PHRM3550 Respiratory

Name the obstructive pulmonary diseases.

- asthma

- COPD

- CF

- TB

Name the restrictive pulmonary diseases.

- Pulmonary Fibrosis

- Pulmonary Hypertension

- Lung emergencies

Describe obstructive pulmonary disease.

- characterized by airway obstruction that is worse with expiration

- either more force is required to expire, emptying is slowed, or both

Asthma Attack Signs and Symptoms

- Signs: dyspnea (SOB)

- Symptoms: wheezing and cough

Characterizations of an Asthma Attack

- chest tightness

- bronchial hyper-responsiveness

- thick mucus deposition

Risk factors for asthma

- atopy (sensitive to IgE allergens)

- family history

- allergen exposure

Mechanism of asthma attack

airways react strongly to a certain substance, the muscles around them tighten causing airways to narrow and less air flow to lungs

What is the pathology of asthma?

- airway mucosa is thickened, swollen with fluid, and filled with inflammatory cells

- smooth muscle hypertrophied & contracted airway

- bronchial cells damaged

- stripped airway lumen --> airway hyperactive to triggers

What is the pathology in severe asthma?

1. secretory gland hyperplasia (grows larger & more active)

2. mucus hypersecretion (too much thick mucus)

3. mucus plugging of airways (blocks airways)

What happens when subepithelial myofibroblasts proliferate?

They produce increased interstitial collagen (scar tissue) leading to fixed airway obstruction (permanent blockage)

What is the fundamental problem in asthma?

increased reactivity of airways to stimuli (the airways are extra sensitive to everything)

Describe provocative factors.

things that can trigger or worsen asthma symptoms by making the airways tighten or overreact

What are some physiologic/pharmacologic provocative factors of asthma?

- histamine

- methacholine

- ATP

How is methacholine measured?

spirometer

What are some physiochemical agents (real-life triggers) that are provocative factors for asthma?

- exercise

- air pollutants like SO2 and NO2

- viral respiratory infections

- ingestants like propanolol and aspirin/NSAIDS

What are some allergens that are provocative factors for asthma?

- low MW chemicals (penicillins, isocyanates, anhydrides, chromate)

- complex organic molecules (animal danders, dust mites, enzymes, wood dusts)

Acute treatment of asthma

- elimination of causative agents

- drugs that reverse bronchospasms and airway inflammation

- immediate management: oxygen and inhaled bronchodilators

Describe COPD.

- progressive lung disease characterized by airflow limitation that is not reversible

- abnormal inflammatory response to harmful particles or gases

What is COPD primarily caused by (over 90%)?

cigarette smoke (active and second-hand)

Why does less air flow through airways in COPD?

- airways/air sacs lose elastic quality

- walls between air sacs are destroyed, become thick and inflamed

- airways make more mucus, clogging airways

Describe emphysema.

walls between many of the air sacs are damaged, causing them to lose their shape and become floppy

How does emphysema affect gas exchange?

- walls become destroyed --> fewer and larger air sacs

- less surface area, less gas exchange

Clinical signs of COPD Emphysema

- dyspnea on exertion (SOB)

- little coughing and very little sputum (mucus) produced

General Treatments for COPD Emphysema

- supplemental oxygen

- inhaled steroids

- inhaled bronchodilators

- antibiotics if infectious

- smoking cessation drugs

What is chronic bronchitis?

- hypersecretion of yellow-grey mucus

- defined by a history of chronic productive cough that continues for at least 3 months of the year for 2 consecutive years

What can chronic bronchitis develop from?

- a cold, sore throat or flu

- most common among smokers and workers exposed to air pollution

How does chronic obstructive bronchitis affect the airways?

- constantly irritates and inflames the lining

- leads to permanent narrowing of airways

What do asthma and COPD bronchitis have in common?

both cause swelling in airways that makes it difficult to breathe

How is asthma different from COPD bronchitis?

- asthma usually triggered by allergens or activity, bronchitis is usually result of smoking

- asthma can be acute and usually gets better, bronchitis is usually chronic and gets worse

Clinical signs of chronic bronchitis

- decreased tolerance and ability to exercise

- hypoxemia

- wheezing, SOB, cough

- cyanosis

What is Dyspnea?

- difficult or labored respiration (SOB)

- 5 grades/degrees of dyspnea

What is orthopnea?

type of dyspnea that occurs when lying down and is relieved by sitting upright

PND (paroxysmal nocturnal dyspnea)

respiratory distress that awakens the patient from sleep

What is the most common lethal genetic disease among Caucasians?

CF

What is CF characterized by?

- pancreatic insufficiency (mucus blocks digestive enzymes)

- chronic airway infections

- repeated pulmonary exacerbations (flare-ups)

Symptoms of CF

- thick mucus build-up

- bacterial infections that are unresponsive to standard antibiotics

- infections block airways and cause bloody cough

- frequent sinusitis, bronchitis, and pneumonia

What happens in a mutant CFTR channel?

does not move Cl ions causing sticky mucus to build up on the outside of the cell

What causes infections in CF?

failure of mucus to detach from ducts that slows mucociliary transport

What defenses does CFTR loss reduce the effectiveness of?

mucociliary transport and antimicrobial activity

What is bronchiectasis?

- localized irreversible dilation of part of a bronchial tree

- usually result of infection or other condition that prevents the airways from clearing mucus

Clinical signs of bronchiectasis

- cupful amounts of pus which are foul in odor

- recurrent lower respiratory tract infections

Signs and symptoms of TB

- cough lasting > 3 weeks

- chest pain, dyspnea

- coughing up blood

- lethargy

- weight loss/anorexia

- chills, fever, night sweats

- pus in sputum

How is TB spread through air?

- acquired from breathing in droplets generated during coughing, sneezing and talking by someone with active TB

What is the bacteria that causes TB?

mycobacterium tuberculosis

Latent TB

- bacteria lives in body without causing illness

- asymptomatic, cannot spread bacteria

- positive skin test

- may develop TB if no treatment for latent infection

Active TB

- active bacteria multiply in body

- individuals feel sick and have symptoms

- can spread bacteria

- positive skin and blood tests

- abnormal chest x-ray

- need treatment

What are the 5 lung emergencies?

- pneumonia

- acute respiratory failure

- aspiration

- acute respiratory distress syndrome

- COVID-19

What does IPF stand for and what is it?

- idiopathic pulmonary fibrosis

- fatal, incurable, chronic, and progressive lung disease

- end stage of interstitial lung diseases

What does pulmonary fibrosis (PF) look like in the imaging?

- distinct chronic, fibrosing (scarring), interstitial pneumonia

- thick, stiff scarring in the interstitial space

What is shown in PF histology (microscope view)?

- fibroblastic foci formation (clusters of scar-making cells)

- excessive deposition of ECM (build-up of extracellular matrix)

Signs and Symptoms of IPF

- SOB

- dry hacking cough

- rapid shallow breathing

- fatigue or malaise

- aching muscles and joints

- chest pain

- cyanosis

- gradual, unintended weight loss

- digital clubbing

What is an exclusion diagnosis?

there's not a single test to prove someone has the disease, so they diagnose by ruling out other possible options

What are used for exclusion diagnosis of IPF?

- Patient history

- chest x-ray (may look normal)

- high resolution computed tomography

- pulmonary function test

- arterial blood gas test

- TB skin test

- Lung biopsy (best way to diagnose)

What does High-Res Computed Tomography show?

shows scar tissue and degree of lung damage

What does arterial blood gas test do?

- measure oxygen and CO2 levels

- rules out infections

Tests/clinical factors for predicting disease progression in IPF.

- DLco

- 6MWT

- FVC

What is DLco ?

diffusing capacity of the lung for CO

6MWT (6-minute walk test) purpose relating to IPF

walk distance correlates with mortality

FVC (forced vital capacity) purpose relating to IPF

initial value correlates with mortality

change over time correlates with progression

What is pulmonary arterial hypertension?

- enlarged right ventricle & constricted pulmonary arteries

- rapidly progressive, fatal, and incurable condition

- characterized by hypertension in the lungs

What does pulmonary arterial hypertension lead to?

right-sided heart failure and premature death

Signs and symptoms of pulmonary arterial hypertension?

- dyspnea

- angina pectoris (chest pain)

- dizziness

- syncope (fainting)

- fatigue

- edema

- dry cough

- Raynaud's (chalky white or dusty blue fingers)

Methods of diagnosis for Pulmonary Arterial Hypertension?

- blood test

- chest x-ray

- doppler EKG

- 6MWT

- right heart catheterization (most reliable)

Pathophysiology of pulmonary arterial hypertension

- hypertrophy of smooth muscle (grow too much)

- endothelial dysfunction (lining can't relax)

- adventitial proliferation (outer layers grow too much)

- thrombosis and lesions (clots and scars)

What is Acute Respiratory Failure?

- life-threatening respiratory failure resulting from direct injury to the lungs, airways, or chest wall

- respiratory failure = inadequate gas exchange

Hypoxia vs Hypoxemia vs Hypercapmia

- hypoxia: reduced oxygen of cells in any tissues

- hypoxemia: reduced oxygen in arterial blood

- hypercapmia: too much CO2 in arterial blood

Treatment for hypercapnia

ventilator support/mechanical ventilation

Treatment for hypoxemia

- supplemental oxygen

- treat underlying cause

- respiratory stimulants

What is pulmonary edema?

- excess water in lungs

- emergency situation

Symptoms of pulmonary edema

dyspnea, increased work of breathing, excessive sweating, anxiety, hypoxemia, pale skin

Classic sign of pulmonary edema

pink frothy sputum

Most common cause of pulmonary edema

congestive heart failure

What is Aspiration?

- passage of solid particles into the lung

- can lead to bacterial pneumonia

Predisposing factors of aspiration

altered level of consciousness, seizure disorders, cerebrovascular accident and myasthenia gravis

When is aspiration severe?

large food particles

gastric fluid with pH <2.5

Clinical signs of aspiration

onset of choking, intractable cough

What causes initial development of ARDS (acute respiratory distress syndrome)?

- massive lung inflammatory response

- neutrophils overreact and release a lot of stuff that shouldn't be

Timeline of ARDS

- lungs fill with fluid and collapse

- then forms a thick sticky coating inside air sacs (hyaline membranes)

- finally leads to scarring that makes long-term damage

What is a hyaline membrane?

composed of proteins and dead cells that line the alveoli making gas exchange difficult or impossible

ARDS/ALI treatment

- mechanical ventilation

- prone positioning

- sedation to decrease O2 consumption

- neuromuscular blockers

- drugs to increase cardiac output and manage fluids

SARS CoV2

- enveloped, ssRNA virus

- possesses club-like spikes and an unusually large RNA genome

- genome encodes 4 essential structural proteins

SARS CoV 2 genome encodes for

- Spike protein (S)

- Nucleocapsid protein (N)

- Membrane protein (M)

- Envelope protein (E)

What are the primary reasons for death in COVID19 patients?

- respiratory distress

- infection

- pneumonia

What are the two FDA approved treatments for Covid-19?

- Remdesivir (hospital/IV use)

- Paxlovid (outpatient/oral use)

Remdesivir

- developed and tested to treat ebola

- in vitro antiviral activity against SARS CoV2

- outcompetes proofreading ability of exonuclease

Paxlovid (Nirmatrelvir and Ritonavir)

- Nirmatrelvir: main protease inhibitor

- Ritonavir: anti-HIV-1 protease and strong CYP3A inhibitor