L8 Pathology Pneumonia

Overview

Pneumonia is inflammation of the lung parenchyma usually caused by an infectious organism. The lecture covers how pneumonia is classified, the factors that predispose to pulmonary infection, the pathogenesis of Acute Respiratory Distress Syndrome (ARDS) and diffuse alveolar damage, the pathology of bacterial pneumonia (lobar vs bronchopneumonia, including Legionella), viral pneumonia (including RSV, measles, COVID-19 and influenza), and the distinct infection patterns seen in the immunocompromised host.

Definition and classification

• Definition: inflammation of the lung parenchyma usually caused by an infectious organism.
• Classified in three ways:
  • By clinical setting, e.g. community-acquired pneumonia, aspiration pneumonia
  • By organism, e.g. mycoplasma, pneumococcal
  • By morphology, e.g. lobar pneumonia, bronchopneumonia

Organisms by clinical setting

• Community-acquired: Pneumococcus (30-60%), H. influenzae (10%), Moraxella catarrhalis, Staphylococcus aureus, Mycoplasma (10-30%), Legionella (2-10%), Chlamydophila (5-10%), Gram-negative bacteria, viruses (influenza, HMPV, RSV, adenovirus); unknown in 40-50%
• Nosocomial: Gram-negative bacteria, Klebsiella (4%), E. coli, Pseudomonas (5%), MRSA, polymicrobial (13%); unknown in 33%
• Immunocompromised: cytomegalovirus (CMV), Pneumocystis jiroveci, Mycobacterium avium, aspergillosis, candidiasis, and others
• Aspiration: anaerobic oral flora (Bacteroides, Prevotella, Fusobacterium, Peptostreptococcus); aerobic organisms (pneumococcus, Staph. aureus, H. influenzae, Pseudomonas aeruginosa)

Predisposing factors

• Decreased cough reflex
• Injury to cilia
• Decreased function of alveolar macrophages
• Oedema or congestion
• Retention of secretions

ARDS and diffuse alveolar damage

ARDS progresses through two phases:

• Proliferative phase (1-3 weeks): proliferation of type II pneumocytes; macrophages remove cell debris.
• Fibrotic phase: either resolution with minimal fibrosis, or repair/fibrosis with thick alveolar walls, or progressive fibrosis (honeycomb lung).

Sequence of the ARDS response: a damaging stimulus to the lung causes damage to both the alveolar lining cells and the alveolar capillary endothelium. Both lead to interstitial oedema and high-protein exudation into the alveoli (forming hyaline membranes). From here the process branches: death in the acute phase (70%), or regeneration of type II alveolar lining cells with inflammation of the interstitium, which proceeds to organization and interstitial fibrosis. This fibrosis has three possible outcomes: mild focal fibrosis with recovery and minimal residual respiratory dysfunction (10%); marked interstitial fibrosis (honeycomb lung); or death due to chronic severe respiratory impairment (20%).

At the cellular level, diffuse alveolar damage (DAD) has two phases:

• Acute phase DAD: injury to all three layers of the alveolar-capillary interface (alveolar epithelium, capillary endothelium, and the intervening interstitial space including the fused basement membrane). This damage triggers an immune response that allows cells to fill the alveoli through the now-leaky capillaries. A hyaline membrane forms as sloughed alveolar cells, plasma membranes and fluid coalesce.
• Organizing phase: alveolar collapse; type 2 pneumocytes proliferate to replace the injured epithelium; fibroblasts proliferate.

Bacterial pneumonia: lobar vs bronchopneumonia

Bacterial pneumonia has two morphological patterns: Lobar Pneumonia and Bronchopneumonia.

Lobar pneumonia

• Confluent consolidation involving a complete lung lobe, spreading via infection through the pores of Kohn.
• Most often due to Streptococcus pneumoniae (pneumococcus); can also be seen with other organisms (Klebsiella, Legionella).
• Clinical setting: usually community-acquired; classically occurs in otherwise healthy young adults.
• Pathology is a classical acute inflammatory response: exudation of fibrin-rich fluid, neutrophil infiltration, macrophage infiltration, resolution. Antibodies contribute by opsonising bacteria for phagocytosis.
• Stages, in order:
  1. Congestion: capillaries become congested and the lung becomes oedematous.
  2. Red hepatisation: red cells enter the alveolus by diapedesis, followed by polymorphs; bacteria are ingested by polymorphs, aided by opsonisation.
  3. Grey hepatisation: macrophages ingest and remove dead inflammatory cells and fibrinous exudate.
  4. Resolution.
• Microscopically, red hepatisation shows alveoli filled with red blood cells and neutrophils; grey hepatisation shows a denser fibrinous/inflammatory exudate of macrophages and neutrophils with less red cell content.

Legionella

• Legionella can be acquired from soil, e.g. via potting mix.
• Legionella can live and grow in biofilm in water/air-conditioning pipe systems: within a pipe, a secreted slime layer (biofilm) forms at the pipe wall containing biofilm-associated bacteria, while free-floating bacteria are present in the water itself.

The slide on Legionella-in-soil was a generic public-health infographic about handling potting mix/soil safely rather than lung-pathology-specific content; the environmental exposure point above is transcribed as shown in the source.

Bronchopneumonia

• Consolidation is patchy and not confined by lobar architecture; spreads through the airways.
• Predisposing associations: post-viral infection, depressed cough reflex, distal to an obstruction, aspiration, immunosuppression, cardiac failure.
• Organisms are varied: Strep. pneumoniae, Haemophilus influenzae, Staphylococcus, anaerobes, coliforms. Clinical context can help narrow this down: Staph, anaerobes and coliforms are seen particularly in aspiration.
• Imaging shows bilateral patchy opacities/infiltrates on chest X-ray.
• Gross and histological appearance: patchy, pale areas of consolidation scattered irregularly through otherwise dark, congested lung tissue, rather than a single confluent lobe.

Bacterial vs viral pneumonia, and specific viral causes

Comparing the two immune pathways (example: pneumococcal pneumonia vs COVID-19):

• Bacterial pneumonia: driven by neutrophils and macrophages. Bacteria enter the alveoli and begin to grow → capillaries open and neutrophils enter to fight the bacteria (oedema) → macrophages clean up debris once the infection has cleared → the lungs return to normal over subsequent weeks.
• Viral pneumonia: driven by lymphocytes. Virus enters cells and multiplies → cells are destroyed as virus particles burst through → a hyaline membrane forms → lymphocytes detect and destroy virus-infected cells while type 2 pneumocytes proliferate to replace damaged cells → the lungs return to normal over subsequent weeks.

Histologically, early viral pneumonia shows thickened alveolar septa infiltrated with inflammatory cells (an interstitial pattern), with alveolar spaces still relatively open and red cells visible in septal capillaries. Later viral pneumonia gives a pattern of acute injury similar to ARDS: acute inflammatory infiltration is less obvious, and viral inclusions are sometimes seen in epithelial cells.

Causes of viral pneumonia: influenza, respiratory syncytial virus (RSV), measles, adenoviruses, coronaviruses, and others.

Respiratory syncytial virus (RSV) — in a healthy infant, RSV infection follows one of two pathways:

1. Cold-like symptoms → a balanced immune response → viral clearance → recovery.
2. RSV-induced bronchiolitis, influenced by genetic predisposition (e.g. IL-8): an excessive neutrophil response arises, which via IL-9 production recruits mast cells (together with lung-resident mast cells) causing airway hyper-reactivity; the same excessive response, via proteases, reactive oxygen species (ROS), neutrophil extracellular traps (NETs) and viral clearance, causes lung injury that disrupts alveolarisation and leads to lasting pulmonary impairment. Both airway hyper-reactivity and lasting pulmonary impairment converge on a predisposition to asthma.

Measles pneumonia: characterised histologically by multinucleated giant cells within the lung tissue (giant cell pneumonia).

COVID-19 pneumonia progresses through three phases over time, each with characteristic clinical features:

1. Early infection (viral invasion and replication, via binding of the coronavirus to ACE2/TMPRSS2 receptors): mild constitutional symptoms, fever, dry cough, sore throat; sign of lymphopenia; normal imaging; treated with antiviral agents (nirmatrelvir/ritonavir, remdesivir, molnupiravir).
2. Pulmonary phase (host inflammatory response, with T-cell, B-cell, macrophage and NK cell activation): shortness of breath and hypoxaemia; abnormal chest imaging; organizing pneumonia pattern on imaging; treated with immunomodulatory therapy (corticosteroids, tocilizumab, baricitinib).
3. Hyperinflammatory phase (dysregulated immune response/cytokine storm affecting lung, heart, brain and kidney): ARDS, shock, cardiac and multiorgan failure, coagulation disorder (including DIC); elevated acute phase reactants (CRP, IL-6, ferritin, D-dimer, troponin, NT-proBNP); diffuse alveolar damage pattern on imaging; treated with anticoagulation (prophylactic or therapeutic-dose heparin).

Influenza pneumonia pathogenesis: sialidase activity alters the respiratory epithelium, producing altered mucus, decreased mucociliary velocity and down-regulation of antimicrobial peptides (AMPs), alongside enhanced virus dissemination, enhanced bacterial colonisation and attachment, receptor up-regulation, and reduced repair/regeneration of cells. This leads to impaired alveolar macrophage functionality and altered cytokine responses, alveolar macrophage death and impaired killing (allowing bacterial overgrowth), and impaired NK cell recruitment/function. In the vasculature, altered TLR pathways lead to increased neutrophil death and impaired neutrophil function.

Pneumonia in the immunocompromised host

Causes of immunocompromise: primary immune deficiencies, HIV/AIDS, trauma, diabetes mellitus, and secondary causes such as transplant and chemotherapy.

Two patterns of infection are seen:

• Virulent infection with a common organism, e.g. tuberculosis (described as “the African pattern”).

• Infection with an opportunistic pathogen: viruses (cytomegalovirus, CMV), bacteria (Mycobacterium avium intracellulare), fungi (aspergillus, candida, pneumocystis), or protozoa (cryptosporidia, toxoplasma).

• Fungal pneumonia: histology shows branching fungal hyphae within lung tissue with an associated inflammatory infiltrate.

• CMV pneumonia: histology shows enlarged cells with characteristic large intranuclear inclusions (“owl’s eye” cytomegalic cells).

Self-test

1. Define pneumonia.
2. Give the three ways pneumonia is classified, with an example of each.
3. List the organisms most associated with community-acquired pneumonia, and separately those most associated with nosocomial pneumonia.
4. List the five predisposing factors for pulmonary infection described in the lecture.
5. Describe the proliferative and fibrotic phases of ARDS.
6. Describe the sequence from a damaging stimulus to the lung through to the possible outcomes of ARDS, including the proportions of patients affected by each outcome.
7. Describe the acute phase and organizing phase of diffuse alveolar damage.
8. Distinguish lobar pneumonia from bronchopneumonia in terms of distribution and the organisms typically responsible.
9. Describe the four stages of lobar pneumonia, in order, with what happens at each stage.
10. Describe a route by which Legionella can be acquired from the environment, and how it colonises water/air-conditioning pipe systems.
11. What factors predispose to bronchopneumonia?
12. Distinguish the immune cell involvement and pathway of bacterial pneumonia from that of viral pneumonia.
13. Describe the two possible outcomes of RSV infection in a healthy infant, and explain how genetic predisposition alters the pathway.
14. What histological feature is characteristic of measles pneumonia?
15. Describe the three phases of COVID-19 pneumonia progression, including the associated clinical signs and imaging findings.
16. Explain how influenza infection predisposes the lung to secondary bacterial pneumonia.
17. List the causes of immunocompromise mentioned, and distinguish the two patterns of infection seen in the immunocompromised host.
18. What histological finding is characteristic of CMV pneumonia?
19. Explain how the hyaline membrane formation seen in ARDS/diffuse alveolar damage relates to the later stage of viral pneumonia.

Answers

Reveal answers

1. Inflammation of the lung parenchyma usually caused by an infectious organism.
2. By clinical setting (e.g. community-acquired pneumonia, aspiration pneumonia), by organism (e.g. mycoplasma, pneumococcal), and by morphology (e.g. lobar pneumonia, bronchopneumonia).
3. Community-acquired: Pneumococcus (30-60%), H. influenzae, Moraxella catarrhalis, Staph. aureus, Mycoplasma, Legionella, Chlamydophila, Gram-negative bacteria, viruses (influenza, HMPV, RSV, adenovirus). Nosocomial: Gram-negative bacteria, Klebsiella, E. coli, Pseudomonas, MRSA, polymicrobial infection.
4. Decreased cough reflex, injury to cilia, decreased alveolar macrophage function, oedema or congestion, retention of secretions.
5. Proliferative phase (1-3 weeks): proliferation of type II pneumocytes, macrophages removing cell debris. Fibrotic phase: resolution with minimal fibrosis, or repair/fibrosis with thick alveolar walls, or progressive fibrosis (honeycomb lung).
6. Damaging stimulus → damage to alveolar lining cells and alveolar capillary endothelium → interstitial oedema and high-protein exudation into alveoli (hyaline membranes) → either death in the acute phase (70%) or regeneration of type II cells with interstitial inflammation → organization → interstitial fibrosis → mild focal fibrosis with recovery and minimal dysfunction (10%), marked interstitial fibrosis (honeycomb lung), or death from chronic severe respiratory impairment (20%).
7. Acute phase: injury to all three layers of the alveolar-capillary interface, triggering an immune response that lets cells fill the alveoli through leaky capillaries, forming a hyaline membrane from sloughed alveolar cells, plasma membranes and fluid. Organizing phase: alveolar collapse, type 2 pneumocyte proliferation to replace injured epithelium, fibroblast proliferation.
8. Lobar pneumonia is confluent consolidation of a whole lung lobe (spread via the pores of Kohn), most often due to Strep. pneumoniae. Bronchopneumonia is patchy consolidation not confined by lobar architecture, spread through the airways, caused by varied organisms (Strep. pneumoniae, H. influenzae, Staphylococcus, anaerobes, coliforms).
9. Congestion (capillaries congested, lung oedematous) → red hepatisation (RBCs enter alveolus by diapedesis, then polymorphs; bacteria ingested by polymorphs aided by opsonisation) → grey hepatisation (macrophages ingest and remove dead inflammatory cells and fibrinous exudate) → resolution.
10. Legionella can be acquired from soil, e.g. via potting mix. It also colonises biofilm in water/air-conditioning pipes: a secreted slime layer forms at the pipe wall harbouring biofilm-associated bacteria, with free-floating bacteria present in the water.
11. Post-viral infection, depressed cough reflex, being distal to an obstruction, aspiration, immunosuppression, cardiac failure.
12. Bacterial pneumonia: neutrophils and macrophages; bacteria grow in alveoli, neutrophils cause oedema fighting them, macrophages clear debris once infection clears. Viral pneumonia: lymphocytes; virus multiplies within and destroys cells, a hyaline membrane forms, lymphocytes destroy infected cells while type 2 pneumocytes replace damaged cells.
13. (1) Cold-like symptoms → balanced immune response → viral clearance → recovery. (2) With genetic predisposition (e.g. IL-8), an excessive neutrophil response develops that, via IL-9, recruits mast cells causing airway hyper-reactivity, and via proteases/ROS/NETs and viral clearance causes lung injury, disrupted alveolarisation and lasting pulmonary impairment; both outcomes predispose to asthma.
14. Multinucleated giant cells within the lung tissue.
15. Early infection (viral invasion/replication via ACE2/TMPRSS2): mild constitutional symptoms/fever/cough/sore throat, lymphopenia, normal imaging. Pulmonary phase (host inflammatory response): shortness of breath/hypoxaemia, abnormal imaging, organizing pneumonia pattern. Hyperinflammatory phase (cytokine storm): ARDS/shock/multiorgan failure/coagulation disorder, elevated CRP/IL-6/ferritin/D-dimer/troponin/NT-proBNP, diffuse alveolar damage pattern.
16. Sialidase activity alters the epithelium (altered mucus, decreased mucociliary velocity, AMP down-regulation) and enhances bacterial colonisation/attachment and virus dissemination while reducing epithelial repair; it also impairs alveolar macrophage function and causes macrophage death (allowing bacterial overgrowth) and impairs NK cell recruitment, and alters neutrophil death/function via TLR pathways in the vasculature.
17. Primary immune deficiencies, HIV/AIDS, trauma, diabetes mellitus, and secondary causes (transplant, chemotherapy). The two patterns are virulent infection with a common organism (e.g. TB, “the African pattern”) and infection with an opportunistic pathogen (virus, bacteria, fungi or protozoa).
18. Enlarged cells with large intranuclear inclusions (“owl’s eye” cytomegalic cells).
19. In ARDS/DAD, damage to the alveolar-capillary interface causes leaky capillaries that allow protein-rich exudate to fill the alveoli, forming a hyaline membrane. Later-stage viral pneumonia gives a pattern of acute injury similar to ARDS, including hyaline membrane formation, showing the two processes converge on the same alveolar injury pathway.