Respiratory Dysfunction & Cardiac Consequences Notes

Working Problem 15: Respiratory Dysfunction & Cardiac Consequences

Learning Objectives

• Identify factors that provide opportunity for infections to become chronic.
• Distinguish chronic infection from other types of infection (acute, subacute, latent).
• Describe changes in the lung that predispose patients with CF or COPD to chronic lung infection.
• Briefly describe the consequences of chronic infection on lung structure and function.
• Briefly describe the role of the immune system in lung tissue destruction and repair during chronic infection.

Opportunistic Infection

• Pathogen takes advantage of an opportunity not normally available such as breached barrier, weakened immune system, or altered microbiota.
• Leading cause of death in cancer patients and recipients of organ transplants.
• Secondary infections with opportunistic organisms in patients with primary or acquired immunodeficiency disease.
• Major cause of death in patients with AIDS.

Opportunistic Organisms

• Main features:
  • Usually low pathogenicity (e.g., Cytomegalovirus, S. aureus, P. aeruginosa, and C. albicans).
  • May cause serious infection due to severely impaired host defense system.
  • May cause atypical clinical presentations or systemic infection.
• Major opportunistic pathogens:
  • Bacteria (Gram-negative/Gram-positive bacteria, mycobacterium).
  • Fungi.
  • Virus.
  • Protozoa and helminths (intestinal worms).

Risk Factors for Opportunistic Infection

• Impaired host defense (three main types: severe neutropenia, cellular immunity, and humoral immunity).
• Low weight neonates and elderly.
• Consequence of certain diseases (in addition to direct impairment of immune function) e.g., Cystic Fibrosis, COPD.
• Cytotoxic and immunosuppressive treatments e.g., glucocorticosteroids.
• Radiotherapy (bone marrow transplant or cancer patients).
• Multiple antibiotic-resistant strains of bacteria.
• Long-term use of broad-spectrum antibiotics.
• Host organ/system damage.
• Implantation of foreign materials.

Types of Infection

• Acute infection: Immune response targets pathogen while limiting tissue damage.
  • Range of pathogen strategies to optimize production.
  • Recovery: Return to homeostasis after successful pathogen clearance.
• Chronic infection: Pathogen persistence through successful immune evasion and/or mechanisms to limit tissue damage.

Strategies for Chronic Viral Infection

• Acute infection results in the expression of antigens associated with the production of new viruses.
• When a virus persists via continuous productive replication, the virus has the opportunity to evolve under immune pressure and produce viral variants capable of immune escape and persistence.
• Viruses that persist via latency and reactivation generate antigens associated with productive replication, associated with latent infection, and in extreme cases, no antigens resulting in immunological silence.

Cystic Fibrosis (CF)

• Autosomal recessive disorder of the secretory glands including those that make mucus and sweat.
• Multisystem disorder characterized by genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7, which encrypts a protein essential for the regulation of transmembrane chloride reabsorption.
• Affects: lungs (mostly), pancreas, liver, intestines, sinuses, sex organs.
• Epidemiology:
  • Life-limiting.
  • Occurs in approximately 1:3500 live births.
  • One in every 25 babies in Australia carries the cystic fibrosis gene.
  • Each year 70 newborns are affected by this disease in Australia.
  • 1:1600 to 1:2500 of infants with Caucasian background are affected.

Pathophysiology of CF

• Reduced Cl^- ion transport at the epithelial surface.
• Production of thick, sticky mucus due to reduced water content.
• Elevated salt in sweat.
• Mucus obstruction of the exocrine glands.
• Distal airway obstruction and frequent lung infections.
• Intestinal blockage.
• Filled sinuses.
• Fibrotic pancreas.
• Respiratory failure is the major cause of death for patients with CF.

Pathogenesis of Cystic Fibrosis

• In the CF lung, reduced CFTR protein causes the mucus secreted by the goblet cells of the pulmonary epithelium to become thicker and impairs the mucociliary clearance responsible for the elimination of pathogens.
• This favors infections and leads to chronic inflammation and bronchiectasis.
• The osmotic imbalance causes the airway surface liquid (ASL) in CF to be lower than in a healthy individual, impairing pulmonary function.

Cystic Fibrosis Transmembrane Regulator (CFTR)

• Genetically transmitted disease caused by dysfunctional chloride ion transport.
• Gene located on the 7th chromosome.
• 189kb in length, 27 exons & 26 introns.
• Two copies (i.e., recessive) of the disease alleles are needed to inherit the disease.
• One copy of the defective gene results in a healthy carrier.

CFTR Dysfunction

• Mutations can have a range of effects on CFTR function and/or quantity.
• More than 1600 specific mutations are recognized.
• Classified based on effect on CFTR.

Pathophysiology of Cystic Fibrosis (cont.)

• NaCl levels are elevated in the sweat of patients with CF.
• One of the common causes of morbidity and mortality in CF patients is mucus accumulation and obstruction of the exocrine glands.
• Obstruction occurs in the distal airways of the lung and submucosal glands.
• Mucosal obstruction causes the ducts to dilate, which results in the coating of lung surfaces by thick, viscous, neutrophil-dominated debris.
• These secretions initiate a cascade of events that lead to inflammation and formation of scar tissue in the lungs.
• Respiratory failure is the major cause of death for patients with CF.

Regulation of Water Content in Mucus

• Regulation of water content is critical for mucus function.
• CF mucus is sticky because it contains less water due to abnormal epithelial salt and water transport.

Dysfunctional Immune Responses in CF Patients

1. CFTR deficiency in neutrophils and macrophages is associated with the inability to effectively kill bacteria.
2. Inadequate Th1 activation of macrophages by CFTR-deficient helper T cells.
3. CFTR-deficient mast cells overproduce the pro-inflammatory cytokine IL-6.
4. CFTR-deficient epithelial cells produce decreased levels of glutathione and increased amounts of pro-inflammatory prostaglandins.

Advance of Lung Disease in CF Patients

• Pulmonary exacerbations of respiratory symptoms (e.g., change in sputum, increased haemoptysis / cough / dyspnoea / respiratory rate / blood neutrophil count, decrease in Forced Vital Capacity (FVC) by 10%) are very common in patents with CF.
• The CFTR defect leads to mucus abnormalities, airway inflammation, and infection, which in turn lead to early lung disease.
• Pulmonary exacerbations can be caused by viral infections (e.g., respiratory syncytial virus) or bacterial infections (e.g., S. aureus, P. aeruginosa, S. maltophilia, H. influenzae, and B. cepacia).
• The last four bacteria are often considered as opportunistic pathogens.
• Polymicrobial infections are the norm in CF respiratory infections.

Prevalence of Respiratory Pathogens in CF Patients by Age (2017)

• P. aeruginosa is a common pathogen across all age groups.
• S. aureus and MRSA are more prevalent in younger patients.
• H. influenzae, Achromobacter, B. cepacia complex, and S. maltophilia show varying prevalence with age.

Host & Microbial Factors Contributing to CF Progression

• Acquisition of new organisms or a changed bacterial density of colonizing flora that thrive in altered mucus, leading to the formation of bacterial microenvironments (biofilms).
• Clonal expansion of existing bacterial strains also contributes to the disease progression.
• Damage to the epithelial surfaces leads to increased attachment of, and eventual replacement by, Pseudomonas aeruginosa.
• Increases in IL-8, IL-6, IL-1β, TNFɑ, leukotriene B4, and neutrophil elastase have been documented during pulmonary disease worsening in CF patients.
• Early infections with P. aeruginosa are sensitive to antibiotic treatments (e.g., β-lactam antibiotics and aminoglycosides). Antibiotic resistance appears more often when CF patients age.

Adaption of Inhaled Bacteria to the CF Airway

• P. aeruginosa aggregates and forms a biofilm.
• Increase alginate production, release CpG DNA (TLR9 activation), and express virulence factors such as pyocyanin that kills resident bacteria.
• Bacterial LPS activates TLR4 and production of IL-8 leading to neutrophilic inflammation.
• P. aeruginosa inhibits recycling of CFTR.

Treatment of P. aeruginosa Infection in CF Patients

• The presence of P. aeruginosa on sputum culture is a predictor of morbidity and mortality in CF.
• Antibiotics available include extended-spectrum penicillins, select cephalosporins, select carbapenems, aztreonam, quinolones, colistimethate, and aminoglycosides.
• After years of drug exposure, older CF patients will exhibit multidrug-resistant P. aeruginosa.
• At this point, sputum cultures can be sent to specialized laboratories that will test combinations of antibiotics and report out any synergy results.

Chronic Obstructive Pulmonary Disease (COPD)

• COPD is a lung disease characterized by lung airflow limitation and can be from exposure to harmful substances causing emphysema and chronic bronchitis.
• COPD increases with age and is currently the third most common cause of morbidity and mortality worldwide. In 2015, the prevalence of COPD was 174 million, and there were approximately 3.2 million deaths due to COPD worldwide.
• COPD is caused by prolonged exposure to harmful particles or gases, and cigarette smoking is the most common cause of COPD worldwide. Other causes may include second-hand smoke, environmental and occupational exposures, and alpha-1 antitrypsin deficiency (AATD).

Risk Factors for Development & Progression of COPD

• Damage from COPD is usually permanent and irreversible.
• Risk factors include:
  • Smoking, active or passive exposure.
  • Air pollution, indoor or outdoor.
  • Occupational exposure to dust and chemicals (e.g., vapors and fumes).
  • Repeated lower respiratory infection.
  • Asthma (?).
  • Genetic factors (such as α-1 antitrypsin deficiency).

Pathological Changes in the Small Airways in COPD

• Small airways (<2 mm) at the level of the terminal and transitional respiratory bronchioles.
• In healthy airways, the epithelium is predominantly composed of ciliated, club, and basal cells, and cells intermediate between differentiated cell types.
• In tobacco smokers, inhalational exposures reprogram the epithelium, stimulating basal cell hyperplasia and differentiation into squamous cells and mucus-producing goblet cells.

Pathophysiologic Features of COPD

• Airflow limitation.
• Lung volume increase - hyperinflation.
• Ventilation/perfusion (V/Q) mismatch because of progressive airflow limitation and destruction of the pulmonary capillary bed.
• Arterial hypoxemia & hypercarbia.
• Often intrinsic airway inflammation (usually neutrophils, whereas they are usually eosinophils in asthma).
• Smoke/air pollution and α1-antitrypsin deficiency lead to chronic bronchitis and emphysema.
• Chronic bronchitis involves bronchial edema, mucus hypersecretion, chronic cough, and bronchospasm.
• Emphysema involves the breakdown of elastin in lung tissues, alveolar septa destruction, and airway instability.
• The combination of these factors leads to airway destruction, air trapping, dyspnea, frequent infections, abnormal ventilation-perfusion ratio, hypoxemia, hyperventilation, and cor pulmonale.

Pathological Changes Found in the Emphysema Lungs

• Centriacinar:
  • Focal destruction limited to the respiratory bronchioles and the central portions of the acinus.
  • Associated with cigarette smoking.
  • Most severe in the upper lobes.
• Panacinar:
  • Involves the entire alveolus distal to the terminal bronchiole.
  • Develops in patients with homozygous alpha1-antitrypsin (AAT) deficiency.
  • Most severe in the lower lung zones.
• Distal acinar (also called paraseptal):
  • Least common form, involves distal airway structures, alveolar ducts, and sacs.
  • Localized to fibrous septa or to the pleura and leads to the formation of bullae (can result in pneumothorax).

Pathological Changes Found in the Lung of COPD Patients

• Inflammation and swelling of the lining of the airways resulting in narrowing and obstruction of the airways.
• The inflammation stimulates the production of mucus (sputum), causing further obstruction of the airways.
• Congestion of the bronchial mucosa and a prominent increase in the number and size of the bronchial mucus glands.
• Airway atrophy, focal squamous metaplasia, ciliary abnormalities, variable amounts of airway smooth muscle hyperplasia.
• Respiratory bronchioles display a mononuclear inflammatory process, lumen occlusion by mucous plugging, goblet cell metaplasia, smooth muscle hyperplasia, and distortion due to fibrosis.
• Obstruction of the airways, especially with mucus, increases the likelihood of bacterial lung infections.

Chronic Inflammation in the Lung of COPD Patients

• Epithelial/endothelial cells undergo recurring damage.
• Fibrosis predominantly occurs around small airways (small airways disease).
• Lung macrophages produce chemokines that attract neutrophils, monocytes, and T cells, and matrix metallopeptidase (e.g., MMP9 and MMP12) that contribute to lung damage.
• CD4+ TH1 cells and CD8+ Tc1 cells expressing IFN-γ correlate with airflow obstruction and activate immune cells.
• Neutrophils are associated with disease severity and produce proteolytic enzymes (e.g., elastase) that damage lung tissue.

Immune Responses in COPD Lung

• CD4+ Th1 cells expressing IFN-$\gamma$ correlate with the degree of airflow obstruction. These cells regulate the function of other immune cells.
• Numbers of neutrophils are associated with COPD disease severity and related to increased production of chemokines (CXCL1 and CXCL8). Neutrophils produce proteolytic enzymes (e.g., elastase) that damage lung tissue.
• Large numbers of lung macrophages produce chemokines that attract neutrophils, monocytes, and T cells, and matrix metallopeptidase (e.g., MMP9 and MMP12) also contribute to lung destruction.
• Although smoking leads to the expansion of the dendritic cell population in the airways and alveolar walls of smokers, the precise role of these cells in COPD pathogenesis is unclear.
• Epithelial/endothelial cells undergo apoptosis, likely induced by infiltrated CD8+ T cells.
• Fibrosis predominantly occurs around small airways, and sub-epithelial fibrosis is not apparent.

Acute and Chronic Disease Mechanisms in COPD

• Acute Cycle:
  • Impaired lung defense leading to infections and acute inflammation.
  • Recurrent inflammation causes tissue damage and further impaired defense.
• Chronic Cycle:
  • Chronic microbial colonization.
  • Chronic persistent inflammation.
  • Progressive loss of lung function.

Pathogens That May Cause Acute Exacerbation of COPD

• Both infectious and non-infectious stimuli can induce an acute COPD exacerbation.
  • 20% non-infectious
  • 80% infectious
• Causes include bacterial infection, atypical bacterial infection, viral infection, environmental factors, and non-compliance with treatment.
• Heightened adverse effects of COVID-19 in individuals with COPD have been observed, including more frequent treatment in hospital, readmissions to hospital, admissions to intensive care units, necessity for mechanical ventilation, cardiovascular events, and higher mortality than among patients without COVID-19.
• The ACE2 receptor that binds SARS-CoV-2 has been shown to be increased in the small airways of patients with COPD.

Mechanisms of Bacterial-Induced COPD Exacerbation

• Pathogen factors: Intracellular persistence, biofilm, phase variation of surface molecules, molecular mimicry, mucin binding, and mucoid phenotype.
• Host factors: Inadequate innate immunity, ineffective adaptive immunity.
• Immunosuppressants: e.g., glucocorticosteroids.