Cystic Fibrosis: Diagnosis and Treatment

Cystic Fibrosis Overview

• Median survival among CF individuals is under 30 years in Latin America, contrasting with over 45 years in the US.
• Disparities are due to lack of diagnostics and insufficient access to advanced treatment.
• State-of-the-art management can improve outcomes and mitigate health disparities.

Further Reading

• The discovery of CFTR genes have improved diagnosis, counseling, & preventative therapy.
• Microbiome in cystic fibrosis is an active area of research.
• New treatments targeting specific genetic mutations in CF exist.
• Focus on precision medicine is growing to address genetic diversity.
• Lung transplant referral guidelines for CF have been created due to the severe complications.
• Researchers are defining the disease-variants to understand disease progression.
• Healthcare improvements for cystic fibrosis provide lessons for other chronic diseases.
• Research is advancing to understand the origin of lung disease in relation to cystic fibrosis

Mucociliary Clearance and CFTR

• Normal periciliary fluid allows chloride and bicarbonate to be secreted across the respiratory surface through CFTR.
• In CF, there is failure of anion transport, leading to depletion of the periciliary layer.
• This results in cilia getting stuck and mucus accumulation.
• Bacterial infection results from this.

Pharmacology and CFTR

• Mutant CFTRs with ion transport defects can be modulated by potentiator molecules.
• Some CFTR mutations cause protein misfolding, leading to being broken down.
• Correction molecules can help improve protein folding and function.

Overview of COPD

• Distinguishing features include chronic cough, phlegm, and small airway disease
• COPD requires airflow obstruction which occurs with cigarette smoking or biomass fuels.
• Emphysema, chronic bronchitis, and small airway disease are common in COPD, as well as genetic factors, including lung development.
• COPD diagnosis involves domains of exposure, imaging, respiratory symptoms and physiology.
• COPD is the fourth leading cause of death in The US.
• Globally, an estimated 250 million with COPD.

Pathogenesis of COPD

• COPD can result from airway disease or emphysema.
• Small airways are narrowed through diverse mechanisms, including cell changes, mucus, and fibrosis; small airway destruction is a hallmark.
• The precise biological mechanisms aren't determined of leading to COPD.
• Emphysema pathogenesis is more clearly defined than small airway disease.
• There is pulmonary vascular destruction with small airway disease and emphysema.

Emphysema

• There are interrelated events of COPD development, beginning with chronic exposure to smoke.
• Inflammation leads to proteinases that damage the lung's extracellular matrix.
• Structural cell death and disordered reapir of elastin contribute to emphysema.
• Elastin is critical for lung integrity and extracellular matrix.

Elastase-Antielastase Hypothesis

• Elastase and antielastase determine lung destruction susceptibility.
• Alpha antitrypsin deficiency leads to proteinase inhibitor neutrophil elastase.
• This hypothesis remains important for emphysema development.
• Cigarette smoke exposure leads to immune and inflammatory infiltration in lung
• Epithelial cells and immune cells attract proteinase and chemokines.
• Oxidative stress is a key feature.

Cell Death in COPD

• Mitochondrial dysfunction worsens oxidative stress.
• Macrophage activation relates to oxidant-induced HDAC2 inactivation, resulting in transcription of MMPs and proinflammatory cytokines.
• CD8+ T cells release IP-10, leading to MMP-12 production.
• MMPs and serine proteinases degrade elastin, leading to lung destruction and chemokine feedback for neutrophils.
• Elastin degradation are primary mechanisms of emphysema.
• Autoimmune mechanisms can promote disease progression.

Cell Death And Impaired Repair

• Neutrophilia and bacterial infection can result from loss of cilia and impaired macrophage phagocytosis.
• Cigarette smoke causes structural cell death through various mechanisms.
• mTOR involvement suggests emphysema resembles premature lung aging and HHIP gene related to aging-related emphysema.
• Repair is limited, uptake of apoptotic cells is reduced, limiting repair.

Pathology

• Affects large airways, small airways (≤2 mm), and aleveoi are all impacted by cigarette smoking
• Large airway changes lead to cough and sputum, small airway changes to alveolar issues and impact physiology.

Large Airways

• Cigarette smoking can result in goblet cell hyperplasia and mucus gland, leading to chronic bronchitis.
• Goblet cells increase through the bronchial tree and bronchial disruption of the squamous cells increase cancer and mucociliary failure.
• Hyperreactivity and smooth muscle hypertrophy might lead to airflow obstruction.
• Neutrophil influx contributes to purulent sputum during infections.

Small Airways

• Most individuals increased resistance in airways ≤2 mm in diameter.
• Goblet cell metaplasia and smooth muscle hypertrophy can occur.
• Luminal narrowing caused by fibrosis, mucus, edema, and infiltration.
• Reduced surfactant can leads to airway narrowing or collapse.
• Destruction of elastic fibers can occur around alveolar entrances from the cells collecting along the tissues airway.
• Small airways drop out and a significant lung microvasculature.

Lung Perenchyma

• There is gas-exchanging air, destruction of the alveolar space, the respiratory and alveolar
• Macrophages increase and lymphocytes are increased in space
• Emphysema is divided into distinct types like centrilobular, paraseptal, and panlobular.
• Centrilobular: enlarged spaces connect with bronchioles more associated with smoking.
• Panlobular: spaces evenly are distrubuted through acinar observed in alpha 1 deficiency.
• Paraseptal: Distributed along the pleura

Pathophysiology

• Persistent expiratory flow reduction is persistent.
• There's increased lung capacity, hyperinflation, non-uniform distribution of ventilation, and ventilation-perfusion mismatching.

Airflow Obstruction

• Airflow obstruction is related by spirometry which include maximal force.
• FEV1 ratio of <0.7 is usually related to COPD
• Little to no improvement of dialators is observed

Hyperinflation

• Lung volume is assessed through routine testing
• Volume is often trapped
• Hyperinflaiton of breath to increase the volume so resistance decreases
• The diaphragm falls to a flatten positioning, hindering rib cage movement and impair inspiration to generate tidal breathing
• In the transpulmonary tension greater due to inspiration for muscle
• Further inflation instead chest wall must recoil

Hyperinflation

• There is considerable variability in the relationships between the FEV1 and other in COPD
• Partial pressure to to be normal to the air is decreased to be to be below 50%
• Elevation of the alveolar causes
• Concomitant and the heterogenous of the diseas

Risk Factors

• Cigarette Smoking
• Concluded to include chronic bronchitis-accelerated decline of FEV1.
• Increased risks of copd due to the increase prevalence

Air Way Responsiveness and COPD

• A increased broncho constriction
• The chronic asthmatic smokers are presented.

Infections

• Impacts adult
• There

Other Risk Factors

• Air pollution increased in Urban compared to rural, biomass
• Genetic Consideration deficiency, and many alleles a, AT. smoking cigerrette

Treatment

• Pharmocology
• Stable stage: two main to reduce and provide symptom relief on

Bronchodialators

• Improves symptoms by improving FEV1

Chronic Obstructive Pulmonary Disease Treatment and Management

• Broncodialators: for every patient
• Antibiotics: For data and pathegonical data, can use to increase long term use
• Long term mangament strategies and goals

Explore Cystic Fibrosis (CF), contrasting survival rates in Latin America and the US, emphasizing disparities due to lack of diagnostics and treatment access. Learn how advanced management improves outcomes and mitigates health disparities. Discover CFTR genes, microbiome research, targeted treatments, and lung transplant guidelines.