Pulmonary Host Defenses

Host Defenses

While utilization of recently developed clinical practice guidelines may permit a “cookbook” approach to prevention and treatment of pneumonia and bronchitis, many clinical decisions are not clear-cut and involve clinical judgment and application of physiologic and biochemical principles. Therefore, thorough grounding in normal host physiology permits a rational approach to diagnosis, treatment and prevention. This section will review normal pulmonary host-defense mechanisms and the ways in which pathology and breach of these barriers interfere with normal host-pathogen relationships, resulting in community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP). Specific aspects covered include the following (Table 2-1):

• Mechanical and structural host defenses:
  • Airway configuration
  • Cough
  • Mucociliary clearance
• Cellular host defenses:
  • Leukocytes (macrophages and neutrophils)
  • Lymphoid tissue
  • Ciliated epithelium
• Inflammatory and molecular host defenses:
  • Circulating mediators (cytokines)
  • Immunoglobulins
  • Colony-stimulating factors (CSFs)
• Humoral defenses.

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Mechanical Barriers

Mechanical barriers to pathogen invasion include the configuration of the upper airway and nasal filtering function. The continual branching of the bronchial tree, up to 20 times, into progressively smaller subdivisions results in impaction of airborne particulate matter, sedimentation and diffusion. The epithelium in the nasopharynx entraps inhaled material in a layer of mucus, where ciliary beat results in propulsion to the pharynx where it is swallowed. Ciliated epithelium is present down to the level of the respiratory bronchioles and includes at least eight different types of cells. Bacteria such as P aeruginosa and H influenzae produce soluble products that are ciliotoxic and change mucus consistency. Changes in ciliary function occur in oxygen toxicity following inhalation of pollutant gases like SO₂, NO₂, and cigarette smoke.

Mucus, which is composed predominantly of water, lipid and glycoprotein (95%, 3%, 1%, respectively) with a small component mineral, has bacteriostatic and barrier functions. This glycoprotein is produced in goblet cells, serous cells and Clara cells. Mucus is altered, structurally and functionally, by both acute and chronic inflammation. The squamous epithelium of the oropharynx interacts in a highly organized fashion with endogenous colonizing flora to prevent pathogenic bacteria from gaining a foothold.

The first stage of pathogenesis of lower respiratory tract infection is colonization of the upper airway and stomach with pathogens. This process is especially accelerated in critically ill, immunocompromised, or debilitated patients. For example, gram-negative bacilli are unusual inhabitants of the oropharynx of healthy individuals and will be rapidly cleared. In contrast, during critical illness these bacterial species readily adhere to the oropharyngeal mucosa. This is thought to result from stasis of mucus, as well as increased secretion of proteolytic enzymes, altered epithelial glycoproteins and pH. Aspiration, which occurs even in normal individuals, increases as changes in mental status, neurologic disease and severe illness supervene. This process shifts the balance of the host-pathogen relationship to one favoring respiratory infection.

The cough reflex, dependent on glottic closure, also ensures against prolonged infectious contamination of the normally sterile lower airways. In the cough maneuver, the glottis is closed for a fraction of a second after a rapid breath inhalation. When intrathoracic pressure rises >50 mm Hg, rapid exhalation occurs as the glottis opens. High airflow (reaching the speed of sound) progressively mobilizes mucus toward the trachea through repeated exhalations. Cough is impaired in chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), tracheotomy and intubation due to absent glottic closure. Physicians have sought to augment clearance through:

• Tracheotomy
• Supraglottic secretion removal
• The use of aerosol and parenteral medications exemplified by β-agonists, theophylline and mucolytic agents, such as acetylcysteine.

Current evidence suggests that supraglottic secretion drainage protects against early-onset pneumonia in intubated patients, but it has not been shown to reduce mortality.

Cellular Components

The cellular components of airway defenses include:

• Multiple classes of leukocytes
• Ciliated and columnar epithelium of the oropharynx and nasopharynx.

Alveolar macrophages are the primary line of defense of the lower airway. These cells engulf and kill bacteria such as pneumococcus and H influenzae when they reach the lower airway. Cell-mediated immunity is required to kill organisms which replicate inside macrophages, including Mycobacterium tuberculosis, Legionella and Nocardia. If the bacterial inoculum is too large or the organism too virulent, the macrophage acts to recruit neutrophils to the site of invasion. This recruitment is the result of the initiation of the inflammatory response through complement activation, release of proinflammatory cytokines, such as interleukin (IL)-8 and tumor necrosis factor (TNF), and inflammatory arachidonic acid metabolites.

Experimental studies have demonstrated a significant role for TNF in neutrophil recruitment after endotoxin challenge (lipopolysaccharide) in the lung. Similar observations suggest that TNF and IL-1 act to stimulate IL-8 production, which is a direct chemo­attractant agent. This response is believed to be compartmentalized within the lung, thereby promoting local containment of bacteria without stimulating a systemic inflammatory response. Dysregulation and overexuberance of the cytokine response appear to underlie the development of the septic response. IL-10 is now recognized as a major modulator of the immune response to bacteria and serves to down-regulate the response of TNF and interferon g, as well as other cytokines. Later, multiorgan failure may be related to the release of high molecular weight group B protein (HMGB1) from macrophages.

Inflammatory and Molecular Host Defenses

In addition to the role of alveolar macrophages, airway epithelia and bronchial epithelia contribute to the inflammatory process through the production of cationic, arginine-rich antimicrobial peptides called defensins, as well as the production of chemokines and IL-10. The airways of patients with cystic fibrosis (CF) demonstrate excessive production of inflammatory cytokines, such as IL-8, which correlates with increased adherence of P aeruginosa. The anti-inflammatory agents prednisone and ibuprofen have been demonstrated to improve pulmonary function in CF patients. Macrolide agents may also improve pulmonary function by down-regulating the inflammatory response to Pseudomonas and interference with bacterial adherence.

Inflammatory cytokines, such as IL-1 and TNF, also appear to have a role in increasing adherence of S pneumoniae, which binds more efficiently to type II cells and endothelium when pretreated with these inflammatory mediators. The role of platelet-activating factor receptor in this process has also been reported to enhance binding and encourage internalization of S pneumoniae into epithelial and endothelial cells in vitro.

Neutrophils are the most common leukocytes in the peripheral circulation as evidenced by the significant proportion of the bone marrow devoted to their production. These cells are essential for containment of bacterial and fungal invasion and are recruited by cytokines, such as IL-8, when alveolar macrophages are overwhelmed in the lower respiratory tract. Following active phagocytosis, fusion of phagolysosomes results in the production of potent oxidants, such as hypochlorous acid.

Hypochlorous acid reacts with amines to form formidable bactericidal products. The granules of neutrophils contain numerous proteases and acid hydrolases, as well as myeloperoxidase, which contribute to their bactericidal properties. Neutrophils also actively produce defensins, which act against many bacterial species and bactericidal permeability increasing protein, which acts to neutralize endotoxin. The defensins specifically interfere with the lipid membrane of the bacteria, destroying its barrier function. Reduction in circulating neutrophils <1000/mL results in dramatically increased risk of bacterial infection of skin, mucous membrane and blood. Likewise, defective neutrophil function is seen in a variety of rare genetic diseases. In chronic granulomatous disease, there is impaired respiratory burst; in Chédiak-Steinbrinck-Higashi syndrome, lack of normal lysosomal granules is the key defect. These illnesses increase the risk of pneumonia as well as other skin and soft tissue infections.

Studies have explored the potential of granulocyte CSF (G-CSF) as a promoter of endogenous neutrophil host defense (Table 2-2). As a class, CSFs are glycoproteins that increase the production of all blood cells and enhance their differentiation. Circulating G-CSF is increased dramatically (up to 100-fold) in patients with pneumonia and sepsis, presumably as a result of macrophage production. The response of G-CSF is not compartmentalized in the lung.

Previously used only to increase neutrophil (granulocyte) production in the bone marrow, it is now hypothesized that G-CSF may improve host survival when a non-neutropenic host is challenged by severe infection. Using G-CSF, survival has been increased in ethanol-treated mice challenged with K pneumoniae and in splenectomized animals infected with S pneumoniae. Clinical trials in CAP and severe pneumonia complicated by sepsis have produced inconclusive results. These data suggest beneficial effects, especially in patients with markers of severe infection, such as multilobar infiltrates on chest radiograph.

Another CSF that has potential therapeutic value is granulocyte monocyte CSF (GM-CSF). Though less well studied than the related G-CSF, benefit has been observed in in vitro models of Leishmania and Cryptococcus, as well as in mice infected with Pneumocystis. Studies have suggested that polymorphisms in genes affecting host defense molecules like TNF may affect the likelihood of progression of pneumonia into development of septic shock. Thus some individuals are at greater genetic risk for severe consequences of pneumonia.

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Humoral Defenses

Humoral defenses include multiple classes of immunoglobulins A and G (IgA and IgG). In the upper airway, IgA predominates and may account for up to one tenth of all protein in nasal secretions. Proteolytic degradation of IgA by bacterial enzymes has been demonstrated by gram-negative bacteria, including Pseudomonas, Escherichia coli, and Serratia and Proteus spp. IgG gradually becomes predominant in the lower respiratory tract.

Increased IgG in the bronchoalveolar lavage (BAL) of patients with inflammatory lung disease suggests the ability to recruit immunoglobulin-secreting cells into the lower airway. IgA deficiency has been associated with the propensity to develop airway infection and bronchiectasis. Pneumonia, recurrent bronchitis, sinusitis, and otitis have been associated with both total deficiency of IgG as well as with decrements in subclass concentrations (IgG₂, IgG₄, etc.).

Pulmonary Microbiome

Although the lower respiratory tract, including the lungs, was long believed to be a sterile environment, research in the last two decades has revealed it to contain a dynamic microbial population of bacteria, fungi and viruses. While the relative biomass of the lung microbiome is lower than that of the upper respiratory tract due to rapid microbial clearance, it nevertheless plays an important part in host-pathogen dynamics and can influence disease outcomes. Microbial colonization of the lung starts in the first days of post-uterine life, with the early-life microbiome consisting of either Ureaplasma (a vaginal commensal genus of bacteria) or Staphylococcus (a common skin commensal genus), depending on the mode of delivery (vaginal or caesarean). The lung microbiome continues developing after birth, becoming fully established in the first few years of life. The mature, healthy lung microbiome is dominated by Bacteroidetes, Proteobacteria and Firmicutes bacteria, but other microorganisms are present as well. The most common bacterial genera are Streptococcus, Prevotella and Veillonella, while the most common viruses include anelloviruses, herpes viruses and human papillomavirus. The mycobiome by contrast represents a much smaller fraction of the lung microbiome biomass, with the most common fungi being Ceriporia lacerate, Saccharomyces cerevisiae and Penicillium brevicompactum. The population structure of the lung microbiome and its clearance dynamics are now understood to contribute to the lung immune tone – i.e., the immunological readiness of the lung to respond to pathogens; these effects are mediated through control of immune-related receptor expression, activation of immune cells, and secretion of anti-inflammatory mediators.

Recent evidence suggests that the composition of the lower respiratory microbiota may influence the development of and outcomes in pneumonia. For example, enrichment in certain genera (Prevotella, Streptococcus, Clostridium, Roseburia and Veillonella) is associated with subclinical inflammation in the lungs. One study of patients with HIV and pneumonia revealed three clusters of patients with distinct bacterial microbiomes. The first group had a microbiome dominated by Pseudomonadaceae (with Sphingomonadaceae, Prevotellaceae and Streptococcaceae as smaller components), the second had a microbiome dominated by Streptococcaceae (with associated Prevotellaceae and Veillonellaceae as other significant components) and the third a microbiome dominated by Prevotellaceae (with Veillonellaceae and Streptococcaceae as minor but significant components). Mortality was higher in the third group (22%) compared to the first (13%) or second (16%); however, the differences in mortality did not reach statistical significance (P=0.08) and further research is necessary to elucidate the relationship between adverse outcomes in pneumonia and specific lung microbiome composition. A study of patients on mechanical ventilation showed that Streptococcus, Haemophilus and Neisseria were relatively more abundant in patients who survived, while Corynebacterium and Alloprevotella were relatively more abundant in patients who died; a low abundance of Streptococci was strongly linked to increased 28-day mortality. These observations in humans are in concordance with experimental results in mice, which showed that sterile injury to the lungs produces changes in the microbiome composition; when transplanted to the lungs of uninjured mice, injury-altered microbiota were associated with greater inflammation and lung tissue damage. However, the study of the effects (protective or deleterious) that changes to the lung microbiome have on the risk of pneumonia and its clinical outcomes is still in the very early stages.

Airway Colonization and Bacterial Adherence

Colonization refers to the continued recovery of bacteria from sites in the body in the absence of a local or systemic inflammatory response. Colonization of the upper airway is thought to be the primary step in the development of pneumonia, although in some instances, the gastrointestinal (GI) tract (particularly the stomach and the trachea) may be colonized simultaneously or sequentially with the oropharynx. Bacterial colonization is initiated shortly after birth by numerous species of bacteria whose presence is thought to prevent the establishment of pathogenic bacteria. In acute or chronic illness, patterns of colonization change. Aging and the use of antibiotics also change the balance of upper airway flora to one in which pathogenic gram-negative bacteria predominate. Poor dental hygiene with increased colonization of dental plaques and on buccal surfaces in community-dwelling and institutionalized elderly contributes to increased pneumonia risk.

While the lower airway is usually sterile, primary colonization during acute illness may occur with P aeruginosa. In addition, recurrent or large-volume aspirations with pathogenic bacteria may eventually overwhelm the defenses of the lower airway.

Chronic lower airway colonization with gram-negative bacteria (e.g., Pseudomonas spp) characterizes advancing COPD and CF. Bacterial adherence is the microphysiologic interaction between host and pathogen. In the microenvironment, changes in epithelial glycoprotein receptors, pH and mucins enhance bacterial adherence. Injury to the airway is also thought to unmask binding sites to bacterial adhesion. Degradation of IgA in the airway also promotes adherence, and it has been hypothesized that vaccination to promote IgA production might reduce adherence in chronically colonized or infected individuals.

Although alteration in a single point in the integrated host-defense apparatus may occur as in selective IgA deficiency and ciliary dysfunction, more often an acute or chronic illness interferes with multiple host-defense barriers and mechanisms. For example, in COPD, cough and mucociliary clearance are impaired. In addition, associated malnutrition damages cell-mediated immunity. Chronic colonization results in inflammation and further increases bacterial adherence and breakdown of IgA. This results in a vicious circle of inflammation, infection and bronchial and alveolar damage (Figure 2-1).

There are numerous chronic medical illnesses associated with increased risk of lower respiratory infection (Table 2-3). Iatrogenic factors may also negatively alter host-defense balance. Among these, the use of antibiotics has been identified as a risk factor for acquisition of pneumonia with resistant organisms, such as P aeruginosa and
S aureus. The increasing pH of stomach contents observed in critical illness has been associated with progressive gastric colonization with gram-negative organisms. The use of H₂-receptor antagonists for stress-bleeding prophylaxis has also been suggested as a potential factor increasing the risk of VAP. Available data suggest an enhanced risk of CAP in patients taking proton pump inhibitors. Patients who are mechanically ventilated have a risk for ventilator-associated pneumonia (VAP) of approximately 1% per day for the first 2 weeks after intubation (Table 2-4). This risk is clearly associated not only with concomitant immunodeficiency but also with the direct access the artificial airway provides for bacteria to the lower respiratory tract (Figure 2-2). Bacterial biofilm forms on the surface of endotracheal tubes, which provides a matrix for bacterial growth and colonization. Bacteria also pool in secretions on top of endotracheal tube cuffs. Thus the use of noninvasive mechanical ventilation by avoiding tube placement reduces the risk of VAP. The production of mucus and epithelial damage invoked by the tube and the infectious inoculum of secretions pooled above the endotracheal cuff are also significant in the pathogenesis of pneumonia.

The risk of pneumonia is also increased by the use of sedation. Available data substantiate the positive effect of sedation-interrupting protocols upon many different patient outcomes.

Although less often observed today, contamination originating in the ventilator circuit and infected condensate were previously significant sources of HAP. To address this problem, reducing ventilator tubing changes from daily to every 48 hours or longer has been instituted in most hospitals. The abandonment of all routine ventilator tubing changes is a practice that evidence suggests may reduce the incidence of pneumonia and the cost of care.

The systemic inflammatory response to infections like pneumonia can itself result in impaired immune response. This is observed particularly in macrophages, neutrophils, T cells, and dendritic cells. This is the likely explanation for the enhanced risk of pneumonia in adult respiratory distress syndrome and postoperatively in patients with burns or multiple trauma.

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