Respirology

Burdick Notes

TUTORIAL
JAMES FEDERLINE
Session Date: September 23, 2011

Global Objective
Upon completion of this case, students should be able to describe the mechanism of hypoxia in alveolar inflammation.

Case Overview
James, a 47-year-old gentleman with a history of chronic alcoholism and poor eating habits, goes to his physician's office with a complaint of chest
pain. He smokes two packs of cigarettes daily. He has not been feeling well for over one week due to an upper respiratory infection. Two days ago he
developed a fever, chills and a sharp pain over his right chest that is worse when he breathes in. James had a dry cough initially, but today he has
coughed up rusty sputum with some blood in it. Although James is not normally short of breath, he has had difficulty climbing the stairs to the office
because of breathlessness.
On examination, he is in some distress with a respiratory rate of 32 and shallow breathing. Although he does not look cyanosed, his oxygen saturation
is 84% which increases to 93% when administered oxygen through nasal cannulae at 4 liters per min. His temperature is 39.2C by mouth. On chest
examination, he cannot take a deep breath but a rub is heard at the lower base of the right lung. He is dull to percussion over this area and breath
sounds are heard. His pulse is 115 bpm and regular. Blood pressure is 130/80. The remainder of the examination is normal, and no swelling or
tenderness of his legs is noticed.
Microscopic sputum analysis reveals large numbers of a single species of bacteria, red blood cells, epithelial cells neutrophils and macrophages.
Chest x-ray confirms the presence of lower lobe opacity, suggesting consolidation.

Biological Points
o
o
o
o
o
o
o
o

47-year-old male
Chronic alcoholism
Poor eating habits
Complaint of chest pain
Smokes 2 packs/day
+1 week, feels ill due to upper respiratory infection
Fever (2 days), chills, sharp pain over his right chestworse
when he breathes in
Dry cough initially, now rust sputum with blood

o
o
o
o
o
o
o

Breathlessness (difficulty climbing the stairs)

Respiratory rate: 32
O2 saturation: 84%, increases to 93% when given O2 at 4 L/min
Temperature: 39.2C (oral)
Pulse: 115 ppm, regular
BP: 130/80
Normal exam, no swelling or tenderness of legs

Objectives
1.

Immunology of the lungs & response of lungs to infection

a.
Cell types
b.
Defense mechanism
c.
What is inflammation?

2.

Mechanism behind hypoxia in lung inflammation

a.
How to reverse hypoxia (treatment)

3.

Clinical features of upper respiratory infection

a.
Risk factors
b.
Understand the signs (why there was a rub)
c.
Tests for Dx
d.
Pathophysiology of upper respiratory infection

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Burdick Notes

OBJECTIVE 1
Immune System Overview
Main function of the immune system is self/non-self discrimination.
Immune system is divided into two major subdivisions:
(1)

(2)

Innate (non-specific) Systemfirst line of defense

Cellular, humoral and anatomical components

Defenses are constitutively present and ready to be mobilized upon infection

Not antigen specific and reacts equally well to a variety of organisms

Does not demonstrate immunological memory

Adaptive (specific) System

Second line of defense & protection against re-exposure to the same pathogen

Cellular and humoral components

Requires time to react to an invading organism

Antigen specific and reacts only with the organism that induced the response

Demonstrates immunological memory, it remembers that it has encountered an invading organisms and reacts rapidly on subsequent exposure to the
same organism

All cells of the immune system have their origin in the bone marrow. They include:
(1)

Myeloid cells

Neutrophils

Basophils

Eosinophils

Macrophages

Dendritic cells

(2)

Lymphoid cells

B lymphocyte

T lymphocyte

Natural Killer cells

Myeloid progenitor (stem) cells in the bone marrow give rise to erythrocytes, platelets, neutrophils, monocytes/macrophages and dendritic cells
Lymphoid progenitor (stem) cells give rise to natural killer cells, T cells, and B cells

Innate Immune System
Elements include anatomical barriers, secretory molecules, and cellular components.
A.

Anatomical Barriers
a.

b.

c.

Mechanical Factors

Epithelial surfaces form a physical barrier is impermeable to most infectious agents

Desquamation of skin epithelium also helps remove bacteria and other infectious agents.

Movement due to cilia or peristalsis helps keep air passages and the gastrointestinal tract free from microorganisms. The flushing
action of tears and saliva helps prevent infection of the eyes and mouth.

The trapping effect of mucus that lines the respiratory and gastrointestinal tract helps protect the lungs and digestive systems from
infection.

Chemical Factors

Lysozyme and phospholipase found in tears, saliva and nasal secretions can breakdown the cell wall of bacteria and destabilize
bacterial membranes.

Defensins (low molecular weight proteins) found in the lung and gastrointestinal tract have antimicrobial activity.

Surfactants in the lung act as opsonins (substances that promote phagocytosis of particles by phagocytic cells)

Biological Factors

B.

Normal flora of the skin and in the gastrointestinal tract can prevent the colonization of pathogenic bacteria by secreting toxic
substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces.

Humoral Barriers
Humoral factors play an important role in inflammation, which is characterized by edema and the recruitment of phagocytic cells. These humoral factors are
found in serum or they are formed at the site of infection.
1.

2.

C.

Complement System

Major humoral non-specific defense mechanism

Once activated, can lead to increased vascular permeability, recruitment of phagocytic cells, and lysis and opsonization of bacteria

Coagulation System

Some products of this system can contribute to the non-specific defenses because of their ability to increase vascular permeability and act as
chemotactic agents for phagocytic cells.

Some products are directly antimicrobial such as beta-lysin.

3.

Lactoferrin & Transferrinbind iron (essential for bacteria), thus limiting bacterial growth.

4.

Interferonproteins that limit virus replication in cells.

5.

Lysozymebreaks down the cell wall of bacteria.

6.

Interluekin-1induces fever and the production of acute phase proteins.

Cellular Barriers
Part of the inflammatory response is the recruitment of polymorphonuclear eosinophils and macrophages to sites of infection. These cells are the main line of
defense in the innate system.
1.

Neutrophils

Polymorphonuclear cells are recruited to the site of infection where they phagocytize invading organisms and kill them intracellularly.

Contribute to collateral tissue damage that occurs during inflammation.

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2.

3.

4.

Burdick Notes

Macrophages

Function in Phagocytosis and intracellular killing of microorganisms.

Capable of extracellular killing of infected or altered self-target cells.

Contribute to tissue repair and act as antigen-presenting cells, which are required for the induction of specific immune responses.

Natural Killer (NK) & Lymphokine Activated Killer (LAK) cells

Can non-specifically kill virus infected and tumor cells

These cells are not part of the inflammatory response but are important in non-specific immunity to viral infections and tumor
surveillance.

Eosinophils

These cells have proteins in granules that are effective in killing certain parasites.
Physio-Chemical Barriers to Infections

System/Organ

Active Component

Effector Mechanism

Skin

Squamous cells; sweat

Desquamation; flushing, organic acids

GI tract

Columnar cells

Peristalsis, low pH, bile acid, flushing, thiocyanate

Lung

Tracheal cilia

Ciliary elevator, surfactant

Nasopharynx & Eye

Mucus, saliva, tears

Flushing, lysozyme

Phagocytic cells

Phagocytosis and intracellular killing

NK cells and K-cell

Direct and antibody dependent cytolysis

LAK

IL2-activated cytolysis

Lactoferrin & Transferrin

Iron binding

Interferons

Antiviral proteins

TNF-alpha

Antiviral, phagocyte activation

Lysozyme

Peptidoglycan hydrolysis

Fibronectin

Opsonization and Phagocytosis

Complement

Opsonization, enhanced Phagocytosis, inflammation

Circulation

Serum

Primary Defense Mechanisms of the Respiratory System
First Line of Defense

Mucous membranes secrete mucus that lubricates and moistens the cavity surface.

The ciliated cells along these cavities move the mucus and trapped substances to an area to be coughed or sneezed out.

It can trap microbes and foreign substances.

Free Cells

These are large mononuclear amoeboid phagocytes called alveolar macrophages that rest on the epithelial layers.
o

Alveolar macrophages are rich in lysosomes, which attach themselves to the phagocytes membrane surrounding the ingested bacteriathen the
lytic enzymes kill and digest the bacteria.

In the case of pulmonary infection, the pool of free cells may be enriched by other cell types from the blood.

Macrophages

Assisted by local proteins (e.g. surfactant proteins A & D) that have intrinsic opsonizing properties or antibacterial or antiviral activity.

Once engulfed, the pathogens (even if not killed by macrophages) are eliminated via either the mucociliary elevator or the lymphaticsno longer represent an
infectious challenge.

Only when the capacity of the alveolar macrophages to ingest or kill the microorganisms is exceeded does clinical pneumonia occur.

It has been shown that the bactericidal activity of the lungs is reduced by ethanol intoxication, hypoxia, cigarette smoke, acute starvation, and corticosteroid
injection.

Inflammation
Inflammation is a non-specific defense response of the body to tissue damage. It attempts to dispose of microbes, toxins, or foreign material at the site of injury, to prevent
their spread to other tissues and to prepare the site for tissue repair.

Inflammation can be induced by:

o

Pathogens

Abrasions

Chemical irritations

Distortion or disturbance of cells

Extreme temperatures

Four characteristic signs & symptoms: redness, pain, heat, swelling

Basic Stages of Inflammatory Response:

1.

Vasodilation & Increased Permeability of Blood Vessels

Increased permeabilitysubstances normally retained in blood are permitted to pass from blood vessels; defensive proteins such as Ab and
clotting factors enter the injured area from the blood.

Vasodilation allows more blood to flow through the damaged area. Increase blood flow also helps remove microbial toxins and dead cells.

Release of immune signals that increase vasodilation and permeability as well as attracts phagocytic cells and makes infected cells sticky to
macrophages.

Dilation and increased permeability cause heat and swelling (edemafluid moves from blood plasma into tissue spaces)

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2.

Burdick Notes

Emigration of Phagocytes

Neutrophils begin to stick to the endothelium of the blood vessel wall. They begin to squeeze through the wall of the blood vessel to reach the
damaged area. They accumulate and try to phagocytize the microbe.

Later monocytes appear and transform into wandering macrophages that are additive to the fixed macrophages already present in the tissue. Dead
neutrophils and body tissue accumulate and form pus at the siteover time will be dispersed.

Infection of Lung
Parenchyma

Recognition of
pathogen by
alveolar
macrophages

Inklammatory
Mediator release
(IL-1 & TNF)

Vasodilation

Endothelial
Activation

Increased
Permeability

Neutrophils
extravosate

Cells &plasma leak

Exudate (kluid)

Enters Alveoli

Impairment of
diffusion, decrease
surface area for gas
exchange

Hypoxemia
(V/Q mismatch)

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Burdick Notes

OBJECTIVE 2
Respiratory Inflammation

In that situation, the alveolar macrophages initiate the inflammatory response to bolster lower respiratory tract defenses. The host inflammatory response (not the
proliferation of microorganisms) triggers the clinical syndrome of pneumonia.

The release of inflammatory mediators, such as interleukin (IL) 1 & tumor necrosis factor (TNF), results in fever.

Chemokines, such as IL-8 and granulocyte colony-stimulating factor, stimulate the release of neutrophils and their attraction to the lung, producing both
peripheral leukocytosis and increased purulent secretions.

Inflammatory mediators released by macrophages and the newly recruited neutrophils create an alveolar capillary leak equivalent to that seen in the acute
respiratory distress syndrome (ARDS), although in pneumonia this leak is localized (at least initially).

Even erythrocytes can cross the alveolar-capillary membrane, with consequent hemoptysis. The capillary leak results in a radiographic infiltrate detectable on
auscultation, and hypoxemia results from alveolar filling.

Moreover, some bacterial pathogens appear to interfere with the hypoxic vasoconstriction that would normally occur with fluid-filled alveoli, and this interference
can result in severe hypoxemia.

Increased respiratory drive in the systemic inflammatory response syndrome (SIRS) leads to respiratory alkalosis.

Decreased compliance due to capillary leak, hypoxemia, increased respiratory drive, increased secretions, and occasionally infection-related bronchospasm all
lead to dyspnea. If severe enough, the changes in lung mechanics secondary to reductions in lung volume and compliance and the intrapulmonary shunting of
blood may cause the patient's death.

Drug intoxification can compromise epiglottic closures and lead to aspiration of oropharynx flora into the lower respiratory tract.

Also it has shown to increase colonization of oropharynx with aerobic gram-negative bacilli, decrease mobilization of neutrophils, abnormal phagocyte
oxidative metabolism, and abnormal chemotaxis.

It also block TNFs response to endotoxin, which decreases recruitment of neutrophils to the lung.

Alcohol enhances production of IL-10, a cytokine with anti-inflammatory properties

Cigarette smoke has been shown to compromise natural pulmonary defense mechanisms disrupts mucociliary function and macrophage activity

Ventilation-Perfusion ScenariosHypoxia
Venous-admixture-like perfusion (low Va/Q)

When there is perfusion of inadequately ventilated alveoli or perfusion of non-ventilated alveoli, a low V/Q ratio is present. Under such
circumstances, a portion of the pulmonary blood is only slightly aerated, if at all.

This poorly aerated blood leaves the capillary & then mixes with fully arterialized blood coming from the other pulmonary capillaries.

This leads to hypoxia & slight hypercapnia (wont develop is there is significant hyperventilation of the remaining perfused alveoli) in the arterial
blood. Because of the oxyhemoglobin dissociation curve, hyperventilation of these alveoli will only add a limited amount of oxygen to the blood.

Dead-space Ventilation (high Va/Q):

When the ventilation for alveoli is maintained but the blood perfusion is limited, or when there is no perfusion, a high ventilation-perfusion ratio is
present.

The gas entering these alveoli takes little part, if any, in gas exchange, and the small amount of blood flowing through these alveoli contributes
relatively little to the composition of the mixed arterial blood.

The gas leaving such alveoli tens to have a composition more nearly like the gas in the tracheobronchial tree, thus contributing to the physiological
dead space.

The large amount of wasted ventilation means that alveolar ventilation will be low unless the total ventilation is increased.

Adequate gas exchange will occur as long as normally perfused alveoli are hyperventilated.

Hypoxia can occur if the ratio of the alveolar ventilation to the perfusion is not uniform throughout the lungs, even thought the total alveolar
ventilation and the total pulmonary blood flow are normal.

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Burdick Notes

OBJECTIVE 3

Pneumonia

An inflammatory illness of the lung. Frequently, it is described as lung parenchyma/alveolar inflammation and abnormal alveolar filling with fluid.

Incidence rates are highest at the extremes of age (because of compromised immune systems)

Risk Factors for CAP: alcoholism, asthma, immunosuppression, institutionalization, age of >70 years

Risk Factors for pneumococcal pneumonia: dementia, seizure disorders, heart failure, cerebrovascular disease, alcoholism, tobacco smoking, COPD, HIV infection

Risk Factors
A.

Institutional and Hospital-Acquired Pneumonia (Nosocomial)

Elderly and very young

Chronic or severe medical conditions such as lung problems, heart disease, nervous system disorders, cancer

Recent surgery, particularly those over age 80.

Patients in the ICU; particularly true for newborns or patients on breathing machines. Patients who lie flat on their backs are at particular risk for
aspiration pneumonia.

Patients who have received sedation.

B.

Community Acquired Pneumonia (CAP)

Elderly, infants, and young children

Chronic lung disease patients, those with chronic obstructive lung disease (COPD)chronic bronchitis and emphysema.

Patients with compromised immune systems. Conditions include:

o

HIV and AIDS

Adult and pediatric cancers, especially leukemia and Hodgkins lymphoma

Chemotherapy

Organ transplantation

Using corticosteroids or other medications that suppress the immune system

Patients on drugs that treat gastroesophageal reflex (GERD)

Swallowing disorders, including dysphagia

Dementia

Dormitory or barrack conditions

Smoke and environmental pollutants

Drug and alcohol abuse

C.

High risk surgeries: removal of the spleen, abdominal aortic aneurysm repair, or operations that impair coughing

Elderly patients with dementia who are treated with antipsychotic drugs for psychosis have a 60% increased risk of developing pneumonia.

Recurrent Pneumonia in Children

Abnormalities in muscle coordination of the mouth and throat

Asthma

Cystic fibrosis

Bronchopulmonary dysplasia, and other chronic lung diseases

Prematurity

Sickle cell disease

Gastroesophageal reflex disorder

Impaired immune system

Clinical Features

Patient frequently febrile, with a tachycardia response.

Cough that is either nonproductive or productive of mucoid, purulent, or blood-tinged sputum.

o

Scant or watery sputum is more often seen with bacterial pneumonia or bronchitis.

Rusty sputum suggests alveolar involvement and has been most commonly associated with pneumococcal pneumonia.

Dark red, mucoid sputum (currant-jelly sputum) suggests Friedlanders pneumonia caused by encapsulated Klebsiella pneumonia.

Foul-smelling sputum is associated with mixed anaerobic infections most commonly seen with aspiration.

Patient may experience pleuritic chest pain due to inflammation, pleura layers rub together.

Crackles, bronchial breath sounds, and possibly a pleural friction rub may be heard on auscultation.

A sharp or stabbing pain, either experienced during deep breaths or coughs

The clinical presentation may not be so obvious in the elderly, who may initially display new-onset or worsening confusion and few other
manifestations.

Severely ill patients who have septic shock secondary to CAP are hypotensive.

Increased respiratory rate and use of accessory muscles of respiration are common.

Up to 20% of patients may have gastrointestinal symptoms such as nausea, vomiting, and/or diarrhea. Pneumonia caused by Legionella may cause abdominal
pain while that of TB can cause diarrhea.

May have chills and/or sweats. Fever occurs on 65-90% of patients.

Examining the thorax might reveal splinting or an inspiratory lag on the side of the infected, which is suggestive of bacterial pneumonia.

It can be sustained, remittent or hectic. The pulse typically increases by 10 bpm for every degree of temp elevation. I pulse-temp deficit should
suggest viral infection, mycoplasm infection, chlamydial infection.

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Burdick Notes

General Investigations
1.

Chest X-ray

2.

Confirms the diagnosis of pneumonia by demonstrating consolidation, detects complications such as lung abscess or empyema, and helps to exclude
any underlying disease (e.g. bronchial carcinoma)

Haematology and biochemistry tests

Useful in assessing the severity of the disease

Specific Investigations
Aimed at detecting the pathogen causing the pneumonia.
1.

Sputum Gram stain: valuable and rapid to assess what kind of organism caused pneumonia.

2.

Sputum Culture: main test used to detect bacterial causes of pneumonia but contamination of the sample by oropharyngeal organisms, prior use of antibiotics
and inability to produce sputum limit the sensitivity and specificity of the test.

3.

Blood cultures: should be performed on all patients admitted to the hospital, but are positive in only ~15%.

4.

Pleural fluid: should be aspirated in all patients with pleural effusions and may yield a causative organism or reveal epyema.

5.

Antigen detection tests: available for some pathogens. Pneumococcal antigen may be identified in sputum, urine, pleural fluid or blood.

6.

Serological tests: allow a retrospective diagnosis of the infecting organism if a rising titre is found between acute and convalescent samples. Most useful when
viruses and pneumonia are caused by atypical organisms

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