirmed on chest x-ray. Ipsilateral deviation: atelectasis, spontaneous (simple) pneumothorax Contralateral deviation: pneumothorax, large pleural effusion

Anaerobes

Part of normal oral flora. Associated with aspiration pneumonia. Treat Clindamycin

Pneumonia Because the right mainstem bronchus is positioned more vertically than the left mainstem bronchus, aspiration pneumonia typically affects the right lower and middle lobes. Egophony refers to modified voice transmission through the body during lung auscultation. It is classically detected by having the patient produce and hold an "E" sound. In cases of egophony, transmission will be such that the examiner hears an "A" sound through the stethoscope.

Pneumonia is infection of the lung parenchyma. It is classified as either community acquired or nosocomial (hospital acquired). This distinction is important because individuals in the hospital setting undergo various interventions (eg, mechanical ventilation, urinary catheterization), which may predispose them to a different set of microorganisms than in the community. Specifically, Pseudomonas aeruginosa causes pneumonia almost exclusively in the healthcare setting. Community-acquired pneumonia can be further classified according to presentation (typical or atypical) as well as the infiltration pattern seen on chest x-ray (lobar, patchy, or interstitial). These classifications are outlined in Figure 10-52 and elaborated on in the following discussions. Aspiration pneumonia is another type of pneumonia that develops when oral flora (including anaerobes) are aspirated into the lung. Risk factors for developing aspiration pneumonia include decreased consciousness (eg, in the elderly and alcoholics, and in seizures) and neuromuscular diseases. Aspiration pneumonia can be acquired in the community or in a hospital setting. The most common causes of pneumonia vary with the patient's age and are associ- ated with specific risk factors. These organisms are listed in Tables 10-17 and 10-18, respectively. PRESENTATION ■ Community-acquired pneumonia: ■ Typical pneumonia: Acute onset of fever, dyspnea, and productive cough with purulent sputum. Sputum can also be blood-tinged or "rusty" in appearance due to rupture of pulmonary microvasculature. Pleuritic chest pain can also be present due to inflammation adjacent to the pleura. In some cases, elderly patients can present with epigastric pain rather than chest pain. ■ Atypical pneumonia: More indolent course and usually presents with dry cough. ■ Nosocomial pneumonia and aspiration pneumonia have a similar presentation to typical pneumonia. Look for additional risk factors, such as an extended hospital stay or decreased consciousness. DIAGNOSIS ■ Physical exam: ■ Tachycardia, tachypnea, fever. ■ Crackles over the affected area on auscultation. ■ If affected airways are patent, bronchial breath sounds (louder, especially during exhalation) can be heard on auscultation. If the airways are completely blocked from consolidation, breath sounds will be decreased in affected areas. ■ Dullness to percussion, increased fremitus, and egophony suggest frank con- solidation or associated effusion. ■ Chest x-ray: Gold standard. Allows classification of pneumonia as lobar, patchy (bronchopneumonia), or interstitial (atypical). KEY FACT Mycoplasma, Chlamydia, and Legionella are commonly referred to as atypical organisms because they cause atypical pneumonia and do not appear on Gram stain. Their special staining and culture requirements are as follows: ■ Mycoplasma—Eaton agar ■ Chlamydia—Giemsa stain ■ Legionella—Charcoal yeast extract agar (buffered with cysteine and iron) Lobar pneumonia: Consolidation involves the entire lobe from intra-alveolar exudates. Can involve one or more lobes (Figure 10-53A,B). Most common organism is Streptococcus pneumoniae. Also Legionella and Klebsiella. Bronchopneumonia: Patchy consolidation distributed around bronchioles and adjacent alveoli (Figure 10-53C). Often multifocal and bilateral (Figure 10-53D). Most common organisms are S pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Klebsiella. ■ Interstitial (atypical) pneumonia: Diffuse patchy inflammation localized to the interstitial areas at alveolar walls (Figure 10-53E). Sometimes very subtle on x-ray. Most common organisms are Mycoplasma, Legionella, Chlamydia, and viruses (influenza, respiratory syncytial virus [RSV], adenovirus). ■ Arterial blood gas testing: Reduced Pao2 with normal or reduced Paco2 due to tachypnea. ■ Sputum Gram stain and culture: Depends on the infecting organism. Of note, the organisms causing atypical pneumonia do not show up on Gram stain. Hence, they are commonly referred to as "atypical" organisms. The most common organisms associated with pneumonia, along with their distinguishing features and specific treatment options, are outlined in Tables 10-19 and 10-20. TREATMENT Antimicrobial therapy is the mainstay for bacterial and fungal pneumonia. Community-acquired pneumonia: ■ In general, patients without comorbidities (eg, diabetes, COPD, heart failure, renal failure, liver failure) should be treated with macrolides (eg, azithromycin, clarithromycin) or doxycycline. ■ The elderly and patients who have comorbidities or require hospitalization should be treated with a fluoroquinolone. Nosocomial pneumonia: ■ Treatment should be tailored toward gram-negative rods. This includes cepha- losporins (specifically, ceftazidime or cefepime for Pseudomonas coverage), car- bapenems, or piperacillin/tazobactam. Fungal infections: ■ If pneumonia is due to endemic mycoses, treat with itraconazole or fluconazole. Amphotericin B and newer generation -azoles are used in cases of disseminated infection. ■ All HIV patients with a CD4+ count lower than 200 cells/mm3 should receive prophylaxis against Pneumocystis jirovecii (PCP). Therapy can include trimethoprim-sulfamethoxazole (TMP-SMX; most common, except with sulfa allergy), pentamidine, dapsone, or atovaquone. Existing PCP infections can be treated with TMP-SMX or pentamidine. ■ Viral pneumonias are usually self-limited, requiring only supportive care, although the use of certain antiviral agents (eg, oseltamivir, zanamavir) has been shown to decrease the duration of influenza infections by approximately 24 hours. ■ Refer to Table 10-19 and Table 10-20 for organism-specific treatments. PROGNOSIS In most cases, appropriate treatment results in complete recovery without long-term sequelae, but morbidity and mortality increase with age. Complications include: ■ Lung abscess: Localized pus collection within the lung parenchyma (Figure 10-54A). Common complication of aspiration pneumonia or bronchial obstruction (eg, tumor). Infecting organisms include anaerobic oral flora (eg, Bacteroides, Fusobacterium, Peptostreptococcus) or S aureus. Patients typically present with symptoms of pneumonia unresponsive to antibiotics. Chest imaging shows cavitations with air-fluid levels, often in the right lung in the case of aspiration (Figure 10-54B). Treat with clindamycin. ■ Empyema: Pus in the pleural space. Often caused by anaerobes and staphylococci. Requires drainage

Poor Muscular Effort

Poor muscular effort is often due to one of several neuromuscular diseases. In each case, hypoventilation develops as the diaphragm and accessory muscles become fatigued. Patients alter their breathing pattern, taking more frequent, shallow breaths. This increases the Vd:Vt ratio, reducing alveolar ventilation and increasing Paco2. Ineffective cough can lead to decreased secretion clearance, atelectasis, and recurrent respiratory infections. Common causes of neuromuscular disease include ■ Poliomyelitis (polio): Picornavirus infection, which leads to ablation of anterior motor neurons and therefore symptoms of lower motor neuron (LMN) paralysis. ■ Myasthenia gravis: Autoimmune disorder that causes muscle weakness due to auto- antibodies targeting nicotinic acetylcholine receptors in the neuromuscular junction. ■ Amyotrophic lateral sclerosis (ALS): Neurodegenerative motor neuron disease affecting both the lateral corticospinal tracts and anterior horns of the spinal cord, leading to signs of upper motor neuron (UMN) and LMN paralysis, respectively. ■ Guillain-Barré syndrome (GBS): Transient autoimmune destruction of Schwann cells, leading to peripheral demyelination. Classically presents with symmetric ascending paralysis, starting from the lower extremities; symptoms can also include autonomic dysregulation (eg, cardiac arrhythmias, hypertension, or hypotension). Usually follows gastroenteritis (most commonly caused by Campylobacter jejuni).

Lung Cancer

Primary lung cancer is the second-most-common cancer by incidence, as well as the leading cause of cancer-related death in both males and females Cigarette smoking is clearly related to certain types of lung cancer. While quitting reduces subsequent risk of developing lung cancer, this risk likely never drops to that of a nonsmoker. Family history and occupational exposures, including arsenic, radon, haloethers, hydrocarbons, and agents associated with pneumoconioses (eg, asbestosis, silicosis), can predispose to lung cancer. Lung cancer is broadly categorized as small cell or non-small cell subtypes. Non-small cell is further classified as adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and bronchial carcinoid tumors. The five major types of primary lung cancer are discussed below.

Coal workers' pneumoconiosis

Prolonged coal dust exposure (coal miners) Black lungs; coal dust contains silica and carbon D . Progresses from anthracosis (mild, asymptomatic form seen in city dwellers and smokers). Interstitial fibrosis primarily affects the upper lobes and develops secondary to activation of carbon- laden macrophages. Not associated with lung cancer.

Cystic fibrosis

Pseudomonas, S aureus, S pneumoniae

Pulmonary Hypertension

Pulmonary hypertension is the elevation of intravascular pressure within the pulmonary circulation and includes pulmonary arterial hypertension (PAH) as well as pulmonary venous hypertension. PAH is defined as a mean pulmonary artery pressure > 25 mm Hg at rest or > 35 mm Hg with exertion. Idiopathic (primary) pulmonary arterial hyper- tension has no known cause and carries a poor prognosis. It occurs in the absence of underlying heart or lung disease and is more common in women than in men. Primary pulmonary hypertension is associated with mutations in genes linked to transforming growth factor beta (TGF-β) signaling and is characterized by vascular hyperreactivity with proliferation of smooth muscle. Congenital idiopathic pulmonary hypertension is associated with abnormally thickened vasculature. Secondary pulmonary hypertension is more common and is related to lung or heart disease, including: ■ Chronic thromboembolic disease. ■ Loss of vessels by scarring or destruction of alveolar walls. ■ Chronic hypoxemia. ■ Increased flow (left-to-right shunt). ■ Elevated left atrial pressure, as in CHF or mitral stenosis. ■ Chronic respiratory acidosis (eg, chronic bronchitis, obstructive sleep apnea). ■ Meconium aspiration at birth, the most common cause of persistent pulmonary hypertension of the newborn. PRESENTATION Dyspnea and exertional fatigue. Substernal chest pain, similar to angina pectoris, is sometimes seen. If cardiac output falls enough, syncope can result. DIAGNOSIS ■ Physical exam: ■ Lung examination often normal unless pulmonary hypertension is due to con- comitant lung disease. ■ Loud P2, right-sided S3 and S4. ■ JVD. ■ Right ventricular heave. ■ CT: Increased prominence and size of hilar pulmonary arteries, which rapidly taper off. Enlarged cardiac silhouette (particularly RV and RA enlargement). Redistribution of blood flow to the upper lungs (Figure 10-49). ■ PFT: Spirometry and lung volumes usually normal, with a decreased Dlco. ■ Arterial blood gas testing: Useful in determining whether hypoxemia or acidosis plays a role in the disease's cause. ■ Echocardiogram: Elevated right ventricular systolic pressure with possible right ventricular dysfunction or hypertrophy. ■ Pathology: Intimal hyperplasia and medial hypertrophy of small arteries and arterioles, leading to obliteration of the lumen. Plexogenic (web-like) lesions are typically seen in idiopathic disease. Thickening of the walls of larger arteries is also seen. Right ventricular hypertrophy is also a feature. TREATMENT Supplemental O2 therapy, various vasodilators (eg, sildenafil, bosentan, prostacyclins), inhaled nitric oxide, and possibly anticoagulation therapy. See the Pharmacology section of this chapter for a more detailed discussion. PROGNOSIS ■ Right-sided heart failure can occur due to elevated right-sided pressures. ■ Idiopathic (primary) pulmonary hypertension: Poor prognosis, often resulting in death within a few years of diagnosis if untreated.

RESTRICTIVE LUNG DISEASES FEV1:FVC ratio > 80% is characteristic of restrictive lung disease. Restrictive lung disease due to poor muscular effort can also arise from diaphragmatic paralysis, in which one or both phrenic nerves are damaged (eg, trauma) or impinged on (eg, tumor).

Restrictive lung diseases are characterized by reduced lung expansion (decreased lung volume). TLC and RV are reduced. In turn, FEV1 and FVC are decreased. FEV1 and FVC decrease proportionately, resulting in a normal FEV1:FVC, or FVC is decreased to a greater degree than FEV1, resulting in an increased FEV1:FVC. Restrictive lung disease can develop from both pulmonary and extrapulmonary sources (Figure 10-40).

Asthma In contrast to other organs in the body, such as the brain, the pulmonary circulation actually vasodilates in response to high O2 and vasoconstricts in response to low O2. "Silent chest" is the absence of wheezing and other breath sounds during an asthma attack due to air flow rates too low to generate sound. It is a marker of disease severity and portends a poor prognosis for an acute asthma exacerbation. Not all that wheezes is asthma and not all asthma wheezes. Anaphylaxis, foreign body aspiration, COPD, and cardiac wheeze (pulmonary edema due to HF) may present with wheezing. However, a severe asthma exacerbation can result in respiratory muscle failure or so severely obstruct airways that air flow rates are insufficient to produce audible wheezing. Some asthmatics may be sensitive to aspirin, which inhibits cyclooxygenase and favors the production of leukotrienes from arachidonic acid. Leukotrienes play a role in airway inflammation and are potent bronchoconstrictors. Pulsus paradoxus is a decrease in systolic blood pressure by 10 mm Hg or more during inspiration. On board exams, it is most commonly tested in the context of cardiac tamponade but can also be seen in asthma, obstructive sleep apnea, and croup. Release of major basic protein (MBP) by eosinophils is a major cause of damage to the alveolar lining in asthma. Immune cytokines: IL-4 is responsible for B-cell class switching to IgE. IL-5 is responsible for eosinophil recruitment. Asthma exacerbations are typically associated with respiratory alkalosis from tachypnea. Signs of acidosis (eg, decreased pH, increased PaCO2) suggest impending respiratory failure as the patient's muscles of respiration become fatigued. This is a potential emergency requiring intubation.

Reversible obstructive disease characterized by hyperreactive and hyperresponsive air- ways that lead to exuberant bronchoconstriction with minimal irritation. Prevalence is approximately 9% in the United States, although there is variation between races and sexes. Asthma is frequently seen in patients with a family history of eczema and allergic rhinitis, both of which are also hypersensitivity-mediated conditions. Children exposed to secondhand smoke, as well as infants of mothers who smoke, are at increased risk of developing asthma. Extrinsic and intrinsic subtypes exist, although patients frequently have a combination of the two. ■ Extrinsic asthma: Mediated by a type I hypersensitivity reaction involving IgE and mast cells (see also the section on Allergy at the end of this chapter). Often begins in childhood in patients with a family history of allergies. Common allergens include animal dander (especially cats), pollen, mold, and dust mites. ■ Intrinsic asthma: Due to nonallergic causes. Precipitating factors include viral URIs, exercise, cold temperatures, air pollutants (eg, cigarette smoke), chronic bronchitis, acid reflux, stress, and medications (especially aspirin). In both types of asthma, airway inflammation leads to bronchial hyper-responsiveness. Implicated in this inflammation are eosinophils, lymphocytes, histamine, leukotrienes, and IgE (see Table 10-14 for specific mediators). As a result of airway smooth muscle contraction, mucosal edema, and secretions within the lumen, the airway narrows, thereby increasing resistance and reducing airflow, especially during expiration. Unlike COPD, the process in asthma is generally reversible, so between attacks, most asthmatics have relatively normal physiology. PRESENTATION Acute exacerbation manifests with: ■ Sudden-onset dyspnea, wheezing, and tachypnea, usually following an inciting event. ■ Patients can also present with coughing, chest tightness, or chest pain. DIAGNOSIS ■ Physical exam: Tachypnea. Prolonged expiration and wheezing on auscultation. ■ Methacholine challenge test: Inhalation of methacholine (direct cholinergic ago- nist). When performed in asthmatic patients, this precipitates bronchoconstriction at lower doses (hyperreactivity) and increased severity (hyperresponsiveness) com- pared to normal patients. ■ Pulmonary function testing (PFTs): During an acute attack, airflow obstruction results in decreased FEV1 and FEV1:FVC ratio (FVC is often normal), and dynamic hyperinflation leads to a normal or increased TLC, and an increased FRC and RV. Between attacks, PFTs are often normal, although there may be small changes, such as decreased maximal midexpiratory flow (appearing as a marked concavity on the exhalation curve termed expiratory coving) and increased RV (Figure 10-19). ■ Patients with asthma can often monitor their own respiratory status with portable peak flow meters. ■ Arterial blood gas testing: During an attack, Pao2 is often reduced due to hypoxemia resulting from V ̇ /Q ̇ mismatch. Paco2 is also reduced due to hyperventilation. Paco2 levels that normalize or become elevated during an asthma attack may indicate worsening airway obstruction or a tiring individual who can no longer maintain a high minute ventilation rate. ■ Pathology: ■ Edema of the bronchial walls with smooth muscle hypertrophy and cellular infiltrates (eosinophils and lymphocytes). ■ Denuded epithelium, enlarged mucous glands, and increased number of goblet cells. ■ Curschmann spirals (whorled mucus plugs) containing shed epithelial cells (Figure 10-37) and eosinophilic crystals (Charcot-Leyden crystals) on sputum microscopy. ■ Mucus plugging (Figure 10-38). TREATMENT Treatments are listed below. Refer to the Pharmacology section at the end of the chapter for a more detailed discussion of each agent. ■ β2-agonists: albuterol, salmeterol, formoterol ■ Corticosteroids: beclomethasone, fluticasone ■ Muscarinic antagonists: ipratropium ■ Antileukotrienes: montelukast, zafirlukast, zileuton ■ Omalizumab ■ Magnesium sulfate PROGNOSIS May improve with age or be a life-long condition. Avoidance of triggers can avert the worst symptoms. A severe attack that is refractory to bronchodilators (status asthmaticus) may require assisted ventilation and can result in death.

Coxiella burnetii

Rickettsial organism. Obligate intracellular. Causes Q fever, which presents as pneumonia. Transmitted by spore inhalation from cattle/sheep amniotic fluid Treat Doxycycline

Postviral

S aureus, Haemophilus influenzae, S pneumoniae

Nosocomial

S aureus, Pseudomonas, Escherichia coli, other enteric gram-negative rods

Immunocompromised

S aureus, enteric gram-negative rods, fungi, viruses, Pneumocystis jirovecii (with HIV)

ADULTS (40-65 YR)

S pneumoniae Haemophilus influenzae Anaerobes Viruses Mycoplasma

ELDERLY (> 65 YR)

S pneumoniae Influenza virus Anaerobes H influenzae Gram Negative rods

Pleural rub

Scratching sound when inflamed parietal and visceral pleura rub against one another during respiration. Usually heard during both inspiration and expiration. Often localized to a small area of the chest wall. Connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis) Infections (viral, bacterial, fungal)

Inspection

Signs of respiratory distress include dyspnea (labored breathing), tachypnea (respiratory rate > 20 breaths/min), cyanosis, grunting, nasal flaring, retractions, and using accessory muscles of respiration. Retractions refer to the inward "pulling" of muscles during inspiration and are commonly seen in the intercostal, subcostal, suprasternal, and abdominal areas. Accessory muscles refer to the muscles primarily involved in forced breathing rather than unlabored diaphragmatic breathing. Increased work of breathing not in the context of exercise or physical exertion is concerning. Hyperinflated lungs can be a sign of COPD, in particular the "barrel chest" seen in emphysema.

Silicosis

Silica (associated with sandblasting; also seen in foundries and mines; quartz and other minerals "Eggshell" calcification of hilar lymph nodes. Silicotic nodules E . Interstitial fibrosis primarily affects upper lobes. Silica disrupts phagolysosome in macrophages, increasing susceptibility to tuberculosis. Associated with increased risk of bronchogenic carcinoma.

Stridor

Similar to a wheeze, but louder (often heard without auscultation) and almost entirely inspiratory. High pitch, best heard over trachea, loudest in the neck. Indicates partial obstruction of laryngeal or trachea; often a medical emergency. Laryngotracheitis (croup), FBA

Sleep Apnea Obesity hypoventilation syndrome (OHS) is a clinical picture in which obese patients have decreased respiratory drive. This condition is characterized by obesity (BMI ≥ 30) and hypercapnia (PaCO2 > 45) during the waking hours. Most patients with OHS also have coexisting OSA. Cheyne-Stokes respirations refer to a cyclic breathing pattern in which a period of apnea is followed by a gradual increase in tidal volume and respiratory rate, then a gradual decrease until the next apneic period. This occurs when damage to the respiratory center causes a delay between the brain stem's detection of changes in blood gas levels (afferent response) and the compensatory adjustments in respiration (efferent response).

Sleep apnea is characterized by repeated cessation of breathing for at least 10 seconds during sleep. Apneic episodes disrupt normal sleep cycles, preventing individuals from getting adequate rest. Thus, daytime somnolence is a hallmark presentation of sleep apnea. Etiology of sleep apnea is classified as either obstructive or central. With obstructive sleep apnea (OSA), the airways collapse during sleep. This is due to excess weight of the chest wall pressing down on the airways (associated with obesity) and/or decreased vagal tone, which decreases smooth muscle tone and increases the tendency for the airways to collapse on themselves during sleep. Central sleep apnea (CSA) is characterized by a lack of respiratory drive during sleep (airways remain patent) and is associated with central nervous system (CNS) injury/toxicity and congestive heart failure. PRESENTATION ■ OSA: Daytime sleepiness (most common) or fatigue. Patients are obese adults with a history of excessive snoring (often reported by the patient's spouse or partner). OSA can also present in children with tonsillar hypertrophy. ■ CSA: Daytime sleepiness and morning headaches. The patient's spouse or partner might report seeing the patient stop breathing during the night, sometimes in the context of Cheyne-Stokes respirations (see Key Fact). Look for a previous history of CNS injury. DIAGNOSIS ■ Physical exam: If OSA is suspected, look for obesity and/or enlarged tonsils. Physical exam is usually unremarkable in patients with CSA. ■ Polysomnography (sleep study) is the gold standard. ■ Arterial blood gas: Both OSA and CSA are associated with hypoxemia (decreased Pao2) and hypercapnia (increased Paco2) during sleep secondary to hypoventilation. If associated with obesity hypoventilation syndrome (see Key Fact), these patients will also have increased Paco2 during the waking hours. ■ Chest radiography: Right ventricular hypertrophy if sleep apnea is complicated by cor pulmonale. TREATMENT The mainstay of treatment for sleep apnea is positive airway pressure (PAP) during sleep. ■ Continuous positive airway pressure (CPAP): Continuous delivery of positive pres- sure keeps the airways open in patients with OSA. ■ Bi-level positive airway pressure (BiPAP): Provides a baseline CPAP but also provides additional positive airway pressure whenever the patient initiates a breath. This helps patients with CSA take full breaths during sleep. BiPAP can also be programmed to initiate breaths whenever patients fail do so on their own. PROGNOSIS If untreated, chronic hypoxemia causes vasoconstriction of pulmonary vessels, leading to pulmonary hypertension and cor pulmonale. This is prevented by using PAP during sleep, especially in the case of OSA.

Small Cell Lung Cancer

Small cell lung cancer (SCLC), previously known as oat cell carcinoma, is a neu- roendocrine tumor arising from Kulchitsky cells. It typically arises centrally in the lung from bronchi and is strongly associated with smoking. Commonly associated with upregulation of c-Kit and amplification of the L-myc (MYCL1) oncogene (gain-of- function transcription factor mutation), SCLC is composed of undifferentiated cells and is very aggressive. A key feature of SCLC is that it is usually surgically unresectable due to lymph node invasion and/or distant metastasis at diagnosis. Treatment is therefore chemotherapy and/or radiation, but the prognosis and long-term survival after diagnosis are grim. Histology shows small round "blue" cells with sparse cytoplasm, finely dispersed chromatin, and no distinct nucleoli (Figure 10-50A) that usually stain positive for synaptophysin, neuron-specific enolase, and chromogranin A. SCLC is commonly associated with paraneoplastic syndromes such as Cushing syn- drome, syndrome of inappropriate antidiuretic hormone secretion (SIADH), cerebellar ataxia, and Lambert-Eaton myasthenic syndrome (LEMS). LEMS is an autoimmune condition involving autoantibodies against presynaptic voltage-gated calcium channels. Inhibition of these channels prevents the release of neurotransmitters. It presents with proximal muscle weakness that improves with activity and signs of autonomic dysfunction, such as dry mouth and impotence.

TREATMENT for Emphysema Obstructive lung disease— ABCDE Asthma Bronchiectasis Chronic bronchitis Decreased FEV1:FVC ratio Emphysema

Smoking cessation is most important. ■ Supplemental oxygen is useful in patients with severe hypoxemia. ■ Only smoking cessation and supplemental oxygen are proven to reduce mortality. All other treatments, including pharmacotherapy, only reduce symptoms. ■ If hospitalization is required for an acute exacerbation, appropriate antibiotics, such as levofloxacin, improve outcome. ■ Inhaled bronchodilators can reduce airflow obstruction. These include: ■ β2-agonists (albuterol, salmeterol, formeterol) ■ Anticholinergics (ipratropium, tiotropium) ■ Corticosteroids are used in acute exacerbations (PO/IV) and for long-term control PROGNOSIS Lifelong and chronic. Often coexists with, or may be complicated by, chronic bron- chitis. Spontaneous pneumothorax can occur due to rupture of a surface bleb or tear in the airways.

Squamous Cell Carcinoma

Squamous cell carcinoma develops centrally in the lung, arising from squamous epithelium of proximal large airways. It can be seen on chest radiographs as a hilar mass (sometimes with cavitation) arising from the bronchus (Figure 10-50C). Squamous cell carcinoma is strongly associated with smoking and more common in men than women. Classically, squamous cell carcinoma is associated with the paraneoplastic syndrome hypercalcemia of malignancy secondary to production of parathyroid hormone-related peptide (PTHrP). On histology, keratin pearls (Figure 10-50D) and intercellular bridges are characteristic. Staining for desmoglein is usually positive.

Populations Predisposed to Pneumonia with Associated Organisms Alcoholism, IV drug use

Streptococcus pneumoniae, Klebsiella, Staphylococcus aureus

Bacterial Causes of Pneumonia Gram-Positive Bacteria

Streptococcus pneumoniae-Gram-positive cocci (chains). Most common cause of community-acquired pneumonia. Treat Penicillins First- and second-generation cephalosporins Macrolides (if penicillin allergic) Quinolones

Nasopharyngeal Carcinoma EBV produces several proteins that modulate growth signaling in B lymphocytes. This property explains why EBV infection can lead to Burkitt lymphoma, Hodgkin lymphoma, or nasopharyngeal carcinoma, in addition to many other lymphoproliferative disorders. PSaMMoma bodies are seen in Papilllary carcinoma of the thyroid Serous papillary cystadenocarcinoma of the ovary Meningioma Malignant mesothelioma

Strong link to Epstein-Barr virus (EBV) infection. EBV infects the host by replicating in the nasopharyngeal epithelium and then infecting nearby tonsillar B lymphocytes. High frequency in the Chinese population

Interstitial Lung Diseases

The restrictive defect is due to abnormalities within the lung parenchyma. It is most commonly due to fibrosis, with the exceptions of ARDS and neonatal respiratory distress syndrome (NRDS), which are discussed below. Because diffusing capacity through the alveolar walls is impaired, A-a gradient is increased.

Palpation

The chest wall can be palpated to check for symmetrical chest wall expansion, tenderness, crepitus, as well as tactile fremitus. The patient's neck can also be palpated to check for tracheal deviation. Refer to Table 10-13 for more details.

Malignancies of the Upper Respiratory Tract Benign Laryngeal Tumors

The most common clinical presentation is hoarseness. ■ Vocal cord nodules: Smooth hemispheric protrusions located on the true vocal cords. These occur chiefly in heavy smokers and singers. ■ Laryngeal papilloma: A benign neoplasm on the true vocal cords that forms a soft, raspberry-like excrescence. Rarely more than 1 cm in diameter. ■ Juvenile laryngeal papillomas: Usually singular in adults but multiple in children. Associated with human papillomavirus types 6 and 11.

PATHOLOGY ON PHYSICAL EXAMINATION Suspect foreign body aspiration in a child who presents with acute onset wheezing.

The pulmonary physical examination has four components: inspection, auscultation, percussion, palpation. This section provides an overview of each component in the context of the USMLE Step 1. The technical aspects of the physical examination are beyond the scope of this text.

PULMONARY VASCULAR DISEASES

The pulmonary vasculature receives the entire cardiac output and is susceptible to a number of disease processes. The four major entities discussed here are deep venous thrombosis (DVT), pulmonary embolism (PE), pulmonary hypertension, and sleep apnea

OBSTRUCTIVE LUNG DISEASES FEV1/FVC ratio < 0.7 is characteristic of obstructive lung disease. While FEV1/ FVC is used to diagnose obstructive lung disease, FEV1 is used to determine the severity of disease.

The three major obstructive disorders are COPD (includes emphysema and chronic bronchitis), asthma, and bronchiectasis. These diseases are characterized by air outflow obstruction (+/− inflow obstruction) and subsequent air trapping within the lungs. Obstruction can occur from the bronchioles to the mainstem bronchi. Spirometry (pulmonary function tests [PFTs]) shows a markedly decreased FEV1 and decreased (although possibly normal) FVC. As such, a decreased FEV1:FVC ratio is the hallmark of obstructive disease. RV is increased because of air trapping. Impaired ventilation results in a decreased V ̇/Q ̇ ratio on ventilation-perfusion scan.

Tenderness

Trauma, costochondritis

NO PGE2 15-HETE

Vasodilation

Tactile fremitus

Vibrations palpated as the patient vocalizes. Detected by placing the ulnar surface of your hands just medial to each of the patient's scapulae and having him/her vocalize. Decreased tactile fremitus: nonspecific (eg, chronic obstructive pulmonary disease, pleural effusion, pneumothorax, atelectasis, thick chest wall) Increased tactile fremitus: lobar pneumonia

CHILDREN (4 WK-18 YR)

Viruses (RSV) Mycoplasma Chlamydia trachomatis (infants−3 yr) Chlamydophila pneumoniae (school-aged children) S pneumonia

Wheezes

Whistling sound. Can be heard during inspiration or expiration. Caused by air passing through narrowed airways. Obstructive diseases: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, foreign body aspiration (FBA)

Mycoplasma, Chlamydia, and Legionella

are commonly referred to as atypical organisms because they cause atypical pneumonia and do not appear on Gram stain. Their special staining and culture requirements are as follows: ■ Mycoplasma—Eaton agar ■ Chlamydia—Giemsa stain ■ Legionella—Charcoal yeast extract agar (buffered with cysteine and iron)

Fremitus

refers to the vibrations transmitted through the body whenever the patient vocalizes. With increased fremitus, transmission of the patient's voice will be louder (vocal fremitus) and vibrations will be stronger (tactile fremitus) on lung auscultation and palpation, respectively.

DIAGNOSIS of Emphysema

■ Physical exam: ■ Thin or cachectic. ■ Leaning forward on extended arms ("tripoding"), using accessory muscles of respiration. ■ Signs of hyperinflation: Resonance to percussion; diminished breath sounds bilaterally. ■ Breathing through pursed lips. This increases pressure within the airways and prevents airway collapse during expiration. ■ Prolonged expiration and associated wheezing on auscultation. ■ Chest film: Barrel-shaped chest due to hyperinflated lungs and flattened diaphragm (Figure 10-35). Classic emphysema (smoking related) has decreased vascular mark- ings (arterial deficiency) in the upper lobes with or without bullae. These changes can be seen in the lower lobes in α1-antitrypsin deficiency. ■ Pulmonary function testing: ■ Spirometry: Decreased FEV1 and FEV1:FVC ratio. FVC is often preserved. ■ Lung volumes: Increased TLC, FRC, and RV due to hyperinflation and air trapping. ■ Diffusing capacity (DLCO): DLCO is directly proportional to the surface area available to participate in gas exchange. Thus, the DLCO is reduced in emphysema due to destruction of alveolar walls and associated capillary beds. ■ Arterial blood gas testing: Early in the disease, Pao2 may be mildly decreased or normal but decreases as alveolar damage progresses. More severely affected patients often chronically retain CO2, resulting in compensated respiratory acidosis (elevated PCO2, elevated HCO3, and slightly decreased pH). During an acute exacerbation, Pao2 drops and Paco2 increases, resulting in acute respiratory acidosis. ■ Pathology: Two major subtypes of emphysema. ■ Panacinar (panlobar) emphysema: Characterized by dilation of the entire acinus (includes the respiratory bronchioles, alveolar ducts, and alveolar sacs). Primarily affects the lower lobes. Associated with α1-antitrypsin deficiency. ■ Centriacinar (centrilobular) emphysema (Figure 10-36): Characterized by dilation of the proximal part of the acinus (the respiratory bronchioles). The pattern of involvement is more irregular and is often localized to the upper parts of the lungs. Associated with smoking.

Two major causes of emphysema: Air resistance decreases with inhalation and increases with exhalation. This difference in resistance explains why it takes longer to fully exhale than it does to fully inhale (normal I:E ratio is 1:2).

■ Smoking: The most significant risk factor across the population for developing emphysema, so significant that those who do not smoke rarely develop emphysema unless an underlying genetic disorder or uncommon environmental exposure is present. Ash particles in cigarette smoke enter alveoli and attract increased numbers of neutrophils and macrophages, which produce elastase. Over time, excess elastase overwhelms local production of α1-antitrypsin. ■ Hereditary α1-antitrypsin deficiency: Autosomal dominant. Accounts for 1% of emphysema cases. Emphysema develops secondary to unopposed elastase activity. Patients with α1-antitrypsin deficiency often develop emphysema at a much younger age than smokers, often younger than 45 years. Air trapping develops in emphysema secondary to loss of radial traction. Radial traction is the outward pull on airway walls by lung interstitium. Normally, as the lungs deflate during expiration, the interstitial tissues pull the airways open (ie, increase radial trac- tion), allowing airflow. In emphysema, radial traction is lost (ability to expire is compromised) as the interstitium is destroyed, leading to airway collapse and subsequent air trapping during expiration. This loss of elastic recoil also explains the prolonged expiration time needed to completely empty the lungs. This increases the overall duration of a single respiratory cycle. Because of the ongoing need to ventilate at a high-enough rate to maintain oxygenation, patients often begin inhaling their next breath before exhaling all of the air from the previous breath. This traps nonventilated air in the lungs. As a result, the volume of trapped air increases over the course of several breaths (dynamic hyperinflation). PRESENTATION ■ Chronic dyspnea with or without cough. Dyspnea and desaturation are often wors- ened by exertion and can be exacerbated by respiratory tract infections, air pollutants, bronchospasm, or CHF. ■ "Pink puffer": Pao2 is well preserved, so patients are not cyanotic ("pink"). Although ventilation and perfusion are both decreased, they are often well matched (alveoli and pulmonary capillaries are destroyed equally), so V ̇/Q ̇ mismatch is not severe. Patients require a high minute ventilation to maintain normal levels of Po2 and Pco2, so they "puff," working hard to get air in. Although this is the classic presentation, many patients do not fit this description.