Respiratory system host defense 2025

Goals of Lecture

• Understand the microbial relationship between the Upper Respiratory Tract (Oropharynx) and Lower Respiratory Tract (Lung).
• Overview of the 3 levels of host defense mechanisms in the respiratory system. 3 levels.
• Integration of interactions among the respiratory defense mechanisms.
• Clinical application with representative disease manifestations that result from specific respiratory defense defects.
• The goal is to apply general concepts of host defense to the respiratory system and provide concrete clinical examples.

Relevance to Dental Medicine

• The oropharyngeal cavity forms the first portion of the respiratory tract.
• The oropharynx is the source of lung bacteria in healthy lungs, and the first stop for pathogens in disease.

The Oropharynx and Lung Infections

• Direct effects: The oropharynx is the source of lung microorganisms.
  • Pneumonia with virulent respiratory pathogens (e.g., S. pneumoniae) is usually preceded by oropharyngeal colonization.
  • Other types of pneumonia originate in the oropharynx, including aspiration pneumonia.
  • Gram-negative organisms may colonize the oropharynx in states of debilitation or chronic illness.
  • Viruses such as SARS-CoV-2 infect the upper respiratory tract (including the oropharynx) before invading the lungs.
• Indirect mechanisms (new area of research): The oropharyngeal microbiome may set host immune tone and regulate response to pathogens throughout the respiratory tract.

The Oropharynx as the Source of Bacteria in the Healthy Lung

• Bacteria in the normal lung are nearly identical to those in the oropharynx, but at much lower levels.
• Bacteria enter the lung passively by micro-aspiration from the oropharynx and are cleared.
• Bacteria are defined by sequencing of the ribosomal RNA gene (microbiome approach).
• Evidence: Bacteria in the lung (lung tissues) and oropharynx show similarity in bacterial families (e.g., Charlson et al., AJRCCM 2011).

Bacterial Ecology of the Normal Lung Microbiome

• Derived passively from the upper respiratory tract via physiological microaspiration.
• Reflects an equilibrium between entry and local clearance with limited local replication.
• Micro-aspiration pathway and clearance mechanisms:
  • Cough
  • Mucociliary clearance
  • Innate & adaptive immunity
• Normal lung: Increased local replication due to structural lung disease or virulent pathogen; Decreased clearance (mechanical or immunological); Increased entry (micro- or macro-aspiration); Abnormal upper respiratory microbes (dysbiosis).
• Pathologic state: dysbiosis and altered entry/clearance balance can predispose to infection.

How the Lung Protects Itself from Colonization and Infection

• With constant exposure to microbe-rich oropharynx, protection is maintained by:
  • Microbial Clearance
  • Microbial Entry balance
  • Health and injury can shift balance toward infection.
• Infection occurs when:
  • Excessive entry from the upper respiratory tract
  • Deficient clearance (mechanical or immunological)
  • Exuberant replication by a virulent pathogen
• Healthy lung typically exhibits low microbial entry and efficient clearance.

Integrated Pulmonary Defenses

1) Mechanical protection

• Upper airway: turbulence, glottis, cough
• Lower airway: branching, mucus, cilia
  2) Innate immune mechanisms
• Soluble: complement, collectins, defensins
• Cellular: respiratory epithelium, phagocytes
  3) Adaptive immunity
• Cellular immunity (CD4, CD8 T cells)
• Humoral immunity (antibody - B cells)

Mechanical protection - the upper airway

• Nares & hypopharynx:
  • Nasal hairs filter
  • Nasal turbinates create turbulence causing particulate matter to settle on surfaces
  • Rhinorrhea: cellular desquamation & sneezing
  • Highly effective for particles ≥ 10\,B5m
• Epiglottis/glottis:
  • Swallowing, gag, cough
• Respiratory mucus:
  • Impedes bacterial adherence

Mechanical protection - the upper airway: Defects

• Defects of the upper airway with loss of mechanical protection:
  • Altered consciousness (drug overdose, anesthesia, CNS events)
  • Laryngeal dysfunction (swallowing) – bulbar dysfunction (e.g., myasthenia gravis, neuromuscular diseases, strokes)
  • Oropharyngeal surgical procedures
  • Endotracheal tube or tracheostomy – major risk factor for pneumonia (ventilator-associated pneumonia, VAP)
  • Oropharyngeal flora & respiratory mucosa adhesive properties: increased anaerobic flora with extensive dental disease; in a patient without teeth there is a shift to lower anaerobic flora
  • Within a week of illness & hospitalization, normal respiratory flora can be replaced with gram-negative bacteria (opportunistic)

Case Example 1: Defective mechanical defense - upper airway

• 63-year-old man with poor dentition and heavy alcohol use presents to the ED with fever, chest pain, cough, foul-smelling sputum.
• Diagnosis exemplifies mechanical defense defect leading to respiratory infection.

Case Example 1: Lung abscess due to aspiration

• Lung abscess due to aspiration of oral flora caused by loss of consciousness with decreased gag & cough.
• Usually mixed oral bacteria, including anaerobes (foul smell).
• Radiographic feature: cavity with air-fluid level.

Case Example 2: Defective mechanical defense - upper airway and VAP

• Elderly man with emphysema and respiratory failure, recent tracheostomy, ICU care with weaning from ventilator.
• Ventilator-associated pneumonia (VAP) due to endotracheal tube or tracheostomy bypassing upper airway protection.
• VAP statistics: VAP occurs in up to 30 hspace ext{ ext{%}} of intubated patients and causes 40{,}000 - 70{,}000 deaths in the US each year.

Mechanical protection: the lower (conducting) airways

• Bronchial branching: 20 orders of branching from trachea to alveolar ducts.
• Increased total cross-sectional area leads to decreased forward velocity and increased contact with mucosal surface, allowing particles to settle.
• Effective for particles 5 - 10\,\mu\text{m}.
• Mucous: lower sol (liquid) layer; mucinous layer (proteoglycans).
• Cilia: 200\,\text{per cell} at 12 - 15\text{ beats per second}.
• Cough reflex coordination with muco-ciliary clearance is essential.

Mechanical protection - lower airways: Defects

• Bronchial branching defects: bronchiectasis, diffuse CF, focal post-pneumonia or TB, cavities or bullae with poor connection to conducting airways may become infected.
• Mucous defects: cystic fibrosis.
• Cilia defects: immotile ciliary syndromes (Kartagener).
• Airway clearance & cough defects: endobronchial obstruction (tumor, foreign body) with post-obstructive pneumonia; right middle lobe bronchiectasis due to voluntary cough suppression.

Case Example 3: Defective mechanical defense – conducting airways

• AB, a 19-year-old man presented with fever, SOB, green sputum for 7 days.
• PMH: “bronchitic” and one episode of pneumonia as a child; sinusitis 3 years ago.
• Exam: fever (T=39^ ext{°C}), tachypnea, crackles on the right lung.
• WBC elevated (e.g., 19k).
• Sputum Gram stain: Gram-positive cocci in clusters; grew Staphylococcus aureus; treated with cefazolin; improved and discharge.
• Over the next 12 years, recurrent bronchitis with several episodes of fever, sputum, SOB; treated empirically with antibiotics.
• Last episode poor exercise recovery; persistent sputum production with green color and occasional blood.

Case Example 4: Defective mechanical defense – conducting airways (Bronchiectasis)

• 68-year-old man with a history of whooping cough in childhood and several episodes of left lower lung pneumonia.
• Case demonstrates focal bronchiectasis related to defective mechanical defense.

Case Example 5: Post-obstructive pneumonia

• Former heavy smoker with incomplete resolution of infiltrate after second recent left-sided pneumonia.
• Post-obstructive pneumonia due to bronchogenic carcinoma.
• Bronchoscopic appearance of airways on the left (image described in the slides).

Case Example 6: Aspirated foreign body and non-draining cavity

• Aspirated foreign body (e.g., aspirated tooth or dental bridge).
• Case shows aspirated tooth in the left lower lobe bronchus; removed by bronchoscopy.
• Aspergilloma: fungal colonization within an old cavity (non-draining bulla or cavity).

Case Example 7: Defective innate cellular immunity

• 14-year-old boy post bone marrow transplant with prolonged pancytopenia (including neutropenia) presents with fever, SOB, hemoptysis.
• Chest X-ray: nodular infiltrates; classic pattern for invasive aspergillosis.

Innate immunity in the lung

• Cellular innate immunity:
  • Macrophages are the primary immune defense in the lung (≥85\%).
  • Neutrophils (PMN) are rare in lung (≤5\%) but recruited in response to stimuli.
  • NK cells contribute to direct killing.
  • Respiratory epithelial cells secrete soluble products and antimicrobials.
• Soluble innate defense:
  • Surfactant collectins; complement; defensins.
  • Collectins: SP-A & SP-D (part of surfactant system) and soluble mannose-binding lectin (MBL).
  • Complement components (C3a, C5a, properdin B) contribute to direct lysis, chemotaxis, and opsonization.
  • Other antimicrobial factors: lactoferrin, lysozyme, transferrin.
• Example: Complement deficiency leads to recurrent pyogenic infections, especially encapsulated bacteria.

Cellular innate immunity: pattern recognition and activation

• How cells recognize foreign material via Pattern Recognition Receptors (PRRs):
  • Toll-like receptors (TLRs) bind conserved microbial components (e.g., LPS/endotoxin, flagellin, lipoproteins, peptidoglycan).
  • Nucleic acids not present in mammalian genomes (dsRNA, unmethylated DNA) are recognized.
  • In the lung: macrophages and respiratory epithelial cells express TLRs.
• Lectins: surface receptors recognizing microbial carbohydrate patterns (e.g., macrophage mannose receptor).
• Opsonization: soluble pattern-recognition proteins coat microbes to target them for phagocytosis and to trigger immune cell activation.
  • In the lung: Collectins (Surfactant) and complement participate in opsonization.

Innate immunity: epithelial cell contribution

• Epithelial cells contribute to innate defense via recognition of microorganisms by PRRs and secretion of antimicrobial peptides and mediators to recruit immune cells.
• The slide emphasizes that innate defense is not only from specialized immune cells but also from airway epithelial cells themselves.

Defects of cellular innate immunity

• Neutropenia (e.g., chemotherapy, leukemia, bone marrow transplant):
  • Invasive fungal disease; rapid progressive bacterial infections.
  • Gram-negative pneumonia and invasive aspergillosis in bone marrow transplant or chemotherapy patients.
• Desquamated and injured respiratory epithelium:
  • Airway burns / smoke inhalation
  • Post-influenza
  • Increased susceptibility to bacterial pneumonia (e.g., S. pneumoniae, Staphylococcus)

Pulmonary innate defense: soluble antimicrobial proteins

• Collectins: SP-A, SP-D (surfactant proteins) and soluble mannose-binding lectin (MBL).
  • Function: aggregate, opsonize, and fix complement.
• Complement system: components such as C3a, C5a, Properdin contribute to direct lysis, chemotaxis, and opsonization.
• Other antimicrobial proteins with direct activity: lactoferrin, lysozyme, transferrin.
• Example: Collectin and complement pathways illustrate redundant, overlapping innate defenses.

Defensins

• Alpha-defensins and beta-defensins
• Produced by airway epithelial cells.
• Function: direct lysis of microbes; broad microbicidal activity against Gram-negative and Gram-positive bacteria, mycobacteria, fungi, and some viruses; also chemotactic.
• In CF, abnormal osmotic environment leads to defective folding and function of defensins, compromising defense.

Case Example 7: Defective innate cellular immunity

• A patient with acute leukemia, 3 weeks post-BMT with prolonged pancytopenia, including neutropenia, presents with fever, SOB, hemoptysis.
• Chest imaging: multiple CXR infiltrates with nodular appearance; classic pattern for invasive aspergillosis.

Pulmonary Defense: Specific (adaptive) immunity

• Adaptive immunity comprises humoral and cell-mediated components.
• Humoral immunity (B cells and antibodies) and cell-mediated immunity (T cells) play central roles.

Adaptive immunity: central role of antigen presenting cells & CD4 T cells

• Cellular immunity (CD8 T cells): direct killing via perforin and granzyme; activation of other immune cells (IFN-γ, IL-2); chemotaxis.
• Humoral immunity (B cells & antibodies): direct killing (lysis) via antibodies; indirect killing via complement and ADCC; opsonization.
• CD4 T cell receptor (TCR) recognizes antigen presented by APCs.
• Antigen Presenting Cells (APCs) in the lung include lung macrophages and lung dendritic cells.
• Co-stimulation: MHC II presentation with antigen; activation of T cells via PRR signals and opsonization.
• Innate-to-adaptive transition involves uptake (via PRRs, lectins, or opsonized by soluble proteins) and cellular activation (TLRs, pathogen signals).

Humoral immunity: antibody functions and Ig classes

• Antibody functions:
  • Direct lysis (with complement via classical pathway)
  • Opsonization for enhanced phagocytosis (local and splenic)
  • Antibody-dependent cell-mediated cytotoxicity (ADCC)
• IgA: principal antibody in upper & conducting airways.
• IgG: main antibody in alveolar lining fluid.
• IgE: mainly involved in pathological responses (hypersensitivity pneumonitis, asthma, allergic bronchopulmonary aspergillosis).

Antibody function and defects

• Defects may be quantitative or functional.
• Inherited agammaglobulinemias (rare): X-linked or autosomal recessive; agammaglobulinemia.
• Acquired defects are common: multiple myeloma (quantitative & functional), nephrotic syndrome (quantitative), sickle cell disease (functional antibody defect and asplenia), asplenia (functional), AIDS (functional - often with hypergammaglobulinemia).
• These defects are associated with susceptibility to pneumonia and risk of overwhelming sepsis from encapsulated bacteria (e.g., S. pneumoniae).

Case Example 8: Defective humoral immunity

• 14-year-old boy with sickle cell disease (SS) presented with fever, cough, SOB, chest pain.
• Sputum Gram stain showed Gram-negative cocco-bacilli; blood cultures grew Haemophilus influenzae.
• Functional asplenia (auto-infarction) in sickle cell disease.
• Defect in both antibody production and clearance of opsonized organisms; high risk for encapsulated bacteria.

Cell-mediated immunity in the lung

• Susceptibility to all organisms, with specific vulnerabilities:
  • Fungi: Pneumocystis jiroveci (PCP), Histoplasmosis, Cryptococcus
  • Viruses: Cytomegalovirus, Kaposi's sarcoma (HHV-8)
  • Bacteria: Mycobacterium tuberculosis (M. tb), Mycobacterium avium (M. avium), Nocardia
• Defects can be caused by AIDS, corticosteroids, organ transplantation immunosuppression (e.g., cyclosporin, tacrolimus, mycophenolate).

Case Example 9: Defective adaptive immunity (mixed humoral and cellular)

• GH, 32-year-old man with pleuritic chest pain, fever, SOB, rusty sputum for 3-4 days.
• PMH: chronic hepatitis C infection; former IV drug user.
• Exam: fever, tachypnea, hypotension; diffuse crackles. WBC 9.5k with neutrophil predominance.
• Sputum Gram stain: Gram-positive cocci in pairs and short chains; culture negative but blood cultures grew Streptococcus pneumoniae.
• Treated with IV penicillin and improved; HIV testing performed with positive result.
• CD4 count: 390; viral load: 23{,}000.
• Over the next several years the patient moved, had poor follow-up; progression of disease.

Case Example 9 (continued) and AIDS-related adaptive failure

• Four years later, patient developed respiratory distress requiring intubation and ICU admission.
• CXR: bilateral diffuse infiltrates; bronchoscopy with BAL showed Pneumocystis organisms.
• Treated with high-dose trimethoprim/sulfamethoxazole and corticosteroids.
• CD4 count decreased to 76 with viral load 120{,}000.
• Despite therapy, patient deteriorated and died after 5 weeks on ventilator.
• Advanced AIDS with defective cell-mediated and humoral immunity.
• Image: Pneumocystis jiroveci detected on silver stain (GMS).

AIDS: Defective cell-mediated AND humoral immune function

• Defective cellular immunity (CD8 T cells) and defective humoral immunity (B cells & antibody).
• Antigen Presenting Cells (APCs): lung macrophages and lung dendritic cells.
• CD4 is the cellular receptor for HIV binding and entry into target cells; progressive CD4 T cell infection leads to loss.

Cell-mediated immunity in the lung

• Susceptibility to all organisms, with notable patterns:
  • Fungi: Pneumocystis jiroveci, Histoplasma, Cryptococcus
  • Viruses: Cytomegalovirus, Kaposi's sarcoma (HHV-8)
  • Bacteria: Mycobacterium tuberculosis, Mycobacterium avium, Nocardia
• Causes of defective cell-mediated immunity include AIDS, corticosteroids, and transplant immunosuppression (e.g., cyclosporin, tacrolimus, mycophenolate).

Tuberculosis and HIV

• TB in HIV+ individuals shows pattern depending on immune status:
  • Normal host: typical reactivation TB in upper lobes with cavitation.
  • Immunocompromised host (HIV+ with low CD4): atypical patterns, noncavitary disease, lower lobe involvement, adenopathy only, milliary (diffuse disseminated) TB, and extrapulmonary TB (up to 50%).
• TB pathology: granuloma formation visible on H&E stain; confirmed with acid-fast staining.

Case Example 10-11: Tuberculosis in HIV (Botswana)

• Case Example 10: HIV+ with high CD4 (e.g., CD4=600) presenting with cough, sputum, hemoptysis.
• Case Example 11: Advanced HIV disease with low CD4 (
  • Classic pattern with right upper lobe TB and chronic fibro-cavitary appearance
  • Milliary TB: atypical disseminated pattern

Relationship between immune deficiency (by CD4 count) and lung disease in HIV infection

• A graphical general relationship shows how disease patterns shift with decreasing CD4 counts:
  • Disease progression: CD4 count vs. susceptibility to various pathogens.
  • TB, bacterial pneumonia, Histoplasmosis, Pneumocystis, Cryptococcus, Mycobacterium avium, Cytomegalovirus, and disseminated infections become more likely as CD4 declines.
• Representative organisms listed in the notes show a spectrum of infections associated with immune deficiency.

Summary: Defective pulmonary defense mechanisms and disease

• A consolidated table of pathological conditions, manifestations, and mechanisms:
• Mechanical defenses:
  • Gag/cough; nasal hairs; turbinates; bronchial branching; mucous; ciliary function
  • Risk factors: Endotracheal intubation, tracheostomy, oropharyngeal procedures; stroke; alcohol/drug use
  • Defects lead to: bronchiectasis, dysmotile cilia syndromes, aspiration pneumonia, lung abscess, ventilator-associated pneumonia, post-obstructive pneumonia
• Innate immunity (cellular and soluble):
  • Neutropenia and phagocyte dysfunction; complement cascade; defensins
  • Conditions: chemotherapy-induced neutropenia; chronic granulomatous disease; complement deficiencies
  • Resultant infections: invasive aspergillosis; chronic bacterial infections; encapsulated bacteria in specific defects (e.g., asplenia, CF)
• Adaptive immunity (humoral and cell-mediated):
  • CD4 and CD8 T cell function; B cell/antibody function
  • Diseases: AIDS/SCID/DiGeorge; immunosuppression; myeloma; nephrotic syndrome; agammaglobulinemia; asplenia; sickle cell disease
  • Infections: tuberculosis, other mycobacteria, Pneumocystis, Cryptococcus, fungi, herpesviruses; encapsulated bacterial infections

Key points for clinical practice and understanding

• Mechanical barriers of the upper airway are the first defense of the respiratory system and represent the most common defects leading to lung infection; these are frequently breached iatrogenically.
• Mechanical protection by the conducting airway is the second line of defense; it can be compromised by primary defects or prior infection/injury and may create cycles of repeated infection and damage.
• Innate defense comprises soluble and cellular components; there are lung-specific elements (respiratory epithelium, surfactant) in addition to common components across organ systems.
• Adaptive immune function acts as a “last resort” and involves a minority of immune cells in the normal lung that are recruited as needed.
• The pulmonary defense system relies on integration and cross-talk among mechanical, innate, and adaptive defenses, with overlap ensuring redundancy.
• Infections arise from pathogens capable of breaching defenses (virulent organisms) and/or host defenses that are defective, allowing opportunistic infections.
• The type and degree of host defense defect influence clinical presentation and disease trajectory; some diseases involve multiple defects.
• Oropharyngeal health has direct relevance to lung health, underlining the dental medicine importance in maintaining oropharyngeal flora balance and preventing aspiration-related complications.
• Practical implications include the prevention of ventilator-associated pneumonia, management of post-obstructive processes, and consideration of immune status in diagnosis and therapy (e.g., TB in HIV, PCP in AIDS, invasive aspergillosis in neutropenia).
• The material emphasizes case-based understanding to connect basic defense mechanisms to real-world clinical manifestations.

References and contact

• For further information, contact Ron Collman, MD (collmanr@pennmedicine.upenn.edu).

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