Host defenses against respiratory infection

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HOST DEFENSES AGAINST RESPIRATORY INFECTION Shawn J. Skerrett, MD

"everyone knows that this earthly air is terribly infected with the nameless miseries of the numberless mortals who have died exhaling it." HERMAN MELVILLE

MOBY DICK83

The lungs are remarkably resistant to infection. The alveolar membrane covers a surface area of over 140 m 2, nearly three fourths the size of a tennis court, and is exposed to the external environment with every breath. 37,87 Each day, more than 10,000 L of ambient air pass in and out of the respiratory tract, air that is contaminated with viable particles shed by animals, plants, and soil. The air on a city street may contain more than 100 bacteria/m3,s and indoor environments are often more polluted, containing hundreds to thousands of microorganisms per cubic meter, depending on the activities and ventilation in the room. S• 110 Humans contribute to bacterial and viral airborne contamination by talking, coughing, sneezing, and releasing microbes from skin and clothing. A cough generates hundreds of respirable droplets, and sneezing releases up to 40,000 droplets, each of which may contain many microorganisms,4s.72 It has been estimated that a million bacteria-laden particles may be released into the air by a person undressing and dressing over a 2-minute period. s In addition to the hazard posed by airborne microorganisms, there is evidence that the aspiration of oropharyngeal bacteria is a common occurrence during sleep. Huxley et a146 reported that 9 of 20 normal subjects aspirated a radiolabeled tracer deposited in the nasopharynx during sleep, and aspiration was observed in all subjects who slept soundly. Despite these onslaughts, the lower respiratory tract is kept nearly sterile, and pneumonia is a relatively infrequent event. The local defenses of the respiratory tract are sufficient to eliminate most microbial transgressions without clinical sequelae. Pneumonia occurs when the From the University of Washington School of Medicine; and the Pulmonary and Critical Care Medicine Section, Veterans Affairs Medical Center, Seattie, Washington MEDICAL CLINICS OF NORTH AMERICA VOLUME 78 • NUMBER 5 • SEPTEMBER 1994

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offending challenge overwhelms the resident defenses, leading to microbial replication, inflammation, and an immune response. The outcome of this battle depends on microbial virulence, infectious inoculum, and host susceptibility. A vigorous pathogen or legions of less robust invaders are required to triumph over intact host defenses, but a meager challenge may suffice when resistance is weak. This article reviews the local defense mechanisms of the respiratory tract and the pathways for the amplification of these defenses through the inflammatory and immune responses. Common defects in pulmonary defenses that predispose to infection as well as to opportunities to augment host resistance are considered. LOCAL DEFENSES OF THE RESPIRATORY TRACT Colonization of the Respiratory Tract: The Normal Flora

Oropharyngeal aspiration is an important route of infection of the lung, and thus the nature of the resident oropharyngeal flora is important. Maintenance of the normal upper respiratory tract flora, to the exclusion of more virulent potential pathogens, may be considered among the body's defenses. The mouth is the major repository of microorganisms in the upper respiratory tract. Saliva contains approximately 10" bacteria per milliliter, with anaerobic organisms outnumbering aerobic bacteria by a ratio of 10:1.'2 Bacteroides and Fusobacterium are the predominant genera among the anaerobic flora, and streptococci are the most common aerobic organisms. 32 Staphylococci, Haemophilus species, Neisseria species, Moraxella (Branhamella) catarrhalis, corynebacteria, and lactobacilli also are found?4 Candida is the most common fungus. A similar spectrum of organisms colonizes the nose and nasopharynx, albeit in smaller numbers than found in the mouth. 74 These organisms reside in the upper respiratory tract because they thrive in the local environment and because they stick to an available surface. Successful colonization requires that organisms be firmly anchored, to avoid mechanical removal by the sweeping action of the tongue, the flow of secretions, the mucociliary apparatus, and the expulSive forces of coughing and sneezing?4, 108 The attachment of microorganisms to host tissues may be mediated by nonspecific ionic and hydrophobic interactions and by specific binding of microbial attachment proteins, or adhesins, to receptors on host cells. lOB Microbial adhesins may interact directly with epithelial cells, such as the attachment of Escherichia coli fimbriae to mannose residues of surface glycoproteins/ or bridging molecules may recognize ligands on both the microorganism and the host cel1.108 For example, the adherence of gram-positive bacteria to epithelial cells is mediated by fibronectin, which attaches to epithelial cells and to a lipoteichoic acid/protein complex on the bacterial surface? Most bacteria can express several adhesins and thus have alternate attachment mechanisms. Microbial adhesins usually recognize carbohydrate moieties, particularly mannose, galactose, and sialic acid, but the target structures of most bacterial adhesins have not been identified?, 108 The binding of microbial adhesins to host cell receptors can be remarkably specific and probably plays a major role in the tissue tropism of some organisms,6, 74, 108, 146 In general, bacteria avidly bind to epithelial cells taken from sites where the organisms are usually found in vivo. Thus, gram-negative bacilli preferentially bind to intestinal and genitourinary epithelium, whereas viridans streptococci stick avidly to oral epithelial cells,6, 74 Even within the oropharynx, the distribution of normal flora is site-specific. For example, Streptococcus sanguis

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and Streptococcus mutans are found on the surface of teeth, Streptococcus salivarius resides on the dorsal tongue, and Streptococcus mitis colonizes the buccal mucosa.1 46 Mucosal secretions and microbial competition help restrict the colonizing flora. A variety of substances are present in mucus and saliva that are directly toxic to microorganisms (e.g., lysozyme), impair microbial growth (e.g., lactoferrin), or block adherence (e.g., IgA). These are discussed further later on. Soluble factors may promote colonization by some organisms while discouraging others. For example, fibronectin mediates the binding of gram-positive bacteria to epithelium but inhibits the binding of gram-negative bacilli?' 108, 122 The indigenous flora can prevent the adherence of unwelcome guests by occupying binding sites or by releasing substances that block the adherence of competing microorganisms?4 Viridans streptococci produce antimicrobial proteins and other products that inhibit the growth of other bacteria?4 Commensal organisms also stimulate mucosal immune mechanisms, judging by the immunologic deficiencies of germfree animals. 74 The nature of the oropharyngeal flora is altered by local and systemic disease.94, 122 Oral anaerobes are fewer in number in edentulous patients and are more plentiful in the presence of periodontal disease. 32 Systemic illnesses can lead to changes in the interaction of epithelial cells with microorganisms,94, 122 For example, Johanson et aJ5 1 demonstrated that postoperative colonization of the oropharynx with gram-negative bacilli was associated with an increase in the binding of gram-negative bacteria by buccal epithelial cells in vitro. The production of salivary proteases by these traumatized patients may have digested fibronectin from the cell surface, exposing binding sites for gram-negative bacteria and reducing the binding sites for gram-positive flora. 146 In contrast to the abundant upper respiratory flora, few if any bacteria are found below the larynx in the absence of airway disease,94 The tracheobronchial tree usually is colonized in patients with chronic bronchitis, cystic fibrosis, bronchiectasis, and lung cancer.9. 40, 94. 95 Among patients with chronic bronchitis, the colonizing flora often include Haemophilus species, Streptococcus pneumoniae, and M. catarrhalis;9, 38, 40. 84 the spectrum broadens to include staphylococci, Pseudomonas species, and other gram-negative bacilli in patients with bronchiectasis and cystic fibrosis. 3, 9, 66 Colonization of the trachea also is common in patients with endotracheal tubes and tracheostomies,94 Niederman et aP6 found that Pseudomonas aeruginosa bound more readily to tracheal epithelial cells harvested from patients with tracheostomies than to cells from normal volunteers. Moreover, the bacteria bound most avidly to cells from malnourished patients. 96 Thus, the sterility of the lower respiratory tract is lost in the setting of epithelial injury and impaired airway clearance mechanisms. PhYSical Barriers

Aerodynamic Filtration

The anatomy of the respiratory tract insures that most inhaled or aspirated microorganisms will be stopped in the conducting airways, well before reaching the alveoli. Air entering the nares passes through the curtain of nasal hairs (vibrissae), then negotiates the narrow, tortuous passageways over the nasal turbinates before taking an abrupt 90-degree turn at the nasopharynx. In the tracheobronchial tree, inhaled air twists and turns through more than 20 progressively smaller divisions of the branching airways before reaching the gas exchange units,87 The frequent changes of direction along narrow channels encour-

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age the deposition of airborne particles by the processes of inertial impaction, sedimentation, and diffusion. lO, "7, 93 Inertial impaction refers to the deposition of particles that fail to change direction with air currents. Inertial forces are proportional to the mass and velocity of the object and thus are most important in the deposition of relatively large particles (> 10 JJ.m) in the upper airway, where airflow is fastest. 87,93 Sedimentation results from the settling effect of gravity in regions of low airflow and mainly affects the deposition of 0.2 to 5 JJ.m particles in peripheral airways.s7, 93 Diffusion is the random (brownian) motion of small particles resulting from their bombardment by gas molecules and accounts for the deposition of particles less than 0.1 JJ.m in the distal airspaces. lo, 87, 93 Most inhaled particles between 0.1 and 0.5 JJ.m in size remain suspended and are exhaled. 10, 87, 93 Infectious aerosols generated by coughing, sneezing, and environmental sources contain droplets ranging in size from less than 1 JJ.m to greater than 100 JJ.m.lO Nearly all particles larger than 10 JJ.m in size are deposited in the nose. lD, 87,93 Droplets from 4 to 10 JJ.m are deposited mostly in the upper respiratory tract or the conducting airways, and only particles less than 5 JJ.m readily reach the alveolU 7,93 Boluses of material aspirated from the oropharynx deposit mainly in dependent zones of the conducting airways. Airway geometry thus insures that most inhaled or aspirated microorganisms will be deposited on a mucosal surface and thus be subject to mechanical clearance or inactivation by mucosal secretions. Larynx and the Gag Reflex

The larynx is the gateway to the lower airway, and its closure by the gag reflex and during normal glutition is the major barrier to aspiration. Failure of glottic closure may result from anatomic distortion or functional impairment of the larynx or from loss of the gag reflex. Distortion of the larynx may be caused by local tumors or edema, and functional loss of glottic closure may result from neurologic injury. The gag reflex may be impaired by brain stem disease; seizure disorder; or the effects of central nervous system depressants such as alcohol, barbiturates, and opiates. Huxley et a146 demonstrated that 7 of 10 patients with impaired consciousness aspirated oropharyngeal material, and the amount of aspiration was greater than that observed in sleeping normal volunteers. Epithelium

The epithelial lining of the respiratory tract provides a continuous barrier to microbial invasion. From the ciliated pseudostratified columnar epithelium of the proximal airways to the flattened nonciliated epithelium of the terminal respiratory units, the epithelial cells are joined by tight junctions and backed by a basement membrane. 87 The respiratory epithelium is more than a passive barrier, however. As discussed later, epithelial secretions are inhospitable to would-be pathogens, and ciliary activity expels unwelcome guests. There is also mounting evidence that epithelial cells participate in the regulation of the inflammatory and immune responses.25 Mechanical Clearance Cough

Coughing is an effective means of expelling material from the central airways and the larynx. In contrast to other protective reflexes, such as gagging or

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sneezing, coughing may be voluntary or involuntary. A normal cough begins with a rapid inspiration, followed by glottic closure; contraction of the thoracic and abdominal musculature generates intra abdominal and intrathoracic pressures of 50 to 100 mm Hg or more before the glottis is opened and air is expelled. 6s,93 The rise in intrathoracic pressure compresses the central airways by greater than 50%, which increases the velocity of airflow in the trachea to upward of 250 m/sec (three fourths the speed of sound).68 This creates a tremendous shear force that expels mucus and entrapped particles from the airway. The expulsive force is greatest in the central airways, where airflow is fastest and the airways most compressible.6s, 93 Cough is less effective in clearing the distal airways, although the increase in expiratory airflow and slight airway compression may help milk secretions more proximally.6B,93 An optimal cough requires a closed glottis and intact thoracic and abdominal musculature. The effectiveness of coughing is thus compromised when the glottis cannot be closed, as in the presence of an endotracheal tube, and when abdominal and thoracic musculature is weakened by age, inanition, or neuromuscular injury.6B Mucociliary Clearance

The mucociliary apparatus is a continuously operating system for disposing of particles that alight on the lining of the nose or conducting airways. Ciliated cells are found in the upper respiratory tract from the posterior two thirds of the nose to the nasopharynx and in the lower respiratory tract from the proximal trachea to the terminal bronchioles.87,93 Ciliated epithelium is covered with two layers of fluid: a watery phase that surrounds the cilia and a layer of mucus that floats on the surface. 66, 87, 93 The major constituents of mucus are complex glycoproteins called mucins, which contain binding sites for the adhesins of many bacteria.66 Microorganisms trapped in the mucus layer are unable to reach target epithelial cells and are subject to removal by ciliary action (Fig. 1).66 The cilia beat in a coordinated manner, moving the mucus in waves to the oropharynx, where it can be swallowed or expectorated.93, 141 In the nasal passages, mucus is transported posteriorly at a rate of approximately 6 mm/min. '03 In the tracheobronchial tree, mucus is carried cephalad at a rate of 10 to 20 mm/min in the trachea and more slowly in the distal airways.8?, 93, 141 The overall contribution of mucociliary clearance to the removal of microbial invaders from the lung is uncertain, but studies with experimental animals have shown that more than 80% of aspirated or inhaled bacteria remain in the lung 4 hours after inoculation. B4, 133 Deficiencies in mucociliary clearance may result from reductions in the number or function of cilia, and alterations in the viscoelastic properties of mucus. Rare genetic disorders of ciliary function, such as primary ciliary dyskinesia and the immotile cilia (Kartagener) syndrome, lead to recurrent respiratory infections and bronchiectasis.B6, 145 Mucociliary function is impaired in conditions associated with chronic airway inflammation, such as cystic fibrosis, bronchiectasis, and chronic bronchitis, owing to loss of ciliated epithelium and changes in mucus viscosity.3, 66, 141, 145 Acute infection may damage the ciliary apparatus as well. Mycoplasma pneumoniae and influenza destroy ciliated epithelium, and many bacteria release products that inhibit ciliary activity.l4l, 145 Antimicrobial Secretions

In addition to mucus, a variety of other respiratory tract secretions contribute to host defenses (Table 1). These factors act by impairing the binding of micro-

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Figure 1. Scanning electron micrograph of bronchial epithelium. A neutrophil is in pursuit of bacilli (Pseudomonas aeruginosa) that are adherent to cilia. Bar = 10 j-Lm. (Courtesy of Emil Y. Chi, PhD.)

Table 1. RESPIRATORY TRACT DEFENSES Local Defenses

Systemic Defenses

Normal flora Physical barriers Aerodynamic filtration Larynx Epithelium Mechanical clearance Cough,sneeze Mucociliary escalator Secretions Mucus Lysozyme Lactoferrin, transferrin Fibronectin Complement Immunoglobulins Surfactant Lipopolysaccharide binding protein Cellular defenses Epithelial cells Lymphoid tissue Alveolar macrophages

Phagocytes Neutrophils Monocytes Plasma proteins Complement Immunoglobulins C·reactive protein Lipopolysaccharide binding protein Immune responses Specific antibody Cell·mediated immunity

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organisms to respiratory mucosa, exerting direct antimicrobial activity, or facilitating the interaction of infectious agents with phagocytes. Lysozyme was discovered in nasal secretions by Fleming.58,67 Named for its bacteriolytic effect, lysozyme cleaves the peptidoglycan of bacterial cell walls and kills a limited spectrum of bacteria.'6,31 Lysozyme also triggers autolysis of pneumococci by a nonenzymatic mechanism'6,19 and has a nonlytic microbicidal effect against other bacteria and fungi. 31,67 Lysozyme is secreted by the serous cells of submucosal epithelial glands as well as by alveolar macrophages.58, 131 It is found throughout the respiratory tract, although concentrations are higher in the conducting airways than in the alveoliY' Neutrophils also are potent sources of lysozyme, and airway levels rise with acute and chronic inflammationY' In addition to its bactericidal activity, lysozyme may interfere with the binding of bacteria to epithelium.'4 Lactoferrin and transferrin are iron-binding proteins that contribute to host defense mainly by withholding an essential nutrient from invading microorganisms. A wide variety of pathogens are killed or rendered less virulent by iron deprivation, including enteric gram-negative bacilli, p, aeruginosa, staphylococci, streptococci, legionella, and mycobacteria. '6,33 Lactoferrin is produced by submucosal glands in the respiratory epithelium and is found in higher concentrations in respiratory secretions than transferrin, which is a product of alveolar macrophages. '6,131 Lactoferrin also is released by activated neutrophils, contributing to the increase in airway levels of lactoferrin with inflammation. 131 In contrast to transferrin, lactoferrin retains its iron at low pH, a characteristic that may be important in the acidic environment of acute inflammation.'6,131 Lactoferrin also has a direct microbicidal effect against some bacteria that is unrelated to iron.67 Fibronectin is found in respiratory secretions of the upper and lower respiratory tract and influences the interaction of microorganisms with host cells. As mentioned earlier, fibronectin mediates the binding of gram-positive bacteria to buccal epithelial cells but inhibits the epithelial adherence of gram-negative bacteria." 108, 122 Fibronectin also promotes the binding of Pneumocystis carinii to alveolar epithelium102 and stimulates the phagocytosis of yeast particles by alveolar macrophages. 21 Small quantities of complement have been found in bronchoalveolar lavage fluid, including the components of the alternative pathway (C3-C9).133 This pathway can be activated by microbial products in the absence of specific antibody and may contribute to host defenses by generating nonspecific opsonins (C3b), chemotactic factors for neutrophils (C5a), and the membrane attack complex that lyses susceptible bacteria (C5b-C9),>4 The complement in the normal lung probably derives from the transudation of plasma as well as the synthesis of some components by alveolar macrophages and alveolar epithelial cells. 128, 133 Complement is particularly important in host defense against respiratory pathogens with antiphagocytic capsules, such as H. injluenzae and S, pneumoniae. Complement fragments promote the uptake and killing of these organisms in the presence of specific antibody by alveolar macrophages and neutrophils, and the terminal attack complex of complement can lyse H. injluenzae and Neisseria in the presence of specific antibody.>4,49 Animal studies of the effect of complement depletion in early bacterial clearance have been inconclusive,'33 but human deficiencies of complement are associated with recurrent sinopulmonary infections with encapsulated organisms. 24 Immunoglobulins are present in respiratory secretions, with IgA predominating in the upper respiratory tract and conducting airways and IgG more prevalent in the alveoli,105 The role of immunoglobulins in host defense is based

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on their antibody activity against specific microbial antigens. 43 Although immunoglobulins present in normal respiratory secretions have antibody activity against a variety of microorganisms,104 probably reflecting past exposures and cross-reactivity, the importance of resident immunoglobulins to general host defense is unclear. The critical role of antibodies in defending the lung from infection is discussed with the immune response later. The surfactant in alveolar lining fluid contributes to host defenses in several ways. Surfactant is a lipid/protein complex produced by type II alveolar epithelial cells that serves to lower surface tension in the gas exchange units, thereby preventing alveolar collapse. 69 This property may facilitate clearance mechanisms in the distal airspaces because the atelectatic lung is more prone to infection. 62 ,69 Surfactant may have additional, more direct roles in host defense, Free fatty acids found in the lipid fraction of rat surfactant have bactericidal activity against pneumococci and other streptococci found in the respiratory tract, although not against staphylococci or gram-negative bacilli. 16, 17 Bacterial killing, however, has not been found to be a property of human surfactant, which contains less free fatty acid,16,55 Rat surfactant also has been found to stimulate the phagocytosis and killing of Staphylococcus aureus by alveolar macrophages in the presence of serum opsonins,57, 65, 97, 137 a property attributed to surfactant protein (SP)-A,!37 but this effect has not been consistently identified in human surfactant.55, 57, 81 The glycoproteins associated with surfactant bind to microbial lectins, which may influence the attachment of these organisms to host cells, For example, SP-A binds to p, carinii/48 and SP-D agglutinates E. COli,63 Surfactant may also regulate the inflammatory and immune responses to infection, SP-D binds to E. coli lipopolysaccharide and may help scavenge endotoxin in the airway,63 Synthetic surfactant (Exosurf) inhibits cytokine release by lipopolysaccharide (LPS)-stimulated alveolar macrophages,13o and surfactant inhibits lymphocyte responses,69 LPS-binding protein (LBP) has been identified in human bronchoalveolar lavage fluid?9 This glycoprotein binds to the LPS (endotoxin) of gram-negative bacteria, and the LBP /LPS complex attaches to the CD14 receptor of mononuclear phagocytes,!32 LBP markedly potentiates the cytokine response of alveolar macrophages to LPS?9 LBP is synthesized mainly in the liver, and hepatic production increases as part of the acute phase response,132 Low levels of LBP are detectable in normal bronchoalveolar lavage fluid, probably as a result of transudation from plasma, and higher concentrations are found in lavage fluids from patients with adult respiratory distress syndrome (ARDS)?9 LBP may be important in regulating inflammatory responses to gram-negative infection, Alveolar Macrophages

Alveolar macrophages are the resident phagocytic cells in the lung and constitute the initial defense against infectious agents that reach the alveolar spaces (Figs, 1 and 2),31, 118 In addition to their intrinsic antimicrobial activity, alveolar macrophages play a major role in orchestrating the inflammatory and immune responses, Alveolar macrophages are avidly phagocytic, and the uptake of microorganisms is facilitated by opsonins (from the Greek word opsono, meaning "1 prepare victuals for"),43 The binding of opsonin-coated particles with receptors on the surface of phagocytic cells triggers phagocytosis,31 Specific IgG is the most effective opsonin for alveolar macrophages, but complement components (C3b) promote the uptake of many organisms when antibody is in low titer or unavailable?l, 44, 54, 118 Both complement and specific antibody are required for the optimal

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phagocytosis of organisms with anti phagocytic capsules, such as S. pneumoniae, H. infiuenzae. E. coli, and P. aeruginosa. 31 .49 Other potential opsonins present in the alveolar space include fibronectin and surfactant, as described previously. Alveolar macrophages can ingest some organisms in the absence of extrinsic opsonins because of direct binding of microbial ligands to receptors on the surfaces of macrophages. For example, the ingestion of some strains of S. aureus is mediated by the attachment of staphylococcal protein A to surface-bound immunoglobulins on alveolar macrophages. 31 Similarly the uptake of P. carinii by alveolar macrophages is mediated by the mannose receptor. 28 Alveolar macrophages readily kill some ingested organisms, such as S. pneumoniae and H. infiuenzae,31.54 but are less effective in disposing of S. aureus and E. coli.44.9o A variety of microorganisms evade the microbicidal activities of alveolar macrophages and replicate intracellularly (Table 2). The eradication of these organisms requires the development of cell-mediated immunity, as described subsequently. Alveolar macrophages are pluripotential cells that regulate the amplification of host defenses in the lung, The remarkably diverse secretory products of alveolar macrophages include bioactive lipids with chemotactic and immunoregulatory properties, such as leukotriene B4 and prostaglandin E2,'1. 118 and a growing list of cytokines. These include chemotactic peptides such as interleukin-8 (IL-8) and related chemokines, antiviral interferons, and proinflammatory cytokines

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Table 2. INTRACELLULAR PATHOGENS IN THE LUNG Bacteria Mycobacterium spp Nocardia spp Legionella spp Francisella tularensis Chlamydiae Rickettsiae Coxiella burnetii

Fungi Histoplasma capsulatum Coccidioides immitis Blastomyces dermatitidis Para coccidioides brasiliensis Cryptococcus neoformans Protozoa Toxoplasma gondii

with broad-spectrum activities such as IL-l, IL-6, tumor necrosis factor-a (TNF), and colony-stimulating factors.6o, 118 Alveolar macrophages also produce proteases and antioxidants that help protect the lung from microbial and inflammatory injury.31, 118 Alveolar macrophages have a limited capacity to present antigen in the initiation of humoral and cell-mediated immunity and can act as effector cells in the eradication of intracellular parasites when activated by lymphokines such as interferon-,),.90, 116, 120 Although selective defects in alveolar macrophage function have not been described, the protean contributions of alveolar macrophages to host defense may be impaired in various clinical settings. For example, cigarette smoking and alcoholic liver disease have been associated with impaired phagocytosis and killing of some microorganisms by alveolar macrophages, as described subsequently.bl, 139 Furthermore, immunosuppressive drugs such as corticosteroids impair the secretion of inflammatory mediators by alveolar macrophages, which may contribute to the frequency and severity of pulmonary infections in immunosuppressed patients. 122,125

SYSTEMIC DEFENSES Inflammatory Response

When the resident defenses of the lung are insufficient to meet a microbial challenge, an inflammatory response is initiated that brings phagocytic cells and plasma proteins from the blood to the site of infection. Neutrophils and monocytes are more effective than alveolar macrophages in the phagocytosis and killing of many organisms, and plasma proteins contribute to the opsonization of microorganisms as well as the amplification of the inflammatory response. Evidence from experimental models suggests that the capacity of resident lung defenses to eliminate microbial challenges depends on the organism and the inoculum.133 For example, low numbers of S. aureus are dispatched by alveolar macrophages without inciting an inflammatory response, but higher inocula of staphylococci and any challenge with gram-negative bacilli require the assistance of neutrophilsY3 Granulocytes are essential to host defense against many bacterial and fungal infections. Neutrophils are as actively phagocytic as alveolar macrophages and are more heavily armed for killing ingested organisms. 31 , 44 The antimicrobial weapons of neutrophils include a potent respiratory burst that generates toxic products from the reduction of oxygen and granules containing an array of microbicidal proteins, including lysozyme, lactoferrin, bactericidal/permeability increasing factor, defensins, and proteases. 67,117 Many of these products are re-

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leased extracellularly, helping to contain organisms that are resistant to phagocytosis.67 Although neutrophils kill most organisms more efficiently than alveolar macrophages, the cooperation of phagocytes is important to host defense. The antimicrobial activity of neutrophils is stimulated by TNF, IL-l, and other factors released by alveolar macrophages,117, 127 and the elimination of some organisms requires the synergistic action of different phagocytes. For example, macrophages can inactivate aspergillus spores but are helpless against the hyphal form of the fungus. Neutrophils can destroy the growing hyphae but cannot inactivate the spores. m Animal models have shown that neutrophil depletion impairs pulmonary clearance of many organisms but is most deleterious for host defense against gram-negative bacilli, such as P. aeruginosa and Klebsiella pneumoniae.!33 This mirrors the epidemiology of opportunistic pneumonia in granulocytopenic patients, in whom gram-negative, staphylococcal, and aspergillus infections are particularly troublesome."6, 118, 122 The recruitment of neutrophils to the lung begins with the margination of circulating cells and their attachment to vascular endothelium, a process mediated by adhesion moleculesY' 118, 126, 127 Initially, E- and P-selectins expressed by stimulated endothelial cells interact with L-selectin constitutively expressed by leukocytes. As a result of this reversible interaction, neutrophils roll on the surface of endothelial cells. Exposure of rolling neutrophils to factors that activate leukocyte ~2 integrins leads to firm attachment of the granulocytes to the intercellular adhesion molecule 1 on the surface of endothelial cells. The neutrophils then emigrate through the vessel wall and migrate down a chemotactic gradient to the site of infection. Pulmonary infection stimulates the recruitment and activation of neutrophils by several pathways. Bacteria release formylated peptides such as F-met-Ieu-phe that stimulate leukocyte adhesion and migrationP' 126 Microorganisms also activate the alternate pathway of the complement cascade, generating C5a, which is another potent chemotactic factor."7,133 Alveolar macrophages, stimulated by the ingestion of microorganisms or by contact with microbial products such as gramnegative endotoxin, release a variety of mediators that promote the inflammatory response. 117, 127 As described earlier, these secretory products include neutrophil chemotactic factors such as leukotriene B4 and IL-S. Alveolar macrophages also secrete proinflammatory cytokines such as IL-l and TNF, which directly promote neutrophil migration and antimicrobial activation and also amplify the inflammatory response indirectly by stimulating other cells in the alveolar environment, such as epithelial cells, fibroblasts, and endothelial cells, to release chemotactic factors. 117,127 Neutrophils also release IL-S in response to microbial stimuli, further augmenting the inflammatory response. 127 The net result of this cascade is the accumulation in the airspaces of the lung of granulocytes with activated antimicrobial mechanisms. The alteration in vascular permeability that accompanies the inflammatory response to infection results in the exudation of plasma proteins into the lung. 143 This increases the availability of complement, which has opsonic, microbicidal, and proinflammatory properties that have been described. LBP also accumulates in the inflamed lung, further amplifying the inflammatory response to gramnegative infection. Another plasma protein that may play a role in host defense is C-reactive protein. This is an acute phase reactant made by the liver that contributes to the clearance of pneumococci in experimental animals, probably because of its opsonic activity.", 49 Plasma exudation also increases the concentration of immunoglobulins in the lower airway, which improves the antimicrobial activity in the lung if the antibodies are of appropriate specificity.

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Specific Immune Responses

The resident and inflammatory defenses of the lung are supplemented by specific immune responses to microbial antigens. The humoral immune response refers to the production of specific antibody by B cell-derived plasma cells, which is particularly important in host defense against extracellular pathogens such as the pneumococcus and H. injluenzae. Cell-mediated immunity refers to sensitization of T cells to microbial antigens, leading to macrophage activation and cytotoxic responses. Cell-mediated immunity is essential to the host response to intracellular infections such as tuberculosis and legionellosis. Humoral Immunity

The production of specific antibody is a cornerstone of the host response to infection. Antibodies are produced by plasma cells, which are B lymphocytes that have differentiated after recognition of a specific antigen!' B cells can respond directly to polysaccharide antigens, such as the pneumococcal capsule, but require the direct cooperation of T cells to respond to protein antigens.'!' 43 B cell responses to all antigens are regulated by lymphokines released by T cellsY' 43 On differentiation to plasma cells, B cells become committed to the secretion of antibodies of a single immunoglobulin class: IgM, IgA, IgG, or IgE.43 All of these immunoglobulin classes can be found in respiratory tract secretions, as a result of local and systemic synthesis.59, 105 Secretory IgA is the major immunoglobulin in the upper respiratory tract, and IgG predominates in the lower airway.92, 104, 105 There are two classes of IgA: IgAI and IgA2' Both are produced in dimeric form by submucosal plasma cells and conjugated with a secretory component before secretion by the serous glands of the upper respiratory tract and the conducting airways. 58, 92,105 Secretory IgA functions mainly to prevent the attachment of specific microorganisms to epithelium. Thus, IgA plays important roles in stopping respiratory viruses from infecting their target cells and in blocking bacterial colonization. The agglutination of bacteria by IgA also facilitates their removal by the mucociliary apparatus!" 59, 105 IgA is a poor opsonin, however, and does not activate complement-mediated microbial lysis.43, 105 Some bacteria, including S, pneumoniae, H. injluenzae, Neisseria species, and P. aeruginosa, secrete proteases that cleave IgA.42, 105 These proteases may be virulence factors that contribute to colonization and infection by these organisms. 105 Isolated IgA deficiency is the most common primary immunodeficiency. Most of those afflicted are asymptomatic, but a minority of these patients have recurrent sinopulmonary infections.43 ,105 IgG is the most prevalent immunoglobulin found in bronchoalveolar lavage fluid. There are four subclasses of IgG, with IgG I and IgG2 predominating in the lung. 104 Trace amounts of IgM also are found.59, 104 These immunoglobulins are probably derived from transudation of plasma combined with local production by mucosal and lumenallymphocytes.59,104, 105 The IgG in normal bronchoalveolar lavage fluid has antibody activity against a variety of microbial antigens, reflecting past exposures and cross-reactivity.104 In a primary immune response to pneumonia, specific antibodies appear in the blood and bronchoalveolar lavage fluid within 5 to 7 days after infection. 59, lOS, 133 In previously immune subjects, specific IgG and IgM appear in bronchoalveolar lavage fluids within hours of infection, as a result of exudation from the plasmaY3 The binding of microorganisms by IgM or IgG activates the classic pathway of the complement cascade, promoting ingestion of the organisms by phagocytes as well as complementmediated lysis of susceptible bacteria.>4, 43,104 IgG is an even more effective opso-

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nin than complement, promoting phagocytosis via Fc receptors on alveolar macrophages and neutrophils. 31 IgM and IgG also contribute to antiviral defenses, by neutralizing respiratory viruses in the same manner as IgAY The binding of IgG to viral antigens expressed by infected cells can promote destruction of the infected cells by Fc receptor-bearing natural killer (NK) cells, cytotoxic T lymphocytes, and phagocytes, a process known as antibody-dependent, cell-mediated cytotoxicity.43 Humoral immunity is particularly important for host defenses against organisms with antiphagocytic capsules, such as S. pneumoniae, H. injluenzae, Neisseria species, and some gram-negative bacillL 11 , 43, 49 These are extracellular pathogens in that they replicate independently of host cells and are readily killed by phagocytes once ingested; their survival thus depends on avoiding phagocytosis. For example, S. pneumoniae is readily ingested only when coated with both specific antibody and complement. 11 • 49 H. injluenzae and Neisseria species can be killed by complement-mediated lysis in the presence of specific antibody?4 The importance of humoral immunity in the resolution of these infections is further supported by the marked propensity for serious infections with this group of pathogens in patients with congenital or acquired defects in antibody production, such as primary immunoglobulin deficiencies, chronic lymphocytic leukemia, multiple myeloma, and splenectomyy,43, 116 Cell-Mediated Immunity

Cell-mediated immunity refers to the interaction of T lymphocytes and macrophages in the control of infection, The induction of cell-mediated immunity requires the presentation of microbial antigens by macrophages or dendritic cells to T lymphocytes, which undergo antigen-specific clonal expansion under the influence of IL-I, IL-2, and other cytokines. 14, 71, 116, 144 Activated T cells elaborate lymphokines that stimulate antibody production and augment the microbicidal pathways of phagocytic cells.14, 144 T cell activation also leads to the arming of cytotoxic lymphocytes that lyse host cells, which are supporting the growth of invading microorganisms.14, 116, 144 Both helper (CD4) and suppressor/cytotoxic (CD8) T cells participate in these responses. CD4 cells recognize antigen presented with class II molecules of the major histocompatibility complex (MHC) and are a major source of interferon-I', the principal lymphokine that activates macrophages to resist intracellular infection.H, 85 CD8 cells recognize antigen together with MHC class I molecules, display cytotoxic activity against infected cells, and also produce regulatory lymphokines. 14,116 NK cells also contribute to this line of defense. NK cells are lymphocytes that are not antigen-specific, but when activated by cytokines such as TNF, IL-2 and IL-I2, they elaborate interferon-I' and can lyse infected cells.'1 Cell-mediated immunity is essential for host defense against intracellular pathogens of the lung (see Table 2). All of these organisms are capable of replicating in alveolar macrophages, and many can parasitize respiratory epithelium as well. Intracellular sequestration protects these organisms from antibodies and neutrophils. Cellular immunity also is necessary for the eradication of P. carinii, an extracellular pathogen that is resistant to other host defenses. 14o The importance of cell-mediated immunity in host resistance to these organisms is underscored by the frequency and severity of infections caused by this group of opportunistic pathogens in patients with T cell defects resulting from immunosuppressive therapy, marrow transplantation, T cell malignancies, and human immunodeficiency virus (HIV) infection. 116, 122,144

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Table 3. CAUSES OF RESPIRATORY TRACT INFECTION IN RELATION TO UNDERLYING CONDITIONS Condition COPD Advanced age Alcoholism Critical care

Common Infectious Agents

S. pneumoniae, H. influenzae, M. catarrhalis

S. pneumoniae, H. influenzae, S. aureus, gram-negative bacilli, influenza, tuberculosis S. pneumoniae, anaerobes, gram-negative bacilli, H. influenzae, S. aureus Gram-negative bacilli, S. aureus

COMMON DEFECTS IN RESPIRATORY TRACT DEFENSES

Most patients that are hospitalized with pneumonia have underlying conditions that compromise respiratory tract defenses,>9,78 Different host factors predispose to different infectious agents by altering respiratory tract flora and disrupting particular elements of local and systemic defenses (Tables 3 and 4). Evaluating the status of host defenses in an individual patient thus can provide clues to the potential causes of pneumonia. Consideration of some common conditions illustrates the influence of underlying disease on host defenses. Cigarette Smoking

Cigarette smoking has been associated with an increased incidence and severity of lower respiratory tract infection, even in the absence of airflow obstruction?6 The risk of infection in smokers is associated with alterations in respiratory tract flora, mechanical clearance, and cellular defenses. Respiratory tract pathogens such as S. pneumoniae and H. inJLuenzae adhere more strongly to the upper respiratory epithelium of smokers than nonsmokers, and bacterial colonization of the lower respiratory tract is more prevalent in smokers than nonsmokers. 47. 76 Mucociliary clearance is impaired in smokers, owing to a reduction in ciliary beat frequency and changes in the volume and viscoelastic properties of respiratory secretions?6. 93. 141 Alveolar macrophages harvested from smokers display abnormalities of number, structure, and function?7,76 The antimicrobial activities of smokers' macrophages against pyogenic bacteria such as H. inJLuenzae, P. aeruginosa, and 5, aureus are preserved/6 ,b1, 76,106 but the resistance of smokers' macrophages to intracellular infection may be impaired. Alveolar Table 4. CAUSES OF RESPIRATORY TRACT INFECTION WHEN SYSTEMIC HOST DEFENSES ARE IMPAIRED Defect Neutrophils Humoral immunity Cell-mediated immunity

Examples Chemotherapy, acute myeloid leukemia Multiple myeloma, chronic lymphocytic leukemia, immunoglobulin deficiency HIV infection, Hodgkin's disease, corticosteroid therapy

CMV ~ Cytomegalovirus; HSV ~ herpes simplex virus.

Infectious Agents Gram-negative bacilli, S. aureus, Aspergillus S. pneumoniae, H. influenzae, Neisseria spp Mycobacterium, Nocardia, Legionella, Coccidioides, Histoplasma, Cryptococcus, CMV, HSV, p, carinii, Toxoplasma

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macrophages harvested from smokers kill Listeria monocytogenes less effectively than macrophages harvested from nonsmokers and exhibit diminished resistance to the intracellular replication of Legionella pneumophila. 50 • 61 The susceptibility of smokers' macrophages to parasitism by L. pneumophila may be related to their increased expression of the CDllb/CD18 integrin complex,111 which mediates bacterial uptake,99 and to their increased content of iron,80 which is an essential nutrient of L. pneumophilaY Chronic Obstructive Pulmonary Disease

Lower respiratory tract infection is a frequent complication of chronic obstructive pulmonary disease (COPD). Pneumonia is disproportionately common and associated with greater morbidity in patients with underlying COPD, and tracheobronchial infections contribute to the episodic exacerbations of COPD.38. 84 Lower respiratory tract infection in the setting of COPD is often due to S. pneumoniae, unencapsulated (nontypable) strains of H. influenzae, and M. catarrhalis, organisms that frequently colonize the upper and lower respiratory tract in these patients.9. 38. 40. 84 Mucociliary clearance is markedly impaired in COPD, owing to loss of ciliated epithelium, mucus plugging, and changes in the rheologic properties of mucus. 141 The effectiveness of coughing is diminished in COPD by reduced airflow, airway collapse, and respiratory muscle fatigue. 6s • 93 In addition to these defects in mechanical clearance, host defenses in COPD often suffer from the coexistent effects of cigarette smoking and malnutrition. lol • 122 Medications used to treat COPD, such as corticosteroids and theophylline, may further compromise resistance to infection.26 • 122 Advanced Age

Among persons over the age of 65 years, pneumonia occurs more commonly than in younger age groups and is more likely to follow a complicated course??' 122 Pulmonary defenses in the elderly are compromised by age-related defects in mechanical clearance and in humoral and cell-mediated immunity as well as the cumulative effects of chronic diseases and their treatments. 39. 119. 122 Advanced age is associated with a loss of elastic recoil in the lung and a reduction in respiratory muscle strength, thereby reducing the effectiveness of coughing in clearing the airways.68. 122. 134 Mechanical defenses are further impaired by an age-related decline in mucociliary clearance.39.122 Little information is available regarding the effects of aging on alveolar macrophage function. Alveolar macrophages harvested from healthy donors over the age of 40 years have been reported to kill L. monocytogenes less avidly than cells harvested from younger adults,"1 but the antibacterial activities of alveolar macrophages are normal in senescent mice. 27 Some neutrophil functions are impaired in the elderly, but the microbicidal activities of neutrophils and monocytes are generally preserved?9. 119. 122 Antibody responses to immunization and infection are diminished in the elderly, possibly because of defective T cell regulation. 39. 119. 122 Advancing age is accompanied by involution of the thymus and alterations in T cell subsets. 39. 122 The proliferative response of T cells is diminished in the geriatric population, in association with impaired production of and response to IL-2. The waning of cell-mediated immunity among the elderly is manifested by diminished delayedtype hypersensitivity and an increased risk of tuberculosis. 20. 119. 122 The effects of aging on pulmonary defenses are compounded by the high prevalence of chronic disease in the geriatric population. Neurologic impair-

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ments, heart disease, diabetes mellitus, rheumatologic disorders, malnutrition, and cancer are increasingly common with advancing age, and all of these conditions may diminish resistance to infection. 36,77, 122 The many medications that are often prescribed for the treatment of these diseases may further interfere with host defenses,>6 Finally, declining ambulation and confinement in a nursing home are associated with oropharyngeal colonization with gram-negative bacillLl36 Alcoholism

Alcoholism is strongly associated with an increased incidence and poorer outcome of pneumonia.'3, 122 Ethanol intoxication and alcoholic liver disease interfere with virtually all respiratory tract defenses, resulting in alterations in normal flora, an aspiration diathesis, impaired mechanical and cellular clearance, and deficiencies of humoral and cellular immunity.73,122 The effects of alcoholism on host defense are often compounded by the consequences of malnutrition, cigarette smoking, and chronic lung disease. 122 Oropharyngeal colonization with gram-negative bacilli has been found in 35% to 59% of ambulatory alcoholics, in comparison with 14% to 18% of controls. 34,75 Alcoholics are prone to aspirate oropharyngeal bacteria because of the relaxation of pharyngeal musculature and the loss of reflexive glottic closure associated with acute intoxication, alcohol withdrawal seizures, or hepatic encephalopathy.32, 122 The mechanical clearance of aspirated material may be impaired in alcoholics owing to suppression of the cough reflex and diminished ciliary motility.73, 122 Impairments in intrapulmonary bacterial killing have been well documented in rodent models of acute and chronic alcohol intoxication, suggesting that microbial killing by phagocytes is defective in these animals. 22 ,73, 91,122 Alveolar macrophages harvested from patients with alcoholic cirrhosis have been reported to be deficient in the killing of S. aureus and E. coliY9 The microbicidal activities of neutrophils are not directly affected by ethanol or liver disease, but transient neutropenia may develop in chronic alcoholics and acute intoxication impairs the recruitment of neutrophils to sites of infection. 73 Plasma complement levels and opsonic activity may be normal or reduced, and the bactericidal effect of serum is diminished with acute intoxication. 73 ,122 Total serum immunoglobulin concentrations are elevated in patients with alcoholic liver disease/3 but IgG subclass deficiencies in blood and bronchoalveolar lavage fluid have been identified in some patients. 124 Acute and chronic ethanol ingestion impairs the antibody response to new antigens, but nondrinking patients with cirrhosis respond normally to vaccination.73. 122 Studies of cell-mediated immunity have shown that cutaneous delayed-type hypersensitivity, lymphocyte sensitization, and NK cell activity are depressed in patients with alcoholic liver disease.73. 122 Critical Illness and Critical Care

Nosocomial pneumonia occurs more commonly in the critically ill than in other hospitalized patients. 9s , 113 This increased risk reflects impairments in host defense that result from underlying disease as well as the consequences of therapeutic interventions in the intensive care unit setting. Critically ill patients are often colonized with gram-negative bacilli, and this alteration in oropharyngeal flora is associated with an increased risk of pneumonia. Johanson et a1'2 demonstrated that the prevalence of colonization with gram-

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negative bacilli among hospitalized patients correlated with the severity of illness, from 6% of normal subjects or psychiatry inpatients to 73% of moribund patients on a medical service. In a subsequent study, these investigators reported that 45% of patients become colonized with gram-negative bacilli within 5 days of admission to a medical intensive care unit; 23% of these patients developed pneumonia in comparison with 3% of uncolonized patients. 53 The oral epithelium of critically ill patients is abnormally receptive to adherence by gram-negative bacilli, possibly as a result of increased production of salivary proteases that remove fibronectin from the cell surface and expose binding sites. 94, 122, 146 The stomach may be an important source of these bacteria, particularly when gastric acidity has been lost."s, 101, 113 Thus, interventions that raise gastric pH, such as antacids, histamine type 2 receptor blockers, and continuous enteral feeding, may promote gastric overgrowth and subsequent oropharyngeal colonization with enteric flora. 9s, 101, 113 Nasogastric tubes may contribute to oropharyngeal colonization by promoting gastroesophageal reflux, by providing a conduit for bacterial migration, and by fostering a nidus of infection in the sinuses. 95, 101 The use of broad-spectrum antibiotics also predisposes to oropharyngeal colonization with gram-negative bacilli, presumably by eliminating the protective effects of the normal flora?4,95, 122 Other therapeutic interventions in critically ill patients increase the risk of aspiration and interfere with clearance mechanisms. Endotracheal and tracheostomy tubes bypass the defense mechanisms of the upper airway and encourage colonization of the trachea. 95 , 101 Oral secretions pool around these tubes, and the balloon cuffs do not prevent aspiration, particularly when the patient is kept in the supine position. '35 Artificial airways injure the tracheal mucosa, thereby facilitating bacterial adherence while inhibiting ciliary clearanceYs, 101 These tubes also prevent closure of the glottis, thus reducing the efficiency of coughing. Tracheal suctioning and fiberoptic bronchoscopy provide further opportunities for microbial inoculation and epithelial injury in the lower airway. Sedating drugs may inhibit the gag and cough reflexes, and other medications commonly used in the intensive care unit, such as corticosteroids, digoxin, and theophylline, have additional effects on host defenses. 26, 122 Cancer

Pneumonia is the most common serious infection in patients with underlying malignancy and the most common cause of death. 122 The respiratory tract defenses of patients with cancer may be compromised by the direct effects of the malignancy, the influence of associated chronic diseases, and the consequences of cancer treatment. A broad range of defects may result, including alterations in normal flora, an aspiration diathesis, impaired mechanical clearance, and depressed inflammatory and immune responses. Patients with cancer are prone to colonization of the oropharynx with gramnegative bacilli, particularly when hospitalized for chemotherapy or when treated with antibiotics. 122 Oropharyngeal colonization with gram-negative bacilli and neutropenia have been found to be additive and independent risk factors for lower respiratory tract infection among patients with leukemia. 122 A predisposition to oropharyngeal aspiration develops in some patients with cancer. Laryngeal competence may be compromised by neurologic deficits or by local tumors. Mucositis caused by cytotoxic chemotherapy or radiation may be associated with severe pain and edema, leading to impaired glutition and pooled secretions. Analgesic and sedating medications may add to the risk of aspiration.

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The mechanical clearance of aspirated material also may be compromised in patients with cancer. The obstruction of an airway by tumor or adenopathy commonly leads to postobstructive pneumonia. The mucociliary apparatus may be damaged by radiation or chemotherapy, and ciliary activity may be suppressed by narcotic analgesics. 141 The cough reflex may be stifled by central nervous system disease and by medications that impair consciousness. Neutropenia is a feature of acute myeloid leukemia and other infiltrative malignancies of the marrow as well as a frequent complication of cytotoxic chemotherapy. Disorders of granulocyte function also have been described in patients undergoing cancer treatment. 122 Neutropenia is a major risk factor for the incidence and fatality rate of pneumonia. '14, 116, 122 Common organisms in this setting are gram-negative bacilli, staphylococci, and aspergillus. '14, 116, 122 The immune responses also may be disrupted by cancer and its treatment. Diminished antibody production is a characteristic of chronic lymphocytic leukemia, multiple myeloma, and treated Hodgkin's disease: 3, 116, 122 This impairment in humoral immunity accounts for the risk of serious infections with S. pneumoniae and H. injluenzae in these settings:3, 122 Cell-mediated immunity is depressed in Hodgkin's disease and other lymphoproliferative disorders, leading to opportunistic infection with herpesviruses, fungi, protozoa, and intracellular bacteria. '14, 122 Chemotherapeutic agents also may suppress humoral and cellmediated immune responses. '22 Human Immunodeficiency Virus Infection (HIV)

A wide variety of opportunistic pulmonary infections are major causes of morbidity and mortality in patients infected with HIV.82, 88, 89, 116 All arms of the immune response are affected by HIV infection, and additional defects in host defenses result from associated conditions and therapeutic interventions. Numerical depletion and functional impairment of helper (CD4) T cells are the central effects of HIV infection, resulting in dysregulation of the immune system and progressive deterioration of cell-mediated immunity.9s,116 The clinical manifestations of HIV infection are related to the number of circulating CD4 cells.23. 116, 138 Loss of T cell function leads to an inability to contain latent or new infections with P. carinii or intracellular pathogens, such as mycobacteria, cryptococci, and herpesviruses.23, 30, 82 Antibody responses to infection and vaccination also are impaired by HIV infection because of disordered T cell regulation and the depletion of antigen presenting cells as well as direct effects of HIV on B lymphocytes?O, 49, 98 This defect in humoral immunity is evident by an increased risk of pneumococcal and H. injluenzae infections among patients with HIV infection:9 HIV replicates in alveolar macrophages and other mononuclear phagocytes, but the consequences of this for host defense are unclear. 2 ,23 Further impairments in pulmonary defenses may result from comorbid illnesses and from the effects of treating HIV infection and its sequelae. For example, bacterial pneumonia is more common among intravenous drug users than among other groups with HIV infection, possibly because intravenous drug users are more likely to suffer losses of consciousness and exhibit defects in neutrophil function.>3, 138 Severe inanition often accompanies advanced HIV infection, and malnutrition has many deleterious effects on host defenses. 122 Coinfection with cytomegalovirus or Epstein-Barr virus may further depress immune responses. 2 Myelosuppressive drugs such as zidovudine, ganciclovir, and trimethoprim/ sulfamethoxazole may cause neutropenia, further compromising resistance to bacterial and fungal infections.

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Other Conditions

Host defenses may be subtly or profoundly affected by many other conditions, including diabetes mellitus, renal failure, heart disease, rheumatologic disorders, and transplantation. l22 In all of these circumstances, the effects of the underlying disease on host defenses may be compounded by the effects of its treatment. AUGMENTATION OF RESPIRATORY TRACT DEFENSES

The augmentation of host defenses has been a goal in the prevention and treatment of infectious diseases for more than a century. With the ever-expanding population of immunocompromised patients subject to opportunistic infection, the need to stimulate native resistance has never been greater. Advances in molecular technology have led to many new prospects for manipulating host responses, including recombinant cytokines, soluble receptors, monoclonal antibodies, recombinant vaccines, and gene therapy. Two approaches in current practice include immunization and the use of recombinant cytokines. Immunization

Effective vaccines have been developed against a variety of viral and bacterial pathogens of the respiratory tract, including measles, mumps, rubella, influenza, adenovirus, pertussis, S. pneumoniae, and H. inJluenzae.15, 35 These vaccines augment host defenses mainly through the induction of neutralizing or opsonizing antibodies,!s. 123 Influenza vaccine is highly effective in preventing or attenuating influenza and should be given annually to patients with chronic diseases or immunodeficiency as well as to the elderly, health care workers, and anyone else that is interested in avoiding this disease!' 35 Pneumococcal vaccine is clearly effective in immunocompetent young adults with high attack rates of pneumococcal infection, but its efficacy is controversial in other groups,35, 123 Nonetheless, it is widely recommended that pneumococcal vaccine be given to the elderly, patients with chronic diseases or immunodeficiencies, and populations with high attack rates of pneumococcal infection, such as Alaskan Native Americans'"35 H. inJluenzae B vaccine may be beneficial in some adults at high risk of infection, such as those with HIV infection, Hodgkin's disease, and functional or anatomic splenectomy ,15,35 Passive immunization to augment respiratory tract defenses has a long history. Antiserum was first used to treat pneumococcal pneumonia 100 years ago, and type-specific horse serum was used with some success until penicillin became available in the 1940s.142 More recently, immune globulin has been found to prevent pneumonia and other respiratory tract infections in certain high-risk populations. Patients with recurrent infections associated with hypogammaglobulinemia owing to primary immunodeficiency, chronic lymphocytic leukemia, or multiple myeloma benefit from regular administration of intravenous immune globulin. 15,18 Preoperative treatment with immune globulin has been reported to reduce the incidence of postoperative pneumonia in patients undergoing highrisk abdominal surgeryY9 Polyclonal and monoclonal immunoglobulin preparations also have been promising in the prevention and treatment of p, aeruginosa pneumonia in experimental models and limited human trials, 100 Immune globulin preparations are effective in the postexposure prophylaxis of immunocompro-

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mised patients exposed to measles or varicella zoster. 15 Passive immunization with immune globulin may be helpful in the prevention and treatment of cytomegalovirus infections in marrow transplant recipients.!47 The adoptive transfer of antigen-specific cytotoxic T cells has been shown to suppress cytomegalovirus infection in marrow transplant patients. 'O ? Cytokine Therapy

Cytokines are natural regulators of host defenses, and molecular technology has provided the opportunity to stimulate beneficial responses selectively. Recombinant cytokines are particularly useful in compromised patients but may have therapeutic applications in immunocompetent individuals as well. The manipulation of cytokine pathways is potentially hazardous because of the pluripotential activities of each protein and the complexity of cytokine interactions. Many recombinant cytokines have shown promise in the prevention or treatment of a variety of infections in experimental models, but the agents that have been most thoroughly studied in humans are the colony-stimulating factors and interferon-'{. The colony-stimulating factors stimulate the production, survival, and antimicrobial properties of myeloid cells, with the net effect of increasing the availability and function of phagocytes at sites of infection?O, 109 Granulocyte colonystimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are approved for the stimulation of hematopoietic reconstitution after cytotoxic chemotherapy and marrow transplantation?O, 109 These agents decrease the duration of cytopenia and the attendant infectious complications of myelosuppression?O, 109 Studies in experimental animals suggest that colony-stimulating factors may have a role in the management of respiratory infections in less severely compromised patients. Pretreatment with G-CSF has been shown to improve survival or bacterial clearance in splenectomized mice with pneumococcal pneumonia!' in hypovolemic mice with P. aeruginosa pneumonia,' and in normal and ethanol-intoxicated rats with K. pneumoniae pneumonia. 91 Clinical trials of G-CSF in the treatment of selected patients with community-acquired pneumonia are underway. Interferon-'{ is a potent stimulator of phagocytic cell function that plays a critical role in the activation of macrophages to resist intracellular infection. 85 Recombinant interferon-,{ is licensed for the prevention of infection in chronic granulomatous disease but may have broad therapeutic applications. Experimental and human studies have shown that interferon-,,{ is effective in the prevention and treatment of many opportunistic infections.86 In the lung, animal models have shown interferon-,{ to be promising in the treatment of established infection with P. carinii or L. pneumophila. 8 , 115, 121 Topical administration of interferon-,{ appears to be more effective in activating pulmonary host defenses and less toxic than systemic administration.48, 121 Clinical trials of systemic and aerosolized interferon-'{ for the prophylaxis and treatment of respiratory tract infections are in progress. SUMMARY

The respiratory tract is protected from infection by its formidable mechanical and cellular defenses, supplemented when necessary by inflammatory and immune responses. Impairments in these defenses develop as a result of underlying

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disease and therapeutic interventions. Specific defects in host defenses often predispose to infection with particular etiologic agents. New opportunities for the therapeutic augmentation of defenses are emerging that may be particularly helpful in the care of immunocompromised patients. References 1. Abraham E, Stevens P: Effects of granulocyte colony-stimulating factor in modifying mortality from Pseudomonas aeruginosa pneumonia after hemorrhage. Crit Care Med 20:1127,1992 2. Agostini C, Trentin L, Zambello R, et al: HIV-l and the lung. Infectivity, pathogenic mechanisms and cellular immune responses taking place in the lower respiratory tract. Am Rev Respir Dis 147:1038, 1993 3. Aitken ML, Fiel SB: Cystic fibrosis. Disease-a-month 39:1,1993 4. American Thoracic Society: Prevention of influenza and pneumonia. Am Rev Respir Dis 142:487, 1990 5. Andersen I: The ambient air. In Brain JD, Proctor DF, Reid LM (eds): Respiratory Defense Mechanisms. Part 1. New York, Marcel Dekker, 1977, p 25 6. Beachey EH: Bacterial adherence: Adhesin-receptor interactions mediating the attachment of bacteria to mucosal surfaces. J Infect Dis 143:325, 1981 7. Beachey EH, Giampapa CS, Abraham SN: Bacterial adherence: Adhesin receptormediated attachment of pathogenic bacteria to mucosal surfaces. Am Rev Respir Dis 138:545, 1988 8. Beck JM, Liggitt HD, Brunette EN, et al: Reduction in intensity of Pneumocystis carinii pneumonia in mice by aerosol administration of gamma interferon. Infect Immunol 59:3859, 1991 9. Bjerkestrand G, Digranes A, Schreiner A: Bacteriological findings in transtracheal aspirates from patients with chronic bronchitis and bronchiectasis. Scand J Respir Dis 56:201, 1975 10. Brain JD, Valberg PA: Deposition of aerosol in the respiratory tract. Am Rev Respir Dis 120:1325, 1979 11. Bruyn GAW, Zegers BJM, van Furth R: Mechanisms of host defense against infection with Streptococcus pneumoniae. Clin Infect Dis 14:251, 1992 12. Butcher EC: Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity. Cell 67:1033, 1991 13. Byrd TF, Horwitz MA: Interferon gamma-activated human monocytes downregulate transferrin receptors and inhibit the intracellular multiplication of Legionella pneumophila by limiting the availability of iron. J Clin Invest 83:1457,1989 14. Campbell PA: T cell involvement in resistance to facultative intracellular pathogens of the lung. Chest 103:113S, 1993 15. Centers for Disease Control and Prevention: Recommendations of the advisory committee on immunization practices (ACIP): Use of vaccines and imune globulins in persons with altered immunocompetence. MMWR 42(RR-4):1, 1993 16. Coonrod JD: The role of extracellular bactericidal factors in pulmonary host defense. Semin Respir Infect 1:118, 1986 17. Coonrod JD, Yoneda K: Detection and partial characterization of antibacterial factors in alveolar lining material of rats. J Clin Invest 71:129, 1983 18. Cooperative group for the study of immunoglobulins in chronic lymphocytic leukemia: Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. N Engl J Med 319:902,1988 19. Cottagnoud P, Tomasz A: Triggering of pneumococcal autolysis by lysozyme. J Infect Dis 167:684, 1993 20. Couser JI, Glassroth J: Tuberculosis: An epidemic in older adults. Clin Chest Med 14:491, 1993 21. Czop JK, McGowan SE, Center DM: Opsonin-mediated phagocytosis by human alveolar macrophages: Augmentation by human plasma fibronectin. Am Rev Respir Dis 125:607, 1982

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22. Davis Cc, Mellencamp MA, Preheim LC: A model of pneumococcal pneumonia in chronically intoxicated rats. J Infect Dis 163:799, 1991 23. Davis L, Beck JM, Shellito J: Update: HIV infection and pulmonary defenses. Semin Respir Infect 8:75, 1993 24. Densen P: Complement. In Mandell GL, Douglas RG Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases, ed 3. New York, Churchill Livingstone, 1990, p 62 25. Devalia JL, Davies RT: Airway epithelial cells and mediators of inflammation. Respir Med 87:405,1993 26. Esposito AL: The effect of common pharmacologic agents on pulmonary antibacterial defenses: Implications for the geriatric patient. Clin Chest Med 8:373, 1987 27. Esposito AL: An assessment of the respiratory burst and bactericidal activity of alveolar macrophages from adult and senescent mice. J Leukocyte Bioi 43:445, 1988 28. Ezekowitz RAB, Williams DJ, Koziel H, et al: Uptake of Pneumocystis carinii mediated by the macrophage mannose receptor. Nature 351:155,1991 29. Fang G-D, Fine M, Orloff J, et al: New and emerging etiologies for communityacquired pneumonia with implications for therapy. A prospective multicenter study of 359 cases. Medicine 69:307,1990 30. Fauci AS: Multifactorial nature of human immunodeficiency virus disease: Implications for therapy. Science 262:1011, 1993 31. Fels AO, Cohn ZA: The alveolar macrophage. J Appl PhysioI60:353, 1986 32. Finegold SM: Aspiration pneumonia. Rev Infect Dis 13(suppl 9):5737, 1991 33. Finkelstein RA, Sciortino CV, McIntosh MA: Role of iron in microbe-host interactions. Rev Infect Dis 5(suppI4):S759, 1983 34. Fuzench-Lopez Z, Ramirez-Ronda CH: Pharyngeal flora in ambulatory alcoholic patients. Arch Intern Med 138:1815, 1978 35. Gardner P, Schaffner W: Immunization of adults. N Engl J Med 328:1252, 1993 36. Granton JT, Grossman RF: Community-acquired pneumonia in the elderly patient. Clin Chest Med 14:537, 1993 37. Green GM, Jakab GJ, Low RB, et al: Defense mechanisms of the respiratory membrane. Am Rev Respir Dis 479:508,1977 38. Griffith DE, Mazurek DE: Pneumonia in chronic obstructive lung disease. Infect Dis Clin North Am 5:467, 1991 39. Gyetko MR, Toews GB: Immunology of the aging lung. Clin Chest Med 14:379, 1993 40. Haas H, Morris JF, Samson S, et al: Bacterial flora of the respiratory tract in chronic bronchitis: comparison of transtracheal, fiberbronchoscopic, and oropharyngeal sampling methods. Am Rev Respir Dis 116:41, 1977 41. Hebert Jc, O'Reilly M, Garnelli RL: Protective effect of recombinant granulocyte colony-stimulating factor against pneumoccoal infections in splenectomized mice. Arch Surg 125:1075, 1990 42. Heck LW, Alarcon PG, Kulhavy RM, et al: Degradation of IgA proteins by Pseudomonas aeruginosa. J ImmunoI144:2253, 1990 43. Heinzel FP, Root RK: Antibodies. In Mandell GL, Douglas RG Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases, ed 3. New York, Churchill Livingstone, 1990, p 41 44. Hoidal JR, Schmelling D, Peterson PK: Phagocytosis, bacterial killing, and metabolism by purified human lung phagocytes. J Infect Dis 144:61, 1981 45. Hopewell PC: Factors influencing the transmission and infectivity of Mycobacterium tuberculosis: Implications for public health management. In Sande MA, Hudson LD, Root RK (eds): Contemporary Issues in Infectious Diseases, vol 5: Respiratory Infections, New York, Churchill Livingstone, 1986, p 191 46. Huxley EJ, Viroslav J, Gray WR, et a1: Pharyngeal aspiration in normal adults and patients with depressed consciousness. Am J Med 64:564, 1978 47. Irwin RS, Erickson AD, Pratter MR, et al: Prediction of tracheobronchial colonization in current cigarette smokers with chronic obstructive bronchitis. J Infect Dis 145:234, 1982 48. Jaffe HA, Buhl R, Mastrangeli A, et al: Organ specific cytokine therapy. Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon--y to the human lung. J Clin Invest 88:297, 1991 49. Janoff EN, Breiman RF, Daley CL, et al: Pneumococcal disease during HIV infection. Epidemiologic, clinical, and immunologic perspectives. Ann Intern Med 117:314, 1992

HOST DEFENSES AGAINST RESPIRATORY INFECTION

963

50. Jenson WA, Rose RM, Wasserman AS, et al: In vitro activation of the antibacterial activity of human pulmonary macrophages by recombinant gamma interferon. J Infect Dis 155:574, 1987 51. Johanson WG, Higuchi JH, Chaudhuri TR, et al: Bacterial adherence to epithelial cells in bacillary colonization of the respiratory tract. Am Rev Respir Dis 121:55, 1980 52. Johanson WG, Pierce AK, Sanford JP: Changing flora of hospitalized patients. Emergence of gram negative bacilli. N Engl J Med 281:1138,1969 53. Johanson WG, Pierce AK, Sanford JP, et al: Nosocomial respiratory infections with gram-negative bacilli. Ann Intern Med 77:701, 1972 54. Jonsson 5, Musher DM, Chapman A, et al: Phagocytosis and killing of common bacterial pathogens of the lung by human alveolar macrophages. J Infect Dis 152:4, 1985 55. Jonsson 5, Musher DM, Goree A, et al: Human alveolar lining material and antibacterial defenses. Am Rev Respir Dis 133:136, 1986 56. Jonsson 5, Musher DM, Lawrence EC: Phagocytosis and killing of Haemophilus influenzae by alveolar macrophages: No difference between smokers and non-smokers. Eur J Respir Dis 70:309, 1987 57. Juers JA, Rogers RM, McCurdy JB, et al: Enhancement of bactericidal capacity of alveolar macrophages by human alveolar lining material. J Clin Invest 58:271,1976 58. Kaliner MA: Human nasal respiratory secretions and host defense. Am Rev Respir Dis 144:552,1991 59. Kaltreider HB: Immune defenses of the lung. In Sande MA, Hudson LD, Root RK (eds): Contemporary Issues in Infectious Diseases, vol 5: Respiratory Infections. New York, Churchill Livingstone, 1986, p 47 60. Kelly J: Cytokines of the lung. Am Rev Respir Dis 141:765, 1990 61. King TE Jr, Savici D, Campbell PA: Phagocytosis and killing of Listeria monocytogenes by alveolar macrophages: Smokers versus nonsmokers. J Infect Dis 158:1309, 1988 62. Kisala JM, Ayala A, Stephan RN, et al: A model of pulmonary atelectasis in rats: Activation of alveolar macrophage and cytokine release. Am J PhysioI264:R61O, 1993 63. Kuan S-F, Rust K, Crouch E: Interactions of surfactant protein D with bacteriallipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage. J Clin Invest 90:97,1992 64. LaForce FM, Boose DS: A radiolabel method for measuring pulmonary clearance of intratracheal bacterial challenges. J Lab Clin Med 111:158, 1988 65. LaForce FM, Kelly WJ, Huber GL: Inactivation of staphylococci by alveolar macrophages with preliminary observations on the importance of alveolar lining material. Am Rev Respir Dis 108:784, 1973 66. Lamblin G, Roussel P: Airway mucins and their role in defense against microorganisms. Respir Med 87:421, 1993 67. Lehrer RI, Ganz T, Selsted ME, et al: Neutrophils and host defense. Ann Intern Med 109:127, 1988 68. Leith DE: Cough. In Brain JD, Proctor DF, Reid LM (eds): Respiratory Defense Mechanisms. Part n. New York, Marcel Dekker, 1977, p 545 69. Lewis JF, Jobe AH: Surfactant and the adult respiratory distress syndrome. Am Rev Respir Dis 147:218, 1993 70. Lieschke GJ, Burgess AW: Granulocyte colony-stimulating factor and granulocytemacrophage colony stimulating factor (second of two parts). N Engl J Med 327:99, 1992 71. Locksley RM: Interleukin 12 in defense against microbial pathogens. Proc Natl Acad Sci USA 90:5879, 1993 72. Loudon RG, Roberts RM: Droplet expulsion from the respiratory tract. Am Rev Respir Dis 95:435,1967 73. MacGregor RR: Alcohol and immune defense. JAMA 256:1474, 1986 74. Mackowiak PA: The normal microbial flora. N Engl J Med 307:83,1982 75. Mackowiak PA, Martin RM, Jones SR, et al: Pharyngeal colonization by gram negative bacilli in aspiration-prone persons. Arch Intern Med 138:1224, 1978 76. Marcy TW, Merrill WW: Cigarette smoking and respiratory tract infection. Clin Chest Med 8:381, 1987 77. Marrie TJ: Epidemiology of community-acquired pneumonia in the elderly. Semin Respir Infect 5:260, 1990

964

SKERRETT

78. Marrie TJ, Durant H, Yates L: Community-acquired pneumonia requiring hospitalization. Rev Infect Dis 11:586, 1989 79. Martin TR, Mathison JC, Tobias P, et al: Lipopolysaccharide binding protein enhances the responsiveness of alveolar macrophages to bacterial lipopolysaccharide. Implications for cytokine production in normal and injured lungs. J Clin Invest 90:2209,1992 80. McGowan SE, Henley SA: Iron and ferritin contents and distribution in human alveolar macrophages. J Lab Clin Med 111:611, 1988 81. McNeely TB, Coonrod JD: Comparison of the opsonic activity of human surfactant protein A for Staphylococcus aureus and Streptococcus pneumoniae with rabbit and human macrophages. J Infect Dis 167:91, 1993 82. Meduri GD, Stein DS: Pulmonary manifestations of acquired immunodeficiency syndrome. Clin Infect Dis 14:98, 1992 83. Melville H: Moby Dick or the Whale. New York, Modern Library, 1922 84. Murphy TF, Sethi S: Bacterial infection in chronic obstructive pulmonary disease. Am Rev Respir Dis 146:1967, 1992 85. Murray HW: Interferon-gamma, the activated macrophage, and host defense against microbial challenge. Ann Intern Med 108:595, 1988 86. Murray HW: Cytokines as antimicrobial therapy for the T cell-deficient patient: Prospects for treatment of nonviral opportunistic infections. Clin Infect Dis 17(suppl 2):5407,1993 87. Murray JF: The Normal Lung, ed 2. Philadelphia, WB Saunders, 1986 88. Murray JF, Mills J: Pulmonary infectious complications of human immunodeficiency virus infection. Part n. Am Rev Respir Dis 141:1582, 1990 89. Murray JF, Mills J: Pulmonary infectious complications of human immunodeficiency virus infection. Part I. Am Rev Respir Dis 141:1356, 1990 90. Nash TW, Libby DM, Horwitz MA: Interaction between Legionnaires' disease bacterium (Legionella pneumophila) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone. J Clin Invest 74:771,1984 91. Nelson S, Summer W, Bagby G, et al: Granulocyte colony-stimulating factor enhances pulmonary host defenses in normal and ethanol-treated rats. J Infect Dis 164:901, 1991 92. Newhouse M, Sanchis J, Bienenstock J: Lung defense mechanisms (second of two parts). N Engl J Med 295:1045, 1976 93. Newhouse M, Sanchis J, Bienenstock J: Lung defense mechanisms (first of two parts). N Engl J Med 295:990,1976 94. Niederman MS: Gram negative colonization of the respiratory tract: Pathogenesis and clinical consequences. Semin Respir Infect 5:173,1990 95. Niederman MS, Craven DE, Fein AF, et al: Pneumonia in the critically ill hospitalized patient. Chest 97:170, 1990 96. Niederman MS, Merrill WW, Ferranti RD, et al: Nutritional status and bacterial binding in the lower respiratory tract in patients with chronic tracheostomy. Ann Intern Med 100:795, 1984 97. O'Neill S, Lesperance E, Klaas DJ: Rat lung surfactant enhances bacterial phagocytosis and intracellular killing by alveolar macrophages. Am Rev Respir Dis 130:225, 1984 98. Pantaleo G, Graziosi C, Fauci AS: The immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 328:327, 1993 99. Payne NR, Horwitz MA: Phagocytosis of Legionella pneumophila is mediated by human complement receptors. J Exp Med 166:1377, 1987 100. Pennington JE: Immunological perspectives in prevention and treatment of nosocomial pneumonia. Inten Care Med 18:535, 1992 101. Pingleton SK: Complications of acute respiratory failure. Am Rev Respir Dis 137:1463, 1988 102. Pottratz ST, Paulsrud J, Smith JS, et al: Pneumocystis carinii attachment to cultured lung cells by pneumocystis gp 120, a fibronectin binding protein. J Clin Invest 88:403, 1991 103. Proctor DF: The upper airways. I. Nasal physiology and defense of the lungs. Am Rev Respir Dis 115:97, 1977 104. Reynolds HY: Immunoglobulin G and its function in the human respiratory tract. Mayo Clin Proc 63:161, 1988 105. Reynolds HY: Immunologic system in the respiratory tract. Physiol Rev 71:1117, 1991

HOST DEFENSES AGAINST RESPIRATORY INFECTION

965

106. Reynolds HY, Kazmierowski JA, Newball HH: Specificity of opsonic antibodies to enhance phagocytosis of Pseudomonas aeruginosa by human alveolar macrophages. J Clin Invest 56:376, 1975 107. Riddell SR, Watanabe KS, Goodrich JM, et al: Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257:238, 1992 108. Roberts DD: Interactions of respiratory pathogens with host cell surface and extracellular matrix components. Am J Respir Cell Mol Bioi 3:181, 1990 109. Rose RM: The role of colony-stimulating factors in infectious disease: current status, future challenges. Semin OncoI19:415, 1992 110. Samet JM, Marbury MC, Spengler JD: Health effects and sources of indoor air pollution. Part 1. Am Rev Respir Dis 136:1486, 1987 111. Schaberg T, Lauer C, Lode H, et al: Increased number of alveolar macrophages expressing adhesion molecules of the leukocyte adhesion molecule family in smoking subjects. Am Rev Respir Dis 146:1287, 1992 112. Schaffner A, Douglas H, Braude A: Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to aspergillus. J Clin Invest 69:617, 1982 113. Scheld WM, Mandell GL: Nosocomial pneumonia: Pathogenesis and recent advances in diagnosis and therapy. Rev Infect Dis 13(suppl 9):5743,1991 114. Schimpff Se: Infections in the compromised host-an overview. In Mandell GL, Douglas RG Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases, ed 3. New York, Churchill Livingstone, 1990, p 2258 115. Shear HL, Valladares G, Narachi MA: Enhanced treatment of Pneumocystis carinii pneumonia in rats with interferon-"y and high doses of trimethoprim/ sulfamethoxazole. J Acquired Immune Defic Syndr 3:943,1990 116. Shelhamer JH, Toews GB, Masur H, et al: Respiratory disease in the immunosuppressed patient. Ann Intern Med 117:415, 1992 117. Sibille Y, Marchandise F-X: Pulmonary immune cells in health and disease: Polymorphonuclear neutrophils. Eur J Respir Dis 6:1529,1993 118. Sibille Y, Reynolds HY: Macrophages and polymorphonuclear neutrophils in lung defense and injury. Am Rev Respir Dis 141:471, 1990 119. Simons RI, Reynolds HY: Altered immune status in the elderly. Semin Respir Infect 5:251, 1990 120. Skerrett SI, Martin TR: Alveolar macrophage activation in experimentallegionellosis. J ImmunoI147:337, 1991 121. Skerrett SI, Martin TR: Intratracheal interferon-"y augments pulmonary defenses in experimentallegionellosis. Am J Respir Crit Care Med 149:50, 1994 122. Skerrett SI, Niederman MS, Fein AM: Respiratory infections and acute lung injury in systemic illness. Clin Chest Med 10:469, 1989 123. Spika JS, Fedson DS, Facklam RR: Pneumococcal vaccination. Controversies and opportunities. Clin Infect Dis 4:11, 1990 124. Spinozzi F, Cimignoli E, Gerli R, et al: IgG subclass deficiency and sinopulmonary bacterial infections in patients with alcoholic liver disease. Arch Intern Med 152:99, 1992 125. Standiford TI, Kunkel SL, Rolfe MW, et al: Regulation of human alveolar macrophageand blood monocyte-derived interleukin-8 by prostaglandin E2 and dexamethasone. Am J Respir Cell Mol Bioi 6:75, 1992 126. Stoolman LM: Adhesion molecules involved in leukocyte recruitment and lymphocyte recirculation. Chest 103:795, 1993 127. Strieter RM, Lukacs NW, Standiford TI, et al: Cytokines and lung inflammation: mechanisms of neutrophil recruitment to the lung. Thorax 48:765, 1993 128. Strunk RC, Eidlen DM, Mason RJ: Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways. J Clin Invest 81:1419, 1988 129. The Intravenous Immunoglobulin Collaborative Study Group: Prophylactic intravenous administration of standard immune globulin as compared with core-lipopolysaccharide immune globulin in patients at high risk for porsurgical infection. N Engl J Med 327:234, 1992 130. Thomassen MI, Meeker DP, Antal JM, et al: Synthetic surfactant (Exosurf) inhibits

966

131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148.

SKERRETT

endotoxin-stimulated cytokine secretion by human alveolar macrophages. Am J Respir Cell Mol Bioi 7:257, 1992 Thompson AB, Bahling T, Payvandi F, et al: Lower respiratory tract lactoferrin and lysozyme arise primarily in the airways and are elevated in association with chronic bronchitis. J Lab Clin Med 115:148, 1990 Tobias PS, Mathison J, Mintz D, et al: Participation of lipopolysaccharide-binding protein in lipopolysaccharide-dependent macrophage activation. Am J Respir Cell Mol Bioi 7:239, 1992 Toews CB: Determinants of bacterial clearance from the lower respiratory tract. Semin Respir Infect 1:68, 1986 Tolep K, Kelsen SC: Effect of aging on respiratory skeletal muscles. Clin Chest Med 14:363,1993 Torres A, Serra-Batlles J, Ros E, et al: Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: The effects of body position. Ann Intern Med 116:540, 1992 Valenti WM, Trudell RC, Bentley DW: Factors predisposing to oropharyngeal colonization with gram negative bacilli in the aged. N Engl J Med 298:1108, 1978 van Iwaarden F, Welmers B, Verhoef J, et al: Pulmonary surfactant protein A enhances the host-defense mechanisms of rat alveolar macrophages. Am J Respir Cell Mol Bioi 2:91, 1990 Wallace JM, Rao AV, Classroth J, et al: Respiratory illness in patients with human immunodeficiency virus infection. Am Rev Respir Dis 148:1523, 1993 Wallaert B, Aerts C, Columbel JF, et al: Human alveolar macrophage antibacterial activity in the alcoholic lung. Am Rev Respir Dis 144:278, 1991 Walzer PD: Immunopathogenesis of Pneumocystis carinii infection. J Lab Clin Med 118:206, 1991 Wanner A: Clinical aspects of mucociliary transport. Am Rev Respir Dis 116:73, 1977 Watson DA, Musher DM, Jacobson JW, et al: A brief history of the pneumococcus in biomedical research: A panoply of scientific discovery. Clin Infect Dis 17:913, 1993 Wiener-Kronish JP, Albertine KH, Matthay MA: Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest 88:864, 1991 Wilson CB: The cellular immune response and its role in host defense. In Mandell CL, Douglas RC Jr, Bennett JE (eds): Principles and Practice of Infectious Diseases, ed 3. New York, Churchill Livingstone, 1990, p 101 Wilson R, Cole PJ: The effect of bacterial products on ciliary function. Am Rev Respir Dis 138:549, 1988 Woods DE: Bacterial colonization of the respiratory tract: Clinical significance. In Pennington JE (ed): Respiratory Infections: Diagnosis and Management, ed 2. New York, Raven Press, 1988, p 34 Zaia JA: Prevention and treatment of cytomegalovirus pneumonia in transplant recipients. Clin Infect Dis 17(suppl 2):5392, 1993 Zimmerman PE, Voelker DR, McCormack FX, et al: 120-kD surface glycoprotein of Pneumocystis carinii is a ligand for surfactant protein A. J Clin Invest 89:143,1992

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