Chapter 28: Respiratory Problems

Respiratory infections and chronic lung diseases are among the most common reasons why patients consult primary care physicians. Most respiratory problems encountered by primary care physicians are acute, with the majority comprising respiratory infections, exacerbations of asthma, chronic obstructive pulmonary diseases (COPDs), and pulmonary embolism (PE).

COMMON COLDS/UPPER RESPIRATORY TRACT INFECTIONS

General Considerations

Although colds are mild, self-limiting, and short in duration, they are a leading cause of sickness in industrial and school absenteeism. Each year, colds account for 170 million days of restricted activity, 23 million days of school absence, and 18 million days of work absence.

Most colds are caused by viruses. Rhinoviruses are the most common type of virus and are found in slightly more than half of all patients. Coronaviruses are the second most common cause. Rarely (0.05% of all cases) can bacteria be cultured from individuals with cold symptoms. It is not clear whether these bacteria cause the cold, are secondary infectious agents, or are simply colonizers. Bacterial pathogens that have been identified include Chlamydia pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, and Mycoplasma pneumoniae.

Prevention

The mechanisms of transmission suggest that colds can be spread through contact with inanimate surfaces, but the primary transmission appears to be via hand-to-hand contact. The beneficial effects of removing viruses from the hands are supported by observations that absences of children have been reduced through the use of antiseptic hand wipes throughout the day at school or daycare.

Clinical Findings

Colds generally last 12–14 days. Reassurance and education to patients reduces misconceptions that symptoms lasting >1 week are abnormal. When the symptoms of congestion persist longer than 2 weeks, other causes of chronic congestion should be considered (Table 28-1).

Symptoms of colds include sore throat, congestion, low-grade fever, and mild myalgias and fatigue. In general, early in the development of a cold the discharge is clear. As more inflammation develops, the discharge takes on some coloration. A yellow, green, or brown-tinted nasal discharge is an indicator of inflammation, not secondary bacterial infection. Discolored nasal discharge raises the likelihood of sinusitis, but only if other predictors of sinusitis are present. Therefore education to patients and reassurance is needed, and not reflexive antibiotic prescriptions, which some patients ultimately desire.

Complications

Primary complications from upper respiratory tract infection are otitis media and sinusitis. These complications develop from obstruction of the eustachian tube or sinus ostia from nasal passage edema. Although treatment of these infections with antibiotics is common, the vast majority of infections clear without antibiotic therapy.

One misconception is that using antibiotics during the acute phase of a cold can prevent these complications. Evidence shows that taking antibiotics during a cold does not reduce the incidence of sinusitis or otitis media. Nor do antibiotics give a faster recovery than placebos.

Differential Diagnosis

The differential diagnosis of colds includes complications of the cold such as sinusitis or otitis media, acute bronchitis, and noninfectious rhinitis. Influenza shares many of the symptoms of a common cold, but generally patients have a much higher fever, myalgias, and more intense fatigue.

Treatment

Despite the widespread recognition that viruses cause common colds, several studies have shown that patients with the common cold who are seen in physicians’ offices are often treated with antibiotics. The prescribing of antibiotics for colds occurs more often in adults than children. Although this practice appears to have declined in adults, the use of broad-spectrum antibiotics for colds is still common in children. The need to reduce the use of antibiotics for viral conditions has important ramifications on communitywide drug resistance; in areas in which prescribing antibiotics for respiratory infections has been curtailed, reversals in antibiotic drug resistance have been observed.

Currently, the most effective treatment is symptom reduction with over-the-counter (OTC) decongestants, the most popular of which include pseudoephedrine hydrochloride and topically applied vasoconstrictors. These agents produce short-term symptomatic relief. However, patients must be warned to use topical agents for a limited duration because prolonged use is associated with rebound edema of the nasal mucosa (rhinitis medicamentosa).

Several OTC medications contain a mix of decongestants, cough suppressants, and pain relievers. Again, the use of these preparations will not cure the common cold but will provide symptomatic reduction and relief.

Antihistamines, with a few exceptions, have not been shown to provide effective treatment. Zinc gluconate lozenges are available without a prescription, but a meta-analysis of 15 previous studies on zinc concluded that zinc lozenges were not effective in reducing the duration of cold symptoms.

Some herbal remedies are useful for treatment of the common cold. Echinacea, also known as the “American coneflower,” has been purported to reduce the duration of the common cold by stimulating the immune system; however, evidence for its efficacy is mixed. Echinacea should be used for only 2–3 weeks to avoid liver damage and other possible side effects that have been reported during long-term use of this herb. Ephedra, also known as ma huang, has decongestant properties that make it similar to pseudoephedrine. Ephedra is more likely than pseudoephedrine to cause increased blood pressure tachyarrhythmia. This is especially true if used in conjunction with caffeine.

SINUSITIS

General Considerations

Sinusitis is most often a complication of an upper respiratory viral infection, so the incidence peaks in the winter cold season. Medical conditions that may increase the risk for sinusitis include cystic fibrosis, asthma, immunosuppression, and allergic rhinitis. Cigarette smoking may also increase the risk of bacterial sinusitis during a cold because of reduced mucociliary clearance.

Most cases of acute sinusitis are caused by viral infection. The inflammation associated with viral infection clears without additional therapy. Bacterial superinfection of upper respiratory infections (URIs) is rare and occurs in only 0.5–1% of colds. Fungal sinusitis is very rare and usually occurs in immunosuppressed individuals or those with diabetes mellitus.

Clinical Findings

Acute sinusitis has considerable overlap in its constellation of signs and symptoms with URIs. One-half to two-thirds of patients with sinus symptoms seen in primary care are unlikely to have sinusitis. URIs are often precursors of sinusitis, and at some point symptoms from each condition may overlap. Sinus inflammation from a URI without bacterial infection is also common.

The signs and symptoms that increase the likelihood that the patient has acute sinusitis are a “double-sickening” phenomenon (whereby the patient seems to improve following the URI and then deteriorates), maxillary toothache, purulent nasal discharge, poor response to decongestants, and a history of discolored nasal discharge. Also on examination, patients will have tenderness to palpation of their sinuses and worsening pain with bending forward.

Treatment

Nonsevere symptoms, such as mild pain and afebrile state of <7 days’ duration should be treated with supportive care. Treatment would include analgesics, decongestants, and saline nasal irrigation. Narrow-spectrum antibiotics should be reserved for patients with no improvement in 7 days or worsening symptoms. No radiologic imaging is required. A rare complication of sinusitis to be aware of is orbital and/or intracranial bony involvement. If symptoms fail to improve with therapy course, consider referral to ENT. The effectiveness of antibiotics is unclear. Amoxicillin/clavulanate acid (ACA) is preferred over amoxicillin alone in treatment of children and adults, provided the patient is not allergic to the components. High doses of ACA at 90 mg/kgm daily in BID dosing is recommended for regions with >10% endemic rate of sinusitis, severe infection, children who attend daycare, a child <2 years old, an adult aged > 65 years, a recently hospitalized patient, any recent antibiotic use, or if a patient is immunocompromised. There are increasing rates of resistance to macrolides and septra and should not be used for empiric therapy. Alternatives if with allergy to ACA would be doxycycline, or levoflox/moxifloxacin. Treatment should be for 5–7 days for adults and 10–14 days for children on antibiotics for sinusitis.

INFLUENZA (ADULTS)

Diagnosis, treatment, and prevention of influenza in children are reviewed extensively in Chapter 5.

General Considerations

Although most cases of the flu are mild and usually resolve without medical treatment within 2 weeks, some will develop complications. Currently, three types of viruses causing influenza have been identified in the United States: A, B, and C. Seasonal epidemics from influenza types A and B are seen every winter. Type C influenza usually causes a mild respiratory illness and is not responsible for epidemics. If a new strain emerges and infects a population, an influenza pandemic can result.

Influenza A is identified by two proteins on the virus surface: a hemagglutinin (H) and a neuraminidase (N). These proteins result in 16 different H subtypes and 9 different N subtypes. The A form of influenza can be further divided into strains. The two subtypes of influenza A found in humans currently are A(H1N1) and A(H3N2). In 2009, an influenza pandemic occurred when a very different strain of influenza A(N1H1) developed in humans. The influenza B is broken down by different strain, but not by subtypes.

Prevention

Vaccination is the most effective prevention against influenza. The seasonal flu vaccination is a trivalent vaccine with each component selected to protect against one of the three main groups of influenza viruses circulating in humans. The influenza viruses in the seasonal flu vaccine are selected each year from surveillance-based forecasts about which viruses are most likely to cause illness in the upcoming season. The World Health Organization (WHO) recommends specific vaccine viruses for inclusion, but each country decides independently which strains should be included. The US Food and Drug Administration (FDA) determines which vaccine viruses will be used in US-licensed vaccines. Influenza vaccinations require annual dosing for adults and children aged >1 year. Therefore, the influenza vaccine does not cover all strains of the influenza virus, and patients who have received their annual vaccination can still develop influenza; this is an important education point for all patients. A complete listing of who should be immunized can be found on the Centers for Disease Control and Prevention’s (CDC’s) Advisory Committee on Immunization Practices (ACIP) website and others.

The spread of influenza is from person to person by sneezing or coughing. Therefore, everyday care to stay healthy can help prevent contracting the flu and/or spreading the flu to others. Simple steps, such as covering nose and mouth when sneezing or coughing with a tissue; avoiding touching mouth, nose, and eyes if sick; washing hands frequently with soap or germicide solution; and staying home if sick to avoid others, may help prevent the spread of influenza. Additionally, if a patient has been exposed to influenza by another, influenza antiviral prescription drugs can be used as chemoprophylaxis of influenza.

Clinical Findings

The flu can last from 3 days to 2 weeks. Mild cases may be assumed to have the common cold and receive no medical treatment. Symptoms include high fever, extreme fatigue, and myalgias. Other symptoms associated with the flu include sore throat, rhinorrhea, cough, headache, and chills. Some people experience nausea, vomiting, and diarrhea. The diagnosis is most commonly clinical, but there are laboratory confirmation tests available with rapid influenza diagnostic tests (RIDTs), viral cultures, and immunoflourescence, and reverse transcription-PCR. Clinicians should realize that a negative RIDT result does not exclude a diagnosis of influenza, as sensitivities are 40–70%. When there is a clinical suspicion of influenza and antiviral treatment is indicated, the treatment should be started without waiting for results of additional influenza testing.

Complications

Complications can lead to hospitalization and even death. These complications include, but are not limited to, otitis media, sinusitis, acute bronchitis, and pneumonia. Exacerbations of chronic illnesses such as asthma, congestive heart failure, and chronic obstructive lung disease are further complications of the flu.

Differential Diagnosis

One must consider other viruses, such as the common cold viruses, which have many of the same symptoms in less severity.

Treatment

People who develop flu symptoms should seek medical treatment as soon as possible, especially those in the high-risk group, as shown in Table 28-2. If treatment with antivirals is begun within 48 hours of the first signs or symptoms of illness, the patient gets the greatest benefit. These benefits include shortening the illness by at least 24 hours, preventing serious complications, and decreasing the likelihood of spreading the disease to others. Treatment with oseltamivir or zanamivir is effective against all forms of human influenza, including A (H1N1)/(H3N2), 2009 A(H1N1), and B. Two older medications, amantadine and rimantadine, remain susceptible to influenza A but not to B. The CDC recommends the use of oseltamivir or zanamivir at this time, due to the emergence of the new strain of A (N1H1). Treatment guidelines differ for age groups and high-risk groups. Therefore, it is important when considering treatment options to refer to the Physician’s Desk Reference (PDR) to ensure that appropriate treatment is given. Symptomatic treatment can be given with an antipyretic for the fever and an anti-inflammatory for pain and myalgias.

ACUTE BRONCHITIS

General Considerations

Viral infection is the primary cause of most episodes of acute bronchitis. A wide variety of viruses have been shown to cause acute bronchitis, including influenza, rhinovirus, adenovirus, coronavirus, parainfluenza, and respiratory syncytial virus. Nonviral pathogens, including M. pneumoniae and Chlamydophila pneumoniae (TWAR), have also been identified as causes.

The etiologic role of bacteria such as H. influenzae and S. pneumoniae in acute bronchitis is unclear because these bacteria are common upper respiratory tract flora. Sputum cultures for acute bronchitis are therefore difficult to evaluate because it is unclear whether the sputum has been contaminated by pathogens colonizing the nasopharynx.

Clinical Findings

Patients with acute bronchitis may have a cough for a significant time. Although the duration of the condition is variable, one study showed that 50% of patients had a cough for >3 weeks and 25% for >4 weeks. Other causes of chronic cough are shown in Table 28-3.

Both acute bronchitis and pneumonia can present with fever, constitutional symptoms, and a productive cough. Although patients with pneumonia often have rales, this finding is neither sensitive nor specific for the illness. When pneumonia is suspected because of the presence of a high fever, constitutional symptoms, severe dyspnea, and certain physical findings or risk factors, a chest radiograph should be obtained to confirm the diagnosis.

Differential Diagnosis

Asthma and allergic bronchospastic disorders can mimic the productive cough of acute bronchitis. When obstructive symptoms are not obvious, mild asthma may be diagnosed as acute bronchitis. Further, because respiratory infections can trigger bronchospasm in asthma, patients with asthma that occurs only in the presence of respiratory infections resemble patients with acute bronchitis.

Finally, nonpulmonary causes of cough should enter the differential diagnosis. In older patients, congestive heart failure may cause cough, shortness of breath, and wheezing. Reflux esophagitis with chronic aspiration can cause bronchial inflammation with cough and wheezing. Bronchogenic tumors may produce a cough and obstructive symptoms.

Treatment

Clinical trials of the effectiveness of antibiotics in treating acute bronchitis have had mixed results. Meta-analyses indicated that the benefits of antibiotics in a general population are marginal and should be weighed against the impact of excessive use of antibiotics on the development of antibiotic resistance as well as complications of developing Clostridium difficile.

Data from clinical trials suggest that bronchodilators may provide effective symptomatic relief to patients with acute bronchitis. Treatment with bronchodilators demonstrated significant relief of symptoms, including faster resolution of cough and return to work. The effect of albuterol in a population of patients with undifferentiated cough was evaluated, and no beneficial effect was found. Because various conditions present with cough, there may have been some misclassification in generalizing this finding to acute bronchitis.

COMMUNITY-ACQUIRED PNEUMONIA

General Considerations

Pneumonia is the cause of over 10 million visits to physicians annually, accounts for 3% of all hospitalizations, and is the eighth leading cause of death in the United States, per the American Lung Association. A variety of factors, including increasing age, increase the risk of pneumonia. Among the elderly, institutionalization and debilitation further increase the risk for acquiring pneumonia. Patients aged ≥55 years, smokers, and patients with chronic respiratory diseases are more likely to require hospitalization for pneumonia. Those with congestive heart failure, cerebrovascular diseases, cancer, diabetes mellitus, and poor nutritional status are more likely to die. Thus, age and comorbidities are important factors to consider when deciding whether to hospitalize a patient with pneumonia. These risk factors are summarized in Table 28-4.

Prevention

Pneumococcal pneumonia may be prevented through immunization with multivalent pneumococcal vaccine. There are currently two pneumococcal vaccines. The penumococal conjugate vaccine, PCV13, is currently recommended for all children aged <5 years and adults aged ≥19 years with certain medical conditions. The other is a 23-valent pneumococcal polysaccharide vaccine (PPSV23) and is indicated for all adults aged >65 years and children aged ≥2 years with high risk for disease (ie, diabetes mellitus, chronic pulmonary or cardiac disease, without a spleen, or with immunocompromise). The PPSV23 is also recommended for adults aged 19–64 years who smoke cigarettes or have asthma. Additionally, anyone who lives in a long-term care facility should be vaccinated. CDC recommends immunization of all patients with the following medical conditions: immunosuppressed patients, including those with human immunodeficiency virus (HIV) infection; alcoholism; cirrhosis; chronic renal failure; nephrotic syndrome; functional or anatomic asplenia (eg, sickle cell disease or splenectomy); cochlear implants; cerebrospinal fluid leaks; or multiple myeloma.

In addition to initial vaccination, clinicians should advise patients that the duration of protection is uncertain. For those at particularly high risk of mortality from pneumococcal pneumonia, such as patients with chronic pulmonary disease; lacking a spleen; or with chronic renal disease or nephrotic disease, functional or anatomic asplenia, or immunocompromising conditions, should receive a one-time revaccination after 5 years from their first vaccination. For patients aged >65 years, a one-time revaccination is also recommended if their last vaccination was earlier than 5 years ago or if they were <65 when they received their first vaccination.

Clinical Findings

The most common presenting complaints for patients with pneumonia are fever and a cough that may be either productive or nonproductive. As an example, in one study, 80% of patients with pneumonia had a fever. Other symptoms that may be suggestive of pneumonia include dyspnea and pleuritic chest pain. However, none of these symptoms is specific for pneumonia.

Symptoms of pneumonia may be nonspecific in older patients. Elderly individuals who suffer a general decline in their function, become confused or have worsening dementia, or experience more frequent falls should increase suspicion of infection. Elderly patients who have preexisting cognitive impairment or depend on someone else for support of their daily activities are at highest risk for not exhibiting typical symptoms of pneumonia.

The most consistent sign of pneumonia is tachypnea. In one study of elderly patients, tachypnea was observed to be present 3–4 days before the appearance of other physical findings of pneumonia. Rales or crackles are often considered the hallmark of pneumonia, but these may be heard in only 75–80% of patients. Other signs of pneumonia such as dullness to percussion or egophony, which are usually believed to be indicative of consolidation, occur in less than a third of patients with pneumonia.

Chest radiography is the standard for diagnosing pneumonia. In rare cases, the chest x-ray may be falsely negative. This generally occurs in patients exhibiting profound dehydration, early pneumonia (first 24 hours), infection with Pneumocystis, and severe neutropenia.

Microbiological testing for pneumonia is not very useful in relatively healthy patients with nonsevere pneumonia. Blood and sputum cultures are most likely to be beneficial in patients with risk factors for unusual organisms or who are very ill.

Differential Diagnosis

Other conditions such as postobstructive pneumonitis, pulmonary infarction from an embolism, radiation pneumonitis, and interstitial edema from congestive heart failure all may produce infiltrates that are indistinguishable from an infectious process.

Treatment

With the emergence of other pathogens causing pneumonia and the development of resistance to penicillin and other drugs in S. pneumoniae, treatment decisions have become more complex. The 2007 update to the Infectious Disease Society of America (ISDA) and American Thoracic Society (ATS) guidelines for the treatment of community-acquired pneumonia differ depending on the health and age of patients (ie, those aged ≥65 years), whether they have recently been treated with an antibiotic, and whether they are at risk for an aspiration pneumonia or influenza superinfection (Table 28-5). For patients with no serious comorbidities, the ISDA/ATS recommends a respiratory quinolone or an advanced macrolide plus high-dose amoxicillin [or amoxicillin-clavulanic acid (ACA)] as first-line therapy. If an antibiotic has been used recently, then either a respiratory quinolone or an advanced macrolide plus a second- or third-generation cephalosporin is a recommended option. If aspiration is suspected, the ISDA/ATS guidelines include a choice of ACA or clindamycin as initial treatment.

Suitable empiric antimicrobial regimens for inpatient pneumonia include an intravenous β-lactam antibiotic, such as cefuroxime, ceftriaxone sodium, or cefotaxime sodium, or a combination of ampicillin sodium and sulbactam sodium plus a macrolide. New fluoroquinolones with improved activity against S. pneumoniae can also be used to treat adults with community-acquired pneumonia. Vancomycin hydrochloride is not routinely indicated for the treatment of community-acquired pneumonia or pneumonia caused by drug-resistant S. pneumoniae.

ASTHMA

General Considerations

Asthma is one of the most common illnesses in childhood. Risk factors for the development of asthma include living in poverty and being in a nonwhite racial group. Part of the difference in asthma rates noted among different races may be related to increased exposure to allergens and other irritants such as air pollution, cigarette smoke, dust mites, and cockroaches in less affluent families, but racial differences persist even after adjusting for socioeconomic status.

Allergy is an important factor in asthma development in children but does not appear to be as significant a factor in adults. Although as many as 80% of children with asthma also are atopic, 70% of adults aged <30 years and fewer than half of all adults aged 30 years have any evidence of allergy. Therefore, although an allergic component should be sought in adults, it is less commonly found than in children with asthma.

Clinical Findings

In most cases, the diagnosis of asthma is based on symptoms of recurrent wheezing, shortness of breath, or cough. Children with recurrent cases of “bronchitis” who experience nighttime cough or have difficulty with exercise tolerance should be suspected of having asthma. An additional history of allergies is useful, because 80% of childhood asthma is associated with atopy.

Formal spirometry testing can usually be accomplished in children as young as 5 years of age and can confirm the diagnosis of asthma. Both the forced expiratory volume in 1 second (FEV₁) and FEV₁ to forced vital capacity (FVC) ratio are useful in documenting obstruction to airway flow. Further confirmation is provided by improvement of the FEV₁ by ≥12% following the use of a short-acting bronchodilator. For a valid test, though, children should avoid using a long-acting β-agonist in the previous 24 hours or a short-acting β-agonist in the previous 6 hours.

In some patients with asthma, spirometry may be normal. When there is a high index of suspicion that asthma may still be present, provocative testing with methacholine may be necessary to make the diagnosis.

It is useful to stratify patients with asthma by the severity of their illness. The severity of asthma is based on the frequency, intensity, and duration of baseline symptoms; level of airflow obstruction; and the extent to which asthma interferes with daily activities. Stages of severity range from severe persistent (step 4), in which symptoms are chronic and limit activity, to mild intermittent (step 1), in which symptoms are present no more than twice a week and pulmonary function studies are normal between exacerbations (Table 28-6). Patients are classified as to severity on the basis of their worst symptom and frequency, regardless of whether they met all or the majority of the criteria in any category.

Treatment

The approach to managing asthma relies on acute management of exacerbations, treatment of chronic airway inflammation, monitoring of respiratory function, and control of the factors that precipitate wheezing episodes. For all of these, patient and family education is vital.

Treatment of persistent asthma requires daily medication to prevent long-term airway remodeling. Mild, intermittent asthma may require therapy only during wheezing episodes. Guidelines for the management of asthma are based on the child’s age (≤6 years) and are stratified by severity of illness. Guidelines for older children, adults, and younger children are provided in Table 28-7.

The treatment of exacerbations of asthma relies on fast-acting bronchodilators to produce rapid changes in airway resistance along with management of the late-phase changes that occur several hours after the initial symptoms are manifested. The failure to recognize the late-phase component of an acute exacerbation may lead to a rebound of symptoms several hours after the patient has left the office or emergency department. Corticosteroids are the mainstay for preventing the late-phase response.

For patients with persistent symptoms (step 2 and higher), chronic therapy is required. The management of persistent asthma may include long-acting bronchodilators to control intermittent symptoms and nighttime cough, but also should provide chronic anti-inflammatory therapy to prevent long-term remodeling. Both inhaled steroids and nonsteroidal anti-inflammatory medications (ie, cromoglycates) can provide anti-inflammatory therapy. When symptoms are recurrent or large doses of anti-inflammatory agents are required, treatment with a leukotriene inhibitor can provide additional anti-inflammatory therapy and may allow a reduction in the dose of other anti-inflammatory agents such as steroids.

When drugs are selected for the treatment of asthma, the potential side effects of each agent need to be weighed against the potential benefits. For children, chronic use of inhaled steroids has been associated with a small decrease in total height attained. Although the difference in height attainment is small, it might be preferable to use nonsteroidal anti-inflammatory agents such as cromolyn and nedocromil in children.

In addition to pharmacologic management, patients with asthma should avoid known and possible airway irritants. These include cigarette smoke (including second-hand inhalation of smoke), environmental pollutants, suspected or known allergens, and cold air. Children who have difficulty participating in sports may benefit from the use of a short-acting β-agonist such as albuterol before participating in exertion to prevent wheezing or cough.

The monitoring of pulmonary function is an important component of asthma management for all patients with persistent disease. Children and adults should be provided with a peak-flow meter and instructed on how to use the device reliably. The use of a peak-flow meter can detect subtle changes in respiratory function that may not cause symptoms for several days. To use a peak-flow meter, patients must establish a “personal best,” which represents the best reading that they can obtain when they are as asymptomatic as possible. Daily or periodic recordings of peak flows are compared with this personal best to gauge the current pulmonary function. Readings between 80% and 100% of the personal best indicate that the patient is doing well. Peak flows between 50% and 80% of an individual’s personal best are cause for concern even if symptoms are mild. Patients should be instructed beforehand how to respond in these instances. If a repeat of the peak flow later in the day after appropriate measures have been taken does not show improvement, patients should seek further medical attention. Patients should be told that severe decreases in peak flow to <50% are cause for immediate medical attention.

For patients with allergic symptoms, the use of immunotherapy should be considered. However, although immunotherapy usually results in improvements in symptoms of allergic rhinitis, it seldom improves asthma symptoms.

General Considerations

Chronic airway disease is the second leading cause of disability in the United States after coronary artery disease. It is also fourth in the list of leading causes of death in the United States. Consistently more women died secondary to chronic obstructive pulmonary disease (COPD) than men. Symptoms of chronic bronchitis first develop when patients are between 30 and 40 years of age and become increasingly common as patients reach their 50s and 60s. The development of chronic bronchitis is associated with heavier cigarette use; those smoking over 25 cigarettes per day have a risk of chronic bronchitis that is 30 times higher than that for nonsmokers. Although chronic bronchitis affects both genders and all socioeconomic strata, it is more commonly observed in men and in those of lower socioeconomic classes. It is presumed that these populations may be at higher risk due to higher consumption of cigarettes observed in these groups.

In addition to smoking, air pollution may affect the development and exacerbation of symptoms in patients with chronic bronchitis. Patients with COPDs who live in industrialized areas with heavy levels of particulate air pollution may be at increased risk of recurrent disease and death.

Only 10–15% of smokers will develop COPD, so other factors must also play a role in the progression from acute to chronic lung damage. The development of chronic bronchitis is assumed to include both a predisposition to inflammatory damage and exposure to the proper stimuli that cause inflammation, such as cigarette smoke or pollutants. Genetic factors, prolonged heavy exposure to other inflammatory mediators such as environmental pollutants, preexisting lung impairment from other inflammatory processes such as recurrent infection or childhood passive smoke exposure, and other mechanisms may all predispose individuals to the development of chronic bronchitis from smoking.

α₁-antitrypsin deficiency is a rare genetic abnormality that causes panlobular emphysema in adults and is responsible for approximately 2–3% of cases of COPD. This trait is inherited in an autosomal-recessive pattern. Nonsmokers with this genetic defect develop emphysema at young ages. Those with this trait who smoke develop progressive emphysema at very early ages. Emphysema related to α₁-antitrypsin deficiency rarely shows up below age 25 and rarely in nonsmokers.

Clinical Findings

Chronic obstructive pulmonary disease includes both chronic bronchitis and emphysema, and these two often coexist. Chronic bronchitis is characterized by a productive cough featuring sputum production for ≥3 months for 2 consecutive years. Emphysema causes chronic dyspnea due to destruction of lung tissue, resulting in enlargement of airspace and reduced compliance. In most cases, chronic bronchitis and emphysema can be differentiated according to whether the predominant symptom is a chronic cough or dyspnea. In contrast to asthma, changes in COPD are relatively fixed and only partially reversible with bronchodilator use.

When suspected clinically, COPD can be confirmed with chest radiography and spirometry. Although chest radiographic findings occur much later in the course of the disease than alterations in pulmonary function testing, a chest x-ray may be useful in patients suspected of having COPD because it can detect several other clinical conditions often found in these patients.

Spirometry is generally used to diagnose COPD because it can detect small changes in lung function and is easy to quantify. Changes in the FEV₁ and the FVC can provide an estimate of the degree of airway obstruction in these patients. Symptoms of COPD usually develop when FEV₁ falls below 80% of the predicted rate. In addition, a peak expiratory flow rate (PEFR) of <350 L/min in adults is a sign that COPD is likely to be present.

Spirometry also is useful in gauging the severity of COPD. Decreases in FEV₁ on serial testing are associated with increased mortality rates (ie, patients with a faster decline in FEV₁ have a higher rate of death). The major risk factor associated with an accelerated rate of decline of FEV₁ is continued cigarette smoking. Smoking cessation in patients with early COPD improves lung function initially and slows the annual loss of FEV₁. Once FEV₁ falls below 1 L, 5-year survival is approximately 50%.

The United States Preventive Services Task Force (USPSTF) has recommended against the use of spirometry to screen asymptomatic adult patients for COPD, which carries a D recommendation.

Treatment

A. Nonpharmacologic Therapy

The first step in treating the patient with chronic bronchitis or COPD is to promote a healthy lifestyle. Regular exercise and weight control should be started and smoking stopped to maximize the patient’s therapeutic options.

Smoking cessation is the first and most important treatment option in the management of chronic bronchitis or COPD. Several interventions to assist patients in smoking cessation are available. These include behavioral modification techniques as well as pharmacotherapy (see the next section). A combination of behavioral and pharmacologic approaches such as nicotine replacement appears to yield the best results. Even minimal counseling from the provider improves the effectiveness of the nicotine patch.

Once patients have stopped smoking, those who are hypoxemic with a Pao₂ (partial pressure of oxygen in arterial blood) of ≤55 mmHg or an O₂ saturation of ≤88% while sleeping should receive supplemental oxygen. Along with smoking cessation, home oxygen is the only therapy shown to reduce mortality in COPD. Continuous long-term oxygen therapy (LTOT) should be considered in those patients with stable chronic pulmonary disease with Pao₂ of <55 mmHg on room air, at rest, and awake. The presence of polycythemia, pulmonary hypertension, right heart failure, or hypercapnia (Pao₂ >45 mmHg) is also an indication for use of continuous LTOT.

Exercise and pulmonary rehabilitation may also be beneficial as adjunct therapies for patients whose symptoms are not adequately controlled with appropriate pharmacotherapy. Exercise and pulmonary rehabilitation are most useful for patients who are restricted in their activities and have decreased quality of life.

B. Pharmacotherapy

1. Smoking cessation pharmacotherapy

Multiple medications are available to assist with smoking cessation. Nicotine can be substituted 1 mg (1 cigarette) per milli-gram with the use of the patch, gum, or inhaler to help with symptoms of nicotine withdrawal. Patches and gum are both available over the counter as well as by prescription. Some evidence suggests that use of the patch and gum simultaneously enhances quit rates, but use of both is not approved by the Food and Drug Administration. Although all these products state that patients must not smoke while using nicotine replacement because of early case reports of myocardial infarction, more recent studies show that smoking is relatively safe when using nicotine replacement and may help reduce smoking before a patient actually quits. However, even at best, the cessation rate is only ~20–30% at 1 year.

Bupropion also is approved for smoking cessation as an adjunct to behavior modification. The main effect of bupropion is to reduce symptoms of nicotine withdrawal. Bupropion should be instituted for 2 weeks before the quitting target date. Then a nicotine substitute can be used in combination to maximize alleviation of symptoms of nicotine withdrawal. Because many patients with chronic bronchitis are already taking multiple medications, potential drug interactions and adverse effects must be considered before instituting therapy with bupropion.

A third agent to assist in smoking cessation is varenicline tartrate. Varenicline is a selective nicotine receptor partial agonist. The drug stimulates nicotine receptors to produce a nicotine replacement–type effect but also blocks the receptors from additional exogenous nicotine stimulation. Use of varenicline has been reported to achieve quit rates of 40% at 12 weeks and continuous quit rates of ~22% after 1 year, which was significantly more than either bupropion or nicotine replacement alone. Adverse effects of varenicline occur in 20–30% of patients and include nausea, insomnia, headache, and abnormal dreams but necessitated discontinuation of the drug in 2–3% of patients in clinical trials.

2. Bronchodilators

An anticholinergic agent such as ipratropium bromide is the drug of choice for patients with persistent symptoms of chronic bronchitis. Anticholinergic agents such as ipratropium bromide or tiotropium have fewer side effects and a better response than intermittent β-agonists. Although both of these agents have a delayed onset of action compared with short-acting β-agonists, the beneficial effects are prolonged. Ipratropium requires dosing several times a day; in contrast, tiotropium can be used once a day.

For patients with mild to moderately severe symptoms, intermittent use of a β-agonist inhaler such as albuterol is sometimes beneficial even without significant changes in their FEV₁. Adverse effects of β-agonist agents include tachycardia, nervousness, and tremor. Short-acting β-agonists may not last through the night; when nighttime symptoms develop, long-acting β-agonists such as salmeterol may be more useful. Levalbuterol, the active agent of racemic albuterol, has recently been studied and appears to have greater efficacy than albuterol with fewer side effects.

Combination inhalers of ipratropium bromide and albuterol have also been used in the treatment of patients with chronic bronchitis but have demonstrated only minimal changes in outcomes compared with single agents.

3. Antibiotics

Patients with acute exacerbations of chronic bronchitis pose a more difficult therapeutic dilemma. Many of these exacerbations are probably due to viral infections. However, a meta-analysis of studies using a wide range of antibiotics (ampicillin, sulfamethoxazole-trimethoprim, and tetracyclines) demonstrated some benefit from empiric use of antibiotics for exacerbations of chronic bronchitis.

4. Other agents

As symptoms increase, addition of inhaled β-agonists, theophylline, and corticosteroids may provide symptomatic relief of symptoms of chronic bronchitis. In a multicenter randomized placebo-controlled trial, patients who used inhaled fluticasone had improved peak expiratory flows, FEV₁, FVC, and midexpiratory flow. At the end of treatment, patients also showed increased exercise tolerance compared with the placebo group. Corticosteroids at a therapeutic dose of 60 mg/d for 5 days have been shown to provide some symptomatic relief for severe exacerbations.

Mucolytics have not been shown to be beneficial. Iodinated glycerol has not been shown to improve any objective outcome measurements.

Newer agents such as aerosolized surfactant also have been used to treat stable chronic bronchitis. A prospective randomized controlled trial showed a minimal but statistically significant improvement in spirometry and sputum clearance. However, the cost of such a treatment regimen is high and may not add any advantage to the underlying treatment.

For the treatment of cough, agents that may be of benefit for patients with chronic bronchitis include ipratropium bromide, guaimesal, dextromethorphan, and viminol.

Anabolic steroids have recently been used for patients who have severe malnutrition and in those in whom weight loss is a concern. These agents show some beneficial effects.

General Considerations

Pulmonary embolism (PE) usually results from the mobilization of blood clots from thromboses in the lower extremities or pelvis. However, embolization of other materials, including air, fat, and amniotic fluid, also can obstruct the pulmonary vasculature. The symptoms of pulmonary embolism range from mild, intermittent shortness of breath or pleuritic chest pain to complete circulatory collapse and death.

The most common source of embolism is the disruption of thrombi formed in the deep veins. Mortality in untreated cases is 30% but can be reduced to 2% with prompt recognition and appropriate management. Recurrent pulmonary embolism carries a very high mortality in the range of 45–50%.

Strong risk factors for pulmonary embolism are leg or hip fracture, major general surgery, knee or hip replacement, spinal cord injury, and major trauma. Other risk factors include venous stasis, trauma, abnormalities in the deep veins, and hypercoagulable states. Hypercoagulability occurs with some cancers as well as with inherited conditions such as factor V Leiden mutation that results in resistance to the anticoagulant effects of protein C. Other congenital hypercoagulation disorders include protein C deficiency, protein S deficiency, and antithrombin III deficiency.

Hypercoagulation states also exist with the use of certain medications. Use of estrogens either as part of hormone replacement therapy or for contraception increases the risk by a factor of 3. The effects of these drugs are compounded in patients with factor V Leiden mutation. Pregnancy and postpartum states increase the risk of pulmonary embolism.

In addition, smoking appears to be an independent risk factor for deep-vein thrombosis (DVT) and pulmonary embolism. The presence of more than two of these risk factors places the patient at a synergistic increased risk for the development of venous thromboembolism.

Prevention

Because pulmonary emboli usually arise from lower extremity thromboses, prophylactic anticoagulation can be used to reduce the incidence of these thrombi in high-risk individuals. Both low-molecular-weight heparin products and unfractionated heparin are effective in preventing DVT. Selection of the agent and the dose is based on the risk. The decision to initiate VTE prophylaxis should be based on the patient’s individual risk of thromboembolism and bleeding, and the balance of benefits versus harms. Risk factors for thromboembolism are inherited (eg, factor V Leiden mutation, prothrombin gene mutation, protein S or C deficiency, antithrombin deficiency) or are acquired (eg, surgery, cancer, immobilization, trauma, presence of a central venous catheter, pregnancy, medication use, congestive heart failure, chronic renal disease, antiphospholipid antibody syndrome, obesity, smoking, older age, history of thromboembolism). Although there are many tools for assessing thromboembolism risk, there is insufficient evidence to recommend one over the others. General evidence regarding risk factors also may be used to make decisions about the need for prophylaxis.

Heparin or a related drug can increase the risk of bleeding, especially in older patients; women; patients with diabetes mellitus, hypertension, cancer, alcoholism, liver disease, severe chronic kidney disease, peptic ulcer disease, anemia, poor treatment adherence, previous stroke or intracerebral hemorrhage, bleeding lesions, or bleeding disorder; and in patients taking certain concomitant medications.

Prophylaxis with heparin has been shown to significantly reduce pulmonary embolisms in hospitalized patients, although bleeding events were increased. In most patients, the clinical benefit of decreased pulmonary embolisms outweighs the risk of bleeding. Evidence is insufficient to conclude that these risks and benefits differ in patients with stroke, although prevention of recurrent stroke may be an added benefit in these patients.

The optimal duration of heparin therapy is unclear. The benefits and risks are not significantly different between low-molecular-weight heparin and unfractionated heparin, and fondaparinux (Arixtra) has not been directly compared with heparin. The choice of medication should be based on ease of use, adverse effect profile, and cost.

Use of graduated compression stockings was not shown to be effective in preventing VTE or reducing mortality, and can cause clinically important damage to the skin. Intermittent pneumatic compression may be a reasonable option if heparin is contraindicated, because evidence suggests that it is beneficial in patients undergoing surgery. However, the therapy has not been sufficiently evaluated as a standalone intervention in other patients.

In addition to preventing initial thrombi, the pulmonary embolism can be reduced through the use of a venacaval filter in patients with known thrombi and contraindications to long-term anticoagulation. The long-term impact of intravenacaval (IVC) filters has not been studied extensively. One study showed a complication rate, such as thrombi trapped in the filter or the filter tilting, malpositioning, or migrating, in nearly 50% of those who survived 3 years. However, given the high mortality rates from recurrent pulmonary embolism, the complication rates from long-term IVC filter insertion appear to be a worthwhile tradeoff in high-risk patients.

Clinical Findings

Patients with pulmonary emboli usually exhibit dyspnea and hypoxia, and often have pleuritic chest pain. However, other than hypoxia, most routine studies including chest radiographs may be normal. The clinical assessment of the patient should include the criteria in the Wells score looking at signs and symptoms consistent with DVT, different diagnosis less likely, a heart rate of >100 bpm, previous PE or DVT, surgery within the last 4 weeks or immobilization, current malignancy, and presence of hemoptysis. Scores placed patients in either a low, intermediate, or high probability of having a PE. The Christopher study (modified Wells study) further divided the scoring into PE likely or unlikely. Suspicious signs of embolism on a chest radiograph include a wedge-shaped infiltrate resulting from lobar infarction, new pleural effusion, or both. Confirmation of a pulmonary embolism is based on either demonstrating obstruction of vascular flow through pulmonary angiography, finding a mismatch of perfusion and ventilation, or visualization of a clot on spiral (helical) computed tomography (CT) scanning. Although pulmonary angiography is considered the gold standard, because of its invasiveness, spiral CT and ventilation-perfusion scan are usually employed to make the diagnosis. Of the noninvasive tests available, spiral CT has the best sensitivity for detecting pulmonary artery thrombi (95–100%), although it is not as useful in identifying subsegmental emboli.

D-dimer testing has been evaluated as a serum marker for pulmonary embolism or DVT. The presence of D-dimer is not specific for thrombotic disease because D-dimer also rises in other conditions such as recent surgery, congestive heart failure, myocardial infarction, and pneumonia. Although the presence of D-dimer is not useful in diagnosing thrombosis or embolism, the negative predictive value of the absence of D-dimer is very high (97–99%), so this test can be useful in ruling out embolism. Clinically predictive rules, such as the modified Wells, can be used together with the D-dimer test to identify those in the “PE unlikely” group who would not require further study. On the basis of these two tools, clinical assessment and laboratory test, those that fall into the “PE likely” category can be further evaluated with CT angiography or spiral CT.

Treatment

Options for management of patients with an acute pulmonary embolism include anticoagulation to prevent further embolism from occurring, clot lysis with thrombolytic agents, or surgical removal of the clot.

Patients without life-threatening embolism can be managed with acute anticoagulation with heparin followed by long-term maintenance on warfarin. Heparin may be administered as either unfractionated heparin or low-molecular-weight heparin. Unfractionated heparin is generally administered intravenously with the dosage rate titrated to produce a suitable anticoagulation state. The use of a weight-based nomogram for loading and maintenance dosing can improve the time to achieve adequate anticoagulation and reduce the risks of bleeding. The drawbacks of unfractionated heparin include the need for hospitalization to monitor coagulation status and administer the intravenous drug plus the possibility of thrombocytopenia associated with the use of this agent. Should bleeding occur as a complication of treatment with unfractionated heparin, stopping the heparin is the first step to stop further anticoagulation. If bleeding continues after stopping the heparin, protamine can be given to reverse the anticoagulation.

In contrast, low-molecular-weight heparin can be administered as a daily intramuscular dose without titration or frequent anticoagulation monitoring. As a result, low-molecular- weight heparin therapy usually can be provided in the patient’s home.

To achieve long-term anticoagulation, warfarin should be started promptly at a dose of 5 mg/d. Starting with a higher dose of warfarin does not appear to achieve oral anticoagulation any faster or reduce the total number of days when heparin is needed. Heparin can be discontinued when a prothrombin time indicates that the international normalized ratio (INR) has reached 2.0–3.0. Should excessive anticoagulation resulting from administering warfarin and bleeding occur, vitamin K can be given to reverse the effect of warfarin.

The duration of anticoagulation for pulmonary embolism depends on whether the precipitating event is known and reversible or whether the cause is unknown. In situations in which the thrombosis and embolism are the result of an acute event such as an injury or surgery, treatment for 6 months is recommended. If the risk factor associated with the embolic event is not reversible, such as cancer or coagulation disorder, then lifetime anticoagulation is advisable. When a risk factor or event causing the embolism is not known, so-called idiopathic embolism, treatment with anticoagulants for 6 months is indicated.

The use of thrombolytic agents for pulmonary embolism is usually reserved for patients with extensive embolism who show hemodynamic instability. Thrombolytic agents available for use in this situation include urokinase, streptokinase, tissue plasminogen activator (tPA), and reteplase. Embolectomy is rarely performed and is reserved for patients in whom embolism is rapidly diagnosed and a very large embolism is suspected that completely occludes the pulmonary arteries. In most situations, this is treated as a “last ditch” effort to save the patient.