Pulmonary disease · Primary functions RS •Brings O2 and eliminates CO2 •Keeps pH of an organism •Protection from inhaled pathogens and irritating substances •Vocalization

Pulmonary diseaseRoman Gardlik

www.imbm.sk

[email protected]

Outline

• Basic terminology and physiology

• Restrictive pulmonary diseases

• Obstructive pulmonary diseases

• Pneumonia

• Respiratory insufficiency

Primary functions RS

• Brings O2 and eliminates CO2

• Keeps pH of an organism

• Protection from inhaled pathogens and irritatingsubstances

• Vocalization

• 4 steps of respiration:1. Ventilation – exchange of gases between lungs and background2. Outside breathing – exchange of gases between alveoli and blood 3. Transport – towards or away from tissues (by cardiovascular system)4. Inner breathing – change of gases between blood and tissue

Dead spacethe space or volume of those parts of respiratory systemwhere is no exchange of gases between air and blood(Vd=150 ml)• Upper airways- nose, pharynx,

larynx

• Trachea

• Primary bronchi

• Secundary bronchi

• Tertialy bronchi

• Bronchioli

• Terminal bronchioli

• Respiratory bronchioli

• Ductuli alveolares

• Sacculi alveolares

• Alveoli pulmonis

• TOTAL (PHYSIOLOGICAL) DEAD SPACE

1. ANATOMIC DEAD SPACE

- The respiratory passageways conducting to and fromalveoli

2. ALVEOLAL DEAD SPACE

- The volume of non-functional alveoli

- Together anatomic and alveolal dead space = 150 mL

• Functions od conducting zone

1. Warming and humidificarion of the inspired air

2. Filtration (particles > 1 µm)

3. Cleaning (mucus)

CONDUCTING ZONE

No gas changes

RESPIRATORY ZONE

Exchange of respiratory gases

Transient zone

The Lungs and Thoracic Cavity

On external view, the right lung is dividedinto three lobes, and the left lung isdivided into two lobes.

Apex

Superior

lobe

Middle

lobe

Inferior

lobe

Cardiac notchBase

Superior

lobe

Inferior

lobe

Alveoli

Bronchiole

Secondary

bronchus

The primary bronchus

divides 22 more times,terminating in a cluster

of alveoli.

The trachea

branches into two primary

bronchi.

Left primary

bronchus

Trachea

Cartilage

ring

Larynx

Branching of airways createsabout 80 million bronchioles.

The Bronchi and Alveoli

Epithelial cells lining the airways and submucosalglands secrete saline and mucus.

Cilia move the mucus layer toward the pharynx, removing trappedpathogens and particulate matter.

Dust particle

Submucosalgland

Movement of mucus

Mucus layer

Lumen of airway

Ciliatedepithelium

Mucus layer trapsinhaled particles.

Watery saline layerallows cilia to

push mucustoward pharynx.

Cilia

Goblet cellsecretes mucus.

Nucleus ofcolumnar

epithelial cell

Basementmembrane

Alveocapillary membrane

• Endothelial cell layer

• Endothelial basement membrane

• Alveolar basement membrane

• Alveolar cell layer

Pulmonary surfactant

- is a surface-active lipoprotein complex(phospholipoprotein) formed by type II alveolar cells

- reduces surface tension

- increases the lung compliance

(is the ability of lungs and thorax to

expand)

- stabilizes the system of lung alveoli

- prevent the collapse

- prevents lung to dry out

- enables the conduction of air

Restrictive PD

• Restriction of lung expansion (hard to get air in)

• Decreased lung volume

• Increased work/breathing

• Inadequate oxygenation

• Extrapulmonary

• Pleural

• Parenchymal disorders of lung

Presentation

• Difficulty to fully expand the lungs with air

• Shortness of breath

• Dry cough

Causes

• Intrinsic• Pneumoconiosis – asbestosis, silicosis

• Radiation fibrosis in cancer treatment

• Drugs – amiodarone, bleomycin, methotrexate

• Rheumatoid arthritis

• Hypersensitivity pneumonitis – allergic reaction do inhaled particles

• ARDS in critical illnes or injury

• Infant respiratory distress syndrome – lack of surfactant

• Tuberculosis

Causes

• Idiopathic• Idiopathic pulmonary fibrosis

• Idiopathic interstitial pneumonia

• Sarcoidosis

• Eosinophilic pneumonia

• Pulmonary Langerhans’ cell histiocytosis

• …

Causes

• Extrinsic• Nonmuscular diseases of upper thorax – kyphosis,

pectus carinatum, pectus excavatum

• Diseases restricting lower thoracic/abdominal volume –obesity, diaphragmatic hernia, ascites

• Neuromuscular diseases

• Pleural thickening

Atelectasis

-Post-surgical-Tuberculosis-Surfactant-Pneumothorax

Causes - PAINTCauses Examples Diagnosis PFT Findings

Pleural

Trapped lung, pleural scarring, large pleural effusions, chronic empyema, asbestosis

Radiography, CT scanning, pleural manometry, pleural biopsy

Low RVa, low TLC, low FVC

Alveolar Edema, hemorrhageRadiography, CT scanning, physical examination

Increased DLCOb in hemorrhage (Intrapulmonary hemoglobin absorbs the carbon monoxide, thus increasing the DLCO reading.)

InterstitialInterstitial lung disease including IPFc, NSIPd, COPe

Radiography, CT scanning, physical examination, echo often shows pulmonary hypertension

Low RV, low FVC, low TLC, decreased DLCO, poor lung compliance

NeuromuscularMyasthenia gravis, ALSf, myopathy

Physical examination, EMGsg, serology

Low RV, low TLC, low NIFh, low MMVi

Thoracic/extrathoracic

Obesity, kyphoscoliosis, ascites

Physical examinationLow ERVj and FRC in obesity, low VCk, TLC, FRCl in kyphoscoliosis

Interstitial lung disease

Idiopathic pulmonary fibrosis

• Chronic scarring lung

Disease - fibrosis

• Shortness of breath

+ dry cough

• Tiredness, nail clubbing

(vasodilation, change in

Vascular connective tissue)

-Unknown cause

Sarcoidosis

• Abnormal accumulation of inflammatory cells thatform granulomas

• Lungs (90%), skin, lymph nodes, (eyes, liver, heart)

• Wheezing, cough, shortness

of breath, pain, large lymph nodes

-Unknown cause – genes, infection,

autoimmunity

Diagnosis

• Pulmonary function test

• Decrease in:• Forced vital capacity FVC

• (Forced expiratory volume 1 FEV1)

• FEV1/FVC ratio is higher than 0.8 (as opposed to obstructive lung disease – less than 0.7)

• Total lung capacity less than 80% of expected value

Obstructive PD

• Airway obstruction

• Difficulty exhaling

Diagnosis

• Pulmonary function test

• Decrease in:• FEV1

• FEV1/FVC ratio is less than 0.7

• FEV1 is less than 70% of expected

Types

• Chronic obstructive pulmonary disease• Emphysema

• Chronic bronchitis

• Asthma

• Cystic fibrosis

COPD

• Chronic bronchitis

• Emphysema

• 3rd leading cause of death worldwide

• 5th in terms of disease burden

• Cumulated lifetime risk 25%

• Tobacco smoke

Pathology

• Main pathological features• Obstructive bronchiolitis• Emphysema• Mucus hypersecretion

• Early feature – small airway loss

• Leads to initial progression of airway obstruction

• Structural changes in small pulmonary arterioles as a result of inflammation or hypoxic vasoconstriction• Intimal thickening• Smooth muscle proliferation

Pathogenesis

• Several distinct and overlapping phenotypes

• Several underlying mechanisms

• Not all smokers develop COPD (30%) –susceptibility mechanisms• Genetic

• Epigenetic

• Environmental

Genetics

• COPD cluster in families

• Significant heritability accounting for 30% of variation in COPD risk

• Genetic determinants that interact with smoking

• Α1-antitrypsin deficiency – heterozygosity

• Cutis laxa – mutation in elastin gene

• Ciliary abnormalities

• GWAS studies – several susceptibility loci

Chronic inflammation

• Predominantly peripheral airways and parenchyma

• Increases with the disease progress

• Air irritants activate TLR – innate immune response• Neutrophils• Macrophages• Activation of epithelial cells• Mucus secretion

• Activation of adaptive immunity – later• T lymphocytes (CD8+ Tc, CD4+ Th1, CD4+ Th17) • B lymphocytes• Dendritic cells

Chronic inflammation

• Pro-inflammatory mediators• Activation of NFkB and MAPK

• Cytokines, chemokines, proteases (elastase, MMPs)

• Inflammation persists in COPD after smoking cessation – maintained by some autonomousmechanisms:

Chronic inflammation –autonomous mechanisms• Lower respiratory tract is often colonized by:

• Heamophilus influenzae

• Streptococcus pneumoniea

• Defect in the uptake of bacteria and apoptoticinflammatory cells by macrophages

• Autoimmune mechanisms?

Defective phagocytosis in COPD

Accelerated aging

• Accelerated aging of parenchyma?

• Defective anti-aging mechanisms (decreasedexpression of sirtuin) leading to telomereshortening and cellular senescence

• Also found in endothelial progenitor cells in COPD • less effective vascular repair

• higher risk of cardiovascular disease

• Defective autophagy• Accumulation of damaged proteins and organelles

Oxidative stress

• Key driving mechanism

• Mitochondria are fragmented in epithelial cells –uptake (mitophagy) – mitochondrial deficiency and cell death

Pathophysiology

• Obstruction in small airways in the periphery

• Reduction in FEV1 and FEV1/FVC ratio

• Fixed narrowing of airways

• Loss of alveolar attachments (emphysema)

• Premature closure of small airways upon expiration

• Air trapping

• Lung hyperinflation – increased total lung capacity

• Reduced alveolar surface area

• Impaired gas exchange and hypoxia

Exacerbations

• Triggered by respiratory viral infections (60%)

• Frequent exacerbations – irrespective of diseaseseverity• Worse prognosis

• More hospital admissions

• Faster disease progression

Chronic bronchitis vs emphysema

Presentation

GOLD

• Global Initiative for Chronic Obstructive LungDisease

• Airflow limitation defined by FEV1/FVC < 0.7• GOLD1: FEV1 > 80% mild

• GOLD2: FEV1 79% - 50% moderate

• GOLD3: FEV1 49% - 30% severe

• GOLD4: FEV < 30% very severe

Management

Osmosis

• https://www.youtube.com/watch?v=Y29bTzKK_P8

• https://www.youtube.com/watch?v=TEuSV_7gWA8

Asthma

• Most common inflammatory disease of the lungs

• Heterogenous disease characterized by:• Chronic airway inflammation

• Variable remodelling

• Results in range of: • Clinical presentations

• Treatment responses

History

• Recognized in ancient Egypt

• Officially named as a specific respiratory problem by Hippokrates 450 BC

• 200 BC believed to be partly related to emotions

• 12th century Jewish physician Maimonides emphasizesimportance of climate and clean air

• 1873 first paper in modern medicine explaining pathophysiology

• 1880 treatment with pilocarpin

• 1905 treatment with adrenaline

• 1930 – 1950 psychosomatic illness treated with psychoanalysis

• 1950 oral corticosteroids

• 1960 inhaled corticosteroids

Epidemiology

• Low-to-high income countries gradient

• Rural-urban gradient

• Latitudinal gradient

• Epidemic in late 70s consistent with other immune-mediated diseases (T1D, IBD, MS)• Changes in maternal diet in pregnancy• Gut and airway microbiota• Prematurity• Paracetamol during pregnancy

Epidemiology

• More common in boys in early childhood

• In puberty boys experience remission and girlsacquire it more often

• Key role of hormones

Adult-onset asthma

• Most cases begin in childhood, but can emergelater in life

• In absence of allergy

• Can be accompanied by intolerance to NSAIDs, rhinosinusitis and nasal polyps

• New asthma in adults tends to be more severe thanasthma that develops in childhood

Features

• Respiratory symptoms vary in time and intesity:• Wheeze

• Shortness of breath

• Chest tightness

• Cough

• Variable expiratory airflow limitation

• Airway hyper-responsiveness to stimuli (exercise, irritants)

• Origin and severity are driven by strong genetic and environmental factors

Pathophysiology

• Airway inflammation

• Airway remodelling

Airway inflammation

• Th2-type inflammation found in 80% of childrenand majority of adults

• Eosinophils, mast cells, basophils, neutrophils, monocytes and macrophages

• Cellular activation and release of mediators• Mast cell degranulation

• Eosinophil vacuolation

• T-cells control inflammatory cell profile

• Pro-allergic cytokines

Airway inflammation

• Allergen sensitisation• Processing of allergen

• MHC II presentation to naive T-cells

• Th2 type

• Pro-allergic cytokines IL3, IL4, IL5, IL9, IL13

• IgE, mast cell, eosinophil response

Airway inflammation

• Further exposure leads to mast cell driven earlytype bronchoconstrictor response• Lasts for 5-90 minutes• IgE dependent release of histamine, PGD2, LTC4

• Late phase response• Evolves over 3-12 hours• Infiltration and activation of eosinophils, Th2 cytokine

release from mast cells and T cells

• Not related to chronic persistent inflammationfound in most cases

Airway remodelling

• Airway wall thickening in proportion to severityand duration

• Increase in airway smooth muscle

• Thickening of subepithelial lamina – deposition of collagens

• Matrix deposition throughout the wall

• Angiogenesis

• Neuronal proliferation

• Epithelial metaplasia

Airway remodelling

• Enhanced growth factor production• Consequence of epithelial injury and delayed repair

• Resembles chronic wound remodelling

• TGFb – drives fibrosis and smooth muscle proliferation

• Proliferation of fibroblasts – mucosal fibrosis

• Muscle hyperplasia

Classification

• By symptom severity

• By disease control achieved• 5 groups according to controller drugs

• Subphenotypes

SeveritySymptom frequency

Night-timesymptoms

%FEV1 of predicted

FEV1

variabilitySABA use

Intermittent ≤2/week ≤2/month ≥80% <20%≤2 days/week

Mildpersistent

>2/week 3–4/month ≥80% 20–30%>2 days/week

Moderate persistent

Daily >1/week 60–80% >30% daily

Severe persistent

ContinuouslyFrequent (7/week)

<60% >30% ≥twice/day

Risk factors

Risk factors

Triggers

Diagnosis

• Symptoms

• Documented airflow limitation and/or hyper-responsiveness

• Airway inflammation – eosinophils in sputum

• FEV1

• FEV1/FVC ratio

• PEF – peak expiratory flow

• Reversibility of lung function with SABA

Treatment

Co-morbidities

• Multi-organ allergies• Allergic rhinitis

• Conjunctivitis

• Atopic dermatitis

• Food allergy

• Obesity

• GERD

• Psychiatric conditions

Osmosis

• https://www.youtube.com/watch?v=fEKc37vrQ_I

Pneumonia

• Inflammation of the lungs affecting alveoli

• Consolidation of the affected part - liquid instead of air

• Filling of the alveoli with exudate, inflammatorycells and fibrin

Signs and symptoms

Symptoms frequency[19]

Symptom Frequency

Cough 79–91%

Fatigue 90%

Fever 71–75%

Shortness of breath 67–75%

Sputum 60–65%

Chest pain 39–49%

Cause

• Bacteria• S. pneumoniae (50%)

• H. influenzae (20%)

• Chlamydophila pneumoniae (13%)

• Mycoplasma pneumoniae (3%)

• S. aureus

• M. catarrhalis

• Legionella pneumophila

• Gram negative bacteria

• ...

Cause

• Viruses (30%)• Rhinoviruses• Coronaviruses• Influenza• RSV• Adenovirus• Parainfluenza

• Fungi (immunocompromised)• Histoplasma capsilatum• Cryptococcus neoformans• Pneumocystis

Cause

• Parasites• Toxoplasma gondii

• Strongyloides stercoralis

• Ascaris lumbricoides

• Plasmodium malariae

• Non-infectious• Idiopathic interstitial pneumonia

Pathophysiology

• Extrinsic factors – exposure to causative agent, pulmonary irritants, direct pulmonary injury

• Intrinsic factors – related to host• Loss of protective upper airway mechanisms allow

aspiration from upper airways to lungs

• Due to intoxication, metabolic states, neurologic causes, intubation

• Bacteria from upper airways or hematogenous spread reach lung parenchyma

• Combination of factors that determine the progress:

Pathophysiology

• 1. Virulence of the microorganism, 2. status of local defenses, 3. overall health of the patient

• Most cases – breakdown in body’s natural defenses

• Germs invade and multiply

• Rapid accumulation of neutrophils in alveoli

• Phagocytosis and ROS, AMPs, degradative enzymes

• Alveoli filled with microorganisms and leukocytes

• Cough that produces thick blood-tinged or yellowish-greenish sputum with pus

Risk factors

• Children younger 2 years

• Older than 65

• Hospitalization

• Chronic disease (lung, periodontitis)

• Smoking

• Weakened or suppressed immune system

• Influenza

• Intoxication or CNS impairment

Diagnosis

• Physical exam• Auscultation

• Percussion

• Chest X-ray

• CT

• Ultrasound

• Microbiology - blood, sputum

• Bronchoscopy

Severity asessment

• PSI/PORT• Pneumonia severity index / Patient Outcomes Research

Team Score

• APACHE• Acute physiology and chronic health evaluation

• CURB-65 CURB-65

Symptom Points

Confusion 1

Urea>7 mmol/l 1

Respiratory rate>30 1

SBP<90mmHg, DBP<60mmHg

1

Age>=65 1

Treatment

• Antibiotics• Based on sensitivity

• Cough medicine

• Fever reducers and pain relievers

• Intravenous fluid

• Oxygen

• Positioning

• Ventilation

• Systemic support

Complications

• Bacteremia and spreading of infection

• Mechanical ventilation

• Fluid accumulation around lungs - pleural effusion

• Lung abscess

Classification

• Where or how it was acquired• Community-acquired• Aspiration• Healthcare-associated• Hospital-acquired• Ventilator-associated

• Area of lung affected• Lobar (focal), multifocal (bronchopneumonia),

interstitial (focal diffuse)

• Organism

• Severity

Stages

• Congestion – hyperemia

• Red hepatization – consolidation, red cells, leukocytes, fibrin

• Grey hepatization – red cells disintegrate, persistence of neutrophils and fibrin

• Resolution

Respiratory insufficiency

• Respiratory failure

• Inadequate gas exchange by lungs

• Arterial O2 or CO2 or both cannot be kept at normal levels

• Normal PaO2 >80 mmHg (11 kPa)

• Normal PaCO2 <45 mmHg (6 kPa)

Respiratory insufficiency

• Type 1• Hypoxemia without hypercapnia

• Failure of oxygenation• Low ambient oxygen (high altitude)

• Ventilation-perfusion mismatch (pulmonary embolism)

• Diffusion problem (parenchymal disease – pneumonia, ARDS)

• Right-to-left shunt

Respiratory insufficiency

• Type 2• Hypoxemia with hypercapnia

• Inadequate alveolar ventilation• Increased airway resistance (COPD, asthma, suffocation)

• Reduced breathing effort (drugs, brain stem lesion)

• Decreased area for gas exchange (bronchitis)

• Neuromuscular disease

• Deformed or rigid chest (kyphoscoliosis, ankylosing spondylitis)

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