Respiratory Disorders: Case 1-Asthma

Case Presentation

An 11 year-old girl is brought by her parents to the pediatrician because of a

history o coughing and wheezing and repeated attacks of difficulty breathing. The

attacks are more common in spring, but are also triggered by going out into the cold in

the winter. She has been afebrile during these attacks. On physical examination, her

lungs are hyperresonant to percussion, and some wheezing is heard throughout the lung

fields. Laboratory tests show increased eosinophil count on the blood differential smear

and subsequent tests document increased serum IgE levels.A sputum sample shows

increased eosinophils and Curschmann’s spirals (whorls of sloughed surface epithelial

cells embedded in mucin).

What is the diagnosis and how should she be managed?

Introduction to Respiratory Function

The respiratory system is responsible for providing adequate oxygen to meet the

ceaseless metabolic demands of the trillions of body cells and disposing of carbon

dioxide produced during aerobic metabolism by these cells. Recall that oxygen is the

final electron acceptor for all of the metabolic processes taking place within

mitochondria, including fatty acid oxidation, the tricarboxylic acid cycle, and the

electron transport chain, which culminate in generation of ATP. All told, these metabolic

processes consume ~250 ml/min of oxygen and produce about 200 ml/min of carbon

dioxide. To meet this demand for oxygen, three systems work together to meet varying

metabolic demands. These three are: (1) the lungs and associated muscular pumping

mechanism which inhale oxygen and exhale carbon dioxide, (2) the blood and

circulatory system with hemoglobin rich erythrocytes that transport oxygen and carbon
dioxide, and (3) the nervous system (medulla) which controls the rhythmic action of the

respiratory system.

Organization of the Respiratory System

The two lungs located in the chest cavity predominantly consist of 300 million

hollow alveoli (air sacs) arranged in grape-like clusters, each one in intimate association

with ~80 capillaries, which traverse the surface of each alveolus. This arrangement

ensures that gas exchange takes place over a minimum distance and with sufficient time

to be in contact with red blood cells carried in the capillaries. Carrying inhaled oxygen to

the alveoli and exhaled carbon dioxide to the atmospheric gas are a series of tubes

beginning with the trachea, bronchi, bronchioles and terminal bronchioles which

conduct the gases to and from the respiratory bronchioles, alveolar ducts and alveolar

sacs (Fig). All together these are 23 generations of branching, each successive branch

more narrow, shorter, and more numerous. The larger tubes are called the conducting

zone and normally provide a low-resistance conduit for air flow. The conducting zone

removes microbes, toxic chemicals, and foreign matter by use of mucus, cilia, and

macrophages. Because we breathe about 12 times/min throughout life, and the inspired

air contains viruses and microbes, it is not surprising that respiratory infections are the

most common infections in humans.

The Alveoli Are the Site of Gas Exchange

The 300 million alveoli in the two lungs provide a surface area about the size of a

singles tennis court. Two types of cells make up the one cell thick lining of the alveolus.

The most numerous are type I alveolar cells, which are squamous (flat) epithelial cells.

The thin alveolar walls are in close contact with the endothelium of capillaries. A second

cell, type II alveolar cells are cuboidal epithelial cells which are randomly dispersed

among the type I cells and which secrete a detergent-like mixture of lipids and proteins

called surfactant. Surfactant lines the inner alveolar surface, reducing surface tension

(the attraction of the water molecules for each other) and thereby prevents collapse of
alveoli during inhalation. While type I cells cover >90% of the alveolar surface, there are

almost as many type II cells as type I. In addition to synthesizing surfactant, type II cells

are believed to function in repair, replacing damaged type I cells.

Breathing Requires Muscles to Create Pressure Differences Between Alveoli and

Atmosphere

The diaphragm and intercostals determine the pressure in the chest cavity.

Contracting these muscles expands the chest as the diaphragm moves downward,

causing the pressure within the alveoli to fall below atmospheric pressure, allowing air to

enter during inspiration. When these muscles relax, the chest cavity grows smaller,

alveolar pressure increases and expiration occurs. The lungs are resistant to expansion

much in the way a balloon resists inflation. Unless a pressure difference exists between

the inside and outside of the lungs, because of elastic recoil there is a natural tendency

for the lungs to collapse. Elastic recoil is the property of an elastic structure to resist

stretching or distortion.

Between breaths the inward elastic recoil of the lungs is exactly counterbalanced

by the outward elastic recoil of the chest wall, so that the lungs remain expanded,

because all the air within them cannot be expelled (the residual volume—see later).

Each lung is invested by a sac consisting of areolar connective tissue covered by

a thin sheet of squamous epithelial cells the covers both the lungs and lines the walls of

the chest and diaphragm. These two pleural surfaces, visceral (attached to the lungs)

and parietal (attached to chest wall) are separated by a very thin layer of pleural fluid

(normally <10ml). While these two layers easily slide over each other, they are very

difficult to pull apart, much in the same way two microscope slides that share a drop of

water strongly resist separation.

Ventilation is the exchange of air between atmosphere and alveoli and with air

moving into or out because the alveolar pressure (Palv) is alternately made less than

(inspiration) or greater than (expiration) atmospheric pressure (Patm). Again, the changes
in alveolar pressure are the result of changes in the volume of the lungs and thoracic

cavity.

By Boyle’s law (P1V1= P2V2), it can be shown that if the volume of a container

increases, the pressure of the gas decreases, whereas a decrease in the volume of the

container increases the pressure (a piston in an automobile cylinder demonstrates this

nicely). Since the lungs are tethered to the chest wall through the pleural fluid, so that

their volume depends on the difference between alveolar pressure and the pressure of

the intrapleural fluid surrounding the lungs, when the chest wall expands by contraction

of the bellows muscles, the pressure of the intrapleural fluid falls causing the lungs to

expand. This lowers alveolar pressure causing air to flow into the lungs. By contrast, when

the respiratory muscles relax the volume of the chest cavity decreases. Consequently,

pressure in the alveoli increases and this brings about exhalation.

If the chest wall is pierced by surgery or trauma, air will rush into the interpleural

space, causing a pneumothorax. In that situation, the intrapleural pressure goes from

-4mmHg to 0mmHg (atmospheric pressure) and since the transpulomanry pressure that

was acting to keep the lungs expanded has been eliminated, the lung collapses.

During inspiration, with contraction of the diaphragm and intercostals, the thorax

enlarges and intrapleural fluid pressure becomes even more subatmospheric and with

expansion of the lungs air flows into the alveoli. At the end of inspiration, the muscles of

inspiration relax and the chest wall is no longer expanded, causing a decrease in

transpulmonary pressure, compression of air in the alveoli and expiration of air. Thus,

expiration at rest is a purely passive process.

Lung Compliance

Pulmonary compliance is a measure of how easy it is to expand the lungs and is

considered the opposite of stiffness. A less compliant lung requires more energy to be

expanded. There are two major factors determining lung compliance: (1) the ease of
stretching of their elastic connective tissue, and (2) the surface tension within the alveoli.

For example, in pulmonary fibrosis, the deposition of fibrous tissue within the lung

parenchyma makes the lung stiff and consequently more difficult to inflate. In contrast,

emphysema, the destruction of lung tissue by unrestrained elastase activation, makes

the lungs floppy, which makes the airways prone to collapse during respiration. This

dramatically increases airway resistance during expiration, even if patients experience

less resistance to inflate their lungs.

The alveoli are air filled sacs lined with a layer of water. At the air-water interface,

the molecules of water exert a powerful force of attraction on each other, so that they

surface they occupy contracts to a minimal value. Two examples of the effects of

surface tension are soap bubbles and beads of water on a highly polished automobile

surface, As noted earlier, surfactant secreted by type II alveolar cells reduces the force

of attraction between the water molecules. Ninety per cent of surfactant is lipid, and the

major lipid is dipalmitoylphosphatidylcholine. Surfactant lowers surface tension and

increases lung compliance, thus facilitating lung expansion. In respiratory distress

syndrome in premature infants, inadequate synthesis of surfactant causes the neonate to

become exhausted as it struggles to breath in the absence of surfactant. Unless placed

on a ventilator, such an infant will die.

Lung Volume and Capacities

The spirometer measures the volume of inspired and expired air, and therefore

various lung volumes. The amount of gas entering and leaving the lungs with each

breath is called the tidal volume (VT) and is ~500 ml. If at the end of a quiet inspiration,

the subject is asked to inhale as deeply as possible (in practice this may take several

attempts) this additional volume is called the inspiratory reserve volume (IRV) and is

between 2.5 to 3 L.

The amount of air that remains in the lungs after expiring a resting tidal volume is

called the functional residual capacity (FRC) and is about 2.5 L. The FRC is a buffer
against large changes in alveolar PO2 with each breath, and accounts for 40% of the

total lung capacity (5-6.4 L). If a vigorous effort is made to exhale after a quiet inspiration,

this additional expired volume is called the expiratory reserve volume (ERV) and amounts

to ~1.5 L. Notably, even after a maximal expiration, ~1L remains in the lungs and is called

the residual volume. The residual volume is important because once an airway collapses

a very high pressure is needed to reinflate it. Further, even though ventilation is episodic,

blood flow is continuous so that perfusion and ventilation can be matched.

The vital capacity (VC) is the volume expired from maximal inspiration to maximal

expiration and thus is the sum of the TV + IRV + ERV and is ~80% of the TLC.

A particularly clinically useful measurement is the forced expiratory volume in 1

sec (FEV1) which is the volume of air that can be expelled in the first second after an

inspiration followed by a maximal expiration—as quickly as possible. FEV1 is normally 80%

of the forced vital capcity (FVC) (i.e the vital capcity performed with forced expiration).

In obstructive lung disease, such as asthma, FEV1 is more than FVC so that the FEV1/FVC

ratio is deceased to ~50%. By contrast, with restrictive lung disease, such as pulmonary

fibrosis, both the FEV1 and FVC are reduced and their ratio is either normal or increased

(>80%).

Alveolar Ventilation

Ventilation denotes the entry of air into the lungs with its ultimate arrival in the

alveoli, where gas exchange with the blood occurs. It is important to note that ~150 ml of

air is found in the conducting airways and that this air is not available for exchange with

the blood. This volume of air is called dead space.

Gas Exchange

The air in the alveoli contains less oxygen and more carbon dioxide than

atmospheric air. Oxygen diffuses into the blood of the pulmonary capillaries and carbon

dioxide diffuses from the cells into the venous blood entering the capillaries. The concept

of partial pressure or tension is fundamental to understanding gas exchange, because

gases are exchanged between alveolar air and pulmonary capillary blood in response

to differences in partial pressure. In any volume, the total gas pressure of all the gases

present (e.g. oxygen, carbon dioxide, nitrogen, water vapor) is the sum of the individual

pressures of each of the different gases. The idea of partial pressure rests on the

assumption that the gas molecules do not interact. To calculate partial pressure one

multiples the concentration of the gas by the total pressure (e.g. 760 mmHg at sea level).

For example, dry air has 20.9% oxygen. The PO2 in dry air at sea level with a barometric

pressure of 760 mmHg is therefore 20.9/100 x 760 = 159 mmHg (the partial pressure of

oxygen). But air inhaled into the upper airways is warmed and saturated with water

vapor. The water vapor pressure at 37oC is 47 mmHg. Thus, it is necessary to subtract 47

from 760 to arrive at 713 mmHg, the total dry gas air pressure. Consequently, the PO2 of

moist inspired air is 20.9/100 x 713 = 149 mmHg.

Remember that the movement of oxygen into the peripheral tissues is by passive

diffusion and that the mitochondria are the target of the oxygen transport system.

Notably, mitochondrial oxygen concentration is ~2-4mmHg, representing a dramatic

decrease from the PO2 of arterial blood. Nevertheless, this paltry pressure head of oxygen

is usually sufficient to meet the metabolic demands of mitochondria for oxygen.

As regards carbon dioxide, there is essentially no carbon dioxide in inspired air

and the alveolar PCO2 is ~40 mmHg. Normally, arterial and alveolar PCO2 values are the

same, whereas PCO2 of mixed venous blood is ~47 mmHg.

Transport of Oxygen by Hemoglobin

We have been emphasizing the partial pressure of oxygen and it would be easy

to assume the bulk of oxygen carried in the blood is as dissolved gas—but that would be

wrong. In fact, hemoglobin, which can carry 1.34 ml of oxygen/g, transports 60 times

more oxygen than can be dissolved in plasma. Plasma can dissolve 0.3 ml of

oxygen/dl—a very small amount relative to oxygen that is carried by hemoglobin.

Nevertheless, the arterial PO2 is the tension of oxygen that represents the driving force for

oxygen to leave the alveoli and enter the red cell.

Normal adult hemoglobin (HbA) is a tetramer (m.w. 68kD) made up of two alpha

chains and two beta chains which surround a heme (Fe2+ containing) porphryin ring). We

know that free iron is toxic (hemochromatosis), but when heme is part of hemoglobin, a

group of amino acids interact with heme so that oxygen binds loosely and reversibly to

the Fe2+ in heme. Obviously, this easy reversibility makes it possible to pick up and deliver

oxygen in the repetitive fashion required by metabolism. When each of the four hemes in

hemoglobin are free of oxygen (deoxyHb) the tetramer assumes a taut or tense (T)

conformation which inhibits approach of oxygen, accounting for the low affinity of

deoxyHb for oxygen.

But, when oxygen binds to one of the hemes it facilitates binding of the next until

all four chains bear oxygen. This binding produces the relaxed(R) conformation which

has an affinity for oxygen ~150 times the affinity of the T state. This was one of the first

examples of allosterism, and has had a profound influence on understanding how the

binding a small molecule to a protein communicates biochemical information to that

protein.

The Hemoglobin-Oxygen Dissociation Curve is Sigmoidal

The normal Hb-O2 dissociation curve (Fig) is S-shaped and is termed sigmoidal,

because of cooperative interactions among the four oxygen binding sites on the

hemoglobin tetramer. As seen in the figure, at low PO2 values, increases in PO2 produce

small increments in oxygen binding because hemoglobin is mostly in the T state. But, at

moderate PO2 values, the amount of oxygen bound increases in the steep part of the

curve as PO2 increases, reflecting the increased oxygen affinity of the R state. Finally, at a

PO2 of ~80mmHg the curve flattens out. From the curve it can be seen that at the PO2 of

normal arterial blood, which is ~100 mmHg, the hemoglobin saturation (SaO2) is ~98%.
Also, in mixed-venous blood in which the PO2 is ~40mmHg, hemoglobin is still 75%

saturated.

When a red blood cell enters a systemic capillary, the PO2 in the adjacent tissue is

lower than in the blood and oxygen diffuses out of the capillary into the tissue. With

diffusion of oxygen into the tissue, the PO2 in the plasma bathing the red cell falls. The

decrease in PO2 causes oxygen to dissociate from hemoglobin inside the red cell and

diffuse into the plasma. Thus the hemoglobin bound oxygen is the reservoir for the

plasma dissolved oxygen. Under normal circumstances, by the time the red cell exits the

capillaries it will have released 25% of the oxygen it was carrying, leaving a significant

reserve of un-extracted oxygen to support exercise or other demands.

Hemoglobin Releases Oxygen in Metabolically Active Tissues

Metabolically active tissues produce large amounts of carbon dioxide and some

lactic acid. It is therefore fitting that CO2 and the hydrogen ion can cause hemoglobin to

loosen its grip on oxygen and to deliver more oxygen to these metabolically active sites.

In addition, 2,3 –bisphosphoglyceric acid (2,3 BPG), a glycolytic intermediate in the red

cell is the most potent stimulus to release oxygen from hemoglobin. Glycolysis will

increase in the face of anemia or hypoxia and lead to increase in 2,3 BPG levels.

Transport of Carbon Dioxide in the Blood

At rest, an adult produces ~200 ml of carbon dioxide/min as a result of aerobic

metabolism, mostly in the tricarboxylic acid cycle. As we will see in Case 2 on COPD and

breathlessness, buildup of carbon dioxide can lead to accumulation of carbonic acid,

which could cause respiratory acidosis. To prevent accumulation of carbonic acid in the

tissues, carbon dixodie must be ferried back to the lung and eliminated in the exhaled

gas. Demonstrating the production of carbon dioxide by tissues, while at rest systemic

arterial blood delivering oxygen to the body’s tissues has a PCO2 of ~40 mmHg, while

blood returning from the tissues to the lungs has a PCO2 of ~47 mmHg (or torr).
 Carbon dioxide is carried in three forms in the blood: bicarbonate ions, as

carbamino compounds in combination with hemoglobin and dissolved in plasma. The

major form of transport is as bicarbonate ions, which accounts for 60% of carbon dioxide

transport. In a reaction, accelerated by carbonic anhydrase, water combines with

carbon dioxide to form bicarbonate and H+. About 30% of carbon dioxide is in chemical

combination with amino acid residues in hemoglobin, at sites distinct from where oxygen

binds. Finally, ~10% of carbon dioxide is physically dissolved in the plasma and red blood

cells. These three forms are measured in the laboratory as total carbon dioxide.

Notably, the hydrogen ion produced in the carbonic anhydrase reaction is

buffered by deoxyhemoglobin, which has a much greater affinity for H+ than does

oxyhemoglobin. This is known as the Haldane effect. This buffering is so effective that

under normal circumstances, venous blood has a pH of 7.36, which is marginally more

acidic than arterial blood (pH 7.4).

Ventilation and Perfusion of the Lungs

Ventilation is the exchange of gases between the atmosphere and the alveoli

and perfusion is the flow of blood to the lungs that delivers oxygen and picks up carbon

dioxide from the body’s cells. We saw earlier that of a normal inspiration of ~500 ml, 150

ml is wasted in the anatomic dead space, because these areas are not perfused and so

there cannot be any exchange of gas with the blood.

Alveolar PCO2 is generally inversely proportional to alveolar ventilation, so that if

the ventilation rate is doubled alveolar PCO2 will be halved. Not only does alveolar PCO2

fall, but so does arterial PCO2 which causes respiratory alkalosis. By the same token,

halving alveolar ventilation will double arterial PCO2 causing respiratory acidosis. It is also

true that as alveolar ventilation increases, alveolar PO2 will to approach the value in

inspired air.

The 300 million alveoli are richly endowed with capillary segments that perfuse

the alveoli and facilitate gas exchange between the capillaries and the alveoli.
Matching Ventilation to Perfusion

In the lungs of healthy individuals, both ventilation and perfusion vary among

alveoli. For instance, even though the base of the lungs receives the greatest ventilation,

it is not matched to the still higher blood flow and so the base is somewhat

underventilated. In contrast, even though the apex receives less ventilation than the

base it is in excess of blood perfusing that region and so the apex is overventilated

relative to perfusion.

Pathologic situations exacerbate these normal inequalities in matching

ventilation and perfusion. For example, when a group of alveoli are ventilated but not

perfused, as occurs with pulmonary embolism this creates alveolar dead space. Thus,

while receiving air these alveoli receive no blood and therefore cannot engage in air

exchange. This is a common example of ventilation (V): perfusion (Q) [V/Q mismatch].

Since no gas exchange occurs between these unperfused alveoli and pulmonary

capillary blood, the composition of the alveolar gas will be the same as moist inspired air,

with a PO2 of 149 mmHg and a PCO2 of ~zero. In an alveolar dead space, hypoxia will

provoke bronchoconstriction to divert blood to perfused areas. In addition, surfactant

production by unperfused type II alveolar cells will decrease, making its difficult to keep

alveoli patent.

At the other extreme are alveoli that are perfused but not ventilated, a situation

termed a shunt, an extreme case of V/Q inequality. Causes of no ventilation with

continued perfusion include a foreign body or tumor in a conducting airway, atelectasis

(collapse of alveoli) or consolidation from pneumonia. In this setting no gas exchange

takes place and alveolar oxygen and carbon dioxide are the same as mixed venous

blood. Since shunted blood has no contact with inspired air, no amount of breathing

100% oxygen will correct the fall in systemic arterial PO2. By comparison, a low V/Q region

does come in contact with inspired air and breathing 100% oxygen will increase alveolar
and systemic PO2. This is because all alveoli will receive some ventilation, and the

alveolar PO2 can be increased even in those with poor ventilation.

Control of Ventilation

Since the diaphragm and intercostals play a commanding role in respiration,

control of their contractions must ultimately reside in the nervous system. Research has

shown that centers in the medulla generate the automatic rhythm for contraction of the

respiratory muscles. In addition, chemoreceptors in the carotid and aortic bodies sense

changes in PCO2, pH, and PO2 and adjust respiration to shifting metabolic demands.

Neural Control of Breathing

Since we breathe during sleep, it should be clear that central nervous system

neurons drive the rhythm of breathing. These neurons are situated in the medulla in what

is termed the respiratory rhythm generator and they provide neural input to the

diaphragm and intercostals via cranial and spinal motor neurons. The medullary neurons

receive modulatory input form neurons located in the pons. The medulla also is home to

the cardiovascular control center.

Role of Peripheral and Central Chemoreceptors

Peripheral chemoreceptors located near the bifurcation of the carotid and aortic

bodies (under the aortic arch) react to decrease in arterial PO2, transmitting their sensory

information to the medulla via cranial nerves IX (glossopharyngeal) and X (vagus).

Central chemoreceptors are located in the medulla and react to increases in arterial

PCO2 and in a delayed fashion to increases in hydrogen ion concentration, as a

consequence of carbonic acid or organic acid accumulation. Both peripheral and

central chemoreceptors stimulate increase in alveolar ventilation. It is not surprising that

PCO2, PO2, and pH should be monitored by these receptors, because all three are

affected by the adequacy of ventilation.

 The chemosensitive cells of the carotid body are glomus cells, which are like

peripheral neurons and adrenal chromaffin cells. They are equipped with a variety of

voltage-gated channels and can generate an action potential. The glomus cell is able

to sense hypoxia, hypercapnia, and acidemia, and responds by inhibiting flux through

potassium channels which leads to depolarization of the cell. In turn this causes

increased calcium entry and release of neurotransmitters, most probably dopamine. (This

chain of events is reminiscent of the release of insulin by the beta cells of the pancreas,

except in the case of the pancreas dopamine is not involved).

We should note that hypoxia is not a potent stimulus for hyperventilation because

an increased ventilatory response will decrease arterial PCO2 and hydrogen ion

concentration, which would decrease ventilatory rate. But, in diseases such as

emphysema or pneumonia, in which hyperventilation is not able to effect a decrease in

arterial PCO2 and hydrogen ion concentration, hypoxia may exert a more potent

influence. From a clinical point of view, one must be careful in administering

supplemental oxygen to such patients, because by removing the hypoxic stimulus to

breathing one can inhibit the ventilatory drive, causing severe hypercapnia, respiratory

acidosis, and even death.

We now turn to our discussion of asthma.

ASTHMA—Introduction

Asthma is a very common disease of the respiratory tract which occurs in 5 to 10%

of the U. S. population. It is now recognized to be primarily an inflammatory disorder of

small conducting airways with bronchospasm occurring secondary to the underlying

immune and inflammatory responses. Some triggers attract inflammatory cells to the

airways which releases leukotrienes, cytokines and other mediators that induce

bronchospasm and mucus hypersecretion. The classic presentation of the acute attack is

marked by wheezing, shortness of breath, and coughing. Triggers of an attack include

allergens, heat or cold, occupational irritants, drugs and exercise. On spirometry, the
most characteristic feature of asthma is a decreased FEV1. The standard of care

recommends personal use of peak-flow meters by the patient, because the severity of

symptoms does not always correlate with objective measures like FEV1. In fact, while

uncommon, fatalities do occur and some have been attributed to lack of recognition of

the severity of the attack and delay in seeking aggressive therapy.

We will begin by examining the pathogenesis of asthma and then consider the

clinical manifestations and treatment.

Pathogenesis

Most authorities believe that airway inflammation and remodeling (thickening) of

small airway walls is pivotal to the development of the asthma phenotype. The major

features of asthma are recurrent episodes of airway obstruction that resolve with

treatment, bronchial hyperresponsiveness to a number of stimuli and inflammation of the

airways. Many cells participate in the inflammatory response including mast cells,

eosinophils, T lymphocytes, macrophages, neutrophils, and airway epithelial cells. Among

these cells, recruited CD4 T lymphocytes (especially Th2 and Th17 cells) orchestrate the

immune response (see below).

An asthmatic attack can be provoked by allergens, occupational irritants, and

viral respiratory infections, each of which likely acts through different pathways to

produce inflammation involving multiple cell types, airway hyperresponsiveness (AHR),

and obstruction to airflow.

Airway inflammation includes inflammatory cell infiltrates of the airways,

hyperplasia and hypertrophy of airway smooth muscle and thickening of the lamina

reticularis with increased collagen deposition, just below the basement membrane.

Mucus plugs obstruct the airways, aggravating the obstruction to airflow, and are

composed of mucus, serum proteins, inflammatory cells, and cellular debris, arranged in

a spiral pattern called Curschmann’s spirals.

 Evidence gathered over a number of years points to a major role for T helper type

2 cells in the pathogenesis of asthma. This role has been partially explained by the

“hygiene hypothesis” which posits that the dramatic rise in allergies in children is a

by-product of improvements in hygiene, which have decreased the rate of infection in

early childhood. There is good evidence that allergic disease depends on a

predominance of Th2 cells. Th2 lymphocytes secrete a number of cytokines including IL4,

5, 9, and 13 which induce the production of IgE (important in type 1 hypersensitivity

reactions) and encourage maturation and recruitment of mast cells and eosinophils. In

contrast, Th1 lymphocytes produce interferon- γ (IFN-γ) and IL-2, which contribute to a

defense against microbes. The immunologic set of the fetus is distinctly toward Th2 and

this is found in the neonate as well. According to the hygiene hypothesis, unless the

pattern of immunologic response of the airway is reprogrammed to a Th1 pattern, the

infant will remain at risk for sensitization to aeroallergens. Further, it is postulated that the

incentive to create a balance between Th1 and Th2 arms is exposure to pathogenic and

commensal microorganisms at the body’s mucosal surfaces, especially the GI mucosa

associated lymphoid tissue (MALT). Inferential support for this hypothesis comes from

showing decreased incidence of asthma in children with older siblings, those who attend

daycare in infancy, and those who have dogs or cats in infancy. The common thread

that runs through these is exposure to intestinal microbes. This hypothesis has spurred on

considerable research to see if harmless commensals might be added to food to reduce

the risk of developing allergies and asthma.

Notwithstanding the assumed role of Th2 lymphocytes in asthma, there is

evidence for an additional cell type, i.e. Th17 cells. For example, downregulating IgE

synthesis with IFN-γ while encouraging T cells toward Th1 development does not

ameliorate asthmatic symptoms. Further, there is new evidence in severe asthma for the

participation of Th17 cells, a third type of helper T cell and their signature cytokine, IL-17.

Of note, Th17 cells have been detected in Crohn’s disease, rheumatoid arthritis, and
multiple sclerosis. IL-17 is an important regulator of neutrophilic infiltration, suggesting that

overproduction of IL-17 may contribute to development of severe asthma. A key

pro-inflammatory cytokine IL-1β, has been shown to be crucial to the production of IL-17.

Other cytokines driving differentiation of T cells into the Th17 phenotype are TGF-β, IL-23

and IL-6. Of course, neutrophils are known to secrete a number of pro-inflammatory

cytokines and growth factors, some of which contribute to the thickening of the airway.

Leukotriene B4 (LTB4) is an important chemoattractant for neutrophils and is secreted by

several cells.

Other cells participating in asthma pathogenesis besides lymphocytes,

eosinophils and neutrophils include mast cells, alveolar macrophages, dendritic cells,

and airway epithelial cells. How all of them interact is the focus of on-going research.

And, of course, there is evidence for genetic predisposition to developing asthma that

must include interaction with the environment and the immune system. Next we will

briefly consider some potential genetic influences.

Genetic Influences in Asthma

Polymorphisms in a number of genes have been potentially linked to developing

asthma. These include the β2-adrenoceptor gene in which some variants have a muted

response to β2-agonists like epinephrine. Another group encodes human leukocyte

antigens (HLA), which have been linked to aspirin-induced asthma. Still another is the

gene for ADAM 33 (a disintegrin and metalloproteinase 33) which encodes membrane

anchored proteolytic enzymes that are involved in intracellular signaling in mesenchymal

cells. Expression of this gene has been tied to airway hyperresponsiveness. There is also a

locus on chromosome 17 that encodes endoplasmic reticulum proteins that have been

associated with asthma.

Biochemical Mediators in Asthma

Products of arachidonic acid including the cysteinyl leukotrienes LTC4, LTD4, LTE4,

and LTB4 are produced by 5-lipoxygengenase pathways. These compounds are potent
inflammatory mediators which play a role in the pathogenesis of asthma. Mast cells,

eosinophils, and alveolar macrophages express this enzymatic pathway and are the

source of the cysteinyl leukotrienes. LTB4 is produced by neutrophils and has a

predominant chemoattractant action. LTC4 and LTD4 are potent stimulators of airway

smooth muscle contraction. They activate G proteins coupled receptors and increase

cytosolic calcium leading to bronchoconstriction and increased mucus production. The

use of antagonists of these compounds has demonstrated considerable therapeutic

value in ameliorating chronic asthma and permitting a decrease of corticosteroid

dosage.

Goblet cell hyperplasia is found in asthma. Normally, mucus traps foreign matter,

bacteria, and viruses working in tandem with cilia to clear the airway. But, in asthma

excessive production of mucus is a major contributor to airway obstruction.

Summary of the Pathogenesis of Asthma

Asthma is characterized by chronic airway inflammation and

hyperresponsiveness to irritants and allergens. The chronic inflammatory reaction involves

a number of cells, paramount of which are activated Th2 cells which secrete IL-4,5 and

13. This leads to recruitment and activation of eosinophils and mast cells which further

feed this chronic inflammation and airway hyperresponsiveness. Increased production of

mucus and development of airway hypertrophy, further compromise airflow.

In some patients with severe asthma there is evidence for participation of another

subset of T helper cells, Th17 cells that create an inflammatory infiltrate that is skewed

toward neutrophils rather than eosinophils. Viral infections which often exacerbate

asthma also call forth neutrophils rather than eosinophils, and viral-induced wheezing

does not respond as completely to bronchodilators and inhaled corticosteroids. Thus

there is reason to believe that viral aggravated asthma has a different pathogenesis

than allergen-induced asthma. Viral infections, especially rhinovirus cause over 75% of
exacerbations of asthma in children and ~50% of asthmatic episodes in adults in

individuals with established asthma.

Clinical Manifestations

During an asthmatic attack patients experience shortness of breath, chest

tightening, coughing, wheezing and anxiety, the last more related to the acuteness of

the attack. Symptoms are often precipitated by exercise, allergens or viral respiratory

infections. Symptoms are typically worse at night. Some patients only manifest cough or

hoarseness, while others produce large amounts of sputum suggesting chronic bronchitis.

In most patients with recurrent attacks, the patient’s symptoms are characteristic and

easily recognized as an asthma attack. Some patients develop dyspnea when exposed

to rapid changes in temperature of inspired cold air. Aspirin is a known trigger of asthma

as are occupational irritants.

On physical examination, the respiratory rate is 25-40 breaths/min (normal ~12).

Pulse oximetry shows an O2 saturation of 90%. The presence of intercostal retractions

points to a moderate to severe attack. The chest is likely to be hyperinflated and there

will usually be wheezing, louder during expiration than on inspiration. But the adage “all

that wheezes is not asthma” must be kept in mind with patients without a history of

established asthma.

Pulmonary Function Tests in Asthma

Patients previously diagnosed with asthma use a peak flow meter to determine

peak expiratory flow rate, which in moderate asthma is ~60% of normal while in severe

asthma is <50% of normal. FEV1 and maximal mid-expiratory flow rate (MMEFR) are also

decreased reflecting obstruction to airflow.

In mild attacks arterial blood gases (ABG) are not necessary, but in more severe

attacks they are indicated and will reveal hypoxemia and hypocapnia (PaCO2

25-35mmHg). An alarm sign is a normal PaCO2 in a patient with moderate to severe

obstruction to airflow, because it means that the increased ventilatory rate cannot

compensate and eliminate carbon dioxide. Such a patient may be on the brink of

respiratory failure and severe respiratory acidosis.

The sputum of the asthmatic patient should be examined by Gram stain or

Wright’s stain. It should reveal the presence of esosinophils, crystallized eosinophil

enzymes (Charcot-Leyden crystals), bronchiolar casts of mucus and cells (Curschmann’s

spirals) and clusters of airway epithelial cells (Creola bodies).

For laboratories equipped to measure the fraction of exhaled nitric oxide (FENO) a

level >16 parts per billion can establish the diagnosis of asthma as opposed to another

cause of wheezing such as COPD, bronchiectasis, cystic fibrosis and narrowing of the

upper airway.

Treatment

Treatment of asthma is divided between rescue treatments with bronchodilators

and controller treatments to suppress inflammation and bronchial reactivity. Use of

rescue agents centers around short acting β-adrenergics such as albuterol given by

inhaler. Patients need to be instructed in their use.

Controller treatments depend on corticosteroids, which are the mainstay of drug

therapy because of their potent anti-inflammatory actions. Corticosteroids inhibit the

production of pro-inflammatory cytokines. They are used in all asthmatic patients who

use inhaled β-agonists more than once a day. Leukotriene inhibitors block synthesis of

leukotrienes or binding to their receptor. A monoclonal antibody to IgE, omalizumab,

binds circulating IgE. Another monoclonal antibody is directed against IL-5.

Treatment of status asthmaticus in the emergency department is beyond the

scope of our discussion.

Comment of Case Presentation

This child has allergic asthma (spring predominance of pollen exposure), in which

presensitized, IgE coated mast cells congregate on mucosal surfaces and the
submucosa of airways. When the mast cells make contact with allergen the cells release

leukotrienes, histamine, and other mediators which acting as chemokines attract other

cells, especially eosinophils and lymphocytes. Some of the mediators promote

bronchoconstriction.

The bronchial basement membrane becomes thickened and bronchial smooth

muscle undergoes hypertrophy and hyperplasia. Both of these responses contribute to

interference with airflow. It is estimated that as many as 30% of individuals with chronic

cough may be suffering from cough-variant asthma. Some of these patients come to

medical attention because they are non-smokers whose exercise tolerance is

compromised. A positive metacholine challenge will uncover the reversible

bronchoconstriction in patients with cough-variant asthma.

As discussed above, management of asthma relies on bronchodilators,

corticosteroids, and leukotriene antagonists.

References

Textbooks

Boron, W, and Boulpaep, E. Medical Physiology Saunders 2005

Goldman, L. and Schaefer, A. Cecil’s Medicine 24e 2011

Guyton, A.C. and Hall, J.E. Textbook of Medical Physiology 11e Saunders 2006

Kasper, D. L. et al Harrison’s Principles of Internal Medicine 16e McGraw Hill 2005

Kumar, V. et al Robbins Pathologic Basis of Disease 7e 2004

Leff, A.R. and Schumacker, P.T. Respiratory Physiology: Basics and Applications Saunders

1993

Levitzky, M.G. Pulmonary Physiology 3e McGraw Hill 1991

Mason, R.J. et al Murray and Nadel’s Textbook of Respiratory Medicine 4e Saunders 2005

Staub, N.C. Basic Respiratory Physiology Churchill Livingstone 1991

Widmaier, E.P. et al Vander’s Human Physiology 9e McGraw Hill 2004

Articles and Chapters

Busse, W,W. and Lemanske,R.R., Asthma N Engl J Med 344: 350-362, 2001

Crapo, R.O., Pulmonary Function Testing in Baum, G. et al Textbook of Pulmonary

Diseases 6e Lippincott-Raven 1998

Drazen, J.M. Asthma in Goldman, L. Cecil’s Medicine 24e Saunders, 2011

Gern, J. E. and Busse, W. W., Relationship of viral infections to wheezing illnesses and

asthma Nature Rev Immunol 2: 132-138, 2002

Holgate, S. T, et al, Asthma Pathogenesis in Atkinson, N.F. Middleton’s Allergy: Principles

and Practice 7e Mosby 2008

Holgate, S. T., Asthma: a simple concept but in reality a complex disease European J Clin

Investig. 41: 1339-1352, 2011

Lugogo, N. et al, in Murray and Nadel’s Textbook of Respiratory Medicine 5e Saunders

2010

McFadden, E. Asthma in Harrison’s Principles of Internal Medicine 16e McGraw Hill 2005

Strickland, D.H. and Holt, P.G.. T regulatory cells in childhood asthma Trends in

Immunology 32: 420-427, 2011

Wang, Y.H. and Willis-Karp, M., The Potential Role of Interleukin-17 in Severe Asthma Curr

Allergy Arthritis Rep 11: 388-394, 2011