Environmental Exposures in the Normal Host

59

ENVIRONMENTAL EXPOSURES IN THE NORMAL HOST Alan P. Knutsen, MD, James Temprano, MD, MHA, Jamie L. Wooldridge, MD, Deepika Bhatla, MD, and Raymond G. Slavin, MD, MS

858

HYPERSENSITIVITY PNEUMONITIS Hyper­sen­si­ ti­vity pneumonitis (HP) is an immune-­mediated lung disease occurring in response to repeated inhalation of an antigen. It appears to be an under­diagnosed con­ dition often masquerading as a recurrent ­pneumonia, ­idiopathic pulmonary fibrosis, ­Hamman-Rich disease, or interstitial pneumonia. HP primarily affects adults and older children, and less commonly, children under the age of 2 years.1 HP has several synonyms, ­including pulmonary hypersensitivity syndrome and ­ extrinsic allergic alveolitis. The last term seems particularly ­appropriate because it describes the disease in graphic terms: “extrinsic,” meaning it comes from an outside source; ­“allergic,” denoting a hypersensitivity basis; and “alveolitis,” referring to that part of the lung most affected by the disease. Whichever term is used, it refers to the same basic process, a hypersensitivity reaction of the lung in response to inhalation of an antigen, most often an organic dust. A number of factors determine the response to inha­ lation of an organic dust. First is the basic immuno­ logic reactivity of the host. An atopic individual will characteristically respond with production of IgE anti­ body. A nonatopic person will more likely produce IgG. Second is the nature and source of the antigen. Is it small enough to reach the distal part of the lung? Is it a ther­ mophilic organism, such that it will grow in the respira­ tory tract? Finally, the nature and circumstances of the exposure, is it intense and intermittent, or is it low grade and chronic? An intermittent short-term extensive expo­ sure such as that experienced by a pigeon breeder while cleaning out the coops will cause acute reversible dis­ ease. A pet-store employee, who has intermittent, lower grade but long-term exposure, will develop a subacute form that is usually reversible. Finally, a long-term, lowgrade exposure experienced by a parakeet owner may result in chronic irreversible disease.2 Many antigens have been implicated as causes of HP, and they can come from a wide variety of sources includ­ ing animal proteins, fungi, amoeba, bacteria, medica­ tions, and chemicals. Table 59-1 classifies the causes of HP. The first example of HP was farmer's lung due to a thermophilic organism. These are unicellular branch­ ing organisms that resemble true bacteria.3 A previously common occupational form of HP was bagassosis, or Louisiana sugarcane workers' disease.4 Mold also can be a cause of HP, with two examples being maple bark stripper's disease, which develops in loggers who strip the bark and are exposed to Cryptostroma corticale underneath the bark, and malt worker's lung, which develops in brewery workers exposed to Aspergillus

­clavatus present in the moldy barley on brewery floors.5 Probably the most common cause of HP today is avian antigen. Birds are becoming an increasingly popular as pets and serve as a potent source of antigens responsible for HP.6 Finally, an example of a chemical source is tolu­ ene diisocyanate, which may cause disease in bathtub refinishers.7

Pathogenesis The pathogenesis of HP is incompletely understood. The initial event involves sensitization to an inhaled antigen in the distal airway, but the level and duration of anti­ gen exposure that is required for sensitization is unknown (Fig. 59-1). After antigen exposure in a sensitized indi­ vidual, an acute alveolitis develops with an increase in neutrophils.8–13 This typically peaks at 48 hours and is followed by an increase in the number of macrophages and lymphocytes.14,15 Although a low CD4+/CD8+ T cell ratio is typically seen, a predominance of CD4 + T cells also can be found.16 Type III and Type IV Hypersensitivity Responses It does appear that both type III antigen-antibody complex and type IV cell-mediated delayed hypersen­ sitivity responses are involved (see Fig. 59-1). Antigenspecific precipitating antibodies are found in patients with HP in response to the offending antigen support­ ing a type III reaction17; however, precipitating anti­ bodies also can be found in exposed subjects without evidence of clinical disease.18 Inhaled soluble antigens can bind to immunoglobulin and cause complement activation, leading to increased vascular permeability and an influx of neutrophils and macrophages.19,20 This leads to the production of interleukin (IL)-1 and IL-8, tumor necrosis factor (TNF)-α, monocyte chemoat­ tractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, RANTES (regulated on activation, normal T cell expressed and secreted) and CCL18, with resultant migration of leukocytes into the alveo­ lar interstitium.21,22 Several studies illustrate the role of cell-mediated immunity in the pathogenesis of HP.24–30 A variety of factors, such as MIP-1α, MCP-1, CCL18, and IL-2, leads to an influx and proliferation of lym­ phocytes in the lung of patients with HP.24–27 Secretion of IL-12 and MIP-1α by alveolar macrophages pro­ motes the polarization of CD4+ Th0 lymphocytes to Th1 cells (T helper type 1), which produce interferon (IFN)-γ and are essential for granulomatous inflamma­ tion and the development of HP.28,29

Environmental Exposures in the Normal Host

DISEASE

ANTIGENIC SOURCE

ANTIGEN

Mold and Bacteria Farmer's lung bagassosis

Moldy hay and moldy plant materials

Saccharopolyspora rectivirgula (Micropolyspora faeni) Thermophilic actinomycetes Thermoactinomyces vulgaris

Humidifier lung

Ultrasonic cool mist humidifiers

Bacillus subtilis Klebsiella oxytoca

Ventilation pneumonitis

Contaminated air conditioners, humidifiers, or ventilation systems

Amebas Thermophilic actinomycetes Thermoactinomyces saccharii

Air conditioner lung

Moldy water in HVAC system

Aureobasidium pullulans

Maple bark stripper's disease

Contaminated maple logs

Cryptostroma corticale

Cephalosporium HP

Contaminated basement (sewage)

Cephalosporium spp.

Malt worker's lung disease

Contaminated brewery

Aspergillus clavatus

Basement shower HP

Moldy basement shower

Epicoccum nigrum

Summer-type HP

Japanese house dust

Trichosporon cutaneum

Pigeon- or bird-breeder's disease; bird fancier's lung; bird handler's lung

Pigeons, parakeets, parrots, doves and cockatiels

Avian proteins from bird excreta, feathers, or bloom

Laboratory worker's lung

Rat or gerbil urine

Rodent urinary protein

Wheat weevil disease

Infested wheat flour

Sitophilus granaries

Oyster shell lung

Oyster/mollusk shell protein

Shell dust

Paint refinisher's disease, bathtub refinisher's lung

Toluene diisocyanate

Varnishes, lacquer, foundry casting, polyurethane foam

Pyrethrum lung

Insecticide

Pyrethrum

 Drug-induced HP

Medications

Amiodarone, cyclosporine, gold, minocycline, chlorambucil, sulafasalazine, nitrofurantoin, methotrexate, beta blockers, mesalamine

Animal Protein

Chemicals and Drugs

Cells, Cytokines, and Other Pulmonary Factors Several other factors may play a role in the pathogenesis of HP. Natural killer cells (NK) are increased in the bron­ choalveolar lavage (BAL) fluid and lung tissue of patients with HP and appear to provide a protective effect.23,24 Aberrant regulatory T cell and Th17 cell function also may play a pathologic role.25–30 Up-regulation of co-stimulatory molecules on alveolar macrophages and increased expres­ sion of L-, E-, and P-selectins may lead to the influx of various leukocytes into the lung.31–34 MyD88, an adapter protein that interacts with several toll-like receptors (TLRs), has been found to play an important role in the inflammatory response seen in HP.35,36 Surfactant protein A, which stimulates inflammatory cytokine release, is increased in BAL fluid from patients with HP.37 Increased formation of free radicals, through a variety of mecha­ nisms, also contributes to lung inflammation.17,38–40

Excessive accumulation of extracellular matrix compo­ nents through increased levels of fibrinolysis inhibitors, such as thrombin-activatable fibrinolysis inhibitor and protein C inhibitor, or decreased activity of matrix metal­ loproteinases, contributes to the fibrotic process seen in chronic HP.41,42 Susceptibility Factors Multiple susceptibility factors have been implicated in the pathogenesis of HP, such as cigarette smoking, viral infections, endotoxin, and genetic predisposition. Several studies have observed a negative relationship between cigarette smoking and the development of HP in simi­ larly exposed individuals.43–48 Many patients with HP report a viral type illness or flulike symptoms during the initial stage of disease. An acute viral infection could enhance the antigenic response in HP by increasing the

Chapter 59

TABLE 59-1  COMMON ETIOLOGIC ANTIGENS AND SOURCES IN HYPERSENSITIVITY PNEUMONITIS

859

chILD ? Adjuvants Alveolar space Viral infection Glutathione Antigen Catalase Abnormal surfactant

Section IX

860

Interstitial lung space

Complement activation Cigarette smoke

C3a C5a IL-8

Chemotaxis

MHCl CD28 B7

Eosinophil Neutrophil

Cytokines IL-2 IL-8 IL-12 IL-16 MIF IL-10

Inflammation and cytotoxicity Neutrophilia (48 hrs) Acute

TCR  

IFN-

Antibodies Heat shock protein

Processing Presentation

CD8 lymph

CD8

Superoxide anion Hydroxyl radical Toxic oxygen species

Alveolar macrophage

Activated alveolar macrophage

Antibody secreting

MHCII CD41 lymph

B cell

CD4

IL-1

Cytokines Arachidonic acid products IL-1 IL-8 MIP1 MCAF TNF

Plasma cell

TNF-

Superoxide anion Hydroxyl radical

Noncaseating granulomas

Collagen synthesis Vitronectin Fibronectin Pro-collagen III peptide

Lymphocytosis (48 hrs) CD8  CD4 Hypersensitivity pneumonitis

Vascular space Sialyl-Lewisx (sLex) Activated endothelium E-selectin ICAM-1 PMN Monocyte Lymphocyte sIL-2rc

Chronic

FIGURE 59-1.  Pathogenesis of hypersensitivity pneumonitis. Small molecular weight antigen that enters the alveoli is engulfed by alveolar macrophages, which become activated and interact with both CD4 + and CD8 + T cells. Other cell types are attracted through chemokines and release a variety of inflammatory mediators typical of T helper cell type 1 (Th1) profile. Many factors, including adjuvants, environmental influences, surfactant composition, and balance of cytokines, influence the inflammatory responses. This response eventually leads to a lymphocytic infiltration and granuloma formation in the interstitial lung spaces and alveoli. (Used with permission from Dr. Jordan Fink and Elsevier Publishing.)

antigen presentation ability of alveolar macrophages, decreasing the clearance of antigens, and inducing the release of proinflammatory cytokines.49 Endotoxin coex­ posure with antigen has been shown to augment lung pathology in a murine model of HP and may act through TLRs on macrophages, leading to a Th1 T cell response or play an indirect role in the pathogenesis of HP as an adjuvant.24,50 Finally, various HLA haplotypes and genetic polymorphisms, such as those of the TNF-α gene ­promoter and IL-6 gene, have been associated with sus­ ceptibility to HP.51–61

Clinical Manifestations The clinical manifestations of HP depend on the nature and circumstances of exposure; HP is divided into three stages, acute, subacute, and chronic. Acute Stage In the acute form of HP, such as that seen in pigeon breeders, chills, fever up to 40o C, cough, and short­ ness of breath are seen 4 to 6 hours after exposure. Symptoms may persist for up to 18 hours. Patients usu­ ally recover in 2 to 5 days, with episodes occurring after each subsequent exposure. Physical examination reveals only crackling and rales in the lower lung fields. HP is an example of an interstitial pneumonia in which there is a disparity between the symptoms of the patient and

the physical findings. Wheezing is uncommon because most patients exposed to organic dusts do not develop HP and asthma. Subacute Stage The subacute form occurs as a result of an intermittent low grade but continuous long-term exposure such as seen is in a pet-store employee. The symptoms are milder and include malaise, low-grade fever, cough, chills and progressive dyspnea often associated with anorexia and weight loss. This form is usually reversible.62 Chronic Stage A long-term low-grade exposure experienced by a para­ keet owner or from a contaminated home humidifier may result in chronic irreversible disease. These patients pres­ ent with dyspnea, chronic cough, fatigue, anorexia and weight loss.63 Immunologic Studies Laboratory evaluation generally reveals a marked leukocy­ tosis with prominent neutrophilia during the acute phase of HP.64 An elevation of markers of inflammation, such as erythrocyte sedimentation rate and C-reactive protein, may be seen. An elevated rheumatoid factor is found in 50% of patients along with elevation in serum IgG, IgA, and IgM.64 Skin testing has limited value in the workup of HP. Results of a number of studies are ­conflicting. A high

Environmental Exposures in the Normal Host

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Chapter 59 FIGURE 59-3.  HRCT scan of the chest in a child with HP, demonstrating ground-glass opacities.

FIGURE 59-2.  Ouchterlony double immunodiffusion (agar gel immu-

nodiffusion). The center well contains patient serum and the outer wells contain different antigens. Note the strong line of precipitation between the patient's serum and the antigen (arrow).

percentage of patients without the disease have positive skin tests reactions, and there is a lack of commercially available standardized extracts. A diagnostic hallmark of HP is an IgG precipitating antibody seen on a double gel diffusion plate (Fig. 59-2). However, the presence of precipitating antibody is only a marker of exposure, and sensitization and does not correlate with disease activity. Approximately 40% to 50% of asymptomatic exposed individuals will have precipitating antibody to the offending antigen.65 Reports from commercial laboratories are some­ times inaccurate, and selection of a laboratory experienced in assays for the diagnosis of HP is important. Methods more sensitive than gel diffusion are available, includ­ ing counterimmunoelectrophoresis (CIE), enzyme linked immunosorbent assays (ELISA), and radioimmunoas­ say (RIA). Lymphocyte proliferation assays to the offend­ ing antigen are usually positive in patients with HP.66 In one study, alveolar macrophages from patients with HP enhanced the lymphoproliferative response while the response was inhibited in normal patients. This suggests that a defect in the ability of alveolar macrophages to sup­ press the lymphoproliferative response leads to the devel­ opment of the observed lymphocytic alveolitis seen in patients with HP.66 It should be emphasized that these stud­ ies are available only in research laboratories. Radiologic Findings Radiologic findings in HP correlate with the stage of dis­ ease. In acute HP, chest radiography usually demonstrates poorly defined, nodular infiltrates, but patchy groundglass opacities or diffuse infiltrates also may occur.24,64,67,68 It is important to note that patients with acute HP may have a normal chest radiograph after cessation of expo­ sure and resolution of the acute episode. High-resolution computed tomography (HRCT) of the chest typically demonstrates ground-glass opacities in acute HP, but the

presence of ground-glass opacities is generally a nonspe­ cific finding (Fig. 59-3).69,70 Ground-glass opacification represents cellular interstitial infiltration, small granulo­ mata within the alveolar septa, or both.70 These opacities may be found either centrally or peripherally, but are pre­ dominantly in the lower lung zones with sparing of the apices in acute HP.20,71 In subacute HP, a reticulonodular appearance with fine linear shadows and small nodules is typically pres­ ent on chest radiograph, although the chest radiograph also may be normal as seen in acute HP.20,71 The infil­ trates in subacute HP usually predominate in the mid to upper lung zones.20,71 HRCT of the chest in subacute HP typically demonstrates centrilobular nodules associ­ ated with larger areas of ground-glass opacity, as well as air trapping and mosaic perfusion (see Fig. 59-2).70 Centrilobular nodules correspond to the presence of poorly marginated granulomata and active alveolitis, while mosaic perfusion indicates the redistribution of blood flow, and air trapping denotes obstructive bron­ chiolitis.70 The presence of ground glass opacities, air trapping, mosaic perfusion, and areas of normal lung attenuation on the same film yields an appearance on HRCT known as the headcheese sign.70 This is charac­ teristic for subacute HP. Chronic HP is characterized by diffuse reticulono­ dular infiltrates, volume loss, and coarse linear opacities on chest radiography.20,67,71 The findings in chronic HP appear to be more severe in the mid to upper zones of the lung.20,71 HRCT often demonstrates fibrotic changes that include irregular linear opacities, honeycombing, and traction bronchiectasis.70 These changes also can be found in several other disorders such as sarcoidosis, interstitial pulmonary fibrosis, and collagen vascular dis­ eases.70 Centrilobular nodules are often found in chronic HP when ongoing antigen exposure is occurring. The radiographic findings in chronic HP, unlike acute HP, are unlikely to resolve when antigen exposure ceases. Several findings are not characteristically found and may be help­ ful in differentiating HP from other disorders. Pleural effusions or pleural thickening, as well as ­ cavitation,

Section IX

862

chILD c­alcification, or atelectasis, are usually absent in HP.68 Hilar adenopathy, commonly seen in sarcoidosis, is rarely seen in HP.64 Pulmonary Function Testing and Bronchial Challenge Pulmonary function testing typically reveals restriction with a reduction in lung volumes and a decrease in dif­ fusion capacity for carbon monoxide (DLCO); however, obstructive, mixed obstructive and restrictive, or normal pulmonary function tests can be seen.* A decrease in air­ way compliance is often seen with a shift in the pressurevolume curve down and to the right.64,71 A decrease in arterial oxygen tension (Pao2) on arterial blood gas anal­ ysis is most commonly seen in chronic HP, but can be found in both acute and subacute forms of the disease.16 The hypoxemia and decreased diffusion capacity may be accounted for by filling of the alveolar space with fluid and inflammatory cells. Oxygen desaturation with exer­ cise or with sleep is not an uncommon finding.71 Twenty percent to 40% display nonspecific airway reactivity and 5% to 10% have asthma.68,73,74 Additionally, in patients with farmer's lung, Karjalainen and colleagues75 showed an increased risk in developing asthma after their diag­ nosis of HP. The concomitant or future development of asthma after HP also has been shown in HP caused by diisocyanates, after summer-type HP and after residential mold exposure.74,76–79 Bronchial challenge has been studied in adults but is infrequently used in children.71,80 These challenges can be performed either through re-exposure to the suspected setting or through a controlled challenge in an expe­ rienced laboratory. In a review by Fan,71 20 of 86 chil­ dren with HP underwent bronchial challenge, and only 55% of these patients had positive challenges. In a large cohort of patients with bird fancier's lung, Morell and colleagues16 reported a sensitivity of 92% and specificity of 100% using bronchial challenge to avian extracts. As the authors note in their study, bronchial challenge test­ ing should be performed in a hospital setting with expe­ rienced staff and high-quality antigenic extracts.16 Some difficulties that may be encountered in bronchial provo­ cation are poor standardization of the antigen dose used for the challenge, difficulties in objectively defining a positive test, and the difficulty that many young children have in performing routine pulmonary function testing.81 Bronchoalveolar Lavage and Lung Biopsy The BAL from normal individuals typically reveals a pre­ ponderance of alveolar macrophages with approximately 10% lymphocytes that have a CD4+/CD8+ ratio of 1.8.110 After acute antigen exposure, the BAL in patients with HP reveals a predominance of neutrophils that is then followed by a lymphocytic alveolitis, which usually com­ prises 60% or greater of the white blood cell differential.† Historically, a low CD4+/CD8 + ratio has been associated with HP, while a CD4+/CD8 + ratio of over 3.5:1 has been associated with sarcoidosis.‡ More recent studies, how­ ever, have disputed this finding with the demonstration *References 20, 24, 64, 67, 68, 71, and 72. † References 8, 9, 12, 20, 63, and 82. ‡ References 20, 24, 63, 64, and 82–85.

of HP cases with higher CD4+/CD8+ ratios.16,61,86 A study by Ando and colleagues86 also suggested that the CD4+/ CD8+ ratio may differ by the causative antigen and the smoking status of the patient. The BAL findings in HP also may differ based on the age of the patient. Ratjen and colleagues23 evaluated BAL findings in children with HP. Nine subjects, 6 to 15 years of age, with acute HP were included in this study. The BAL uniformly revealed an increase in the percentage of lymphocytes and foamy macrophages in children with HP. All patients were found to either have an increased expression of HLA-DR (7 of 8 children) on BAL lymphocytes or an increase in NK cells (5 of 8 children) in BAL fluid. Importantly, there were no significant differences between normal controls and patients with HP with respect to the CD4+/CD8+ T cell ratio. Histologic findings in HP vary based on the stage of disease.19,21,87 Reports on the pathology associated with acute HP are few, but most note the presence of interstitial mononuclear cell infiltrates.18,87 Granulomata and macro­ phages with foamy cytoplasm also have been reported.88 The classic triad of subacute HP includes an interstitial lymphocytic-histiocytic cell infiltrate; bronchiolitis oblit­ erans; and scattered, poorly formed, non-necrotizing granulomata.16,19 In a large series of patients with bird fancier's lung, however, this triad was only seen in 9% of cases that underwent transbronchial lung biopsy, but at least one of the findings was present in 69% of cases.16 Other findings commonly seen in HP include interstitial giant cells, interstitial granulomata, or Schaumann bod­ ies.89 In a pathologic review of 25 cases with chronic HP, giant cells, granulomata or Schaumann bodies were seen in 88% of cases, and 72% of cases exhibited a usual interstitial pneumonia (UIP)–like pattern.89 A nonspecific interstitial pneumonia (NSIP)–like pattern or a bronchiol­ itis obliterans organizing pneumonia–like disease also can be seen in chronic HP.90,91 Multiple studies have demon­ strated decreased survival rates in patients with UIP-like or NSIP-like patterns of fibrosis.89,92,93 The usefulness of biopsy for the diagnosis of HP has been questioned.21,94 Although the aforementioned find­ ings are commonly seen in various stages of HP, none of the findings are pathognomonic for the disease because they can be found in other lung disorders. Most patients with HP can be diagnosed based on signs, symptoms, exposure history, radiographic, laboratory and BAL find­ ings, obviating the need for lung biopsy. When a biopsy is performed, a surgical lung biopsy is the preferred method because it has greater diagnostic yield.21 A study in patients with farmer's lung found limited usefulness of transbron­ chial biopsies as a diagnostic tool in HP.95 Because the utility of transbronchial biopsies in HP is questioned and the majority of cases can be diagnosed without biopsy, surgical lung biopsy is usually reserved for cases when other studies do not yield a definitive diagnosis. Etiology There are over 200 antigens known to cause HP. The eti­ ology of HP differs between adults and children and is due to differences in exposure. The majority of adult cases of HP are due to various occupational exposures. In chil­ dren, most cases are due to household exposures, with

Environmental Exposures in the Normal Host

Bird Fancier's Lung Avian antigens are the most commonly reported cause of HP in children.71,96 Proteins derived from the bloom, serum, or excrement of several avian species have been demonstrated to cause HP. Bloom, a dust coating the feathers composed of keratin covered with IgA, is pro­ duced in large quantities by flying birds. While pigeons are the principal source of avian antigen in HP, several other birds have been implicated, such as parakeets, par­ rots, doves, and cockatiels.97–103 Although bird fancier's lung is the commonest form of HP seen in children, it is still a rare disease.96 Most pediatric reports note that chil­ dren were initially treated for pulmonary infections or had multiple health care encounters before a diagnosis was made.96,104–106 The diagnosis should be considered in any child with persistent, unexplained respiratory symptoms. The mainstay of therapy is bird avoidance, and therapy with corticosteroids is frequently required. Importantly, bird antigens have been found to persist at high levels as long as 18 months after bird elimination from the home.107 As is the case with other forms of HP, patients with acute forms of the disease have the best prognosis, while those with chronic disease have higher morbidity.108 Other Environmental Exposures HP also may result from exposure to various fun­ gal or bacterial antigens. Thermophilic actinomycetes, Neurospora, and Candida albicans have been reported as causes of HP in patients that used covered swim­ ming pools.109,110 Residential mold contamination with Auerobasidium pullulans has been reported to cause HP in an adult and in child siblings.74,111 This same species has been implicated as the etiologic agent causing HP in a child exposed to indoor hydroponics.112 Household exposure to a fungus, Trichosporon cutaneum, causes summer-type HP, a common form of HP in Japan.113 Contamination of the home with the fungus Bjerkandera adusta was found to cause HP in an elderly male.77 A report of two children with HP secondary to expo­ sure from an unventilated basement shower identified Epicoccum nigrum as the causative mold.114 Fusarium napiforme also was found to be the etiologic agent in a 17 year old with HP due to residential mold exposure.115 Exposure to mold or various bacteria through ultrasonic humidifiers and saunas also has been demonstrated to cause HP.116–118 Aspergillus fumigatus was found to be the causative agent in a child with HP who had repeated exposure to organic compost on a playground.119 There are also numerous reports of “hot-tub lung,” caused by Mycobacterium avium complex, a non-tuberculous mycobacteria.120–125 This disease typically occurs after exposure to hot water aerosols from hot tubs, show­ ers, and swimming pools.123 Most reports note that poor hot tub maintenance or poor personal hygiene practices contribute to the development of the disease. Some con­ troversy does exist on whether this disease is a true rep­ resentation of HP or has an infectious etiology. Patients with hot tub lung have well-formed, sometimes necrotic,

granulomata, obstructive lung disease, and usually lack serum precipitating antibodies to the offending antigen, all supporting an infectious nature of the illness.122,123 However, the clinical presentation, BAL lymphocytosis, HRCT findings, and therapeutic response to cessation of exposure and treatment with corticosteroids are con­ sistent with HP.121–125 Cladosporium also has been impli­ cated as a cause of HP in an enclosed hot tub area.126 Finally, “lifeguard lung,” a granulomatous pneumonitis from indoor swimming pool exposure, was reported in several lifeguards exposed to water spray features at an indoor pool.127

Therapeutic Considerations and Prognosis In the acute form, simple removal from the offending environment generally suffices. If symptoms are severe, the patient should be started on a tapering dose of pred­ nisone beginning with 60 mg per day. Supportive mea­ sures might include O2, antitussives, and antipyretics as indicated. For the repeated, acute, or subacute form, exposures should be decreased as much as possible with administration of long-term corticosteroids emphasizing alternate day therapy. The chronic form can be treated with long-term corticosteroids but only if radiographic findings and physiologic changes indicate a response.128 Clinical follow-up should include spirometry with lung volume and diffusion capacity and chest radiograph. It is vital that the antigen responsible for HP be determined so that appropriate environmental control measures can be carried out. Several initiatives can decrease the antigenic burden. Chemicals can be added to prevent growth of an agent. A good example is propionic acid, which when added to sugarcane, eliminates the growth of the thermo­ philic organism responsible for bagassosis. Water should be changed frequently in humidification or air condition­ ing units. Storage dryers decrease the growth of mold and thermophilic organism in hay and straw. Finally, crops should be harvested when the moisture content is low. There are many ways to decrease exposure to organic dust. Dusty materials within closed spaces should be mechanically handled. Effective ventilation will remove dust from the ambient air. In some instances, personal respirators or masks may be used. Finally, when these measures have failed, the worker should be removed from the disease-producing environment. The prognosis for patients with HP is generally good if the offending antigen is detected and avoidance mea­ sures are enforced during the acute and subacute stages. In a review of HP in children by Fan,71 97% of reported pediatric cases of HP had a favorable outcome when exposure was eliminated. A study in patients with farm­ er's lung demonstrated a recovery in DLCO up to 2 years from initial diagnosis.129 In chronic HP, the prognosis is not as good, especially in patients with continued antigen exposure.108 The presence of fibrosis seems to be the most important factor in prognosis because antigen class, symp­ tom duration, and pulmonary function did not appear to be significant predictors for survival in patients with HP.130 Fortunately, with early identification and treatment, pro­ gression to the chronic stage of HP can be avoided.

Chapter 59

avian antigens being the most common etiology, followed by molds.71 A classification of the types of HP with the respective causative antigens is given in Table 59-1.

863

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chILD

EOSINOPHILIC PULMONARY DISEASES The eosinophilic lung diseases include a group of disorders that are characterized by increased peripheral blood and/ or pulmonary eosinophilia (Box 59-1).131–133 The ­clinical presentation of pulmonary eosinophilia consists of pulmo­ nary symptoms, abnormal chest radiographs, and blood/ sputum eosinophilia.

Biology of Eosinophils Eosinophils are inflammatory granulocytes important in host defense principally against helminth parasites. They also play an important inflammatory role in a variety of diseases, including asthma, allergic diseases, eosinophilic esophagitis, and hypereosinophilic syndrome. Eosinophils are bone-­ marrow derived granulocytes.134 The key cyto­ kines that are critical for bone production of eosinophils are interleukin (IL)-3, IL-5, and granulocyte-monocyte-colony stimulating factor (GM-CSF), produced by CD4+ T cells. Activation of eosinophils is principally by IL-5 stimulation, which also increases tissue eosinophil survival. Tissue recruit­ ment of eosinophils from the vascular system is stimulated by the chemokines platelet activating factor (PAF), leukot­ riene (LT)-D4, C5a, CCL11/eotaxin, and CCL5/RANTES. Stimulation by eotaxin is selective for only eosinophils. Eosinophils possess a number of preformed granulederived proteins (major basic protein, eosinophil per­ oxidase, eosinophil cationic protein, eosinophil-derived neurotoxin, and Charcot-Leyden crystal protein), de novo synthesized lipid mediators (LTC4, PGE1, PGE2, TXB2, 15-HETE, and PAF), and reactive oxygen species that are released upon stimulation and result in inflamma­ tion. Eosinophils synthesize a number of Th2 cytokines (IL-4 and IL-5), Th1 cytokines (IFN-γ), and chemokines (eotaxin, RANTES). Eosinophils also have Fc receptors, principally for IgA, which may regulate antibody depen­ dent cellular cytotoxicity (ADCC) eosinophil degran­ ulation. Thus, eosinophils are principally Th2-driven granulocytes that have potent inflammatory and tissue destructive properties.

Drug-Induced Eosinophilia Many different drugs have been associated with the devel­ opment of pulmonary eosinophilia (Box 59-2).135–142 In fact, drug reactions are one of the most commonly reported causes of pulmonary infiltrates with blood or pulmonary eosinophilia. Sulfonamides, including sulfasalazine, were the first recognized cause of this reaction; however, more recently, it has been described with the structurally similar

BOX 59-1 Pulmonary Diseases with Eosinophilia 1. Drug- and toxin-induced eosinophilic disease 2. Helminth-associated eosinophilic lung disease 3. Fungal-associated eosinophilic lung disease 4. Acute eosinophilic pneumonia 5. Chronic eosinophilic pneumonia 6. Eosinophilic granuloma (formerly Histiocytosis X) 7. Churg-Strauss syndrome (Allergic angiitis and granulomatosis) 8. Hypereosinophilic syndrome

drugs, sulfonylurea and chlorpropamide, and the antitu­ berculous drug, p-aminosalicylic acid. The tricyclic com­ pounds imipramine and ­carbamazepine also may cause pulmonary eosinophilia. Of the hydantoins (nitrofuran­ toin, dantrolene, and phenytoin), nitrofurantoin is most likely to cause an adverse pulmonary reaction. The reac­ tion may be seen within days of starting treatment. Other drugs that have been implicated in pulmonary eosino­ philia are listed in Box 59-2. In addition to drugs, toxins from occupational expo­ sures, such as rubber workers exposed to aluminum silicate and particulate metals, sulfite-exposed grape workers, and workers affected by Scotchguard inhalation are also linked to pulmonary eosinophilia. A Löffler's-like syndrome has been seen in crack cocaine users. Drug reactions may be associated with the simple form of pulmonary eosinophilia-like syn­ drome, fulminant acute eosinophilic pneumonia-like syndrome, or they may follow a more chronic source. Symptoms normally start within a month of start­ ing the drug and include cough, dyspnea, and fever. Histologically, there is pulmonary interstitial edema with a lymphocytic and eosinophilic infiltrate, and the alveoli contain eosinophils and histiocytes. Peripheral eosinophilia, though common, is not an invariable finding. Chest radiographs show interstitial or alve­ olar infiltrates and often demonstrate Kerley B lines. HRCT chest scans demonstrate areas of ground-glass attenuation; airspace consolidation; nodules; irregu­ lar lines, and sometimes, hilar adenopathy or pleural effusion.143,144 Drug-induced eosinophilic lung disease resembles other eosinophilic lung diseases, such as Löffler’s syndrome. Thus, other causes need to be evaluated. Confirmation of the adverse reactions may be carried out by challenging the patient with a single dose of the drug. Skin testing with

BOX 59-2  Drugs that Cause Eosinophilic Lung Disease Ampicillin Aspirin Beclomethasone dipropionate (inhaled) Bleomycin Captopril Carbamazepine Chlorpromazine Clarithromycin Chlorpropamide Clofibrate Cocaine (inhaled) Cromolyn (inhaled) Desipramine Diclofenac Febarbamate Fenbufen Glafenine GM-CSF Gold Ibuprofen Imipramine IL-2 IL-3 Iodinated contrast dye

L-Tryptophan Mephenesin carbamate Methotrexate Minocycline Naproxen Nickel Nitrofurantoin p-Aminosalicyclic acid Penicillamine Penicillin Pentamidine (inhaled) Phenytoin Pyrimethamine Rapeseed oil Sulfadimethoxine Sulfadoxine Sulfasalazine Sulindac Tamoxifen Tetracycline Tolazamide Tolfenamic acid Vaginal sulfonamide cream

Environmental Exposures in the Normal Host

Helminth-Associated Eosinophilic Lung Diseases Helminth-associated eosinophilic lung diseases can be characterized based on the natural life-cycle or history of the parasites145–151 (Box 59-3). Infection in humans may occur by ingestion of eggs or larvae, penetration of skin by larvae, or inoculation of larvae by biting insects. Eosinophilic inflammation is a host response mecha­ nism to resist these infections. Helminth infections also may lead to elevated serum IgE levels and a dominant Th2 cytokine profile. In developing countries, this Th2 response to parasites appears to decrease expression of asthma and allergic diseases.

BOX 59-3 Helminth-Associated Eosinophilic Lung Diseases 1. Transpulmonary passage of helminth larvae (Löffler ’s syndrome) • Ascaris lumbricoides, Ancylostoma duodenale, Necator ­americanus, Strongyloides stercoralis 2. Hematogenous seeding with helminth larvae • Cutaneous larva migrans—nonhuman ascarids and hookworms, Trichinella spiralis, Schistosoma • Visceral larva migrans—aberrant infection—Toxocara canis • Disseminated Strongyloides 3. Pulmonary parenchymal invasion with helminths • Paragonimus westermani lung flukes 4. Tropical pulmonary eosinophilia—Filaria • Wucheria bancrofti, Brugia malayi

Transpulmonary Passage of Helminth Larvae In 1932, Löffler described transient or migratory pulmo­ nary infiltrates and peripheral blood eosinophilia in Swiss patients (132 with Ascaris infection acquired from soil containing human feces used as fertilizer. The nematodes that cause Löffler's syndrome are Ascaris lumbricoides, the hookworms Ancylostoma duodenale and Necator americanus, and Strongyloides stercoralis.146,147 These organ­ isms have infecting larvae that pass through the lungs as part of their life cycle. The larvae penetrate into the alveoli from the circulation and then ascend the airway to transit down the esophagus into the small intestines. In the intes­ tines, the larvae mature and become adult worms. Ascaris lumbricoides is the principal cause of Löffler's syndrome.146,147 Ascaris is a ubiquitous parasite present in the soil of temperate and tropical zones. Infection is acquired by ingestion of the eggs, which hatch in the upper small intestine and free the larvae. The pulmonary symp­ toms develop 9 to 12 days after ingestion of the Ascaris eggs. Common symptoms include a nonproductive cough and substernal pain. Rales and wheezing occur in 50% of patients. Chest radiographs show nonsegmental infiltrates ranging in size from several millimeters to centimeters. The infiltrates are transitory and migratory and usually resolve over several weeks. Histopathology of the pulmonary infil­ trates shows an eosinophilic inflammatory reaction to the Ascaris larvae. Peripheral blood eosinophilia peaks during pneumonic involvement and resolves over many weeks. Diagnosis of Ascaris infection is difficult at the time of pneumonitis because this would require identification of the larvae either from pulmonary secretions or gastric aspi­ rates. Typically, the diagnosis is established by identifica­ tion of Ascaris eggs in stool specimens, but this may not occur until 2 to 3 months after the pulmonary infiltrates (Table 59-2). IgG and IgE antibodies to the ABA-1 allergen of Ascaris develop earlier and may be ­protective. The treat­ ment of Ascaris infection is albendazole or mebendazole.

TABLE 59-2  DIAGNOSIS OF HELMINTH INFECTIONS PARASITE

MICROSCOPIC DIAGNOSIS

SEROLOGIC

Stage Specimen Intestinal Nematodes Ascaris lumbricoides Ancylostoma duodenale Necator americanus Strongyloides stercoralis

Eggs Eggs, larvae Eggs, larvae Larvae

Feces Feces Feces Feces, sputum, duodenal fluid

IgE and IgG antibodies (I, Q, S)

Larvae Larvae Microfilariae Microfilariae

Muscle biopsy Liver biopsy, other tissues Blood, urine Blood, urine

IgG antibodies (Q, S) IgG antibodies (Q, S) (preferred) IgG (CDC), antigen (blood) IgG (CDC), antigen (blood)

Schistosoma spp.

Eggs

Feces, rectal snips

Paragonimus westermani

Eggs

Sputum, feces

IgG antibodies (Q, S, CDC) Antigens (serum, urine) IgG (CDC)

IgG antibodies (Q, S)

Tissue Nematodes Trichinella spiralis Toxocara canis Wuchereria bancrofti Brugia malayi Flukes—Trematodes

CDC, Division of Parasitic Diseases, Centers for Disease Control and Prevention; I, IBT Laboratories; Q, Quest Laboratories; S, Speciality Laboratories..

Chapter 59

either patch or prick tests is usually negative. In vitro lym­ phocyte transformation tests have been positive with some drugs, such as nitrofurantoin and carbamazepine. When the offending drug is discontinued, there is usually resolution of the symptoms and the eosinophilia, together with clearing of the chest radiograph. When resolution is slow, cortico­ steroid drugs may hasten the recover, though not invariably.

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chILD Hookworms Infection with hookworms also may cause Löffler's syn­ drome, but more rarely. Hookworms are prevalent in tropical and subtropical zones. Infection is acquired from larvae contaminated soil via ingestion or exposure to skin by A. duodenale and N. americanus.146,147 The larvae that enter the skin cause a pruritic skin rash characterized by papules and papulovesicles, especially on the feet. The larvae are then carried by the venous circulation to the right side of the heart and to the lungs. From here, the lar­ vae follow the route described for Ascaris. Larvae that are ingested develop entirely within the gastrointestinal tract, similar to Ascaris. Clinical symptoms, besides eosino­ philic pneumonitis and eosinophilia, or include anemia caused by blood loss, abdominal pain, diarrhea, nausea, and anorexia. The diagnosis is established by identifica­ tion of hookworm eggs and worms in stool specimens (see Table 59-2). S. stercoralis has a worldwide distribution but is most prevalent in tropical and subtropical regions.146,147 Similar to hookworm infection, S. stercoralis infection is acquired by exposure of the skin to larvae in the soil. Larval migration through the skin results in erythema­ tous maculopapular lesions, especially on the feet, and creeping eruptions, “larva currens.” The migration of lar­ vae from skin to heart and lungs and then gastrointesti­ nal tract is similar to hookworms; it takes approximately 1 month for mature eggs to develop in the intestines. The clinical manifestations include an eosinophilic pneu­ monitis, eosinophilia, and gastrointestinal symptoms of watery mucous diarrhea. The diagnosis is established by identification of the larvae in stool, sputum, or duode­ nal fluid specimens (see Table 59-2). IgG antibodies for Strongyloides also may be detected.

Hematogenous Seeding with Helminth Larvae In this category, there is heavy hematogenous infection by helminth larvae or eggs causing eosinophilic pneumo­ nitis. The etiologic helminths include nonhuman Ascaris and hookworms, which cause cutaneous larva migrans, and Toxocara canis, which causes visceral larva migrans, Trichinella spiralis, Schistosoma, and disseminated Strongyloides.148–150 Toxocara canis infection is characterized by visceral larva migrans, eosinophilia, fever, hepatomegaly, and eosinophilic pneumonitis in 32% to 44% of patients.148–150 Toxocara eggs are prevalent wherever dogs are found. Infection occurs through ingestion of contaminated soil, most commonly by young children. Because the larvae do not mature, they migrate throughout the body caus­ ing visceral larva migrans.149 A pronounced eosinophilia develops and eosinophilic granuloma formation occurs in the target organs that include the liver, lungs, brain, and eye. Serologic diagnosis is available through the Division of Parasitic Diseases, Centers for Disease Control and Prevention, Atlanta, GA (see Table 59-2). Trichinella spiralis causing trichinellosis is acquired by ingestion of undercooked meat, primarily domestic pigs.149 T. spiralis has a worldwide distribution. Two to

3 weeks after ingestion, adult worms mature in the small intestine. Larvae migrate from the gastrointestinal tract throughout the body via blood and lymphatics to prin­ cipally striated muscle. The worms and larvae evoke an eosinophilic and lymphocytic inflammatory response. Clinical symptoms include myositis and, with high infec­ tious burden, eosinophilic pneumonia, myocarditis, and encephalitis may develop. Diagnosis can be established by detection of antibodies to Trichinella (see Table 59-2). Treatment is with mebendazole or albendazole. Schistosomiasis is caused by helminth parasites of the class Trematoda, which includes flukes.148,150 Each species of Schistosoma uses fresh-water snails as its intermediate host. Its geographic distribution is limited to certain snail habitats, such as China, Indonesia, sub-Saharan Africa, Egypt, the Middle East, and Brazil. Humans are infected in fresh water contaminated by the fork-tailed cercar­ iae, which penetrate the skin. Within hours of penetra­ tion, erythematous or vesicular lesions develop caused by eosinophilic and monocytic inflammatory reactions, termed “swimmer's itch.” The Schistosoma larvae then migrate through the lungs causing fever and eosinophilic pneumonitis. These reactions typically resolve spontane­ ously. Acute schistosomiasis begins 1 to 2 months later when mature worms begin to produce eggs. At this time, there is characteristically marked eosinophilia, elevated IgE levels, elevated specific IgE and IgG antibodies to Schistosoma, and a Th2 cytokine response. The eosino­ philic pneumonitis, which occurs during larval migra­ tions, occurs early in infection and is manifested by fever, cough, and basilar rales, and wheezing. Chest x-rays may show basilar mottling. There is peripheral blood and pul­ monary eosinophilia. Symptoms typically resolve spon­ taneously over a 1-month period. In patients with a heavy parasite load, a reactive pneumonitis may be seen. Diagnosis is established serologically or by identification of eggs in stool specimens (see Table 59-2). Praziquantel is the treatment of choice. Paragonimus westermani is a helminth in the Trematodes class.150 P. westermani is a lung fluke. Human infection is acquired by eating fresh-water crab or crawfish. The lar­ vae penetrate the wall of the intestine and migrate through the diaphragm to reach the lungs. Pulmonary infection may be asymptomatic or cause a chronic cough produc­ tive of blood-streaked sputum. Eosinophilia is common. Pulmonary paragonimiasis is diagnosed by identification of eggs in stool or sputum specimens (see Table 59-2). In addition, serologic studies are useful. Treatment is with praziquantel. Tropical pulmonary eosinophilia is caused by Wuchereria bancrofti and Brugia malayi.146,147 Wuchereria and Brugia are classified as filarial parasites in the hel­ minth family. These parasites are prevalent primarily in the tropics. Infection is acquired through insect bites, during which larvae are transmitted. Migration of micro­ filariae to the lungs causes eosinophilic pneumonitis manifested by wheezing, cough, chest pain, pulmonary infiltrates, and eosinophilia. Diagnosis is established by identification of microfilaria in blood or urine specimens (see Table 59-2). Serologic studies of IgG antibodies and filarial antigens are helpful. Diethylcarbamazine is the treatment of choice.

Environmental Exposures in the Normal Host

Allergic Bronchopulmonary Aspergillosis (ABPA) Allergic bronchopulmonary aspergillosis (ABPA) is a Th2 hypersensitivity lung disease caused by bronchial coloni­ zation with Aspergillus fumigatus that affects approxi­ mately 1% to 2% of patients with asthma and 7% to 9% of cystic fibrosis (CF) subjects.153–157 It is relatively uncom­ mon in childhood, although it has been reported in chil­ dren with CF from England and the United States. It was first described in adults in 1952 in England. The disease is most commonly caused by A. fumigatus. This is a ubiq­ uitous mold that is commonly encountered around farm buildings, barns, stables, silos, and compost heaps. Human disease has been reported from most countries of the world. ABPA should be distinguished from other lung dis­ eases caused by A. fumigatus, such as invasive aspergillo­ sis, aspergilloma, IgE-mediated asthma from A. fumigatus sensitivity, and HP due to A. fumigatus or A. clavus (malt worker's disease). ABPA is characterized by exacerba­ tions of asthma, recurrent transient chest radiographic infiltrates, and peripheral and sputum eosinophilia. A. fumigatus hyphae are generally found in the sputum at the time of acute exacerbations of ABPA. ABPA may lead to corticosteroid-dependent asthma, bronchiectasis, or pulmonary fibrosis. The diagnostic features of ABPA are (1) asthma or CF, (2) pulmonary infiltrates, (3) elevated total serum IgE >1000  U/mL, (4) IgE anti-Aspergillus antibody, (5) IgG anti-Aspergillus antibody, (6) periph­ eral blood and pulmonary eosinophilia, and (7) proximal bronchiectasis. Pathology The gross pathology of ABPA demonstrates cylindrical bronchiectasis of the central airways, particularly those to the upper lobes.153–157 These airways may be occluded by “mucoid impaction,” a condition in which large air­ ways are occluded by impacted mucus and hyphae. Airway occlusion may lead to atelectasis of a segment or lobe, and if the atelectasis is long-standing, saccular bronchiectasis may result. Typically, ABPA is worse in the upper lobes than in the lower lobes. Microscopic examination of the airways shows infiltration of the airway wall with eosinophils, lymphocytes, and plasma cells. The airway lumen may be occluded by mucus-containing hyphal elements and inflam­ matory cells, especially eosinophils. Squamous metaplasia of the bronchial mucosa commonly develops, and some­ times granulomata form. Rarely, bronchiolitis obliterans or bronchocentric granulomatosis develops. Pathogenesis In the pathogenesis of ABPA, A. fumigatus spores 3 to 5 μm in size are inhaled and germinate deep within the bronchi into hyphae.153–157 In addition, fragments of the hyphae can be identified within the pulmonary parenchyma. The implication of this is that there is the potential for high concentrations of A. fumigatus allergens to be exposed to the respiratory epithelium

and immune system. A. fumigatus releases a variety of proteins, including superoxide dismutases, catalases, proteases, ribotoxin, phospholipases, hemolysin, glio­ toxin, phthioic acid, and other toxins. The first line of defense against Aspergillus colonization in the lungs is macrophage and neutrophil killing of the conidia and the hyphae. In the development of ABPA, Kauffman's group proposed that Aspergillus proteins have a direct effect on the pulmonary epithelium and macrophage inflammation.158,159 They demonstrated that Aspergillus proteases induce epithelial cell detachment. In addi­ tion, protease-containing culture filtrates of Aspergillus induce human bronchial cell lines to produce proin­ flammatory chemokines and cytokines, such as IL-8, IL-6, and MCP-1. Thus, various Aspergillus proteins have significant biological activity that disrupts the epi­ thelial integrity and induces a monokine inflammatory response. This protease activity allows for enhanced allergen exposure to the bronchoalveolar lymphoid tis­ sue immune system. This is evident by the bronchoal­ veolar lymphoid tissue synthesis of Aspergillus-specific IgE and IgA antibodies. Recently, two genetic susceptibility factors have been proposed in the development of ABPA. Chauhan and colleagues160–162 observed that asthmatic and CF patients who expressed HLA-DR2 and/or DR5 and lacked HLA-DQ2 were at increased risk to develop ABPA after exposure to A. fumigatus. Furthermore, within HLA-DR2 and HLA-DR5, there are restricted genotypes. In particular, HLA-DRB1*1501 and HLA-DRB1*1503 were reported to produce high rel­ ative risk. On the other hand, 40% to 44% of nonABPA atopic Aspergillus-sensitive individuals have the HLA-DR2 and/or HLA-DR5 genotype. Additional studies indicated that the presence of HLA-DQ2 (espe­ cially HLA-DQB1*0201) provided protection from the development of ABPA. Recently, increased sensitivity to in vitro IL-4 stimulation as measured by enhanced expression of the low-affinity IgE receptor (CD23) on B cells was observed in ABPA patients. This was associ­ ated with single-nucleotide polymorphisms of the IL-4 receptor alpha chain (IL-4Rα) in 92% of ABPA subjects, principally the IL-4-binding single-nucleotide polymor­ phism ile75val.153,155,157 This increased sensitivity to IL-4 is demonstrated by increased expression of CD23 and CD86 on B cells of ABPA subjects and increased CD23 expression during flares of ABPA.153,157 CD23 is expressed on a variety of cells, including B cells, natural killer cells, subpopulations of T cells, and a subpopulation of dendritic cells. T-cell CD23 and B cell CD21 form a costimulatory pathway. T-cell CD28 and B cells CD80 and CD86 costimulatory pathways activate both T and B cells, and CD28:CD86 is important in IgE synthesis. CD86 also is found on dendritic cells that have the histamine receptor 2, which skews anti­ gen-specific T cells to a Th2 response. In a murine model of ABPA, Kurup and colleagues have found that CD86 expression is up-regulated in the lung tissue (V.P. Kurup, Medical College of Wisconsin, personal communication). Recently, we also have observed increased CD86 expres­ sion on monocyte-derived dendritic cells of ABPA sub­ jects. Thus, antigen-presenting cells such as monocytes

Chapter 59

Disseminated strongyloidiasis may occur as a result of a hyperinfective cycle in which larvae invade all tissues.152

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chILD and dendritic cells bearing HLA-DR2 and/or HLA-DR5 and increased sensitivity to IL-4 stimulation probably play a critical role in skewing A. fumigatus-specific Th2 responses in ABPA. Brouard and co-workers163 recently reported a third genetic risk, the association of the -1082GG genotype of the IL-10 promoter with colonization by A. fumigatus and the development of ABPA in CF. The -1082GG polymorphism has been associated with increased IL-10 synthesis; whereas the -1082A allele has lower IL-10 syn­ thesis. Thus, dendritic cells expressing HLA-DR2/DR5 that have an HR2 phenotype, increased IL-10 synthesis, and increased sensitivity to IL-4 stimulation due to IL-4RA polymorphisms, may be responsible for skewing Aspergillus-specific Th2 responses in ABPA. Recent studies in asthma have implicated the role of bronchial epithelia and mesenchymal cells forming the epithelial-mesenchymal trophic unit (EMTU) with a profibrotic response when stimulated with proteases ­ such as Der p1 and with IL-4 and IL-13.164 In ABPA sub­ jects, Aspergillus proteases and allergen stimulation of the EMTU in conjunction with increased sensitivity to IL-4 due IL-4RA SNPs may result in increased bronchial epithelial secretion of IL-8, GM-CSF, and transforming growth factor (TGF-α), the ligand for epidermal growth factor leading to bronchial destruction and fibrosis. Clinical Manifestations Clinical symptoms of ABPA include increased coughing, episodes of wheezing, anorexia, malaise, fever, and expec­ toration of brown plugs. ABPA can present acutely with acute symptoms and signs associated with transient pul­ monary infiltrates and eosinophilia or with mucoid impaction; it also may present an exacerbation of a chronic disease characterized by proximal bronchiectasis. It is thought that the chronic form of the disease devel­ ops following the acute process and that it can be pre­ vented by effective therapy. In chronic ABPA, the acute episodes are superimposed on a background of chronic cough and sputum production. In adults, ABPA usually affects the younger age group of adult asthmatics, and most cases occur before 40 years of age. In pediatrics, ABPA rarely affects children with asthma, and it is usu­ ally seen in children with CF, who may simply appear to have a worsening of their pulmonary status or an acute pulmonary exacerbation of CF. ABPA does sometimes affect children with asthma, and there is a report of 3 children who developed it before 2 years of age. Physical examination shows the signs of chronic lung disease from CF or asthma, such as hyperaeration of the lungs, expira­ tory wheezing, a chronic productive cough, and crackles or wheezes. The chronically ill patient with bronchiec­ tasis may have coarse crackles, weight loss, and digital clubbing. The clinical criteria for the diagnosis of ABPA devel­ oped at a recent Cystic Fibrosis Foundation consensus conference are shown in Box 59-4. It has been suggested that a certain numbers of these criteria should be present to make the diagnosis of ABPA, although this approach has not been validated in childhood. A problem with applying the criteria in children is that usually ABPA occurs in children with CF in whom many of the criteria

BOX 59-4  Criteria for Diagnosis of Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis Classic Case

• Acute or subacute clinical deterioration not attributable to another etiology • Total serum IgE concentration greater than 1000 IU/mL unless patient is receiving corticosteroid therapy • Immediate cutaneous reactivity to Aspergillus fumigatus while the patient is not being treated with antihistamines or in vitro presence of serum IgE antibody to A. fumigatus • Precipitating antibodies or serum IgG antibody to A. fumigatus • New or recent abnormalities on chest radiography or chest CT that have not cleared with antibiotics and standard physiotherapy

Minimal Diagnostic Criteria

• Acute or subacute clinical deterioration not attributable to another etiology • Total serum IgE concentration greater than 500 IU/mL unless patient is receiving corticosteroid therapy. If ABPA is suspected and the total level of 200 to 500 IU/mL, repeat testing in 1 to 3 months is ­recommended. If patient is taking steroids, repeat when steroid ­treatment is discontinued. • Immediate cutaneous reactivity to Aspergillus fumigatus while the patient is not being treated with antihistamines or in vitro presence of serum IgE antibody to A. fumigatus • One of the following: (1) precipitins to A. fumigatus or in vitro ­documentation of IgG antibody to A. fumigatus or (2) new or recent abnormalities on chest radiography or chest CT that have not cleared with antibiotics and standard physiotherapy

could be due to the underlying disease. Some children with CF appear to have a clinical variant of ABPA with­ out having all the typical criteria, and they may respond clinically to corticosteroids. Patients being considered for this diagnosis should have skin testing with A. fumigatus antigen. Differential Diagnosis Several diseases cause pulmonary infiltrates in children with asthma or CF. The differential diagnosis of ABPA should include the following: viral or bacterial pneumo­ nia, poorly controlled asthma with mucoid impaction or atelectasis, inhaled foreign body, CF (with or without ABPA), immotile cilia syndrome, tuberculosis with eosin­ ophilia, sarcoidosis, pulmonary infiltrates with eosino­ philia, HP, and pulmonary neoplasm. Clinical Staging The spectrum of ABPA varies widely, from individuals with mild asthma and occasional episodes of pulmonary eosinophilia (with no long-term sequelae), to patients with fibrosis, honey-comb lung, and respiratory failure. Patterson and colleagues165 have suggested a clinical clas­ sification with five clinical stages. Stage I is the acute stage of ABPA with many of the typical features of the dis­ ease. If this stage goes into remission, the infiltrates clear, symptoms reduce, and the serum IgE value will decline by up to 35% within 6 weeks. Stage II is remission. Stage III is an exacerbation associated with the recurrence of the initial symptoms and a twofold increase in serum IgE level. Stage IV is reached when patients need continuous corticosteroids either to control their asthma or to pre­ vent a recurrence of ABPA. Stage V is the fibrotic stage,

Environmental Exposures in the Normal Host

Radiographic Findings There are several characteristic radiographic abnormali­ ties associated with ABPA.154,165 The most common lesion is a large, homogeneous shadow in one of the upper lobes with no change in volume. The shadow may be triangular, lobar, or patchy, and it frequently moves to another site. “Tram line” shadows are fine parallel lines radiat­ ing from the hila that represent inflammation of airway walls. Mucoid impaction causes toothpaste shadows or gloved-finger shadows. Several adult patients have been reported with normal chest radiographs, so radiographic abnormalities are not invariably present. In these indi­ viduals, cylindrical bronchiectasis was demonstrated by tomography or CT scan. Laboratory Investigations Laboratory tests that support the diagnosis of ABPA are those that demonstrate allergy to the mold, such as a positive specific IgE test and positive Aspergillus pre­ cipitins.153–157 The precipitins are only weakly positive compared with the strong reactions seen in patients with mycetomas. Culture of A. fumigatus from the sputum is only a secondary criterion for the diagnosis of ABPA because a large proportion of individuals with CF with­ out ABPA have Aspergillus on sputum cultures. Some normal individuals and many individuals with lung dis­ eases have small numbers of spores in their sputum; these are probably present because of passive inhalation. The presence of hyphae is more specific, and the presence of eosinophils in association with hyphal elements is sug­ gestive of the diagnosis. The presence of eosinophilia in sputum or blood is suggestive of ABPA and is a primary diagnostic criterion. The PB eosinophil count is usually greater than 1000/mm3, and values greater than 3000/mm3 are common. An increased serum IgE value is very characteristic of ABPA, and values may reach as high as 30,000 IU/mL. Usually, the value is greater than 1000 IU/mL. Much of the IgE is not specific to Aspergillus but is the result of polyclonal B cell activation. The IgE level is a very use­ ful marker of disease activity, and it can be used to fol­ low outpatients for “flares.” The simple skin-prick test is a useful screening test because ABPA is very unlikely in patients with a negative reaction. A dual-reaction skin test with an immediate (10 to 15 minutes) and a late (4 to 8 hours) reaction occurs in one third of patients with ABPA. Alternatively, serum may be measured for the presence of specific IgE and IgG antibodies. Patients with ABPA and Aspergillus-sensitive asthma will have elevated Aspergillus specific IgE antibody, but patients with ABPA will have quantitatively increased Aspergillusspecific IgE levels. Crameri's group168 has reported that ABPA and Aspergillus-sensitive patients have elevated

IgE antibodies to recombinant Aspergillus Asp f1, Asp f3, Asp f4, and Asp f6 allergens, and that IgE levels to Asp f4 and Asp f6 are highly specific for ABPA. The usual pattern of serum precipitins is that immuno­ electrophoresis shows one to three precipitin lines, often to only one extract.158,165 Patients with aspergilloma will have multiple precipitin lines to all antigen extracts. Extracts of A. fumigatus contain a complex mixture of proteins that are mainly derived from the hyphae. Antigenic composi­ tion varies between batches according to the culture condi­ tions, even within the same laboratory. There is, therefore, a lack of standardization that makes it difficult to compare results among laboratories. However, there has been some success with purification of the major antigenic compo­ nents that may lead eventually to improved diagnosis. We find it best to send all our testing to one central laboratory that has well-established methods for the characterization of the serologic responses to A. fumigatus. Therapy Treatment is designed first to control the acute episodes and then to limit the development of chronic lung dis­ ease.158,165 Most cases of ABPA require treatment with systemic corticosteroids, and the treatment of choice is prednisone. Steroid therapy rapidly clears the eosin­ ophilic infiltrates and the associated symptoms; how­ ever, it is less effective at treating mucous impaction. The usual starting dose is 0.5 mg/kg/day, taken each morning, and this dose is maintained for 2 to 4 weeks while following the patient clinically and checking the chest radiograph for resolution of the acute process. After this induction treatment, the dose of predni­ sone should be reduced to 0.5 mg/kg given on alternate days. If mucous impaction persists and is associated with atelectasis, bronchoscopy should be performed to confirm the diagnosis and to attempt to remove the mucous plugs. Following resolution of the acute process, the dose of prednisone should be reduced over 1 to 3 months. Chronic treatment with corticosteroids is controversial, especially in adults, because only a minority of patients with ABPA is at risk of chronic lung disease. The relation­ ship between acute episodes and lung damage is unclear, and the precise dose of prednisone is not certain because acute exacerbations may continue while the patients are on low doses of steroids. However, children with ABPA usually have CF and may need treatment with longterm corticosteroids to prevent progressive lung damage. Therefore, we usually maintain therapy with a dose of 0.5 mg/kg on alternate days for 3 months and then, after 3 months, the dose of prednisone is tapered over a further 3 months while checking the chest radiograph and the serum IgE level for evidence of relapse. Initially, the serum IgE level should be checked at every visit, and if the level increases by twofold or more, the steroid dose should be increased. We recommend that patients are followed with serum IgE levels and chest radiographs every 6 months for the first 1 to 2 years, and then, if the child remains in remission, it should be possible to reduce the frequency of these studies. The antifungal agent itraconazole has been used to reduce the doses of steroids that are required.166,167

Chapter 59

which is present when there is severe upper lobe fibrosis present on the chest radiograph, and it may be associated with honeycombing. The stage V lesions may not respond to corticosteroids although steroids are often necessary to maintain a bronchodilator response, and severe wheez­ ing may develop if steroids are discontinued. Pulmonary fibrosis is an advanced complication that can lead to pulmonary hypertension and cor pulmonale.

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chILD Initially, there were only open nonrandomized studies that indicated that itraconazole is a useful adjunct to systemic corticosteroid therapy. Two recent randomized controlled trials also have favored itraconazole use. A double-blind, randomized, placebo-controlled trial of itraconazole 200 mg twice daily dose resulted in decreased IgE level and an increase in pulmonary function and exercise toler­ ance. Another randomized, controlled trial showed that treatment of stable ABPA in adults with 400 mg/day itra­ conazole resulted in a significant reduction in sputum eosinophil count, sputum eosinophilic cationic protein levels, serum IgE concentrations, and Aspergillus-specific IgG. There also was a reduction in episodes of exacer­ bation requiring treatment with systemic steroids. In the treatment of children with ABPA, we have used a dose of 10 mg/kg/day of itraconazole. Omalizumab, an antiIgE monoclonal antibody, has been used in uncontrolled reports. Anecdotally, it has been effective, but a random­ ized controlled trial is necessary. There is no place for immunotherapy in children with ABPA because it is ineffective and potentially danger­ ous. Inhaled anti-inflammatory agents, such as cromo­ glycate and beclomethasone are not generally thought to be effective. The role of inhaled spores in the pathogen­ esis of ABPA is unclear, but there is a seasonal incidence of ABPA that is probably related to seasonal changes in mold spore counts. Therefore, it is reasonable to advise patients with ABPA to avoid exposure to places with high spore counts, such as damp basements, barns, and com­ post heaps.

Prognosis The prognosis for children with ABPA is good if the dis­ ease is detected early and treatment is started promptly. It is important that the diagnosis is made and treatment commenced before there is permanent lung damage from bronchiectasis. In such patients, there should be no pro­ gression of the disease, although relapses can occur many years later, and long-term follow-up is recommended. In children with CF, the relapses seem to be more frequent than they are in people with asthma, and careful sur­ veillance is necessary to ensure resolution of the disease process. In some CF patients, it is difficult to wean the steroids without an increase in symptoms, such as dys­ pnea and wheezing; whether this is due to the underly­ ing CF lung disease or due to patients going from stage I to stage III ABPA on withdrawal of steroids is unclear. Symptoms are not a reliable guide to therapy; therefore, it is important to reevaluate the chest radiograph and the serum IgE at regular intervals until a long-term remission is established.

Acute Eosinophilic Pneumonia Acute eosinophilic pneumonia is a distinct clinical entity that occurs in both adults and children, with a male pre­ ponderance169–176 (Table 59-3). Other causes of eosin­ ophilic lung diseases, such as parasitic, drug-induced, fungal hypersensitivities, need to be excluded. The clin­ ical manifestations include acute onset of fever, cough, and dyspnea for 1 to 5 days. There may be associated

TABLE 59-3  CHARACTERISTICS OF ACUTE AND CHRONIC EOSINOPHILIC PNEUMONITIS CHARACTERISTIC

ACUTE

CHRONIC

Ages

Children and adults

Adults 40–50 years of age peak

Sex

Male preponderance

Female preponderance 2:1

Underlying asthma

None

50%

Symptoms

Acute febrile illness 1–5 days Fever, dyspnea, cough, myalgias, pleuritic chest pain, hypoxemia

Insidious over 7–8 months Fever, night sweats, weight loss, cough, wheezing, anorexia

PE

High fever, basilar rales, wheezing

Fever, wheezing, lymphadenopathy, hepatomegaly

Chest radiograph And CT scan

Diffuse alveolar or mixed alveolar interstitial infiltrates, pleural effusions

Dense peripheral infiltrates (negative image of pulmonary edema)

PFT

Restrictive pattern

Restrictive pattern

Lung biopsy

Diffuse acute organizing alveolar damage, eosinophilic infiltration of alveoli, interstitium, bronchial epithelium

Eosinophils and lymphocytes in alveoli and interstitium, thickened alveolar walls. Interstitial fibrosis in 50%; BO in 25%

BAL

45±11% eosinophils, 20±11% lymphocytes

>25% eosinophils, lymphocytes

Blood eosinophilia

Absent

Present

IgE level

Elevated in some

Elevated in most

Corticosteroids

Prompt response. No relapse if corticosteroids tapered over 8 weeks

Prompt response; relapse if corticosteroids discontinued within 6 months

BAL, bronchoalveolar lavage; BO, bronchiolitis obliterans; CT, computed tomography; PE, physical examination; PFT, pulmonary function testing.

Environmental Exposures in the Normal Host

Chronic Eosinophilic Pneumonia Chronic eosinophilic pneumonitis is a disorder that affects primarily middle-age adults with a 2:1 female preponder­ ance177–181 (see Table 59-3). The etiology is unknown, and other conditions that cause eosinophilic lung diseases need to be excluded. A risk factor may be asthma, which occurs in 50% of patients. The symptoms are insidious, developing over a 7 to 8 month period. They include fever, night sweats, weight loss, cough, and wheezing. The cough is typically nonproductive. Some patients also experience lymphadenopathy or hepatomegaly. Chest radiographs reveal extensive, bilateral, periph­ eral infiltrates, the so-called “negative image of pulmo­ nary edema,” which is diagnostic of chronic eosinophilic pneumonia. Chest CT scans show peripheral airspace ­disease and may show hilar adenopathy. Peripheral blood eosinophilia is prominent. BALF examination reveals increased eosinophils >25% and increased lymphocytes. IgE levels are also frequently elevated. Lung biopsy specimens display moderate to exten­ sive accumulation of eosinophils and lymphocytes in the alveoli and the interstitium with thickened alveolar walls. Sometimes multinucleated histiocytic giant cells, lymphocytes, and plasma cells are found in the alveoli, a noncaseating granuloma reaction. There is also a mild perivascular cuffing of venules with eosinophils and lym­ phocytes. Interstitial fibrosis has been reported in 50% of patients and bronchiolitis obliterans in 25% of patients. Response to high-dose corticosteroids is dramatic, with resolution of symptoms within 24 to 48 hours. Radiographically, pulmonary infiltrates resolve over 10 to 21 days. Taper of corticosteroids needs to be pro­ longed typically more than 6 months to prevent relapse. The mean duration of corticosteroid treatment is approx­ imately 19 months. Recurrent attacks have occurred in about one third of the patients, especially in those with

asthma. Some patients have subsequently developed Churg-Strauss syndrome, raising the possibility of over­ lap of the two diseases. Nonetheless, long-term prognosis is excellent for most patients.

Eosinophilic Granuloma Eosinophilic granuloma, formerly called histiocytosis X, is the benign form of the three forms of Langerhans cell his­ tiocytosis: Letterer-Siwe disease, Hand-Schuller-Christian disease, and eosinophilic granuloma.182 Eosinophilic granu­ loma affects children and young adults, particularly males. Typically, there is only a solitary lesion, but there may be multiple lesions that may be asymptomatic or may cause pain. Any bone may be involved, with the calvarium, ribs, and femur being the most common sites. Histologically, the lesions are comprised of foamy vacuolated histiocytes with variable numbers of eosinophils, neutrophils, ­lymphocytes, and plasma cells. The histiocytosis X cells are derived from Langerhans cell origin and are positive for CD1a and HLA-DR. Pulmonary interstitial lung disease occurs in approx­ imately 20% of patients with eosinophilic granuloma. Chest radiographs demonstrate an alveolar pattern in an early state. This may be followed by 3 to 10  mm nodu­ lar shadows or a reticulonodular pattern with a predi­ lection for the apices. Fibrosis and honeycombing also may ensue. Histologically, eosinophils are present in the lesions; however, they are not present in BALF specimens.

Churg-Strauss Syndrome—Allergic Angiitis and Granulomatosis Churg-Strauss syndrome (CSS) is also named allergic angiitis and granulomatosis because of its association in patients with asthma, allergic rhinitis, and sinusitis and with its findings of eosinophilic vasculitis and granulo­ matous lesions183–196 (Box 59-5). Nearly all patients have allergic rhinitis and pansinusitis. Three phases have been described in CSS. The first phase involved development of asthma with variable severity, typically in adults. Tapering of systemic corticosteroid treatment of asthma may unmask CSS.188 This has been reported as a risk in asthmatic patients treated with omalizumab and when the prednisone is decreased or discontinued. The second phase is characterized by the development of peripheral blood eosinophilia and eosinophilic tissue infiltrates. The third phase involves eosinophilic vasculitis of extrapul­ monary organs, typically the skin, gastrointestinal tract, heart, and nervous system. Cutaneous lesions are common, occurring in 70% of patients, variably manifesting as maculopapular rashes; petechiae; purpura or ecchymoses; and cutaneous and subcutaneous nodules, commonly on the scalp or extrem­ ities.191 Peripheral neuropathies are common includ­ ing mononeuritis multiplex and polyneuropathies.190 Cerebral infarctions may occur and can be a cause of death. Cardiac involvement is a common cause of death and occurs in a third of patients. Gastrointestinal prob­ lems include abdominal pain, diarrhea, bleeding, and obstruction.183–187 Pulmonary symptoms are present

Chapter 59

pleuritic chest pain and myalgias. Patients then develop hypoxemia and respiratory failure often requiring a mechanical ventilator. Physical examination reveals high fever, respiratory distress, and basilar rales, sometimes with fever. Initial chest radiographs reveal interstitial infiltrates171,172 that progress to diffuse alveolar infiltrates. Chest CT scans demonstrate diffuse alveolar infiltrates, pleural effusions, pronounced septal markings, and nor­ mal lymph nodes. Pulmonary function studies demonstrate a restrictive pattern with decreased diffusing capacity. Bronchoalveolar lavage fluid reveals eosinophilia (45±11%) and lympho­ cytosis (20±11%). Pleural effusions are common with up to 42% eosinophils on cell count. There is evidence of eosinophil degranulation in the pleural fluid with an ­elevated pH. Lung biopsy specimens demonstrate eosino­ phil infiltration of the interstitium, alveoli and epithelium. Peripheral blood eosinophilia is typically absent; however, serum IgE levels may be elevated in some patients. The etiology of acute eosinophilic pneumonia is unknown. However, there is a dramatic response to high-dose cor­ ticosteroids, typically within 24 to 48 hours. Steroids are then tapered over an 8-week course. Relapses or recur­ rences are unusual.

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chILD

BOX 59-5 Findings in Churg-Strauss Syndrome • History of asthma • Pulmonary • Patchy, transient infiltrates • Eosinophilic infiltration of alveoli, interstitium, blood vessels • Necrotizing and non-necrotizing granulomata • Eosinophilic angiitis • Systemic vasculitis involving ≥ 2 extrapulmonary organs • Small and medium size arteries and veins, eosinophilic vasculitis • Eosinophilic granulomata • Nasal symptoms • Allergic rhinitis • Pansinusitis • Cutaneous • Maculopapular rash • Petechiae, purpura, ecchymoses • Cutaneous and subcutaneous nodules on scalp and extremities • Cardiac • Hypertension • Pericarditis • Heart failure • Gastrointestinal • Abdominal pain • Diarrhea • Bleeding • Obstruction • Peripheral neuropathy • Mononeuritis multiplex • Polyneuropathy • Central nervous system • Cerebral infarction • Hematologic • >1500 eosinophils/μL • Radiologic • Chest x-ray: Transient pulmonary infiltrates • CT scan: airspace consolidation or ground-glass appearance, septal lines, bronchial wall thickening

in nearly all patients. This is seen as patchy and transient pulmonary infiltrates demonstrated on chest radiographs.192 Chest HRCT scans reveal a variety of findings that include airspace consolidation or interstitial ground-glass opacities, septal lines, and bronchial wall thickenings.193 Eosinophilia ≥1500 cells/mm3 is uniformly present.183–187 Lung biopsy specimens demonstrate extensive eosinophil infiltration present in the interstitium, air spaces, and peri­ vascularly.183,184,193,194 In addition, both necrotizing and non-necrotizing granulomata may be present, involving blood vessels. The angiitis varies from eosinophilic infil­ tration of blood vessels to necrotizing vasculitis of small and medium-sized vessels. Biopsies of the cutaneous nod­ ules reveal eosinophilic infiltration. The treatment of CSS is principally with prolonged sys­ temic corticosteroids.183–187 If untreated, the mortality is sig­ nificant, as high as 50% in the first 3 months of the onset of vasculitis. In treated patients, the mean survival is 9 years. 183–187

Hypereosinophilic Syndrome Hypereosinophilic syndrome (HES) was first defined by Chusid and colleagues196 in 1975, who specified the following three criteria for diagnosis: (1) absolute eosinophil count ≥1500/mm3 in peripheral blood for more than 6 months; (2) lack of evidence for parasitic,

a­ llergic, and other recognized causes of eosinophilia; and (3) end-organ dysfunction due to eosinophilic infiltration. It is now recognized that HES repre­ sents a spectrum of disorders that includes not only the previously described idiopathic HES (IHES) but also disorders characterized with eosinophilic organ infiltration that may or may not be accompanied by peripheral blood eosinophilia (i.e., eosinophilic pneu­ monia, eosinophil-associated gastrointestinal disor­ ders [EGID], CSS, and eosinophilic dermatitis [Wells syndrome]).197–199 A revised classification of HES was presented in 2006 by Klion and colleagues.200 This clas­ sification system was the culmination of a workshop conducted by the Hypereosinophilic Diseases Working Group of the International Eosinophil Society with the intent of allowing accurate identification of the cause of hypereosinophilia, which in turn guides the clinical management of these patients. HES was classified into the following categories: myeloproliferative, lympho­ cytic, familial, idiopathic, overlap (blood eosinophilia ≥ 1500/mm3 with single organ involvement) and asso­ ciated (blood eosinophilia ≥1500/mm3 in association with a distinct second diagnosis, such as inflammatory bowel disease etc). This classification has been subse­ quently revised by the same group based on disease pathophysiology (myeloproliferative vs. lymphocytic) (Box 59-6), as it is recognized that this defines not only the clinical features but also the prognosis and manage­ ment of HES.201

BOX 59-6 Hypereosinophilia Syndromes 1. Myeloproliferative variant a. Clonal eosinophilia • FIP1L1/PDGFRA-associated HES • Chronic eosinophilic leukemia with cytogenetic abnormalities and/ or blasts on peripheral smear b. Features of myeloproliferative disease without proof of clonality 2. Lymphocytic variant c. Clonal lymphocyte population d. No demonstrable T cell clone but may have evidence of marked T cell activation 3. Familial e. Family history documented persistent eosinophilia of unknown cause 4. Undefined f. Benign • Asymptomatic with no evidence of organ involvement g. Complex • Organ dysfunction, but does not meet criteria for ­myeloproliferative or lymphocytic variants h. Episodic • Cyclical angioedema and eosinophilia 5. Overlap i. Eosinophil-associated gastrointestinal disease j. Eosinophilic pneumonia k. Eosinophilia myalgia syndrome l. Other organ-restricted eosinophilic disorders 6. Associated m. Churg-Strauss syndrome n. Systemic mastocytosis o. Inflammatory bowel disease p. Sarcoidosis q. HIV r. Other disorders Adapted from Simon et al (2010).201

Environmental Exposures in the Normal Host The evaluation of patients with hypereosinophilia should begin with a meticulous search for triggering ­factors—drug history, travel history and habitat, and his­ tory of allergies with exclusion of underlying malignancy or collagen vascular disease. Careful assessment of organ function to evaluate eosinophil-mediated organ damage is critical.202 In the absence of underlying disease, or if fea­ tures of myeloproliferative disease are present, patients with HES should be referred to hematology/oncology for complete evaluation to exclude malignancies, which includes bone marrow examination and radiologic imag­ ing to exclude lymphoma. The evaluation also should include exclusion of a cytogenetic abnormality by TCR gene rearrangement, and RT-PCR or FISH for FIP1L1PDGFRA. Plasma cytokine levels, especially IL-5, should be measured, as should serum tryptase; however, these may be elevated in both the myeloproliferative and lym­ phocytic forms of HES.202 Control of the eosinophilia is important to pre­ vent organ damage from deposition of eosinophilic mediators. Corticosteroids have been the mainstay of treatment and remain the first-line treatment for FIP1L1PDGFRA–negative HES. Imatinib mesylate (Gleevec 100 to 400 mg per day) is a tyrosine kinase inhibitor that targets the fusion protein FIP1L1-PDGFRA209–211; it now constitutes the treatment of choice for the FIP1L1PDGFRA–positive myeloproliferative variant of HES. Dramatic clinical responses to imatinib are described in FIP1L1-PDGFRA–positive HES with eosinophilia resolving within a 1-week period and reversal of organ dysfunction as early as 1 month. Other myeloprolifera­ tive variants that are negative for the FIP1L1-PDGFRA fusion protein also may respond to imatinib.211 Other drugs including azathioprine, cyclosporine A, and hydroxyurea have been used in conjunction with cor­ ticosteroids or as steroid-sparing agents, particularly for the lymphocytic variant of HES.202 These patients need careful monitoring for development of a lymphoid malignancy. Immunomodulatory therapy with IFN-α and monoclonal antibody to IL-5 (mepolizumab) also has been described. In two recent reports, patients with HES were treated with three doses of antibody to IL-5.212,213 Blood eosinophils declined by tenfold and were sustained for 12 weeks after the last dose of anti­ body. The anti-CD52 monoclonal antibody alemtu­ zumab has been used to successfully treat two patients with HES.200 Allogeneic stem cell transplant can be curative for HES.214,215

BRONCHIOLITIS OBLITERANS Bronchiolitis obliterans (BO) is a rare disease of the small airways caused by severe injury leading to fibrosing and narrowing or complete obliteration.216 It has been described in all age groups. Causes of BO include inha­ lation of toxic chemicals such as hydrochloric acids or nitric acids. Other associated cases include lupus ery­ thematosus, rheumatoid arthritis, Stevens-Johnson syndrome, lung transplantation, and bone marrow trans­ plant. The focus of this section is BO as a sequel to respi­ ratory infection.

Chapter 59

HES is more common in males and in patients 20 to 50 years old, but it also affects children. The onset of symptoms of HES are often insidious. The common presenting symptoms include fatigue, cough, dyspnea, myalgias, rash, and retinal lesions. HES may affect and damage many organs, including cardiac, cutaneous, neu­ rologic, pulmonary, splenic, hepatic, ocular, and gastro­ intestinal organs. Cardiac involvement is the major cause of mortality in patients with HES. Eosinophilic endo­ myocardial disease and mucosal ulcers are common. Eosinophilic granules and mediators are deposited on the endocardium, resulting in myocardial degeneration and fibrosis.197,202–208 Cardiac disease is characterized by eosinophilic endocardial myelofibrosis, cardiomyopathy, valvular disease, and mural thrombus formation. Serum tryptase levels are often elevated, and splenomegaly is present. Pulmonary disease affects up to 49% of patients with HES, and symptoms consist of chronic nonproduc­ tive cough. Asthma is not typically present. Pulmonary infiltrates may develop and may be focal or diffuse. Pulmonary fibrosis may develop. CSS may occur as an associated variant of HES. The myeloproliferative or “classic” HES presents with features of myeloproliferative disease (i.e., hepatospleno­ megaly, cytopenias, circulating myeloid precursors and increased bone marrow cellularity). Elevated serum vita­ min B12 levels or tryptase levels may be seen. This form of HES is thought to arise from a muta­ tion in the hematopoietic stem cell that results in clonal expansion, predominantly of eosinophils. The major­ ity of these patients have a cryptic interstitial deletion on chromosome 4 q12 that results in the formation of a fusion protein FIP1L1-PDGFRA that brings together the FIP1L1 and the gene for the cytoplasmic domains of the PDGFRα receptor. This gene fusion results in the formation of a constitutively active tyrosine kinase that is responsible for clonal expansion of eosinophils.209–211 Other cytogenetic abnormalities that involve PDGFRB and fibroblast growth factor receptor have been reported in patients presenting with the myeloprolifera­ tive form of HES. This category also includes HES with features of myeloproliferative disease without proof of clonality, as well as chronic eosinophilic leukemia as defined in the World Health Organization (WHO) classification.197 The lymphoproliferative subtype of HES is charac­ terized by polyclonal expansion of eosinophils, usu­ ally in response to chemokines like IL-5 produced by dysregulated T-cells. These cells have a characteristic immunophenotype (CD4+CD3- or CD3+CD4-CD8-) and may show monoclonal or polyclonal expansion. Cutaneous manifestations are common in this group of patients. Some may progress to an overt T-cell lymphoma.200–202 The undefined subtype comprises asymptomatic eosinophilia, necrotizing eosinophilic vasculitis, episodic angioedema with eosinophilia, and other symptomatic forms of eosinophilia that do not have features of the myeloproliferative or lympho­ cytic forms.200–201 It is possible that patients with these forms of HES, as well as those with the overlapping or associated HES, also have dysregulated IL-5 produc­ ing T lymphocytes.

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874

chILD Postinfectious BO occurs following a lower respiratory tract infection usually of viral etiology. Adenovirus is the leading cause of postinfectious BO worldwide. Adenoviral serotypes 3, 7, and 21 demonstrate the highest virulence. A retrospective analysis of 415 pediatric patients in Argentina with acute adenoviral lower respiratory tract infections found serotype Ad7h in 76.3% of the cases.217 Of those cases, 34% developed respiratory sequelae, and 61% died either during the acute phase of the illness or due to long-term progressive respiratory failure. A casecontrol study of 109 pediatric postinfectious BO cases found adenoviral infection to be strongly and indepen­ dently associated with an increased risk for BO.218 Other viruses associated with postinfectious BO include influ­ enza, parainfluenza, measles, respiratory syncytial virus (RSV), varicella, and metapneumovirus. Mycoplasma pneumoniae also has been associated with postinfectious BO. Case reports of patients developing BO following acute bronchiolitis due to co-infection of RSV and adeno­ virus suggests that adenovirus remains the primary etiol­ ogy of postinfectious bronchiolitis obliterans.219,220 Postinfectious BO is more prevalent in the southern hemisphere including Argentina, Brazil, Chile, Uruguay, New Zealand, and Australia.221 However, postinfec­ tious bronchiolitis also is diagnosed in the United States, Canada, Turkey, South Korea, and Taiwan.216 A recent study reported an increased frequency of HLA haplotype DR8-DQB1*0302 in children with postinfectious bron­ chiolitis obliterans.222 This allele has a high frequency in the Amerindian population and may explain the high ­frequency in South American countries. The initial presentation of infants and children with postinfectious BO does not differ from that of acute bronchiolitis caused by RSV or other viruses. The infant becomes ill with cough and fever and then develops dys­ pnea and wheezing. On auscultation of the chest, wheezes and crackles are heard. The chest radiographic features consist of peribronchial thickening, increased intersti­ tial markings, and areas of patchy bronchopneumonia. Collapse and consolidation of segments or lobes are common. Castro-Rodriguez found that in children with acute adenoviral infection, those with atelectasis on chest radiograph were more likely to develop than those with­ out atelectasis.223 Risk factors associated with the initial illness and subsequent development of BO includes hospi­ talization for more than 30 days, multifocal pneumonia, hypoxia, hypercapnia, need for intensive care, and need for mechanical ventilation.217 The use of corticosteroids and beta-agonists during the acute illness is reported more frequently in children who developed BO than in those who do not.223 These studies suggest that infants and children presenting with severe acute bronchiolitis should undergo testing to identify the viral etiology and assess risk factors associated with BO. In children who develop BO, the clinical and radio­ graphic features of the acute presentation wax and wane for weeks to months, with incomplete recovery. They demonstrate persistent tachypnea, crackles, wheezing, and hypoxemia for at least 60 days after the initial illness. There are recurrent episodes of atelectasis, pneumonia, and wheezing. A high proportion of patients with docu­ mented adenoviral pneumonia eventually develop chronic

lung disease including persistent atelectasis, bronchiecta­ sis, recurrent pneumonia, hyperinflation, and increased pulmonary markings on chest radiographs. The devel­ opment of unilateral hyperlucent lung (Swyer-James syndrome) is a long-term complication of adenoviral infection. Pulmonary function testing in infants with BO show severe fixed airflow obstruction, decreased compliance, and increased resistance, with only a small number of patients responding to bronchodilators.218 Spirometry in older children demonstrates airflow obstruction with decreased forced expiratory volume in 1 second, decreased ratio of forced expiratory volume in 1 second to forced vital capacity, and markedly decreased forced midexpiratory flow rates. The flow-volume curve shows a severely concave expiratory loop consistent with small airway disease. Lung volumes reveal a marked increase in residual volume and total lung capacity with increase in residual volume/total lung capacity ratio. These pul­ monary function test findings are typical for air trapping and hyperinflation. However, one study that used CT to diagnosis BO in children found normal impulse oscillom­ etry in one third and mild abnormalities in another third of the cases.223 This study suggests that BO may have a wider spectrum of severity then previously recognized. Bronchoscopy, with collection of BAL fluid, can be use­ ful in identifying the infectious agent causing the acute illness. In the chronic phase of the disease, negative viral studies are common. Cytology from BAL shows a high white cell count with markedly increased neutrophils and increased lymphocytes. Lymphocyte subsets show an increase in activated T lymphocytes, and a decreased CD4+/CD8+ ratio suggesting that the pathogenesis of the disease involves B and T lymphocytes.224 HRCT of the chest has become an important tool in the diagnosis of BO.216 Mosaic perfusion, vascular attenua­ tion, and expiratory air trapping are diagnostic features of BO (Fig. 59-4). These findings occur in up to 100% of cases.224,225 Bronchial wall thickening, bronchiectasis, and atelectasis also are frequent findings. The Bhalla CT scoring system was initially developed to quantify lung disease in cystic fibrosis patients.226 However, one study suggests that the use of this scoring system in pediatric BO patients may be useful to predict the severity of lung impairment later in life.227 It has been suggested that chest HRCT findings can have high specificity but incomplete sensitivity for the diagnosis of BO.216 To further aid in the diagnosis in young children, a BO score has been proposed.228 Zero to 4 points were assigned for typical clinical history, 0 to 3 points were assigned for documented adenoviral infection, and 0 to 4 points were assigned for HRCT of the chest showing mosaic perfusion. A score ≥7 predicted the diagnosis of BO with a specificity of 100% and a sensitivity of 67%. However, a score <7 does not accurately rule out the diagnosis. Lung biopsy has been considered the gold standard for diagnosis of BO. Because of the heterogeneous distribu­ tion of airway involvement through the lung, sampling error can occur.216 In 30 children undergoing lung biopsy, histologic changes consistent with BO were found in 97% of the cases, but many of the lesions were mild and did

Environmental Exposures in the Normal Host

875

Chapter 59

FIGURE 59-4. HRCT scan of the chest of a child with bronchiolitis

obliterans demonstrating mosaic perfusion and vascular attenuation. Air-trapping is demonstrated by lack of increase in attention or decrease in lung volume in dependent lung. (Image courtesy of Alan Brody, MD, at Cincinnati Children's Hospital Medical Center, Ohio.)

not correlate with the clinical severity of the disease.221 In addition, totally obliterated airways were found in only 23% of lung biopsies versus 100% with lobectomy or autopsy. Lung biopsies have been reported as normal or nondiagnostic in up to one third of patients.216 Thus, it is important to recognize the potential diagnostic and prog­ nostic limitations of lung biopsy, and increasingly, the diagnosis of BO is one best considered in the context of clinical-radiographic-pathologic correlation. When a biopsy is indicated, morphometric evaluation of the lung architecture reveals areas of hyperinflation predominating over areas of collapse.221 On histologic examination, postinfectious BO is characterized by inflammation and fibrosis in the small airways. Chronic inflammatory cells fill the lumen of the small airways in the lung. These inflammatory cells can extend into the peribronchiolar region and less frequently into the alveoli. Small lymphoid aggregates without exuberant reactive germinal centers also have been described.221 The inflam­ matory infiltrate is composed of T lymphocytes with a predominance of the CD8+ subset.229 These findings sug­ gest T lymphocyte-mediated airway injury as the cause of bronchiolitis obliterans. The second histologic feature of BO is fibrous tissue creating varying degrees of luminal occlusion in the small airway. Total obliteration of the lumen by fibrotic tissue is frequently seen221 (Fig. 59-5). An elastic stain is useful in identifying the elastic layer remnants of bronchiolar walls within the fibrotic tissue. Foamy macrophages, mucostasis, and bronchiectasis are other frequent findings. Viral inclusion bodies are usually not present. Previously, BO was histologically classified into two subgroups—constrictive, described above, or prolifera­ tive. The proliferative type is characterized by the presence of granulation tissue plugs (Masson bodies) within the

FIGURE 59-5. Residual peribronchial smooth muscle (arrow) with adjacent maturing fibroblastic plug occluding the lumen of a bronchiole (10 × magnification). (Image courtesy of Todd Boyd, MD, at Cincinnati Children's Hospital Medical Center, Ohio.)

lumens of the small airways, alveolar ducts, and alveoli. Another term for the proliferative type is bronchiolitis obliterans organizing pneumonia (BOOP). More recent literature uses the term cryptogenic organizing pneumo­ nia (COP). This disease has similar etiologies to constric­ tive bronchiolitis obliterans including viral infection, inhalation injuries, connective tissue disorders, and immunosuppression. The clinical features include flulike illness, dry cough, and dyspnea. Radiographic imaging reveals patchy consolidation and ground-glass opacities. Pulmonary function testing frequently shows a restrictive abnormality.230 The connection, if any, between the two classifications of BO is unknown. The proliferative type is rarely found in the pediatric population.221 Treatment options for BO are limited, with most therapies having limited evidence supporting their use. Supportive care includes oxygen therapy, adequate nutritional intake, avoidance of smoke and other irritants, influenza vaccina­ tions, and pulmonary rehabilitation. Aggressive treatment of gastroesophageal reflux may be necessary to prevent ongoing lung injury from gastric acid. A small number of patients demonstrate improvement with bronchodilators and inhaled corticosteroids. Systemic corticosteroids are frequently used in BO, regardless of the etiology. However, the effectiveness of systemic corticosteroids remains unproven. The degree of reversible inflammation versus fibrosis in the airway most likely affects individual patient responsiveness. If bene­ ficial, a response to systemic corticosteroids probably occurs in the earlier stages of disease before complete airway fibrosis. While there are no controlled studies, pulse therapy consisting of intravenous methylprednis­ olone, 30  mg/kg (maximum 1 g) infused over 1 hour daily for 3 consecutive days has been proposed.216 If the

Section IX

876

chILD patient demonstrates benefit, the therapy is repeated monthly for 3 to 6 months, depending on the patient's ongoing responsiveness. Other therapies reported (anec­ dotally) include immunomodulatory doses of intrave­ nous immunoglobulin as a steroid-sparing agent216 and selective TNF-α blockade for BO following lung trans­ plantation.231 Small studies support the use of azithro­ mycin as a chronic immunomodulatory agent to prevent further decline in lung function.232,233 The outcome of patients with postinfectious BO is unclear. Multiple studies of postadenoviral BO report improvement or resolution of chronic hypoxia and wheezing episodes.223,218 Other studies show a progres­ sive decline in pulmonary function suggesting lifelong

­pulmonary impairment.224 Death has been reported sec­ ondary to postinfectious BO.234 Postinfectious BO remains a rare disease of the small airways, with adenovirus as the leading cause. Although the disease is well described from a clinical, radio­ graphic, and histologic standpoint, ongoing research is needed to identify treatment options and long-term outcomes.

References The complete reference list is available online at www. expertconsult.com