Ebook Egan''s fundamentals of respiratory care (11/E): Part 2

(BQ) Part 2 book Egan''s fundamentals of respiratory care has contents: Pulmonary infections, interstitial lung disease, pleural diseases, pulmonary vascular disease, acute respiratory distress syndrome, lung cancer, mechanical ventilators,

S E C T I O N I V

REVIEW OF CARDIOPULMONARY

DISEASE

◆ Recognize the pathophysiology and common causes of lower respiratory tract infections in specific clinical settings.

◆ Discuss strategies to prevent pneumonia.

◆ Describe how the respiratory therapist aids in diagnosis and management of patients with suspected pneumonia.

CHAPTER OUTLINE

Classification Pathogenesis Microbiology Clinical Manifestations Chest Radiograph Risk Factors for Mortality and Assessing the Need for Hospitalization

Diagnostic Studies Community-Acquired Pneumonia Health Care–Associated Pneumonia, Hospital- Acquired Pneumonia, and Ventilator-Associated Pneumonia

Antibiotic Therapy Community-Acquired Pneumonia Health Care–Associated Pneumonia, Hospital- Acquired Pneumonia, and Ventilator-Associated Pneumonia

Prevention Community-Acquired Pneumonia Health Care–Associated Pneumonia, Hospital- Acquired Pneumonia, and Ventilator-Associated Pneumonia

Tuberculosis Epidemiology Pathophysiology Diagnosis Precautions Treatment Role of the Respiratory Therapist in Pulmonary Infections

KEY TERMS

antibiotic therapy atypical pathogens community-acquired pneumonia fomites

health care–associated pneumonia hospital-acquired pneumonia lower respiratory tract infection nosocomial pneumonia

pneumonia tuberculosis ventilator-associated pneumonia

Pulmonary Infections • CHAPTER 24 495

initiated based on the most likely cause of infection when the specific causative organism is still unknown.)

Community-acquired pneumonia (CAP) can be divided into two types—acute and chronic—based on its clinical pre-

sentation Acute pneumonia presents with sudden onset over a

few hours to several days The clinical presentation may be typical or atypical, depending on the pathogen The onset of

chronic pneumonia is more insidious, often with gradually

esca-lating symptoms over days, weeks, or months

Pneumonia acquired in health care settings is often caused

by microorganisms different from those that cause CAP ously termed nosocomial pneumonia, this clinical entity has been further classified as health care–associated pneumonia

Previ-(HCAP), hospital-acquired pneumonia (HAP), and

ventilator-associated pneumonia (VAP).3 HCAP is defined as pneumonia occurring in any patient hospitalized for 2 or more days in the past 90 days in an acute-care setting or who in the past 30 days has resided in a long-term care or nursing facility; attended a hospital or hemodialysis clinic; or received intravenous antibi-otics, chemotherapy, or wound care HAP is defined as an LRTI that develops in hospitalized patients more than 48 hours after admission and excludes community-acquired infections that are incubating at the time of admission VAP is defined as an LRTI that develops more than 48 to 72 hours after endotracheal intubation

HAP is a common clinical problem and represents the second most common nosocomial infection in the United States, accounting for 15% to 22% of all such infections.4-6

Current estimates suggest that more than 150,000 individuals develop HAP each year HAP increases hospital length of stay 7

to 9 days at an average incremental per-patient cost of $40,000

In selected populations, such as patients in the intensive care unit (ICU) and bone marrow transplant recipients, the crude mortality rate from HAP may approach 30% to 70%, with attributable mortality of 33% to 50% Certain microorganisms,

such as Pseudomonas aeruginosa and Acinetobacter species, are

associated with higher rates of mortality.7

PATHOGENESISSix pathogenetic mechanisms may contribute to the develop-ment of pneumonia (Table 24-2) Knowledge of these mecha-nisms is important to both the understanding of the various disease processes and the formulation of effective strategies within the hospital to minimize nosocomial spread Inhalation

of infectious particles is a common route of inoculation; this method of acquiring an infection occurs with pulmonary tuberculosis and justifies the policy of respiratory isolation for patients with suspected or proved tuberculosis who are coughing

Aspiration of oropharyngeal secretions is the second anism that may contribute to the development of LRTI Healthy individuals may aspirate periodically, especially during sleep Aspiration of even a small volume of oropharyngeal secretions, which can be colonized with potential pathogens

mech-such as Streptococcus pneumoniae and Haemophilus influenzae,

I nfection involving the lungs is termed pneumonia or

lower respiratory tract infection (LRTI) and is a common

clinical problem in the practice of respiratory care Today,

pneumonia remains a major cause of morbidity and mortality

in the United States and worldwide Each year, 5 million people

die from pneumonia worldwide Five million cases of

pneumo-nia occur annually in the United States, of which approximately

1.1 million require hospitalization at a projected yearly cost of

more than $20 billion.1 Pneumonia is the ninth leading cause

of death in the United States and the leading cause of

infection-related mortality.2

CLASSIFICATION

Pneumonia can be classified based on the clinical setting in

which it occurs (Table 24-1) This classification is useful because

it predicts the likely microbial causes and guides empiric

anti-microbial therapy while a definitive microbiologic diagnosis is

awaited (The term empiric therapy refers to treatment that is

TABLE 24-1

Classifications and Possible Causes of Pneumonia

Classification Likely Organisms

Community-Acquired: Acute

Typical Streptococcus pneumoniae

Haemophilus influenzae Moraxella catarrhalis Staphylococcus aureus

Atypical Legionella pneumophila

Chlamydophila pneumoniae Mycoplasma pneumoniae

Health care-associated Mixed aerobic and anaerobic mouth flora

S aureus

Enteric gram-negative bacilli Influenza

Nosocomial

Aspiration Mixed aerobes and anaerobes,

gram-negative bacilli Health care-associated S aureus

Ventilator-associated Pseudomonas aeruginosa

496 SECTION IV • Review of Cardiopulmonary Disease

abscesses involving the dome of the liver in whom rupture of the abscess through the diaphragm leads to the development of pulmonary infection or empyema

Hematogenous dissemination is the spread of infection

through the bloodstream from a remote site; it is an uncommon cause of pneumonia It may occur in the setting of right-sided bacterial endocarditis, in which fragments of an infected heart valve break off and embolize through the pulmonary arteries to the lungs, producing either pneumonia or septic pulmonary infarcts Certain parasitic pneumonias, including strongyloidia-sis, ascariasis, and hookworm, arise through hematogenous dis-semination In such cases, migrating parasite larvae travel to the lungs through the bloodstream from remote sites of infection, such as the skin or the gastrointestinal (GI) tract

Pneumonia may develop when a latent infection, acquired earlier in life, is reactivated This may occur for no apparent reason, as in the case of reactivation pulmonary tuberculosis However, reactivation is usually attributable to the development

of cellular immunodeficiency, as is the case with Pneumocystis jiroveci (previously called Pneumocystis carinii) pneumonia In

developed countries, most healthy individuals have acquired

P jiroveci by age 3 years and show serologic evidence of prior

infection The organism remains dormant in the lung but may reactivate later in life and produce pneumonia in individuals with compromised cell-mediated immunity, such as patients with human immunodeficiency virus (HIV) infection or recipi-ents of long-term immunosuppressive therapy Cytomegalovi-rus pneumonia is another example of a latent infection that can reactivate during chronic immunosuppression, especially in solid organ and bone marrow transplant recipients Immuno-suppressive drugs used to modify inflammatory diseases, such

as tumor necrosis factor (TNF) inhibitors, have been associated with the development of pulmonary and extrapulmonary tuberculosis.10

MICROBIOLOGYThe microbiology of CAP and nosocomial pneumonia has been studied extensively Knowledge of which organisms are most commonly associated with pneumonia in different settings is essential because the microbial differential diagnosis guides the diagnostic evaluation and the selection of empiric antimicrobial therapy

In most studies, S pneumoniae, also called pneumococcus, is

the most commonly identified cause of CAP, accounting for 20% to 75% of cases (Table 24-3) Various other organisms have

been implicated with varying frequencies H influenzae, ylococcus aureus, and gram-negative bacilli each account for 3%

Staph-to 10% of isolates in many reports.11 Notably, the incidence of

H influenzae pneumonia has decreased dramatically since the introduction of the type B H influenzae (also known as Hib) vaccine in the 1980s Legionella species, Chlamydophila pneu- moniae, and Mycoplasma pneumoniae together account for 10%

to 20% of cases These latter organisms, called atypical patho

-gens, vary in frequency in more recent reports, depending on the age of the patient population, the season of the year, and

may contribute to development of CAP Certain patient

popu-lations are at risk for large-volume aspiration, such as patients

with impaired gag reflexes from narcotic use, alcohol

intoxica-tion, or prior stroke Aspiration also may occur after a seizure,

cardiac arrest, or syncope

Aspiration seems to be the major mechanism responsible for

the development of some types of mixed aerobic and anaerobic,

gram-negative, and staphylococcal HAPs In intubated patients,

chronic aspiration of colonized secretions through a tracheal

cuff has been linked to the subsequent occurrence of

pneumo-nia,4 which led to the development of strategies to prevent HAP,

such as continuous suctioning of subglottic secretions in

mechanically ventilated patients and elevation of the head of

the bed.8,9

Direct inoculation of microorganisms into the lower airway

is a less common cause of pneumonia In mechanically

venti-lated patients who undergo frequent suctioning of lower airway

secretions, passage of a suction catheter through the

orophar-ynx may result in inoculation of colonizing organisms into the

trachea and subsequent development of VAP

Contiguous spread of microorganisms to the lungs or pleural

space from adjacent areas of infection, such as

subdiaphrag-matic or liver abscesses, is an infrequent cause of pneumonia

This may occur in patients with pyogenic or amebic liver

TABLE 24-2

Pathogenetic Mechanisms Responsible for

the Development of Pneumonia

Mechanism of Disease Examples of Specific Infections

Inhalation of aerosolized

infectious particles TuberculosisHistoplasmosis

Cryptococcosis Blastomycosis Coccidioidomycosis

Q fever Legionellosis Aspiration of organisms

colonizing the oropharynx Community-acquired bacterial pneumonia

Aspiration pneumonia Hospital-acquired pneumonia Ventilator-associated pneumonia Direct inoculation of organisms

into the lower airway Hospital-acquired pneumoniaVentilator-associated pneumonia

Spread of infection to the

lungs from adjacent

structures

Mixed anaerobic and aerobic pneumonia from

subdiaphragmatic abscess Amebic pneumonia from rupture

of amebic liver abscess into the lung

Spread of infection to the lung

through the blood Staphylococcus aureuspneumonia arising from

right-sided bacterial endocarditis Parasitic pneumonia:

Strongyloidiasis, ascariasis, hookworm

Pulmonary Infections • CHAPTER 24 497

consideration in patients with fulminant community-acquired LRTI.17 To date, inhalation anthrax remains a rare disease Several new coronaviruses have emerged as important patho-

gens within the past decade Severe acute respiratory syndrome

(SARS) emerged out of Asia and spread globally in 2002 to

2003 Fortunately, no cases have been identified since 2004.18

More recently, Middle East respiratory syndrome (MERS) has

arisen as a global health concern First described in Saudia Arabia in 2012, the virus is found within the Arabian peninsula and causes a severe respiratory illness with a 30% mortality rate The first cases imported to the United States were confirmed in

2014, both in travelers from Saudia Arabia.19 Albeit rare in the United States, both viruses also should be considered in the appropriate clinical and epidemiologic setting In addition, enterovirus D68 is an emerging cause of pneumonia in children.20

In most published series, no microbiologic diagnosis is established in 50% of patients This is attributable to many factors, including:

• Inability of many patients to produce sputum

• Acquisition of sputum specimen after antibiotics have been started

• Failure to perform numerous serologic studies routinely in all patients

• The fact that many organisms (e.g., viruses and anaerobic bacteria) were not routinely sought

• Failure, until more recently, to recognize pneumonia

patho-gens, such as C pneumoniae and some viral agents.

The common microbial agents producing HCAP, HAP, and VAP are summarized in Table 24-1 and include gram-negative

bacilli, S aureus, Legionella species, and rarely viruses such as

influenza or respiratory syncytial virus The last-mentioned viruses are considerations only during the winter months, when they are endemic in the community and may enter the hospital via health care workers, visitors, or patients with incubating or active infections

The relative frequencies and antimicrobial susceptibilities of these respective bacteria may vary considerably from one insti-tution to another Knowledge of which nosocomial isolates are most common within one’s own institution and community, along with their drug-sensitivity profiles, has important impli-cations with regard to selecting antibiotic therapy, formulating infection control policies, investigating potential outbreaks, and selecting antimicrobial agents for the hospital formulary For example, patients developing severe VAP in ICUs with a high prevalence of carbapenem resistance among gram-negative

organisms such as Klebsiella pneumoniae and Acinetobacter mannii may warrant empiric antimicrobial therapy for these

bau-organisms pending culture information Similarly, nosocomial legionellosis occurs with variable frequency at different institu-tions, such that empiric therapy in critically ill patients with nosocomial LRTI may or may not require coverage of this pathogen

Nosocomial pathogens capable of producing HAP can be transmitted directly from one patient to another, as in the case for tuberculosis However, transmission from health care

geographic locale Legionellosis and C pneumoniae, in

particu-lar, exhibit significant geographic variation in incidence

Many studies examining the epidemiology and microbiology

of CAP are potentially biased because they focus on patients

requiring hospitalization In patients with less severe illnesses

not requiring hospitalization, more recent studies suggest that

M pneumoniae and C pneumoniae account for 38% of cases

and may be more common than typical bacterial pathogens

such as pneumococcus and H influenzae.12 In patients who

are ill enough to require admission to the ICU, Legionella

species, gram-negative bacilli, and pneumococcus are

dispro-portionately more common.13 A virulent strain of

methicillin-resistant S aureus (MRSA) has emerged as a cause of severe

necrotizing CAP.14

In urban settings that have a high incidence of endemic HIV

infection, P jiroveci may be an occasional cause of CAP.15 Viruses

such as influenza, respiratory syncytial virus, parainfluenza, and

adenovirus can cause CAP, especially in patients with milder

illnesses not requiring hospitalization, and are encountered in

the late fall and winter months A worldwide pandemic of

H1N1 influenza during 2009 to 2010 and ongoing sporadic

cases of transmission of H5N1 influenza from birds to humans

have led to heightened international awareness of influenza

epidemiology, pathogenesis, and prevention.16

Mixed aerobic and anaerobic aspiration pneumonia may

account for 10% of cases This cause of pneumonia is an

impor-tant consideration for nursing home residents and for

individu-als with impaired gag reflexes or recent loss of consciousness

The outbreak in 2000 to 2001 of inhalation anthrax in the

United States adds another microbial differential diagnostic

498 SECTION IV • Review of Cardiopulmonary Disease

symptoms, diarrhea, and cough, often with minimal sputum production Cough was often a relatively minor symptom at the outset, and the illness was initially dominated by nonrespi-ratory symptoms Such a presentation was thought to be more

common with pathogens such as M pneumoniae, C moniae, Legionella species, and viruses More recent studies have

pneu-shown that considerable overlap exists in the clinical tions of pneumonia with typical and atypical pathogens.21 The occurrence of concomitant diarrhea, previously considered indicative of legionellosis, is now known to be common in pneumococcal and mycoplasmal pneumonia

presenta-Despite the limitations in predicting the microbial diagnosis based on the clinical presentation, clinicians use certain histori-cal clues and physical findings at the bedside to determine the likely cause of pneumonia in patients presenting from the com-munity In patients presenting with high fever, teeth-chattering chills, pleuritic pain, and a cough producing rust-colored sputum, pneumococcal pneumonia is the most likely diagnosis Patients with pneumonia accompanied by foul-smelling breath,

an absent gag reflex, or recent loss of consciousness are most likely to have a mixed aerobic and anaerobic infection as a consequence of aspiration CAP accompanied by hoarseness

suggests C pneumoniae Pneumonia in a patient with a history

of splenectomy suggests infection with an encapsulated

patho-gen such as pneumococcus or H influenzae Pneumonia

occur-ring after resolution of a flulike illness raises concern for

S aureus Epidemics of pneumonia occurring within

house-holds or closed communities, such as dormitories or military

barracks, suggest pathogens such as M pneumoniae or C moniae Pneumonia accompanied by splenomegaly suggests psittacosis (caused by Chlamydophila psittaci and associated with bird exposure) or Q fever (caused by Coxiella burnetii and

pneu-associated with exposure to farm animals) Bullous myringitis

and erythema multiforme are associated with Mycoplasma

infection Relative bradycardia (defined as a heart rate <100 beats/min) in the presence of fever and in the absence of pre-existing cardiac conduction system disease or beta-blocker therapy may suggest infection with an atypical pathogen Pneumonia accompanied by conjunctivitis suggests adenovirus infection

The clinical presentation of CAP in elderly patients warrants special mention because it may be subtle Older individuals with pneumonia may not have a fever or cough and may simply present with shortness of breath, confusion, worsening conges-tive heart failure (CHF), or failure to thrive

Inhalation anthrax is a rare disease, but warrants mention because of the small epidemic believed to have been an act of bioterrorism.17 This outbreak affected mainly postal workers who were exposed to mail containing anthrax spores Most patients presented with a febrile flulike illness of several days’ duration accompanied by dry cough and shortness of breath Some patients went on to develop septic shock, meningitis, and disseminated intravascular coagulation over several days, cul-minating in death

Because of a lack of prior host immunity or unique viral virulence factors, patients infected with pandemic influenza

workers (including respiratory therapists [RTs]), contaminated

equipment, or fomites (objects capable of transmitting

infec-tion through physical contact with them) is more common,

especially for gram-negative bacilli, S aureus, and viruses The

RT has an important role to play in preventing the transmission

and development of nosocomial pneumonia

MINI CLINI

Distinguishing Between Different Types

of Nosocomial Pneumonia

PROBLEM:  A 52-year-old man with a history of severe low

back pain is admitted to the hospital with a GI bleed in the

setting of excessive NSAID use He has not seen a doctor in 5

years His presenting symptoms include epigastric abdominal

pain, black stools, and dizziness with standing Admission

hemoglobin is 5.2 g/dl and white blood count (WBC) count is

6.2 × 10 9 He is transfused red blood cells (RBCs) and

under-goes upper GI endoscopy, which reveals a large bleeding

duo-denal ulcer Three days into his admission, the patient develops

a fever to 40.2° C, shortness of breath, and cough Laboratory

testing reveals a WBC count of 16.8 × 10 9 Chest radiography

reveals a patchy infiltrate in the right lower lobe What type of

pneumonia does this patient have? How might this infection

have developed?

DISCUSSION:  The patient has HAP, because he did not have

any evidence of pneumonia at the time of admission and

devel-oped his infection more than 48 hours into his hospital stay

He may have developed pneumonia secondary to inhalation of

infectious particles via exposure to patients or health care

pro-viders working with a respiratory illness More likely, he

aspi-rated oropharyngeal or gastric secretions during his upper

endoscopy procedure or during a vomiting episode Empiric

antimicrobial coverage should target mixed aerobic and

anaer-obic mouth flora, S.aureus, enteric gram-negative bacilli, and

potentially influenza, depending on the season.

CLINICAL MANIFESTATIONS

Patients with CAP typically have fever and respiratory

symp-toms, such as cough, sputum production, pleuritic chest pain,

and dyspnea Not all of these symptoms are present all the time,

especially in elderly patients in whom the presentation may

be subtle Other problems, such as hoarseness, sore throat,

headache, and diarrhea, may accompany certain pathogens

Fever, cough, and sputum production may occur in other

ill-nesses such as acute bronchitis or exacerbations of chronic

bronchitis

In the past, clinicians often distinguished between typical

and atypical clinical syndromes as a means of predicting the

most likely microbial causes A typical presentation consisted of

the sudden onset of high fever, shaking, chills, and cough with

purulent sputum Such a presentation was considered more

common with bacterial pathogens such as pneumococcus and

H influenzae An atypical presentation was an illness

character-ized by the gradual onset of fever, headache, constitutional

Pulmonary Infections • CHAPTER 24 499

strains may have unusually severe presentations During the

2009 to 2010 pandemic of H1N1 influenza, clinical

presenta-tions varied from mild upper respiratory syndromes to

fulmi-nant pneumonias with acute respiratory distress syndrome

(ARDS) and shock.16 SARS manifests with high fever and

myalgia for 3 to 7 days followed by nonproductive cough

and progressive hypoxemia with progression to mechanical

ventilation in 20%.18 MERS presents similarly, with an added

history of travel to or close contact with a symptomatic person

who has traveled to the Arabian peninsula within 14 days of

symptom onset.19

HCAP, HAP, and VAP usually manifest with new onset of

fever in hospitalized or institutionalized patients Nonintubated

patients may have a recent history of vomiting, seizure, or

syncope, during which aspiration of oropharyngeal or gastric

secretions may have occurred In intubated patients, VAP

tradi-tionally manifests with new onset of fever, leukocytosis,

puru-lent endotracheal secretions, and a new pulmonary infiltrate

The diagnosis of HCAP, HAP, or VAP can be extremely difficult

to make in patients with preexisting abnormalities on the chest

radiograph, such as CHF or ARDS In mechanically ventilated

patients, purulent tracheobronchitis may be accompanied by

fever, and in patients with preexisting abnormalities on chest

radiograph, the distinction between bronchitis and pneumonia

can be especially difficult

CHEST RADIOGRAPH

In patients with a compatible clinical syndrome, the diagnosis

of CAP is established by the presence of a new pulmonary

infiltrate on the chest radiograph Not all healthy outpatients

with suspected pneumonia require a chest radiograph, and

phy-sicians may choose not to obtain a chest radiograph and treat

empirically for CAP in individuals with mild illnesses who are

at low risk for morbidity or mortality

Also, a normal chest radiograph does not exclude the

diag-nosis of pneumonia The chest radiograph may be normal

in patients with early infection, dehydration, or P jiroveci

infection The pattern of radiographic abnormality is not

diag-nostic of the causative agent, although specific radiographic

findings should suggest specific microbial differential diagnoses

Consolidation involving an entire lobe is called lobar

consoli-dation (Figure 24-1), whereas bronchopneumonia refers to the

presence of a patchy infiltrate surrounding one or more bronchi,

without opacification of an entire lobe Both radiographic

pat-terns suggest the presence of a bacterial pathogen Pleural

effu-sions are common in patients with bacterial pneumonia and

uncommon in patients with viral, P jiroveci, C pneumoniae, or

fungal pneumonia Pleural effusions are seen in approximately

10% of patients with M pneumoniae and Legionella

pneumoph-ila pneumonia and occur occasionally in patients with

reactiva-tion pulmonary tuberculosis Interstitial infiltrates (Figure

24-2), especially if diffuse, suggest viral disease, P jiroveci, or

miliary tuberculosis in patients with CAP Cavitary infiltrates

TABLE 24-4 Radiographic Patterns Produced by Pathogens in Community-Acquired Pneumonia

Lobar consolidation Bacterial Bronchopneumonia Bacterial Pleural effusion Bacterial

Inhalation anthrax Interstitial infiltrates Viruses

P jiroveci (rare) Mediastinal widening without

infiltrates Inhalation anthraxRapidly progressive multilobar Legionella species

Streptococcus pneumoniae

Endobronchial tuberculosis

FIGURE 24-1 Lobar pneumonia caused by Streptococcus pneumoniae. A 36-year-old previously healthy woman presents with abrupt onset of fevers and shaking chills, cough productive

of yellow sputum, and right-sided pleuritic chest pain Chest radiograph reveals lobar consolidation Sputum culture yields

S pneumoniae

fungal pneumonias, such as histoplasmosis, blastomycosis, and aspergilosis; nocardiosis; pyogenic lung abscess; and, rarely,

P jiroveci pneumonia Patients with severe staphylococcal or

gram-negative pneumonias may develop small cavities called

pneumatoceles Legionellosis should be considered in sicker

500 SECTION IV • Review of Cardiopulmonary Disease

FIGURE 24-2 Pneumocystis jiorveci pneumonia (PCP) A

patients with pneumonia of a single lobe, which quickly spreads

to involve multiple lobes over 24 to 48 hours

The chest radiograph may be helpful in diagnosing HCAP

or HAP in nonintubated patients with a suspected aspiration event and a prevously normal chest film In such cases, develop-ment of a new infiltrate may confirm the clinical suspicion of aspiration pneumonia The chest radiograph is often less helpful

in the diagnosis of VAP because mechanically ventilated patients often have other reasons for radiographic abnormalities, such

as ARDS, CHF, pulmonary thromboembolism, alveolar rhage, or atelectasis In these patients, the accurate diagnosis of

hemor-a new nosocomihemor-al LRTI chemor-an be difficult Clinichemor-al dihemor-agnosis,

defined as the presence of fever, purulent respiratory secretions, new leukocytosis, and a new pulmonary infiltrate, is sensitive but not specific for the diagnosis of VAP Other strategies to diagnose VAP more accurately have been investigated

RISK FACTORS FOR MORTALITY AND ASSESSING THE NEED FOR HOSPITALIZATION

Many cases of CAP can be managed successfully on an tient basis The challenge for the clinician is to identify indi-viduals at higher risk of morbidity and mortality for whom hospitalization is indicated Over the past 20 years, numerous studies have analyzed risk factors for mortality in patients with CAP.21-23 Risk factors predicting a high risk for death are sum-marized in Box 24-1

outpa-Fine and associates23 performed a meta-analysis of 127 cohorts of patients with CAP to examine risk factors for death The overall mortality for the 33,148 patients in these cohorts was 13.7% Eleven prognostic variables were significantly asso-ciated with mortality, including male sex, absence of pleuritic chest pain, hypothermia, systolic hypotension, tachypnea, dia-betes mellitus, cancer, neurologic disease, bacteremia, leukope-nia, and multilobar infiltrates on chest radiograph Mortality

varied according to the infecting agent and was highest for P aeruginosa (61.1%), Klebsiella species (35.7%), Escherichia coli (35.3%), and S aureus (31.8%) Mortality rates for more common pathogens were lower but still substantial: Legionella species (14.7%), S pneumoniae (12.3%), C pneumoniae (9.8%), and M pneumoniae (1.4%).

Because some variables are unknown at the time a patient seeks treatment for pneumonia, such as the causative agent and whether bacteremia is present, more recent studies have sought

to assess the risk for fatal outcome by using clinical and tory data that are readily available at the time of the initial evaluation Based on an analysis of the 30-day mortality in more than 40,000 patients, Fine and associates24 proposed a prediction rule to identify low-risk and high-risk patients with CAP Their algorithm uses the demographic, clinical, and labo-ratory data available at presentation to stratify the risk for death and the criteria for hospitalization in outpatient groups Points are assigned for the presence of numerous variables, and cumulative point scores are used to stratify patients into one

labora-of five different risk groups with predictable mortality rates

Pulmonary Infections • CHAPTER 24 501

in large prospective cohorts of patients, the patients at the

lowest risk for death fall into groups I and II In most instances,

these patients may be treated successfully as outpatients, unless

they are hypoxemic, vomiting and unable to take oral

antibiot-ics, noncompliant, or immunocompromised Patients in group

I are patients younger than 50 years of age without comorbid

illnesses and abnormal physical findings at presentation (see

risk for death

Because of the complexity of the pneumonia severity index,

many practitioners prefer a simpler stratification system,

CURB-65 Risk criteria in this system include confusion, blood

urea nitrogen greater than 20 mg/dl, respiratory rate greater

Box 24-1 Risk Factors for Mortality in

Community-Acquired Pneumonia from Multiple Studies

Age

Nursing home resident +10 Comorbid illnesses

Cerebrovascular disease +10 Congestive heart failure +10 Physical findings

Tachypnea >30 breaths/min +20 Systolic hypotension <90 mm Hg +20 Temperature <35° C or >40° C +15 Heart rate >125 beats/min +10 Laboratory and radiographic findings

Acidemia (arterial pH <7.35) +30 Azotemia (blood urea nitrogen >30 mg/dl) +20 Hyponatremia (sodium <130 mmol/L) +20 Hypoxia (PaO2 <60 mm Hg) +10 Hyperglycemia (glucose >250 mg/dl) +10 Anemia (hematocrit <30%) +10

Modified from Fine MJ, Auble TE, Yealy DM, et al: A prediction rule to identify low-risk patients with community-acquired pneumonia N Engl J Med 336:243–250, 1997.

N OTE : Plus sign (+) denotes adding points; minus sign (−) denotes subtracting

points (e.g., for women, points assigned equal age in years − 10).

TABLE 24-6 Risk Class Mortality Rates Using Prediction Model Cumulative Point Scores in Patients With

Community-Acquired Pneumonia Risk Class (Cumulative Point Score) Mortality Rate (%)

N OTE : Patients in risk class I are <50 years old and lack existing illness or

physical findings listed in Table 19-5 Points are assigned to patients in risk classes II and higher.

than 30 breaths/min, systolic blood pressure less than 90 mm Hg

or diastolic blood pressure less than 60 mm Hg, and age older than 65 years Based on their data analysis, the authors recom-mend that patients with one or two risk criteria should be treated as outpatients, patients with two criteria treated on general hospital wards, and patients with three or more criteria admitted to the ICU.25

502 SECTION IV • Review of Cardiopulmonary Disease

MINI CLINIEstimating Risk from Pneumonia

PROBLEM:  The RT is called to the emergency department to perform an arterial blood gas analysis on a 70-year-old woman who has been sent from a nursing home with confusion and shortness of breath Her history is notable for end-stage renal disease caused by hypertension and a recent stroke, which has resulted in left-sided hemiplegia The emergency physician ordered a chest x-ray examination, which revealed a right lower lobe infiltrate and a right pleural effusion.

On physical examination, the patient is somnolent Her vital signs are temperature, 35° C; blood pressure, 85/50 mm Hg; and heart rate, 130 beats/min Additional findings include the following:

• Absent gag reflex

• Right basilar rales (crackles) and left hemiplegia

• Peripheral white blood cell (WBC) count, 3000 cells/mm 3

• Blood urea nitrogen, 100 mg/dl

• Hematocrit, 31%

• Blood glucose, 110 mg/dl

• Serum sodium, 144 mmol/L The RT collects the arterial blood gas on room air, which shows a pH of 7.30; PaO 2 , 58 mm Hg; and PCO 2 , 25 mm Hg Should the patient be admitted to the hospital, or should she

be sent back to the nursing home? What is her risk for 30-day mortality?

DISCUSSION:  This patient is at substantial risk for dying from pneumonia and should be admitted to the hospital The Fine prediction rule 24 may be used as follows to estimate the risk for 30-day mortality (see Tables 24-5 and 24-6):

Many studies have examined risk factors for the

develop-ment of HAP and VAP, which in broad terms can be divided

into (1) factors that interfere with host defense and (2) factors

that encourage exposure to large numbers of bacteria.7

Exam-ples of factors that interfere with host defense include the

following:

• Underlying illnesses such as diabetes mellitus, malignancy,

chronic heart and lung disease, and renal failure

• Critical illnesses such as sepsis syndrome and ARDS

• Therapeutic interventions such as endotracheal intubation,

tracheostomy, and administration of medications such as

sedatives and corticosteroids

Factors that promote exposure of the lung to pathogenic

microorganisms include the following:

• Use of endotracheal or nasogastric tubes

• Contaminated ventilator equipment or water supplies

• Prior antibiotic therapy

• Neutralization of gastric pH

Although many studies have emphasized the substantial

mortality rate (20% to 50%) for patients who develop HAP or

VAP, few studies have examined the specific risk factors

associ-ated with mortality in hospital-acquired LRTI For

nonventi-lated patients, risk factors for mortality include bilateral

infiltrates, respiratory failure, and infection with high-risk

organisms.26,27 In mechanically ventilated patients, factors

asso-ciated with fatal outcome include the following27,28:

• Infection with high-risk organisms such as P aeruginosa,

Acinetobacter species, and Stenotrophomonas maltophilia

• Multisystem organ failure

• Inappropriate antibiotic therapy

• Hospitalization in a noncardiac ICU

Her cumulative point score is 225, she belongs in risk class

V, and her estimated risk for mortality is 29.2% (see Table 24-6)

She should be admitted to the hospital for treatment

DIAGNOSTIC STUDIES

Community-Acquired Pneumonia

Many patients with CAP who are treated as outpatients never

have a microbiologic diagnosis established Many are treated

based on the history and examination findings, with or without

a chest radiograph to confirm the presence of an infiltrate

Patients who are sick enough to warrant hospitalization or

consideration of hospitalization should undergo appropriate

studies to stratify risk for mortality and establish a

microbio-logic diagnosis (Box 24-2) Complete blood count, blood

glucose, serum sodium, and blood urea nitrogen are all

neces-sary to derive a point score for estimating mortality risk An

arterial blood gas analysis is used to detect the presence of hypoxemia and acidemia, which indicate more serious illness.The value of Gram stain and culture of expectorated sputum has been debated for years.29 Many patients lack a productive cough, making collection of an adequate specimen difficult Prior antibiotic therapy reduces the yield from both tests Only 50% of patients with bacteremic pneumococcal pneumonia have a positive sputum culture.30 Nevertheless, the finding of a predominant organism on Gram stain in an appropriately col-lected specimen can be very helpful in selecting appropriate

Pulmonary Infections • CHAPTER 24 503

organisms can colonize the oropharynx, and their presence in culture may not signify true LRTI The culture isolation of other

organisms, such as Mycobacterium tuberculosis, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and Legionella species is diagnostic of disease because these organ-

isms almost never colonize the respiratory tract

With Community-Acquired Pneumonia Warranting Consideration of Hospitalization

antibiotic therapy.31 A routine sputum culture must be

inter-preted within the context of the sputum Gram stain Specimens

contaminated with oropharyngeal epithelial cells are

unsatisfac-tory for analysis and specimens lacking neutrophils from

non-neutropenic patients are unlikely to be helpful

The RT has an important role in collecting an appropriate

specimen of expectorated sputum Patients should be advised

to rid the mouth of contaminating saliva by rinsing with water

or by spitting and then to expectorate a specimen from deep

within the tracheobronchial tree into a collection container

Prompt transportation to the laboratory is essential and

improves the diagnostic yield from culture.12 Most

microbiol-ogy laboratories screen the adequacy of the specimen by

cyto-logic examination A satisfactory specimen contains more than

25 leukocytes and fewer than 10 squamous epithelial cells per

high-power field.32 In routine sputum culture, the isolation of

bacteria such as S pneumoniae and H influenzae must be

inter-preted within the context of the Gram stain because these

Other stains and cultures of expectorated sputum should be obtained as dictated by the clinical circumstance, when man-agement would be changed, or for purposes of tracking unusual

or resistant organisms in an institution or population In patients with suspected tuberculosis, the finding of acid-fact bacilli in stained sputum specimens often prompts initiation of

antituberculous therapy because culture isolation of M culosis may take 6 weeks A direct fluorescence antibody stain

tuber-of sputum for Legionella species may reveal the organism in

25% to 80% of individuals with Legionnaire’s disease, and tures are positive in 50% to 70%.33 Toluidine blue O stains

cul-of sputum may disclose the organism in 80% cul-of patients with

P jiroveci pneumonia Potassium hydroxide preparations of

sputum show fungi in only a few patients with histoplasmosis, blastomycosis, or coccidioidomycosis but are very helpful if positive

Blood cultures should be obtained in hospitalized patients with CAP and may be helpful in establishing the diagnosis in patients with typical bacterial pathogens Blood cultures are positive in approximately 30% of patients with pneumococcal

pneumonia and in 70% of patients with H influenzae

pneu-monia.34 Blood cultures are not helpful in patients with

legio-nellosis, M pneumoniae, C pneumoniae, P jiroveci, or viral

infections Collection of blood cultures within 24 hours of pitalization in elderly patients with pneumonia has been associ-ated with improved survival.35

hos-Parapneumonic pleural effusions are common and occur in 30% to 50% of patients with CAP.11 Thoracentesis is indicated for patients with large pleural effusions and patients with smaller effusions who fail to respond to therapy or for whom the microbiologic diagnosis is not established Pleural fluid should be tested for cell count, glucose, protein, pH, lactate dehydrogenase, Gram and acid-fast bacilli stains, and routine (aerobic and anaerobic) and mycobacterial cultures Effusions with a fluid pH less than 7.20, a positive Gram stain or culture,

or fluid that appear grossly purulent on inspection require tube thoracostomy for drainage.36

Other studies may be helpful in establishing a microbiologic

diagnosis in the appropriate clinical setting L pneumophila

serogroup 1 accounts for 80% of cases of Legionnaire’s disease.37

The urinary antigen test for L pneumophila serogroup 1 is a

sensitive and rapid test and usually becomes positive within 3 days of illness onset, but the test has limitations First is its

504 SECTION IV • Review of Cardiopulmonary Disease

MINI CLINIImportance of Clinical Setting for Determining the Cause of Pneumonia

PROBLEM:  The RT is caring for a 32-year-old man admitted

to the hospital 24 hours earlier with fever, shaking chills, and a new left lower lobe infiltrate His WBC count on admission was

3500 cells/mm 3 , with 96% neutrophils and 4% lymphocytes A sputum Gram stain disclosed many polymorphonuclear leuko- cytes and lancet-shaped, gram-positive diplococci Blood cul-

tures have grown S pneumoniae at 24 hours He remains febrile

24 hours into therapy with penicillin G While checking pulse oximetry, the RT notes that the patient is emaciated and that multiple needle tracks are present in each antecubital fossa He tells the RT that he uses intravenous heroin What other tests are indicated?

DISCUSSION:  This patient, who is an intravenous drug user, has bacteremic pneumococcal pneumonia These findings, along with the presence of cachexia and leukopenia with lym- phopenia, should suggest the possibility of underlying HIV infection An HIV test is indicated and should be performed after the patient’s consent is obtained.

Both pneumococcal and H influenzae pneumonia occur

with higher frequency in HIV-infected individuals than in the general population Occasionally, an HIV-infected patient has his or her first contact with the health care system as a result

of one of these infections New guidelines recommend that all average-risk individuals ages 15 to 65 undergo testing for HIV once in their lives and persons at higher risk for HIV infection undergo more frequent testing 40

other individuals who engage in behaviors that put them at risk for HIV infection

Molecular techniques, such as DNA probes and polymerase chain reaction (PCR), used for detecting specific organisms

such as M pneumoniae or M tuberculosis or for confirming the

identity of culture isolates, are being developed and used in some larger centers Rapid diagnostic testing of nasopharyngeal specimens for viral pathogens such as influenza, parainfluenza, and respiratory syncytial virus may be helpful in diagnosing CAP because of these organisms in patients with compatible clinical presentations

inability to detect the non–serogroup 1 L pneumophila and

non–L pneumophila species that account for 20% of cases of

Legionnaire’s disease Second, it can be negative if patients

present very early in the disease course, potentially misleading

clinicians with a negative result and requiring repeat testing if

clinical suspicion remains high Third, the test may remain

positive for 1 year, obviating the ability to distinguish new

from remote infection in patients with a recent history of

pneumonia

Serologic tests for immunoglobulin M (IgM) and IgG

anti-bodies to M pneumoniae, Legionella species, or C pneumoniae

are rarely helpful during the initial stages of pneumonia, but

convalescent titers 3 to 4 weeks later may permit a retrospective

microbiologic diagnosis by showing a fourfold increase in IgG

titer or the development of IgM antibody against a specific

pathogen Acute sera should be analyzed in patients who are

critically ill with pneumonia and for whom the microbiologic

diagnosis is unavailable Fungal serologic findings are

occasion-ally helpful in supporting the diagnosis of blastomycosis,

histo-plasmosis, or coccidioidomycosis, pending culture isolation of

the organism

Fungal antigen assays are increasingly being used in settings

in which there is a high clinical suspicion for invasive fungal

infection Invasive aspergillosis is is an important cause of

pneumonia in immunocompromised hosts, particularly in

those with prolonged neutropenia Galactomannan is a

polysac-charide that is a major constituent of Aspergillus cell walls A

large meta-analysis revealed that galactomannan antigen assays

have a sensitivity of 71% and specificity of 89% for Aspergillus

infection.38 However, the sensitivity of the test is decreased by

concomitant administration of antifungal therapy and

false-positive results can occur in patients receiving the antibiotic

combination piperacillin-tazobactam in infections with other

fungi that share cross-reacting antigens (Fusarium and

Penicil-lium species, H capsulatum) and in patients with

chemotherapy-induced mucositis or transplant-associated graft-versus-host

disease (in whom bacteria with cross-reactive antigens

translo-cate across the intestinal mucosal wall) Similarly,

1,3-beta-D-glucan is a cell wall component of many fungi, and levels of this

molecule are elevated in many types of invasive fungal

infec-tion, including those with Aspergillus, P jiroveci, H capsulatum,

and C immitis Beta-D glucan assays have a sensitivity of 77%

and specificity of 85% for invasive fungal infection.39 Like the

galactomannan assay, there are some drawbacks to this test

First, the assay cannot distinguish between infections from

various fungal pathogens False-positive results can occur in

patients receiving intravenous immunoglobulin or albumin

infusions, in patients undergoing hemodialysis or receiving

intravenous infusions that use cellulose filters, in patients with

glucan-containing gauze packing of serosal surfaces, and

patients who are bacteremic with certain organisms, including

Pseudomonas aeruginosa.39

Because pneumococcal and H influenzae pneumonia occur

with higher frequency in patients with HIV infection than in

the average population, an HIV test is recommended for patients

ages 15 to 65 with CAP HIV testing is also recommended for

Flexible bronchoscopy is usually reserved for severe cases of CAP, for immunocompromised individuals in whom opportu-

nistic pathogens must be excluded, or for cases in which P oveci infection is suspected The yield from flexible bronchoscopy

jir-is higher if performed before starting antibiotic therapy in patients with bacterial pneumonia Open lung biopsy is rarely indicated for patients with CAP

Health Care–Associated Pneumonia, Hospital-Acquired Pneumonia, and Ventilator-Associated Pneumonia

The accurate diagnosis of nosocomial pneumonia is ing and has been the subject of intense investigation over the

challeng-Pulmonary Infections • CHAPTER 24 505

Nonbronchoscopic techniques using telescoping protected catheters have also been developed to obtain specimens for quantitative culture from the lower airway In most studies, sensitivity has been comparable to bronchoscopic techniques, but results have disagreed in 20% of cases.41

Bronchoalveolar lavage (BAL), in which a lung segment is lavaged with sterile saline through the bronchoscope and recov-ered fluid is quantitatively cultured, has been studied exten-sively as a tool for diagnosing nosocomial pneumonia (see Chapter 24) Some studies have supported the usefulness of this technique, and others have questioned its specificity because of upper airway contamination.47,48 BAL has proved useful for obtaining alveolar cells for microscopic analysis; several studies have suggested that the presence of intracellular bacteria in 3%

to 5% of BAL cells distinguishes patients with nosocomial pneumonia from patients without pneumonia.47,48 In one study, the combination of PSB cultures and microscopic examination

of BAL cells for intracellular bacteria was 100% sensitive and 96% specific in identifying patients with nosocomial pneumonia.47

Mini-BAL performed by RTs also has been advocated for diagnosing VAP In one study, results obtained using this tech-nique were comparable with results obtained by bronchoscopy using PSB.49 Some centers use this technique as the primary method of sampling respiratory secretions in suspected noso-comial pneumonia Transthoracic ultrathin needle aspiration of the lung in nonventilated patients with nosocomial pneumonia also has been studied and in one report was found to have a sensitivity of 60%, a specificity of 100%, and a positive predic-tive value of 100%.50

Accurately diagnosing HAP, HCAP, and VAP remains a lenge for the physician and the RT None of the available diag-nostic techniques is 100% sensitive or specific; all are limited

chal-in the populations at greatest risk for gettchal-ing nosocomial pneumonia—mechanically ventilated patients and patients receiving prior antibiotic therapy

ANTIBIOTIC THERAPY

Community-Acquired Pneumonia

The selection of antibiotic therapy for patients with CAP should

be guided by several considerations, including the age of the patient, severity of the illness, presence of risk factors for specific organisms, and results of initial diagnostic studies Pathogen-specific therapy should be used when clinical circum-stances and initial evaluation strongly suggest the microbiologic diagnosis or when cultures or other studies confirm the cause

In many instances, initial studies fail to establish a diagnosis, and empiric therapy must be started Major classes of antibiot-ics used to treat pneumonia are listed in Table 24-7 Consensus guidelines for therapy have been published by the American Thoracic Society (ATS) and the Infectious Diseases Society of America (IDSA) (Table 24-8).51-53 Therapy initiated within 4 hours of hospital admission has been associated with improved survival.35

past three decades Numerous techniques have been extensively

evaluated (Box 24-3); however, none is absolutely sensitive and

specific.41,42 Clinical diagnosis has been defined as the

develop-ment of a new infiltrate on chest radiograph in the setting of

fever, purulent tracheal secretions, and leukocytosis in a

hospi-talized patient Clinical diagnosis lacks specificity because many

other causes of pulmonary infiltrates exist in hospitalized

patients, especially in patients on mechanical ventilation.43 In

addition, the upper airway commonly is colonized with

noso-comial gram-negative bacilli and staphylococci, even in the

absence of pneumonia The qualitative culture isolation of these

organisms from tracheal secretions correlates poorly with the

presence or absence of pneumonia

Direct visualization of the lower airway by bronchoscopy in

ventilated patients is sometimes helpful to support the

diagno-sis of VAP In one study, the presence of distal, purulent

secre-tions, persistence of secretions surging from distal bronchi

during exhalation, and a decrease in the PaO2/FiO2 ratio of less

than 50 were independently associated with the presence of

pneumonia The presence of two of three of these factors had

a sensitivity of 78% in the diagnosing nosocomial pneumonia;

these factors were absent 89% of the time when there was no

pneumonia (89% specific).44

Because the specificity of qualitative sputum cultures has

been unreliable, several studies have examined the role of

quan-titative cultures of endotracheal aspirates using various

break-points ranging from 103 to 107 colony-forming units (CFUs) per

milliliter of respiratory secretions Results with this technique

have been best using a breakpoint of 106 CFU/ml, but

sensitivi-ties have been only 68% to 82%, with specificisensitivi-ties of 84% to

96% with this test.45,46

The protected specimen brush (PSB) was developed in the

1970s and uses a special double-catheter brush system to

mini-mize contamination by upper airway flora Specimens obtained

with this technique are cultured quantitatively Numerous

studies have validated the sensitivity of PSB in diagnosing

noso-comial pneumonia.47,48 However, PSB may be less useful in cases

in which antibiotics have already been started, in cases of early

infection, and in cases in which the wrong lobe is sampled.41

506 SECTION IV • Review of Cardiopulmonary Disease

TABLE 24-8

Empiric Regimens for Treatment of Hospitalized Adults With Community-Acquired Pneumonia

Patient Group Likely Pathogens Empiric Regimens

Hospitalized on

ward Streptococcus pneumoniae, Haemophilus influenzae, Chlamydophila pneumoniae, Staphylococcus aureus,

Mycoplasma pneumoniae, anaerobes, viruses

Respiratory fluoroquinolone (levofloxacin, moxifloxacin, gemifloxacin) alone or beta-lactam (cefotaxime, ceftriaxone, ampicillin, ertapenem) and macrolide

Critically ill, ICU S pneumoniae, Legionella species, S aureus,

Modified from Mandell MA, Wunderink RG, Anzueto A, et al: Infectious Disease Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults Clin Infect Dis 44:S27–S72, 2007.

IV , Intravenous; PO, by mouth.

TABLE 24-7

Major Classes of Antibiotics Used in

the Treatment of Pneumonia

Antibiotic Class Representative Drugs

azithromycin Tetracyclines Doxycycline

Glycopeptides Vancomycin

Oxazolidinones Linezolid

For hospitalized patients who are not critically ill and who

are admitted to the ward, an empiric regimen of a respiratory

fluoroquinolone alone or an advanced macrolide plus a

beta-lactam (cefotaxime, ceftriaxone, or ampicillin) is recommended

(see Table 24-8) For critically ill patients requiring admission

to the ICU, the IDSA and ATS recommend as empiric therapy

a beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam)

plus either an advanced macrolide or a respiratory

fluoroqui-nolone for legionella coverage Certain pathogens require

specific consideration in the ICU setting If Pseudomonas is

a concern, recommended regimens include two drugs with

antipseudomonal coverage: an antipseudomonal beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) and ciprofloxacin or levofloxacin; an antipseudomonal beta-lactam, an aminoglycoside, and azithromycin; or an antipseu-domonal beta-lactam, an aminoglycoside, and a respiratory fluoroquinolone (see Table 24-8) When MRSA is a concern, addition of vancomycin or linezolid is recommended

When a microbiologic diagnosis is established, the crobial regimen should be tailored to the isolated pathogen Pathogen-specific treatment recommendations from the IDSA and ATS are summarized in Table 24-9 For isolates of S pneu- moniae susceptible to penicillin, penicillin remains the preferred agent Many strains of H influenzae produce beta-lactamase,

antimi-making them resistant to penicillin Second- or third-generation cephalosporins and amoxicillin/clavulanate are the agents of choice Legionellosis should be treated with a macrolide or with

a fluoroquinolone alone Pneumonia caused by M pneumoniae and C pneumoniae should be treated with a macrolide or doxy-

cycline Trimethoprim-sulfamethoxazole (TMP-SMX) is the

drug of choice for P jiroveci pneumonia However, 50% of

HIV-infected patients may develop fever or a rash while taking this medication For patients with mild to moderate disease, atova-quone, clindamycin, and primaquine, or trimethoprim and dapsone, are treatment alternatives; pentamidine is indicated for severe infection in patients unable to tolerate TMP-SMX Treatment for staphylococcal or gram-negative pneumonias is dictated by the antibiotic susceptibility profiles of the offending organism For patients with staphylococcal pneumonia, vanco-mycin is preferred, pending antibiotic susceptibility results If the isolate is methicillin-susceptible, a semisynthetic penicillin, such as oxacillin or nafcillin, should be used because these anti-biotics kill the bacteria more effectively than vancomycin; in seriously ill patients, rifampin or an aminoglycoside may be added A detailed discussion regarding the treatment of fungal and viral pneumonias is beyond the scope of this chapter.The duration of therapy of CAP is guided by the specific pathogen and the patient’s clinical course Recommendations

Pulmonary Infections • CHAPTER 24 507

Health Care–Associated Pneumonia, Hospital-Acquired Pneumonia, and Ventilator-Associated Pneumonia

Empiric and definitive therapy of nosocomial pneumonia is determined by institution-specific data regarding the most common organisms and their antibiotic-susceptibility profiles and by patient-specific risk factors Although general guidelines have been published,3 the importance of local data cannot be overemphasized because there is great variation across regions and across health care facilities regarding the prevalence and susceptibility profiles of specific pathogens

Generally, in-hospital aspiration should be treated with a regimen that provides coverage against anaerobes and gram-negative bacilli, such as a beta-lactam/beta-lactamase inhibitor combination or clindamycin with a third-generation cephalo-sporin Although vancomycin has been the traditional drug of choice for MRSA pneumonia, evolving data suggest that line-zolid may be better than vancomycin In a randomized con-trolled trial of vancomycin versus linezolid for treatment of MRSA pneumonia, clinical resolution of pneumonia occurred more frequently in patients treated with linezolid, but there was

have evolved from the traditional 14 days to a minimum of 5

days of therapy with clinical stability Exceptions include

Legionnaire’s disease or staphylococcal pneumonia, for which a

minimum of 2 weeks of therapy is recommended Older

indi-viduals and patients with comorbidities also may require longer

courses of treatment When fever has resolved and patients

begin to improve clinically, oral therapy may be used to

com-plete the treatment program Failure of the patient’s

tempera-ture to normalize within 4 or 5 days suggests a missed pathogen,

a metastatic or closed-space infection (e.g., empyema), drug

fever, or the presence of an obstructing endobronchial lesion

Empyema should be treated with tube thoracostomy Abnormal

findings on physical examination may persist beyond 1 week in

20% to 40% of patients, despite clinical improvement By 1

month, radiographic resolution occurs in 90% of individuals

younger than 50 years.54 After 1 month, radiographic

abnor-malities may persist in 70% of cases involving older individuals

or in patients with significant underlying illnesses.54

TABLE 24-9

Pathogen-Specific Treatment Recommendations

for Adults With Community-Acquired Pneumonia:

Infectious Disease Society of America Guidelines

Pathogen Recommended Regimen

Legionella species Macrolide ± rifampin or

fluoroquinolone alone

Mycoplasma pneumoniae Macrolide or doxycycline

Chlamydophila pneumoniae Macrolide or doxycycline

Staphylococcus aureus

Methicillin susceptible Semisynthetic penicillin ± rifampin

or gentamicin Methicillin resistant Vancomycin or linezolid

Enterobacteriaceae Third-generation cephalosporin ±

aminoglycoside or carbapenem

Pseudomonas aeruginosa Aminoglycoside + antipseudomonal

beta-lactam or carbapenem Influenza with suspected

secondary pneumococcal

or staphylococcal infection

Neuraminidase inhibitor (oseltamivir

or zanamivir) and vancomycin or linezolid

in Pneumonia

PROBLEM:  The RT is caring for a 68-year-old man admitted

1 week ago with bacteremic H influenzae pneumonia His

admitting chest radiograph showed right lower lobe tion and a large right pleural effusion He has a history of chronic obstructive pulmonary disease (COPD) and reports a

consolida-100 pack-year smoking history He was treated initially with erythromycin and ceftizoxime until his blood cultures became positive The organism was susceptible to ceftizoxime, which was continued as monotherapy (i.e., treatment with one anti- biotic drug) Despite treatment, the patient has remained per- sistently febrile (39° C) and his chest radiograph has not shown improvement Why is he not responding to therapy?

DISCUSSION:  Patients with CAP who have comorbid nesses such as alcoholism or COPD may recover more slowly than healthy individuals despite appropriate therapy Neverthe- less, persistent fever 7 days into optimal treatment should prompt several considerations.

ill-The two most likely concerns for this patient are (1) an undrained empyema and (2) an obstructing endobronchial malignancy, given his substantial smoking history Other less likely considerations are drug fever; a new nosocomial infec- tion; a missed pathogen that is not responsive to ceftizoxime, contributing to his pneumonia; or a deep venous thrombosis resulting from bed rest.

The next step should be to repeat the history and physical examination If these do not reveal a cause of the persistent fever, a thoracentesis should be performed to exclude empyema

If thoracentesis findings are negative, further investigation looking for an endobronchial-obstructing lesion should be considered.

508 SECTION IV • Review of Cardiopulmonary Disease

TABLE 24-10 Strategies for Prevention of Nosocomial Pneumonia

Handwashing Probably effective Isolation of patients with resistant organisms Probably effective Infection control and surveillance Probably effective Enteral feeding, rather than total parenteral

nutrition Possibly effectiveSemierect position Possibly effective Sucralfate for bleeding prophylaxis Possibly effective Careful handling of respiratory therapy

equipment Possibly effectiveSubglottic secretion aspiration Possibly effective Selective digestive decontamination Unproved efficacy Topical tracheobronchial antibiotics Unproved efficacy

no difference in 60-day mortality between the two groups.55 For

VAP, empiric coverage may be targeted at organisms known to

colonize the patient’s oropharynx or pathogens that are present

in the ICU Patients with P aeruginosa pneumonia usually are

treated with two agents, such as a ureidopenicillin or

antipseu-domonal cephalosporin together with an aminoglycoside or

fluoroquinolone Other gram-negative pneumonias generally

are treated with a single agent, except in cases involving

criti-cally ill patients, for whom a second drug is sometimes added

If nosocomial legionellosis is present within an institution, a

macrolide may be added to the empiric regimen

Similar to CAP, the duration of therapy for cases of

nosoco-mial pneumonia is dictated by the clinical course A study

com-paring 8 days versus 15 days of therapy in patients with VAP

found that short-course therapy was associated with

compa-rable outcomes to long-course therapy, although the rate of

relapse was slightly higher in patients with Pseudomonas or

Acinetobacter infections.56 More prolonged courses of therapy

may be required in patients who are slow to respond but are

associated with a greater risk for new colonization with other

organisms Failure of the patient to improve should prompt the

following considerations: the presence of an occult empyema;

an unrecognized pathogen; a new, unrelated nosocomial

infec-tion; or other noninfectious causes of fever common in the ICU,

such as deep venous thrombosis, drug fever, occult pancreatitis,

or acalculous cholecystitis (gallbladder inflammation without

gallstones)

The RT has an important role in diagnosing and managing

patients with CAP and nosocomial pneumonia Helping

patients clear infected secretions aids clinical improvement and

maintaining adequate oxygenation is essential The usefulness

of chest physiotherapy in the treatment of pneumonia is still

unproved but some patients seem to benefit from it

PREVENTION

Community-Acquired Pneumonia

Preventive strategies for CAP have focused on immunizing

high-risk individuals against influenza and S pneumoniae

Influenza is a risk factor for subsequent development of CAP

during the fall and winter months In 2010, the Advisory

Com-mittee on Immunization Practices (ACIP) expanded its

recom-mendation for influenza vaccination to include all individuals

older than 6 months.57 Immunization is particularly important

for individuals older than 60 years (because it reduces the

inci-dence of illness for this age group by half 58) and for those

with chronic lung or heart disease in whom the morbidity of

influenza may be substantial Recent studies suggest that

wide-spread immunization of healthy working adults is cost-effective

because the number of sick days taken and the number of visits

to a physician are reduced.59 Health care workers, including RTs,

should be immunized annually to prevent transmission of

influenza to patients

Currently available pneumococcal vaccines provide

protec-tion against the 23 serotypes of S pneumoniae, which cause

85% to 90% of invasive pneumococcal infections in the United States Vaccination is indicated for all individuals older than 65 years and for individuals older than 2 years who have functional

or anatomic asplenia (i.e., lack a spleen) Vaccination is also indicated in patients with chronic illnesses such as CHF, chronic lung disease, or chronic liver disease; alcoholism; cerebrospinal fluid leaks; or conditions characterized by impaired immunity.60

Routine pneumococcal vaccination of all health care workers is not currently recommended; health care workers who possess one of the specific indications for vaccination outlined previ-ously should be immunized

Immunity against Bordetella pertussis fades over time, leading

to transmission from older adults to other adults and infants Because secondary bacterial pneumonia occurs in a significant number of cases of pertussis, the ACIP has recommended that the tetanus-diphtheria-acellular pertussis (Tdap) vaccine replace the tetanus-diphtheria (Td) vaccine in the adult immu-nization schedule.61

Health Care–Associated Pneumonia, Hospital-Acquired Pneumonia, and Ventilator-Associated Pneumonia

Preventing nosocomial pneumonia has been intensely studied over the past 30 years Table 24-10 summarizes currently avail-able strategies and their relative efficacy No preventive strategy

is uniformly effective Many institutions now employ a tor bundle” including several of these measures

“ventila-Handwashing is an important but frequently overlooked measure that can reduce transmission of nosocomial bacteria from one patient to another Handwashing is especially impor-tant for RTs who may be caring for several ventilated patients

in the ICU Failure to wash the hands between patient contacts may result in transmission of respiratory pathogens from one patient to another Handwashing is important even if gloves are worn Gloves should be changed between patient contacts because they also can become contaminated with and transmit bacteria

Pulmonary Infections • CHAPTER 24 509

tions of the disease Multidrug-resistant tuberculosis, defined as

resistance of M tuberculosis to both isoniazid and rifampin,

emerged as a major public health problem in some populations and areas Compared with frequency of the era before AIDS, tuberculosis now more often occurs in younger individuals with HIV infection, especially inner-city minority populations with

a history of injection drug use Foreign-born nationals residing

in the United States have accounted for half of cases reported annually in recent years

Tuberculosis has increasingly become a disease affecting individuals of lower socioeconomic status in whom home-lessness or crowded living conditions, poor access to health care, and unemployment have contributed to the persistence of the disease.67 Other risk factors include the presence of hema-tologic malignancies, head and neck cancer, celiac disease (a bowel disease characterized by poor absorption), and the receipt of medications such as corticosteroids and TNF-alpha antagonists.67-70

Pathophysiology

Tuberculosis is acquired by inhaling airborne droplets

contain-ing the responsible microorganism, M tuberculosis, and the

lungs are the major site of infection Microorganism-laden droplets are deposited in the terminal airways and cause a host immune response Most exposed individuals successfully con-tain the infection and remain asymptomatic, although they remain at risk for reactivation of infection later in life, especially

if they become immunosuppressed

Patients with tuberculosis can present with pulmonary or extrapulmonary manifestations The major syndromes of pul-monary tuberculosis include primary, reactivation, and endo-bronchial tuberculosis and tuberculoma

Primary Tuberculosis

Symptomatic primary tuberculosis occurs in a few individuals shortly after exposure Primary tuberculous pneumonia is a more common clinical presentation in children and in HIV-infected individuals compared with non–HIV-infected adults Fever is the most common symptom and occurs in 70% of patients; it persists for 14 to 21 days on average.71 Chest pain occurs in approximately 25%; cough is even less common The chest radiograph shows hilar lymphadenopathy in 65%, pleural effusion in 33%, and an infiltrate in approximately 25% Diag-nosis may be difficult given the infrequency of cough and a pulmonary infiltrate

Reactivation and Endobronchial Tuberculosis

Reactivation tuberculosis develops months to years after initial infection and may occur spontaneously or in the setting of immunosuppression In individuals without HIV infection, reactivation disease accounts for 90% of cases of tuberculosis The most common symptoms include fever, cough, night sweats, and weight loss Sputum production increases as the infection progresses and is occasionally accompanied by hemoptysis, which is seldom massive Older patients may

Infection control surveillance to detect outbreaks of

nosoco-mial pneumonia with specific pathogens and to monitor

anti-biotic resistance patterns is important Isolation and caring for

infected patients in the same place can limit the scope and

dura-tion of outbreaks, especially in ICUs

In patients requiring nutrition support, the use of enteral

feeding via jejunostomy has been associated with a lower risk

for nosocomial pneumonia than the use of total parenteral

nutrition.62 In addition, patients who are fed enterally (i.e.,

using the gut to feed) have a lower incidence of pneumonia if

kept semierect rather than recumbent.8

Two studies suggest that GI bleeding prophylaxis with

sucralfate is associated with a lower risk for pneumonia

com-pared with antacid or H2-blockers.63,64 Careful handling of

respiratory therapy equipment may reduce the risk for LRTI in

ventilated patients Condensate within the tubing may be

colo-nized with bacteria and should be drained away from the

patient because passage of this material into the airway may

encourage colonization with nosocomial pathogens One study

found that continuous subglottic aspiration of secretions was

effective in reducing the incidence of nosocomial pneumonia

in intubated patients.65 Many studies have failed to show that

selective digestive decontamination is effective to prevent

noso-comial pneumonia; this is a strategy that uses topical

antibiot-ics in the oropharynx and GI tract along with a brief course of

systemic therapy A meta-analysis suggested that topical oral

decontamination may reduce the incidence of VAP but not

mortality, duration of mechanical ventilation, or length of

ICU stay.66

Prevention of nosocomial pneumonia remains a challenge

to the RT Careful attention to basic infection control practices,

such as frequent handwashing, using new gloves with each

patient contact, and careful handling of respiratory care

equip-ment, is important in preventing nosocomial pneumonia

TUBERCULOSIS

Tuberculosis, caused by M tuberculosis, can sometimes mimic

CAP and poses special management challenges for the RT

Knowledge of the epidemiology, clinical manifestations,

diag-nosis, infection control management, and treatment of patients

with suspected or proved tuberculosis is essential

Epidemiology

The epidemiology of tuberculosis in the United States has

changed over the past 25 years After the introduction of

effec-tive drugs to treat tuberculosis in the 1950s, the incidence of

tuberculosis steadily declined Tuberculosis increasingly became

a disease affecting elderly patients, and most cases represented

reactivation of old latent disease With the emergence of the

acquired immunodeficiency syndrome (AIDS) epidemic in the

early 1980s, there was a resurgence of tuberculosis in the United

States and worldwide This resurgence began in 1985 and

peaked in 1992 Since 1992, the incidence of tuberculosis has

declined This resurgence of tuberculosis was accompanied by

dramatic shifts in the patients at risk and the clinical

manifesta-510 SECTION IV • Review of Cardiopulmonary Disease

Diagnosis

The history is important in diagnosing and managing patients with suspected tuberculosis In addition to eliciting the patient’s symptoms, the clinician should inquire about any history of tuberculosis, the presence of risk factors for acquiring tubercu-losis and/or HIV infection, any history of travel, and potential contacts with individuals with known or suspected tuberculo-sis In patients with a history of tuberculosis, outside medical records, including drug susceptibility results of prior isolates, should be obtained If the patient has been previously treated, the drugs chosen, duration of treatment, and adherence to therapy should be evaluated Risk factors for drug-resistant tuberculosis should be sought, which include prior treatment for tuberculosis, exposure to individuals with known drug-resistant disease, exposure to individuals with active tuberculo-sis who have been previously treated, travel to parts of the world with a high prevalence of drug resistance, or exposure to indi-viduals with active tuberculosis from those areas

The gold standard for diagnosing tuberculosis from nary and extrapulmonary sites is culture isolation of the organ-ism on solid or liquid media The major disadvantage of culture

pulmo-is that M tuberculospulmo-is may take 4 to 6 weeks to grow, thereby

delaying diagnosis Acid-fast staining of expectorated sputum, bronchoscopic specimens, and other body fluids or tissues may

be used in patients with suspected pulmonary or nary disease In patients with pulmonary tuberculosis, it is esti-mated that 104 organisms/ml is required for the smear to be positive Acid-fast smears of both sputum and other body sites are less sensitive than culture for detecting disease The presence

extrapulmo-of acid-fast bacilli on a smear is not synonymous with a

diag-nosis of M tuberculosis because nontuberculous mycobacteria

(NTM) can produce pulmonary and extrapulmonary disease in selected populations More rapid diagnostic techniques for

identifying M tuberculosis in clinical specimens and for

con-firming the identity of the organism in culture are being oped and are available in some centers These techniques include nucleic acid amplification, nucleic acid probes, PCR genomic analysis, and molecular tests for chromosomal mutations asso-ciated with drug resistance

devel-A 5 tuberculin unit purified protein derivative (5 TU PPD) skin test or interferon-gamma release assay (IGRA) may be performed in individuals with suspected tuberculosis Both tests evaluate for cell-mediated immunity to tuberculosis in indi-viduals with prior exposure to the organism A PPD consists of intradermal injection of tuberculin material, which stimulates

a delayed-type hypersensitivity response mediated by T cells and causes skin induration within 48 to 72 hours False-positive results can occur in patients with prior bacille Calmette-Guérin (BCG) vaccination or infection with NTM species IGRAs are blood tests that measure T-cell release of the cytokine interferon-

gamma after stimulation by antigens unique to M tuberculosis

IGRAs are unaffected by BCG vaccination status and most NTM

infections (except Mycobacterium marinum and Mycobacterium kansasii) and require only a single patient encounter, all of

which are advantages over the PPD.72 Both tests become positive

present with a more indolent illness in which fever and night

sweats are absent Physical examination is often unrevealing in

patients with reactivation tuberculosis Chest radiograph shows

apicoposterior upper lobe disease in 80% to 90% of patients,

and cavities are present in 20% to 40%

Endobronchial tuberculosis involves the airways and may be

seen in both primary and reactivation tuberculosis In primary

tuberculosis, hilar nodal enlargement may impinge on the

bronchi, resulting in compression and ultimately ulceration In

patients with reactivation disease, endobronchial involvement

may occur as a result of direct extension from the parenchyma

or pooling of secretions from upper lobe cavities in the

depen-dent distal airways Symptoms of endobronchial tuberculosis

include a barking cough in two-thirds of patients, sputum

pro-duction, wheezing, and hemoptysis On physical examination,

wheezing is common The chest radiograph most often shows

an upper lobe cavitary infiltrate with an ipsilateral (i.e., on the

same side) lower lobe infiltrate Extensive endobronchial disease

may produce bronchiectasis

Tuberculomas

Tuberculomas are rounded solitary mass lesions and may occur

in primary or reactivation tuberculosis They are often

asymp-tomatic and may mimic malignancy Tuberculoma is in the

differential diagnosis of solitary pulmonary nodule and may be

difficult to diagnose without biopsy or excision because

expec-torated sputum in patients with tuberculoma rarely shows

M tuberculosis on smear or culture.

Complications

Complications of pulmonary tuberculosis include tuberculous

empyema, bronchiectasis, extensive pulmonary parenchymal

destruction, spontaneous pneumothorax, and massive

hemop-tysis from rupture of a Rasmussen aneurysm in the wall of a

cavity

Extrapulmonary Tuberculosis

Extrapulmonary tuberculosis is defined as spread of M

tuber-culosis infection beyond the lung and may involve virtually any

organ The central nervous system, musculoskeletal system,

genitourinary tract, and lymph nodes (scrofula) are the most

common sites of extrapulmonary tuberculosis HIV-infected

patients who acquire tuberculosis often present with unique

clinical manifestations compared with non–HIV-infected

pa-tients HIV-infected patients may develop rapidly progressive

primary infection and present with both pulmonary and

extra-pulmonary disease In patients with advanced AIDS,

tubercu-losis may manifest as disseminated disease with involvement of

multiple organs, including lymph nodes, bone marrow, liver,

and spleen Symptoms in this setting include high fevers, sweats,

and progressive weight loss Findings on examination may

include fever, wasting, and hepatosplenomegaly Laboratory

testing may show pancytopenia (decreased cell counts in WBCs,

RBCs, and platelets) and advanced immunodeficiency Imaging

studies often show mediastinal and abdominal

lymphadenopa-thy and hepatosplenomegaly

Pulmonary Infections • CHAPTER 24 511

Diagnostically, RTs participate in the collection of sputum by expectoration or assisting physicians during bronchoscopy In some settings, RTs may perform mini-BAL

RTs often administer chest physiotherapy when indicated,

as in patients with bronchiectasis and cystic fibrosis They also may be involved in counseling patients in other clearance techniques, such as autogenic drainage and positive expiratory pressure (PEP) therapy RTs also play key roles in modeling optimal infection control and prevention practices (e.g., hand-washing, implementing and complying with respiratory pre-cautions, vaccination) and in advising patients about preventive interventions, such as influenza, pneumococcal, and Tdap vaccines

3 to 8 weeks after acquisition of infection A positive skin test

or IGRA supports the diagnosis in the appropriate clinical

setting, but a negative result does not exclude the diagnosis

Patients with HIV infection, other causes of immunodeficiency,

advanced age, or other comorbidities may be anergic and unable

to mount either a positive skin test or IGRA result.72,73

Precautions

Patients hospitalized with suspected or proved active

pulmo-nary tuberculosis should be placed in respiratory isolation in

private negative pressure airflow rooms because they pose a risk

for transmitting infection to others by coughing up aerosolized

droplets containing M tuberculosis Individuals entering the

patient’s room should wear fit-tested National Institute for

Occupational Safety and Health–approved N-95 or higher

masks or respirators A surgical mask should be placed on a

patient with suspected or proved active pulmonary tuberculosis

during transport outside the negative pressure room

Treatment

Treatment recommendations for tuberculosis have been

pub-lished by the ATS, U.S Centers for Disease Control and

Preven-tion (CDC), and the IDSA.74 The goals of therapy are to cure

the patient and prevent transmission of M tuberculosis to

others Treatment must address clinical and social issues and

should be customized to the patient’s circumstance At the

outset, daily observed therapy (DOT) should be part of the

treatment program; this consists of observing the patient taking

the antituberculous medications Treatment programs that use

comprehensive case management and DOT have a higher rate

of successful completion of therapy than other treatment

strate-gies Social service support, housing assistance, and treatment

for substance abuse may be required for selected individuals

with tuberculosis and should be part of the treatment plan

Patients with tuberculosis must be promptly reported to the

local department of public health so that contact tracing can be

performed This includes identification, if possible, of the index

case from whom the patient has contracted the infection and

identification of close personal contacts to whom the patient

may have transmitted M tuberculosis.

Isoniazid, rifampin, pyrazinamide, and ethambutol are

first-line antituberculous medications Pending antimicrobial

sus-ceptibility results, treatment with four drugs at the outset is

recommended In patients with drug-susceptible pulmonary

tuberculosis, many 6- to 9-month treatment regimens have

been shown to be effective as outlined in guidelines by the ATS,

CDC, and IDSA.74 Patients with multidrug-resistant

tuberculo-sis require more prolonged courses of therapy with multidrug

regimens

ROLE OF THE RESPIRATORY

THERAPIST IN PULMONARY

INFECTIONS

The RT plays a key role in managing patients with pulmonary

infections, including helping to diagnose and treat the illnesses

SUMMARY CHECKLIST

◗ CAP and nosocomial pneumonia are common and important clinical problems with significant morbidity and mortality.

◗ S pneumoniae remains the most common cause of CAP Gram-negative bacilli and S aureus are the most common

causes of nosocomial pneumonia, but their relative incidence and antimicrobial susceptibility profiles may vary across institutions.

◗ The mortality risk can be quantified at presentation for most patients with CAP, which helps in determining the need for hospitalization.

◗ Routine sputum cultures for patients with CAP must be interpreted within the context of the sputum Gram stain, which provides valuable information regarding the adequacy of the specimen and the predominance of potential pathogens.

◗ The accurate diagnosis of nosocomial pneumonia remains

a challenge; none of the diagnostic methods currently available is completely reliable.

◗ Guidelines exist for the treatment of CAP and nosocomial pneumonia When possible, pathogen-specific antibiotic therapy should be used.

◗ Immunizing high-risk individuals against influenza and

S pneumoniae is the major strategy in preventing CAP.

◗ Strategies for preventing nosocomial pneumonia are not uniformly effective.

◗ Pulmonary tuberculosis may mimic CAP; the recognition and appropriate isolation, diagnostic evaluation, and management of individuals with possible pulmonary tuberculosis are essential.

◗ The RT can help prevent nosocomial pneumonia by careful attention to basic infection control procedures such as handwashing.

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Obstructive Lung Disease: Chronic Obstructive Pulmonary

ENRIQUE DIAZ-GUZMAN AND JAMES K STOLLER

Establishing the Diagnosis Optimizing Lung Function Maximizing Functional Status Preventing Progression of Chronic Obstructive Pulmonary Disease and Enhancing Survival Additional Therapies

Asthma Definition Incidence Etiology and Pathogenesis

Clinical Presentation and Diagnosis Management

Objective Measurement and Monitoring Pharmacotherapy

Emergency Department and Hospital Management Bronchial Thermoplasty

Immunotherapy Environmental Control Patient Education Special Considerations in Asthma Management Bronchiectasis

Clinical Presentation Evaluation

Management Role of the Respiratory Therapist in Obstructive Lung Disease

KEY TERMS

acute exacerbation of COPD airway hyperresponsiveness airway inflammation

airway obstruction asthma

bronchiectasis bronchodilator bronchospasm chronic bronchitis

cystic fibrosis emphysema noninvasive ventilation supplemental oxygen

Obstructive Lung Disease • CHAPTER 25 515

FIGURE 25-1 Schema of chronic obstructive pulmonary disease (COPD) This nonproportional Venn diagram shows subsets of patients with chronic bronchitis, emphysema, and asthma The

subsets constituting COPD are shaded Subset areas are not

proportional to actual relative subset sizes Asthma is by definition associated with reversible airflow obstruction, although in variant asthma special maneuvers may be necessary to make the obstruction evident Patients with asthma whose airflow obstruction

is completely reversible (subset 9) are not considered to have

COPD Because in many cases it is virtually impossible to differentiate patients with asthma whose airflow obstruction does not remit completely from patients with chronic bronchitis and emphysema who have partially reversible airflow obstruction with airway hyperreactivity, patients with unremitting asthma are

obstruction caused by diseases with a known cause or specific pathologic process, such as cystic fibrosis or obliterative

bronchiolitis (subset 10), are not included in this definition

Emphysema Chronic

bronchitis

COPD

Airflow obstruction Asthma

4 5

8 7 6

3

9

10

T he category of obstructive lung diseases is broad

and includes chronic obstructive pulmonary disease

(COPD) and asthma as the most common diseases and

bronchiectasis and cystic fibrosis as less common forms

Airflow obstruction also may be a feature of other lung diseases

such as sarcoidosis, lymphangioleiomyomatosis, and congestive

heart failure This chapter reviews the major obstructive lung

diseases, emphasizing their defining features, epidemiology,

pathophysiology, clinical signs and symptoms, prognosis, and

management Cystic fibrosis is discussed in Chapter 34

CHRONIC OBSTRUCTIVE

PULMONARY DISEASE

Overview and Definitions

The term chronic obstructive pulmonary disease (COPD), or

sometimes chronic obstructive lung disease (COLD), refers to a

disease state characterized by the presence of incompletely

reversible airflow obstruction Current guidelines by the

Ameri-can Thoracic Society (ATS) and the Global Initiative for Chronic

Obstructive Lung Disease (GOLD) guidelines recommend the

use of the term COPD to encompass both chronic bronchitis

and emphysema The ATS guidelines statement regarding

COPD defines this entity as follows1:

Chronic obstructive pulmonary disease (COPD) is a preventable

and treatable disease state characterized by airflow limitation

that is not fully reversible The airflow limitation is usually

progressive and is associated with an abnormal inflammatory

response of the lungs to noxious particles or gases, primarily

caused by cigarette smoking Although COPD affects the lungs, it

also produces significant systemic consequences.

Similarly, the GOLD guidelines define COPD as follows2:

A disease state characterized by persistent airflow limitation that

is usually progressive, and is associated with an enhanced

inflammatory response in the airways and the lung to noxious

particles or gases Exacerbations and comorbidities contribute to

the overall severity in individual patients.

The spectrum of COPD is shown in Figure 25-1, which

presents a nonproportional Venn diagram representing the

major components of COPD—chronic bronchitis and

emphy-sema Although asthma is no longer conventionally considered

to be part of the spectrum of COPD, the diagram shows that

there is overlap between asthma and COPD In actual practice,

it may not be possible to distinguish between individuals with

a history of asthma but with incompletely reversible airflow

obstruction and individuals with COPD

The two major diseases that make up COPD—emphysema

and chronic bronchitis—are defined in different ways Emphy

-sema is defined in anatomic terms as a condition characterized

by abnormal, permanent enlargement of the airspaces beyond

the terminal bronchiole, accompanied by destruction of the

walls of the airspaces without fibrosis Chronic bronchitis is

defined in clinical terms as a condition in which chronic

pro-ductive cough is present for at least 3 months per year for at least 2 consecutive years The definition specifies further that other causes of chronic cough (e.g., gastroesophageal reflux, asthma, and postnasal drip) have been excluded Figure 25-1shows considerable overlap between chronic bronchitis and emphysema and some overlap with asthma—that is, when airflow obstruction is incompletely reversible Figure 25-1 also shows that chronic bronchitis and emphysema can occur without airflow obstruction, although the clinical significance

of these diseases usually comes from obstruction to airflow

Epidemiology

COPD is one of the most frequent causes of morbidity and mortality worldwide.3 The World Health Organization predicts

516 SECTION IV • Review of Cardiopulmonary Disease

FIGURE 25-2 Mean postbronchodilator FEV1 for participants in the smoking intervention and placebo groups who were sustained

quitters (red circles) and continuing smokers (purple circles) The

two curves diverge sharply after baseline (From Anthonisen SR, Connett JE, Kiley JP, et al: Effects of smoking intervention and the use of an anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study JAMA 272:1497–1504, 1994.)

2.9 2.8

2.7 2.6

that COPD will become the fifth most prevalent disease in the

world and the third leading cause of worldwide mortality by

2030 In the United States, COPD is currently the third leading

cause of death; it was responsible for 134,676 deaths and 715,000

hospitalizations in 2010.4 Estimates suggest that 24 million

Americans are affected, though only 15 million U.S adults have

been diagnosed.4-6 Data from the National Health and Nutrition

Examination Survey (NHANES) suggest that among adults 25

to 75 years old in the United States, mild COPD (defined as

forced expiratory volume in 1 second [FEV1]/forced vital

capac-ity [FVC] < 70%, and FEV1> 80% predicted) occurs in 6.9%

and moderate COPD (defined as FEV1/FVC < 79% and FEV1 ≤

80% predicted) occurs in 6.6%.3 COPD prevalence increases

with aging, with a five-fold increased risk for adults older than

65 years compared with adults younger than 40 years, and some

studies estimate a prevalence of 20% to 30% in adults older

than 70 years.7

The growing health burden from COPD is caused in part by

the aging of the population but mainly by the continued use of

tobacco The socioeconomic burden of COPD is also

substan-tial In 2010, COPD caused 715,000 hospitalizations (which

accounted for 1.9% of all hospitalizations in the United States),

and, in 2010, COPD resulted in a total health expenditure of

$49.9 billion.4 In this regard, COPD is a problem that is a

fre-quent challenge for the respiratory clinician

Risk Factors and Pathophysiology

Although many risk factors exist for COPD (Box 25-1), the two

most common are cigarette smoking (which has been estimated

to account for 80% to 90% of all COPD-related deaths) and

alpha-1 antitrypsin (AAT) deficiency.8 Evidence linking cigarette

smoking to the development of COPD is strong and includes the following:

• Symptoms of COPD (e.g., chronic cough and phlegm production) are more common in smokers than in nonsmokers

• Impaired lung function with evidence of an obstructive pattern of lung dysfunction is more common in smokers than in nonsmokers

• Pathologic changes of airflow obstruction and chronic chitis are evident in the lungs of smokers

bron-• So-called susceptible smokers, who represent approximately

15% of all cigarette smokers, experience more rapid rates of decline of lung function than nonsmokers

Information from the Lung Health Study (Figure 25-2) lighted the accelerated rate of decrease of FEV1 in smokers compared with former smokers who have achieved sustained quitting.9,10 Overall, the strength of evidence implicating ciga-rette smoking as a cause of COPD has allowed the U.S Surgeon General to conclude, “Cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women The contribution of cigarette smoking to chronic obstructive lung disease morbidity and mortality far outweighs all other factors.”11

high-As the second well-recognized cause of emphysema, AAT

deficiency, sometimes called genetic emphysema or alpha-1 protease deficiency, is a condition that features a reduced amount

anti-of the protein alpha-1 antitrypsin (AAT), which may result in the early onset of emphysema and which is inherited as a

so-called autosomal codominant condition AAT deficiency

Obstructive Lung Disease • CHAPTER 25 517

accounts for 2% to 3% of all cases of COPD and affects 100,000

Americans but is underrecognized by health care providers In

one 1995 survey, the mean interval between the first onset of

pulmonary symptoms and initial diagnosis of AAT deficiency

was 7.2 years, and 43% of individuals with severe deficiency

of AAT reported seeing at least three physicians before the

diagnosis of AAT deficiency was first made.12 More recent

studies suggest that underrecognition of AAT deficiency persists

and that the diagnostic delay interval has not decreased

significantly.12-15

Identifying individuals with AAT deficiency is simple, often

requiring only a blood test of the serum AAT level Respiratory

therapists (RTs) can contribute importantly to detecting

indi-viduals with AAT deficiency (e.g., by suggesting or offering

testing when airflow obstruction is diagnosed in the pulmonary

function laboratory by an RT performing the test and by making

patients aware of available free, home-based testing kits) (see

sug-gest the importance of detection: (1) first-degree relatives (e.g.,

siblings, parents, and children) also may be affected but unaware

of their risk; (2) early detection allows appropriate monitoring

and therapy, including the very important step of smoking

ces-sation; and (3) for individuals with established emphysema,

consideration can be given to available specific therapy, called

intravenous augmentation therapy (which is the administration

of purified AAT intravenously to individuals with severe

defi-ciency of AAT) The risk for developing emphysema for

indi-viduals with AAT deficiency increases as the serum AAT level

decreases to less than 11 µmol/L, or less than approximately

57 mg/dl using a testing technique called nephelometry; these

levels in serum define the so-called protective threshold value,

which is the serum level below which the risk for emphysema

is felt to increase Cigarette smoking markedly accelerates

the rate of emphysema progression in individuals with AAT

deficiency.14

Study of AAT deficiency has helped formulate the

protease-antiprotease hypothesis of emphysema.14,16 In this explanatory

model (Figure 25-3), lung elastin, a major structural protein

that supports the alveolar walls of the lung, is normally

pro-tected by AAT, a protein that defends the lung against tissue

destruction by neutrophil elastase Neutrophil elastase is a

protein contained within a category of white blood cells called

neutrophils that is released when neutrophils are attracted to

the lung during inflammation or infection Under normal

cir-cumstances of an adequate amount of AAT, neutrophil elastase

is counteracted so as not to digest lung elastin However, in the

face of a severe deficiency of AAT (i.e., when serum levels

decrease below the “protective threshold” serum value of

11 µmol/L, or 57 mg/dl), neutrophil elastase may go unchecked,

causing breakdown of elastin and of alveolar walls This

protease-antiprotease model explains the pathogenesis of

emphysema in AAT deficiency, but evidence suggesting its role

in COPD in individuals with normal amounts of AAT is

con-flicting Also, other enzymes that break down proteins (e.g.,

matrix metalloproteinases) are thought to contribute to the

destruction of alveolar walls that produces emphysema.17

FIGURE 25-3 Proposed biochemical links between cigarette

smoking and the pathogenesis of emphysema (I) Smoking recruits

monocytes, macrophages, and (through macrophage chemotactic factors) polymorphonuclear neutrophils to the lung, elevating the connective tissue “burden” of elastolytic serine and

metalloproteases (III) At the same time, oxidants in smoke plus

oxidants produced by smoke-stimulated lung phagocytes (and oxidizing products of chemical interactions between these two) inactivate bronchial mucus proteinase inhibitor and alpha-1 antitrypsin (AAT), the latter representing the major antielastase

“shield” of the respiratory units (II) Other, unidentified water-soluble,

gas-phase components of cigarette smoke (cyanide, copper chelators) inhibit lysyl oxidase–catalyzed oxidative deamination of epsilon-amino groups in tropoelastin and block formation of desmosine and presumably other cross-links during elastin

synthesis, decreasing connective tissue repair (IV) Antioxidants

(ceruloplasmin, methionine-sulfoxide-reductase) may protect or reactivate elastase inhibitors, and other unidentified factors may modulate the chemical lesions induced in the lung by smoking to influence the risk for developing COPD (Modified from Janoff A, Carp H, Laurent P, et al: The role of oxidative processes in emphysema Am Rev Respir Dis 127[Suppl]:S31, 1983.)

III

IV

II I

elastases

Anti-New synthesis

Oxidant-Scavengers protect?

MET S reductase reactivates?

The mechanisms of airflow obstruction in COPD include inflammation and obstruction of small airways (<2 mm in diameter); loss of elasticity, which keeps small airways open when elastin is destroyed in emphysema; and active broncho -

spasm Although traditionally considered to be characteristic

of asthma, some reversibility of airflow obstruction has been observed in up to two-thirds of patients with COPD when tested multiple times with inhaled bronchodilators.20

Clinical Signs and Symptoms

Common symptoms of COPD include cough, phlegm tion, wheezing, and shortness of breath, typically on exertion Dyspnea is often slow but progressive in onset and occurs later

produc-in the course of the disease, characteristically produc-in the late sixth

or seventh decade of life One notable exception is AAT

518 SECTION IV • Review of Cardiopulmonary Disease

deficiency, in which dyspnea characteristically begins sooner

(mean age approximately 45 years).8

and chronic bronchitis and emphasizes traits that should

suggest the possibility of AAT deficiency, including early onset

of emphysema, emphysema in a nonsmoker, a family history of

emphysema, or emphysema with a chest x-ray (Figure 25-4) or

computed tomography (CT) (Figure 25-5), in which

emphyse-matous changes are more pronounced at the lung bases than at

Chronic cough, phlegm Common Less common Less common, but may be present

Airflow (FEV1, FEV1/FVC) Decreased Decreased Decreased

Lung volumes, residual volume Normal Increased, suggesting air trapping Increased

Gas exchange, diffusion PaO2 Often decreased Often preserved until advanced stage Often preserved until advanced stage PaCO2 May be increased Often preserved until advanced

disease, then elevated Often preserved until advanced disease, then elevated Diffusion capacity Often normal Decreased Decreased

Static lung compliance Normal Increased Increased

Chest radiograph “Dirty lungs” with

peribronchial cuffing, suggesting thickened bronchial walls

Hyperinflation, with evidence of emphysema; greater at lung apex than at lung base

Hyperinflation, with evidence of emphysema; frequently greater at lung base than at lung apex (basilar hyperlucency)

FIGURE 25-4 Posteroanterior plain chest radiograph in a patient

with severe deficiency of alpha-1 antitrypsin and emphysema Note

that the emphysematous changes (hyperlucency) are more

pronounced at the lung bases than at the apexes

the apexes (so-called basilar hyperlucency) Suspicion of AAT

deficiency should lead to a simple blood test by which the serum level can be established.8,14

Physical examination of the chest early on in a patient with COPD may reveal wheezing or diminished breath sounds Later, signs of hyperinflation may be evident—that is, increased

anteroposterior diameter of the chest (sometimes called a barrel chest), diaphragm flattening, and dimpling inward of the chest

wall at the level of the diaphragm on inspiration (called the

Hoover sign) Other late signs of COPD include use of accessory

muscles of respiration (e.g., sternocleidomastoid), edema from cor pulmonale, mental status changes caused by hypoxemia

or hypercapnia (especially in acute exacerbations of chronic, severe disease), or asterixis (i.e., involuntary flapping of the hands when held in an extended position, as in “stopping traffic”)

RULE OF THUMB

Digital clubbing is not caused by COPD alone, even if hypoxemia is present Clubbing in a patient with COPD warrants consideration of another cause (e.g.,

bronchogenic cancer, bronchiectasis).

RULE OF THUMB

In patients with COPD, PaCO2 is usually preserved until airflow obstruction is severe (i.e., FEV1 < 1 L), when PaCO2 may increase.

Obstructive Lung Disease • CHAPTER 25 519

pulmonary aspergillosis, the major challenge facing the cian who encounters a patient with airflow obstruction is to distinguish COPD (i.e., emphysema or chronic bronchitis or both) from asthma Distinguishing asthma from COPD may be very difficult in practice; features that tend to favor COPD include chronic daily phlegm production, which establishes the diagnosis of chronic bronchitis; diminished vascular shadows

clini-on the chest radiograph (called hyperlucency); and a decreased

diffusing capacity The diagnosis of asthma is favored if the diminished FEV1 obtained on spirometry returns to normal after bronchodilator treatment

After the diagnosis of COPD is established, another issue is for the clinician to consider whether the patient has an under-lying predisposition to COPD, such as AAT deficiency or other cause listed in Box 25-1.18,19 Underlying causes are present in fewer than 5% of patients with COPD, with AAT deficiency being the most common (2% to 3% of all patients with COPD)

irre-as a 12% and 200-ml increirre-ase in post-bronchodilator FEV1 or FVC or both For this reason, as shown in an algorithm devel-oped by GOLD (Figure 25-6),2,22,25,26 bronchodilator therapy is recommended for patients with COPD

Bronchodilators produce smooth muscle relaxation ing in improved airflow obstruction, improved symptoms and exercise tolerance, and decrease in the frequency and severity of exacerbations, but they do not enhance survival The results

result-of the Lung Health Study,9 which compared the effects of inhaled ipratropium bromide (two puffs four times daily) with placebo in patients with mild, stable COPD, showed that regular,

Management

In managing patients with chronic, stable COPD, the following

goals must guide the clinician1,2:

• Establish the diagnosis of COPD

• Optimize lung function

• Maximize the patient’s ability to perform daily activities

• Simplify the medical treatment program as much as

possible

• Avoid exacerbations of COPD

• Prolong survival

In managing an acute exacerbation of COPD , additional

considerations are to reestablish the patient to baseline status

as quickly and with as little morbidity and mortality as

possi-ble.21,22 Each of the treatments that are discussed in this section

is considered in regard to these goals, recognizing differences in

management between patients with chronic, stable COPD

versus an acute exacerbation of COPD In patients with COPD,

PaCO2 usually is generally preserved until airflow obstruction

is severe (FEV1 < 1 L), when the PaCO2 level may increase

Establishing the Diagnosis

Although a spectrum of diseases can give rise to obstructive

lung disease, including some unusual entities such as chronic

eosinophilic pneumonia, bronchiectasis, and allergic

520 SECTION IV • Review of Cardiopulmonary Disease

MINI CLINI

Determining the Severity of Chronic Obstructive Pulmonary Disease

PROBLEM:  You are asked to see a new patient in clinic who was

recently discharged from the hospital with a COPD exacerbation

The patient describes being hospitalized at least twice per year

because of lung problems and complains of severe dyspnea when

walking up a hill Spirometry revealed an FEV 1 of 40% predicted

How do you characterize the severity of COPD in this patient?

DISCUSSION:  In 2001 GOLD created a classification system

based on the severity of airflow obstruction 2 According to this

staging system, severity of COPD was graded based on the degree

of airflow obstruction into one of the following four stages:

Stage Description

I Patients with FEV1/FVC < 70% and FEV1 > 80% predicted

II Patients with FEV1/FVC < 70% and FEV1 50%-79% predicted

III Patients with FEV1/FVC < 70% and FEV1 30%-49% predicted

IV Patients with FEV1/FVC < 70% and FEV1 < 30% or FEV1 <

50% predicted plus chronic respiratory failure

The GOLD guidelines were revised in 2011 to include

symp-toms and exacerbation history, and now COPD severity is graded

(A to D) as follows:

A = Low risk, low symptom burden

• Low symptom burden (mMRC of 0 to 1 OR CAT score <

10) AND

• FEV 1 of 50% or greater (old GOLD 1 to 2) AND low

exacerbation rate (0 to 1/year)

B = Low risk, higher symptom burden

• Higher symptom burden (mMRC of 2 or more OR CAT

of 10 or more) AND

• FEV1 of 50% or greater (old GOLD 1 to 2) AND low

exacerbation rate (0 to 1/year)

C = High risk, low symptom burden

• Low symptom burden (mMRC of 0 to 1 OR CAT score <

10) AND

• FEV 1 < 50% (old GOLD 3 to 4) AND/OR high

exacerba-tion rate (2 or more/year)

D = High risk, higher symptom burden

• Higher symptom burden (mMRC of 2 or more OR CAT

Based on severity of airflow obstruction, high symptom burden, and history of exacerbations, this patient is classified as GOLD D, indicating severe COPD with high risk for complications.

mMRC

1 Dyspnea with strenuous exercise

2 Dyspnea when hurrying on the level or walking up a slight hill

3 Walks slower than most people on the level, stops after a mile

or so, or stops after 15 minutes of walking at own pace

4 Stops for breath after walking 100 yards or after a few minutes

Dyspnea walking flight of stairs: Total 0 to 5 (none to severe) Limitation for home activities: Total 0 to 5 (none to severe) Confident leaving home despite lung condition: Total 0 to 5 (very confident to nonconfident)

Sleep quality: Total 0 to 5 (sound sleep to no sleep because of lung condition)

Energy: Total 0 to 5 (full energy to none)

long-term use of ipratropium did not change the rate of decline

of lung function but offered a one-time, small increase in FEV1

Both anticholinergic and adrenergic (beta agonist)

broncho-dilators can improve airflow in patients with COPD, although

some clinicians favor an inhaled anticholinergic medication

(e.g., ipratropium bromide or tiotropium25,26) as first-line

ther-apy (see Figure 25-6) More recent concerns about the possible

adverse cardiovascular effects of anticholinergic therapy in

patients with COPD27,28 have been dismissed by the results of a

multicenter trial (Understanding Potential Long-Term Impacts

on Function with Tiotropium [UPLIFT]), which found a

sig-nificantly lower rate of cardiac adverse events and

cardiovascu-lar death in patients who received tiotropium.27

The GOLD guidelines2 recommend the use of short-acting

beta-adrenergic agents (≤6 hours) for symptomatic

manage-ment of all patients with COPD Also, the use of a long-acting

beta agonist (e.g., salmeterol) or a long-acting anticholinergic

drug (e.g., tiotropium) can lessen the frequency of acute erbations of COPD.26

exac-Other treatment options to optimize lung function include administering corticosteroids and, as a second-line option, methylxanthines Systemic corticosteroids can produce signifi-cant improvements in airflow in a few (6% to 29%) patients with stable COPD.29,30 To assess whether airflow obstruction is completely reversible (i.e., the patient has asthma) and whether

a patient with COPD is responsive to steroids, a brief course of corticosteroids (20 to 40 mg/day of prednisone or equivalent for 5 to 8 days) is sometimes recommended Patients with a significant clinical response often are treated with long-term inhaled corticosteroids or, rarely, with the smallest necessary dose of systemic corticosteroids, recognizing that long-term systemic steroid therapy has risks.31 Also, results of several major clinical trials (e.g., Lung Health Study II, Euroscop, Inhaled Steroids in Obstructive Lung Disease [ISOLDE] study,

Obstructive Lung Disease • CHAPTER 25 521

Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Strategies for improving lung function during acute tions of COPD generally include inhaled bronchodilators (especially beta-2 agonists), antibiotics, and systemic cortico-steroids Because of their rapid onset of action and efficacy, short-acting beta-2 agonists are first-line therapy for patients with COPD exacerbation Inhaled beta-2 agonists are fre-quently administered through a nebulizer, although metered dose inhaler devices may have equal efficacy if administered appropriately.2 A common practice is to administer 2.5 mg of albuterol by nebulizer every 1 to 4 hours as needed Higher doses of albuterol (i.e., 5 mg) do not produce further improve-ment in pulmonary function and may cause cardiac side effects.36 Similarly, continuous nebulization of short-acting beta-2 agonists in patients with COPD exacerbation is not recommended

exacerba-In addition to inhaled bronchodilator therapy, short-term systemic corticosteroids are recommended to reduce inflamma-tion and improve lung function An early randomized, con-trolled trial of intravenous methylprednisolone for patients with acute exacerbations showed accelerated improvement in FEV1 within 72 hours.37 Larger, more recent trials have con-firmed the benefits of systemic corticosteroids in acute exacer-bations and have shown that short-term oral courses (i.e., approximately 2 weeks) are as effective as longer courses (i.e., 8 weeks) with fewer adverse steroid effects.38 For patients with acute exacerbations characterized by purulent phlegm, oral antibiotics (e.g., trimethoprim-sulfamethoxazole, amoxicillin,

or doxycycline) administered for 7 to 10 days have produced

and Copenhagen City Study, but not another trial, Towards a

Revolution in COPD Health [TORCH] study) agree that inhaled

corticosteroids do not change the rate of decline of FEV1 in

patients with COPD, although their use is associated with a

decreased frequency of acute exacerbations.32-34

Studies of combined salmeterol and fluticasone versus

placebo in patients with COPD suggest that adding an inhaled

corticosteroid (fluticasone) to the long-acting beta agonist

(sal-meterol) can improve FEV1 and reduce the frequency of acute

exacerbations of COPD but does not improve survival.32,33 The

finding of a higher rate of pneumonia in inhaled corticosteroid

users is concerning Overall, the GOLD guidelines2 recommend

use of inhaled corticosteroids in patients with FEV1 less than

50% and history of recurrent exacerbations (three episodes in

the last 3 years), whereas the ATS/European Respiratory Society

(ERS) guidelines recommend use of inhaled corticosteroids in

patients with FEV1 less than 50% who have required use of

oral corticosteroids or oral antibiotics at least once within the

last year.3

Treatment with methylxanthines offers little additional

bronchodilation in patients using inhaled bronchodilators and

generally is reserved for patients with debilitating symptoms

from stable COPD despite optimal inhaled bronchodilator

therapy Controlled trials show lessened dyspnea in

methylxan-thine recipients despite a lack of measurable increases in

airflow.35 Side effects of methylxanthines include anxiety,

jitteriness (tremulousness), nausea, cardiac arrhythmias, and

seizures To minimize the chance of toxicity, current

recom-mendations suggest maintaining serum theophylline levels at 8

to 10 mcg/ml

FIGURE 25-6 Initial Pharmacologic Management of COPD (From The Global Strategy for the Diagnosis, Management and Prevention of COPD Global Initiative for Chronic Obstructive Lung Disease [GOLD], 2014 http://www.goldcopd.com Accessed July 29, 2015.)

IV: Very Severe III: Severe

II: Moderate I: Mild

Therapy at Each Stage of COPD

Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation

Add inhaled glucocorticosteroids if repeated exacerbations

Active reduction of risk factor(s); influenza vaccination

Add short-acting bronchodilator (when needed)

term-oxygen if chronic respiratory failure

Considersurgical treatments

or FEV1 < 50%

522 SECTION IV • Review of Cardiopulmonary Disease

peripheral muscles in patients with COPD Studies have shown significant improvements in quadriceps muscle function, exer-cise tolerance (including walk distance), and health status in patients with severe COPD.49

accelerated improvement of peak flow rates compared with

placebo recipients.21,39,40 Because of the risk for being infected

with more virulent bacteria (e.g., Pseudomonas aeruginosa),

patients who have severe COPD and an exacerbation may

benefit from broader spectrum antibiotics, such as

fluoroqui-nolones or aminoglycosides

Finally, intravenous methylxanthines offer little benefit in

the setting of acute exacerbations of COPD and have fallen into

disfavor.41,42 Taken together, important elements of managing

an acute exacerbation of COPD caused by purulent bronchitis

include supplemental oxygen (O2) to maintain arterial

satura-tion at greater than 90%, inhaled bronchodilators, oral

antibiot-ics, and a brief course of systemic corticosteroids.21

For patients with hypercapnia and acute respiratory

acide-mia, the clinician also must decide whether to provide

ventila-tory assistance Although intubation and mechanical ventilation

historically have been the preferred approach, more recent

studies suggest that noninvasive positive pressure ventilation

can be an effective and preferred alternative for patients with

acute exacerbations of COPD, especially with severe

exacerba-tions characterized by pH less than 7.30.43 Specifically, based on

studies that show that noninvasive positive pressure ventilation

can shorten intensive care unit (ICU) stay and avoid the need

for intubation, the American Association for Respiratory Care

consensus conference and guidelines on noninvasive ventilation

from other official societies have endorsed use of noninvasive

ventilation for such patients (unless a contraindication to

non-invasive ventilation is present).44,45 Criteria defining candidacy

for noninvasive ventilation include acute respiratory acidosis

(without frank respiratory arrest), hemodynamic stability,

ability to tolerate the interface needed for noninvasive

ventila-tion, and ability to protect the airway Relative

contraindica-tions include craniofacial trauma or burns, copious secrecontraindica-tions,

or massive obesity.4

Maximizing Functional Status

In symptomatic patients with stable COPD, maximizing their

ability to perform activities of daily living is a priority

Pharma-cologic treatments to maximize functional status include

administration of bronchodilators to enhance lung function as

much as possible and consideration of methylxanthine therapy,

based on data that such drugs can lessen dyspnea and improve

functional status ratings even though airflow is not increased.3

Comprehensive pulmonary rehabilitation is another

impor-tant treatment for patients with COPD that has the goal of

improving patients’ ability to function.46 Pulmonary

rehabilita-tion is a multidisciplinary intervenrehabilita-tion that consists of lower

and upper extremity exercise conditioning, breathing

retrain-ing, education, and psychosocial support Randomized,

con-trolled trials show that although pulmonary rehabilitation does

not improve lung function or survival, pulmonary

rehabilita-tion results in decreased dyspnea perceprehabilita-tion, improved

health-related quality of life, fewer days of hospitalization, and

decreased health care usage.47,48

Finally, transcutaneous neuromuscular electrical stimulation

is a newer therapy that has been successfully used to stimulate

MINI CLINIRecognizing and Managing an Acute Exacerbation of Chronic Obstructive Pulmonary Disease

PROBLEM:  A 70-year-old man with long-standing COPD is admitted to the hospital with an acute exacerbation On physi- cal examination, he is not dehydrated and examination shows diminished breath sounds bilaterally without wheezing Perti- nent laboratory values show a hematocrit of 54% (normal is 40% to 47%) An arterial blood gas (ABG) analysis performed with the patient on room air showed the following:

PaO 2 = 47 mm Hg PCO 2 = 67 mm Hg

pH = 7.30 HCO 3 − = 34 mEq/L How do you describe his current status, what do his current laboratory values suggest about his long-term gas exchange status, and what treatment should be considered?

SOLUTION:  The patient has an acute exacerbation of COPD The acidemia (pH 7.30) on his ABG analysis suggests an acute increase in PCO 2 superimposed on chronic hypercapnia, which

is suggested by the elevated serum bicarbonate (HCO 3 − ), cating renal compensation for chronic respiratory acidosis Although his current hypoxemia may be due to worsened gas exchange accompanying the current flare-up of COPD, his elevated hematocrit, in the absence of dehydration, suggests chronic hypoxemia and secondary erythrocytosis The goal of therapy is to restore his gas exchange to baseline and to avoid invasive or high-risk interventions, while optimizing survival.

indi-To achieve these goals, treatment would consist of aggressive use of bronchodilators, intravenous corticosteroids, supple-mental O2, and antibiotics (if there is evidence of acute lung infection, either bronchitis or pneumonia) In view of the patient’s acute chronic respiratory acidemia, ventilatory support should be implemented As indicated by several randomized, controlled trials, noninvasive positive pressure ventilation is an effective alternative to intubation

Preventing Progression of Chronic  Obstructive Pulmonary Disease and  Enhancing Survival

Cigarette smoking is widely recognized as the major risk factor for accelerating airflow obstruction in smokers who are “sus-ceptible.” For these individuals, smoking cessation can generally slow the rate of decline of FEV1 and restore the rate of lung decline to that seen in healthy, age-matched nonsmokers.Follow-up data from the Lung Health Study9 confirm that a comprehensive smoking cessation program (including instruc-tion, group counseling, and nicotine replacement therapy) can

Obstructive Lung Disease • CHAPTER 25 523

achieve sustained smoking cessation in 22% of participants and

that the rate of annual FEV1 decline in these sustained

non-smokers was significantly less than it was for continuing

smokers, even over 11 years of follow-up.10 Participation in

aggressive smoking cessation can enhance survival rates in

patients with COPD.10

Critical elements in achieving successful smoking cessation

include identifying “teachable moments” (i.e., during episodes

of illness in which smoking can be identified as a contributing

factor50), identifying the role of smoking in adverse health

out-comes, negotiating a “quit date,” and providing frequent

follow-up reminders from health care providers.51 A helpful

strategy during counseling is to use the five As of smoking

cessation2:

Ask if they are smoking

Advise to quit

Assess willingness to quit

Assist by providing a plan

Arrange a follow-up

In this regard, the RT, who sees the patient frequently, has a

special responsibility to provide frequent, constructive

remind-ers about the advisability of smoking cessation.52

Among available treatments for COPD, supplemental

oxygen is important because, similar to smoking cessation and

lung volume reduction surgery in selected individuals (see later

discussion), it can prolong survival.53-56Box 25-2 reviews the

indications for supplemental O2, and Figure 25-7 shows the

results of the American Nocturnal Oxygen Therapy Trial53 and

the British Medical Research Council trial of domiciliary O2

(1980 to 1981).54,55 Survival was improved when eligible patients

used supplemental O2 for as close to 24 hours as possible;

FIGURE 25-7 Cumulative percent survival of patients in the Nocturnal Oxygen Therapy Trial (NOTT) and Medical Research Council (MRC) controlled trials of long-term domiciliary O2 therapy

for men older than 70 years MRC control subjects (red line)

received no O2 NOTT subjects (purple line) received O2 for 12 hours in the 24-hour day, including the sleeping hours MRC O2

subjects (blue line) received O2 for 15 hours in the 24-hour day,

including the sleeping hours, and continuous O2 therapy (COT)

subjects (green line) received O2 for 24 hours in the 24-hour day

(on average, 19 hours) (Modified from Flenley DC: Long-term oxygen therapy Chest 87:99–193, 1985.)

100 90 80 70 60 50 40 30 20 10

a key role in ensuring compliance with this recommendation and optimizing O2 therapy.57,58

Finally, preventive strategies such as annual influenza and pneumococcal vaccinations are recommended for all patients with chronic debilitating conditions such as COPD.59 Specific indications for pneumococcal vaccination are presented in

also include a 13-valent pneumococcal vaccine in addition to the existing 23-valent pneumococcal vaccine

Other measures to prevent exacerbations of COPD include use of long-acting anticholinergic agents (e.g., tiotro-pium, aclidinium, umeclidinium), inhaled corticosteroids, especially in combination with long-acting beta agonists, macrolide antibiotics (e.g., erythromycin and azithromycin),60

phosphodiesterase-4 inhibition with roflumilast,61 and dants such as oral N-acetylcysteine.62

antioxi-524 SECTION IV • Review of Cardiopulmonary Disease

Additional Therapies

Additional therapies for individuals with end-stage COPD include lung transplantation63 and lung volume reduction surgery (LVRS),64-66 in which small portions of emphysematous lung are removed to reduce hyperinflation and improve lung mechanics of the remaining tissue COPD is the most common current indication for lung transplantation Lung transplanta-tion is a consideration for patients with severe airflow obstruc-tion (i.e., FEV1 < 20% predicted and a Body-mass index, Obstruction, Dyspnea, and Exercise [BODE] index > 7 who are younger than 70 years old, and who are psychologically suitable and motivated) Double lung transplantation is preferred; nevertheless, because the supply of donor lungs to transplant

is less than the number of patients needing lung tion, single-lung transplantation is also frequently performed Although lung transplantation may be associated with signifi-cantly improved quality of life and functional status, major risks include rejection (manifested as bronchiolitis obliterans and progressive, debilitating airflow obstruction), infection with unusual opportunistic organisms, and death from these and other complications The 5-year actuarial survival rate after lung transplantation in patients with COPD is approximately

LVRS has regained popularity after initial experiences were reported in 1957.64 Results of randomized controlled trials of LVRS, including the large National Emphysema Treatment

FIGURE 25-8 Adult recipient Kaplan-Meier survival by diagnosis (transplants: January 1990 to June 2011) The overall survival rate of patients with alpha-1 antitrypsin (AAT) deficiency is significantly higher than the survival rate of patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD), which includes idiopathic pulmonary fibrosis (IPF) Similarly, the overall survival rate of

patients with COPD is higher than the survival rate of patients with idiopathic pulmonary fibrosis AATD, alpha-1 antitrypsin deficiency associated COPD; COPD, non-AATD associated COPD; CF, cystic fibrosis; IPAH, idiopathic pulmonary arterial hypertension (From Yusen

RD, Christie JD, Edwards LB, et al: 30th official adult lung and heart-lung transplant report, 2013 in the Registry of the International Society for Heart and Lung Transplantation http://www.ishlt.org Accessed September 17, 2014.)

Years

Median survival (years):

AATD = 6.3

CF = 7.8 COPD = 5.4 ILD = 4.5 IPAH = 5.2 Sarcoidosis = 5.4

Obstructive Lung Disease • CHAPTER 25 525

Incidence

Asthma is a chronic illness that has been increasing in lence in the United States since 1980 The number of people with asthma in the United States grew from 20 million in 2001

preva-to 25 million in 2010 (8% of the U.S population) According

to data from the National Health Interview Survey performed

by the Centers for Disease Control and Prevention in 2012, 18.7 million adults and 6.8 million children (9.3% of American chil-dren) reported having asthma Asthma accounted for 1.8 million emergency room visits, or 25% of all emergency room visits Asthma also accounted for 14.2 million outpatient visits, 439,000 hospitalizations, and, approximately 3400 deaths in

2010 Asthma costs in the United States grew from mately $53 billion in 2002 to about $56 billion in 2007.76,77

approxi-Etiology and Pathogenesis

In the genetically susceptible host, allergens, respiratory tions, certain occupational and environmental exposures, and many unknown hosts or environmental stimuli can produce the full spectrum of asthma, with persistent airway inflammation, bronchial hyperreactivity, and subsequent airflow obstruction When inflammation and bronchial hyperreactivity are present, asthma can be triggered by additional factors, including exer-cise; inhalation of cold, dry air; hyperventilation; cigarette smoke; physical or emotional stress; inhalation of irritants; and pharmacologic agents, such as methacholine and histamine.78-80

infec-When a patient with asthma inhales an allergen to which he

or she is sensitized, the antigen cross-links to specific globulin E (IgE) molecules attached to the surface of mast cells

immuno-in the bronchial mucosa and submucosa The mast cells ulate rapidly (within 30 minutes), releasing multiple mediators

degran-including leukotrienes (previously known as slow-reacting stance of anaphylaxis [SRS-A]), histamine, prostaglandins,

sub-platelet-activating factor, and other mediators These mediators lead to smooth muscle contraction, vascular congestion, and leakage resulting in airflow obstruction, which can be assessed clinically as a decline in FEV1 or peak expiratory flow rate (PEFR)

response, which is an immediate hypersensitivity reaction that

usually subsides in approximately 30 to 60 minutes In mately 50% of asthmatic patients, however, airflow obstruction recurs in 3 to 8 hours.80 This late asthmatic response is usually

approxi-more severe and lasts longer than the early asthmatic response (see Figure 25-10).81 The late asthmatic response is character-ized by increasing influx and activation of inflammatory cells such as mast cells, eosinophils, and lymphocytes.81,82

of asthma are episodic wheezing, shortness of breath, chest

Trial, indicate that in selected subsets of patients with COPD

(i.e., patients with heterogeneous emphysema that is upper

lobe–predominant and who have low exercise capacity after

pulmonary rehabilitation), LVRS can prolong survival, improve

quality of life, and increase exercise capacity.65,66 LVRS should

not be considered in individuals with very severe COPD (i.e.,

characterized by FEV1<20% predicted with either a

homoge-neous pattern of emphysema or a diffusing capacity <20%

pre-dicted), because the mortality rate of LVRS is higher in such

individuals than in medically treated patients.67

Given the positive results associated with LVRS in selected

patients with COPD, nonsurgical bronchoscopic techniques

have been developed in an attempt to reduce costs and expand

treatment options for patients with high operative risk.68 With

the use of the bronchoscope, deployment of unidirectional

endobronchial valves or coils into the airways results in collapse

of the targeted lung parenchyma Other techniques that have

been studied include application of biodegradable gel to induce

lung collapse or application of bronchial stents to create

fenes-trations and allow gas escape from hyperinflated areas of the

lung None of the aforementioned devices is currently approved

by the U.S Food and Drug Administration (FDA) for treatment

of emphysema in the United States.69

Finally, for patients with AAT deficiency and established

COPD, so-called intravenous augmentation with a purified

preparation of AAT from human blood donors is

recom-mended.14 The best available evidence70,71 suggests that for

indi-viduals with severe AAT deficiency and moderate degrees of

airflow obstruction (i.e., FEV1 35% to 60% predicted), weekly

augmentation therapy may be associated with a slower rate of

decline of lung function, a slower rate of loss of lung density on

chest CT, and improved survival Difficulties with intravenous

augmentation therapy include the substantial expense

(approx-imately $100,000 per year); the inconvenience of frequent

intra-venous infusions for life; and the infusion itself, which poses

a theoretical risk for transmitting a blood-borne infection

Despite these drawbacks, the facts that augmentation therapy

can slow the rate of FEV1 decline, can possibly slow the rate of

CT lung density loss, and is currently the only specific therapy

for AAT deficiency have led to its endorsement in official

guide-lines from the ATS, the ERS, and the Canadian Thoracic

Society.14,72

ASTHMA

Definition

Asthma is a clinical syndrome characterized by airway obstruc

-tion , which is partially or completely reversible either

spontane-ously or with treatment; airway inflammation ; and airway

hyperresponsiveness (AHR) to various stimuli.73-75 Past

defini-tions of asthma emphasized AHR and reversible obstruction;

however, newer and more accurate definitions of asthma focus

on asthma as a primary inflammatory disease of the airways,

with clinical manifestations of increased airway hyperreactivity

and airflow obstruction caused by the inflammation

526 SECTION IV • Review of Cardiopulmonary Disease

tightness, and cough The absence of wheezing does not exclude asthma, and sometimes a cough can be the only manifestation (cough-variant asthma) Not all wheezing is due to asthma, however Obstruction of the upper airway by tumors, laryngo-spasm, aspirated foreign objects, tracheal stenosis, or functional laryngospasm (vocal cord dysfunction) can mimic the wheezing

of asthma

Confirmation of the diagnosis of asthma requires stration of reversible airflow obstruction Pulmonary function tests may be normal in asymptomatic patients with asthma, but more commonly they reveal some degree of airway obstruction manifested by decreased FEV1 and FEV1/FVC ratio By conven-tion, improvement in the FEV1 by at least 12% and 200 ml after administration of a bronchodilator is considered evidence of reversibility Spontaneous variation in self-recorded PEFR by 15% or more also can provide evidence of reversibility of airway obstruction Elevated values of exhaled nitric oxide also can be used to support the diagnosis of asthma when eosinophilic inflammation is present.83

demon-Patients with asthma evaluated in a symptom-free period may have a normal chest x-ray examination and normal pul-monary function tests Under these circumstances, provocative testing can be used to induce airway obstruction Broncho-provocation is a well-established method to detect and quantify

FIGURE 25-9 Inflammation in asthma Cross sections of an airway from a healthy individual and a patient with asthma are shown Multiple cells and multiple mediators are involved in asthma Inflammatory cells, such as mast cells, eosinophils, lymphocytes, and

macrophages, release a variety of chemical mediators, such as histamine, prostaglandins, and leukotrienes These mediators result in increased wall thickness, airway smooth muscle hypertrophy and constriction, epithelial sloughing, mucus hypersecretion, mucosal edema,

and stimulation of nerve endings Top, Daily variability in peak airflow measurements The normal increase in smooth muscle tone in the early morning, which causes airway narrowing in healthy individuals, is more exaggerated in asthmatics Bottom, Dose-response curves to

methacholine (Modified from Woolcock AJ: Asthma In: Murray JF, Nadel JA, editors: Textbook of respiratory medicine, Philadelphia, 1994, Saunders.)

Wall thickness Smooth muscle bulk Contractility of S.M.

Local elastic recoil Epithelial factors Sensory nerves

Obstructive Lung Disease • CHAPTER 25 527

MINI CLINI

Recognizing Severity of Asthma

PROBLEM:  A 20-year-old woman with a diagnosis of asthma is seen in the outpatient clinic for increased dyspnea with exertion requiring daily use of short-acting bronchodilators The patient complains of difficulty attending classes in college and wakes up a couple of times a week feeling short of breath She describes two visits to the emergency department in the last 12 months because of asthma, requiring use of corticosteroids for a short period Physical examination shows normal breath sounds bilaterally without wheez- ing Spirometry shows FEV 1 of 78% percent predicted with FEV 1 /FVC of 75% How do you describe the severity of her asthma?

SOLUTION:  Classification of asthma severity is based on a combination of symptoms, medication requirements, and lung function Although this patient has a spirometry consistent with mild airflow obstruction, her asthma is classified as moderately persistent because

of the presence of daily symptoms, daily use of short-acting bronchodilators, frequent nighttime awakenings, limitation with normal activities, and history of exacerbations (see the following table).

Components of Severity Classification of Asthma Severity (Youths ≤12 Years of Age and Adults)

Persistent Intermittent Mild Moderate Severe

agonist use for symptom control (not prevention

of exercise-induced bronchospasm)

≤2 days/wk >2 days/wk but not

>1 time/day Daily Several times per day

Interference with normal activity

None Minor limitation Some limitation Extremely limited Lung function Normal FEV1 between

exacerbations FEV1 > 80% predicted FEV1/FVC normal

FEV1 ≥ 80% predicted FEV1/FVC normal

FEV1 ≥ 60% but < 80%

predicted FEV1/FVC reduced > 5%

FEV1 ≥ 60% predicted FEV1/FVC reduced > 5%

0-1/yr ≥ 2/yr Consider severity and interval since last exacerbation Frequency and severity may fluctuate over time for patients in any severity category.

Risk Exacerbations requiring

oral systemic corticosteroids

Relative annual risk for exacerbations may be related to FEV1.

AHR Pharmacologic agents, including acetylcholine,

metha-choline, histamine, cysteinyl leukotrienes, and prostaglandins,

and physical stimuli such as exercise and isocapnic

hyperventi-lation with cold, dry air have been used to detect, quantify, and

characterize nonspecific AHR in asthma

The most commonly used stimulus for bronchoprovocation

is methacholine The generally accepted criterion for

hyperre-sponsiveness is a decrease in FEV1 by 20% or more below the

baseline value after inhalation of methacholine

The methacholine provocation test has few false-negative

results (<5%), but a false-positive result may be found in 7% to

8% of the average population and patients with other

obstruc-tive lung diseases Elevated IgE levels and eosinophilia may be

present in patients with asthma, but their presence is not

spe-cific and their absence does not exclude asthma, making them

less useful for the diagnosis.73-75 Although ABG analysis is not

helpful or necessary in diagnosing asthma, it can be helpful in

assessing the severity of an acute asthma attack

A patient experiencing an acute asthma attack usually has a

low PaCO as a result of hyperventilation A normal PaCO in

such a situation is concerning because it indicates a severe attack and impending respiratory failure

Management

The goal of asthma management is to maintain a high quality

of life for the patient, uninterrupted by asthma symptoms, side effects from medications, or limitations on the job or during exercise This goal can be accomplished by preventing acute exacerbations, with their potential mortality and morbidity, or

by returning the patient to a stable baseline when exacerbations occur Asthma management relies on the following four impor-tant components recommended by the National Asthma Edu-cation Program (NAEP) expert panel73:

1 Objective measurements and monitoring of lung function

2 Pharmacologic therapy

3 Environmental control

4 Patient education

recom-mended for long-term management of asthma This approach provides a framework for adjusting the dose of medication

528 SECTION IV • Review of Cardiopulmonary Disease

ity of airflow obstruction It is recommended that spirometry

be performed as part of the initial assessment of all patients being evaluated for asthma and periodically thereafter as needed

Either spirometry or PEFR measurement can be used to assess response to therapy in the outpatient setting, emergency department, or hospital NAEP guidelines also recommend that home PEFR measurement be used for patients with moderate

to severe asthma

When patients learn how to take PEFR measurements at home, the clinician is better able to recommend effective treat-ment Daily monitoring of PEFR helps detect early stages of airway obstruction All PEFR measurements are compared with the patient’s personal best value, which can be established during a 2- to 3-week asymptomatic period when the patient is being treated optimally.73-75

based on the severity of asthma in any patient at a particular

time This approach also takes into consideration the fact that

asthma is a chronic and dynamic disease, which needs optimum

control Control of asthma is defined as minimal to no chronic

diurnal or nocturnal symptoms, infrequent exacerbations,

minimal to no need for beta-2 agonists, no limitation to exercise

activity, PEFR or FEV1 greater than 80% predicted with less

than 20% diurnal variation, and minimal to no adverse effects

of medication.73-75

Objective Measurement  

and Monitoring

Objective measurement of lung function is particularly

impor-tant in asthma because subjective measures, such as patient

reports of the degree of dyspnea and physical examination

findings, often do not correlate with the variability and

sever-TABLE 25-2

Stepwise Approach to Long-Term Management of Asthma Based on Severity

Severity* Clinical Features Before Treatment † PEFR or FEV 1 Long-Term Preventive Medications Quick Relief Medications Step 4

Severe

persistent Continuous symptoms ≤60% predicted

Inhaled corticosteroids ≥800-2000 mcg/day Inhaled beta-2 agonist as needed for symptoms

Red zone Frequent exacerbations >30% variability Long-acting bronchodilator ‡

Yellow zone Exacerbations affect activity and

sleep >30% variability Long-acting bronchodilator, ‡

especially for nocturnal symptoms Nocturnal symptoms more than

once per week Daily use of short-acting beta-2

agonist Step 2

Mild persistent Symptoms at least once per

week but <1 time per day ≥80% predicted Inhaled corticosteroid, 200-500 mg/day Inhaled beta-2 agonist as needed for symptoms, not

to exceed 3-4 times per day

Yellow zone Exacerbations may affect activity

or sleep 20%-30% variability Long-acting bronchodilator

‡ for nocturnal symptoms

Nocturnal symptoms more than

twice per month Step 1

Intermittent Intermittent symptoms less than

once per week ≥80% predicted None needed Inhaled beta-2 agonist

needed for symptoms but less than once per week

Green zone Nocturnal symptoms not more

than twice per month <20% variability Inhaled beta-2 agonist or

cromolyn before exercise or exposure to allergen Asymptomatic with normal lung

function between exacerbations

Modified from: Global Initiative for Asthma: Asthma management and prevention: a practical guide for public health officials and health care professionals, NIH publication no 96-3659A, Bethesda, MD, 1995, National Institutes of Health, National Heart, Lung, and Blood Institute, and World Health Organization.

*Step-down: Review treatment every 3 to 6 months If control is sustained for at least 3 months, consider a gradual stepwise reduction in treatment Step-up:

If control is not achieved, consider step-up, but first review patient medication technique, compliance, and environmental control.

† The presence of one of the features of severity is sufficient to place a patient in that category.

‡ Long-acting beta-2 agonist or sustained-release theophylline.

Obstructive Lung Disease • CHAPTER 25 529

effects Spacer devices can be used to improve delivery of inhaled medication, but training and coordination are still required for patients using metered dose inhalers Table 25-3lists commonly used medications in the treatment of asthma

Corticosteroids

Corticosteroids are the most effective medication currently available for the treatment of asthma Although their mode of action is still unclear, corticosteroids probably act on various components of the inflammatory response in asthma.84 Inhaled corticosteroids are effective locally, and regular use suppresses inflammation in the airways, decreases bronchial hyperreactiv-ity and airflow obstruction, and reduces the symptoms of and mortality from asthma Long-term, high-dose inhaled cortico-steroids have far fewer side effects than oral corticosteroids Side effects such as oropharyngeal candidiasis and dysphonia are controllable with spacer use and by rinsing the mouth after each treatment Patients should be informed of other side effects of chronic inhaled corticosteroid use such as skin bruising and increased risks for glaucoma and cataracts

Oral corticosteroids are effective for treating asthma, but the potential for devastating side effects during long-term use restricts their use to patients not responding to other forms of asthma therapy Short-term, high-dose (0.5 to 1 mg/kg/day) oral corticosteroid therapy during exacerbation reduces the severity and duration, decreases the need for emergency depart-ment visits and hospitalization, and reduces mortality.84

Leukotriene Inhibitors

Leukotrienes are mediators of inflammation and striction and are thought to play a role in the pathogenesis of asthma Three leukotriene antagonists are currently available for the treatment of asthma Montelukast (Singulair; Merck, Whitehouse Station, NJ) and zafirlukast (Accolate; Astra Zeneca, London, UK) are leukotriene receptor antagonists, and zileuton (Zyflo; Abbott Laboratories, Chicago, IL) is a leukotriene syn-thesis inhibitor These agents all are modestly effective for main-tenance of mild to moderate asthma, but their exact role in asthma therapy remains to be determined Inhaled steroids remain the preferred antiinflammatory drugs for treating asthma.84,85

bronchocon-Beta-2–Adrenergic Agonists

Inhaled beta-2–adrenergic agents are the most rapid and tive bronchodilators for treating asthma They are the drugs of choice for all types of acute bronchospasm, and they provide protection from all bronchoconstrictor challenges when given prophylactically However, they do not prevent the late asth-matic response Beta-2 agonists are the drugs of choice for exercise-induced asthma They exert their action by attaching

effec-to beta recepeffec-tors on the cell effec-to produce smooth muscle ation and by blocking mediator release from mast cells.The effectiveness of beta-2 agonists as bronchodilators is not disputed, and they are the drug of choice for acute emergency management of asthma However, there is concern that they may worsen asthma control if used regularly and that excessive

relax-To help patients understand home PEFR monitoring, a zonal

system corresponding to the traffic light system may be helpful

(see Table 25-2) A PEFR measurement of 80% to 100% of the

personal best is considered to be in the green zone No asthma

symptoms are present, and maintenance medications can be

continued or tapered A PEFR in the 60% to 80% range of the

personal best is in the yellow zone and may indicate an acute

exacerbation and requires a temporary step-up in treatment A

PEFR less than 60% of the personal best is in the red zone and

signals a medical alert, requiring immediate medical attention

if the patient does not return to the yellow zone or green zone

with bronchodilator use.75

Pharmacotherapy

Pharmacotherapy for asthma reflects the basic understanding

that asthma is a chronic inflammatory airway disease that

requires long-term antiinflammatory therapy for adequate

control.73-82 Antiinflammatory agents such as corticosteroids

suppress the primary disease process and its resultant airway

hyperreactivity Bronchodilators, such as beta-2–adrenergic

agonists, anticholinergics, and theophylline, relieve asthma

symptoms Because asthma is a disease of the airways,

inhala-tion therapy is preferred to oral or other systemic therapy

Inhaled therapy using metered dose inhalers or dry powder

inhalers allows high concentration of the medication to be

delivered directly to the airways, resulting in fewer systemic side

MINI CLINI

Diagnosis of Wheezing

PROBLEM:  You are asked to see a patient with a history of

wheezing The patient notes that the wheezing has been

con-tinuous, has been present for several months, and has been

unresponsive to bronchodilator medications, including

sys-temic corticosteroids and various inhaled bronchodilators.

SOLUTION:  The patient has either refractory asthma or a

condition mimicking asthma The aphorism “all that wheezes

is not asthma” applies here, and the clinician should suspect

alternative diagnoses Features that are atypical for asthma in

this patient are the continuous nature of the wheezing and its

complete refractoriness to medication With this in mind,

con-sideration of other “wheezy” disorders should include

abnor-malities of the upper airway Specifically, tracheal stenosis or

fixed upper airway obstruction (e.g., caused by tracheal tumors)

could account for the patient’s symptoms Another condition

that mimics asthma is vocal cord dysfunction

Characteristi-cally, vocal cord dysfunction causes stridor with convergence

of the vocal cords on inspiration (a paradoxical response)

However, vocal cord dysfunction also can cause expiratory

wheezing, with closure of the vocal cords on expiration Further

assessment of this patient might include a flow-volume loop or

a flexible bronchoscopic examination of the upper airway,

observing both the vocal cords and the trachea to the level of

the main stem bronchi.

530 SECTION IV • Review of Cardiopulmonary Disease

TABLE 25-3

Medications Commonly Used in the Treatment of Asthma or Chronic Obstructive

Pulmonary Disease

Medication Trade Names Available Preparations Usual Dosage Comment

Inhaled Corticosteroids (Single Medication)

Beclomethasone Beclovent,

QVAR MDI 42 mcg/puff, 200 puffs/canister 2 puffs tid-qid, maximum 20 puffs/day Flunisolide Aerobid MDI 250 mg/puff, 100 puffs/canister 2 puffs bid, maximum 8

puffs/day Fluticasone Flovent MDI 44, 110, 220 mcg/puff 88-880 mcg/day

Mometasone Asmanex DPI 220 mcg/spray 1-2 sprays daily-bid,

maximum 4 puffs/day Budesonide Pulmicort DPI 90, 180 mcg/puff 360-720 mcg/day

Inhaled Corticosteroids (Combined Medication)

Fluticasone and

salmeterol Advair DPI 100 mcg fluticasone/50 mcg salmeterol/puff, 250 mcg/50 mcg,

500 mcg/50 mcg/puff MDI HFA 45 mcg/21 mcg/puff,

115 mcg/21 mcg/puff, and

230 mcg/21 mcg/puff

400-2000 mcg/day (corticosteroid dose)

Budesonide and

formoterol Symbicort 160 mcg budesonide/4.5 mcg formoterol/puff and

80 mcg/4.5 mcg/puff

160-640 mcg/day (corticosteroid dose) Fluticasone and

vilanterol Breo Ellipta DPI 100 mcg fluticasone/25 mcg vilanterol/puff 100 mcg/day (corticosteroid dose) Only approved for patients with COPD Systemic Corticosteroids

Prednisone Many Tablets 1, 5, 20, 50 mg 5-50 mg/day

Methylprednisolone Medrol Tablets 2, 4, 8, 16, 24, 32 mg 4-48 mg/day

Solu-Medrol IV 40, 125, 500, 1000 mg 1-2 mg/kg q4-6h Hydrocortisone Solu-Cortef IV 100, 250, 500, 1000 mg 4 mg/kg q4-6h

Beta-2 Agonists

Albuterol Proventil MDI 90 mcg/puff, 200 puffs/canister 2-4 puffs q4-6h,

maximum 20 puffs/day Ventolin Solution for nebulizer 0.083% and

Tablets 2, 4 mg 2-4 mg q6-8h Volmax Sustained-release tablets 4, 8 mg 4-8 mg q12h Metaproterenol Alupent MDI 650 mcg/puff, 200 puffs/

canister 2-3 puffs q3-4h, maximum 12 puffs/day Metaprel Solution 0.5% 2.5-10 mg q4-6h

Tablets 10, 20 mg 10 mg q6-8h Pirbuterol Maxair MDI 200 mcg/puff, 300 puffs/

canister 1-2 puffs q4-6h, maximum 12 puffs/day Terbutaline Breathaire MDI 200 mcg/puff, 300 puffs/

canister 1-2 puffs q4-6h Bricanyl Tablets 2.5, 5 mg 2.5-5 mg tid, maximum

15 mg/day Solution 1 mg/ml 0.25 mg subcutaneously

q15-30min Long-Acting Beta Agonists

Salmeterol Serevent MDI 50 mcg/puff 2 puffs q12h

Formoterol Foradil DPI 12 mcg/capsule 1 capsule inhaled q12h

Indacaterol Arcapta DPI 75 mcg/capsule 75 mcg/day Not indicated in patients with

asthma.

Arformoterol Brovana Solution 15 mcg/ml 15 mcg inhaled bid

Anticholinergics (Single Medication)

Ipratropium

bromide Atrovent MDI 18 mcg/puff, 200 puffs/canisterSolution for nebulizer 0.02% 2-4 puffs q6h

0.5 mg/2.5 ml vial, 0.5 mg qid Tiotropium Spiriva DPI 18 mcg/capsule 1 capsule inhaled/day

Aclinidium Tudorza DPI 400 mcg/actuation 800 mcg/day M2/M3 muscarinic antagonist

Only approved for COPD.

Obstructive Lung Disease • CHAPTER 25 531

NAEP guidelines recommend that inhaled beta-2 agonists be used as needed If a patient needs more than 3 or 4 puffs per day of a beta-2 agonist, additional antiinflammatory therapy should be considered.84

Longer acting (12 to 24 hours) beta-2 agonists, such as meterol and formoterol, are available in the United States Their mechanism of action is different from that of the shorter acting beta-2 agonists discussed earlier Long-acting beta-2 agonists have use in treating nocturnal asthma but again, should not be used alone in managing asthma.73-75,86-88

sal-Inhaled corticosteroids remain the first choice of therapy in asthma

use may increase the risk for death from asthma, which makes

the role of beta-2 agonists alone in long-term maintenance

therapy questionable It is clear that excessive beta-2 agonist use

by asthmatics indicates an increased risk for death from asthma

and indicates the need for more effective antiinflammatory

therapy Furthermore, because use of long-acting

beta-2-agno-sists in asthmatics has been associated with increased mortality,

such agents should not be used in asthmatics but rather in

combination with an anti-inflammatory drug such as an

inhaled corticosteroid medication Treatment with

conven-tional doses of the short-acting beta-2 agonists available in the

United States is felt to be safe for asthmatic patients.82,84,86 The

Medication Trade Names Available Preparations Usual Dosage Comment

Anticholinergics (Combined Medication)

Umeclidinium and

vilanterol Anoro Ellipta DPI 62.5 mcg umeclidinium/25 mcg vilanterol/puff 62.5 mcg of umeclidinium/day Umeclidinium is a muscarinic antagonist Vilanterol is a

long-acting bronchodilator Not approved for patients with asthma.

Methylxanthines

maintenance Tablets or capsules 0.5-0.9 mg/kg/hr

Zafirlukast Accolate Tablets 20 mg 20 mg bid

Zileuton Zyflo Tablets 600 mg 600 mg qid

Montelukast Singulair Tablets 10 mg 10 mg daily

Other

Roflumilast Daliresp Tablets 500 mcg 500 mcg/day PDE-4 inhibitor Primary use

prevention of COPD exacerbations, not indicated for acute bronchospasm or asthma.

Azithromycin Zithromax Tablets 250 mg, 500 mg 250 mg/day Macrolide antibiotic associated

with reduction in number of COPD exacerbations *

N-Acetylcysteine

(NAC) Mucomyst Tablets 300 mg, 600 mg 1200 mg/day High dose NAC is associated with decrease in exacerbation

frequency in patients COPD † Omalizumab Xolair 150 mg / 5 mL 150-375 mg

subcutaneously every month

Anti-IgE therapy only approved for patients with moderate to severe asthma.

532 SECTION IV • Review of Cardiopulmonary Disease

mended that omalizumab should be considered as adjunctive therapy for patients with severe persistent asthma.73

Emergency Department and   Hospital Management

Emergency management of acute asthma should include early and frequent administration of aerosolized beta-2 agonists and therapy with systemic corticosteroids Frequent assessment for response with PEFR should be performed The NAEP guide-lines recommend that only selective beta-2 agonists (i.e., alb-uterol, levalbuterol, pirbuterol) should be used in high doses to avoid cardiotoxicity.73

Hospital and ICU care for patients with asthma should be aggressive The goal is to decrease mortality and morbidity and to return the patient to preadmission stability and function

as quickly as possible Management includes O2 tion, periodic administration of high doses of aerosolized beta-2 agonists (limited only by tachycardia or tremor), high-dose parenteral corticosteroids (>0.5 to 1 mg/kg/day), and anti-biotics if there is evidence of infection Sedatives and hypnotics should be avoided Symptoms, PEFR, and ABGs should be monitored

supplementa-Patients with severe asthma and respiratory failure emia, hypercapnia, increased work of breathing) need ventila-tory support and present special challenges Mortality rates for these patients can reach 22%, and complications are common, especially barotrauma These complications can be minimized

(hypox-by limiting peak inspiratory pressure to less than 50 cm H2O and by the use of small tidal volumes, allowing “permissive hypercapnia” if necessary When asthma control is achieved, hospital discharge criteria include not needing supplemental

O2; having a PaO2 greater than 60 mm Hg and a stable PEFR or FEV1, with values close to the patient’s best or greater than 70%

of predicted; feeling that asthma symptoms are returning to preadmission levels and are not occurring at night; and 12- to 24-hour stability on discharge medications.73-75

Methylxanthines

The role of theophylline and similar drugs in the treatment of

acute asthma is controversial The NAEP expert panel did not

recommend using theophylline routinely in the emergency

treatment of asthma but did recommend its use orally or

intra-venously for patients admitted to the hospital for an acute

asthma attack Sustained-release theophylline drugs added to

long-term asthma management therapy may be helpful in

con-trolling nocturnal asthma symptoms because they maintain

therapeutic plasma concentrations overnight They also are

helpful in soothing the symptoms of patients with labile asthma

However, the efficacy of theophylline is limited by its side effects

of nausea, vomiting, headache, insomnia, seizures, and cardiac

arrhythmias Toxicity increases with blood levels greater than

15 mcg/ml, but levels of 8 to 10 mcg/ml are adequate for

long-term therapy and are associated with fewer side effects

Several factors affect the plasma levels of theophylline by

increasing or decreasing hepatic metabolism of the drug

Con-ditions that tend to increase plasma concentrations include

acute viral infections, cardiac failure, hepatic disease, and

con-comitant use of certain medications such as erythromycin or

cimetidine In these cases, the maintenance dose should be

halved and the theophylline blood levels should be monitored

Conditions that tend to decrease plasma levels of theophylline

include cigarette smoking and use of medications that increase

hepatic clearance, such as phenobarbital.73-75

Anticholinergics

Inhaled anticholinergic agents, such as ipratropium bromide,

are effective dilators of airway smooth muscles Ipratropium

produces bronchodilation by reduction of intrinsic vagal tone

and blocking vagal reflex bronchospasm However, ipratropium

does not stabilize mast cells or prevent mediator release and is

a less potent bronchodilator than beta-2 agonists Ipratropium

has few side effects, is safe because it is poorly absorbed, adds a

bronchodilator effect to beta-2 agonists, and is useful for

treat-ing cough-variant asthma Ipratropium also can be used in

treating acute asthma when first-line bronchodilators are

inef-fective The long-acting anticholinergic agent tiotropium has

been shown to enhance asthma control (e.g., improved peak

expiratory flow, increased FEV1, and improved symptoms)

when added to an inhaled corticosteroid compared with

dou-bling the inhaled steroid dose.89

Anti–Immunoglobulin E Therapy

IgE plays a key role in the pathogenesis of asthma, and many

asthmatic patients have elevated levels of IgE.90 Corticosteroids

do not inhibit synthesis of IgE by activated lymphocytes

Omal-izumab, an antibody that binds IgE and blocks its biologic

effects, has been approved by the FDA for patients with a history

of allergy and with moderate to severe asthma that is poorly

controlled with inhaled corticosteroids.91 Studies have shown

that treatment with omalizumab results in a reduction in the

dose of inhaled glucocorticoids required to control symptoms

and a reduction in the number of asthma exacerbation

epi-sodes.92 For this reason, the NAEP asthma guidelines

recom-

RULE OF THUMB

In a patient presenting with an acute asthma attack, PaCO2 is usually low because of hyperventilation A normal PaCO2 in this situation indicates a severe attack and impending respiratory failure.

Bronchial Thermoplasty

Bronchial thermoplasty is an approved addition to treatment options for adults whose asthma remains uncontrolled despite use of inhaled steroids and long-acting beta agonists.93 Bron-chial thermoplasty is a procedure in which a probe is intro-duced into the central airways through a bronchoscope and heat

is applied (through radiofrequency waves) to airways of 3 to

10 mm diameter with the goal to reduce the airway smooth muscle mass, reducing the ability of the airways to constrict Studies have shown that bronchial thermoplasty improves asthma-specific quality of life and reduces the number of severe