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InternalMed_Harrison. Advances in computer technology have allowed the development of digital or computed radiography, which has several benefits: (1) immediate availability of the images; (2) significant postprocessing analysis of images to improve diagnostic information; and (3) ability to store images electronically and to transfer them within or between health care systems.


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InternalMed_Harrison. Diagnostic ultrasound (US) produces images using echoes or reflection of the US beam from interfaces between tissues with differing acoustic properties. US is nonionizing and safe to perform on pregnant patients and children. It can detect and localize pleural abnormalities and is a quick and effective way of guiding percutaneous needle biopsy of peripheral lung, pleural, or chest wall lesions. US is also helpful in identifying septations within loculated collections and can facilitate placement of a needle for sampling of pleural liquid (i.e., for thoracentesis), improving the yield and safety of the procedure. Bedside availability makes it valuable in the intensive care setting. Real-time imaging can be used to assess the movement of the diaphragm. Because US energy is rapidly dissipated in air, it is not useful for evaluation of 1664 the pulmonary parenchyma and cannot be used if there is any aerated lung between the US probe and the abnormality of interest. Endobronchial US, in


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InternalMed_Harrison. in air, it is not useful for evaluation of 1664 the pulmonary parenchyma and cannot be used if there is any aerated lung between the US probe and the abnormality of interest. Endobronchial US, in which the US probe is passed through a bronchoscope, is a valuable adjunct to bronchoscopy, allowing identification and localization of pathology adjacent to airway walls or within the mediastinum.


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InternalMed_Harrison. Nuclear imaging depends on the selective uptake of various compounds by organs of the body. In thoracic imaging, these compounds are concentrated by one of three mechanisms: blood pool or compartmentalization (e.g., within the heart), physiologic incorporation (e.g., bone or thyroid) and capillary blockage (e.g., lung scan). Radioactive isotopes can be administered by either the IV or inhaled routes or both. When injected intravenously, albumin macroaggregates labeled with technetium-99m (99mTc) become lodged in pulmonary capillaries; the distribution of the trapped radioisotope follows the distribution of blood flow. When inhaled, radiolabeled xenon gas can be used to demonstrate the distribution of ventilation. Using these techniques, ventilation-perfusion lung scanning was a commonly used technique for the evaluation of pulmonary embolism. Pulmonary thromboembolism produces one or more regions of ventilation-perfusion mismatch (i.e., regions in which there is a defect in perfusion


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InternalMed_Harrison. technique for the evaluation of pulmonary embolism. Pulmonary thromboembolism produces one or more regions of ventilation-perfusion mismatch (i.e., regions in which there is a defect in perfusion that follows the distribution of a vessel and that is not accompanied by a corresponding defect in ventilation [Chap. 300]). However, with advances in computed tomography (CT) scanning, scintigraphic imaging has been largely replaced by CT angiography in patients with suspected pulmonary embolism.


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InternalMed_Harrison. Another common use of ventilation-perfusion scans is in patients with impaired lung function, who are being considered for lung resection. Many patients with bronchogenic carcinoma have coexisting chronic obstructive pulmonary disease (COPD), and the question arises as to whether or not a patient can tolerate lung resection. The distribution of the isotope(s) can be used to assess the regional distribution of blood flow and ventilation, allowing the physician to estimate the level of postoperative lung function. CT offers several advantages over routine chest radiography (Figs. 307-1A, B and 307-2A, B; see also Figs. 315-3, 315-4, and 322-4). First, the use of cross-sectional images allows distinction between densities that would be superimposed on plain radiographs. Second, CT is far better than routine radiographic studies at characterizing tissue density and providing accurate size assessment of lesions.


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InternalMed_Harrison. CT is particularly valuable in assessing hilar and mediastinal disease (often poorly characterized by plain radiography), in identifying and characterizing disease adjacent to the chest wall or spine (including pleural disease), and in identifying areas of fat density or calcification in pulmonary nodules (Fig. 307-2). Its utility in the assessment of mediastinal disease has made CT an important tool in the staging of lung cancer (Chap. 107). With the additional use of contrast material, CT also makes it possible to distinguish vascular from nonvascular structures, which is particularly important in distinguishing lymph nodes and masses from vascular structures primarily in the mediastinum, and vascular disorders such as pulmonary embolism.


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InternalMed_Harrison. In high-resolution CT (HRCT), the thickness of individual cross-sectional images is ~1–2 mm, rather than the usual 7–10 mm in conventional CT. The visible detail on HRCT scans allows better recognition of subtle parenchymal and airway disease, thickened interlobular septa, ground-glass opacification, small nodules, and the abnormally thickened or dilated airways seen in bronchiectasis. Using HRCT, characteristic patterns are recognized for many interstitial lung diseases such as lymphangitic carcinoma, idiopathic pulmonary fibrosis, sarcoidosis, and eosinophilic granuloma. However, there is debate about the settings in which the presence of a characteristic pattern on HRCT eliminates the need for obtaining lung tissue to make a diagnosis. Helical CT and Multidetector CT Helical scanning is currently the standard method for thoracic CT. Helical CT technology results in faster scans with improved contrast enhancement and thinner collimation.


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InternalMed_Harrison. FIGURE 307-1 Chest x-ray (A) and computed tomography (CT) scan (B) from a patient with emphysema. The extent and distribution of emphysema are not well appreciated on plain film but clearly evident on the CT scan obtained. Images are obtained during a single breath-holding maneuver that allows less motion artifact and collection of continuous data over a larger volume of lung than is possible with conventional CT. Data from the imaging procedure can be reconstructed in coronal or sagittal planes (Fig. 307-3A), as well as the traditional cross-sectional (axial) view. Further refinements in detector technology have allowed production of scanners with additional detectors along the scanning axis (z-axis). These multidetector CT (MDCT) scanners can obtain multiple slices in a single rotation that are thinner and can be acquired in a shorter period of time. This results in enhanced resolution and


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InternalMed_Harrison. FIGURE 307-2 Chest x-ray (A) and computed tomography (CT) scan (B) demonstrating a right lower-lobe mass. The mass is not well appreciated on the plain film because of the hilar structures and known calcified adenopathy. CT is superior to plain radiography for the detection of abnormal mediastinal densities and the distinction of masses from adjacent vascular structures. increased image reconstruction ability. As the technology has progressed, higher numbers (currently up to 64) of detectors are used to produce clearer final images. MDCT allows for even shorter breath holds, which are beneficial for all patients but especially children, the elderly, and the critically ill. However, it should be noted that despite the advantages of MDCT, there is an increase in radiation dose compared to single-detector CT to consider.


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InternalMed_Harrison. FIGURE 307-3 Spiral computed tomography (CT) with reconstruction of images in planes other than axial view. Spiral CT in a lung transplant patient with a dehiscence and subsequent aneurysm of the anastomosis. CT images were reconstructed in the sagittal view (A) and using digital subtraction to view images of the airways only (B), which demonstrate the exact location and extent of the abnormality. In MDCT, the additional detectors along the z-axis result in improved use of the contrast bolus. This and the faster scanning times and increased resolution have all led to improved imaging of the pulmonary vasculature and the ability to detect segmental and subsegmental emboli. CT pulmonary angiography (CTPA) also allows simultaneous detection of parenchymal abnormalities that may be contributing to a patient’s clinical presentation. Secondary to these


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InternalMed_Harrison. FIGURE 307-4 Virtual bronchoscopic image of the trachea. The view projected is one that would be obtained from the trachea looking down to the carina. The left and right main stem airways are seen bifurcating from the carina. advantages and increasing availability, CTPA has rapidly become the test of choice for many clinicians in the evaluation of pulmonary embolism; compared with pulmonary angiography, it is considered equal in terms of accuracy and with less associated risks.


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InternalMed_Harrison. The three-dimensional (3D) image of the thorax obtained by MDCT can be digitally stored, reanalyzed, and displayed as 3D reconstructions of the airways down to the sixth to seventh generation. Using these reconstructions, a “virtual” bronchoscopy can be performed (Fig. 307-4). Virtual bronchoscopy has been proposed as an adjunct to conventional bronchoscopy in several clinical situations: It can allow accurate assessment of the extent and length of an airway stenosis, including the airway distal to the narrowing; it can provide useful information about the relationship of the airway abnormality to adjacent mediastinal structures; and it allows preprocedure planning for therapeutic bronchoscopy to help ensure the appropriate equipment is available for the procedure.


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InternalMed_Harrison. Virtual bronchoscopy can be used to help target the area of peripheral lung for endobronchial lung volume reduction surgery that is being used in the management of pulmonary emphysema. The extent of emphysema in each segmental region together with other anatomic details may help in choosing the most appropriate subsegments. However, software packages for the generation of virtual bronchoscopic images are relatively early in development, and their utilization and potential impact on patient care are still unknown. Electromagnetic navigational bronchoscopy systems (EMN or ENB) using virtual bronchoscopy have been developed to allow accurate navigation to peripheral pulmonary target lesions, using technology similar to a car global positioning system (GPS) unit.


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InternalMed_Harrison. Positron emission tomographic (PET) scanning is commonly used to identify malignant lesions in the lung, based on their increased uptake and metabolism of glucose. The technique involves injection of a radiolabeled glucose analogue, [18F]-fluoro-2-deoxyglucose (FDG), which is taken up by metabolically active malignant cells. However, FDG is trapped within the cells following phosphorylation, and the unstable [18F] decays by emission of positrons, which can be detected by a specialized PET camera or by a gamma camera that has been adapted for imaging of positron-emitting nuclides. This technique has been used in the evaluation of solitary pulmonary nodules and in staging lung cancer. Detection or exclusion of mediastinal lymph node involvement and identification of extrathoracic disease can be achieved. The limited anatomical definition of radionuclide imaging has been improved by the development of hybrid imaging that allows the superimposition of PET and CT images, a technique known


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InternalMed_Harrison. be achieved. The limited anatomical definition of radionuclide imaging has been improved by the development of hybrid imaging that allows the superimposition of PET and CT images, a technique known as functional–anatomical mapping. Hybrid PET/CT scans provide images that help pinpoint the abnormal metabolic activity to anatomical structures seen on CT and provide more accurate diagnoses than the two scans performed separately. FDG-PET can differentiate benign from malignant lesions as small as 1 cm. However, false-negative findings can occur in lesions with low metabolic activity such as carcinoid tumors and bronchioloalveolar cell carcinomas, or in lesions <1 cm in which the required threshold of metabolically active malignant cells is not present for PET diagnosis. False-positive results can be seen due to FDG uptake in inflammatory conditions such as pneumonia and granulomatous diseases.


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InternalMed_Harrison. The role of magnetic resonance imaging (MRI) in the evaluation of respiratory system disease is less well-defined than that of CT. Magnetic resonance (MR) provides poorer spatial resolution and less detail of the pulmonary parenchyma and, for these reasons, is currently not considered a substitute for CT in imaging the thorax. However, the use of hyperpolarized gas in conjunction with MR has led to the investigational use of MR for imaging the lungs, particularly in obstructive lung disease. In addition, imaging performed during an inhalation and exhalation can provide dynamic information on lung function. Of note, MR examinations are difficult to obtain among several subgroups of patients. Patients who cannot lie still or who cannot lie on their backs may have MRIs that are of poor quality; some tests require patients to hold their breaths for 15–25 seconds at a time in order to get good MRIs. MRI is generally avoided in unstable and/ or ventilated patients and those with severe


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InternalMed_Harrison. some tests require patients to hold their breaths for 15–25 seconds at a time in order to get good MRIs. MRI is generally avoided in unstable and/ or ventilated patients and those with severe trauma because of the hazards of the MR environment and the difficulties in monitoring patients within the MR room. The presence of metallic foreign bodies, pacemakers, and intracranial aneurysm clips also preclude use of MRI.


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InternalMed_Harrison. An advantage of MR is the use of nonionizing electromagnetic radiation. Additionally, MR is well suited to distinguish vascular from nonvascular structures without the need for contrast. Blood vessels appear as hollow tubular structures because flowing blood does not produce a signal on MRI. Therefore, MR can be useful in demonstrating pulmonary emboli, defining aortic lesions such as aneurysms or dissection, or other vascular abnormalities (Fig. 307-5) if radiation and IV contrast medium cannot be used. Gadolinium can be used as an intravascular contrast agent for MR angiography (MRA); however, synchronization of data acquisition with the peak arterial bolus is one of the major challenges of MRA. The flow of contrast medium from the peripheral injection site to the vessel of interest is affected by a number of factors including heart rate, stroke volume, and the presence of proximal stenotic lesions.


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InternalMed_Harrison. The pulmonary arterial system can be visualized by pulmonary angiography, in which radiopaque contrast medium is injected through a catheter placed in the pulmonary artery. When performed in cases of pulmonary embolism, pulmonary angiography demonstrates the consequences of an intravascular thrombus—either a defect in the lumen of a vessel (a filling defect) or an abrupt termination (cutoff) of the vessel. Other, less common indications for pulmonary angiography include visualization of a suspected pulmonary arteriovenous malformation and assessment of pulmonary arterial invasion by a neoplasm. The risks associated with modern arteriography are small, generally of greatest concern in patients with severe pulmonary hypertension or chronic kidney disease. With advances in CT scanning, MDCT


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InternalMed_Harrison. FIGURE 307-5 Magnetic resonance angiography image of the vasculature of a patient after lung transplant. The image demonstrates the detailed view of the vasculature that can be obtained using digital subtraction techniques. Images from a patient after lung transplant show the venous and arterial anastomosis on the right; a slight narrowing is seen at the site of the anastomosis, which is considered within normal limits and not suggestive of obstruction. angiography (MDCTA) is replacing conventional angiography for the diagnosis of pulmonary embolism.


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InternalMed_Harrison. angiography (MDCTA) is replacing conventional angiography for the diagnosis of pulmonary embolism. Sputum can be collected either by spontaneous expectoration or induced (after inhalation of an irritating aerosol such as hypertonic saline). Sputum induction is used either because sputum is not spontaneously being produced or because of an expected higher yield of certain types of findings. Because sputum consists mainly of secretions from the tracheobronchial tree rather than the upper airway, the finding of alveolar macrophages and other inflammatory cells is consistent with a lower respiratory tract origin of the sample, whereas the presence of squamous epithelial cells in a “sputum” sample indicates contamination by secretions from the upper airways.


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InternalMed_Harrison. In addition to processing for routine bacterial pathogens by Gram’s method and culture, sputum can be processed for a variety of other pathogens, including staining and culture for mycobacteria or fungi, culture for viruses, and staining for Pneumocystis jiroveci. In the specific case of sputum obtained for evaluation of P. jiroveci pneumonia, for example, sputum should be collected by induction rather than spontaneous expectoration, and an immunofluorescent stain should be used to detect the organisms. Traditional stains and cultures are now also being supplemented in some cases by immunologic techniques and by molecular biologic methods, including the use of polymerase chain reaction amplification and DNA probes. Cytologic staining of sputum for malignant cells, using the traditional Papanicolaou method, allows noninvasive evaluation for suspected lung cancer.


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InternalMed_Harrison. A needle can be inserted through the chest wall into a pulmonary lesion to obtain an aspirate or tissue core for cytologic/histologic or micro-biologic analysis. Aspiration can be performed to obtain a diagnosis or to decompress and/or drain a fluid collection. The procedure is usually carried out under CT or ultrasound guidance to assist positioning of the needle and assure localization in the lesion. The low potential risk 1667 of this procedure (intrapulmonary bleeding or creation of a pneumothorax with collapse of the underlying lung) in experienced hands is usually acceptable compared with the information obtained. However, a limitation of the technique is sampling error due to the small size of the tissue sample. Thus, findings other than a specific cytologic or microbiologic diagnosis are of limited clinical value.


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InternalMed_Harrison. Sampling of pleural liquid by thoracentesis is commonly performed for diagnostic purposes or, in the case of a large effusion, for palliation of dyspnea. Diagnostic sampling, either by blind needle aspiration or after localization by US, allows the collection of liquid for micro-biologic and cytologic studies. Analysis of the fluid obtained for its cellular composition and chemical constituents allows classification of the effusion and can help with diagnosis and treatment (Chap. 316).


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InternalMed_Harrison. Bronchoscopy is the process of direct visualization of the tracheobronchial tree. Although bronchoscopy is now performed almost exclusively with flexible fiberoptic instruments, rigid bronchoscopy, generally performed in an operating room on a patient under general anesthesia, still has a role in selected circumstances, primarily because of a larger suction channel and the fact that the patient can be ventilated through the bronchoscope channel. These situations include the retrieval of a foreign body and the suctioning of a massive hemorrhage, for which the small suction channel of the bronchoscope may be insufficient.


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InternalMed_Harrison. This outpatient procedure is usually performed in an awake but sedated patient (conscious sedation). The bronchoscope is passed through either the mouth or the nose, between the vocal cords, and into the trachea. The ability to flex the scope makes it possible to visualize virtually all airways to the level of subsegmental bronchi. The bronchoscopist is able to identify endobronchial pathology, including tumors, granulomas, bronchitis, foreign bodies, and sites of bleeding. Samples from airway lesions can be taken by several methods, including washing, brushing, and biopsy. Washing involves instillation of sterile saline through a channel of the bronchoscope and onto the surface of a lesion. A portion of the liquid is collected by suctioning through the bronchoscope, and the recovered material can be analyzed for cells (cytology) or organisms (by standard stains and cultures). Brushing or biopsy of the surface of the lesion, using a small brush or biopsy forceps at the end of a long


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InternalMed_Harrison. can be analyzed for cells (cytology) or organisms (by standard stains and cultures). Brushing or biopsy of the surface of the lesion, using a small brush or biopsy forceps at the end of a long cable inserted through a channel of the bronchoscope, allows recovery of cellular material or tissue for analysis by standard cytologic and histopathologic methods.


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InternalMed_Harrison. The bronchoscope can be used to sample material not only from the regions that can be directly visualized (i.e., the airways) but also from the more distal pulmonary parenchyma. With the bronchoscope wedged into a subsegmental airway, aliquots of sterile saline can be instilled through the scope, allowing sampling of cells and organisms from alveolar spaces. This procedure, called bronchoalveolar lavage, has been particularly useful for the recovery of organisms such as P. jiroveci.


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InternalMed_Harrison. Brushing and biopsy of the distal lung parenchyma can also be performed with the same instruments that are used for endobronchial sampling. These instruments can be passed through the scope into small airways. When biopsies are performed, the forceps penetrate the airway wall, allowing biopsy of peribronchial alveolar tissue. This procedure, called transbronchial biopsy, is used when there is either relatively diffuse disease or a localized lesion of adequate size. With the aid of fluoroscopic imaging, the bronchoscopist is able to determine not only whether and when the instrument is in the area of abnormality, but also the proximity of the instrument to the pleural surface. If the forceps are too close to the pleural surface, there is a risk of violating the visceral pleura and creating a pneumothorax; the other potential complication of transbronchial biopsy is pulmonary hemorrhage. The incidence of these complications is less than several percent.


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InternalMed_Harrison. 1668 TRANSBRONCHIAL NEEDLE ASPIRATION (TBNA) Another procedure involves use of a hollow-bore needle passed through the bronchoscope for sampling of tissue adjacent to the trachea or a large bronchus. The needle is passed through the airway wall (transbronchial), and cellular material can be aspirated from mass lesions or enlarged lymph nodes, generally in a search for malignant cells. Mediastinoscopy has been considered the gold standard for mediastinal staging; however, transbronchial needle aspiration (TBNA) allows sampling from the lungs and surrounding lymph nodes without the need for surgery or general anesthesia.


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InternalMed_Harrison. Further advances in needle aspiration techniques have been accomplished with the development of endobronchial ultrasound (EBUS). The technology uses an ultrasonic bronchoscope fitted with a probe that allows for needle aspiration of mediastinal and hilar lymph nodes guided by real-time US images. EBUS allows sampling of mediastinal lymph nodes and masses under direct vision to better identify and localize peribronchial and mediastinal pathology and offers access to more difficult-to-reach areas and smaller lymph nodes in the staging of malignancies. EBUS-TBNA has the potential to access the same paratracheal and subcarinal lymph node stations as mediastinoscopy, but also extends out to the hilar lymph nodes (levels 10 and 11). The usefulness of EBUS for clinical indications other than lung cancer is improving and has been recommended in the evaluation of mediastinal masses of unknown origin early in the diagnostic process.


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InternalMed_Harrison. Emerging techniques that can be performed using bronchoscopy include video/autofluorescence bronchoscopy (AFB), narrow band imaging (NBI), optical coherence tomography (OCT), and endomicroscopy using confocal fluorescent laser microscopy (CFM). AFB uses bronchoscopy with an additional light source to screen high-risk individuals and identify premalignant lesions (airway dysplasia) and carcinoma in situ. NBI capitalizes on the increased absorption of blue and green wavelengths of light by hemoglobin to enhance the visibility of vessels of the mucosa and differentiate between inflammatory versus malignant mucosal lesions. CFM uses a blue laser to induce fluorescence, and its high degree of resolution provides a real-time view of living tissue at an almost histologic resolution. OCT uses near-infrared light source and has spatial resolution advantages over CT and MRI. It can penetrate the airway wall up to three times deeper than CFM and is less susceptible to motion artifacts from


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InternalMed_Harrison. near-infrared light source and has spatial resolution advantages over CT and MRI. It can penetrate the airway wall up to three times deeper than CFM and is less susceptible to motion artifacts from cardiac pulsation and respiratory movements. However, careful assessment is required before these methods find a place in the evaluation strategy of early lung cancer and other lung diseases.


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InternalMed_Harrison. The bronchoscope may provide the opportunity for treatment as well as diagnosis. A central role of the interventional pulmonology (IP) physician is the performance of therapeutic bronchoscopy. For example, an aspirated foreign body may be retrieved with an instrument passed through the bronchoscope (either flexible or rigid), and bleeding may be controlled with a balloon catheter similarly introduced. Newer interventional techniques performed through a bronchoscope include methods for achieving and maintaining patency of airways that are partially or completely occluded, especially by tumors. These techniques include laser therapy, cryotherapy, argon plasma coagulation, electrocautery, balloon bronchoplasty and dilation, and stent placement. Many IP physicians are also trained in performing percutaneous tracheotomy.


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InternalMed_Harrison. Medical thoracoscopy (or pleuroscopy) focuses on the diagnosis of pleural-based problems. The procedure is performed with a conventional rigid or a semi-rigid pleuroscope (similar in design to a bronchoscope and enabling the operator to inspect the pleural surface, sample and/or drain pleural fluid, or perform targeted biopsies of the parietal pleura). Medical thoracoscopy can be performed in the endoscopy suite or operating room with the patient under conscious sedation and local anesthesia. In contrast, video-assisted thoracoscopic surgery (VATS) requires general anesthesia and is only performed in the operating room. A common diagnostic indication for medical thoracoscopy is the evaluation of a pleural effusion or biopsy of presumed parietal pleural carcinomatosis. It can also be used to place a chest tube under visual guidance, or perform chemical or talc pleurodesis, a therapeutic intervention to prevent a recurrent pleural effusion (usually malignant) or recurrent pneumothorax.


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InternalMed_Harrison. The increasing availability of advanced bronchoscopic and pleuroscopic techniques has motivated the development of IP programs. IP can be defined as “the art and science of medicine as related to the performance of diagnostic and invasive therapeutic procedures, that which require additional training and expertise beyond that which required in a standard pulmonary medicine training program.” IP physicians provide alternatives to surgery for patients with a wide variety of thoracic disorders and problems. Evaluation and diagnosis of disorders of the chest commonly involve collaboration between pulmonologists and thoracic surgeons. Although procedures such as mediastinoscopy, VATS, and thoracotomy are performed by thoracic surgeons, there is overlap in many minimally invasive techniques that can be performed by a pulmonologist, an interventional pulmonologist, or a thoracic surgeon.


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InternalMed_Harrison. Proper staging of lung cancer is of paramount concern when determining a treatment regimen. Although CT and PET scanning are useful for determining the size and nature of mediastinal lymph nodes as part of the staging of lung cancer, tissue biopsy and histopathologic examination are often critical for the diagnosis of mediastinal masses or enlarged mediastinal lymph nodes. The two major surgical procedures used to obtain specimens from masses or nodes in the mediastinum are mediastinoscopy (via a suprasternal approach) and mediastinotomy (via a parasternal approach). Both procedures are performed under general anesthesia by a qualified surgeon. In the case of suprasternal mediastinoscopy, a rigid mediastinoscope is inserted at the suprasternal notch and passed into the mediastinum along a pathway just anterior to the trachea. Tissue can be obtained with biopsy forceps passed through the scope, sampling masses or nodes that are in a paratracheal or pretracheal position (levels 2R, 2L,


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InternalMed_Harrison. pathway just anterior to the trachea. Tissue can be obtained with biopsy forceps passed through the scope, sampling masses or nodes that are in a paratracheal or pretracheal position (levels 2R, 2L, 3, 4R, 4L). Aortopulmonary lymph nodes (levels 5, 6) are not accessible by this route and thus are commonly sampled by parasternal mediastinotomy (the Chamberlain procedure). This approach involves a parasternal incision and dissection directly down to a mass or node that requires biopsy.


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InternalMed_Harrison. As an alternative to surgery, a bronchoscope can be used to perform TBNA to obtain tissue from the mediastinum, and, when combined with EBUS, can allow access to the same lymph node stations associated with mediastinoscopy, but also extend access out to the hilar lymph nodes (levels 10, 11). Finally, endoscopic ultrasound (EUS)– fine-needle aspiration (FNA) is a second procedure that complements EBUS-FNA in the staging of lung cancer. EUS-FNA is performed via the esophagus and is ideally suited for sampling lymph nodes in the posterior mediastinum (levels 7, 8, 9). Because US imaging cannot penetrate air-filled spaces, the area directly anterior to the trachea cannot accurately be assessed and is a “blind spot” for EUS-FNA. However, EBUS-FNA can visualize the anterior lymph nodes and can complement EUS-FNA. The combination of EUS-FNA and EBUSFNA is a technique that is becoming an alternative to surgery for staging the mediastinum in thoracic malignancies.


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InternalMed_Harrison. VATS has become a standard technique for the diagnosis and management of pleural as well as parenchymal lung disease. This procedure is performed in the operating room using single-lung ventilation with double-lumen endotracheal intubation and involves the passage of a rigid scope with a distal lens through a trocar inserted into the pleura. A high-quality image is shown on a monitor screen, allowing the operator to manipulate instruments passed into the pleural space through separate small intercostal incisions. With these instruments the operator can biopsy lesions of the pleura under direct visualization. In addition, this procedure is now used commonly to biopsy peripheral lung tissue or to remove peripheral nodules for both diagnostic and therapeutic purposes. This much less invasive procedure has largely supplanted the traditional “open lung biopsy” performed via thoracotomy. The decision to use a VATS technique versus performing an open thoracotomy is made by the thoracic


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InternalMed_Harrison. procedure has largely supplanted the traditional “open lung biopsy” performed via thoracotomy. The decision to use a VATS technique versus performing an open thoracotomy is made by the thoracic surgeon and is based on whether a patient can tolerate the single-lung ventilation that is required to allow adequate visualization of the lung. With further advances in instrumentation and experience, VATS can be used to perform procedures previously requiring thoracotomy, including stapled lung biopsy, resection of pulmonary nodules, lobectomy, pneumonectomy, pericardial window, or other standard thoracic surgical procedures, but allows them to be performed in a minimally invasive manner.


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InternalMed_Harrison. Although frequently replaced by VATS, thoracotomy remains an option for the diagnostic sampling of lung tissue. It provides the largest amount of material, and it can be used to biopsy and/or excise lesions 166that are too deep or too close to vital structures for removal by VATS. The choice between VATS and thoracotomy needs to be made on a case-by-case basis. Atlas of Chest Imaging Patricia A. Kritek, John J. Reilly, Jr. This atlas of chest imaging is a collection of interesting chest radiographs and computed tomograms (CTs) of the chest. The readings of the films are meant to be illustrative of specific, major findings. The associated text is not intended as a comprehensive assessment of the images. 308e


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InternalMed_Harrison. FIGURE 308e-1 Normal chest radiograph—review of anatomy. 1. Trachea. 2. Carina. 3. Right atrium. 4. Right hemidiaphragm. 5. Aortic knob. 6. Left hilum. 7. Left ventricle. 8. Left hemidiaphragm (with stomach bubble). 9. Retrosternal clear space. 10. Right ventricle. 11. Left hemidiaphragm (with stomach bubble). 12. Left upper lobe bronchus. FIGURE 308e-2 Normal chest tomogram—note anatomy. 1. Superior vena cava. 2. Trachea. 3. Aortic arch. 4. Ascending aorta. 5. Right mainstem bronchus. 6. Descending aorta. 7. Left mainstem bronchus. 8. Main pulmonary artery. 9. Heart. 10. Esophagus. 11. Pericardium. 12. Descending aorta. CT scan demonstrating left upper lobe collapse. FIGURE 308e-5 Left upper lobe scarring with hilar retraction with less prominent scarring in right upper lobe as well. Findings consistent with previous tuberculosis infection in an immigrant from Ecuador. CHAPTER 308e Atlas of Chest Imaging


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InternalMed_Harrison. CHAPTER 308e Atlas of Chest Imaging The patient was found to have an endobronchial lesion (not visible on the CT scan) resulting in this finding. The superior vena cava (black arrow) is partially opacified by intravenous contrast. FIGURE 308e-4 CT scan revealing chronic left lower lobe collapse. Note dramatic volume loss with minimal aeration. There is subtle mediastinal shift to the left. FIGURE 308e-6 Apical scarring, traction bronchiectasis (red arrow), and decreased lung volume consistent with previous tuberculosis infection. Findings most significant in left lung. FIGURE 308e-7 Chest radiograph demonstrating right upper lobe collapse (yellow arrow). Note the volume loss as demonstrated by the elevated right hemidiaphragm as well as mediastinal shift to the right. Also apparent on the film are an endotracheal tube (red arrow) and a central venous catheter (black arrow).


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InternalMed_Harrison. FIGURE 308e-8 Opacity in the right upper lobe. Note the volume loss as indicated by the elevation of the right hemidiaphragm, eleva-tion of minor fissure (yellow arrow), and deviation of the trachea to the right (blue arrow). FIGURE 308e-9 CT scan of the same right upper lobe opacity. Note the air bronchograms and areas of consolidation. FIGURE 308e-10 Emphysema with increased lucency, flattened diaphragms (black arrows), increased anteroposterior (AP) diameter, and increased retrosternal clear space (red arrow). FIGURE 308e-11 CT scan of diffuse, bilateral emphysema. FIGURE 308e-12 CT scan of bullous emphysema. Atlas of Chest Imaging FIGURE 308e-13 Lymphangioleiomyomatosis—note multiple thin-walled parenchymal cysts.


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InternalMed_Harrison. FIGURE 308e-12 CT scan of bullous emphysema. Atlas of Chest Imaging FIGURE 308e-13 Lymphangioleiomyomatosis—note multiple thin-walled parenchymal cysts. FIGURE 308e-14 Two cavities on posteroanterior (PA) and lateral chest radiograph. Cavities and air-fluid levels identified by red arrows. The smaller cavity is in the right lower lobe (located below the major fissure, identified with the yellow arrow), and the larger cavity is located in the right middle lobe, which is located between the minor (red arrow) and major fissures. There is an associated opacity surrounding the cavity in the right lower lobe. FIGURE 308e-15 CT scan of parenchymal cavity. FIGURE 308e-16 Thick-walled cavitary lung lesions. The mass in the right lung has thick walls and advanced cavitation, whereas the smaller nodule on the left has early cavitary changes (arrow). This patient was diagnosed with Nocardia infection.


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InternalMed_Harrison. FIGURE 308e-17 Mild congestive heart failure. Note the Kerley B lines (black arrow) and perivascular cuffing (yellow arrow) as well as the pulmonary vascular congestion (red arrow). FIGURE 308e-18 Pulmonary edema. Note indistinct vasculature, perihilar opacities, and peripheral interstitial reticular opacities. Although this is an anteroposterior film making cardiac size more difficult to assess, the cardiac silhouette still appears enlarged. CHAPTER 308e Atlas of Chest Imaging FIGURE 308e-19 Chest radiograph demonstrates reticular nodular opacities bilaterally with small lung volumes consistent with usual interstitial pneumonitis (UIP) on pathology. Clinically, UIP is used interchangeably with idiopathic pulmonary fibrosis (IPF).


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InternalMed_Harrison. FIGURE 308e-20 CT scan of usual interstitial pneumonitis (UIP), also known as idiopathic pulmonary fibrosis (IPF). Classic findings include traction bronchiectasis (black arrow) and honeycombing (red arrows). Note subpleural, basilar predominance of the honeycombing. FIGURE 308e-21 A. PA chest film—note presence of paratracheal (blue arrow), aortopulmonary window (yellow arrow), and hilar lymphadenopathy (purple arrows). B. Lateral film—note hilar lymphadenopathy (purple arrow). FIGURE 308e-22 Sarcoid—CT scan of stage I demonstrating bulky hilar and mediastinal lymphadenopathy (red arrows). 4.86 mm‡ A FIGURE 308e-23 Sarcoid—chest radiograph of stage II. A. PA film with hilar lymphadenopathy (black arrows) and parenchymal changes. B. Lateral film with hilar adenopathy (black arrow) and parenchymal changes. FIGURE 308e-24 Sarcoid—CT scan of stage II (calcified lymphade tracking along bronchovascular bundles). nopathy, parenchymal infiltrates).


InternalMed_Harrison

InternalMed_Harrison. FIGURE 308e-24 Sarcoid—CT scan of stage II (calcified lymphade tracking along bronchovascular bundles). nopathy, parenchymal infiltrates). CHAPTER 308e Atlas of Chest Imaging FIGURE 308e-26 Sarcoid—stage IV with fibrotic lung disease and cavitary areas (yellow arrow). FIGURE 308e-27 Right middle lobe opacity illustrates major (black arrow) and minor fissures (red arrows) as well as the “silhouette sign” on the right heart border. The silhouette sign is the loss of clear demarcation between normal lung and soft tissue (e.g., heart, diaphragm). This occurs when the lung parenchyma is no longer filled with air and the contrast between air and soft tissue is lost. FIGURE 308e-28 Right lower lobe pneumonia—subtle opacity on PA film (red arrow), while the lateral film illustrates the “spine sign” (black arrow) where the lower spine does not become more lucent.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 308e-28 Right lower lobe pneumonia—subtle opacity on PA film (red arrow), while the lateral film illustrates the “spine sign” (black arrow) where the lower spine does not become more lucent. FIGURE 308e-30 Chest radiograph reveals diffuse, bilateral alveolar opacities without pleural effusions, consistent with acute respiratory distress syndrome (ARDS). Note that the patient has an endotracheal tube (red arrow) and a central venous catheter (black arrow). FIGURE 308e-29 CT scan of diffuse, bilateral “ground-glass” opacities. This finding is consistent with fluid density in the alveolar space. FIGURE 308e-31 CT scan of ARDS demonstrates “ground-glass” opacities with more consolidated areas in the dependent lung zones. Atlas of Chest Imaging FIGURE 308e-32 Three examples of air bronchograms (red arrows) on chest CT. BRONCHIECTASIS AND AIRWAY ABNORMALITIES FIGURE 308e-33 Cystic fibrosis with bronchiectasis, apical disease.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 308e-32 Three examples of air bronchograms (red arrows) on chest CT. BRONCHIECTASIS AND AIRWAY ABNORMALITIES FIGURE 308e-33 Cystic fibrosis with bronchiectasis, apical disease. FIGURE 308e-34 CT scan of diffuse, cystic bronchiectasis (red arrows) in a patient with cystic fibrosis. FIGURE 308e-35 CT scan of focal right middle lobe and lingular bronchiectasis (yellow arrows). Note that there is near total collapse of the right middle lobe (red arrow). FIGURE 308e-36 “Tree in bud” opacities (red arrows) and bronchiectasis (yellow arrow) consistent with atypical mycobacterial infection. “Tree in bud” refers to small nodules clustered around the centrilobular arteries as well as increased prominence of the centrilobular branching. These findings are consistent with bronchiolitis. FIGURE 308e-37 CT scan demonstrating tracheomalacia (yellow arrow). Tracheomalacia is dynamic collapse of the trachea, most prominent during exhalation, due to loss of cartilaginous support.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 308e-37 CT scan demonstrating tracheomalacia (yellow arrow). Tracheomalacia is dynamic collapse of the trachea, most prominent during exhalation, due to loss of cartilaginous support. FIGURE 308e-38 Large right pneumothorax with near complete collapse of right lung. Pleural reflection highlighted with red arrows. CHAPTER 308e Atlas of Chest Imaging FIGURE 308e-39 Basilar pneumothorax with visible pleural reflection (red arrows). Also note, patient has subcutaneous emphysema (yellow arrow). FIGURE 308e-40 CT scan of large right-sided pneumothorax. Note significant collapse of right lung with adhesion to anterior chest wall. Pleural reflection highlighted with red arrows. The patient has severe underlying emphysema.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 308e-41 Small right pleural effusion (red arrows highlight blunted right costophrenic angles) with associated pleural thickening. Note fluid in the major fissure (black arrow) visible on the lateral film as well as the meniscus of the right pleural effusion. FIGURE 308e-42 Left pleural effusion with clear meniscus seen on both PA and lateral chest radiographs. FIGURE 308e-43 Asbestosis. Note calcified pleural plaques (red arrows), pleural thickening (black arrow), and subpleural atelectasis (green arrows). CHAPTER 308e Atlas of Chest Imaging FIGURE 308e-44 Left upper lobe mass, which biopsy revealed to be squamous cell carcinoma. FIGURE 308e-45 Solitary pulmonary nodule on the right (red arrow) with a spiculated pattern concerning for lung cancer. Note also that the patient is status post left upper lobectomy with resultant volume loss and associated effusion (black arrow).


InternalMed_Harrison

InternalMed_Harrison. FIGURE 308e-47 Left lower lobe lung mass (red arrow) abutting pleura. Biopsy demonstrated small-cell lung cancer. FIGURE 308e-46 Metastatic sarcoma. Note the multiple, well-circumscribed nodules of different size. FIGURE 308e-48 CT scan of soft tissue mass encircling the trachea (red arrow) and invading tracheal lumen. Biopsy demonstrated ade-noid cystic carcinoma (cylindroma). FIGURE 308e-49 Mycetoma. Fungal ball (red arrow) growing in preexisting cavity on the left. Right upper lobe has a large bulla (black arrow). FIGURE 308e-50 Pulmonary arteriovenous malformation (AVM) demonstrated on reformatted CT angiogram (red arrow). CHAPTER 308e Atlas of Chest Imaging FIGURE 308e-51 Large bilateral pulmonary emboli (intravascular filling defects in contrast scan identified by red arrows). FIGURE 308e-52 Chest radiograph of a patient with severe pulmonary hypertension. Note the enlarged pulmonary arteries (red arrows) visible on both PA and lateral films.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 308e-52 Chest radiograph of a patient with severe pulmonary hypertension. Note the enlarged pulmonary arteries (red arrows) visible on both PA and lateral films. FIGURE 308e-53 CT scan of the same patient as in Fig. 308e-52. Note the markedly enlarged pulmonary arteries (red arrow).


InternalMed_Harrison

InternalMed_Harrison. FIGURE 308e-53 CT scan of the same patient as in Fig. 308e-52. Note the markedly enlarged pulmonary arteries (red arrow). asthma Peter J. Barnes Asthma is a syndrome characterized by airflow obstruction that varies markedly, both spontaneously and with treatment. Asthmatics harbor a special type of inflammation in the airways that makes them more responsive than nonasthmatics to a wide range of triggers, leading to 309 SeCtion 2 excessive narrowing with consequent reduced airflow and symptomatic wheezing and dyspnea. Narrowing of the airways is usually reversible, but in some patients with chronic asthma there may be an element of irreversible airflow obstruction. The increasing global prevalence of asthma, the large burden it now imposes on patients, and the high health care costs have led to extensive research into its mechanisms and treatment.


InternalMed_Harrison

InternalMed_Harrison. Asthma is one of the most common chronic diseases globally and currently affects approximately 300 million people worldwide. The prevalence of asthma has risen in affluent countries over the last 30 years but now appears to have stabilized, with approximately 10–12% of adults and 15% of children affected by the disease. In developing countries where the prevalence of asthma had been much lower, there is a rising prevalence, which is associated with increased urbanization. The prevalence of atopy and other allergic diseases has also increased over the same time, suggesting that the reasons for the increase are likely to be systemic rather than confined to the lungs. Most patients with asthma in affluent countries are atopic, with allergic sensitization to the house dust mite Dermatophagoides pteronyssinus and other environmental allergens, such as animal fur and pollens.


InternalMed_Harrison

InternalMed_Harrison. Asthma can present at any age, with a peak age of 3 years. In childhood, twice as many males as females are asthmatic, but by adulthood the sex ratio has equalized. Long-term studies that have followed children until they reach the age of 40 years suggest that many with asthma become asymptomatic during adolescence but that asthma returns in some during adult life, particularly in those with persistent symptoms and severe asthma. Adults with asthma, including those with onset during adulthood, rarely become permanently asymptomatic. The severity of asthma does not vary significantly within a given patient; those with mild asthma rarely progress to more severe disease, whereas those with severe asthma usually have severe disease at the onset.


InternalMed_Harrison

InternalMed_Harrison. Deaths from asthma are uncommon, and in many affluent countries have been steadily declining over the last decade. A rise in asthma mortality seen in several countries during the 1960s was associated with increased use of short-acting inhaled β2-adrenergic agonists (as rescue therapy), but there is now compelling evidence that the more widespread use of inhaled corticosteroids (ICS) in patients with persistent asthma is responsible for the decrease in mortality in recent years. Major risk factors for asthma deaths are poorly controlled disease with frequent use of bronchodilator inhalers, lack of or poor compliance with ICS therapy, and previous admissions to hospital with near-fatal asthma. It has proved difficult to agree on a definition of asthma, but there is good agreement on the description of the clinical syndrome and disease pathology. Until the etiologic mechanisms of the disease are better understood, it will be difficult to provide an accurate definition.


InternalMed_Harrison

InternalMed_Harrison. Asthma is a heterogeneous disease with interplay between genetic and environmental factors. Several risk factors that predispose to asthma have been identified (Table 309-1). These should be distinguished from triggers, which are environmental factors that worsen asthma in a patient with established disease. Atopy Atopy is the major risk factor for asthma, and nonatopic individuals have a very low risk of developing asthma. Patients with asthma commonly suffer from other atopic diseases, particularly allergic rhinitis, which may be found in over 80% of asthmatic patients, and atopic dermatitis (eczema). Atopy may be found in 40–50% of the population in affluent countries, with only a proportion of atopic Drugs (β blockers, aspirin)


InternalMed_Harrison

InternalMed_Harrison. Drugs (β blockers, aspirin) Irritants (household sprays, paint fumes) individuals becoming asthmatic. This observation suggests that some other environmental or genetic factor(s) predispose to the development of asthma in atopic individuals. The allergens that lead to sensitization are usually proteins that have protease activity, and the most common allergens are derived from house dust mites, cat and dog fur, cockroaches (in inner cities), grass and tree pollens, and rodents (in laboratory workers). Atopy is due to the genetically determined production of specific IgE antibody, with many patients showing a family history of allergic diseases.


InternalMed_Harrison

InternalMed_Harrison. Genetic Predisposition The familial association of asthma and a high degree of concordance for asthma in identical twins indi cate a genetic predisposition to the disease; however, whether or not the genes predisposing to asthma are similar or in addition to those predisposing to atopy is not yet clear. It now seems likely that different genes may also contribute to asthma specifically, and there is increasing evidence that the severity of asthma is also genetically determined. Genetic screens with classical linkage analysis and single-nucleotide polymorphisms of various candidate genes indicate that asthma is polygenic, with each gene identified having a small effect that is often not replicated in different populations. This observation suggests that the interaction of many genes is important, and these may differ in different populations. The most consistent findings have been associations with polymorphisms of genes on chromosome 5q, including the T helper 2 (TH2) cells


InternalMed_Harrison

InternalMed_Harrison. is important, and these may differ in different populations. The most consistent findings have been associations with polymorphisms of genes on chromosome 5q, including the T helper 2 (TH2) cells interleukin (IL)-4, IL-5, IL-9, and IL-13, which are associated with atopy. There is increasing evidence for a complex interaction between genetic polymorphisms and environmental factors that will require very large population studies to unravel. Novel genes that have been associated with asthma, including ADAM-33, and DPP-10, have also been identified by positional cloning, but their function in disease pathogenesis is not yet clear. Recent genome-wide association studies have identified further novel genes, such as ORMDL3, although their functional role is not yet clear. Genetic polymorphisms may also be important in determining the response to asthma therapy. For example, the Arg-Gly-16 variant in the β2-receptor has been associated with reduced response to β2-agonists, and repeats of an


InternalMed_Harrison

InternalMed_Harrison. may also be important in determining the response to asthma therapy. For example, the Arg-Gly-16 variant in the β2-receptor has been associated with reduced response to β2-agonists, and repeats of an Sp1 recognition sequence in the promoter region of 5-lipoxygenase may affect the response to antileukotrienes. However, these effects are small and inconsistent and do not yet have any implications for asthma therapy.


InternalMed_Harrison

InternalMed_Harrison. It is likely that environmental factors in early life determine which atopic individuals become asthmatic. The increasing prevalence of asthma, particularly in developing countries, over the last few decades also indicates the importance of environmental mechanisms interacting with a genetic predisposition. Infections Although viral infections (especially rhinovirus) are common triggers of asthma exacerbations, it is uncertain whether they play a role in etiology. There is some association between respiratory syncytial virus infection in infancy and the development of asthma, but the specific pathogenesis is difficult to elucidate because this infection is very common in children. Atypical bacteria, such as Mycoplasma and Chlamydophila, have been implicated in the mechanism of severe asthma, but thus far, the evidence is not very convincing of a true association.


InternalMed_Harrison

InternalMed_Harrison. The observation that allergic sensitization and asthma were less common in children with older siblings first suggested that lower levels of infection may be a factor in affluent societies that increase the risks of asthma. This “hygiene hypothesis” proposes that lack of infections in early childhood preserves the TH2 cell bias at birth, whereas exposure to infections and endotoxin results in a shift toward a predominant protective TH1 immune response. Children brought up on farms who are exposed to a high level of endotoxin are less likely to develop allergic sensitization than children raised on dairy farms. Intestinal parasite infection, such as hookworm, may also be associated with a reduced risk of asthma. Although there is considerable epidemiologic support for the hygiene hypothesis, it cannot account for the parallel increase in TH1-driven diseases such as diabetes mellitus over the same period.


InternalMed_Harrison

InternalMed_Harrison. Diet The role of dietary factors is controversial. Observational studies have shown that diets low in antioxidants such as vitamin C and vitamin A, magnesium, selenium, and omega-3 polyunsaturated fats (fish oil) or high in sodium and omega-6 polyunsaturated fats are associated with an increased risk of asthma. Vitamin D deficiency may also predispose to the development of asthma. However, interventional studies with supplementary diets have not supported an important role for these dietary factors. Obesity is also an independent risk factor for asthma, particularly in women, but the mechanisms are thus far unknown.


InternalMed_Harrison

InternalMed_Harrison. Air Pollution Air pollutants, such as sulfur dioxide, ozone, and diesel particulates, may trigger asthma symptoms, but the role of different air pollutants in the etiology of the disease is much less certain. Most evidence argues against an important role for air pollution because asthma is no more prevalent in cities with a high ambient level of traffic pollution than in rural areas with low levels of pollution. Asthma had a much lower prevalence in East Germany compared to West Germany despite a much higher level of air pollution, but since reunification, these differences have decreased as eastern Germany has become more affluent. Indoor air pollution may be more important with exposure to nitrogen oxides from cooking stoves and exposure to passive cigarette smoke. There is some evidence that maternal smoking is a risk factor for asthma, but it is difficult to dissociate this association from an increased risk of respiratory infections.


InternalMed_Harrison

InternalMed_Harrison. Allergens Inhaled allergens are common triggers of asthma symptoms and have also been implicated in allergic sensitization. Exposure to house dust mites in early childhood is a risk factor for allergic sensitization and asthma, but rigorous allergen avoidance has not shown any evidence for a reduced risk of developing asthma. The increase in house dust mites in centrally heated poorly ventilated homes with fitted carpets has been implicated in the increasing prevalence of asthma in affluent countries. Domestic pets, particularly cats, have also been associated with allergic sensitization, but early exposure to cats in the home may be protective through the induction of tolerance.


InternalMed_Harrison

InternalMed_Harrison. Occupational Exposure Occupational asthma is relatively common and may affect up to 10% of young adults. Over 300 sensitizing agents have been identified. Chemicals such as toluene diisocyanate and trimellitic anhydride, may lead to sensitization independent of atopy. Individuals may also be exposed to allergens in the workplace such as small animal allergens in laboratory workers and fungal amylase in wheat flour in bakers. Occupational asthma may be suspected when symptoms improve during weekends and holidays. Obesity Asthma occurs more frequently in obese people (body mass index >30 kg/m2) and is often more difficult to control. Although mechanical factors may contribute, it may also be linked to the pro-inflammatory adipokines and reduced anti-inflammatory adipokines that are released from fat stores.


InternalMed_Harrison

InternalMed_Harrison. Other Factors Several other factors have been implicated in the etiology of asthma, including lower maternal age, duration of breast-feeding, prematurity and low birthweight, and inactivity, but are unlikely to contribute to the recent global increase in asthma prevalence. There is also an association with acetaminophen (paracetamol) consumption in childhood, which may be linked to increased oxidative stress.


InternalMed_Harrison

InternalMed_Harrison. Intrinsic Asthma A minority of asthmatic patients (approximately 10%) have negative skin tests to common inhalant allergens and normal serum concentrations of IgE. These patients, with nonatopic or intrinsic asthma, usually show later onset of disease (adult-onset asthma), commonly have concomitant nasal polyps, and may be aspirin-sensitive. They usually have more severe, persistent asthma. Little is understood about mechanism, but the immunopathology in bronchial biopsies and sputum appears to be identical to that found in atopic asthma. There is recent evidence for increased local production of IgE in the airways, suggesting that there may be common IgEmediated mechanisms; staphylococcal enterotoxins, which serve as “superantigens,” have been implicated.


InternalMed_Harrison

InternalMed_Harrison. Asthma Triggers Several stimuli trigger airway narrowing, wheezing, and dyspnea in asthmatic patients. Although a previous view held that these stimuli should be avoided, the triggering of asthma by these stimuli is now seen as evidence for poor control and an indicator of the need to increase controller (preventive) therapy.


InternalMed_Harrison

InternalMed_Harrison. ALLERGENS Inhaled allergens activate mast cells with bound IgE directly leading to the immediate release of bronchoconstrictor mediators, resulting in the early response that is reversed by bronchodilators. Often, experimental allergen challenge is followed by a late response when there is airway edema and an acute inflammatory response with increased eosinophils and neutrophils that are not very reversible with bronchodilators. The most common allergens to trigger asthma are Dermatophagoides species, and environmental exposure leads to low-grade chronic symptoms that are perennial. Other perennial allergens are derived from cats and other domestic pets, as well as cockroaches. Other allergens, including grass pollen, ragweed, tree pollen, and fungal spores, are seasonal. Pollens usually cause allergic rhinitis rather than asthma, but in thunderstorms, the pollen grains are disrupted and the particles that may be released can trigger severe asthma exacerbations (thunderstorm asthma).


InternalMed_Harrison

InternalMed_Harrison. VIRUS INFECTIONS Upper respiratory tract virus infections such as rhinovirus, respiratory syncytial virus, and coronavirus are the most common triggers of acute severe exacerbations and may invade epithelial cells of the lower as well as the upper airways. The mechanism whereby these viruses cause exacerbations is poorly understood, but there is an increase in airway inflammation with increased numbers of eosinophils and neutrophils. There is evidence for reduced production of type I interferons by epithelial cells from asthmatic patients, resulting in increased susceptibility to these viral infections and a greater inflammatory response.


InternalMed_Harrison

InternalMed_Harrison. PHARMACOLOGIC AGENTS Several drugs may trigger asthma. Betaadrenergic blockers commonly acutely worsen asthma, and their use may be fatal. The mechanisms are not clear, but are likely mediated through increased cholinergic bronchoconstriction. All β blockers need to be avoided, and even selective β2 blockers or topical application (e.g., timolol eye drops) may be dangerous. Angiotensin-converting enzyme inhibitors are theoretically detrimental as they inhibit breakdown of kinins, which are bronchoconstrictors; however, they rarely worsen asthma, and the characteristic cough is no more frequent in asthmatics than in nonasthmatics. Aspirin may worsen asthma in some patients (aspirin-sensitive asthma is discussed below under “Special Considerations”).


InternalMed_Harrison

InternalMed_Harrison. EXERCISE Exercise is a common trigger of asthma, particularly in children. The mechanism is linked to hyperventilation, which results in increased osmolality in airway lining fluid and triggers mast cell 1671 mediator release, resulting in bronchoconstriction. Exercise-induced asthma (EIA) typically begins after exercise has ended and resolves spontaneously within about 30 min. EIA is worse in cold, dry climates than in hot, humid conditions. It is, therefore, more common in sports activities such as cross-country running in cold weather, overland skiing, and ice hockey than in swimming. It may be prevented by prior administration of β2-agonists and antileukotrienes, but is best prevented by regular treatment with ICSs, which reduce the population of surface mast cells required for this response.


InternalMed_Harrison

InternalMed_Harrison. PHYSICAL FACTORS Cold air and hyperventilation may trigger asthma through the same mechanisms as exercise. Laughter may also be a trigger. Many patients report worsening of asthma in hot weather and when the weather changes. Some asthmatics become worse when exposed to strong smells or perfumes, but the mechanism of this response is uncertain.


InternalMed_Harrison

InternalMed_Harrison. FOOD AND DIET There is little evidence that allergic reactions to food lead to increased asthma symptoms, despite the belief of many patients that their symptoms are triggered by particular food constituents. Exclusion diets are usually unsuccessful at reducing the frequency of episodes. Some foods such as shellfish and nuts may induce anaphylactic reactions that may include wheezing. Patients with aspirin-induced asthma may benefit from a salicylate-free diet, but these are difficult to maintain. Certain food additives may trigger asthma. Metabisulfite, which is used as a food preservative, may trigger asthma through the release of sulfur dioxide gas in the stomach. Tartrazine, a yellow food- coloring agent, was believed to be a trigger for asthma, but there is little convincing evidence for this. AIR POLLUTION Increased ambient levels of sulfur dioxide, ozone, and nitrogen oxides are associated with increased asthma symptoms.


InternalMed_Harrison

InternalMed_Harrison. AIR POLLUTION Increased ambient levels of sulfur dioxide, ozone, and nitrogen oxides are associated with increased asthma symptoms. OCCUPATIONAL FACTORS Several substances found in the workplace may act as sensitizing agents, as discussed above, but may also act as triggers of asthma symptoms. Occupational asthma is characteristically associated with symptoms at work with relief on weekends and holidays. If removed from exposure within the first 6 months of symptoms, there is usually complete recovery. More persistent symptoms lead to irreversible airway changes, and thus, early detection and avoidance are important.


InternalMed_Harrison

InternalMed_Harrison. HORMONES Some women show premenstrual worsening of asthma, which can occasionally be very severe. The mechanisms are not completely understood, but are related to a fall in progesterone and in severe cases may be improved by treatment with high doses of progesterone or gonadotropin-releasing factors. Thyrotoxicosis and hypothyroidism can both worsen asthma, although the mechanisms are uncertain. GASTROESOPHAGEAL REFLUX Gastroesophageal reflux is common in asthmatic patients because it is increased by bronchodilators. Although acid reflux might trigger reflex bronchoconstriction, it rarely causes asthma symptoms, and antireflux therapy usually fails to reduce asthma symptoms in most patients. STRESS Many asthmatics report worsening of symptoms with stress. Psychological factors can induce bronchoconstriction through cholinergic reflex pathways. Paradoxically, very severe stress such as bereavement usually does not worsen, and may even improve, asthma symptoms.


InternalMed_Harrison

InternalMed_Harrison. Asthma is associated with a specific chronic inflammation of the mucosa of the lower airways. One of the main aims of treatment is to reduce this inflammation.


InternalMed_Harrison

InternalMed_Harrison. Pathology The pathology of asthma has been revealed through examining the lungs of patients who have died of asthma and from bronchial biopsies. The airway mucosa is infiltrated with activated eosinophils and T lymphocytes, and there is activation of mucosal mast cells. The degree of inflammation is poorly related to disease 1672 severity and may even be found in atopic patients without asthma symptoms. This inflammation is usually reduced by treatment with ICS. There are also structural changes in the airways (described as remodeling). A characteristic finding is thickening of the basement membrane due to subepithelial collagen deposition. This feature is also found in patients with eosinophilic bronchitis presenting as cough who do not have asthma and is, therefore, likely to be a marker of eosinophilic inflammation in the airway as eosinophils release fibrogenic mediators. The epithelium is often shed or friable, with reduced attachments to the airway wall and increased numbers of


InternalMed_Harrison

InternalMed_Harrison. of eosinophilic inflammation in the airway as eosinophils release fibrogenic mediators. The epithelium is often shed or friable, with reduced attachments to the airway wall and increased numbers of epithelial cells in the lumen. The airway wall itself may be thickened and edematous, particularly in fatal asthma. Another common finding in fatal asthma is occlusion of the airway lumen by a mucous plug, which is comprised of mucous glycoproteins secreted from goblet cells and plasma proteins from leaky bronchial vessels (Fig. 309-1). There is also vasodilation and increased numbers of blood vessels (angiogenesis). Direct observation by bronchoscopy indicates that the airways may be narrowed, erythematous, and edematous. The pathology of asthma is remarkably uniform in different phenotypes of asthma, including atopic (extrinsic), nonatopic (intrinsic), occupational, aspirin-sensitive, and pediatric asthma. These pathologic changes are found in all airways, but do not extend to the lung


InternalMed_Harrison

InternalMed_Harrison. of asthma, including atopic (extrinsic), nonatopic (intrinsic), occupational, aspirin-sensitive, and pediatric asthma. These pathologic changes are found in all airways, but do not extend to the lung parenchyma; peripheral airway inflammation is found particularly in patients with severe asthma. The involvement of airways may be patchy, and this is consistent with bronchographic findings of uneven narrowing of the airways.


InternalMed_Harrison

InternalMed_Harrison. Airway Inflammation There is inflammation in the respiratory mucosa from the trachea to terminal bronchioles, but with a predominance in the bronchi (cartilaginous airways); however, it is still uncertain as to how inflammatory cells interact and how inflammation translates into the symptoms of asthma (Fig. 309-2). There is good evidence that the specific pattern of airway inflammation in asthma is associated with airway hyperresponsiveness (AHR), the physiologic abnormality of asthma, which is correlated with variable airflow obstruction. The pattern of inflammation in asthma is characteristic of allergic diseases, with similar inflammatory cells seen in the nasal mucosa in rhinitis. However, an indistinguishable pattern of inflammation is found in intrinsic asthma, and this may reflect local rather than systemic IgE production. Although most attention has focused on the acute inflammatory changes seen in asthma, this is a chronic condition, with inflammation persisting over many


InternalMed_Harrison

InternalMed_Harrison. local rather than systemic IgE production. Although most attention has focused on the acute inflammatory changes seen in asthma, this is a chronic condition, with inflammation persisting over many years in most patients. The mechanisms involved in persistence of inflammation in asthma are still poorly understood. Superimposed on this chronic inflammatory state are acute inflammatory episodes, which correspond to exacerbations of asthma. Although the common pattern of inflammation in asthma is characterized by eosinophil infiltration, some patients with severe asthma show a neutrophilic pattern of inflammation that is less sensitive to corticosteroids. However, many inflammatory cells are involved in asthma with no key cell that is predominant (Fig. 309-3).


InternalMed_Harrison

InternalMed_Harrison. MAST CELLS Mast cells are important in initiating the acute bronchoconstrictor responses to allergens and several other indirectly acting stimuli, such as exercise and hyperventilation (via osmolality changes), as well as fog. Activated mucosal mast cells are found at the airway surface in asthma patients and also in the airway smooth-muscle layer, whereas this is not seen in normal subjects or patients with eosinophilic bronchitis. Mast cells are activated by allergens through an IgE-dependent mechanism, and binding of specific IgE to mast cells renders them more sensitive to activation by physical stimuli such as osmolality. The importance of IgE in the pathophysiology of asthma has been highlighted by clinical studies with humanized anti-IgE antibodies, which inhibit IgE-mediated effects, reduce asthma symptoms, and reduce exacerbations. There are, however, uncertainties about the role of mast cells in more chronic allergic inflammatory events. Mast cells release several


InternalMed_Harrison

InternalMed_Harrison. effects, reduce asthma symptoms, and reduce exacerbations. There are, however, uncertainties about the role of mast cells in more chronic allergic inflammatory events. Mast cells release several bronchoconstrictor mediators, including histamine, prostaglandin D2, and cysteinyl-leukotrienes, but also several cytokines, chemokines, growth factors, and neurotrophins.


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InternalMed_Harrison. FIGURE 309-1 Histopathology of a small airway in fatal asthma. The lumen is occluded with a mucous plug, there is goblet cell metaplasia, and the airway wall is thickened, with an increase in basement membrane thickness and airway smooth muscle. (Courtesy of Dr. J. Hogg, University of British Colombia.)


InternalMed_Harrison

InternalMed_Harrison. MACROPHAGES AND DENDRITIC CELLS Macrophages, which are derived from blood monocytes, may traffic into the airways in asthma and may be activated by allergens via low-affinity IgE receptors (FcεRII). Macrophages have the capacity to initiate a type of inflammatory response via the release of a certain pattern of cytokines, but these cells also release anti-inflammatory mediators (e.g., IL-10), and thus, their roles in asthma are uncertain. Dendritic cells are specialized macrophage-like cells in the airway epithelium, which are the major antigen-presenting cells. Dendritic cells take up allergens, process them to peptides, and migrate to local lymph nodes where they present the allergenic peptides to uncommitted T lymphocytes to program the production of allergen-specific T cells. Immature dendritic cells in the respiratory tract promote TH2 cell differentiation and require cytokines, such as IL-12 and tumor necrosis factor α (TNF-α), to promote the normally preponderant TH1 response.


InternalMed_Harrison

InternalMed_Harrison. dendritic cells in the respiratory tract promote TH2 cell differentiation and require cytokines, such as IL-12 and tumor necrosis factor α (TNF-α), to promote the normally preponderant TH1 response. The cytokine thymic stromal lymphopoietin (TSLP) released from epithelial cells in asthmatic patients instructs dendritic cells to release chemokines that attract TH2 cells into the airways.


InternalMed_Harrison

InternalMed_Harrison. Allergens Sensitizers Viruses Air pollutants? InflammationChronic eosinophilic bronchitis SymptomsCough Wheeze Chest tightness Dyspnea TriggersAllergens Exercise Cold air SO2 Particulates Airwayhyperresponsiveness FIGURE 309-2 Inflammation in the airways of asthmatic patients leads to airway hyperresponsiveness and symptoms. SO2, sulfur dioxide. Allergen bronchial biopsies have demonstrated a 1673 preponderance of natural killer CD4+ T lymphocytes that express high levels of IL-4. Regulatory T cells play an important role in determining the expression of other T cells, and there is evidence for a reduction in a certain subset of regulatory T cells (CD4+CD25+) in asthma that is associated with increased TH2 cells. Recently, innate T cells (ILC2) without T cell receptors have been identified that release TH2 cytokines and are Eosinophil Neutrophil regulated by epithelial cytokines, such as IL-25 and IL-33. STRUCTURAL CELLS Structural cells of the


InternalMed_Harrison

InternalMed_Harrison. Eosinophil Neutrophil regulated by epithelial cytokines, such as IL-25 and IL-33. STRUCTURAL CELLS Structural cells of the Epithelial airways, including epithelial cells, fibroshedding blasts, and airway smooth-muscle cells, are also important sources of inflam- Nerve activation matory mediators, such as cytokines and lipid mediators, in asthma. Indeed, because structural cells far outnumber Subepithelial fibrosis inflammatory cells, they may become the major sources of mediators driv-Plasma leak Myofibroblast airways. In addition, epithelial cells may inflammatory response and are probably major target cells for ICS. Brochoconstriction asthma, and they may have a variety of effects on the airways that account for the pathologic features of asthma (Fig. FIGURE 309-3 The pathophysiology of asthma is complex with participation of several interact 309-4). Mediators such as histamine, pros ing inflammatory cells, which result in acute and chronic inflammatory effects on the airway.


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InternalMed_Harrison. EOSINOPHILS Eosinophil infiltration is a characteristic feature of asthmatic airways. Allergen inhalation results in a marked increase in activated eosinophils in the airways at the time of the late reaction. Eosinophils are linked to the development of AHR through the release of basic proteins and oxygen-derived free radicals. Eosinophil recruitment involves adhesion of eosinophils to vascular endothelial cells in the airway circulation due to interaction between adhesion molecules, migration into the submucosa under the direction of chemokines, and their subsequent activation and prolonged survival. Blocking antibodies to IL-5 causes a profound and prolonged reduction in circulating and sputum eosinophils, but is not associated with reduced AHR or asthma symptoms, although in selected patients with steroid-resistant airway eosinophils, there is a reduction in exacerbations. Eosinophils may be important in release of growth factors involved in airway remodeling and in exacerbations


InternalMed_Harrison

InternalMed_Harrison. patients with steroid-resistant airway eosinophils, there is a reduction in exacerbations. Eosinophils may be important in release of growth factors involved in airway remodeling and in exacerbations but probably not in AHR.


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InternalMed_Harrison. NEUTROPHILS Increased numbers of activated neutrophils are found in sputum and airways of some patients with severe asthma and during exacerbations, although there is a proportion of patients even with mild or moderate asthma who have a predominance of neutrophils. The roles of neutrophils in asthma that are resistant to the anti-inflammatory effects of corticosteroids are currently unknown.


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InternalMed_Harrison. T LYMPHOCYTES T lymphocytes play a very important role in coordinating the inflammatory response in asthma through the release of specific patterns of cytokines, resulting in the recruitment and survival of eosinophils and in the maintenance of a mast cell population in the airways. The naïve immune system and the immune system of asthmatics are skewed to express the TH2 phenotype, whereas in normal airways, TH1 cells predominate. TH2 cells, through the release of IL-5, are associated with eosinophilic inflammation and, through the release of IL-4 and IL-13, are associated with increased IgE formation. Recently, taglandin D2, and cysteinyl-leukotrienes contract airway smooth muscle, increase microvascular leakage, increase airway mucus secretion, and attract other inflammatory cells. Because each mediator has many effects, the role of individual mediators in the pathophysiology of asthma is not yet clear. Although the multiplicity of mediators makes it unlikely that preventing the


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InternalMed_Harrison. each mediator has many effects, the role of individual mediators in the pathophysiology of asthma is not yet clear. Although the multiplicity of mediators makes it unlikely that preventing the synthesis or action of a single mediator will have a major impact in clinical asthma, recent clinical studies with antileukotrienes suggest that cysteinyl-leukotrienes have clinically important effects.


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InternalMed_Harrison. CYTOKINES Multiple cytokines regulate the chronic inflammation of asthma. The TH2 cytokines IL-4, IL-5, and IL-13 mediate allergic inflammation, whereas proinflammatory cytokines, such as TNF-α and IL-1β, amplify the inflammatory response and play a role in more FIGURE 309-4 Many cells and mediators are involved in asthma and lead to several effects on the airways. AHR, airway hyperresponsiveness; PAF, platelet-activating factor. Dendritic cell CCL17, CCL22 CCL11 TSLP Allergens Viruses IL-25, IL-33 ILC2TH2 IL-5 IL-5 Eosinophils


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InternalMed_Harrison. Dendritic cell CCL17, CCL22 CCL11 TSLP Allergens Viruses IL-25, IL-33 ILC2TH2 IL-5 IL-5 Eosinophils FIGURE 309-5 T lymphocytes in asthma. Allergen interacts with dendritic cells and releases thymus stimulated lymphopoeitin (TSLP), which stimulates activated dendritic cells to release the chemokines CCL17 and CCL22, which attract T helper 2 (TH2) lymphocytes. Allergens and viral infection may release interleukin (IL)-25 and -33, which recruit and activate type 2 innate lymphoid cells (ILC2). Both TH2 and ILC2 cells release IL-5 and epithelial cells release CCL11 (eotaxin), which together lead to recruitment of eosinophils into the airways. severe disease. TSLP is an upstream cytokine released from epithelial cells of asthmatics that orchestrates the release of chemokines that selectively attract TH2 cells. Some cytokines such as IL-10 and IL-12 are anti-inflammatory and may be deficient in asthma.


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InternalMed_Harrison. CHEMOKINES Chemokines are involved in attracting inflammatory cells from the bronchial circulation into the airways. Eotaxin (CCL11) is selectively attractant to eosinophils via CCR3 and is expressed by epithelial cells of asthmatics, whereas CCL17 (TARC) and CCL22 (MDC) from epithelial cells attract TH2 cells via CCR4 (Fig. 309-5). OXIDATIVE STRESS Activated inflammatory cells such as macrophages and eosinophils produce reactive oxygen species. Evidence for increased oxidative stress in asthma is provided by the increased concentrations of 8-isoprostane (a product of oxidized arachidonic acid) in exhaled breath condensates and increased ethane (a product of lipid peroxidation) in the expired air of asthmatic patients. Increased oxidative stress is related to disease severity, may amplify the inflammatory response, and may reduce responsiveness to corticosteroids.


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InternalMed_Harrison. NITRIC OXIDE Nitric oxide (NO) is produced by NO synthases in several cells in the airway, particularly airway epithelial cells and macrophages. The level of NO in the expired air of patients with asthma is higher than normal and is related to the eosinophilic inflammation. Increased NO may contribute to the bronchial vasodilation observed in asthma. Fractional exhaled NO (FENO) is increasingly used in the diagnosis and monitoring of asthmatic inflammation, although it is not yet used routinely in clinical practice. TRANSCRIPTION FACTORS Proinflammatory transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1, are activated in asthmatic airways and orchestrate the expression of multiple inflammatory genes. More specific transcription factors that are involved include nuclear factor of activated T cells and GATA-3, which regulate the expression of TH2 cytokines in T cells.


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InternalMed_Harrison. Effects of Inflammation The chronic inflammatory response has several effects on the target cells of the airways, resulting in the characteristic pathophysiologic and remodeling changes associated with asthma. Asthma may be regarded as a disease with continuous inflammation and repair proceeding simultaneously, although the relationship between chronic inflammatory processes and asthma symptoms is often obscure.


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InternalMed_Harrison. AIRWAY EPITHELIUM Airway epithelial shedding may be important in contributing to AHR and may explain how several mechanisms, such as ozone exposure, virus infections, chemical sensitizers, and allergens (usually proteases), can lead to its development, as all of these stimuli may lead to epithelial disruption. Epithelial damage may contribute to AHR in a number of ways, including loss of its barrier function to allow penetration of allergens; loss of enzymes (such as neutral endopeptidase) that degrade certain peptide inflammatory mediators; loss of a relaxant factor (so called epithelial-derived relaxant factor); and exposure of sensory nerves, which may lead to reflex neural effects on the airway.


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InternalMed_Harrison. FIBROSIS In all asthmatic patients, the basement membrane is apparently thickened due to subepithelial fibrosis with deposition of types III and V collagen below the true basement membrane and is associated with eosinophil infiltration, presumably through the release of profibrotic mediators such as transforming growth factor-β. Mechanical manipulations can alter the phenotype of airway epithelial cells in a profibrotic fashion. In more severe patients, there is also fibrosis within the airway wall, which may contribute to irreversible narrowing of the airways.


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InternalMed_Harrison. AIRWAY SMOOTH MUSCLE In vitro airway smooth muscle from asthmatic patients usually shows no increased responsiveness to constrictors. Reduced responsiveness to β-agonists has also been reported in postmortem or surgically removed bronchi from asthmatics, although the number of β-receptors is not reduced, suggesting that β-receptors have been uncoupled. These abnormalities of airway smooth muscle may be secondary to the chronic inflammatory process. Inflammatory mediators may modulate the ion channels that serve to regulate the resting membrane potential of airway smooth-muscle cells, thus altering the level of excitability of these cells. In asthmatic airways there is also a characteristic hypertrophy and hyperplasia of airway smooth muscle, which is presumably the result of stimulation of airway smooth-muscle cells by various growth factors such as platelet-derived growth factor (PDGF) or endothelin-1 released from inflammatory or epithelial cells.


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InternalMed_Harrison. VASCULAR RESPONSES There is increased airway mucosal blood flow in asthma, which may contribute to airway narrowing. There is an increase in the number of blood vessels in asthmatic airways as a result of angiogenesis in response to growth factors, particularly vascular endothelial growth factor. Microvascular leakage from postcapillary venules in response to inflammatory mediators is observed in asthma, resulting in airway edema and plasma exudation into the airway lumen. MUCUS HYPERSECRETION Increased mucus secretion contributes to the viscid mucous plugs that occlude asthmatic airways, particularly in fatal asthma. There is hyperplasia of submucosal glands that are confined to large airways and of increased numbers of epithelial goblet cells. IL-13 induces mucus hypersecretion in experimental models of asthma.


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InternalMed_Harrison. NEURAL REGULATION Various defects in autonomic neural control may contribute to AHR in asthma, but these are likely to be secondary to the disease, rather than primary defects. Cholinergic pathways, through the release of acetylcholine acting on muscarinic receptors, cause bronchoconstriction and may be activated reflexly in asthma. predominant nonproductive cough (cough-variant asthma). There 1675 may be no abnormal physical findings when asthma is under control. The diagnosis of asthma is usually apparent from the symptoms of variable and intermittent airways obstruction, but must be confirmed by objective measurements of lung function.


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InternalMed_Harrison. The diagnosis of asthma is usually apparent from the symptoms of variable and intermittent airways obstruction, but must be confirmed by objective measurements of lung function. Lung Function Tests Simple spirometry confirms airflow limitation with a reduced FEV1, FEV1/FVC ratio, and PEF (Fig. 309-6). Reversibility is demonstrated by a >12% and 200-mL increase in FEV1 15 min after an inhaled short-acting β2-agonist or in some patients by a 2to 4-week trial of oral corticosteroids (OCS) (prednisone or prednisolone 30–40 mg daily). Measurements of PEF twice daily may confirm the diurnal variations in airflow obstruction. Flow-volume loops show reduced peak flow and reduced maximum expiratory flow. Further lung function tests are rarely necessary, but whole-body plethysmography shows increased airway resistance and may show increased total lung capacity and residual volume. Gas diffusion is usually normal, but there may be a small increase in gas transfer in some patients.


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InternalMed_Harrison. Inflammatory mediators may activate sensory nerves, resulting in reflex cholinergic bronchoconstriction or release of inflammatory neuropeptides. Inflammatory products may also sensitize sensory nerve endings in the airway epithelium such that the nerves become hyperalgesic. Neurotrophins, which may be released from various cell types in airways, including epithelial cells and mast cells, may cause proliferation and sensitization of airway sensory nerves. Airway nerves may also release neurotransmitters, such as substance P, which have inflammatory effects. Airway Remodeling Several changes in the structure of the airway are characteristically found in asthma, and these may lead to irreversible narrowing of the airways. Population studies have shown a greater decline in lung function over time than in normal subjects; however, most patients with asthma preserve normal or near-normal lung function throughout life if appropriately treated.


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InternalMed_Harrison. The accelerated decline in lung function occurs in a smaller proportion of asthmatics, and these are usually patients with more severe disease. There is some evidence that the early use of ICS may reduce the decline in lung function. The characteristic structural changes are increased airway smooth muscle, fibrosis, angiogenesis, and mucus hyperplasia.


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InternalMed_Harrison. Physiology Limitation of airflow is due mainly to bronchoconstriction, but airway edema, vascular congestion, and luminal occlusion with exudate may contribute. This results in a reduction in forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC) ratio, and peak expiratory flow (PEF), as well as an increase in airway resistance. Early closure of peripheral airway results in lung hyperinflation (air trapping) and increased residual volume, particularly during acute exacerbations and in severe persistent asthma. In more severe asthma, reduced ventilation and increased pulmonary blood flow result in mismatching of ventilation and perfusion and in bronchial hyperemia. Ventilatory failure is very uncommon, even in patients with severe asthma, and arterial PCO2 tends to be low due to increased ventilation.


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InternalMed_Harrison. Airway Hyperresponsiveness AHR is the characteristic physiologic abnormality of asthma and describes the excessive bronchoconstrictor response to multiple inhaled triggers that would have no effect on normal airways. The increase in AHR is linked to the frequency of asthma symptoms, and, thus, an important aim of therapy is to reduce AHR. Increased bronchoconstrictor responsiveness is seen with direct bronchoconstrictors such as histamine and methacholine, which contract airway smooth muscle, but is characteristically also seen with many indirect stimuli, which release bronchoconstrictors from mast cells or activate sensory nerves. Most of the triggers for asthma symptoms appear to act indirectly, including allergens, exercise, hyperventilation, fog (via mast cell activation), irritant dusts, and sulfur dioxide (via a cholinergic reflex).


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InternalMed_Harrison. The characteristic symptoms of asthma are wheez ing, dyspnea, and coughing, which are variable, both spontaneously and with therapy. Symptoms may be worse at night, and patients typically awake in the early morning hours. Patients may report difficulty in filling their lungs with air. There is increased mucus production in some patients, with typically tenacious mucus that is difficult to expectorate. There may be increased ventilation and use of accessory muscles of ventilation. Prodromal symptoms may precede


InternalMed_Harrison

InternalMed_Harrison. Airway Responsiveness The increased AHR is normally measured by methacholine or histamine challenge with calculation of the provocative concentration that reduces FEV1 by 20% (PC20). This is rarely useful in clinical practice, but can be used in the differential diagnosis of chronic cough and when the diagnosis is in doubt in the setting of normal pulmonary function tests. Occasionally exercise testing is done to demonstrate the postexercise bronchoconstriction if there is a predominant history of EIA. Allergen challenge is rarely necessary and should only be undertaken by a specialist if specific occupational agents are to be identified. Hematologic Tests Blood tests are not usually helpful. Total serum IgE and specific IgE to inhaled allergens (radioallergosorbent test [RAST]) may be measured in some patients.


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InternalMed_Harrison. Hematologic Tests Blood tests are not usually helpful. Total serum IgE and specific IgE to inhaled allergens (radioallergosorbent test [RAST]) may be measured in some patients. Imaging Chest roentgenography is usually normal but in more severe patients may show hyperinflated lungs. In exacerbations, there may be evidence of a pneumothorax. Lung shadowing usually indicates pneumonia or eosinophilic infiltrates in patients with bronchopulmonary aspergillosis. High-resolution computed tomography (CT) may show areas of bronchiectasis in patients with severe asthma, and there may be thickening of the bronchial walls, but these changes are not diagnostic of asthma. Skin Tests Skin prick tests to common inhalant allergens (house dust mite, cat fur, grass pollen) are positive in allergic asthma and negative


InternalMed_Harrison

InternalMed_Harrison. Skin Tests Skin prick tests to common inhalant allergens (house dust mite, cat fur, grass pollen) are positive in allergic asthma and negative Flow (liters/min) FEV1 = 3.5 L FVC = 4.0 L FEV1 = 2.2 L FVC = 3.6 L Normal Asthma Spirometry 10 5 0 Normal Asthma Flow-volume loop FEV1/FVC = 61% PEF an attack, with itching under the chin, discomfort between the scapulae, or inexplicable fear (impend ing doom). FIGURE 309-6 Spirometry and flow-volume loop in asthmatic compared to nor- Typical physical signs are inspiratory, and to mal subject. There is a reduction in forced expiratory volume in 1 second (FEV1) but a greater extent expiratory, rhonchi throughout less reduction in forced vital capacity (FVC), giving a reduced FEV1/FVC ratio (<70%). the chest, and there may be hyperinflation. Some The flow-volume loop shows reduced peak expiratory flow and a typical scalloped patients, particularly children, may present with a appearance indicating widespread airflow obstruction.


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InternalMed_Harrison. 1676 in intrinsic asthma, but are not helpful in diagnosis. Positive skin responses may be useful in persuading patients to undertake allergen avoidance measures. Exhaled Nitric Oxide FENO is now being used as a noninvasive test to measure airway inflammation. The typically elevated levels in asthma are reduced by ICS, so this may be a test of compliance with therapy. It may also be useful in demonstrating insufficient anti-inflammatory therapy and may be useful in down-titrating ICS. However, studies in unselected patients have not convincingly demonstrated improved clinical outcomes, and it may be necessary to select patients who are poorly controlled.


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InternalMed_Harrison. Differential Diagnosis It is usually not difficult to differentiate asthma from other conditions that cause wheezing and dyspnea. Upper airway obstruction by a tumor or laryngeal edema can mimic severe asthma, but patients typically present with stridor localized to large airways. The diagnosis is confirmed by a flow-volume loop that shows a reduction in inspiratory as well as expiratory flow, and bronchoscopy to demonstrate the site of upper airway narrowing. Persistent wheezing in a specific area of the chest may indicate endobronchial obstruction with a foreign body. Left ventricular failure may mimic the wheezing of asthma, but basilar crackles are present in contrast to asthma. Vocal chord dysfunction may mimic asthma and is thought to be an hysterical conversion syndrome.


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InternalMed_Harrison. Eosinophilic pneumonias and systemic vasculitis, including Churg-Strauss syndrome and polyarteritis nodosa, may be associated with wheezing. Chronic obstructive pulmonary disease (COPD) is usually easy to differentiate from asthma as symptoms show less variability, never completely remit, and show much less (or no) reversibility to bronchodilators. Approximately 10% of COPD patients have features of asthma, with increased sputum eosinophils and a response to OCSs; these patients probably have both diseases concomitantly.


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InternalMed_Harrison. The treatment of asthma is straightforward, and the majority of patients are now managed by internists and family doctors with effective and safe therapies. There are several aims of therapy (Table 309-2). Most emphasis has been placed on drug therapy, but several nonpharmacologic approaches have also been used. The main drugs for asthma can be divided into bronchodilators, which give rapid relief of symptoms mainly through relaxation of airway smooth muscle, and controllers, which inhibit the underlying inflammatory process.


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InternalMed_Harrison. Bronchodilators act primarily on airway smooth muscle to reverse the bronchoconstriction of asthma. This gives rapid relief of symptoms but has little or no effect on the underlying inflammatory process. Thus, bronchodilators are not sufficient to control asthma in patients with persistent symptoms. There are three classes of bronchodilators in current use: β2-adrenergic agonists, anticholinergics, and theophylline; of these, β2-agonists are by far the most effective. β2-Agonists β2-Agonists activate β2-adrenergic receptors, which are widely expressed in the airways. β2-Receptors are coupled through a stimulatory G protein to adenylyl cyclase, resulting in increased aiMS of aSthMa therapy (ideally no) chronic symptoms, including nocturnal (ideally no) use of a required β2-agonist limitations on activities, including exercise intracellular cyclic adenosine monophosphate (AMP), which relaxes smooth-muscle cells and inhibits certain inflammatory cells, particularly mast cells.