Immunology

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Antibiotics are indicated for primary bacterial aspiration pneumonia and secondary bacterial infection of aspiration (chemical) pneumonitis, but not for uncomplicated chemical pneumonitis.

THREE TYPES OF ‘ASPIRATION PNEUMONIA’

Aspiration pneumonia is a broad and vague term mainly used to refer to the pulmonary consequences of abnormal entry of exogenous or endogenous substances into the lower airways. It can be classified as:

• Aspiration (chemical) pneumonitis
• Primary bacterial aspiration pneumonia
• Secondary bacterial infection of chemical pneumonitis.

These three are sometimes difficult to differentiate, as their signs and symptoms can overlap.

CHEMICAL PNEUMONITIS

Aspiration of stomach contents is relatively common, even in healthy people, and usually has no clinical consequences.¹ However, it has also been closely related to community-acquired and nosocomial pneumonia in some studies.^2,3

Chemical pneumonitis is usually a consequence of the aspiration of a large volume (≥ 4 mL/kg) of sterile acidic (pH < 2.5) gastric contents into the lower airways (Mendelson syndrome).^4,5 The clinical picture varies from asymptomatic to signs of severe dyspnea, hypoxia, cough, and low-grade fever; these signs and symptoms may develop rapidly, within minutes to hours after a witnessed or suspected episode of aspiration.^2,6,7 However, they represent an inflammatory reaction to the gastric acid rather than a reaction to bacterial infection.^8–10

Chemical pneumonitis affects the most dependent regions of the lungs

Chest radiography shows infiltrates in the most dependent regions of the lung. If aspiration occurs while the patient is supine, the posterior segments of the upper lobes and the apical segments of the lower lobes are most affected. The basal segments of the lower lobes are usually affected if aspiration occurs while the patient is standing or upright.^1,2,11,12

Clinical course varies

The clinical course varies. In almost 60% of cases, the patient’s condition improves and the lung infiltrates resolve rapidly, within 2 to 4 days. On the other hand, in about 15% of cases, the patient’s condition deteriorates quickly, within 24 to 36 hours, and progresses to hypoxic respiratory failure and acute respiratory distress syndrome.

In the other 25% of cases, the patient’s condition may improve initially but then worsen as a secondary bacterial infection sets in. The death rate in these patients is almost three times higher than the rate in patients with uncomplicated chemical pneumonitis.^11,13

Treatment of uncomplicated cases is mainly supportive

The treatment of uncomplicated chemical pneumonitis involves supportive measures such as airway clearance, oxygen supplementation, and positive pressure ventilation if needed. An obstructing foreign body may need to be removed.^12,14 Corticosteroids have been tried, without success.^11–13,15

Empiric antibiotic treatment is controversial

Chemical pneumonitis can be difficult to differentiate from bacterial aspiration pneumonia, and whether to give antibiotics is controversial. ¹⁶ A survey of current practices among intensivists showed that antimicrobial therapy was often given empirically for noninfectious chemical pneumonitis.¹⁷ This practice raises concerns of higher treatment costs and antibiotic resistance.^16,18,19 Additionally, antibiotics do not seem to alter the clinical outcome, including radiographic resolution, duration of hospitalization, or death rate, nor do they influence the subsequent development of infection.^1,11,13,20

In cases of witnessed or strongly suspected aspiration of gastric contents, antibiotics are not warranted since bacterial infection is not likely to be the cause of any signs or symptoms. ^2,7,16 However, to detect secondary infection early, the patient’s respiratory status should be monitored carefully and chest radiography should be repeated.

In less clear-cut cases, ie, if it is not clear whether the patient actually has chemical pneumonitis or primary bacterial aspiration pneumonia, it is prudent to start antibiotics empirically after obtaining lower-respiratory-tract secretions for stains and cultures, and then to reassess within 48 to 72 hours. The antibiotics can be discontinued if the patient has rapid clinical and radiographic improvement and negative cultures. Those whose condition does not improve or who have positive cultures should receive a full course of antibiotics.^21,22

PRIMARY BACTERIAL ASPIRATION PNEUMONIA

Primary bacterial aspiration pneumonia—ie, caused by bacteria residing in the upper airways and stomach gaining access to lower airways through aspiration in small or large amounts—is the most common form of aspiration pneumonia, although the actual episode of aspiration is seldom observed.

Signs of bacterial pneumonia

Primary bacterial aspiration pneumonia bears the hallmarks of bacterial pneumonia.¹² The clinical picture is more indolent than chemical pneumonitis and includes cough, fever, and putrid sputum, mainly in patients who have clinical conditions predisposing to aspiration (eg, coma, stroke, alcoholism, poor dentition, tube feedings).^1,12,20

The characteristic signs on chest radiography are infiltrates involving mainly the lung bases (the right more then the left). If untreated or inadequately treated, complications such as lung abscess, empyema, bronchiectasis, and broncopleural fistula are common.²³

Are aerobic organisms replacing anaerobic ones in the community?

The causative organisms in community-acquired aspiration pneumonia are still debated despite abundant research. Older studies^1,24,25 found mostly anaerobic organisms (pepto-streptococci, peptococci, Fusobacterium, Prevotela, Bacteroides) as the underlying pathogens, whereas more recent studies^16,26,27 found mostly aerobic organisms (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Enterobacteriaceae) and failed to recover anaerobic organisms. These discrepancies may be the result of different techniques used to isolate organisms: older studies used transtracheal sampling, and transtracheal aspirates may be easily contaminated or colonized by oropharyngeal flora; more recent studies used protected specimen brushes to collect lower-airway specimens.²

In addition, the pathogenic organisms that predominate in community-acquired aspiration pneumonia, as listed above, are different from those most often found in nosocomial cases; gram-negative bacilli (Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli) are most often isolated in patients with aspiration pneumonia acquired in hospitals and nursing homes.^16,27,28S aureus also is an important causative organism in nosocomial cases.^16,28

Knowing the causative organisms in bacterial aspiration pneumonia is important for guiding antimicrobial therapy.

Antibiotics are required for bacterial aspiration pneumonia

A course of antibiotics is required for bacterial aspiration pneumonia. While there are no definitive recommendations for the duration of treatment, 7 to 8 days is probably appropriate in uncomplicated cases (ie, no lung abscess, empyema, bronchopleural fistula).^22,29 Patients who have complications may need drainage of abscesses or empyema along with a longer duration of antibiotic therapy until clinical and radiographic signs improve.

For community-acquired cases of aspiration pneumonia, a number of antibiotics have proven effective:

• Clindamycin (Cleocin) is still the agent most commonly used, although it lacks gram-negative bacterial coverage.
• Beta-lactam penicillins and newer quinolones have been used successfully.^2,29–31 In addition to covering the previously mentioned bacteria, these antibiotics have the added benefit of covering anaerobic bacteria.
• Metronidazole (Flagyl) should not be used alone because it has a higher clinical failure rate.^32,33

For nosocomial aspiration pneumonia, giving a broad-spectrum antibiotic empirically is warranted. Beta-lactam penicillins with extended gram-negative coverage, carbapenems, or monobactams in combination with an anti-staphylococcal drug have been advocated for nosocomial aspiration.^2,22 A strategy of broad-spectrum coverage followed by narrowing or de-escalating coverage according to lower respiratory tract cultures is encouraged.^21,22,34

SECONDARY BACTERIAL INFECTION OF CHEMICAL PNEUMONITIS

Nearly 25% of patients with chemical pneumonitis improve initially, then show clinical deterioration secondary to superimposed bacterial infection.¹³ Chest radiographs show worsening of initial infiltrates or the development of new ones. The causative organisms and treatment depend on whether the superimposed infection is community-acquired or nosocomial, as is the case in primary bacterial aspiration pneumonia.

PREVENTING ASPIRATION

Measures should be taken to prevent aspiration pneumonia and chemical pneumonitis, especially in institutionalized patients at high risk.¹²

Elevation of the head of the bed while feeding, dental prophylaxis, and good oral hygiene are known to reduce the incidence of these problems.^35–37

A swallowing evaluation for patients with dysphagia can identify those at higher risk of aspiration. These patients may be candidates for postural adjustments, diet modification, strengthening, and other measures offered by the speech and language pathology teams to improve swallowing physiology, biomechanics, safety, and endurance.^2,35

Although percutaneous endoscopic gastrostomy tubes are often placed in patients who have aspirated or who are at high risk of aspiration, they do not protect against aspiration, nor do orogastric or nasogastric tubes.³⁸

To date, we have no evidence that prophylactic antibiotic therapy prevents bacterial aspiration pneumonia. In addition, this practice encourages the development of resistant organisms.^19,39,40

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

Yes. A number of large randomized controlled trials have shown inhaled corticosteroids to be beneficial in low doses for patients who have mild persistent asthma, and therefore these drugs are strongly recommended in this situation.¹

Asthma care providers should, however, consider this “yes” in the context of asthma severity, the goals of therapy, and the benefits and risks associated with inhaled corticosteroids.

CLASSIFICATION OF ASTHMA SEVERITY

Although the studies of asthma prevalence had methodologic limitations and therefore the true prevalence of mild persistent asthma cannot be determined, it is common. Fuhlbrigge et al² reported that most asthma patients have some form of persistent asthma. In contrast, Dusser et al³ reviewed available studies and concluded that most patients with asthma have either intermittent or mild persistent asthma.

GOALS: REDUCE IMPAIRMENT AND RISK

The goals of asthma management are to:

Reduce impairment by controlling symptoms so that normal activity levels can be maintained, by minimizing the need for short-acting bronchodilator use, and by maintaining normal pulmonary function; and to

Reduce risk by preventing progressive loss of lung function and recurrent exacerbations, and by optimizing pharmacotherapy while minimizing potential adverse effects.¹

EVIDENCE OF BENEFIT

The OPTIMA trial⁴ (Low Dose Inhaled Budesonide and Formoterol in Mild Persistent Asthma) was a double-blind, randomized trial carried out in 198 centers in 17 countries. Compared with those randomized to receive placebo, patients who were randomized to receive an inhaled corticosteroid, ie, budesonide (Pulmicort) 100 μg twice daily, had 60% fewer severe exacerbations (relative risk [RR] 0.4, 95% confidence interval [CI] 0.27–0.59) and 48% fewer days when their asthma was poorly controlled (RR 0.52, 95% CI 0.4–0.67). Adding a long-acting beta-agonist did not change this outcome.

The START study⁵ (Inhaled Steroid Treatment as Regular Therapy in Early Asthma) showed that, compared with placebo, starting inhaled budesonide within the first 2 years of asthma symptoms in patients with mild persistent asthma was associated with better asthma control and less need for additional asthma medication.

The IMPACT study⁶ (Improving Asthma Control Trial) showed that inhaled steroids need to be taken daily, on a regular schedule, rather than intermittently as needed. Patients received either inhaled budesonide as needed, budesonide 200 μg twice daily every day, or zafirlukast (Accolate) 20 mg twice daily. Daily budesonide therapy resulted in better asthma control, less bronchial hyperresponsiveness, and less airway inflammation compared with intermittent use, zafirlukast therapy, or placebo. Daily zafirlukast and intermittent steroid treatment produced similar results for all outcomes measured.

Despite this strong evidence supporting regular use of inhaled corticosteroids in patients with mild persistent asthma, many patients choose to take them intermittently.

Suissa et al⁷ found, in a large observational cohort study, that fewer patients died of asthma if they were receiving low-dose inhaled corticosteroids than if they were not. The rate of death due to asthma was lower in patients who had used more inhaled corticosteroids over the previous year, and the death rate was higher in those who had discontinued inhaled corticosteroids in the previous 3 months than in those who continued using them.

STEROIDS DO NOT SLOW THE LOSS OF LUNG FUNCTION

Compared with people without asthma, asthma patients have substantially lower values of forced expiratory volume in the first second of expiration (FEV₁). They also have a faster rate of functional decline: the average decrease in FEV₁ in asthma patients is 38 mL per year, compared with 22 mL per year in nonasthmatic people.⁹

Although inhaled corticosteroids have been shown to increase lung function in asthma patients in the short term, there is little convincing evidence to suggest that they affect the rate of decline in the long term.¹⁰ In fact, airway inflammation and bronchial hyperresponsiveness return to baseline within 2 weeks after inhaled corticosteroids are discontinued.¹⁰

DO INHALED CORTICOSTEROIDS STUNT CHILDREN’S GROWTH?

The safety of long-term low-dose inhaled corticosteroids is well established in adults. However, two large randomized controlled trials found that children treated with low-dose inhaled steroids (budesonide 200–400 μg per day) grew 1 to 1.5 cm less over 3 to 5 years of treatment than children receiving placebo.¹¹ However, this effect was primarily evident within the first year of therapy, and growth velocity was similar to that with placebo at the end of the treatment period (4 to 6 years).¹²

Agertoft and Pedersen¹³ found that taking inhaled corticosteroids long-term is unlikely to have an effect on final height. Children who took inhaled budesonide (up to an average daily dose of 500 μg) into adulthood ended up no shorter than those who did not.

Based on these and other data, inhaled corticosteroids are generally considered safe at recommended doses. However, the decision to prescribe them for long-term therapy should be based on the risks and benefits to the individual patient.¹

ALTERNATIVE DRUGS FOR MILD PERSISTENT ASTHMA

Leukotriene-modifying drugs include the leukotriene receptor antagonists montelukast (Singulair) and zafirlukast and the 5-lipoxygenase inhibitor zileuton (Zyflo CR). These drugs have been associated with statistically significant improvement in FEV₁ compared with placebo in patients with mild to moderate asthma, reductions in both blood and sputum eosinophils,¹⁴ and attenuation of bronchoconstriction with exercise.¹¹

Large randomized trials comparing leukotriene modifier therapy with low-dose inhaled steroids in adults and children with mild persistent asthma have found that although outcomes improve with either therapy, the improvement is statistically superior with inhaled steroids for most asthma-control measures. ^6,8 Low-dose inhaled steroid therapy in patients with mild persistent and moderate persistent asthma has been associated with superior clinical outcomes as well as greater improvement in pulmonary function than treatment with antileukotriene drugs (Table 2).⁸

Asthma is heterogeneous, and properly selected patients with mild persistent asthma may achieve good control with leukotrienemodifier monotherapy.¹⁵ Alternatives for patients with mild persistent asthma include the methylxanthine theophylline, but this drug is less desirable due to its narrow therapeutic index. ¹ The inhaled cromones nedocromil (Tilade) and cromolyn (Intal) were other options in this patient population, but their short half-lives made them less practical, and US production has been discontinued.

THE BOTTOM LINE

Though leukotriene receptor antagonists can be effective, the daily use of inhaled corticosteroids results in higher asthma control test scores, more symptom-free days, greater pre-bronchodilator FEV₁, and decreased percentage of sputum eosinophils⁶ in patients with mild persistent asthma, and the addition of a long-acting beta agonist does not provide additional benefit.⁴ Furthermore, daily use of inhaled corticosteroids in these patients has also been associated with a lower rate of asthma-related deaths and with less need for systemic corticosteroid therapy,^7,8 even though inhaled corticosteroids have not yet been shown to alter the progressive loss of lung function.¹⁰

More children and even adults seem to be allergic to various foods these days than in the past. Also apparently on the rise is a linked condition, eosinophilic esophagitis.

The reason for these increases is not clear. This article confines itself to what we know about the mechanisms of food allergies and eosinophilic esophagitis, how to diagnose them, and how to treat them.

FOOD ALLERGIES ARE COMMON, AND MORE PREVALENT THAN EVER

Food allergies—abnormal immune responses to food proteins¹—affect an estimated 6% to 8% of young children and 3% to 4% of adults in the United States,^2,3 and their prevalence appears to be rising in developed countries. Studies in US and British children indicate that peanut allergy has doubled in the past decade. ⁴

Any food can provoke a reaction, but only a few foods account for most of the significant allergic reactions: cow’s milk, soy, wheat, eggs, peanuts, tree nuts, fish, and shellfish.

Approximately 80% of allergies to milk, egg, wheat, and soy resolve by the time the patient reaches early adolescence.⁶ Fewer cases resolve in children with tree nut allergies (approximately 9%) or peanut allergy (20%),^7,8 and allergies to fish and shellfish often develop or persist in adulthood.

A family history of an atopic disease such as asthma, allergic rhinitis, eczema, or food allergy is a risk factor for developing a food allergy. ³ Considering that the rate of peanut allergy has doubled in children over the past 10 years, environmental factors may also play a role.³

How we tolerate foods or become allergic to them

The gut, the largest mucosal organ in the body, is exposed to large quantities of foreign proteins daily. Most protein is broken down by stomach acid and digestive enzymes into lessantigenic peptides or is bound by secretory immunoglobulin A (IgA), which prevents it from being absorbed. Further, the epithelial cells lining the gut do not allow large molecules to pass easily, having tight intracellular junctions and being covered with mucus.

For these reasons, less than 2% of the protein in food is absorbed in an allergenic form.⁹ The reason food allergies are more prevalent in children is most likely that children have an immature gut barrier, lower IgA levels, a higher gastric pH, and lower proteolytic enzyme levels.

When dietary proteins do cross the gut barrier, the immune system normally suppresses the allergic response. Regulatory T cells, dendritic cells, and local immune responses play critical roles in the development of tolerance. Several types of regulatory T cells, such as Tr1 cells (which secrete interleukin 10), TH3 cells (which secrete transforming growth factor beta), CD4+CD25+ regulatory T cells, gamma-delta T cells, and CD8+ suppressor cells can all contribute to suppressing allergic responses.¹⁰ Dendritic cells also help induce tolerance by stimulating CD4+ T cells to secrete transforming growth factor beta, which leads to the production of interleukin 10 and additional transforming growth factor beta.¹¹

Factors that contribute to food allergy

Many factors may contribute to whether a person becomes tolerant to or sensitized to a specific food protein.

The dose of antigen. Tolerance can develop after either high or low doses of antigens, but by different mechanisms.

The antigen structure. Soluble antigens are less sensitizing than particulate antigens.^12,13

Processing of foods. Dry-roasted peanuts are more allergenic than raw or boiled peanuts, partly because they are less soluble.¹³

The route of initial exposure. Sensitization to food proteins can occur directly through the gut or the skin. Alternatively, it can occur indirectly via the respiratory tract. Skin exposure may be especially sensitizing in children with atopic dermatitis.^14,15

The gut flora. When mice are raised in a germ-free environment, they fail to develop normal tolerance.¹⁶ They are also more likely to become sensitized if they are treated with antibiotics or if they lack toll-like receptors that recognize bacterial lipopolysaccharides.¹⁷ Furthermore, human studies suggest that probiotics promote tolerance, especially in preventing atopic dermatitis, although the studies have had conflicting results.^18–21

The gastric pH. Murine and human studies reveal that antacid medications increase the risk of food allergy.^22,23

Genetic susceptibility. A child with a sibling who is allergic to peanuts is approximately 10 times more likely to be allergic to peanuts than predicted by the rate in the general population. Although no risk-conferring gene has been identified, a study of twins showed concordance for peanut allergy in 64.3% of identical twins vs 6.8% of fraternal twins.²⁴

 

 

Three types of immune responses to food

Immunologic reactions to foods can be divided into three categories: mediated by immunoglobulin E (IgE), non-IgE-mediated, and mixed. Therefore, these disorders can present as an acute, potentially life-threatening reaction or as a chronic disease such as eosinophilic gastoenteropathy.

IgE-mediated reactions are immediate hypersensitivity responses. In most patients, an IgE-mediated mechanism can be confirmed by a positive skin test or a test for food-specific IgE in the serum. In this article, the term “food allergy” refers to an IgE-mediated reaction to a food, unless otherwise indicated.

Non-IgE-mediated reactions have a delayed onset and chronic symptoms. Commonly, they are confined to the gastrointestinal tract; examples are food-protein-induced enterocolitis, proctitis, and proctocolitis and celiac disease.^3,26,27 However, other diseases such as contact dermatitis, dermatitis herpetiformis, and food-induced pulmonary hemosiderosis (Heiner syndrome) are also considered non-IgE-mediated allergies.

Mixed-reaction disorders are chronic and include the eosinophilic gastroenteropathies, ie, eosinophilic proctocolitis, eosinophilic gastroenteritis, and eosinophilic esophagitis.²⁸ The pathophysiology of these diseases is poorly understood. Many patients have evidence of allergic sensitivities to food or to environmental allergens, or both, but whether these sensitivities have a causal role in these disorders is not clear.

Atopic dermatitis, another complicated disease process, may be associated with mixedreaction food allergy, as approximately 35% of young children with moderate to severe atopic dermatitis have food allergies.²⁹

Diagnosis of IgE-mediated food allergies

A thorough history and physical examination are key to diagnosing an IgE-mediated food allergy.

The history should include potential culprit foods, the quantity eaten, the timing of the onset of symptoms, and related factors such as exercise, alcohol intake, or medication use. Symptoms of an IgE-mediated reaction are generally rapid in onset but may be delayed up to a few hours, while non-IgE mediated symptoms may present several hours to days later.

Food challenge. A double-blind, placebocontrolled oral food challenge is the gold standard for the diagnosis of food allergies. (The food to be tested is hidden in other food or in capsules.) However, this test poses significant risks, and other diagnostic methods are more practical for screening.

Skin-prick tests with commercially available extracts are a rapid and sensitive method of screening for allergy to several foods.

Negative skin-prick tests have an estimated negative predictive value of more than 95% and can therefore exclude IgE-mediated food allergies.

A positive test indicates the presence of IgE against a specific food allergen and suggests a clinical food allergy, although the specificity of the test is only about 50%, making a positive result difficult to interpret. Although the size of the skin-test response does not necessarily correlate with the potential severity of a reaction, a response larger than 3 mm does indicate a greater likelihood of clinical reactivity. A positive test is most helpful in confirming the diagnosis of IgE-mediated food allergy when combined with a clear history of food-induced symptoms.

The proteins in commercially based extracts of most fruits and vegetables are often labile; therefore, skin testing with fresh fruits and vegetables may be indicated.³⁰

Immunoassays. Radioallergosorbent tests (RASTs) and fluorescent enzyme immunoassays are used to identity food-specific IgE antibodies in the serum. The commercially available tests do not use radioactivity, but the term “RAST” is still commonly used.

Immunoassays are generally less sensitive and more costly than skin-prick tests, and their results are not immediately available, unlike those of skin-prick testing. However, these in vitro tests are not affected by antihistamine use and are useful in patients with severe dermatologic conditions or severe anaphylaxis, for whom skin-prick testing would not be appropriate.

However, unlike a negative skin-prick test, an undetectable serum food-specific IgE level has a low negative predictive value, and an undetectable level may be associated with symptoms of an allergic reaction for 10% to 25% of patients.²⁹ Therefore, if one suspects an allergic reaction but no food-specific IgE can be detected in the serum, confirming the absence of a clinical allergy must be done with a skin-prick test or with a physician-supervised oral challenge, or both.

Managing food allergy by avoiding the allergen

Food allergies are managed by strictly avoiding food allergens and by taking medications such as self-injectable epinephrine for anaphylactic symptoms.

Patients and caregivers must be educated about reading food labels, avoiding high-risk situations such as eating at buffets and other restaurants with high risk of cross-contamination, wearing a medical-alert bracelet, recognizing and managing early symptoms of an allergic reaction, and calling for emergency services if they are having an allergic reaction. Since January 2006, the US Food and Drug Administration has required food manufacturers to list common food allergens on food labels (cow’s milk, soy, wheat, egg, peanut, tree nuts, fish, and shellfish), and the labeling must use simple, easily understood terms, such as “milk” instead of “whey.” However, it is still prudent to read all ingredients listed on the label.

 

 

Experimental treatments for food allergies

Humanized monoclonal anti-IgE antibodies such as talizumab (also known as TNX-901) and omalizumab (Xolair) have been developed, but their use in food allergy has been limited. In a study in patients with peanut allergy, injections of talizumab increased the threshold for sensitivity to peanuts in most patients, but 25% of the patients did not have any improvement.³² A study of omalizumab in patients with peanut allergy was stopped after adverse reactions developed during oral peanut challenges.³³

Oral immunotherapy. Recent studies suggest it may be possible to induce oral tolerance in patients with IgE-mediated food allergy. Pilot studies have shown that frequent, increasing doses of food allergens (egg, milk, and peanut) may raise the threshold at which symptoms occur.^34–36 Though these studies suggest that oral immunotherapy may protect some patients against a reaction if they accidentally ingest a food they are allergic to, some patients could not reach the goal doses because allergic symptoms were provoked.

At this early stage, these strategies must be considered investigational, and more randomized, placebo-controlled studies are needed. Further studies will also be needed to assess whether oral immunotherapy induces only short-term desensitization (in which case the allergen needs to be ingested daily to prevent reactions) or sustained tolerance (in which case the antigenic protein can be ingested without symptoms despite periods of abstinence).

THE ROLE OF FOOD ALLERGY IN EOSINOPHILIC ESOPHAGITIS

Eosinophilic esophagitis has been recognized with increasing frequency in both children and adults over the past several years. Symptoms can include difficulty feeding, failure to thrive, vomiting, epigastric or chest pain, dysphagia, and food impaction.

Diagnostic criteria for eosinophilic esophagitis are³⁷:

• Clinical symptoms of esophageal dysfunction
• At least 15 eosinophils per high-power field in at least one esophageal biopsy specimen
• No response to a proton-pump inhibitor in high doses (up to 2 mg/kg/day) for 1 to 2 months, or normal results on pH probe monitoring of the esophagus (the reason for this criterion is that patients with gastroesophageal reflux disease can also have large numbers of eosinophils in the esophagus—more than 100 per highpower field³⁸)
• Exclusion of other causes.

Though the cause of eosinophilic esophagitis is not completely understood, atopy has been strongly implicated as a factor. More than 50% of patients with eosinophilic esophagitis also have an atopic condition (eg, atopic dermatitis, allergic rhinitis, asthma), as well as positive results on skin-prick testing or measurement of antigen-specific IgE in the serum.^39–41 Also, since most patients improve with either dietary restriction or elemental diets, food sensitization appears to play a considerable role.

As with atopic conditions such as asthma, atopic dermatitis, allergic rhinitis, and food allergy, eosinophilic esophagitis has been linked with immune responses involving helper T cell 2 (T_H2). Adults and children with eosinophilic esophagitis have been found to have elevated eosinophil counts and total IgE levels in peripheral blood.³⁷ In the esophagus, patients have elevated levels of the T_H2 cytokines often seen in atopic patients (eg, interleukins 4, 5, and 13) and mast cells.^42,43 In mice, eosinophilic esophagitis can be induced by allergen exposure and overexpression of T_H2 cytokines.^44,45 Expression of eotaxin-3, a potent eosinophil chemoattractant, was noted to be higher in children with eosinophilic esophagitis than in controls.⁴⁶

Of interest, some patients with eosinophilic esophagitis say their symptoms vary with the seasons, correlating with seasonal changes in esophageal eosinophil levels.^47,48

Studies linking eosinophilic esophagitis and food allergy in children

Kelly et al⁴⁹ reported that 10 children with chronic symptomatic gastroesophageal reflux and eosinophilic esophagitis all had partial or complete resolution of symptoms on an elemental diet.

Markowitz et al⁵⁰ found that symptoms of chronic reflux disease and eosinophilic esophagitis improved in 49 of 51 children on an elemental diet, and the number of eosinophils in the distal esophagus decreased significantly.

Liacouras et al³⁹ reported similar findings in a 10-year experience. Of 132 children who had eosinophilic esophagitis, 75 improved with dietary restriction based on results of skin-prick and patch testing. The 57 patients who did not respond and 115 others were started on an elemental diet. Of the 164 patients who complied with the elemental diet, 160 had significant improvement of symptoms and a significant decrease in the number of eosinophils in the esophagus. Individual foods were reintroduced approximately every 5 days, and esophagogastroduodenoscopy with biopsies was performed 4 to 8 weeks after the last was reintroduced into the diet.

In a retrospective study, Kagalwalla et al⁵¹ reported that 60 children with eosinophilic esophagitis were treated with either an elemental diet or a six-food elimination diet (no milk, soy, wheat, egg, peanut, or seafood). The two groups showed similar clinical and histologic improvements.

Collectively, these studies in pediatric patients imply that food allergy is a significant factor in the pathogenesis of eosinophilic esophagitis.

 

 

Studies in adults

Fewer studies of the link between food allergy and eosinophilic esophagitis have been done in adults.

In a preliminary study, 18 adults followed the six-food elimination diet. Symptoms improved in 17 (94%), and histologic findings improved in 14 (78%).⁵²

On the other hand, in six adult patients with eosinophilic esophagitis, Simon et al⁵³ found that only one had improvement in symptoms after eliminating wheat and rye from the diet, and none had significant changes in the number of eosinophils in the esophagus.

In a 37-year-old man with eosinophilic esophagitis, symptoms improved after eliminating egg from his diet.⁵⁴

Yamazaki et al⁵⁵ measured expression of interleukin 5 and interleukin 13 in 15 adult patients with eosinophilic esophagitis. Food and aeroallergens that included milk, soy, dust mite, ragweed, and Aspergillus induced significantly more interleukin 5 production in these patients than in atopic controls, suggesting that both foods and aeroallergens may have a role in the pathogenesis of eosinophilic esophagitis in adults.

How to identify potential food triggers of eosinophilic esophagitis

Though elemental diets have been associated with a decrease in symptoms and esophageal eosinophilia, elemental formulas are expensive and unpalatable and pose a risk of nutritional deprivation. Identifying specific food allergens to eliminate from the diet in patients with eosinophilic esophagitis may be less expensive and more desirable than a very limited or elemental diet.

However, potential food triggers have been hard to identify in eosinophilic esophagitis. A recent consensus report did not recommend in vitro food allergy testing,³⁷ owing to a lack of positive or negative predictive values for food-specific IgE level testing in eosinophilic esophagitis. Furthermore, the absence of IgE does not eliminate a food as a potential trigger, since non-IgE mechanisms may play a role.

Skin-prick testing is one of the currently validated diagnostic methods. Several studies have used skin-prick testing of foods in patients with eosinophilic esophagitis. In these studies, approximately two-thirds of patients had positive test reactions to at least one food, most often to common food allergens such as cow’s milk, egg, soy, wheat, and peanut, but also to rye, beef, and bean.³⁷ In a recent article,⁵⁶ 81% of adult patients with eosinophilic esophagitis had one or more allergens identified by skin-prick testing, and 50% of the patients tested positive for one or more food allergens.

Atopy patch testing. The combination of skin-prick testing and atopy patch testing may be more effective than skin-prick testing alone in identifying potential food triggers. Atopy patch testing has been used in the diagnosis of non-IgE cell-mediated (delayed) immune responses, in which T cells may play a significant role.

Atopy patch testing is similar to patch testing for contact dermatitis. It involves placing a small quantity of food on the skin and evaluating for a local delayed reaction after a set time.

In two studies,^50,57 146 children with biopsy-proven eosinophilic esophagitis had foods eliminated from the diet on the basis of positive skin-prick tests and atopy patch tests. Approximately 77% of the children had significant reduction of esophageal eosinophils in biopsy specimens (from 20 per high-power field to 1.1). The foods most commonly implicated by skin-prick testing were cow’s milk, egg, wheat, peanut, shellfish, peas, beef, fish, rye, and tomato; those identified by atopy patch testing were cow’s milk, egg, wheat, corn, beef, milk, soy, rye, chicken, oats, and potato. The combination of both types of testing had a negative predictive value of 88% to 100% for all foods except milk, while the positive predictive value was greater than 74% for the most common foods causing eosinophilic esophagitis.⁵⁸

Though atopy patch testing shows some usefulness in identifying foods that may elicit non-IgE-mediated reactions, currently these tests are not validated and have been evaluated in only a small number of studies. Currently, no standardized testing materials, methods of application, or interpretation of results exist, and no studies have included a control population to validate atopy patch testing. More studies are needed to validate atopy patch testing as a reliable diagnostic tool before it can be recommended as a component of routine diagnostic evaluation in patients with eosinophilic esophagitis.

More children and even adults seem to be allergic to various foods these days than in the past. Also apparently on the rise is a linked condition, eosinophilic esophagitis.

The reason for these increases is not clear. This article confines itself to what we know about the mechanisms of food allergies and eosinophilic esophagitis, how to diagnose them, and how to treat them.

FOOD ALLERGIES ARE COMMON, AND MORE PREVALENT THAN EVER

Food allergies—abnormal immune responses to food proteins¹—affect an estimated 6% to 8% of young children and 3% to 4% of adults in the United States,^2,3 and their prevalence appears to be rising in developed countries. Studies in US and British children indicate that peanut allergy has doubled in the past decade. ⁴

Any food can provoke a reaction, but only a few foods account for most of the significant allergic reactions: cow’s milk, soy, wheat, eggs, peanuts, tree nuts, fish, and shellfish.

Approximately 80% of allergies to milk, egg, wheat, and soy resolve by the time the patient reaches early adolescence.⁶ Fewer cases resolve in children with tree nut allergies (approximately 9%) or peanut allergy (20%),^7,8 and allergies to fish and shellfish often develop or persist in adulthood.

A family history of an atopic disease such as asthma, allergic rhinitis, eczema, or food allergy is a risk factor for developing a food allergy. ³ Considering that the rate of peanut allergy has doubled in children over the past 10 years, environmental factors may also play a role.³

How we tolerate foods or become allergic to them

The gut, the largest mucosal organ in the body, is exposed to large quantities of foreign proteins daily. Most protein is broken down by stomach acid and digestive enzymes into lessantigenic peptides or is bound by secretory immunoglobulin A (IgA), which prevents it from being absorbed. Further, the epithelial cells lining the gut do not allow large molecules to pass easily, having tight intracellular junctions and being covered with mucus.

For these reasons, less than 2% of the protein in food is absorbed in an allergenic form.⁹ The reason food allergies are more prevalent in children is most likely that children have an immature gut barrier, lower IgA levels, a higher gastric pH, and lower proteolytic enzyme levels.

When dietary proteins do cross the gut barrier, the immune system normally suppresses the allergic response. Regulatory T cells, dendritic cells, and local immune responses play critical roles in the development of tolerance. Several types of regulatory T cells, such as Tr1 cells (which secrete interleukin 10), TH3 cells (which secrete transforming growth factor beta), CD4+CD25+ regulatory T cells, gamma-delta T cells, and CD8+ suppressor cells can all contribute to suppressing allergic responses.¹⁰ Dendritic cells also help induce tolerance by stimulating CD4+ T cells to secrete transforming growth factor beta, which leads to the production of interleukin 10 and additional transforming growth factor beta.¹¹

Factors that contribute to food allergy

Many factors may contribute to whether a person becomes tolerant to or sensitized to a specific food protein.

The dose of antigen. Tolerance can develop after either high or low doses of antigens, but by different mechanisms.

The antigen structure. Soluble antigens are less sensitizing than particulate antigens.^12,13

Processing of foods. Dry-roasted peanuts are more allergenic than raw or boiled peanuts, partly because they are less soluble.¹³

The route of initial exposure. Sensitization to food proteins can occur directly through the gut or the skin. Alternatively, it can occur indirectly via the respiratory tract. Skin exposure may be especially sensitizing in children with atopic dermatitis.^14,15

The gut flora. When mice are raised in a germ-free environment, they fail to develop normal tolerance.¹⁶ They are also more likely to become sensitized if they are treated with antibiotics or if they lack toll-like receptors that recognize bacterial lipopolysaccharides.¹⁷ Furthermore, human studies suggest that probiotics promote tolerance, especially in preventing atopic dermatitis, although the studies have had conflicting results.^18–21

The gastric pH. Murine and human studies reveal that antacid medications increase the risk of food allergy.^22,23

Genetic susceptibility. A child with a sibling who is allergic to peanuts is approximately 10 times more likely to be allergic to peanuts than predicted by the rate in the general population. Although no risk-conferring gene has been identified, a study of twins showed concordance for peanut allergy in 64.3% of identical twins vs 6.8% of fraternal twins.²⁴

 

 

Three types of immune responses to food

Immunologic reactions to foods can be divided into three categories: mediated by immunoglobulin E (IgE), non-IgE-mediated, and mixed. Therefore, these disorders can present as an acute, potentially life-threatening reaction or as a chronic disease such as eosinophilic gastoenteropathy.

IgE-mediated reactions are immediate hypersensitivity responses. In most patients, an IgE-mediated mechanism can be confirmed by a positive skin test or a test for food-specific IgE in the serum. In this article, the term “food allergy” refers to an IgE-mediated reaction to a food, unless otherwise indicated.

Non-IgE-mediated reactions have a delayed onset and chronic symptoms. Commonly, they are confined to the gastrointestinal tract; examples are food-protein-induced enterocolitis, proctitis, and proctocolitis and celiac disease.^3,26,27 However, other diseases such as contact dermatitis, dermatitis herpetiformis, and food-induced pulmonary hemosiderosis (Heiner syndrome) are also considered non-IgE-mediated allergies.

Mixed-reaction disorders are chronic and include the eosinophilic gastroenteropathies, ie, eosinophilic proctocolitis, eosinophilic gastroenteritis, and eosinophilic esophagitis.²⁸ The pathophysiology of these diseases is poorly understood. Many patients have evidence of allergic sensitivities to food or to environmental allergens, or both, but whether these sensitivities have a causal role in these disorders is not clear.

Atopic dermatitis, another complicated disease process, may be associated with mixedreaction food allergy, as approximately 35% of young children with moderate to severe atopic dermatitis have food allergies.²⁹

Diagnosis of IgE-mediated food allergies

A thorough history and physical examination are key to diagnosing an IgE-mediated food allergy.

The history should include potential culprit foods, the quantity eaten, the timing of the onset of symptoms, and related factors such as exercise, alcohol intake, or medication use. Symptoms of an IgE-mediated reaction are generally rapid in onset but may be delayed up to a few hours, while non-IgE mediated symptoms may present several hours to days later.

Food challenge. A double-blind, placebocontrolled oral food challenge is the gold standard for the diagnosis of food allergies. (The food to be tested is hidden in other food or in capsules.) However, this test poses significant risks, and other diagnostic methods are more practical for screening.

Skin-prick tests with commercially available extracts are a rapid and sensitive method of screening for allergy to several foods.

Negative skin-prick tests have an estimated negative predictive value of more than 95% and can therefore exclude IgE-mediated food allergies.

A positive test indicates the presence of IgE against a specific food allergen and suggests a clinical food allergy, although the specificity of the test is only about 50%, making a positive result difficult to interpret. Although the size of the skin-test response does not necessarily correlate with the potential severity of a reaction, a response larger than 3 mm does indicate a greater likelihood of clinical reactivity. A positive test is most helpful in confirming the diagnosis of IgE-mediated food allergy when combined with a clear history of food-induced symptoms.

The proteins in commercially based extracts of most fruits and vegetables are often labile; therefore, skin testing with fresh fruits and vegetables may be indicated.³⁰

Immunoassays. Radioallergosorbent tests (RASTs) and fluorescent enzyme immunoassays are used to identity food-specific IgE antibodies in the serum. The commercially available tests do not use radioactivity, but the term “RAST” is still commonly used.

Immunoassays are generally less sensitive and more costly than skin-prick tests, and their results are not immediately available, unlike those of skin-prick testing. However, these in vitro tests are not affected by antihistamine use and are useful in patients with severe dermatologic conditions or severe anaphylaxis, for whom skin-prick testing would not be appropriate.

However, unlike a negative skin-prick test, an undetectable serum food-specific IgE level has a low negative predictive value, and an undetectable level may be associated with symptoms of an allergic reaction for 10% to 25% of patients.²⁹ Therefore, if one suspects an allergic reaction but no food-specific IgE can be detected in the serum, confirming the absence of a clinical allergy must be done with a skin-prick test or with a physician-supervised oral challenge, or both.

Managing food allergy by avoiding the allergen

Food allergies are managed by strictly avoiding food allergens and by taking medications such as self-injectable epinephrine for anaphylactic symptoms.

Patients and caregivers must be educated about reading food labels, avoiding high-risk situations such as eating at buffets and other restaurants with high risk of cross-contamination, wearing a medical-alert bracelet, recognizing and managing early symptoms of an allergic reaction, and calling for emergency services if they are having an allergic reaction. Since January 2006, the US Food and Drug Administration has required food manufacturers to list common food allergens on food labels (cow’s milk, soy, wheat, egg, peanut, tree nuts, fish, and shellfish), and the labeling must use simple, easily understood terms, such as “milk” instead of “whey.” However, it is still prudent to read all ingredients listed on the label.

 

 

Experimental treatments for food allergies

Humanized monoclonal anti-IgE antibodies such as talizumab (also known as TNX-901) and omalizumab (Xolair) have been developed, but their use in food allergy has been limited. In a study in patients with peanut allergy, injections of talizumab increased the threshold for sensitivity to peanuts in most patients, but 25% of the patients did not have any improvement.³² A study of omalizumab in patients with peanut allergy was stopped after adverse reactions developed during oral peanut challenges.³³

Oral immunotherapy. Recent studies suggest it may be possible to induce oral tolerance in patients with IgE-mediated food allergy. Pilot studies have shown that frequent, increasing doses of food allergens (egg, milk, and peanut) may raise the threshold at which symptoms occur.^34–36 Though these studies suggest that oral immunotherapy may protect some patients against a reaction if they accidentally ingest a food they are allergic to, some patients could not reach the goal doses because allergic symptoms were provoked.

At this early stage, these strategies must be considered investigational, and more randomized, placebo-controlled studies are needed. Further studies will also be needed to assess whether oral immunotherapy induces only short-term desensitization (in which case the allergen needs to be ingested daily to prevent reactions) or sustained tolerance (in which case the antigenic protein can be ingested without symptoms despite periods of abstinence).

THE ROLE OF FOOD ALLERGY IN EOSINOPHILIC ESOPHAGITIS

Eosinophilic esophagitis has been recognized with increasing frequency in both children and adults over the past several years. Symptoms can include difficulty feeding, failure to thrive, vomiting, epigastric or chest pain, dysphagia, and food impaction.

Diagnostic criteria for eosinophilic esophagitis are³⁷:

• Clinical symptoms of esophageal dysfunction
• At least 15 eosinophils per high-power field in at least one esophageal biopsy specimen
• No response to a proton-pump inhibitor in high doses (up to 2 mg/kg/day) for 1 to 2 months, or normal results on pH probe monitoring of the esophagus (the reason for this criterion is that patients with gastroesophageal reflux disease can also have large numbers of eosinophils in the esophagus—more than 100 per highpower field³⁸)
• Exclusion of other causes.

Though the cause of eosinophilic esophagitis is not completely understood, atopy has been strongly implicated as a factor. More than 50% of patients with eosinophilic esophagitis also have an atopic condition (eg, atopic dermatitis, allergic rhinitis, asthma), as well as positive results on skin-prick testing or measurement of antigen-specific IgE in the serum.^39–41 Also, since most patients improve with either dietary restriction or elemental diets, food sensitization appears to play a considerable role.

As with atopic conditions such as asthma, atopic dermatitis, allergic rhinitis, and food allergy, eosinophilic esophagitis has been linked with immune responses involving helper T cell 2 (T_H2). Adults and children with eosinophilic esophagitis have been found to have elevated eosinophil counts and total IgE levels in peripheral blood.³⁷ In the esophagus, patients have elevated levels of the T_H2 cytokines often seen in atopic patients (eg, interleukins 4, 5, and 13) and mast cells.^42,43 In mice, eosinophilic esophagitis can be induced by allergen exposure and overexpression of T_H2 cytokines.^44,45 Expression of eotaxin-3, a potent eosinophil chemoattractant, was noted to be higher in children with eosinophilic esophagitis than in controls.⁴⁶

Of interest, some patients with eosinophilic esophagitis say their symptoms vary with the seasons, correlating with seasonal changes in esophageal eosinophil levels.^47,48

Studies linking eosinophilic esophagitis and food allergy in children

Kelly et al⁴⁹ reported that 10 children with chronic symptomatic gastroesophageal reflux and eosinophilic esophagitis all had partial or complete resolution of symptoms on an elemental diet.

Markowitz et al⁵⁰ found that symptoms of chronic reflux disease and eosinophilic esophagitis improved in 49 of 51 children on an elemental diet, and the number of eosinophils in the distal esophagus decreased significantly.

Liacouras et al³⁹ reported similar findings in a 10-year experience. Of 132 children who had eosinophilic esophagitis, 75 improved with dietary restriction based on results of skin-prick and patch testing. The 57 patients who did not respond and 115 others were started on an elemental diet. Of the 164 patients who complied with the elemental diet, 160 had significant improvement of symptoms and a significant decrease in the number of eosinophils in the esophagus. Individual foods were reintroduced approximately every 5 days, and esophagogastroduodenoscopy with biopsies was performed 4 to 8 weeks after the last was reintroduced into the diet.

In a retrospective study, Kagalwalla et al⁵¹ reported that 60 children with eosinophilic esophagitis were treated with either an elemental diet or a six-food elimination diet (no milk, soy, wheat, egg, peanut, or seafood). The two groups showed similar clinical and histologic improvements.

Collectively, these studies in pediatric patients imply that food allergy is a significant factor in the pathogenesis of eosinophilic esophagitis.

 

 

Studies in adults

Fewer studies of the link between food allergy and eosinophilic esophagitis have been done in adults.

In a preliminary study, 18 adults followed the six-food elimination diet. Symptoms improved in 17 (94%), and histologic findings improved in 14 (78%).⁵²

On the other hand, in six adult patients with eosinophilic esophagitis, Simon et al⁵³ found that only one had improvement in symptoms after eliminating wheat and rye from the diet, and none had significant changes in the number of eosinophils in the esophagus.

In a 37-year-old man with eosinophilic esophagitis, symptoms improved after eliminating egg from his diet.⁵⁴

Yamazaki et al⁵⁵ measured expression of interleukin 5 and interleukin 13 in 15 adult patients with eosinophilic esophagitis. Food and aeroallergens that included milk, soy, dust mite, ragweed, and Aspergillus induced significantly more interleukin 5 production in these patients than in atopic controls, suggesting that both foods and aeroallergens may have a role in the pathogenesis of eosinophilic esophagitis in adults.

How to identify potential food triggers of eosinophilic esophagitis

Though elemental diets have been associated with a decrease in symptoms and esophageal eosinophilia, elemental formulas are expensive and unpalatable and pose a risk of nutritional deprivation. Identifying specific food allergens to eliminate from the diet in patients with eosinophilic esophagitis may be less expensive and more desirable than a very limited or elemental diet.

However, potential food triggers have been hard to identify in eosinophilic esophagitis. A recent consensus report did not recommend in vitro food allergy testing,³⁷ owing to a lack of positive or negative predictive values for food-specific IgE level testing in eosinophilic esophagitis. Furthermore, the absence of IgE does not eliminate a food as a potential trigger, since non-IgE mechanisms may play a role.

Skin-prick testing is one of the currently validated diagnostic methods. Several studies have used skin-prick testing of foods in patients with eosinophilic esophagitis. In these studies, approximately two-thirds of patients had positive test reactions to at least one food, most often to common food allergens such as cow’s milk, egg, soy, wheat, and peanut, but also to rye, beef, and bean.³⁷ In a recent article,⁵⁶ 81% of adult patients with eosinophilic esophagitis had one or more allergens identified by skin-prick testing, and 50% of the patients tested positive for one or more food allergens.

Atopy patch testing. The combination of skin-prick testing and atopy patch testing may be more effective than skin-prick testing alone in identifying potential food triggers. Atopy patch testing has been used in the diagnosis of non-IgE cell-mediated (delayed) immune responses, in which T cells may play a significant role.

Atopy patch testing is similar to patch testing for contact dermatitis. It involves placing a small quantity of food on the skin and evaluating for a local delayed reaction after a set time.

In two studies,^50,57 146 children with biopsy-proven eosinophilic esophagitis had foods eliminated from the diet on the basis of positive skin-prick tests and atopy patch tests. Approximately 77% of the children had significant reduction of esophageal eosinophils in biopsy specimens (from 20 per high-power field to 1.1). The foods most commonly implicated by skin-prick testing were cow’s milk, egg, wheat, peanut, shellfish, peas, beef, fish, rye, and tomato; those identified by atopy patch testing were cow’s milk, egg, wheat, corn, beef, milk, soy, rye, chicken, oats, and potato. The combination of both types of testing had a negative predictive value of 88% to 100% for all foods except milk, while the positive predictive value was greater than 74% for the most common foods causing eosinophilic esophagitis.⁵⁸

Though atopy patch testing shows some usefulness in identifying foods that may elicit non-IgE-mediated reactions, currently these tests are not validated and have been evaluated in only a small number of studies. Currently, no standardized testing materials, methods of application, or interpretation of results exist, and no studies have included a control population to validate atopy patch testing. More studies are needed to validate atopy patch testing as a reliable diagnostic tool before it can be recommended as a component of routine diagnostic evaluation in patients with eosinophilic esophagitis.

More children and even adults seem to be allergic to various foods these days than in the past. Also apparently on the rise is a linked condition, eosinophilic esophagitis.

The reason for these increases is not clear. This article confines itself to what we know about the mechanisms of food allergies and eosinophilic esophagitis, how to diagnose them, and how to treat them.

FOOD ALLERGIES ARE COMMON, AND MORE PREVALENT THAN EVER

Food allergies—abnormal immune responses to food proteins¹—affect an estimated 6% to 8% of young children and 3% to 4% of adults in the United States,^2,3 and their prevalence appears to be rising in developed countries. Studies in US and British children indicate that peanut allergy has doubled in the past decade. ⁴

Any food can provoke a reaction, but only a few foods account for most of the significant allergic reactions: cow’s milk, soy, wheat, eggs, peanuts, tree nuts, fish, and shellfish.

Approximately 80% of allergies to milk, egg, wheat, and soy resolve by the time the patient reaches early adolescence.⁶ Fewer cases resolve in children with tree nut allergies (approximately 9%) or peanut allergy (20%),^7,8 and allergies to fish and shellfish often develop or persist in adulthood.

A family history of an atopic disease such as asthma, allergic rhinitis, eczema, or food allergy is a risk factor for developing a food allergy. ³ Considering that the rate of peanut allergy has doubled in children over the past 10 years, environmental factors may also play a role.³

How we tolerate foods or become allergic to them

The gut, the largest mucosal organ in the body, is exposed to large quantities of foreign proteins daily. Most protein is broken down by stomach acid and digestive enzymes into lessantigenic peptides or is bound by secretory immunoglobulin A (IgA), which prevents it from being absorbed. Further, the epithelial cells lining the gut do not allow large molecules to pass easily, having tight intracellular junctions and being covered with mucus.

For these reasons, less than 2% of the protein in food is absorbed in an allergenic form.⁹ The reason food allergies are more prevalent in children is most likely that children have an immature gut barrier, lower IgA levels, a higher gastric pH, and lower proteolytic enzyme levels.

When dietary proteins do cross the gut barrier, the immune system normally suppresses the allergic response. Regulatory T cells, dendritic cells, and local immune responses play critical roles in the development of tolerance. Several types of regulatory T cells, such as Tr1 cells (which secrete interleukin 10), TH3 cells (which secrete transforming growth factor beta), CD4+CD25+ regulatory T cells, gamma-delta T cells, and CD8+ suppressor cells can all contribute to suppressing allergic responses.¹⁰ Dendritic cells also help induce tolerance by stimulating CD4+ T cells to secrete transforming growth factor beta, which leads to the production of interleukin 10 and additional transforming growth factor beta.¹¹

Factors that contribute to food allergy

Many factors may contribute to whether a person becomes tolerant to or sensitized to a specific food protein.

The dose of antigen. Tolerance can develop after either high or low doses of antigens, but by different mechanisms.

The antigen structure. Soluble antigens are less sensitizing than particulate antigens.^12,13

Processing of foods. Dry-roasted peanuts are more allergenic than raw or boiled peanuts, partly because they are less soluble.¹³

The route of initial exposure. Sensitization to food proteins can occur directly through the gut or the skin. Alternatively, it can occur indirectly via the respiratory tract. Skin exposure may be especially sensitizing in children with atopic dermatitis.^14,15

The gut flora. When mice are raised in a germ-free environment, they fail to develop normal tolerance.¹⁶ They are also more likely to become sensitized if they are treated with antibiotics or if they lack toll-like receptors that recognize bacterial lipopolysaccharides.¹⁷ Furthermore, human studies suggest that probiotics promote tolerance, especially in preventing atopic dermatitis, although the studies have had conflicting results.^18–21

The gastric pH. Murine and human studies reveal that antacid medications increase the risk of food allergy.^22,23

Genetic susceptibility. A child with a sibling who is allergic to peanuts is approximately 10 times more likely to be allergic to peanuts than predicted by the rate in the general population. Although no risk-conferring gene has been identified, a study of twins showed concordance for peanut allergy in 64.3% of identical twins vs 6.8% of fraternal twins.²⁴

 

 

Three types of immune responses to food

Immunologic reactions to foods can be divided into three categories: mediated by immunoglobulin E (IgE), non-IgE-mediated, and mixed. Therefore, these disorders can present as an acute, potentially life-threatening reaction or as a chronic disease such as eosinophilic gastoenteropathy.

IgE-mediated reactions are immediate hypersensitivity responses. In most patients, an IgE-mediated mechanism can be confirmed by a positive skin test or a test for food-specific IgE in the serum. In this article, the term “food allergy” refers to an IgE-mediated reaction to a food, unless otherwise indicated.

Non-IgE-mediated reactions have a delayed onset and chronic symptoms. Commonly, they are confined to the gastrointestinal tract; examples are food-protein-induced enterocolitis, proctitis, and proctocolitis and celiac disease.^3,26,27 However, other diseases such as contact dermatitis, dermatitis herpetiformis, and food-induced pulmonary hemosiderosis (Heiner syndrome) are also considered non-IgE-mediated allergies.

Mixed-reaction disorders are chronic and include the eosinophilic gastroenteropathies, ie, eosinophilic proctocolitis, eosinophilic gastroenteritis, and eosinophilic esophagitis.²⁸ The pathophysiology of these diseases is poorly understood. Many patients have evidence of allergic sensitivities to food or to environmental allergens, or both, but whether these sensitivities have a causal role in these disorders is not clear.

Atopic dermatitis, another complicated disease process, may be associated with mixedreaction food allergy, as approximately 35% of young children with moderate to severe atopic dermatitis have food allergies.²⁹

Diagnosis of IgE-mediated food allergies

A thorough history and physical examination are key to diagnosing an IgE-mediated food allergy.

The history should include potential culprit foods, the quantity eaten, the timing of the onset of symptoms, and related factors such as exercise, alcohol intake, or medication use. Symptoms of an IgE-mediated reaction are generally rapid in onset but may be delayed up to a few hours, while non-IgE mediated symptoms may present several hours to days later.

Food challenge. A double-blind, placebocontrolled oral food challenge is the gold standard for the diagnosis of food allergies. (The food to be tested is hidden in other food or in capsules.) However, this test poses significant risks, and other diagnostic methods are more practical for screening.

Skin-prick tests with commercially available extracts are a rapid and sensitive method of screening for allergy to several foods.

Negative skin-prick tests have an estimated negative predictive value of more than 95% and can therefore exclude IgE-mediated food allergies.

A positive test indicates the presence of IgE against a specific food allergen and suggests a clinical food allergy, although the specificity of the test is only about 50%, making a positive result difficult to interpret. Although the size of the skin-test response does not necessarily correlate with the potential severity of a reaction, a response larger than 3 mm does indicate a greater likelihood of clinical reactivity. A positive test is most helpful in confirming the diagnosis of IgE-mediated food allergy when combined with a clear history of food-induced symptoms.

The proteins in commercially based extracts of most fruits and vegetables are often labile; therefore, skin testing with fresh fruits and vegetables may be indicated.³⁰

Immunoassays. Radioallergosorbent tests (RASTs) and fluorescent enzyme immunoassays are used to identity food-specific IgE antibodies in the serum. The commercially available tests do not use radioactivity, but the term “RAST” is still commonly used.

Immunoassays are generally less sensitive and more costly than skin-prick tests, and their results are not immediately available, unlike those of skin-prick testing. However, these in vitro tests are not affected by antihistamine use and are useful in patients with severe dermatologic conditions or severe anaphylaxis, for whom skin-prick testing would not be appropriate.

However, unlike a negative skin-prick test, an undetectable serum food-specific IgE level has a low negative predictive value, and an undetectable level may be associated with symptoms of an allergic reaction for 10% to 25% of patients.²⁹ Therefore, if one suspects an allergic reaction but no food-specific IgE can be detected in the serum, confirming the absence of a clinical allergy must be done with a skin-prick test or with a physician-supervised oral challenge, or both.

Managing food allergy by avoiding the allergen

Food allergies are managed by strictly avoiding food allergens and by taking medications such as self-injectable epinephrine for anaphylactic symptoms.

Patients and caregivers must be educated about reading food labels, avoiding high-risk situations such as eating at buffets and other restaurants with high risk of cross-contamination, wearing a medical-alert bracelet, recognizing and managing early symptoms of an allergic reaction, and calling for emergency services if they are having an allergic reaction. Since January 2006, the US Food and Drug Administration has required food manufacturers to list common food allergens on food labels (cow’s milk, soy, wheat, egg, peanut, tree nuts, fish, and shellfish), and the labeling must use simple, easily understood terms, such as “milk” instead of “whey.” However, it is still prudent to read all ingredients listed on the label.

 

 

Experimental treatments for food allergies

Humanized monoclonal anti-IgE antibodies such as talizumab (also known as TNX-901) and omalizumab (Xolair) have been developed, but their use in food allergy has been limited. In a study in patients with peanut allergy, injections of talizumab increased the threshold for sensitivity to peanuts in most patients, but 25% of the patients did not have any improvement.³² A study of omalizumab in patients with peanut allergy was stopped after adverse reactions developed during oral peanut challenges.³³

Oral immunotherapy. Recent studies suggest it may be possible to induce oral tolerance in patients with IgE-mediated food allergy. Pilot studies have shown that frequent, increasing doses of food allergens (egg, milk, and peanut) may raise the threshold at which symptoms occur.^34–36 Though these studies suggest that oral immunotherapy may protect some patients against a reaction if they accidentally ingest a food they are allergic to, some patients could not reach the goal doses because allergic symptoms were provoked.

At this early stage, these strategies must be considered investigational, and more randomized, placebo-controlled studies are needed. Further studies will also be needed to assess whether oral immunotherapy induces only short-term desensitization (in which case the allergen needs to be ingested daily to prevent reactions) or sustained tolerance (in which case the antigenic protein can be ingested without symptoms despite periods of abstinence).

THE ROLE OF FOOD ALLERGY IN EOSINOPHILIC ESOPHAGITIS

Eosinophilic esophagitis has been recognized with increasing frequency in both children and adults over the past several years. Symptoms can include difficulty feeding, failure to thrive, vomiting, epigastric or chest pain, dysphagia, and food impaction.

Diagnostic criteria for eosinophilic esophagitis are³⁷:

• Clinical symptoms of esophageal dysfunction
• At least 15 eosinophils per high-power field in at least one esophageal biopsy specimen
• No response to a proton-pump inhibitor in high doses (up to 2 mg/kg/day) for 1 to 2 months, or normal results on pH probe monitoring of the esophagus (the reason for this criterion is that patients with gastroesophageal reflux disease can also have large numbers of eosinophils in the esophagus—more than 100 per highpower field³⁸)
• Exclusion of other causes.

Though the cause of eosinophilic esophagitis is not completely understood, atopy has been strongly implicated as a factor. More than 50% of patients with eosinophilic esophagitis also have an atopic condition (eg, atopic dermatitis, allergic rhinitis, asthma), as well as positive results on skin-prick testing or measurement of antigen-specific IgE in the serum.^39–41 Also, since most patients improve with either dietary restriction or elemental diets, food sensitization appears to play a considerable role.

As with atopic conditions such as asthma, atopic dermatitis, allergic rhinitis, and food allergy, eosinophilic esophagitis has been linked with immune responses involving helper T cell 2 (T_H2). Adults and children with eosinophilic esophagitis have been found to have elevated eosinophil counts and total IgE levels in peripheral blood.³⁷ In the esophagus, patients have elevated levels of the T_H2 cytokines often seen in atopic patients (eg, interleukins 4, 5, and 13) and mast cells.^42,43 In mice, eosinophilic esophagitis can be induced by allergen exposure and overexpression of T_H2 cytokines.^44,45 Expression of eotaxin-3, a potent eosinophil chemoattractant, was noted to be higher in children with eosinophilic esophagitis than in controls.⁴⁶

Of interest, some patients with eosinophilic esophagitis say their symptoms vary with the seasons, correlating with seasonal changes in esophageal eosinophil levels.^47,48

Studies linking eosinophilic esophagitis and food allergy in children

Kelly et al⁴⁹ reported that 10 children with chronic symptomatic gastroesophageal reflux and eosinophilic esophagitis all had partial or complete resolution of symptoms on an elemental diet.

Markowitz et al⁵⁰ found that symptoms of chronic reflux disease and eosinophilic esophagitis improved in 49 of 51 children on an elemental diet, and the number of eosinophils in the distal esophagus decreased significantly.

Liacouras et al³⁹ reported similar findings in a 10-year experience. Of 132 children who had eosinophilic esophagitis, 75 improved with dietary restriction based on results of skin-prick and patch testing. The 57 patients who did not respond and 115 others were started on an elemental diet. Of the 164 patients who complied with the elemental diet, 160 had significant improvement of symptoms and a significant decrease in the number of eosinophils in the esophagus. Individual foods were reintroduced approximately every 5 days, and esophagogastroduodenoscopy with biopsies was performed 4 to 8 weeks after the last was reintroduced into the diet.

In a retrospective study, Kagalwalla et al⁵¹ reported that 60 children with eosinophilic esophagitis were treated with either an elemental diet or a six-food elimination diet (no milk, soy, wheat, egg, peanut, or seafood). The two groups showed similar clinical and histologic improvements.

Collectively, these studies in pediatric patients imply that food allergy is a significant factor in the pathogenesis of eosinophilic esophagitis.

 

 

Studies in adults

Fewer studies of the link between food allergy and eosinophilic esophagitis have been done in adults.

In a preliminary study, 18 adults followed the six-food elimination diet. Symptoms improved in 17 (94%), and histologic findings improved in 14 (78%).⁵²

On the other hand, in six adult patients with eosinophilic esophagitis, Simon et al⁵³ found that only one had improvement in symptoms after eliminating wheat and rye from the diet, and none had significant changes in the number of eosinophils in the esophagus.

In a 37-year-old man with eosinophilic esophagitis, symptoms improved after eliminating egg from his diet.⁵⁴

Yamazaki et al⁵⁵ measured expression of interleukin 5 and interleukin 13 in 15 adult patients with eosinophilic esophagitis. Food and aeroallergens that included milk, soy, dust mite, ragweed, and Aspergillus induced significantly more interleukin 5 production in these patients than in atopic controls, suggesting that both foods and aeroallergens may have a role in the pathogenesis of eosinophilic esophagitis in adults.

How to identify potential food triggers of eosinophilic esophagitis

Though elemental diets have been associated with a decrease in symptoms and esophageal eosinophilia, elemental formulas are expensive and unpalatable and pose a risk of nutritional deprivation. Identifying specific food allergens to eliminate from the diet in patients with eosinophilic esophagitis may be less expensive and more desirable than a very limited or elemental diet.

However, potential food triggers have been hard to identify in eosinophilic esophagitis. A recent consensus report did not recommend in vitro food allergy testing,³⁷ owing to a lack of positive or negative predictive values for food-specific IgE level testing in eosinophilic esophagitis. Furthermore, the absence of IgE does not eliminate a food as a potential trigger, since non-IgE mechanisms may play a role.

Skin-prick testing is one of the currently validated diagnostic methods. Several studies have used skin-prick testing of foods in patients with eosinophilic esophagitis. In these studies, approximately two-thirds of patients had positive test reactions to at least one food, most often to common food allergens such as cow’s milk, egg, soy, wheat, and peanut, but also to rye, beef, and bean.³⁷ In a recent article,⁵⁶ 81% of adult patients with eosinophilic esophagitis had one or more allergens identified by skin-prick testing, and 50% of the patients tested positive for one or more food allergens.

Atopy patch testing. The combination of skin-prick testing and atopy patch testing may be more effective than skin-prick testing alone in identifying potential food triggers. Atopy patch testing has been used in the diagnosis of non-IgE cell-mediated (delayed) immune responses, in which T cells may play a significant role.

Atopy patch testing is similar to patch testing for contact dermatitis. It involves placing a small quantity of food on the skin and evaluating for a local delayed reaction after a set time.

In two studies,^50,57 146 children with biopsy-proven eosinophilic esophagitis had foods eliminated from the diet on the basis of positive skin-prick tests and atopy patch tests. Approximately 77% of the children had significant reduction of esophageal eosinophils in biopsy specimens (from 20 per high-power field to 1.1). The foods most commonly implicated by skin-prick testing were cow’s milk, egg, wheat, peanut, shellfish, peas, beef, fish, rye, and tomato; those identified by atopy patch testing were cow’s milk, egg, wheat, corn, beef, milk, soy, rye, chicken, oats, and potato. The combination of both types of testing had a negative predictive value of 88% to 100% for all foods except milk, while the positive predictive value was greater than 74% for the most common foods causing eosinophilic esophagitis.⁵⁸

Though atopy patch testing shows some usefulness in identifying foods that may elicit non-IgE-mediated reactions, currently these tests are not validated and have been evaluated in only a small number of studies. Currently, no standardized testing materials, methods of application, or interpretation of results exist, and no studies have included a control population to validate atopy patch testing. More studies are needed to validate atopy patch testing as a reliable diagnostic tool before it can be recommended as a component of routine diagnostic evaluation in patients with eosinophilic esophagitis.

Many questions about systemic lupus erythematosus (SLE, lupus) remain unanswered. Why is this disease so difficult to diagnose even for rheumatologists? Why does lupus tend to develop in previously healthy young women? Why does the disease manifest in so many ways? Why are our current treatments suboptimal?

This article addresses these questions in a brief overview and update of SLE, with an emphasis on clinical pearls regarding prevention and treatment that are relevant to any physician who sees patients with this disease.

WOMEN AND MINORITIES ARE OVERREPRESENTED

Women have a much higher prevalence of almost all autoimmune diseases. SLE has a 12:1 female-to-male ratio during the ages of 15 to 45 years, but when disease develops in either children or the elderly, the female-to-male ratio is only 2:1.

African Americans, Asian Americans, and Hispanics have about a three to four times higher frequency of lupus than white non-Hispanics and often have more severe disease.

WHY IS SLE SO DIFFICULT TO DIAGNOSE?

SLE is frequently overlooked; patients spend an average of 4 years and see three physicians before the disease is correctly diagnosed. Part of the problem is that presentations of the disease vary so widely between patients and that signs and symptoms evolve over time. Often, physicians do not consider SLE in the differential diagnosis.

On the other hand, SLE is also often over-diagnosed. Narain et al¹ evaluated 263 patients who had a presumptive diagnosis of SLE. Only about half of the patients had a confirmed diagnosis; about 5% had a different autoimmune disease, such as scleroderma, systemic sclerosis, Sjögren syndrome, or polymyositis; 5% had fibromyalgia; 29% tested positive for ANA but did not have an autoimmune disease; and 10% had a nonrheumatic disease, such as a hematologic malignancy with rheumatic disease manifestations. For patients referred by a community rheumatologist, the diagnostic accuracy was better, about 80%.

The traditional classification criteria for SLE^2,3 are problematic. Some criteria are very specific for SLE but are not very sensitive—eg, anti-double-stranded DNA is present in about half of patients with SLE. Others tests, like ANA, are sensitive but not specific—although ANA is present in 95% of patients with SLE, the positive predictive value of the test for SLE for any given patient is only 11%.

Other criteria are highly subjective, including oral ulcers and photosensitivity. These signs may be present in normal individuals who get an occasional aphthous ulcer or who are fair-skinned and burn easily with prolonged sun exposure. It takes a trained clinician to distinguish these from the photosensitivity and oral ulcers associated with lupus.

Many diseases can mimic SLE

Fibromyalgia frequently presents in women and may include joint and muscle aches, fatigue, and occasionally a positive ANA. ANA may be seen in about 15% of healthy women.

Sjögren syndrome can also present with arthritis, fatigue, and a positive ANA; it is commonly overlooked because physicians do not often think to ask about the classic symptoms of dry eyes and dry mouth.

Dermatomyositis causes rashes that have many features in common with SLE. Even the skin biopsy is often indistinguishable from SLE.

Hematologic problems, such as idiopathic or thrombotic thrombocytopenic purpura, primary antiphospholipid syndrome, and hematologic neoplasms, can cause serologic changes, a positive ANA, and other manifestations seen in SLE.

Drug-induced lupus should always be considered in older patients presenting with SLE-like disease. Now with the use of minocycline (Minocin) and other related agents for the treatment of acne, we are seeing younger women with drug-induced lupus.

PATIENTS ASK ‘WHY ME?’

Lupus typically develops in a young woman who was previously healthy. Such patients inevitably wonder, why me?

Lupus is like a puzzle, with genetics, gender, and the environment being important pieces of the puzzle. If all the pieces come together, people develop defective immune regulation and a break in self-tolerance. Everyone generates antibodies to self, but these low-affinity, nonpathologic antibodies are inconsequential. In SLE, autoantibodies lead to the formation of immune complexes, complement activation, and tissue damage.

Genetics plays an important role

Genetics plays an important role but is clearly not the only determining factor. Clustering in families has been shown, although a patient with lupus is more likely to have a relative with another autoimmune disease, especially autoimmune thyroid disease, than with SLE. The likelihood of an identical twin of a patient with SLE having the disease is only 25% to 30%, and is only about 5% for a fraternal twin.

In the first few months of 2008, four major studies were published that shed light on the genetics of SLE.^4–7 Together, the studies evaluated more than 5,000 patients with SLE using genome-wide association scans and identified areas of the genome that are frequently different in patients with lupus than in healthy controls. Three of the four studies identified the same genetic area as important and supported the concept that B cells and complement activation play important roles in the disease pathogenesis.

Although over 95% of cases of SLE cannot be attributed to a single gene, there are rare cases of lupus that may provide important clues to mechanisms of disease. For example a homozygous deficiency of C1q (an early component of complement) is extremely rare in lupus but is associated with the highest risk (nearly 90%) of developing the disease. Deficiencies in other components of the complement cascade also carry a high risk of disease development.

Investigators discovered that C1q plays an important role in clearing away apoptotic cellular debris. If a person is deficient in C1q, clearance of this debris is impaired. In a person genetically predisposed to getting lupus, the immune system now has an opportunity to react to self-antigens exposed during apoptosis that are not being cleared away.

Even though lupus cases cannot be explained by an absence of C1q, a defect in the clearance of apoptotic cells is a common, unifying feature of the disease.

Immune response is enhanced by environmental factors

Environmental factors, especially sun exposure, are also important. Following sunburn, skin cells undergo massive cell death, and patients with lupus have a huge release of self-antigens that can be recognized by the immune system. Sunburn is like having a booster vaccine of self-antigen to stimulate autoantibody production. Not only does the skin flare, but internal organs can also flare after intense sun exposure.

LUPUS SURVIVAL HAS IMPROVED; DISEASES OF AGING NOW A FOCUS

In 1950, only 50% of patients with SLE survived 5 years after diagnosis; now, thanks to better treatment and earlier diagnosis, 80% to 90% survive at least 10 years.

Early on, patients tend to die of active disease (manifestations of vasculitis, pulmonary hemorrhage, kidney problems) or infection. Over time, cardiovascular disease and osteoporosis become more of a problem. Patients also have a higher risk of cancer throughout life.

Lupus has an unpredictable course, with flares and remissions. But underlying the reversible inflammatory changes is irreversible organ damage caused by the disease itself and, possibly, by treatment. Preventing bone disease, heart disease, and cancer now play more prominent roles in managing SLE.

Increased bone disease

Fracture rates are higher than expected in women with lupus; Ramsey-Goldman et al⁸ calculated the rate as five times higher than in the general population. The increased risk of osteoporosis is partly due to treatment with corticosteroids, but it is also likely caused by inflammation from lupus. Even controlling for steroid use, increased bone loss is still evident in patients with SLE.

African American women with lupus are not exempt. Lee et al⁹ found that, after adjusting for body mass, steroid use, thyroid disease, and menopausal status, African American women with SLE had more than five times the risk of low bone mineral density in the spine than white women with the disease.

Increased cancer risk

Patients with SLE have an increased risk of hematologic cancer and possibly lung and hepatobiliary cancers.

Bernatsky et al¹⁰ evaluated cancer risk in an international cohort of patients with SLE from 23 sites. Among patients with SLE, for all cancers combined, the standardized incidence ratio was 1.2; for hematologic cancers the ratio was 2.8; and for non-Hodgkin lymphoma it was 2.4. Surprisingly, although SLE is primarily a disease of women, reproductive cancer rates in patients with SLE did not differ from background rates. Bernatsky et al did not compare rates of cervical cancer, as many cancer registries do not record it. However, studies from the National Institutes of Health indicate that cervical dysplasia is common in patients with lupus.

Other interesting findings included an increased risk of hepatobiliary cancer, especially among men with SLE. Lung cancers were also increased, which has been observed in patients with other autoimmune diseases such as scleroderma and polymyositis. Smoking is a strong predictor for developing autoimmune conditions and may play a role in the observed increased cancer risk.

Early and advanced cardiovascular disease

Patients with SLE are at high risk of atherosclerotic cardiovascular disease. At the University of Pittsburgh Medical Center from 1980 to 1993, we compared the incidence of myocardial infarction in nearly 500 women with SLE and more than 2,000 women of similar age in the Framingham Offspring Study. At ages 15 to 24, women with lupus had a rate of 6.33 per 1,000 person-years; at age 25 to 34, the rate was 3.66 per 1,000 person-years. None of the Framingham women in those age groups had events.

Women ages 35 to 44 with lupus had a risk of heart attack 50 times higher than women in the Framingham cohort, and women in older age groups had a risk 2.5 to 4 times higher.¹¹

Subclinical cardiovascular disease is also increased in women with SLE. Asanuma et al¹² used electron-beam computed tomography to screen for coronary artery calcification in 65 patients with SLE and 69 control subjects with no history of coronary artery disease matched for age, sex, and race. Calcification was present in 31% of patients with lupus vs 9% of controls (P = .002). Roman et al¹³ performed carotid ultrasonography on 197 patients with lupus and 197 matched controls and found more plaque in patients with lupus (37%) than in controls (15%, P < .001).

Other data also suggest that women with lupus have advanced cardiovascular disease and develop it early, with most studies finding the greatest relative risk of cardiovascular disease between ages 18 and 45 years.

Traditional risk factors for cardiovascular disease cannot fully explain the increased risk. Many patients with lupus have metabolic syndrome, hypertension, and renal disease, but even after adjusting for these risk factors, patients with lupus still have about a 7 to 10 times higher risk of nonfatal coronary heart disease and a 17 times higher risk of fatal coronary heart disease.¹⁴

Many investigators are now exploring the role of immune dysfunction and inflammation in cardiovascular disease. A number of biomarkers have been proposed for predicting risk of cardiovascular disease in the general population. The list includes many inflammatory factors that rheumatologists have been studying for decades, including myeloperoxidase, autoantibodies, inflammatory cytokines, tumor necrosis factor alpha, and adhesion molecules, many of which also play a role in autoimmunity.

In our patients with SLE, we found that about 90% had three or more modifiable cardiovascular risk factors that were not being addressed appropriately (unpublished data). Lipid management was the least often addressed by rheumatologists and primary caregivers.

There is reason to believe that lupus patients are a high-risk group that merit aggressive risk-factor management, but no formal recommendations can be made without clear evidence that this approach improves outcomes.

SLE INCREASES THE RISK OF ADVERSE PREGNANCY OUTCOMES

Women with SLE more commonly miscarry and deliver low-birth-weight babies than do other women. A history of renal disease is the factor most predictive of poor pregnancy outcome, and the presence of certain autoantibodies increases the risk of neonatal lupus.

We recommend that women with lupus have inactive disease for at least 6 months before becoming pregnant.

ORAL CONTRACEPTIVES AND HORMONE REPLACEMENT

Hormone replacement therapy and oral contraceptives do not increase the risk of significant disease activity flares in lupus. However, women with lupus have an increased risk of cardiovascular disease and thrombosis.

Buyon et al¹⁵ randomly assigned 351 menopausal women with inactive or stable active SLE to receive either hormone replacement therapy or placebo for 12 months. No significant increase in severe flares of the disease was observed, although the treatment group had a mild increase in minor flares.

Petri et al¹⁶ randomly assigned 183 women with inactive or stable active SLE to receive either combined oral contraceptives or placebo for 12 months and found similar rates of disease activity between the two groups.

A weakness of these trials is that women with antiphospholipid antibodies in high titers or who had previous thrombotic events were excluded.

TREATMENTS ON THE HORIZON?

In the past 50 years, only three drug treatments have been approved for lupus: corticosteroids, hydroxychloroquine, and aspirin. Fortunately, research in autoimmune diseases has rapidly expanded, and new drugs are on the horizon.

Mycophenolate mofetil (CellCept) may be a reasonable alternative to cyclophosphamide (Cytoxan) for lupus nephritis and may be appropriate as maintenance therapy after induction with cyclophosphamide.

Ginzler et al,¹⁷ in a randomized, open-label trial in 140 patients with active lupus nephritis, gave either oral mycophenolate mofetil (initial dosage 1,000 mg/day, increased to 3,000 mg/day) or monthly intravenous cyclophosphamide (0.5 g/m², increased to 1.0 g/m²). Mycophenolate mofetil was more effective in inducing remission than cyclophosphamide and had a better safety profile.

The Aspreva Lupus Management Study was designed to assess the efficacy of oral mycophenolate mofetil compared with intravenous cyclophosphamide in the initial treatment of patients with active class III–V lupus nephritis and to assess the long-term efficacy of mycophenolate mofetil compared with azathioprine in maintaining remission and renal function. It was the largest study of mycophenolate mofetil in lupus nephritis to date. There were 370 patients with SLE enrolled. In the 24-week induction phase, patients were randomized to receive open-label mycophenolate mofetil with a target dose of 3 g/day or intravenous cyclophosphamide 0.5 to 1.0 g/m² in monthly pulses. Both groups received prednisone. Response to treatment was defined as a decrease in proteinuria (as measured by the urinary protein-creatinine ratio) and improvement or stabilization in serum creatinine.

The results (presented at the American College of Rheumatology Meeting, November 6–11, 2007, in Boston, MA) showed that 104 (56%) of the 185 patients treated with mycophenolate mofetil responded, compared with 98 (53%) of the 185 patients treated with intravenous cyclophosphamide (P = .575). The study therefore did not meet its primary objective of showing a superior response rate with mycophenolate mofetil compared with cyclophosphamide. There was no difference in adverse events. It is this author’s opinion that having an agent that is at least as good as cyclphosphamide in treating lupus nephritis is a major step forward.

Mycophenolate mofetil can cause fetal harm and should not be used during pregnancy. It is recommended that the drug be stopped for 3 to 6 months before a woman tries to conceive.

New drugs target B cells

Many new drugs for lupus target B cells.

Rituximab (Rituxan) is a monoclonal antibody that depletes B cells by targeting the B-cell-specific antigen CD20. It has been studied for treating lupus in several open-label studies that altogether have included more than 400 patients.^18–21 Regimens included either those used in oncology for treatment of lymphoma or those used in rheumatoid arthritis, coupled with high-dose corticosteroids and cyclophosphamide. In early studies, nearly 80% of treated patients entered at least partial remission, and 25% to 50% are still in remission more than 12 months later.

The first randomized controlled trial of rituximab vs placebo was recently completed and presented at the American College of Rheumatology meeting, October 24–28, 2008, in Boston, MA. The EXPLORER trial (sponsored by Genentech) included 257 patients with moderate to severe disease activity. The results showed that there was no difference in major or partial clinical response (based on a change in the British Isles Lupus Assessment Group index) in those on rituximab (28.4%) vs placebo (29.6%) at 12 months (P = .97). Overall, adverse events were balanced between the groups. It is this author’s opinion that the bar for “response” was set very high in this study, considering that all patients who entered were fairly sick and received significant doses of corticosteroids that were tapered over the course of the trial.

B-cell toleragens, which render B cells incapable of presenting specific antigens, are also of interest.

Other experimental drugs target the soluble cytokine BLyS, which normally binds to a B-cell receptor and prolongs B-cell survival. It may also be possible to inhibit costimulatory pathways (which are normally important for inducing activation, proliferation, and class-switching of B cells) with the use of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin inhibitor (CTLA4Ig) and anti-CD40 ligand.

The results of a 12-month exploratory, phase II trial of abatacept (Bristol-Myers Squibb) in patients with SLE and active polyarthritis, serositis, or discoid lesions were presented at the American College of Rheumatology meeting in 2008. The primary and secondary end points (based on an adjudicated British Isles Lupus Assessment Group index) were not met. There were no differences in adverse events. Post hoc analyses of other clinical end points and biomarkers suggested that abatacept may have benefit in lupus. Further studies are under way.

Downstream blockade may also be useful, with drugs that inhibit inflammatory cytokines, particularly interferon alfa. This is now being tested in clinical trials.

Many questions about systemic lupus erythematosus (SLE, lupus) remain unanswered. Why is this disease so difficult to diagnose even for rheumatologists? Why does lupus tend to develop in previously healthy young women? Why does the disease manifest in so many ways? Why are our current treatments suboptimal?

This article addresses these questions in a brief overview and update of SLE, with an emphasis on clinical pearls regarding prevention and treatment that are relevant to any physician who sees patients with this disease.

WOMEN AND MINORITIES ARE OVERREPRESENTED

Women have a much higher prevalence of almost all autoimmune diseases. SLE has a 12:1 female-to-male ratio during the ages of 15 to 45 years, but when disease develops in either children or the elderly, the female-to-male ratio is only 2:1.

African Americans, Asian Americans, and Hispanics have about a three to four times higher frequency of lupus than white non-Hispanics and often have more severe disease.

WHY IS SLE SO DIFFICULT TO DIAGNOSE?

SLE is frequently overlooked; patients spend an average of 4 years and see three physicians before the disease is correctly diagnosed. Part of the problem is that presentations of the disease vary so widely between patients and that signs and symptoms evolve over time. Often, physicians do not consider SLE in the differential diagnosis.

On the other hand, SLE is also often over-diagnosed. Narain et al¹ evaluated 263 patients who had a presumptive diagnosis of SLE. Only about half of the patients had a confirmed diagnosis; about 5% had a different autoimmune disease, such as scleroderma, systemic sclerosis, Sjögren syndrome, or polymyositis; 5% had fibromyalgia; 29% tested positive for ANA but did not have an autoimmune disease; and 10% had a nonrheumatic disease, such as a hematologic malignancy with rheumatic disease manifestations. For patients referred by a community rheumatologist, the diagnostic accuracy was better, about 80%.

The traditional classification criteria for SLE^2,3 are problematic. Some criteria are very specific for SLE but are not very sensitive—eg, anti-double-stranded DNA is present in about half of patients with SLE. Others tests, like ANA, are sensitive but not specific—although ANA is present in 95% of patients with SLE, the positive predictive value of the test for SLE for any given patient is only 11%.

Other criteria are highly subjective, including oral ulcers and photosensitivity. These signs may be present in normal individuals who get an occasional aphthous ulcer or who are fair-skinned and burn easily with prolonged sun exposure. It takes a trained clinician to distinguish these from the photosensitivity and oral ulcers associated with lupus.

Many diseases can mimic SLE

Fibromyalgia frequently presents in women and may include joint and muscle aches, fatigue, and occasionally a positive ANA. ANA may be seen in about 15% of healthy women.

Sjögren syndrome can also present with arthritis, fatigue, and a positive ANA; it is commonly overlooked because physicians do not often think to ask about the classic symptoms of dry eyes and dry mouth.

Dermatomyositis causes rashes that have many features in common with SLE. Even the skin biopsy is often indistinguishable from SLE.

Hematologic problems, such as idiopathic or thrombotic thrombocytopenic purpura, primary antiphospholipid syndrome, and hematologic neoplasms, can cause serologic changes, a positive ANA, and other manifestations seen in SLE.

Drug-induced lupus should always be considered in older patients presenting with SLE-like disease. Now with the use of minocycline (Minocin) and other related agents for the treatment of acne, we are seeing younger women with drug-induced lupus.

PATIENTS ASK ‘WHY ME?’

Lupus typically develops in a young woman who was previously healthy. Such patients inevitably wonder, why me?

Lupus is like a puzzle, with genetics, gender, and the environment being important pieces of the puzzle. If all the pieces come together, people develop defective immune regulation and a break in self-tolerance. Everyone generates antibodies to self, but these low-affinity, nonpathologic antibodies are inconsequential. In SLE, autoantibodies lead to the formation of immune complexes, complement activation, and tissue damage.

Genetics plays an important role

Genetics plays an important role but is clearly not the only determining factor. Clustering in families has been shown, although a patient with lupus is more likely to have a relative with another autoimmune disease, especially autoimmune thyroid disease, than with SLE. The likelihood of an identical twin of a patient with SLE having the disease is only 25% to 30%, and is only about 5% for a fraternal twin.

In the first few months of 2008, four major studies were published that shed light on the genetics of SLE.^4–7 Together, the studies evaluated more than 5,000 patients with SLE using genome-wide association scans and identified areas of the genome that are frequently different in patients with lupus than in healthy controls. Three of the four studies identified the same genetic area as important and supported the concept that B cells and complement activation play important roles in the disease pathogenesis.

Although over 95% of cases of SLE cannot be attributed to a single gene, there are rare cases of lupus that may provide important clues to mechanisms of disease. For example a homozygous deficiency of C1q (an early component of complement) is extremely rare in lupus but is associated with the highest risk (nearly 90%) of developing the disease. Deficiencies in other components of the complement cascade also carry a high risk of disease development.

Investigators discovered that C1q plays an important role in clearing away apoptotic cellular debris. If a person is deficient in C1q, clearance of this debris is impaired. In a person genetically predisposed to getting lupus, the immune system now has an opportunity to react to self-antigens exposed during apoptosis that are not being cleared away.

Even though lupus cases cannot be explained by an absence of C1q, a defect in the clearance of apoptotic cells is a common, unifying feature of the disease.

Immune response is enhanced by environmental factors

Environmental factors, especially sun exposure, are also important. Following sunburn, skin cells undergo massive cell death, and patients with lupus have a huge release of self-antigens that can be recognized by the immune system. Sunburn is like having a booster vaccine of self-antigen to stimulate autoantibody production. Not only does the skin flare, but internal organs can also flare after intense sun exposure.

LUPUS SURVIVAL HAS IMPROVED; DISEASES OF AGING NOW A FOCUS

In 1950, only 50% of patients with SLE survived 5 years after diagnosis; now, thanks to better treatment and earlier diagnosis, 80% to 90% survive at least 10 years.

Early on, patients tend to die of active disease (manifestations of vasculitis, pulmonary hemorrhage, kidney problems) or infection. Over time, cardiovascular disease and osteoporosis become more of a problem. Patients also have a higher risk of cancer throughout life.

Lupus has an unpredictable course, with flares and remissions. But underlying the reversible inflammatory changes is irreversible organ damage caused by the disease itself and, possibly, by treatment. Preventing bone disease, heart disease, and cancer now play more prominent roles in managing SLE.

Increased bone disease

Fracture rates are higher than expected in women with lupus; Ramsey-Goldman et al⁸ calculated the rate as five times higher than in the general population. The increased risk of osteoporosis is partly due to treatment with corticosteroids, but it is also likely caused by inflammation from lupus. Even controlling for steroid use, increased bone loss is still evident in patients with SLE.

African American women with lupus are not exempt. Lee et al⁹ found that, after adjusting for body mass, steroid use, thyroid disease, and menopausal status, African American women with SLE had more than five times the risk of low bone mineral density in the spine than white women with the disease.

Increased cancer risk

Patients with SLE have an increased risk of hematologic cancer and possibly lung and hepatobiliary cancers.

Bernatsky et al¹⁰ evaluated cancer risk in an international cohort of patients with SLE from 23 sites. Among patients with SLE, for all cancers combined, the standardized incidence ratio was 1.2; for hematologic cancers the ratio was 2.8; and for non-Hodgkin lymphoma it was 2.4. Surprisingly, although SLE is primarily a disease of women, reproductive cancer rates in patients with SLE did not differ from background rates. Bernatsky et al did not compare rates of cervical cancer, as many cancer registries do not record it. However, studies from the National Institutes of Health indicate that cervical dysplasia is common in patients with lupus.

Other interesting findings included an increased risk of hepatobiliary cancer, especially among men with SLE. Lung cancers were also increased, which has been observed in patients with other autoimmune diseases such as scleroderma and polymyositis. Smoking is a strong predictor for developing autoimmune conditions and may play a role in the observed increased cancer risk.

Early and advanced cardiovascular disease

Patients with SLE are at high risk of atherosclerotic cardiovascular disease. At the University of Pittsburgh Medical Center from 1980 to 1993, we compared the incidence of myocardial infarction in nearly 500 women with SLE and more than 2,000 women of similar age in the Framingham Offspring Study. At ages 15 to 24, women with lupus had a rate of 6.33 per 1,000 person-years; at age 25 to 34, the rate was 3.66 per 1,000 person-years. None of the Framingham women in those age groups had events.

Women ages 35 to 44 with lupus had a risk of heart attack 50 times higher than women in the Framingham cohort, and women in older age groups had a risk 2.5 to 4 times higher.¹¹

Subclinical cardiovascular disease is also increased in women with SLE. Asanuma et al¹² used electron-beam computed tomography to screen for coronary artery calcification in 65 patients with SLE and 69 control subjects with no history of coronary artery disease matched for age, sex, and race. Calcification was present in 31% of patients with lupus vs 9% of controls (P = .002). Roman et al¹³ performed carotid ultrasonography on 197 patients with lupus and 197 matched controls and found more plaque in patients with lupus (37%) than in controls (15%, P < .001).

Other data also suggest that women with lupus have advanced cardiovascular disease and develop it early, with most studies finding the greatest relative risk of cardiovascular disease between ages 18 and 45 years.

Traditional risk factors for cardiovascular disease cannot fully explain the increased risk. Many patients with lupus have metabolic syndrome, hypertension, and renal disease, but even after adjusting for these risk factors, patients with lupus still have about a 7 to 10 times higher risk of nonfatal coronary heart disease and a 17 times higher risk of fatal coronary heart disease.¹⁴

Many investigators are now exploring the role of immune dysfunction and inflammation in cardiovascular disease. A number of biomarkers have been proposed for predicting risk of cardiovascular disease in the general population. The list includes many inflammatory factors that rheumatologists have been studying for decades, including myeloperoxidase, autoantibodies, inflammatory cytokines, tumor necrosis factor alpha, and adhesion molecules, many of which also play a role in autoimmunity.

In our patients with SLE, we found that about 90% had three or more modifiable cardiovascular risk factors that were not being addressed appropriately (unpublished data). Lipid management was the least often addressed by rheumatologists and primary caregivers.

There is reason to believe that lupus patients are a high-risk group that merit aggressive risk-factor management, but no formal recommendations can be made without clear evidence that this approach improves outcomes.

SLE INCREASES THE RISK OF ADVERSE PREGNANCY OUTCOMES

Women with SLE more commonly miscarry and deliver low-birth-weight babies than do other women. A history of renal disease is the factor most predictive of poor pregnancy outcome, and the presence of certain autoantibodies increases the risk of neonatal lupus.

We recommend that women with lupus have inactive disease for at least 6 months before becoming pregnant.

ORAL CONTRACEPTIVES AND HORMONE REPLACEMENT

Hormone replacement therapy and oral contraceptives do not increase the risk of significant disease activity flares in lupus. However, women with lupus have an increased risk of cardiovascular disease and thrombosis.

Buyon et al¹⁵ randomly assigned 351 menopausal women with inactive or stable active SLE to receive either hormone replacement therapy or placebo for 12 months. No significant increase in severe flares of the disease was observed, although the treatment group had a mild increase in minor flares.

Petri et al¹⁶ randomly assigned 183 women with inactive or stable active SLE to receive either combined oral contraceptives or placebo for 12 months and found similar rates of disease activity between the two groups.

A weakness of these trials is that women with antiphospholipid antibodies in high titers or who had previous thrombotic events were excluded.

TREATMENTS ON THE HORIZON?

In the past 50 years, only three drug treatments have been approved for lupus: corticosteroids, hydroxychloroquine, and aspirin. Fortunately, research in autoimmune diseases has rapidly expanded, and new drugs are on the horizon.

Mycophenolate mofetil (CellCept) may be a reasonable alternative to cyclophosphamide (Cytoxan) for lupus nephritis and may be appropriate as maintenance therapy after induction with cyclophosphamide.

Ginzler et al,¹⁷ in a randomized, open-label trial in 140 patients with active lupus nephritis, gave either oral mycophenolate mofetil (initial dosage 1,000 mg/day, increased to 3,000 mg/day) or monthly intravenous cyclophosphamide (0.5 g/m², increased to 1.0 g/m²). Mycophenolate mofetil was more effective in inducing remission than cyclophosphamide and had a better safety profile.

The Aspreva Lupus Management Study was designed to assess the efficacy of oral mycophenolate mofetil compared with intravenous cyclophosphamide in the initial treatment of patients with active class III–V lupus nephritis and to assess the long-term efficacy of mycophenolate mofetil compared with azathioprine in maintaining remission and renal function. It was the largest study of mycophenolate mofetil in lupus nephritis to date. There were 370 patients with SLE enrolled. In the 24-week induction phase, patients were randomized to receive open-label mycophenolate mofetil with a target dose of 3 g/day or intravenous cyclophosphamide 0.5 to 1.0 g/m² in monthly pulses. Both groups received prednisone. Response to treatment was defined as a decrease in proteinuria (as measured by the urinary protein-creatinine ratio) and improvement or stabilization in serum creatinine.

The results (presented at the American College of Rheumatology Meeting, November 6–11, 2007, in Boston, MA) showed that 104 (56%) of the 185 patients treated with mycophenolate mofetil responded, compared with 98 (53%) of the 185 patients treated with intravenous cyclophosphamide (P = .575). The study therefore did not meet its primary objective of showing a superior response rate with mycophenolate mofetil compared with cyclophosphamide. There was no difference in adverse events. It is this author’s opinion that having an agent that is at least as good as cyclphosphamide in treating lupus nephritis is a major step forward.

Mycophenolate mofetil can cause fetal harm and should not be used during pregnancy. It is recommended that the drug be stopped for 3 to 6 months before a woman tries to conceive.

New drugs target B cells

Many new drugs for lupus target B cells.

Rituximab (Rituxan) is a monoclonal antibody that depletes B cells by targeting the B-cell-specific antigen CD20. It has been studied for treating lupus in several open-label studies that altogether have included more than 400 patients.^18–21 Regimens included either those used in oncology for treatment of lymphoma or those used in rheumatoid arthritis, coupled with high-dose corticosteroids and cyclophosphamide. In early studies, nearly 80% of treated patients entered at least partial remission, and 25% to 50% are still in remission more than 12 months later.

The first randomized controlled trial of rituximab vs placebo was recently completed and presented at the American College of Rheumatology meeting, October 24–28, 2008, in Boston, MA. The EXPLORER trial (sponsored by Genentech) included 257 patients with moderate to severe disease activity. The results showed that there was no difference in major or partial clinical response (based on a change in the British Isles Lupus Assessment Group index) in those on rituximab (28.4%) vs placebo (29.6%) at 12 months (P = .97). Overall, adverse events were balanced between the groups. It is this author’s opinion that the bar for “response” was set very high in this study, considering that all patients who entered were fairly sick and received significant doses of corticosteroids that were tapered over the course of the trial.

B-cell toleragens, which render B cells incapable of presenting specific antigens, are also of interest.

Other experimental drugs target the soluble cytokine BLyS, which normally binds to a B-cell receptor and prolongs B-cell survival. It may also be possible to inhibit costimulatory pathways (which are normally important for inducing activation, proliferation, and class-switching of B cells) with the use of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin inhibitor (CTLA4Ig) and anti-CD40 ligand.

The results of a 12-month exploratory, phase II trial of abatacept (Bristol-Myers Squibb) in patients with SLE and active polyarthritis, serositis, or discoid lesions were presented at the American College of Rheumatology meeting in 2008. The primary and secondary end points (based on an adjudicated British Isles Lupus Assessment Group index) were not met. There were no differences in adverse events. Post hoc analyses of other clinical end points and biomarkers suggested that abatacept may have benefit in lupus. Further studies are under way.

Downstream blockade may also be useful, with drugs that inhibit inflammatory cytokines, particularly interferon alfa. This is now being tested in clinical trials.

Many questions about systemic lupus erythematosus (SLE, lupus) remain unanswered. Why is this disease so difficult to diagnose even for rheumatologists? Why does lupus tend to develop in previously healthy young women? Why does the disease manifest in so many ways? Why are our current treatments suboptimal?

This article addresses these questions in a brief overview and update of SLE, with an emphasis on clinical pearls regarding prevention and treatment that are relevant to any physician who sees patients with this disease.

WOMEN AND MINORITIES ARE OVERREPRESENTED

Women have a much higher prevalence of almost all autoimmune diseases. SLE has a 12:1 female-to-male ratio during the ages of 15 to 45 years, but when disease develops in either children or the elderly, the female-to-male ratio is only 2:1.

African Americans, Asian Americans, and Hispanics have about a three to four times higher frequency of lupus than white non-Hispanics and often have more severe disease.

WHY IS SLE SO DIFFICULT TO DIAGNOSE?

SLE is frequently overlooked; patients spend an average of 4 years and see three physicians before the disease is correctly diagnosed. Part of the problem is that presentations of the disease vary so widely between patients and that signs and symptoms evolve over time. Often, physicians do not consider SLE in the differential diagnosis.

On the other hand, SLE is also often over-diagnosed. Narain et al¹ evaluated 263 patients who had a presumptive diagnosis of SLE. Only about half of the patients had a confirmed diagnosis; about 5% had a different autoimmune disease, such as scleroderma, systemic sclerosis, Sjögren syndrome, or polymyositis; 5% had fibromyalgia; 29% tested positive for ANA but did not have an autoimmune disease; and 10% had a nonrheumatic disease, such as a hematologic malignancy with rheumatic disease manifestations. For patients referred by a community rheumatologist, the diagnostic accuracy was better, about 80%.

The traditional classification criteria for SLE^2,3 are problematic. Some criteria are very specific for SLE but are not very sensitive—eg, anti-double-stranded DNA is present in about half of patients with SLE. Others tests, like ANA, are sensitive but not specific—although ANA is present in 95% of patients with SLE, the positive predictive value of the test for SLE for any given patient is only 11%.

Other criteria are highly subjective, including oral ulcers and photosensitivity. These signs may be present in normal individuals who get an occasional aphthous ulcer or who are fair-skinned and burn easily with prolonged sun exposure. It takes a trained clinician to distinguish these from the photosensitivity and oral ulcers associated with lupus.

Many diseases can mimic SLE

Fibromyalgia frequently presents in women and may include joint and muscle aches, fatigue, and occasionally a positive ANA. ANA may be seen in about 15% of healthy women.

Sjögren syndrome can also present with arthritis, fatigue, and a positive ANA; it is commonly overlooked because physicians do not often think to ask about the classic symptoms of dry eyes and dry mouth.

Dermatomyositis causes rashes that have many features in common with SLE. Even the skin biopsy is often indistinguishable from SLE.

Hematologic problems, such as idiopathic or thrombotic thrombocytopenic purpura, primary antiphospholipid syndrome, and hematologic neoplasms, can cause serologic changes, a positive ANA, and other manifestations seen in SLE.

Drug-induced lupus should always be considered in older patients presenting with SLE-like disease. Now with the use of minocycline (Minocin) and other related agents for the treatment of acne, we are seeing younger women with drug-induced lupus.

PATIENTS ASK ‘WHY ME?’

Lupus typically develops in a young woman who was previously healthy. Such patients inevitably wonder, why me?

Lupus is like a puzzle, with genetics, gender, and the environment being important pieces of the puzzle. If all the pieces come together, people develop defective immune regulation and a break in self-tolerance. Everyone generates antibodies to self, but these low-affinity, nonpathologic antibodies are inconsequential. In SLE, autoantibodies lead to the formation of immune complexes, complement activation, and tissue damage.

Genetics plays an important role

Genetics plays an important role but is clearly not the only determining factor. Clustering in families has been shown, although a patient with lupus is more likely to have a relative with another autoimmune disease, especially autoimmune thyroid disease, than with SLE. The likelihood of an identical twin of a patient with SLE having the disease is only 25% to 30%, and is only about 5% for a fraternal twin.

In the first few months of 2008, four major studies were published that shed light on the genetics of SLE.^4–7 Together, the studies evaluated more than 5,000 patients with SLE using genome-wide association scans and identified areas of the genome that are frequently different in patients with lupus than in healthy controls. Three of the four studies identified the same genetic area as important and supported the concept that B cells and complement activation play important roles in the disease pathogenesis.

Although over 95% of cases of SLE cannot be attributed to a single gene, there are rare cases of lupus that may provide important clues to mechanisms of disease. For example a homozygous deficiency of C1q (an early component of complement) is extremely rare in lupus but is associated with the highest risk (nearly 90%) of developing the disease. Deficiencies in other components of the complement cascade also carry a high risk of disease development.

Investigators discovered that C1q plays an important role in clearing away apoptotic cellular debris. If a person is deficient in C1q, clearance of this debris is impaired. In a person genetically predisposed to getting lupus, the immune system now has an opportunity to react to self-antigens exposed during apoptosis that are not being cleared away.

Even though lupus cases cannot be explained by an absence of C1q, a defect in the clearance of apoptotic cells is a common, unifying feature of the disease.

Immune response is enhanced by environmental factors

Environmental factors, especially sun exposure, are also important. Following sunburn, skin cells undergo massive cell death, and patients with lupus have a huge release of self-antigens that can be recognized by the immune system. Sunburn is like having a booster vaccine of self-antigen to stimulate autoantibody production. Not only does the skin flare, but internal organs can also flare after intense sun exposure.

LUPUS SURVIVAL HAS IMPROVED; DISEASES OF AGING NOW A FOCUS

In 1950, only 50% of patients with SLE survived 5 years after diagnosis; now, thanks to better treatment and earlier diagnosis, 80% to 90% survive at least 10 years.

Early on, patients tend to die of active disease (manifestations of vasculitis, pulmonary hemorrhage, kidney problems) or infection. Over time, cardiovascular disease and osteoporosis become more of a problem. Patients also have a higher risk of cancer throughout life.

Lupus has an unpredictable course, with flares and remissions. But underlying the reversible inflammatory changes is irreversible organ damage caused by the disease itself and, possibly, by treatment. Preventing bone disease, heart disease, and cancer now play more prominent roles in managing SLE.

Increased bone disease

Fracture rates are higher than expected in women with lupus; Ramsey-Goldman et al⁸ calculated the rate as five times higher than in the general population. The increased risk of osteoporosis is partly due to treatment with corticosteroids, but it is also likely caused by inflammation from lupus. Even controlling for steroid use, increased bone loss is still evident in patients with SLE.

African American women with lupus are not exempt. Lee et al⁹ found that, after adjusting for body mass, steroid use, thyroid disease, and menopausal status, African American women with SLE had more than five times the risk of low bone mineral density in the spine than white women with the disease.

Increased cancer risk

Patients with SLE have an increased risk of hematologic cancer and possibly lung and hepatobiliary cancers.

Bernatsky et al¹⁰ evaluated cancer risk in an international cohort of patients with SLE from 23 sites. Among patients with SLE, for all cancers combined, the standardized incidence ratio was 1.2; for hematologic cancers the ratio was 2.8; and for non-Hodgkin lymphoma it was 2.4. Surprisingly, although SLE is primarily a disease of women, reproductive cancer rates in patients with SLE did not differ from background rates. Bernatsky et al did not compare rates of cervical cancer, as many cancer registries do not record it. However, studies from the National Institutes of Health indicate that cervical dysplasia is common in patients with lupus.

Other interesting findings included an increased risk of hepatobiliary cancer, especially among men with SLE. Lung cancers were also increased, which has been observed in patients with other autoimmune diseases such as scleroderma and polymyositis. Smoking is a strong predictor for developing autoimmune conditions and may play a role in the observed increased cancer risk.

Early and advanced cardiovascular disease

Patients with SLE are at high risk of atherosclerotic cardiovascular disease. At the University of Pittsburgh Medical Center from 1980 to 1993, we compared the incidence of myocardial infarction in nearly 500 women with SLE and more than 2,000 women of similar age in the Framingham Offspring Study. At ages 15 to 24, women with lupus had a rate of 6.33 per 1,000 person-years; at age 25 to 34, the rate was 3.66 per 1,000 person-years. None of the Framingham women in those age groups had events.

Women ages 35 to 44 with lupus had a risk of heart attack 50 times higher than women in the Framingham cohort, and women in older age groups had a risk 2.5 to 4 times higher.¹¹

Subclinical cardiovascular disease is also increased in women with SLE. Asanuma et al¹² used electron-beam computed tomography to screen for coronary artery calcification in 65 patients with SLE and 69 control subjects with no history of coronary artery disease matched for age, sex, and race. Calcification was present in 31% of patients with lupus vs 9% of controls (P = .002). Roman et al¹³ performed carotid ultrasonography on 197 patients with lupus and 197 matched controls and found more plaque in patients with lupus (37%) than in controls (15%, P < .001).

Other data also suggest that women with lupus have advanced cardiovascular disease and develop it early, with most studies finding the greatest relative risk of cardiovascular disease between ages 18 and 45 years.

Traditional risk factors for cardiovascular disease cannot fully explain the increased risk. Many patients with lupus have metabolic syndrome, hypertension, and renal disease, but even after adjusting for these risk factors, patients with lupus still have about a 7 to 10 times higher risk of nonfatal coronary heart disease and a 17 times higher risk of fatal coronary heart disease.¹⁴

Many investigators are now exploring the role of immune dysfunction and inflammation in cardiovascular disease. A number of biomarkers have been proposed for predicting risk of cardiovascular disease in the general population. The list includes many inflammatory factors that rheumatologists have been studying for decades, including myeloperoxidase, autoantibodies, inflammatory cytokines, tumor necrosis factor alpha, and adhesion molecules, many of which also play a role in autoimmunity.

In our patients with SLE, we found that about 90% had three or more modifiable cardiovascular risk factors that were not being addressed appropriately (unpublished data). Lipid management was the least often addressed by rheumatologists and primary caregivers.

There is reason to believe that lupus patients are a high-risk group that merit aggressive risk-factor management, but no formal recommendations can be made without clear evidence that this approach improves outcomes.

SLE INCREASES THE RISK OF ADVERSE PREGNANCY OUTCOMES

Women with SLE more commonly miscarry and deliver low-birth-weight babies than do other women. A history of renal disease is the factor most predictive of poor pregnancy outcome, and the presence of certain autoantibodies increases the risk of neonatal lupus.

We recommend that women with lupus have inactive disease for at least 6 months before becoming pregnant.

ORAL CONTRACEPTIVES AND HORMONE REPLACEMENT

Hormone replacement therapy and oral contraceptives do not increase the risk of significant disease activity flares in lupus. However, women with lupus have an increased risk of cardiovascular disease and thrombosis.

Buyon et al¹⁵ randomly assigned 351 menopausal women with inactive or stable active SLE to receive either hormone replacement therapy or placebo for 12 months. No significant increase in severe flares of the disease was observed, although the treatment group had a mild increase in minor flares.

Petri et al¹⁶ randomly assigned 183 women with inactive or stable active SLE to receive either combined oral contraceptives or placebo for 12 months and found similar rates of disease activity between the two groups.

A weakness of these trials is that women with antiphospholipid antibodies in high titers or who had previous thrombotic events were excluded.

TREATMENTS ON THE HORIZON?

In the past 50 years, only three drug treatments have been approved for lupus: corticosteroids, hydroxychloroquine, and aspirin. Fortunately, research in autoimmune diseases has rapidly expanded, and new drugs are on the horizon.

Mycophenolate mofetil (CellCept) may be a reasonable alternative to cyclophosphamide (Cytoxan) for lupus nephritis and may be appropriate as maintenance therapy after induction with cyclophosphamide.

Ginzler et al,¹⁷ in a randomized, open-label trial in 140 patients with active lupus nephritis, gave either oral mycophenolate mofetil (initial dosage 1,000 mg/day, increased to 3,000 mg/day) or monthly intravenous cyclophosphamide (0.5 g/m², increased to 1.0 g/m²). Mycophenolate mofetil was more effective in inducing remission than cyclophosphamide and had a better safety profile.

The Aspreva Lupus Management Study was designed to assess the efficacy of oral mycophenolate mofetil compared with intravenous cyclophosphamide in the initial treatment of patients with active class III–V lupus nephritis and to assess the long-term efficacy of mycophenolate mofetil compared with azathioprine in maintaining remission and renal function. It was the largest study of mycophenolate mofetil in lupus nephritis to date. There were 370 patients with SLE enrolled. In the 24-week induction phase, patients were randomized to receive open-label mycophenolate mofetil with a target dose of 3 g/day or intravenous cyclophosphamide 0.5 to 1.0 g/m² in monthly pulses. Both groups received prednisone. Response to treatment was defined as a decrease in proteinuria (as measured by the urinary protein-creatinine ratio) and improvement or stabilization in serum creatinine.

The results (presented at the American College of Rheumatology Meeting, November 6–11, 2007, in Boston, MA) showed that 104 (56%) of the 185 patients treated with mycophenolate mofetil responded, compared with 98 (53%) of the 185 patients treated with intravenous cyclophosphamide (P = .575). The study therefore did not meet its primary objective of showing a superior response rate with mycophenolate mofetil compared with cyclophosphamide. There was no difference in adverse events. It is this author’s opinion that having an agent that is at least as good as cyclphosphamide in treating lupus nephritis is a major step forward.

Mycophenolate mofetil can cause fetal harm and should not be used during pregnancy. It is recommended that the drug be stopped for 3 to 6 months before a woman tries to conceive.

New drugs target B cells

Many new drugs for lupus target B cells.

Rituximab (Rituxan) is a monoclonal antibody that depletes B cells by targeting the B-cell-specific antigen CD20. It has been studied for treating lupus in several open-label studies that altogether have included more than 400 patients.^18–21 Regimens included either those used in oncology for treatment of lymphoma or those used in rheumatoid arthritis, coupled with high-dose corticosteroids and cyclophosphamide. In early studies, nearly 80% of treated patients entered at least partial remission, and 25% to 50% are still in remission more than 12 months later.

The first randomized controlled trial of rituximab vs placebo was recently completed and presented at the American College of Rheumatology meeting, October 24–28, 2008, in Boston, MA. The EXPLORER trial (sponsored by Genentech) included 257 patients with moderate to severe disease activity. The results showed that there was no difference in major or partial clinical response (based on a change in the British Isles Lupus Assessment Group index) in those on rituximab (28.4%) vs placebo (29.6%) at 12 months (P = .97). Overall, adverse events were balanced between the groups. It is this author’s opinion that the bar for “response” was set very high in this study, considering that all patients who entered were fairly sick and received significant doses of corticosteroids that were tapered over the course of the trial.

B-cell toleragens, which render B cells incapable of presenting specific antigens, are also of interest.

Other experimental drugs target the soluble cytokine BLyS, which normally binds to a B-cell receptor and prolongs B-cell survival. It may also be possible to inhibit costimulatory pathways (which are normally important for inducing activation, proliferation, and class-switching of B cells) with the use of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin inhibitor (CTLA4Ig) and anti-CD40 ligand.

The results of a 12-month exploratory, phase II trial of abatacept (Bristol-Myers Squibb) in patients with SLE and active polyarthritis, serositis, or discoid lesions were presented at the American College of Rheumatology meeting in 2008. The primary and secondary end points (based on an adjudicated British Isles Lupus Assessment Group index) were not met. There were no differences in adverse events. Post hoc analyses of other clinical end points and biomarkers suggested that abatacept may have benefit in lupus. Further studies are under way.

Downstream blockade may also be useful, with drugs that inhibit inflammatory cytokines, particularly interferon alfa. This is now being tested in clinical trials.