Complement Deficiencies

Background

The complement system is part of the innate immune system. The complement system plays an important part in defense against pyogenic organisms. It promotes the inflammatory response, eliminates pathogens, and enhances the immune response. Deficiencies in the complement cascade can lead to overwhelming infection and sepsis.

In addition to playing an important role in host defense against infection, the complement system is a mediator in both the pathogenesis and prevention of immune complex diseases, such as systemic lupus erythematosus (SLE). These findings underscore the duality of the complement system. It has a protective effect when functioning in moderation against pathogens; at the same time, the inflammation promoted by complement activation can result in cellular damage when not kept in check.

Knowledge about the complement system is continuing to expand. New studies point to the complex interplay between the complement cascade and adaptive immune response, and complement is also being studied in association with ischemic injury as a target of therapy. Although the complement system is part of the body's innate, relatively nonspecific defense against pathogens, its role is hardly primitive or easily understood. This article outlines some of the disease states associated with complement deficiencies and their clinical implications.

Pathophysiology

The complement cascade consists of 3 separate pathways that converge in a final common pathway. The pathways include the classical pathway (C1qrs, C2, C4), the alternative pathway (C3, factor B, properdin), and the lectin pathway (mannan-binding lectin [MBL]). The classical pathway is triggered by interaction of the Fc portion of an antibody (immunoglobulin [Ig] M, IgG1, IgG2, IgG3) or C-reactive protein with C1q. The alternative pathway is activated in an antibody-independent manner. Lectins activate the lectin pathway in a manner similar to the antibody interaction with complement in the classical pathway. These 3 pathways converge at the component C3. Although each branch is triggered differently, the common goal is to deposit clusters of C3b on a target. This deposition provides for the assembly of the membrane attack complex (MAC), components C5b-9. The MAC exerts powerful killing activity by creating perforations in cellular membranes.

Deficiencies in complement predispose patients to infection via 2 mechanisms: (1) ineffective opsonization and (2) defects in lytic activity (defects in MAC). Specific complement deficiencies are also associated with an increased risk of developing autoimmune disease, such as SLE.

An intricate system regulates complement activity. The important components of this system are various cell membrane–associated proteins such as complement receptor 1 (CR1), complement receptor 2 (CR2), and decay accelerating factor (DAF).

In addition to these cell surface–associated proteins, other plasma proteins regulate specific steps of the classic or alternative pathway; for example, the proteins factor H and factor I inhibit the formation of the enzyme C3 convertase of the alternative pathway. Similarly, the enzyme C1q esterase acts as an inhibitor of the classic pathway serine proteases C1r and C1s. Deficiency of any of these regulatory proteins results in a state of overactivation of the complement system, with damaging inflammatory effects. Two clinical manifestations of such deficiencies are paroxysmal nocturnal hemoglobinuria and hereditary angioedema, both of which are discussed in other eMedicine articles.

Frequency

International

Complement deficiencies are relatively rare worldwide, and estimates of prevalence are based on results from screening high-risk populations. Retrospective studies of persons with frequent meningococcal infections report varying prevalence based on geographic location. In populations with recurrent meningococcal infection, the prevalence rate is as high as 30%. Individuals with C1q deficiency have a 93% chance of developing SLE. Similarly, C1rs deficiency has a 57% association with SLE and C4 deficiency has a 75% association with SLE.

Mortality/Morbidity

• Individuals with complement deficiencies that hinder opsonization present with frequent recurrent infections and a high rate of morbidity and mortality. Deficiency of C3, the major opsonin, results in recurrent pyogenic infections, particularly with encapsulated bacteria.

• Deficiencies of early classical pathway components (C1, C4, C2) do not usually predispose individuals to severe infections but are associated with autoimmune disorders, especially SLE.

• Patients with a defect in formation of the MAC have a lesser degree of morbidity and mortality than, for example, patients with a defect in C3; the deficiency in the lytic component of the complement cascade is thought to have some protective effect against the generation of full-blown sepsis. These patients are at high risk for recurrent infection with Neisseria gonorrhoeae or Neisseria meningitidis. Severe pyogenic infections and sepsis occur in children and neonates who have a deficiency of a MAC component.

Race

• While no definitive racial patterns of association have been established for the majority of complement deficiencies, ethnic predispositions have been described for certain complement deficiencies. For example, deficiencies in properdin and C2 have been associated with the white race, C6 deficiencies have been shown to have a possible predisposition in African populations, and deficiencies in C8 and C9 have been associated with an Asian racial background. However, for most of these deficiencies, the absolute number of patients studied has been quite small.

Sex

• Most complement deficiencies affect both sexes equally.

• The majority of complement deficiencies are inherited in an autosomal recessive pattern (although MBL deficiency has been described as having both an autosomal dominant and recessive pattern). An exception to the autosomal pattern of inheritance is properdin deficiency, which is an X-linked trait.

Age

• Individuals with complement deficiencies that hinder opsonization often present at an early age (months to a few years) because of increased susceptibility to overwhelming infection.

• Patients with deficiencies in formation of the MAC tend to present when slightly older (late-teenage years).

• Complement deficiencies associated with immune complex diseases, such as SLE, do not show a clear pattern of age at first presentation.

Treatment

Medical Care

• Definitive treatment of complement deficiencies requires replacing the missing component of the cascade, either through direct infusion of the protein or through gene therapy. Because neither of these options is currently available, treatment of these patients focuses on managing the sequelae of the particular complement deficiencies.
• • For many patients, treatment must be focused on eradicating a particular infection, especially with encapsulated organisms such as N meningitidis. In most cases of meningococcal disease, treatment with meningeal doses of a third-generation cephalosporin covers most strains of N meningitidis.

  • For other patients, the complement deficiency may manifest as episodic flares of autoimmune diseases; treatment of these patients focuses on immunosuppressive therapy of these diseases.

  • Importantly, note that some overlap often exists between an increased susceptibility to infection and the greater tendency to develop autoimmune disease; both of these clinical situations may need to be addressed simultaneously in any one patient.

Consultations

• In a patient with a possible complement deficiency, consider consultation with an allergist and immunologist to determine appropriate diagnostic tests.

• Also, consider consultation with a rheumatologist or infectious disease specialist to help manage acute complications of the complement deficiency.

Diet

• No specific diet restrictions are required.

Activity

• Activity can continue as tolerated by the patient.

Medication

Cephalosporins are often used for treatment of N meningitidis infection in patients with complement deficiency. Third- or fourth-generation cephalosporins are used for coverage of infection with any of the encapsulated bacteria.

Drug Category: Antibiotics

Therapy must cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity results whenever feasible.

Drug Name	Ceftriaxone (Rocephin)
Description	Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins.
Adult Dose	Meningitis: 2 g IV qd for 14-21 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; caution in breastfeeding and allergy to penicillin

Drug Name	Cefepime (Maxipime)
Description	Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage.
Adult Dose	1-2 g IV q12h for 5-10 d; may administer higher or more frequent doses depending on severity of infection
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase effects; aminoglycosides increase nephrotoxic potential
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); prolonged use may predispose to superinfection

Anaphylaxis

Background

Portier and Richet first coined the term anaphylaxis in 1902 when a second vaccinating dose of sea anemone toxin caused a dog's death. The response was the opposite of prophylaxis and thus was referred to as anaphylaxis, meaning without protection.

Anaphylaxis is an acute systemic reaction caused by the release of mediators from mast cells and basophils. More than one organ system should be involved for the reaction to be considered anaphylaxis. The most common organ systems involved include the cutaneous, respiratory, cardiovascular, and gastrointestinal systems.

The phrase anaphylactic reaction usually refers to a type I hypersensitivity reaction with mast cell and basophil degranulation mediated by antigen binding of specific immunoglobulin E (IgE). The term anaphylactoid reaction refers instead to a non–IgE-mediated mechanism of mast cell/basophil activation. The term anaphylaxis refers to the physiologic events due to either mechanism.

Pathophysiology

When mast cells and basophils degranulate, whether by IgE- or non–IgE-mediated mechanisms, preformed histamine and newly generated leukotrienes and prostaglandins are released. The physiologic responses to these mediators include smooth muscle spasm in the respiratory and gastrointestinal tract, vasodilation, increased vascular permeability, and stimulation of sensory nerve endings. These physiologic events lead to the classic symptoms of anaphylaxis: flushing; urticaria; pruritus; bronchospasm; and abdominal cramping with nausea, vomiting, and diarrhea. Hypotension and shock can result from intravascular volume loss, vasodilation, and myocardial dysfunction. Increased vascular permeability can result in a shift of 50% of vascular volume to the extravascular space within 10 minutes.

Additional mediators activate other pathways of inflammation: the neutral proteases, tryptase and chymase; proteoglycans such as heparin and chondroitin sulfate; and chemokines and cytokines. These mediators can activate the kinin system, the complement cascade, and coagulation pathways. Working together, these inflammatory pathways recruit other inflammatory cells, including eosinophils and lymphocytes, resulting in prolonged, biphasic, and/or intensified reactions.

Despite the potential contribution of multiple mediators, histamine infusion alone is sufficient to produce most of the symptoms of anaphylaxis. Histamine mediates its effects through activation of histamine 1 (H1) and histamine 2 (H2) receptors. Vasodilation is mediated by both H1 receptors and H2 receptors. H2 receptors exert a direct effect on vascular smooth muscle, whereas H1 receptors stimulate endothelial cells to produce nitric oxide. Cardiac effects of histamine are largely mediated through H2 receptors. H1 receptors are primarily responsible for extravascular smooth muscle contraction (eg, bronchial tree, gastrointestinal tract). Both H1 receptors and H2 receptors mediate glandular hypersecretion.

Frequency

United States

The true incidence is unknown. Moneret-Vautrin et al recently reviewed the published literature and stated that severe anaphylaxis affects at least 1-3 persons per 10,000 population. Neugut et al estimated that 1-15% of the US population are at risk of experiencing an anaphylactic or anaphylactoid reaction. They estimated that the rate of actual anaphylaxis to food was 0.0004%, 0.7-10% for penicillin, 0.22-1% for radiocontrast media (RCM), and 0.5-5% after insect stings.

A population-based study from Olmsted County, Minnesota, detected an average annual incidence of anaphylaxis of 21 cases per 100,000 person-years. Ingestion of a suspect food was the cause in 36% of cases; a medication, allergy immunotherapy, or a diagnostic agent was the cause in 17% of cases; and an insect sting was the cause in 15% of cases. Thirty-two percent of cases were considered idiopathic. Episodes of anaphylaxis occurred more frequently in the summer months of July through September, which is attributable to insect stings.

In a study of patients referred to an allergy practice in Memphis, Tennessee, food was the cause of anaphylaxis in 34% of patients, medications in 20%, and exercise in 7% (insect sting anaphylaxis was excluded from the study). The cause of anaphylaxis was undetermined in 37% of patients. A separate study estimated the number of cases of idiopathic anaphylaxis in the United States to be 20,000-47,000 cases per year (approximately 8-19 episodes per 100,000 person-years).

International

Geographic location is not thought to exert a major effect on incidence. Two European studies detected a lower average annual incidence than found in the Olmsted County study (3.2 cases of anaphylactic shock per 100,000 person-years in Denmark; 9.8 cases of out-of-hospital anaphylaxis per 100,000 person-years in Munich, Germany). Rates in Europe range from 1-3 cases per 10,000. Simons and colleagues examined the rate of epinephrine prescriptions for a population of 1.15 million patients in Manitoba, Canada, and found that 0.95% of this population was prescribed epinephrine, an indicator of perceived risk that future anaphylaxis may occur.

Mortality/Morbidity

• Fatalities from anaphylaxis are infrequent but not rare. Estimates range from 0.65-2% of patients with anaphylaxis. The case-fatality rate from the Olmsted County study was 0.65%. Severe reactions to penicillin occur with a frequency of 1-5 cases per 10,000 patient courses, with fatalities in 1 case per 50,000-100,000 courses. Insect stings cause 25-50 deaths per year. Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside of the hospital and are estimated to cause 125 deaths per year in the United States. Anaphylactoid reactions to RCM were estimated to have caused 500 deaths in 1982, although this number has likely decreased because of increased awareness and the use of pretreatment regimens and/or lower osmolar agents for patients with a history of RCM reaction.

• In the United Kingdom, one half of fatal anaphylaxis episodes have an iatrogenic cause (ie, anesthesia, antibiotics, or radiocontrast), while foods and insect stings each account for a quarter of the fatal episodes.

• The most common causes of death are cardiovascular collapse and laryngeal edema.

Race

• Race has no known effect on the risk of anaphylaxis.

Sex

• In the Olmsted County study, men and women were equally affected.

• The Memphis study showed a slight female predominance.

• Earlier studies have suggested that episodes of anaphylaxis to intravenous muscle relaxants, aspirin, and latex are more common in women, while insect sting anaphylaxis is more common in men. These sex discrepancies are likely a function of exposure frequency.

Age

• Anaphylaxis can occur at any age. In the Olmsted County study, the age range was 6 months to 89 years. The mean age was 29 ±19 years. The Memphis study had an age range of 12-75 years, with a mean of 38 years.

• Simons and colleagues noted the highest frequency of prescriptions for epinephrine in boys aged 12-17 months (5.3%). The rate was 1.4% for those younger than 17 years, 0.9% for those aged 17-64 years, and 0.3% for those aged 65 years or older.

• Severe food allergy is more common in children than in adults. However, since severe food allergy often persists into adulthood, the frequency in adults may be rising.

• Anaphylaxis to RCM, insect stings, and anesthetics has been reported to be more common in adults than in children. Whether this is a function of exposure frequency or increased sensitivity is unclear.

Other risk factors:

• Atopy is risk factor. In the Olmsted County study, 53% of the patients with anaphylaxis had a history of atopic diseases (eg, allergic rhinitis, asthma, atopic dermatitis). The Memphis study detected atopy in 37% of the patients. Other studies have shown atopy to be a risk factor for anaphylaxis from foods, exercise-induced anaphylaxis, idiopathic anaphylaxis, radiocontrast reactions, and latex reactions. Underlying atopy does not appear to be a risk factor for reactions to penicillin or insect stings.

• Route and timing of administration affect anaphylactic potential. The oral route of administration is less likely to cause a reaction, and the reaction is usually less severe, although fatal reactions occur following ingestions of foods by someone who is allergic. The longer the interval between exposures, the less likely an anaphylactic (IgE-mediated) reaction will recur. This is thought to be due to catabolism and decreased synthesis of specific IgE over time. This does not appear to be the case for anaphylactoid reactions.

• Asthma is a risk factor for fatal outcomes.

• Delay in administration of epinephrine is also a risk factor for fatal outcomes.

Treatment

Medical Care

Anaphylaxis is a medical emergency that requires immediate recognition and intervention. Basic equipment and medication should be readily available in the physician's office. Lieberman et al have recently described this in great detail.

• For the initial assessment, check the airway closely and secure as needed. Assess the level of consciousness and obtain blood pressure, pulse, and oximetry values.

• Place the patient in the supine position, and begin supplemental oxygen.

• Remove the source of the antigen if possible (eg, stinger after bee sting).

• A tourniquet applied to the extremity with the antigen source can retard antigen exposure to the systemic circulation. Release the tourniquet every 5 minutes, and do not leave it in place for longer than 30 minutes.

• Administer intramuscular epinephrine into a different extremity immediately. Epinephrine maintains the blood pressure, antagonizes the effects of the released mediators, and inhibits further release of mediators from mast cells and basophils. Physicians are sometimes reluctant to administer epinephrine for fear of adverse effects. However, epinephrine is usually well tolerated and is lifesaving. Anaphylactic deaths correlate with a delay in the administration of epinephrine. The initial dose can be repeated as necessary, depending on the response.

• Intramuscular administration of epinephrine results in higher and more rapid maximum plasma concentrations of epinephrine compared with the subcutaneous route in both rabbit animal models and a small number of children.

• Antihistamine therapy is considered adjunctive to epinephrine. Administer both an H1 blocker and an H2 blocker because studies have shown the combination to be superior to an H1 blocker alone in relieving the histamine-mediated symptoms. Diphenhydramine and ranitidine are an appropriate combination.

• Establish intravenous access for (1) the administration of adjunctive medications and (2) the administration of intravenous fluids to maintain blood pressure, if needed.

• Racemic epinephrine via a nebulizer can be used to reduce laryngeal swelling but does not replace intramuscular administration of epinephrine.

• Treat bronchospasm that has not responded to subcutaneous epinephrine with inhaled beta2-adrenergic agonists such as albuterol.

• Corticosteroids do not have an immediate effect on anaphylaxis; however, administer them early to prevent a potential late-phase reaction (biphasic anaphylaxis).

• Maintaining proper blood pressure is important in the treatment of anaphylactic reactions.
• • Hypotension is often the most difficult manifestation of anaphylaxis to treat.

  • Persons with protracted hypotension must be monitored in an intensive care unit setting.

  • Because hypotension in anaphylaxis is due to a dramatic shift of intravascular volume, the fundamental treatment intervention (after epinephrine) is aggressive intravenous fluid administration. Large volumes of crystalloid may be required, potentially exceeding 5 L. The exact amount should be individualized, based on blood pressure recovery and urine output. In severe cases, invasive monitoring of central venous pressure and cardiac output may be required.

  • Pressors may also be needed to support blood pressure. Intravenous epinephrine (1:10,000 preparation) can be administered as a continuous infusion, especially when the response to intramuscular or subcutaneous epinephrine (1:1000) is poor. Dopamine infusion can also be used.

  • Military antishock trousers have also been used successfully to maintain blood pressure in persons with anaphylaxis.

  • Patients with anaphylaxis who are taking a beta-adrenergic blocking agent (eg, for hypertension, migraine prophylaxis) can have refractory anaphylaxis that is poorly responsive to standard measures. Glucagon is the drug of choice in this situation. It has both inotropic effects and chronotropic effects on the heart by increasing intracellular levels of cyclic adenosine 3,'5'-monophosphate, independent of the beta-adrenergic receptors.

• Respiratory compromise in the acute setting (ie, respiratory failure) mandates endotracheal intubation. If the endotracheal tube cannot be passed because of severe laryngeal edema, tracheotomy is required.

• For vascular collapse, depending on severity, refractory hypotension may require placement of an invasive cardiovascular monitor (Swan-Ganz catheter) and arterial line.

• Treatment of cardiopulmonary arrest is discussed elsewhere.

• Anti-IgE (omalizumab) complexes circulating (but not receptor-bound) IgE and keeps it from binding to its receptors. It does not remove IgE bound to receptors and takes several months to have a substantial effect. It is not to be used in an acute setting.

Surgical Care

This is limited to the possible need for surgical airway intervention.

Consultations

• Most patients with an episode of anaphylaxis should be referred to an allergist/immunologist for further evaluation and treatment. Despite the logic of this recommendation, the Olmsted County study demonstrated that only 52% of patients were referred for such a consultation.

• In the case of severe anaphylaxis requiring admission to the intensive care unit, an intensivist should be consulted.

• Prophylaxis for intravenous RCM involves prednisone (or hydrocortisone), diphenhydramine, ranitidine (or another type 2 antihistamine), with or without ephedrine, and/or the use of a different contrast agent.
• • Administer prednisone (50 mg PO) or hydrocortisone (200 mg IV) at 12, 6, and 1 hour before the radiocontrast procedure.

  • Administer diphenhydramine (50 mg PO/IV) and ranitidine (150 mg PO or 50 mg IV) with or without ephedrine (25 mg PO) 1 hour before the procedure. Ephedrine should not be used in patients with hypertension, CAD, older patients with a strong family history of CAD, arrhythmia, thyrotoxicosis, monoamine oxidase inhibitor use, or porphyria.

  • Consider using a contrast agent with lower osmolarity.

• Desensitization procedures can be used for a medication allergy.
• • Published protocols exist for desensitization to various medications. Consult an allergist/immunologist skilled in desensitization procedures to perform these protocols. The patient should usually be in an intensive care unit setting with intravenous access and epinephrine and parenteral diphenhydramine at the bedside. Obtain informed consent prior to the procedure. Anaphylactic reactions that may result in death is a potential complication of this procedure.

  • A typical desensitization protocol for beta-lactam antibiotics involves starting at a dose that is 6-7 logs below the usual therapeutic dose and increasing the dose by 1 log every 20-30 minutes.

• Pretreatment protocols do not work for IgE-mediated anaphylaxis.

• Patients should be given epinephrine autoinjectors and should be instructed in the use of the device. Good evidence suggests that physicians underprescribe epinephrine and that patients (or their parents) fail to use epinephrine as quickly as possible.

Diet

The only dietary consideration is the future avoidance of a suspect or culprit food.

Activity

Once the acute episode of anaphylaxis has resolved, no activity limitations are necessary, with the rare exception of exercise-induced anaphylaxis.

Medication

The primary medication for acute anaphylaxis is epinephrine. All other therapies are adjunctive, including antihistamines, corticosteroids, and albuterol. Dopamine may be required to maintain blood pressure, and glucagon can be used in patients taking beta-blockers who have refractory anaphylaxis.

Drug Category: Adrenergic agonists

These agents help maintain blood pressure, antagonize effects of released mediators, and prevent further release of mediators.

Drug Name	Epinephrine (Adrenalin, EpiPen, EpiPen Jr)
Description	DOC for treating anaphylaxis. Has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.
Adult Dose	0.3-0.5 mL (0.3-0.5 mg) of 1:1000 solution IM; administer fraction of total dose (0.1-0.2 mL) at site of antigenic exposure, if accessible, and 0.3 mL into different extremity (thigh muscle is preferable); repeat prn, depending on response 1-2 mL (0.1-0.2 mg) of 1:10,000 preparation (0.1 mg/mL) IV q5-20min prn or continuous IV infusion of 2-10 mcg/min for more critical situations
Pediatric Dose	0.01 mg/kg IM prn 2 mcg/min IV infusion
Contraindications	No absolute contraindications in life-threatening anaphylaxis; documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; during labor (may delay second stage of labor)
Interactions	Beta-blockers antagonize physiologic effects; increases toxicity of alpha-blocking agents and halogenated inhalational anesthetics; TCAs and MAOIs potentiate effects; digoxin potentiates arrhythmogenic effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in elderly persons and those with prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, or cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias; adverse effects include anxiety, headache, palpitations, and hypertension

Drug Category: Antihistamines

These agents block effects of released histamine at H1 receptor, thereby treating flushing, urticarial lesions, vasodilation, and smooth muscle contraction in bronchial tree and GI tract.

Drug Name	Diphenhydramine (Benadryl)
Description	Widely available with a long history of efficacy and relative safety. FDA indication for anaphylaxis. IV administration provides faster onset of action.
Adult Dose	10-50 mg IV/IM q4h prn; IV rate not to exceed 25 mg/min; not to exceed 400 mg/d 25-50 mg PO q6-8h prn; not to exceed 400 mg/d
Pediatric Dose	12.5-25 mg PO tid/qid or 5 mg/kg/d or 150 mg/m2/d divided tid/qid; not to exceed 300 mg/d 5 mg/kg/d IV/IM or 150 mg/m2/d divided qid; IV rate not to exceed 25 mg/min; daily dose not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; concurrent use of MAOIs
Interactions	Potentiates effect of alcohol and other CNS depressants (eg, hypnotics, sedatives, tranquilizers); MAOIs prolong and intensify anticholinergic effects of antihistamines
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in breastfeeding and newborns secondary to risk of convulsions and death in the baby; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; adverse effects include drowsiness, reduced mental alertness, and xerostomia

Drug Category: Histamine2-receptor antagonists

These agents block effects of released histamine at H2 receptors, thereby treating vasodilation, possibly some cardiac effects, and glandular hypersecretion. H2 blockers with H1 blockers have additive benefit over H1 blockers alone in treating anaphylaxis. Ranitidine (Zantac) probably preferred over cimetidine (Tagamet) in anaphylaxis in light of the risk for hypotension with rapidly infused cimetidine and the multiple, complex drug interactions with cimetidine. Famotidine (Pepcid) IV is another good alternative.

Drug Name	Ranitidine (Zantac)
Description	H2 antagonist, which, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.
Adult Dose	50 mg/dose IV/IM q6-8h IV bolus administration: Dilute 50 mg in 20 mL NS (concentration of 2.5 mg/mL), inject at rate not >4 mL/min (5 min) Alternatively, 150 mg PO bid; not to exceed 600 mg/d
Pediatric Dose	<12>12 years: 1.25-2.5 mg/kg/dose PO q12h; not to exceed 300 mg/d 0.75-1.5 mg/kg/dose IV/IM q6-8h; not to exceed 400 mg/d
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; if CrCl is <50>5 d may cause ALT elevations; case reports suggest ranitidine may precipitate acute porphyria

Drug Category: Bronchodilators

These agents stimulate beta2-adrenergic receptors in bronchial smooth muscle, causing bronchodilation.

Drug Name	Albuterol (Proventil, Ventolin)
Description	Beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility.
Adult Dose	Nebulizer: 2.5-5 mg q4-6h in 2-5 mL sterile NS or water; to make solution, dilute 0.5 mL (2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS (more frequent administration can be used for severe bronchospasm) MDI: 1-2 puffs q4-6h; more frequent administration can be used for severe bronchospasm
Pediatric Dose	Nebulizer <5>5 years: Administer as in adults MDI <12>12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents; may exacerbate diuretic-induced hypokalemia; may decrease digoxin levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiovascular disorders (eg, coronary artery disease, cardiac arrhythmias, severe hypertension), hyperthyroidism, diabetes mellitus, and seizure disorder; adverse effects include tremor and mild tachycardia

Drug Category: Corticosteroids

Bind to the intracellular glucocorticoid receptors in inflammatory cells with multiple downstream immunomodulating effects. Glucocorticoids ameliorate delayed effects of anaphylaxis.

Drug Name	Methylprednisolone (Solu-Medrol)
Description	May help prevent late-phase allergic reactions (biphasic anaphylaxis). No immediate effects.
Adult Dose	Loading: 125-250 mg IV over several min Maintenance: 0.25-1 mg/kg/dose IV q6h for up to 5 d
Pediatric Dose	Loading: 2 mg/kg IV Maintenance: Administer as in adults
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics; concomitant use with NSAIDs increases risk of peptic ulcer
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use (most are unlikely with short-term use for acute anaphylaxis)

Drug Category: Positive inotropic agents

These agents help maintain blood pressure independent of adrenergic receptors by increasing intracellular levels of cyclic AMP. In addition, stimulate release of endogenous catecholamines.

Drug Name	Glucagon (GlucaGen)
Description	DOC for severe anaphylaxis in patients taking beta-blockers (should be used in addition to epinephrine, not as a substitute). Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Exerts opposite effects of insulin on blood glucose. Elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources, such as proteins and fats (gluconeogenesis). Increases hydrolysis of glycogen to glucose (glycogenolysis) in liver in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Also increases force of contraction in heart and has a relaxant effect on GI tract. Dose used for anaphylaxis is higher than usual dose of 1 mg (1 U) IV/IM/SC used to treat hypoglycemia.
Adult Dose	1-5 mg IV bolus, followed by infusion of 5-15 mcg/min titrated against blood pressure
Pediatric Dose	Hypoglycemia <20>20 kg: 1 mg (1 U) IV/IM/SC Anaphylaxis: May need higher doses
Contraindications	Documented hypersensitivity; pheochromocytoma
Interactions	Effects of anticoagulants may be enhanced (although onset may be delayed); monitor prothrombin activity for signs of bleeding in patients receiving anticoagulants and adjust dose accordingly
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse effects include nausea, vomiting, sudden and marked increase in blood pressure in patients with pheochromocytoma, and severe rebound hypoglycemia in patients with insulinoma

Drug Category: Vasopressors

These agents are useful as adjunctive therapy to IV fluids to treat refractory hypotension from anaphylaxis.

Drug Name	Dopamine (Intropin)
Description	Considered DOC for anaphylaxis-induced refractory hypotension. Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on dose. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and peripheral vasoconstriction produced by higher doses. More than 50% of patients are satisfactorily maintained on doses <20>
Adult Dose	2-5 mcg/kg/min IV; after initiating therapy, increase dose by 1-4 mcg/kg/min q10-30min until optimal response obtained; not to exceed 50 mcg/kg/min
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; pheochromocytoma; ventricular fibrillation
Interactions	Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure closely during infusion; prior to infusion, correct hypovolemia; monitoring central venous pressure or left ventricular filling pressure may be helpful for detecting and treating hypovolemia; extravasation can cause necrosis of surrounding tissue, which is treated with phentolamine injected at the site

Alloimmunization From Transfusions

Background

Allogeneic blood transfusion is a form of temporary transplantation. This procedure introduces a multitude of foreign antigens and living cells into the recipient that will persist for a variable time. A recipient who is immunocompetent often mounts an immune response to the donor antigens, resulting in a variety of clinical consequences depending on the blood cells and specific antigens involved. The antigens most commonly involved are classified in the following categories: (1) HLAs, class I shared by platelets and leukocytes and class II present on some leukocytes; (2) granulocyte-specific antigens; (3) platelet-specific antigens (human platelet antigen [HPA]); and (4) RBC-specific antigens.

The consequences of alloimmunization to blood include the following clinical manifestations:

• Alloimmunization against RBCs
  • Acute intravascular hemolytic transfusion reaction, which is rarely a consequence of alloimmunization

  • Delayed hemolytic transfusion reactions (DHTRs)

  • Hemolytic disease in newborns (mother's alloimmunization against fetal antigens, most often resulting from previous pregnancies)

• Alloimmunization against platelets (platelet-specific or HLA class I antigens)
  • Refractoriness to platelet transfusion

  • Posttransfusion purpura

  • Neonatal alloimmune thrombocytopenia (mother's alloimmunization against fetal antigens, most often resulting from previous pregnancies)

• Alloimmunization against granulocytes (granulocyte-specific or HLA antigens)
  • Refractoriness to granulocyte transfusion

  • Febrile nonhemolytic transfusion reactions

  • Transfusion-related acute lung injury, ie, a transfusion reaction in which donor HLA antibodies react against recipient antigens

• Transplant rejection
  • Alloimmunization against HLA antigens

  • Alloimmunization against blood cell antigens (in bone marrow transplantation)

Hemolytic transfusion reactions, posttransfusion purpura, febrile nonhemolytic transfusion reactions, and transfusion-related acute lung injury are discussed in Transfusion Reactions. Hemolytic disease in newborns and neonatal alloimmune thrombocytopenia are discussed in the Neonatology section of eMedicine. Transplant rejection is discussed in Renal Transplantation (Medical).

DHTR and refractoriness to platelet transfusions are discussed in this article. Refractoriness to granulocyte transfusions involves either anti-HLA or granulocyte-specific antibodies and is similar to platelet refractoriness, except that refractoriness to granulocyte transfusions results in the patient failing to respond to the granulocyte transfusions. Because granulocyte transfusions are rarely used, they are not discussed further in this article.

Pathophysiology

The main mechanism for alloimmunization to antigens present in transfused cells may involve presentation of the donor antigens by donor antigen–presenting cells (APCs), ie, monocytes, macrophages, dendritic cells, B cells, to recipient T cells. Recognition of the MHC class I alloantigens by CD4⁺ recipient T cells and their subsequent activation requires a co-stimulatory signal from either the donor or recipient APCs. Alloimmunization by non–leukoreduced platelets involves shared donor HLA antigens (HLA-restricted) and live functional donor APCs. The T_H2 subset of CD4⁺ T helper cells secretes interleukin (IL)–4, IL-5, IL-6, and IL-10; activates B cells; and initiates the antibody response.

Leukoreduction of transfused platelets virtually eliminates donor APCs, but 20% of patients still develop alloimmunization. Alloimmunization from leukoreduced platelets involves recognition of the alloantigen and activation of recipient CD4⁺ T cells by alloantigen-presenting recipient APCs. This process also involves initial recognition of alloantigens by natural killer cells, which secrete interferon-gamma. This cytokine, in turn, is involved in the activation of CD4⁺ T_H2 cells.

After initial activation and development of the primary immune response, T cells become memory cells. Memory T cells do not need co-stimulatory signals to become activated and can recognize signals in the absence of class II HLA molecules. Thus, donor RBCs, platelets, and inactivated APCs can induce restimulation of the immune response. Blood transfusion (mainly through the T_H2 subset) can actively suppress the host immune response and induce tolerance to donor antigens. Another mechanism of immunosuppression involves stimulation of CD8⁺ suppressor T cells, which can recognize MHC class I alloantigens in platelets as well as donor APCs. Primary immunization with blood transfusion reflects the balance between clonal expansion and tolerogenic mechanisms. The secondary response depends on the restimulation of memory cells. Repeated immunization eventually results in sustained clonal expansion and clinically significant antibody production.

Refractoriness to platelet transfusions

The presence of HLA antibodies on the platelet surface is the most common cause of platelet refractoriness. Other non-HLA antigens present on the platelet surface (eg, platelet-specific antigens, HPA) are also involved in a number of cases. Patients not previously sensitized develop antiplatelet antibodies approximately 3-4 weeks (10 d to 26 wk) after the transfusion. Patients previously immunized by transfusion, pregnancy, or organ transplantation develop antiplatelet antibodies as early as 4 days after transfusion. Macrophages in the liver, spleen, and other tissues of the mononuclear phagocyte system phagocytize and destroy antibody-coated platelets.

Risk factors for developing antiplatelet antibodies include the presence of more than 1 million donor leukocytes in transfused products, transfusing ABO-mismatched platelets, the presence of an intact immune system (ie, absence of cytotoxic or immunosuppressive therapy), female sex (approximately 75% of cases), and a history of multiple transfusions (>20).

Delayed hemolytic transfusion reactions

DHTRs occur between 24 hours and 3 months (frequently 2 wk) after transfusion and usually represent a secondary immune response. Anti-RBC antibody titers frequently drop below detectable levels. Patients are transfused with incompatible RBCs, resulting in restimulation of memory cells and an increase in antibody titer. Antibodies bind to the surface of RBCs and, depending on the number of antigen-antibody interactions, activate complement with deposition of C3b. Usually, more than 10⁵ antigenic sites per cell are required for potent complement activation.

Rarely, binding of immunoglobulin M antibodies to RBCs activates the classic complement pathway and leads to intravascular hemolysis. RBCs coated with immunoglobulin G antibodies and/or complement bind to C3b and immunoglobulin Fc receptors present on mononuclear phagocytes and are destroyed by phagocytosis (ie, extravascular hemolysis). Immunoglobulin G antibodies that efficiently activate complement (eg, those in Kidd and Duffy systems) tend to cause more intense extravascular hemolysis compared with antibodies that do not efficiently activate complement (eg, Rh and Kell).

Frequency

United States

Refractoriness to platelet transfusions

With regard to the frequency of alloimmunization, approximately 20-85% of patients who receive multiple transfusions become immunized against platelet antigens (eg, HLA, HPA), and approximately 30% of patients who are alloimmunized develop refractoriness to platelet transfusions.

Platelet refractoriness occurs in approximately 20-70% of patients who receive multiple transfusions. In approximately 66% of these patients, nonimmune factors alone are the cause, whereas alloimmunization may be involved in 33% of refractory patients, often in combination with nonimmune causes.

With regard to the frequency of type of antibody involved in platelet refractoriness, HLA class I antibodies are involved in most alloimmunization cases, whereas platelet-specific antigens (ie, HPA) may be involved in approximately 10-20% of refractory cases. Both types of antibodies are involved in approximately 5% of cases. A single random RBC or platelet transfusion induces anti-HLA antibodies in less than 10% of recipients (most likely related to the tolerogenic effect of blood transfusions). If patients have more than 20 transfusions, they become sensitized in increasing proportions; after 50 transfusions, most (as many as 70%) patients have anti-HLA antibodies.

The presence of HLA antibodies shows better correlation with platelet refractoriness than antibodies directed against platelet-specific antigens. In the minority of cases of platelet refractoriness due to HPA antibodies, HPA-1b, HPA-5b, and HPA-1a antibodies are most commonly involved. Platelet-specific antigen systems are listed in Table 1.

Table 1. Human Platelet-Specific Antigen Systems

Platelet Antigen System	Protein Antigen	Synonyms	Alleles	Antigen Frequency
HPA-1	GPIIIa	PlA,Zw	HPA-1a = PlA1

HPA-1b = PlA2

97%

26%
HPA-2	GPIb	Ko, Sib	HPA-2A

HPA-2b

99%

14%
HPA-3	GPIIb	Bak, Lek	HPA-3a

HPA-3b

85%

66%
HPA-4	GPIIa	Pen, Yuk	HPA-4a

HPA-4b

>99%

<1%
HPA-5	GPIa	Br, Hc, Zav	HPA-5a

HPA-5b

99%

20%

Delayed hemolytic transfusion reactions

Approximately 0.1-2% of patients who receive transfusions develop anti-RBC antibodies. In patients who are transfused regularly (eg, patients with sickle cell disease), the frequency of alloimmunization is much higher, affecting 10-38%. Despite the relatively high frequency of RBC alloimmunization, clinical manifestations of hemolytic transfusion reactions are rare (approximately 0.05% of patients transfused). The most frequent clinically significant RBC antibodies are shown in Table 2.

Table 2. Frequent Clinically Significant Anti-RBC Antibodies

Antigen	System	Frequency Among All Detected Alloantibodies	Frequency of Antigen

(Whites)	Frequency of Antigen

(Blacks)	Potency*
E	Rh	16-40%	30%	2%	4%
Kell (Kl)	Kell	5-40%	9%	3%	9%
D	Rh	8-33%	85%	92%	70%
c	Rh	4-15%	80%	99%	4%
Jk(a)	Kidd	2-13%	77%	91%	0.14%
Fy(a)	Duffy	4-12%	63%	10%	0.46%
C	Rh	2-10%	70%	32%	0.22%
e	Rh	2-3%	98%	98%	1%
Jk(b)	Kidd	2%	72%	43%	0.06%
S	MNSs	1-2%	55%	31%	0.08%
s	MNSs	<1%	89%	97%	0.06%

*Percentage of antigen-negative recipients who become alloimmunized if transfused with antigen-positive units

Mortality/Morbidity

• The risk of death from a DHTR is approximately 1 fatality per 3.85 million units (1 per 1.15 million U in patients who have received transfusions).

• Data regarding the impact of platelet refractoriness on morbidity and mortality for thrombocytopenic patients are inconsistent. Failure to achieve platelet counts greater than 5 X 10⁹/L significantly increases the probability of life-threatening bleeding.

Race

Individuals from ethnic minority groups have an increased risk of alloimmunization from transfusion because notable differences exist in the frequency of blood cell antigens between races. Efforts to increase the blood supply from minority donors are essential to reduce the frequency of alloimmunization in these groups.

Sex

DHTRs and platelet refractoriness are more common in females than in males, possibly because of previous sensitization from pregnancy.

Age

Older patients (ie, >50 y) tend to have reduced immune responsiveness to blood transfusions.

Treatment

Medical Care

• Delayed hemolytic transfusion reactions
• • Most patients tolerate DHTR well and only require observation and supportive care.

  • Good communication with a blood bank is essential to attempt to provide transfusion support with antigen-negative RBCs. If these RBCs are not available, weigh the risk of further hemolysis against the indications for transfusion.

  • If the load of antigen-positive packed RBCs is large (>5 U), consider exchange transfusion. Administer intravenous human immunoglobulin (IVIG) to block further hemolysis in cases in which antigen-positive blood is transfused. The IVIG dose is 400 mg/kg, infused slowly within 24 hours posttransfusion.

• Refractoriness to platelet transfusions
• • Avoiding the use of platelet transfusions as much as possible is important in alloimmunized patients. Preventive transfusions are not recommended. Measures to minimize the likelihood and extent of bleeding (eg, rapid treatment of infection; avoidance of invasive procedures; correction of coagulation deficiencies, anemia, and renal insufficiency; use of antifibrinolytic agents) should be used extensively.

  • After diagnosing alloimmune platelet refractoriness, use the sequence of measures that follows, initiating each subsequent intervention if the previous one fails.

  • Rule out nonimmune, autoimmune, and drug-related causes of platelet refractoriness, or treat accordingly.

  • Transfuse ABO-compatible fresh (aged <48>3 d) platelets.

  • Transfuse with platelets from blood relatives. Obtaining platelets from blood relatives is worthwhile because the chance of matching 2 or more HLA and platelet antigens is high (resulting in good recovery) and relatives are often willing to donate frequently. Irradiation of blood products from relatives is mandatory to prevent graft versus host disease.

  • Select HLA-matched platelets. Perform HLA typing of patients who receive multiple transfusions before they become pancytopenic. Matching for both private (ie, HLA-A, HLA-B) and public (ie, cross-reacting groups) antigens is best achieved by computerized selection of donors, based on the results of the PRA assay.

  • Select crossmatched platelets. Crossmatch-compatible platelets can significantly improve platelet recovery in approximately 50% of patients who are refractory to random-donor platelets. Selecting crossmatched platelets is indicated especially for patients with high PRA levels or those who do not respond to HLA-matched platelets.

  • The use of HPA1a/5b-negative platelets has been successful in cases of posttransfusion purpura and neonatal platelet alloimmunization. These antigens are involved in most (95%) cases of neonatal or posttransfusion purpura, but they represent no more than 10-20% of immune refractoriness to platelet transfusions.

  • Pretreat with IVIG before transfusion. IVIG pretreatment can result in successful recovery after platelet transfusion in patients who are alloimmunized. Success rates vary (as much as 70%) and depend on the degree of alloimmunization. IVIG does not reduce the number of alloantibodies but does decrease platelet-associated immunoglobulins and possibly interferes with platelet destruction mechanisms.

  • Use high-dose platelet transfusion. Empirical use of high doses of random platelet units (eg, 1 U per 10 kg tid) may result in titration of the antibody, overwhelming of the mononuclear-phagocyte system, and increased survival of transfused platelets.

  • Attempt large-volume plasmapheresis. Plasmapheresis (eg, 2 plasma volumes for 1-3 d) before bone marrow transplantation results in beneficial responses in most patients alloimmunized to platelets. Perfusion of the plasma through a staphylococcal protein A column is an experimental treatment undergoing evaluation.

  • Consider administering immunosuppressive drugs. Isolated reports suggest that immunosuppressive therapy is effective for reverting platelet refractoriness. The use of vincristine and cyclosporin A has been successful but requires 2-3 weeks to take effect.

Consultations

Transfusion medicine specialist or hematologist

Medication

Immunosuppressive agents such as IVIG can be as much as 70% effective in patients with platelet refractoriness resulting from alloimmunization. Consider using cytotoxic agents only in person clearly unresponsive to the other treatment modalities. Only physicians familiar with the use and toxicity of cytotoxic agents should prescribe these drugs because few data support their use for alloimmunization. This indication is considered investigational.

Drug Category: Immunosuppressive agents

Inhibit activity of immune system.

Drug Name	Immunoglobulin intravenous IVIG (Gamimune, Sandoglobulin, Gammagard)
Description	Fractionated human immunoglobulins treated to inactivate viruses and filtered to eliminate high molecular weight complexes. Neutralizes circulating myelin antibodies through antiidiotypic antibodies. Down-regulates proinflammatory cytokines, including INF-gamma. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. Promotes remyelination. May increase CSF IgG (10%).
Adult Dose	400 mg/kg/d IV for 5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; IgA deficiency (except IgA-depleted IVIG) and anti-IgE/IgG antibodies; relatively contraindicated in patients with renal failure and in patients with history of migraines
Interactions	Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Ensure that medical emergency resources are immediately available to manage possible rash, dyspnea, hypotension, or anaphylaxis; administer slowly the first time to detect adverse effects and watch for fluid overload in predisposed patients; mild adverse effects (eg, chills, headache, fever, rash, pruritus) can be prevented or modified by oral acetaminophen (15 mg/kg; maximum required dose in adults generally 650 mg) or diphenhydramine (1 mg/kg; maximum required dose in adults generally 50 mg) Consider checking serum IgA before IVIG, use IgA-depleted IVIG (eg, G-Gard-SD) if indicated IVIG may increase serum viscosity and thromboembolic events; reported adverse effects include migraine attacks, 10% increased risk of aseptic meningitis, and increased risk of urticaria, pruritus, or petechiae 2-5 d postinfusion that may last as long as 1 mo; increased risk of renal tubular necrosis in older patients, diabetic patients, volume-depleted patients, and patients with preexisting kidney disease IVIG can lead to the following changes in laboratory values: elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increased ESR for 2-3 wk, and apparent hyponatremia

Drug Category: Cytotoxic agents

Inhibit immune cell growth and proliferation.

Drug Name	Vincristine (Oncovin)
Description	Only one report describes effectiveness, in an 18-mo-old child with platelet refractoriness. Several reports, however, describe its use for treating autoimmune thrombocytopenia. Use for platelet alloimmunization remains investigational.
Adult Dose	Not established
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Acute pulmonary reaction may occur when taken concurrently with mitomycin-C
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in severe cardiopulmonary or hepatic impairment and patients with preexisting neuromuscular disease

Drug Name	Cyclosporin A (Sandimmune, Neoral)
Description	Two reports describe use in patients with aplastic anemia and platelet refractoriness. Both patients dramatically improved in response to platelet transfusions after treatment. Use for platelet alloimmunization remains investigational.
Adult Dose	Not established
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis because may increase risk of cancer
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Allergic and Environmental Asthma

Background

Asthma is a clinical syndrome characterized by episodic reversible airway obstruction, increased bronchial reactivity, and airway inflammation. Asthma results from complex interactions among inflammatory cells, their mediators, airway epithelium and smooth muscle, and the nervous system. In genetically susceptible individuals, these interactions can lead to symptoms of breathlessness, wheezing, cough, and chest tightness.

Risk factors for asthma include a family history of allergic disease, the presence of allergen-specific immunoglobulin E (IgE), viral respiratory illnesses, exposure to aeroallergens, obesity, and lower socioeconomic status.

Environmental exposure in sensitized individuals is a major inducer of airway inflammation, which is a hallmark finding in the asthmatic lung. Although triggers induce inflammation through different pathways, the resulting effects all lead to increased bronchial reactivity.

Exposure to dust mites within the first year of life is associated with later development of asthma and, possibly, atopy. Mite and cockroach antigens are common, and exposure and sensitization has been shown to increase asthma morbidity. Allergies trigger asthma attacks in 60-90% of children and in 50% of adults. Approximately 75-85% of patients with asthma have positive (immediate) skin test results. In children, this sensitization is associated with disease activity. The level of IgE is associated with the prevalence and severity of airway hyperresponsiveness (AHR) and asthma.

Although most people with asthma have aeroallergen-induced symptoms, some individuals manifest symptoms with nonallergic triggers. As many as 3-10% of people with asthma are sensitive to nonsteroidal anti-inflammatory drugs (NSAIDs). Approximately 5-10% of people with asthma have occupation- or industry-induced airway disease. Many individuals develop symptoms after viral respiratory tract infections.

Allergen avoidance and other environmental control efforts are feasible and effective. Symptoms, pulmonary function test findings, and AHR improve with avoidance of environmental allergens. Removing even one of many allergens can result in clinical improvement. However, patients frequently are not compliant with such measures.

Pathophysiology

The allergic response in the airway is the result of a complex interaction of mast cells, eosinophils, T lymphocytes, macrophages, dendritic cells, and neutrophils. Inhalation-challenge studies with allergens reveal an early allergic response (EAR), which occurs within minutes and peaks at 20 minutes following inhalation of the allergen. Clinically, the manifestations of the EAR in the airway include bronchial constriction, airway edema, and mucus plugging. These effects are the result of mast cell–derived mediators. Four to 10 hours later, one sees the late allergic response, which is characterized by infiltration of inflammatory cells into the airway and is most likely caused by cytokine-mediated recruitment and activation of lymphocytes and eosinophils.

Antigen-presenting cells (ie, macrophages, dendritic cells) in the airway capture, process, and present antigen to helper T cells, which, in turn, become activated and secrete cytokines. Helper T cells can be induced to develop into T_H1 (ie, interferon-gamma, interleukin [IL]–2) or T_H2 (ie, IL-4, IL-5, IL-9, IL-13). Allergens drive the cytokine pattern towards T_H2, which promotes B-cell IgE production and eosinophil recruitment. Subsequently, IgE binds to the high-affinity receptor for IgE, Fc-epsilon-RI, on the surface of mast cells and, with subsequent exposure to the allergen, the IgE is cross-linked. This leads to degranulation of the mast cell. Preformed mast cell mediators, such as histamine and proteases, are released, leading to the EAR.

Newly formed mediators such as leukotriene C₄ and prostaglandin D₂ also contribute to the EAR. Proinflammatory cytokines (IL-3, IL-4, IL-5, tumor necrosis factor-alpha) are released from mast cells and are generated de novo after mast cell activation. These cytokines contribute to the late allergic response by attracting neutrophils and eosinophils. The eosinophils release major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, and eosinophil peroxidase into the airway, causing epithelial denudation and exposure of nerve endings. The lymphocytes that are attracted to the airway continue to promote the inflammatory response by secreting cytokines and chemokines, which further potentiate the cellular infiltration into the airway. The ongoing inflammatory process eventually results in hypertrophy of smooth muscles, hyperplasia of mucous glands, thickening of basement membranes, and continuing cellular infiltration. These long-term changes of the airway, referred to as airway remodeling, can ultimately lead to fibrosis and irreversible airway obstruction in some, but not most, patients.

Frequency

United States

Prevalence is difficult to determine because definitions and survey methods vary, but it is likely increasing as a result of greater sensitization to common allergens and the redefinition of some nonatopic wheezing as asthma. From 1982-1992, the average age-adjusted prevalence rate increased 42% (from 34.7/1000 to 49.4/1000). Asthma may affect 31 million people, including 9.2 million children (7.2% of adults by self-report).

International

Asthma affects more than 100 million people worldwide. Some reports suggest asthma prevalence has peaked at 8-12%, perhaps because of improved management or because asthma has already been induced in the maximal number of genetically available individuals.

Mortality/Morbidity

• The death rate from asthma is 17.7 deaths per million people. Mortality has increased, especially in children who live in inner-city areas, despite advances in disease understanding and therapy.

• Annually, asthma is responsible for 1.5 million emergency department (ED) visits, 500,000 hospital admissions (third leading preventable cause), and 100 million days of restricted activity. Medical expenses and lost work and productivity cost an estimated $12.7 billion in 1998. Increased morbidity is multifactorial and may include increased exposure to indoor allergens, less exposure to viral infections early in life, more environmental pollution, overuse of short-acting beta-2 agonists, underuse of anti-inflammatory medications, and limited access to, or education about, health care.

Race

• Females, ethnic minorities, people with a low annual family income (<$20,000/y in the United States), and persons with poor access to, or education about, health care have worse outcomes than other individuals.

• Hospitalization and death rates are 3 times greater in African Americans.

• Asthma is rare in Eskimos

Sex

• Boys have been shown to be at greater risk for asthma than girls. In children younger than 14 years, the prevalence is twice as high in boys compared with girls.

• The difference narrows with age, and women aged 40 years have a greater prevalence than men of the same age.

Age

• Disease onset can occur in persons of any age, but children often present when younger than 6 years. Asthma is the most common chronic disease of childhood.

• Many young children “outgrow” asthma, especially boys who have no personal or family history of atopy. However, clinical experience shows that many teenagers who become asthma-free develop asthma again in their 20s and 30s. Perinatal exposure to allergens or passive smoke has been postulated to make outgrowing asthma less likely.

Treatment

Medical Care

The goals of treatment are to minimize symptoms, improve quality of life, decrease need for urgent care or hospitalizations, normalize pulmonary function test results, and decrease the inflammatory process that leads to airway remodeling. For this discussion, treatment is divided into pharmacotherapy, environmental control, allergen immunotherapy, antibodies against IgE, and education.

• Pharmacotherapy
  
  
  • The most important facet of medical care is the use of anti-inflammatory medication (usually inhaled glucocorticoids) in patients at all stages beyond mild intermittent asthma. These medications improve the long-term outcomes for children with asthma and do not appear to have significant adverse effects at moderate doses (eg, on growth, bone density, eyes, adrenal sufficiency). Unfortunately, in some series, fewer than half the patients admitted to the hospital for asthma were receiving the recommended anti-inflammatory medications.
  
  
  • NHLBI guidelines suggest that initial medical care should be aggressive to rapidly gain control and then should be tapered as tolerated.
  
  
  • Severe exacerbations require standard care that includes supplemental oxygen (goal PaO₂ >60 mm Hg, arterial oxygen saturation >90%), nebulized medications, intravenous fluids, and even noninvasive or invasive ventilatory support. Heliox (helium-oxygen gas mixture) is an option but has not been systematically shown to be helpful.
  
  
  • Antibiotics offer no added benefit during an asthma exacerbation.

  • In emergency situations, nebulized magnesium sulfate during acute asthma attacks—when added to short-acting beta-2 agonists—may improve pulmonary function and reduce admissions, based on a limited number of studies.

  • All patients should receive assistance with quitting tobacco use. While smoking cessation is essential for a number of reasons, it particularly appears to increase corticosteroid responsiveness in patients with asthma.

  • All patients should receive an annual flu shot. A pneumococcal pneumonia vaccination is not required unless indicated based on age (ie, >65 y). Asthma symptoms do not increase after these shots because the antigens in the vaccinations are not alive.

  • Evaluating and treating patients for associated conditions (eg, rhinitis, GERD, sinusitis) can be important components of therapy. In one study, treating the GERD symptoms of patients with asthma with a proton pump inhibitor for 6 months reduced asthma exacerbations and improved quality of life but did not improve asthma symptoms or pulmonary function or reduce albuterol usage.

• Environmental control
  
  

  • Allergen avoidance takes different forms depending on the specific allergen size and characteristic. Improvement in symptoms after avoidance of the allergen may take 1-6 months.

  • Efforts should focus on the home, where 30-60% of time is spent. Patients should clean and dust their homes regularly. If patients cannot avoid vacuuming, they should use a face mask or a double-bagged vacuum with a high-efficiency particulate air filter. Consideration can be given to moving to a higher floor in the house (less dust and mold) or different neighborhood (fewer cockroaches) if possible. Active smoking and exposure to passive smoke must be avoided. Room air ionizers have not been proven effective to help persons with chronic asthma and the generation of ozone by these machines may be harmful to some. Other factors related to the home include the following:
    
    

    • Dust mites (Dermatophagoides pteronyssinus or "dead skin feeders," size 30 µm): The primary allergen is an intestinal enzyme on fecal particles. The allergen settles on fabric because of its relatively large size; therefore, air filtration is not as important. Measures to avoid dust mites include using impervious covers (eg, on mattresses, pillows, comforters), washing other bedding in hot water (130°F [54.4°C] most effective), removing rugs from the bedroom, limiting upholstered furniture, reducing the number of window blinds, and putting clothing away in closets and drawers. Minimize the number of soft toys, and wash them weekly or periodically put them in the freezer. Decrease room humidity (<50%);>
      
      
    • Cats and other animals (dander or saliva, urine, or serum proteins, size 1-20 µm): Because of its small size, this allergen is predominantly an airborne indoor allergen. Avoidance involves removing animals from the home (or at least from the bedroom), using dense filtering material over heating and cooling duct vents, and washing cats and dogs as often as twice weekly.
    
    
    
    • Cockroaches (size 30 µm): Twenty percent of homes without visible infestation still produce sensitizing levels of allergen. Successful allergen elimination measures are difficult, especially in poor living conditions. To control cockroaches, exterminate and use poison baits and traps, keep food out of the bedroom, and never leave food out in the open.
    
    
    
    • Wet molds (size 1-150 µm): Avoidance includes keeping areas dry (eg, remove carpets from wet floors), removing old wallpaper, cleaning with bleach products, and storing firewood outdoors.
    
    
    
    • Pollen (size 1-150 µm): Avoidance includes closing windows and doors, using air conditioning and high-efficiency particulate air filters in the car and home, staying inside during the midday and afternoon when pollen counts are highest, wearing glasses or sunglasses, and wearing a face mask over the nose and mouth when mowing the lawn. In addition, consider increasing medications preseason and vacationing out of the area.
      
• Allergen immunotherapy
  
  
  • Repeated injections of small doses of allergen have been used for more than 90 years to treat allergic rhinitis. This treatment is clearly effective, and positive effects may persist even years after treatment is stopped. This treatment is also considered mandatory for life-threatening bee and wasp sting reactions. The role of repeated allergen injections in patients with asthma has been more controversial, ranging from a relative indication to no indication. Benefit has been shown in individuals with allergy-induced asthma.
  
  
  
  • Supporters argue that compliance can be ensured, and evidence shows that the underlying disease process can be modified or even prevented (eg, preventing asthma in children with allergic rhinitis).
  
  
  
  • In a 2003 review of 75 randomized controlled trials, Abramson et al reported that immunotherapy decreased asthma symptoms and need for medication. Another study showed improved PEFR and decreased use of medications in a highly selected group of children, but only for the first year of therapy.
  
  
  

  • The cost may be $800 for the first year and then $170/y thereafter (1996 estimate). No direct comparisons with medical therapy have been made to allow a cost-benefit analysis.

  • Allergen immunotherapy should be considered if specific allergens have a proven relationship to symptoms; the individual is sensitized (ie, positive skin test or RAST findings); the allergen cannot be avoided and is present year-round (eg, industrial); or symptoms are poorly controlled with medical therapy, and a vaccine to the allergen is available. As discussed above, this treatment is especially useful if asthma is associated with allergic rhinitis.

  • Referral to an allergist is required. The patient must commit to a course of 3-5 years of therapy (although a trial of several months can be considered).

  • Precautions include serious adverse reactions (occurring in 1 per 30-500 people, usually within 30 min). The estimated crude annual death rate is 0.7 deaths per million population. Monitoring and resuscitation personnel and equipment are required. Also, allergen immunotherapy should be avoided if the patient is taking beta-blockers or is having an asthma exacerbation (ie, PEFR <70%>

  • Dosing of allergen extracts is in bioequivalent allergy units (BAU), weight per volume (w/v), or protein nitrogen units (PNU), but "major allergen content" may be a more standardized and reliable method of dosing and characterizing allergen extracts.

  • Sublingual immunotherapy has been shown to improve allergic rhinitis symptoms, but effectiveness compared with the standard injection type is unclear. Sublingual immunotherapy and allergoids (modified or peptide-associated allergens) are not currently used in the United States.

• Antibodies to IgE antibody - Omalizumab
  
  

  • Omalizumab (Xolair) was approved by the FDA in 2003 for adults and adolescents (>12 y) with moderate-to-severe persistent asthma who have a positive skin test result or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids.

  • This is a humanized murine IgG antibody against the Fc component of the IgE antibody (the part that attaches to mast cell surfaces). Use of this antibody prevents IgE from binding directly to the mast cell surface, thereby preventing cell degranulation.

  • Therapy has been shown to decrease IgE antibody levels by 99% and cell receptor sites for IgE antibody by 97%. This decrease, in turn, is associated with reduced histamine production (90%), early-phase bronchospasm (40%), and late-phase bronchospasm (70%) and a decrease in the number, migration, and activity of eosinophils. levels drop quickly and remain low for at least a month.

  • This therapy is also effective for allergic rhinitis.
  
  
  
  • Multiple phase 3 trials show that, compared to placebo injections, treatment is associated with larger median inhaled steroid dose reduction (83% vs 50%), higher percentage of discontinuation of inhaled steroids (42% vs 19%), and fewer asthma exacerbations (approximately 15% vs 30%). Quality of life and use of rescue inhaler and the emergency department may also be improved. Omalizumab is approved for reduction of exacerbations.
  
  
  

  • Adverse effects are rare and include upper respiratory infection symptoms, headache, urticaria (2%) without anaphylaxis, and anaphylaxis (0.1%). Transient thrombocytopenia has also been noted but not in humans. Antibodies are formed against the anti-IgE antibody, but these do not appear to cause immune-complex deposition or other significant problems. To date, decreased IgE levels have not been shown to inhibit one’s ability to fight infection (including parasites). Registration trials raised a question of increased risk of malignancy, but this has not been seen in the postmarketing data.

  • Omalizumab is given by subcutaneous injection every 2-4 weeks based on initial serum IgE level and body weight. Patients are usually treated for a trial period lasting at least 12 weeks. Costs may be $12,000/y, so omalizumab is likely to be cost-effective only in patients with severe persistent asthma who have frequent exacerbations requiring hospitalization.

Consultations

• Consult a pulmonologist, allergist/immunologist, or both for any of the following:
• • Difficulty controlling disease after 3-6 months, including frequent attacks, need for rescue inhaler (>1 rescue inhaler used per mo), use of oral steroids more than 2 times per year, or step 4 therapy required (or step 2 or higher if aged <3>
    
  • Poor quality of life
  • Immunotherapy under consideration
  • Intensive education needed
  • Refractory cough
  • Abnormal chest radiograph findings
  • Life-threatening asthma exacerbation
  • Patient or parent request


• Appropriate referral is needed if significant psychological, social, or family problems are present.

Diet

Aside from avoiding known food allergens or additives, diet is not restricted.

Activity

Maintaining physical activity and exercise is essential to avoid deconditioning. Susceptible individuals should decrease outdoor activity during midday and afternoon when pollen counts are highest. A short-acting beta-2 agonist and/or cromolyn metered-dose inhaler (MDI) can be used 15-30 minutes before exercise if needed.

Medication

Anti-inflammatory medications (especially inhaled glucocorticosteroids) are now the mainstay of therapy and the single most effective therapy for adults with asthma. Anti-inflammatory medications are proven to improve lung function (ie, FEV₁, AHR) and to decrease symptoms, exacerbation frequency, and the need for rescue inhalers.

Short-acting inhaled beta-2 agonists, as needed, are most effective for rapid relief of asthma symptoms. No benefit and some risk of developing tolerance occur with regular long-term use. These agents should still be available to the patient, even if he or she is using a long-acting beta-2 agonist (eg, salmeterol).

Of note, the list of medications that combine 2 drugs in a single delivery device in an effort to increase patient convenience and compliance is expanding. These include a combination of albuterol and ipratropium bromide (Combivent) and a combination of fluticasone and salmeterol (Advair). Another combination product, composed of formoterol and budesonide (Symbicort), may be approved in the United States within 2 years.

Glucocorticoids may increase cell beta-2 agonist receptors, which, in turn, may enhance the action of the combination products.

According to the 1998 Leukotriene Working Group, leukotriene pathway modifiers may be useful as first-line therapy for mild persistent asthma or as an add-on or glucocorticoid-sparing medication in others. These agents are less effective than glucocorticoid inhalers but tend to improve compliance because dosing is oral and once daily, and usage appears more reasonable for those unable or unwilling to take glucocorticoids. Leukotriene synthesis inhibitors montelukast, zafirlukast, and zileuton are available.

When adding to a medication regimen for asthma (referred to as stepping up therapy), consider adding LABA for persistent symptoms with impaired FEV₁. Patients with symptoms but normal lung function (especially those with symptomatic allergic rhinitis) might benefit first from a leukotriene pathway modifier. Of course, some patients will ultimately be treated with both types of medications for optimum management.

Mast cell stabilizers can also be used. Cromolyn sodium (Intal) indirectly blocks calcium influx into mast cells, preventing inflammatory mediator release. Adults can use it in an MDI (2-4 puffs 3-4 times daily) or in a nebulized form (1 ampule 3-4 times daily). Because of its safety profile, this agent is often tried in children; however, it may take a month to work. The pediatric dose is 1-2 puffs via an MDI 3-4 times daily or 1 ampule via a nebulizer 3-4 times daily. Cromolyn sodium tends to work best in young and highly allergic patients.

Nedocromil (Tilade) has similar effects, although it is structurally distinct. The adult dose is 2-4 puffs via an MDI 2-3 times daily. The pediatric regimen is 1-2 puffs via an MDI 2-4 times daily. MDIs may be used with a spacer as necessary (mask if <2>

Drug Category: Bronchodilators

Provide immediate relief of bronchospasm. Preferentially (but not exclusively) bind beta2-adrenergic receptors, resulting in conversion of ATP to cyclic AMP, relaxation of bronchial smooth muscle, and decreased release of inflammatory mediators. Anticholinergic agent ipratropium is included here because it has an additive beneficial effect when given with bronchodilators in acute, severe asthma.

Drug Name	Albuterol (Proventil, Ventolin, Airet)
Description	Beta-agonist. Relaxes bronchial smooth muscle by action on beta-2 receptors with little effect on cardiac muscle contractility.
Adult Dose	4 mg PO q12h; not to exceed 32 mg/d MDI: 1-2 puffs q4-6h prn; not to exceed 12 puffs/d Nebulizer: 2.5 mg tid/qid
Pediatric Dose	PO <12>12 years: Administer as in adults MDI <4>4 years: Administer as in adults Nebulizer 2-12 years: 0.1-0.15 mg/kg/dose, not to exceed 2.5 mg tid/qid prn >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; used regularly during pregnancy; can cause paradoxical bronchospasm; increasing need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Drug Name	Ipratropium (Atrovent)
Description	DOC for beta-2 agonist-induced bronchospasm. Chemically related to atropine and has antisecretory properties. Inhibits vagally mediated reflexes by increasing cyclic GMP, causing local bronchial smooth muscle dilation. Not effective for exercise-induced symptoms. Additive to, but slower than, effects of beta-2 agonists.
Adult Dose	Nebulizer: 1 U dose vial (500 mcg) q30min for 3 doses, then q2-4h prn MDI: 4-8 puffs prn initially; not to exceed 12 puffs/d
Pediatric Dose	Nebulizer: 250 mcg q20min for 3 doses, then q2-4h prn MDI: 4-8 puffs prn initially; not to exceed 6 puffs/d
Contraindications	Documented hypersensitivity
Interactions	Drugs with anticholinergic properties (eg, dronabinol) may increase toxicity; albuterol may increase effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Not indicated for acute episodes of bronchospasm; caution in narrow-angle glaucoma, prostatic hypertrophy, and bladder neck obstruction

Drug Name	Bitolterol (Tornalate); Pirbuterol (Maxair)
Description	Stimulates beta-2 receptors directly to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.
Adult Dose	Bitolterol: 2 puffs q8h prn Pirbuterol: 1-2 puffs q4-6h prn
Pediatric Dose	<12>12 years: Administer as in adults
Contraindications	Documented hypersensitivity; tachycardia resulting from cardiac arrhythmia
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increased need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Drug Name	Metaproterenol (Alupent, Metaprel)
Description	Relaxes bronchial smooth muscle by action on beta2-adrenergic receptors with little effect on cardiac muscle contractility. Generally not recommended because of excessive cardiac stimulation, especially in high doses.
Adult Dose	MDI: 2-3 puffs q3-4h prn Nebulizer: 0.01 mg/kg; not to exceed 0.3 mL of 5% solution q4h prn PO: 20 mg tid/qid
Pediatric Dose	<6>9 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hyperthyroidism, diabetes mellitus, and cardiovascular disorders; can cause paradoxical bronchospasm; increased need for this rescue medication may indicate clinical destabilization that requires medical reevaluation

Drug Name	Terbutaline (Brethaire, Brethine, Bricanyl)
Description	Acts directly on beta-2 receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance.
Adult Dose	MDI: 2 puffs q4-6h prn SC: 0.25 mg PO: 5 mg tid
Pediatric Dose	<12>15 years: Administer as in adults
Contraindications	Documented hypersensitivity; tachycardia resulting from cardiac arrhythmias
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilation; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Through intracellular shunting, may decrease serum potassium levels, which can produce adverse cardiovascular effects; decrease is usually transient and may not require supplementation

Drug Name	Salmeterol (Serevent)
Description	Long-acting bronchodilator - works by relaxing smooth muscles of bronchioles and relieving bronchospasms. Effect may also facilitate expectoration. Inhaler does not replace anti-inflammatory medications but can be added to decrease rescue inhaler use. Evening dose may be useful for nocturnal symptoms. SR PO albuterol has greater systemic sympathomimetic adverse effects and is considered an alternate therapy only. WARNING: Data from a large placebo-controlled US study (SMART trial) that compared the safety of salmeterol or placebo added to usual asthma therapy showed a small but significant increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks) versus those on placebo (3 of 13,179).
Adult Dose	PO: 4 mg q12h MDI: 2 puffs (or 1 blister pack) q12h
Pediatric Dose	PO: 0.3-0.6 mg/kg/d; not to exceed 8 mg MDI: 1-2 puffs (or 1 blister pack) q12h
Contraindications	Documented hypersensitivity; angina, tachycardia, and cardiac arrhythmia associated with tachycardia
Interactions	Concomitant use of beta-blockers may decrease bronchodilating and vasodilating effects of beta-agonists; concurrent administration with methyldopa may increase pressor response; coadministration with oxytocic drugs may result in severe hypotension; ECG changes and hypokalemia due to diuretics may worsen
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not indicated to treat acute asthmatic symptoms; sympathomimetic responses (tremor, tachycardia) can occur and may be significant in some patients with cardiovascular disease; onset of action can be delayed (does not preclude need for short-acting bronchodilators)

Drug Name	Theophylline (Theo-24, Theolair, Theo-Dur, Slo-bid)
Description	Structurally classified as a methylxanthine, it acts as a bronchodilator. Potentiates exogenous catecholamines and stimulates endogenous catecholamine release and diaphragmatic muscular relaxation, which, in turn, stimulates bronchodilation. For bronchodilation, near toxic (>20 mg/dL) levels are usually required. Less effective than glucocorticoids but may be glucocorticoid-sparing agent. Routine drug level monitoring required (goal: 5-15 mcg/mL).
Adult Dose	10 mg/kg/d (not to exceed 300 mg) PO initially; not to exceed 800 mg/d maintenance
Pediatric Dose	<1>1 year: 16 mg/kg/d PO; not to exceed 400 mg/d; alternatively, 10 mg/kg/d IV
Contraindications	Documented hypersensitivity; uncontrolled arrhythmia; peptic ulcers; hyperthyroidism; uncontrolled seizure disorders
Interactions	Aminoglutethimide, barbiturates, carbamazepine, ketoconazole, loop diuretics, charcoal, hydantoins, phenobarbital, phenytoin, rifampin, isoniazid, and sympathomimetics may decrease effects Effects may increase with allopurinol, beta-blockers, ciprofloxacin, corticosteroids, disulfiram, quinolones, thyroid hormones, ephedrine, carbamazepine, cimetidine, erythromycin, macrolides, propranolol, and interferon
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in peptic ulcer, hypertension, tachyarrhythmia, hyperthyroidism, and compromised cardiac function; do not inject IV solution >25 mg/min; patients diagnosed with pulmonary edema or liver dysfunction are at greater risk of toxicity because of reduced drug clearance

Drug Category: Monoclonal antibodies

Recombinant, DNA-derived agents inhibit IgE binding to the high-affinity IgE receptor on mast cells and basophils, causing a decrease in release of mediators of the allergic response.

Drug Name	Omalizumab (Xolair)
Description	Recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE receptor on surface of mast cells and basophils. By inhibiting IgE binding, release of mediators of allergic response is inhibited. Indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.
Adult Dose	150-375 mg SC q2-4wk; inject slowly over 5-10 seconds due to viscosity; not to exceed 150 mg/injection site Precise dose and frequency established by serum total IgE level (IU/mL)
Pediatric Dose	<12>12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not effective to treat acute asthma; do not abruptly discontinue inhaled corticosteroids when initiating omalizumab; malignancy rate among treated patients (0.5%) was numerically higher than among control patients (0.2%); malignancies varied, and further long-term observation needed to fully assess risk; may cause injection-site reaction

Drug Category: Glucocorticoids

Maintenance medications that decrease inflammatory mediators to limit airway remodeling. Must be taken regularly to be beneficial. Do not relieve acute bronchospasm; short-acting bronchodilators must be available. The multiple formulations are not equivalent on a per-dose or per-mcg basis. Inhaled corticosteroids are one of the most important developments in asthma management because they decrease inflammation. Proven to improve lung function (ie, FEV₁, airway hyperactivity) and decrease symptoms, exacerbation frequency, and need for rescue inhalers. Dose ranges as recommended by NHLBI.

Drug Name	Beclomethasone (Beclovent, Vanceril)
Description	Inhibits bronchoconstriction, produces direct smooth muscle relaxation, decreases number and activity of inflammatory cells, and decreases airway hyperresponsiveness.
Adult Dose	Low dose: 2-6 puffs (84-mcg MDI) or 4-12 puffs (42-mcg MDI) Medium dose: 6-10 puffs (84-mcg MDI) or 12-20 puffs (42-mcg MDI) High dose: >10 puffs (84-mcg MDI) or >20 puffs (42-mcg MDI)
Pediatric Dose	Low dose: 1-4 puffs (84-mcg MDI) or 2-8 puffs (42-mcg MDI) Medium dose: 4-8 puffs (84-mcg MDI) or 8-16 puffs (42-mcg MDI) High dose: >8 puffs (84-mcg MDI) or >16 puffs (42-mcg MDI)
Contraindications	Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	Coadministration with ketoconazole may increase plasma levels but does not appear to be clinically significant
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not for acute attack; weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Budesonide (Pulmicort Respules, Pulmicort Turbuhaler, Rhinocort Aqua Intranasal)
Description	Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness.
Adult Dose	DPI Low dose: 200-600 mcg Medium dose: 600-1200 mcg High dose: 1200 mcg
Pediatric Dose	Inhalation suspension for children Low dose: 0.5 mg Medium dose: 1 mg High dose: 2 mg
Contraindications	Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Flunisolide (AeroBid)
Description	Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness.
Adult Dose	Low dose: 2-4 puffs Medium dose: 4-8 puffs High dose: >8 puffs
Pediatric Dose	Low dose: 2-3 puffs Medium dose: 4-5 puffs High dose: >5 puffs
Contraindications	Documented hypersensitivity: bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Fluticasone (Flovent)
Description	Has extremely potent vasoconstrictive and anti-inflammatory activity. Has a weak hypothalamic-pituitary-adrenocortical axis inhibitory potency when applied topically.
Adult Dose	MDI Low dose: 88-264 mcg Medium dose: 264-660 mcg High dose: >660 mcg DPI Low dose: 100-300 mcg Medium dose: 300-600 mcg High dose: >600 mcg
Pediatric Dose	MDI Low dose: 88-176 mcg Medium dose: 176-440 mcg High dose: >440 mcg DPI Low dose: 100-200 mcg Medium dose: 200-400 mcg High dose: >400 mcg
Contraindications	Documented hypersensitivity; bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Triamcinolone (Azmacort)
Description	Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability.
Adult Dose	Low dose: 4-10 puffs Medium dose: 10-20 puffs High dose: >20 puffs
Pediatric Dose	Low dose: 4-8 puffs Medium dose: 8-12 puffs High dose: >12 puffs
Contraindications	Documented hypersensitivity, bronchospasm, status asthmaticus, other types of acute episodes of asthma
Interactions	Coadministration with barbiturates, phenytoin, and rifampin decreases effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Weight gain, increased bruising, cushingoid features, acneiform lesions, mental disturbances, and cataracts may occur (taper medication slowly if these changes occur); adverse effects include dysphonia and oral thrush (minimize by rinsing mouth); long-term high-dose use may cause osteoporosis, adrenal suppression, or growth impairment; universally safer than PO steroids and are necessary to avoid permanent lung damage in some patients with asthma

Drug Name	Prednisone (Deltasone, Orasone)
Description	Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Goal is lowest dose and shortest duration effective for disease control. Conversion: methylprednisolone (Medrol) dose equal to four fifths of desired prednisone dose. Prednisolone (Prelone, Pediapred) dose equal to prednisone dose.
Adult Dose	40-60 mg/d PO for 3-10 d as burst; 5-60 mg/d PO qd or qod for long-term use prn for disease control; divided doses (20 mg tid) are more effective than 60 mg qd but are also associated with more adverse effects
Pediatric Dose	1-2 mg/kg/d PO for 3-10 d as burst; not to exceed 60 mg/d; 0.25-2 mg/kg qd or qod for long-term use prn for disease control
Contraindications	Documented hypersensitivity; peptic ulcer disease, hepatic dysfunction; viral infection, connective tissue infections, fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Category C for methylprednisolone and prednisolone; abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, weight gain, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur; qod therapy lessens adverse effects

Drug Category: Leukotriene-modifying agents

Consist of leukotriene receptor antagonists (eg, zafirlukast and montelukast) and synthesis inhibitors (eg, zileuton).

Drug Name	Zafirlukast (Accolate), montelukast (Singulair), zileuton (Zyflo)
Description	Leukotriene pathway inhibitors. Not for use in acute episodes of asthma.
Adult Dose	Zafirlukast: 20 mg PO bid Montelukast: 10 mg PO qd Zileuton: 600 mg PO qid
Pediatric Dose	<12>6 years (montelukast): 5 mg PO qd
Contraindications	Documented hypersensitivity
Interactions	Warfarin and theophylline levels must be followed closely if coadministered with zafirlukast or zileuton; do not take with food
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category C for zileuton; association with Churg-Strauss vasculitis (zileuton), although may be unrelated and only reflect coincidental corticosteroid withdrawal; monitor liver enzymes; not a bronchodilator; have appropriate rescue medication available