5 курс / Пульмонология и фтизиатрия / Clinical_Manifestations_and_Assessment_of_Respiratory

•Exercise-induced bronchoconstriction (EIB): Physical activity is often a stimulus for asthma symptoms in many patients. For example, athletes, especially those competing at a high level, have an increased incidence of asthma symptoms compared with nonathletes.

•Pregnancy: Asthma control often worsens in women who have a history of asthma and who are pregnant. Exacerbations are common in pregnancy, especially during the second trimester.

•Occupational asthma: Once a diagnosis of occupational asthma has been established, complete avoidance of the relevant exposure is an important component of management.

•The elderly: With increasing age, lung function generally decreases because of stiffness of the chest wall, reduced muscle function, loss of elastic recoil, and airway remodeling. Older patients may not report asthma symptoms and often attribute breathlessness to normal aging or comorbidities such as cardiovascular disease or obesity.

•Aspirin-exacerbated respiratory disease: The clinical course of aspirin-exacerbated respiratory disease (AERD, previously called aspirin-induced asthma) is well documented. It begins with nasal congestion and anosmia and progresses to chronic rhinosinusitis with nasal polyps that regrow rapidly after surgery. Asthma and hypersensitivity to aspirin develop shortly afterward. After ingestion of aspirin or NSAIDs, an acute asthma episode develops.

•Difficult-to-treat and severe asthma: Refers to patients who have ongoing factors such as comorbidities, poor adherence, and allergen exposure that interfere with achieving good asthma control. Treatment-resistant asthma refers to the patient with confirmed diagnosis of asthma, but whose symptoms or exacerbations remain poorly controlled in spite of high-dose ICS and second controllers such as LABA. Severe asthma includes patients with refractory asthma and those who have not fully responded to treatment of comorbidities.

Respiratory Care Treatment Protocols

Aerosolized Medication Protocol

Inhaled beta2 agents, anticholinergic agents, and corticosteroid agents via a metered dose inhaler (pMDI) spacer, dry

powder inhaler (DPI), or small volume nebulizer (SVN) are commonly used in the treatment of asthma to induce bronchial smooth muscle relaxation (see Aerosolized Medication Protocol, Protocol 10.4). Continuous nebulization of albuterol is often used in the management of status asthmaticus to prevent acute ventilatory failure.

Oxygen Therapy Protocol

Oxygen therapy may be required to treat hypoxemia, decrease the work of breathing, and decrease myocardial work. The hypoxemia that develops in asthma is usually caused by the ventilation-perfusion mismatch and shunt-like effect associated with bronchospasm and increased airway secretions. Hypoxemia caused by this shunt-like effect can at least partly be corrected by oxygen therapy (see Oxygen Therapy Protocol, Protocol 10.1).

Airway Clearance Therapy Protocol

Because of the excessive mucous production and secretion accumulation associated with asthma, a number of bronchial hygiene treatment modalities may be used to enhance the mobilization of bronchial secretions (see Airway Clearance Therapy Protocol, Protocol 10.2). These modalities should be attempted with patients with acute asthma when they can effectively move enough air to deep breathe and cough.

Mechanical Ventilation Protocol

Because acute ventilatory failure is associated with status asthmaticus, continuous mechanical ventilation may be required to maintain an adequate ventilatory status.

Status asthmaticus is defined as a severe asthma episode that does not respond to conventional pharmacologic therapy. When the patient becomes fatigued, the ventilatory rate decreases. Clinically, the patient demonstrates a progressive decrease in PaO2 and pH and a steady increase in PaCO2 (acute ventilatory failure). Noninvasive ventilatory assistance

(continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BPAP]9) may be indicated to provide expiratory resistance, while also providing frequent or continuous aerosolized bronchodilator therapy. If ventilation does not improve and hypercarbia is not reversed, intubation and mechanical ventilation becomes necessary (see Ventilator Initiation and Management Protocol, Protocol 11.1, and Ventilator Weaning Protocol, Protocol 11.2).

Case Study Asthma

A 7-year-old girl was admitted to the emergency department (ED) in severe respiratory distress. Her history of wheezing dated back to age 6 months, when she was hospitalized with viral bronchiolitis. Over the past 3 years she was hospitalized in different hospitals on a number of occasions and was usually managed satisfactorily with aerosolized albuterol and oral steroids. She began coughing and wheezing the night before admission and became progressively worse during the night. Her cough was nonproductive. At 8.00 a.m., she was brought to the ED after she did not get relief from her albuterol MDI at home.

Physical examination revealed an extremely anxious, well-developed female child in acute respiratory distress. She stated in short, terse phrases: “It's hard … for me … to breathe.” Her vital signs were as follows: blood pressure 128/84, pulse 148 beats/min, and respiratory rate 30 breaths/min. Her temperature was 99.1°F. Her SpO2 was 88% on room air on

arrival. She was actively using her accessory muscles of respiration. On auscultation, her breath sounds were decreased bilaterally with faint expiratory wheezes and coarse crackles.

The ED physician ordered three back-to-back SVN treatments with a combination of albuterol and ipratropium bromide. The patient's level of distress prompted a need to begin bronchodilator treatment with oxygen without attempting serial peak flow measurements. Posttreatment PEFR was less than 70 L/min. (Her personal best was about 200 to 250 L/min.) The patient was then placed on 2 L/min nasal cannula oxygen, and a capillary blood gas (CBG) was drawn: pH 7.27, PaCO2

52 mm Hg, 22 mEq/L, PaO2 76 mm Hg, and SaO2 91%. A chest x-ray examination was ordered but not performed.

The physician ordered a respiratory care consultation and stated that she did not want to commit the patient to a ventilator at this time if possible. The physician asked that aggressive noninvasive pulmonary care be tried first. At this time the respiratory therapist documented the following.

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Intravenous aminophylline in the emergency treatment of acute asthma is controversial and rarely used in children. Care must be taken to avoid theophylline toxicity, and symptoms of toxicity often do not reflect serum concentrations of the drug. Almost continuous assessment by the respiratory therapist is necessary if more invasive therapy (including induced sedation, paralysis, and mechanical ventilation) is to be avoided.

The acutely ill patient with asthma requires almost continuous monitoring and frequent SOAP notes if the patient care team is to be constantly apprised of the patient's progress. (The one such note recorded here is but a small portion of the more than 14 notes that we found on analysis of the patient's medical record from her ED admission alone.) Current best practice would require that the first SOAP assessment would have included a statement about the patient's preadmission asthma control status, which in this case would have been (at best) “partly controlled.”

Self-Assessment Questions

1.During an asthma episode, the smooth muscles of the bronchi may hypertrophy as much as:

a.Two times normal thickness

b.Three times normal thickness

c.Four times normal thickness

d.Five times normal thickness

2.Asthma is associated with which of the following?

1.Increase in goblet cells

2.Damage to cilia and reduced mucous clearance

3.Increase in bronchial gland size

4.Decrease in eosinophils

a.1 and 3 only

b.2 and 4 only

c.1, 2, and 3 only

d.2, 3, and 4 only

3.Which of the following have gained a widespread acceptance for assessing and monitoring a patient's airflow limitation?

1.PEFR

2.FEF200–1200

3.FEV1

4.FEV1/FVC ratio a. 1 and 3 only

b. 2 and 4 only

c. 1, 3, and 4 only d. 2, 3, and 4 only

4.A patient clinical history presents the following: Daytime asthma symptoms more than two per week, no limitation in activities, no nocturnal symptoms or awakening, the need for reliever/rescue medications once per week, and a normal PEFR and FEV1. Which of the following would best classify this patient's level of asthma

control?

a.Controlled

b.Partly controlled

c.Uncontrolled

d.Severe exacerbation

5.Which of the following can be used to help confirm the diagnosis of asthma? 1. Exercise challenge

2. Response to inhaled mannitol

3.Response to inhaled histamine

4.Response to inhaled methacholine

a.1 and 3 only

b.2 and 4 only

c.2, 3, and 4 only

d.1, 2, 3, and 4

6.When pulsus paradoxus appears during an asthma attack:

1.Left ventricle filling decreases during inspiration

2.Cardiac output increases during expiration

3.Left ventricle filling increases during expiration

4.Cardiac output increases during inspiration

a.1 only

b.2 only

c.3 and 4 only

d.1 and 2 only

7.During an asthma episode, which of the following abnormal lung volume and capacity findings are found?

1.Increased FRC

2.Decreased ERV

3.Increased VC

4.Decreased RV

a.1 only

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C H A P T E R 1 5

Cystic Fibrosis

CHAPTER OUTLINE

Anatomic Alterations of the Lungs

Etiology and Epidemiology

How the Cystic Fibrosis Gene Is Inherited Screening and Diagnosis

Newborn Screening Sweat Test

Molecular Diagnosis (Genetic Testing) Nasal Potential Difference

Prenatal Testing Stool Fecal Fat Test

Overview of the Cardiopulmonary Clinical Manifestations Associated With Cystic Fibrosis

General Management of Cystic Fibrosis

Respiratory Care Treatment Protocols

Other Medications and Special Procedures Prescribed by the Physician

Lung or Heart-Lung Transplantation Case Study: Cystic Fibrosis Self-Assessment Questions

CHAPTER OBJECTIVES

After reading this chapter, you will be able to:

•Describe the anatomic alterations of the lungs associated with cystic fibrosis.

•Describe the etiology and epidemiology of cystic fibrosis.

•Describe how the cystic fibrosis gene is inherited.

•Discuss the screening and diagnosis of cystic fibrosis.

•Discuss the cardiopulmonary clinical manifestations associated with cystic fibrosis.

•Describe the general management of cystic fibrosis.

•Describe the clinical strategies and rationales of the SOAPs presented in the case study.

•Define key terms, and complete self-assessment questions at the end of the chapter and on Evolve.

KEY TERMS

Amniocentesis Conductance Defect

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Electrical Potential Difference

Fecal fat test Gating Defect Genetic Counseling Genetic Test

Immunoreactive Trypsin Test (IRT) Inhaled dNASE

Inhaled Tobramycin Ivacaftor

Lung or Heart-Lung Transplantation Meconium Ileus

Nasal Potential Difference (NPD) Pilocarpine

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FIGURE 15.2 Abnormalities in the CFTR protein prevent chloride flux in the airway epithelium, resulting in abnormal reabsorption of water creating thick mucus and inadequate mucociliary function. (A) Chloride channel defect in the sweat duct causes increased chloride and sodium concentration in sweat. (B) In the airway, patients with cystic fibrosis have decreased chloride secretion and increased sodium and water reabsorption, leading to dehydration of the mucous layer coating epithelial cells, defective mucociliary action, and mucous plugging of the airways. CFTR, Cystic fibrosis transmembrane conductance regulator;

ENaC, epithelial sodium channel. (Modified from Kumar, V., Abbas, A. K., & Aster, J. C. [2015]. Robbins and Cotran pathologic basis of disease [9th ed.]. Philadelphia, PA: Elsevier.)

As shown in Fig. 15.3, six classes of CFTR mutations have been identified. These six different mutations can further be divided into three broad categories affecting either the quantity or function of the CFTR protein. For example, classes I and II can be placed in the “little or no functional CFTR category. Classes III and IV represent the “function of CFTR at the cell surface is affected category.” The “reduced quantity of functional CFTR protein category” comprises classes V and VI.

FIGURE 15.3 CFTR mutation classifications: A basis for categorizing CFTR mutations. Note: The red ballloon-like icon above represents the CFTR protein.

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The CFTR mutations are also classified as either a gating defect (e.g., class III) in which the channel does not open or a conductance defect (e.g., class IV) in which the channel is open but chloride does not move efficiently. Note that with class I mutations, the gene contains a stop signal that prevents CFTR protein from being made. With class II mutations, there is a defect in the CFTR protein processing, and CFTR never reaches the cell membrane. With class III mutations, CFTR protein is made and reaches the cell's surface but is unable to move out of the cell (gating defect). With class IV, the mutations reduce the passage of chloride ions through the channel opening. Class V CFTR is normal but produced in smaller than normal quantities. Class VI mutations are characterized by accelerated turnover.

How the Cystic Fibrosis Gene Is Inherited

Because CF is a recessive gene disorder, the child must inherit two copies of the defective CF gene—one from each parent (cystic fibrosis carriers)—to have the disease. Even though the carrier of the CF gene may be identified through genetic testing, the carrier (heterozygote) does not demonstrate evidence of the disease. However, if both parents carry the CF gene, the possibility of their children having CF (regardless of gender) follows the standard Mendelian pattern: there is a 25% chance that each child will have CF, a 25% chance that each child will be completely normal (and not carry the gene), and a 50% chance that each child will be a carrier. Thus when both patients carry a CF gene mutation, there is a one in four chance that the child will have CF (Fig. 15.4). It is estimated that more than 10 million Americans are unknowing, symptomless carriers of a mutant CF gene.

FIGURE 15.4 Standard Mendelian pattern of inheritance of cystic fibrosis.

According to the Cystic Fibrosis Foundation, CF affects about 30,000 children and adults in the United States and about 70,000 worldwide. About 1000 new cases of CF are diagnosed each year in the United States. More than 90% of the patients are diagnosed by newborn screening. More than 50% of the patient population with CF are age 18 years or older. The median age of survival for individuals with CF is in the late 30s, but many patients with CF live into their 40s and beyond.2 CF occurs most often in Caucasians (1 : 3000). The occurrence in Hispanics is 1 : 9200, Native Americans 1 : 10,900, African-Americans 1 : 15,000, and Asian-Americans 1 : 30,000. Death is usually caused by pulmonary complications.

Screening and Diagnosis

The diagnosis of CF is based on the clinical manifestations associated with CF, family history of CF, and laboratory findings. The following two criteria must be met to diagnose CF:

1.Clinical symptoms consistent with CF in at least one organ system—for example, pulmonary system, sinus disease, pancreatic disease, meconium ileus, biliary disease, and male infertility. Box 15.1 provides common clinical indicators that justify evaluation for CF. A useful mnemonic, “CF PANCREAS” is seen in Box 15.2.

Box 15.1

Clinical Indicators Justifying the Initial Evaluation for Cystic Fibrosis

Pulmonary

•Wheezing

•Chronic cough

•Sputum production

•Frequent respiratory infections (Staphylococcus aureus, Pseudomonas aeruginosa, Haemophilus influenzae)

•Abnormal chest radiograph and/or computed tomography scan

•Nasal polyps

•Parasinusitis

•Digital clubbing

Gastrointestinal Disorders

• Failure to thrive

•Foul-smelling, greasy stools

•Voracious appetite

•Milk and formula intolerance

•Rectal prolapse

•Meconium ileus

•Meconium peritonitis

•Distal intestinal obstruction syndrome

•Pancreatic insufficiency

•Pancreatitis

•Hepatobiliary disfunction

•Hepatomegaly

•Focal biliary cirrhosis

•Prolonged neonatal jaundice

•Cholelithiasis

Nutritional Deficits

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

•Hypoproteinemia

•Hypochloremia (metabolic alkalosis)

Infertility (Male)

• Obstructive azoospermia

Box 15.2

CF Pancreas Mnemonic

C Chronic respiratory disease

F Failure to thrive

P Polyps

A Alkalosis, metabolic

N Neonatal intestinal obstruction

C Clubbing of fingers

R Rectal prolapse

E Electrolyte increase in sweat

A Aspermia/absent vas deferens

S Sputum: Staphylococcus aureus, Pseudomonas aeruginosis

2.Clinical evidence of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction—any of the following:

•Elevated sweat chloride greater than 60 mEq/L (on two occasions)

•Molecular diagnosis (genetic testing). Presence of two disease-causing mutations in CFTR

•Abnormal nasal potential difference

Newborn Screening

Newborn screening for CF has been a part of the newborn genetic testing protocol in all 50 states since 2011. Most infants with CF have an elevated blood level of immunoreactive trypsin (also called trypsin-like immunoreactivity and serum trypsin), which can be measured by radioimmunoassay or by an enzyme-linked immunoassay. The immunoreactive trypsin level (IRT) is measured from the blood dots collected on all newborn infants on the Guthrie cards.

The CF screening protocol varies among states and will identify more than 90% of infants with CF. The most common protocol is to perform DNA screening for 32 to 85 of the most common CF mutations on 2% to 5% of the samples with the highest IRT levels. Detection of at least one CF mutation is considered a positive screen and is referred to a CF center in most states for further testing.

The diagnosis of CF is established by a positive sweat test and/or genetic analysis for CF mutations. A negative or normal sweat test identifies the newborn as a CF carrier. All families of infants identified through newborn screening programs should receive genetic counseling. These newborn screening programs now identify 95% of infants with CF. It should be remembered that it is always appropriate to sweat test an individual of any age with symptoms consistent with the possible diagnosis of CF.

Sweat Test

The sweat test (sometimes called the sweat chloride test) is the gold standard diagnostic test for CF. The sweat test is a reliable test for the identification of about 98% of patients with CF. This test measures the amount of sodium and chloride in the patient's sweat. During the procedure a small amount of a colorless, odorless sweat-producing chemical called pilocarpine is applied to the patient's arm or leg—usually the forearm. An electrode is attached to the chemically prepared area, and a mild electric current is applied to stimulate sweat production (Fig. 15.5). The test is usually done twice.

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FIGURE 15.5 Sweat test. During the procedure a small amount of a colorless, odorless, sweat-producing chemical called pilocarpine is applied to the patient's arm or leg—usually the forearm. An electrode is attached to the chemically prepared area, and a mild electric current is applied to stimulate sweat production. (Used with permission from Wescor, Inc., an ELITech Group Company.)

Although the sweat glands of patients with CF are microscopically normal, the glands secrete up to four times the normal amount of sodium and chloride. The actual volume of sweat, however, is no greater than that produced by a normal individual. In both infants and adults, a sweat chloride concentration greater than 60 mEq/L is considered to be a diagnostic sign of CF. Box 15.3 provides an overview for sweat test interpretations for infants 6 months or younger and infants older than 6 months, children, and adults.

Box 15.3

Sweat Test Interpretations

Infants 6 Months or Younger

•≤29 mmol/L: Normal (cystic fibrosis very unlikely)

•30 to 59 mmol/L: Intermediate (possible cystic fibrosis)

•≥60 mmol/L: Abnormal (diagnosis of cystic fibrosis)

Infants Older Than 6 Months, Children, and Adults

•≤39 mmol/L: Normal (cystic fibrosis very unlikely)

•40 to 59 mmol/L: Intermediate (possible cystic fibrosis)

•>60 mmol/L: Abnormal (diagnosis of cystic fibrosis)

All patients with the following characteristics should undergo a sweat test to help confirm the diagnosis of CF:

•Infants with positive CF newborn screening results (performed after 2 weeks of age and greater than 2 kg if asymptomatic)

•Infants with symptoms suggestive of CF (see Box 15.1)

•Older siblings (including adults) with symptoms suggestive of CF

•Members of the patient's family with confirmed CF

Molecular Diagnosis (Genetic Testing)

With a sample of the patient's blood or cheek cells, a genetic test (also called a genotype test, gene mutation test, or mutation analysis) can be performed to analyze deoxyribonucleic acid (DNA) for the presence of CFTR gene mutations. Intermediate results of sweat chloride testing should be further investigated with a DNA analysis using the CFTR multimutation method. The sweat chloride test should also be repeated.

Most of the diagnostic laboratories in the United States are able to screen for at least 30 to 100 of the most common mutations, including gene mutation Delta F508 (ΔF508), which is the most common gene mutation associated with CF. When two CF gene mutations are detected, and the sweat test is intermediate or positive, the diagnosis of CF is confirmed. Although genetic testing for CF is considered a valuable diagnostic tool, it does have its limitations. For example, some individuals have CFTR mutations but demonstrate no typical clinical manifestations of CF. In addition, some patients may have CFTR mutations, but the mutations cannot be identified without special gene analysis methods. It is estimated that genetic testing can confirm CF in about 90% to 96% of the patients tested.

Nasal Potential Difference

The impaired transport of sodium (Na+) and chloride (Cl−) across the epithelial cells lining the airways of the patient with CF can be measured. As the Na+ and Cl− ions move across the epithelial cell membrane they generate what is called an electrical potential difference—the amount of energy required to move an electrical charge from one point to another. In the nasal passages this electrical potential difference is called the nasal potential difference (NPD). The NPD can be measured with a surface electrode over the nasal epithelial cells lining the inferior turbinate. An increased (i.e., more negative) NPD strongly suggests CF. The NPD is recommended for patients with clinical features of CF who have borderline or normal sweat test values and nondiagnostic CF genotyping.

Prenatal Testing

Both the American College of Obstetrics and Gynecology and the American College of Medical Genetics recommend that pregnant females be offered screening for CF mutations using a 32 to 85 mutation panel. Females who test positive for a