dence supports the importance of bradykininANGIOEDEMA in the clinical manifestations of angioedema. Other kinins may also be pathogenic. The specific trigger responsible for inducing the release of these vasoactive peptides is un-Angioedema,Acquired clear. Factor XII activation (Hageman factor) may be secondary to phospholipid releaseSynonyms and related keywords: AAE, from damaged or apoptotic cells and may beCaldwell syndrome, acquired angioedema important in the generation of bradykinin from endothelial activation. This hypothesisBackground encompasses the role of illness or tissue in- jury in the generation of bradykinin. The pre-Acquired angioedema (AAE) is characterized cise pathophysiology of AAE-I remains to beby painless, nonpruritic, nonpitting swelling defined. Diminished levels of C1-INH areof the skin that is classified into 2 forms: ac- due to its increased catabolism.quired angioedema type I (AAE-I) and ac- In AAE-I, the associated disorders (usuallyquired angioedema type II (AAE-II). AAE-I is lymphoproliferative malignancies) produceassociated with other diseases, most com- complement-activating factors, idiot-monly B-cell lymphoproliferative disorders. ype/anti-idiotype antibodies, or other im-AAE-II is an autoimmune process defined by mune complexes that destroy C1-INH func-the presence of an autoantibody directed tion. Neoplastic lymphatic tissue has beenagainst the C1 inhibitor molecule (C1-INH). found to play an active role in the consump- tion of C1-INH and the complement compo-Pathophysiology nents of the classic pathway. The most com- monly associated malignancy, B-cell lympho-The gene for C1-INH (SERPING1) has been ma, has shown that anti-idiotypic antibodymapped to chromosome 11 (11q12-q13.1). attached to immunoglobulin on the surfaceC1-INH is a multifunctional serine protease of B-cells causes C1-INH deficiency. In-inhibitor that is normally present in high con- creased consumption of C1q followed by C2centrations in plasma. It is the only plasma and C4 results in subsequent release of vaso-inhibitor of C1r and C1s, the activated pro- active peptides that act on postcapillary ven-teases of the first component of complement. ules.It is also the major plasma inhibitor of acti- In AAE-II, a normal 105-kd C1-INH moleculevated Hageman factor, the first protease in is synthesized in adequate amounts, but, be-the contact system. Additionally, C1-INH is cause of an unknown event, a subpopulationone of the major inhibitors of plasma kallik- of B cells secretes autoantibodies to therein, the contact system protease that cleaves C1-INH molecule. This autoantibody, whichkininogen and releases bradykinin. may be any of the major immunoglobulinPresumably, uncontrolled activation of the classes, binds to the reactive center ofcontact system allows for release of kininlike C1-INH. After binding to C1-INH and alter-mediators, resulting in vascular permeability ing its structure, its regulatory capacity is di-with edema of subcutaneous and mucosal tis- minished or abrogated.sues. Although the issue of which vasoactive In all reported cases of C1-INH deficiencypeptide is ultimately responsible for these caused by an autoantibody, C1-INH circu-changes remain controversial, direct evi- lates in the blood in a form that has been
cleaved by target proteases from its native is not obtained, which distinguishes AAEmolecule to a 95-kd fragment. Because of the from HAE.higher affinity of the autoantibody for native Regarding angioedema, symptoms are refer-C1-INH, the 95-kd antibody/C1-INH com- able to 3 prominent sites: subcutaneous tis-plex dissociates, and the freed antibody can sues (eg, face, hands, arms, legs, genitals, but-bind to another native C1-INH molecule, al- tocks); abdominal organs (eg, stomach, intes-lowing for the further depletion of C1-INH. tines, bladder), which may manifest as nau-The distinction between AAE-I and AAE-II sea, vomiting, and/or colicky pain andmay be difficult to make at times and it is im- mimic a surgical emergency; and the upperperative to stress that overlap does occur. For airway (eg, larynx), which may result in lar-instance, cases of monoclonal gammopathy yngeal edema.of undetermined significance ( MGUS) have Occasionally, patients may experience heatshown the monoclonal immunoglobulin it- and pain in the affected areas.self to be the C1-INH antibody. Regarding Other symptoms may be related to underly-malignancies and/or other diseases associ- ing disorders, such as lymphoproliferativeated with AAE-I, it has been demonstrated malignancies or connective tissue disease.that these patients may initially present withautoantibodies to C1-INH, or they may de- Physicalvelop as the disease progresses. Physical signs include overt, noninflamma- tory swelling of the skin and mucous mem-Frequency branes.International Although urticaria does not usually occur,AAE is rare, with approximately 150 cases re- occasionally, erythema or mild urticarialported in the medical literature worldwide. eruptions may precede the edema.Mortality/Morbidity CausesAlthough mortality may occur because of lar- AAE-I is most frequently associated with B-yngeal edema, it is more likely due to the cell lymphoproliferative disease. To date, on-complications of the associated disorder. ly 2 reports of a T-cell lymphoma associated with AAE-I have been documented. OtherRace disorders have included multiple myeloma,Presumably, all races are affected. chronic lymphocytic leukemia, myelofibrosis, Waldenström macroglobulinemia, non-Sex Hodgkin lymphoma, MGUS, rectal carcino-Men and women may be affected. ma, essential cryoglobulinemia, erythrocyte sensitization, livedo reticularis, cold urtica-Age ria, lupus anticoagulant, and infection withThe onset of AAE is most common after the Helicobacter pylori or Echinococcus granulosis.fourth decade of life, whereas the onset of he- By definition, AAE-II is not associated withreditary acquired angioedema (HAE) is in any specific disorder but rather by the pres-the second decade. ence of the autoantibody directed against C1-INH. However, the occasional existenceHistory of features of both AAE-I and AAE-II has been noted, most notably with a MGUS.A family history for hereditary angioedema One case of AAE with C1-INH deficiency
state was identified in association with liver Other Teststransplantation. The status of the liver donorwas unknown, but it is speculated that the Other laboratory findings are related to asso-donor may have been C1-INH deficient. ciated illnesses.Another case of AAE was reported withacute upper airway angioedema in associa- Histologic Findingstion with the local anesthetic articaine. Histologic features include reticular dermal,DIFFERENTIALS subcutaneous, or submucosal edema without infiltrating inflammatory cells. VasodilationAngioedema,Hereditary may be seen.Drug EruptionsUrticaria,Acute TREATMENTUrticaria,CholinergicUrticaria,Chronic Medical CareUrticaria,Contact SyndromeUrticaria,Dermographism Depending on the symptoms and the site ofUrticaria,Solar the angioedema, intensive support may beUrticarial,Vasculitis necessary, including intravenous fluids. When possible, the underlying disorderOther Problems to be Considered should be treated. The resolution of angioe- dema has been reported with the treatmentACE inhibitor–induced angioedema of underlying disease, although recurrencesEpisodic angioedema with angioedema have occurred despite appropriate treatmentLeukocytoclastic vasculitis of the disorder.Urticaria, cold In AAE-I, treatment of the associated lym- phoproliferative process may result in correc-Lab Studies tion of the abnormality. AAE-I and AAE-II Surgical Care Low C1-INH levels Low C1q levels (except 1 reported case) Intubation may be necessary in cases of lar- Low C4 levels yngeal edema. Low C2 levels AAE-II - Positive immunoblot assay find- MEDICATION ings for 95-kd C1-INH cleavage product AAE, therapy for acute attacks may beImaging Studies aborted with C1-INH concentrates or, if un- available, fresh-frozen plasma. However,Abdominal radiographs may demonstrate rapid catabolism of C1-INH occurs in AAE,features of ileus. Other findings may be refer- so higher doses of C1-INH plasma concen-able to an associated illness. trate may be needed. Androgens, such as danazol or stanozolol, may be beneficial in AAE-I but are of no val- ue in AAE-II. Prostate cancer and pregnancy
preclude the use of androgens. neoplastic cells.Antifibrinolytics, such as epsilon-aminocap-roic acid and tranexamic acid, have been Adult Dose 500-750 mg/m2found to be more effective for long-term pro- Pediatric Administer as in adultsphylaxis in those with AAE. DoseImmunosuppressive therapy directed towarddecreasing autoantibody production may be Contraindi- Documented hypersensitivity;of value in patients with AAE-II, which may cations severely depressed bone mar-be accomplished by the use of plasmaphere- row functionsis with cyclophosphamide. Interactions Allopurinol may increase riskA recent paper reported effective treatment of bleeding or infection andof 3 severe AAE cases with a series of 4 enhance myelosuppressive ef-weekly injections with rituximab (a chimeric fects; may potentiate doxoru-monoclonal antibody to CD 20). After treat- bicin-induced cardiotoxicity;ment with rituximab, normalization of may reduce digoxin serumC1-INH and C4 levels and long-term remis- levels and antimicrobial ef-sion of angioedema attacks was achieved. fects of quinolones; chloram-New medications are currently being studied phenicol may increase half-lifefor the treatment of AAE. One such treat- while decreasing metabolitement is a synthetic kallikrein inhibitor (DX- concentrations; may increase88), which is thought to be able to stop the effect of anticoagulants; coad-generation of bradykinin by inhibiting kallik- ministration with high dosesrein activation. This drug allows for a de- of phenobarbital may increasecrease in the rate of C1-INH catabolism, al- rate of metabolism and leuko-lowing for C1-INH concentrate to be more ef- penic activity; thiazide diu-fective. retics may prolong cyclophos-Other new products in trial are genetically phamide-induced leukopeniaengineered C1 esterase inhibitor and bradyki- and neuromuscular blockadenin B2 receptor antagonist. by inhibiting cholinesterase activityDrug Category: Alkylating agents Pregnancy D - Unsafe in pregnancySome agents in this class have potent immu- Precautions Regularly examine hemato-nosuppressive activity. logic profile (particularly neu- Drug Name Cyclophosphamide (Cytoxan, trophils and platelets) to mon- Neosar) itor for hematopoietic sup- pression; regularly examineDescription Chemically related to nitrogen urine for RBCs, which may mustards. As an alkylating precede hemorrhagic cystitis; agent, the mechanism of ac- hematologic myelosuppres- tion of the active metabolites sion, primarily leukopenia, is may involve cross-linking of most common adverse effect; DNA, which may interfere thrombocytopenia and ane- with growth of normal and mia occur less frequently; gas-
trointestinal adverse effects in- Interactions Coadministration with estro- clude anorexia, nausea, eme- gens may cause increase in sis, and stomatitis; urologic clotting factors, leading to a adverse effects include dysu- hypercoagulable state; coad- ria, urgency, hematuria, blad- ministration with tretinoin my der fibrosis, and necrosis; increase risk of both venous death from hemorrhagic cysti- and arterial thrombosis tis has occurred; encourage ex- Pregnancy C - Safety for use during preg- cessive fluid intake; interferes nancy has not been estab- with oogenesis and spermato- lished. genesis; may cause irreversi- ble sterility in both sexes Precautions Do not administer unless a definite diagnosis of hyperfi-Drug Category: Antifibrinolytic agents brinolysis has been made; cau- tion in cardiac, hepatic or re-Act through the inhibition of plasmin. nal disease; because amino- caproic acid can be fatal in pa-Drug Name Aminocaproic acid (Amicar) tients with DIC, important toDescription Lysine analog that inhibits fi- differentiate between hyperfi- brinolysis via inhibition of brinolysis and DIC; thrombi plasminogen activator sub- that form during treatment stances; to a lesser degree, are not lysed and effectiveness through antiplasmin activity. is uncertain; associated ad- Widely distributed. Half-life is verse effects are postural hy- 1-2 h. Peak effect occurs with- potension, thrombosis, and in 2 h. Hepatic metabolism is muscular pain and weakness; minimal. Can be used PO/IV. monitor CK levels; caution in patients with upper urinaryAdult Dose 8 g q4h IV, then 16 g/d in tract bleeding; caution with acute attacks rapid infusions; do not admin- 6-10 g/d PO maintenance ister with factor IX complexPediatric 8-10 g/d PO concentrates or anti-inhibitorDose Not recommended in new- coagulant complexes; adverse borns effects include bradyarrhyth-Contraindi- Documented hypersensitivity; mia, drug-induced myopathy,cations evidence of active intravascu- and hypotension lar clotting process; coadmi- nistration with factor IX com- Drug Name Tranexamic acid (Cyklokap- plex concentrates or anti-in- ron) hibitor coagulant complexes; Description Alternative to aminocaproic injection in premature neo- acid. Inhibits fibrinolysis by nates (injectable product con- displacing plasminogen from tains benzyl alcohol) fibrin.
Adult Dose Up to 8 g PO/IV for acute at- tacks Drug Category: Antigonadotropic agents 1-2 g PO for maintenance 3-4.5 g PO/IV qd divided These agents have immunosuppressive prop- tid/qid pc; continue for peri- erties. od long enough for at least 3-4 Drug Name Danazol (Danocrine) attacks to have normally oc- Description Increases levels of C4 compo- curred nent of complement and pre-Pediatric 12-25 mg/kg/dose (not to ex- vents attacks associated withDose ceed 1.5 g) PO tid/qid for angioedema. acute attack or as prophylaxis Adult Dose 200 mg PO bid/tid initially; if for 5 d efficacious, taper dose by 50%Contraindi- Documented hypersensitivity; over following 2-3 mocations active intravascular clotting Pediatric Not established process; acquired defective Dose color vision; subarachnoid hemorrhage Contraindi- Documented hypersensitivity; cations seizure disorders; renal orInteractions Not established hepatic insufficiency; cardiacPregnancy B - Usually safe but benefits disease; breastfeeding; condi- must outweigh the risks. tions influenced by edema; undiagnosed genital bleeding; porphyria; carcinoma of thePrecautions Caution in renal impairment; breast adverse effects are not com- mon but include headaches, Interactions Decreases insulin require- nausea, abdominal pain, and ments and increases effects of diarrhea; evidence of tumor anticoagulants; concomitant formation in retina and liver administration with carbama- found in experimental animal zepine may result in toxicity; models after long-term use; coadministration with HMG- although no evidence has sup- CoA reductase inhibitors may ported these findings in hu- increase risk for rhabdomyoly- mans, annual funduscopic ex- sis; cyclosporine and/or tacro- aminations and LFT monitor- limus toxicity may increase if ing recommended q6mo if on coadministered with danazol; long-term therapy; perform concomitant use with carba- baseline ophthalmologic ex- mazepine may increase risk of amination before initiating carbamazepine toxicity; con- therapy; caution in history of comitant administration with thromboembolic disease and cyclosporine or tacrolimus disseminated intravascular co- and anabolic steroids may re- agulation sult in increased cyclosporine or tacrolimus blood levels and
toxicity; may result in in- Pediatric <6 years: 1 mg/d PO creased lovastatin plasma con- Dose 6-12 years: 2 mg/d PO centrations when adminis- >12 years: Administer as in tered concurrently (use only if adults potential benefit justifies po- Contraindi- Documented hypersensitivity; tential risk of developing cations nephrosis; breast or prostate myopathy/rhabdomyolysis) cancerPregnancy X - Contraindicated in preg- Interactions Increases hypoprothrombine- nancy mic effects of oral anticoagu- lants and hypoglycemic ef-Precautions Caution in renal, hepatic, or fects of insulin and sulfonylur- cardiac insufficiency and seiz- eas ure disorders; peliosis hepati- Pregnancy X - Contraindicated in preg- tis and benign hepatic adeno- nancy ma have been observed with long-term therapy; throm- boembolic events and pseudo- Precautions May cause peliosis hepatitis, tumor cerebri reported; andro- liver cell tumors, and blood genlike effects, including lipid changes with increased weight gain, acne, hirsutism, risk of arteriosclerosis; caution edema, hair loss, voice in cardiac, renal, or hepatic change, and menstrual distur- disease or epilepsy; adverse bances, occur; temporary al- effects include cholestatic teration of lipoproteins may jaundice syndrome and/or occur; consider the impact on hepatic necrosis (causing the risk of atherosclerosis and death); may cause premature coronary artery disease; se- epiphyseal closure in children; rum total testosterone values caution in diabetic patients may be falsely elevated if ra- and pediatric patients; may dioimmunoassay done to cause suppression of clotting measure testosterone in wom- factors II, V, VII, and X and an en taking danazol increase in prothrombin timeDrug Name Stanozolol (Winstrol) FOLLOW-UPDescription Synthetic androgen with im- munosuppressive properties. Prognosis Increases levels of C1 esterase inhibitor and C4 component The prognosis is variable, but it predomi- of the complement. nantly depends on control of the underlyingAdult Dose 2 mg PO tid and reduce to disorder. maintenance dose of 2 mg/d Compared with the general population, pa- or 2 mg qod after 1-3 mo tients with AAE have a higher incidence of B-cell malignancies.
Patients with AAE and a concurrent diagno- Angioedema, Hereditarysis of MGUS do not have an increased riskfor progression to malignancy compared Synonyms and related keywords: hereditarywith patients with a sole diagnosis of MGUS. angioedema, HAE, C1-INH, C1 inhibitor, swelling of the skinPatient EducationFor excellent patient education resources, vis- Backgroundit eMedicines Allergy Center and Skin, Hair, Hereditary angioedema (HAE) is an autoso-and Nails Center. Also, see eMedicines pa- mal dominant disorder of C1 inhibitortient education article Hives and Angioede- (C1-INH) deficiency manifested by painless,ma. nonpruritic, nonpitting swelling of the skin. Type I HAE is defined by low plasma levelsMISCELLANEOUS of a normal C1-INH protein. Type II HAE is characterized by the presence of normal or elevated levels of a dysfunctional C1-INH.Special Concerns Type III HAE has been recently identified as an estrogen-dependent inherited form of an-Tranexamic acid may be used during preg- gioedema occurring mainly in women withnancy. normal functional and quantitative levels of C1-INH. Pathophysiology The gene for C1-INH (SERPING1) has been mapped to 11q12-q13.1. C1-INH is a multi- functional serine protease inhibitor that is normally present in high concentrations in plasma. It is the only known plasma inhibitor of C1r and C1s, the activated proteases of the first component of complement. It is also the major plasma inhibitor of activated factor XII (Hageman factor), the first protease in the contact system. Additionally, C1-INH is one of the major inhibitors of plasma kallikrein, the contact system protease that cleaves kini- nogen and releases bradykinin. Presumably, uncontrolled activation of the contact system allows for the release of kinin- like mediators, resulting in edema of subcu- taneous or submucosal tissues. Although the issue of which vasoactive peptide is ulti- mately responsible for these changes remains controversial, direct evidence supports the importance of bradykinin in the clinical man- ifestations of angioedema. Other kinins may
also be pathogenic. The inciting factor re- Mortality/Morbiditysponsible for inducing the release of these Mortality rates are estimated at 15-33%, re-vasoactive peptides is unclear. Factor XII acti- sulting from laryngeal edema and asphyxia-vation may be secondary to a genetic muta- tion.tion or phospholipid release from damagedor apoptotic cells and may be important in Racethe generation of bradykinin from endothe-lial activation. This hypothesis encompasses Persons of any race can be affected, with nothe role of illness or tissue injury in the gener- reported bias in different ethnic groups.ation of bradykinin.HAE is due to mutations within the C1-INH Sexgene (C1NH) and is transmitted as an autoso- Men and women are equally affected formal dominant trait. Approximately 150 dif- HAE types I and II. HAE type III was ini-ferent genetic mutations have been described tially thought to occur only in women, but re-in HAE, and a spontaneous mutation rate of cent family studies have described males25% has been reported. The 2 variants of with HAE and normal C1 inhibitor levels.HAE related to C1-INH function are type I Although a few male cases have been cited in(85%) and type II(15%). the literature, HAE type III is still thought to predominantly affect women.Type I HAE is characterized by low antigenicand functional plasma levels of a normal AgeC1-INH protein. Type II HAE is character- C1-INH deficiency is present at birth,ized by the presence of normal or elevated although only a few patients have been re-antigenic levels of a dysfunctional mutant ported with perinatal angioedema. Symp-protein together with reduced levels of the toms usually become apparent in the first orfunctional protein. C1-INH deficiency allows second decade of life. Approximately 40% ofautoactivation of C1, with consumption of C4 people with HAE experience their first epi-and C2. In type III HAE, the C1-INH protein sode before age 5 years, and 75% present be-is both qualitatively and functionally normal. fore age 15 years. Patients typically experi-The exact mechanism of action responsible ence minor swelling in childhood that mayfor the link between estrogen and angioede- go unnoticed, with increased severity aroundma is unclear. One theory suggests that estro- puberty. HAE is a lifelong affliction,gen plays a role in up-regulating the produc- although some report decreased symptomstion of bradykinin and decreasing its degra- with age. Five percent of adults with HAEdation by angiotensin-converting enzyme are asymptomatic while carrying the C1NH(ACE). A more recent theory suggests a mu- mutation, and they are only identified aftertation in factor XII that allows for the inap- their children are found to be symptomatic.propriate activation of the kinin cascade. CLINICALFrequency HistoryInternationalHAE is estimated to occur in 1 in A family history of HAE is typically ob-50,000-150,000 individuals. tained, although spontaneous mutations may occur. Symptoms are referable to 3 prominent
sites: subcutaneous tissues (face, hands, nal involvement.arms, legs, genitals, and buttocks); ab-dominal organs (stomach, intestines, blad- Physicalder, and kidneys), which may manifest as Physical signs include overt, noninflam-vomiting, diarrhea, or paroxysmal colicky matory swelling of the skin and mucouspain and mimic a surgical emergency; and membranes. Typical involvement includesthe upper airway (larynx) and tongue, the face, hands, arms, legs, genitalia, andwhich may result in laryngeal edema and buttocks, although the edema can localizeupper airway obstruction. subcutaneously at any site. In some pa-Attacks usually occur at a single site, but tients with severe edema, tension vesiclessimultaneous involvement of subcutane- or bullae may develop.ous tissue, viscera, and the larynx is not In approximately 25% of patients, erythe-uncommon. Nonpitting cutaneous swel- ma may precede the occurrence of edema.ling is the most commonly reported symp- An estimated 30-50% of patients withtom, and it mainly affects the extremities, HAE reportedly have erythema margina-the genitalia, and the face. Acute abdomi- tum preceding or accompanying the at-nal pain, nausea, and vomiting are the tacks. Urticaria is not usually associateddominant symptoms in 25% of patients with HAE.with HAE and are rarely seen in people Abdominal examination may reveal signswith other forms of angioedema. The life- consistent with acute abdomen or abdomi-time incidence of a laryngeal attack is esti- nal obstruction. Ascites is often presentmated at 70%. with an abdominal attack associated withMucosal edema of the bladder or urethra angioedema.can result in urinary retention, stammer- Mucosal involvement with glossal, phar-ing, pain, or anuria. yngeal, or laryngeal edema may cause res-Episodes of severe headaches, visual dis- piratory obstruction and signs of distress.turbances (eg, blurred vision, diplopia), Additional rare physical findings thatand ataxia have been reported. have been reported are pleuritic symp-Cases of painful muscle swelling and uni- toms with pleural effusions, seizures andlateral hip or shoulder involvement have hemiparesis secondary to cerebral edema,also been cited. and bladder edema.Attacks may be preceded several hours in Causesadvance by sudden mood changes, anxi-ety, sensory changes, or exhaustion. Precipitating factors of attacks may in-Patients often report episodes of swelling clude trauma (especially dental trauma),worsening over a period of 12-24 hours, anxiety, menstruation, infection, exercise,usually with resolution within 72 hours. alcohol consumption, and stress. Medica-Symptoms can persist for up to 5 days, tions (eg, estrogen, ACE inhibitors, angio-with migration of swelling to different tensin II type 1 receptor antagonists) havesites. The edema is usually unresponsive also been shown to induce attacks.to antihistamines. Attacks are usually peri- During pregnancy, symptoms may in-odic and are commonly followed by crease or decrease for HAE types I and II.weeks of remission. In HAE type III, studies have reportedPediatric episodes are usually less fre- first episodes or recurrences associatedquent and commonly manifest as abdomi- with estrogen-containing oral contracep-
tives, estrogen replacement therapy, or Type II HAE pregnancy. C1-INH level is normal or elevated but As many as 2% of patients with HAE may dysfunctional. have systemic lupus erythematosus. Less C4 and C2 levels are low. commonly, other autoimmune disorders, C1q level is normal. such as glomerulonephritis, rheumatoid Type III HAE arthritis, thyroiditis, Sjögren syndrome, C1-INH level is normal. and pernicious anemia, may be associated C1-INH functional assay is normal. with HAE. C4 level may be normal. Those HAE patients infected with Helico- bacter pylori have been found to be more Imaging Studies symptomatic than those who are not in- Abdominal radiographs may demonstrate fected. features of ileus. Abdominal ultrasonography or computedDIFFERENTIALS tomography may show edematous thick- Angioedema,Acquired ening of the intestinal wall, a fluid layer Drug Eruptions around the bowel, and large amounts of Urticaria,Acute free peritoneal fluid. Urticaria,Cholinergic Chest radiographs may demonstrate pleu- Urticaria,Chronic ral effusions. Urticaria,Contact yndrome Urticaria,Dermographism Histologic Findings Urticaria,Pressure Histologic features include edema in the re- Urticaria,Solar ticular dermis or subcutaneous or submu- Urticarial Vasculitis cosal edema without infiltrating inflamma- tory cells. Vasodilation may be present.Other Problems to be Considered TREATMENTACE inhibitor–induced angioedemaEpisodic angioedema with eosinophiliaVibratory- or pressure-induced angioedema Medical Care Depending on the symptoms and the sitesWORKUP of the angioedema, intensive support mayLab Studies be necessary, including intravenous fluids. In cases of serious laryngeal edema caus-Routine laboratory test results are usually ing respiratory obstruction, intubation ornormal, although a leukocytosis may occur tracheostomy should be performed. Inwith gastrointestinal episodes. Elevation of HAE types I and II, the treatment of choicethe hematocrit value may be observed be- in acute attacks consists of replacementcause of intravascular fluid loss. with commercially available C1-INH con- centrates or, if unavailable, fresh-frozen Type I HAE plasma. In HAE type III, infusion of C1-INH level is low. C1-INH has proven to be ineffective. C4 and C2 levels are low. Prophylactic treatment is instituted if pa- C1q level is normal. tients are afflicted with frequent and/or
severe episodes. nin-2 receptor antagonist (icatibant), mayDanazol or stanozolol may be used at offer safer and more effective treatmentdoses that prevent attacks; normalizing options. Several protease inhibitors havethe levels of C1-INH is not necessary. The been found to have functional overlapmost significant complication of long-term with C1-INH (eg, antithrombin III, beta-use may be arterial hypertension. The macroglobulin, alpha1-antitrypsin) and17-alpha-alkylated androgens rarely cause may be therapeutic options in the future.hepatotoxicity and liver tumors, but theyshould be used at the lowest effective dos- Surgical Careage. Regular monitoring of liver functiontest results, lipid levels, and liver ultraso- Intubation may be necessary in cases compli-nography findings is recommended. cated by laryngeal edema.Although virilization may be an issue withwomen, keeping to the lowest possible MEDICATIONdose usually obviates this concern.Contraindications to the use of androgensinclude prostate cancer, pregnancy, child- The goals of pharmacotherapy are to reducehood, and breastfeeding. morbidity and to prevent complications.Antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid can Drug Category: Antigonadotropic agentsalso be used for prophylaxis, althoughthey have not been found to be as effective These agents may be used at doses that pre-as the androgenic agents. These agents are vent attacks.the option for pregnant women. Drug Name Danazol (Danocrine)Short-term prophylaxis for surgical proce- Description Increases levels of C4 compo-dures, especially dental work, is neces- nent of complement and re-sary. C1-INH infusions can be given 24 duces attacks associated withhours before the procedure or just prior to angioedema. In HAE, danazolit. Alternatives, such as antifibrinolytics or increases level of deficient C1androgens, can be used, and they should esterase inhibitor.be started 5 days before the procedure andcontinued for 2 days afterwards. Adult Dose Short-term prophylaxis:Eradication of the underlying cause of the 100-600 mg/d POattack, such as H pylori or another infec- Long term prophylaxis: 200tious agent, may lead to resolution of mg PO tid; taper to lowest ef-symptoms. Careful attention should be fective dosegiven to medications being taken by thepatient that may have contributed to an at- Pediatric Not establishedtack, such as contraceptives, hormone re- Doseplacement therapy, or ACE inhibitors.Clinical trials are currently underway for Contraindi- Documented hypersensitivity;several new therapies for acute attacks of cations seizure disorders; renal orangioedema. The new therapies, such as hepatic insufficiency; cardiacrecombinant human C1-INH, recombinant disease; breastfeeding; condi-kallikrein inhibitor (DX-88), and bradyki- tions influenced by edema;
undiagnosed genital bleeding; Interactions Increases hypoprothrombine- porphyria mic effects of oral anticoagu- lants and hypoglycemic ef-Interactions Decreases insulin require- fects of insulin and sulfonylur- ments and increases effects of eas anticoagulants; may increase carbamazepine levels Pregnancy X - Contraindicated in preg- nancyPregnancy X - Contraindicated in preg- nancy Precautions May cause peliosis hepatitis, liver cell tumors, and bloodPrecautions Caution in renal, hepatic, or lipid changes with increased cardiac insufficiency and seiz- risk of arteriosclerosis; caution ure disorders; peliosis hepati- in cardiac, renal, or hepatic tis and benign hepatic adeno- disease or epilepsy; may in- ma have been observed with crease PT; phallic or clitoral long-term therapy (>10 y); enlargement, hirsutism, gyne- thromboembolic events and comastia, acne, edema, nau- pseudotumor cerebri re- sea, vomiting, and diarrhea ported; androgenlike effects, may occur including weight gain, acne, hirsutism, edema, hair loss, voice changes, and menstrual disturbances, occur Drug Category: Antifibrinolytic agents Act through the inhibition of plasmin.Drug Name Stanozolol (Winstrol) Drug Name Epsilon-aminocaproic acidDescription Synthetic androgen with im- (Amicar) munosuppressive properties. Description Lysine analog that inhibits fi- Increases levels of C1 esterase brinolysis via inhibition of inhibitor and C4 component plasminogen activator sub- of complement. stances and, to a lesser degree,Adult Dose 2 mg PO tid and reduce to through antiplasmin activity. maintenance dose of 2 mg/d Widely distributed. Half-life is PO or 2 mg PO qod after 1-3 1-2 h. Peak effect occurs with- mo in 2 h. Hepatic metabolism isPediatric <6 years: 1 mg/d PO minimal. Can be used PO/IV.Dose 6-12 years: 2 mg/d PO >12 years: Administer as in Adult Dose Acute attack: 8 g q4h IV, then adults 16 g/dContraindi- Documented hypersensitivity; Maintenance: 6-10 g/d POcations nephrosis; breast or prostate cancer Pediatric 8-10 g/d PO Dose Not recommended in new-
borns displacing plasminogen from fibrin.Contraindi- Documented hypersensitivity;cations evidence of active intravascu- Adult Dose Acute attack: Up to 8 g PO/IV lar clotting process; coadmi- Maintenance: 1-2 g PO nistration with factor IX com- plex concentrates or anti-in- Pediatric 12-25 mg/kg/dose (not to ex- hibitor coagulant complexes Dose ceed 1.5 g) PO tid/qid recom-Interactions Coadministration with estro- mended gens may cause increase in Contraindi- Documented hypersensitivity clotting factors, leading to a cations hypercoagulable state Interactions Not establishedPregnancy C - Safety for use during preg- nancy has not been estab- Pregnancy B - Usually safe but benefits lished. must outweigh the risks.Precautions Do not administer unless a Precautions Caution in renal impairment; definite diagnosis of hyperfi- adverse effects are not com- brinolysis has been made; cau- mon but include headaches, tion in cardiac, hepatic, or re- nausea, abdominal pain, and nal disease; because amino- diarrhea; evidence of tumor caproic acid can be fatal in pa- formation in retina and liver tients with DIC (important to found in experimental animal differentiate between hyperfi- models after long-term use; brinolysis and DIC); thrombi although no evidence has sup- that form during treatment ported these findings in hu- are not lysed and effectiveness mans, annual funduscopic ex- is uncertain; associated ad- aminations and LFT monitor- verse effects are postural hy- ing recommended q6mo if on potension, thrombosis, and long-term therapy; perform muscular pain and weakness; baseline ophthalmologic ex- monitor CK levels; caution in amination before initiating patients with upper urinary therapy tract bleeding; caution with rapid infusions; do not admin- FOLLOW-UP ister with factor IX complex concentrates or anti-inhibitor coagulant complexes Prognosis Patients with an early onset of attacksDrug Name Tranexamic acid (Cyklokap- have a worse prognosis than those with a ron) late onset of attacks. With appropriate use of prophylactic ther-Description Alternative to aminocaproic apy, the prognosis for patients with HAE acid. Inhibits fibrinolysis by is excellent.
PathophysiologyPatient Education The pathophysiology of AD is poorly under- stood. Several cell types seem to be involved, For more information, visit the United including T lymphocytes, eosinophils, Lan- States Hereditary Angioedema Associa- gerhans cells, and keratinocytes. Other fac- tion. tors, including cytokines and IgE, are also im- For excellent patient education resources, plicated. visit eMedicines Allergy Center and Skin, Laboratory findings suggest a number of dif- Hair, and Nails Center. In addition, see ferent pathogenetic mechanisms. One in- eMedicines patient education article vokes an immune defect involving an abnor- Hives and Angioedema. mality of T 2 cells that interacts with Langer- H hans cells and results in increased produc- tion of interleukin (IL)–4, IL-5, IL-6, IL-10, and IL-13. This leads to increased IgE and de- creased gamma interferon levels. The imbal- ance of T 2 cells occurs in the acute process,Atopic Dermati- H with a swing toward T 1 cells in the chronic Htis stages of the disease. Another theory in- volves defective barrier function in the stra- tum corneum leading to the entry of anti-Synonyms and related keywords: infantile gens, which results in the production of vari-eczema, Besniers prurigo, intrinsic ecze- ous inflammatory cytokines.ma, extrinsic eczema, atopiform eczema, Xerosis is known to be an associated sign inasthma, food allergy, peanut allergy, allergic most AD patients. The xerosis is thought toreaction involve defective lipid (particularly ceram- ide) production. A third mechanism involves environmental antigens from food (the gut),INTRODUCTION dust mites (the lungs), and other factors and portals of entry that react with antibodies toBackground produce increased levels of IgE and, possi-Atopic dermatitis (AD) is a pruritic disease of bly, increased histamine reactions from mastunknown origin that usually starts in early dells. Superimposed with these mechanismsinfancy and is typified by pruritus, eczema- is a genetic predisposition to react to varioustous lesions, xerosis (dry skin), and lichenifi- environmental allergens.cation on the skin (thickening of the skin andincrease in skin markings). AD is associated Frequencywith other atopic diseases (eg, asthma, aller-gic rhinitis, urticaria, acute allergic reactions United Statesto foods, increased immunoglobulin E [IgE] The prevalence rate is 10-12% in children andproduction) in many patients. It is a disease 0.9% in adults.of great morbidity, and the incidence appearsto be increasing. International The prevalence rate is as high as 18% and is
rising, especially in developed countries. In beta-hemolytic group A Streptococcus.China and Iran, the prevalence rate is ap- Urticaria and acute anaphylactic reactionsproximately 2-3%. The frequency is increased to food occur with increased frequency inin patients who immigrate to developed patients with AD. The food groups mostcountries from underdeveloped countries. commonly implicated include peanuts, eggs, milk, soya, fish, and seafood.Mortality/Morbidity Latex allergy is more common in patientsIncessant itch and work loss in adult life is a with AD than in the general population.great financial burden. A number of studies Of patients with AD, 30% develop asthmahave reported that the financial burden to and 35% have nasal allergies.families and government is similar to that ofasthma, arthritis, and diabetes mellitus. In Racechildren, the disease causes enormous psy- AD may be more common among whites,chological burden to families and loss of but it affects persons of all races.school days. Mortality due to AD is unusual. Sex Kaposi varicelliform eruption (eczema her- The male-to-female ratio is 1:1.4. peticum) is seen with some frequency in patients with AD. It usually occurs with a Age primary herpes simplex infection, but it al- so may be seen recurrently. Vesicular le- In 85% of cases, AD occurs in the first year of sions can begin at any location, but they life; in 95% of cases, it occurs before age 5 are particularly common in areas of ecze- years. ma. The virus spreads rapidly to involve all eczematous areas and healthy skin. Le- Disease is most prevalent in early infancy sions may become secondarily infected. and childhood. The disease may have peri- Although vaccination with the vaccinia ods of complete remission, particularly in vaccine for the prevention of small pox is adolescence, and may then recur in early now no longer mandatory, patients with adult life. AD can contract eczema vaccinatum either In the adult population, the rate of AD fre- from the vaccination of themselves or their quency diminishes to 0.9%. Rarely, onset relatives. This condition had a high mor- may be delayed until adulthood, when the tality rate (up to 25%). In the current cli- disease is more difficult to control. mate of threats of bioterrorism, vaccina- tion may once again become necessary and physicians should be aware of eczema vaccinatum in this setting. CLINICAL With regard to bacterial infection (eg, with Staphylococcus aureus or Streptococcus pyo- History genes), note that the skin of most patients Incessant pruritus is the only symptom. with AD is colonized by S aureus. Clinical Although pruritus may be present in the first infection may occur and is worsened by few weeks of life, parents become more scratching and occlusion from medica- aware of the itch as the itch-scratch cycle ma- tions. Eczematous and bullous lesions on tures when the patient is approximately age the palms and soles are often infected with
3 months; children then scratch themselves Lesions become more diffuse with anuncontrollably. underlying background of erythema. The face is commonly involved and has a dry,Physical scaling appearance.Primary findings include xerosis, lichenifica- Xerosis is prominent.tion, and eczematous lesions. The eczema- Lichenification is present.tous changes are seen in different locations, A brown macular ring around the neck isand the morphology changes with age. typical but not always present. Hanifin diagnostic criteria: In 1980, Hani- 1 Infancy fin and Rajka developed criteria for the AD may be noticed soon after birth. Xero- diagnosis of AD. They developed main cri- sis also occurs in the neonatal period. Xe- teria and numerous minor criteria. Many rosis involves the whole body but usually articles have questioned the validity of the spares the diaper area. minor criteria, and the original criteria The earliest lesions are often evident in the have been modified on numerous occa- creases (ie, antecubital and popliteal fos- sions. sae), where the lesions consist of erythema with exudation. Over the following few Following are the criteria for 2001. weeks, lesions localize to the cheeks and forehead and extensors of the lower legs, Essential features: These features must be but they may occur in any location on the present and, if complete, are sufficient for body, often sparing the diaper area. Le- diagnosis. sions are xerotic, erythematous, and scaly Pruritus (eczematous) ill-defined patches and pla- Eczematous changes ques. Typical and age-specific changes: Pat The scalp is frequently involved with a terns in clude facial, neck, and pruritic scaly dermatitis. extensor involvement in infants Lichenification is seldom seen in infancy. and children, current or prior Childhood flexural lesions in adults or per Xerosis is often generalized. The skin is sons of any age, and sparing of flaky and rough. the groin and axillary regions. Lichenification is characteristic of child- Chronic and relapsing course hood AD. It signifies repeated rubbing of Important features (seen in most the skin and is seen mostly over the folds cases): These features are seen and bony protuberances. in most cases and add support Lesions are eczematous and exudative. to the diagnosis Pallor of the face is common; erythema Early age of onset and scaling occur around the eyes. Den- Atopy (IgE reactivity) nie-Morgan folds (increased folds below Xerosis the eye) are often seen. Flexural creases, Associated features (clinical associations): particularly the antecubital and popliteal These changes help in suggesting the diag- fossae, and buttock-thigh creases are often nosis of AD but are too nonspecific to be affected. used for defining or detecting AD for re- Excoriations and crusting are common. search and epidemiologic studies. Adulthood Keratosis pilaris/ichthyosis/palmar
hyperlinearity aureus has been proposed as a cause of AD Atypical vascular responses by acting as a superantigen. Perifollicular changes AD flares occur in extremes of climate. Ocular/periorbital changes Heat is poorly tolerated, as is extreme Perioral/periauricular lesions cold. A dry atmosphere increases xerosis. Exclusions: Note that a firm diagnosis of Sun exposure improves lesions, but sweat- AD depends on excluding conditions such ing increases pruritus. All these external as scabies, allergic contact dermatitis, se- factors may act as antigens, ultimately set- borrheic dermatitis (SD), cutaneous lym- ting up an inflammatory cascade. phoma, ichthyosis, psoriasis, and other pri- The role of food antigens in the pathogene- mary disease entities. sis of AD is controversial, both in the pre- vention of AD and by their effect with Williams diagnostic criteria: According to withdrawal of certain foods in persons the criteria of Williams et al, proposed di- with established AD. Most reported re- agnostic guidelines include the following: search has methodologic flaws. One article1. Patients must have an itchy skin condition showed improvement at 1 year with con- (or parental report of scratching or rub- tinued breastfeeding. At 4 years, no differ- bing in children). ence was noted in the incidence of AD be-2. Patients also must have 3 or more of the tween the group that had not been exclu- following: sively breastfed and the group that had. A role for aeroallergens and house dust History of involvement of the skin mites has been proposed, but this awaits creases, such as folds of the elbows, behind further corroboration. the knees, fronts of the ankles, or neck Personal history of asthma or hay fever or a history of atopic disease in a first-degree DIFFERENTIALS relative in patients younger than 4 years History of generally dry skin in the last Contact Dermatitis, year Allergic Contact Dermatitis, Visible flexural dermatitis or dermatitis in- Irritant volving the cheeks or forehead and outer LichenSimplexChronicus limbs in children younger than 4 years NummularDermatitis Onset younger than age 2 years (not used Psoriasis, if child is <4 y) Plaque ScabiesCauses SeborrheicDermatitis TineaCorporis A genetic abnormality is possibly related to bands 11q13 or 5q31.These findings Other Problems to be Considered have yet to be corroborated; a family his- tory of AD is common. Immunodeficiency The skin of patients with AD is colonized Mycosis fungoides by S aureus. Lesions flare following infec- tion by S aureus, but they may occur with AD occasionally is indistinguishable from any type of skin or systemic infection. S other causes of dermatitis. In infancy, the
most common difficulty is distinguishing it age of appearance, and an early onset (infrom SD. This entity is not seen with the AD) help distinguish between the 2 condi-same frequency as a decade ago. Both AD tions.and SD are associated with cradle cap (ascale found on the vertex of the scalp), whichis greasy and yellow in individuals with SD WORKUPand dry and crusted in individuals with AD.Other areas of involvement in SD are the in- Lab Studiestertriginous areas, where marked erythemaand a greasy scale can be seen over the eye-brows and the sides of the nose. In AD, xero- Laboratory testing is seldom necessary.sis of the skin and severe pruritus are seen, Allergy and radioallergosorbent testing iswhich are not usually features of SD. Both of little value.conditions should be distinguished from A platelet count for thrombocytopeniapsoriasis. helps exclude Wiskott-Aldrich syndrome,Scabies manifests in infancy or childhood as and testing to rule out other immunodefi-a pruritic eruption. Other members of the ciencies may be helpful.family may be itchy, and the primary sites of Scraping to exclude tinea corporis is occa-involvement are moist warm areas. The erup- sionally helpful.tion is polymorphic with a dermatitis, nod-ules, urticaria, and 6-10 burrows. Pustules onthe hands and feet are common in infancy. Histologic FindingsFacial involvement is rare, and xerosis does Biopsy shows an acute, subacute, or chronicnot occur. dermatitis, but no specific findings are dem-Other causes of dermatitis, particularly con- onstrated.tact dermatitis from nickel in infants, aresometimes difficult to distinguish from AD.A central area of dermatitis (from nickel TREATMENTsnaps in undershirts or snaps in jeans) ishelpful for making the diagnosis, although a Medical Caredermatitic eruption may occur as an Id reac-tion in other areas, particularly the antecubi- Patients with AD do not usually requiretal fossae. Xerosis and facial involvement are emergency therapy, but they may visit theabsent. AD usually starts earlier than contact emergency department for treatment of acutedermatitis. flares caused by eczema herpeticum and bac-Children with a severe itch and generalized terial infections.dermatitis in the setting of recurrent infec-tions should be investigated for evidence of Moisturizationan immunodeficiency. Failure to thrive and Depending on the climate, patients mayrepeated infections help distinguish the erup- benefit from short, cool showers or bathstion from AD. followed by the application of a moistur-Tinea corporis usually manifests as a single izer such as white petrolatum. Anotherlesion, but inappropriate treatment with ste- regimen includes "soaking and greasing."roids may cause a widespread dermatitis. Fa- Frequent baths with oil (1 capful of emulsi-cial involvement, the presence of xerosis, the fying oil added to lukewarm bath water)
for 5-10 minutes comprise this regimen. In modulator and acts as a calcineurin inhibi-infants, 3 times a day is not a great bur- tor. Studies have shown excellent resultsden; in adults, once or twice a day is usu- compared with placebo and hydrocorti-ally all that can be achieved. Leave the sone 1%. Little absorption occurs. A sting-body wet after bathing. Oil and water are ing sensation may occur following applica-kept in solution by an emulsifier in the oil, tion, but this can be minimized by apply-thus preventing evaporation of water to ing the medication only when the skin isthe outside environment. very dry. The burning usually disappearsAdvise patients to apply an emollient such within 2-3 days. Tacrolimus is available inas petrolatum all over the body while wet, 2 strengths, 0.1% for adults and 0.03% forto seal in moisture and allow water to be children, although some authorities rou-absorbed through the stratum corneum. tinely use the 0.1% preparation in chil-The ointment spreads well on wet skin. dren. Tacrolimus is an ointment and is in-Topical steroids dicated for moderate-to-severe AD. TheTopical steroids are currently the mainstay latter is indicated for children older than 2of treatment. In association with moisturi- years.zation, responses to this regimen are excel- Pimecrolimus 1% is also an immunomodu-lent. lator and calcineurin inhibitor. It is moreOintment bases are preferred, particularly effective than placebo. Pimecrolimus isin dry environments. produced in a cream base for use twice aPatients with AD may develop a contact day; it is indicated for mild AD in personsallergy to topical medications and moistur- older than 2 years.izers. The allergy may be to a preservative A recent black box warning has been is-or the active ingredient. Allergy to hydro- sued in the United States based on re-cortisone is recognized with increasing fre- search that has shown an increase in ma-quency. Preservatives are less commonly lignancy in associated with the calcineurinpresent in ointments. inhibitors. While these claims are being in-Initial therapy consists of hydrocortisone vestigated further, the medication should1% powder in an ointment base applied 3 likely only be used as indicated (ie, for ADtimes daily to lesions on the face and in in persons older than 2 y and only whenthe folds. first-line therapy had failed).A midstrength steroid ointment (desonide Other treatments, effective and ineffectivefor milder areas or higher-strength ste- Probiotics have recently been explored asroids such as triamcinolone or betametha- a therapeutic option for the treatment ofsone valerate for more severe areas) is ap- AD. The rationale for their use is that bac-plied daily to lesions on the trunk until the terial products may induce an immune re-eczematous lesions clear. sponse of the T 1 series instead of T 2 H HSteroids are discontinued when lesions and could therefore inhibit the develop-disappear and are resumed when new ment of allergic IgE antibody production.patches arise. This research, although garnering fairlyFlares may be associated with seasonal convincing support, has yet to be proven.changes, stress, activity, staphylococcal in- UV-A, UV-B, a combination of both, psora-fection, or contact allergy. len plus UV-A (PUVA), or UV-B1 (narrowImmunomodulators band UV-B) therapy may be used. Long-Tacrolimus (topical FK506) is an immuno- term adverse effects of skin malignancies
in fair-skinned individuals should be Clothes should be washed in a mild deter-weighed against the benefits. gent with no bleach or fabric softener.In patients with eczema herpeticum, acy-clovir is effective. ConsultationsIn patients with severe disease, and partic- Consulting an allergist may be necessary,ularly in adults, phototherapy, methotrex- particularly if the patient develops asthmaate (MTX), azathioprine, and cyclosporine and/or hay fever or an acute reaction to ahave been used with success. type of food.Both hydroxyzine and diphenhydraminehydrochloride provide a certain degree ofrelief from itching but are not effective Dietwithout other treatments.Ketotifen (a calcium channel blocker) may Avoid foods that provoke acute allergic re-be effective. actions (hives, anaphylaxis). Most fre-Oil of evening primrose was believed to be quently, allergic reactions occur to peanutseffective, but in a randomized controlled (peanut butter), eggs, fish and seafood,study, it showed no benefit in children milk, soya, and chocolate.and little improvement in adults. Advise patients to apply a barrier of petro-Results with many other medications, leum jelly around the mouth prior to eat-such as thymopentin, gamma interferon, ing to prevent irritation from tomatoes, or-and Chinese herbs, have been disappoint- anges, and other irritating foods.ing. Many medications are not practical touse, and they can be expensive. Some Chi-nese herbal preparations contain prescrip- Activitytion medications, including prednisone. Advise patients to avoid activities thatAntibiotics are used for the treatment of cause excessive sweating.clinical infection caused by S aureus or Swimming in an outdoor pool (or wadingflares of disease. They have no effect on pool for babies) in summer provides thera-stable disease in the absence of infection. peutic benefit by exposing the person toLaboratory evidence of S aureus is not evi- the sun but avoiding the heat.dence of clinical infection because staphy-lococcal organisms commonly colonize the MEDICATIONskin of patients with AD.Nonmedical efforts The basis of treatment is to provide moisturi-Clothing should be soft next to the skin. zation for dryness, allay pruritus, and man-Cotton 100% is comfortable and can be lay- age inflammation of the eczematous lesions.ered in the winter.Cool temperatures, particularly at night, Drug Category: Anti-inflammatory agentsare better because sweating causes irrita-tion and itch. Provide relief of inflammation of eczematousA humidifier (cool mist) prevents excess lesions. Ointment base provides moisturiza-drying and should be used in both winter, tion. White petrolatum is useful to avoid po-when the heating dries the atmosphere, tential sensitization to preservatives in water-and in the summer, when the air condi- based moisturizers.tioning absorbs the moisture from the air.
Drug Name Hydrocortisone (LactiCare and reversing capillary per- HC, Cortaid, Westcort, Der- meability. Affects production macort, DermaGel) of lymphokines and has inhib- itory effect on LangerhansDescription Mild topical corticosteroid cells. mixed in petrolatum for facial Use 0.05-0.1% ointment in application. Has mineralocor- adults and 0.05% ointment in ticoid and glucocorticoid ef- pediatrics. fects, resulting in anti-inflam- matory activity. Adult Dose Apply topically bid/tid until Use 1% ointment daily. response; discontinue when clearedAdult Dose Apply sparingly to affected areas bid/tid; discontinue Pediatric Administer as in adults when cleared DosePediatric Apply as in adults Contraindi- Documented hypersensitivity;Dose cations skin infectionsContraindi- Documented hypersensitivity; Interactions None reportedcations clinical viral, fungal, and bac- Pregnancy C - Fetal risk revealed in stud- terial skin infections ies in animals but not estab-Interactions None reported lished or not studied in hu- mans; may use if benefits out-Pregnancy C - Fetal risk revealed in stud- weigh risk to fetus ies in animals but not estab- lished or not studied in hu- mans; may use if benefits out- Precautions Do not use in skin with de- weigh risk to fetus creased circulation; can cause atrophy of groin, face, and ax- illae; may cause striae disten-Precautions Caution around eyes and in sae in teenagers or rosacealike stasis dermatitis, prolonged eruption; may increase skin use, and application over fragility; rarely, may suppress large surface areas; occlusive HPA axis; if infection is dressings may increase sys- present, discontinue use until temic absorption of corticoste- infection is under control roidsDrug Name Betamethasone valerate (Beta- Drug Category: Antihistamines trex, Valisone, Luxiq)Description Medium-strength topical cor- Provide symptomatic relief of pruritus. ticosteroid for body areas. De- Drug Name Hydroxyzine hydrochloride creases inflammation by sup- (Atarax) pressing migration of poly- Description Antihistamine with antiprur- morphonuclear leukocytes itic, anxiolytic, and mild seda-
tive effects. Antagonizes H1 Pediatric Cap receptors in periphery. May Dose <10 years: Not recommended suppress histamine activity in >10 years: 25 mg PO tid/qid subcortical region of CNS. prn Syrup available as 10 mg/5 Elix (12.5 mg/5 mL) mL. 6-12 years: 5-10 mL PO q4-6h prn; not to exceed 4 doses/dAdult Dose 25-50 mg PO tid/qid prn >12 years: Administer as inPediatric <6 years: 30-50 mg/d PO (2 adultsDose mg/kg/d) in divided doses Childrens liquid (6.25 mg/5 >6 years: 50-100 mg/d PO in mL) divided doses <2 years: 2.5 mL q4-6h prnContraindi- Documented hypersensitivity 2-6 years: 5 mL q4-6h prncations 6-12 years: 10-20 mL q4-6h prn; not to exceed 4 doses/dInteractions CNS depression may increase or 5 mg/kg/d with alcohol or other CNS de- pressants Contraindi- Documented hypersensitivity; cations children with chronic lungPregnancy C - Fetal risk revealed in stud- disease; glaucoma ies in animals but not estab- lished or not studied in hu- Interactions Potentiates effect of CNS de- mans; may use if benefits out- pressants; as a result of alco- weigh risk to fetus hol content, do not administer elix to patient taking medica- tions that can cause disulfir-Precautions Associated with clinical exac- amlike reactions erbations of porphyria (may not be safe for patients with Pregnancy C - Fetal risk revealed in stud- porphyria); ECG abnormal- ies in animals but not estab- ities (alterations in T waves) lished or not studied in hu- may occur; may cause drowsi- mans; may use if benefits out- ness; caution operating auto- weigh risk to fetus mobiles and other dangerous machinery; anticholinergic ef- Precautions May exacerbate angle-closure fects (ie, dry mouth) may oc- glaucoma, hyperthyroidism, cur peptic ulcer, or urinary tract obstruction; xerostomia mayDrug Name Diphenhydramine (Benadryl) occur; caution operating auto- mobiles and other dangerousDescription Antihistamine used for pruri- machinery because of possible tus and allergic reactions. sedation; as a result of atro-Adult Dose Cap: 25-50 mg tid/qid prn pinelike action, caution in his- Elix: 10-20 mL (12.5 mg/5 mL) tory of bronchial asthma, in- q4-6h; not to exceed 4 doses/d creased intraocular pressure, hyperthyroidism, cardiovas-
cular disease, or hypertension cations uncontrolled hypertension or malignancies; do not adminis- ter concomitantly with PUVA or UV-B radiation in psoriasis because may increase risk ofDrug Category: Immunomodulators cancer Interactions Carbamazepine, phenytoin,For treatment of patients with severe disease isoniazid, rifampin, and phe-in whom conventional therapy is ineffective. nobarbital may decrease con-In more severe cases and particularly in centrations; azithromycin, itra-adults, consider using both MTX and cyclo- conazole, nicardipine, ketoco-sporine. The latter is more efficacious, but le- nazole, fluconazole, erythro-sions recur when it is stopped. mycin, verapamil, grapefruit Drug Name Cyclosporine (Neoral, San- juice, diltiazem, aminoglyco- dimmune) sides, acyclovir, amphotericin B, and clarithromycin may in-Description Demonstrated to be helpful in crease toxicity; acute renal fail- a variety of skin disorders, es- ure, rhabdomyolysis, myosi- pecially psoriasis. Acts by in- tis, and myalgias increase hibiting T-cell production of when taken concurrently with cytokines and ILs. Like tacroli- lovastatin mus and pimecrolimus (asco- mycin), cyclosporine binds to Pregnancy C - Fetal risk revealed in stud- macrophilin and then inhibits ies in animals but not estab- calcineurin, a calcium-de- lished or not studied in hu- pendent enzyme, which, in mans; may use if benefits out- turn, inhibits phosphorylation weigh risk to fetus of nuclear factor of activated T cells and inhibits transcription Precautions Evaluate renal and liver func- of cytokines, particularly IL-4. tions often by measuring Discontinue treatment if no re- BUN, serum creatinine, serum sponse within 6 wk. bilirubin, and liver enzymeAdult Dose 2 mg/kg/d PO divided bid; if levels; may increase risk of in- no improvement within 1 mo, fection and lymphoma; re- may be increased gradually; serve IV use only for patients not to exceed 5 mg/kg/d who cannot take PO; develop- As skin lesions improve, re- ment of malignancies (particu- duce dose by 0.5-1 larly skin) has been reported; mg/kg/d/mo; lowest effec- perform biopsy on skin sug- tive dose for maintenance gestive of malignancy or pre- malignancy and, if malignant,Pediatric 3-5 mg/kg/d PO discontinueDoseContraindi- Documented hypersensitivity;
Drug Name Methotrexate (Folex PFS, Pregnancy D - Fetal risk shown in hu- Rheumatrex) mans; use only if benefits out- weigh risk to fetusDescription Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA syn- Precautions Monitor CBC counts monthly thesis and cell reproduction. and liver and renal function Satisfactory response seen in q1-3mo during therapy (moni- 3-6 wk following administra- tor more frequently during in- tion. itial dosing, dose adjustments, Adjust dose gradually to at- or when risk of elevated MTX tain satisfactory response. levels, eg, dehydration); has toxic effects on hematologic,Adult Dose 10-25 mg/wk PO/IM or renal, GI, pulmonary, and 2.5-7.5 mg PO q12h for 3 neurologic systems; discon- doses/wk tinue if significant drop inPediatric Not established blood counts occurs; fatal re-Dose actions reported when admin-Contraindi- Documented hypersensitivity; istered concurrently withcations alcoholism; hepatic insuffi- NSAIDs ciency; documented immuno- deficiency syndromes; preex- Drug Name Tacrolimus (Protopic) isting blood dyscrasias (eg, bone marrow hypoplasia, leu- Description Immunomodulator that sup- kopenia, thrombocytopenia, presses humoral immunity (T- significant anemia); renal in- lymphocyte) activity. Used for sufficiency refractory disease.Interactions Oral aminoglycosides may de- Adult Dose Apply a thin layer to affected crease absorption and blood areas bid; continue for 1 wk levels of concurrent oral MTX; after symptoms clear charcoal lowers MTX levels; Pediatric <2 years: Not established coadministration with etreti- Dose 2-15 years: Administer as in nate may increase hepatotox- adults icity of MTX; folic acid or its Contraindi- Documented hypersensitivity derivatives contained in some cations vitamins may decrease re- sponse to MTX; probenecid, Interactions Topical tacrolimus is mini- NSAIDs, salicylates, procarba- mally absorbed; however, lev- zine, and sulfonamides, in- els may increase with diltia- cluding TMP-SMZ, can in- zem, nicardipine, clotrima- crease MTX plasma levels; zole, verapamil, erythromy- may decrease phenytoin plas- cin, ketoconazole, itracona- ma levels; may increase plas- zole, fluconazole, bromocrip- ma levels of thiopurines tine, grapefruit juice, metoclo-
pramide, methylprednisolone, acted on by DNA polymerase. danazol, cyclosporine, cimeti- Patients experience less pain dine, or clarithromycin; levels and faster resolution of cuta- may reduce with rifabutin, ri- neous lesions when used with- fampin, phenobarbital, pheny- in 48 h of rash onset. May pre- toin, and carbamazepine vent recurrent outbreaks. Early initiation of therapy isPregnancy C - Fetal risk revealed in stud- imperative. Zoster dose is 4 ies in animals but not estab- times higher than that for her- lished or not studied in hu- pes simplex. Duration of ther- mans; may use if benefits out- apy varies. weigh risk to fetus Adult Dose 200-800 mg PO qid for 5-10 d started within 24 h of appear-Precautions Do not use with occlusive ance of rash dressings; may be associated with an increased risk of vari- Pediatric 5-20 mg/kg PO qid for 5-10 d cella zoster virus infection, Dose (susp 200 mg/5 mL) started HSV infection, or eczema her- within 24 h of appearance of peticum; increased risk for rash myeloma development (if de- Contraindi- Documented hypersensitivity velop lymphadenopathy, in- cations vestigate etiology); may cause local burning sensation, sting- Interactions Concomitant use of probene- ing, soreness, or pruritus (typ- cid or zidovudine prolongs ically improve as lesions heal); half-life and increases CNS for external use only; mini- toxicity mize exposure to natural or Pregnancy C - Fetal risk revealed in stud- artificial sunlight (eg, tanning ies in animals but not estab- beds or UVA/B treatment); be lished or not studied in hu- sure skin is completely dry be- mans; may use if benefits out- fore application weigh risk to fetus Precautions Caution in renal failure orDrug Category: Antiviral agents when using nephrotoxic drugs; has caused mutagene-For management of herpetic infections and to sis in some studies at hightreat AD in patients who develop chicken- concentrationspox. Drug Name Acyclovir (Zovirax)Description Inhibits activity of both HSV-1 Drug Category: Antibiotics and HSV-2. Has affinity for vi- ral thymidine kinase and, Empiric antimicrobial therapy must be com- once phosphorylated, causes prehensive and should cover all likely patho- DNA-chain termination when gens in the context of the clinical setting. For
the treatment of clinical infection by S aureus, Drug Name Cloxacillin (Cloxapen, Te-cloxacillin or cephalexin is used. In strepto- gopen)coccal infections, cephalexin is preferred. Ifnot effective, penicillin and clindamycin in Description For treatment of infectionscombination are effective. Consider staphylo- caused by penicillinase-pro-coccal infection in every flare of AD. ducing staphylococci. May be used to initiate therapy when Drug Name Cephalexin (Keflex) a staphylococcal infection isDescription First-generation cephalospor- suspected. in arrests bacterial growth by Adult Dose 250-500 mg PO q6h inhibiting bacterial cell wall synthesis. Bactericidal activity Pediatric <20 kg: 50-100 mg/kg/d PO against rapidly growing or- Dose divided q6h ganisms. Primary activity >20 kg: 250 mg PO q6h against skin flora; used for Contraindi- Documented hypersensitivity skin infections or prophylaxis cations in minor procedures. Available susp include mauve Interactions Decreases efficacy of oral con- granules (125 mg/5 mL) and traceptives; may decrease ef- peach granules (250 mg/5 fects of anticoagulants; probe- mL). necid and disulfiram may in- crease penicillin levelsAdult Dose 1-4 g/d PO in divided doses Pregnancy B - Fetal risk not confirmed inPediatric 25-50 mg/kg/d PO divided studies in humans but hasDose q6h been shown in some studies inContraindi- Documented hypersensitivity animalscationsInteractions Coadministration with amino- Precautions Monitor PT in patients taking glycosides increase nephro- anticoagulant medications; toxic potential toxicity may increase in renal impairmentPregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in Drug Name Penicillin VK (Beepen-VK, Be- animals tapen-VK, Veetids) Description Inhibits biosynthesis of cellPrecautions Adjust dose in severe renal in- wall mucopeptide. Bacterici- sufficiency (high doses may dal against sensitive organ- cause CNS toxicity); superin- isms when adequate concen- fections and promotion of trations are reached, and most nonsusceptible organisms effective during stage of active may occur with prolonged use multiplication. Inadequate or repeated therapy concentrations may produce only bacteriostatic effects.
Adult Dose 500 mg PO q6h for 10d colitis, hepatic impairment, antibiotic-associated colitisPediatric <12 years: 25-50 mg/kg/dDose divided tid/qid up to 3 g/d Interactions Increases duration of neuro- >12 years: Administer as in muscular blockade induced adults by tubocurarine and pancuro- nium; erythromycin may an-Contraindi- Documented hypersensitivity tagonize effects; antidiarrhealscations may delay absorptionInteractions Probenecid may increase ef- Pregnancy B - Fetal risk not confirmed in fectiveness by decreasing studies in humans but has clearance; tetracyclines are been shown in some studies in bacteriostatic, causing a de- animals crease in the effectiveness of penicillins when administered concurrently Precautions Adjust dose in severe hepatic dysfunction; no adjustmentPregnancy B - Fetal risk not confirmed in necessary in renal insuffi- studies in humans but has ciency; associated with severe been shown in some studies in and possibly fatal colitis by al- animals lowing overgrowth of Clostri- dium difficilePrecautions Caution in renal impairmentDrug Name Clindamycin (Cleocin) FOLLOW-UPDescription Lincosamide for treatment of Further Outpatient Care serious skin and soft tissue Monitor patients frequently. staphylococcal infections. Al- Reinforce therapeutic regimens with pa- so effective against aerobic tients. and anaerobic streptococci (except enterococci). Inhibits In/Out Patient Meds bacterial growth, possibly by Medications are used as described in Med- blocking dissociation of pep- ication. tidyl t-RNA from ribosomes, causing RNA-dependent pro- Deterrence/Prevention tein synthesis to arrest. Moisturization is important on an ongoingAdult Dose 150-450 mg/dose PO q6-8h; basis and seems to prevent flares. not to exceed 1.8 g/d ComplicationsPediatric 8-20 mg/kg/d PO as hydro-Dose chloride or 8-25 mg/kg/d as If topical corticosteroids are used inap- palmitate divided tid/qid propriately or if superpotent steroids are used in teenagers during rapid growth,Contraindi- Documented hypersensitivity; striae may occur. Skin thinning can resultcations regional enteritis, ulcerative if steroids are used inappropriately in old-
er patients. apply medication and that discuss the role Whether verrucae vulgaris and mollusca of moisturization. contagiosa are more frequent is difficult to For excellent patient education resources, assess, but certainly, they can be more visit eMedicines Skin, Hair, and Nails widespread and difficult to eliminate. Center. Also, see eMedicines patient edu- Tachyphylaxis to topical steroids occurs if cation article Eczema. they are not used on a stop-start basis. MISCELLANEOUSPrognosis Medical/Legal Pitfalls Most patients improve; this can occur at Failure to explain the adverse effects of any age. While the frequency of AD is as topical steroids to patients may result in high as 20% in childhood, it is 0.9% in medicolegal problems. adults. One third of patients develop allergic rhi- Special Concerns nitis. One third of patients develop asthma. Other children in the family may develop AD.Patient Education Patients may develop acute food allergies Frequently reinforce treatment and main- (eg, to peanuts and/or eggs). EpiPen tenance regimens with patients. should be available. Advise patients to contact the National Ec- Patients may develop a generalized reac- zema Association for Science and Educa- tion to herpes simplex virus (eczema her- tion at 4460 Redwood Hwy, Suite 16-D, peticum). San Rafael, CA 94903-1953. One third of patients develop asthma, and Show videos to patients that show how to one third develop allergic rhinitis.