PATHOLOGY: Implications for the Physical Therapist

ENVIRONMENTAL AND OCCUPATIONAL DISEASES

The relationship between occupations and disease has been observed, studied, and documented for many years. An in-depth discussion of this broad topic is included in Chapter 4. This chapter discusses only environmental and occupational diseases related to the lung. Occupational diseases can be divided into three major categories: (1) inorganic dusts (pneumoconioses); (2) organic dusts (hypersensitivity pneumonitis); and (3) fumes, gases, and smoke inhalation. These three categories have pathologic characteristics in common, including involvement of the pulmonary parenchyma with a fibrotic response.

Pneumoconiosis

Overview

Any group of lung diseases resulting from inhalation of particles of industrial substances, particularly inorganic dusts, such as those from iron ore or coal, with permanent deposition of substantial amounts of such particles in the lung, is included in the generic term of pneumoconiosis (dusty lungs). Clinically common pneumoconioses include coal workers’ pneumoconiosis, silicosis, and asbestosis. Other types of pneumoconiosis include talc, beryllium lung disease (berylliosis), aluminum pneumoconiosis, cadmium workers’ disease, and siderosis (inhalation of iron or other metallic particles). Farmers in dry climate regions exposed to respirable dust (inorganic agricultural dusts) during farming activities (e.g., plowing and tilling) and toxic gases (e.g., from animal confinement) may develop chronic bronchitis, hypersensitivity pneumonitis, and pulmonary fibrosis.

Incidence and Etiologic Factors

Obviously occurring in occupational groups, pneumoconiosis is most common among miners, sandblasters, stonecutters, asbestos workers, insulators, and agriculture workers. There is an increasing incidence with age because of cumulative effects of exposure, but overall incidence of diseases caused by mineral dust has declined recently in postindustrial countries. Instead, there is a rise in occupational asthma and illnesses caused by exposure in new office buildings and hospitals.³⁵

Silicosis, formerly called potters’ asthma, stonecutters’ cough, miners’ mold, and grinders’ rot, is most likely to be contracted in today’s industrial jobs involving sandblasting in tunnels, hard-rock mining (extraction and processing of ores), and preparation and use of sand. It can occur in anyone habitually exposed (usually over a period of 10 years) to the dust contained in silica, and any miner is subject to it. Usually, silicosis is associated with extensive or prolonged inhalation of free silica (silicon dioxide) particles in the crystalline form of quartz.

Risk Factors

Higher-risk workplaces are those with obvious dust, smoke, or vapor or those in which there is spraying, painting, or drying of coated surfaces. Heavier exposure occurs when there is friction, grinding, heat, or blasting; when very small particles are generated; and in enclosed spaces.

Not all clients exposed to occupational inhalants will develop lung disease. Harmful effects depend on the (1) type of exposure, (2) duration and intensity of exposure, (3) presence of underlying pulmonary disease, (4) smoking history, and (5) particle size and water solubility of the inhalant. The larger the particle, the lower the probability of its reaching the lower respiratory tract; highly water-soluble inhalants tend to dissolve and react in the upper respiratory tract, whereas poorly soluble substances may travel as far as the alveoli.

The risk of lung cancer in those who both smoke and are exposed to asbestosis is increased in a multiplicative way.⁴⁴ Exposure to significant amounts of asbestos is most common when asbestos materials are disturbed during renovation, repair, or demolition of older buildings containing asbestos materials.

Exposure while washing clothes soiled with these toxic substances has caused mesothelioma (malignancy associated with asbestos exposure) and berylliosis (beryllium lung disease associated with exposure to beryllium used in the manufacture of fluorescent lamps before 1950). Beryllium is used today as a metal in structural materials employed in aerospace industries, in the manufacture of industrial ceramics, and in atomic reactors, so exposure is still possible.

Pathogenesis

Dust particles (indestructible mineral fibers) that are not filtered out by the nasociliary mechanism or mucociliary escalator may be deposited anywhere in the respiratory tract and lungs, especially the small airways and alveoli. Each disease has its own pathogenesis, but in general the most dangerous dust particles measure 2 μm or less and are deposited in the smallest bronchioles and the acini (see Fig. 15-2). The particles are ingested by alveolar macrophages, and most of the phagocytosed particles ascend to the mucociliary lining and are expectorated or swallowed. Some migrate into the interstitium of the lung and then into the lymphatics. These indestructible mineral fibers can actually pierce the lung cells. In response to the continued presence of these fibers and to the cell damage, activated macrophages secrete fibroblast-stimulating factor, which in turn mediates excessive fibrosis (i.e., the thickening and scarring of lung tissue that occur around the mineral fiber).

In coal workers’ pneumoconiosis, ingestion of inhaled coal dust by alveolar macrophages leads to the formation of coal macules, which appear on the radiograph as diffuse small opacities (or white areas) in the upper lung. Anthracite or hard coal is associated with a higher incidence of black lung than is bituminous or soft coal.

In the pathogenesis of silicosis, groups of silicon hydroxide on the surface of the particles form hydrogen bonds with phospholipids and proteins, an interaction that is presumed to damage cellular membranes and thereby kill the macrophage. The dead macrophages release free silica particles and fibrogenic factors. The released silica is then reingested by macrophages, and the process is amplified.

Between 10 and 40 years after initial exposure to silica, small rounded opacities called silicotic nodules form throughout the lung. These fibrotic nodules scar the lungs and make them receptive to further complications (e.g., TB, bronchitis, or emphysema).

Asbestosis is characterized by inhalation of asbestos fibers, a fibrous magnesium and calcium silicate nonburning compound used in roofing materials, insulation for electric circuits, brake linings, and many other products that must be fire-resistant. As with the other pneumoconioses, asbestos particles are engulfed by macrophages. Once activated, macrophages then release inflammatory mediators resulting in nodular interstitial fibrosis that can be seen on radiographs along with thickened pleura.

After an interval of 10 to 20 years between exposure and further complications, calcified pleural plaques on the dome of the diaphragm or lateral chest wall develop. The lower portions of the lungs are more often involved than the upper portions in asbestosis.

How asbestos causes mesothelioma is unclear; the formation of oxygen free radicals by macrophages can be a cause of chromosomal damage, or there may be a growth factor that governs individual susceptibility to mineral fiber–induced mesothelioma. Other mechanisms of oncogenesis have been proposed but remain unconfirmed.^76,353

Clinical Manifestations

Symptoms of pneumoconioses from dust exposure include progressive dyspnea, chest pain, chronic cough, and expectoration of mucus containing the offending particles. In rare cases, rheumatoid arthritis coexisting primarily with coal workers’ pneumoconiosis but also with silicosis and asbestosis causes Caplan’s syndrome, a condition characterized by the presence of rheumatoid nodules in the periphery of the lung. Long-term exposure to acid and other substances produces ulceration and perforation of the septum, whereas nickel and certain wood dusts cause nasal carcinoma.

Work-related asthma can be an exacerbation of asthma that was previously subclinical or in remission (work-aggravated asthma), a new onset of asthma caused by a sensitizing exposure (asthma with latency), or asthma that results from a single heavy exposure to a potent respiratory irritant (referred to as asthma without latency, irritant asthma, or reactive airways dysfunction syn drome). Symptoms are as discussed in the section on Asthma in this chapter.

Simple silicosis is usually asymptomatic and has no effect on routine pulmonary function tests. As the disease progresses, mucus tinged with blood, loss of appetite, chest pain, and general weakness may occur. In complicated silicosis, dyspnea and obstructive and restrictive lung dysfunction occur.

Asbestosis is characterized by dyspnea, inspiratory crackles (on auscultation), and sometimes clubbing and cyanosis. As in the case of the other pneumoconioses, the simple or uncomplicated form of coal workers’ pneumoconiosis is uncommon, but the chronic form is often associated with chronic bronchitis and infections.

MEDICAL MANAGEMENT

PREVENTION.

Prevention is the first line of defense against occupational diseases. Workplace-based education, preemployment screening, yearly physical examinations, surveillance and exposure reduction, and elimination of the pathogen are essential components of a strategy to prevent occupational lung disorders. Precautions, such as the use of facemasks, protective clothing, and proper ventilation, are essential. Regular chest films are recommended for all workers exposed to silica as a means of early detection.

In 1971, asbestos became the first material to be regulated by the U.S. Occupational Safety and Health Administration (OSHA). The Environmental Protection Agency (EPA) has classified asbestos as a Group A human carcinogen, causing both lung cancer and mesothelioma. It is still unclear if lung cancer can occur as result of exposure to asbestos without the presence of asbestosis.¹⁹⁴ The EPA maintains the Integrated Risk Information System database on health effects of exposure to various substances. This agency also controls the National Emission Standards for Hazardous Air Pollutants (http://www.epa.gov).

DIAGNOSIS.

Identifying a workplace-related cause of disease is important because it can lead to cure and to prevention for others. The recognition of occupational causes can be difficult because of the latency period, delayed responses that occur at home either after work or years after exposure. Diagnosis is by history of exposure (which may be minimal with asbestosis and far removed in time from the onset of disease; the person may even be unaware of the exposure), sputum cytology, lung biopsy, chest film showing nodular or interstitial fibrosis, and pulmonary function studies.

Other pulmonary imaging techniques used in conjunction with the initial chest radiograph include conventional CT, high-resolution CT, and gallium scintigraphy. High-resolution CT scanning is the best imaging method to differentiate different origins of pneumoconiosis as presentation varies with the stimulus (silica, coal dust, iron dust, or asbestos). Magnetic resonance imaging (MRI) is helpful to distinguish progressive fibrosis from lung cancer^87,275 (see the section on Diagnosis under Lung Cancer in this chapter). Imaging alone is inadequate to make most diagnoses; clinical presentation of symptoms and lung function are also important.³⁶³ Genetic susceptibility may be associated with beryllium-induced disease and may play a role in mediating other types of pneumoconiosis.¹³⁶

TREATMENT.

There is no standard treatment for these diseases. The dust deposits are permanent so treatment is directed toward relief of symptoms. Corticosteroids may produce some improvement in silicosis. Although there is no cure for any of the pneumoconioses, the complications of chronic bronchitis, pulmonary hypertension, and cor pulmonale must be treated. When lung neoplasm occurs, surgical removal and therapeutic modalities, such as radiotherapy or chemotherapy, may be employed.

PROGNOSIS.

The devastating feature of pneumoconioses is that there may be no obvious symptoms until the disease is in an advanced state. Once fully developed, prognosis is poor for most occupational lung diseases, with progressive and disabling results. Simple silicosis is not ordinarily associated with significant respiratory dysfunction unless complicated by emphysema and chronic bronchitis from cigarette smoking.

Although now uncommon, acute silicosis resulting from heavy exposure to silica rarely responds to treatment and progresses rapidly over a few years when it occurs. The increased incidence of TB among people with silicosis presents an additional negative factor to the prognosis.

Exposure to asbestos, radon, silica, chromium, cadmium, nickel, arsenic, and beryllium may result in neoplasm. Crystalline silica is a known human carcinogen, but this link is not defined and may be overestimated.^253,339 Both bronchogenic carcinoma and mesotheliomas of the pleura and peritoneum have been linked to asbestos. The exposure typically occurs 20 years before the development of bronchogenic carcinoma and approximately 30 to 40 years before the appearance of mesothelioma. The disease culminates in the sixth decade, with few cases occurring before age 40 years. Although progress has been made, mesothelioma still has a 5-year survival rate of only 9%. New chemotherapy drugs have increased the life expectancy but are not curative.

Coal workers’ pneumoconiosis was once thought to cause severe disability, but it is now clear that black lung causes minor impairment of pulmonary function at its worst. When coal miners have severe air-flow obstruction, it is usually due to smoking.

15-15 SPECIAL IMPLICATIONS FOR THE THERAPIST

Pneumoconioses

PREFERRED PRACTICE PATTERNS

Other pulmonary pathologic conditions frequently occur in conjunction with pneumoconioses. Preferred practice patterns for chronic bronchitis, cor pulmonale, lung cancer, emphysema, or tuberculosis may also apply.

6C:

Impaired Ventilation, Respiration/Gas Exchange, and Aerobic Capacity/Endurance Associated with Airway Clearance Dysfunction

6E:

Impaired Ventilation and Respiration/Gas Exchange Associated with Ventilatory Pump Dysfunction or Failure

New materials are being introduced into the workplace at a faster rate than their potential toxicities can be evaluated despite the fact that many have a pathologic effect on the pulmonary system. The possibility of occupational lung disease should be considered whenever a working or retired person has unexplained respiratory illness.

The minute V/VO₂ ratio during exercise is more predictive of clinical dyspnea than airway obstruction in pneumoconioses. This ratio documents the degree of V/Q mismatch and can be useful for therapists in prescribing exercise programs.³³

Steam inhalation and airway clearance techniques, such as controlled coughing and segmental bronchial drainage with chest percussion and vibration, help clear secretions. Exercise tolerance must be increased slowly over a long period beginning with increasing regular activities of daily living. Daily activities should be planned carefully to conserve energy (see Box 9-8), to decrease the WOB, and to afford frequent rest periods.

Graded progression from increasing tolerance for daily activities to a conditioning program may precede or replace an aggressive exercise program. In severe cases, oxygen may be necessary for any increase in activity level or exercise and the person may not progress beyond self-care skills.

Hypersensitivity Pneumonitis

Exposure to organic dusts may result in hypersensitivity pneumonitis, also called extrinsic allergic alveolitis. The alveoli and distal airways are most often involved as a result of inhalation of organic dusts and active chemicals. Most of the diseases are named according to the specific antigen or occupation and involve organic materials such as molds (e.g., mushroom compost, moldy hay, sugar cane, or logs left unprotected from moisture), fungal spores (e.g., stagnant water in air conditioners and central heating units), plant fibers or wood dust (particularly redwood and maple and cotton), cork dust, coffee beans, bird feathers, and hydroxyurea (cytotoxic agent).

Gram-bacterial endotoxins may be more to blame than dust in causing pneumonitis in cotton textile workers.⁴⁴⁰ Mycobacteria have also been shown to be responsible for hypersensitivity pneumonitis in industrial metal grinding and in “hot tub lung.”^7,187

Regardless of the specific antigen involved in the pathogenesis of hypersensitivity pneumonitis, the pathologic alterations in the lung are similar. A combination of immune complex–mediated and T cell–mediated hypersensitivity reactions occurs, although the exact mechanism of these processes is still unknown.

Host factors, such as cigarette smoking and the presence of some human leukocyte antigen (HLA) proteins, also play an important role in the development or suppression of the disease. Most characteristic is the presence of scattered, poorly formed granulomas that contain foreign body giant cells. Mild fibrosis may occur, usually in the alveolar walls.

The diagnosis of hypersensitivity pneumonitis of an organic origin is made by history of exposure, pulmonary function studies, inflammatory mediators in sputum, and clinical manifestations, which commonly include abrupt onset of dyspnea, fever, chills, and a nonproductive cough.

Initially, symptoms may be reversed by removing the worker from the exposure (the only adequate treatment), modifying the materials-handling process, or using protective clothing and masks. The symptoms typically remit within 24 to 48 hours but return on reexposure and with time and in some people, may become chronic.

Hypersensitivity pneumonitis may present as acute, subacute, or chronic pulmonary disease depending on the frequency and intensity of exposure to the antigen. The prognosis is poor with repeated exposure to these organic dusts, resulting in nonreversible interstitial fibrosis and other adverse respiratory effects.

Noxious Gases, Fumes, and Smoke Inhalation

Exposure to toxic gases and fumes is an increasing problem in modern industrial society. Any time oxygen in the air is replaced by another toxic or nontoxic agent, asphyxia (deficient blood oxygen and increased carbon dioxide in blood and tissues) occurs. Such is the case when products manufactured from synthetic compounds are heated at high temperatures, releasing fumes. For example, workers who use heating elements to seal meat in plastic wrappers and workers involved in the manufacture of plastics and packaging materials made of polyvinyl chlorides are exposed to these fumes. Workers exposed to the artificial butter flavoring for popcorn, diacetyl, have developed significant respiratory obstruction.²⁵¹

The most common mechanism of injury is local irritation, the specific type and extent depending on the type and concentration of gas and the duration of exposure. For example, highly soluble gases, such as ammonia, rapidly injure the mucous membranes of the eye and upper airway, causing an intense burning pain in the eyes, nose, and throat. Insoluble gases, such as nitrogen dioxide, encountered by farmers cause diffuse lung injury.

Metal fume fever is a systemic response to inhalation of certain metal dusts and fumes such as zinc oxide used in galvanizing iron, the manufacture of brass, and chrome and copper plating. Symptoms include fever and chills, cough, dyspnea, thirst, metallic taste, salivation, myalgias, headache, and malaise. Welding fumes create exposure to multiple hazardous agents and cause varied respiratory and systemic pathology.²⁹⁷ Polymer fume fever, associated with heating of polymers, may cause similar symptoms. With brief exposures, the symptoms associated with these two syndromes are self-limiting, but prolonged exposure results in chronic cough, hemoptysis, and impairment of pulmonary function associated with a wide range of lung pathologic conditions.

Chemical pneumonitis can result from exposure to toxic fumes. The acute reaction may produce diffuse lung injury characterized by air space disease typical of pulmonary edema. In its chronic form, bronchiolitis obliterans develops.

Smoke inhalation injury produces direct mucosal injury secondary to hot gases, tissue anoxia caused by combustion products, and asphyxia as oxygen is consumed by fire. Thermal injury seen in the upper airway is characterized by edema and obstruction. Incomplete combustion of industrial compounds produces ammonia, acrolein, sulfur dioxide, and other substances in today’s fires.

Environmental tobacco smoke (ETS), or exposure to secondhand smoke among nonsmokers, is widespread. Home and workplace environments are major sources of exposure. A total of 15 million children are estimated to be exposed to secondhand smoke in their homes annually. ETS increases the risk of heart disease and respiratory infections in children, increases the risk of lung cancer by a factor of 2 to 3, and is responsible for an estimated 3000 cancer deaths of adult nonsmokers and 2300 deaths from suden infant death syndrome (SIDS) annually.³⁴⁴

Infants born to women exposed to ETS during pregnancy have an increased chance of decreased birth weight and intrauterine growth retardation.¹⁹⁵ Prenatal exposure to mainstream smoke from the mother and even to ETS from the mother has been shown to change fetal lung devel opment and cause air-flow obstruction, promote airway hyperresponsiveness and early development of asthma and allergy, and double the odds of future attention deficit hyperactivity disorder.^214,256

Newborns, infants, and children under the age of 2 years are at high risk for cardiovascular effects if they are exposed to household ETS during this time. Endothelial cells of the blood vessels damaged as a result of exposure to passive smoking can be measured during the first decade of life. ETS over a period of more than 10 years changes the intima/media ratio by enhancing the thickness of the vessel wall. Other effects of involuntary smoking among children may include middle ear disease, upper and lower respiratory infections, and asthma.^215,416

ETS is associated with rhinitis symptoms of runny nose and nasal congestion in some people and is associated with decreased flow in the airways, bronchial hyperresponsiveness, and increased respiratory infections.¹⁶⁴ Other symptoms following exposure to secondhand tobacco smoke may include headache, chest discomfort or tightness, and cough. See also the section on Lung Cancer in this chapter.

CONGENITAL DISORDERS

Cystic Fibrosis

Definition and Overview

CF is an inherited disorder of ion transport (sodium and chloride) in the exocrine glands affecting the hepatic, digestive, male reproductive (the vas deferens is functionally disrupted in nearly all cases), and respiratory systems (Fig. 15-14). The basic genetic defect predisposes to chronic bacterial airway infections, and almost all persons develop obstructive lung disease associated with chronic infection that leads to progressive loss of pulmonary function.

Figure 15-14 Various effects of exocrine gland dysfunction in cystic fibrosis. (From Wong DL: Whaley and Wong’s essentials of pediatric nursing, ed 4, St Louis, 1993, Mosby.)

Incidence

CF is the most common inherited genetic disease in the white population, affecting approximately 30,000 children and young adults (equal gender distribution) in the United States. More than 1000 new cases are diagnosed each year. The disease is inherited as an autosomal recessive trait, meaning that both parents must be carriers so that the child inherits a defective gene from each one. In the United States, 5% of the population, or 12 million people, carry a single copy of the CF gene. Each time two carriers conceive a child, there is a 25% chance (1: 4) that the child will have CF, a 50% (1: 2) chance that the child will be a carrier, and a 25% chance that the child will be a noncarrier.

Ten percent of new cases are diagnosed in those over 18 years of age.¹⁰⁴ The severity of the disease is strongly correlated with socioeconomic status and access to health care.³⁷⁶

Etiologic Factors

In recent years, there have been major advances in understanding the underlying genetic factors related to this disease. In 1985, the CF gene was located on the long arm of chromosome 7. In 1989, the gene for CF was cloned and abnormalities in the CF transmembrane conductance regulator (CFTR) protein were attributed to CF. Clones are identical copies of genes used to study the DNA sequence that allows scientists to determine the nature and function of the protein encoded by the gene. Cloning opens up the possibility of gene therapy for a disorder. It should be noted that the CFTR genotype is not a good predictor of disease severity, and a modifier gene has yet to be identified.^101,109

In healthy people, this CFTR protein provides a channel by which chloride (a component of salt) can pass in and out of the plasma membrane of many epithelial cells, including those of the kidney, gut, and conducting airways. Clients with CF have a defective gene that normally enables cells to form or regulate that channel.

At least two gating mechanisms of CFTR are now known; one relies on hydrolysis and the second depends on stable adenosine triphosphate (ATP) binding.¹⁸⁸ There are complex relationships between CFTR, the epithelial sodium channel, and mucociliary clearance, which are currently being examined.²⁰⁶ The loss of CFTR function appears to be as important as the defective transport channel.³⁷

Over 300 mutations in the CF gene affecting the CFTR protein have been described, but not all of the mutations have been identified, so mass screening cannot yet identify individuals carrying the gene for CF who would otherwise test negative. New tests are being developed to more reliably detect for mutations.²³²

Inflammation plays a role in lung damage associated with CF unrelated to the genetic defect.¹¹⁰ The role of polymorphism (individual variation) of a gene that regulates protection from lung injury (by producing a sub- stance called glutathione) has strong association with the severity of CF lung disease.²⁹²

Pathogenesis

Much about the complex pathogenesis of CF is still unknown, but it does appear that this impermeability of epithelial cells to chloride results in (1) dehydrated and increased viscosity of mucous gland secretions, primarily in the lungs, pancreas, intestine, and sweat glands; (2) elevation of sweat electrolytes (sodium chloride); and (3) pancreatic enzyme insufficiency. The dehydration resulting in thick, viscous mucous gland secretions causes the mechanical obstruction responsible for the multiple clinical manifestations of CF.

Bronchial and bronchiolar obstruction by the abnormal mucus predisposes the lung to infection and causes patchy atelectasis with hyperinflation. The disease progresses from mucous plugging and inflammation of small airways (bronchiolitis) to bronchitis, followed by bronchiectasis, pneumonia, fibrosis, and the formation of large cystic dilations that involve all bronchi. A summary of differences among these various respiratory diseases is provided (Table 15-10).

Table 15-10

Respiratory Disease Summary of Differences

Disease	Primary Area Affected	Result
Acute bronchitis	Membrane lining bronchial tubes	Inflammation of lining.
Bronchiectasis	Bronchial tubes (bronchi or air passages)	Bronchial dilation with inflammation.
Pneumonia	Alveoli (air sacs)	Causative agent invades alveoli with resultant outpouring from lung capillaries into air spaces and continued healing process.
Chronic bronchitis	Larger bronchi initially; all airways eventually	Increased mucus production (number and size) causing airway obstruction.
Emphysema	Air spaces beyond terminal bronchioles (alveoli)	Breakdown of alveolar walls; spaces enlarged.
Asthma	Bronchioles (small airways)	Bronchioles obstructed by muscle spasm, swelling of mucosa, thick secretions.
Cystic fibrosis	Bronchioles	Bronchioles become obstructed and obliterated; later larger airways become involved; mucous plugs cling to airway walls, leading to bronchitis, bronchiectasis, atelectasis, pneumonia, or pulmonary abscess.

From Goodman CC, Snyder TE: Differential diagnosis for the physical therapist, ed 4, Philadelphia, 2007, Saunders

New findings about how specific molecules signal the onset of inflammation and tissue-damaging enzymes and how these chemicals all interact are adding to the knowledge base of CF pathophysiology. For example, in CF lungs, a decreased level of nitric oxide (NO; this is not the same as nitrous oxide [N₂O]), a chemical that decreases inflammation, may be explained by the loss of an enzyme needed to produce NO.

Several laboratories are working to identify how a defect in CFTR causes the loss of NO or the needed enzymes. The inflammatory response against bacteria in the airways of individuals with CF involves the generation of reactive oxygen species (formation of free radicals) leading to further inflammation and tissue damage. Without the necessary NO, a vicious cycle of inflammatory-immune processes and bacteria survival persists. Restoring the balance of oxidants and antioxidants could restore health in the CF lung.

New data on the structure of CFTR, including the size and shape of the channel through which the chloride must pass, how to stabilize the channel and increase the time it stays open, and the life cycle of this protein, are being used to provide scientists with ideas for new treatments.

Other researchers are investigating why the CF lung is so receptive to the onslaught of infection by examining the role of defensin and other bacteria-killing molecules in the CF airway and the inhibition of these antimicrobial peptides by high salt concentrations.

Clinical Manifestations

The consistent finding of abnormally high sodium and chloride concentrations in the sweat is a unique characteristic of CF. Parents frequently observe that their infants taste salty when they kiss them. Almost all clinical manifestations of CF are a result of overproduction of extremely viscous mucus and deficiency of pancreatic enzymes.

A complete list of clinical manifestations by organ and in order of progression is given in Box 15-7. Recurrent pneumothorax, hemoptysis, pulmonary hypertension, and cor pulmonale are serious and life-threatening complications of severe and diffuse CF pulmonary disease.

Box 15-7 CLINICAL MANIFESTATIONS OF CYSTIC FIBROSIS

Early Stages

Persistent coughing

Sputum production

Persistent wheezing

Recurrent pulmonary infection

Excessive appetite, poor weight gain

Salty skin and sweat

Bulky, foul-smelling stools

Pulmonary

Initial

Wheezy respirations

Dry, nonproductive cough

Progressive Involvement

Increased dyspnea

Decreased exercise tolerance

Paroxysmal cough

Tachypnea

Obstructive emphysema

Patchy areas of atelectasis

Nasal polyps, chronic sinusitis

Advanced Stage

Barrel chest

Kyphosis

Pectus carinatum

Cyanosis

Clubbing (fingers and toes)

Recurrent bronchitis

Recurrent bronchopneumonia

Pneumothorax

Hemoptysis

Right-sided heart failure secondary to pulmonary hypertension

Gastrointestinal

Voracious appetite (early)

Anorexia (late)

Weight loss

Failure to thrive or grow; protein-calorie malnutrition

Distended abdomen

Thin extremities

Sallow (yellowish) skin

Acute gastroesophageal reflux (GERD)

Intussusception

Distal Intestinal Obstruction Syndrome (Meconium Ileus)

Abdominal distention

Colicky, abdominal pain

Vomiting

Failure to pass stools (constipation)

Rapid development of dehydration

Anemia

Liver

Cirrhosis

Portal hypertension

Pancreatic

Large, bulky, loose, frothy, foul-smelling stools (pancreatic enzyme insufficiency)

Fat-soluble vitamin deficiency (vitamins A, D, E, K)

Recurrent pancreatitis

Iron deficiency anemia

Malnutrition

Diabetes mellitus

Genitourinary

Male urogenital abnormalities

Delay in sexual development

Sterility (most males); infertility (some females)

Musculoskeletal

Marked tissue wasting, muscle atrophy

Myalgia

Osteoarthropathy (adult)

Rheumatoid arthritis (adult)

Osteopenia/osteoporosis (adult)

Pancreas.: Approximately 90% of clients have pancreatic insufficiency with thick secretions blocking the pancreatic ducts and causing dilation of the small lobes of the pancreas, degeneration, and eventual progressive fibrosis throughout. The blockage also prevents essential pancreatic enzymes from reaching the duodenum, thus impairing digestion and absorption of nutrients. Clinically, this process results in bulky, frothy (undigested fats because of a lack of amylase and tryptase enzymes), and foul-smelling stools (decomposition of proteins producing compounds such as hydrogen sulfide and ammonia).

As the life expectancy for people with CF has improved, the incidence of glucose intolerance and CF-related diabetes has increased because pancreatic damage can eventually affect the beta-cells. Hyperglycemia may adversely influence nutritional status and weight, pulmonary function, and development of late microvascular complications.⁴⁴⁸

Gastrointestinal.: The earliest manifestation of CF, meconium ileus (sometimes referred to as distal intestinal obstruction syndrome), is present in approximately 10% to 15% of newborns with CF; the small intestine is blocked with thick, puttylike tenacious meconium. Prolapse of the rectum is the most common gastrointestinal complication associated with CF, occurring most often in infancy and childhood.

Children of all ages with CF are susceptible to intestinal obstruction from thickened, dried, or impacted stools (inspissated meconium). Advances in investigative techniques have led to increasing reports of Crohn’s disease and ischemic bowel disease in persons with CF. Prolonged administration of excessive doses of pancreatic enzymes is associated with the development of fibrosing colonopathy. To avoid this complication, current recommendation for a daily dose of pancreatic enzymes for most people with CF is below 10,000 units of lipase per kilogram per day.

A new enzyme, TheraCLEC-Total (TCT), has been shown to be promising in improving absorption of fat and nutrients and is ready for type 2 clinical trials.⁵⁰ Poor nutrition and weight loss are common as a result of malabsorption, inadequate oral intake, early satiety, and increased utilization of calories.

Pulmonary.: Chronic cough and purulent sputum production are symptomatic of lung involvement. The child is unable to expectorate the mucus because of its increased viscosity. This retained mucus provides an excellent medium for bacterial growth, placing the individual at increased risk for infection. Reduced oxygen–carbon dioxide exchange causes variable degrees of hypoxia, clubbing (see Fig. 15-4), cyanosis, hypercapnia, and resultant acidosis. Chronic pulmonary infection and hyperinflation lead to secondary manifestations of barrel chest, pectus carinatum, and kyphosis.

The most common complication of CF is an exacerbation of pulmonary disease requiring medical and physical therapy intervention. Early warning signs (Box 15-8) must be recognized and treatment initiated (referred to as a “tune-up”), preferably at home but sometimes in the hospital. Respiratory failure is a frequent complication of severe pulmonary disease in persons with CF and is the most common cause of CF-related deaths.

Box 15-8 SIGNS AND SYMPTOMS OF PULMONARY EXACERBATION IN CYSTIC FIBROSIS

Increased cough

Increased sputum production and/or a change in appearance of sputum

Fever

Weight loss

School or work absenteeism (because of illness)

Increased respiratory rate and/or WOB

New findings on chest examination (e.g., wheezing, crackles)

Decreased exercise tolerance

Decrease in FEV₁ of 10% or more from baseline value within past 3 months

Decrease in hemoglobin saturation of 10% or more from baseline value within past 3 months

New finding(s) on chest x-ray

WOB, Work of breathing; FEV₁, forced expiratory volume in 1 second.

From Cystic Fibrosis Foundation: Clinical practice guidelines for cystic fibrosis, Bethesda, Md, 1997, The Foundation.

Liver.: Liver involvement in CF is much less frequent than both pulmonary and pancreatic diseases, which are present in 80% to 90% of individuals with CF. Liver disease affects only one third of the CF population; however, because of the decreasing mortality from extrahepatic causes, its recognition and management are becoming a relevant clinical issue.^92a

Recent observations suggest that clinical expression of liver disease in CF may be influenced by genetic modifiers; their identification is an important issue because it may allow recognition of people at risk for the development of liver disease at the time of diagnosis of CF and early institution of prophylactic strategies.^92a

Genitourinary.: Genitourinary manifestations are primarily related to reproduction; infertility once thought to be universal in men and common in women may be treated successfully with new techniques for in vitro fertilization. The vas deferens may be absent bilaterally, or if present, it is obstructed so that although sperm production is normal, blockage or fibrosis of the vas deferens prevents release of the sperm into the semen (azoospermia). Women experience decreased fertility because thick mucus in the cervical canal prevents conception. As the disease progresses, there is also an increased incidence of amenorrhea.

Musculoskeletal.: Muscle pain is reported and may be alleviated with proper nutrition and exercise, although this is based on anecdotal information and has not been verified in studies. Decreased BMD and bone mineral content are common at all ages in CF, attributed to multifactorial causes (e.g., nutrition, exposure to glucocorticoid therapy, gonadal dysfunction, age, body mass, or activity). Spinal consequences of bone loss include excessive kyphosis and neck and back pain. Lung transplant is also associated with increased osteoporosis from long-term immunosuppression.

Hypertrophic pulmonary osteoarthropathy occurs with increasing frequency with increasing age and severity of disease in 2% to 7% of affected individuals. This condition is accompanied by clubbing of the fingers and toes; arthritis; painful periosteal new bone formation (especially over the tibia); and swelling of the wrists, elbows, knees, or ankles. The periostitis is observed radiographically in the diaphysis of the tubular bones and may be a single layer or a solid cloaking of the bone.

Separately and usually without association with other manifestations of CF, attacks of episodic arthritis accompanied by severe joint pain, stiffness, rash, and fever may occur intermittently but repeatedly. Also related to CF are rheumatoid arthritis, spondyloarthropathies, sarcoidosis, and amyloidosis, which are caused by coexistent conditions and drug reactions.⁵¹

MEDICAL MANAGEMENT

DIAGNOSIS.

Now that the gene responsible for CF has been identified, prenatal diagnosis and screening of carriers are possible as part of genetic counseling. The tests only detect mutations already observed but account for 70% (those with the DF508 mutation) of all CF carriers. In 2004, the CDC issued a recommendation that all newborns should be screened for CF and currently 18 states and the District of Columbia do routine screening. Prepregnancy genetic testing that involves DNA analysis of oocytes is available for couples at risk for having children with CF.

About one-half of all children with CF present in infancy with failure to thrive, respiratory compromise, or both. The age at presentation can vary, and some people are not diagnosed until adulthood. CF is traditionally diagnosed using the sweat test; a positive test occurs when the sodium chloride concentration is greater than 60 mEq/L for anyone younger than 20 years (reference value: 40 mEq/L) and above 80 mEq/L for those over 20 years.³⁹⁶

Although elevated sweat electrolytes are associated with other conditions, a positive sweat test coupled with the clinical picture usually confirms the diagnosis. The test should be performed at a certified CF center and repeated a second time. Alternatively, CF can be diagnosed by genotype analysis (performed prenatally or postnatally). CF can be diagnosed on DNA alone.

Pancreatic elastase-1 (EL-1), a marker of exocrine pancreatic insufficiency in CF, can be measured in feces. EL-1 is a specific human protease synthesized by the acinar cells of the pancreas and is a reliable test of pancreatic sufficiency over the age of 2 weeks. Fecal elastase has good sensitivity and specificity and predictive values for severe cases of pancreatic insufficiency. This test can be used to rule out the diagnosis of CF, to confirm the need for pancreatic enzymes, and for annual monitoring of pancreatic-sufficient individuals to detect the onset of pancreatic insufficiency. Other tests, including a breath test, are being developed and tested.⁵⁰

Pulmonary function tests are performed in affected individuals from the age of 6 and up to measure and monitor lung function over time (see Table 40-22). These tests are used to classify the severity of baseline lung disease. Almost all measures are based on the flow of air into and out of the lungs in a given period of time.

The two most common lung function measures are FEV₁ (forced expiratory volume in 1 second) and FVC (forced vital capacity). These tests should be repeated two to four times each year for adults to assess the effectiveness of treatment; pulmonary function declines with progressive lung disease.

Diabetes mellitus should be identified early by screening with a glucose tolerance test from the age of 15 years and treated with insulin, dietary management, and exercise from the time of diagnosis of diabetes. Symptoms of CF-related diabetes are often confused with pulmonary infection. Diabetes significantly impacts the course of CF, though the relationship is not clear. The microvascular system should be screened annually for complications.⁹⁶

Several scoring systems have been developed to assess disease severity, measure acute changes, and evaluate appropriateness for lung transplant. The most reliable and useful are the modified Shwachman and modified Huang scores. There is a need for a longitudinal assessment tool to follow individuals with milder CF.¹⁸³

Diagnosis of CF in adulthood is generally due to a milder presentation of the disease and has a more favorable prognosis. Adults with unexplained chronic respiratory infections, bronchiectasis, pancreatitis, or absence of vas deferens should be screened for CF.^319,396

TREATMENT.

A multidisciplinary approach must be taken in treating CF toward the goal of promoting a normal life for the individual. The treatment of CF depends on the stage of the disease and which organs are involved. Medical management is oriented toward alleviating symptoms and includes the use of antibiotics, aggressive pulmonary therapy with drugs (mucolytics) to thin mucous secretions, airway clearance techniques, supplemental oxygen, and adequate hydration and enhanced nutrition with pancreatic enzymes administered before or with meals.

Pharmacotherapy.: Drug therapy for CF has been primarily directed at prophylaxis and treatment of infections with antibiotics, targeting inflammation, and supplementing digestive enzymes and vitamins. Pharmacotherapy (Table 15-11) to date has included broad-spectrum antimicrobials to protect the respiratory epithelium from damage and aerosolized antibiotics (e.g., tobramycin) that deliver a more concentrated dose directly to the site of infection.

Table 15-11

Pharmacotherapy for Cystic Fibrosis

Courtesy Susan Queen, PT, PhD, University of New Mexico, Albuquerque, NM.

Macrolides, a class of antibiotics, have the added benefit of suppressing inflammatory mediators and interfering with biofilm that is produced by Pseudomonas aeruginosa.¹⁵² Although no randomized control studies have been conducted, a totally implantable venous intravenous access device (TIVAD) for adults is widely used for CF as a means of providing long-term intravenous access for those individuals requiring intermittent antibiotics. The risks of mechanical failure, sepsis, and thrombosis have made this device more successful when inserted and cared for at a CF center.^17,129,235

Other pharmacologic treatment may include sympathomimetics to control bronchospasm, parasympatholytics to offset smooth muscle constriction and bronchodilation, inhaled antiinflammatory agents to decrease the amount of inflammation in the airways, and mucolytics to thin mucous secretions. Inhaled bronchodilators are effective in individuals who have bronchial hyperresponsiveness.¹⁸⁵

Recombinant human deoxyribonuclease I (rhDNAase I), or Dornase alfa, a mucolytic, is effectively used to reduce sputum viscosity and increase mucociliary clearance.⁴⁰⁹ The use of hypertonic saline, an inexpensive, “low-tech” intervention, has gained in popularity since the hypertonic saline study in Australia. First, a bronchodilator is administered to open the airways, then the saline solution is used to replenish salt depleted from the liquid that lines the airways. This combination of treatment results in fewer flare-ups and faster recovery and is just one of many newer CF treatments.¹²⁶

Hypertonic saline improves airway clearance but is not as effective as DNAase in longer term lung improvement.⁴⁴² Administered 30 minutes before airway clearance treatments, these combined treatment interventions improve the quality of life for people with CF by decreasing their hypoxemia and reducing their dyspnea. The end result is improved sleep patterns, increased activity, and improved nutritional status.

High-dose ibuprofen (the generic name for the drug found in Advil, Motrin, and Nuprin) may be used to slow the deterioration of the lungs by reducing inflammation and breaking the cycle of mucus buildup, infection, and inflammatory destruction. Neutrophils are responsible for much of the inflammatory response and are unresponsive to traditional chemotherapeutic treatment.

New knowledge as to the mechanisms controlling Ca(2+) homeostasis is stimulating novel approaches to stemming the inflammatory response.⁴²¹ Leukotriene-receptor antagonists also have shown the potential to reduce inflammation and improve lung function.³⁷⁸ Investigations into the role of platelets in contributing to the inflammatory response in CF are currently underway.³²⁸

Pharmacologic intervention with microencapsulated pancreatic enzymes is critical when pancreatic involve ment is severe. Aggressive nutritional management is needed to ameliorate the effects of malabsorption and the side effects of therapeutic intervention. Calcium supplements are warranted because of the high incidence of osteopenia and fractures.²⁰

Supplemental oxygen may improve exercise endurance and peak performance. Mild hypercapnia (too much carbon dioxide in the blood) can occur with exercise and during sleep. More research is needed to assess the benefits of oxygen therapy.²⁷¹ Oral bile acid therapy, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the only available therapeutic approach for CF-associated liver disease.^92a

Gene Therapy.: The identification of the mutated CF gene in 1989 was followed by the first phase of gene therapy in 1993 to correct the basic defect in CF cells, rather than relying on treatment of the symptoms. Finding a way to deliver the normal copy of the gene into the lung or intrahepatic biliary epithelial cells with adequate gene expression remains a challenge. Obstacles include vector toxicity and ineffective transgene expression.⁴¹⁷

It is possible that delivery through an aerosolized technique will incorporate sufficient quantities of the CFTR gene into the cells without toxicity and stimulating an immune response.¹¹⁴ The expectation is that the normal CFTR will reverse the physiologic defect in CF cells.

In the future, current therapeutic measures, such as intravenous antimicrobial treatment, will be improved by the additional delivery of new drugs to the bronchial tree by aerosol. Antibiotics, as well as protease inhibitors delivered by aerosol, should help to prevent damage by infection and inflammation and increase the probability of successful somatic gene therapy in this disease.

Transplantation.: Double-lung or heart-lung transplants have been used with children and adults with advanced pulmonary vascular disease and who are severely disabled by dyspnea and hypoxia. In the United States, the United Network for Organ Sharing has addressed perceived inequities in organ distribution by allocating organs by illness severity rather than time on the waiting list. A lung allocation score ranks severity for patients 12 years of age and older for transplantation based on variables, including lung function, oxygen and ventilatory needs, diabetes, weight, and physical performance.^261a

Liver transplantation should be offered to anyone with CF and progressive liver failure and/or with life-threatening sequelae of portal hypertension, who also have mild pulmonary involvement that is expected to support long-term survival.^92a

Long-term survival has yet to be determined, but improved quality of life has been achieved. The new lungs do not acquire the CF ion-transport abnormalities but are subject to the usual posttransplant complications. CF problems in other organ systems persist and may be worsened by some of the immunosuppressive regimens.⁴⁵⁹

CNS complications occur more frequently in CF transplant recipients than in other lung transplant recipients.¹⁶⁸ Criteria for lung transplant are published, and early referral and continuous monitoring are required to anticipate decline as a result of the long waiting period.¹⁶⁰

PROGNOSIS.

Using its innovative CF patient registry, which tracks information on approximately 23,000 clients who receive care through the CF Foundation’s Care Center Network, researchers have analyzed the numbers and continue to assess trends in the health status of registered individuals. When first distinguished from celiac disease in 1938, life expectancy with CF was approximately 6 months.¹¹⁰ Data shows that the prognosis has steadily improved over the past 20 years with a gradual increase in longevity; at the time of this publication the median survival had risen to 36.8 years.

More than 50% of children with CF live into adulthood. The new median age of survival is based on 2005 data that includes date of birth, date of death, gender, and date of diagnosis. A detailed CF Foundation Annual Patient Registry Data Report is available.

Improvement in both the length and quality of life for adults with CF is primarily the result of standardization of care, implementation of best practices, continuous multidisciplinary care provided by specialists in CF centers, improved CF therapies, and improved nutrition and pulmonary function, which are two main prognostic factors for improved survival.²⁶⁹

Children whose presenting symptoms were gastrointestinal at diagnosis have a good clinical course; those whose initial symptoms at diagnosis were pulmonary frequently demonstrate subsequent clinical deterioration. Pulmonary failure is still the most common cause of death. Males have a more favorable prognosis than females. New agents and gene therapy may substantially change the morbidity and mortality of this disease with continued improved survival time.

Lung disease is the primary cause of death for 80% for individuals with CF. Lung transplantation is an important therapeutic option for this group, comprising the third largest group of transplant recipients receiving lung transplantation (after people with chronic obstructive lung disease and IPF). The primary goal of transplant has always been to treat individuals with CF with end-stage lung disease for whom medical therapies have failed. The secondary goal has been to improve quality of life.^261a

Since the first lung transplant for CF in 1983, survival rates have improved. Refinements in surgical technique, medications, and improved selection criteria have gradually improved postsurgical survival.^261a Individuals with CF who are listed for lung transplantation may require mechanical ventilatory support before transplant. Pretransplant mechanical ventilation increases short-term morbidity and mortality in pediatric clients.^125a Besides ventilator dependence, other negative predictive factors for prognosis after transplantation include Burkholderia cepacia infection, young age, and arthropathy.^261a

The 3-year predicted survival rate after lung transplantation was reported as 55% at centers that performed more than 10 transplants. The 5-year rate was 48% in 1996 and expected to continue to improve over time.^457a The 1-year survival rate after liver transplantation for this population is approximately 80%, with beneficial effects on lung function, nutritional status, body composition, and quality of life in most cases.^92a

Improved quality of life after lung transplantation remains tightly linked to survival and is difficult to evalu ate. Current information suggests that quality of life increases after lung transplantation for survivors but that it decreases with time and complications such as bronchiolitis obliterans.^261a

15-17 SPECIAL IMPLICATIONS FOR THE THERAPIST

Cystic Fibrosis

PREFERRED PRACTICE PATTERNS

4A:

Primary Prevention/Risk Reduction for Skeletal Demineralization

4C:

Impaired Muscle Performance

6C:

Impaired Ventilation, Respiration/Gas Exchange, and Aerobic Capacity/Endurance Associated with Airway Clearance Dysfunction

6E:

Impaired Ventilation and Respiration/Gas Exchange Associated with Ventilatory Pump Dysfunction or Failure

6F:

Impaired Ventilation and Respiration/Gas Exchange Associated with Respiratory Failure

Airway Clearance Techniques

The therapist must always be aware that anyone with CF is susceptible to infections, in particular Burkholderia cepacia. Care must be taken to avoid transmission via equipment, other patients, or oneself. Handwashing is essential, and high alcohol hand rubs may be more effective.¹⁶³ The therapist will be involved with airway clearance techniques carried out several times per day or as often as the person is able to tolerate it without undue fatigue. Airway clearance techniques should not be performed before or immediately after meals, so treatment must be scheduled to avoid mealtimes.

Aerosol therapy to deliver medication to the lower respiratory tract should be administered just before airway clearance techniques to maximize the effectiveness of both treatments. Breathing exercises, improving posture, mobilizing the thorax through active exercise, and manual therapy are part of promoting good breathing patterns and improving inspiratory muscle endurance. Specifics of airway clearance techniques for this population are beyond the scope of this text; the reader is referred to more detailed materials available.^{102,103,105,140}

The many difficulties surrounding percussion and postural drainage (e.g., poor compliance, time consuming, and requiring the assistance of a trained individual) have resulted in the development of alternative airway clearance techniques that can be accomplished without the assistance of another caregiver.

Each of these techniques (e.g., autogenic drainage, active cycle breathing, positive expiratory pressure [PEP], Flutter valve therapy, Acapella, and Quake) requires a certain level of compliance, motivation, understanding, neuromuscular function, and breath control. The therapist is very instrumental in evaluating each individual’s needs, motivation, abilities, resources, and preferences in determining the best intervention or interventions to use.

Autogenic drainage, active cycle breathing, and PEP help the individual to move the mucus up to the larger airways where it can be coughed out more easily. Autogenic drainage comprises a series of sequential breathing exercises designed to clear the small, medium, and large airways in that order. The PEP device maintains pressure in the lungs, keeping the airways open and allowing air to get behind the mucus (Fig. 15-15). This device has been shown to be effective in increased sputum production, improved lung function, and improved oxygenation.¹⁰⁷

Figure 15-15 PARI PEP. The positive expiratory pressure (PEP) device maintains pressure in the lungs, keeping the airways open and allowing air to get behind the mucus to improve airway clearance, lung volume capacity, and oxygenation. The device can be used by children (A) and adults (B). (PARI PEP is a registered trademark of PARI GmbH. Used with permission. Please note: the authors have no commercial gain from inclusion of this product.)

The Flutter valve is similar to the PEP device but utilizes a stainless steel ball that vibrates, alternately opening and closing the device’s air hole, pulsing air back into the airways (Fig. 15-16). Current practice is to use one of the devices (PEP or Flutter valve) followed by autogenic breathing techniques. The total treatment time is about 15 minutes and can be carried out independently by some children and most adolescents and adults with mild-to-moderate disease who can follow the directions and control their breathing.

Figure 15-16 The Flutter mucus clearance device. A, Flutter device can be used in anyone with chronic obstructive pulmonary disease (COPD). B, Flutter valve shown in this schematic utilizes a stainless steel ball that vibrates, alternately opening and closing the device’s air hole, pulsing air back into the airways. (Courtesy Axcan Pharma, Birmingham, AL, 2007. Used with permission.)

Preliminary studies on the Flutter device suggest that Flutter valve therapy is an acceptable alternative postural drainage and percussion and may be more effective than postural drainage in prolonging the ability to raise secretions. Sputum production increased significantly 30 minutes after the end of treatment, and 1 hour after the end of treatment, it was significantly greater than the amount produced after postural drainage.^26,170 In a comparison study lasting 1 year, PEP was superior to the Flutter in maintaining pulmonary function, reducing hospitalizations, and reducing antibiotic use.²⁹¹

A high-frequency chest wall oscillation vest can provide mucus clearance for those individuals who lack the ability to perform the simpler techniques and is especially helpful with children (although the cost may seem prohibitive, it is less than a single hospitalization for a pulmonary exacerbation). The device consists of an inflatable vest (The Vest) attached to an air pulse generator (Fig. 15-17). The generator, a compressor-like device, rapidly inflates and deflates the vest, gently compressing and releasing the chest wall to create airflow within the lungs. This device treats all lobes simultaneously for the duration of the time it is activated. This process moves mucus toward the larger airways where it can be cleared by coughing.

Figure 15-17 A, 4-year-old wearing American Biosystems, Inc (ABI) Vest to self-administer high-velocity oscillations. The vest can accommodate a child as young as 2 years old and is worn 30 minutes twice each day. Medications used to open airways and relax bronchospasms are administered through a nebulizer during the first 10 minutes of treatment, and the machine automatically shuts off every 10 minutes to allow the person to clear secretions. B, A foot-pad control mechanism (not shown) can be used to manually stop the machine anytime to allow the client to cough and clear mucus. Any position can be assumed, and at this age, the child can do everything himself. This device promotes compliance and is accompanied by reduced use of medications and infections. (Courtesy Kerry Resch, Missoula, MT, 2001.)

The effectiveness of this mechanized device has been supported by the limited research published to date. Results from The Vest are becoming quite well documented, demonstrating decreased hospitalizations and slower rate of FEV₁ decline.^255,377 The Vest Clearance System web site (http://www.thevest.com/research/bibliography.asp) has an extensive bibliography. Future research should determine optimal compression frequencies and wave forms.^255,299,377 The Vest is comparable to PEP in effectiveness, but arterial oxygen saturation may drop during its use, so this must be monitored during exacerbations.¹⁰⁷

Nutrition

Malnutrition and deterioration of lung function are closely interrelated and interdependent in the person with CF. Each affects the other, leading to a spiral decline in both. The occurrence of malnutrition during childhood seems to be associated with impaired growth and repair of the airway walls. In children, when growth in body length occurs, good nutrition is associated with better lung function. When adequate nutrition is combined with physical training and aerobic exercise, improved body weight, respiratory muscle function, lung function, and exercise tolerance occur with increases in both respiratory and other muscle mass.¹⁹²

Exercise

Increasingly, exercise and sport are being advanced as core components of treatment for individuals with CF of all ages. A large portfolio of exercise literature has already established that supervised exercise programs enhance fitness (and thereby improve survival), increase sputum clearance, delay the onset of dyspnea, delay declines in pulmonary function, prevent decrease in bone density,⁴⁴⁴ enhance cellular immune response,⁴⁶ and increase feelings of well-being, thereby potentially improving self-image, self-confidence, and quality of life for the person with CF. Both short-and long-term aerobic and anaerobic training have positive effects on exercise capacity, strength, and lung function.⁵⁵

Reduced systemic oxygen extraction is an important factor, limiting exercise in many individuals with CF, but the specific parameters of this limitation remain unknown and probably vary from person to person.^312,325 Even unsupervised programs produce a training effect and pulmonary benefits.³⁰⁶ Inspiratory muscle training alone in individuals with CF has shown improved lung function and increased work capacity, as well as improved psychosocial status.^113,127

The therapist can be very instrumental in providing client and family education about the importance of combining good nutrition and exercise/activity. The therapist helps each individual develop an exercise routine that includes strengthening, stretching, aerobic, and endurance components with special attention to breathing exercises to aerate all areas of the lungs. Weight loss with exercise is of special concern in this population, especially for the individual with CF and diabetes mellitus.

Energy expenditure is higher than usual for individuals with CF and diabetes during periods of recovery from mild exercise or activity because of increased work of breathing (WOB) consistent with higher ventilatory requirements.⁴⁴¹ This requires careful collaboration among client/family, therapist, and nutritionist. In addition, systemic inflammatory response to exercise may be greater for individuals with CF, potentially exacerbating the disease.²¹³

As longevity increases with CF, quality of life issues are more important, thus these issues, such as posture, arthropathies, and neuromuscular control, are becoming more important for the physical therapist.^121,285 When treating anyone with CF who has sustained trauma, a multisystem approach is critical for optimal outcomes in physical therapy.⁴¹¹

Individuals with CF awaiting a transplant must remain as active as possible; whenever possible, the therapist can design a safe but effective exercise program. If significant oxygen desaturation or severe breathlessness limits activity, then exercise on a treadmill, stationary bike, or even a stationary device for seated pedaling is recommended with supplemental oxygen supplied at sufficient flow to match minute ventilatory requirements.⁴⁴⁴

Studies of exercise performance in lung transplant recipients with end-stage CF report that exercise performance improves after transplantation but remains well below normal.³²⁵ In a study of 12 individuals 8 to 95 months after lung transplant, the diaphragm and abdominal muscle strength was preserved relative to healthy controls, but quadriceps strength was significantly diminished and affected exercise performance. Corticosteroid use partly contributed to this strength deficit.³⁴²

Athletes with Cystic Fibrosis

For those individuals who are able and interested in participating in sports (Fig. 15-18), special considerations must be addressed. Calorie intake and maintaining weight, nutrition, and fluid and electrolyte balance are major concerns. Each individual must be assessed, evaluated, and monitored carefully. The therapist, family, and nutritionist can work together to minimize exercise and nutrition-induced complications. The information presented here is only a general guideline and may need to be modified for individual needs, metabolism, personal health, level and type of sports participation, and so on.

Figure 15-18 A, 18-month-old shortly after diagnosis; face-mask is a nebulizer (device designed to create and throw an aerosol) that is delivering albuterol (bronchodilator). B, This same individual in 1999 at age 15 years (6 feet tall; 145 lb) competing in a regional soccer tournament. C, Same young man at 23 years (6 feet 2 inches, 175 lb), still actively hiking, cycling, running, and playing intramural sports, while enrolled in graduate school. (Courtesy Kevin Hanson, Helena, MT, 2007. Used with permission.)

During the off-training season, the individual (especially children and adolescents) will need to eat one and one-half times the protein and calories of an athlete who does not have CF in order to maintain weight. During the sport season, calorie intake must be increased with the goal of maintaining weight.

Hyponatremia (deficiency of sodium in the blood; see discussion in Chapter 5) can be a serious problem for athletes with CF who excrete three to five times the sodium (in sweat) of an athlete without CF during sports participation. This situation combined with increased intake of water further dilutes the sodium levels in the body. Sodium loss combined with losses of potassium and magnesium can result in lifethreatening situations for these individuals.

Some guidelines for these athletes include weighing before and after exercise and considering the loss as a loss of fluids accompanied by electrolytes; replacing fluid loss with electrolytes (e.g., drinks such as Gatorade or Recharge) instead of water; taking an appropriate number of salt tablets; and eating a meal with sodium-, potassium-, and magnesium-rich foods.

Sporting activities should not be undertaken during infective exacerbations. Sports that carry a medical risk for people with CF (e.g., bungee and parachute jumping, skiing, or scuba diving) should be avoided. Individuals with CF who have portal hypertension with significant enlargement of the spleen and liver should be advised against contact sports, such as rugby and football, in addition to bungee and parachute jumping.

Skiing for anyone with CF who is already hypoxic is not advised; episodes of acute right-sided heart failure brought on by a combination of altitude and unaccustomed strenuous anaerobic and aerobic exercise have been reported. Scuba diving is contraindicated for anyone with lung disease if there is any evidence of air trapping. On ascent, the air expands, increasing the risk of developing a pneumothorax.⁴⁴⁴

Transition to Adult Care

CF centers and other centers providing life-long care for clients with CF have realized the need for a transition phase between pediatric and adult care and the provision of counseling for parents and the young adult with CF to assist them with this marked change in approach to the young adult’s care.

The physical therapist can and should have an integral role in preparing families and clients for various phases in care from pediatrics to adolescent care to a more independent model of adult care. If such a program does not exist in your current facility, materials and resources are available to help get such a program started and established.^{40,85,289,458}

Many families receive care for their child for years at a pediatric center and develop life-long relationships with health care agencies and staff. Every effort should be made to accomplish a smooth transition for the client and the family, since the move from the well-established pediatric facility to a new facility or medical team can be a stressful transition for all.

Families in rural settings or who travel distances to benefit from centralized services in CF clinics or centers have some unique needs that should be addressed as well. For example, maintaining a complete medical record in more than one facility is not always possible. Without a good systems coordinator, gaps in the medical record from one clinic to another become all too common.

Transition to adult care should be a planned process over time. Every effort should be made to avoid an abrupt transfer. The pediatric team has the responsibility to “set the stage” for the transition. The process can be started early with expectations for an eventual adult transition reinforced in intervals. Written information about the transition, setting an actual time frame, and planning each step in the process are important.²⁸⁹

Three guiding principles are suggested, regardless of the format chosen for transition. First, there must be an adult team that is both interested and able to provide care. Second, there needs to be a very well planned, coordinated approach to the transition. Third, there must be excellent communication and interaction between the pediatric and adult teams.²⁸⁹ Transition programs should be flexible enough to meet the needs of a wide range of young people, health conditions, and circumstances. The actual transfer of care should be individualized to meet the specific needs of young people and their families.³⁶² Family involvement, including parents, guardians, and/or partner and the client, is essential to the success of any transition phase. The omission of any key people from the transition team can result in frustration, feelings of abandonment, and miscommunication, which could ultimately lead to compromised care for the individual with CF.

Adults With Cystic Fibrosis

As individuals with CF survive longer into adulthood, the unique needs of this population group are being considered. Health care in the adult setting encourages independence and increased self-reliance.⁴⁵⁹ Achieving an ideal nutritional status is an integral part of management of people with CF, but how these requirements change as the individual ages remains unknown. Emphasis is continually placed on dietary intake and weight; the effects of this on eating behavior and self-perceptions are under investigation.^1,424,446

Other concerns include the effects of long-term use of pancreatic enzymes, osteoporosis associated with late-stage CF and its complications of increased fracture rates and severe kyphosis,^19,20,191 the effects of hormonal changes in relation to the menstrual cycle on lung function,²²⁴ psychosocial-spiritual issues,²⁰⁰ and infertility issues.²⁰⁹

The origin of bone disease in CF is multifactorial and not completely understood. However, glucocorticoid therapy, delayed pubertal maturation, malabsorption of vitamin D, poor nutritional status, inactivity, and hypogonadism are all potential contributing factors.^105a In addition, chronic pulmonary inflammation causes increased circulating levels of cytokines that augment bone resorption and suppress bone formation. Decreases in BMD resulting from these factors can lead to osteoporosis, fragility fractures, and possible exclusion from lung transplant candidacy.^105a

Although a number of therapeutic options are now available for osteoporosis, it is likely that prevention, prompt recognition, and early treatment will be far more effective in achieving bone health than intervention at later stages of the problem. An in-depth discussion of bone health and disease in CF is available.^105a

Stress urinary incontinence has also been shown to affect many girls and women with CF, probably caused by the forceful and prolonged coughing bouts characteristic of the disease.^94,294 Interventions aimed at improving pelvic floor muscle strength and coordination may be appropriate for these individuals.

MEDICAL MANAGEMENT

DIAGNOSIS.

Atelectasis is suspected in penetrating or other chest injuries. X-ray examination may show a shadow in the area of collapse. If an entire lobe is collapsed, the radiograph will show the trachea, heart, and mediastinum deviated toward the collapsed area, with the diaphragm elevated on that side (see Figs. 15-13 and 15-22). Chest auscultation and physical assessment add to the clinical diagnostic picture. Blood gas measurements may show decreased oxygen saturation.

Figure 15-22 A, Pneumothorax. Lung collapses as air gathers in the pleural space between the parietal and visceral pleurae. B, Massive hemothorax, blood in the pleural space (arrow) below the left lung, causing collapse of lung tissue. C, Open pneumothorax (sucking chest wound). Air movement (solid arrows) and structural movement (open arrows). A chest wall wound connects the pleural space with atmospheric air. During inspiration, atmospheric air is sucked into the pleural space through the chest wall wound. Positive pressure in the pleural space collapses the lung on the affected side and pushes the mediastinal contents toward the unaffected side. This reduces the volume of air in the unaffected side considerably. During expiration, air escapes through the chest wall wound, lessening positive pressure in the affected side and allowing the mediastinal contents to swing back toward the affected side. Movement of mediastinal structure from side to side is called mediastinal flutter. D, Tension pneumothorax. If an open pneumothorax is covered (e.g., with a dressing), it forms a seal, and tension pneumothorax with a mediastinal shift develops. A tear in lung structure continues to allow air into the pleural space. As positive pressure builds in the pleural space, the affected lung collapses, and the mediastinal contents shift to the unaffected side. Tension pneumothorax is corrected by removing the seal (i.e., dressing), allowing air trapped in the pleural space to escape.

TREATMENT AND PROGNOSIS.

Once atelectasis occurs, treatment is directed toward removing the cause whenever possible. Suctioning or bronchoscopy may be employed to remove airway obstruction. Airway clearance techniques are helpful to remove secretions and promote segmental inflation after the obstruction has been removed.

Surfactant has been used to resolve atelectasis in infants with respiratory distress syndrome, meconium aspiration, and other pathologies.¹³² Antibiotics are used to combat infection accompanying secondary atelectasis. Reexpansion of the lung is often possible, but the final prognosis depends on the underlying disease. Chronic atelectasis may require surgical removal of the affected segment or lobe of lung.

15-18 SPECIAL IMPLICATIONS FOR THE THERAPIST

Atelectasis

PREFERRED PRACTICE PATTERNS

See also Special Implications for the Therapist: Pneumothorax and Special Implications for the Therapist: Chest Wall Disease or Injury in this chapter.

6B:

Impaired Aerobic Capacity/Endurance Associated with Deconditioning

6C:

Impaired Ventilation, Respiration/Gas Exchange, and Aerobic Capacity/Endurance Associated with Airway Clearance Dysfunction

6F:

Impaired Ventilation and Respiration/Gas Exchange Associated with Respiratory Failure

Atelectasis is a postoperative complication of thoracic or high abdominal surgery. Left lower lobe atelectasis can occur following cardiac surgery. Within a few hours after surgery, atelectasis becomes increasingly resistant to reinflation. This complication is exacerbated in people receiving narcotics. Although there has not been sufficient research to support its use, one of the goals of acute care therapy is to prevent atelectasis in the high-risk client.³³⁵

Diminished respiratory movement as a result of postoperative pain is often addressed by the therapist. Frequent, gentle position changes, deep breathing, coughing, and early ambulation help promote drainage of all lung segments. Deep breathing and effective coughing enhance lung expansion and prevent airway obstruction. Deep breathing is beneficial because it promotes the ciliary clearance of secretions, stabilizes the alveoli by redistributing surfactant, and permits collateral ventilation of the alveoli, through Kohn’s pores in the alveolar septa.

Kohn’s pores, which open only during deep breathing, allow air to pass from well-ventilated alveoli to obstructed alveoli, minimizing their tendency to collapse and facilitating removal of the obstruction. To minimize postoperative pain during deep-breathing and coughing exercises, teach the client to hold a pillow firmly over the incision.

There is evidence that vigorous airway clearance techniques are as effective in resolving atelectasis from mucous plugs as bronchoscopy.²⁵⁰ Bronchoscopy has the adverse effect of temporarily lowering oxygen saturation and further irritation of lung tissue.

Pulmonary Edema

Definition and Incidence

Pulmonary edema or pulmonary congestion is an excessive fluid in the lungs that may accumulate in the interstitial tissue, in the air spaces (alveoli), or in both. The fluid is a barrier to gas exchange. Pulmonary edema is a common complication of many disease processes. It occurs at any age but with increasing incidence in older people with left-sided heart failure.

Etiologic and Risk Factors

Most cases of pulmonary edema are caused by left ventricular failure (see Fig. 12-12, A), acute hypertension, or mitral valve disease, but noncardiac conditions, especially kidney or liver disorders prone to the development of sodium and water retention, can also produce pulmonary edema. These causes of pulmonary edema include intravenous narcotics, increased intracerebral pressure, brain injury, high altitude, diving and submersion, sepsis, medications, inhalation of smoke or toxins (e.g., ammonia), blood transfusion reactions, shock, and disseminated intravascular coagulation.^32,90,146

Other risk factors include hyperaldosteronism, Cushing’s syndrome, use of glucocorticoids, and use of hypotonic fluids to irrigate nasogastric tubes. Pulmonary edema itself is a major predisposing factor in the development of pneumonia that complicates heart failure and ARDS.

Pathogenesis

Pulmonary edema occurs when the pulmonary vasculature fills with fluid that leaks into the alveolar spaces, decreasing the space available for gas exchange. Normally the lung is kept dry by lymphatic drainage and a balance among capillary hydrostatic pressure, capillary oncotic pressure, and capillary permeability.

Pulmonary edema develops as a result of (1) fluid overload, (2) decreased serum and albumin, (3) lymphatic obstruction, and (4) disruption of capillary permeability (tissue injury or immunoresponse) (Fig. 15-19). New studies show that loss of sodium transport capacity may be a factor in the development of some types of pulmonary edema.⁴⁴⁹

Figure 15-19 Mechanisms of pulmonary edema formation. A, Fluid overload. B, Decreased serum and albumin. C, Lymphatic obstruction. D, Tissue injury. (From Black JM, Hawks JH, eds: Medical-surgical nursing, ed 7, St Louis, 2005, WB Saunders.)

Fluid Overload.: When the filling pressures on the left side of the heart increase, pulmonary capillary hydrostatic pressure increases. If it surpasses the oncotic pressure that holds fluid in the capillaries, fluid is drawn from capillaries in the lungs into the interstitial space. Normally, the lymphatic system removes this fluid from the lungs, but if the flow of fluid into the interstitium exceeds the ability of the lymphatic system to remove it, fluid overload and consequently pulmonary edema develop.^* When osmotic pressure in the venous end of the capillary exceeds interstitial pressure, fluid cannot return to the bloodstream and peripheral and pulmonary edema may result. Fluid overload may also occur from decreased sodium and water excretion associated with renal disorders.

As the fluid pressure increases in the tissues, it also increases in the left ventricle, which increases pressure in the left atrium. The disturbed pressure gradient results in less forward flow, resulting in pulmonary edema. Pulmonary edema is commonly seen when the left side of the heart is distended and fails to pump adequately (e.g., myocardial ischemia or infarction or mitral or aortic valve damage).

In atrial fibrillation, the left atrium may be unable to efficiently pump blood into the left ventricle, resulting in fluid pooling and subsequent edema. If the right side of the heart fails, peripheral edema occurs through the same process. Left-sided heart failure leads to right-sided failure (and vice versa), so both pulmonary and peripheral edema may exist simultaneously.

Decreased Serum and Albumin.: In the case of liver cirrhosis, the serum protein and albumin levels are reduced in the vascular fluids. Thus less fluid reabsorption from the tissue spaces occurs, which results in pulmonary and peripheral edema and ascites.

Lymphatic Obstruction.: When lymphatic channels are obstructed, tissue oncotic pressure rises and results in edema. This obstruction can occur as a result of tumor infiltration but most often occurs in association with cardiogenic causes of pulmonary edema. When hemodynamic alterations (changes in the movement of blood and the forces involved) in the heart increase the perfusion pressure in the pulmonary capillaries, effective lymphatic drainage is blocked.

Tissue Injury.: Disruption of capillary permeability is the cause of pulmonary edema in acute lung injury associated with ARDS, inhalation of toxic gases, aspiration of gastric contents, viral infections, and uremia. In these conditions, destruction of endothelial cells or disruption of the tight junctions between them alters capillary permeability (see Figs. 6-10 and 6-11). Transfusion reactions are due to leukocyte antibodies and result in increased capillary permeability.¹⁰⁰

Clinical Manifestations

Clinical manifestations of pulmonary edema occur in stages. During the initial stage, clients may be asymptomatic or they may complain of restlessness and anxiety and the feeling that they are developing a common cold. Other signs include a persistent cough, slight dyspnea, diaphoresis, and intolerance to exercise. As fluid continues to fill the pulmonary interstitial spaces, the dyspnea becomes more acute, respirations increase in rate, and there is audible wheezing. If the edema is severe, the cough becomes productive of frothy sputum tinged with blood, giving it a pinkish hue. If the condition persists, the person becomes hypoxic, less responsive, and may lose consciousness.

MEDICAL MANAGEMENT

PREVENTION.

Prevention is a key component with persons at increased risk for the development of pulmonary edema. Preventive measures may be as simple as lowering salt intake or pharmacologic treatment such as the use of digoxin and diuretics.

DIAGNOSIS.

Pulmonary edema is usually recognized by its characteristic clinical presentation. Cardiogenic pulmonary edema is differentiated from noncardiac causes by the history and physical examination; an underlying cardiac abnormality can usually be detected clinically or by the electrocardiogram (ECG), chest film, or echocardiogram. A chest film may show increased vascular pattern; increased opacity of the lung, especially at the bases; and pleural effusion.

There are no specific laboratory tests diagnostic of pulmonary edema; when the condition progresses enough to cause liver involvement the physician may observe the hepatojugular reflex (positional or palpatory pressure on the liver results in distention of the jugular vein). Auscultation reveals distinct abnormal breath sounds with crackles or rales. Blood gas measurements indicate the degree of functional impairment, and sputum cultures may indicate accompanying infection.

TREATMENT.

Once pulmonary edema has been diagnosed, treatment is aimed at enhancing gas exchange, reducing fluid overload, and strengthening and slowing the heartbeat. Oxygen by mask or through ventilatory support is used along with diuretics, diet, and fluid restriction to remove excess alveolar fluid.

Morphine to relieve anxiety and reduce the effort of breathing may be used for people who do not have narcotic-induced pulmonary edema. Other pharmacologic-based treatment may be used to help dilate the bronchi and increase cardiac output, strengthen contractions of the heart, and increase cardiac output.

PROGNOSIS.

The prognosis depends on the underlying condition. The presence of pulmonary edema is a medical emergency requiring immediate intervention to prevent further respiratory distress and death. It is often reversible with clinical management.

15-19 SPECIAL IMPLICATIONS FOR THE THERAPIST

Pulmonary Edema

PREFERRED PRACTICE PATTERNS

6B:

Impaired Aerobic Capacity/Endurance Associated with Deconditioning

6C:

Impaired Ventilation, Respiration/Gas Exchange, and Aerobic Capacity/Endurance Associated with Airway Clearance Dysfunction

6F:

Impaired Ventilation and Respiration/Gas Exchange Associated with Respiratory Failure

Signs and symptoms of pulmonary edema that may come to the therapist’s attention include engorged neck and hand veins (because of peripheral vascular fluid overload), pitting edema of the extremities, adventious breath sounds, and of course, the paroxysmal nocturnal dyspnea so common with this condition. One of the first signs of dyspnea may be an increased difficulty breathing when lying down, relieved by sitting up (orthopnea). Pulmonary edema can become life-threatening within minutes, requiring immediate action by the therapist to get medical assistance for this person.

Jugular vein distention may occur with liver involvement. Positional or palpatory pressure on the liver may result in right upper quadrant or right shoulder pain, as well as jugular vein distention. The distention may be best observed with the person positioned sitting 30 to 45 degrees up from a fully supine position.

Any liver involvement requires precautions when performing any soft tissue mobilization techniques to the anterior part of the abdomen, including the diaphragm. Indirect techniques or mobilization away from the liver is recommended.

When working with a client already diagnosed with pulmonary edema, the sitting (high Fowler’s) position is preferred with legs dangling over the side of the bed or plinth. This facilitates respiration and reduces venous return. Monitor for decreased respiratory drive (less than 12 breaths per minute is significant), which should be documented and reported immediately. If oxygen is being administered, the therapist monitors the oxyhemoglobin saturation levels and titrates oxygen accordingly. It may be necessary to increase oxygen levels before exercise, but respiratory rate and breathing pattern must be monitored.

The client may be taking nitroglycerin sublingually, which will further increase vasodilation and decrease ventricular preload. Monitor blood pressure closely, and observe for signs of hypotension because nitroglycerin can drop blood pressure dangerously. The therapist should consult with nursing or respiratory staff for any special considerations for each individual client.

Gradual exercise intolerance usually occurs as the dyspnea progresses. The client may comment about weight gain or difficulty fastening clothes. Check for peripheral edema in the immobile or bedridden client. In this group of people, edema can occur in the sacral hollow rather than in the feet and legs because the sacrum is the lowest place on the trunk. Care must be taken to prevent pressure ulcers in this area.

Acute Respiratory Distress Syndrome

Definition

ARDS is a form of acute respiratory failure after a systemic or pulmonary insult. It is also called adult respiratory distress syndrome, shock lung, wet lung, stiff lung, hyaline membrane disease (adult or newborn), posttraumatic lung, or diffuse alveolar damage (DAD). It is often a fatal complication of serious illness (e.g., sepsis), trauma, or major surgery.

Incidence

ARDS has only been identified within the last 40 years, affecting a reported 150,000 people per year in the United States. This figure has been challenged, and part of the reason for the uncertainty of numbers is the lack of uniform definitions for ARDS and the heterogeneity of diseases underlying ARDS. The incidence has increased as improvements in intensive care have allowed more people to survive the catastrophic illnesses that precede ARDS. Any age can be affected, but often young adults with traumatic injuries develop ARDS.

Etiologic and Risk Factors

ARDS occurs as a result of injury to the lung by a variety of unrelated causes; the most common are listed in Box 15-9.

Box 15-9 CAUSES OF ACUTE (ADULT) RESPIRATORY DISTRESS SYNDROME^*

Severe trauma (e.g., multiple bone fractures)

Septic shock

Pancreatitis

Cardiopulmonary bypass surgery

Diffuse pulmonary infection

Burns

High concentrations of supplemental oxygen

Aspiration of gastric contents

Massive blood transfusions

Embolism: fat, thrombus, amniotic fluid, venous, air

Near drowning

Radiation therapy

Inhalation of smoke or toxic fumes

Thrombotic thrombocytopenic purpura

Indirect: chemical mediators released in response to systemic disorders (e.g., viral infections, pneumonia)

Drugs (e.g., aspirin, narcotics, lidocaine, phenylbutazone, hydrochlorothiazide, most chemotherapeutic and cytotoxic agents)

^*Listed in order of decreasing frequency.

Pathogenesis

Alveolocapillary units, alveolar spaces, alveolar walls, and lungs are the site of initial damage (thus the name diffuse alveolar damage). Although the mechanism of lung injury varies with the cause, damage to capillary endothelial cells and alveolar epithelial cells is common in ARDS regardless of cause. Both necrosis (cell death by injury and swelling) and apoptosis (programmed cell death) play a role in this syndrome.²⁸⁰ Damage to the cell inactivates surfactant and allows fluids, proteins, and blood cells to leak from the capillary bed into the pulmonary interstitium and alveoli. The increased vascular permeability and inactivation of surfactant lead to interstitial and alveolar pulmonary edema and alveolar collapse. Fibroproliferation also occurs, thickening alveolar septa and impairing respiration (gas exchange).

Pulmonary edema decreases lung compliance and impairs gas exchange. The loss of surfactant leads to atelectasis and further impairment in lung compliance and hypoxia and hypercapnia. These are only the pulmonary manifestations of what is now recognized as a more systemic process called multiple organ dysfunction syndrome (MODS), formerly called multiple organ failure (MOF). See Chapter 5 for a discussion of MODS.

Clinical Manifestations

The clinical presentation is relatively uniform regardless of cause and occurs within 12 to 48 hours of the initiating event. The earliest sign of ARDS is usually an increased respiratory rate characterized by shallow, rapid breathing. Pulmonary edema, atelectasis, and decreased lung compliance cause dyspnea, hyperventilation, and the changes observed on chest radiographs (Fig. 15-20).

Figure 15-20 A, Normal chest film taken from a posteroanterior (PA) view. The backward L in the upper right corner is placed on the film to indicate the left side of the chest. Some anatomic structures can be seen on the x-ray study and are outlined: A, diaphragm; B, costophrenic angle; C, left ventricle, D, right atrium; E, aortic arch; F, superior vena cava; G, trachea; H, right bronchus; I, left bronchus; J, breast shadows. B, This chest film shows massive consolidation from pulmonary edema associated with acute (adult) respiratory distress syndrome (ARDS) after multisystem trauma. (A, from Black JM, Hokanson Hawks, J, editors: Medical-surgical nursing, ed 7, St Louis, 2005, WB Saunders; B, from Fraser RG, Paré JA, Paré PD, et al: Diagnosis of diseases of the chest, ed 3, Philadelphia, 1990, WB Saunders.)

As breathing becomes increasingly difficult, the individual may gasp for air and exhibit intercostal, clavicular, or sternal retractions and cyanosis. Unless the underlying disease is reversed rapidly, especially in the presence of sepsis (toxins in the blood), the condition quickly progresses to full-blown MODS, involving kidneys, liver, gut, CNS, and the cardiovascular system.

MEDICAL MANAGEMENT

DIAGNOSIS.

Since ARDS is a collection of symptoms rather than a specific disease, differential diagnosis is through a process of diagnostic elimination. Cardiogenic pulmonary edema and bacterial pneumonia must be ruled out because there are specific treatments for those disorders. By definition, respiratory failure in the proper clinical setting (history and physical findings) constitutes ARDS. Physical examination, blood gas analysis to assess the severity of hypoxemia, microbiologic cultures to identify or exclude infection, and radiographs may be part of the diagnostic process.

TREATMENT.

Specific treatment is administered for any underlying conditions (e.g., sepsis or pneumonia). Otherwise, treatment is supportive and toward prevention of complications. Supportive therapy to maintain adequate blood oxygen levels may include administration of humidified oxygen by a tight-fitting face mask, allowing for CPAP. Traditional ventilator management of ARDS emphasized normalization of blood gases and promoted high rates of further lung damage. It is now known that overdistention and cyclic inflation of injured lung can exacerbate lung injury and promote systemic inflammation. Mechanical ventilation with PEEP can minimize these effects, but evidence for protective ventilation is still lacking.^156,309 A technique called “open lung maneuver,” which opens all alveoli and prevents them from collapsing, shows promise.¹⁸⁴

Other strategies for protective ventilation (e.g., low-volume ventilation, permissive hypercapnia, prone positioning combined with airway pressure release ventilation [APRV], and high-frequency percussive ventilation) have reduced ARDS morbidity or mortality in some cases.^371,429,430

Sedation to reduce anxiety and restlessness during ventilation is required in some cases. If tachypnea, restlessness, or respirations out of phase with the ventilator (bucking) cannot be managed by sedation, pharmacologic paralysis may be induced. Other pharmacologic agents have been ineffective in altering morbidity or mortality.^5,215 Inhaled NO is a vasodilator and may be useful in life-threatening situations but has no advantage in changing the course of ARDS.¹⁷⁹

Many studies are under way investigating new methods of prevention or treatment of ARDS, including intravascular oxygenators implanted in the vena cava to improve systemic oxygenation and extracorporeal membrane oxygenation, which fully replaces lung function.

Tracheal gas insufflation, an adjunct to mechanical ventilation, allows ventilation of the central airway while carbon dioxide is cleared and may help reduce the amount of peak airway pressure required to maintain blood oxygen levels. High-frequency ventilation may have some benefits over conventional ventilation in children.⁴⁵⁵ No randomized trials have been conducted with this technique, and no commercial product is available.²³¹

Prophylactic immunotherapy, antibodies against endotoxin, and inhibition of various inflammatory mediators are among the possibilities being tested. β2-Agonists have been proposed as treatment for reducing the pulmonary edema.²⁸⁷

PROGNOSIS.

The final outcome is difficult to predict at the onset of disease, but associated multiorgan dysfunction and uncontrolled infection contribute to the mortality rate for ARDS of 50% to 70%. The major cause of death in ARDS is nonpulmonary MODS, often with sepsis. If ARDS is accompanied by sepsis, the mortality rate may reach 90%. Median survival in such cases is 2 weeks. The mortality rate increases with age, and clients older than 60 years of age have a mortality rate as high as 90%.

Most survivors are asymptomatic within a few months and have almost normal lung function 1 year after the acute illness. Lung fibrosis is the most common post-ARDS complication; the fibrosis may resolve completely; may result in respiratory dysfunction and in some cases, pulmonary hypertension; or may result in death.

15-20 SPECIAL IMPLICATIONS FOR THE THERAPIST

Acute (Adult) Respiratory Distress Syndrome

PREFERRED PRACTICE PATTERNS

See also Special Implications for the Therapist: Atelectasis and Special Implications for the Therapist: Pulmonary Edema in this chapter.

6B:

Impaired Aerobic Capacity/Endurance Associated with Deconditioning (pulmonary edema; progression to multisystem failure)

6C:

Impaired Ventilation, Respiration/Gas Exchange, and Aerobic Capacity/Endurance Associated with Airway Clearance Dysfunction

6F:

Impaired Ventilation and Respiration/Gas Exchange Associated with Respiratory Failure (pulmonary edema; atelectasis)

6G:

Impaired Ventilation, Respiration/Gas Exchange, and Aerobic Capacity/Endurance Associated with Respiratory Failure in the Neonate

7A:

Primary Prevention/Risk Reduction for Integumentary Disorders (pressure ulcers in the case of ventilatory support and/or prone positioning)

ARDS requires careful monitoring and supportive care; one case study even suggests 24-hour access to physical therapy intervention in acute respiratory failure as a means of avoiding invasive medical procedures. Timely physical therapy interventions improve gas exchange and reverse pathologic progression, thereby curtailing or avoiding artificial ventilation.⁴⁵²

Assess the client’s respiratory status frequently, and observe for retractions on inspiration, the use of accessory muscles of respiration, and developing or worsening dyspnea. On auscultation, listen for adventitious (rales or rhonchi) or diminished breath sounds and report any clear, frothy sputum that may indicate pulmonary edema.

Closely monitor heart rate and blood pressure watching for arrhythmias (see Special Implications for the Therapist: Arrhythmias in Chapter 12) that may result from hypoxemia, acid-base disturbances, or electrolyte imbalance. With pulmonary artery catheterization, know the desired pulmonary capillary wedge pressure (PCWP)^* level and check the readings; report any significant elevations (see Table 40-17) or changes in waveform that indicate the catheter has become wedged. Empty condensation from the tubing of the ventilator to ensure maximal oxygen delivery during therapy.

Critical illness polyneuropathy is a neurologic complication of ARDS, multiple organ failure, and other trauma. Therapists should be alert for signs of motor or sensory changes in clients with ARDS.⁶

V/Q mismatch is common in ARDS and can be altered by position changes that can facilitate lung expansion and redistribute fluid in the lungs. Oxygenation in clients with ARDS may sometimes be improved by turning them from the supine to the prone position, dramatically reducing pulmonary dead space and improving aeration.¹³⁰ This change takes the weight off (and improves ventilation in) the posterior regions of the lungs while promoting perfusion in the anterior aspects. The net result is improved oxygenation, expansion of atelectatic alveoli, and increased functional residual lung capacity.

Caregivers may be reluctant to use the prone position. The therapist can be very instrumental in providing education on proper technique and rationale. Selection criteria for this type of positioning may include individuals receiving ventilatory support at an oxygen concentration greater than 50%, with poor ABG levels and PEEP of 10 to 15 mm Hg or higher. Prone positioning should be considered if routine ventilator management has not been enough to improve the ventilatory status in an individual who is already pharmacologically immobilized or sedated (sedation is a requirement for prone positioning).

The client should be turned as far as possible on the abdomen; a 270-degree turn can improve oxygenation in some individuals, but ideally the full prone position is optimal. The person can be turned almost fully prone and supported with two or three pillows to help protect the airway, permit visualization, and allow suctioning as necessary. The better the person responds to the prone position, the longer that position can be maintained, although tolerance may build up with repeated use of the position. It is the repeated change from supine to prone positioning that redistributes pulmonary fluid and improves aeration and oxygenation overall.

Before turning, identify all invasive lines and bring them above the person’s waist and over the head; lines inserted in the groin area can be moved over to the side that will remain nondependent. Taking these precautions will reduce the chances that the lines will get kinked or dislodged. One person should be in charge of the person’s airway during the turning, supporting the client’s head and watching the intravenous lines. Any side-port line of a pulmonary artery catheter must be monitored especially carefully because it is closest to the client and more likely to kink. When the turn is completed, this same clinician turns the client’s head to one side, making sure the airway is visible and open. Extra pillows or foam/gel pads may be needed to make room for the airway and increase comfort level. The dependent shoulder should be positioned with the elbow directly to the side and the hand facing up toward the head to prevent dislocation. A pad around the mouth to absorb bronchial secretions will decrease the potential for eye contamination.

The prone position promotes secretion removal by propelling secretions toward the upper airways. It also makes it easy to perform back care and help maintain sacral and heel skin integrity. Disadvantages include the potential for facial skin irritation (especially on the forehead), loss of important vascular accesses, and difficulty performing CPR if required. Blood pressure may drop after the turn but should stabilize within a few minutes; unstable blood pressure will necessitate returning the person to the supine position. Other indicators of poor position tolerance include a decline in SaO₂, SVO₂, or the tidal volume over time.^120,130

^*Pulmonary artery catheterization measures left ventricular pressure and diastolic pressure. PCWP can indicate left ventricular failure coinciding with the onset of pulmonary congestion and pulmonary edema. PCWP can also register insufficient volume and pressure in the left ventricle indicating hypovolemic shock in other conditions.

Postoperative Respiratory Failure

Postoperative respiratory failure can result in the same pathophysiologic and clinical manifestations as ARDS but without the severe progression to MODS (see previous discussion of ARDS). Risk factors include surgical procedures of the thorax or abdomen, limited cardiac reserve, chronic renal failure, chronic hepatic disease, infection, period of hypotension during surgery, sepsis, and smoking, especially in the presence of preexisting lung disease. In the pediatric population, a difficult respiratory course may result in necrotizing enterocolitis, a postoperative gastrointestinal complication related to ischemia of the bowel. This condition occurs when oxygen depletion in the heart or brain causes blood to be shunted away from less vital organs, such as the intestine.

The most common postoperative pulmonary problems include atelectasis, pneumonia, pulmonary edema, and pulmonary emboli. Prevention of any of these problems involves frequent turning, deep breathing, humidified air to loosen secretions, antibiotics for infection as appropriate, supplemental oxygen for hypoxemia, and early ambulation.

If respiratory failure develops, mechanical ventilation may be required, and treatment is very similar to that for ARDS.

Sarcoidosis

Definition

Sarcoidosis is a systemic disease of unknown cause involving any organ that is characterized by granulomatous inflammation present diffusely throughout the body. Technically, this condition could be discussed earlier in this chapter in the Infectious and Inflammatory Diseases section but without a better sense of the underlying etiology, it remains here under diseases that affect the lung parenchyma. The granulomas consist of a collection of macrophages surrounded by lymphocytes taking a nodular form. In fact, granulomatous inflammation of the lung is present in 90% of clients with sarcoidosis. Secondary sites include the skin, eyes, liver, spleen, heart, and small bones in the hands and feet.

Incidence

Sarcoidosis occurs predominantly in the third and fourth decades (between the ages of 20 and 40 years) and has a slightly higher incidence in women than men. It is present worldwide with some interesting differences in prevalence among ethnic groups. It is three to four times more frequent in blacks than whites in the United States. Socioeconomic, environmental, and genetic factors appear to influence the occurrence.⁹⁷

Etiologic Factors and Pathogenesis

The etiologic factors and pathogenesis of sarcoidosis are unknown, but there appears to be an exaggerated cellular immune response on the part of the helper T lymphocytes to a foreign antigen whose identity remains unclear. Increasing evidence points to a triggering agent that may be genetic, infectious (bacterial or viral), immunologic, or toxic. Abnormalities of immune function, as well as autoantibody production, including rheumatoid factor and antinuclear antibodies, are seen in sarcoidosis and in connective tissue diseases, suggesting a common immunopathogenetic mechanism.

IFN-γ, TNF, and IL-12 and-18 all have a part in the granulomatous process.³²⁴ A series of interactions between the excessive accumulation of T lymphocytes and monocytes and macrophages leads to the formation of noncaseating (i.e., do not undergo necrotic degeneration) granulomas in the lung and other organs characteristic of the disease. Granuloma formation may regress with therapy or as a result of the disease’s natural course but may also progress to fibrosis and restrictive lung disease.

Clinical Manifestations

Sarcoidosis can affect any organ, including bones, joints, muscles, and vessels. Lungs and thoracic lymph nodes are most often involved with acute or insidious respiratory problems sometimes accompanied by symptoms affecting the skin, eyes, or other organs. The diverse manifestations of this disorder lend support to the hypothesis that sarcoidosis has more than one cause. The clinical impact of sarcoidosis is directly related to the extent of granulomatous inflammation and its effect on the function of vital organs.

Pulmonary sarcoidosis has a variable natural course from an asymptomatic state to a progressive life-threatening condition. Signs and symptoms may develop over a period of a few weeks to a few months and include dyspnea, cough, fever, malaise, weight loss, skin lesions (Fig. 15-21), and erythema nodosum (multiple, tender, nonulcerating nodules). This condition may be entirely asymptomatic, presenting with abnormal findings on routine chest radiographs. Respiratory symptoms of dry cough and dyspnea without constitutional symptoms (symptoms of systemic illness, including fatigue, weakness, malaise, weight loss, sweating, and fever) occur in over one-half of all people with sarcoidosis, and up to 15% develop progressive fibrosis. Chest pain, hemoptysis, or pneumothorax may be present.

Figure 15-21 Sarcoidosis. A, Cutaneous sarcoidosis usually consists of papules and plaques with a typical reddish-brown color. B, Lesions often favor the lips and perioral region. (From Bolognia JL, Jorizzo JL, Rapini RP: Dermatology, St Louis, 2003, Mosby. Courtesy Jean Bolognia, MD. Used with permission.)

Sarcoidosis may present with extrapulmonary symptoms referable to bone marrow, skin, eyes, cranial nerves or peripheral nerves (neurosarcoidosis), liver, or heart (Box 15-10). Neurosarcoidosis is an uncommon but severe and sometimes life-threatening manifestation of sarcoidosis occurring in 5% to 15% of cases. Sarcoidosis appears to be associated with a significantly increased risk for cancer in affected organs (e.g., skin, liver, lymphoma, or lung). Chronic inflammation is the mediator of this risk.²²

Box 15-10 CLINICAL MANIFESTATIONS OF SARCOIDOSIS

Pulmonary

Asymptomatic with abnormal chest film

Gradually progressive cough and shortness of breath (SOB)

Pulmonary fibrosis with pulmonary insufficiency

Laryngeal and endobronchial obstruction

Extrapulmonary

Löfgren’s syndrome: fever, arthralgias, bilateral hilar adenopathy, erythema nodosum

Heerfordt’s syndrome (uveoparotid fever): fever, swelling of parotid gland and uveal tracts, seventh cranial nerve palsy

Erythema nodosum

Peripheral lymphadenopathy/splenomegaly

Lymphoma

Eyes: excessive tearing, swelling, uveitis, iritis, glaucoma, cataracts

Skin: nodules or skin plaques (see Fig. 15-21); skin cancer

Central nervous system: cranial nerve palsies, subacute meningitis, diabetes insipidus

Joints: polyarticular and monarticular arthritis

Bones: punched-out cystic lesions in phalangeal and metacarpal bones

Heart: paroxysmal arrhythmias, conduction disturbances, congestive heart failure, sudden death

Kidney: hypercalcemia with nephrocalcinosis or nephrolithiasis

Liver: granulomatous hepatitis, liver cancer

MEDICAL MANAGEMENT

DIAGNOSIS.

There is no specific test other than history for sarcoidosis so diagnosis is based on clinical examination, radiographic, CT, pulmonary function and laboratory test findings, and biopsy of easily accessible granulomas (e.g., skin lesions, salivary gland, or palpable lymph nodes). When lung involvement is suspected, further testing may be required and new imaging techniques improve detection. Other granulomatous diseases (e.g., TB, berylliosis, lymphoma, carcinoma, or fungal disease) must be ruled out.

CNS involvement in sarcoidosis poses a difficult diagnostic problem. Although neurologic involvement may occur long before the onset of symptoms, contrast-enhanced CT does not always reveal parenchymal and meningeal involvement.

TREATMENT.

Treatment may not be required, especially in those clients who are asymptomatic. Short-term (less than 6 months) use of inhaled steroids may improve symptoms especially in people who mainly have cough. The long-term use of corticosteroids is the treatment of choice for those clients who have impaired lung function with pulmonary granulomas. Corticosteroids are quite effective in reducing the acute granulomatous inflammation as seen on radiograph, but their efficacy in improving lung function and altering the long-term prognosis is unproven. Oral steroids may be beneficial for stage 2 and 3 disease.^324,333

Other immunosuppressant and cytotoxic agents, such as methotrexate, chloroquine, cyclosporine, indomethacin, and azathioprine, have been used for symptomatic skin and eye involvement but have not been shown to be effective in pulmonary sarcoidosis.^48,334 New drugs targeting TNF-α are being developed.

People with sarcoidosis who smoke are encouraged to quit because smoking aggravates impaired lung function and promotes osteoporosis. Management of osteoporosis in this population requires special attention because there is often an underlying disorder in calcium metabolism that results in hypercalciuria and hypercalcemia.

Prolonged exposure to direct sunlight should be avoided because vitamin D aids absorption of calcium, which can contribute to elevated serum and urinary calcium levels and the formation of kidney stones. Bronchoscopy may be required if fibrosis or swelling leads to stenosis of the airways.²⁵⁸

In cases of end-stage sarcoidosis, lung transplantation has been proven successful.²⁵⁸ Selection of clients with pulmonary sarcoidosis for transplantation requires that medical therapy, including the use of corticosteroids and alternative medications, has been exhausted and that other contraindicated variables are not present (see the section on Lung Transplantation in Chapter 21). Sarcoidosis frequently recurs in the allograft but rarely causes symptoms or pulmonary dysfunction.²³⁰

PROGNOSIS.

The prognosis is usually favorable, with complete resolution of symptoms and chest radiographic changes within 1 to 2 years. Most clients do not manifest clinically significant sequelae. However, because sarcoidosis is a multisystem disease that can cause complex problems, it can have a variable prognosis ranging from spontaneous remissions to progressive lung disease with pulmonary fibrosis in active sarcoidosis. In such cases, respiratory insufficiency and cor pulmonale may eventually occur. In 65% to 70% of cases there are no residual manifestations, 20% are left with permanent lung or ocular changes, and 10% of all cases die. Active sarcoidosis responds well to the administration of corticosteroids.

15-21 SPECIAL IMPLICATIONS FOR THE THERAPIST

Sarcoidosis

PREFERRED PRACTICE PATTERNS

4A:

Primary Prevention/Risk Reduction for Skeletal Demineralization (prolonged use of corticosteroids)

6E:

Impaired Ventilation and Respiration/Gas Exchange Associated with Ventilatory Pump Dysfunction or Failure (progressive pulmonary fibrosis)

6F:

Impaired Ventilation and Respiration/Gas Exchange Associated with Respiratory Failure (hemothorax)

6H:

Impaired Circulation and Anthropometric Dimensions Associated with Lymphatic System Disorders

In the case of extrapulmonary manifestations of sarcoidosis (e.g., skin, cranial or peripheral nerve, heart involvement), other practice patterns may be identified.

There is a distinct arthritic component associated with sarcoidosis, variously reported in 10% to 35% of people who develop extrapulmonary involvement. The knees or ankles are the most common sites of acute arthritis. Distribution of joint involvement is usually polyarticular and symmetric, and the arthritis is commonly self-limiting after several weeks or months. Occasionally, the arthritis is recurrent or chronic, but even then, joint destruction and deformity are rare.

Treatment of arthritis in sarcoidosis is usually as for any other form of arthritis. The arthritic symptoms may develop early as the first manifestation of the disease or late in the disease and are usually accompanied by erythema nodosum. When further complicated by bilateral hilar adenopathy (enlargement of hilum or roots of the lung where the main bronchi enter the lungs), this triad of symptoms is called Löfgren’s syndrome. Recurrent Löfgren’s syndrome is extremely rare and is usually self-limiting.

Therapists should be alert to any presenting signs or symptoms of increased disease activity associated with sarcoidosis since medical vigilance with attention to new symptoms is important in the management of sarcoidosis. This disease presents in many and diverse patterns, but observe especially for exertional dyspnea that progresses to dyspnea at rest, chest pain, joint swelling, or increased fatigue and malaise, reducing the client’s functional level or ability to participate in therapy. Muscle involvement and bone involvement are frequently underdiagnosed. Symptoms of muscle weakness, aches, tenderness, and fatigue, often accompanied by neurogenic atrophy, may indicate sarcoid myositis.²⁹

Cranial nerve palsies (especially facial palsy), multiple mononeuropathy, and less commonly, symmetric polyneuropathy may all occur. Symmetric polyneuropathy can affect either motor or sensory fibers solely or both disproportionately. An unusual combination of neurologic deficits affecting the CNS or peripheral nerves (or both) suggests sarcoidosis and should be evaluated medically. Improvement of neurologic function may occur with the use of corticosteroids.

For clients receiving steroid therapy, increased side effects of the medication should be reported to the physician. For example, long-term use of steroids lowers resistance to infection, may induce diabetes and myopathy, and is associated with weight gain, loss of potassium in the urine, and gastric irritation (see the section on Corticosteroids in Chapter 5 and Tables 5-4 and 5-5).

Lung Cancer

Overview

Lung cancer, a malignancy of the epithelium of the respiratory tract, is the most frequent cause of cancer death in the United States. The term lung cancer, also known as bronchogenic carcinoma, excludes other pulmonary tumors such as sarcomas, lymphomas, blastomas, hematomas, and mesotheliomas.

Types of Lung Cancer

At least a dozen different types of tumors are included under the broad heading of lung cancer. Clinically, lung cancers are classified as small cell lung cancer (SCLC), or 20% of all lung cancers, and non–SCLC (NSCLC), or 80% of all lung cancers. Within these two broad categories, there are four major types of primary malignant lung tumors: SCLC includes small cell carcinoma (oat cell carcinoma); NSCLC includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The characteristics of these four lung cancers are summarized in Table 15-12. Adenocarcinoma, the most common form of lung cancer in the United States, tends to arise in the periphery, usually in the upper lobes at different levels of the bronchial tree. An individual tumor may reflect the cell structure of any part of the respiratory mucosa from the large bronchi to the smallest bronchioles. Because of this, adenocarcinoma refers to a heterogeneous group of neoplasms that have in common the formation of glandlike structures. Adenocarcinoma is further subdivided into four categories: acinar, papillary, bronchioloalveolar, and solid carcinoma. Increasing incidence of adenocarcinoma cell type lung cancer is currently attributed to changes in smoking patterns (e.g., deeper and more intense inhalation) in response to reduced tar and nicotine in cigarettes. Presumably, the excess volume inhaled to satisfy addictive needs for nicotine delivers increased amounts of carcinogens and toxins to the peripheral areas of the lungs.³⁹⁹

Table 15-12

Characteristics of Lung Cancer

^*A major histologic change has occurred over the last 3 decades as the most common cell type has shifted from squamous cell to adenocarcinoma. This shift appears to be the result of physiochemical changes in the late twentieth century smoke (e.g., increased levels of tobacco-specific nitrosamines).²³

Statistical data from the U.S. Department of Health Services. Publication No. 96-691. Washington, D.C., 1996.

Large cell carcinomas are so poorly differentiated that they cannot be classified with the other three categories above and require special diagnostic testing procedures to differentiate from other lung pathologic conditions.

Incidence

Lung cancer remains the leading cause of cancer death in the United States (estimated 167,050 deaths in 2006) and one of the world’s leading causes of preventable death.²²¹ More people die of lung cancer than of colon, breast, and prostate cancer combined. In 1987, lung cancer overtook breast cancer to become the most common cause of death from cancer among women in the United States.

Among men and women, both incidence and mortality have slowed with the decline in cigarette smoking. Smoking among adolescents peaked in 1996 and has been on the decline, yet a survey in 2002 showed that 9.8% of middle school students and 22.5% of high school students reported that they currently smoke cigarettes.²⁷⁸ Deaths from lung cancer increase at ages 35 to 44 years, with a sharp increase between ages 45 and 55 years. Incidence continues to increase up until age 74 years, after which the incidence levels off and decreases among the very old. There are differences in mortality rates for racial and ethnic groups.

Black males have the highest death rate and Asian/Pacific Islanders, American Indian/Alaska natives, and Hispanic males have the lowest death rate. Among women, blacks and whites have the highest mortality, whereas Asian/Pacific Islander and Hispanic females have the lowest death rate from lung cancer.²²⁰ Women taking hormone replacement therapy have an earlier onset and greater mortality with lung cancer.¹⁵⁰

Risk Factors

Contributions to lung cancer include environment (smoking, secondhand smoke, occupational exposure, or air pollution), nutrition, genetic factors (enzymes for carcinogen metabolism, enzymes that detoxify, and the capacity to repair DNA damage).²⁴⁴ Age, family history, and medical history, especially lung disease, also influence the occurrence, morbidity, and mortality.

Cigarette Smoking.: Cigarette smoking (more than 20 cigarettes per day) remains the greatest risk factor for lung cancer; 85% to 90% of all lung cancers occur in smokers, although remarkably, fewer than 20% of cigarette smokers develop lung cancer. The relative risk of lung cancer increases with the number of cigarettes smoked per day and the number of years of smoking history. The people at highest risk began smoking in their teens, inhale deeply, and smoke at least one-half pack per day.

The number of pack years is calculated by multiplying the packs of cigarettes consumed per day by the number of years of smoking. Lung cancer increases proportionately to the history of packs smoked per year and also depends on other variables such as time of breath holding, amount of cigarette smoked, and size of puff. The risk for dying of lung cancer is 20 times higher among people who smoke two or more packs of cigarettes per day than among those who do not smoke.

Smoking is a major cause of cancers of the oropharynx and bladder among women. Evidence is also strong that women who smoke have increased risks for liver, colorectal, and cervical cancer and cancers of the pancreas and kidney. There is also an increased risk for stroke, death from ruptured abdominal aortic aneurysm, and peripheral vascular disease among smokers compared to nonsmokers.¹⁹⁵ For other effects of smoking see the section on Tobacco in Chapter 3.

Former smokers have about one-half the risk for dying from lung cancer than do current smokers (see Table 3-4). Compared with current smokers, the risk for lung and bronchus cancer among former smokers declines as the duration of abstinence lengthens, but it takes over 20 years to reach the risk level of people who never smoked.²⁴⁴ These statistics support the fact that lung cancer is the most preventable of all cancers. The elimination of cigarette smoking would virtually eliminate SCLC. Smoking cessation also appears to slow the rate of progression of carotid atherosclerosis and other vascular disease.

There are approximately 50 known carcinogens and promoting substances found in tobacco smoke; the major causal agents of lung cancer are the polynuclear aromatic hydrocarbons (PAHs) and tobacco-specific N-nitrosamines (nicotine). Tobacco smoking also results in increased exposure to ethylene oxide, aromatic amines, and other agents that cause damage to DNA.³⁴⁰ For this reason, the risk of lung cancer is increased in a smoker who is also exposed to other carcinogenic agents, such as radioactive isotopes, polycyclic aromatic hydrocarbons and arsenicals, vinyl chloride, metallurgic ores, and mustard gas.

Marijuana.: Marijuana contains many of the same organic and inorganic compounds that are carcinogens, co-carcinogens, or tumor promoters found in tobacco smoke. Marijuana produces inflammation, edema, and cell injury in the tracheobronchial mucosa of smokers and contributes to oxidative stress, which is a precursor for DNA mutations.⁴¹⁰ However, cannabinoids modulate and minimize free radical production and inhibit tumor angiogenesis. In addition, cannabinoid receptors are not found in the lung epithelial cells.²⁹⁵ Cannabinoids have been shown to inhibit certain breast, lung, and brain cancers,²⁴⁶ although other studies have shown an increase in head, neck, and lung cancers.¹⁹⁰ Unfortunately, most studies do not examine the magnitude of exposure and concurrent tobacco use.

The risk of marijuana smoking does not appear to approach that of smoking tobacco and any increased risk may be associated with the route of delivery (the heat and particulate irritation of smoking) rather than the drug itself. Further studies are needed.

Environmental Tobacco Smoke.: In 1992, the U.S. EPA declared secondhand smoke or ETS to be a group A human carcinogen. ETS increases the relative risk for lung cancer about 1.5-fold and there are 3000 lung cancer deaths each year from ETS.⁸¹ This exposure increases the risk for the children and partners of smokers and becomes an occupational hazard in individuals working in bars, restaurants, or other places that are not smoke-free. See previous section on Environmental Tobacco Smoke in this chapter.

Occupational Exposure.: Studies on whether occupational factors increase the risk of cancer development in the nonsmoker are limited in number but confirm that certain occupational exposures are associated with an increased risk for lung cancer among both male and female nonsmokers.³⁴⁵ The inhalation of asbestos fibers is associated with higher cancer risks for both smokers and nonsmokers, although the rate is considerably higher for smokers.

The rate of lung cancer in people who live in urban areas is 2.3 times greater than that of those living in rural areas, possibly implicating air pollution as a risk factor in lung cancer. The exact role of air pollution is still unknown, but carcinogens with known genotoxicity continue to be released into outdoor air from industrial sources, power plants, and motor vehicles; epidemiologic research provides evidence for an association between air pollution and lung cancer.^91,433

Indoor exposure to radon, which is a colorless, odorless gas that is a product of uranium and radium produced from the decomposition of rocks and soil, is a known carcinogen and the second leading cause of lung cancer. Concentrations vary geographically (more in the northern United States), and radon gas levels are highest in basements, nearest the soil.¹⁴¹ Other sources of radon exposure include radioactive waste and underground mines; exposure to tobacco smoke multiplies the risk of concurrent exposure to radon.

Other occupational or environmental risk factors associated with lung cancer include diesel exhaust, benzopyrenes, silica, formaldehyde, copper, chromium, cadmium, arsenic, alkylating compounds, sulfur dioxide, and ionizing radiation.

Previous Lung Disease.: The presence of other lung diseases, such as pulmonary fibrosis, scleroderma, and sarcoidosis, may increase the risk of developing lung cancer. COPD or fibrosis of the lungs inhibits the clearance of carcinogens from the lungs, thereby increasing the risk of alteration of DNA with resultant malignant cell growth.

Nutrition.: Other risk factors may include low consumption of fruits and vegetables, reduced physical activity, increased dietary fat (especially diets high in saturated or animal fat and cholesterol), and high alcohol intake. A recent prospective study demonstrated positive effects of fruit consumption, but not of vegetables.¹⁷¹

Studies have shown no beneficial effect of vitamin E (α-tocopherol), beta-carotene, and retinol, and several studies have determined that beta-carotene supplementation in smokers increases the risk for lung cancer. The mechanism for this carcinogenic action remains unknown.³⁶⁷

Genetic Susceptibility.: Several published studies suggest that lung cancer can aggregate in some families, and it has been hypothesized that the defect in the body’s ability to defend against the carcinogens in tobacco smoke may be inherited.⁴⁵³ A first-degree smoking relative of an individual with lung cancer has an increased risk of developing lung cancer. This predilection may be due to a genetic predisposition, but the trait (lung cancer) may be expressed only in the presence of its major predisposing factor (i.e., tobacco). Carcinogenic chemicals may induce genomic instability either directly or indirectly through inflammatory processes in the lung epithelial cells.

Lung cancer is used as a model for the study of the interplay between genetic factors and environmental exposure since the primary etiology is well established. Developments in molecular biology have led to the identification of biologic markers that may increase predisposition to smoking-related carcinogenesis. In the future, lung cancer screening may be possible by using specific biomarkers.²⁴³

Pathogenesis

As mentioned, there is a clear relationship between cigarette smoking and the development of SCLC. The effects of smoking include structural, functional, malignant, and toxic changes. DNA-mutating agents in cigarettes produce alterations in both oncogenes and tumor suppressor genes, as well as genes that detoxify and assist with DNA repair. Normal polymorphism (variations in genes) also plays a role in the development of or resistance to cancer.

Understanding of the molecular pathology of lung cancer is advancing rapidly, with several specific genes and chromosomal regions being identified. Lung cancer appears to require many mutations in both dominant and recessive oncogenes before they become invasive. Several genetic and epigenetic changes are common to all lung cancer histologic types, whereas others appear to be tumor-type specific. The sequence of changes remains unknown.²⁴⁴ There appears to be an interaction between estrogen receptors and epidermal growth factor in the lung that plays a role in women’s susceptibility to lung cancer.¹²⁴

All lung cancers are thought to arise from a common bronchial precursor cell, with differentiation then proceeding along various histologic pathways from poorly differentiated small cell cancer to the more intermediate undifferentiated large cell tumors, to the more differentiated adenocarcinomas and squamous cell tumors. Perhaps the histologic changes (thickening of bronchial epithelium, damage to and loss of protective cilia, mucous gland hypertrophy and hypersecretion of mucus, and alveolar cell rupture) that occur more frequently in long-term smokers than nonsmokers predispose the lungs to changes. This results in a multistep process involving the development of hyperplasia, metaplasia, dysplasia, carcinoma in situ, invasive carcinoma, and metastatic carcinoma. As the details of the carcinogenic process are unraveled, one goal is to identify intermediate (preneoplastic) markers of exposure and inherent predisposition that will help assess the risk of lung cancer and allow for early detection.

Small Cell Lung Cancer.: When the cells become so dense that there is almost no cytoplasm present and the cells are compressed into an ovoid mass, the tumor is called small cell carcinoma or oat cell carcinoma. SCLC develops most often in the bronchial submucosa, the layer of tissue beneath the epithelium, and tends to be located centrally, most often near the hilum of the lung. These tumors can produce hormones that stimulate their own growth and the rapid growth of neighboring cells causing bronchial obstruction and pneumonia with early intralymphatic invasion. Lymphatic and distant metastases are usually present at the time of diagnosis.

Non–Small Cell Lung Cancer.: Squamous cell carcinomas arise in the central portion of the lung near the hilum, projecting into the major or segmental bronchi. Although these tumors tend to grow rapidly, they often remain located within the thoracic cavity, making curative treatment more likely compared with other NSCLC types. These tumors may be difficult to differentiate from TB or an abscess because they often undergo central cavitation (formation of a cavity or hollow space).

Clinical Manifestations

Symptoms of early stage localized lung cancer do not differ much from pulmonary symptoms associated with chronic smoking (e.g., cough, dyspnea, and sputum production), so the person does not seek medical attention. Women with lung cancer have lower incidence or severity of COPD, so symptoms may be fewer and diagnosis delayed.²⁶² Symptoms may depend on the location within the pulmonary system, whether centrally located, peripheral, or in the apices of the lungs. Systemic symptoms, such as anorexia, fatigue, weakness, and weight loss, are common, especially with advanced disease (metastases) and associated with poor prognosis.³⁶

Bone pain associated with bone metastasis is common; other symptoms resulting from metastases depend on the site of involvement (e.g., hepatomegaly and jaundice with liver metastasis and seizures, headaches, confusion, or focal neurologic signs with brain metastasis). Other signs and symptoms of disease include recurring bronchitis or pneumonia; productive cough with hemoptysis; wheezing; poorly defined persistent chest pain; difficulty swallowing or hoarseness; orthopnea; nerve involvement (phrenic, laryngeal, brachial plexus, or sympathetic ganglion); and vascular (superior vena cava), cardiac, and esophageal compression as a result of local tumor invasion.^36,142,347

Small Cell Lung Cancer.: Signs and symptoms of SCLC depend on the size and location of the tumor and the presence and extent of metastases. Because SCLCs most commonly arise in the central endobronchial location in people who are almost exclusively long-term smokers, typical symptoms are a result of obstructed air flow and consist of persistent, new, or changing cough, dyspnea, stridor, wheezing, hemoptysis, and chest pain.⁶¹

Intercostal retractions on inspiration and bulging intercostal spaces on expiration indicate obstruction. As obstruction increases, bronchopulmonary infection (obstructive pneumonitis) often occurs distal to the obstruction. Centrally located tumors cause chest pain with perivascular nerve or peribronchial involvement that can refer pain to the shoulder, scapula, upper back, or arm.

SCLC is (more often than NSCLC) associated with several paraneoplastic syndromes, including ectopic hormone production (adrenocorticotropic hormone [ACTH]) with Cushing’s syndrome, production of hormones by tumors of nonendocrine origin, or production of an inappropriate hormone (antidiuretic hormone) by an endocrine gland. Neuroendocrine cells containing neurosecretory granules exist throughout the tracheobronchial tree. This phenomenon is important because resulting signs and symptoms may be the first manifestation of underlying cancer. See Special Implications for the Therapist: Ling Cancer in this section; see also the section on Paraneoplastic Syndromes in Chapter 9.

Non–Small Cell Lung Cancer.: The less common peripheral pulmonary tumors (large cell) often do not produce signs or symptoms until disease progression produces localized, sharp, and severe pleural pain increased on inspiration, limiting lung expansion; cough and dyspnea are present. Pleural effusion may develop and limit lung expansion even more.

Tumors in the apex of the lung, called Pancoast’s tumors, occur both in squamous cell and adenocarcinomatous cancers. Symptoms do not occur until the tumors invade the brachial plexus (see Special Implications for the Therapist: Lung Cancer in this section). Destruction of the first and second ribs can occur. Paralysis, elevation of the hemidiaphragm, and dyspnea secondary to phrenic nerve involvement can also occur.

Other manifestations may include digital clubbing, skin changes, joint swelling associated with hypertrophic pulmonary osteoarthropathy (see previous discussion of this condition in the section on Cystic Fibrosis), decreased or absent breath sounds on auscultation, or pleural rub (inflammatory response to invading tumor).

Metastasis

The rich supply of blood vessels and lymphatics in the lungs allows the disease to metastasize rapidly.^60b Lung cancers spread by direct extension, lymphatic invasion, and blood-borne metastases. Tumors spread by direct invasion in the bronchus of origin; others may invade the bronchial wall and circle and obstruct the airway. Intrapulmonary spread may lead to compression of lung structures other than airways such as blood or lymph vessels, alveoli, and nerves.

Direct extension through the pleura can result in spread over the surface of the lung, chest wall, or diaphragm. Carcinomas of the lung of all types metastasize most frequently to the regional lymph nodes, particularly the hilar and mediastinal nodes. Supraclavicular, cervical, and abdominal channels may also be invaded. Tumors originating in the lower lobes tend to spread through the lymph channels.

Lung cancer generally has a widespread pattern of hematogenous metastases. This is caused by the invasion of the pulmonary vascular system. After tumor cells enter the pulmonary venous system, they can be carried through the heart and disseminated systemically. Tumor emboli can become lodged in areas of organ systems where vessels become too narrow for their passage or where blood flow is reduced.

The most frequent site of extranodal metastases is the adrenal gland. Lung cancer can also metastasize to the brain, bone, and liver before presenting symptomatically. Brain metastases constitute nearly one-third of all observed recurrences in people with resected NSCLC of the adenocarcinoma type. Metastases to the brain usually result in CNS symptoms of confusion, gait disturbances, headaches, or personality changes.

Tumor spread intrathoracically to the mediastinum and beyond can produce superior vena cava (SVC) syndrome with swelling of the face, neck, and arms and neck and thoracic vein distention more common in the early morning or after being recumbent for several hours. SVC syndrome is usually a sign of advanced disease. If left untreated, SVC syndrome results in cerebral edema and possible death. Increased intracranial pressure, headaches, dizziness, visual disturbances, and alteration in mental status are signs of progressive compression. Cardiac metastasis can occur and results in arrhythmias, congestive heart failure, and pericardial tamponade.

As a form of secondary malignancy, the lungs are the most frequent site of metastases from other types of cancer. Any tumor cell dislodged from a primary neoplasm can find its way into the circulation or lymphatics, which are filtered by the lungs. Carcinomas of the kidney, breast, pancreas, colon, and uterus are especially likely to metastasize to the lungs.

PROGNOSIS.

Restrictive Lung Disease

Clinical Manifestations

MEDICAL MANAGEMENT

Pulmonary Fibrosis

Etiologic and Risk Factors

Pathogenesis and Clinical Manifestations

MEDICAL MANAGEMENT

TREATMENT AND PROGNOSIS.

Systemic Sclerosis Lung Disease

Incidence

Pathogenesis and Clinical Manifestations

MEDICAL MANAGEMENT

TREATMENT.

PROGNOSIS.

Chest Wall Trauma or Lung Injury

Clinical Manifestations

MEDICAL MANAGEMENT

TREATMENT.

Ventilator-Induced Injury

ENVIRONMENTAL AND OCCUPATIONAL DISEASES

Pneumoconiosis

Incidence and Etiologic Factors

Risk Factors

Pathogenesis

Clinical Manifestations

MEDICAL MANAGEMENT

DIAGNOSIS.

TREATMENT.

PROGNOSIS.

Hypersensitivity Pneumonitis

Noxious Gases, Fumes, and Smoke Inhalation

NEAR DROWNING

Definition

Incidence and Risk Factors

Pathogenesis

Clinical Manifestations

MEDICAL MANAGEMENT

TREATMENT.

PROGNOSIS.

CONGENITAL DISORDERS

Definition and Overview

Incidence

Etiologic Factors

Pathogenesis

Clinical Manifestations

MEDICAL MANAGEMENT

TREATMENT.

PROGNOSIS.

PARENCHYMAL DISORDERS

Definition

Etiologic Factors and Pathogenesis

Clinical Manifestations

MEDICAL MANAGEMENT

TREATMENT AND PROGNOSIS.

Pulmonary Edema

Etiologic and Risk Factors

Pathogenesis

Clinical Manifestations

MEDICAL MANAGEMENT

DIAGNOSIS.

TREATMENT.

PROGNOSIS.

Acute Respiratory Distress Syndrome

Incidence

Etiologic and Risk Factors

Pathogenesis

Clinical Manifestations

MEDICAL MANAGEMENT

TREATMENT.

PROGNOSIS.

Postoperative Respiratory Failure

Sarcoidosis

Incidence

Etiologic Factors and Pathogenesis

Clinical Manifestations

MEDICAL MANAGEMENT

TREATMENT.

PROGNOSIS.

Lung Cancer