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InternalMed_Harrison. MODE OF ACTION The primary action of β2-agonists is to relax airway smooth-muscle cells of all airways, where they act as functional antagonists, reversing and preventing contraction of airway smooth-muscle cells by all known bronchoconstrictors. This generalized action is likely to account for their great efficacy as bronchodilators in asthma. There are also additional nonbronchodilator effects that may be clinically useful, including inhibition of mast cell mediator release, reduction in plasma exudation, and inhibition of sensory nerve activation. Inflammatory cells express small numbers of β2receptors, but these are rapidly downregulated with β2-agonist activation so that, in contrast to corticosteroids, there are no effects on inflammatory cells in the airways and there is no reduction in AHR.


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InternalMed_Harrison. CLINICAL USE β2-Agonists are usually given by inhalation to reduce side effects. Short-acting β2-agonists (SABAs) such as albuterol and terbutaline have a duration of action of 3–6 h. They have a rapid onset of bronchodilatation and are, therefore, used as needed for symptom relief. Increased use of SABA indicates that asthma is not controlled. They are also useful in preventing EIA if taken prior to exercise. SABAs are used in high doses by nebulizer or via a metered-dose inhaler with a spacer. Long-acting β2-agonists (LABAs) include salmeterol and formoterol, both of which have a duration of action over 12 h and are given twice daily by inhalation; indacaterol is given once daily. LABAs have replaced the regular use of SABAs, but LABAs should not be given in the absence of ICS therapy because they do not control the underlying inflammation. They do, however, improve asthma control and reduce exacerbations when added to ICS, which allows asthma to be controlled at lower doses of


InternalMed_Harrison

InternalMed_Harrison. because they do not control the underlying inflammation. They do, however, improve asthma control and reduce exacerbations when added to ICS, which allows asthma to be controlled at lower doses of corticosteroids. This observation has led to the widespread use of fixed-combination inhalers that contain a corticosteroid and a LABA, which have proved to be highly effective in the control of asthma.


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InternalMed_Harrison. SIDE EFFECTS Adverse effects are not usually a problem with β2agonists when given by inhalation. The most common side effects are muscle tremor and palpitations, which are seen more commonly in elderly patients. There is a small fall in plasma potassium due to increased uptake by skeletal muscle cells, but this effect does not usually cause any clinical problem. TOLERANCE Tolerance is a potential problem with any agonist given chronically, but although there is downregulation of β2-receptors, this does not reduce the bronchodilator response because there is a large receptor reserve in airway smooth-muscle cells. By contrast, mast cells become rapidly tolerant, but their tolerance may be prevented by concomitant administration of ICS.


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InternalMed_Harrison. SAFETY The safety of β2-agonists has been an important issue. There is an association between asthma mortality and the amount of SABA used, but careful analysis demonstrates that the increased use of rescue SABA reflects poor asthma control, which is a risk factor for asthma death. The slight excess in mortality that has been associated with the use of LABA is related to the lack of use of concomitant ICS, as the LABA therapy fails to suppress the underlying inflammation. This highlights the importance of always using an ICS when LABAs are given, which is most conveniently achieved by using a combination inhaler.


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InternalMed_Harrison. Anticholinergics Muscarinic receptor antagonists such as ipratropium bromide prevent cholinergic nerve-induced bronchoconstriction and mucus secretion. They are less effective than β2-agonists in asthma therapy because they inhibit only the cholinergic reflex component of bronchoconstriction, whereas β2-agonists prevent all bronchoconstrictor mechanisms. Anticholinergics, including once-daily tiotropium bromide, may be used as an additional bronchodilator in patients with asthma that is not controlled by ICS and LABA combinations. High doses may be given by nebulizer in treating acute severe asthma but should only be given following β2-agonists, because they have a slower onset of bronchodilatation. Side effects are not usually a problem because there is little or no systemic absorption. The most common side effect is dry mouth; in elderly patients, urinary retention and glaucoma may also be observed.


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InternalMed_Harrison. Theophylline Theophylline was widely prescribed as an oral bronchodilator several years ago, especially because it was inexpensive. It has now fallen out of favor because side effects are common and inhaled β2-agonists are much more effective as bronchodilators. The bronchodilator effect is due to inhibition of phosphodiesterases in airway smooth-muscle cells, which increases cyclic AMP, but doses required for bronchodilatation commonly cause side effects that are mediated mainly by phosphodiesterase inhibition. There is increasing evidence that theophylline at lower doses has anti-inflammatory effects, and these are likely to be mediated through different molecular mechanisms. Theophylline activates the key nuclear enzyme histone deacetylase-2 (HDAC2), which is a critical mechanism for switching off activated inflammatory genes and may, therefore, reduce corticosteroid insensitivity in severe asthma.


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InternalMed_Harrison. CLINICAL USE Oral theophylline is usually given as a slow-release preparation once or twice daily because this gives more stable plasma concentrations than normal theophylline tablets. It may be used as an additional bronchodilator in patients with severe asthma when plasma concentrations of 10–20 mg/L are required, although these concentrations are often associated with side effects. Low doses of theophylline, giving plasma concentrations of 5–10 mg/L, have additive effects to ICS and are particularly useful in patients with severe asthma. Indeed, withdrawal of theophylline from these patients may result in marked deterioration in asthma control. At low doses, the drug is well tolerated. IV aminophylline (a soluble salt of theophylline) was used for the treatment of severe asthma but has now been largely replaced by high doses of inhaled SABA, which are more effective and have fewer side effects. Aminophylline is occasionally used (via slow IV infusion) in patients with severe


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InternalMed_Harrison. has now been largely replaced by high doses of inhaled SABA, which are more effective and have fewer side effects. Aminophylline is occasionally used (via slow IV infusion) in patients with severe exacerbations that are refractory to SABA.


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InternalMed_Harrison. SIDE EFFECTS Oral theophylline is well absorbed and is largely inactivated in the liver. Side effects are related to plasma concentrations; measurement of plasma theophylline may be useful in determining the correct dose. The most common side effects are nausea, vomiting, and headaches and are due to phosphodiesterase inhibition. Diuresis and palpitations may also occur, and at high concentrations, cardiac arrhythmias, epileptic seizures, and death may occur due to adenosine A1-receptor antagonism. Theophylline side effects are related to plasma concentration and are rarely observed at plasma concentrations below 10 mg/L. Theophylline is metabolized by CYP450 in the liver, and thus, plasma concentrations may be elevated by drugs that block CYP450 such as erythromycin and allopurinol. Other drugs may also reduce clearance by other mechanisms leading to increased plasma concentrations (Table 309-3).


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InternalMed_Harrison. induction (rifampicin, phenobarbitone, ethanol) (tobacco, marijuana) • High-protein, • Enzyme inhibition (cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton, zafirlukast) CONTROLLER THERAPIES 1677 Inhaled Corticosteroids ICSs are by far the most effective controllers for asthma, and their early use has revolutionized asthma therapy. MODE OF ACTION ICSs are the most effective anti-inflammatory agents used in asthma therapy, reducing inflammatory cell numbers and their activation in the airways. ICSs reduce eosinophils in the airways and sputum and the numbers of activated T lymphocytes and surface mast cells in the airway mucosa. These effects may account for the reduction in AHR that is seen with chronic ICS therapy.


InternalMed_Harrison

InternalMed_Harrison. The molecular mechanism of action of corticosteroids involves several effects on the inflammatory process. The major effect of corticosteroids is to switch off the transcription of multiple activated genes that encode inflammatory proteins such as cytokines, chemokines, adhesion molecules, and inflammatory enzymes. This effect involves several mechanisms, including inhibition of the transcription factor NF-κB, but an important mechanism is recruitment of HDAC2 to the inflammatory gene complex, which reverses the histone acetylation associated with increased gene transcrip tion. Corticosteroids also activate anti-inflammatory genes, such as mitogen-activated protein (MAP) kinase phosphatase-1, and increase the expression of β2-receptors. Most of the metabolic and endocrine side effects of corticosteroids are also mediated through transcriptional activation.


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InternalMed_Harrison. CLINICAL USE ICSs are by far the most effective controllers in the management of asthma and are beneficial in treating asthma of any severity and age. ICSs are usually given twice daily, but some may be effective once daily in mildly symptomatic patients. ICSs rapidly improve the symptoms of asthma, and lung function improves over several days. They are effective in preventing asthma symptoms, such as EIA and nocturnal exacerbations, but also prevent severe exacerbations. ICSs reduce AHR, but maximal improvement may take several months of therapy. Early treatment with ICS appears to prevent irreversible changes in airway function that occur with chronic asthma. Withdrawal of ICS results in slow deterioration of asthma control, indicating that they suppress inflammation and symptoms, but do not cure the underlying condition. ICSs are now given as first-line therapy for patients with persistent asthma, but if they do not control symptoms at low doses, it is usual to add a LABA as the


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InternalMed_Harrison. do not cure the underlying condition. ICSs are now given as first-line therapy for patients with persistent asthma, but if they do not control symptoms at low doses, it is usual to add a LABA as the next step.


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InternalMed_Harrison. SIDE EFFECTS Local side effects include hoarseness (dysphonia) and oral candidiasis, which may be reduced with the use of a large-volume spacer device. There has been concern about systemic side effects from lung absorption, but many studies have demonstrated that ICS have minimal systemic effects (Fig. 309-7). At the highest recommended doses, there may be some suppression of plasma and urinary cortisol concentrations, but there is no convincing evidence that long-term treatment leads to impaired growth in children or to osteoporosis in adults. Indeed effective control of asthma with ICS reduces the number of courses of OCS that are needed and, thus, reduces systemic exposure to ICS.


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InternalMed_Harrison. Systemic Corticosteroids Corticosteroids are used intravenously (hydrocortisone or methylprednisolone) for the treatment of acute severe asthma, although several studies now show that OCSs are as effective and easier to administer. A course of OCS (usually prednisone or prednisolone 30–45 mg once daily for 5–10 days) is used to treat acute exacerbations of asthma; no tapering of the dose is needed. Approximately 1% of asthma patients may require maintenance treatment with OCS; the lowest dose necessary to maintain control needs to be determined. Systemic side effects, including truncal obesity, bruising, osteoporosis, diabetes, hypertension, gastric ulceration, proximal myopathy, depression, and cataracts, may be a major problem, and steroid-sparing therapies may be considered if side effects are a significant problem. If patients require maintenance treatment with OCS, it is important to monitor bone density so that preventive treatment with bisphosphonates or estrogen in


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InternalMed_Harrison. if side effects are a significant problem. If patients require maintenance treatment with OCS, it is important to monitor bone density so that preventive treatment with bisphosphonates or estrogen in postmenopausal women may be initiated if bone density is low.


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InternalMed_Harrison. FIGURE 309-7 Pharmacokinetics of inhaled corticosteroids. GI, gastrointestinal; MDI, metered-dose inhaler. Intramuscular triamcinolone acetonide is a depot preparation that is occasionally used in noncompliant patients, but proximal myopathy is a major problem with this therapy.


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InternalMed_Harrison. Antileukotrienes Cysteinyl-leukotrienes are potent bronchoconstrictors, cause microvascular leakage, and increase eosinophilic inflammation through the activation of cys-LT1-receptors. These inflammatory mediators are produced predominantly by mast cells and, to a lesser extent, eosinophils in asthma. Antileukotrienes, such as montelukast, block cys-LT1-receptors and provide modest clinical benefit in asthma. They are less effective than ICS in controlling asthma and have less effect on airway inflammation, but are useful as an add-on therapy in some patients not controlled with low doses of ICS, although less effective than LABA. They are given orally once or twice daily and are well tolerated. Some patients show a better response than others to antileukotrienes, but this has not been convincingly linked to any genomic differences in the leukotriene pathway.


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InternalMed_Harrison. Cromones Cromolyn sodium and nedocromil sodium are asthma controller drugs that appear to inhibit mast cell and sensory nerve activation and are, therefore, effective in blocking trigger-induced asthma such as EIA and allergenand sulfur dioxide–induced symptoms. Cromones have relatively little benefit in the long-term control of asthma due to their short duration of action (at least four times daily by inhalation). They are very safe and were popular in the treatment of childhood asthma, although now low doses of ICS are preferred because they are more effective and have a proven safety profile.


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InternalMed_Harrison. Steroid-Sparing Therapies Various immunomodulatory treatments have been used to reduce the requirement for OCS in patients with severe asthma who have serious side effects with this therapy. Methotrexate, cyclosporin A, azathioprine, gold, and IV gamma globulin have all been used as steroid-sparing therapies, but none of these treatments has any long-term benefit, and each is associated with a relatively high risk of side effects.


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InternalMed_Harrison. Anti-IgE Omalizumab is a blocking antibody that neutralizes circulating IgE without binding to cell-bound IgE and, thus, inhibits IgE-mediated reactions. This treatment has been shown to reduce the number of exacerbations in patients with severe asthma and may improve asthma control. However, the treatment is very expensive and is only suitable for highly selected patients who are not controlled on maximal doses of inhaler therapy and have a circulating IgE within a specified range. Patients should be given a 3to 4-month trial of therapy to show objective benefit. Omalizumab is usually given as a subcutaneous injection every 2–4 weeks and appears not to have significant side effects, although anaphylaxis is very occasionally seen.


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InternalMed_Harrison. Immunotherapy Specific immunotherapy using injected extracts of pollens or house dust mites has not been very effective in controlling asthma and may cause anaphylaxis. Side effects may be reduced by sublingual dosing. It is not recommended in most asthma treatment guidelines because of lack of evidence of clinical efficacy. Alternative Therapies Nonpharmacologic treatments, including hypnosis, acupuncture, chiropraxis, breathing control, yoga, and speleotherapy, may be popular with some patients. However, placebo-controlled studies have shown that each of these treatments lacks efficacy and cannot be recommended. However, they are not detrimental and may be used as long as conventional pharmacologic therapy is continued.


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InternalMed_Harrison. Future Therapies It has proved very difficult to discover novel pharmaceutical therapies, particularly because current therapy with corticosteroids and β2-agonists is so effective in the majority of patients. There is, however, a need for the development of new therapies for patients with refractory asthma who have side effects with systemic corticosteroids. Antagonists of specific mediators have little or no benefit in asthma, apart from antileukotrienes, which have rather weak effects, presumably reflecting the fact that multiple mediators are involved. Blocking antibodies against IL-5 may reduce exacerbations in highly selected patients who have sputum eosinophils despite high doses of corticosteroids, whereas anti-TNF-α antibodies are not effective in severe asthma. Novel anti-inflammatory treatments that are in clinical development include inhibitors of phosphodiesterase-4, NF-κB, and p38 MAP kinase. However, these drugs, which act on signal transduction pathways common to many


InternalMed_Harrison

InternalMed_Harrison. treatments that are in clinical development include inhibitors of phosphodiesterase-4, NF-κB, and p38 MAP kinase. However, these drugs, which act on signal transduction pathways common to many cells, are likely to have troublesome side effects, necessitating their delivery by inhalation. Safer and more effective immunotherapy using T cell peptide fragments of allergens or DNA vaccination is also being investigated. Bacterial products, such as CpG oligonucleotides that stimulate TH1 immunity or regulatory T cells, are also currently under evaluation.


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InternalMed_Harrison. There are several aims of chronic therapy in asthma (Table 309-2). It is important to establish the diagnosis objectively using spirometry or PEF measurements at home. Triggers that worsen asthma control, such as allergens or occupational agents, should be avoided, whereas triggers, such as exercise and fog, which result in transient symptoms, provide an indication that more controller therapy is needed. It is important to assess asthma control, determined by Controlled (all of Partly Characteristic the following) Controlled Uncontrolled features of partly controlled Limitation of None Any activities Abbreviations: FEV1, forced expiratory volume in 1 s; PEF, peak expiratory flow.


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InternalMed_Harrison. Limitation of None Any activities Abbreviations: FEV1, forced expiratory volume in 1 s; PEF, peak expiratory flow. symptoms, night awakening, need for reliever inhalers, limitation of activity, and lung function (Table 309-4). Avoidance of side effects and expense of medications are also important. There are several validated questionnaires for quantifying asthma control, such as the Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Test (ACT).


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InternalMed_Harrison. Stepwise Therapy For patients with mild, intermittent asthma, a short-acting β2-agonist is all that is required (Fig. 309-8). However, use of a reliever medication more than twice a week indicates the need for regular controller therapy. The treatment of choice for all patients is an ICS given twice daily. It is usual to start with an intermediate dose (e.g., 200 μg bid of beclomethasone dipropionate [BDP]) or equivalent and to decrease the dose if symptoms are controlled after 3 months. If symptoms are not controlled, a LABA should be added, which is most conveniently given by switching to a combination inhaler. The dose of controller should be adjusted accordingly, as judged by the need for a rescue inhaler. Low doses of theophylline or an antileukotriene may also be considered as an add-on therapy, but these are less effective than LABA. In patients with severe asthma, low-dose oral theophylline is also helpful, and when there is irreversible airway narrowing, the long-acting


InternalMed_Harrison

InternalMed_Harrison. an add-on therapy, but these are less effective than LABA. In patients with severe asthma, low-dose oral theophylline is also helpful, and when there is irreversible airway narrowing, the long-acting anticholinergic tiotropium bromide may be tried. If asthma is not controlled despite the maximal recommended dose of inhaled therapy, it is important to check compliance and inhaler technique. In these patients, maintenance treatment with an OCS may be needed, and the lowest dose that maintains control should be used. Occasionally omalizumab may be tried in steroid-dependent asthmatics who are not well controlled. Once asthma is controlled, it is important to slowly decrease therapy in order to find the optimal dose to control symptoms.


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InternalMed_Harrison. Education Patients with asthma need to understand how to use their medications and the difference between reliever and controller FIGURE 309-8 Stepwise approach to asthma therapy according to the severity of asthma and ability to control symptoms. ICS, inhaled corticosteroids; LABA, long-acting β2-agonist; OCS, oral corticosteroid. therapies. Education may improve compliance, particularly with ICS. 1679 All patients should be taught how to use their inhalers correctly. In particular, they need to understand how to recognize worsening of asthma and how to step up therapy. Written action plans have been shown to reduce hospital admissions and morbidity rates in adults and children, and are recommended particularly in patients with unstable disease who have frequent exacerbations.


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InternalMed_Harrison. Exacerbations of asthma are feared by patients and may be life threatening. One of the main aims of controller therapy is to prevent exacerbations; in this respect, ICS and combination inhalers are very effective.


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InternalMed_Harrison. Clinical Features Patients are aware of increasing chest tightness, wheezing, and dyspnea that are often not or poorly relieved by their usual reliever inhaler. In severe exacerbations, patients may be so breathless that they are unable to complete sentences and may become cyanotic. Examination usually shows increased ventilation, hyperinflation, and tachycardia. Pulsus paradoxus may be present, but this is rarely a useful clinical sign. There is a marked fall in spirometric values and PEF. Arterial blood gases on air show hypoxemia, and PCO2 is usually low due to hyperventilation. A normal or rising PCO2 is an indication of impending respiratory failure and requires immediate monitoring and therapy. A chest roentgenogram is not usually informative but may show pneumonia or pneumothorax.


InternalMed_Harrison

InternalMed_Harrison. A high concentration of oxygen should be given by face mask to achieve oxygen saturation of >90%. The mainstay of treatment are high doses of SABA given either by nebulizer or via a metered-dose inhaler with a spacer. In severely ill patients with impending respiratory failure, IV β2-agonists may be given. A nebulized anticholinergic may be added if there is not a satisfactory response to β2-agonists alone, as there are additive effects. In patients who are refractory to inhaled therapies, a slow infusion of aminophylline may be effective, but it is important to monitor blood levels, especially if patients have already been treated with oral theophylline. Magnesium sulfate given intravenously or by nebulizer is effective when added to inhaled β2-agonists, and is relatively well tolerated but is not routinely recommended. Prophylactic intubation may be indicated for impending respiratory failure, when the PCO2 is normal or rises. For patients with respiratory failure, it is necessary


InternalMed_Harrison

InternalMed_Harrison. but is not routinely recommended. Prophylactic intubation may be indicated for impending respiratory failure, when the PCO2 is normal or rises. For patients with respiratory failure, it is necessary to intubate and institute ventilation. These patients may benefit from an anesthetic such as halothane if they have not responded to conventional bronchodilators. Sedatives should never be given because they may depress ventilation. Antibiotics should not be used routinely unless there are signs of pneumonia.


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InternalMed_Harrison. SPECIAL CONSIDERATIONS Refractory Asthma Although most patients with asthma are easily controlled with appropriate medication, a small proportion of patients (approximately 5–10% of asthmatics) are difficult to control despite maximal inhaled therapy. Some of these patients will require maintenance treatment with OCS. In managing these patients, it is important to investigate and correct any mechanisms that may be aggravating asthma. There are two major patterns of difficult asthma: some patients have persistent symptoms and poor lung function, despite appropriate therapy, whereas others may have normal or near-normal lung function but intermittent, severe (sometimes life-threatening) exacerbations.


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InternalMed_Harrison. MECHANISMS The most common reason for poor control of asthma is noncompliance with medication, particularly ICS. Compliance with ICS may be low because patients do not feel any immediate clinical benefit or may be concerned about side effects. Compliance with ICS is difficult to monitor because there are no useful plasma measurements that can be made, but measuring the fractional excretion of 1680 induced NO (FENO) may identify the problem. Compliance may be improved by giving the ICS as a combination with a LABA that gives symptom relief. Compliance with OCS may be measured by suppression of plasma cortisol and the expected concentration of prednisone/ prednisolone in the plasma. There are several factors that may make asthma more difficult to control, including exposure to high, ambient levels of allergens or unidentified occupational agents. Severe rhino-sinusitis may make asthma more difficult to control; upper airway disease should be vigorously treated. Drugs such as


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InternalMed_Harrison. ambient levels of allergens or unidentified occupational agents. Severe rhino-sinusitis may make asthma more difficult to control; upper airway disease should be vigorously treated. Drugs such as beta-adrenergic blockers, aspirin, and other cyclooxygenase (COX) inhibitors may worsen asthma. Some women develop severe premenstrual worsening of asthma, which is unresponsive to corticosteroids and requires treatment with progesterone or gonadotropin-releasing factors. Few systemic diseases make asthma more difficult to control, but hyper-and hypothyroidism may increase asthma symptoms and should be investigated if suspected. Bronchial biopsy studies in refractory asthma may show the typical eosinophilic pattern of inflammation, whereas others have a predominantly neutrophilic pattern. There may be an increase in TH1 cells, TH17 cells, and CD8 lymphocytes compared to mild asthma and increased expression of TNF-α. Structural changes in the airway, including fibrosis, angiogenesis, and


InternalMed_Harrison

InternalMed_Harrison. may be an increase in TH1 cells, TH17 cells, and CD8 lymphocytes compared to mild asthma and increased expression of TNF-α. Structural changes in the airway, including fibrosis, angiogenesis, and airway smooth-muscle thickening, are more commonly seen in these patients.


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InternalMed_Harrison. Corticosteroid-Resistant Asthma A few patients with asthma show a poor response to corticosteroid therapy and may have various molecular abnormalities that impair the anti-inflammatory action of corticosteroids. Complete resistance to corticosteroids is extremely uncommon and affects less than 1 in 1000 patients. It is defined by a failure to respond to a high dose of oral prednisone/prednisolone (40 mg once daily over 2 weeks), ideally with a 2-week run-in with matched placebo. More common is reduced responsiveness to corticosteroids where control of asthma requires OCS (corticosteroiddependent asthma). In patients with poor responsiveness to corticosteroids, there is a reduction in the response of circulating monocytes and lymphocytes to the anti-inflammatory effects of corticosteroids in vitro and reduced skin blanching in response to topical corticosteroids. There are several mechanisms that have been described, including an increase in the alternatively spliced form of the


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InternalMed_Harrison. in vitro and reduced skin blanching in response to topical corticosteroids. There are several mechanisms that have been described, including an increase in the alternatively spliced form of the glucocorticoid receptor (GR)-β, an abnormal pattern of histone acetylation in response to corticosteroids, a defect in IL-10 production, and a reduction in HDAC2 activity (as in COPD). These observations suggest that there are likely to be heterogeneous mechanisms for corticosteroid resistance; whether these mechanisms are genetically determined has yet to be decided.


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InternalMed_Harrison. Brittle Asthma Some patients show chaotic variations in lung function despite taking appropriate therapy. Some show a persistent pattern of variability and may require oral corticosteroids or, at times, continuous infusion of β2-agonists (type 1 brittle asthma), whereas others have generally normal or near-normal lung function but precipitous, unpredictable falls in lung function that may result in death (type 2 brittle asthma). These latter patients are difficult to manage because they do not respond well to corticosteroids, and the worsening of asthma does not reverse well with inhaled bronchodilators. The most effective therapy is subcutaneous epinephrine, which suggests that the worsening is likely to be a localized airway anaphylactic reaction with edema. In some of these patients, there may be allergy to specific foods. These patients should be taught to self-administer epinephrine and should carry a medical warning accordingly.


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InternalMed_Harrison. Refractory asthma is difficult to control, by definition. It is important to check compliance and the correct use of inhalers and to identify and eliminate any underlying triggers. Low doses of theophylline may be helpful in some patients, and theophylline withdrawal has been found to worsen in many patients. Most of these patients will require maintenance treatment with oral corticosteroids, and the minimal dose that achieves satisfactory control should be determined by careful dose titration. Steroid-sparing therapies are rarely effective. In some patients with allergic asthma, omalizumab is effective, particularly when there are frequent exacerbations. Anti-TNF therapy is not effective in severe asthma and should not be used. A few patients may benefit from infusions of β2-agonists. New therapies are needed for these patients, who currently consume a disproportionate amount of health care spending.


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InternalMed_Harrison. Aspirin-Sensitive Asthma A small proportion (1–5%) of asthmatics become worse with aspirin and other COX inhibitors, although this is much more commonly seen in severe cases and in patients with frequent hospital admission. Aspirin-sensitive asthma is a well-defined phenotype of asthma that is usually preceded by perennial rhinitis and nasal polyps in nonatopic patients with a late onset of the disease. Aspirin, even in small doses, characteristically provokes rhinorrhea, conjunctival injection, facial flushing, and wheezing. There is a genetic predisposition to increased production of cysteinyl-leukotrienes with functional polymorphism of cys-leukotriene C4 synthase. Asthma is triggered by COX inhibitors but is persistent even in their absence. All nonselective COX inhibitors should be avoided, but selective COX2 inhibitors are safe to use when an anti-inflammatory analgesic is needed. Aspirin-sensitive asthma responds to usual therapy with ICS. Although antileukotrienes should be


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InternalMed_Harrison. avoided, but selective COX2 inhibitors are safe to use when an anti-inflammatory analgesic is needed. Aspirin-sensitive asthma responds to usual therapy with ICS. Although antileukotrienes should be effective in these patients, they are no more effective than in allergic asthma. Occasionally, aspirin desensitization is necessary, but this should only be undertaken in specialized centers.


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InternalMed_Harrison. Asthma in the Elderly Asthma may start at any age, including in elderly patients. The principles of management are the same as in other asthmatics, but side effects of therapy may be a problem, including muscle tremor with β2-agonists and more systemic side effects with ICS. Comorbidities are more frequent in this age group, and interactions with drugs such as β2-blockers, COX inhibitors, and agents that may affect theophylline metabolism need to be considered. COPD is more likely in elderly patients and may coexist with asthma. A trial of OCS may be very useful in documenting the steroid responsiveness of asthma.


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InternalMed_Harrison. Pregnancy Approximately one-third of asthmatic patients who are pregnant improve during the course of a pregnancy, one-third deteriorate, and one-third are unchanged. It is important to maintain good control of asthma because poor control may have adverse effects on fetal development. Compliance may be a problem because there is often concern about the effects of antiasthma medications on fetal development. The drugs that have been used for many years in asthma therapy have now been shown to be safe and without teratogenic potential. These drugs include SABA, ICS, and theophylline; there is less safety information about newer classes of drugs such as LABA, antileukotrienes, and anti-IgE. If an OCS is needed, it is better to use prednisone rather than prednisolone because it cannot be converted to the active prednisolone by the fetal liver, thus protecting the fetus from systemic effects of the corticosteroid. There is no contraindication to breast-feeding when patients are using these


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InternalMed_Harrison. to the active prednisolone by the fetal liver, thus protecting the fetus from systemic effects of the corticosteroid. There is no contraindication to breast-feeding when patients are using these drugs.


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InternalMed_Harrison. Cigarette Smoking Approximately 20% of asthmatics smoke, which may adversely affect asthma in several ways. Smoking asthmatics have more severe disease, more frequent hospital admissions, a faster decline in lung function, and a higher risk of death from asthma than nonsmoking asthmatics. There is evidence that smoking interferes with the anti-inflammatory actions of corticosteroids by reducing HDAC2, necessitating higher doses for asthma control. Smoking cessation improves lung function and reduces the steroid resistance, and thus, vigorous smoking cessation strategies should be used. Some patients report a temporary worsening of asthma when they first stop smoking, possibly due to the loss of the bronchodilating effect of NO in cigarette smoke.


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InternalMed_Harrison. Surgery If asthma is well controlled, there is no contraindication to general anesthesia and intubation. Patients who are treated with OCS will have adrenal suppression and should be treated with an increased dose of OCS immediately prior to surgery. Patients with FEV1 <80% of their normal levels should also be given a boost of OCS prior to surgery. High-maintenance doses of corticosteroids may be a contraindication to surgery because of increased risks of infection and delayed wound healing. hypersensitivity pneumonitis and pulmonary infiltrates with eosinophilia Praveen Akuthota, Michael E. Wechsler HYPERSENSITIVITY PNEUMONITIS 310


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InternalMed_Harrison. Bronchopulmonary Aspergillosis Bronchopulmonary aspergillosis (BPA) is uncommon and results from an allergic pulmonary reaction to inhaled spores of Aspergillus fumigatus and, occasionally, other Aspergillus species. A skin prick test to A. fumigatus is always positive, whereas serum Aspergillus precipitins are low or undetectable. Characteristically, there are fleeting eosinophilic infiltrates in the lungs, particularly in the upper lobes. Airways become blocked with mucoid plugs rich in eosinophils, and patients may cough up brown plugs and have hemoptysis. BPA may result in bronchiectasis, particularly affecting central airways, if not suppressed by corticosteroids. Asthma is controlled in the usual way by ICS, but it is necessary to give a course of OCS if any sign of worsening or pulmonary shadowing is found. Treatment with the oral antifungal itraconazole is beneficial in preventing exacerbations.


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InternalMed_Harrison. Hypersensitivity pneumonitis (HP), also referred to as extrinsic allergic alveolitis, is a pulmonary disease that occurs due to inhalational exposure to a variety of antigens leading to an inflammatory response of the alveoli and small airways. Systemic manifestations such as fever and fatigue can accompany respiratory symptoms. Although sensitization to an inhaled antigen as manifested by specific circulating IgG antibodies is necessary for the development of HP, sensitization alone is not sufficient as a defining characteristic, because many sensitized individuals do not develop HP. The incidence and prevalence of HP are variable, depending on geography, occupation, avocation, and environment of the cohort being studied. As yet unexplained is the decreased risk of developing HP in smokers.


InternalMed_Harrison

InternalMed_Harrison. HP can be caused by any of a large list of potential offending inhaled antigens (Table 310-1). The various antigens and environmental conditions described to be associated with HP give rise to an expansive list of monikers given to specific forms of HP. Antigens derived from fungal, bacterial, mycobacterial, bird-derived, and chemical sources have all been implicated in causing HP.


InternalMed_Harrison

InternalMed_Harrison. Categories of individuals at particular risk in the United States include farmers, bird owners, industrial workers, and hot tub users. Farmer’s lung occurs as a result of exposure to one of several possible sources of bacterial or fungal antigens such as grain, moldy hay, or silage. Potential offending antigens include thermophilic actinomycetes or Aspergillus species. Bird fancier’s lung (also referred to by names corresponding to specific birds) must be considered in patients who give a history of keeping birds in their home and is precipitated by exposure to antigens derived from feathers, droppings, and serum proteins. Occupational exposure to birds may also cause HP, as is seen in poultry worker’s lung. Chemical worker’s lung is provoked by exposure to occupational chemical antigens such as diphenylmethane diisocyanate and toluene diisocyanate. Mycobacteria may cause HP rather than frank infection, a phenomenon observed in hot tub lung and in HP due to metalworking fluid.


InternalMed_Harrison

InternalMed_Harrison. Grain, moldy hay, silage Thermophilic actinomycetes (e.g., Bird fancier’s lung (also Proteins derived by named by specific bird parakeets, pigeons, exposures) budgerigars Duck fever Duck feathers, serum proteins Fish meal worker’s lung Fish meal dust Furrier’s lung Dust from animal furs Laboratory worker’s lung Rat urine, serum, fur Pituitary snuff taker’s lung Animal proteins Bird feathers, droppings, serum proteins Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia Humidifier fever (and air Several microorconditioner lung) ganisms including: Woodworker’s lung Alternaria species; Bacillus subtilis Polyurethane foam, varnish, lacquer Contaminated water, mold on ceiling House dust mites, bird droppings


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InternalMed_Harrison. Oak, cedar, pine, mahogany dusts 1682 PATHOPHYSIOLOGY The pathophysiology of HP has not been characterized in depth on an immunologic level, although it has been established that HP is an immune-mediated condition that occurs in response to inhaled antigens that are small enough to deposit in distal airways and alveoli. From a lymphocyte perspective, HP has been categorized as a condition with a TH1 inflammatory pattern. However, emerging evidence suggests that TH17 lymphocyte subsets may be involved in the pathogenesis of the disease as well. Although the presence of precipitating IgG antibodies against specific antigens in HP suggests a prominent role for adaptive immunity in the pathophysiology of HP, innate immune mechanisms may also make an important contribution. This is highlighted by the observation that Toll-like receptors and downstream signaling proteins such as MyD88 are activated in HP. Although no clear genetic basis for HP has been established, in specific cohorts,


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InternalMed_Harrison. by the observation that Toll-like receptors and downstream signaling proteins such as MyD88 are activated in HP. Although no clear genetic basis for HP has been established, in specific cohorts, polymorphisms in genes involved in antigen processing and presentation, including TAP1 and major histocompatibility complex type II, have been observed.


InternalMed_Harrison

InternalMed_Harrison. Given the heterogeneity among patients, variability in offending antigens, and differences in the intensity and duration of exposure to antigen, the presentation of HP is accordingly variable. Although these categories are not fully satisfactory in capturing this variability, HP has been traditionally categorized as having acute, subacute, and chronic forms. Acute HP usually manifests itself 4–8 h following exposure to the inciting antigen, often intense in nature. Systemic symptoms, including fevers, chills, and malaise, are prominent and are accompanied by dyspnea. Symptoms resolve within hours to days if no further exposure to the offending antigen occurs. In subacute HP resulting from ongoing antigen exposure, the onset of respiratory and systemic symptoms is typically more gradual over the course of weeks. A similar presentation may occur as a culmination of intermittent episodes of acute HP. Although respiratory impairment may be quite severe, antigen avoidance generally results


InternalMed_Harrison

InternalMed_Harrison. the course of weeks. A similar presentation may occur as a culmination of intermittent episodes of acute HP. Although respiratory impairment may be quite severe, antigen avoidance generally results in resolution of the symptoms, although with a slower time course, on the order of weeks to months, than that seen with acute HP. Chronic HP can present with an even more gradual onset of symptoms than subacute HP, with progressive dyspnea, cough, fatigue, weight loss, and clubbing of the digits. The insidious onset of symptoms and frequent lack of an anteceding episode of acute HP make diagnosing chronic HP a challenge. Unlike with the other forms of HP, there can be an irreversible component to the respiratory impairment that is not responsive to removal of the responsible antigen from the patient’s environment. The disease progression to hypoxemic respiratory failure can mirror that seen in idiopathic pulmonary fibrosis (IPF). Fibrotic lung disease is a potential feature of chronic HP


InternalMed_Harrison

InternalMed_Harrison. patient’s environment. The disease progression to hypoxemic respiratory failure can mirror that seen in idiopathic pulmonary fibrosis (IPF). Fibrotic lung disease is a potential feature of chronic HP due to exposure to bird antigens, whereas an emphysematous phenotype may be seen in farmer’s lung.


InternalMed_Harrison

InternalMed_Harrison. The categories of acute, subacute, and chronic HP are not completely sufficient in classifying HP. The HP Study Group found on cluster analysis that a cohort of HP patients is best described in bipartite fashion, with one group featuring recurrent systemic signs and symptoms and the other featuring more severe respiratory findings. Concordant with the variability in the presentation of HP is the observed variability in outcome. HP that has not progressed to chronic lung disease has a more favorable outcome with likely resolution if antigen avoidance can be achieved. However, chronic HP resulting in lung fibrosis has a poorer prognosis, with patients with chronic pigeon breeder’s lung having demonstrated a similar mortality as seen in IPF.


InternalMed_Harrison

InternalMed_Harrison. Although there is no set of universally accepted criteria for arriving at a diagnosis of HP, diagnosis depends foremost on establishing a history of exposure to an offending antigen that correlates with respiratory and systemic symptoms. A careful occupational and home exposure history should be taken and may be supplemented if necessary by a clinician visit to the work or home environment. Specific inquiries will be influenced by geography and the occupation of the patient. When HP is suspected by history, the additional workup is aimed at establishing an immunologic and physiologic response to inhalational antigen exposure with chest imaging, pulmonary function testing, serologic studies, bronchoscopy, and, on occasion, lung biopsy.


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InternalMed_Harrison. Chest Imaging Chest x-ray findings in HP are nonspecific and can even lack any discernible abnormalities. In cases of acute and subacute HP, findings may be transient and can include ill-defined micronodular opacities or hazy ground-glass airspace opacities. Findings on chest x-ray will often resolve with removal from the offending antigen, although the time course of resolution may vary. With chronic HP, the abnormalities seen on the chest radiograph are frequently more fibrotic in nature and may be difficult to distinguish from IPF.


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InternalMed_Harrison. With the wide availability of high-resolution computed tomography (HRCT), this modality has become a common component in the diagnostic workup for HP. Although the HRCT may be normal in acute forms of HP, this may be due to lack of temporal correlation between exposure to the offending antigen and obtaining the imaging. Additionally, because of the transient nature of acute HP, HRCT is not always performed. In subacute forms of the disease, ground-glass airspace opacities are characteristic, as is the presence of centrilobular nodules. Expiratory images may show areas of air trapping that are likely caused by involvement of the small airways (Fig. 310-1). Reticular changes and traction bronchiectasis can be observed in chronic HP. Subpleural honeycombing similar to that seen in IPF may be present in advanced cases, although unlike in IPF, the lung bases are frequently spared.


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InternalMed_Harrison. Pulmonary Function Testing (PFT) Either restrictive or obstructive PFTs can be present in HP, so the pattern of PFT change is not useful in establishing the diagnosis of HP. However, obtaining PFTs is of use in characterizing the physiologic impairment of an individual patient and in gauging the response to antigen avoidance and/or corticosteroid therapy. Diffusion capacity for carbon monoxide may be significantly impaired, particularly in cases of chronic HP with fibrotic pulmonary parenchymal changes.


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InternalMed_Harrison. Serum Precipitins Assaying for precipitating IgG antibodies against specific antigens can be a useful adjunct in the diagnosis of HP. However, the presence of an immunologic response alone is not sufficient for establishing the diagnosis, because many asymptomatic individuals with high levels of exposure to antigen may display serum precipitins, as has been observed in farmers and in pigeon breeders. It should also be noted that panels that test for several specific serum precipitins often provide false-negative results, because they represent an extremely limited proportion of the universe of potential offending environmental antigens. FIGURE 310-1 Chest computed tomography scan of a patient with subacute hypersensitivity pneumonitis in which scattered regions of ground-glass infiltrates in a mosaic pattern consistent with air trapping are seen bilaterally. This patient had bird fancier’s lung. (Courtesy of TJ Gross; with permission.)


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InternalMed_Harrison. FIGURE 310-2 Open-lung biopsy from a patient with subacute hypersensitivity pneumonitis demonstrating a loose, nonnecrotiz-ing granuloma made up of histiocytes and multinucleated giant cells. Peribronchial inflammatory infiltrate made up of lymphocytes and plasma cells is also seen. (Courtesy of TJ Gross; with permission.) Bronchoscopy Bronchoscopy with bronchoalveolar lavage (BAL) may be used in the evaluation of HP. Although not a specific finding, BAL lymphocytosis is characteristic of HP. However, in active smokers, a lower threshold should be used to establish BAL lymphocytosis, because smoking will result in lower lymphocyte percentages. Most cases of HP have a CD4+/CD8+ lymphocyte ratio of less than 1, but again, this is not a specific finding and has limited utility in the diagnosis of HP.


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InternalMed_Harrison. Lung Biopsy Tissue samples may be obtained by a bronchoscopic approach using transbronchial biopsy, or more architecturally preserved specimens may be obtained by a surgical approach (videoassisted thoracoscopy or open approach). As is the case with BAL, histologic specimens are not absolutely necessary to establish the diagnosis of HP, but they can be useful in the correct clinical context. A common histologic feature in HP is the presence of noncaseating granulomas in the vicinity of small airways (Fig. 310-2). As opposed to pulmonary sarcoidosis, in which noncaseating granulomas are well defined, the granulomas seen in HP are loose and poorly defined in nature. Within the alveolar spaces and in the interstitium, a mixed cellular infiltrate with a lymphocytic predominance is observed that is frequently patchy in distribution. Bronchiolitis with the presence of organizing exudate is also often observed. Fibrosis may be present as well, particularly as the disease progresses to its


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InternalMed_Harrison. that is frequently patchy in distribution. Bronchiolitis with the presence of organizing exudate is also often observed. Fibrosis may be present as well, particularly as the disease progresses to its chronic form. Fibrotic changes may be focal but can be diffuse and severe with honeycombing in advanced cases, similar to findings in IPF.


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InternalMed_Harrison. Clinical Prediction Rule Although not meant as a set of validated diagnostic criteria, a clinical prediction rule for predicting the presence of HP has been published by the HP Study Group. They identified six statistically significant predictors for HP, the strongest of which was exposure to an antigen known to cause HP. Other predictive criteria were the presence of serum precipitins, recurrent symptoms, symptoms occurring 4–8 h after antigen exposure, crackles on inspiration, and weight loss.


InternalMed_Harrison

InternalMed_Harrison. Differentiating HP from other conditions that cause a similar constellation of respiratory and systemic symptoms requires an increased index of suspicion based on obtaining a history of possible exposure to an offending antigen. Presentations of acute or subacute HP can be mistaken for respiratory infection. In cases of chronic disease, HP must be differentiated from interstitial lung disease, such as IPF or 1683 nonspecific interstitial pneumonitis (NSIP); this can be a difficult task even with lung biopsy. Given the presence of pulmonary infiltrates and noncaseating granulomas on biopsy, sarcoidosis is also a consideration in the differential diagnosis of HP. Unlike in HP, however, hilar adenopathy may be prominent on chest x-ray, organs other than the lung may be involved, and noncaseating granulomas in pathologic specimens tend to be well formed. Other inhalational syndromes, such as organic toxic dust syndrome (OTDS), can be misdiagnosed as HP. OTDS occurs with exposure to


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InternalMed_Harrison. granulomas in pathologic specimens tend to be well formed. Other inhalational syndromes, such as organic toxic dust syndrome (OTDS), can be misdiagnosed as HP. OTDS occurs with exposure to organic dusts, including those produced by grains or mold silage, but neither requires prior antigen sensitization nor is characterized by positive serum precipitins.


InternalMed_Harrison

InternalMed_Harrison. The mainstay of treatment for HP is antigen avoidance. A careful exposure history must be obtained to attempt to identify the potential offending antigen and to identify the location where a patient is exposed. Once a potential antigen and location are identified, efforts should be made to modify the environment to minimize patient exposure. This may be accomplished with measures such as removal of birds, removal of molds, and improved ventilation. Personal protective equipment including respirators and ventilated helmets can be used but may not provide adequate protection for sensitized individuals. In some cases, fully avoiding specific environments may be necessary, although such a recommendation must be balanced against the effects to an individual’s lifestyle or occupation. It is not uncommon for patients with HP due to exposure to household birds to be unwilling to remove them from the home.


InternalMed_Harrison

InternalMed_Harrison. Because acute HP is generally a self-limited disease after a discrete exposure to an offending antigen, pharmacologic therapy is generally not necessary. However, in so-called subacute and chronic forms of the disease, there is a role for glucocorticoid therapy. In patients with particularly severe symptoms as a result of subacute HP, antigen avoidance may be insufficient after establishing the diagnosis. Although glucocorticoids do not change the long-term outcome in these patients, they can accelerate the resolution of symptoms. While there is significant variability in the approach to glucocorticoid therapy by individual clinicians, prednisone therapy can be initiated at 0.5–1 mg/kg of ideal body weight per day (not to exceed 60 mg/d or alternative glucocorticoid equivalent) over a duration of 1–2 weeks, followed by a taper over the next 2–6 weeks. In chronic HP, a similar trial of corticosteroids may be used, although a variable component of fibrotic disease may be irreversible.


InternalMed_Harrison

InternalMed_Harrison. As the ever-expanding list of antigens and exposures associated with the development of HP suggests, populations at risk for HP will vary globally based on specifics of local occupational, avocational, and environmental factors. Specific examples of geographically limited HP include summer-type pneumonitis seen in Japan and suberosis seen in cork workers in Portugal and Spain. Although eosinophils are normal constituents of the lungs, there are several pulmonary eosinophilic syndromes that are characterized by pulmonary infiltrates on imaging along with an increased number of eosinophils in lung tissue, in sputum, and/or in BAL fluid, with resultant increased respiratory symptoms and the potential for systemic manifestations. Because the eosinophil plays such an important role in each of these syndromes, it is often difficult to distinguish between them, but there are important clinical and pathologic differences as well as differences in prognosis and treatment paradigms.


InternalMed_Harrison

InternalMed_Harrison. Because there are so many different diagnoses associated with pulmonary infiltrates with eosinophilia, the first step in classifying pulmonary Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia DiagnoStiC Criteria of aCute eoSinophiLiC pneuMonia Acute eosinophilic pneumonia Chronic eosinophilic pneumonia Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) Hypereosinophilic syndrome Pulmonary Disorders of Known Cause Associated with Eosinophilia Lung Diseases Associated with Eosinophilia Malignant Neoplasms Associated with Eosinophilia Leukemia Lymphoma Lung cancer Adenocarcinoma of various organs Squamous cell carcinoma of various organs


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InternalMed_Harrison. Lung Diseases Associated with Eosinophilia Malignant Neoplasms Associated with Eosinophilia Leukemia Lymphoma Lung cancer Adenocarcinoma of various organs Squamous cell carcinoma of various organs Systemic Disease Associated with Eosinophilia eosinophilic syndromes is distinguishing between primary pulmonary eosinophilic lung disorders and those with eosinophilia that are secondary to a specific cause such as a drug reaction, an infection, a malignancy, or another pulmonary condition such as asthma. Table 310-2 lists primary and secondary pulmonary eosinophilic disorders.


InternalMed_Harrison

InternalMed_Harrison. For each patient, a detailed history is of utmost importance and can help elucidate what the underlying disease is. Details regarding onset, timing, and precipitants of specific symptoms can help discern one diagnosis from another. History regarding pharmacologic, occupational, and environmental exposures is instructive, and family and travel history are crucial. In addition to details about the sinuses and lungs, it is important to inquire about systemic manifestations and assess for physical findings of cardiac, gastrointestinal (GI), neurologic, dermatologic, and genitourinary involvement, all of which may give clues to specific diagnoses. Once the details from history and physical are teased out, laboratory testing (including measurements of blood eosinophils, cultures, and markers of inflammation), spirometry and radiographic imaging can help distinguish between different diseases. Often, however, BAL, transbronchial, or open lung biopsies are required. In many cases, biopsies or


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InternalMed_Harrison. inflammation), spirometry and radiographic imaging can help distinguish between different diseases. Often, however, BAL, transbronchial, or open lung biopsies are required. In many cases, biopsies or noninvasive diagnostic studies of other organs (e.g., echocardiogram, electromyogram, or bone marrow biopsy) can be helpful.


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InternalMed_Harrison. Pathologically, the pulmonary eosinophilic syndromes are characterized by tissue infiltration by eosinophils (Fig. 310-2). In eosinophilic granulomatosis with polyangiitis (EGPA), extravascular granulomas and necrotizing vasculitis may occur in the lungs, as well as in the heart, skin, muscle, liver, spleen, and kidneys, and may be associated with fibrinoid necrosis and thrombosis. The exact etiology of the various pulmonary eosinophilic syndromes is unknown; however, it is felt that these syndromes result from dysregulated eosinophilopoiesis or an autoimmune process because of Acute febrile illness with respiratory manifestations of <1 month in duration Absence of parasitic, fungal, or other infection Absence of drugs known to cause pulmonary eosinophilia Quick clinical response to corticosteroids


InternalMed_Harrison

InternalMed_Harrison. Absence of parasitic, fungal, or other infection Absence of drugs known to cause pulmonary eosinophilia Quick clinical response to corticosteroids Failure to relapse after discontinuation of corticosteroids the prominence of allergic features and the presence of immune complexes, heightened T cell immunity, and altered humoral immunity as evidenced by elevated IgE and rheumatoid factor. Because of its integral involvement in eosinophilopoiesis, interleukin 5 (IL-5) has been hypothesized to play an etiologic role, and efforts to block this cytokine are being investigated. Antineutrophil cytoplasmic antibodies (ANCAs) are present in about half of patents with EGPA; binding of ANCAs to vascular walls likely contributes to vascular inflammation and injury as well as chemotaxis of inflammatory cells.


InternalMed_Harrison

InternalMed_Harrison. Acute eosinophilic pneumonia is a syndrome characterized by fevers, acute respiratory failure that often requires mechanical ventilation, diffuse pulmonary infiltrates, and pulmonary eosinophilia in a previously healthy individual (Table 310-3).


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InternalMed_Harrison. Clinical Features and Etiology At presentation, acute eosinophilic pneumonia is often mistaken for acute lung injury or acute respiratory distress syndrome (ARDS), until a BAL is performed and reveals >25% eosinophils. Although the predominant symptoms of acute eosinophilic pneumonia are cough, dyspnea, malaise, myalgias, night sweats, and pleuritic chest pain, physical exam findings include high fevers, basilar rales, and rhonchi on forced expiration. Acute eosinophilic pneumonia most often affects males between age 20 and 40 with no history of asthma. Although no clear etiology has been identified, several case reports have linked acute eosinophilic pneumonia to recent initiation of tobacco smoking or exposure to other environmental stimuli including dust from indoor renovations.


InternalMed_Harrison

InternalMed_Harrison. In addition to a suggestive history, the key to establishing a diagnosis of acute eosinophilic pneumonia is the presence of >25% eosinophilia on BAL fluid. While lung biopsies show eosinophilic infiltration with acute and organizing diffuse alveolar damage, it is generally not necessary to proceed to biopsy to establish a diagnosis. Although patients present with an elevated white blood cell count, in contrast to other pulmonary eosinophilic syndromes, acute eosinophilic pneumonia is often not associated with peripheral eosinophilia upon presentation. However, between 7 and 30 days of disease onset, peripheral eosinophilia often occurs with mean eosinophil counts of 1700. Erythrocyte sedimentation rate (ESR), C-reactive protein, and IgE levels are high but nonspecific, whereas HRCT is always abnormal with bilateral random patchy ground-glass or reticular opacities, and small pleural effusions in as many as two-thirds of patients. Pleural fluid is characterized by a high pH with marked


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InternalMed_Harrison. abnormal with bilateral random patchy ground-glass or reticular opacities, and small pleural effusions in as many as two-thirds of patients. Pleural fluid is characterized by a high pH with marked eosinophilia.


InternalMed_Harrison

InternalMed_Harrison. Clinical Course and Response to Therapy Although some patients improve spontaneously, most patients require admission to an intensive care unit and respiratory support with either invasive (intubation) or noninvasive mechanical ventilation. However, what distinguishes acute eosinophilic pneumonia from both other cases of acute lung injury as well as some of the other pulmonary eosinophilic syndromes is the absence of organ dysfunction or multisystem organ failure other than respiratory failure. One of the characteristic features of acute eosinophilic pneumonia is the high degree of corticosteroid responsiveness and the excellent prognosis. Another distinguishing feature of acute eosinophilic pneumonia is that complete clinical and radiographic recovery without recurrence or residual sequelae occurs in almost all patients within several weeks of initiation of therapy.


InternalMed_Harrison

InternalMed_Harrison. In contrast to acute eosinophilic pneumonia, chronic eosinophilic pneumonia is a more indolent syndrome that is characterized by pulmonary infiltrates and eosinophilia in both the tissue and blood. Most patients are female nonsmokers with a mean age of 45, and patients do not usually develop the acute respiratory failure and significant hypoxemia appreciated in acute eosinophilic pneumonia. Similar to EGPA, a majority have asthma, with many having a history of allergies.


InternalMed_Harrison

InternalMed_Harrison. Patients present with a subacute illness over weeks to months, with cough, low-grade fevers, progressive dyspnea, weight loss, wheezing, malaise, and night sweats, and a chest x-ray with migratory bilateral peripheral or pleural-based opacities. Although this “photographic negative pulmonary edema” appearance on chest x-ray and chest CT is pathognomonic of chronic eosinophilic pneumonia, less than 25% of patients present with this finding. Other radiographic findings include atelectasis, pleural effusions, lymphadenopathy, and septal line thickening.


InternalMed_Harrison

InternalMed_Harrison. Almost 90% of patients have peripheral eosinophilia, with mean eosinophil counts of over 30% of total white blood cell count. BAL eosinophilia is also an important distinguishing feature with mean BAL eosinophil counts of close to 60%. Both peripheral and BAL eosinophilia are very responsive to treatment with corticosteroids. Other laboratory features of chronic eosinophilic pneumonia include increased ESR, C-reactive protein, platelets, and IgE. Lung biopsy is also often not required to establish a diagnosis, but may show accumulation of eosinophils and histiocytes in the lung parenchyma and interstitium, as well as cryptogenic organizing pneumonia, but with minimal fibrosis. Nonrespiratory manifestations are uncommon, but arthralgias, neuropathy, and skin and GI symptoms have all been reported; their presence may suggest EGPA or hypereosinophilic syndrome. Another similarity is the rapid response to corticosteroids with quick resolution of peripheral and BAL eosinophilia and


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InternalMed_Harrison. been reported; their presence may suggest EGPA or hypereosinophilic syndrome. Another similarity is the rapid response to corticosteroids with quick resolution of peripheral and BAL eosinophilia and improvement in symptoms. In contrast to acute eosinophilic pneumonia, though, over 50% of patients relapse, and many require prolonged courses of corticosteroids for months to years.


InternalMed_Harrison

InternalMed_Harrison. Previously known as allergic angiitis granulomatosis or Churg-Strauss syndrome, this complex syndrome is characterized by eosinophilic vasculitis that may involve multiple organ systems including the lungs, heart, skin, GI tract, and nervous system. Although EGPA is characterized by peripheral and pulmonary eosinophilia with infiltrates on chest x-ray, the primary features that distinguish EGPA from other pulmonary eosinophilic syndromes are the presence of eosinophilic vasculitis in the setting of asthma and involvement of multiple end organs (a feature it shares with hypereosinophilic syndrome). Although perceived to be quite rare, in the last few years, there has appeared to be an increased incidence of this disease, particularly in association with various asthma therapies.


InternalMed_Harrison

InternalMed_Harrison. The primary features of EGPA include asthma, peripheral eosinophilia, neuropathy, pulmonary infiltrates, paranasal sinus abnormality, and presence of eosinophilic vasculitis. It typically occurs in several phases. The prodromal phase is characterized by asthma and allergic rhinitis, and usually begins when the individual is in his or her twenties or thirties, typically persisting for many years. The eosinophilic infiltrative phase is characterized by peripheral eosinophilia and eosinophilic tissue infiltration of various organs including the lungs and GI tract. The third phase is the vasculitic phase and may be associated with constitutional signs and symptoms including fever, weight loss, malaise, and fatigue. The mean age at diagnosis is 48 years, with a range of 14 to 74 years; the average length of time between diagnosis of asthma and vasculitis is 9 years.


InternalMed_Harrison

InternalMed_Harrison. Similar to other pulmonary eosinophilic syndromes, constitutional symptoms are very common in EGPA and include weight loss of 10–20 lb, fevers, and diffuse myalgias and migratory polyarthralgias. Myositis may be present with evidence of vasculitis on muscle biopsies. In contrast to the eosinophilic pneumonias, EGPA involves many organ systems including the lungs, skin, nerves, heart, GI tract, and kidneys. Symptoms and Clinical Manifestations • RESPIRATORY Most EGPA 1685 patients have asthma that arises later in life and in individuals who have no family history of atopy. The asthma can often be severe, and oral corticosteroids are often required to control symptoms but may lead to suppression of vasculitic symptoms. In addition to the more common symptoms of cough, dyspnea, sinusitis, and allergic rhinitis, alveolar hemorrhage and hemoptysis may also occur.


InternalMed_Harrison

InternalMed_Harrison. NEUROLOGIC Over three-fourths of EGPA patients have neurologic manifestations. Mononeuritis multiplex most commonly involves the peroneal nerve, but also involves the ulnar, radial, internal popliteal, and occasionally, cranial nerves. Cerebral hemorrhage and infarction may also occur and are important causes of death. Despite treatment, neurologic sequelae often do not completely resolve. DERMATOLOGIC Approximately half of EGPA patients develop dermatologic manifestations. These include palpable purpura, skin nodules, urticarial rashes, and livedo.


InternalMed_Harrison

InternalMed_Harrison. DERMATOLOGIC Approximately half of EGPA patients develop dermatologic manifestations. These include palpable purpura, skin nodules, urticarial rashes, and livedo. CARDIOVASCULAR Granulomas, vasculitis, and widespread myocardial damage may be found on biopsy or at autopsy, and cardiomyopathy and heart failure may be seen in up to half of all patients but are often at least partially reversible. Acute pericarditis, constrictive pericarditis, myocardial infarction, and other electrocardiographic changes all may occur. The heart is a primary target organ in EGPA, and cardiac involvement often portends a worse prognosis. GI GI symptoms are common in EGPA and likely represent an eosinophilic gastroenteritis characterized by abdominal pain, diarrhea, GI bleeding, and colitis. Ischemic bowel, pancreatitis, and cholecystitis have also been reported in association with EGPA and usually portend a worse prognosis.


InternalMed_Harrison

InternalMed_Harrison. GI bleeding, and colitis. Ischemic bowel, pancreatitis, and cholecystitis have also been reported in association with EGPA and usually portend a worse prognosis. RENAL Renal involvement is more common than once thought, and approximately 25% of patients have some degree of renal involvement. This may include proteinuria, glomerulonephritis, renal insufficiency, and rarely, renal infarct. Lab Abnormalities Systemic eosinophilia is the hallmark laboratory finding in patients with EGPA and reflects the likely pathogenic role that the eosinophil plays in this disease. Eosinophilia greater than 10% is one of the defining features of this illness and may be as high as 75% of the peripheral white blood cell count. It is present at the time of diagnosis in over 80% of patients but may respond quickly (often within 24 h) to initiation of systemic corticosteroid therapy. Even in the absence of systemic eosinophilia, tissue eosinophilia may be present.


InternalMed_Harrison

InternalMed_Harrison. Although not specific to EGPA, ANCAs are present in up to two-thirds of patients, mostly with a perinuclear staining pattern. Nonspecific lab abnormalities that may be present in patients with EGPA include a marked elevation in ESR, a normochromic normocytic anemia, an elevated IgE, hypergammaglobulinemia, and positive rheumatoid factor and antinuclear antibodies (ANA). Although BAL often reveals significant eosinophilia, this may be seen in other eosinophilic lung diseases. Similarly, PFT often reveals an obstructive defect similar to asthma.


InternalMed_Harrison

InternalMed_Harrison. Radiographic Features Chest x-ray abnormalities are extremely common in EGPA and consist of bilateral, nonsegmental, patchy infiltrates that often migrate and may be interstitial or alveolar in appearance. Reticulonodular and nodular disease without cavitation can be seen, as can pleural effusions and hilar adenopathy. The most common CT findings include bilateral ground-glass opacity and airspace consolidation that is predominantly subpleural. Other CT findings include bronchial wall thickening, hyperinflation, interlobular septal thickening, lymph node enlargement, and pericardial and pleural effusions. Angiography may be used diagnostically and may show signs of vasculitis in the coronary, central nervous system, and peripheral vasculature. Treatment and Prognosis of EGPA Most patients diagnosed with EGPA have previously been diagnosed with asthma, rhinitis, and sinusitis, and have received treatment with inhaled or systemic corticosteroids.


InternalMed_Harrison

InternalMed_Harrison. Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia 1686 Because these agents are also the initial treatment of choice for EGPA patients, institution of these therapies in patients with EGPA who are perceived to have severe asthma may delay the diagnosis of EGPA because signs of vasculitis may be masked. Corticosteroids dramatically alter the course of EGPA: up to 50% of those who are untreated die within 3 months of diagnosis, whereas treated patients have a 6-year survival of over 70%. Common causes of death include heart failure, cerebral hemorrhage, renal failure, and GI bleeding. Recent data suggest that clinical remission may be obtained in over 90% of patients treated; approximately 25% of those patients may relapse, often due to corticosteroid tapering, with a rising eosinophil count heralding the relapse. Myocardial, GI, and renal involvement most often portend a poor prognosis. In such cases, treatment with higher doses of corticosteroids or the addition


InternalMed_Harrison

InternalMed_Harrison. rising eosinophil count heralding the relapse. Myocardial, GI, and renal involvement most often portend a poor prognosis. In such cases, treatment with higher doses of corticosteroids or the addition of cytotoxic agents such as cyclophosphamide is often warranted. Although survival does not differ between those treated or untreated with cyclophosphamide, cyclophosphamide is associated with a reduced incidence of relapse and an improved clinical response to treatment. Other therapies that have been used successfully in the management of EGPA include azathioprine, methotrexate, intravenous gamma globulin, and interferon α. Plasma exchange has not been shown to provide any additional benefit. Recent studies examining the efficacy of anti-IL-5 therapy have shown promise.


InternalMed_Harrison

InternalMed_Harrison. Hypereosinophilic syndromes (HES) constitute a heterogeneous group of disease entities manifest by persistent eosinophilia >1500 eosinophils/μL in association with end organ damage or dysfunction, in the absence of secondary causes of eosinophilia. In addition to familial, undefined, and overlap syndromes with incomplete criteria, the predominant HES subtypes are the myeloproliferative and lymphocytic variants. The myeloproliferative variant may be divided into three subgroups: (1) chronic eosinophilic leukemia with demonstrable cytogenetic abnormalities and/or blasts on peripheral smear; (2) the platelet-derived growth factor receptor α (PDGFRα)–associated HES, attributed to a constitutively activated tyrosine kinase fusion protein (Fip1L1-PDGFRα) due to a chromosomal deletion on 4q12; this variant is often responsive to imatinib; and (3) the FIP1-negative variant associated with clonal eosinophilia and at least four of the following: dysplastic peripheral eosinophils, increased


InternalMed_Harrison

InternalMed_Harrison. this variant is often responsive to imatinib; and (3) the FIP1-negative variant associated with clonal eosinophilia and at least four of the following: dysplastic peripheral eosinophils, increased serum vitamin B12, increased tryptase, anemia, thrombocytopenia, splenomegaly, bone marrow cellularity >80%, spindle-shaped mast cells, and myelofibrosis.


InternalMed_Harrison

InternalMed_Harrison. Extrapulmonary Manifestations of HES More common in men than in women, HES occurs between the ages of 20 and 50 and is characterized by significant extrapulmonary involvement, including infiltration of the heart, GI tract, kidney, liver, joints, and skin. Cardiac involvement includes myocarditis and/or endomyocardial fibrosis, as well as a restrictive cardiomyopathy. Pulmonary Manifestations of HES Similar to the other pulmonary eosinophilic syndromes, these HES are manifest by high levels of blood, BAL, and tissue eosinophilia. Lung involvement occurs in 40% of these patients and is characterized by cough and dyspnea, as well as pulmonary infiltrates. Although it is often difficult to discern the pulmonary infiltrates and effusions seen on chest x-ray from pulmonary edema resulting from cardiac involvement, CT scan findings include interstitial infiltrates, ground-glass opacities, and small nodules. HES are typically not associated with ANCA or elevated IgE.


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InternalMed_Harrison. Course and Response to Therapy Unlike the other pulmonary eosinophilic syndromes, less than half of patients with these HES respond to corticosteroids as first-line therapy. Although other treatment options include hydroxyurea, cyclosporine, and interferon, the tyrosine kinase inhibitor imatinib has emerged as an important therapeutic option for patients with the myeloproliferative variant. Anti-IL-5 therapy with mepolizumab also holds promise for these patients and is currently being investigated.


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InternalMed_Harrison. Allergic bronchopulmonary aspergillosis (ABPA) is an eosinophilic pulmonary disorder that occurs in response to allergic sensitization to antigens from Aspergillus species fungi. The predominant clinical presentation of ABPA is an asthmatic phenotype, often accompanied by cough with production of brownish plugs of mucus. ABPA has also been well described as a complication of cystic fibrosis. A workup for ABPA may be beneficial in patients who carry a diagnosis of asthma but have proven refractory to usual therapy. ABPA is a distinct diagnosis from simple asthma, characterized by prominent peripheral eosinophilia and elevated circulating levels of IgE (>417 IU/mL). Establishing a diagnosis of ABPA also requires establishing sensitivity to Aspergillus antigens by skin test reactivity, positive serum precipitins for Aspergillus, and/or direct measurement of circulating specific IgG and IgE to Aspergillus. Central bronchiectasis is described as a classic finding on chest imaging in ABPA


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InternalMed_Harrison. serum precipitins for Aspergillus, and/or direct measurement of circulating specific IgG and IgE to Aspergillus. Central bronchiectasis is described as a classic finding on chest imaging in ABPA but is not necessary for making a diagnosis. Other possible findings on chest imaging include patchy infiltrates and evidence of mucus impaction.


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InternalMed_Harrison. Systemic glucocorticoids may be used in the treatment of ABPA that is persistently symptomatic despite the use of inhaled therapies for asthma. Courses of glucocorticoids should be tapered over 3–6 months, and their use must be balanced against the risks of prolonged steroid therapy. Antifungal agents such as fluconazole and voriconazole given over a 4-month course reduce the antigenic stimulus in ABPA and may therefore modulate disease activity in selected patients. The use of monoclonal antibody against IgE (omalizumab) has been described in treating severe ABPA, particularly in individuals with ABPA as a complication of cystic fibrosis. ABPA-like syndromes have been reported as a result to sensitization to several non-Aspergillus species fungi. However, these conditions are substantially rarer than ABPA, which may be present in a significant proportion of patients with refractory asthma.


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InternalMed_Harrison. Infectious etiologies of pulmonary eosinophilia are largely due to helminths and are of particular importance in the evaluation of pulmonary eosinophilia in tropical environments and in the developing world (Table 310-4). These infectious conditions may also be considered in recent travelers to endemic regions. Loffler syndrome refers to transient pulmonary infiltrates with eosinophilia that occurs in response to passage of helminthic larvae through the lungs, most Immunologic Response to Organisms in Lungs Tuberculosis Source: Adapted from P Akuthota, PF Weller: Clin Microbiol Rev 25:649, 2012.


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InternalMed_Harrison. Tuberculosis Source: Adapted from P Akuthota, PF Weller: Clin Microbiol Rev 25:649, 2012. occupational and environmental Lung Disease John R. Balmes, Frank E. Speizer Occupational and environmental lung diseases are difficult to dis-tinguish from those of nonenvironmental origin. Virtually all major 311 commonly larvae of Ascaris species (roundworm). Symptoms are generally self-limited and may include dyspnea, cough, wheeze, and hemoptysis. Loffler syndrome may also occur in response to hookworm infection with Ancylostoma duodenale or Necator americanus. Chronic Strongyloides stercoralis infection can lead to recurrent respiratory symptoms with peripheral eosinophilia between flares. In immunocompromised hosts, including patients on glucocorticoids, a severe, potentially fatal, hyperinfection syndrome can result from Strongyloides infection. Paragonimiasis, filariasis, and visceral larval migrans can all cause pulmonary eosinophilia as well.


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InternalMed_Harrison. A host of medications are associated with the development of pulmonary infiltrates with peripheral eosinophilia. Therefore, drug reaction must always be included in the differential diagnosis of pulmonary eosinophilia. Although the list of medications associated with pulmonary eosinophilia is ever expanding, common culprits include nonsteroidal anti-inflammatory medications and systemic antibiotics, most specifically nitrofurantoin. Additionally, various and diverse environmental exposures such as particulate metals, scorpion stings, and inhalational drugs of abuse may also cause pulmonary eosinophilia. Radiation therapy for breast cancer has been linked with eosinophilic pulmonary infiltration as well. The mainstay of treatment is removal of the offending exposure, although glucocorticoids may be necessary if respiratory symptoms are severe.


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InternalMed_Harrison. In the United States, drug-induced eosinophilic pneumonias are the most common cause of eosinophilic pulmonary infil trates. A travel history or evidence of recent immigration should prompt the consideration of parasite-associated disorders. Tropical eosinophilia is usually caused by filarial infection; however, eosinophilic pneumonias also occur with other parasites such as Ascaris spp., Ancylostoma spp., Toxocara spp., and Strongyloides stercoralis. Tropical eosinophilia due to Wuchereria bancrofti or Wuchereria malayi occurs most commonly in southern Asia, Africa, and South America and is treated successfully with diethylcarbamazine. In the United States, Strongyloides is endemic to the southeastern and Appalachian regions. We acknowledge the contributions of Dr. Alicia K. Gerke and Dr. Gary W. Hunninghake to the previous edition of this chapter.


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InternalMed_Harrison. We acknowledge the contributions of Dr. Alicia K. Gerke and Dr. Gary W. Hunninghake to the previous edition of this chapter. categories of pulmonary disease can be caused by environmental agents, and environmentally related disease usually presents clinically in a manner indistinguishable from that of disease not caused by such agents. In addition, the etiology of many diseases may be multifactorial; occupational and environmental factors may interact with other factors (such as smoking and genetic risk). It is often only after a careful exposure history is taken that the underlying workplace or general environmental exposure is uncovered.


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InternalMed_Harrison. Why is knowledge of occupational or environmental etiology so important? Patient management and prognosis are affected significantly by such knowledge. For example, patients with occupational asthma or hypersensitivity pneumonitis often cannot be managed 1687 adequately without cessation of exposure to the offending agent. Establishment of cause may have significant legal and financial implications for a patient who no longer can work in his or her usual job. Other exposed people may be identified as having the disease or prevented from getting it. In addition, new associations between exposure and disease may be identified (e.g., nylon flock worker’s lung disease and diacetyl-induced bronchiolitis obliterans).


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InternalMed_Harrison. Although the exact proportion of lung disease due to occupational and environmental factors is unknown, a large number of individuals are at risk. For example, 15–20% of the burden of adult asthma and chronic obstructive pulmonary disease (COPD) has been estimated to be due to occupational factors.


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InternalMed_Harrison. The patient’s history is of paramount importance in assessing any potential occupational or environmental exposure. Inquiry into specific work practices should include questions about the specific contami nants involved, the presence of visible dusts, chemical odors, the size and ventilation of workspaces, the use of respiratory protective equipment, and whether co-workers have similar complaints. The temporal association of exposure at work and symptoms may provide clues to occupation-related disease. In addition, the patient must be questioned about alternative sources of exposure to potentially toxic agents, including hobbies, home characteristics, exposure to secondhand smoke, and proximity to traffic or industrial facilities. Short-term and long-term exposures to potential toxic agents in the distant past also must be considered.


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InternalMed_Harrison. Workers in the United States have the right to know about potential hazards in their workplaces under federal Occupational Safety and Health Administration (OSHA) regulations. Employers must provide specific information about potential hazardous agents in products being used through Material Safety Data Sheets as well as training in personal protective equipment and environmental control procedures. However, the introduction of new processes and/or new chemical compounds may change exposure significantly, and often only the employee on the production line is aware of the change. For the physician caring for a patient with a suspected work-related illness, a visit to the work site can be very instructive. Alternatively, an affected worker can request an inspection by OSHA. If reliable environmental sampling data are available, that information should be used in assessing a patient’s exposure. Because many of the chronic diseases result from exposure over many years, current


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InternalMed_Harrison. environmental sampling data are available, that information should be used in assessing a patient’s exposure. Because many of the chronic diseases result from exposure over many years, current environmental measurements should be combined with work histories to arrive at estimates of past exposure.


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InternalMed_Harrison. Exposures to inorganic and organic dusts can cause interstitial lung disease that presents with a restrictive pattern and a decreased diffusing capacity (Chap. 306e). Similarly, exposures to a number of organic dusts or chemical agents may result in occupational asthma or COPD that is characterized by airway obstruction. Measurement of change in forced expiratory volume (FEV1) before and after a working shift can be used to detect an acute bronchoconstrictive response.


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InternalMed_Harrison. The chest radiograph is useful in detecting and monitoring the pulmonary response to mineral dusts, certain metals, and organic dusts capable of inducing hypersensitivity pneumonitis. The International Labour Organisation (ILO) International Classification of Radiographs of Pneumoconioses classifies chest radiographs by the nature and size of opacities seen and the extent of involvement of the parenchyma. In general, small rounded opacities are seen in silicosis or coal worker’s pneumoconiosis, and small linear opacities are seen in asbestosis. Although useful for epidemiologic studies and screening large numbers of workers, the ILO system can be problematic when applied to an individual worker’s chest radiograph. With dusts causing rounded opacities, the degree of involvement on the chest radiograph may be extensive, whereas pulmonary function may be only minimally impaired. In contrast, in pneumoconiosis causing linear, irregular opacities like those seen in asbestosis, the


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InternalMed_Harrison. the chest radiograph may be extensive, whereas pulmonary function may be only minimally impaired. In contrast, in pneumoconiosis causing linear, irregular opacities like those seen in asbestosis, the radiograph may lead to 1688 underestimation of the severity of the impairment until relatively late in the disease. For patients with a history of asbestos exposure, conventional computed tomography (CT) is more sensitive for the detection of pleural thickening, and high-resolution CT (HRCT) improves the detection of asbestosis. Other procedures that may be of use in identifying the role of environmental exposures in causing lung disease include skin prick testing or specific IgE antibody titers for evidence of immediate hypersensitivity to agents capable of inducing occupational asthma (flour antigens in bakers), specific IgG precipitating antibody titers for agents capable of causing hypersensitivity pneumonitis (pigeon antigen in bird handlers), and assays for specific cell-mediated


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InternalMed_Harrison. antigens in bakers), specific IgG precipitating antibody titers for agents capable of causing hypersensitivity pneumonitis (pigeon antigen in bird handlers), and assays for specific cell-mediated immune responses (beryllium lymphocyte proliferation testing in nuclear workers or tuberculin skin testing in health care workers). Sometimes a bronchoscopy to obtain transbronchial biopsies of lung tissue may be required for histologic diagnosis (chronic beryllium disease). Rarely, video-assisted thoracoscopic surgery to obtain a larger sample of lung tissue may be required to determine the specific diagnosis of environmentally induced lung disease (hypersensitivity pneumonitis or giant cell interstitial pneumonitis due to cobalt exposure).


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InternalMed_Harrison. The chemical and physical characteristics of inhaled agents affect both the dose and the site of deposition in the respiratory tract. Water-soluble gases such as ammonia and sulfur dioxide are absorbed in the lining fluid of the upper and proximal airways and thus tend to produce irritative and bronchoconstrictive responses. In contrast, nitrogen dioxide and phosgene, which are less soluble, may penetrate to the bronchioles and alveoli in sufficient quantities to produce acute chemical pneumonitis.


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InternalMed_Harrison. Particle size of air contaminants must also be considered. Because of their settling velocities in air, particles >10–15 μm in diameter do not penetrate beyond the nose and throat. Particles <10 μm in size are deposited below the larynx. These particles are divided into three size fractions on the basis of their size characteristics and sources. Particles ~2.5–10 μm (coarse-mode fraction) contain crustal elements such as silica, aluminum, and iron. These particles mostly deposit relatively high in the tracheobronchial tree. Although the total mass of an ambient sample is dominated by these larger respirable particles, the number of particles, and therefore the surface area on which potential toxic agents can deposit and be carried to the lower airways, is dominated by particles <2.5 μm (fine-mode fraction). These fine particles are created primarily by the burning of fossil fuels or high-temperature industrial processes resulting in condensation products from gases, fumes, or vapors.


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InternalMed_Harrison. fraction). These fine particles are created primarily by the burning of fossil fuels or high-temperature industrial processes resulting in condensation products from gases, fumes, or vapors. The smallest particles, those <0.1 μm in size, represent the ultrafine fraction and make up the largest number of particles; they tend to remain in the airstream and deposit in the lung only on a random basis as they come into contact with the alveolar walls. If they do deposit, however, particles of this size range may penetrate into the circulation and be carried to extrapulmonary sites. New technologies create particles of this size (“nanoparticles”) for use in many commercial applications. Besides the size characteristics of particles and the solubility of gases, the actual chemical composition, mechanical properties, and immunogenicity or infectivity of inhaled material determine in large part the nature of the diseases found among exposed persons.


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InternalMed_Harrison. Table 311-1 provides broad categories of exposure in the workplace and diseases associated with chronic exposure in those industries. Asbestos is a generic term for several different mineral silicates, including chrysolite, amosite, anthophyllite, and crocidolite. In addition to workers involved in the production of asbestos products (mining, milling, and manufacturing), many workers in the shipbuilding and construction trades, including pipe fitters and boilermakers, were occupationally exposed because asbestos was widely used during the twentieth century for its thermal and electrical insulation properties. Asbestos also was used in the manufacture of fire-resistant textiles, in cement and floor tiles, and in friction materials such as brake and clutch linings. Occupational Exposures Nature of Respiratory Responses Comment Asbestos: mining, processing, construction, ship repair Silica: mining, stone cutting, sandblasting, quarrying Coal dust: mining


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InternalMed_Harrison. Occupational Exposures Nature of Respiratory Responses Comment Asbestos: mining, processing, construction, ship repair Silica: mining, stone cutting, sandblasting, quarrying Coal dust: mining Beryllium: processing alloys for high-tech industries Other metals: aluminum, chromium, cobalt, nickel, titanium, tungsten carbide, or “hard metal” (contains cobalt) Fibrosis (asbestosis), pleural disease, cancer, mesothelioma Fibrosis (silicosis), progressive massive fibrosis (PMF), cancer, tuberculosis, chronic obstructive pulmonary disease (COPD) Fibrosis (coal worker’s pneumoconiosis), PMF, COPD Acute pneumonitis (rare), chronic granulomatous disease, lung cancer (highly suspect) Wide variety of conditions from acute pneumonitis to lung cancer and asthma Virtually all new mining and construction with asbestos done in developing countries Risk persists in certain areas of United States, increasing in countries where new mines open New diseases appear with new process


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InternalMed_Harrison. Risk persists in certain areas of United States, increasing in countries where new mines open New diseases appear with new process Cotton dust: milling, processing Grain dust: elevator agents, dock workers, milling, bakers Other agricultural dusts: fungal spores, vegetable products, insect fragments, animal dander, bird and rodent feces, endotoxins, microorganisms, pollens Toxic chemicals: wide variety of industries; see Table 311-2 Other respiratory environmental agents: uranium and radon daughters, secondhand tobacco smoke, polycyclic aromatic hydrocarbons (PAHs), biomass smoke, diesel exhaust, welding fumes, wood finishing Byssinosis (an asthma-like syndrome), chronic bronchitis, COPD Asthma, chronic bronchitis, COPD Hypersensitivity pneumonitis (farmer’s lung), asthma, chronic bronchitis Asthma, chronic bronchitis, COPD, hypersensitivity pneumonitis, pneumoconiosis, and cancer


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InternalMed_Harrison. Asthma, chronic bronchitis, COPD Hypersensitivity pneumonitis (farmer’s lung), asthma, chronic bronchitis Asthma, chronic bronchitis, COPD, hypersensitivity pneumonitis, pneumoconiosis, and cancer Occupational exposures estimated to contribute to up to 10% of all lung cancers; chronic bronchitis, COPD, and fibrosis Increasing risk in developing countries with drop in United States as jobs shift overseas Risk shifting more to migrant labor pool Reduced risk with recognized hazards; increasing risk for developing countries where controlled labor practices are less stringent In-home exposures important; in developing countries, biomass smoke is a major risk factor for COPD among women


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InternalMed_Harrison. In-home exposures important; in developing countries, biomass smoke is a major risk factor for COPD among women Exposure to asbestos is not limited to persons who directly handle the material. Cases of asbestos-related diseases have been encountered in individuals with only bystander exposure, such as painters and electricians who worked alongside insulation workers in a shipyard. Community exposure resulted from the use of asbestos-containing mine and mill tailings as landfill, road surface, and playground material (e.g., Libby, MT, the site of a vermiculite mine in which the ore was contaminated with asbestos). Finally, exposure can occur from the disturbance of naturally occurring asbestos (e.g., from increasing residential development in the foothills of the Sierra Mountains in California).